PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY HEARINGS £BEFORE THE SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE SECOND SESSION ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 17 ORAL CONTRACEPTIVES (VOLUME THREE) APPENDIXES 0 Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 40-471 0 WASHINGTON: 1970 For sale bythe Superintendent of Documents, U.S. Government Printing Office Washington D C 20402 Price $225 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS [Created pursuant to S. Res. 58, 81st Cong.] ALAN BIBLE, Nevada, Chairman JACOB K. JAVITS, New York PETER H. DOMINICK, Colorado HOWARD H. BAKER, JR., Tennessee MARK 0. HATFIELD, Oregon ROBERT DOLE, Kansas MARLOW W. COOK, Kentucky TED STEVENS, Alaska CHESTER H. SMITH, Staff Director and General Counsel DENNISON YouNG, Jr., Acting Minority Counsel GAYLORD NELSON, Wisconsin, Chairman. MARK 0. HATFIELD, Oregon ROBERT DOLE, Kansas MARLOW W. COOK, Kentucky JACOB K. JAVITS,* New York BENJAMIN GORDON, Staff Economist ELAINE C. DYE, Clerical Assistant JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana JENNINGS RANDOLPH, West Virginia HARRISON A. WILLIAMS, Ja., New Jersey GAYLORD NELSON, Wisconsin JOSEPH M. MONTOYA, New Mexico FRED R. HARRIS, Oklahoma THOMAS J. McINTYRE, New Hampshire MIKE GRAVEL, Alaska SUBCOMMITTEE ON MoNoPoLY JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana THOMAS J. McINTYRE, New Hampshire ALAN BIBLE,* Nevada *Ex officio member. (II) PAGENO="0003" CONTENTS APPENDIXES I. Second Report on the Oral Contraceptives, by the Advisory Commit- tee on Obstetrics and Gynecology, Food and Drug Adminis- Page tration, August 1, 1969 6839 II. First Report on. the Oral Contraceptives, by the Advisory Commit- tee on Obstetrics and Gynecology, Food and Drug Adminis- tration, August 1, 1966 6917 III. Dear doctor letters: Dated January 12, 1970, from Dr. Charles C. Edwards, Acting Commissioner, Food and Drug Administration, with accompanying revised labeling for oral contracep- tives 7017 Dated June 28, 1968, from Dr. James L. Goddard, Com- missioner, Food and Drug Administration, with accom- panying revised uniform labeling for oral contraceptives - 7022 IV. Articles: "Survey Links The Pill To Cancer," by Barbara Yuncker, from the New York Post, February 14, 1970 7026 "Editorial-The Pill Problem," from the New York Times, January 17, 1970 7027 "Commonsense Advice on Contraceptives," from Family Health, January 1970, pp. 36-38 7028 "Controversy Over `The Pill,'" by Bill Surface, from Good Housekeeping, January 1970, pp. 64-65, 123-12L 7031 "The Better Way-Why There is Growing Concern About the Safety of `The Pill,'" from Good Housekeeping, January 1970, pp. 129-131 7037 "Original Articles-Vascular Lesions in Women Taking Oral Contraceptives," by N. S. Irey, M.D., W. C. Manion, M.D., and H. B. Taylor, M.D., from Archives of Pathology, Vol. 89, No. 1, January 1970, pp. 1-8~~ 7042 "Researcher Predicts Ban On The Pill," by Barbara Yuncker, from the New York Post, December 22, 1969, p. 3 7050 "Oral Contraception and Depression," from the British Medical Journal, November 15, 1969, pp. 380-381 7051 "OCs Can Deeply Alter Glucose Metabolism," from OB- GYN News, November 15, 1969, pp. 2, 46 7052 "Why Would the U.S. Ban Cyclamates and Not The Pill?" by Morton Mintz, from the St. Louis Globe-Democrat, November 5, 1969, p. 5A 7054 "Chapter 7-Implications of Contraception-A. Meta- bolic Effects of Oral Contraceptives," by Philip A. Corf- man, M.D., from the Journal of Medical Education, Vol. 44, Part 2, No. 11, November 1969, pp. 64-68 7056 "Metabolic Effects of Oral Contraceptives," from The Lan- cet, October 11, 1969, pp. 783-784 7060 "Family Planning and Public Policy: Who Is Misleading Whom?" from Science, September 19, 1969, pp. 1203- 1204 7062 "Prevalence Rates of Uterine Cervical Carcinoma in situ for Women Using the Diaphram or Contraceptive Oral Steroids," by M. R. Melamed, M.D., L. G. Koss, M.D., B. J. Flehinger, Ph. D., R. P. Kelisky, Ph. D., and H. Dubrow, M.D., from the British Medical Journal, July 26, 1969, pp. 195-200 7064 (~) PAGENO="0004" Iv IV. Articles-Continued "Family Planning and Public Policy: Who Is Misleading Whom?" by 0. Harkavy, F. S. Jaffe, and S. M. Wishik, Page from Science, July 25, 1969, pp. 367-373 7074 "The Association of Mortality From Thromboembolic Disorders and Oral Contraceptive Use," by D. G. Seigel, Sc. D., reprinted from the Journal of Reproduc- tive Medicine, July 1969, Vol. 3, No. 1, pp. 44-49 7086 "Population Policy for Americans: Is the Government Being Misled?" by Judith Blake, Chairman, Dept. of Demography, University of California, Berkeley, from Science, May 2, 1969, pp. 522-529 7092 "Oral Contraceptives and Mortality Trends From Throm- boembolism in the United States," by R. E. Markush, M.D., M.P.H., and D. G. Seigel, S.D., reprinted from American Journal of Public Health, Vol. 59, No. 3, March 1969, pp. 418-434 7105 "Pill Experts Perplexed By Data On Pap Smears," from Medical World News, February 14, 1969, pp. 20-2L - - - 7122 "Oral Contraceptives: Government-Supported Programs Are Questioned," by M. Mueller, from Science, Febru- ary 7, 1969, pp. 553-555~~_ 7124 "Oral Contraceptives and Cerebrovascular Complications," by R. T. Bergeron, M.D., and E. H. Wood, M.D., re- printed from Radiology, Vol. 92, No. 2, pp. 231-238, 258, February 1969 7127 "Editorial-Oral Contraceptives and Thromboembolic Disease," by M. P. Vessey, M.B., B.S., from the American Heart Journal, Vol. 77, No. 2, February 1969, pp. 153- 157 7136 "The Pill: Press and Public at the Experts' Mercy-First Part," by Morton Mintz, from Columbia Journalism Review, Winter, 1968-1969, pp. 4-10 7140 "The Pill: Press and Public at the Experts' Mercy-Second Part," by Morton Mintz, from Columbia Journalism Review, Spring, 1969, pp. 28-35 7146 "Caution On The Pill," by Louis Lasagna, M.D., from SR, November 2, 1968, pp. 64-69 7154 "Puerperal Thromboembolism in Relation to the Inhibition of Lacation by Oestrogen Therapy," by T. N. A. Jeff- coate, M.D., J. Miller, M.B., R. F. Roos, M.B., and V. R. Tindall, M.D., from the British Medical Journal, Octo- ber 5, 1968, pp. 19-25 7165 "Thrombosis and Inhibition of Lactation," from the British Medical Journal, October 5, 1968, pp. 1-2 7176 "Effect of Oral Contraceptives on Depressive Mood Changes and on Endometrial Monoamine Oxidase and Phosphatases," by E. C. G. Grant, M.B., and J. Pryse- Davies, M.D., from the British Medical Journal, Septem- ber28, 1968, pp. 777-780 7178 "Oral Contraceptives and Thromboembolism," from the British Medical Journal, April 27, 1968, pp.187-188 7185 "Papers and Originals-Investigation of Deaths from Pul- monary, Coronary, and Cerebral Thrombosis and Em- bolism in Women of Child-Bearing Age," by W. H. W. Inman, M.A., and M. P. Vessey, M.B., from the British Medical Journal, April 27, 1968, pp. 193-199 7186 "Investigation of Relation Between Use of Oral Contra- ceptives and Thromboembolic Disease," by M. P. Vessey, M.B., and R. Doll, M.D., from the British Medical Journal, April 27, 1968, pp. 199-205 7198 "Research-Biochemistry of the Pill Largely Unknown," from Chemical and Engineering News, March 27, 1967, pp. 44-49 7210 "Oral Contraceptives Safe, FDA Says," from the AMA News, Vol. 9, No. 34, August 22, 1966, pp. 1, 6 7218 PAGENO="0005" V IV. Articles-Continued "Special Report Based On New Medical Evidence-Must We Now Ban The Birth Control Pills?" from Good Page Housekeeping, February 1966, pp. 67-68 7219 "One Noted Authority Says: `Yes, I'll Still Prescribe The Pills,'" by Dr. Alan F. Guttmacher, from Good House- keeping, February 1966, pp. 68-701. 7220 "How Does The Pill Work?" from Good Housekeeping February 1966, p.70 7223 "Are Birth Control Pills Safe?-Some Doctors Doubt That The Drug Has Been Tested Well Enough for Possible Side Effects," by Morton Mintz, from the Washington Post, December 19, 1965, pp. El,E5 7224 "Birth-Control Pills-Have They Side-Effects?-An Authoritative Answer to a Question Many Women Are Asking," by E. J. DeCosta, M.D., from This Week Maga- zine, July 12, 1964, p.13 7233 V. Wright Committee Reports on Enovid by the Ad Hoc Com- mittees for the Evaluation of a Possible Etiologic Relation With Thromboembolic Conditions: Dated August 4, 1963 7235 Dated September 12, 1963 7247 VI. Letter, dated February 26, 1970, to Subcommittee on Monopoly, Select Committee on Small Business, U.S. Senate, from Education and Public Welfare Division, Legislative Reference Service, Library of Congress, re study of pharmaceutical advertising and critical reactions regarding oral contraceptives in selected medical journals 7254 VII. Letter, dated March 4, 1970, to Subcommittee on Monopoly, Select Committee on Small Business, U.S. Senate, from Education and Public Welfare Division, Legislative Reference Service, Library of Congress, re articles discussing side effects of oral contraceptives 7257 VIII. Planned Parenthood-World Population news release, "Mass Oral Contraceptive Study Findings Released," June 1965 7263 IX. Medical and Pharmaceutical Information Bureau of Science Public Relations, Inc. news release, "Oral Contraceptive Not Cause of Thromboembolisms: Dr. Guttmacher," February 17, 1966 7282 X. Washington Women's Liberation Statement on Birth Control Pills with accompanying questionnaire 7283 XI. Letter, dated March 10, 1970, to Benjamin Gordon, from Senator Bob Dole, with accompanying articles on oral contraceptives: "Health-IUD Hazards," by Morton Mintz, from the Washington Post, March 5, 1970 7296 "Medical Report-'Pill' Warning to Set a Precedent," by Judith Randal, from The Evening Star, March 8, 1970 7297 "Pill' Sales and Stocks Cooled by Controversy," by Bailey Morris, from The Evening Star, March 8, 1970 7298 XII. Letter, dated January 30, 1963, to G. D. Searle & Co., from Arthur Ruskin, M.D., Acting Medical Director, IND, and Haimo Trees, M.D., Division of New Drugs, re Enovid medication and in- creased blood clotting 7300 XIII. Statement of John R. Rague, Executive Director, Association for Voluntary Sterilization, Inc., re voluntary contraceptive steriliza- tion as a major method of birth control 7301 XIV. Excerpts from testimony in the case of Raymond Black vs. G. D. Searle & Co 7306 XV. Memorandum dated May 11, 1960, from W. H. Kessenich, Bureau of Medicine, to George P. Larrick, Commissioner of Food and Drugs, re Enovid tablets, NDA 10-976 7322 Novx.-Appendixes are to Parts 15 and 16 (Oral Contraceptives-Volumes 1 and 2). PAGENO="0006" PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Preseilt Status of Competition in the Pharmaceutical Industry) APPENDIXES APPENDIX I SECOND REPORT ON THE ORAL CONTRACEPTIVES BY THE ADVISORY COMMITTEE ON OBSTETRICS AND GYNECOLOGY, FOOD AND DRUG ADMINISTRATION, AUGUST 1, 19~9 CONTENTS Members and consultants of advisory committee on obstetrics and gynecology Preface Chairman's Summary a. Action on recommendations of the 1966 report on the oral contraceptives b. Utilization c. Efficacy d. Methods under evaluation e. Thromboembolic disorders f. Carcinogenesis g. Metabolic effects Committee Recommendations Conclusion TASK FORCE REPORTS Appendix 1.-Report of the task force on utilization, effectiveness and current investigations-S. J. Segal, chairman Appendix 2.-Report of the task force on Thromboembolic disorders-P. E. Sartwell, chairman Appendix 2A.-Thromboembolism and oral contraceptives: An epidemio- logical case-control study-Philip Sartwell, Alfonse Masi, Federico Arthes, Gerald Greene, Helen Smith Appendix 2B.-Trends in mortality from thromboembolic disorders-Philip Sartweil, Charles Anello Appendix 2C.-Trends in mortality from cerebrovascular diseases-Gerald R. Greene Appendix 2D.-Effects of the oral contraceptives on blood clotting-Marion Dugdale, Alfonse Masi Appendix 2E.-Cerebrovascular diseases associated with the use of oral contraceptives: A review of the literature-Alfonse Masi, Marion Dugdale Appendix 3.-Report of the task force on carcinogenesis-R. Hertz, chairman Appendix 4.-Report of the task force on biologic effects-P. A. Corfman, chairman (6839) PAGENO="0008" 6840 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMBERS OF ADVISORY COMMITTEE ON OBSTETRICS AND GYNECOLOGY Louis M. Heilman, M.D., Chairman, Professor and Chairman, Obstetrics and Gynecology, State University of. New York, Brooklyn, N.Y. Karlis Adamsons, Jr., M.D., Ph. D., Professor of Obstetrics and Gynecology, Columbia University, New York, N.Y. Elsie R. Carrington, M.D., Professor and Chairman of Obstetrics and Gynecol- ogy, Women's Medical College, Philadelphia, Pa. Philip A. Corfman, M.D., Director, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Md. Eleanor M. Delfs, M.D., Professor of Obstetrics and Gynecology, Marquette University, Milwaukee, Wis. H. Fleming Fuller, M.D., Clinical Associate Professor of Obstetrics and Gyne- cology, University of North Carolina, Chapel Hill, N.C. Roy Hertz, M.oD., Ph. D., Associate Medical Director, Bio-Medical Division, Population Council, Rockefeller University, New York, N.Y. Schuyler G. Kohl, M.D., Dr. P.H., Professor of Obstetrics and Gynecology, State University of New York, Brooklyn, N.Y. Alfonse T. Masi, M.D., Dr. P.H., Professor of Medicine and Preventive Medi- cine, University of Tennessee, Memphis, Tenn. Ben Peckham, M.D., Professor and Chairman, Obstetrics and Gynecology, Uni- versity of Wisconsin Medical School, Madison, Wis. Philip E. Sartwell, M.D., M.P.H., Professor of Epidemiology, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Md. Roger B. Scott, M.D. *, Professor of Obstetrics and Gynecology, Western Reserve University, Cleveland, Ohio Sheldon J. Segal, Ph. D., Director, Bio-Medical Division, Population Council, Rockefeller University, New York, N.Y. Christopher Tietze, M.D., Associate Director, Bio-Medical Division, Population Council, Rockefeller University, New York, N.Y. CONSULTANTS Charles Anello, Sc. D.; (formerly) Assistant Professor of Epidemiology and Biostatistics, Johns Hopkins University School of Hygiene and Public Health; (presently) Director, Division of Statistics, Bureau of Medicine, Food and Drug Administration, Washington, D.C. Marion Dugdale, M.D., Associate Professor of Medicine, University of Tennes- see, Memphis, Tenn. Gerald Greene, 1~I.D.; (formerly) Epidemic Intelligence Service Officer, Com- municable Disease Center, Public Health Service, Atlanta, Ga., (presently) Assistant Resident in Pediatrics Johns Hopkins Hospital, Baltimore, Md. Ralph M. Wynn, M.D., Professor and Head, Obstetrics and Gynecology, Univer- sity of Illinois Medical Center, Chicago, Ill. PREFACE The Committee on Obstetrics and Gynecology expresses its appreciation to the Commissioner of the Food and Drug Administration and his staff for coop- eration in the arrangements for its meetings, the preparation of reference material, and in particular, for their readily available consultation. The Com- mittee also thanks the representatives of the pharmaceutical industry for their assistance and prompt submission of requested reports. The preparation of this report has required consultation with numerous sci- entists whose help is gratefully acknowledged. Their continuing cooperation ensures that this report and others to follow will attain a crucial goal-a fully aware and accurately informed medical profession and public. The Committee thanks Dr. Ralph M. Wynn, Professor and Head, Depart- ment of Obstetrics and Gynecology, University of Illinois at the Medical Center, Chicago, Illinois, Dr. John J. Schrogie, Bureau of Medicine, Food and Drug Administration, ma Friedelson, Press Relations Staff, Food and Drug Administration and Florence Gubitz, State University of New York, Downstate Medical Center for assistance in preparation of this manuscript. The Committee reports with deep regret the untimely death of Dr. Roger B. Scott, which deprived it of his sage counsel. * Deceased. PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6841 CHAIRMAN'S SUMMARY LOUIS M. HELLMAN, M.D. Since the publication of the last Report on the Oral Contraceptives in 1966,* scientific as well as public interest in this method of family planning has remained high. The reservations of the first report appear to have been justi- fied. Concern about the immediate and long-range side effects of the hormonal contraceptives has increased as scientific investigations have uncovered a host of diverse biologic effects, and as the drugs have become available to increas- ingly large segments of the world's population. Adverse reactions are continually reported in the scientific literature and the lay press. Since the vast majority of the reported adverse experiences are con- ditions which occur spontaneously in women of reproductive age, identification of an etiologic relation has been difficult and slow. An increased risk of thromboembolic disease attributable to the use of hor- monal contraceptives has now been defined in both Great Britain and the United States. Other risks, such as those of hypertension, liver disease and reduced tolerance to carbohydrates, have not been quantitated with the same precision. Some of the risks have been recognized by isolated clinical observa- tions, whereas others have been predicted on the basis of experiments with animals or merely on theoretical grounds. Controversy has centered about two areas: the scientific data required to establish an etiologic relation and the balance between acceptable risk and potential benefit. The voluntary submission of reports by individual doctors to scientific journals, to the pharmaceutical industry, or directly to the Food and Drug Administration is fregmentary at best. Since the data on the natural incidence of the disorders in question are not available, it is impossible to ascertain whether the haphazard voluntary reporting of an adverse reaction in fact represents an increase in the suspected complication. The limitations as well as the value of a voluntary reporting system for providing an initial warning of serious complication have been noted frequently. There is no easy escape from this dilemma. The current aggregate pharmacological experience with the oral contraceptives is unique, however, in that large numbers of healthy young women are using potent drugs for a purpose other than the con- trol of disease. An improvement in national reporting of some of the alleged complications is therefore merited. If the annual national rates of incidence of the various complications thought to be associated with hormonal contracep- tives were known, trends presently unsuspected might be quickly uncovered. This pharmacological experience is unique also in the attention it has received by the press throughout the world. Particularly in Great Britain and the United States the Press has attempted to keep the public informed Of each discovery and each reported difficulty. Such reporting is the quickest way to satisfy the public's right to know. The task of conveying complicated scientific information to the public is a responsibility requiring well-informed and accurate reporting, based on a judi- cious appraisal of data. Neither the public nor the press is well served if information is exaggerated, mitigated, or suppressed. In the final analysis, both the physician and the layman must evaluate the risks of the hormonal contra- ceptives in comparison with other methods of contraception or no contracep- tion at all. They can do so wisely only when they have access to all available information, accurately and dispassionately presented. It is difficult to separate fact from fiction at the forefront of scientific dis- covery. Evaluation in the area of hormonal contraception has proved formida- ble to the best informed scientists. The epidemiological problems are unique, requiring refinements in technique not yet fully realized. Case reporting, par- ticularly isolated experiences, may be inconclusive. Thromboembolic disease is but one example. Eight years were required from the time of the first reported death to establish the relative risk and an etiologic relation to the hormonal contraceptives. By reviewing a welter of scientific studies of varied value, the press has acquired an increasing awareness of the problems through hard work and study. So too have physicians and the public. This difficult course could have been shortened and made more efficient by periodic, well structured, and responsibly led impartial conferences of scientific writers. The pattern was * Report on the Oral Contraceptives, Advisory Committee on Obstetrics and Gynecol- ogy, Food and Drug Administration, August 1, 1966. PAGENO="0010" 6842 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY established 11 years ago by the American Cancer Society, when its science writers seminars were created. The risk of thromboembolism associated with the oral contraceptives has been compared with that from pregnancy, cigarette smoking, and automobile accidents. Such comparisons are probably irrelevant, contributing little ta eval- uation of the relative risk. The task of balancing the risk against the benefit to the individual and to society must eventually be met. As contraceptive prac- tices spread to all segments of our society, it becomes virtually essential that the requirements of effectiveness and safety, and the desirability of inexpen- siveness and lack of association with coitus be satisfied. Oral contraceptives have proved to be highly acceptable to many couples who had found other methods inconvenient or impractical. (a) Action on recommendations of the 1966 report on the oral contraceptives The Committee is gratified by the prompt response of the Food and Drug Administration to the majority of its previous recommendations as follows: Recommendation 1.-A large case-control (retrospective) study of the possi- ble relation of oral contraceptives to thromboembolism. Result.-A study was developed at Johns Hopkins University School of Hygiene and Public Health with Food and Drug Administration support. Results document an increased risk in the drug users, roughly comparable to that observed in the epidemiological studies in Great Britain. Recommendation II.-Oontinuation and support of studies such as the ones being carried out by the Kaiser Permanente group in California and the Uni- versity of Pittsburgh group in Lawrence County, Pa. Result.-The Kaiser study is operating under support from the National Institute of Child Health and Human Development. Food and Drug Adminis- tration support to the project in Lawrence County, Pa. was discontinued for administrative reasons, but a locally sponsored central audit of prescriptions is operating. - Recommendation 111.-Support of additional controlled population prospec- tive studies utilizing groups of subjects that are especially amenable to long- term followup, such as married female employees of certain large industries and graduate nurses. Result.-A prospective study of the effects of oral contraceptives on cervical epithelium has been underway since 1967. Other prospective studies of effects of contraceptives on cervical cytology have been initiated recently. Corollary studies of possible effects on the breast will also be implemented. Recommendation IV.-Continuation and strengthening of the present surveil- lance system of the Food and Drug Administration. Result.-At the present time, all adverse reactions to the oral contraceptives reported to the Food and Drug Administration from the Hospital Reporting Program, manufacturers, consumers and physicians are collected and reviewed by the Division of Drug Experience, Bureau of Medicine, where they are coded and stored in a computerized facility. Reports are then transmitted to the Division of Metabolic and Endocrine Drug Surveillance, Office of Marketed Drugs where serious reactions are collected separately in a card file. This Division is responsible for preparation of a yearly tabulation of these serious adverse effects which is submitted to the Commissioner. A separate listing is also made by staff in the Office of Marketed Drugs. Recommendation V.-Review of the mechanism of storage, retrieval, and analysis of surveillance data. Result-The data are stored by both computer and hand-tabulated forms. The data still cannot be retrieved easily or quickly. In addition, there is a serious difficulty with followup of individual cases because there is no uniform index- ing or coding method between source and recipient. Thus, reduplication of reports or difficulties may result. Data are analyzed according to simple crite- ria of drug used, age of patient, severity, and nature of adverse reactions, etc. But further statistical analysis is not useful since the total population provid- ing the date is not known. Recommendation VI.-A. conference be held between the Food and Drug Administration and the respective drug firms concerning uniformity and increased efficiency of reporting. Result.-Not held. Recommendation VII.-Priority be given to support laboratory investigations concerning all aspects of the hormonal contraceptive compounds. PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6843 Result.-The Food and Drug Administration and the National Institutes of Health are supporting several studies on carbohydrate metabolism, lipid metab- olism, renal function, blood coagulation mechanisms, potential carcinogenic effects and other studies in animals and man. Recommendation VIII.-Uniformity in labeling contraceptive drugs. Result.-Accomplished. Recommendation IX.-Discontinuance of time limitation of ad~ministration of contraceptive drugs. Result.-Accomplished. Recommendation X.-Simplification of Administrative procedures to allow reduction in dosage of already approved compounds. Result-Although no formal policy has been enunciated, the sponsors of new products that represent either reductions in dosage or changes in dosage sched- ule have been permitted to submit reduced quantities of preclinical and clinical information. It has been suggested, however, in view of these reduced require- ments that the quality of the studies submitted in support of efficacy be improved; that is, the majority of studies should include patients beginning therapy rather than those being switched over from another hormonal contra- ceptive and should not generally include postpartum patients or those who are breast feeding. (b) Utilization American women are sufficiently interested in oral contraception to continue its use despite some alarming reports in the national press. By early 1969 twenty preparations of oral contraceptives, combined and sequential, were being distributed in the United States at the rate of approximately 8.5 million cycles per month. Combined progestin-estrogen products prescribed in 20- or 21-day cycles account for 80 per cent of this total. As a result of the gradual trend toward the use of lower dosages, over 90 per cent of the combination tablets now prescribed contain 2.5 mg. or less of the synthetic progestin. The estimates of use for 1969 are twice as high as those listed in the national fer- tility survey of 1965. This apparent doubling of the numbers suggests a much wider use among older women and those of limited education. Such a trend could be forecast from the increased availability of contraceptive services in many of the poorer areas of our big cities. The use of oral contraceptives has spread in foreign countries as well. Among the countries without laws prohibiting the distribution of contracep- tives, only Japan and the ,U.S.S.R. now prescribe the general distribution or sale of these drugs. The estimate of world-wide distribution of oral contracep- tives is now approximately 18.5 million cycles per month. All available evidence indicates that the continuation rates of oral contra- ceptives are higher than those of traditional methods of contraception, such as the diaphragm, and lower than those of intrauterine devices. In its previous report the Committee indicated an anticipated use of 6 million cycles monthly in the United States in 1970. If the present estimate of 8.5 million cycles is correct, the Committee's projections were conservative. (c) Efficacy The theoretical effectiveness of the combined hormonal contraceptives is reflected in a pregnancy rate of approximately 0.1 per hundred women per year. The theoretical effectiveness of the sequential oral contraceptives appears to be somewhat lower as indicated by a pregnancy rate of 0.5 per hundred women per year. The usually given pregnancy rates, reflecting "use-effective- ness," average 0.7 per hundred women per year for the combined regimen and 1.4 per hundred women per year for the sequential regimen. Effectiveness, judged by the total number of pregnancies, is significantly higher with oral contraceptives, combined or sequential, than with intrauterine devices or any of the traditional methods. The pregnancy rates among users of diaphragms with contraceptive paste thus appear to be 10 to 30 `times higher than those among users of oral contraceptives; those among users of intrauter- ine devices are 2 to 4 times higher. (d) Methods under evaluation Since the Committee's last report, pharmaceutical firms have continued to investigate synthetic progestins and estrogens in an effort to reduce side effects while maintaining maximal efficacy. For example, the most recently PAGENO="0012" 6844 COMPETITIVE PROBLEMS IN THE DRUG LNDUS~RY approved combination product contains one-third the dose of estrogen and about one-tenth the dose of progestin as was present in the original contracep- tive. Steroids that are stored in and slowly released from adipose tissue after oral ingestion are currently under study with the aim of creating a pill that may require administration only once a month. Unpredictable uterine bleeding remains a problem, however. Intramuscularly injected steroids with a prolonged effect that may last for one or more months have been widely studied. Although these compounds may suppress ovulation, uterine bleeding is often an unpredictable complication. The delay before resumption of ovulatory cycles often lasts from 12 to 21 months. There is considerable variation among patients. To regulate the uter- ine bleeding some investigators have administered oral or parenteral estrogen. Doing so, however, detracts from the simplicity of this purely progestational regimen. Low-dose continuous progestin therapy has been investigated in several coun- tries. Drugs of this kind exert their contraceptive effect without the addition of estrogen and without the inhibition of ovulation. The pregnancy rate appears to be approximately 2 per hundred women per year. Approximately two-thirds of the women studied have some cycle irregularity. The contraceptive action of low-dose progestins provides for the first time the possibility of long-term, reversible control of fertility by single administra- tion of a hormone. Steroids may be released at a low and constant rate from capsules, made of various silicones, that are small enough to be inserted under the skin with a hypodermic syringe and that may last possibly as long as three years. Such implants could be removed if subsequent fertility were desired. If the clinical studies that have recently been initiated prove fruitful, this form of hormone administration may well become an important develop- ment in contraception. (e) Thromboembolic disorders An etiologic relation between oral contraceptives and an increase in some thromboembolic disorders has been disclosed by several groups of investigators using retrospective methods of inquiry and studies of mortality trends. In 1967 the Royal College of General Practitioners in Great Britain undertook inter- views of young women with vascular disease. By comparing patients with superficial thrombophlebitis with a suitably matched series of controls, it could be shown that the risk of developing thrombophlebitis was tripled in women who used oral contraceptives. In a second study, Vessey and Doll investigated young women admitted to several hospitals in the northwest of London with a diagnosis of idiopathic thrombophlebitis. These patients also were matched with suitable controls. A third study involved all of the deaths that occurred in England, Wales and Northern Ireland during 19643 in women between the ages of 20 and 44 whose death certificates referred to thrombosis or embolism of the pulmonary, cerebral or coronary vessels. The results of the second and third studies are summarized in Table 1. TABLE 1.-USE OF ORAL CONTRACEPTIVES IN WOMEN SUFFERING FROM `IDIOPATHIC" THROMBOEMBOLIC DISORDERS (EXPECTED NUMBERS IN PARENTHESES) . No. of affected women Source of with a history of oral contraceptives No. studied Affected Control Relative risk: users Disorder data Used Not used women women to nonusers Deep-vein thrombosis pulmonary embolism or Cerebral thrombosis Coronary thrombosis Inpatients {Deaths (Inpatients iDeaths clnpatients ~Deaths 26 (5.0) 32 (53.0) 16(4.2) 10(21.8) 5(1.0) 4(8.0) 5 (1.5) 5 (8.5) 0 (07) 13 (12.3) 18 (11.4) 66 (72.6) 58 26 9 10 13 84 116 998 1 (1) (1) (1) 8.6 to 1 8.3 to 1 10.0 to 1 5.7 to 1 1.7 to 1 1 As in the corresponding control groups for women with deep vein thrombosis or pulmonary embolism. (From Doll, R.: Brit. Med. J. 2:69-76, 1969.) Accor~ii~ ~ tIU~Z Btiti~1i lilY Stl~lt0T~, 111 tIi~ I1)3IIe!1~ of other predisposing causes the risk of developing deep vein thrombosis, pulmonary embolism, or PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6845 cerebral thrombosis is increased about eight times by the use of oral contra- ceptives,, while the risk of developing coronary thrombosis is apparently unchanged. The results of these three studies led the Food and Drug Adminis- tration to order the following change of labeling for the oral contraceptives: "1. The physician should be alert to the earliest manifestations of throm- botic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embol- ism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. "Studies conducted in Great Britain and reported in April, 19681 estimate there is a seven to tenfold increase in mortality and morbidity due to throm- boembolic diseases in women taking oral contraceptives. "The conclusions reached in the studies are summarized in the table below: COMPARISON OF MORTALITY AND HOSPITALIZATION RATES DUE TO THROMBOEMBOLIC DISEASE IN USER AND NON-USERS OF ORAL CONTRACEPTIVES IN BRITAIN Category Mortalit y rates Hospitalization rates (morbidity) Age 20-34 Age 35-44 Age 20-44 Users of oral contraceptives Nonusers 1. 5/100, 000 0. 2/100, 000 3. 9/100, 000 0. 5/100, 000 47/100, 000 5/100, 000 "No comparable studies are yet available in the United States. The British data, especially as they indicate the magnitude of the increased risk to the individual patient, cannot be directly applied to women in other countries in which the incidences of spontaneously occurring thromboembolic disease may be different." Since that time Vessey and Doll 2 have continued their retrospective study to include a larger group of patients matched with controls. The results of this study confirm the findings of the previous investigation. Another retrospective study of cases of thromboembolism and an equal number of matched controls has been completed as detailed in Appendix 2A. This study necessitated a search for cases in five large cities in the United States. The subjects were women of reproductive age who were discharged alive over a recent three-year period from 43 teaching hospitals. Additional requirements for inclusion in the study were the absence of a history of any acute or chronic condition that might predispose to thromboembolism, absence of a history of a prior attack of the disease, reasonable certainty of diagnosis, and presumption of fertility. The controls were women admitted to the same hospitals in the same six-month period. These controls were matched by race, age, marital status, parity, residence, and hospital-pay status. The controls were in good health prior to hospitalization and free from evidence of steril- ity. The cases and the controls were interviewed in their honles after dis- charge from the hospital to ascertain whether they had used oral contracep- tives before hospitalization. Other topics were included in the questionnaires. Most of the acceptable cases had thrombophlebitis, pulmonary embolism, or both; a few had cerebral or retinovascular disease. The risk of thromboembol-. ism to a woman using hormonal contraceptives was estimated by indirect methods to be 4.4 times that of the non-user. The excess risk did not persist after cessation of use, nor did prolonged continuation of use enhance the risk. No striking differences among contraceptive products were found except for an excess of the use of sequential compounds among the cases, as compared with the controls. The excess relative risk was calculated for each diagnostic grouping and for each demographic class of subjects in which the numbers were large enough 1 Inman, W. H. W. and Vessey, M. P.. British Medical Journal, 2 :193-199, 1968. Vessey, M. P. and Doll, R., British Medical Journal, 2 :199-205, 1968. °Vessey, M. P. and Doll, R., Investigation of Relation Between Use of Oral Contra- ceptives and Thromboembolic Disease. A Further Report. British Medical Journal, 2 :651, 1969. PAGENO="0014" 6846 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to permit evaluation. The findings of this study are in general agreement with those previously reported from Great Britain. These studies together establish an etiologic relation between thromboem- bolic disorders and the use of oral contraceptives. Quantitatively they suggest that the mortality from thromboembolic disorders attributable to the oral con- traceptives is about three per 100,000 women per year adding slightly less than 3 per cent to the total age-specific mortality in users of these drugs. (f) Carcinogencsi$ Much indirect evidence suggests that steroid hormones, particularly estrogen may be carcinogenic in man. These data are derived from experiments on labo- ratory animals in which long-term administration of estrogen resulted in cancer in five species. Although all physical and chemical agents that are car- cinogenic in man produce malignant tumors in experimental animals also, evi- dence of the carcinogenicity of estrogen in other species cannot be transposed directly to man. Suspicion lingers, however, that the results in laboratory ani- mals may be pertinent to man. Many difficulties arise in the epidemiological elucidation of this suspected relation. The principal obstacle is the long latent period between the administration of a known carcinogen and the development of cancer in man. Thus far, no properly devised prospective or retrospective studies have provided an adequate solution to this problem. The Committee has focused its attention on three target organs: cervix, endometrium, and breast. Estrogens may produce a variety of epithelial changes in the human cervix of uncertain prognostic significance. A study of women attending the Planned Parenthood Clinics in New York City has revealed a higher prevalence of epithelial abnormalities that the investigators considered to be carcinoma in situ among women using oral contraceptives than in those who use the diaphragm. The Committee believes that this study does not prove or disprove an etiologic relation between the oral contraceptives and these cervical changes. The epidemiological and diagnostic problems inher- ent in these studies are discussed in the Task Force Report. Although estrogen causes epithelial changes in the human breast, its carcino- genic effect on that organ has never been proved. Even in women with frank mammary carcinoma, estrogen produces variable changes in the clinical course of the disease. For example, ovariectomy leads to regression of metastatic breast carcinoma in approximately half of premenopausal women. Exogenous estrogens cause either regression or stimulation of similar tumors in mens- truating women but induce regression in about half of post-menopausal women. The reasons for these paradoxical effects of estrogen on breast cancer are not clear. In accordance with suggestions in the last report, the Food and Drug Administration has required mandatory testing for all currently licensed and investigational hormonal contraceptives on monkeys throughout their lifetimes and on dogs for 7 years. Thus far the presently licensed compounds have not produced tumors in these two groups of laboratory animals. Two estrogen- progestin combinations have, however, induced mammary tumors in beagles. Because these two compounds offered no clear therapeutic advantage over pre- viously available hormonal contraceptives, clinical investigation was discontin- ued. This decision still leaves unresolved the question of similarity in hor- monal induction of mammary tumors in a highly suceptible canine strain and in man. Continued testing of the presently available drugs is indicated. Currently available data on death rates from genital and mammary cancer in women in the United States do not clarify the problem of association between steroids and carcinoma. The long latent period of action of known carcinogens (10 years) and the length of time between diagnosis and death eliminate vital statistics as a source of information about this association until the mid-1970's or later. The massive program of prophylaxis launched against cervical cancer in this country has accomplished a steady decline in deaths from the disease. The common practice of repeating cervical cancer in this country has accomplished a steady decline in deaths from the disease. The common practice of repeating cervical smears, annually or semi-annually, in women taking oral contracep- tives has contributed to the decline, but it has clouded the question of the effect of oral contraceptives on cervical cancer. Since there is no method of early detection of mammary carcinoma compara- PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6847 ble in efficacy to that of the cervical Papanicolaou smear, the problem of the possible carcinogenic effect of oral contraceptives on the breast remains unre- solved. The Committee suggests that carefully designed retrospective studies using a case-control method similar to that employed in the investigation of thromboembolism may answer this perplexing question. A pilot study to ascer- tain feasibility is already in progress at the Johns Hopkins Hospital. If this method proves successful, several larger studies should be immediately initi- ated. Lacking conclusive information about the applicability of existing animal data to women and sufficient observations of human disease the Committee concludes that potential carcinogenicity of the oral contraceptives can be nei- ther affirmed nor excluded at this time. Clinical surveillance of all women taking oral contraceptives must be continued. A major effort to resolve the questions about steroid-induced neoplasia in human beings should be under- taken. (g) Metabolic effects Hormonal contraceptives produce numerous effects on many organs, for example, the liver, the thyroid, and the adrenal. They also affect some of the body's homeostatic mechanism; for example, they produce changes in salt and water metabolism and occasionally induce hypertension. Recently morphologic changes in blood vessels have been described. In many areas where alteration in function or structure has been noted, basic information is lacking. Little is known, for example, about the effects of the oral contraceptives on water metabolism or renal function. Observations that large doses of estrogen hasten epiphyseal closure in girls has created fear that oral contraceptives may limit growth. Such concern is unjustified, however, because these drugs are usually prescribed only after the growth spurt and in doses far smaller than those required to stunt growth. There is no evidence at this time that any of these drug-induced metabolic alterations pose serious hazards to health. The systemic effects of the drugs are so fundamental and widespread, however, that continued medical surveil- lance and investigation is required. COMMITTEE RECOMMENDATIONS 1. Well designed studies be initiated and supported to elucidate or eliminate the relation of the hormonal contraceptives and carcinoma of the breast and uterus. The relation of exogenous steroid hormones to the induction of cancer in man is the major unsolved question in the widespread use of the current hor- monal contraceptives. Funds to investigate this relation are urgently needed. An international conference on epidemiologic design or projected studies should be beneficial. 2. Long term support be supplied to investigate the basis and prognosis of the metabolic alterations produced by the hormonal contraceptives. The Task Force Report on Metabolic Effects of the hormonal contraceptives reveals a paucity of basic knowledge. Substantial research support is needed to close these information gaps. 3. Substantial support be supplied to develop new methods of contraception. The current methods of contraception have inherent risks and disadvantages. These are enhanced when modern contraceptive methods are introduced into underdeveloped countries. Generous research support to discover new methods with decreased risks and fewer disadvantages is essential. 4. The National Institutes of Health support a National Fertility Survey in .1970. Adequate data on contraceptive usage are not available after 1965. Support for a quinquennial survey should be established. 5. Financial support be made available to make possible local reporting of certain diseases.. Reporting of certain diseases such as cancer from selected localities would be of obvious benefit. The annual incidence of cancer reported from Connecti- cut is currently available only as late as 1962 while the report from New York, exclusive of New York City, is more up to date. These reports, if cur- rent, and if extended to include adequate samples of the general population, PAGENO="0016" 6848 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY could be used to indicate trends. With the rapid proliferation of very potent therapeutic agents, such reporting becomes more of a necessity. 6. The Food and Drug Administration assure adequate surveillance of approved contraceptive drugs. The inadequacy of surveillance of contraceptive drug use in the United States and other countries is apparent. Voluntary reporting of adverse reac- tions tends to be capricious and may be misleading. The Committee recom- mends setting up test centers utilizing large contraceptive dines, with identical record systems and good follow-up to record and report adverse reactions. In addition, the Committee recommends the implementation of an international conference to discuss ways and means of promoting rapid and accurate trans- mittal of information about adverse drug reactions to responsible authorities. 7. Strengthen the surveillance system of the Food and Drug Administration. This recommendation from the previous report has not been satisfactorily implemented. A system should be devised so that when adverse reaction reports are received, they are made readily and immediately accessible. 8. An annual conference of scientific writers on contraceptive knowledge and accomplishment be held under auspices of the Food and Drug Administration or the Department of Health, Education and Welfare. Years ago the American Cancer Society sought by means of annual confer- ences of science writers to make available data on research, treatment and etiology of malignant disease. These conferences made for a vastly better informed press. In view of the public interest in population and its control similar conferences in this area appear to have merit. CONCLUSION Although the Kefauver-Harris Amendments of 1962 indicate that the term "safe" has reference to health of man, nowhere do they define safety. Discuss- ing this ubject before the Subcommittee of the Committee on Government Operations of the House of Representatives,3 the Commissioner of FDA pointed out that no effective drug can be absolutely safe. Therefore, evaluation safety of a drug requires weighing benefit against risk. The Advisory Oommittee on Obstetrics and Gynecology has continued to assess the risk of oral contraceptives in this light, weighing knowledge of potential hazards against benefit. It has periodically reviewed the labeling of these compounds, repeatedly advocated strict surveillance by physicians, and recommended the accumulation of additional information about biological action and clinical effects. This report states the benefits of these compounds compared with those of other contraceptives. Specific risks as well as requisite practices for follow-up of patients have been detailed in the labeling of all hormonal contraceptives. When these poten- tial hazards and the value of the drugs are balanced, the Committee finds the ratio of benefit to risk sufficiently high to justify the designation safe within the intent of the legislation. Hearing before Subcommittee of the Committee on Government Operations, Drug Safety, H.R., 88th Cong., 2d Sess. 149-154, 1964. PAGENO="0017" TASK FORCE REPORTS August 1, 1969 As in the previous Report on the Oral Contraceptives, the Committee was divided into four task forces, each headed by a chairman, as follows: TASK FORCES 1. Utilization, Effectiveness, and Current Investigations S. J. Segal, Ph. D., Chairman H. F. Fuller, M.D. C. Tietze, M.D. 2. Thromboembolic Disorders P. E. Sartwell, M.D., Chairman A. T. Masi, M.D. S. G. Kohl, M.D. 3. Carcinogenesis R. Hertz, M.D., Chairman B. M. Peckham, M~D. C. Tietze, M.D. 4. Biologic Effects P. A. Oorfman, M.D., Chairman K. Adamsons, M.D. E. R. Carrington, M.D. E. M. Delfs, M.D. The report of each Task Force and the Chairman's Summary have been care- fully reviewed and unanimously approved by the Committee as a whole. The summary of this report incorporates the conclusions drawn up by the individ- ual task force reports which are appended in detail. APPENDIX 1 REPORT OF THE TASK FORCE ON UTILIZATION, EFFECTIVENESS, AND CURRENT INVESTIGATIONS S. 3. Segal, Ph. D., Chairman UTILIZATION American women are interested in oral contraception. By 1965 they were consuming progestin and estrogen tablets at the rate of 2,660 tons yearly. One of every four married women under age 45 had used or was using an oral con- traceptive. Actual users in 1965 numbered 3.8 million; 2.6 million women more had discontinued use. These estimates from the National Fertility Survey of 1965 (11) are based on interviews with a carefully drawn sample of American women. To the extend that the sample excluded unmarried women, married women separated from their husbands, and users of oral contraceptives over age 45, the figures are underestimates of the total experience with oral contra- ceptives up to 1965. The survey revealed that the use of oral contraceptives was much greater among younger than older women. Of women under 30, more than two-fifths had already used the pill; of women over 40, fewer than one- tenth had used it. The number of years of schooling proved to be a variable of major relevance. The percentage of users varied strongly and positively with the extent of education, from 37 per cent for college graduates to 12 per cent for women with less than high school education. Thus, by 1965 nearly one third of all American women who ever used any method of contraception reported having used the pill (18). 40-471 0-70--pt. 17-2 (6849) PAGENO="0018" 6850 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY National survey data have not been assembled after 1965. Estimates of sub- sequent use of oral contraceptives are based on manufacturers' reports and market surveys. By early 1969, twenty preparations of combination or sequen- tial oral contraceptives were being distributed in the United States at the rate of approximately 8.5 million cycles per month.1 The apparent doubling of the number of current users since 1965 suggests much wider use than four years ago among older women and women of limited education. Combined progestin- estrogen products prescribed in 20- or 21-day cycles account for eighty per cent of this total. There has been a gradual trend toward the use of lower dosage forms, so that over 90 per cent of the combination tablets prescribed contain 2.5 mg. or less of the synthetic progestin.' The use of oral contraceptives abroad has spread rapidly since this Commit- tee's last report was issued. Among countries that regulate drug distribution, only Japan and the USSR proscribe the general distribution or sale of hor- monal steroids for contraceptive purposes. In India hormonal contraceptives are approved for commercial sale but not for general use in the governmental family planning program. It is estimated that the world-wide distribution of oral contraceptives in early 1969 was 18.5 million cycles per month.2 CONTINUANCE OF USE According to the National Fertility Survey of 1965 (11), almost three out of four American women starting oral contraception continued to use the method for at least one year, and more than three out of five continued for at least two years. These estimates are based on terminations as a result of side effects and other problems of use; terminations for reasons not related to the method are excluçled. Continuation rates after two years of use were eleven to twelve points higher for women under thirty years of age and for those with fewer than three births than for older women and those of higher parity. Continuation was related also to the women's level of education, ranging from 50 per cent after two years for women who had not completed high school to seventy-one per cent for those with one or more years of college. The survey also revealed the marked improvement in continuation rates for women who had started oral contraception in 1964 to 1965, compared with those who started earlier, possibly reflecting fewer side effects resulting from lower dosage as well as increased confidence in the method. The maximal rate of discontinuation was observed during the early months of use. Continuation rates reported in clinical studies cannot be compared with the results of the National Fertility Survey without giving appropriate considera- tion to the special curcumstances of each study, including the socioeconomic and cultural characteristics of the patients and the possible effects of any spe- cial efforts on the part of the investigator to encourage continued medication. However, all available evidence indicates that continuation rates with oral contraception are higher than with traditional contraception, such as the dia- phragm and lower than with intrauterine devices in the same or comparable populations (16, 19). FUTURE USE In its previous report the Advisory Committee presented rough estimates of the anticipated future use of oral contraceptives in the United States. Assum- ing, series B. population projection,3 46 per cent of each cohort of married women starting oral contraception at the same rate as the women who were under 25 years of age~ in 1965, no further changes to oral contraceptives by older women, and about 60 per cent of those who ever used the drug remain- ing current users, the following were tabulated. 1 This estimate is based on data provided by the National Prescription Audit, R. A. Gosselin & Company, Inc., Dedham. Massachusetts, October, 1968, and Information pro- vided by the major manufacturers of oral contraceptives In the United States. 2 This estimate was made by R. L. Belsky, Population Council, New York, and was based on information provided to him by major manufacturers, United States Agency for International Development, International Planned Parenthood Federation and Swed- ish Developmental Agency. ~ Current Population Reports, Series P-25, No. 329, March 10, 1966. PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6851 PROJECTED NUMBER OF WOMEN IN MILLIONS USING ORAL CONTRACEPTIVES Current Total women Year Ever users users (15-44 years) 1970 10 6 43.3 1975 13 8 46.9 1980 16 10 51.9 1985 19 12 56.4 If the estimate of 8.5 million cycles distributed monthly reflects reasonably well the number of current users of oral contraceptives in early 1969, it would appear that the Committee's projections were conservative, at least to the present time. EFFECTIVENESS Taken according to the regimen prescribed, oral contraceptives of the com- bined type are almost 100 per cent effective in preventing unwanted pregnancy. Major clinical reports published between 1962 and 1967 cover an aggregate of some 200,000 cycles of medication. In these studies only 15 pregnancies occurred unassociated with the omission of one or more tablets, according to the statements of the users. The corresponding pregnancy rate, reflecting the "theoretical effectiveness" of the method, is approximately 0.1 per 100 women per year. The theoretical effectiveness of the sequential oral contraceptives appears to be somewhat lower, as indicated by a pregnancy rate of 0.5 per 100 women per year, based on 70,000 cycles and 25 pregnancies, apparently result- ing from method failure (15). Computation of pregnancy rates for oral contraceptives comparable to those available for other methods requires the inclusion of so-called patient failures, apparently resulting from the omission of one or more tablets during the cycle. Thus defined, the pregnancy rate reflects "use-effectiveness" and averages 0.7 per 100 women per year under the combined regimen and 1.4 per 100 women per year under the sequential regimen, according to published reports (15.). The absence of any pregnancies in a number of reports results from sampling variation, as do higher rates in other studies. Theoretical effectiveness and use-effectiveness are significantly higher for combined contraceptives than for intrauterine devices (9), the condom, the dia- phragm used with spermicidal jelly or cream, vaginal foam, and vaginal jelly or cream used with the diaphragm (6). The rate shown for "condom or dia- phragm" under the heading of method failures is based on the experience of couples who used these methods for purposes of family limitation, after they had achieved the numb~r of children they wanted (12). Strictly speaking, this rate reflects use-effectiveness in the hands of a highly motivated group of users; the pregnancy rate reflecting theoretical effectiveness should be a little lower. The number of couples available for study was too small to permit the computation of separate rates for the two methods. The pregnancy rates shown in Table 2 do not include unplanned pregnancies after contraception has been stopped for reasons other than the wish to con- ceive. A statistical method for evaluating such pregnancies has recently been developed (17), and several studies are in progress to ascertain their fre- quency after discontinuation of oral contraception. This broader concept of "extended use-effectiveness" is of particular importance for the evaluation of oral contraceptives since the nature of the regimen permits a sharp distinction between cycles of use and cycles of non-use. If a woman fails to take oral med- ication and conceives, as is often the case, the method is usually exonerated. If she fails to use consistently ~a coitus-connected method, and conceives, the preg- nancy is more likely to be charged to method failure. - HORMONAL CONTRACEPTIVES UNDER CURRENT INVESTIGATION Suppression of ovulation-Oral preparations Since 1966, when this Committee issued its last report on oral contracep- tives, pharmaceutical firms continued to investigate different combinations or doses of synthetic progestins and synthetic estrogens in an effort to reduce side effects of antiovulant therapy while maintaining a high degree of effee- PAGENO="0020" 6852 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tiveness. The dose of progestin has gradually been reduced from over 9 mg. in the original preparations to 0.5 mg. The dose of estrogen, ethinyl estradiol or its three-methyl-ether, has been reduced from 0.15 mg in the first marketed product to 0.05 mg. It is not yet possible to draw conclusions concerning the various newer dosage combinations with respect to either efficacy or side effects. The combination product introduced most recently contains 0.5 mg. of a synthetic progestin, norgestrel, and 0.05 mg. of ethinyl estradiol (6). TABLE 2.-PREGNANCY RATES PER 100 WOMEN PER YEAR Method All failures pregnancies Oral contraceptives: Combined regimen 0. 1 0. 7 Sequential regimen ~ 1. 4 Intrauterine devices: Large lippes loop 11. 9 2. 7 Saf-T-Coil 11.9 2.8 Condom or diaphragm 2.6 United States clinics: Diaphragm used with spermicidal jelly or cream 17. 9 Vaginal foam 28.3 Vaginal jelly or cream alone 36. 8 1 Pregnancies with IUD in situ. All rates for IUD's and traditional methods are for the first year of use. Steroids that are stored in adipose tissue after absorption from the gastro- intestinal tract are being investigated for possible one-pill-a-month contraceptive therapy (5). The investigation is aimed at calibrating the oral dose of the combination that will result in a month-long release of steroid from the adi- pose tissue at a level that will suppress ovulation while maintaining an accept- able pattern of endometrial bleeding. The problem of unpredictable endometrial bleeding has not yet been resolved (12). Eluppression of ovulation: Parenteral preparations Intramuscular injections of steroids can give a depot effect, adjusted to last a single month or for several months. The most widely studied compound for injectable hormonal contraception is a 6~alpha~methyl~17~alPha-hydroxyProg esterone acetate; several thousands of women have been included in studies in many countries. The regimen investigated most completely is 150 mg. injected every 90 days, although studies are also in progress with semiannual injections of 400 mg. With this procedure, ovulation is generally suppressed through an interference with the midcycle peak of LII (8). Ovarian follicular development appears, nevertheless, to proceed, so that endogenous estrogen production may not be completely obliterated. The endo- metrial pattern, however, reveals that the established estrogen-progestin balance is far from normal. As a result, uterine bleeding is unpredictable for women on this regimen. There is considerable variation among patients but by the end of a year the majority of women have atrophic endometria and are amenor- rheic. A pregnancy rate below 1 per 100 women per year has been obtained with this procedure. There is, however, considerable delay in the restoration of ovulatory cycles after discontinuation. Delays in ovulation from 12 to 21 months are not uncommon and the time required for the establishment of a regular ovulatory pattern after treatment is still not certain. In order to regu- late the pattern after treatment is still not certain. In order to regulate the pattern of endometrial bleeding, some clinicians have employed the periodic administration of estrogen either orally or by injection as an adjunct to injected progestin. Since this procedure requires monthly return visits, or self- administered monthly courses of oral estrogen, it detracts considerably from the method's simplicity. Hormonal contraception without suppressing ovulation (a) Oral Preparations-A new type of hormonal contraception is now being investigated in several countries. This innovation in hormonal contraceDtiOn is continuous low-dosage progestin therapy, which imparts an antifertility effect PAGENO="0021" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6853 without added estrogen and without inhibiting ovulation. The basis of the antifertility action remains uncertain. During the investigation of oral progestin-estrogen contraceptives, several investigators concluded that ovulation was occurring in a significant percent- age of cycles, even though the antifertility effect was almost absolute. Yet it was not until 1965 that work was reported implying that ovulation suppression could be dispensed with entirely while still retaining a potent antifertility effect (10). In this early study, a synthetic progestin, 6-chloro-6-dehydro-17- alpha-acetoxy-progesterone was given alone at the low dose of 0.5 mg. daily to a group of nearly 1,000 women with normal cycles. The women were seen monthly during the period of investigation, which covered close to 10,000 cycles. Fourteen pregnancies occurred, thirteen of which were ascribed to fail- ure of patients to take the medication regularly. Considering only the single so-called "method-failure," a pregnancy rate of 0.2 per 100 women per year can be calculated. When all unintended pregnancies are considered regardless of reason, the pregnancy rate is 2.1 per 100 women per year. Approximately two- thirds of the patients had some irregularity in the cycle during the twenty- month study period. The studies were subsequently expanded to include obser- vations on 50,000 cycles, with more than 600 women observed for over two years. In this broader experience, 159 method failures were reported, giving a pregnancy rate of roughly 2 per 100 women years of use (7). With this particular compound at the dosage employed, problems with control of the cycle appear to be a handicap, but the contraceptive effectiveness of the continuous progestin method seems clearly established. As a consequence, sev- eral other synthetic progestins have been placed under clinical investigation at doses intended to replicate the low-dose effect. Experience is sufflcient with two of these compounds to indicate confirmatory results. With one of them, norgestrel, anti-fertility activity can be achieved with a daily oral dose of 0.075 mg. (4). More than 1,000 women have been observed for approximately 7.000 cycles, including over 400 women for at least one year. The ten reported pregnancies suggest a pregnancy rate of 1.6 per 100 women per year. Similar results have been achieved with respect to both control of cycle and fertility control with the use of 0.5 mg. daily of megestrol acetate (1). An innovation in the study of this compound is the use of an oil-filled gelatine capsule instead of a tablet, with the aim of achieving more uniform absorption and reduction of a cyclic irregularity. A cooperative statistical evaluation involving thousands of subjects in several countries is now in progress. Although the mechanism by which the uninterrupted daily administration of these progestational agents creates a state of infertility without inhibiting the pituitary and suppressing ovulation remains uncertain, the possibilities can be narrowed down considerably. That the therapy does not interfere with ovula- tion suggests that the mode of action may be transport of sperm or ovum, the fertilization process, transport and development of the zygote, or the prepara- tion of the endometrium for nidation. Histologic evidence from biopsy material suggests that endometrial changes are not responsible for the antifertility effect. Sperm transport could be affected as it passes through the cervical mucus or higher in the female tract. Although the preliminary reports tended to emphasize changes in cervical mucus that could create a barrier hostile to spermatozoa, such changes are not necessarily correlated with the antifertility effect. Future investigation will be required to establish the effect of continu- ous progestins at doses that do not inhibit ovulation on such key factors as tubal transport rates of gametes and the process of fertilization. b) Parenteral Administration-The discovery of the antifertility action of low-dose progestins, based on uninterrupted administration, opens up for the first time the possibility of singly-administered, long-term, reversible control of fertility by hormonal means, in a manner that would allow for maintenance of ovarian function and menstrual cycles. A possible application of this principle is suggested by experiments demonstrating that steroid hormones may be released at low and constant rates from capsules made of various silicone polymers (3, 13). One such material poly-dimethylsiloxane, is already used ~widely in surgery. Capsules containing the synthetic steroid, megestrol acetate, have been inserted subdermally into female rats, rabbits, and monkeys, and biologic evidence of slow and constant release of the hormone has been PAGENO="0022" 6854 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY obtained (2). Animal experiments suggest that this route of administration increases the potency of niegestrol acetate to approximately 10 times that of the oral route. A capsule small enough to be inserted under the skin through a hypodermic needle can be filled with an adequate supply of this progestin to last for more than three years. Contraceptive implants of this type could be removed at will, and there is no reason to believe that subsequent fertility would be impaired. Depending on the outcome of clinical studies that have been recently started (14), this form of low-dose progestin contraception may very well be one of the next developments in contraceptive methodology. References 1. Avendano, S., Tatum, H. J., Rudel, H. W., and Avendano, 0. A clinical study with continuous low doses megestrol acetate for fertility control. Amer J~. Obstet Gynec (in press) 1969. 2. Chang, C. C. and Kind, F. A. Sustained release hormone preparations: 3. Biological effectiveness of 6~methyl~17~alpha~acetOxPyregna4, 6-diene-3, 20-dione. Steroids 12:689, 1968. 3. Folkman, J. and Long, D. M. The use of silicone rubber as a carrier for prolonged drug therapy. J. Surg Res 4:139, 1964. - 4. Foss, G. L. Oral contraception with continuous microdose of norgestrel. J Reprod Fertil Suppl. 5:145, 1968. 5. Guiloff, E., Berman, E., Osorio, R., Monteglio, A. and Lloyd, C. W. Once-a- month contraceptive pill. Presented at 25th Annual Meeting, American Fertility Society, Miami, Fla., 1969. 6. Laurie, R. E. and Lewis, E. F. A clinical review. J Reprod Fertil Suppl. 5:95, 1968. 7. Martinez-ManautoU, J., Giner-Valasquez, J., Cortez-Gallegos, V., Aznar, R., Rojas, B., Guittierez-Najar, A., Rudel, H. W. Daily progestogen for con- traception: Clinical study. Brit Med J 2:730, 1967. 8. Mishell, D. R., El Habashy, M. A., Good, R. G. and Moyer P. L. Contracep- tion with an injectable progestin. Amer J Obstet Gynec 101:1046, 1968. 9. Population Council: Cooperative statistical program for the evaluation of intrauterine devices. Unpublished data. 10. Rudel, H. W., Martinez-ManaUtou, J., and Maqueo-Topete, M. Role of pro- gestogens in hormonal control of fertility. Fertil Steril 16:158, 1965. 11. Ryder, N. B. and Westoff, C. F. Use of oral contraception in the United States, 1965. Science 153 :1199, 1966. 12. Sagi, P. 0., Potter, R. G. and Westoff, C. F. Contraceptive effectiveness as a function of desired family size. Population Studies 15:291, 1962. 13. Segal, S. J. Future aspects in contraception. Excerpta Medica mt. Congr. Series No. 133, Proëeedings Vth World Congr. on Fertility and Sterility. Stockholm, June 16, 1966, p. 1028, 1967. 14. Tatum, H. J. History and current status of implant contraceptives. Prog- ress in Conception Control, J. B. Lippincott Company, Philadelphia (in press) 1969. 15. Tietze, C. Oral and intrauterine contraception: effectiveness and safety. Int J Fertil 13:377, 1968. 16. Tietze, C. Comparison of three contraceptive methods: diaphragm with jelly or cream, vaginal foam, and jelly/cream alone. Journal of Sex Research 3:295, 1967. 17. Tietze, C. and Lewit, S. Statistical evaluation of contraceptive methods: Use-effectiveness and extended use-effectiveness. Demography 5:931, 1969. 18. Westoff, C. F. and Ryder, N. B. United States: Methods of fertility control, 1955, 1960 and 1965. Studies in Family Planning 17:1, 1967. 19. Westoff, C. F. and Ryder, N. B. Duration of use of oral contraception in the United States, 1960-1965. Public Health Rep 83 :277, 1968. PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6855 APPENDIX 2 REPORT OF THE TASK FORCE ON THROMBOEMBOLIC DISORDERS P. E. Sartwell, M. D., Chairman A. THROMBOEMBOLISM AND ORAL CONTRACEPTIVES: AN EPIDEMIOLOGICAL CASE-CONTROL STUDY1' 2, 3 PHILIP E. SARTWELL, ALFONSE T. MASI,4 FEDRICO G. A1ITHES, GERALD R. GREENE5 AND HELEN E. SMITH The suspicion that oral contraceptives might predispose women toward vas- cular occlusive phenomena arose about 1961, largely from the publication of case reports. An ad hoc committee (1) in 1963 advised that "comprehensive and critical" studies to look into the possibility be conducted. Nevertheless, little was done in this direction, despite the great increase in the use of these potent drugs. By the time the Advisory Committee on Obstetrics and Gynecol- ogy of the Food and Drug Administration began to prepare its first report on the oral contraceptives in 1965, it was evident that an epidemiologic study was even more urgently needed than in 1963. The present study was begun in November, 1965, in direct response to this need. The primary aim of this study has been to evaluate the reported association between taking oral contraceptives and development of thromboembolism. The retrospective (case-control) approach was used. This was appropriate in view of the low incidence for idiopathic thromboembolism at the reproductive ages, which made a prospective approach extremely difficult, costly and slow to yield results. A series of previously hospitalized cases of idiopathic thromboembol- ism in women of reproductive age was identified, matched controls were secured from among other hospitalized women, and both groups were inter- viewed to ascertain whether they had used oral contraceptives before the hos- pitalization. The term "idiopathic thromboembolism" is used in this report to refer to cases in women who at the time they developed thromboembolism did not have any medical, surgical or traumatic condition that is associated with this dis- ease. MATERIALS AND METHODS A pilot study was first conducted at the Johns Hopkins Hospital. Ten suita- ble cases were found, and 20 matched controls were selected. One finding of the pilot trial was that a high proportion of women, even at these relatively young ages, who were hospitalized with thromboembolism had medical, surgi- cal or traumatic features in their histories that made them ineligible fOr study. Another important result was that they knew, or at least stated, quite confidently their histories of use of oral contraceptives. This finding was con- sistent with the opinions of workers who had done surveys of contraceptive practices, and justified proceeding with the study. To be sure, the statements of respondents, although given with assurance in most cases, could have been wrong, but it was not feasible to attempt to verify them from independent sources. The finding of six cases who had used oral contraceptives out of a 1 From the Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland, 21205. ~ study was supported by the Food and Drug Administration Contract Number FDA 67-10; the Family Planning and Evaluation Section of the Epidemic Intelligence Service, National Communicable Disease Center, Atlanta, Georgia; and the Population Council, through Grant Number M68.06. ~ for publication in American Journal of Epidemiology. Present address: University of Tennessee School of Medicine, Memphis. Dr. Masi was a Senior Investigator under the Arthritis Foundation. 5 Dr. Greene was, during this study, an Epidemic Intelligence Officer, National Com- municable Disease Center. The authors are grateful to all the persons in the collaborating hospitals who helped in data gathering. There are several hundred such persons and it would be impossible to list them all here, but the liaison physicians are named in Appendix 1. Advice and assistance came willingly from many others who were asked to help. Dr. James W. Long and, later, Dr. John J, Schrogie of the F.D.A. deserve special mention. Dr. Carl W. Tyler and Dr. Sheldon J. Segal provided much-needed support. In the Pittsburgh phase of the study Dr. John C. Cutler, head of the Population Division of the University of Pittsburgh Graduate School of Public Health, kindly assumed a share of the administrative responsibility. Record numbers of potential cases and controls were provided from the Hospital Utilization Project (H.U.P.) through the cooperation of Dr. Paul Lewis and Mr. Donald Doyle. PAGENO="0024" 6856 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY total of 10 cases, while none of 20 controls had used them, made it mandatory to continue the study. The plan was to have the interviews deal with other topics including medi- cations of various types taken before the hospitalization in question (e.g. anal- gesics, tranquillizers and sedatives, drugs for weight control), the respondent's previous health and the medical and reproductive history of her husband and herself. The interview was designed to avoid concentrating the respondents' attention on a possible drug-thromboembolism relationship and thereby possibly obtaining biased answers. Also, this led to the exclusion of a few respondents who had disqualifying conditions not revealed in the hospital history. Informa- tion concerning education, economic status and employment was obtained. Interviews in the main study were done by interviewers employed and super- vised by National Analysts, Incorporated. Respondents were assured that their identity would not be divulged. For the main study, it was decided initially to conduct the search for cases and controls among patients discharged within the past three years from large hospitals affiliated with medical schools and located in large cities closest to the base of operations. Ultimately, hospitals in five cities-Baltimore; Wash- ington, D.C.,; Philadelphia; New York City; and Pittsburgh-were invited to participate. For inclusion, women had to be married, age 15 to 44 inclusive, and discharged alive from the hospitals within three years. The marital requirement was based on the expectation that contraceptive histories would be more reliable and obtained with greater ease from married women. The other requirements were based on considerations of the ages at which women use oral preparations of ovarian hormones and synthetic steroids as contracep- tives and the limits of time over which they would be likely to remember what medications they had been taking before hospitalization. The choice of cities and hospitals was dictated by practical considerations related to ease and economy of case selection and interviewing. Every hospital that was asked to participate in this study, with a single exception, agreed to do so; difficulties in financial arrangements were responsible for the one hospital's inability to take part. As to the medical conditions included, all forms of intravascular (venous or arterial) thrombosis, with or without pulmonary embolism, including cerebral and coronary thrombosis, were investigated, as well as pulmonary emboli with- out a known source. The term thromboembolic disease will be used to indicate this entire group of conditions. Cases were excluded from this study on the following grounds as determined from the hospital history: having a chronic condition which was thought to predispose to thromboembolism; having had recent precipitating events such as surgery or trauma; pregnancy; sterility; having conditions which might be considered as contraindications to oral contraceptives; and having conditions which might be considered as reasons for avoidance of pregnancy. Review of the literature and consultation with many authorities was accomplished to determine conditions or factors associated with or predisposing to thromboem- bolism. The object was to include as cases only those patients who had no known predisposing or precipitating factors. The following are the principal conditions of this type which served to exclude patients: any past history of vascular disorders including varicose veins, or prior thromboembolic event; diabetes; hypertension, with recorded systolic blood pressure of 180 or dias- tolic of 100; rheumatoid, gouty arthritis or any of the rate connective tissue disorders; hypo- or hyperthyroidism, untreated; any history of other chronic systemic conditions known to predispose to thromboembolism, e. g. cancer, heart or blood diseases; obesity (over 15% overweight; hemoglobin values below 8 or above 16 gms percent; childbirth, major trauma or surgery within six weeks prior to onset of thromboembolic event; various systemic infections within four weeks of onset; localized infection (abscess, carbuncle) or pneu- monitis within 14 days prior to onset; minor trauma or inflammation (bursi- tis, tendinitis) of tissues site of subsequent thrombosis within two weeks: and unusually strenuous activity for the individual, or prolonged inactivity or immobility within two weeks. Reasonable medical evidence to support the diagnosis of thromboembolism was required. It is well known that pulmonary embolism, cerebral thrombosis and cerebral embolism are difficult to diagnose accurately in the absence of pathological evidence, unless supported by procedures such as lung scans and PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6857 angiography. Only cases in which the hospital diagnosis was unequivocal were accepted, and the records were reviewed independently by two physicians, one a board-qualified internist, who rejected those cases which they considered doubtful. Controls were female patients discharged alive from the same hospitals in the same 6-month time interval. In addition to these matching factors, they were individually matched to the thromboemboljsm cases on age (within the same five-year span), marital status, residence, race, parity (three classes-O, 1-2, 3 or more prior pregnancies), and hospital pay status (ward, semi-private or private). The small inaccuracies in matching are explained by differences between statements on the hospital records and interviews, the latter being accepted, and also by occasional inability to obtain a perfect match. The same exclusions, on the basis of infertility or chronic disease, applied to the controls as to the cases. Controls for the most part were admitted for acute medical or surgical conditions, trauma including fractures and dislocations, and elective surgery such as nose and throat operations. Two controls were picked for each case in nearly all instances, in order that the case need not be dropped from the study if the first control proved una- vailable for interview. In the course of the study, several changes were made, although the original plan was followed exactly throughout for the main study group of married women with idiopathic thromboembolism. In Philadelphia, New York City and Pittsburgh, unmarried cases and controls were included, as it had become evi- dent that idiopathic thromboenTholjsm was relatively frequent among younger, unmarried women and it seemed unwise to disregard this source of case mate- rial. In Philadelphia, the interviewing of the unmarried cases and controls was undertaken by students at the Woman's Medical College of Pennsylvania, under the direction of Dr. Judith Mausner, instead of by interviewers employed by the market research firm. This was done after the regular inter- viewing session had ended and when it was decided to query unmarried patients. RESULTs The final study group consisted of 175 cases. These cases were selected from 2,648 women who had final diagnoses of thromboembolic illnesses at the 47 participating hospitals and whose illnesses were considered sufficiently likely to meet the study criteria as to warrant the preparation of a medical abstract. Obviously, there was a high degree of selection and the series cannot be con- sidered as representative of all hospitalized thromboembolism, even in these hospitals. Table 1 gives the derivation of the study group. Some exclusions were for uncertainty of diagnosis, some because of a prior attack of thrombophlebitis, but the great majority were for evidence, either in the history or physical or laboratory findings, of conditions that were regarded as possibly predisposing to thromboemboljsm. Three of the most common of these were obesity, varicose veins, and hypertension. Doubtless some patients with these conditions were included, and likewise some patients were probably erroneously excluded, since it was necessary in many instances to interpret conflicting or incomplete statements in the hospital record. For example, many patients were not weighed while in the hospital and the examination record was often uncertain as to the presence of obesity. The diagnoses of the study group are presented in Table 2. Thrombophlebitjs was the most frequent; diagnoses of phlebothrombosjs were, for purposes of this study, included under thrombophlebitis. Pulmonary embolism was encoun- tered with equal frequency as the only diagnosis, and in association with peripheral thrombophlebitis. Cerebral and retinal vascular lesions were infre- quent. Coronary artery disease was not represented, since all cases investi- gated had evidence of a predisposing condition such as hypertension or dia- betes, or else of infertility resulting from surgical procedures. Table 3 indicates that most controls were found among women admitted for elective surgical procedures, with acute surgical conditions, acute infections, trauma, and acute medical conditions appearing less frequently. As in the selection of cases, potential controls with chronic medical conditions were usually rejected. After the records of patients matching a case on those demo- graphic factors which were available in the record room index had been drawn PAGENO="0026" 6858 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY for inspection, it was sometimes necessary to reject more than 100 before finding a patient who met the additional matching criteria for a. control. Three-fifths of the cases were married at the time of the episode, 85% were white, and nearly one-half were treated in New York City hospitals (Table 4). Although records were searched for cases over a three-year span, owing to the duration of the study, illnesses were spread over a five-year period, most of them occurring in the period from 1965 to 1967 inclusive. The highest case- frequency was in the age class 20-24, the next highest at 40-44. Various sources indicate that thromboembolism incidence increases sharply with age, but so also do the chronic illnesses which disqualified patients for this study. The age distribution of the series is a function of these two determinants, and doubt- less others as well, such as patterns of use of oral contraceptives. It should not be taken as reflecting differential risk of thromboembolism. Table 5 shows the distribution of some characteristics on which preliminary matching was not attempted. Differences between cases and controls with regard to the family income, the patient's religion and the patient's maximum weight fell short of conventional levels of significance. There were differences, significant at the 5% probability level, in the patient's education (although not in the husband's education, for married patients), the proportion who were working just before their hospitalization, and the proportion who were work- ing at a medically-related job (or whose husbands had a medically-related job). There were indications that hospital employees, and particularly student nurses, had a greater chance of being hospitalized if they developed throm- boembolism. Therefore the data were reanalyzed excluding those pairs in which the case was a student nurse. The difference in educational level and the difference in proportions working outside the home were found to be no longer statistically significant, but the difference in the proportion employed in a medically-related position remained. The respondents were shown a list of 13 contraceptive method's and asked to identify those they had used within the two years prior to hospitalization, by reading back the corresponding letters (e.g., Method B. Method F). Many had used more than one method. Differences between cases and controls were generally quite small, and statistically not meaningful, except for the oral con- traceptives, which bad been more often used by cases. Thus the birth control practices of the two groups were similar, as indicated additionally by the fact that 114 cases and 101 controls had used one or more methods (Table 6). The time at which the cases and controls who had used oral contraceptives within two years prior to admission terminated their use is presented in Table 7, which shows a marked disparity in use up to the time of admission, but vir- tually none in use that terminated more than one month prior to admission. This is taken as evidence that there is no continuation of excess risk after use of the hormones is stopped, and analysis of case-control differences will there- fore be confined principally to use within one month prior to admission. It is assumed that the few cases who had terminated use during the month before admission were, at the time they stopped, already suffering from the condi- tions for which they were hospitalized. The duration of use of oral contraceptives is shown in Table 8, both for the product used last before hospitalization and for all products used in the two- year period, together with the corresponding percentages based on all users. The probability of a series of differences as large or larger than that observed is greater than 0.5. Thus, there is no evidence from this material that the risk is enhanced with duration of use. No aboslute significance may be attached to the distribution of duration of use in the case series, since it is similar to the controls. It presumably results from the interaction of the increasing pipularity of oral contraceptives over the interval studied, and the tendency of some patients to discontinue their use because of minor side-effects. It cannot be inferred that the period from 1 to 5 months' administration is more likely to be hazardous than any other. Majority opinion holds that the proper analytic method for the study and testing of differences between case and control groups where pairing has been practiced is to preserve the paired relationship, although the results usually are not greatly different from those using the conventional group comparison. The derivation of the relative risk of persons possessing an attribute getting a PAGENO="0027" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6859 disease, compared to persons not having the attribute, can be expressed very simply in the context of a 2 x 2 table constructed as follows: Cases Controls Attribute present Attribute absent Attribute present Attribute absent a c b d The sum of the numbers in the four cells is the number of case-control pairs. The relative risk of acquiring the disease (thromboembolism) for persons having the attribute (use of oral contraceptives) is the number in cell b divided by the number in cell c. A test of significance of the difference between the numbers in cells b and c, where b>c, with correction for con- tinuity, is a x2 test in which x2 = .(b-C-1)2/(b+c), with one degree of freedom. Table 9 shows the relative risks for various subdivisions of the material, computed in this way, together with an indication of the statistical signifi- cance of each difference. For the entire series of 175 case-control pairs the rel- ative risk is 4.4 with confidence limits of 3.1 and 6.8. Since pairing was on so many factors, no statistical adjustments are needed. No material differences in the relative risk are seen according to age, race, or marital status, but the number of pairs of nonwhite subjects and for some other subdivisions is too small to be sure that a difference does not exist. For each diagnostic group in which numbers were sufficiently large to allow any statement to be made, there was a higher risk for users than non-users of oral contraceptives. The brand names of the products used within two years before admission were analyzed. There were 16 cases and 6 controls who had used more than one product during the interval. The respondents were shown samples of the various tablets, as well as a list of the names of 14 different products-in some cases, as many as four produced by a single manufacturer. For many of these products the combined number of case-users and control-users was too few to yield any evidence as to whether they differed in their capacity to pro- duce thromboembolism. A special situation exists with respect to the sequential formulations. Sequential i~ the term for oral contraceptive formulations in which tablets containing only an estrogenic compound are taken for 20 or 21 days of the cycle, followed by the administration for 5 days of estrogen plus a progesto- gen. Three of these products were used by one or more subjects. Altogether, 15 cases and no controls had used them within one month of hospitalization. Con- trasting the ratios of cases to controls-iS :0 for sequential users, 52 :23 for users of all other products-the difference is statistically significant. Of the 15 sequential users, 7 had pulmonary embolism, without a known thrombophlebitis, while only 11 of the other 160 cases had pulmonary embolism. Appendix 2 gives the frequency of use of the different formulations by cases and controls. DISCUSsIoN When case reports began to appear linking the use of oral contraceptives with intravascular occlusive states, two features of the problem made it difficult to decide whether the association was genuine: the fact that millions of women were adopting the use of the method, and the fact that the illnesses often occurred long after beginning use of the product. An ad hoc committee (1) in 1963, the advisory committee on obstetrics and gynecology of the F.D.A. (2) in 1966, and a WHO scientific group (3) in the latter year all found no definite evidence on which to incriminate these hor- mones in the production of thromboembolism, defined as venous thrombosis (exclusive of the veins of head and neck), or embolism of the pulmonary artery, or both. Beginning in 1967, however, there have appeared several reports, all from Britain, which strongly indicate a relationship. The first of PAGENO="0028" 6860 COMPETITIVE PROBLEMS IN THE DRUG INDU&2R'~ these (4) was carried out by selected members of the College of General Prac- titioners who reported on 147 women from their practices with thromboembolic disease (mostly superficial venous thrombosis) and 294 controls. The risk of venous thrombosis was estimated to be increased nearly three-fold among users of oral contraceptives. A study of women who had fatal attacks of pulmonary, coronary and cere- bral thrombosis and embolism in the year 1966 was made by Inman and Vessey (5). Among 26 idiopathic cases of pulmonary embolism, there was a clear excess of users of oral contraceptives over the number expected from the experience of control women; in 49 cases where predisposing conditions existed, there was a small, statistically insignificant excess. Findings for coro- nary thrombosis were conflicting. For cerebral thrombosis, there was again an association with the drugs, limited to patients without predisposing conditions. The most significant study has been that of Vessey and Doll, a second report on which has recently been published (6). Although their study and the one reported in this paper are quite similar in design, they were planned and con- ducted entirely independently. The main differences are that Vessey and Doll excluded patients with only superficial thrombophlebitis but included those who had had previous attacks of thrombophlebitis. They interrogated 87 mar- ried cases of idiopathic deep vein thrombosis or pulmonary embolism, 19 of cerebral thrombosis, and 17 of coronary thrombosis. For 84 of the thromboem- bolism cases they interviewed two matched controls per case, or altogether 168 controls with other diseases. The subjects had been treated between 1964 and 1967 in 19 hospitals in the northwest region of metropolitan London. Large differences between cases and controls in the proportions having used oral con- traceptives within one month before onset (or in the case of controls, entry to hospital) were found for the thromboembolism and cerebral thrombosis series, but none for the coronary thrombosis series. Little difference was seen between thromboembolism cases and controls according to type of contraceptive combi- nation; none of the cases or controls had used the sequential preparations, but this is not remarkable, as only 3% of the oral contraceptives supplied in Brit- ain during this period were sequentials. Duration of use was similar for thromboembolism cases and those controls who had used the hormones. The association was stronger for patients who had never had a previous attack of thromboembolism than for those who had, but interpretation of this observa- tion is considered by the authors as impossible without further knowledge of the interaction between us of oral contraceptives and the predisposing factors associated with a history of previous disease. The thromboembolism cases tended to weigh more than controls, and to be above standard weight, a rela- tionship that held irrespective of use of oral contraceptives. The authors con- sider that a suggestion in the preliminary report of their findings of an inter- action between heavy smoking and use of oral contraceptives in the pathogenesis of thromboembolism is not supported by the complete figures. However, our examination of their data still seems to show an association of at least borderline significance between heavy smoking and thromboembolism. They conclude that the relative risk of hospital admission for deep vein thrombosis or pulmonary embolism among married women who are oral con- traceptive users appears to be 6.3, with confidence limits of 3.4 and 11.6. They also state that their estimate of the annual risk of hospital admission for these conditions plus cerebral thrombosis is about 0.5 per 1,000 for married women who are using oral contraceptives, and 0.06 for those who are not. Drill and Calhoun (7) have reviewed the evidence linking oral contracep- tives to thromboembolic disease, and have concluded that the incidence of thrombophlebitis is not increased when these drugs are employed. Their paper, published when only the preliminary report by Vessey and Doll had appeared, deals with a considerable number of complex issues. It has led to a vigorous correspondence in the columns of the Journal of the American Medical Asso- ciation; the reader's attention is invited especially to the response by Doll, Inman and Vessey (8) and the reply by Drill and Calhoun, as well as the comments of Seltzer, and of Frederiksen and Ravenholt, in the same issue. In view of the importance of the paper by Drill and Calhoun, its major points will be re-examined. Firstly, it placed emphasis on the disparity between the incidence rates of thrombophlebitis in nonpregnant women of child-bearing age as estimated by Vessey and Doll (.05 admissions per thou- PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6861 sand per annum, on the basis of 32 selected cases without evidence of predis- posing cause) and other estimates. They quoted seven such estimates based upon hospital admissions, of which six, not restricted to idiopathic cases, ranged from 0.71 to 1.08. The seventh, for idiopathic cases only (and hence, more nearly comparable to the Vessey and Doll figure) was 0.65. This figure was derived from an unpublished study. In our experience, the proportion of idiopathic cases among patients hospitalized with thromboembolism is only about 15%. It would therefore seem desirable to review the definitions employed before accepting these data as placing the Vessey and Doll findings in question. Furthermore, as Vessey and Doll point out, superficial thrombo- phlebitis was probably included to an unknown extent in the statistics quoted by Drill and Calhoun, but was excluded from their own study. The fact remains that in the prospective trials of oral contraceptives quoted by Drill and Calhoun, no excess risk of thromboembolism has been shown. They cited 51 such trials, reported in a previous review by Drill, which uni- formly failed to show any increased morbidity. In these studies, detection of thrombophiebitis was not the principal aim and some of them were done before this possible risk had become widely recognized. Careful observation would be needed in order to ascertain, in the case of women who became dropouts from a clinic, whether a medical complication of the medication received, such as thrombophiebitis, might not have been one of the reasons for failure to return to the clinic. The largest of these studies-in fact the only one with numbers adequate to test the hypothesis-is not in the medical literature; the only reference to it that could be found was a release issued by a voluntary agency. It is described as an extended trial of an oral contraceptive by women who, in order to be eligible for entry to the study, must already have used it for at least two years. Women who dropped out because of thromboembolism or for other reasons before that time were not included, and hence the woman-years of observation during the first two years of use are not relevant to the risk of getting thromboembolism; and yet these person-years have been included in estimating the expected number of cases. In other words, it appears probable that some at least of the women undergoing the first two years of use of oral contraception developed thromboembolism and discontinued use of the method for that reason, so that to base the rate upon those who did complete the first two years produces a spuriously low figure. Another doubtful feature of this study is that of the 58 occurrences of thrombophlebitis self-reported in this study, all but 17 were later rejected as having inadequate evidence for the diagnosis; yet we do not know if similarly strict criteria were followed in other experiences from which the general compartive incidence of thrombo- phlebitis has been estimated. Finally it should be noted that the authors of this study themselves state: "This study was not designed to provide a comparative incidence of throm- bophiebitis. Such an investigation would require more detailed follow-up exam- inations than were feasible in order to establis'h. (1) a positive diagnosis of the condition, (2) the existence of recognized contributing causes, and (3) whether the patient was hospitalized. Satisfying these criteria is necessary to provide any meaningful comparison with the only reliable base-line incidence data for this disorder which is limited to idiopathic, hospitalized cases." It is our opinion that the evidence presented by Drill and Calhoun, which constitutes the main negative evidence published to date, is inadequate to show that the incidence of thromboembolism is either unaffected or reduced by oral contraceptives. The retrospective study method used by Vessey and Doll, and by ourselves, suffers from two possible biases as applied to thromboembolism. First, women who developed the disease while taking an oral contraceptive might be told by their physicians that the oral contraceptive was responsible, as indeed often happened. Thus, cases might have been more likely than the controls to give an affirmative history of oral contraceptive use. Clearly, the securing of infor- mation on contraceptive use from hospital histories would have led to severely biased classifications, but the interview method has, it is felt, largely elimi- nated this bias. It seems most unlikely that a woman would assert having used several types of contraceptives but deny that she had ever used the orals, PAGENO="0030" 6862 CO~nETIT'VE PROBLEMS IN THE DRUG INDUSTRY as many of the respondents did, if that were not the case. The error, if any, would lie in the controls failing to give affirmative answers to the question on oral contraception, which was asked in several ways in the course of the inter- view. The proportion of affirmative responses by married controls as to current use was similar to what would be expected from the Ryder-Westoff survey (9), specific for age and parity (18 observed, 15.7 expected). The second possible bias is that those women who were oral contraceptive users may have been more likely to be hospitalized than other women with thromboembolism of equal severity. This latter possible bias can be tested for by comparing the findings in women with the more severe illnesses such as those in which pulmonary embolism was a factor, who would be treated in hospitals whatever their history of oral contraceptive use, with women who had only a superficial thrombophlebitis. Table 4) indicates that this bias was not present, since the relative risk for superficial thrombophlebitis is not greater than that for all cases. The most important single difference between cases and controls found in this study which might tend to bias the results was the excessive number of student nurses and other persons who had hospital jobs or medically-related jobs-or whose husbands had such jobs-among the cases. This probably indi- cates a greater likelihood of employees receiving medical attention and being admitted to a teaching hospital if they develop this type of illness while work- ing. Analysis of the 26 unmarried student nurses who were the case-members of case-control pairs showed that all had thrombophlebitis of the lower extremity -of superficial veins in 5, deep in 21. Only 2 of these 26 cases had been using oral contraceptives, in contrast to 16 of 44 for the other unmarried cases. Hence, the relative risk if these student nurses were all excluded would increase from 4.4 to 4.6 (Table 9) and the bias produced by their inclusion tends to reduce the association of oral contraceptives with thromboemboliSm. The diagnosis was superficial thrombophiebitis of the lower extremity in about one-fourth of the medically-related cases, but only one-tenth of the remaining cases, indicating a tendency for milder cases to be admitted when they are either working in a hospital or in contact with medical people. This group included a physician, physicians' wives, physicians' secretaries, graduate nurses, licensed practical nurses, ward maids and others. It is also possible that some hospital jobs, which involve staying on one's feet for considerable periods, are conducive to thrombophlebitis of the lower extremities. Although it was not desired to match cases and controls on religion, analysis showed that there was a tendency for the case and control members to be of the same faith more often than would occur by chance. This presumably resulted from both geographic factors and a trend toward selection of hospi- tals operated by church groups of the patient's faith. The effect of this inad- vertent partial matching is speculative, but it is thought that if the contracep- tive methods selected are related to the religion of the patient, as has been shown in analyses not included in this paper, and if oral contraceptives are associated with thromboembolism, then the relative risk will be underesti- mated, unless the analysis is kept specific for religious groups. The absence of a significant difference in maximum weight between cases and controls does not indicate a lack of association between obesity and thromboembolism. Patients who were noted on the hospital record to be obese were disqualified for study. Furthermore, the cases and controls when inter- viewed were asked, not what they had weighed at admission, but what their maximum weight had been apart from pregnancy, and in what year; the maxi- mum weight in many instances was reached several years before hospitaliza- tion. Criticism has been voiced of some studies similar to this one, on the grounds that the final study group represented too small a proportion of the population of cases to be representative. In answer to such criticisms it is pointed out that while a large majority of hospitalized cases had one or another predispos- ing condition which led to their rejection, most of the women in the population who use oral contraceptives have none of them, and the aim of this study was to determine whether normal women are at risk. In the second place, finding a suitable control for a woman with a particular predisposing factor would pre- sent a great problem. PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6863 The question arises as to which component of the oral contraceptives is responsible for the intravascualr changes. Vessey and Doll were unable to detect any differences suggesting that one formulation carried more risk than another. This study indicated that the sequential products were more hazard- ous. Daniel and others in Cardiff, Wales (10) found that the suppression of lactation in puerperal woman by administration of the synthetic estrogen di- ethylstilbestrol was associated with an increased incidence of thromboembolism, at least among women over 25 years of age, as compared to puerperal women who were lactating. This was confirmed by Tindall (11) who reported that suppression by another estrogen, ethinyl estradiol, increased the incidence threefold. These findings, together with the known effects of estrogen on clot- ting mechanisms as summarized by Dugdale and Masi (12), suggest rather strongly that the estrogen is the more important agent involved in these adverse effects. Even when the relative risk for oral contraceptive users has been estab- lished, it is necessary to estimate what proportion of initial attacks of idi- opathic thromboembousm are attributable to oral contraceptives. This depends on the number of women who use the hormones and the level of incidence in non-users. The following approach was taken to make the estimate: the differ- ence between the number of discrepant pairs in which the case only was a user, minus the number in which the control only was a user, was 57 minus 13, or 44. This may be considered an estimate of the actual number of individ- uals among the cases whose illnesses were attributable to the hormone. They constitute 44/175 or 25.1% of the total cases. This figure is of course subject to sampling error as well as the errors involved in the fact that the case series are not a probability sample of all the cases of thromboembolism in the community and the controls are not a probability sample of women in the same population. Nevertheless the estimate does give emphasis to the fact that the majority of cases of spontaneous, idiopathic thromboembolism, including many cases among hormone users, are not attributable to the hormones. SUMMARY A retrospective study of thromboembolism in females of reproductive age was conducted in five American cities. Cases were 175 women aged 15-44 dis- charged alive from 43 hospitals, after initial attacks of idiopathic thrombophie- bitis, pulmonary embolism, or cerebral thrombosis or embolism. Idiopathic cases constituted only a small fraction of total thromboembolism patients. The 175 hospital controls were matched pair-wise with the cases on hospital, resi- dence, time of hospitalization, race, age, marital status, parity and pay status. Both groups were free of chronic conditions either associated with thromboem- bolism or constituting contraindications to pregnancy, and were presumably fertile. They were interviewed to provide information on their use of oral con- traceptives prior to hospitalization. Sixty-seven cases and 28 controls had used these products until within one month before they were hospitalized; 11 cases and controls had discontinued use earlier. Duration of use did not affect the risk. There were 57 case-control pairs in which only the case had used an oral contraceptive within one month compared to 13 in which only the control had done so. The relative risk of thromboemboljsm for the users is estimated to be 4.4 times that of nonusers. The risk was higher for users of sequential prod- ucts. It is estimated that 25 per cent of the cases in this series were attributa- ble to oral contraceptives. ADDENDUM The interesting observation has recently been made of a deficiency of patients in blood group 0 among cases of thromboembolism in women, and especially in women who were taking oral contraceptives, as compared to controls.6 This difference in blood group distributions, although interesting, requires further substantiation and is not, in our opinion, large enough to war- rant any modification in recommendations for administration of oral contracep- tives at present. ~ Jick, H.. Slone, D., Westerhoim, B., Inman, W. H. W., Vessey, M. P.. ShapIro, S., Lewis, G. P., and Worcester, J. Venous thromboembolic disease and ABO blood type Lancet 1 :S39, 1969. PAGENO="0032" 6864 COMPETITIVE PROBLEMS IN THE DRUG INDUSTR~Y TABLE 1.-Derivation of study group of interviewed cases of idiopathic thromboembolism Records abstracted at all hospitals 2 648 Rejected because of possibly predisposing condition 2, 288 Rejected for other reasons 1 99 Accepted as suitable cases; two controls chosen per case 261 Interview not obtained; case unavailable 56 Interview not obtained; case refused 16 Interview not obtained; neither control available 14 Case-control pairs interviewed 175 I Sterility (35), psychiatric diagnosis (11), unmarried (in first two cities studied) (25), livIng outside area where interviews held (7), deceased (9), other (12). TABLE 2.-Diagnostic classification of interviewed cases Thrombophlebitis of lower extremity: Superficial veins 27 Deep veins 81 Unspecified Tbrombophlebitis, other sites Thrombophlebitis with pulmonary embolism 19 Pulmonary embolism 18 Intracranial (or carotid) vascular lesion 13 Retinal vascular lesion 6 Total 175 TABLE 3.-Diagnostic classification of interviewed control patients Acute surgical condition 33 Elective surgical condition 92 Acute infection 20 Traumatic condition 11 Evaluation and diagnosis 14 Other Total 175 TABLE 4.-DISTRIBUTION OF CASES AND CONTROLS WITH REGARD TO CHARACTERISTICS ON WHICH MATCHING OF CASE AND CONTROL PAIRS WAS DONE Cases Controls Marital status at hospitalization (matched): Married 105 105 Unmarried 70 70 Race (matched, from hospital record): White 1149 150 Nonwhite 26 25 Location of hospital (matched by hospital): Baltimore Washington 17 17 Philadelphia 41 41 New York City 83 83 Pittsburgh 25 25 Year of discharge from hospital (matched within 6 months in either direction): 1964 16 16 1965 1966 1967 1968 15 12 Hospital pay status (matched): Private 31 32 Semi-private 108 110 Ward 34 32 Other 2 1 Age at time of hospitalization (matched to within 5 years): 15-19 27 26 20-24 49 50 25-29 26 26 30-34 23 21 18 19 40-44 32 33 Reproductive events (including women unmarried at hospitalization) (matched by parity classes as follows: 0, 1-2, 3+): Mean number of pregnancies 1.81 1. 81 Mean number of live births 1. 51 1. 53 Mean number of children living in household at hospitalization 1. 34 1. 35 -~ I One control on interview was white contradictory to hospital records-matched on all other variables. PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6865 TABLE 5.-DISTRIBUTION OF CASES AND CONTROLS WITH REGARD TO SOME RELEVANT CHARACTERISTICS ON WHICH MATCHING WAS NOT ATTEMPTED [Numbers in parentheses are exclusive of all pairs in which the thromboembolism case was a student nursej Cates Controls Total 175 (149) 175 (149) Family Income: Under $4,000 19 (18) 17 (16) $4,000 to $8,000 50 (48) 52 (47) $8,000 to $15,000 61 (48) 67 (55) $15,000 and over 42 (33) 32 (26) Religion of patient: Protestant 66 (63) 59 (56) Catholic 56 (47) 63 (53) Jewish 47 (33) 44 (33) Other, none or unstated 6 (6) 9 (7) Education of patient: Lessthanl2grades 28 (28) 32 (30) High school completion 45 (43) 65 (59) Some college 66 (43) 39 (26) College completion, or post-graduate studies 36 (35) 39 (34) Use of cigarettes prior to hospitalization: Nonsmoker 74 (63) 72 (61) Less than 3'~ pack 17 (15) 20 (16) About Y~ pack 15 (13) 21 (16) About 1 pack 55 (45) 42 (38 About2packs,or more 14 (13) 20 (18 Patient's maximum past weight: Under 120 pounds 22 (18) 27 (18) 120-159 pounds 110 (93) 115 (101) 160 and over 43 (38) 33 (30) Employment status at hospitalization: Patient was working outside home 114 (88) 94 (74) Patient not working 61 (61) 81 (75) Patient (or husband) employed in a medical or hospital setting: Yes 77 (51) 36 (25) No 98 (98) 139 (124) TABLE 6.-METHODS OF CONTRACEPTION USED WITHIN 2 YEARS PRIOR TO ADMISSION 1 Cases Controls Oral contraceptives 2 67 30 Condom 41 42 Diaphgram 40 34 Rhythm 21 14 Jelly, creams 19 9 Douche 11 11 Withdrawal 8 8 Other 18 15 Total women using one or more methods 114 101 I Many women had used multiple methods; hence, numbers in table not additive. 2 Totals are smaller than in following tables because some women used the tablets for other than contraceptive purposes. TABLE 7.-TIME OF LAST USE OF ORAL CONTRACEPTIVES PRIOR TO HOSPITALIZATION, FOR CASES AND CONTROLS WHO HAD USED THEM WITHIN 2 YEARS Cases Control Used up to admission Discontinued within 1 month before admission 64 3 22 1 Discontinued ito 5 months before admission 4 5 Discontinued 6to ii months before admission 3 2 Discontinued ito 2 years before admission Uncertain 3 1 4 0 Total 78 34 40-471 O-70-Dt. 17-3 PAGENO="0034" 6866 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY TABLE 8.-DURATION OF USE OF ORAL CONTRACEPTIVES WITHIN THE TWO YEARS PRIOR TO HOSPITALIZATION Last used product All products Cases Controls Cases Controls Less than 1 week 1 week to 1 month Number 3 9 Percent 3. 8 11. 5 Number 0 2 Percent 5.9 Number 2 9 Percent 2. 6 ii. 5 Number Percent 0 2 5.9 ito 5 months 29 37.2 13 38. 2 25 32. 0 12 35. 3 6 to 11 months 15 19. 2 6 17. 6 14 17. 9 5 14. 7 ito2years 2 years Total 13 9 78 16.7 ii. 5 99.9 7 6 34 20.6 17. 6 99. 9 15 13 78 19.2 16. 7 99.9 7 20.6 8 23. 5 34 0 TABLE 9.-PAIRWISE ANALYSIS OF ~SE OF ORAL. CONTRACEPTIVES WITHIN ONE MONTH PRIOR TO ADMISSION ACCORDING TO VARIOUS ATTRIBUTES Total Attribute pairs Used by both members Used by case only Used by control only Used by neither Relative risk I (a) (b) (c) (d) Age: 15-29 102 5 33 7 57 ~ 30-44 73 5 24 6 38 4.0** Marital status: Married 105 8 41 10 46 4. ~ Unmarried 70 2 16 3 49 5 3** Race: White 149 7 46 10 86 4.6*** Nonwhite 26 3 11 3 9 3.7 Location of hospital: Baltimore, Md., and Washington, D.C 26 2 9 4 11 2.2 Philadelphia, Pa 41 2 17 1 21 17. ~ New York City, N.Y 83 5 25 6 47 4. 2** Pittsburgh, Pa 25 1 6 2 16 3.0 Diagnosis: * Thrombophlebitis, lower extremity, super- ficial 27 0 6 2 19 3.0 Thrombophlebitis, lower extremity, deep 81 4 22 5 50 4 4~ Thrombophlebitis, other 11 0 6 1 4 6.0 Thrombophlebitis and pulmonary embolism... 19 3 4 3 9 1.3 Pulmonary embolism alone 18 2 12 1 3 12. 0~ Retinal vascular lesion 6 0 0 1 5 Intracranial vascular lesion 13 1 7 0 5 7.0* Total 175 3 10(10) 57(55) 13(12) 95(72) 4.4(4.6)*** number in which used by case only 1 Computed as: number in which used by control only 2 Probability, by chance alone, of a difference as great as or greater than that observed: *, less than .05; ~, less than .01; ~ less than .001. 3 Figures in parentheses are exclusive of pairs in which the case was a student nurse. PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6867 APPENDIX 1 LIST OF PARTICIPATING HOSPITALS WITH NAMES OF LIAISON PHYSICIANS, NUMBER OF RECORDS ABSTRACTED AND NUMBER OF ACCEPTABLE CASES OF THROMBO- EMBOLISM FOUND 2 Records Cases Hospital Liaison physician abstracted found Baltimore: 1. Johns Hopkins Hospital 3 Dr. Russell Nelson 2. Union Memorial Hospital James B. Brooks, M.D 25 5 3. Sinai Hospital of Baltimore Albert I. Mendeloff, M.D 36 6 4. University Hospital Robert Schultz, M.D 30 1 5. Baltimore City Hospital Julius Krevan, M.D 31 0 Washington, D.C.: 6. George Washington University Hospital James Sites, M.D 36 7 7. Georgetown University Hospital John F. Stapleton, M.D 45 2 8. Washington Hospital Center Frederick W. Wolfe, M.D 75 10 9. Washington Sanitarium and Hospital Mr. H. Stuart Nelson 34 31 Philadelphia: 10. Philadelphia General Hospital John P. Emich, Jr., M.D 73 2 11. Pennsylvania Hospital Leonard L. Weber, M.D 76 8 12. Temple University Hospital Russell R. de Alvarez, M.D 107 5 13 Jefferson Medical___ Abram S. Benenson, M.D 106 17 14. Hahnemann Medical Center Marshall Kalvan, M.D 43 2 15. Woman's Medical College Elsie R. Carrington, M.D 10 0 16. Hospital of the University of Pennsylvania_ - Celso~Ramon Garcia, M.D 97 12 17. Lankenau Hospital Angelo P. Angelides, M.D 29 - 2 18. Albert Einstein Medical Center Mr. Bertram Zimmerman 103 10 New York City: 19. New York Hospital (Cornell) Ellen McDevitt, M.D 121 7 20. Columbia.Presbyterian Hospital Karlis Adamsons, M.D 157 6 21. St Luke's Hospital Harold M. Tovell, M.D 72 10 22. Roosevelt Hospital Ralph Gause, M.D 54 4 23. New York University Hospital Stanley Zinberg, M.D 81 7 24. Long Island Jewish Hospital Alexander H. Rosenthal, M.D 61 4 25. Jewish Hospital of Brooklyn Morton A. Schiffer, M.D 36 13 26. Maimondes Medical Center William Pomerance, M.D 64 27. Methodist Hospital of Brooklyn Allan C. Clemetson, M.D 31 1 28. Coney Island Hospital Alos~Vasicka, M.D 21 4 29. City Hospital at Elmhurst Joseph J. Rovinsky, M.D 22 2 30. Queens Medical Center William A. D'Angelo, M.D 31 3 31. Kings County Medical Center Schuyler G. Kohl, M.D 134 10 32. Mt Sinai Hospital Joseph J. Rovinsky, M.D 20 5 33. Bronx Lebanon Hospital (Concourse) Edward E. Fischel, M.D 7 0 34. Albert Einstein College of Medicine Seymour L. Romney, M.D 19 4 35. Montefiore Hospital Tiffany Lawyer, M.D 24 3 36. St Vincent's Hospital Bernard Pisani, M.D 73 9 37. Brooklyn Hospital Vincent Tricomi, M.D 12 0 38. Beth Israel Hospital George Blinick, M.D 84 24 39. Bronx Municipal-Jacobi Seymour L. Romney, M.D 18 1 40. Lenox Hill Hospital H. R. Barber, M.D 37 5 41. Bronx Lebanon Hospital-Fulton Edward E. Fischel, M.D 16 2 Pittsburgh: 42. Mercy Hospital (1) 88 7 43. Shadyside Hospital (1) 70 5 44. Montefiore Hospital (1) 61 7 45. Magee Woman's Hospital (1) 69 3 46. Presbyterian.University Hospital (1) 84 10 47. St Francis General Hospital (1) 60 2 48. Western Pennsylvania Hospital (1) 65 4 1 Dr. John C. Cutler, Chairman, Population Division, Graduate School of Public Health, University of Pittsburgh, assumed this responsibility in this city. 2 In Baltimore and Washington, only married women were accepted. This list exceeds the number of case-control pairs reported in this paper because some cases, or their controls, could not be interviewed. 3 Johns Hopkins Hospital was utilized for the pilot trial, and the cases secured are not included in the tabulations reported n this paper. PAGENO="0036" 6868 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY APPENDIX 2 ORAL CONTRACEPTION FORMULATIONS USED WITHIN ONE MONTH PRIOR TO AD- MISSION, BY NUMBER OF CASE AND CONTROL USERS WHO COULD IDENTIFY SPECIFIC PRODUCT USED Conte nt of No. of use Case Controls Estrogen mg Progestogen mg. Sequential products: 1 Mestranol Ethinyl estradiol Mestranol Combinations: 2 Mestranol Do Do Do Ethinylestradiol Mestranol Do Do Ethinyl estradiol . 08 Chlormadinone . 1 Dimethisterone . 08 Norethindrone . 1 do . 1 Norethynodrel .075 do . 1 Ethynodiol acetate .05 Norethindron acetate . 05 Norethindrone .06 do . 15 Norethynodrel . 05 Medroxyprogesterone acetate -- 2 25 2 2 2. 5 5 1 2.5 1 10 9. 85 10 8 5 2 14 14 5 4 3 3 2 2 1 0 0 0 9 1 2 3 4 2 1 1 0 I Estrogen administered for 20 or 21 days, estrogen plus progestogen for 5 days. 2 Administered for 20 or 21 days. References 1. Ad Hoc Committee for the Evaluation of a Possible Etiologic Relation of Enovid with Thromboembolic Conditions: Final Report on Enovid, Sept. 12, 1962 2. Advisory Committee on Obstetrics and Gynecology, Food and Drug Admin- istration: Report on the Oral Contraceptives, Aug. 1, 1966. U.S. Govt Printing Office, Washington, D.C. 3. Clinical Aspects of Oral Gestogens. Report of a WHO Scientific Group. WHO Tech. Report Series No. 326, Geneva, 1966. 4. Royal College of General Practitioners: Oral Contraception and Throm- boembolic Disease. J. Coll Gen Pract, 13: 267-279, 1967 5. Inman, W. H. W. and Vessey, M. P. Investigation of Deaths from Pulmo- nary Coronary and Cerebral Thrombosis and Embolism tn Women of Child-Bearing Age, Brit Med J, 2: 193-199, 1968 6. Vessey, M. P. and Doll, R. Investigation of Relation between Use of Oral Contraceptives and Thromboembolic Disease. A Further Report. Brit Med J, 2: 651-657, 1969 7. Drill, V. A. and Calhoun, D. W. Oral Contraceptives and Thromboembolic Disease. JAMA, 206: 77-84, 1968 8. Doll, R., Inman, W. H. W. and Vessey, M. P. "Concerning the British Data" (letter to the editor). JAMA, 297: 1150-1151, 1969 9. Ryder, N. B. and Westoff, C. F., Use of oral contraception in the United States, 1965, SCIENCE, 153: 1199, 1966 10. Daniel, D. G., Campbell, H. and Turnbull, A. C. Puerperal Thromboembo- lism and Suppression of Lactation. Lancet, Aug. 5, 1967, p. 287-289 11. Tindall, V. R. Factors Influencing Puerperal Thrombo-embolism J Obstet Gynaec Brit Comm, 75: 1324-1327, 1968 12. Dugdale, M. and Masi, A. T. Blood clotting effects of the oral contracep- tives IN Report on the Oral Contraceptives, Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, 1969 (in press) B. TRENDS IN MORTALITY FROM THROMBOEMBOLIC DISORDERS Philip E. Sartwell, M.D. and Charles Anello, Sc. D. Mortality rates for thromboembolism have been examined for the main pur- pose of ascertaining whether these rates have changed in a way consistent with an effect of oral contraceptive use. A second purpose of this report is to PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6869 call attention to the dramatic increase in the rates for both males and females. Mr. Dean E. Krueger of the National Office of Vital Statistics has kindly made available the death rates discussed in this report. All deaths of females aged 15 to 49 in the U.S. in the single year 1961 attributed to these causes were studied in order to establish with what other diseases they were linked. A list of decedents whose deaths had been coded to I.C.D.1 numbers 463 (thrombophiebitis of the lower extremity), 464 (throm- bophiebitis of other sites), and 465 (pulmonary embolism) was provided by Mr. Krueger. Other conditions listed on the death certificates were shown on the listing. Deaths certified as having thrombophlebitis of the lower extremity (I.C.D. 463) as the underlying cause almost always bore mention on the certificate of pulmonary embolism as the immediate cause. A great variety of other condi- tions were listed on about half the certificates, and many of them are recog- nized as predisposing to thromboembolism. There were no cases that appeared from the evidence on the certificates to be misclassified in the sense of being properly attributable to surgical procedures, trauma, or childbirth; but in the numerous certificates that classified thrombophiebitis as the underlying cause and mentioned such conditions as subacute bacterial endocarditis, rheumatic heart disease, or carcinoma with metastases, the appropriateness of listing thrombophiebitis as the underlying cause may be questioned. Deaths with thrombophiebitis of other sites (I.C.D. 464) as the underlying cause likewise had pulmonary embolism or infarction generally listed as the immediate cause. The site of thrombophlebitis was frequently the pelvic veins. Other conditions were listed on the certificate much more often than in the case of thrombosis of the lower extremity, and certificates that did not bear one or more other diseases were the small minority. Some certificates were clearly In error, the proper diagnosis being carcinoma, heart disease, blood dyscrasias, trauma, surgery or some other underlying condition. This group was less satisfactory as a series of primary vascular disease than I.C.D. 463. Under I.C.D. 465, pulmonary embolism and infarction, thrombophiebitis was almost never mentioned on the certificate. About two-thirds of these cases had some other condition listed and in many instances, again, they would be con- sidered as predisposing to thromboembolism. This class is considered to include patients presumed to have a thrombosed vein but without evidence of its site. Among the more commonly mentioned conditions in association with all three diagnoses were pneumonia, obesity, diabetes, carcinoma, sepsis, prior sur- gery, rheumatic heart disease, and arteriosclerotic heart disease. It is concluded that lCD. rubric number 463 is the most satisfactory of the three for study of trends of thromboembolism, but even this rubric probably includes some cases that are erroneously charged to thromboembolism by the certifying physician and it certainly includes many with well-recognized pre- disposing conditions. FOr the initial analysis of mortality, the annual rates for each of these dis- eases (lCD. 463-465) as well as I.C.D. 466 (other venous thrombosis and embolism) in the United States were utilized for the period 1960-1966 inclu- sive, and for five 10-year age classes covering the span from 15 to 65, sepa- rately for white males and females. The rates increase approximately loga- rithmically with age over this age span, and somewhat more steeply In males, in such fashion that the male rates are lower in the youngest age groups and higher in the oldest age groups. There is also an increase in rates with time, for all age-sex classes. This increase was approximately linear when plotted on semilogarithmlc paper; that is, the increase was, roughly logarithmic. Therefore, it was decided to take the natural logarithms of the rates and calculate the regression coefficients, fitting the regressions by the method of least squares. These regression coeffi- cients ("b") and their standard errors are shown in Table 1 for the four com- bined thromboembolic conditions. All the 10 values are positive, indicating an upward trend with time, and all are significantly different from zero at a probability level of 0.05 or less, indicating that the increases are real in a sta- tistical sense. Comparisons were next made between the slopes for males and females in each age class. For two classes (15-24 and 55-64) the increase in rates for 1 International Statistical Classification of Diseases, Injuries, and Causes of Death. PAGENO="0038" * 6870 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY males was greater than for females; in the other three age classes the female slopes were steeper than the male, and the differences were somewhat larger. However, statistical significance at the conventional level (p<.05) was not reached for any age class (Table 2). The use of oral contraceptives has rapidly increased since 1960 having become extensive around 1962. Therefore the data were examined to ascertain whether there had been a change in the slope at that time. Two periods were chosen: one of six years, 1956-1961; and one of five years, 1962-1966 (desig- nated 1 and 2 respectively). Regression coefficients were calculated separately for each period in the same fashion as for Table 1 (Table 3). For males, the slope increased in the second period in two of the five age classes, and for females, in four of the age classes (all except the oldest). The magnitude of the increases among females in the second time period is greater than that for males (and greater than that for the first time period), for the three age classes between 25 and 54. Although all the coefficients are positive, they are not significantly different from zero except in the oldest age classes (because of the short periods over which the regressions were computed), and most of the differences by sex are nonsignificant. Mortality data for pulmonary embolism (I.O.D. 465) were examined sepa- rately by the same method for the period 1960-1966. As Tables 4 and 5 will show, these rates also increased significantly over the seven-year span, for both sexes. The rate of increase was greater for females than for males in all age classes studied except the youngest, but most~ of the differences were not statistically significant. Since the number of deaths from this one cause in the younger age classes is quite small, the failure to show a significant difference could be a consequence of the large sampling error. In our opinion, these findings are consistent with the hypothesis that oral contraceptives have produced a small increase in the mortality from throm- boembolism, but they do not add any great support to it. Grounds for deciding whether the increases are wholly the result of changes in certification practice by physicians are lacking at the present time. If the increases are in part real, we should be looking for changed environmental factors that may be producing them. In an endeavor to see whether they are related to oral contraceptives, two analyses of mortality trends have been published. The first, by Vessey and Weatherall (2), examined British statistics for deaths from peripheral, venous thrombophlebitis and pulmonary embolism. There has been an upward trend in both sexes, with a distinct suggestion of an acceleration in females at repro- ductive ages since these agents came into wide use. They concluded that this evidence was consistent with the hypothesis. Markush and Seigel (1) have published a detailed analysis of mortality trends within the United States. Their conclusions also substantiate a possible association between oral contraceptive usage and increased mortality from thromboembolism. Both the British and American groups of researchers employed techniques of study similar to those described in this report. In summary, recorded mortality rates for thromboembolic diseases in the United States at ages 15-64 have been increasing among both white males and white females. The rate of increase is greater for females than males. The increase was accelerated in the period 1962-1966 as contrasted with 1956-1961. These facts are consistent with the hypothesis that an increasing use of oral contraceptives is responsible for some of the thromboembolic mor- tality. However, because of the difficulty in diagnosis of these diseases and the possibility of changes in the practice of certifying underlying causes of death, we do not regard these findings as strong evidence for the hypothesis. PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6871 TABLE 1--TREND OF MORTALITY FROM VENOUS THROMBOEMBOLISM (I.C.D. NUMBERS 463-466) FOR WHITE PERSONS AGED 15-64, UNITED STATES, 1960-66. Age class Sex Regression coefficient b Standard error of b Pr (b=o) 15 to 24 M +.1111 .0367 F 25 to 34 M +.1100 +.0577 .0266 .0211 <.01 <.05 F +. 1092 0254 <.01 35 to 44 M F +.0635 +.1264 . .0199 .0223 <.025 <.005 45 to 54 M +. 0483 0122 F 55 to 64 M F +.0724 +.0630 +0452 . .0168 .0071 .0095 <.01 <.001 <.01 NOTE-Regression coefficient b: numbers in this column represent values of b in the equation yt=a ebt, where: t+year (from 1960 as tr) yt=death rate in year a=death rate when t=o e=natural base of logarithms The regression coefficient expresses the slope of the increase or decrease in rates, values with a positive sign indicating increase; b x 100 is approximately the percent increase per year. All the values of b in this series are positive. Pr (b=o) expresses the probability that a change as great as, or greater than, that observed would occur by chance alone. A two- tailed test was employed, using the F statistic with 1 and 5 degrees of freedom. iF Pr (b='o) is less than .05, as it is in all this series, the slopes are significantly greater than zero. TABLE 2.-DIFFERENCES IN SLOPES (B) BETWEEN FEMALES AND MALES, AND THEIR STANDARD ERRORS (FOR I .C.D. 463-466) Age class Difference in slope (f-rn) Standard error of difference 15 to 24 0011 0453 25 to 34 -. +. 0515 . 0330 35 to 44 +. 0629 . 0299 45 to 54. +. 0241 . 0208 55 to 64 -.0178 . .0119 TABLE 3.-TRENDS OF MORTALITY FROM THROMBOEMBOLIC CONDITIONS FOR 2 PERIODS, BY SEX AND AGE CLASS: WHITE PERSONS, UNITED STATES Regression Age class Sex Time period coefficient b Standard deviation lot * ercept In a 15 to 24 M 1 .02 2 .16 .09 .06 .33 F 1 .05 2 .13 .02 .05 .65 25 to 34 M 1 .03 2 .02 .01 .03 .99 1.22 F 1 .06 2 .11 .02 .05 1.5e 35 to 44 M 1 - 03 2 .03 . 03 .02 2.34 F 1 .04 2 .14 .03 .02 2.67 2.19 45 to 54 M 1 .06 2 .04 .02 .02 2.52 3.34 F 1 .06 .01 3.71 55-64 M 2 .12 1 . 06 2 .08 .01 . 02 .07 3.03 3.25 4.31 F 1 .08 2 .04 .02 .01 4.56 3.90 4.30 Time Periods: 1:1956-19622:19621966. Logarithmic regression. PAGENO="0040" 6872 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 4-TREND OF MORTALITY FROM PULMONARY EMBOLISM AND INFARCT (LCD. NUMBER 465) FOR WHITE PERSONS AGED 15-64 BY SEX, UNITED STATES, 1960-1966. Regression Standard Age class Sex coefficient b error of b Pr (b=o 15 to 24 M +. 1393 . 0428 F +1132 .0386 25 to 34 M +. 0340 . 0183 F +.1340 .0374 35 to 44 M +. 0855 . 0157 F +3119 .0225 45 to 54 M +0756 .0206 .0244 <.025 <.05 N.S. <.025 <.005 <.005 <.025 <.025 F +.0951 55 to 64 M +0690 .0148 F +0753 .0116 <.02 <.005 See footnote to table 1 for interpretation of b and Pr (b=o). TABLE 5.-DIFFERENCES IN SLOPES (B) BETWEEN FEMALES AND MALES, AND THEIR STANDARD ERRORS, FOR lCD. 465 (PULMONARY EMBOLISM AND INFARCT) Difference in Standard error of difference Age class slope (f-rn) 15 to 24 -. 0011 25 to 34 +. 0515 35 to 44 +. 0629 0241 . 0453 . 0330 . 0299 0208 45 to 54 ~ 0178 . 0119 55 to 64 -. . References 1. Markush, R. E. and Seigel, D. G. Oral Oontraceptives and mortality trends from thromboembolism in the United States. Amer J Pub Health 59:418, 1969. 2. Vessey, M. P. and Weatherall, J. A. C. Venous thromboembolic disease and the use of oral contraceptives. Lancet 2:94, 1968. C. TRENDS IN MORTALITY FROM CEREBROVASCULAR DISEASES Gerald R. Greene, M.D. The temporal analysis of cerebrovascular mortality consisted of a compari- son of trends and ratios of white male and female death rates from these causes singly and combined (rubrics 330-334) from 1956 through 1966. Five ten-year age groups (15-64) were studied over this period. Numbers of deaths attributed to specific causes were taken from the annual publications of mor- tality data for the United States. Oral contraceptives came into general use in 1961 and their use increased rapidly thereafter. If they are causing some of the deaths from cerebrovascu- lar disease, female death rates from this cause might have risen more sharply than male death rates in the child-bearing age range, depending upon the inde- pendent factors affecting male mortality from these causes. However, no spe- cific classification exists for death from these conditions occurring during preg- nancy or the puerperium. Thus, if such deaths are included in the rubrics studied, a rise in the female death rates directly attributable to the oral con- traceptives may be concealed by a falling birth rate and a decrease of central nervous system complications attributable to pregnancy and the puerperium. Mortality from these combined causes (rubrics 330-334) declined over the ten-year period, as did intracerebral hemorrhage (rubric 331), which forms the majority of all deaths from this group. Rates in the age group 25-34 became higher for females than for males in 1965 and 1966 for the first ti~ne. This crossover is possibly significant if one assumes that deaths from ~érebra1 embolism or thrombosis are often misclassified as other cerebrovascular deaths and may have been included in the rubric 331. Death rates resulting from subarachnoid hemorrhage (rubric 330) rose PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6873 steeply and steadily for both males and females in the three age groups 35-44, 45-54, and 55-64 over the ten-year period. The rise in mortaifty from this cause was greater in females than males for all but the 15-24 year age group, in which there was little or no rise. No explanation for this finding is readily available. In the lower two age groups, death rates from cerebral embolism and throm- bosis (rubric 332) fluctuated widely with no definite, trends. The actual number of deaths at these ages was very small, such that an excess of five to ten deaths from one year to the next caused a large relative increase in the death rate. In the older three age groups, death rates from cerebral embolism and thrombosis were stable from 1956-66 with the male rate uniformly higher than the female rate. The lack of a rise in female deaths at reproductive ages from cerebral embolism and thrombosis fails to support an association between the use of oral contraceptives and these conditions, barring the possible con- cealment of an effect by a lowering of pregnancy rates, as suggested above. It is possible that such deaths are often coded to other cerebrovascular causes or that the frequency of fatal cerebrovascular complications of oral contraceptive use is so low in relation to other cerebrovascular diseases as not to be evident in mortality statistics. In any case, the analysis of these data does not warrant any conclusions regarding the influence of oral contraceptives on cerebrovascular mortality. D. EFFECTS OF THE ORAL CONTRACEPTIVES ON BLOOD CLOTTING Marion Dugdale, M.D. and Alfonse T. Masi, M.D., Dr. P. H. Hemostasis can be thought of as occurring in stages: initial control of bleed- ing, which is effected by platelets; secondary control of bleeding, which is a function of clotting; and clot removal by fibrinolysis as the tissue heals. The concept of hypercoagulability arose as a natural outgrowth of clinical situa- tions characterized by the inappropriate formation of intravascular clots. Its definition on laboratory grounds has proved more difficult. Using the above outlined concept of normal hemostasis, it is logical to think that intravascular clot formation could arise because of excessive platelet adhesiveness of aggregability, an increased tendency of blood to clot, or insuf- ficient removal of fibrin because of inadequate fibrinolysis. This approach has been used by numerous investigators in the study of clinical hypercoagula- bility. The processes of intravascular clot formation in arteries and veins are different. Platelet adhesion to damaged endothelium (or foreign surfaces) appears to initiate the formation of an arterial thrombus; in veins, clotting plays the major role. Both arterial and venous thromboses have been attrib- uted to the use of oral contraceptives. A large number of reports is available, describing the results of investiga- tions of the coagulation and fibrinolytic system. A smaller number of reports deals with aspects of platelet function. The present report attempts to summa- rize these studies, which cover observations made by 41 investigators on about 1000 patients receiving oral contraceptives. Approximately 412 patients were studied during the first three cycles (short term group) ; 530 women were studied after more than 3 months of cyclic oral contraception (long term group). These results are compared with studies of hemostasis in approxi- mately 650 pregnant women and on smaller groups receiving either estrogens (165 subjects) or progestins alone (104 subjects). Since these reports come from widely scattered laboratories, methods have varied greatly, particularly in studies of the fibrinolytic system. The reviewers have attempted to group together comparable tests even though the methods used may have differed. Readers are referred to the original articles for meth- odologic details. In all articles selected for this review there was an adequate number of appropriate control subjects. In all the tables the results will be given in terms of change from normal based on the normal values given by each inves- tigator. PLATELETS In Table 1 we have summarized the rather scanty data on platelet number and function. Adhesion and aggregation, which are pertinent to the problems of arterial thrombus formation, deserve most attention. The in vitro tests have been grouped under three headings: tests In which PAGENO="0042" 6874 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY adhesion to a foreign surface precedes aggregation, tests in which aggregation is produced directly by chemical means, and electrophoretic responses of plate- lets exposed to aggregating agents. The bleeding time is an in `vivo measure- ment of platelet adhesiveness and aggregability. These data may be summarized as follows: Short-term use of oral contraceptives appears to have little effect on plate- late except for altering their electrophoretic mobility. The physiological significance of this observation is unknown. Long-term use, in addition to changing the electrophoretic mobility, produces a rise in the platelet count in two-thirds of the users, and may increase the ability of the platelets to adhere to foreign surfaces. Pregnancy seems to have little effect on platelets except, however, some studies demonstrate increased aggregability. Administration of estrogens, particularly the synthetic forms, increases the responsiveness of platelets to aggregating agents. Capillary resistance, on the other hand, is increased by natural (Premarin) but not by the synthetic estro- gens. Progestins have no effect on platelet count or function. The number of observations on platelet function is too small to permit any definite conclusions. The estrogenic component of oral contraceptives, however, may have an effect on platelets that favors the development of platelet aggre- gates in vitro, and presumably in vivo also. CLOTTING There is a considerable quantity of data pertaining to clotting in patients receiving oral contraceptives, as presented in Tables 2 and 3. For comparison, data are presented on clotting in pregnancy and in persons receiving estrogens or progestins alone. The clotting tests fall into three groups: those that measure the unaided coagulation of the blood (clotting time, prothrombin consumption test, and thromboplastin generation test) ; those that measure coagulation in the pres- ence of an excess of a procoagulant (the prothrombin and partial thromboplas- tin times) ; and those that measure activity of specific factors (the P & P test and the factor assays). The first two groups measure the speed at which blood clots and they might, therefore, shed some light on the question whether thrombosis is a result of rapid clotting. The factor assays, on the other hand, measure amount of potential coagulant activity. It has not yet been shown that an increase above usual levels in concentration of a procoagulant factor makes blood clot with greater ease or that it causes thrombosis. Examination of the data on oral contraceptives shows that some changes from normal are evident soon after initiation of treatment with these agents. Other changes appear or become prominent only after several months of treat- ment. Early changes indicate an increased rate of clotting: the clotting time (and its variants) and the Prothrombin Consumption tests show rapid coagula- tion in about 20 to 25 per cent of the patients. With prolonged treatment the proportion of patients showing rapid clotting increases to about 35 per cent in these tests. A similar acceleration of clotting is seen in the Prothrombin and Partial Thromboplastin Times. The TGT, a more sensitive test, detects rapid clotting in about GG per cent of the patients early in treatment. This number does not change with prolonged use of oral contraceptives. The changes in pregnancy must be more subtle, since they are detected only in the TGT and PTT but also indicate increased rate of clotting. Data on the estrogens and progestins are scanty, hut they suggest that progestins and natu- ral estrogens do not accelerate clotting, whereas synthetic estrogens do. Data pertaining to concentration of clotting factors during use of oral con- traceptives show that some factors begin to increase promptly. A rise in con- centration of fibrinogen occurs in about one half of the women. About one fourth show an increase in factor VIII, about three fourths in factors II and IX, and all in factor XII. Long-term use does not change in the proportion of patients showing these increases. With factors VII and X the rise in activity is slower. Both factors are increased in only one half of women early in ther- apy but after more than 3 cycles, virtually all women have high levels of activity. The levels reached do not appear to exceed those seen in pregnancy (28, 47). Factors XI and XIII and probably V are not affected by use of oral contraceptives. Once these changes have occurred there is no cyclic fluctuation. PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6875 The changes in pregnancy are not exactly comparable. Factors I and VII Invariably rise from the outset. Factors VIII and X rise during the second and third trimesters in almost all women. Factor IX increases in about half the patients and factor II shows a slight rise in somewhat less than half. Factors V and XII show no change, and factor XIII decreases. The data on effect of progestins alone are very scanty, but it Is noteworthy that they have not been shown to alter the levels of factors I, VII, and X, all of which are increased by oral contraceptives. There are essentially no data of this type on the effect of estrogens. FIBRINOLYSIS Data pertaining to fibrinolysis are summarized in Table 4. The effect of oral contraceptives appears somewhat uncertain and a clear pattern does not emerge. Activator levels rise in all women after several months of use of these drugs, and the euglobulin clot lysis time falls in about half, suggesting increased fibrinolysis. The associated fall in plasminogen expected in such a state does not occur, however. Instead, an increase in plasminogen is seen in about two-thirds of the patients. The pattern in pregnancy is much clearer, demonstrating hypoactivity of the fibrinolytic system with long euglobulin clot lysis time, decreased activator, increased antiplasmins, and increased plasminogen levels. The data on estrogens are so scanty and inconsistent that no conclusions are warranted. Progestins clearly enhance fibrinolysis although additional data on the com- ponents of the fibrinolytic system would be helpful. SUMMARY AND CONCLUSIONS The data as a whole are presented in condensed form in Table 5. If these data are examined in the light of our initial assumptions about the roles of platelets, coagulation and fibrinolysis in thrombus formation, we may form some tentative conclusions. Pregnant women appear to be in danger of inap- propriate intravascular clotting, in that coagulation rate and potential are increased while fibrinolysis is depressed. On the other hand, the women using oral contraceptives is in a more balanced state in that coagulability is increased, but so is fibrinolysis. Clinical experience, however, suggests that the opposite is the case, that is, pregnant women have little problem with thromboembolic disorders, whereas users of oral contraceptives have excessive disease of this type. Perhaps the explanation lies in the platelets. Platelets are little affected by pregnancy, whereas the steroid contraceptives increase their number and possibly their tendency to adhere and clump. The increased arterial thrombosis with oral contraceptives could be explained on this basis, although the increased inci- dence of venous thrombosis might not be so explained. The answer may well lie elsewhere, for example, in changes in the endothelium and vessel wall and in slowing of blood flow.2 With regard to the relation of composition of the oral contraceptives to their effect, the estrogen appears to predispose to enhanced platelet function and the acceleration of clotting, while the progestin leads to increased fibrinolytic activity. The amount of each component does not clearly affect the outlook. A few studies comparing the effects of high-dose and low-dose oral contraceptives did not show any great differences in platelet function, coagulation, or fibrinol- ysis between the two groups (37, 46, 53). There do not appear to be any dif- ferences in the thromboembolic effects of sequential and oral contraceptives other than those reported by Sartwell (Appendix 2A). The changes brought about by the oral steroids are not immediately reversi- ble upon discontinuing the drugs (2, 8, 22). One to several weeks are required for return to the normal pattern. Among the 1000 patients surveyed, two developed thrombotic episodes: one fatal pulmonary embolus (1) and one cerebral artery oclusion (8). It may be significant that the first patient was paraplegic, and that platelets in the second showed a greater alteration in reactivity than in all other patients studied. 2 See Reference 68, AppendIx 4. PAGENO="0044" TABLE 1.-EFFECT OF ORAL CONTRACEPTIVES, PREGNANCY, ESTROGEN, AND PROGESTERONE ON PLATELET NUMBER AND FUNCTION' Estrogens-<17 days. Pregnancy- Natural (premarin) Estrogens-> 1 month; O.C.-short term D.C-long term all trimesters or synthetic synthetic only Progestogens Number of platelets No change 75 (12, 16, 19, No change 34 (28, 38, 58) No change 64 (14, 28, 37, No change 8+? (9, 45) No change 50 (15) No change ? (24) increased 22, 23) increased 3 (2). increased 69 (2, 35, 69). 51, 65). decreased ? (24). ? (24). Bleeding time No change 19 (36) pro- No change 10 (28) pro- No change 18 (28, 51). No change 8 (9) Decreased 13 (18) longed 3 (2). longed 3 (2). Adhesion (glass or latex)~ - No change 35 (38, 53) No change 23 (28, 38) No change 18+? (28, 37, No change 17 (9, 25) No change 3 (8). increased 12 (16). 68). increased 25 (7). Aggregation: No change 10(28) Increased 3(8) no change ADP: Increased 9(25) No change 79(8,24). Response to ADP, 13 (8, 28). Noradr: increased 9 (25). noradrenalin, etc. Electrophoretic: Abrwrmal 3 (8) Abnormal 9 (8) ADP: No change p Response to ADP, premarin; abnormal p noradrenalin, etc. synthetic 9 (25) Noradr: Mm. change p premarin; abnormal p synthetic 9(25). Capillary fragility Decreased 30+? (17, 45, See footnote 2 59). I The number of patients is given for each result, followed by the references (in parenthesis) from which these values were obtained.? indicates that no. of patients studied is not given by the authors. 2 In scorbutic guinea pigs administration of natural, but not of synethetic estrogens, reduced the occurrence of spontaneous hemorrhage and decreased capillary fragility. 113 animals (27, 56). PAGENO="0045" 0 C C 0) t~rj z 0) TABLE 2.-EFFECT OF ORAL CONTRACEPTIVES, PREGNANCY, ESTROGEN AND PROGESTERONE ON COAGULATION TESTS Estrogens-<17 days. Pregnancy- Natural (premarin) Estrogens->1 month; all trimesters or synthetic synthetic only Progestogens O.C.-short term O.C.-Iong term Clotting time and recalcifi- No change 114 (1, 6, 14, No change 133 (1, 38, 64, cation time. 38, 64) decreased 39 (2, 69) decreased 65 (2, 13, 13, 36). 35). Prothrombin consumption_ - No change 91(36, 44) In- No change 105 (28, 44, 49, creased 23 (2, 53). 69) increased 63 (4, 59). T.G.T No change 25 (14, 53) ac- No change 40 accelerated celerated and increased and increased 75 (2, 13, 49 (2, 11, 13). 28, 35) decreased 11 (58). Prothrombin time No change 243 (1, 6, 14, No change 1 383 (1, 29, 46, 23, 36, 46, 47, 56) de- 47, 49, 56, 66, 69) de- creased 49 (2, 11, 13). creased 103 (13, 35, 61, Partial Thromboplastin No change 224 (1, 36, 46, No change 331 (1, 29, 46, time. 47, 56, 64) decreased 53 47, 49, 56, 64, 66, 69) (11, 23, 53). decreased 91(46). 1 Decrease became apparent only after plasma had been stored. 42(61,62). No change 39 (14, 37, 51) Premarin-No change 8 Decreased 13 (18) Decreased 10 (57) no prolonged 11(2). (9) synthetic-decreased change 76 (48). 10 (57). No change 25 (28, 37) Increased 13 (18) No change 16 (14) Acceler- ated and increased 49 (2, 28, 67) (occurs in 2d and 3d trimesters). No change 142 (14, 46, 47, Premarin-No change 8 No change 50 (3) No change 83 (11, 66) de- 56) decreased 15(65). (9) synthetic-decreased creased 10 (57). 10 (57). No change 7 (56) de- Premarin-No change 8 No change 83 (11, 66). creased 134 (10, 46, 47). (9). PAGENO="0046" Estrogens 1 month Progestogens I. Fibrinogen No change 27 1(2, 6, 23, No change 120 (2, 35, 49, Increased 276 (10, 21, 22, Increased 8+? (14, 58), No change 8+? (33, 42). 64), increased 71(22, 64), increased 61(3, 12, 26, 29, 31, 33, 37, 41, 51, variable 8+? (33, 42), 36, 38). 22, 28, 38). 65, 67) (rise starts in 1st decreased 25 (7). trimester). II. Prothrombin No change 34(6,23,36), No change 82(35,49,69), No change 94(22,39,65, No change 82(9) increased 103 (13, 22, increased 166 (3, 13, 22, 67), slight increase 42, 28, 38, 42, 56). 28, 29, 38, 56). (2, 29, 31, 51, 56). V No change 154 (2, 6, 11, No change 93 (2, 13, 22, No change 150 (28, 29, 31, No change 82 (9) 13, 22, 23, 24, 36, 53), 29, 49, 58, 69), question- 37, 39, 51, 56, 65, 67), questionable increase able increase 152 (35, slight increase 11(2). 49 (38, 56). 38, 56, 69), decreased 10(28). VII No change 123 1(6, 34, 46, Increased 433 (13, 22, 28, 47, 53), increased 140 29, 35, 38, 46, 47, 56, 58, (11, 13, 22, 23, 38, 56). 66). VIII No change 170(1,6,22, No change 255 (1, 22, 28, 34, 47, 53), increased 65 29, 47, 66, 69, 4), in- (23, 36, 38, 56), variable creased 81(56, 69), 4 (2). variable 4 (2). Increased 240 (2, 22, 29, No change 76 (48). 31, 39, 47, 51, 56, 65, 67) (rise starts in 1st trimester). No change 18 (28, 51), increased 157 (2, 7, 22, 29, 31, 39, 47, 65, 67) (rise occurs in the 2nd and 3rd trimesters). No change 24 (14, 34, 36), increased 36 (28, 50, 67), rise starts in the 1st trimester). No change 16 (14), in- No change 76 (48). creased 221 (22, 29, 31, 39, 46, 47, 56, 67) (Rise occurs in the 2d and 3rd trimesters). Xl No change 42(23,56) No change 78(56) XII Increased 37(56) Increased 78(56) No change 8(9) XIII No change? (19) Decrease 39 (68) (fall starts in the 2d tri- mester). P & P (11+VII+X) No change 25(4), in- No change 25 (4), in- Increased 99(14, 28, 37, creased 126 (2, 11, 14, creased 132 (29, 38, 56). 39, 56) (rise starts in 36,38, 56). 1st trimester). O.C.-short term O.C.-long term TABLE 3.-EFFECT OF ORAL CONTRACEPTIVES, PREGNANCY, ESTROGEN AND PROGESTERONE ON COAGULATION FACTOR ASSAYS Pregnancy Estrogens 17 days natural or synthetic IX No change 24 (14, 34, 36), No change 30 (28, 38, 69), increased 42 (23, 56). increased 89 (56, 58). X No change 123 (6, 34, 46, No change 11(58), in- 47), increased 118 (11, creased 311 (22, 29, 38, 22, 38, 56). 46, 47, 56). d 1 Increases if a large dose is used (6). a In dogs a single dose of premarin IV produces an immediate rise in II and V which persists for 4 hours. PAGENO="0047" 0 C11 z TABLE 4.-EFFECT OF ORAL CONTRACEPTIVES, PREGNANCY, ESTROGEN AND PROGESTERONE ON FIBRINOLYSIS LI O.C.-short term O.C.-Iong term Pregnancy Estrogens <17 days natural Estrogens Progestogens. (premarin) or synthetic. >1 month Overall fibrinolytic activity__ No change 6 (34) decreased 19(136). Euglobulin clotlysis time__ No change 107 (1, 6, 36), short 24 (22, 28), Van- able 4(2). Plasmin No change 18 (6, 64), in- creased 29 (11). Plasminogen No change 10 (6), in- creased 54 (2, 3, 6, 13, 38, 42), decreased 29 (11). Activator No change 29 (6, 36), increased 41(11, 38). Anti-plasmins (including No change 44 (2, 6, 13, anti-uK). 34, 64) decreased 41 (11, 38), increased 8 (42). No change 16 (49) Decreased 23 (22, 37, 51)~_ Decreased 7 (59) Increased 76 (48). No change 79 (1, 70), short No change 11(2), pro- Synthetic-short 8 (42) Short 84(42,48). 24 (22, 28), Variable 4 longed 105 (5, 26, 28, (2). 63) (rise starts in 1st trimestor). No change 57 (12, 64), No change 65 (10), de- decreased 9 (44). creased 25 (5). No change 27 (2, 12, 69), No change 86 (21, 65), Synthetic-no change 25 Increased 8+? (33, 42). increased 50 (13, 28, increased 131 (2, 5, 22, (7, 33), increased 8 (42), 38, 44, 69, 70.) 35 37, 41) rise starts premarin-increasecj 8 in 1st trimester). (42). Increased 39 (12, 28, 38) - - Decreased 115 (5, 10, 29, Synthetic-no change 25 Increased ? (33), no change 37) (faIl starts in 1st (7), decreased 8 (33). 7(11). trimester), increased 30 (33). No change 79 (2, 13, 28, 49, No change 25 (5), in- Synthetic-increased 8 Increased 8+ ? (33, 42). 64, 70), decreased 29 creased 170 +(10, 22, 29, (42), decreased 25+? (12, 38), increased 16 33, 37, 41) (rise starts (7, 33), premarin- (69, 70). in 1st trimester), increased 8 (42). ci PAGENO="0048" 6880 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 5.-SUMMARY O.C.'s Pregnancy Estrogens Progestogens Platelets Increased number and Little effect Enhanced function No effect. possibly enhanced function. Coagulation Definitely accelerated_ -- Slightly accelerated Accelerated by synthetic Do. forms. Level of activity of Increased Increased Do. factors. Fibrinolysis do Decreased (?) Increased. References 1. Abrams, A. A. Sequential estrogen and progestogen therapy. Amer J Obstet Gynec 96:1005, 1966. 2. Amris, C. J. and Starup, J. The coagulation mechanism in oral contracep- tion. Acta Obstet Gynec Scand 46:78, 1967. 3. Amundson, B. A.. and Pilgeram, L. 0. Observations on a relationship between steroid metabolism and the concentration of plasma fibrinogen. Thromb Diath Haemorrh 10:400, 1963. 4. Banks, A. L., Rutherford, R. N., Coburn, W. A., and Welsh, R. L. The rela- tionship of clotting factors to dosage levels of estrogen and progestogen- like c9mbinations. mt J Fertil 11 :277, 1966. 5. Belier, F. K., Douglas, G. W., Morris, R. H., and 3ohnson, H. J. The fibri- nolytic enzyme system in pregnancy. Amer J Obstet Gynec 101 :587, 1968. 6. Belier, F. K. and Porges, R. F. Blood coagulation and fibrinolytic enzyme studies during cyclic and continuous application of progestational agents. Amer J Obstet Gynec 97:448, 1967. 7. Bennett, N. B., Bennett, P. N., Fullerton, H. W., Ogston, C. M., and Ogston, D. Effect of oestriol on platelet adhesiveness and fibrinolysis in men. Lancet 2 :881, 1966. 8. Bolton, C. H., Hampton, J. R., and Mitchell, J. R. Effect of oral contracep- tive agents on platelets and plasma phospholipids. Lancet 1:1336, 1968. 9. Borchgrevink, C. F.,, Andersen, R., Hall, J., Hatteland, K., and TJrsin-Holm, A. "Premarin" as a haemostatic agent: failure to demonstrate any labo- ratory or clinical effect. Brit Med J 2:1645, 1960. 10. Brakman, P. The fibrinolytic system in human blood during pregnancy. Amer J Obstet Gynec 94:14, 1966. 11. Brakman, P., Albrechtsen, 0. K., and Astrup, T. Blood coagulation, fibrinol- ysis and contraceptive hormones. JAMA 199:69, 1967. 12. Brakman, P. and Astrup, T. Effects of female hormones, used as oral con- traceptives, on the fibrinolytic system in blood. Lancet 2 :10, 1964. 13. Brehm, H. Circulation, blood coagulation and clinical observations during hormonal suppression of ovulation. mt J Fertil 9:45, 1964. 14. Brodsky, I., Lewis, G., and Ross, E. Effect of pregnancy pr a progestational drug on blood coagulation as measured by the Thrombotest. Obstet Gynec 24:213, 1964. 15. Bronstein, S. B., Stough, A., and Long, I. R. Double blind placebo con- trolled efficacy and safety study with Quinestrol. mt J Fertil 12 :274, 1967. 16. Caspary, E. A. and Peberdy, M. Oral contraception and blood platelet adhe- siveness. Lancet 1 :1142, 1965. 17. Clemetson, C. A. B., Blair, L., and Brown, A. B. Capillary strength and the menstrual cycle. Ann NY Acad Sci 93:279, 1962. 18. Cohen, A. Double blind intensive safety and tolerance studies during Qui- nestrol therapy in elderly women. Tnt J Fertil 12 :266, 1967. 19. Coopland, A., Alkjaersig, N., and Fletcher, A. P. Reduction in plasma factor XIII (FSF) concentration during pregnancy. J Lab Clin Med 73 :144, 1969. 20. Daniel, D. G., Bloom, A. L., Giddings, J. C., Campbell, H., and Turnbull, A. C. Increased factor IX levels in puerperium during administration of di- ethylstilboestrol. Brit. Med J 1 :801, 1968. 21. Dieckman, W. J. and Wegner, C. R. Studies of the blood in normal preg- nancy. Arch Intern Med 53:353, 1934. PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6881 22. Donayre, J. and Pincus, G. Effects of Enovid on blood clotting factors. Metabolism 14 Suppl: 418, 1965. 23. Egeberg, 0. and Owren, P. A. Oral contraception and blood coagulability. Brit Med J 1:220, 1963. 24. Elert, R. Per Einfluss der weiblichen Keimdrusenhormone auf die Throm- bozyten. Schweiz Med Wschr 76:1090, 1946. 25. Elkeles, R. S., Hampton, J. R., and Mitchell, J. R. Effect of oestrogens on human platelet behaviour. Lancet 2:315, 1968. 26. Gillman, T., Naidoo, S. S., and Jiathorn, M. Plasma flbrinogen activity in pregnancy. Lancet 2:70, 1959. 27. Hajdu, A., Chappel, C. I., and Rona, G. The influence of estrogens on scor- butic bone lesions in guinea pigs. Experientia 21:466, 1965. 28. Hilden, M., Amris, C. J., and Starup, J. The haemostatic mechanism in oral contraception. Acta Obstet Gynec Scand 46:562, 1967. 29. Hougie, C., Rutherford, R. N., Banks, A. L., and Coburn, W. A. Effect of a progestin-estrogen oral contraceptive on blood clotting factors. Metabo- lism 14 Suppl :411, 1965. 30. Johnson, J. F. Changes in plasma prothrombin, Ac-globulin and antithrom- bin concentration following intravenous administration of estrogens. Proc Soc Exp Biol Med 94 :92, 1957. 31. Kasper, C. K., Hoag, M. S., Aggeler, P. M., and Stone, S. Blood clotting factors in pregnancy; factor VIII concentrations in normal and AHF-de- ficient women. Obstet Gynec 24:242, 1964. 32. Lenahan, J. G., Stough, A., and Bronstein, S. B. Effect of Quinestrol on the coagulation mechanism. mt J Fertil 12:271, 1967. 33. Maki, M., Nagasawa, K., Nagayama, M., and Sasaki, K. Parameters of plasmin system during normal pregnancy, labor and puerperium and relation of sex hormones to plasmin system. Tohoku J Exp 1~Ied 85:1, 1965. 34. Mammen, E. F., Aoki, N., Oliveira, A. C., Barnhart, M. I., and Seegers, W. H. Provest and blood coagulation tests. Tnt J Fertil 8:653, 1963. 35. Margulis, P. R., Ambrus, J. L., Mink, I. B., and Stryker, J. C. Progesta- tional agents and blood coagulation. Amer J Obstet Gynec 93:161, 1965. 36. Miller, S. P., Lee, S. L., and Ritz, N. Progestin-estrogen (SC 11,800) ther- apy and the hemostatic mechanism-a controlled study. Metabolism 14:398, 1965. 37. Nilsson, I. M. and Kullander, S. Coagulation and fibrinolytic studies during pregnancy. Acta Obstet Gynec Scand 46:273, 1967. 38. Nilsson, I. M. and Kullander, S. Coagulation and fibrinolytic studies during use of gestogens. Acta Obstet Gynec Scand 46:286, 1967. 39. Pechet, L. and Alexander, B. Increased clotting factors in pregnancy. New Eng J Med 265 :1093, 1961. 40. Pepper, H. and Lindsay, S. Levels of platelets and eosinophilic leukocytes during the normal menstrual cycle and the administration of norethynod- rd (Enovid). Tnt J Fertil 8:467, 1963. 41. Phillips, L. L. and Skrodelis, V. The fibrinolytic enzyme system in normal, hemorrhagic and disease states. J Olin Invest 37:965, 1958. 42. Phillips, L. L., Turksoy, R. N., and Southam, A. L. Influence of ovarian function on the fibrinolytic enzyme system. IT. Influence of exogenous steroids. Amer J Obstet Gynec 82 :1216, 1961. 43. Pilgeram, L. 0. Blood coagulability and oral contraception. Brit Med J 1:883, 1964. 44. Pilgeram, L. 0., Amundson, B. H., and Lofgren, P. E. Evidence for steroid control of the metabolism of profibrinolysis. Thromb Diath Haemorrh 11 :94, 1964. 45. Polivoda, H. Treatment of thrombocytopenic hemorrhage with oestriol sue- cinate. Nature 191 :400, 1961. 46. Poller, L., Tabiowo, A., and Thomson, J. i\I. Effects of low-dose oral contra- ceptives on blood coagulation. Brit Med J 2 :218, 1968. 47. Poller, L. and Thomson, J. M. Clotting factors during oral contraception: further report. Brit Med J 2 :23, 1966. 48. Poller, L., Thomson, J. M., Tabiowo, A., and Priest, C. M. Progesterone oral contraception and blood coagulation. Brit Med J 1:554, 1969. 40-471 0-70-pt. 17-4 PAGENO="0050" 6882 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 49. Powell, L. C., Guest, M. M., and Bond, T. P. Coagulation and fibrinolytic studies in women receiving an anovulatory drug. Amer J Obstet Gynec 93:167, 1965. 50. Rapaport, S. I. Proceedings of a conference: thromboembolic phenomena in women. p. 154, Chicago, G. D. Searle & Co., 1962. 51. Ratnoff, 0. D. and Holland, T. R. Coagulation components in normal and abnormal pregnancies. Ann NY Acad Sci 75:626, 1959. 52. Reed, D. L. and Coon, W. W. ThromboemboliSm in patients receiving pro- gestational drugs. New Eng J Med 269:622, 1963. 53. Robinson, R. W. Effects of estrogen-progestin combinations on clotting fac- tors. Amer J Obstet Gynec 99:163, 1967. 54. Rona, G. The role of vascular mucopolysaccbarides in the hemostatis action of estrogens. Amer J Obstet Gynec 87:434, 1963. 55. Rona, G. Experimental studies on vascular purpura and capillary hemo- stasis. Rev. Canad Biol 22:465, 1963. 56. Rutherford, R. N., bugle, C., Banks, A. L., and Coburn, W. A. The effects of sex steroids and pregnancy on blood coagulation factors. Obstet Gynec 24:886, 1964. 57. Salvadori, B., Cagnazzo, G., Ciasca, G., and Giorgino, R. Progesteroidi di sintesi ed emocoagulazione. Ann Obstet Ginec 82:705, 1960. 58. Samuels, A. J., Lepowsky, F., and Tyler, E. Assay of selected hematologic and coagulation factors in patients on Provera. Int J Fertil 8:665, 1963. 59. Schersten, B. Remarks on bemostatics with special reference to their clini- cal use. Suom Laak lehti 13:855, 1958. 60. Schiff, M. and Burns, H. F. The effect of estrogens on mast cells and enzymes in connective tissue metabolism in humans. Laryngoscope 71:766, 1961. 61. Schrogie, J. J. and Solomon, H. 1~I. Estrogenic hormones and blood coagula- tion. J Chronic Dis 20:675, 1967. 62. Schrogie, J. J., Solomon, H. M., and Zieve, P. D. Effect of oral contracep- tives on vitamin K-dependent clotting activity. Clin Pharmacol Ther 8:670, 1967. 63. Shaper, A. G., McIntosh, D. M., and Evans, C. M. Fibrinolysis and plasmin- ogen levels in pregnancy and the puerperium. Lancet 2:706, 1965. 64. Sobrero, A. J., Fenichel, R. L., and Singher, H. 0. Effects of a progestin-es- trogen preparation on blood coagulation mechanisms. JAMA 185:136, 1963. 65. Talbert, L. M., and Langdell, R. D. Normal values of certain factors in the blood clotting mechanism in pregnancy. Amer J Obstet Gynec 90:44, 1964. 66. Thomson, J. M. and Poller, L. Oral contraceptive hormones and blood coag- ulability. Brit Med J 2:270, 1965. 67. Todd, M. E., Thompson, J. H., Jr., and Bowie, E. J. Changes in blood coag- ulation during pregnancy. Mayo Clin Proc 40:370, 1965. 68. Wright, H. P. Changes in the adhesiveness of blood platelets following par- turition and surgical operations. J Path Bact 54:461, 1942. 69. Ygge, J., Brody, S., Korsan-Bengtsen, K., and Nilsson, L. Changes in blood coagulation and fibrinolysis in women receiving oral contraceptives. Amer J Obstet Gynec 104:87, 1969. 70. Young, C. C., Mammen, E. F., and Spain, W. T. The effect of sequential hormone therapy on the reproductive cycle. Pacif Med Surg 73 :35, 1965. E. CEREBROVASCULAR DISEASES AssocIATED WITH THE USE OF ORAL CONTRACEPTIVES: A REVIEW OF THE LITERATURE Alfonse T. Masi, M.D., Dr. P. H. and M. Dugdale, M.D. Numerous clinical reports indicate that neurologic complications may result from the. use of oral contraceptives. These include vascular occlusive syn- dromes of the central nervous system and retina, migraine and other assorted cerebrovascular disorders. Retrospective epidemiologic studies by British inves- tigators have demonstrated an etiologic relation between the use of oral con- traceptives and idiopathic cerebrovascular disease. There is no evidence how- ever, that the overall incidence of death or morbidity from cerebrovaScular PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6883 disease has increased with time since the introduction of these compounds.' The most frequent serious complication associated with the oral contraceptives is peripheral venous thrombosis with or without the complication of pulmonary infarction. This report focuses on occlusive disorders of the cerebral vasculature because they are the most common arterial complications reported from the use of these compounds and because they also allow consideration of intrinsic vascular alterations as an etiologic mechanism. CLINICAL REPORTS OF CEREBROVASCJJLAR ACCIDENTS IN WOMEN USING ORAL CONTRACEPTIVES From the time of the first report of an unexplained cerebrovascular accident in a young woman using an oral contraceptive by Lorentz (22) until the report by Walsh and colleagues (31), a total of 10 cases were described. Two of them were included as cases No. 10 and No. 20 in the Proceedings of a Con- ference on Thromboembolic Phenomena in Women Using the Oral Contracep- tives (29) and the other eight, including three deaths, appeared in isolated reports in the British literature. Walsh (31) reviewed the latter eight cases and collected 61 additional ones from numerous colleagues following publica- tion of an Editorial by Cogan (6) requesting that such cases be sent to Dr. l,\Talsh. The available data on the 69 cases were analyzed according to age of onset, duration of oral contraceptive usage, and type of central nervous system involvement. In 63 patients, the mean age at onset of illness of 28.9 years was older than the mean age of American married women using hormonal contraceptives (26). The average duration of usage was 9.7 months, but 60 per cent were using the drugs six months or less at the time of the incident. Some of the reported cases had a predisposing condition. The temporal relations between the onset and course of the disorder and the starting and discontinuation of the oral contraceptive suggested an etiologic role. Pseudotumor cerebri was reported in four cases who were the youngest and had the longest duration of use. Stroke was reported in 17 cases, two of whom succumbed. Ocular involvement occurred in 20 cases; eight had optic neuritis and the remainder had retinal vascular involvement. Migraine was reported in only 10 cases. Finally ten other cases with neurologic syndrOmes had incom- plete information. The authors concluded that the evidence warranted further study. Illis and coworkers (17) from the National Hospital, Queen Square, London, compared the frequency of cerebral arterial occlusion among~ women aged 18-45 years before and after 1961. Only arteriographically proven cases were considered. Although the overall yearly admission rate from January, 1955 to July, 1965 seemed stable, four (22%) of 18 patients admitted since 1961 were known to be using hormonal contraceptives. This proportion of users is proba- bly a conservative one. Nevertheless, of the 18 cases admitted from 1961 to July 1965, the number who might have been expected to be using oral contra- ceptives according to the estimates of the Family Planning Association would be less than one (0.375) as compared with the four observed. Although this thfference is significant statistically, no definite conclusion is possible because of uncertainty as to the use of the drugs in the population from whom the series was drawn. Shafey and Sheinberg (28) described a variety of neurological syndromes including occlusive cerebral artery disease (five cases), thrombosis of cortical veins (one case) and vascular headaches (28 cases). This series contained no patients with a previous history of migraine attacks before starting oral con- traceptives. Three of their six "stroke" patients, including a fatality, were included among the 17 stroke patients reported by Walsh (31). Each of the four patients who had angiographic studies showed "beading" of the vessels supplying the infarcted area of brain. Similar angiographic changes were evi- dent in the case shown to have thrombosis of cortical veins. The authOrs did not place great weight on this finding because of a paucity of degenerative or inflammatory changes in the vascular system of the brain or of the rest of the body. 1 See Appendix 2C, Greene. PAGENO="0052" 6884 COMPETITIVE PItOBLEMS IN THE DRUG INDUSTRY Three of the six cases with brain infarction had hypertension or a family history of vascular disease. Walsh (31) suggested that some women have a naturally increased susceptibility to such vascular complications which may be augmented by the oral contraceptives. Shafey and Sheinberg stated that their experience did not prove a specific relation between the oral contraceptives and neurologic disease. Nevertheless they noted that in the past 18 months they had seen four women under 30 years of age with cerebrovascular occlu- sive disease, whereas they had seen only two cases in this age group in the previous five years. All their patients with vascular headaches were relieved of their symptoms when the synthetic steroids were discontinued. Bickerstaff and Holmes (5) reviewed the cases of cerebral arterial insuffi- ciency from a large neurological referral practice in the Birmingham (Eng- land) area. Of 25 such patients under the age of 45 diagnosed in the three year period from 1964 through 1966, 18 (72%) had been using oral contracep- tives, as compared with an estimated 9 per cent use (17). A personal commu- nication from E. B. Bickerstaff dated January 14, 1969 revealed that of 12 additional cases of cerebral arterial insufficiency in 1967 and 1968, 10 (83%) had been taking hormonal contraceptives. The number of patients under the age of 45 seen with this condition in their practice who were not using oral contraceptives has not changed significantly since 1954 and has continued to average about two per year. Although the vertebral and basilar arteries are rarely involved in young patients, these vessels were affected in 6 of the 18 cases. Gardner and coworkers (14) described focal neurological impairment of varying severity in 9 women between the ages of 23 and 45 years who were taking oral contraceptives. These patients had no predisposing disease except for hypertension in one and transient blood pressure changes in two. The authors stated that precipitation or change in the pattern of vascular head- ache in women taking oral contraceptives is a common clinical experience. All their nine patients experienced this type of change; it was accompanied by transient cerebral signs or symptoms lasting from 3 hours to two months in 5 cases and left a permanent disabling neurologic deficit in 4. During the period of observation they reported seeing no patients with the increasingly severe vascular headaches who were not using the oral contraceptives. Carotid arte- riography performed in 2 patients several weeks after the onset of symptoms disclosed widespread segmental narrowing or occlusion of smaller cerebral arteries as well as the intimal irregularity, or "beading," of the carotid siphon previously reported by Shafey and Sheinberg (28). Jennett and Cross (19) reviewed their experience in 104 females aged 15-45 who were fully investigated between 1956 and 1965, for carotid stroke at the Institute of Neurological Sciences, Glasgow, and concluded that there was no evidence that the oral contraceptives were responsible for cerebral arterial occlusion in young women. They also concluded that full investigation of cases of non-hemorrhagic hemiplegia in pregnancy showed that two-thirds are due to major arterial occlusion, and that cerebral venous thrombosis is not the usual cause as is commonly stated. It should be noted that during the last three years reported (1963-1965) the number of non-pregnant patients increased beyond the number that could have been anticipated from the experience of the preceding seven years. A yearly average of 3 non-pregnant patients with stroke were admitted from 1956 through 1962, but an average of seven occurred yearly thereafter. Jennett and Cross (19) make the interesting statement with regard to cere- brovascular disease that, "mortality and morbidity statistics do not discrimi- nate between pregnant and non-pregnant women, and if our experience were universal it might be expected that the figures for women in this age group in the lCD Rubrics 332 and 334 would include a number of pregnant women: since the contribution made by pregnant women to the deaths is dispropor- tionate, the mortality statistics would be particularly liable to bias from this cause." If this reporting circumstance is true as it seems to be also in the United States and if mortality from cerebrovascular disease in women of child-bearing age shows no increase in the face of an increasing use of the oral contraceptives, then it is possible that the mortality statistics are reflect- ing a substitution of the risk due to oral contraceptives for the risk due to pregnancy. PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6885 Salmon and colleagues (27) reviewed the studies of neuro-ophthalmic seque- lae in users of oral contraceptives as well as other important reports including that of Cole (8). There were 129 cases of migraine and 100 with other neuro- logic and ophthalmalogic diseases. They accumulated 70 cases of stroke in users of oral contraceptives. They classified them according to the presumed location of the lesion. Eighteen (26%) were believed to stem from either the vertebral, basilar or posterior cerebral arteries. The authors stated that prior to the availability of hormonal contraceptives, only 47 cases of spontaneously occur- ring stroke in healthy young females were reported when pregnancy or other predisposing factors were eliminated. None involved areas supplied by the ver- tebral or basilar arteries. Salmon (27) noted also that the reduction of the per cent of pregnant women in the population has not been accompanied by a reduction of morbidity due to these cerebral disorders, associated in part with pregnancy. Ask-TJpmark (2) mentioned similar cases associated with the use of oral contraceptives. One death occurred in a 40 year old woman. The single autopsied case of a neurological catastrophe associated with the use of these drugs is reported by Altsbuler (1). The patient was a 26 year old female in good health except for a long history of mild migraine. After eight months use of oral contraceptives she suddenly developed neurologic signs and symptoms suggestive of subarachnoid hemorrhage. She did not respond to ther- apy and died 7 days after admittance. At autopsy, thromboses of both internal carotid arteries and of the right middle cerebral artery were found with multi- focal fibrinoid degeneration of small arteries and multiple areas of hemor- rhagic infarction. Arteriolar degeneration and endarteritis in the papillary muscles of the heart with infarction was also seen. Microscopic study of the brain revealed several significant features. Small intracerebral vessels were involved. There was dilatation, stasis, erythrodiapedesis, intramural hemato- mas, and laminar splitting and with focal necrosis of the vessel walls. Fibri- noid swelling of minute vessel walls was also seen. The presence of the latter lesions indicated that the damage done by the causative agent was not limited to hypercoagulability in larger vessels but involved the cerebral microvascula- ture as well. The authors reviewed data from seven previously reported autop- sled cases with thrombosis of the central nervous system but none described the microvasculature in such great detail. Bergeron and Wood (3) reported their radiologic experience regarding cere- brovascular complications of the oral contraceptives observed during two twelve month periods at the Neurological Institute of New York. Of the 64 young women studied by cerebral angiography because of ischemic syndromes in 1966, arterial occlusions were documented in 9, of whom 8 had been taking the drugs. The year 1960 was selected for comparison; during this year 60 angiograms were performed but only two cases with arterial occlusion were found. One non-hormone related occlusion was seen in both years studied but the hormone-related occlusive disease increased from one (post-partum) in 1900 to eight women in 1966. Among the eight cases, the median age was 30 years and the average duration of use was 16 months. In all but one, branches of the middle cerebral artery were involved. The authors believe that the number of reported cases of cerebrovascular accidents associated with the oral contraceptive is only a small fraction of the true number. Inman and Vessey (18) indicate that only 15 percent of the thromboembolic deaths of women who were taking the oral contraceptives in Great Britain were reported to the Committee on Safety of Drugs. Their expe- rience like that of Shafey and Sheinberg (28) and Garner and coworkers (14) suggests that these patients almost always have some prodromal warning, usually significant headache, prior to the onset of the paretic event. Levine and Swanson (21) reviewed nonatherosclerotic causes of stroke and contributed a report of a fatal case of a 31 year old woman who had been in good health except for migraine since age 16 and who had been taking oral contraceptives for 4 years. Four days before death she collapsed with a left hemiparesis and developed a right hemicranial headache. Postmortem examina- tion showed no atherosclerosis, but the right middle cerebral artery was dis- tended by an easily expressed clot, which was shown microscopically to be an unorganized thrombus. It evidently developed during the one day antemortem since the artery had been demonstrated previously to be patent. A large infarct was demonstrated in the right hemisphere. This case suggests that PAGENO="0054" 6886 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY interference with the cerebral small vessel had occurred at least four days antemortem and before a large clot developed in a major cerebral artery. Levine and Swanson (21) also presented a differential diagnosis of ischemic strokes in young adults. They basically fall into two classes; the first resulting from atherosclerotic degenerative vascular disease due to diabetes, hyperten- sion and hyperlipidemia, and the second resulting from various rarer diseases. It is likely in the latter class that clues will be found regarding the mecha- nisms of ischemic stroke in women using hormonal contraceptives. The rarer known causes of ischemic stroke in young adults include: 1) inflammatory- degenerative vascular disorders associated with connective tissue disease,, e.g., systemic lupus erythematosus, as reviewed recently by Johnson and Richard- son (20), Takayasu's arteriopathy localized to the aortic arch or major branches, and granulomatous angiitis of the central nervous system; 2) embolic disorders due to fat, micro-organisms, tumor, air or thrombi; 3) liema- tologic-rheologic syndromes, e.g., sickle cell disease or trait, polycythemia and the dysproteinemias; and 4) migraine. The experience of these authors is con- firmed by that of Berlin and colleagues (4), Humphrey and Newton (16) and by Louis and McDowell (23) who reviewed also the subject of cerebrovascular occlusions in young adults. Cross and Jennett (10) emphasized also the impor- tance of pregnancy and the puerperium as a cause of ischemic stroke in young women. EPIDEMIOLOGIC STUDIE5 RELATED To STROKE AND THE USE OF ORAL CONTRACEPTIVES The most definitive statistics currently reported on the association of mor- bidity and mortality from cerebral thrombosis and the oral contraceptives have derived from the retrospective studies initiated in Great Britain by the Com- mittee on Safety of Drugs and by the Medical Research Council. In December 1964, the Committee on Safety of Drugs began an investigation into reports of deaths from thrombosis or embolism in women who were using the oral con- traceptives. In July 1966, the Committee extended its investigation to cover al~ deaths of women aged 15 to 44 years that occurred in 1966, and in which cere- bral thrombosis, coronary thrombosis or pulmonary embolism or infarction was mentioned on the death certificate. The final results of the Committee on Safety of Drugs' investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of child-bearing age was reported by Inman and Vessey (18). After exclusions, justified by the design of this type of retrospective study, 309 deaths among non-pregnant married women in England, Wales and Northern Ireland during 1966 were analyzed according to the presence or absence of pre- disposing conditions and the frequency of use of the oral contraceptives. One hundred and twenty women with adequate history of contraceptive practice were ascertained to have no predisposing condition; 26 dying of pulmonary embolism, 84 of coronary thrombosis and 10 of cerebral thrombosis. The remaining deaths were divided among 175 with predisposing conditions and 14 without sufficient evidence of contraceptive practice. Of the women dying with- out a predisposing condition, 16 of 26 attributed to pulmonary embolism, 18 of 84 to coronary thrombosis and 5 of 10 to cerebral thrombosis were using the oral contraceptive wthereas the expected numbers from the control experience were 4.2, 11.4 and 1.5 respectively. The differences for pulmonary embolism and cerebral thrombosis are statistically significant, (P<0.001) and (P<0.01) respectively. With regard to cerebral thrombosis, five of the six women under 40 years had been using hormonal contraceptives while none of the four over 40 years had taken them. Thus, an association was demonstrated between the use of these compounds and death from idiopathic cerebral thrombosis in healthy British women. The final report by Vessey and Doll (30) compared the use of oral contra- ceptives during the month preceding the onset of illness among the cases of idiopathic deep vein thrombosis, pulmonary embolism, cerebral and coronary thrombosis with that among controls admitted (1964-67) to 19 selected gen- eral hospitals of more than 300 beds in the area of the Northwest Metropoli- tan Hospital Board. Married females between the ages of 16 and 40 years inclusive who had relevant thromboembolic disorders without a predisposing condition or having been pregnant within three months were considered cases PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6887 for further study. Two carefully matched hospitalized control patients of the same age, marital status, parity and without evidence of predisposing condi- tions were selected for each case and the complete "triads" of interviewed idi- opathic cases and matched controls were analyzed. All records were reviewed which were coded under Rubrics 331-334, in order to detect cases of cerebral thrombosis not coded under Rubric 332. Abstracts of the records were reviewed by a neurologist without knowledge of the patients' contraceptive practices. Nineteen cases were accepted, of whom four had angiographic evidence of arterial occlusion. Eleven (58%) had been using hormonal contraception during the month before they became ill whereas 3.5 (18%) would have been expected on the basis of a control experience (P<0.001). The authors estimated that the risk of developing a cerebral thrombosis or other intracranial isch0mic stroke syndrome, in the absence of any known predisposing cause, is about six times higher when oral contracep- tives are used than when they are not.2 Oral contraceptives were used by 3 of the 4 patients in whom the diagnosis was proven arteriographicafly. They also concluded that clinical, angiographic and postmortem evidence from their own and other series indicate that the thrombosis or occlusion affects the cerebral arteries rather than the cerebral veins. A recent analysis of oral contraceptive use and mortality trends from throm- boembolism in the United States was reported by Markusli and Seigel (25). They compared the mortality rates during 1962-1966 among women aged 20-44 years with the rates for men and women in comparable age groups in previous years. They analyzed overall trends of mortality attributed to cere- bral thrombosis and embolism (lCD 332) and could not find evidence of a gen- eral increase in women in the recent period or of an increase in females rela- tive to males. Possibly improvements in the treatment of primary diseases such as hypertension and renal disease have compensated for an increase that would otherwise be seen. Also, as mentioned above, stroke in pregnancy is* included under Rubric 332 and one might expect a downward trend in mortal- ity from this type of stroke with decreasing birth rates. Nevertheless, an increased trend in mortality attributed to lCD 332 was detected for white females aged 25-29 and negro females aged 25-34. Greene (15) analyzed also U.S. cerebrovascular mortality with regard to temporal trends before and after the introduction of the oral contraceptives. The results including ratios of white male to female mortality in the child- bearing ages are consistent with the above-mentioned findings. DISCUSSION The purpose of this review of both clinical reports and statistical evalua- tions of the association of oral contraceptives with cerebrovascular disease is to ascertain whether or not an etiologic relation exists and also to gain clues as to possible biological mechanisms which might be operating. The available clinical data are consistent with an etiologic relation. The clinical reports sug- gest also that an unusual type of stroke, namely that involving the vertebro- basilar area of the brain, is occurring in about a quarter of the young women now experiencing stroke while using hormonal contraceptives. A close temporal association between the use of oral contraceptives and the onset of migraine- like headache has also been reported. These headaches often occur prior tc cer- ebral ischemic infarction. The clinical evidence suggests that various neurciogi- cal syndromes, seemingly related to vascular alterations with or wi~ ~~out thrombosis, are related to use of the oral contraceptives. The results of retrospective epidemiologic studies of mortality and morbidity from idiopathic cerebral thrombosis in Great Britain indicate a statistically significant association with the use of oral contraceptives. It is not possible with the existing data to estimate with assurance the magnitude of the increased morbidity and mortality risk of stroke among women using these compounds but it may be in the neighborhood of sixfold judging by findings of Inman and Vessey (18) and Vessey and Doll (30). 2 This relative risk is estimated from a ratio of cross-products, i.e., proportion of oral contraceptive users among cases (58%) x proportion of non-users among controls (82%) divided by the proportion of non-users among cases (42%) x proportion of users among controls (18%). PAGENO="0056" 6888 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Non-atherogenic causes of stroke were reviewed since atheromata almost never could be documented as the direct cause of stroke in the autopsied women succumbing while on oral contraceptives. Furthermore, only rarely have strokes due to atheromatosis been reported in persons under thirty years of age. Non-atherogenic stroke develops in women during pregnancy or the puer- perium, in women having migraine and in women with various systemic connective tissue diseases and especially system lupus erythematosus. Each of these conditions seems to be related closely to physiological or histological alterations of the vasculature of the brain. Few women who died while using hormonal contraception have had careful studies of the brain, and e5~)ecially of its vasculature. The single reported autopsy revealed significant and impres- sive alterations of the small and medium-sized vessels. Animal experimental studies of vascular effects of oral contraceptives are limited but those of Danforth and coworkers (12) in rabbits revealed an increase in the amount of muscle, a decrease in the amount of collagen, marked fragmentation of the reticulum, apparent loss of elastic tissue and a marked loss of acid mucopolysaccharides in large vessels. Qualitatively similar changes were found in pregnancy. Manalo-Estrella and colleagues (24) showed that these changes disappeared at variable rates after withdrawal of antiovu- latory agents or the termination of pregnancy. The mnucopolysaccharides return to normal within a day while other alterations revert at a slower rate. Cutts (11) demonstrated, in rats, that long-term administration of estrogen predis- poses to vascular lesions resembling polyarteritis nodosa. It is tempting to speculate that oral contraceptives induce changes analogous to those in preg- nancy and thus may alter the composition or architecture of cerebral blood vessels as suggested by Crocker (9) in considering fibromuscular dysplasia of the renal arteries found predominantly in multiparous women. The review by Dugdale and Masi (13) of coagulation studies in women using hormonal contraception suggests that estrogen contributes to increased platelet function and accelerated clotting whereas progestin contributes to increased fibrinolytic activity. A few studies comparing the effects of high dose with low dose oral contraceptives did not show any great differences in plate- let function, coagulation or fibrinolysis. In order to understand the effects of the oral contraceptives on the vascular system and the blood clotting system it is necessary to consider the complex alterations in the endocrine system induced by these compounds as reviewed by Corfman (7). It is invalid to conclude that any changes occurring in women taking the oral contraceptives are entirely due to the estrogen or pro- gestin without considering how these hormones alter the general endocrine and physiologic balance of the body. SUMMARY AND CONCLUSIONS 1. A review of the major clinical reports of cerebrovascular occlusion in women using the oral contraceptives reveals a notable increase in the number of instances of cerebrovascular disease in healthy women of child-bearing age that have appeared since the introduction of the oral contraceptives. 2. Young women suffering from stroke while using the oral contraceptives almost always have some warning, usually significant headache, prior to the onset of the paretic event. In about one-fourth there is ischemia or infarction in the vertebral and basilar arterial system, a location which was previously considered rare in young healty women. 3. Cerebral arteries rather than veins are primarily involved. Limited angio- graphic and autopsy studies suggest intrinsic vascular alterations in addition to possible derangement of the hemostatic mechanisms. 4. Controlled retrospective studies of young women with cerebral thrombosis without a predisposing cause indicate a statistically significant etiologic rela- tion with the oral contraceptives. There is a sixfold estimated increase in the risk of both morbidity and mortality. 5. Available statistical evidence concerning the overall mortality from cere- brovascular disorders in the general population of women of child-bearing age since the time of introduction of the oral contraceptives until 1966 indicates no significant change. There is neither a decrease which one might anticipate due to the decreased number of pregnancies and deliveries in the general popula- tion, nor an increase which might have been evident if the risk from the oral PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6889 contraceptives per se were greater than opposing forces of such mortality oper- ating over this interval. References 1. Altshuler, J. H., i~IcLaughlin, R. A. and Neubuerger, K. T. Neurological catastrophe related to oral contraceptives, Arch Neurol 19 :264, 1968. 2. Ask-TJpniark, B. The relationship between thrombophlebitis, thrombosis, embolism and the use of the oral contraceptive agents, pp. 211-17 In Drug Induced Diseases, Eds. Meyler, L. and Peck, H. M., New York, Excerpta 1\Iedica Foundation, 1968, Vol. 3. 3. Bergeron, R. T. and Wood, E. H. Oral contraceptives and cerebrovascular complications, Radiology 92 :231, 1969. 4. Berlin, L., Tumarkin, B. and Martin, H. L. Cerebral thrombosis in young adults, New Bag J Med 252:162, 1955. 5. Bickerstaff, B. R. and Holmes, J. M. Cerebral arterial insufficiency and oral contraceptives, Brit Med J 1:726, 1967. 6. Cogan, D. G. Do oral contraceptives have neuro-ophthalmic complications? Arch Ophthal 73 :4G1, 1965. 7. Corfman, P., Adamsons, K., Carrington, E. and Delfs, E. Biologic effects of oral contraceptives In Report on the Oral Contraceptives, Advisory Com- mittee on Obstetrics and Gynecology, Food and Drug Administration, 1969. 8. Cole, M. Strokes in young women using oral contraceptives, Arch Intern Med 120 :551, 1967. 9. Crocker, D. W. Fibromuscular dysplasias of renal artery, Arch Path 85 :602, 1968. 10. Cross, J. N., Castro, P. 0. and Jennett, MT. B. Cerebral strokes associated with pregnancy and the puerperium, Brit i~Ied J 3 :214, 1968. 11. Cutts, J. H. Vascular lesions resembling periarteritis nodosa in rats undergoing prolonged stimulation with oestrogen, Brit J Exp Path 47 :401, 1966. 12. Danforth, D. N., Manalo-Estrella, P. and Buckingham, J. C. The effect of pregnancy and of Enovid on the rabbit vasculature, Amer J Obstet Gynec 88:952, 1964. 13. Dugdale, M. and Masi, A. T. Blood clotting effects of the oral contracep- tives IN Report on the Oral Contraceptives, Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, 1969. 14. Gardner, J. H., Van Den Noort, S. and Horenstein, S. Cerebrovascular dis- ease in young women taking oral contraceptives, Neurology 17:297, 1967. 15. Greene, G. R. Trends in mortality from cerebrovascular diseases IN Report on the Oral Contraceptives, Advisory Committee on Obstetrics and Gyne- cology, Food and Drug Administration, 1969. 16. Humphrey, J. G. and Newton, T. H. Internal carotid artery occlusion in young adults, Brain 83:565, 1960. 17. Tills, L., Kocen, R. S., McDonald, W. I. and Mondcar, V. P. Oral contracep- tives and cerebral arterial occlusion, Brit 1~Ied J 2 :1164, 1965. 18. Tnman, MT. H. WT. and Vessey, M. P. Investigation of deaths from pulmo- nary, coronary and cerebral thrombosis and embolism in women of child- bearing age, Brit Med J 2 :193, 1968. 19. Jennett, MT. B. and Cross, J. N. Influence of pregnancy and oral contraception on the incidence of strokes in women of child-bearing age, Lancet 1 :1019, 1967. 20. Johnson, R. T. and Richardson, E. P. The neurological manifestations of systemic lupus erythematosus, i\Iedicine 47 :337, 1968. 21. Levine, J. and Swanson, P. D. Nonatheroscierotic causes of stroke, Ann Intern Med 70 :807, 1969. 22. Lorentz, I. T. Parietal lesion and "Enovid," Brit Med J 2 :1191, 1962. 23. Louis, S. and McDowell, F. Stroke in young adults, Ann Intern Med 66 :932, 1967. 24. Manalo-Estrefla, P., Danforth, D. N. and Buckingham, J. C. Regression rate of vascular effects, induced by pregnancy by norethynodrel-mes- tranol, Fertil Steril 16:81, 1965. 25. Markush, R. E. and Seigel, D. G. Oral contraceptives and mortality trends from thromboembohism in the United States, Amer J Public Health 59:418, 1969. PAGENO="0058" 6890 COMPETITIvE PROBLEMS IN THE DRUG INDUSTRY 26. Ryder, N. B. and Westoff, C. F. Use of oral contraception in the United States-1965, Science 153 :1199, 1966. 27. Salmon, M. L., Winkelman, J. Z. and Gay, A. J. Neuro-ophthalmic sequelae in users of oral contraceptives, JAMA 206:85, 1968. 28. Shafey, S. and Scheinberg, P. Neurological syndromes occurring in patients receiving synthetic steroids (oral contraceptives), Neurology 16:205, 1966. 29. ThromboemboliC phenomena in women, Proceedings of a Conference, Chi- cago, Sept. 10, 1962, Copyright 1962, G. D. Searle & Co., Chicago. 30. Vessey, ~\`I. P. and Doll, R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A Further Report. Brit Med J 2:651, 1969. 31. Walsh, F. B., Clark, D. B., Thompson, R. S. and Nicholson, D. H. Oral con- traceptives and neuro~ophthalmologic interest, Arch Ophthal 74:628, 1965. APPENDIX 3 REPORT OF THE TASK FORCE ON CARCIN0GENESIS R. Hertz, M.D., Chairman INTRODUCTION It has been repeatedly demonstrated that the steroid substances used in oral contraceptives produce a wide variety of tumors in 5 species of experimental animals (10, 13, 17, 22, 31, 32). It is also known that all physical and chemical agents that are carcinogenic in man are also carcinogenic in animals (24). Moreover, these carcinogenic agents frequently produce tumors in the same organs in animals as they do in man. Hence there is a distinct interrelation between animal and human carcinogenic responses. Steroid carcinogenesis in -animals usually requires prolonged administration of hormone at relatively high dosage (13). Such administration of estrogen has elicited a carcinogenic response in rodents and in dogs but not in monkeys (6, 11, 36). It is therefore essential to ascertain whether such experimental findings in rodents and in dogs have any pertinence to the question of a poten- tial carcinogenic effect of steroid contraceptives in women. To date, no prop- erly devised prospective or retrospectiva study providing conclusive data bear- ing on this question has been completed. In consideration of available animal studies and in the light of certain physiopathological considerations it is deemed advisable to focus our interest on the potential effects of steroid contraception on the epidemiology, pathoge- nesis, and clinical course of cancers of the cervix, endometrium, and breast in women. CERVICAL CANCER An extended body of data provides an adequate background for the consider- ation of the major epidemiological aspects of cancer of the cervix (3, 5, 9, 25, 43, 44). However, despite a broad area of common agreement regarding mor- phological criteria for cytological and histological diagnosis of cervical cancer, it is clear that in practice wide differences of interpretation of pathological and normal material are frequently encountered (16, 29, 30, 33, 35, 38). Never- theless, evidence of a variety of cervical epithelial aberrations of indecisive prognostic significance has emerged (4, 41). The complexity of interpreting the true impact of steroid hormonal effects on the occurrence and behavior of these epithelial changes is manifest. This difficulty is augmented by attempts at comparison of such hormonally responsive changes with those seen in the newborn or during pregnancy (34, 39). In addition, certain diagnostic proce- dures such as punch biopsy will in some cases remove all evidence of disease, thereby frustrating any reliable prognostic interpretation. Nevertheless, Barron and Richard (1) have provided a mathematical model for the quantitative assessment of the proportion of cases to be expected to progress from "dysplasia" to "carcinoma in situ" in a given test population. The Task Force considers this model to be eminently applicable to the problem at hand and recommends its use in the evaluation of the validity of further data presented for consideration in this area. Seigel and Corfman (40) and PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6891 Hertz and Bailar (23) have estimated the size of the sample required to answer this question as well as to provide other pertinent epidemiological data. A survey of women attending the clinics of Planned Parenthood of New York City revealed a higher prevalence of epithelial abnormalities, diagnosed as carcinoma in situ, among women using oral contraceptives compared with those using the diaphragm (32a). These women had never been subject to sys- tematic cytologic screening prior to this study, but some of them may have had Papanicolaou smears done in other cancer detection programs. The diagno- sis was made in each case on the basis of a biopsy, examined by two patholo- gists without knowledge of the contraceptive used. Women who had used oral contraceptives for one year or more were individ- ually matched against diaphragm users with respect to five variables: age (5 classes), parity (2 classes), age at first pregnancy (3 classes including nulli- gravida), ethnic group (4 classes), and family income (2 classes). Because more women had used oral contraceptives (0,331) than the diaphragm (3,874) and because the distributions of the two groups of women in terms of the five variables were quite different, three matchings were performed: (1) one woman who had used the diaphragm against one who had used oral; (2) one diaphragm user against two pill users; and (3) one diaphragm user against three pill users. The three matchings produced, respectively, 2,351 pairs, 1,831 triplets, and 1,471 groups of four matched cases. In each matching the preval- ence of epithelial abnormalities, diagnosed as carcinoma in situ, was about twice as high among those who used oral contraceptives as among those who used the diaphragm, and in each instance the difference was significant at the 5 per cent level of confidence. Whereas these findings emphasize the urgent necessity of further research in this area, they do not, in the opinion of either the Task Force or the investi- gators, establish that oral contraceptives have a carcinogenic effect. Several important questions remain unanswered. 1. The prevalence of epithelial abnormalities diagnosed as carcinoma in situ, was higher among the 6,331 women who had used oral contraceptives for one year or more (9.8 per 1,000) than among the 21,177 women who were using other methods at the time of their first clinic attendance (5.6 per 1,000). There appears to be no further increment with duration of use of the pill. This finding is at variance with what would be expected in the case of a causal relation. 2. How do diaphragm users differ from pill users with respect to age at first coitus, frequency of coitus, number of sexual partners, and previous screening, all of which may contribute to the observed level of prevalence? It appears likely that all or most. of these factors are correlated with one or more of the variables used in matching, but important residual differences may remain. 3. Finally, if there is a significant difference in the prevalence and, presuma- bly, incidence of carcinoma in situ, is the reason for this difference a carcino- genic effect of hormonal contraception or a protective effect of the diaphragm, which may shield the cervix from coital trauma and possibly from infection? Accordingly, the Task Force urgently recommends prospective studies of the effect of sustained oral contraception on the immediate and ultimate response of the cervical epithelium in a carefully observed and representative popula- tion of women. ENDOMETRIAL CANCER The demonstrated regression of endometrial cancer in response to large doses of progestin clearly indicates that this is a hormone-sensitive lesion (26, 28). Moreover, retrospective histological studies indicate a prolonged pathoge- netic phase in the development of endometrial carcinoma (18, 19, 21, 42) Because this tumor is more occult, less is known about its incipient phases than about those of cervical cancer. For the same reason interpretation of epi- demiological findings in relation to the pathogenesis of cancer of the corpus is difficult and conclusions are of limited value. Accordingly, the Task Force does not regard studies relating specifically to endometrial cancer as a practical basis for evaluation of the carcinogenic potential of oral contraceptives. PAGENO="0060" 6892 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY BREAST CANCER Concern about potential applicability of findings in laboratory animals to cancer of the breast in women is based on the following observations: ovariec- tomy leads to regression of pre-existing metastatic breast cancer in 30 to 50 per cent of premenopausal women (2, 7) ; a similar proportion of premenopau- sal women with breast cancer will exhibit biochemical evidence of exacerba- tion of disease following administration of exogenous estrogen (20, 37) ; about 50 per cent of postmenopausal women and a few premenopausal women will experience regression of disease following administration of exogenous estrogen (8, 27). It is therefore clear that women with breast cancer may exhibit a pos- itive or negative response to exogenous estrogen. It is, however, completely unknown whether exogenous estrogens or proges- tins significantly alter the preclinical phase of breast cancer detectable by mammography (14). However, qualitative alterations in epithelial elements ot the breast have been observed in surgical material taken from patients taking oral contraceptives (15). Yet no valid data are available to confirm a causal relation between oral contraception and the occurrence of such lesions. In addition, an unknown proportion of women taking oral contraceptives complain of increased tenderness and turgidity of the breasts, but measurable enlarge- ment of the breasts is rarely demonstrable. The Task Force recommends appropriately devised retrospective case-con- trolled studies as well as prospective studies to resolve the problem of an effect of oral contraceptives on the incidence and course of mammary lesions. CONCLUSION Lacking definitive information regarding the potential applicability of exist- ing animal data to women, the Task Force believes that neither the exclusion of a potential carcinogenic role of oral contraceptives nor affirmation of such an effect is justified. However, the inconclusive observations cited for carci- noma of the cervix necessitate a major effort to solve this problem definitively under optimally controlled conditions of study. Meanwhile, the precautions cut- lined in our previous report (12) as desirable for all women of reproductive age are recommended with equal force for those using the oral contraceptives. References 1. Barron, B. A., and Richart, R. M. A statistical model of the natural his- tory of cervical carcinoma based on a prospective study of 557 cases. J Nat Cancer Inst 41 :1343, 1968. 2. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the mammae. Lancet 2 :104, 1896. 3. Boyd, J. T., and Doll, R. A study of the aetiology of carcinoma of the cervix uteri. Brit J Cancer 18 :18, 1964. 4. Candy, M., and Abel, M. R. Progestogen-induced adenomatous hyperplasia of the uterine cervix. JA1~IA 203 :323, 1968. 5. Christopherson, W. M., Parker, J. E., and Drye, J. C. Control of cervical cancer: Preliminary report on community program. JAMA 182 :179, 1962. 6. Crossen, R. J., and Suntzeff, V. Endometrial polyps and hyperplasia pro- duced in an aged monkey with estrogen plus progesterone. Arch Path 50 :721, 1950. 7. Currie, A. R. Endocrine aspects of breast cancer. The Williams & Wilkins Co., Baltimore, 1958. 8. De Nosaquo, N. Androgens and estrogens in the treatment of disseminated mammary carcinoma. JAMA 172:1271, 1960. 9. Dunn, J. E. The relationship between carcinoma in situ and invasive cervi- cal carcinoma. Cancer 6:873, 1953. 10. Dunn, T. B. Cancer of the uterine cervix induced in BALB/C mice by an antifertility drug. Proc Amer Ass Cancer Res 10:21, 1969. 11. Engle, E. T., Krakower, C., and Haagensen, C. D. Estrogen administration to aged female monkeys with no resultant tumor. Cancer Res 3 :858, 1943. 12. Food. and Drug Administration Report on the Oral Contraceptives, Advi- sory Committee on Obstetrics and Gynecology. Aug. 1, 1960, U.S. Gov't Printing Office, Washington, D.C., pg. 8. PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6893 13. Gardner, W. V., Pfeiffer, C. A., and Trentin, J. J. Hormonal factors in experimental carcinogenesis. In Physiopathology of Cancer edited by F. Homburger, and W. H. Fishman, ed. 2, p. 152. Harper & Row Publishers, Inc., New York, 1959. 14. Gerson-Cohen, J., and Borden, A. G. Detection of unsuspected breast cancer by mammography. Ann NY Acad Sd 114:783, 1964. 15. Goldenberg, V. E., Wigenstein, L., and Mottet, N. K. Florid breast fibro- adenomas in patients taking hormonal oral contraceptives. Amer J Clin Path 49:52, 1968. 16. Gore, H., and Hertig, A. T. Definitions in dysplasia, carcinoma in situ and microinvasive carcinoma of the cervix uteri (Gray, L., ed.) Springfield, Charles C. Thomas, 1964, pp. 83-409. 17. Griffiths, C. T., Tomic, M., Craig, J. M., and Kistner, R. W. Effects of pro. gestins and castration on induced endometrial cancer in the rabbit. Surg Forum 14 :399, 1963. 18. Gusberg, S. B. Precursors of corpus carcinoma, estrogens, and adenomatous hyperplasia. Amer J Obstet Gynec 54:905, 1947. 19. Gusberg, S. B. and Kaplan, A. L. Precursors of corpus cancer. Amer J Obstet Gynec 86:662, 1963. 20. Hall, T. C., Dadelick, M. 1~I., Nevinny, H. B., and Kelley, R. M. Cellular prognostic factors in breast cancer hormone therapy. In Biological Activ- ities of Steroids in Relation to Cancer, edited by G. Pincus and E. P. Volimer, p. 483. Academic Press, Inc., New York, 1960. 21. Hertig, A. T., and Sommers, S. C. Genesis of endometrial carcinoma: I. Study of prior biopsies. Cancer 2 :946, 1949. 22. Hertz, R. Experimental and clinical aspects of the carcinogenic potential of steroid contraceptives. Tnt J Fertil 13 :273, 1968. 23. Hertz, R., and Bailar, J. C. III. Estrogen-progestogen combinations for con- traception. JA1\IA 198 :1000, 1966. 24. Hueper, W. C. Environmental cancer. In Physiopathology of Cancer, edited by F. Homburger and W. H. Fishman, ed. 2, p. 919. Harper & ROw Pub- lishers, Inc., New York 1959. 25. Jones, E. 1., MacDonald, I., and Breslow, L. A study of epidemiologic fac- tors in carcinoma of the uterine cervix. Amer J Obstet Gynec 76:1, 1958. 26. Kelley, R. M., and Baker, W. H. Clinical observations of the effect of progesterone in the treatment of metastatic endometrial carcinoma. In Biological Activities of Steroids in Relation to Cancer, edited by 1. Pincus and E. P. Vollmer, pp. 427-439. Academic Prss, Inc., New York, 1960. 27. Kennedy, B. J. Massive estrogen administration in premenopausal women with metastatic breast cancer. Cancer 15:641, 1962. 28. Kistner, R. W. Treatment of carcinoma in situ of the endometrium. Clin Obstet Gynec 5 :1166, 1962. 29. Koss, L. G. Diagnostic cytology and its histopathologic bases. 2nd ed. Phil- adelphia, Toronto: J. B. Lippincott Co., 1968. 30. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, E. Some histologic aspects of behavior of epidermoid carcinoma in situ and related lesions of the uterine cervix. A long-term prospective study. Cancer 16:1160, 1963. 31. Lipschutz, A., Iglesias, R., Panosevich, V., and Salinas, S. Ovarian tumors and other ovarian changes induced in mice by two 19-nor-contraceptives. Brit J Cancer 21:153, 1967. 32. Lipschutz, A., Iglesias, R., and Salinas, S. Ovarian tumors by a sterilizing steroid. Nature 196:946, 1962. 32a. Melamed, 1\I. R., Koss, L. G., Flehinger, B. J., Kelisky, R. P., and Dubrow, H. Prevalence rates of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids. Brit Med J 3:195, 1969. 33. McKay, D. G., Terjanian, B., Poschyachinda, D., Younge, P. A., and Hertig, A. T. Clinical and pathologic significance of anaplasia (atypical hyper- plasia) of the cervix uteri. Obstet Gynec 13 :2, 1959. 34. Nesbitt, R. E. L., and Hellman, L. M. The histopathology and cytology of the cervix in pregnancy. Surg Gynec Obstet 54 :10, 1952. 35. Okagaki, T., Lerch. V., Younge, P. A., McKay, D. G., and Kevorkian, A. Y Diagnosis of anaplasia and carcinoma in situ by differential cell counts. Acta Cytol (Phil) 6:343, 1962. - PAGENO="0062" 6894 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 36. Overholser, M. D., and Allen, E. Atypical growth induced in cervical epi- thelium of monkey by prolonged injections of ovarian hormone combined with chronic trauma. Surg Gynec Obstet 60 :129, 1935. 37. Pearson, 0. H., West, C. D., Hollander, V. P., and Treves, N. E. Evaluation of endocrine therapy for advanced breast cancer. JAMA 154 :234, 1954. 38. Richart, R. M. Colpomicroscopic studies of cervical intraepithelial neopla- sia. Cancer 19:395, 1966. 39. Rosenthal, A. H., and Heliman, L. M. The epithalial changes in the fetal cervix, including the role of the "reserve cell." Amer J Obstet Gynec 64:260, 1952. 40. Seigel, S. J., and Corfman, P. Epidemiological problems associated with studies of the safety of oral contraceptives. JAMA 203 :950, 1968. 41. Taylor, H. B., Irey, N. S., and Norris, H. J. Atypical endocervical hyperpla- sia in women taking oral contraceptives. JAMA 202 :637, 1967. 42. TeLind~, I~. W., Jones, H. W., Jr., and Galvin, G. A. What are earliest endometrial changes to justify diagnosis of endometrial cancer. Amer J Obstet Gynec 66 :953, 1953. 43. Terris, M., and Oahinann, M. C. Carcinoma of the cervix. An epidemiologic study. JAMA 174:1847, 1960. 44. Wydner, E. L., Cornfield, J., Schroff, P. D., and Doraiswami, K. R. A study of environmental factors in carcinoma of the cervix. Amer J Obstet Gynec 68:1016, 1954. APPENDIX 4 REPORT OF THE TASK FORCE ox BIoLoGIC EFFECTS P. A. Corfman, M.D., Chairman INTRODUCTION Many important studies of the biological effects of oral contraceptives have been published since the 1966 FDA Report on Oral Contraceptives (55) and the results have been summarized in part by Diczfalusy (45), Jeffrey and Kiopper (83), and others (74, 103, 184). A detailed review of the nonendocrine effects was undertaken at a pour-day conference in December, 1968, organized by the Harvard Center for Population Studies and supported by the National Institute of Child Health and Human Development. The proceedings of the conference are published under the title "The Metabolic Effects of Gonadal Steroids and Contraceptive Agents" (147). This comparatively brief Task Force report does not attempt to include all of the extensive literature on the biological effects of oral contraceptives but identifies certain topics that the Task Force believes to be of particular impor- tance. The effects of these agents on blood coagulation and thromboembolism are covered in another portion of the report. It is clear, however, that oral contraceptives have many varied effects on many organ systems. Indeed, there app~ars to be no organ system tested that is not affected in some way. The ubiquitous effects of oral contraceptives probably relate to their high degree of contraceptive effectiveness, brought about through interference with several phases of the reproductive process. An influence on the hypothalamus or higher brain centers is probably responsible for the suppression of pituitary production of gonadotropins, leading secondarily to the inhibition of ovulation. The second major effect is on the endometrium. The progestin acts as an antiestrogen, causing alterations in endometrial glands, and as a progestin, causing a pseudodecidual reaction. Both of these effects alter the ability of the endometrium to participate in the process of implantation. The third effect is on the cervical mucus through prevention of the altera- tions that normally occur at the time of ovulation and appear to permit the ascent of sperm into the uterine cavity. Oral contraceptives cause the cervial mucus to remain thick and apparently hostile to the transmission of sperm. Oral contraceptives may affect tubal motility also and may alter the local ovarian reponse to gonadotropic hormones. A consideration of the biological effects of oral contraceptives is complicated by the facts that there are many different compounds and several modes of PAGENO="0063" COMPETITIVE PROBLEMS IN. THE DRUG INDUSTRY 6895 administration and that data derived from the study of one drug may not be relevant to the effects of another. Indeed, specific effects of an oral contracep- tive depend on at least six variables: 1. the specific agent(s) employed 2. the absolute amount of each agent 3. the proportion between the two agents if more than one is used 4. the route of administration (usually oral or parenteral) 5. the length of time the agent is used 6. the age of the user A wide variety of side effects or oral contraceptives has been described including delayed menses, amenorrhea, spotting, headache, nausea, vomiting, gastric distress, pelvic cramps, feeling of abdominal fullness, nervousness, anx- iety, depression, dizziness, leg cramps, breast tenderness, breast enlargement, unusual fatigue, backache, hirsutism, acne, urticaria, chloasma, weight gain, weight loss, and changes in libido. These side effects are dependent on the six variables described. There is some suggestion that selection of specific agents for specific patients may avoid many of the side effects. Certain authors (13, 44) suggest that the selection should be based on a proper balance among the postulated hormonal effects: estrogenic, antiestrogenic, progestational, antiprogestational, and andro- genic. This point of view is valid with respect to the amount of induced cyclic bleeding. Bleeding with sequentials more often simulates natural flow than does bleeding with combined products, which often is diminished. Whether other side effects can be controlled by adjusting medication can be answered only by carefully designed clinical studies, using double blind techniques. DRUG METABOLISM A review of the current literature reveals a paucity of information on the absorption, distribution, excretion, and metabolism of contraceptive steroids (18, 106, 144). This death of information is remarkable in view of the wide- spread use of these effective agents. Of particular interest would be data on the absorption of these materials and the modification of their activity by the gastrointestinal tract. StudIes in these areas are recommended. The aromatization of 19-norsteroids in an acid environment has been reported by several investigators. These studies have demonstrated that a metabolite of norethynodrel (17 alpha-ethnyl-19-nor andros-4-ene-3 beta, 10 beta, 17 beta-triol) possesses a higher estrogenic activity when given orally than when given by injection. Because synergism and antagonism are known to exist between weak and potent estrogens, it is possible that a metabolite is responsible for the biologic and contraceptive effects of these agents. It appears that 10 beta-hydroxy derivatives represent a large portion of the metabolites of some of the contraceptive steroids at least in the case with norethynodrel. Preliminary information from studies of norgestrel indicates that the compound is partially metabolized by a reduètion of ring A. The use of 14C-label in the ethynyl group in the same study indicated that about 6 per cent of the material appearing in the urine was in the "free" form; 33 per cent was a glucuronide and 25 per cent was a sulfate. The fact that a side chain rather than a ring structure was used in labeling the compound limits the usefulness of this information. Since synthetic progestational steroids are usually mixtures of d- and 1- forms, and since only the 1- form has biologic activity identified by the usual means, it is important to know the relative proportions of these fractions in the products now in use. There appears to be no information about the contra- ceptive l)roperties of the d- form and it cannot be inferred a priori that time lack of potency in the standard bioassay for estrogenic compounds indicates ineffectiveness as a contraceptive. It is theoretically possible that this form may interrupt the reproductive process at a stage that has not yet been ascer- tained. REPRODUCTIVE ENDOCRINOLOGY Understanding of the mechanisms and effects of oral contraceptives and sim- ilar steroids on pituitary function is incomplete as indicated by recent reviews (45, 103, 161, 163). Advance has been hampered in part by the lack of uniform and satisfactory assays to differentiate among total gonadotropins, FSH, and PAGENO="0064" 6896 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY LII, but the development of radio-immune techniques for measuring these bio- logic products undoubtedly will lead to progress in this field. Most oral contraceptives produce a contraceptive effect by preventing ovula- tion through the suppression of the hypothalamic-pituitary system. Not all the agents seem to produce this effect in the same way but, in general, the imme- diate effect of dominantly estrogenic compounds is to reduce FSII, whereas the effect of progestins is to suppress the midcycle peak of LII without signifi- cantly altering the basal LII level. Prolonged administration of estrogens or estrogen-progestin combinations causes marked reduction in both FSH and LII (27, 53, 76, 107, 146). Many animal experiments employing various species (51, 76, 94) support the concept that oral contraceptives exert their effect by block- ing estrogen receptor sites in the hypothalamus and pituitary with reduction of gonadotropin release and suppression of ovulation. Resumption of ovulation after cessation of oral contraceptives is usually prompt, within 4 to 8 weeks in most cases. In a few women, however, amenor- rhea persists for 6 months or longer (14, 21, 47, 49, 78, 114, 152, 153). Some believe that this phenomenon simulates the occasional period of extended ano- vulation that may follow pregnancy or lactation. Recovery after long-term sup- pression has been described (53). The pituitary recovers first (FSII first, then LII), followed by the ovary, and then the endometrium, which may require as long as three months to regain its normal histologic appearance and enzymatic activity. Although the small group examined showed resumption of ovulation rather promptly, clinical studies continue to report anovulation and amenor- rhea from weeks to months after discontinuation Qf oral contraceptives. Sev- eral authors have outlined means of evaluating and treating women with this condition. Pregnancy may be considered to be the prime indicator of adequate pituitary and ovarian function. While clinical observers agree that most women conceive "promptly" after the discontinuation of oral contraception, valid statistical information is scanty. To be sure, a number of investigators have reported the percentage of women who conveived among those who discontinued, or the dis- tribution of pregnancies by number of months required for conception, or even conception rates per 100 woman-years of exposure. None of these measures is satisfactory. The first completely neglects the duration of follow-up. The second ignores the women who did not conceive. The third fails to take into account that the conception rate declines with time. The closest approximation to the life table is the percentage of women who conceive during the first cycle after discontinuation. Some such figures have been reported, but they are so far out of line with earlier experience as to raise serious questions as to the completeness or accuracy of the information furnished to the investigators by their informants (67, 130, 169). Pregnancy outcome was deemed satisfactory in these studies with no signifi- cant increase in abortion, prematurity, or developmental anomalies (9, 140). Continued study of this problem should be undertaken, however, since as noted below, there is evidence from laboratory animals that the suspension of ovula- tion is associated with fetal anomalies once fertility is restored. Suppression of ovarian function secondary to pituitary suppression by oral contraceptives is evidenced by low estrogen excretion during treatment (107, 115). Flowers and associates (53) found estrogen levels during prolonged use of oral contraceptives to be much lower than those in normal cycles. The endometrium was found to be atrophic with reduced enzymatic activity. Whether oral contraceptives have direct ovarian suppressive effects is con- troversial. One group (84) gave contraceptive steroids to amenorrheic women; their subsequent response to human gonadotropins showed no inhibition of the ovarian reaction. This observation supports the contention that the major suppression is at the hypothalamic level. Direct effects of oral contraceptives on ovarian weight and on histological and ultrastructural changes are sug- gested by some studies (172). Oral contraceptives in higher doses (5 and 10 mg. of progestins) tend to decrease or stop lactation in many women in the first or second cycle of use (141, 149). Smaller doses are reported to have no significant suppressive effect on lactation (86), but radioactive tagged norethynodrel is excreted in breast milk (101). PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6897 REPRODUCTIVE TRACT Virtually all structures of the reproductive tract are sensitive to the action of ovarian steroid hormones. It is not surprising, therefore that alterations are seen in the various components under the influence of steroid contraceptive agents. Differences depend upon the type and quantity of the compound used, the mode of administration, and the duration of use. Vaginal cytologic effects are not remarkable but there is a shift toward basophilia with a predominance of intermediate cells during treatment with progestational agents (181). A distinct change is noted in the bacterial flora, with marked reduction in Doderlein bacilli, a remarkable increase in fungi, and a greater number of coccoid bacteria and trichomonads. Such alterations may be related to the increased sexual activity thought by some to occur in certain women who elect to use oral contraceptives. Progestational compounds indice characteristic physicochemical changes in the cervical mucus (21, 118), including decreased viscosity, poor Spinnbarkeit, absence of arborization, a continuous alkaline pH with no tendency toward an increase in pH at midcycle, and the secretion of a viscous and cellular mucus that is hostile to sperm, as shown by inhibition of penetration and migration of spermatozoa in most treated subjects. With medication there is no cyclic variation in the content of proteins and no trend toward a specific ratio of the major proteins. In the normal cycle, however, a marked decrease in the albu- min level and an increase in the mucoid level is noted immediately before and concomitant with ovulation, with reversal of this ratio shortly after ovulation. Inhibition of motility and of penetration of cervical mucus by sperm is demonstrable at all dosage levels of these oral contraceptives but these effects are less pronounced when small doses of progestins alone are used (112). Biochemical changes in cervical mucus have not been extensively explored. The alpha-amylase content is increased more markedly after combined than after sequential therapy (71), and the glycogen content of the ectocervix is unaffected by steroid contraceptibes in women. Remarkable morphologic changes induced by progestational hormones have been described (59, 109, 168). Hypersecretion and hyperplasia of the cervical glands, stromal edema, and increased vascularity are the most consistent responses. In Gall's (59) study of 103 randomly selected women receiving oral contraceptives for periods of 1 to 60 months, gross lesions that failed to stain with Schiller's solution were noted in 84 per cent of patients: examined. Endo- cervical erosion or eversion, edema, and softening were the main features. His- tological examination showed an inflammatory infiltrate consisting. ~predomi- nantly of plasma cells. Fibrin thrombi were observed in the capillaries and arterioles in about 50 per cent of the biopsy specimens. Atypical polypoid endocervical hyperplasia was found in three cases. This latter lesion was first described by Taylor and associates (168) in 13 women (median age of 25 years) receiving low-dosage progestational agents. There had been no previous reports of such lesions in women on high-dosage birth control pills. All lesions were associated with an inflammation and they disappeared after discontinuation of the drug. Reversibility of the lesion in cases studied emphasizes the importance of recognition in order to avoid an erroneous diagnosis of adenocarcinoma. The histologic appearance of the endometrium varies considerably with the type of steroid regimen employed, although prolonged administration tends to diminish these differences (45, 139, 142). Combined therapy is associated with a shortened period of proliferation followed by an early but brief and limited secretory activity in the epithelium of the endometrial glands. Thinning or regression of the endometrium takes place after a few cycles and may be so severe that withdrawal bleeding cannot occur. Prolonged periods of amenor- rhea following cessation of treatment may result in part from this action of progestational agents. It is not yet clear whether this oversuppression affects primarily the endometrium, the ovary, the pituitary, or the hypothalamic cycle of gonadotropin-releasing-factors (53, 58, 153). Endometrial effects during sequential treatment are less pronounced. The progestin induces a partial or early secretory pattern comparable to that of the 18th or 19th day of the cycle, but development of the spiral arterioles is suppressed (123). Histochemical studies of endometrial tissues have provided some information 40-471 O-70--pt. 17-5 PAGENO="0066" 6898 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY about changes in enzymatic activity during treatment. Acid and alkaline phos- phatases and DPN diaphorase, which are clearly hormone-dependent, are greatly reduced (53). Alterations are demonstrable in activity of carbonic anhydrase, uterine peroxidase (170), beta glucuronidase, succinic dehydrogen- ase, lactic dehydrogenase, and several other enzymes (35). However, accurate appraisal of the changes described must be deferred because of deficiencies in standard values. Myometrial hypertrophy, dilatation of sinusoids, and edema are recognized effects. Congestion and increased vascularity of tissues are noted during pelvic surgery when oral contraceptives are not discontinued for a sufficient period of time prior to operation (145). Uterine myometrial activity is not significantly changed during treatment, but if medications containing both estrogen and a progestin are used, an increase in contractility is noted on the 8th day after the medication is stopped (15). Little is known regarding the effects of oral contraceptives on the rate of tubal transport of ova in women. Chang (32, 33) demonstrated that ovum transport was accelerated in animals given progestational agents and that early arrival of ova in the nuterus led to failure of fertilization, and to degen- eration and expulsion of eggs from the uterus. He noted also that transport and capacitation of sperm were disturbed, but these effects were less pro- nounced than rapidity of ovum transport in the animals studied. Zanartu (189) found a few motile sperm in the uterus of treated subjects undergoing opera- tions but none in fluid recovered from washings of the fallopian tubes. He therefore suggested that continuous dosage of chlormadinone prevents ascent of spermatozoa. Suppression of ovulation is one of the most consistent although not invaria- ble effects of steroid contraceptive agents. The ovaries appear grossly small and inactive (145). A few early follicles may be seen beneath the tunica but as a rule no corpora lutea are observed. Ostergaard and Starup (126) reported fresh corpora lutea in six women treated during the cycle in which laparotomy was performed; in most cases these corpora lutea were smaller than normal and they were not associated with elevated pregnandiol levels. Total absence of corpora lutea during treatment is reported in other studies in which culdos- copy was performed (8) and during abdominal operation (145). In Ryan's study (145) focal areas of cortical stromal fibrosis were observed in about half the patients on medication for one year or more. It is of particular concern that in this study thrombi were seen in the ovarian and uterine veins in three of the 27 study cases, but the significance of these observations cannot be assessed until data on control subjects are available. LIVER Moderate changes in liver function tests are seen in many symptom-free women on oral contraceptives. BSP (sulfobromophthalein) excretion is dimin- ished with almost all oral contraceptive drugs in up to 40 per cent of women on medication. This effect appears to be dose-dependent (4, 92) and may be related to a fall in serum albumin concentration seen with the use of oral con- traceptives (38). Plasma amino acid levels also fall with the use of these agents (37). BSP is retained in plasma primarily conjugated to albumin, and its reten- tion with oral contraceptives is related to the concomitant alteration in bile transport seen with the use of these agents. Such an effect is produced by all agents that have an alkyl group at the 17-alpha position of the steroid mole- cule. It is thought to result from inhibition of the glucuronyl transferase system, which participates in the metabolism of bilirubin. Another commonly observed alteration in liver function is elevation in trans- aminase values in 20 per cent of patients (50, 100). An increase in SGOT also occurs (99), and in a small proportion of subjects a slight elevation in alka- line phosphatase levels is found. After cessation of treatment, all of these values return to normal over a period of time. These effects are more severe in postmenopausal women. For instance, in two studies BSP retention appeared to occur in most such women on oral contraceptives, and an increase in SGOT was almost universal. In these women, the tests also return to normal after the cessation of treatment. Jaundice occurs in about one woman in 10,000 on oral contraceptives (124). Many patients have a typical history of nausea, malaise, and itching with PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6899 onset several weeks after medication is begun. Shortly thereafter they become jaundiced and they produce dark urine. Liver function tests show increased levels of bilirubin and moderately elevated levels of transaminases. Liver biop- sies show canalicular and hepaticocellular bile stasis. Liver tests in most patients with this condition revert to normal within several weeks after the cessation of therapy. In a few, however, abnormal liver function tests persist for longer periods. Schaffner (151) has divided patients who become jaundiced with oral contra- ceptives into three groups. The first group includes women who have recurrent cholestasis of pregnancy; the jaundice in these patients may result from an idiosyncrasy of the liver to the agents. The second group of patients includes those who have cholestasis without evidence of cellular damage or hypersensi- tivity; a similar effect is produced in the jaundice associated with anabolic steroids, probably a direct action of the oral contraceptives on the bile secre- tory apparatus. The third group shows cellular injury or sensitivity to the drug. Several studies (147) have shown that in some experimental animals, as well as the human being, the inhibition of bile transport seen with oral contra- ceptives is largely an effect of estrogen. Clinical studies have confirmed this concept, and recent investigations of low doses of progestins alone as contra- ceptives have shown little or no effect on bile transport or BSP excretion. The oral contraceptives affect numerous enzyme systems other than those already mentioned (135). Among other effects are increases in activity of beta-glucuronidase and isocitrate dehydrogenase activities and decreases in activity of lactic dehydrogenase, alkaline phosphatase, and transaminase activi- ties. Alteration in the serum naphthylamidase isozymes is thought to be one of the most sensitive indicators of disturbances in liver function caused by oral contraceptives (6). Stoll and coworkers (165) found a correlation between increases in the level of glutamic oxalacetic transaminase and the histological demonstration of damage to liver cells. They believe that. this effect is caused by the progestin rather than the estrogen in the oral contraceptive. Recent reports (29, 154) that oral contraceptives increase ceruloplasmin-oxidase levels reflect the well-established observation that estrogen alone has this effect (57). The recently observed apparent enhancement of hypertension by oral contra- ceptives in certain women may come about in part through the increase in serum-renin substrate levels. The estrogens in oral contrceptives may exert this effect by stimulation of the hepatic biosynthesis of this enzyme. Oral con- traceptives also increase aldosterone levels. Such alterations have been postu- lated to compromise the ability of the renin-angiotensin-aldosterone mechanism to respond to' normal physiological stimuli (97). Another effect of the estrogen in oral contraceptives on enzyme systems con- cerns that metabolism of cortisone. It decreases the ability of the liver to extract cortisol from the blood (148) and is possibly related to the decrease in urinary excretion of cortisol and its metabolites (129) that results from administration of estrogen Sandberg has postulated that the progestins may also participate in displacing cortisol from transcortin. Although the true sig- nificance of these effects is unknown, their relation to pituitary function in particular should be investigated. Several studies have demonstrated the effect of oral contraceptives on ami- nolevulinic acid (ALA) synthetase, an enzyme that participates in the produc- tion of heme. The enzyme is normally produced at a low rate by liver cells. Oral contraceptives have been shown to increase ALA synthetase levels as well as urinary coproporphyrin in a significant proportion of healthy women (26). The relation between this finding and the observation that oral contraceptives protect women with acute intermittent porphyria from attacks, is of considera- ble interest (127). The effects of oral contraceptives on ALA synthetase may also be related to interference by oral contraceptives with the metabolism or detoxification of certain drugs. Their effect on ALA synthetase and on P45O-cyt~chrome, a hemo- protein located in the endoplasmic reticulum of the liver cell, may be related to alteration by oral contraceptives of the capacity of the liver to transform drugs into biologically inactive substances. Oral contraceptives appear to increase the detoxification of meperidine but to decrease the detoxification of normeperidine, a metabolic degradation product. PAGENO="0068" 6900 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY These effects on detoxification are not the result solely of the enxyme-induc- ing potency of these drugs, since steroids are known to serve as substrates for the microsomal drug-metabolizing enzyme system in the liver. The drugs, therefore, compete with various exogenous substances for oxidative transfor- mation by the enzyme system. The dual role played by sex steroids as both inducers and competing substrates makes it difficult to analyze the effect of oral contraceptives on the ability of the liver to detoxify specific agents (85, 89). A recent review (143) of the hepatic toxicity of oral contraceptives con- cludes that these agents produce their effects through modifying permeability of the liver cell rather than causing parenchymal cell damage and that their use is probably not detrimental to the hepatic function of otherwise healthy women. CARBOHYDRATE METABOLISM Ovarian steroid hormones have been known for some time to modify carbo- hydrate metabolism. Early workers reported a decrease of glucose tolerance in diabetic animals treated with estrogen, but others (79, 80) demonstrated amel- ioration of diabetes in estrogen-treated rats; they attributed this effect to the induction of islet cell hyperplasia. Similarly, in human subjects, contradictory effects of gonadal steroids on carbohydrate metabolism are reported. Several (54, 167)) have shown that estrogens may lower the fasting blood sugar levels by as much as 20 per cent and that individuals with onset of diabetes in maturity may show lower insulin needs when estrogens are given. i~Iore recent work (82) has shown that estrogens such as mestranol, administered alone as well as in combination with norethynodrel, can cause a decrease in glucose tol- erance. Androgens generally produce deterioration of carbohydrate metabolism in mammals (54, 96). Explanation for these inconsistencies appears to depend on the chemical structure of the compound, the amount administered, and the individual sensi- tivity to the metabolic actions of these agents (12). The preponderance of evidence indicates that glucose tolerance is diminished in women taking oral contraceptive drugs (61, 129, 132, 133, 157, 159, 186). Evidence of the abnormality is more pronounced with the oral than with the intravenous test. Similar findings with respect to greater frequency of abnor- mality in the oral, compared with the intravenous, test are seen in gravid women (16). The impairment of glucose tolerance is more pronounced in women predis- posed to diabetes and in those with latent or overt diabetes. These effects are well recognized in association with pregnancy. In studies in which a compari- son can be made between the diabetogenic influences of pregnancy and oral contraceptives, the so-called diabetogenic effects of the drugs were shown to be of a lesser degree (12). In nondiabetic subjects increased insulinogenesis is observed following both short-term and long-term use of oral contraceptives (159, 160). Effects are more pronounced with combined than with sequential regimens. In long-term use, the tendency is for glucose tolerance to return to normal while insulin levels remain elevated, suggesting that hyperinsulinism may serve as a com- pensatory mechanism for maintaining homeostasis of glucose. Wynn and Doar (185) tested 67 subjects before and during oral contracep- tive therapy (Group A) and 24 subjects during and after treatment (Group B). Glucose tolerance decreased significantly in approximately three-fourths of the subjects in Group A and improved in virtually 100 per cent of Group B after treatment was stopped. In contrast, there was a significant elevation of plasma insulin levels during therapy in Group A subjects in response to a glu- cose load, whereas insulin response was not significantly different in Group B subjects on or off treatment. These findings support the concept that increased insulinogenesis is essential for prevention of hyperglycemia in subjects receiv- ing steroid contraceptives and raise the question of the capacity of pancreatic islet cells to sustain hyperactivity during long-term use of these agents. In latent diabetic subjects or in women with overt diabetes, insulin response to steroidal contraceptive agents appears to depend upon the functional state of pancreatic beta cell activity. Gershberg (62) found a transient rise in immunoreactive insulin secretion in potentially diabetic patients during the first two months of treatment with oral contraceptives, but after three months glucose tolerance was impaired and insulin secretion returned to initial levels PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6901 despite hyperglycemia. In women with overt diabetes, glucose tolerance deterio- rate promptly and immunoreactive insulin levels decreased at the half-hour and one-hour periods of the test. Gold and his associates (64) showed that oral contraceptive-induced hyper- glycemia demonstrable both during fasting and after glucose loads was accom- panied not only by increased secretion of insulin but also by a significant increase in resistance to exogenous insulin. These findings accentuate the hyperglycemic potency of steroid contraceptives more strikingly than do stud- ies performed in nondiabetic subjects. Whether prolonged administration of steroid contraceptives can result in exhaustion of the insulinogenic reserve and thus induce diabetes in women who are not genetically predisposed has not yet been ascertained. Growth hormone secretion is known to be influenced by sex steroids. Frantz and Rabkin (56) demonstrated an elevation in HGH levels in response to estrogen, and Spellacy (156) showed significant increases also during a hypo- glycemic stimulation test after administration of oral contraceptives. Gershberg (62) found elevation in potentially diabetic subjects of HGH levels that increased progressively during three months of treatment with medroxypro- gesterone acetate. The importance of persistent elevation of HGH produced by oral contraceptives is unknown. A causal relation might be postulated between the increases in HGH and induced hyperglycemia and between increased insu- un resistance and compensatory increases in circulating insulin. Blood pyruvate levels are strikingly increased during oral contraceptive treatment. Elevated levels are demonstrable in the fasting state and after either oral or intravenous glucose tolerance tests in both obese and nonobese subjects (46). These effects can be produced with estrogen alone. The question of whether this is a direct effect of the estrogens or an effect secondary to increases in other circulating hormones such as cortisol, growth hormone, and thyroxin has not been ascertained. These investigators (46) also studied the venous lactate-pyruvate ratio during infusion of sodium 1 (+ ) -lactate solution. Since conversion of lactate to pyruvate is obligatory for lactate metabolism, infusion of the stable solution was used to provide information about whether elevated levels of blood pyru- vate and lactate in patients on oral contraceptives resulted from an increased rate of production or impaired removal of these metabolites. Close correlation of fasting blood lactate levels and the calculated endogenous production rate of lactate was observed in women on oral contraceptives and in controls, sug- gesting an increased rate of production. The authors further suggest that these metabolic alterations are caused by increased cortisol activity, probably at the hepatic level. Substantial increases in plasma triglyceride levels are demonstrable during treatment and they remain elevated for months after discontinuation in long- term administration (60). This effect may have some bearing on the increases in plasma insulin levels previously described. In preliminary reports; Wynn and Doar (187) suggested that there was a slight increase in the nonesterified fatty acid levels in patients receiving progestational agents; in a subsequent study (186), however, with better matched controls, the same investigators found no significant differences in NEFA levels that could be related to treat- ment. THYROID FUNCTION In women receiving combined steroid contraceptives the PBI level is ele- vated approximately 25 to 40 per cent above pretreatment levels. Thyroxine- iodine (T4 by column chromatography) values are similarly increased and T3 resin uptake values are diminished. All demonstrated changes appear to result from estrogen-induced increases in thyroxine-binding globulin (TBG). A signif- icant rise in the PBI can be induced with ethinyl estradiol in amounts as small as 0.01 mg. (3). Progestational agents alone do not alter the PBI or the triiodothyronine red blood cell uptake (77). All of these effects can be explained on the basis of increased protein-bind- ing induced by estrogen. The basal metabolic rate, cholesterol levels, and 1-131 uptakes remain within normal limits. Concentrations of "free" thyroxine remain within normal range, suggesting that the functional status of the thy- roid is unchanged (69). In addition, a normal response of the thyroid gland to small doses of TSH is maintained in patients on prolonged cyclic combination therapy (110). PAGENO="0070" 6902 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Within two to four months after cessation of treatment, thyroid function tests are normal. Development of thyroid adenomas, hyperthyroidism, and hypothyroidism have not been reported. ADRENAL FUNCTION Alterations in adrenocortical function tests observed in patients on combined steroid contraceptives seem to result chiefly from the estrogenic properties of the drugs; there is no evidence of interference with normal pituitary-adrenal relations. Increased protein-binding of aldosterone and cortisol by transcortin (cortisol-binding globulin) is found. Levels of plasma cortisol are increased and the clearance rate of its urinary metabolites is decreased (48, 148). The conclusion that the marked reduction in urinary 17-ketosteroid and 17-keto- genic steroid excretion rates results from impairment of pituitary-adrenal function is based on the reduced response to the metyrapone test during administration of oral contraceptive agents (105, 116). This finding suggests a lack of compensatory increase in pituitary ACTH secretion. The response to the ACTH stimulation test, however, is essentially normal. Furthermore, in the Piromen test, in which the increase in plasma and urinary levels of cortisol and its metabolites presumably results from ACTH secretion, a normal response in the release of ACTH is reported. Although there are discrepancies among these various studies of the effects of oral contraceptives on adrenal function, there is no evidence to date of adrenocortical insufficiency during surgical procedures or other stress in patients on contraceptive drugs. A possible exception is one clinical report of severe adrenocortical insufficiency associated with the use of oral contracep- tives (42). BLOOD VESSEL5 Information regarding the effect of contraceptive steroids on the venous system is limited to clinical observation of increases in the diameter of venous vessels and in venous volume. It remains to be elucidated whether this increase in caliber of the vessels may lead to endothelial injury and exposure of blood to collagen and to the basement membrane. Goodrich and Wood (68) found a significant increase in the distensibility of veins in the calf following administration of contraceptive steroids. This increase was present over the range of venous pressure studied, namel~r between 5 to 30 mm. mercury and was accompanied by a 25 per cent reduction in mean linear velocity of venous blood flow. The concentration of angiotensinogen in plasma appears to change consist- ently following administration of contraceptive steroids. Values up to eight times those of normal have been reported. The rise is observed within 4 days, usually reaching a maximum within 2 weeks. After discontinuation of medica tion the level may remain elevated for more than a month. Changes in the concentration of renin are less consistent. It appears that the normal response to an elevation of angiotensinogen is a decrease in renin con~ centration, suggesting a mechanism of auto-regulation. Because the quantity of angiotensin that can be generated is limited, a large increase in the concentra tion of angiotensinogen is accompanied by only a twofold increase in angiotensin. The clinical implications of these changes in the concentrations of angioten- sinogen, renin, angiotensin, and aldosterone remain to be elucidated, since the changes are observed in most patients without a concomitant rise in blood pressure. No information is available at present regarding factors predisposing to the adverse effect of contraceptive steroids. They may include renal disease and an increased sensitivity to retention of sodium and water. According to present information, increases in blood pressure of susceptible women caused by contraceptive steroids are reversible even after prolonged use of the drug. It should be noted that elevation occurs in both systolic and diastolic pres- sures. It has been suggested that venous hypertension may distend the endothelium of the valve pockets to the point at which injury occurs. Thus, it would be desirable to obtain measurements of venous pressure in peripheral veins in patients on contraceptive steroids and to ascertain whether usual physical ~ictivities lead to exceptional increases in venous pressure in excess of those observed in control subjects. PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6903 BLOOD PRESSURE Estrogen and other contraceptive steroids are known to alter the concentra- tion of substances thought to be important in the regulation of blood pressure. There are now several reports of hypertension associated with the use of oral contraceptives (97, 171, 183). Increase in plasma angiotensinogen following administration of estrogen was reported several years ago (75). More recently, elevated levels of plasma renin were found in normal pregnancy (24), and estrogen and progestin were found to increase the secretion of aldosterone (104). In addition, oral contraceptives are now known to enhance the reactiv- ity to endogenous renin (97, 98). It appears, therefore, that susceptible women may experience an increase in blood pressure following administration of contraceptive steroids. Because of the high prevalence of hypertension in the population it is difficult to identify with certainty the women in whom administration of contraceptive steroids has led to an increase in preexisting hypertension or has produced hyperten- sion in previously normal women. Several cases, however, have been reported in which the etiologic relation has been established beyond reasonable doubt (97). BLOOD CONSTITUENTS Many studies (6, 7, 22, 29, 95, 102, 120, 135, 137, 158, 160, 173) have been reported describing the effect of contraceptive steroids and allied agents on plasma proteins and their metabolism. Their administration leads to decreases in haptoglobin, albumin, and total serum proteins, and dose-dependent increases have been reported for thyroxine-binding globulin and iodine-binding protein. Increases have also been reported for plasminogen, ceruloplasmin, estrogen-binding proteins, C-reactive protein, renin, factors VII and IX, fibrino- gen, beta-glucuronidase and isocitrate dehydrogenase (6, 7, 102, 120, 158, 173). Only a few constituents are decreased by administration of estrogens: lipopro- tein lipase, cholinesterase, lactic acid dehydrogenase, and alkaline phosphatase (23). LIPIDS Contraceptive steroids are known to increase the concentration of triglycer- ides and phospliolipids, particularly lecithin, in the plasma of women (188). The principal effect is on the lipoproteins of very low and high densities. Hypertriglyceridemia has been consistently found to accompany the use of these agents; the responsible component of the contraceptive preparation appears to be the estrogen rather than the progestin. According to presentl~r held views, the site of action of estrogens upon tri- glycerides or lipoprotein synthesis is the liver. Since lipid synthesis requires insulin, it is possible that changes in lipid output are mediated via the effect of estrogens upon plasma concentration of insulin (136). Estrogens have also been implicated in modifying the removal of these lipids from the circulation. It has been demonstrated that the rise in lipolytic activity of plasma brought about by administration of heparin was decreased following administration of estrogens (73a). Although changes in plasma lipids and lipoproteisn are appreciable following the administration of contraceptive steroids, there is no knowledge of the func- tional significance of these changes. No specific clinical disturbance has yet been attributed to the alterations in lipid and lipoprotein composition. SALT AND WATER METABOLISM The effects of oral contraceptives on water and electrolyte metabolism have not been studied in detail, but it is pertinent to describe the changes produced by individual steroids. For instance, progestin in approximately physiological doses causes a diuresis of sodium followed by retention even while the hor- mone is administered. The diuretic effect appears to predominate at higher dose levels, but it is not certain whether long-term progestin administration causes diuresis or retention of sodium. The short-term natriuretic effect of progestin is opposite to that of estra- diol-17 beta, which at high doses causes sodium retention. The effect of oral contraceptives on sodium excretion is sensitive to the proportions of its con- stituents. The overall effect, however, appears to be a decrease of sodium excretion (134). PAGENO="0072" 6904 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The effects of these hormones on water metabolism are complex. Water can be retained or lost in association with sodium, potassium, phosphate, and nitro- gen as part of anabolic or catabolic actions. Water can also be retained or lost in association with sodium and chloride in the expansion or contraction of extracellular fluid volume; these effects also are separate. Furthermore, the effects may be biphasic or even triphasic during hormone administration. MINERALS Several investigators (19, 65, 66) have shown no effect of oral contraceptives on levels or intestinal absorption of calcium, but a decrease in magnesium excretion has been demonstrated with a parallel decrease in serum magnesium levels. The data suggest that suppression of ovulation is associated with ~a poorly understood alteration in magnesium metabolism. Concern has been expressed over the observation that there is an association between soft water supplies and increased levels of cardiovascular disease in certain geographic regions. These interesting observations warrant confirmation. Oral contraceptives have also been noted to increase serum copper and zinc levels (29, 125), as well as serum iron and total iron-binding capacity (25). The significance of these observations is not known, but estrogens have been known for some time to increase serum copper and ceruloplasmin levels (57). KIDNEY In proportion to the widespread use of oral contraceptives, remarkably little is known about their effects on renal function. These agents have been shown in recent years to be the cause of hypertension in certain women and this effect appears to be mediated in part through alterations in the angiotensin- aldosterone-renin system. It may also be mediated in part through the develop- ment of asymptomatic pyelonephritis developing secondary to ureteral dilata- tion, which is known to occur with these agents. TJreteral dilatation is the only well-documented effect of oral contraceptives on the excretory system (111). Such dilatation disappears after medication ceases and it has been postulated to be due to progestins rather than estro- gens. Comparable studies in the rabbit (115) demonstrated no ureteral dilata- tion but did show that these agents result in the disappearance of elastic fibers from the ureters. LUNG Recent studies (108, 162) show that oral contraceptives and allied agents exert a variety of effects on the~ respiratory system. First, progesterone, through some unknown effect on the respiratory center, increases alveolar ven- tilation and produces decreases in the arterial pCO2. This effect is seen during pregnancy and in the luteal phase of the menstrual cycle. The presence of an ethinyl group on the progestin prevents this effect. Second, contraceptive ster- oids cause an increase of bronchial resistance; early work suggests that this effect may be mediated by an increase in histamine, a potent bronchial con- strictor. Third, estrogens alone appear to inhibit gas transfer to a small degree. Fourth, stilbestrol or ethinyl estradiol in large amounts will produce progressive pulmonary lesions characterized by an accumulation of macro- phages in capillaries, migration of macrophages to the alveolar interstitium and diffuse interstitial pneumonitis. Last, fibrosis of the pleura and the inter- stitial tissue of the lung was shown to develop after several months of treat- ment. The relation between these effects and those of oral contraceptives in women has not been elucidated. CENTRAL NERVOU5 SYSTEM Ovarian steroids are known to be essential to production of normal expres- sion of sexual behavior in female animals. In man evidence of the essential role of these substances in the control of sexual activity is still lacking. The few reported studies suggest that an increase in either sexual desire or sexual activity in women as well as Rhesus monkeys coincides with the days preced- ing ovulation, while the second half of the menstrual cycle is characteri~ed by a decrease or lack of sexual interest. One study (117) reports a reduction in male sexual behavior in subhuman primates attendant upon the administration to the female of both sequential PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6905 and combination contraceptive steroids, the effect being more pronounced with the latter. This remarkable effect is mediated through some unexplained mech- anism, possibly an alteration in female sexual pheromones. No definite conclusions can be drawn from data about the effect of oral con- traceptives on human sexual behavior. One study (122) indicates that libido was reduced or lost in about one-third of patients receiving oral contracep- tives. Other investigators (87, 88, 119, 176a), however, report an increased desire and greater satisfaction from sexual intercourse. In these situations it is difficult to separate the actual effect of the contraceptive steroid on sexual perceptivity from the effect brought about by an absence of fear of an un- wanted pregnancy. In lower species, progesterone is known to increase and estrogen to decrease the threshold for seizures induced by electric current (90, 164). The combina- tion of agents used as contraceptives tends to lower the threshold, and the effect appears to be dependent on the ratio of progestin to estrogen. The recently reported increase in frequency of epileptic seizures in patients with documented epilepsy in the immediate premenstrual period implies that the observations made in lowe~r species may be applicable to man (113, 176). No information is available regarding the relation between contraceptive ster- oids and central nervous system excitability. Pregnanolone, a metabolite of progesterone, is a potent hypnotic; in the cat it is more effective as a hypnotic on the basis of weight than is pentobarbital. On the other hand, several syn- thetic progestins such as norethynodrel have minimal hypnotic properties. The effect of contraceptive steroids upon thermoregulatory centers still remains to be elucidated. There is circumstantial evidence that at least proges- terone increases body temperature by a central action. The exact mechanism is not known. Depression has been identified as a side effect of contraceptive steroids, but its relative frequency varies markedly from study to study. Close examination of the data (7a, 62a, 69a) indicates that the depressive episodes encountered are usually not related to the pharmacologic effects of contraceptive steroids but are peculiar to the population under study. Brief periods of depression are not infrequent among young housewives with many small children. Depression is more frequently associated with women of higher educational background. Thus, one investigator (87) studying a small population in a pre- dominantly academic community in which the mean level of education was 15.4 years detected symptoms of depression in 34 per cent. In general, women who suffer from depression before and during the menstrual period seem more susceptible to depression while on contraceptive steroids. Recent observations (69a) indicate that depression and loss of libido are more likely to occur with compounds containing larger quantities of progestins and that the lowest incid- ence of these side effects is observed with the sequential preparations. The incidence in the former group was 28 per cent, whereas that in the latter was only 5 per cent. Another study (119) covering 72 clinic patients followed for 15 months reports no increase in depression attributable to the medication. The incidence of headache among patients attributable to contraceptive ster- oids ranges between 3 and 11 per cent (129a). This kind of headache often has features associated with migraine, and changes in the pattern of pre-exist- ing migraine headaches have been reported (180a). The tendency for migraine to occur when the concentrations of gonadal steroids change is well recognized. It is also known that women with pre-existing migraine headaches tend to develop their attacks while off medication, in contrast to patients without pre- existing headache who are more likely to complain of migraine headaches during the period of medication. It must be stressed that most studies have drawn their samples from selected populations, often with characteristics that make the evaluation of this side effect difficult if not impossible. Evidently, more studies are required to ascertain the true incidence of these phenomena. SKELETAL MATURATION In recent years there have been several reports of the use of estrogen to prevent excessive height in otherwise normal girls through the induction of premature epiphyseal closure. Both estradiol valerate (179, 180) and stilbestrol (177) have been used for this purpose, and the endocrinologic basis for this treatment has been reviewed (182). The effect is said to be mediated by direct PAGENO="0074" 6906 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY metabolic action of the agent on bone structure rather than through suppres- sion of growth hormone (179). Observations of this nature have led to concern over the possible effects of oral contraceptives on bone growth in young women in whom epiphyseal clo- sure has not yet taken place. There is not yet any evidence on which to base this conclusion. First, the use of estrogen even in much larger amounts than those in oral contraceptives is not uniformly successful in inducing epiphyseal closure. Second, there is no evidence that the progestin in oral contraceptives has any effect on bone maturation. Third, in order to be effective at all the estrogen treatment of excessive growth must be started prepuberally, consider- ably earlier than the age at which oral contraceptives are ordinarily used. SKIN Oral contracei~tives have been known for some time to produce chloasma, or melasma. Resnick (138) reported an extensive study of 212 patients, a high percentage of which developed melasma with both combination and sequential oral contraceptives. This condition differs from the melasma of pregnancy in that it does not seem to regress completely after medication is stopped. Eighty- seven per cent of Resnick's patients who developed melasma from oral con- traceptives had had this condition during pregnancy, suggesting that a history of increased skin pigmentation during pregnancy may be used as an indicator for detecting susceptible individuals. A more recent case report (155) describes a woman who developed excep- tionally marked melasma as well as areas of increased pigmentation of other parts of her body, suggestive of the pigmentation seen in Addison's disease. The authors ruled out this condition to their satisfaction and concluded that the effect was due to activity of melanocyte-stimulating hormone. It has been known for some time that oral contraceptives decrease sebum production, and that suppression of sebaceous gland activity can be directly correlated with improvement of acne (166). Erickson and Peterka (52) reported a single case of sensitivity of the skin to sunlight as a result of oral contraceptives; repeated studies in the same patient showed that the effect appeared to be caused by the estrogen. Another effect of these agents on the skin was described by Krane (113), who showed, in rats, that both estrogens and progestins decrease the collagen content of skin and increase its turnover. Progesterone in particular interferes with the generation of cross linkage and the maturation of collagen. Comparable studies have not been carried out in women. Other observations (36) suggest that oral contraceptives may produce a male-type partial alopecia in certain patients. Here again, there is insufficient evidence to confirm this observation (2). OTHER EFFECT5 Studies of the effects of oral contraceptives on the gastrointestinal tract are limited. Crean (39) reviewed the relation between endocrine secretions and gastriè function and described the decrease in severity of peptic `ulcer in women during pregnancy and during the administration of estrogens. Whether these effects occur with the administration of oral contraceptives is not known. A related observation concerns acute colonic lesions in a few women on oral contraceptives (1, 91, 174). The authors postulate that these lesions may result from thromboembolic phenomena. Goh (63) has reported a significant increase in chromosomal abnormalities, particularly breaks, in the peripheral lymphocytes of women on oral contracep- tives. Comparable changes in lymphocytes from male subjects were induced by incubating the lymphocytes with the serum of women on oral contraceptives. These effects disappear on discontinuation of medication. These observations have not yet been confirmed, but they may be related to the findings by Carr (28) of chromosomal abnormalities in abortuses collected from women who became pregnant after taking such agents. Other clincial phenomena that have been described in association with oral contraceptives include abnormal patency of the Eustachian tube (5), hyper- trophic gingivitis (10), myalgia (43), and positive LE cell test without evi- dence of collagen disorders (151a). Only one isolated report of the possible exacerbation of systemic lupus erythematosus by oral contraceptives (131) has appeared. PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6907 EFFECTS ON THE FETUS Several studies implicate oral contraceptive agents in masculinization of the external genitals of female fetuses during the first 16 to 18 weeks of inadvert- ent pregnancy. Masculini-zation varies with the compound, but is most pro- nounced with 19-nor compounds. Jacobson (81), who treated 385 pregnant women with norethindrone, observed maternal masculinization in 5.5 per cent of women and virilization in 23.7 per cent of female newborns. A comparison of the placental transfer of norethindrone dydrogesterone and medroxypro- gesterone showed that norethindrone is the most rapidly transferred (40) ; this is the compound most frequently implicated in masculinization by oral contra- ceptives. A report (24) of medroxyprogesterone therapy in 172 women in the first 12 weeks of pregnancy showed no evidence of genital tract alteration in male fetuses and slight masculinization in one female fetus; this observation may be related to the very rapid metabolism of medroxyprogesterone in the preg- nant woman and fetus (17). Feminization of the male fetus from the estro- genic component of oral contraceptives has not been a problem. It was not observed among male fetuses whose mothers had estrogen therapy in the criti- cal first 12 weeks of pregnancy (72). The experiments of Wharton and Scott (178) studying the effects of oral contraceptives on fetal rhesus monkeys appear to be unequivocal. Norethin- drone was given in large doses to pregnant monkeys (25 mg. per day for 5 days per week) from approximately the 30th day of pregnancy to full term. Eight of the ten fetuses were stillborn. All 5 females were virilized, and males showed a greater degree of cryptorchidism than expected. Six mothers treated with 50 mg. progesterone IM daily during the same period of pregnancy suf- fered no deleterious effects. All were delivered alive at term (3 males and 3 females) and none showed genital malformations. These observations indicated that progesterone was much less harmful than norethindrone, but clinical implications for women cannot be drawn because of the very large doses of norethindrone employed. Deleterious effects of several contraceptive steroids on the ova of rabbits have been described (31, 34, 41). One author (150) described minimal abnor- malities in external genitalia and infertility in female offspring of rats treated with a combination of norethynodrel and mestranol during pregnancy and lac- tation. Others (11) noted disturbances of meiosis and disorganized chromo- somes in ova of rats given norethynodrel. Animals that received norethynodrel throughout pregnancy showed reduced litters. There are no comparable data on effects of contraceptive steroids on ova or chromosomes in the human being or on the eventual fertility of human fetuses exposed to such steroids in utero. CONCLUSIONS AND RECOMMENDATIONS Oral contraceptives are an important and effective means of fertility regula- tion and family planning. For certain women they are undoubtedly the most effective method currently available. Nevertheless, it is evident that prepara- tions now in use have a multitude of effects on many organ systems and although it is not yet possible to draw definite conclusions about their effect on the health of women and infants, the use of these agents warrants close observation and surveillance. Effects of special concern include alterations in carbohydrate metabolism, the character and distribution of lipids, liver func- tion, protein metabolism and the development of hypertension as well as alter- ations in endocrine function. References 1. Anon. Colitis and contraception. New Eng J Med 278:452, 1968. 2. Anon. Oral contraceptives and alopecia. Brit Med J 1:593, 1968. 3. Alexander, R. W., and Marmorston, J. Effects of two synthetic estrogens on the level of serum PBI in men and women with atherosicerotic heart disease. J Clin Endocr 21:243, 1961. 4. Allan, J. S., and Tyler, E. T. Biochemical findings in long-term oral con- traceptive usage. I. Liver function studies. Fertil Steril 18 :112, 1967. 5. Allen, G. W., Abnormal patency of the eustachian tube. JAMA 200:142, 1967. PAGENO="0076" 6908 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6. Arturson, G., Beckman, L., and Persson, B. H. Alterations in serum naphthylamidase isozymes during treatment with oral contraceptives. Nature 214:1252, 1967. 7. Aurell, M., Cramer, K., and Rybo, G. Serum lipids and lipoproteins during long-term administration of an oral contraceptive (anoviar). Lancet 1:291, 1966. 7a. Bakker, C. B., and Dightman, C. R. Side effects of oral contraceptives. Obstet Gynec 28:373, 1966. 8. Balm, H., Wan, L. S., Steven, V., Franklin, R. R., and Goldzieher, J. W. Alterations of ovarian physiology subsequent to oral contraceptive therapy. Presented at AGOG, April 28, 1969. 9. Banks, A. L., Rutherford, R. N., and Coburn, W. A. Pregnancy and prog- eny after use of progestin-like substances for contraception. Obstet Gynec 26:760, 1965. 10. Barber, D. N. Oral contraceptives and dental care. Brit Med J 4:417, 1967. 11. Beaconsfield, P., and Ginsburg, J. Oral contraceptives and cell replica- tion. Lancet 1:592, 1968. 12. Beck, P. Effects of gonadal hormones and contraceptive steroids on glu- cose and insulin metabolism. Salhanick, H. A., Ed. Conference on meta~ bolic effects of gonadal hormones and contraceptive steroids. December 1-5, 1968. 13. Behrman, S. J. Which "pill" to choose? Hosp Prac 4:34, 1969. 14. Bell, E. T., and Loraine, J. A. Urinary steroid and gonadotrophin excretion in women following long-term use of oral contraceptives. Lancet 2:442, 1967. 15. Bengtsson, L. 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Liver-function tests during intake of contraceptive tablets in pre-menopausal women. Brit Med J 1:1416, 1965. 51. Eisenfeld, A. J., and Axelrocl, J. Evidence for estradiol binding sites in the hypothalamus-effect of drugs. Biochem Pharmacol 16:1781, 1967. 52. Erickson, L. R., and Peterka, E. S. Sunlight sensitivity from oral contra- ceptives. JAMA 203 :178, 1968. 53. Flowers, D. E., Vorys, N., Stevens, V., Miller, A. T., and Jensen, L. The effects of suppression of menstruation with ethynodiol diacetate upon the pituitary, ovary and endometrium. Amer J Obstet Gynec 96:784, 1966. 54. Foglia, V. G., Schuster, N., and Rodriguez, R. R. Sex and diabetes. Endo- crinology 41:428, 1967. 55. Food and Drug Administration: Report on oral contraceptives. 1966. 56. Frantz, A. G., and Rabkin, M. T. Effects of estrogen and sex difference on secretion of HGH. J Clin Endocr 25 :1470, 1965. 57. Frieden, E., and Osaki, S. Serum copper and oral estrogen. Science 163:959, 1969. 58. Friedrich, E. R. 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Endocrinology 79:411, 1966. 77. Hollander, C. S., Garcia, A. M., Sturgis, S. H., and Slenkow, H. A. Effects of an ovulatory suppressant of the serum PBI and red cell uptake of radioactive triiodothyronine. New Eng J Med 269:501, 1963. 78. Horowitz, B. J., Solomkin, M., and Edelstein, S. W. The over-suppression syndrome. Obstet Gynec 31 :387, 1968. PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6911 79. Houssay, B. A., Foglia, V. G., and Rodriguez, R. R. Production and pre- vention of some types of experimental diabetes by estrogens and cor- ticosteriods. Acta Endocr 17:146, 1954. 80. Ingle, D. J. The relationship of diabetogenic effect of diethyistilbestrol to the adrenal cortex of the rat. J Physiol 138:557, 1943. 81. Jacobson, B. D. Hazards of norethindrone therapy during pregnancy. Amer J Obstet Gynec 84:962, 1962. 82. Javier, Z., Gershberg, H. and Hulse, M. Ovulating suppressants, estrogens and carbohydrate metabolism. Metabolism 17:443, 1968. 83. Jeffrey, J. d'A., and Kiopper. A. I. Steroid contraceptives: A review. J Reprod Fertil Suppl. 4:81, 1968. 84. Johannisson, E., Tillinger, K. G., and Diczfalusy, E. Effect of oral contra- ceptives on the ovarian reaction to human gonadotropins in amenor- rheic women. Fertil Steril 16 :292, 1965. 85. Juchau, M. R., and Fouts, J. R. Effects of norethynodrel and progester- one on hepatic microsomal drug-metabolizing enzyme systems. Biochem Pharmacol 15:891, 1966. 86. Kaern, T. Effect of an oral contraceptive immediately postpartum on initiation of lactation. Brit Med J 3:644, 1967. 87. Kane, F. J. Psychiatric reactions to oral contraceptives. Amer J Obstet Gynec 102 :1053, 1968. 88. Kane, F. J., Daly, R. J., Ewing, J. A., and Keller, M. H. Mood and behavioural changes with progestational agents. Brit J Psychiat 113 :265, 1967. 89. Kappas, A., and Song, C. S. Sex hormones, the gastrointestinal tract and the liver: Introductory comments. Salhanick, H. A., Ed. Conference on metabolic effects of gonadal hormones and contraceptive steroids. December 1-5, 1968. 90. Kawakami, M., and Sawyer, C. H. Effects of sex hormones and antifertil- ity steroids on brain thresholds in the rabbit. Endocrinology 80:857, 1967. 91. Kilpatrick, Z. M., Silverman, J. F., Betancourt, E., Farman, J., and Lawson, J. P. Vascular occlusion of the colon and oral contraceptives: Possible relation. New Eng J Med 278:438, 1968. 92. Kleiner, G. J., Kresch, L., and Arias, I. M. Studies of hepatic excretory function: II. The effect of norethynodrel and mestranol on bromsulfal- em sodium metabolism in women of childbearing age. New Eng J Med 273 :420, 1965. 93. Krane~ S. Effects of estrogens and progestogens on collagen metabolism. Salhanick, H. A., Ed. Conference on metabolic effects of gonadal hor- mones and contraceptive steroids. December 1-5, 1968. 94. Labhsetwar, A. P. 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Acta Obstet Gynec Scand 45:537, 1967. 123. Ober, W. B. Synthetic progestagen-oestrogen preparations and endo- metrial morphology. J Olin Path 19:138, 1966. 124. Ockner, R. K., and Davidson, C. S. Hepatic effects of oral contraceptives. New Eng J Med 276:331, 1967. 125. O'Leary, J. A., and Spellacy, W. N. Zinc and copper levels in pregnant women and those taking oral contraceptives. Amer J Obstet Gynec 103 :131, 1969. 126. Ostergaard, E., and Starup, J. Occurrence and function of corpora lutea during different forms of oral contraception. Acta Endocr 57:386, 1968. PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6913 127. Perlroth, M. G., Marver, H. S., and Tschudy, D. P. Oral contraceptive agents and the management of acute intermittent porphyria. JAMA 194:1037, 1965. 128. Peterson, W. F., Steel, M. W., and Coyne, R. V. Analysis of the effect of ovulatory suppressants on glucose tolerance. Amer J Obstet Gynec 96:484, 1966. 129. Peterson, et al. 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The effect of oral contraceptives on serum enzymes. Acta Obstet Gynec Scand 46:525, 1967. 136. Reaven, G. M., Lerner, R. L., Stein, 1~I. P., and Farquhar, J. W. Role of insulin in endogenous hypertriglyceridemia. J Clin Invert 46:1756, 1967. 137. Reed, M. The effect of norethandrolone (Nilevar) on serum proteins in the female guinea pig. J Endocr 37:253, 1967. 138. Resnik, S. Melasma induced by oral contraceptive drugs. JAMA 199:601, 1967. 139. Rice-Wray, B., Arana-Rosell, A., Maqueo, M., and Goldzieher, J. Compari- son of the long-term endometrial effects of synthetic progestin used in fertility control. Amer J Obstet Gynec 87 :429, 1963. 140. Rice-Wray, B., Gonzalez, 0., Ferrer, S., Arana-Rosell, A., Maqueo, M. and Munguia, H. Central evaluation of norethindrone acetate in fertility control. Amer J Obstet Gynec 93:115, 1965. 141. Rice-Wray, E., Goldzieher, J. W., and Arana-Rosell, A. Oral progestin in fertility control: A complication study. Fertil Steril 14 :402, 1963. 142. Roland, M., Clyman, M. J., Dicher, A., and Ober, `~V. B. Classification of endometrial response to synthetic progestogen and estrogen compounds. Fertil Steril 15 :143, 1964. 143. Roman, W., and Hecker, R. The liver toxicity of oral contraceptives: A critical review of the literature. Med J Aust 2 :682, 1968. 144. Rooks, `~V. H. II, Kugler, S. L., and Dorfman, R. I. The relative expressed estrogencity of oral contraceptives. Fertil Steril 19:419, 1968. 145. Ryan, G. M., Craig, J., and Reid, D. E. Histology of the uterus and ova- ries after long-term cyclic norethynodrel therapy. Amer J Obstet Gynec 90:715, 1964. 146. Ryan, G. M., Goss, D. A., and Reid, D. B. Pituitary gonadotropins during long-term enovid therapy. Amer J Obstet Gynec 94:515, 1966~ 147. Salhanick, H. A., Kipnis, D., and Vandewiele, R. Metabolic effects of go- nadal hormones and contraceptive steroids. Plenum Press, NYC, 1969. 148. Sandberg, A. A., Rosenthal, E., and Slaunwhite, Jr., W. R. Certain meta- bolic effects of estrogens. Salhanick, H. A., Ed. Conference on meta- bolic effects of gonadal hormones and contraceptive steroids. 149. Satterthwaite, A. P., and Gimble, C. J. Contraception control with norethindrone: Progress report at Puerto Rico. J Amer Med Wom Ass 17 :797, 1962. 150. Saunders, F. J. Effects of norethynodrel combined with mestranol on the offspring when administered during pregnancy and lactation in rats. Endocrinology 80:447, 1967. 151. Schaffner, F. The effect of oral contraceptives on the liver. JAMA 198:1019, 1966. 40-471 0-70-pt. 17-6 PAGENO="0082" 6914 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 151a. Schleicher, E. M. L.E. cells after oral contraceptives. Lancet 1:821, 1968. 152. Shearman, R. P. Amenorrhoea after oral contraceptives. Lancet 1:817, 1968. 153. Shearman, R. P. Investigation and treatment of amenorrhoea developing after treatment with oral contraceptives. Lancet 1:325, 1968. 154. Shokeir, M. Oral contraceptives and caeruloplasmin activity. Lancet 2 :1192, 1968. 155. Sotaniemi, E., Kreus, K. E., Kaipainen, W. J. Pigmentation and oral con- traceptives, Brit Med J 2 :120, 1968. 156. Spellacy, W. N. The effect of ovarian steroids on glucose, insulin, and growth hormone. Salhanick, H. A., Ed. Conference on metabolic effects of gonadal hormones and contraceptive steroids. December 1-5, 1968. 157. Spellacy, W. N. A review of carbohydrate metabolism and the oral con- traceptives. Amer J Obstet Gynec 104:448, 1969. 158. Spellacy, W. N., Birk, S. A., Noer, K. A., and Schade, S. L. Sedimenta- tion rate in the normal menstrual cycle or with oral contraceptives. Minnesota Med 5:645, 1967. 159. Spellacy, W. M., and Carison, K. L. Plasma insulin and blood glucose levels in patients taking oral contraceptives. Amer J Obstet Gynec 95 :474, 1966. 160. Spellacy, W. N., Carlson, K. L. and Schade, S. L. Effect of sequential oral contraceptives on plasma insulin and blood glucose levels after 6 months' treatment. Amer J Obstet Gynec 101:672, 1968. 161. Starup, J., Sele, V;, and Buus, 0. pituitary-adrenal function in oral con- traception. Acta Endocr (Kobenhavn) 53 :1, 1966. 162. Stein, M., Rarabeih, A., Yasutake, T., and Hirose, T. Effects of gonadal hormones and contraceptive steroids on respiration. Salhanick, H. A., Ed. Conference on metabolic effects of gonadal hormones and contra- ceptive steroids. December 1-5, 1968. 163. Stevens, V. C., and Vorys, N. The regulation of pituitary function by sex steroids. Obstet Gynec Survey 22 :781, 19G7. 164. Stitt, S. L., and Kinnard~ W. 3. The effect of certain progestins and estrogens on the threshold of electrically induced seizure patterns. Neurology 18:213, 1968. 165. Stoll, B. A., Andrews, 3. T., and Motteram, R. Liver damage from oral contraceptives. Brit Med J 1:960, 1966. 166. Strauss, J. S., and Pochi, P. E. Effect of cyclic progestin estrogen therapy on sebum and acne in women. JAMA~ 190:315, 1964 167. Tallat, M., Habib, Y. A., Naby, S., Malek, A. Y., and Ibrahim, A. A. The effect of sex hormones on carbohydrate metabolism in normal and dia- betic women. Arch Int Pharmacodyn 154:402, 1965. 168. Taylor, H. B., Irey, N. S., Norris, H. J. Atypical endocervical hyperplasia in women taking oral contraceptives. 3AMA 202:637, 1967. 169. Tietze, C. Fertility after discontinuation of intrauterine and oral contra- ception. Int 3 Fertil 13 :385, 1968. 170. Townsend, 3. F., Hall, D. G., Cavazos, F., and Lucas F. V. Uterine perox- idase activity in abnormal human endometrium. Amer J Obstet Gynec 93:1013, 1965. 171. Tyson, J. E. A. Oral contraception and elevated blood pressure. Amer 3 Obstet Gynec 100:6, 1968. 172. Uhiarik, S., Hoffmeister, H., and Nooke, W. Studies of a possible direct effect of oral contraceptives on the rat ovary. Acta Endocr (Koben- havn) Suppl. 119:166, 1967. 173. Varga, L., Tiboldi, T., Varga, G., and Hegedus, Z. Effect of six months oestrogen and progesterone treatment on the serum proteins and pro- tein-bound carbohydrate compounds in rates. Med Pharm Exp 17:339, 1967. 174. Ward, G. W., and Stevensen, J. R. Colonic disorder and oral contracep- tives. New Eng J Med 278:910, 1968. 175. Weidenfeld, 3., Serr, D., and Finkeistein, M. Effect of 17 a-ethynyl-19- nor-testosterone on the urinary excretion of oesterone, oestradiol-171 and oestriol and of pregnanetriol in normal menstruating women and in oophorectomized patients. J Reprod Fertil 12:107, 1966. 176. West, 3., and West, E. D. The electroencephalogram and personality of women with headaches on oral contraceptives. Lancet :1180, 1966. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6915 176a. Westoff, C. F., Bumpass, L. and Ryder, N. B. Oral Contraception; Coital frequency and the time required to conceive. Soc Biol 16:1-10, 1969. 177. Wettenhall, H. N. B., and Roche, A. F. Tall girls assessment and man~ agement. Paed J 1:210, 1965. 178. Wharton, L. R., and Scott, R. B. Experimental production of genital lesions with norethindrone. Amer J Obstet Gynec 89:701, 1964. 179. Whitelaw, 1'~i. J., and Foster, P. N. Treatment of excessive height in girls: A long-term study. J Pediat 61:566, 1962. 180. Whitelaw, M. J., Foster, N. T., and Graham, W. H. Estradiol valerate: its effects on anabolism and skeletal age in the prepubertal girl. Endo- crinology 23:1125, 1963. 180a. Whitty, C. W., Hockaday, J. M., and Whitty, M. 1sf. The effect of oral contraceptives on migraine. Lancet 1 :856, 1966. 181. Wied, G. L., Davis, M. E., Frank, R., Segal, P. B., Meler, P., and Rosen- thal, E. Statistical evaluation of the effect of hormonal contraceptives on the cytologic smear pattern. Obstet Gynec 27:327, 1966. 182. Wilkins, L. Hormonal influences on skeletal growth. Annals NY Acad Sci 60 :763, 1954. 183. Woods, J. W. Oral contraceptives and hypertension. Lancet 2:653, 1967. 184. World Health Organization Technical Report Series 386: Hormonal ste- roids in contraception, 1968. 185. Wynn, V., and Doar, J. W. H. Fasting serum triglyceride and cholesterol levels during oral contraceptive therapy. Salhanick, H. A., Ed. Confer- ence on metabolic effects of gonadal hormones and contraceptive ste- roids. December 1-5, 1968. 186. Wynn, V., and Doar, J. W. H. Longitudinal studies of the effects of oral contraceptive therapy on plasma glucose, non-esterifled fatty acid, insu- lin and blood pyruvate levels during oral and intravenous glucose tol- erance tests. Salhanick, Ii. A., Ed. Conference on metabolic effects of gonadal hormones and contraceptive steroids. December 1-5, 1968. 187. Wynn, V., and Doar, J. W. H. Some effects of oral contraceptives on car- bohydrate metabolism. Lancet 2:715, 1966. 188. Wynn, V., Doar, J. W. H., and Mills, G. L. Effect of oral contraceptives on serum lipid and lipoprotein levels. Lancet 2 :720, 1966. 189. Zanartu, J., Pupkin, M., Rosenberg, D., Guerrero, R., Rodriquez-Bravo, R., Garcia-Huidobro, M., and Puga, J. A. Effect of oral continuous pro- gestogen therapy in microdosage on human ovary and sperm transport. Brit Med J 2:266, 1968. PAGENO="0084" PAGENO="0085" APPENDIX II ~DA~ REPORT ON TIlE ORAL CONTRACEPTIVES by the ADVISORY COMMITTEE ON OBSTETRICS AND GYNECOLOGY FOOD AND DRUG ADMINISTRATION * AUGUST 1, 1966 6917 PAGENO="0086" 6918 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MEMBERS Karlis Adamsons, M.D., Ph. D. Associate Professor of Obstetrics and Gynecology Columbia University, New York, N.Y. Elsie R. Carrington, M.D. Professor of Obstetrics and Gynecology Women's Medical College, Philadelphia, Pa. Eleanor H. Delis, M.D. Professor of Obstetrics and Gynecology Marquette University, Milwaukee, Wisconsin Nicholson J. Eastman, M.D., D. Sc., LL.D. Professor Emeritus, Obstetrics and Gynecology * Johns Hopkins University, Baltimore, Md. advisory Henry F. Fuller, M.D. Clinical Associate Professor of Obstetrics and Gynecology * University of North Carolina COiltifil ec Roy Hertz, M.D., Ph. D. Professor of Obstetrics and Gynecology On George Washington University, Washington, D.C. Philip E. Sartwell, M.D. b * Professor of Epidemiology O ~tet ~ ~Tohns Hopkins University, Baltimore, Md. Roger B. Scott, M.D. d Professor of Obstetrics and Gynecology all Western Reserve University, Cleveland, Ohio Christopher Tietze, M.D. g 1 g Director of Research Y neco 0 y National Committee on Maternal Health, New York, N.Y. Louis M. Hellman, M.D., Chairman Professor and Chairman, Obstetrics and Gynecology State University of New York, Brooklyn, N.Y. CONSULTANTS Philip A. Corfman, M.D. Reproduction Program National Institute of Child Health and Human Development, Bethesda, Md. Schnyler G. Kohl, M.D., Dr. P.H. Professor of Obstetrics and Gynecology State University of New York, Brooklyn, N.Y. Alfonse T. Masi, M.D., Dr. P.H. Associate Professor of Epidemiology Johns Hopkins University, Baltimore, Md. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6919 IN submitting this report on the oral contraceptives the Advisory Committee on Obstetrics and Gene- cology wishes to express its appreciation to the Commissioner of the Food and Drug Administration i'e ace and to his staff for their helpful and ever ready co- operation in arranging its meetings, submission of data, and preparation of reference material. The Committee is deeply indebted to the drug industry for the preparation of a thorough survey of the liter- ature on the oral contraceptives and for ready sub- mission of their own data. It is grateful also for the cooperation that made possible a survey visit to each of the drug firms concerned and an "on site" appraisal of their respective procedures. By such cooperative efforts alone can the public be made fully aware of the status of these compounds now so widely employed. PAGENO="0088" 6920 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page Members and Consultants of Advisory Committee on Obstetrics and Gynecology inside of cover Preface Introduction 1 Utilization Thromboembolic Disease 6 Carcinogenic Potential 6 Contents Endocrine and Metabolic Effects 9 Miscellaneous Adverse Experiences 10 Efficacy 10 Recommendations 12 Conclusion 13 Appendix TASK FORCE REPORTS (1) Thromboembolic Disease, N. J. EASTMAN 17 (2) Carcinogenic Potential, R. B. SCOTT 21 (3) Metabolic Effects, E. M. DELFS 33 (4) Efficacy, K. ADAMSONS SPECIAL REPORTS (5) Appraisal of Certain Problems Involved in the Use of Steroid 49 Compounds for Contraception, R. HERTZ (6) Review of the Procedures and Reports of the Pharmaceutical Com- panies Concerned With the Manufacture and Sale of the Oral Contraceptives, S. G. KOHL 61 (7) Pilot Study to Test Feasibility of Obtaining Valid Case and Control Data in Idiopathic Thromboembolic Disease, P. E. SARTWELL, A. T. MASS, J. W. LONG 71 PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6921 introduction THE oral contraceptives present society with ~ eutics. Never will so many people have taken sue P0 nt rugs voluntarily over such a pro- or an p ieciveo scan or a ,~Lo~iseas These compounds, further- more, furnish almost completely effective contra- ception, for the first time available to the medi- cally indigent as well as the socially privileged. These factors render the usual standards for safety and surveillance inadequate. Their neces- sary revision must be carefully planned and tested, lest the health and social benefits derived from these contraceptives be seriously reduced. Prob- ably no substance, even common table salt, and certainly no effective drug can be taken over a long period of time without some risk, albeit mini- mal. There will always be a sensitive individual who may react adversely to any drug, and the oral contraceptives cannot be made free of such adverse potentials, which must be recognized and kept under continual surveillance. The potential dangers must also be carefull balanced~gst Ihe hea t an social benefits that effective con- ~ society. The oral contraceptives currently in use are probably not those that will be employed 10 or even 5 years hence. Drugs with even less potentially adverse effect, utilizable in smaller dosage, will un- doubtedly be developed through continuing re- search. At present several such promising com- pounds are under investigation. The research essential to the development sncLtesting ofi~h~ ~ out by the drug industry working in close cooperation with the medical pro- ~ research and testing to be stifled by unnecessarily complicated, unscientifically harsh, and inelastic administrative procedures. It is axiomatic that all drugs must be carefully tested on several species of laboratory animals under comparable conditions before they can be given to human volunteers. It is equally important that the results of such exper- imentation be appropriately interpreted in extend- ing their: application to human beings. Partic- ularly in reproductive functions man differs from experimental animals and other primates. To deprive a population of drugs of great benefit by overattention to adverse effects based on animal data without due consideration of clinical experi- ence is unjustifiable. Throughout this report various types of adverse experience will be dis- cussed. Most of them, however, occur naturally, with a definite though low incidence in our popula- tion. ~he~data nemssary to demonstratenn in- crease in these naturally~oçcurring phenomena innong users of oral contraceptives are not avail i~i~ Most advers~eactions, inclii~j~eathi, have been reported as individual cases or small series. Except in carefully controlled studies, neither the total number of people exposed to the oral contraceptives nor the number of adverse re- actions in any locality is known. The crucial data are the numerator (adverse reactions) and the de- nominator (users) and a control made up of non- users having the same or a different number of adverse reactions. The difficulty of obt~pjqg such datn for the oral contraceptives makes unreli ~~y~ssumptions regarding a cause and e~ffqq~ relation hip pf drngimd adverse reacticia. There are, however, several epidemiological approaches which can shed light on the problem. The simplest and most obvious method is a system of surveillance leading to the reporting by physi- cians of suspicious illness in their patients who are taking the drug. Such a system is essential because it can give the earliest warning of trouble in a situation where quick action may be impera- tive. It should, however, be recognized that when the physician reports a suspected adverse reaction to a drug he usually cannot know with any cer- tainty that what he has seen is in fact an adverse reaction and not a coincidental happening. The major deficiencies of this system are: (a) Incomplete reporting by physicians of adverse experience for medico-legal rea- PAGENO="0090" 6922 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Sons, inertia, and lack of interest or awareness of the value of such data. (b) Selective or biased reporting of incidents which may reflect fashions in medical in- terest rather than the magnitude of a possible hazard. (c) The lack of a denominator population to evaluate the incidence of a possible ad- verse reaction. (d) The lack of control populations not ex- posed to the oral contraceptives to permit comparison of the incidence of possible complications in users and nonusers, to see if, in fact, any excess risk occurs in users. (e). The inability to detect potential long- term effects which might first appear after discontinuation of the oral contra- ceptives or even in the progeny of users. Of the more formal and reliable epidemiologic methods, the one selected should depend upon the type of suspected complication and its temporal relation to the use of the drugs. Prospective studies of users and nonusers are capable of test- ing for each type of complication; however, they are extremely difficult and costly to perform if the suspected complication is thought to be of rare occurrence or if it is expected to occur after a latent period of many years. The prospective method has the advantages that it permits simul- taneous study of all possible complications, in- cluding those which are initially unsuspected, and that certain biases are avoided. However, it doss not reduce the problem that the inferences must be based on observation rather sat differences in disease frequency between the groups of users and nonusers may result from dif- ferences in their initial composition dependent on whatever determines the employment of contra- ceptive methods. Efficient approaches to the principal possible types of complications are as follows: (a) Thromboembolic disease. Here the sup- posed complication is serious, readily recognized in at least some of its forms, and quite rare. It may presumably occur at any time while the drug is being used, but not after termination of use. A case-control (retrospective) approach is the most efficient; a series of cases, and of suitable controls, are chosen and the number of drug users in each group is determined in order to demonstrate as- sociation or independence between drug and disease. (b) Cancer. Here the suspected complication is `again serious and readily recognizable. The situation differs from (a) in two respects: The disease is common and only a small proportion of cases could be expected to be attributable to the drug; an~m re important, the la~gnt,pe~iod would be expected to be very long, frequenti extending un i a r e rmmation o drur use. spective stu y,wou1dbebestbut~ou~er~fldatad exceedingly difficult by the length of latency ~an variations in contraceptive methods emplo ad bL.~ woman over er repro uctive lifetime. The case- ~ of calendar time would also give promise, but no method is really efficient. (a) Diabetes or minor physiologic alterations such `as have been discussed in this report. Serial observations on adequate-sized groups of users and nonusers, incorporating whatever laboratory methods are required, will be needed. Many different compounds administered in slightly different fashions, constitute the available oral contraceptives. The basic mode of action of currently marketed compounds is similar, how-- ever, namely, the inhibition of ovulation and the initiation of periodic bleeding through with- drawal. The committee has therefore chosen to approach broadly the potential problems raised by the massive use of the whole group of effective estrogen-progestogen formulations. For this purpose, the committee has been divided into four task forces with specific assignments, each headed by a chairman, as follows: Task Forces 1. Thromboembolic Disease N. 3. EASTMAN, M.D., Chairman C. TIETzE, M.D. P. E. 5ARTWELL, M.D. A. MASS, M.D. 2. Carcinogenic Potential is. scorr, M.D., Chairman is. HERTZ, M.D. 3. Endocrine and Metabolic Effects E. DELFS, M.D., Chairman E. CARRINGTON, M.D. 4. Efficacy K. ADAM5ONS, M.D., Chairman H. FULLER, M.D. PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6923 The report of each task force has been carefully reviewed and approved by the committee as a whole. A summary of each report constitutes the body of the final report, while the complete reports are included in the appendix. In addition to the task forces, the committee appointed Schuyler G. Kohl, to visit the seven drug firms that manufac- ture these drugs and to review with the responsible personnel their data on adverse effects, deaths, and other pertinent material. Dr. Kohl's report, after review by the committee, was incorporated into the section on thromboembolism. It appears in its entirety in the appendix. A special pilot study to test an epidemiological approach to thrombo- embolic disease has been designed and completed by Dr. Sartwell's group. It is ssirninari~ed in the report mci appears in the appendix. 3 PAGENO="0092" 6924 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY utilization The pharmaceutical industry has estimated the numbers of `women taking oral contraceptives, based on the numbers of tablets distributed in the United States. The approach is straightforward: Since each user takes 20 tablets per cycle and the average woman has 13 cycles per year, the number of tablets sold, divided by 260, gives the average numbers of users during the year. The following estimates have been prepared by this method for the period 1961-65: 1961 408,000 1962 1, 181, 000 1963 2,235, 000 1964 3, 950, 000 1965 5,000,000 Another estimation has been made by Westhof and Ryder' of Princeton University in the study to be published shortly. Using a carefully selected and distributed sample of about 5,600 married women living with their husbands and under the age of 45, they derived the following estimates: Ever used: Using in late 1965 Used previously, may use again_ Will not use again _________ Never used: May use in future Will not use Never heard of it These estimates are in general agreement with those of the drug industry. The discrepancies in thetwo sets of data are accounted for largely by the group of women that uses the drugs for purposes `Westhof, C. F. and Ryder, N. Presented at the annual meeting of the Population Association of America on Friday, April 30,1966, New York City. other than contraception, the unmarried women, and those over 45. Another approach to utiliza- tion is furnished by investigations such as those of Dr. MeEvilla in Lawrence County, Pa. Through the cooperation of the physicians, the pharmacists, and the medical society of the county, every prescription for drugs of all kinds has been placed on a computer program that is capable of yielding data on utilization and adverse reactions with hitherto unavailable precision. In 1965 these data indicate that 7.4 percent of women in Law- rence County between the ages of 15 and 44 had never used oral contraceptive compounds. This figure is somewhat lower than the estimated na- tional average, probably because of the particular population sampled. Finally, based on the following assumptions, a rough estimate of future use of the oral contracep- tives in the United States can be made. Assum- ing (1) Series B. population projection,' (2) 46 percent of each cohort of married women starting oral contraception at the same rate as the women who were under 25 years of age in 1965, (3) no further changes to orals by older women, and (4) about 60 percent of ever-users are current users, the following table is derived: Projected Number of Women in Millions Using Oral Contraceptives in 1985 Year Total women Ever-users Current users 1970 43.3 46.9 10 13 6 8 1975 51.9 16 10 1980 56.4 19 12 1985 `Current Population Reports, Series P-25, No. 329, March 10, 1966. 3, 815, 000 1,341, 000 1,232,000 6,388,000 4, 676, 000 12, 794, 000 787, 000 18,257, 000 PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6925 There are divergent reports in the literature on the effects of the oral contraceptives on b]ood co- agulation. Unfortunately, however, hypercoagu- lability cannot be measured. Although many of the factors in the blood concerned with clot forma- tion may be ascertained, their elevation is not a measure of hypercoagulabiity. For example, although fibrinogen and factors VII-X are el- evated in pregnancy, thromboembolism occurs most commonly in the puerperium, when the levels of these factors have returned to normal. The most recent work on the response of blood coagulation factors to oral contraceptives indicated no statis- tically significant effect. Of greater concern are the deaths from thrombo- embolic disease. The deaths from idiopathic pulmonary embolism in women aged 15 to 44 in the United State.s appear to be of the order of 12 per million per year. The average annual death rate for women of the same age group from cerebral embolism and thrombosis is about 5 per million. From these data one might expect that, of the 5 million women estimated to be taking the oral contraceptives in 1965, there should be about 85 deaths from idiopathic thromboembolic disease. Kohl's report (appendix 6) disclosed 20 such cases from all causes, only 13 of which were idiopathic. There are two possible explanations for this apparent discrepancy: (1) The oral con- traceptives are protective against thromboembolic disease; (2) there has been gross underreporting. The second possibility seems to be the logical ex- planation, for the reported deaths fail to show the increment expected with the fivefold increase in use of the oral contraceptives from 1962 to 1965. The present system of reporting deaths and adverse reactions relies on either the cooperation of physicians or the haphazard filtering of rumors to detail men. The latter route is patently unreli- able, and the former not much better. Physicians are becoming increasingly fearful of reporting deaths or adverse drug reactions because of possible legal reprisal. The data derived from mortality statistics are not adequate to confirm or refute the role of oral contraceptives in thromboembolic disease. They do, however, suggest that if oral contraceptives act as a cause, they do so very infrequently relative to the number of users. The Committee believes, ac- cordingly, that the only way this i~iportant ques- tion can be answered is through large, carefully designed epidemiologic studies, such as those de- tailed in the appendix of this report. carcinogenic potential The committee directed its attention specifically to those lesions which were presumably related to the problem, but did not exclude the possibility of a relationship to other lesions. The available prevalence and incidence rates of cancer of the uterine cervix, cancer of the endome- trium, and cancer of the breast were reviewed in order to establish the expected rates for these can- cers in women. All of the published and submitted data on patients who have received any of the estrogen-progestogen combinations for contra- ceptive and therapeutic purposes over a period of time were reviewed. The animal and clinical studies published and some unpublished, using these hormones, or similar agents, as they relate to the production of cancer or of the influence on an existing cancer, a-ere studied. The following observations were made and conclusions drawn: Uterine Cervix: Dysplasia, carcinoma in situ, and invasive can- cer were considered. The importance of the geo- graphic, socioec'onomic, and ethnic factors of the population sampled was quite evident. For ex- ample, the prevalence of carcinoma in situ and invasive cancer in Puerto Rico was almost six times that of a metropolitan New York group consposed of women, for the most part, from a higher socioeconomic level. Another important factor was the average age of women showing throniboeinbolic disease PAGENO="0094" 6926 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY these changes: Roughly 95 years for dysplasia, 40 years for carcinoma in situ, and 47 years for invasive cancer. The data from the various study groups using contraceptive pills were difficult to analyze for the following reasons: 1. Patients with suspicious smears were ad- mitted to the study or in other instances the initial cytologic status was not stated. 2. The various methods of collecting cyto- logic specimens and the subjective factors in reading and reporting any changes make standardization of data difficult. 3. The frequent failure to record histologic followup after suspicion has been created on cytologic examination. 4. The concentration of contraceptors in age group below 35 yields such a low incidence of maliguancy that very large samples are necessary. 5. The relatively small number of patients followed regularly and thoroughly for 4 years or more. It is to be emphasized that all known hum~qç~~r cinogens require a laten r ima 1 one eca e. Hence any valid conclusion must await accurate data on a much mr er ovou of women stu ied for at least 10 years. Further- ~ the contention that contraceptive pills may protect against the development of carcinoma of the cervix. One possibly significant study sh'~wed an ap- preciable increase of coccoid bacterin, tricho- monads, and fungi in women using contraceptive pills. This alteration in the microorganisms of the genital tract might be related to the use of the pills and could account for some of the changes in cytologic reports. Endometrial Malignancy: End ometrkel carcinoma is primarily a disease of postmenopausal women and only 5 to 8 percent of the cases of this cancer occur before the age of 40. In the data submitted the paucity of endo- metrial biopsies as a routine followup procedure, the limited number of women more than 40 years of age, and the short duration, do not permit any conclusions relative to the effect, either adverse or beneficial, of these contraceptive pills on endo- metrial cancer. There are numerous studies that suggest an effect of a preponderance of estrogen, either endo- genous or exogenous, in women who subsequently develop endometrial adenocarcinoma. While a precise etiologic relationship has not been estab- lished, nevertheless, all women receiving estrogen therapy must be followed with care. Administra- tion of a progestogen periodically to women receiv- ing estrogen, in order to allow periodic "with- drawal" bleeding on the basis that it "prevents" endometrial cancer, is invalid both theoretically and on the basis of the very limited number of postmenopausal patients so treated. Itmust be re- membered, furthermore, that carcinolytic agents may also be potentially carcinogenic. Recent re- ports indicate that progestational compounds may exert a palliative effect on cancer, and adenoma- thus hyperplasia of the endometrium. While this matter is under study at several centers, there is no evidence, at present, that these compounds are curative. It must be remembered, further- more, that cancer-suppressing agents may also be carcinogenic. Breast Cancer The relationship of the oral contraceptives to breast cancer in the human being is unknown. The solution to this problem is made difficult for several reason-s as follows: (a) Contraceptors are predominantly in the lower age groups in which breast carci- noma is sufficiently infrequent as to neces- sitate very large samples for studies of early effects. (b) There are few long-term followup studies and none of sufficient duration to over- come the long h~ent period necessary to produce cancer in the human being. (c) Many studies simply do not state whether the breasts have been routinely examined. There are data that give contributory, although not very strong evidence to both sides of the question. For: There is experimental and clinical evidence that indicate a relationship between both endogenous and exogenous estrogen. There is experimental evidence that estrogens closely related to those used in the oral contracep- tives currently marketed will, when continuously PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6927 given to dogs and other animals, produce breast carcinoma. In many, but not all experiments the dosage was large on the basis of human therapy. Against: Although estrongens have been increasingly em- ployed for a long time and there has been increas- ing use of oral contraceptives for 6 years, there has been no increase in mortality from breast carcinoma. The FDA files contain only one case of breast carcinoma occurring in a patient taking oral contraceptives. Carcinoma of the breast is less prevalent in multiparous than in nulliparous women, although each pregnancy induces an elevation in endogenous estrogen. All this evidence has been carefully considered by the committee. At the present writing, it seems that if the oral contraceptives are at all carcinogenic for the human breast, they cannot be very potent and the occurrence of breast carcinoma from this cause must be extremely rare. Nevertheless, caution and prolonged surveillance are in order. Whenever the oral contraceptives are employed, not only the pelvic organs, but the breasts as well must be ex- amined at periodic followup. Other Cancers: Malignant lesions in the pituitary, kidneys, ovaries and bone marrow have been found in animals after treatment with certain sex hormones, but at present there are no human corollaries. Animal Studies: iSex steriods, particularly estrogens, have been shown to produce malignant lesions and to affect adversely the existing tumors in the mouse, rat, rabbit, hamster, and dog. These neoplasms have occurred in various organs, such as the cervix, endometrium, ovary, breast, testicle, pituitary, kidney, and bone marrow. The observations in animals given progesterone and the newer pro- gestogens have been contradictory; however, these agents clone and in combination with other sex steroids have promoted neoplasia or metastatic growth in a few instances. A recent example is a 5~-week study of six dogs that received massive doses of a combination of mestranol and ethyne- son (MK-665, an experimental progestogen). Four of the dogs developed mammary lesions; one was a carcinoma in situ with early invasion; the second was a carcinoma in situ; the third repre- sented atypical hyperplasia; and the fourth was a benign intraductal papilloma. Animal studies in which certain susceptible strains and species are used and in which the dosage is excessive and con- tinuous, cannot be directly transferred to human beings. There is, nevertheless, a warning that an altered endocrine environment in human tissues might result in an abnormal expression or potenti- ation of growth, as in experimental animals. Zn fact, there has always been the suspicion that ex- perimental animal and human tissues follow the same biological laws in this regard, but conclusive data are not available. A great difficulty in ob- taining a reliable answer involves the prolonged period of latency in human beings exposed to known carcinogens. Future epidemiologic studies must take full recognition of this fact. Statistical Considerations A substantial change in the incidence of certain diseases such as cancer may be difficult to detect even with very large samples. For example, in a study of the incidence of breast cancer with 4-year followup of women aged 20 to 39 years, a sample of about 15,000 to 20,000 women, or 60,000 to 80,000 person-years, would be required to have a reason- able (that is, 90 percent) chance of detecting (at the 95-percent probability level) a twofold increase in risk. Naturally a control group of almost sim- ilar size would have to be studied in order to de- tect this change. Changes in the incidence of cervical cancer could be detected with samples of about the same size; changes in the incidence of endometrial cancer would require samples about six to eight times as large as those for breast cancer. No studies approaching this magnitude have been reported. Since duration of exposure is a critical factor, only those women exposed for prolonged periods provide pertinent information. There are no scientific data to justify the imposi- tion of a time limitation for the oral contracep- tives. PAGENO="0096" 6928 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY endocrine and nietabolic effects Pituitary-Ovarian Function A considerable number of studies indicate that the oral contraceptives inhibit ovulation by a block at the pituitary level, specifically by inhibition of synthesis or release of LH. During such inhibi- tion, the ovaries tend to become smaller, and changes suggestive of cortical stromal fibrosis have been described. After cessation of the medication recovery is usually prompt, with ovulation resum- ing in 4 to 8 weeks in most cases. Occasionally, the reappearance of cyclic ovulation may be de- layed for several months. Fertility appears to be normal immediately after cessation of the oral con- traceptives although a small but unknown number of patients remain amenorrheic. The outcome of pregnancy has been reported to be about the same as in the untreated population with regard to abortion, prematurity, abnormality, and anomaly. There are, however, no prolonged followup studies to ascertain the growth and development of in- fants born after cessation of therapy. There is no evidence that prolonged suppression of ovulation in nulliparas or multiparas will impair future fer- tility. The effects of prolonged suppression of ovulation, however, are unknown and require fur- ther investigation. Pituitary-Adrenal Function Increased cortisol binding by serum proteins under the influence of oral contraceptives tends to obscure the block of the pituitary ACTH that occurs. Prolonged use of oral contraceptives re- duces the response of metopirone but not to ACTH, indicating an inhibition of pituitary ACTH rather than of adrenocortical activity. Recovery of responsiveness occurs in 2 months after cessation of medication. Impaired reaction to stress has not been noted in women on oral con- traceptives. There are insufficient data to ascer- tain the effect of these compounds on women with adrenal insufliciency. Thyroid Function Increased thyroxin-binding globulin has been noted in the majority of women on oral contracep- tives. Most, but not all, investigators report a rise in PBI and a decreased T,-RBC uptake. These changes occur rapidly and are maintained for the duration of medication, returning to nor- mal pretreatment levels in about 2 months. The alterations are secondary to the increase in binding proteins produced by estrogens and are similar to those occurring in normal pregnancy. The level of PBI may be in the hyperthyroid range but there is no clinical evidence of hyperthyroidism. If TSH is blocked at the pituitary level, it may be masked by increased protein binding. No pre- cise data are available on this point. Carbohydrate Metabolism Data regarding effects on carbohydrate metabo- lism in experimental animals and in women are contradictory. Recent studies in women taking oral contraceptives suggest a possible diabetogenic effect of these medications. Abnormal glucose tolerance tests have been observed in as many as 40 percent of women taking oral contraceptives; in women with diabetic family histories, abnormal tests were even more frequent. Plasma insulin levels are above normal in supposedly normal women on oral contraceptives. Some known dia- betic women require larger amounts of insulin while on medication. All of these changes tend to regress after discontinuation, and are similar to those seen in normal pregnancy. Whether preg- nancy itself is diabetogenic is by no means certain, although diabetes seems to be more prevalent in women of high parity. Whether oral contracep- tives can induce diabetes in normal women or even in those predisposed is not known, nor is it clear to what extent the induced changes in carbohy- drate tolerance are reversible. Liver Function Many women on oral contraceptives show ab- normalities of some liver function tests, especially the BSP and transaminase. A few develop clinical jaundice and evidence of mild hepatic damage, demonstrated by biopsy. These lesions resemble cholestasis of pregnancy. In several women with previous history of cholestasis, these changes have been induced by the oral contraceptives. The ab- normal liver function tests revert to normal after cessation of medication. 9 PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6929 Effect on Lactation Oral contraceptives in high doses (5 and 10 mg. of progestogen) tend to decrease or stop lactation in many women in the first or second cycle of use. These compounds appear in breast milk butin miii- imal amounts (0.004-0.1 percent of the adminis- tered dose). Despite the small quantities of the steroids appearing in breast milk, mammary en- largement may occur in nursing infants. Admin- istration of the androgenic steroids to newborn experimental animals at crucial periods can affect sex differentiation and behavior and result in ster- ility. No data on human beings are available. Masculunization Oral contraceptives have not produced serious masculinisation in women taking these agents although all large series have reported some indi- viduals with mild masculinizing symptoms. The 19-nor-compounds appear to have somewhat more masculinizing effect than other synthetic progesto- gens. These effects are mild, including acne and hirsutism. These changes regress with cessation of medication. The effect on the fetus is of greater importance. Synthetic progestogens, in doses used in the treatment of threatened or habitual abortion, may produce superficial masculinization of the genitals of the female fetus. These an- atomic abnormalities are correctable, but the effect upon subsequent reproductive functions and psy- chosexual development is unknown. miscellaneous adverse experiences Ophthalmologic Complications There have been reports of blurring of vision and even blindness in patients taking the oral con- traceptives. The majority of these effects are thought to be of vascular origin, although some may be on a neurological basis. Most of the re- ports are of single cases or small series in which the etiologic relation is uncertain, but in some cases vision improved when the drugs were dis- continued. In several large series of patients on oral contraceptives "eye complaints" and abnor- malities have occurred but not with an increased incidence. The question of possible adverse effects on vision is by no means completely solved, but there appears to be no reason for undue concern at this time. Long-range and carefully controlled studies should be undertaken. Migraine There are instances reported of migraine occur- ring for the first time as well as some with exacer- bation of preexisting migraine in patients taking oral contraceptives. Studies show that women who have preexisting encephalographic changes characteristic of migraine tend to have these ab- normalities brought out but not initiated by the oral contraceptives. Psychological and Emotional Factors Studies are in progress regarding the effects of oral contraceptives on human and animal behav- ior. At present no precise data are available. efficacy The following uses for which therapeutic ef- ficacy has been claimed were reviewed: A. Controlof Fertility B. Amenorrhea C. Dysmenorrhea D. Endometriosis B. FunctionalUterine Bleeding F. Habitual Abortion G. Miscellaneous Uses A. Fertility Control The efficacy of the combined agents is exception- ally high. The more recently introduced sequen- tial regimens are also highly effective in controlling fertility, although to a slightly lesser 40-471 0-70--pt. 17-7 PAGENO="0098" 6930 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY degree. Present evidence indicates that the fre- quency of pregnancies occurring with the patients on sequential medication remained unchanged over the 2½-year period, thus supporting the con- tention that tolerance to or escape from the medi- cation probably does not occur. B. Treatment of Amenorrhea The efficacy of oral contraceptives in the treat- ment of amenorrhea could not be readily ascer- tained from the material available to the Committee because of the endpoint used. Treat- ment was considered successful when uterine bleeding followed cyclic withdrawal of the medi- cation. Such an endpoint does not specifically measure the efficacy in treating amenorrhea, since cyclic withdrawal bleeding and menstrual periods are different biologic phenomena. If efficacy in the treatment of amenorrhea is claimed, it must be based on evidence that menstrual cycles are maintained following discontinuation of drug therapy. Such information was not contained in the submitted material. If, however, the objec- tive of the therapeutic effort is to produce cyclic withdrawal bleeding in the amenorrheic patient, the oral contraceptive drugs can be considered efficacious, since this result was achieved in 80 to 90 percent of treated patients. C. Treatment of Dysmenorrhea The comments pertaining to efficacy of the drugs in the management of patients with dysmenorrhea were similar to those cited in the previous para- graph. The situation was even more complicated because of the difficulty in quantitation of the prin- cipal variable. Dysmenorrhea is known to disap- pear spontaneously, and relatively high "cure rates" have been obtained with placebos. No fol- lowup data were nvailable in the submitted ma- terial; the reports thus pertained to the evaluation of pain during cyclic withdrawal bleeding rather than during a menstrual period. Although the data suggest that in certain patients the progesta- tional agent might be of value in the treatment of dysmenorrhea, additional information is required before the therapeutic efficacy can be proved. Sta- tistically, the submitted material was considered unsatisfactory because of the small number of pa- tients in the individual series. It was surprising to find that a very small sample had been utilized in the study of such a common phenomenon. The members were aware of the difficulties in designing controlled studies, since placebos do not provide contraception, a fact that cannot remain undis- closed to the patient. D. Treatment of Endometriosis In evaluating the material in which the diag- nosis of endometriosis was established by histo- logic examination, the Committee finds continued and prolonged (6 to 12 months) progestational therapy valuable to conservative management of the affected patient. In the well-documented cases it is reasonable to expect a favorable response in 75 to 90 percent. It must, however, be pointed out that recurrence might be expected in an apprecia- ble proportion of patients after cessation of med- ication. In contrast, the therapeutic efficacy in subjects in which the diagnosis of endometriosis had been made by physical examination or history alone, was uncertain. This population undoubt- edly comprises a variety of diseases that should not be expected to improve during therapy with pro- gestational agents. E. Treatment of Functional Uterine Bleeding The claims for therapeutic efficacy in treatment of functional uterine bleeding were met with crit- icism similar to that applied to treatment of dysmenorrhea and amenorrhea. The Committee considers the joining of a variety of conditions under the heading "Functional Uterine Bleeding" inappropriate because the individual diseases have specific and different causes. The index of gen- eral efficacy might not therefore reflect the fa- vorable results achieved in certain categories, or conversely might create the impression of thera- peutic merit in diseases that are not susceptible to therapy. Irregular menstrual periods will re- spond in a high percentage of cases to therapy if cyclic withdrawal bleeding is considered synony- mous with menses, whereas menorrhagia might be and appears to be considerably more resistant to the advocated therapy. Patients with hyper- menorrhea appear to have shorter periods and less loss of blood when placed on cyclic therapy with these compounds. Difficulty in constructing a meaningful endpoint for the various categories was evident since most of the conditions causing functional bleeding are known to be self-limiting. F. Habitual Abortion The Committee found no data to indicate that any of the oral contraceptives are effective in al- tering the natural history of patients with habit- ual abortion. Although the reasons for habitual 11 PAGENO="0099" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6931 abortion are not known, it often results from a cytogenetic defect in the etsbryo. These cases would, therefore, not benefit from steroid therapy. Clearly those synthetic progestogens that are known to have androgenic properties should be avoided in the therapy of threatened abortion or hibitual abortion. G. Miscellaneous Uses The value of oral contraceptives in the treat- ment of conditions such as "menopausal syn- drome", acne, chronic vulvar infections, and psychiatric disorders could not be ascertained be- cause of the preliminary nature of the available reports. reconnnendations In making the following recommendations, the Committee has given careful consideration to this problem, which is unique because of thelarge num- ber of healthy women taking the oral contracep- tives over very long periods of time, the low in- cidence of serious side effects, the metabolic changes induced, paucity of reipiisite stalj~ ~lands~entifid~&a and finally, the health and social benefits to be derived. imposed the requirement for recedented stand- t eyhave ~ of sequelae that are often remote and infre uent; t eyhaveopene o u hods o survei ance and retrieval of data~ and they have require the design of highly refined epide- ~ As our case is new and unique in the history of therapeutics, so have we had to think anew in fram- ing these recommendations. I. A large case.control (retrospective) study of the possible relation of oral contraceptives to Thromboembolism. This study should follow the methods developed in a pilot trial described in appendix 7 (p. 71) to this report. In view of the results of the pilot trial, such a study becomes mandatory. This study must include a considerable number of hospitals, which should be of large size and high clinical standards and quality of medical records. The potential contributions of operations already exist- ing in the Food and Drug Administration to main- tain systematic, unified collaboration with such hospitals should be explored. Most important, the investigation should be under competent epi- demiologic supervision. LI. Continuation and support of studies such as the ones being carried out by the Kaiser Permanente group in California and the University of Pittsburgh group in Lawrence County, Pa. Ill. Support of additional controlled population. based prospective studies utilizing groups of subjects that are especially amendable to long.term followup, such as married female employees of certain large industries, and graduate nurses. Although such prospective studies are difficult and require large populations, they may provide the only feasible method to answer the question of a relationship between the oral contraceptives and carcinoma, as well as the effect of these compounds on the growth and development of subsequent offspring. IV. Continuation and strengthening of the pres- ent surveillance system of the FDA. V. Review of the mechanism of storage, re- trieval, and analysis of survefflance data. If this system is to serve its prime purpose; namely, that of early warning, a much more effi- cient system of "feedback" will have to be insti- tuted. VI. A conference be held between FDA and the respective drug firms concerning uniform- ity and increased efficiency of reporting. There is every evidence that Che drug firms are willing and anxious to cooperate with FDA and with each other to achieve more efficient surveil- lance and more meaningful data. VII. Priority be given to support laboratory in- vestigations concerning all aspects of the hormonal contraceptive compounds. VIIL Uniformity in labeling of contraceptive drugs. PAGENO="0100" 6932 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IX. Discontinuance of time limitation of admin- istration of contraceptive drugs. There is no scientific justification for the pres- ent restrictions. They are often circumvented and serve only to penalize the large indigent popula- tions. X. Simplification of administrative procedures to allow reduction in dosage of already ap. proved compounds. Once safetyhas been establithq~, reduction in dosage should require only minimal proof of effi. cacy, say 3,000-4,000 cycles without a pregnancy. conclusion The foregoing considerations have been brought together to direct the attention of the medical pro- fession and the Food and Drug Administration to those aspects of our knowledge, as well as our ignorance, that seem pertinent to our evaluation of the safety and risks involved in the use of these compounds. The committee finds no adequate scientific data, at this time, rovin afe for ~~use. has nevertheless taken full cog- rnzance of ce tam very infrequent but serious side effects and of possible theoretic risks suggested by animal experimental data and by some of the metabolic changes in human beings. In the final analysis, each physician must evalu- ate the advantages and the risks of this method of contraception .in comparison with other avail- able methods or with no contraception at all. He can do this wisely only when there is presented to him dispassionate scientific knowledge of the available data. 13 PAGENO="0101" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6933 appendix TASK FORCE REPORTS August 1, 1966 PAGENO="0102" 6934 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Appendix 1 Report of the Task force on Throniboenibolic Disease N. J. EASTMAN, M.D., CHAIRMAN The activities of the Task Force on Thrombo- embolic Disease have been as follows: 1. To ascertain the effect, if any, of oral contra- ceptives on the factors responsible for blood coagulation. 2. To ascertain the incidence of fatal thrombo- embolic disease in the total female population of the United States of reproductive age, exclusive of cases associated with pregnancy or a surgical operation. 3. To ascertain the approximate number of women in the United States who have taken oral contraceptives, year by year, from 1961 through 1965. 4. To ascertain the incidence of fatal thrombo- emboliv disease in women who had been users of oral contraceptives prior to death. 5. To specify and recommend for immediate development certain epidemiological studies which promise to establish the risks associated with the use of oral contraceptives, or the absence of such risks, much more effectively than is possible on the basis of the data now available. 1. Blood coagulation in women taking oral con- traceptives has been the subject of many studies by competent investigators. Although the data on the behavior of individual coagulation factors are somewhat conflicting, no clear evidence has been advanced that these preparations signifi- cantly alter the coagulation behavior of the blood. Thus, in a recent and most meticulous investiga- tion, Beller and Porges summarize their findings as follows: "Two different commercially available agents and a placebo were taken by a group of volunteers in a double blind study. There was no statistical difference in blood coagulation factors among the different groups." (In press, Am. J. Obstet. & Gynec.) But even if some of the blood coagulation factors had shown differences between users and nonusers, no blood-coagulation assay at the present time is considered a test for prediction or confirmation of the clinical diagnosis of throm- boembolic disease. (Alexander, B.: Blood coagu- lation and thrombotic disease; Circulation, 25: 872, 1962. Wessler, S.: Stasis, hypercoagulability and thrombosis; Federation Proceedings, 22: 1366-1370, 1963.) 2. Estimates of the incidence of fatal pul- monary embolism among women, 15-44 years of age, not pregnant nor in the puerperal state, in the United States in 1963 are shown below: 12 These estimates were obtained by including in the numerator deaths attributed to pulmonary embo- lism and infarction (lCD 465) plus the deaths assigned to antecedent causes which rarely lead to death except by pulmonary embolism (lCD 463, 464, 466) and including in the denominator only women who are neither pregnant nor in the puerperium. :Theestimates shown above are necessarily rough because the total number of pregnancies is not known.' It is believed, however, that they repre- sent the level and trend of mortality with sufficient accuracy for the purpose at hand. Age-specific death rates from cerebral embolism and thrombosis (lCD 332) among women, 15-44 `It was assumed that one-sixth of all pregnancies in the United States or approximately 1 millIon were ter- minated by spontaneous fetal wastage, and the same number by illegal abortion. Age (yjears) 15-19 20-24 25-29 - 30-34 - 35-39 - 4O-44~ Deatisa 2 10 12 18 22 17 PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6935. years of age, in the United States in 1963 were as follows: Deaths Age per (years) miiUon 15-19 1 20-24 2 25-29 2 30-34 4 35-39 9 40-44 15 15-44 5 It should be realized that mortality statistics for this group of conditions are probably unreliable. This is in part because the classification of causes of death is based upon what is considered the underlying cause. The certifying physician's judgment and the care which he takes in recording these underlying causes are variables which can- not at present be assessed. Thus, for example, we do not know how often he fails to record on the death certificate such underlying causes as surgery, the puerperium, trauma, heart disease, and hyper- tension when these are present. In spite of the limitations of statistics based on death certification, it is pertinent to compare the reported number of deaths from thromboembolic disease among women taking oral contraceptives with the number that might be expected from the above statistics. If, among women taking steriod compounds, the reported number of deaths is significantly greater, a causal relationship is suggested. 3. The number of deaths attributed to diseases of the veins (lCD 460-468), most of which are deaths from pulmonary embolism, and the corre- sponding death rates among women of reproduc- tive age in the United States increased substan- tially from 1950 to 1964. However, parallel in- creases of equal magnitude have occurred among males, suggesting that the upward trend reflects changes in diagnostic practice, death certification, or causesapplicable to both sexes. Death rates from cerebrovascujar accidents (lCD 330-334) have increased among nonwhite women (fewer of whom use oral contraceptives than white women), but have not changed among white women. 4. The pharmaceutical industry has estimated the numbers of women taking oral contraceptives, based on the numbers of tablets distributed in the United States. The approach is straightforward: Since each user takes 20 tablets per cycle and the average woman has 13 cycles per year, the number of tablets sold, divided by 260, gives the average number of users during the year. The following estimates have been prepared by this method for the period 1961-65: 1961 408,000 1962 1,187,000 1963 2,235,964) 1964 3,950,000 1965 5,096 ooo 5. Another estimate of the number of women taking oral contraceptives is based on the responses of a nationwide sample of about 5,600 married women, interviewed in late 1965 (Westof and Ryder, 1966). According to this survey, about 3,800,000 women were using oral contraceptives at the time of the interview and an additional 2,600,000 had been taking them previously but had stopped medication, with or without the intention to resume useat a later date. The difference between the industry estimate (5 million in 1965) and the survey estimate (3,800,000) may be explained, at least in part, by the inclusion of several categories of women in the former but not in the latter. These are: (1) Married women over 45; (2) unmarried women; and (3) women for whom steroid compounds have been prescribed for therapeutic reasons but who do not know the nature of the medication. In addition, it is possible that the industry estimate is inflated by the growth of inventories in the hands of distributors and/or retailers. On the other hand, some of the women interviewed in the survey may have withheld the relevant informa- tion. 6. Oral contraceptives are much more widely used among younger than among older women. According to the 1965 survey, 26 percent of mar- ried women under 30 years of age were current users, compared with 8 percent of those over 30. Among the current users, two out of three were less than 30 years old and two out of five were less than 25 years old. 7. In August 1962, some 275,000 letters were sent by the (1. D. Searle Co., makers of Enovid, to physicians, druggists, and other pertinent per- sons throughout the United States requesting that "any thromboembolic occurrence in women receiv- PAGENO="0104" 6936 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ing Enovid be reported to us and to the Food and Drug Administration."2 In the fall of 1965, a survey of the deaths so reported to the FDA indi- cated gross underreporting. Accordingly, in Jan- uary 1966, arrangements were made for Dr. Schuy- ler Kohl, professor of obstetrics and gynecology at the Downstate Medical Center of the State Uni- versity of New York, to visit all pharmaceutical firms marketing oral contraceptives and make a thorough investigation of the deaths reported and other pertinent facts. Dr. Kohl's report, which is included in ap- pendix 6 (p. 64) confirmed the earlier impres- sion of the Committee in respect to underreport- ing of deaths. In fact, he found the magnitude of underreporting to be so great as to preclude draw- ing any conclusions from these data. The evidence was clear that the pharmaceutical firms concerned reported promptly any adverse reactions of which they were notified; the breakdown of this volun- tary system of reporting was caused rather by the inadequate information about deaths on the part of physicians and other persons who were relied upon to report adverse reactions. 8. Taking into account the preponderance of young women among those using oral contracep- tives, one would expect for each million users about 14 fatal cases of thromboembolic disease per year, including [0 deaths from pulmonary em- bolism and 4 deaths from cerebral embolism and thrombosis. Hence, the numbers of deaths ex- pected in 1962 on the basis of the industry estimate of users (1,187,000) would be on the order of 12 and 5, respectively. It would seem prudent, how- ever, to reduce these figures to, say, 10 and 4, respectively, to allow for a possible inflation of the estimated number of users. According to the information obtained by Dr. Kohl, 20 deaths from all causes were reported to the manufacturers (and subsequently to the FDA) as having occurred among users of oral contracep- tives in 1962. Of these, only 13 were due to "idio- pathic pulmonary embolus"; that is, to an embolus without any demonstrable predisposing factor. This figure (13) is larger than the expected num- ber of deaths from pulmonary embolism alone (10), but the differenceis not statistically signifi- cant. This relationship of reported to expected deaths in 1962 is virtually the same as found by 2 "Dreg Cautlen" letter appended. the Wright Committee which used the same or very similar basic data and a comparable proce- dure. (Report by the ad hoc Committee for the Evaluation of a Possible Etiologic Relation With Thromboembolic Conditions, submitted to the Commissioner of FDA, HEW). 9. It would appear, then, that the intense effort of 1962 produced about as many reports of fatal cases of pulmonary embolism among users of oral contraceptives as would be expected on the basis of the experience of the general female population of reproductive age. It will be noted, further, that the number of women taking oral contracep- tives increased more than fourfold from 1962 to 1965. The survey estimate for the latter year (3,800,000 users) implies 38 expected deaths from pulmonary embolism. Acceptance of the industry estimate (5 million users) would raise this figure to 50 deaths. Even without any causal relationship whatso- ever it would be expected that the numbers of reported deaths among women taking oral con- traceptives would augment proportionally with the increasing numbers of users. This, however, was not the case. The number of reported deaths due to unexplained pulmonary embolism in 1962 and 1965 were the same (13). The data derived from mortality statistics are not adequate to confirm or refute the role of oral contraceptives in thromboendiolic disease. They do, however, suggest that if oral contraceptives act as a cause they do so very infrequently relative to the number of users. The task force believes, nevertheless, that the only way in which this ques- tion can be answered definitively is through well- controlled epidemiological studies. COPY OF LUSTER PROM 0. D. SEARLE & CO. AUGUST7, 1962. IMPORTANT-DRUG CAUTION. DEAR DOCTOR: We are addressing this letter to ypu in keeping with our policy of bringing to you all of the pertinent facts concerning our products and as a response to recent publicity dealing with the occurrence of thromboembolic phenomena. co- incident with women receiving Enovid. Since its introduction there have been reported to us as of this date 28 cases of thromboembolic disease in the more than 1 million users of Enovid in the United States. Among these were 10 cases PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6937 of pulmonary embolism, 5 of which were fatal. In addition, there are press reports of four cases, in- cluding one death from the United Kingdom. In some of these one or more of the usually ac- cepted inciting causes of thrombophlebitis were evident; in some they were not. Reports to the manufacturer do not reflect the accurate incidence of reactions and the available statistics are not adequate to determine whether or not there is a causal relationship, but caution re- quires consideration of this possibility. It must be remembered that pulmonary embo- lism can occur without discernible inciting cause and without preceding peripheral thrombo- phlebitis. Nevertheless, careful studies by investi- gators experienced in the measurement of the extremely complex factors involved in the clotting mechanism are continuing, including an evaluation of the role of fluid accumulation sometimes seen after Enovid administration. This will be re- ported in a technical bulletin at an early date. At the present time the available laboratory data neither prove nor disprove a causal relationship between Enovid administration and the occurrence of thrombophlebitis. The cases of thrombophlebitis reported to us have usually occurred early in the course of Enovid administration and at the lower dosage level. Ex- perience based on patients taking Enovid at higher doses has not demonstrated any dose response relationship. Physicians should be as alert to the possible oc- currence of thrombophlebitis in patients to whom Eno'cid is prescribed as they are in patients taking other medication. The above facts should be given particular atten- tion if Enovid is considered for administration to patients with thrombotic disease or a history of thrombophlebitis. We request that any thromboembolic occurrence in women receiving Enovid be reported to us and to the Food and Drug Administration. Sincerely yours, (S) Irwin C. Winter, IRWIN C. WINrsR, Ph. D., M.D., Vice President, Medical Affairs. PAGENO="0106" 6938 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Appendix 2 Report of the Task force on Carcinogenic Potential B. B. SCOTr, M.D., CHAIRMAN The available prevalence and incidence rates of cancer of the uterine cervix, cancer of the endo- metrium, and cancer of the breast were reviewed in order to establish, as near as possible, the ex- pected normal rates for these cancers in the human female. All of the published and submitted data on pa- tients who have received any of the estrogen- progestogen combinations for contraceptive pur- poses over a period of time were reviewed. The animal experiments, published and some unpublished, using these hormonal agents, or similar agents, as they relate to the production of malignancy or the influence on an existing malig- nancy, were studie~i. The following observations and conclusions were made: Cancer of the Uterine Cervix Dysplasia, carcinoma in situ, and invasive can- cer were considered. The importance of the geo- graphic location and of the socioeconomic level of the population sample were very evident: for example, the prevalence of carcinoma in situ and invasive cancer in Puerto Rico was almost six times that of a Metropolitan New York group composed of women, for the most part, from a higher socioeconomic level. Another important factor was the average age of women showing these changes: roughly 35 years for dysplasia, 40 years for carcinoma in situ, and 47 years for in- vasive cancer (tables 1-7). The data from the various study groups using contraceptive pills were difficult to analyze for the following reasons: 1. Initial cytological status was not given in many instances and in others patients with suspicious or positive Papanicolaou cytol- ogy were admitted to the study. 2. The various methods of collecting cyto- logical specimens and the personal equa- tion in reading and reporting any changes make standardization of data difficult. 3. The frequent absence of histopathology after cytologic suspicion was found. 4. The preponderance of patients in the age group before 35. 5. The relatively small ~iumber of patients followed regularly and thoroughly for 4 years or more. In the data submitted there is no evidence of any increased incidence of premalignant or ma- lignant changes in the uterine cervix which could be attributed to the use of the contraceptive pills in this relatively short time interval (tables 8- 13). Any valid conclusion must await accurate data on a much larger group of women studies for at least 10 years. Also, in the data, there is no evidence to support the statement which has been made-that the use of the contraceptive pills may have a protective effect against the develop- ment of malignancy of the uterine cervix. One study, in need of supporting evidence from other investigators, may ha significant. This study showed an appreciable increase of coccoid bacteria, Trichomonads, and fungi in women using contraceptive pills for a year or more compared to a matched control group. This alteration in the microbiological content of the genital tract might be related to the use of the pills and could account for some increase in such cytological re- ports as atypical cells or class 2 Papanicolaou. Uterine Endometrial Malignancy Endometrial carcinoma is primarily a disease of the postmenopausal years and only 5 to 8 per- cent of these occur before the age of 40. In the data submitted the paucity of endo- metrial biopsies as a routine followup procedure, the limited number of women more than 40 years of age, and the short duration do not permit draw- ing any conclusions relative to the effect, either 21 PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6939 adverse or beneficial, of these contraceptive pills on endometrial malignancy (table 14). There are numerous studies which suggest a pre- ponderance of estrogenic influence, either endoge- nous or exogenous, in women who subsequently develop endometrial adenocarcinoma. A cause- and-effect relationship has by no means been estab- lished. All women receiving estrogen therapy must be followed with the utmost care and thor- oughly investigated at the slightest suspicion; the advice to administer a progestogen periodically to women receiving estrogen, in order to allow peri- odic "withdrawal" bleeding on the basis that it "prevents" endometrial cancer, is not valid either on a theoretical basis or on the basis of the very limited number of postnaenopausal patients so treated. The use of progestogens in the treatment of adenomatous hyperplasia and carcinoma in situ of the endometrium is under investigation in sev- eral centers. At the present time no conclusions can be drawn. There is clinical evidence of some palliative benefit, but not cure, from the adminis- tration of large doses of progestogens in about one- third of the patients with metastatic endometrial cancer. Breast Cancer The mortality rate of cancer of the female breast in the United States has remained remarkably stable since 1930 (table 15). The incidence of cancer of the breast rises with age. Inasmuch as contraceptors are in the younger age groups, very large samples will be necessary to detect an asso- ciation if one exists. In the published reports of women receiving contraceptive pills for variable periods of time there are no observed cases of breast cancer. The FDA files contain one recent instance of a woman, age 44, with a history of previous cystic disease of the breast, who was shown to have a scirrhous carcinoma of the breast after 7 months of cyclic estrogen-progestogen. In the limited data avail- able, with the preponderance of relatively young women and the uncertainty as to the completeness of followup breast examinations, no conclusions can be drawn as to the relationship between the use of the contraceptive pills and cancer of the breast. The animal studies, to be mentioned later, and certain clinical observations indicate the need for a high index of suspicion and continuing alert ob- servation and studies. The acceleration of growth of certain existing breast cancers by the admin- istration of estrogens has been noted. Many in- stances of breast cancer have been reported in males receiving large doses of estrogens for pros- tatic cancer; although this is not proof of the inciting of breast cancer by estrogens, it is strongly suspicious. Any relationship of progesterone or the progestogens to breast cancer is not clear. One recent clinical study of breast biopsies in a limited nunsber of women on the contraceptive pills revealed an increase in the amount of intra- lobular and perilobular fibrosis as compared to controls. The significance of this is not certain and the finding needs confirmation to accept. Other Malignancies Malignant lesions in the pituitary, kidneys, ovaries, and bone marrow have been found in ani- mal studies after treatment with certain of the sex hormones, but at the present time there are no human corollaries. The FDA files contain one instance of malignant melanoma found during the administration of contraceptive pills; this is fa- vorably coincidental, but the alterations of mel- anin distribution during pregnancy and in some patients receiving contraceptive pills are well known and therefore a relationship cannot be en- tirely dismissed. Animal Studies Sex steroids, particularly estrogens, have been shown to produce malignant lesions and to ad- versely affect existing ones in the mouse, rat, rab- bit, hamster, and dog. These neoplasms have been in various organs and organ systems such as the cervix, endometrium, ovary, breast, testicle, pituitary, kidney, and bone marrow. The obser- vations in animals using progesterone and the newer progestogens have been cOntradictory; however, these agents alone and in combination with other sex steroids have promoted tumor formation or not prevented it in a few instances. A recent example is a 52-week study of six dogs which received massive doses of a combination of mestranol and ethynerone (MK-665-an experi- mental progestogen)-four of the dogs developed mammary lesions; one, a carcinoma in situ with early invasion; one, a carcinoma in situ; one, an atypical hyperplasia; and one, a benign intraduc- tile papilloma. The decision of the FDA to dis- continue clinical trials of this agent and advise further animal studies was a correct one. PAGENO="0108" 6940 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Animal studies in which certain susceptible strains and species are used and the dosage, exces- sive and continuous, cannot be transferred ex- actly to human expectancy. Nevertheless, a warn- ing is there and a so-altered endocrine environ- ment in human tissues might result in an abnormal expression or potentiation of growth. Recommendations 1. The more extensive use of dogs and non- human primates in the animal testing of these drugs. 2. To test the presently approved contracep- tive pills, if this has not been done, for mammary effects in dogs. 3. Encourage research in long-term adminis- tration of estrogens and other sex hormones in low and intermediate doses to nonhuman primntes. 4. Continue the study groups on contraceptive pills in order to obtain more long-term data. Assure that the patients in those study groups are regularly and adequately ex- amined and tested and that abnormal find- ings are immediately reported. 5. Continue the warning that the contracep- tive pills are contraindicated in the pres- ence of genital or breast malignancy and to extend this contraindication to any sus- picion of genital or breast malignancy. 0. To establish at least two long-term study groups: one on the contraceptive pills and at least one control group. The minimum number in each group should be 20,000 women and the term of study for each group no less than 10 years. These studies must be within a reasonably stable population and geographic area. These are the mini- mum number required to ascertain a 2x change of genital and breast cancer inci- dence rates with 5 percent acceptable risk rate. 2 Mayo Clinic, Rochester, Minn 3 Ohio State University, Columbus, Ohio 4 Memphis, Tenn 5 Wisconsin State Laboratory, Madison 6 Mecklenburg County, NC 7 San Diego, Calif 9 Honolulu, Hawaii 10 Strang Clinic 12 Floyd County, Ga 11 Los Angeles, Calif 14 Puerto Rico 8 Metropolitan Hospital, N.Y.---Sedlis 15 Tijuans, Mexico 13 Kansao-Hellwig 1 Vancouver, British Columbia Total Table 1.-Cervical carcinonZO4fliti~~l screening1 Rate per thossasd Nsmberef Nsisberof In situ Isvaslve 139, 503 987 7. 1 897 ( 6. 4) 90 ( 0. 7) 113, 758 388 3. 4 213 1. 9) 175 ( 1. 5) 108, 136 724 6. 7 393 3. 6) 331 ( 3. 1) 65, 163 548 8. 4 195 3. 0) 353 ( 5. 4) 48, 697 412 & 5 290 6. 0) 122 ( 2. 5) 33, 746 336 10. 0 259 ( 7. 7) 77 ( 2. 3) 24, 182 134 5. 5 51 ( 2. 1) 83 ( 3. 4) 19, 462 48 2. 5 46 ( 2. 4) 2 ( 0. 1) 17, 761 84 4. 8 56 ( 3. 2) 28 ( 1. 6) 19, 192 145 7. 6 97 ( 5. 1) 48 C 2. 5) 5, 435 119 14. 1 67 C 7. 9) 52 ( 6. 2) 27, 226 123 4. 5 71 ( 2. 6) 52 ( 1. 9) 2, 161 51 23. 6 25 (11. 6) 26 (12. 0) 10, 197 96 9. 4 52 ( 5. 1) 44 ( 4. 3) 322, 352 2, 156 6. 7 1, 228 ( 3. 8) 928 ( 2. 9) 959, 971 6, 351 6. 6 3, 940 ( 4. 0) 2, 411 ( 2. 6) 1 kdapted from Day, 5, tablo4, p.1193, cml. Obst. and Oynec., 4: 1193-1199, 1901,wlth addition. 23 PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6941 Table II.-Prevatence of dysplasia, carcinoma in situ and invasive cancer of the cervix uteri DyspIas~ Stages Stages Stage 2-4 Age Total Percent ___________ ______ Number Rate Number Rate Number Rate Namber Rate 20-29 2,107 8 14 6.6 5 2.4 1 0.5 0 0 30-39 6,322 24 48 7.6 34 5.4 7 1.1 0 0 40-49 6,585 25 23 3. 5 32 ~,o ~ 1.4 ~ . 8 50-59 6, 058 23 25 4. 1 21 3, 5 7 1. 2 7 1.2 60-69 3,951 15 15 3.8 9 2.3 9 2.3 17 4.3 7Oplus 1,317 5 4 3.0 4 3.0 5 3.8 5 3.8 Total 26, 340 129 105 38 34 Average 4.9 4.0 1.4 1.3 From Stern, E., In Cancer, 12: 933, 1019. Table Ill-Results of rescreening of patients with carcinoma of the cervix uteri CarcInoma in sItu Invaaive cancer Number of - ____________ ______________ Study ScreenIng women Number Rate per Number Rate per _________ thousand thousand Memphis, Tenn First 108, 136 393 3 6 331 3. 1 Second 32, 728 72 2. 2 9 . 3 Wisconsin Stnte Laboratory, Madi- First 65, 163 206 3. 2 335 5. 1 son. Second 9, 111 10 1. 1 4 . 4 Floyd County, Ga First 17, 761 56 3. 2 28 1. 6 Second 4, 482 12 2. 7 4 . 9 Ohio State University, Columbus_.._ First 113, 758 213 1. 9 175 L 5 Second 44, 009 40 . 9 7 . 2 Third 16, 137 2 . 1 2 . 1 San Diego First 33, 746 265 7. 8 78 2. 3 Second 9, 725 34 3. 5 2 . 2 Third 4, 213 6 1. 4 Fourth 1, 654 1 . 6 Reproduced from Day, S., table 5, p. 1104, COo. Obst. and Csyaee. 4:1103-1198, 1581. Table IV.-Cervjcal cancerfindings (as of June 30, 1965) -~ Screenlncl Findings per l,550screened Percent stall Age Total No. screened Cervical cancer Dysplasla Other Total Invasive In situ 15 to 29 143, 851 46 3. 8 0. 5 3. 3 7. 4 0. 1 30 to 44 93, 110 30 11. 4 3. 1 8. 3 7. 2 . 4 45 to 59 41, 655 13 12. 5 7. 8 4. 7 4. 9 2. 5 60 plus 30, 228 10 16. 6 11. 9 4. 7 5. 0 7. 0 Total 309, 750 & 5 3. 4 5. 6. 8 1. 2 From data sabmitted Pat Harvey Ocher, Chief, Operational &udfc, Section, Cancer Control Branch, lltrisien of Chronic Biceasee, DHEW, Public Health Service. PAGENO="0110" 6942 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table V.-Cervical cancer findings (as of June 30, 1965) (let year routine repeats( Age Total No. ~ Percent of all screened Pindingsper 1,000 screened Cervical cancer Dysplania Other cancer Totsi Invasive In situ 15 to 29 30 to 44 45 to 59 6Oplus Total 14e 561 13, 833 7,737 6,196 34 33 18 15 2. 3 3.7 1.9 1.9 0. 2 8 .6 1.1 2. 1 2.9 1.3 .8 6. 1 ~ 6 3.4 2.7 0. 1 .2 1.2 2.4 ~42, 330 2. 6 .6 2.0 4.6 .7 `Age not given in some instances. From dotasubmitted by Harvey Getter, Chief, Operational SiudiesSection. Cancer ContcolBraneh, DIvisional Chronic Diseases, DREW, PublleHeslth Sorrier. Table VL-A ge-Specific annual incidence rates for cancer of the uterine corpus plus unspecified uterine cancer (Rates per 100,0001 Ago Connecticat, taco Upstate New York, 1050-60 Age Connecticut, 1160 Upstate New 1058-0)0 Oto4 0.7 SOto 47.5 612 41.59 5067 Sto 55to 52.1 72.28 lOto GOto 63.8 69.19 lSto 0.11 88.1 65.60 2Oto 2.8 .82 7Oto 106.1 60.56 25to 1.3 1.36 75to 57.9 67.33 3Oto 4.5 1.99 and 77. 7 56. 56 35 to 6. 1 5. 17 85 ever 18. 7 15.73 40 to 16. 7 11.94 Age adjustment 45to 39.9 20.18 Prepared by 2ohn C. Bailer III, M.D., National Cancer Imilinie Table VJJ.-Average annual cancer incidence rates and expected numbers of cancers per 1,000 women followed 4 years, Upper New York State, 1958-60 Ago at beginning at study Breast - Cancer of- Cervix' Corpus3 20 to 39 years.. 40 to 54 years Average annual incidence rate per 100,000 23. 96 Expected canes per 1,000 women followed 4 years ` . 96 Average annual incidence rate per 100,000 112. 88 Expected cases per 1,000 women followed 4 years ` 4. 52 31. 08 3. 45 1. 24 . 14 52. 32 29. 73 2. 09 1. 19 I No allowance tsmsde for death orloss to followup amoagmembers at the S Includes allaterlne tmnnrseseept those specified as cervical. If endome' sample; if deaths or tames occur they would decrease the eapeeted numbers trial tumors alone are considered, enpected assonbers per 1,000 sample mom- per 1,060samplo members and increase required sumplo aloes. ben would be decreased and requIred sample sizes Increased. `Iactodingesrcinomasiasilu. tfeuclotumnrsareetcluded,enpecledntem. 4 Weighted averagewtth adjustment Icc advancing age during the f0110wasp ben per 5,000 sample members would be decreased. Required sample sInes Interval. would be Increased moderately at ages 40 is 54 and substnntIally at ages 25 te 30. 25 PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6943 Table VIIl.-Data on Papanicolaou smears during use of oral contraceptives Reference Compound Number women treated Total cycles studied Number smears treated Number smears control Numbersmesrs posItIve Number posItive expected Pincus, 1959 Goldzieher et al., 1962 -- Rice-Wray et al., 1962 Rice-Wray et a!., 1963.__ Pincus, 1961 Tyler, 1961 Tyler, 1964 Enovid Ortho-Novum do Enovid do Enovid, Ortho-Novum.... Exovid, Ortho-Novum and other. 830 210 364 2, 040 1,004 8. 133 6, 232 6, 062 `22, 948 533, 132 (I) (2) (5) (2) 412 6, 746 11, 664 2, 510 0 0 0 0 Positive smears In treated women (percent) 0. 2 .4 . 77 11. 8 Posltlvesmears lncontrolwomen (percent) 1. 1 . 6 1. 23 Numbernot stated. `Data of Lee, for Puerto Rice. `Numbernot stated; smear taken atannual pelvlcexaminations. I Calculated on basIs 0131 months average duration of treatment. `Enovld and Ortho-Novum soul In 85 percent of cycles. From Drill, ~ Table IX.-Cases of cancer during use of oral contraceptives Reference Compound Number of women treated Total cycles studied Number of cuses of cancer observed during treatment Genital Mammary Pincus, 1959 Cook et al., 1961 Pincus, 1961 Tyler, 1961 Goldzieher et a!., 1962 Rice-Wray et xl., 1962 Rice-Wray et a!., 1963 Enovid do do Enovid, Ortho-Novum Ortho-Novum Ortho-Novum Enovid, Ortho-Novum 830 550 1, 004 210 364 2, 040 8, 133 6, 743 20,442 33, 132 6,232 6, 062 `22, 948 0 2 1 (2) 0 0 0 0 0 0 0 0 0 0 5 Calculated on basis of 31 months average duration ef treatment. `No eases reported bused on physical examination, pelvic or biopsy. `Esovld or Oriho.Novum employed in about 85 percent of cycles. Table X.-The rate of developnnent of suspicious Papanicolaou snnears in subjects with negative smears before the use of contraceptives Contraceptivessed Namberof subjects Number/l,Otfwith sospicioussmeurs I Average number efyearsofuse Vaginal Enovid Ovulen Orthonovum Intrauterine devices 208 580 188 105 500 72. 1 ± 18. 0 2 26. 2± 6. 6 21. 3±10.5 2& 6±16. 4 54. 0±10. 0 1. 3 3. 4 1.8 1. 6 1. 1 `Iiallcvaluesdlfferslgsiflcantlyfrom those for vaginal mntraceptIves. From dais aabmilled bsj Dr. Gregory Piscaa (Jan. 6, 156f). PAGENO="0112" 6944 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table XI.-Cervical cytology dl the time of enrollment, 6,583/11,711 women had recorded Papanienlaeusmeacsl Class II Class III Clans IV, clans V Class I At 25 months (percent) 79. 1 20. 4 0. 4 (26/6, 583) 0. 1 (6/6, 583) (5, 208/6, 583) (1, 343/6, 5 3 2 At 30 months (percent) 87. 0 . (8/2, 402) . (4/2, 402) (2, 090/2, 402) (300/2, 402) 20. 1 0 0 At 36 months (percent) 79. 9 (1, 094/1, 369) (275/1. 369) 0 0 0 At 42 months (percent) 88. 0 Conclusion: ThelseideseeofsbnOrmalcytnlngYwaolowiotthmewtmofbxa ned,and nstnbnorvodt seressowithconttsoiod use (2.5 to 42 months). From Planned Parenthood Federation of America-SO Months Club." San Antonio, orals San Antonio, all others_.._. 13 cancers. 24 cancers. 3cancers. From data submItted by Dr. Joseph Goldoleber. Table XIII.-Papanicolaou smears by cycles of treatment with various estrogen -progestin compounds Cycles Numherof Results Cycles Nurnherofj Results Control smears before 6, 157 13 carcinomas of the From 37 to 48 279 108 Negative. Do. Rn. cervix before Rx. (0.21 percent). 1 From 49 to Over 60 57 Do. From 4 to 12 1, 694 Negative. 752 Do. From 13 to 24 1, 730 Do. From 25 to 36 727 Do. lThe incIdence ofcaascerof the cerrin ha Monitors wnmon in 0.3 percent. - NosE: 25 Papanieolans were suspieinus, 24 became snrmal fotlnwint treatmesl otenisting cer'eiciiin, twos test to followup fnra year-st that time she had an invasive cervical cantor (undifferentiated cell). Edna Rice-Wrap. M.D. Table XlT.-PapanicolaoU smears At enrollment or 1 136024 mnnlbs year Rn 25to30 37to48 45tn60 PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6945 Table XIV.-Analysis of endornetrial biopsies in enovid users II. "ABNORMAL" ENDOMETROAL STATES1 Lunar yeses of use Cystic and adenosontous hyporplasia Percent with Atrophy Endosnetritis Anaptasla Carcinoma-in-situ Premeditation 1 to 2 3 to 4 5to9 Postmedicatjon 5. 0±0.49 0.8±0.40 2.8±0. 79 3.5±1.15 6. 0±2. 06 0. 9±0.21 0.6±0.35 0. 9±0.45 1.9±0.85 1. 5± 1. 05 8. 6±0. 63 0.6±0.35 1.2±0.52 0.8±0.56 3. 0±0. 56 0. 14±0. 08 0. 09±0.07 0.0 0 0. 20±0.22 0 0.40±0.39 0 0.40±0. 39 0 iFrom Pines,, Gregory, JunO, 1066. Italic values significantly dliler from premedicntlon values. Table XV.-The epidemiology of breast cancer1 ABRAHAM M. LILIENFELD EDepartment of Chronic Diseases, Johns Hopkins School of Hygiene and Public Heaitb Baltimore, Mdj SUMMARY A review of available data on the epidemiology of breast cancer indicated the following: (a) A remarkable stability of the trend of mortality from female breast cancer in the United States eince 1930; (b) Japan has the lowest death rate for female breast cancer, and Japan and Finland for male breaot cancer, in the world; (c) the logarithm of the age-specific death rates from female breast cancer canbe resolved into two linear components with the slope of the rates prior to 40-50 years of age being greater than the elope of those after 40-45 years of age; a similar change of slope, although to a lesser degree was observed for males. It was noted that for females this age group correspondedto the time of menopause; (d) female patients with breast cancer were more frequently never married or, when married,5married at a later age than women in general. Since female breast cancer patients more often gave a history of having had artificial menopause and single women had had artificial menopause less frequently than married women, it was hypothesized that the single- married differences may reflect the differences in frequency of artificial menopause among single and married women; (e) the inverse relationship between frequency and length of nuroing with female breast is far from being conclusive; (f) studies ehow that females with benign breaot disease have an excess risk of developing breast cancer, but more definitive studies are needed; (g) studies show the existence of familial aggregation of breast cancer among both males and females; (h) a study of male breast cancer patients indicated that a larger proportion of them had a history of orchitis, orchiectomy, therapeutic X-ray exposure and benign breast disease. These data were interpreted as suggesting the influence of hormonal factors as being of importance in the etiology of breast cancer, but more definitive and precise studies are needed. A program of epidemiological research was outlined emphasizing the need for integrating laboratory investigations with the field epidemiological studies. `Presented st asynqasslsm en EpldesssiologyolCancer' glvenat thssnnual meetingoftkeAmericas Association for Caster Research, Toronto, Canada, en May 13, 1563. 28 40-471 O-70-pt. 17-8 PAGENO="0114" 6946. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY bibliography 1. ALvIZOURI, as. AND RAMIREZ DE PITA, v. Experimental carcinon~a of the cervix, Am. J. Obst. and Gynec., 89: 940,1964. 2. ANDERSON, a. K., orI.MORE, c. E., AND scHNELLE, a. B. Utero-ovarian disorders asso- ciated with the use of medroxyprogesterone in dogs, S. Am. Vet. Med. Assn., 146: 1311, 1965. 3. BEECHAM, C. T. AND ANDEOS, 0. J. Cervical conization in pregnancy, Obst. and Gynec., 16: 521,1960. 4. BOYES, n. A.. Personal communication from the Cytological Diagnostic Laboratory of Vancouver, British Columbia, Canada. 5. CAvANAGH, a., MCLEOD, A. 0. w., AND FERGUSON, r. H. Carcinoma of the cervix among women in their twenties, J.A.M.A., 195 :.146, 1966. 6. cHaIsrolmassoN, W. as. The risk of cervical cancer in teenaged girls, J.A.M.A., 194: 176,1965. 7. CHRI5TOPHES5ON, w. ii. AND IABHRR, j. a. Relation of cervical cancer to early mar- riage and childbearing, New Eng. S. of Med., 273: 235,1965. 8. CHBI5TOPHEB5ON, w. as., PARKER, .i. E., AND DBYE, J. C. Control of cervical cancer, J.A.M.A., 179,1962. 9. cooK, u. H., OAMBLE, C. .s., AND SAI-rHEBTHwAITE, A. P. Oral contraception by norethy- nodrel: A 3-year field study, Am. S. Obst. and Gynec, 82: 437, 1961. 10. COPELAND, IC. as. Treatment of mammary dysplasia with special reference to micro- cystic disease of the breast, Am. S. Surg., 106: 382, 1963 11. DAY, a. Evaluation of exfoliative cytology as a screening method for pelvic cancer, Clin. Obst. and Gynec., 4:1183,1961. 12. DOCSCEBTY, M. a., sanva, a. ~., AND 5YMMOND5, B. a. Pseudomalignant endometrial changes induced by administration of new synthetic progestins, Proc. Staff Meet. Mayo ClInic, 34:323,1959. 13. DRill., v. A. Relationship of administered estrogen, progesterone, and oral contracep- tives to cancer of the breast and genital organs of women, Pacific Med. and Surg (West. S. Surg. Obst. and Gynec.), 73: November-December 1964. 14. ERICKsON, c. a., avanrrr, B. E., oaAvEs, L. as., Hr A.I.. Population screening for uterine cancer b~ vaginal cytology, J.A.M.A., 162:167,1956. 15. FERGUSON, 3. H. Positive cancer smears in teenage girls. S.A.M.A., 178: 365, 1961. 16. FERGUsON, .i. as. AND aBowN, 0. c. Cervical conization during pregnancy, Surg. Obst. and Gynec., 111:665,1960. 17. FIDLER, H. K., BOYE5, D. A., AUERSPEBG, N., AND LOCK, D. B. The cytology program in British Columbia. 1. An evaluation of the effectiveness of cytology in the detection of cancer and its application to the detection of carcinoma of the cervix, Canad. Med. Assn. S., 86: 779, 1962. 18. FLoWERS, C. a., JR. Effects of new low-dosage form of norethynodrel-mestranOl, S.A.M.A., 183:1115,1964. 19. poura, a. w. AND STE~A.ET, p* w. Comparative studies of cancerous versus noncancerous breasts, Ann. Snrg., 121:197,1945. 20. on.BERTsEN, v. A. Survival of asymptoniatic breast cancer patients, Surg. Obst. and Gynec., 122: 81,1966. 20a. ool.szisniaa, r. w. ~.im MAA5, r. as. Clinical evaluation of a sequential oral contra- ceptive, presented at the Sixth Pan American Congress of Endocrinology, October 1965, Mexico City. 21. ooaa, as~ AND BxBino, A. T. Carcinoma In situ of the endometriuin, Am. S. Obat and Gynec., 94: 134~ 1966. 22. HELLWIG, C. A. The fate of women with positive smears, S. Tnt. Cot Sung., 40: 465, 1963. 23. H0MBURGER-IISHMAN, Physiopathology of ~ancer, Second Edition, 1959, Hoeber-Rarper, New York. 29 PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6947 24. KAIHIOHFZKY, H. A. AND SWEBDLOw, H. Sex steroids and experimental invasive atypla in mice, Am. J. Obst. and Gynec., 89: 716,1964. 25. KAUFMAN, B. H. Cervico-vaginal cytology in the teenage patient, Acts Cytol., 9: 314, 1965. 26. KELLEY, a. BC. AND BAKER, W. n. Effects of 17.alpha-hydroxy progesterone caproate on metastatic endometrial cancer, Conference on Experimental Cancer Chemotherapy- Monograph 9:235, Bethesda, Md., National Cancer Institute, 1960. 27. KEI.LEY, B. s.c. AND BAKER, w. H. Progestational agents in the treatment of carcinoma of the endometrium, New Eng. J. of Med., 264: 1,1961. 28. KENNEDY, B. j. A progestogen for treatment of advanced endometrial cancer, J~A.M.A., 84: 102, 1963. 29. KISTNER, s. w. Histological effects of progestins on hyperplasia and carcinoma In situ of the endometrium, Cancer, 12:1106,1959. 30. KISTNEB, B. W., GBIYFITH5, C. I., AND CRAIG, 3. H. Use of progestational agents in the management of endometrial cancer, Cancer, 18: 1563,1965. 31. KISTNEB, B. w. Oral contraceptives. Safety factors In prolonged use of progestin~ estrogen combinations, pt. I, Postgrad. Med., 89: 207, 1966. 32. HISTHER, B. w. Hormonal treatment of premaUgnant lesions of the endometriu.m, in press. 33. LEE, BARRY A. Some effects of two oral contraceptive agents on the breast, in press. 34. ants, ~. p~, ra., 55 East 87th Street, New York, N.Y-Personal communication. 35. ui.rxNrsan, A.. s.c. The epidemiology of breast cancer, Cancer Rca., 23: 1503, 1963. 36. LUNesH, F. a., ca., err AL. Morbidity from cervical cancer: Effects of cervical cytology and socioeconomic status, 1. Nat. Cancer Inst., 35: 1015, 1965. 37. MAQDE0, K., err AL. Endometrial histology and vaginal cytology during oral contracep- tion with sequential estrogen and progestin, Am. J. Obst. and Gynec., 90: 395, 1964. 38. MARSHALL, c. a. Effect of cytologic screening on the Incidence of invasive cancer of the cervix in a semiclosed community, Cancer, 18: 153, 1965. 39. MOYER, ts. r.., err AL. Vaginal cytohormonal effects of long-term cyclic administration of synthetic progestins, Fert. and Steril., 15: 164,1964. 40. MUSTACCHI, P. AND OOBDAN, o. s. Frequency of cancer in estrogen treated osteoporotic women in Segaloff, A., Breast Cancer (the Second Biennial Louisiana Cancer Conf., New Orleans, Jan. 22-23, 1958), C. V. Mosby Co., 1958, p.163. 41. NoBLE, B. i.. Hormonal regulation of tumor growth, Pharm. Review, 9: 367, 1957. 42. PiNcus, a. Control of Fertility. Academic Press, New York and London, 1965. 43. PINCUs, 0. AND GARCIA, C-B. Studies on vaginal, cervical, and uterine histology, Metab- olism, 14: 344, 1965. 44. BEAGAN, j. s.c. Presidential address, Acta CytoL. 9: 265, 1965. 45. BICUART, B. M. AND VAILLANT, H. w. Influence of cell collection techniques upon cytologi. cal diagnosis, Cancer, 18: 1474,1965. 46. BUCK, v. c. Diseases of Laboratory Primates. W. B. Saunders Co., Philadelphia, 1959. 47. BUDEI., m w., rv AL. The role of progestogens in the hormonal control of fertility, Fert. and SterIl., 16: 158,1965. 48. BUDEL, H. W. AND EINCL, F. A. The biology of antifertility steroids, to be published in Acts Endocrin. 49. snnoNsxa~, I.. A., srr AL. Cancer of the cervix in a Mexican population, J.A.M.A., 191: 96, 1965. 50. scorr, a. s. External endometriosis. Postgrad. Med., 39:295, 1966. 51. 5EDLI5, A., ET AL. Cytology screening for cervical cancer in a municipal hospital, Cancer, 17:152,1963. 52. sHAPIRO, a., 5TRAX, PHILIP AND VENET, i.. Evaluation of periodic breast cancer screening with mammography, J.A.M.A., 195:111,1966. 53, SHIMKIN, K. B. Cancer of the breast. Some old facts and new prospectives, J.A.M.A., 183:358,1963. 54. aTxBic, a. Rate, stage, and patient age In cervical cancer-an analysis of age specific rates for atypical hyperplasla, in situ cancer, and Invasive cancer in a well population, Cancer, 12: 933,1959. 55. STEBN, E. AND DIXON, W. 3. Cancer of the cervix-A biometric approach to etiology, Cancer, 14: 163,1061. 56. sTERN, E. AND NEELY, s'. s.c. Dysplasia of the uterine cervix, Cancer, 17: 508, 1964. 57. s~vsms, o. s.c. AND WEIGEN, ~. ~, Mammography survey for breast cancer detection, Cancer, 19:51,1966. PAGENO="0116" 6948 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 58. Symposium-SymPosium Ofl the Effects of Progestational Agents, Acta CytoL, 6: 278, 1962. 59. TORRES, ~r. B., ~ Al.. Histological findings in the genital tract of females with class III smears, Acta Cytol., 8: 284,1964. 60. TOTE, F. AND SZONYI, I. The Inhibiting effect of a norsteroid on tumor formation and on the metabolism of tumor cells, Am. 1. Obst. and Gynec., 94: 518,1966. 61. TYLER, E. T. Current status of oral contraception, J.A.1~LA., 187: 562, 1964. 62. VARGA, A. AND KENRIKSEN, E. Clinical and histopathologic evaluation of effect of i7.alpha.hydrOXy~prOgester0ne caproate on endometrial cancer, Obstet. Gynec., 18: 658, 1961. 63. VARGA, A. AND HENRIKSEN, E. Histological observations on the effect of 17-alpha- hydroxyprogesterone-17-n.caPrOate on endometrial carcinoma, Obstet. and Gynec., 26: 656, 1965. 64. WALDROP, a. H. AND PALMER, ~r. p. Carcinoma of the cervix associated with pregnancy, Am. 3. Obst. and Gynec., 86:202,1963. 65. WAI.LACH, S. AND HENNEMAN, s' n. Prolonged estrogen therapy in postmenopausal women, J.A.M.A., 171:1657,1959. 66. WALSH, H., HILDEBBANDT, B. J., AND PBYSTOWSKY, H. Candidial vaginitis associated with the use of oral progestational agents, Am. 3. Obst. and Gynec., 93: 904, 1965. 67. WENTZ, w. is. Effect of a progestational agent on endometrial hyperplasia and endo- metrial cancer, Obstet. Gynec., 24:370,1964. 68. WHITE, T. T. Prognosis of breast cancer for pregnant and nursing women, Surg. Gynec. and Obst., 100: 661,1955. 69. WElD, 0. i. The meaning of class 3 of the Papanicolaou classification of specimens from the female genital tract, Acta Cytol., 8: 99, 1964. 70. WILD, o. L, il~ Al.. Statistical evaluation of the effect of hormonal contraceptives on the cytologic smear pattern, Obst. and Gynec., 27: 327,1966. 71. WISH, `i. L. "~ * * personal submitted data from taped material of patients on contra- ceptive hormones for at least 2 years. 72. WILSON, ii. A. The roles of estrogen and progesterone in breast and genital cancer, J.A.M.A., 182: 327,1962. 73. WILSON, B. A. AND WILSON, T. A. The fate of the nontreated postmenopausal woman; a plea for the maintenance of adequate estrogen from puberty to the grave, 3. Amer. Geriatrics Soc., 11:347,1963. 74. WILSON, B. A., RBEvIIUrI, B. B., AND WILSON, T. A. Specific procedures for the elimination of the menopause, West. 3. Surg. Obst. and Gynee., 71: 110,1965. 75. WILSON, B. A. AND THE WILSON RESEARCH FOUNDATION, INC., 777 Third Avenue, New York, N.Y-Personal communication. 76. WOMACK, N. A. Endocrine relationships between chronic cystic mastitis and cancer of the breast, Amer. Surg., 24: 618,1958. 31 PAGENO="0117" Appendix 3 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Report of the Task force on Metabolic Effects E. M. DELFS, M.D., CHAIRMAN 6949 Pituitary-Ovarian Function The controversy as to whether oral contracep- tives inhibit at the pituitary or at the ovarian level appears now to be resolved. Diczfalusy (1965) and his group present convincing evidence that these compounds inhibit at the pituitary level and that they interfere predominantly with the syn- thesis and/or release of LH rather than FSH. Similar results have been obtained by Lin (1964), Martin (1961), Taymor (1964 and 1965), and Ryan et al. (1966). The differences in these re- sults and those obtained by Loraine and others are probably related to differences in method- ology. Diczfalusy's group employed technics for estimation of LH and FSII individually whereas Loraine's conclusions that progestational com- pounds inhibit ovulation without affecting HPG excretion were based on a method for determina- tion of total gonadotrophic activity. Further- more, in Diczfalusy's study, oral contraceptive steroid combinations were administered simulta- neously with courses of 11MG or RHO followed by HOG. Results showed that administration of these compounds in dosages three times higher than those used for ovulation inhibition did not interfere with the ovarian reaction to exogenous gonadotrophins. Available evidence indicates that resumption of ovulation after cessation of oral contraceptives is prompt, occurring in 4 to 8 weeks in most cases. In a few women, amenorrhea persists for 6 months or more. This is not unlike the occasional pro- tracted anovulation following pregnancy or lacta- tion. Fertility is the best indicator of adequate pituitary-ovarian function. Goldzieher (1962) reported 62 percent success in the first cycle in women discontinuing medication with intent of becoming pregnant, which compares favorably with the 34 percent conception in the first cycle after stopping mechanical or chemical contracep- tives noted by Tietze (1959)~ Pincus (1964) found a pregnancy rate of 233 per 100 years of exposure after oral contraceptives were discontinued as com- pared with a rate of 17 before use in the same women. Pregnancy outcome was satisfactory with no significant increase in abortion, prematur- ity, abnormality, or developmental anomaly- Pincus (1964),Rice-Wray (1965). Long-term effect (beyond 6 to 8 years) of oral contraceptives on the pituitary-ovarian interrela- tion, on normality and duration of ovarian func- tion, and on fertility throughout the reproductive span is not known. Answers will require long- term physiological study and complex statistical control. Pituitary-Adrenal Function Oral contraceptives have been observed to prod- uce increased cortisol-binding by serum proteins but urinary excretion data for 17 hyroxysteroids and 17 ketosteroids have been equivocal. Recent work seems to clarify the effect on pituitary- adrenal function. ACTH activity was studied during progestin treatment by Leach and Margulis Table 1.-Comparison of .4CTH response during and after therapy Patfent Daring therapy After therapy Dffference (mg.) Controt ACTII Contra! ACTH Before After H. J 4. 6 19. 6 9. 3 27. 3 15. 1 18. 0 H.L 5.9 9.1 4.4 14.5 3.2 10.1 A. D 3. 6 5. 7 5. 3 14. 4 2. 1 9. 1 G. E 2. 0 8. 6 8. 8 28. 6 6. 6 19. 8 H. L 6. 4 10. 1 6. 0 14. 0 3. 7 8. 0 P. S 5. 9 9. 3 7. 5 23. 0 3. 4 15. 5 1. W 3. 7 11. 6 7. 6 18. 4 7. 9 11. 4 A. B 8. 1 10. 2 6. 1 31. 4 2. 1 25. 3 C. H 1. 1 9. 6 13. 6 17. 1 8. 5 3. 5 G. K 3. 0 17. 5 7. 7 19. 7 14. 5 12. 0 A. K 3. 6 6. 5 12. 8 16. 3 2. 9 3. 5 N. H 2.6 10.5 5.6 17.9 7.9 12.3 Mean 4. 2 10. 69 7. 8 20. 2 6. 4 12. 38 From Leach and Margals. 33 PAGENO="0118" 6950 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY (1965). Patients had been on oral contraceptives for 2 years or more. The 17 hydroxysteroid ex- cretion was determined during therapy and after metopirone, then after ACTH. A reduced res- ponsiveness to metopirone was found during pro- longed 00 therapy but the response to admin- istered ACTH was not affected. The authors in- ferred that the changes are related to inhibition of pituitary ACTH rather than altered adrenocor- tical activity. Responsiveness to metopirone in- creased significantly 2 months after medication was discontinued. No reports were found in which suppression of adrenal activity resulted in impaired response to stress. Thyroid Function In women taking oral contraceptives there is some variability in response to thyroid function tests. The majority show increase in the blood of thyroxine-binding globulin (TBG) and PBI and decrease in T8-RBC uptake test. The PBI is usually elevated 25-40 percent above pretreat- ment level but may rise into the hyperthyroid range. Hollander et al. (1963) showed that the PBI rises rapidly in the first 7 days after medica- tion is started, reaches a plateau at about 20 days and remains stationary for the duration of medi- cation. After medication is discontinued the tests return to normal levels in about 2 months. (Flor- sheim and Fairclothe-1964). Radioiodine stud- ies.are variable and inconclusive. These thyroid effects are secondary to estrogen increase of the binding proteins. The changes seem to be comparable to those occurring in nor- mal pregnancy and no clinical evidences of hyper- thyroidism have been reported. If TSH secretion is altered by oral contracep- tives, this may be masked by the increased thyrox- ine binding. No data are available on this point. Carbohydrate Metabolism Data available for examination suggests that the effect of oral contraceptive agents on carbo- hydrate metabolism may be unpredictable. Mechanisms of actions described are contradictory and complex. On the one hand evidence indicates that estrogens hinder the genesis of experimental diabetes, reduce glycosuria and in humans, may reduce insulin requirement. The proposed mech- anisms of action include (a) action on the pituitary causing reduction in growth hormone and (b) action on the pancreas causing islet cell hyper- trophy and increased beta cell activity. Several reports indicate that estrogen lowers fasting blood sugar by approximately 20 percent in humans and the higher the initial value for blood glucose the greater the decrease with estrogen. Some dia- betics, mostly maturity onset type, show lower insulin needs when estrogens are given. On the other hand diabetogenic effects have been described with respect to estrogens. This may be an anabolic effect, the increased appetite, increased dietary intake being the causative factors. How- ever, an increase in protein binding of insulin with a reduction in the percentage of biologically active circulating insulin has not been excluded. The relationship of estrogens to elaboration of bind- ing proteins is well recognized. This is of course dependent upon an intact liver function. Estro- gens may stimulate production of anterior pitu- itary ACTH and indirectly increase the produc- tion of adrenal diabetogenic steroids but again, in- creased cortisol binding could offset this effect. Kitay found that after gonadectomy female rats responded with an increase in body and pituitary weight and a decrease in adrenal weight. Treat- ment with estradiol caused an increased secretion of pituitary ACTH and an increase in adrenal weight. In view of these opposing actions a case could be made for either a favorable or an unfavorable effect of drugs containing estrogens upon patients with a diabetic disthesis. It seems im- portant to determine whether the balance of the sum of these bioloric effects is deleterious or favor- able in women predisposed to diabetes. Adverse effect of the progestins upon carbo- hydrate metabolism reported in several recent com- munications indicate a potentially serious problem, if valid. In contrast to less prevalent conditions in which cause and effect relationship to treatment is difficult to assess, diabetes is a common health hazard. Furthermore, the estimated prevalence rate in the United States for 1959 (Remein) was 16.9 per 1,000 with cases about equally divided be- tween cases of known diabetes and cases previously unsuspected. The unrecognized group deserves particular attention. If the current concept of the genesis of diabetes is accepted, i.e., that a genetic predisposition is present from conception and that stress situations can precipitate its appearance or aggravate the existing condition, then individuals with a family history of diabetes, an obstetric 34 PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6951 record suggestive of this disorder or laboratory evidence of reduced carbohydrate tolerance war- rant special study. Investigations to date revealthe following: Javier found reduced glucose tolerance in 40 percent of women on ovulatory suppressants. Gershberg and coworkers performed glucose tolerance tests in women taking Norethynodrel with mestranol, 47 of whom had no family history of diabetes and 12 had a positive family history for diabetes. The instance of abnormal glucose tolerance in each group was as follows: Table 1! tn percent] History FastIng 1 hour 2 hours Negative 8 17 43 Positive 17 33 58 Spellacy is studying the plasma insulin, levels and response to intravenously administered glu- cose loads. In a preliminary report on 25 normal women, the mean values were as follows: TabI e 15! Control Drug Rid F 1/4 1/2 2 F 1/4 1/2 2 Mean Glucose mg % 79 195 125 75 81 215 147 Mean Insulin uU/mL 18 52 39 16 25 76 52 of normal women and in a group of genetically predisposed women before, during and after the use of oral contraceptives. The following ques- tions need to be answered: Are oral contraceptive agents capable of induc- ing diabetes in normal subjects or do the few in- stances in which a significant abnormality was found in the glucose tolerance of control subjects indicate a genetic predisposition about which the patient has no knowledge? What is the incidence and the magnitude of reduced carbohydrate tolerance in genetically pre- disposed individuals after prolonged use of oral contraceptive agents as compared with the re- sponses in genetically predisposed individuals during the same period of time if no oral contra- ceptives are `administered? If an abnormality is found in carbohydrate tol- erance or in insulin activity in either the control or the treated predisposed group, is it of a tempo- rary nature or can permanent diabetes be induced by prolonged use of these agents? These areas have been studied with respect to the diabetogenic effects of pregnancy and similar technics should be applied to the diabetogenic effects of oral contraceptive agents. The following study is proposed: Subjects-Study patients will include women with a family history of diabetes, an obstetric record of large or stillborn infants, an abnormal glucose tolerance test during pregnancy which re- turns to normal postpartum nnd those with a nor- mal glucose tolerance test but abnormal cortisone glucose tolerance test in the nonpregnant state. These will be matched with a group of normal women in whom family histories, and obstetric records are negative for diabetes and the standard 23 glucose tolerance test during pregnancy or the cortisone glucose tolerance test in the nonpregnant state is normal. Methods-Pretreatment values for blood glu- cose and for circulating insulin will be determined in the fasting state and at 1, 2 and 3 hours after a 100 gm. glucose load. The Somogyi-Nelson method for blood glucose and the Grodsky and Forsham immunochemical assay for total extract- able insulin will be used. The study patients will be divided into two groups. Oral contraceptive agents will be administered to one half the total number of study patients. An intrauterine de- vice or, if they choose, nc~ contraceptives will be used in the other half of the study group. Glu- The difference between the control and the treated groups show higher values for both glu- cose and circulating insulin at each time interval of the test but the differences are slight and the top normal values are not stated in the report. Diabetic suspects were not included. Individual case reports (Paros) of patients with known diabetes have shown increased insulin demand while on oral contraceptives with return to previous insulin dosages after withdrawal. There is urgent need for a detailed study of carbohydrate metabolism in a much larger group 76 35 PAGENO="0120" 6952 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cose tolerance tests and insulin assays will be performed during the course of treatment at in- tervals corresponding to 3 months, 6 months, and 12 months. Tests will be repeated at 1 week and at 3 months posttreatment. All subjects in the control group will receive oral contraceptive agents. Pretreatment, interval and posttreatment tests will be identical with those performed in the study groups. Comment.-Based on experiences with the study of carbohydrate metabolism during preg- nancy it is evident the study group requires a group oriented control. Some of the diabetic suspects with relatively minor derangements of the glucose tolerance curve during pregnancy have progressed to an overt diabetic stats spontaneously. It is now known how important an influence preg- nancy exerts in hastening the clinical appearance of the disease or whether it does so at all. It is quite possible that stress hyperglycemia may de- velop in either of the two groups of study patients. If permanent hyperglycemia or abnormal insul- inogenesis should be induced in normal patients by the use of these agents, current concepts of "pre- diabetes" may need to be revised. Liver Function The question of oral contraceptives and the liver has been reemphasized by reports of Bisalo et al. on postmenopausal women who developed de- ranged function tests and (occasionally) jaun- dice on medication. Subsequently, Eisalo has made similar observations on younger women. A number of other workers in the past 2 years have reported altered liver function tests, especially the B.S.P. and serum transaminase. A few investi- gators have not corroborated these observations (tables 4, 5, 6). Thirteen cases of jaundice have been reported in women taking oral contraceptives in which the relationship to the medication seems clear (table 7). The clinical courses and labora- tory findings were similar to cholestasis of preg- nancy. Liver biopsy of several showed changes of cholestasis and some hepatocellular damage. A quarter of the jaundiced women had previously had cholestasis of pregnancy, which suggests an in- born metabolic error or sensitivity reaction. In summary, there have been no hepatic deaths reported, but an occasional woman develops clin- ical jaundice associated with definite though mild liver damage. It seems likely that such cases are more frequent than have been reported. Some de- gree of liver stress is present in many women on oral contraceptives, as evidenced by deranged func- tion tests. These derangements are an exaggera- tion of mild alterations seen in some pregnant women. They regress when medication is stopped. Women who have had cholestasis of pregnancy or who have familial, congenital, or acquired de- fects of biliary secretion are most vulnerable. This may be an acceptable degree of abnormality but would seem to warrant further sequential study and reporting of cases of clinical jaundice and a continuation of caution in labeling. Lactation Oral contraceptives in the higher doses (5 and 10 mg. of progestogen) tend to decrease or stop lactation in many women in the first or second cycle of use. (Satterthwaite & Gamble 1962; Rice- Wray 1963.) Breast enlargement may occur in the nursing infants when the mother takes oral contraceptives. (Curtis, 1964.) In experimental animals, administration of sex steroids to the newborn may affect the "female pattern" or "male pattern" of the development and result in sterility in the adult animal. The human infant appears to have better protective mechan- isms and there is no evidence of such a sterility effect in the human at the present time. Masculinization There is clear evidence that the oral contracep- tive agents can cause congenital malformations of the female genital tract when the fetus in utero is exposed to these drugs during the first 16 to 18 weeks of gestation. Anatomic effects have been demonstrated in the experimental animal and in the human. Experimental production of genital lesions in the rhesus monkey (Wharton & Scott-1964) was unequivocal. Norethindrone was given in rela- tively large doses (25 mg. per day for 5 days per week) from approximately 30 days to term (160 days). Eight of the ten fetuses were stillborn. All five females were virilized; males showed a greater degree of cryptorchidism than expected. Six rhesus mothers treated with 50 mg. proges- terone I.M. daily during the same period of preg- nancy suffered no deleterious effects. All infants were delivered alive at term (three males and three females) and none showed genital malformations. 36 PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6953 In the human, there is no evidence that proges- tins increase the risk of intrauterine death. There is considerable evidence for masculinization. Wilkins (1960-61) collected cases with masculini- zation, as follows: Ethisterone Norethindrone - Norethinodrel Testosterone - Progesterone - Stilbestrel No hormone therapy. Total Jacobson (1962) treated 385 consecutive preg- nant women with norethindrone and observed maternal masculinization effects in 5.5 percent and fetal virilization in 23.7 percent. In summary: Progestins exhibit potentiality for masculini- zation of the female fetus. Anatomic abnormali- ties are easily corrected surgically. Subsequent effect on reproduction in the human is unknown. If any synthetic progestin is to be used in treat- ment of threatened or habitual abortion, consider- ation must be given to its androgenicity for the fetus. The 19 noncompounds are contraindicated for such use. Test (normal values) Number of subjects Number with abnormal results SGOT (35 units) SGPT (35 units) Bilirubin (1 mg./100 ml.) Thymol turbidity test (4 units).__ Alkaline phosphatase (8 units)__ - B.S.P. retention test (<5% at 45 mins.) 243 243 202 202 199 12 14 (5. 8%) 15 (7. 4%) 0 22 (10. 9%) 4 (2%) 5 (41. 6%) Table V-Reports of altered liver function Table VS-Reports of normal liver function Author Medication Time used Cases Teats Abaurmatities Swyer & Littel Orthonovin, Enovid+ (9 preparations). 3 to 6 years 12 Ceph. Chol., T. T., PGOT, bilirubin. Linthorst Lynestrenol, LyndioL.... 14 to 43 months 52 Alk. phos., T. T., SGOT, SGPT. Swaab Lyndiol, Conovid 6 months 60 SGOT (342 tests) Rice-Wray Lyndiol 3 to 12 months 56 SGPT (1 test eaeh)_... 0 0 0 0 34 35 15 Table IV.-Incidence of abnormal results of liver- function tests - 4 * 10 * 101 From Lsrsoa-Cohn. Author Medication Time used Cases Elevated B.S.P. Elevated SOOT SOPT Eisals, et al Larsson-Cohn Borglin Knutsaon Tyler Lynestrenol Volidan Lyndiol Norethindione-mestransL Lynestrenol, Lyndisl Lyndiol 7 compounds 40to42Odays 20 days - 20days 6 to 8 months Months 1 to 2 months To 8 years 109 241 36 10 125 19% to 48%...... (12) 42% 32% 4% to 18% 5% 7% 16% 20% 50% Some abnormal. 37 PAGENO="0122" 6954 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table V11.-Clinical jaundice with oral contraceptives Author Medication Time used Cases Previous pregnancy Relapse Remarks Carlatrom, et aL - Sotanlemi, et aL - - norethisterone- ethinytestradiol. Volidan 6 to 15 days - -- 1 1 epid. hep. at 10 yrs. . Biopsy-hepatocanal. cholestasis. Fawcett, et al Wetterberg Baines Anovlar Lyndiol norethindrone- 4 months 4 months 1 month 1 1 1 Larsson-Cohn Holzbach ethinylestradiol. norethindrone- mestranol. do 1 month 2 1 1 1 1X Biopsy-cholestasis and hepatocell. damage. Sister and mother had pregn. jaun- dice. Cullberg, et a! Tait Alderheuz, et al Lyndiol norethindrone- ethinylestradiol. do 1 month 1 month 1 1 3 1-x2, 1-xlX 3X 3X Biopsy-as above. 2 different drugs. 3 different drugs. Totals 13 4 3 88 PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6955 bibliography 1. ALDER5mEUz & IKONEN. Oral contraceptives and liver damage, Brit. Med. J., 2: 1133, 1964. 2. ALEXANDEB, a. w., AND MARMORST0N, ~. Effect of two synthetic estrogens on the level of serum protein-bound Iodine in men and women with atherosclerotic heart disease, 1. Clin. Endocrinol., and Metab., 21:243,1961. 3. BASSES, 0. F. Jaundice in a patient taking norethisterone compound tablets, Lancet (Let.) 1:108-9,1965. 4. BAKKE, j. Hepatic impairment during intake of contraceptive pills: Observations In postmenopausal women, Brit. Med. J., 1: 631-32,1965. 5. BE5CE, ~. K. srr sr.. Some systemic effects of a progestational agent (Etbynodiol Diace- tate and Mestranol), Metabolism, 14: 387-397, 1965. 6. BosazovASNi, A., GEORGE, A., AND GRUMBACH, M. SO. Masculinization of Female Infants Associated with Estrogenic Therapy Alone During Gestation, J. Clin. EndocrinoL, 19: 1004, 1959. 7. 50551.15, N. E. Oral contraceptives and liver damage, Brit. Med. J., 1: 1289-90, 1965. 8. BRYANS, F. 5. Contraceptives. (Yanad. Med. Ass. J., 92-287-88, 1965. 9. CARLSTBOM, H., ROOLUND, S., AND REIZENSTEIN, s'. Oral contraceptives and liver damage, Brit. Med. J., 1: 992,1965. 10. CARNINOTON, e. B., AND MCwILLIAMS, N. B. Investigation of serum insulin activity during pregnancy in normal and in subclinical diabetic mothers, Am. J. Obst. & Gynec., In press, 1966. 11. CABEINOTON, E. B., AND MES5ICK, B. B. Diabetogenic effects of pregnancy. 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Effects of oral ovulation inhibitors on serum protein-bound iodine and thyroxin binding proteins, Proc Soc. Exp. Biol. & Med., 117- 56-58 (October), 1956. 26. FREEDBERO, I. H., HAMOLSKY, H. W., AND FREEDBERO, A. s. The thyroid gland In pregnancy, New Eng. J. Med., 256: 505-510 and 555,1957. 27. GARCIA, 5. AND PINCUS, o. Ovulation Inhibition by progestin-estrogen combination, list. J. Fertil., 9: 95, 1964. 28. OERSHBERO, H., JAVIER, Z., AND HULSE, as. Glucose tolerance in women receiving an ovulatory suppressant, Diab. 13: 376,1964. 29. 0OLDZIEHER, ~. w., ST AL. Fertility following termination of contraception with nore- thindrone, Am. 1. Obst. & Gyn., 84: 1474,1962. 30. HAMOLSKY, iC w., GOLODETZ, A., AND FREEDBERO, A. s. The plasma protein thyroid hormone complex In man, 1. Gun. Endocrin., 19: 103,1959. 31. Hepatotoxicity of Drugs, Lancet, 1: 1056, May 19, 1962. 32. HOLLANDER, C. S., GARCIA, A. M., STTJRGIS, S. H., AND 5ELENKOW, H. A. Effect of an ovula- tory suppressant on the serum protein-bound iodine and the red-cell uptake of radio- active tri-lodothyronine, New Eng. J. Med., 269: 501,1963. 33. HOLZBAcH, ii. T., AND SANDERS, A. H. Recurrent intrahepatic cholestasis of pregnancy: Observations on pathogenesis, J.A.M.A., 193: 542-44, 1965. 34. JACoBSON, B. D. Hazards of Norethindrone Therapy During Pregnancy, Amer. 1. Obst. & Gynec., 84-962,1962. 35. JAVIER, z. c. The diabetogenic effect of estrogen, Diab., 14: 458, 1965. 36. JOHANNISSON, E., TILLINOER, K. 0., AND DICZPAT.USY, E. Effect of oral contraceptives on the ovarian reaction to human gonadotropins in amenorrheic women, Fertil. & Steril., 16: 292, 1965. 37. JONES, H. W., .ni., AND WILKINS, i.. The Genital Anomaly Associated with Prenatal Exposure to Progestogena, FertiL & Steril., 11:148, 1960. 38. KITAY, r. L Pituitary-Adrenal function in the rat gonadectomy and gonadal hormone replacement, EndocrinoL, 73: 253, 1963. 39. KI.EINER, 0. 3., KKESCH, L., AND ARIAS, I. as. Studies of hepatic excretory function II.: The effect of norethynodral and mestranol on bromsulfalein sodium metabolism in women of childbearing age, New Engi. J. Med., 273: 420-23, 1965. 40. KNUTSSON, s. ET AL. Anovulatory effect of lynestrenol in combination with mestranol, Acta Obst. Gyn. Scand., 54: 325-38,1965. 41. LARSSON-CO5IN, u. Oral contraception and liver-function tests, Brit. Med. 1., 1: 1414-5, 1965. 42. LARSSON-COHN, U., AND STENRAM, U. Jaundice during treatment with oral contraceptive agents; report of two cases, J.A.M.A., 193-422-26, 1965. 43. LEACH, B. Ii., AND SIAROULIS, a. ii. Inhibition of adrenocortical responsiveness during progestin therapy, Am. P. Obst. & Gynec., 92: 762, 1965. 44. I.IN, T. J., DURKIN, J. W., JR., AND KIM, v. j. The control of reproduction and the function of certain endocrine organs as reflected by biochemical and biological assays, Curr. Thor. Res., 6:225,1956. 45. LINTIIORST, o. Liver function after long-torus progestational treatment with and with- out oestrogen, Brit. Med. J., 2: 920,1964. 46. LOP.AINE, A. A. Hormone excretion patterns during and after the long-term administra. tion of oral contraceptives, Acta Endocr., 50: 15, 1965. 40 PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6957 47. LORAINE, j* A. The effect of anti-ororatory compounds on hormone excretion, Internat'l 1. FertiL, 8: 155, 1964. 48. MARTIN, L., AND CUNNINGHAM, K. Inhibition of human pituitary gonadotropin output by 17-alpha.ethinyl, 19-nortestostérone in Human Pituitary Gonadotropins, Ed. A. A. Albert. Springfield, Thomas, 1961, p. 226. 49. PAROR, N. L. Side effect of oral contraceptives, Brit. Med. J., 1: 630, 1964. 50. PA5CHKI5, K. E., CANTAROW, A., AND PEACOCK, W. C. The influence of estrogens on thyroid function as measured by uptake of radioactive Iodine, Proc. Soc. Exper. Biol. & Med., 68: 485,1948. 51. PINCU5, o. The control of fertility, New York and Londdn, Academic Press, 267-268, 1965. 52. P0CHIN, F. E. The iodine uptake of the human thyroid throughout the menstrual cycle and in pregnancy. Clin. Sc., 11: 441, 1952. 53. PROvEST: Med. Let-Drugs & Ther., 7: 5-6, Jan. 15, 1965. 54. RESIEIN, Q. a. A current estimate of the prevalence of diabetes mellitus In the U.S., Ann. N.Y. Acad. Sc!., 82:229,1959. 55. BICE-WRAY, E. Oral contraceptives and liver damage, Brit. Med. J., 2: 1011, 1964. Com- ment on Eisalo, et al.: Ibid. August 15, p.426. 56. RICE-WRAY, E., GOLDZIEHER, J. W., AND ARANDA-RUSSELL, A. Oral progestins in fertility control: a comparative study, FertiL & Steril., 14: 402,1963. 57. RICE-WRAY, F., GONZALEZ, 0., FERRER, S., ET AL. Clinical evalation of norethindrone acetate Infertility control, Am. J. Obst. & Gynec., 93: 115,1965. 58.. BE-WaRY, E., SCHULTZ CONTRERAS, K., GUERRERO, I., AND ARANDA-RTJ5SELL, A. Long. term administration of norethindrone in fertility control, J.A.M.A., 180: 355, 1962. 59. RYAN, A. K., JR., 0055, D. A., AND REID, D. E. Pituitary gonadotrophins during long-term Enovid therapy, Am. 1. Obst. & Gynec., 94: 515,1966. 60. 5ATrERTHWATFE, A. P., AND GAMBLE, C. ~. Conception control with norethinodrel. Progress report of a 4-year field study at Humaco, P.R., J.A.M.Wom.A., 17: 797, 1962. 61. SAUNDERS, F. A., AND DRILL, V. A. Some biological activities of 17 ethynyl and 17 alkyl derivatives of 17 hydroxyestrenones, Ann. N.Y. Acad. Sc!., 71: 516, 1958. 62. BEERLOCK, s. Jaundice, Brit. Med. J., 1: 1359, 1962. 63. SHERLoCK, 5. Jaundice due to drugs, Proc. Roy. Soc. Med., 57: 881-86, 1964. 64. BOTANIEMI, F., KREU5, K. E., AND SCHF.ININ, T. K. Oral contraception and liver dsmage, Brlt. Med. J., 2: 1264-1265, 1964. 65. SPELLACY, W. N., AND GOETZ, F. C. Plasma insulin in normal late pregnancy, N. Eng. J. Med., 263: 988, 1963. 66. SPELLACY, W. N., AND SCHOELLER, K. L. Insulin and glucose changes in the blood of subjects taking oral contraceptives, Clin. Res., 13: 407 (Oct.) 1965; abstr. 67. STOLE, BASIL A., FT AL. Oral contraceptives and liver damtige, Brit. Med. J., 1: 723, 1965: comment on Eisalo, et al. Aug. 15, p. 426, and Tyler, Nov. 14, p. 1264. 68. SWAAB, L. I. Oral contraceptives and liver damage, Brit. Med. J., 2: 755, 1964. 69. sw.e&s, L. I. A field trial with Lyndiol and Conovid, mt. J. Fertil., 9: 107, 1964. 70. SWYER, 0. I. K., AND I.ITTEL, V. Absence of hepatic Impairment in long-term oral contra- ceptive users, Brit. Med. J., 1: 1412-14, 1965; edit. comment, Ibid, p. 1391. 71. ThIT, ALAN S. Oral contraceptives, Med. J. Australia (Let.), 1: 667, 1965. 72. TAYMOR, K. L. The effect of synthetic progestiDs on pituitary gonadotrophin excretion, J. Clin. EndocrinoL, 24: 803, 1964. 73. TAYMOR, K. L., AND BIZKALLAH, T. Effect of norethindrone acetate upon gonadotrophin- Induced ovarian function, J. of Endocr. and Metab., 25: 843, 1965. 74. TIETZE, - ~. Differential fecundity and effectiveness of contraception, Eugenics Rev., 50: 231,1959. 41 PAGENO="0126" 6958 COMPETITIVE PROBLEMS IN THE DRUG INDUS~PRY 75. TYlER, L T. Eight years' experience with oral contraception and an analysis of use of low-dosage norethisterone, Brit. Med. J., 2: 843-47, 1964. 76. WALSER, H. C., MAEOOLIS, a. a., AND I.ADD, s z. Effects of prolonged administration of progestins on the endometrium and the function of the pituitary, thyroid and adrenal glands, mt. 1. FertIl., 9:191,1964. 77. warraaasxo, I.. Oral contraceptives and acute Intermittent porphyria, Lancet (Let. to Ed.), p. 1178-79,1965. 78. WHARTON, L. B., JP.., AND scorr, a. a. Experimental Production of Genital Lesions with Norethindrone, Am. J. Obst. & Gyn., 89: 701,1964. 79. WILKINS, L. Masculinizatlon of Female Fetuses Due to Use of Orally Given Progestins, y.A.M.A., 172:1028,1960. 80. WILKIN5, L., JONES, H. W., Ja., H0LMAN, o. H., AND STEMPFEL, a. 5., JR. Masculinization of the Female Fetus Associated with the Administration of Oral and Intramuscular Progestins During Pregnancy: Nonadrenal Female Pseudohermaphroditism, J. Clin. Enrocrlnol., 18: 559, 1958. 42 PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 6959 Appendix 4 Report of the Task f~rce on Efficacy K. ADAMS0N5~ M.D., CHAIRMAN The following uses for which therapeutic effi- cacy has been claimed were reviewed: A. fertility control B. treatment of amenorrhea C. treatment of dysmenorrhea P. treatment of endometriosis E. treatment of functional uterine bleeding F. habitual abortion G. miscellaneous uses (Note.-With the exception of subject A the comments pertain only to combination prepara- tions containing a progestational agent and an estrogen.) A. Fertility Control The efficacy of the older oral progestational agents in fertility control was considered excep- tional when compared with that of other thera- peutic agents used in medical practice, such as entibiotics, analgesics and tranquilizers. Even when all contraception failures are considered to represent drug failure rather than patient failure in proper administration of the drug, these com- pounds are almost invariably effective. The more recently introduced sequential preparations were also found highly effective in controlling fertility, although to a slightly lesser degree than the pro- gestational agents. The frequency of pregnancies occurring while patients were receiving sequential preparations averaged approximately 1.2 per 100 women years. It was considered that a sufficient number of patients have been studied up to 2½ years to justify statistically valid conclusions. On the other hand, the group sizes representing pa- tients that had been followed for up to 54 cycles were too small to offer anything more than gen- eral impressions. It is noteworthy that the fre- quency of pregnancies occurring while on medica- tion remained unchanged over the 2½ year period, thus supporting the contention that tolerance to or escape from the medication probably does not occur. The Committee commented on the terms "unwanted" and "unplanned" pregnancies used in the submitted material. Since the individual cir- cumstances under which the pregnancies occurred did not appear to be known to the investigator, the use of these terms did not seem to be warranted. From the statistical point of view, difficulties were encountered in the interpretation of "woman years" since the value of large numbers observed for a short period is not comparable to long term observations on a small sample. It was also pointed out that the high efficacy of oral contra- ceptives may not be entirely due to suppression of ovulation but may result from other mechanisms such as changes in cervical mucus and endometrium. B. Treatment of Amenorrhea The efficacy of oral contraceptives in the treat- ment of amenorrhea could not be readily ascer- tained by the material avaiinble to the Committee because of the endpoint used. Successful treat- ment was considered one in which uterine bleeding was accomplished following cyclic withdrawal of the medication. It was the opinion of the Com- mittee that such an endpoint does not specifically measure the efficacy in treating amenorrhea, since cyclic withdrawal bleeding and menstrual periods are different biologic phenomena. If efficacy in the treatment of amenorrhea is being claimed it could be based only on evidence that menstrual cycles are established following discontinuation of drug therapy. Such information was not con- tained in the submitted material. However, it u-as pointed out that if the objective of the thera- peutic effort is to produce cyclic withdrawal bleed- ing in the amenorrheic patient, the oral contra- ceptive drugs can be considered as efficacious since this endpoint was achieved in 80 to 90 percent of treated patients. 43 PAGENO="0128" 6960 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Additional information desired: 1. Followup data on amenorrheic patients af- ter discontinuation of the cyclic therapy with oral contraceptives. 2. Comparison with the frequency of spon- taneous resumption of menstrual periods in similar patient material. C. Treatment of Dysmenorrhea The comments pertaining to drug efficacy in the management of patients with dysmenorrbea were similar to those alluded to in the previous para- graph. The situation was even more complicated because of the difficulty to quantitate the principal variable. Dysmenorrhea is known to disappear spontaneously and relatively "high cure" rates have been obtained with placebo preparations. No followup data were available in the submitted material, and thus, in reality, the reports per- tained to the evaluation of pain during cyclic withdrawal bleeding rather than during a men- strual period. The data suggests that in certain patients the progestational agent might be of value in the treatment of dysmenorrhea. How- ever, additional information is required before the therapeutic efficacy can be considered as demon- strated. From the statistical point of view the submitted material was considered unsatisfactory because of the small number of patients in the individual series. It was surprising to find tint a very small sample had been utilized in the study of such a common phenomenon. The members were cog- nizant of the difficulties in designing controlled studies, since placebo preparations do not pro- vide contraception, a fact that cannot be left un- disclosed to the patient. D. Treatment of Endometriosis In evaluating the material in which the diagno- sis of endometriosis was established by histologic examination, the Committee finds a high thera- peutic value of continued and prolonged (6 to 12 months) progestational therapy in conservative management of the affected patient. In the well documented cases it is reasonable to anticipate a favorable response in 75 to 90 percent. It must be, however, pointed out that recurrence might be expected in an appreciable proportion of patients after succession of medication. In contrast, the therapeutic efficacy in subjects in which the diagnosis of endometriosis had been made on grounds of physical examination or his- tory only, was uncertain. Undoubtedly, this pop- ulation contains a variety of disease entities such as residual pelvic inflammatory disease, adnexal pathology of noninflammatory nature, etc., which are not expected to improve during therapy with progestational agents. E. Treatment of Functional Uterine Bleeding The claims for therapeutic efficacy in treatment of functional uterine bleeding were met with sim- ilar criticism that applied to dysmenorrhea and amenorrhea. The Committee finds the pooling of a variety of conditions summarized under the heading of "Functional Uterine Bleeding" inap- propriate because the individual disease entities have specific and different etiologies. Thus, an overall efficicacy index might not reflect the favor- able results achieved in certain categories or vice versa, and create the impression of therapeutic merit for disease entities which are not susceptible to therapy. Irregular menstrual periods are expected to re- spond in a high percentage of cases to therapy if cyclic withdrawal bleeding is made synonymous to a menstrual period, whereas metrorrhagia might be and appears to be considerably more resistant to the advocated therapy. Patients with hypermenorrhea appear to have shorter periods and less blood loss when placed on cyclic therapy with these compounds. Difficulty in constructing a meaningful endpoint for the various categories was apparent since most of the functional bleeding abnormalities are known to be self-limiting. F. Habitual Abortion The Committee found no data to indicate that any of the oral contraceptives are effective in alter- ing the natural history of patients with habitual abortion. Although the reasons for habitual abortion are not known, it appears that in a con- siderable percentage of cases it is due to a genetic defect in the enThryo. These cases, in all certainty, would not benefit from steroid therapy. It was pointed out that clear distinction should be made between synthetic progestins, some of which have known androgenic properties, and the native product progesterone when their use in the therapy of threatened abortion or habitual abortion is con- sidered. 44 PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6961 G. Miscellaneous Uses The value of oral contraceptives in the treat- ment of conditions such as menopausal syndrome, acne, chronic vulvar infections, psychotic and emotional disorders could not be ascertained at present because of the preliminary nature of the available reports. Summary The efficacy of the older progestational agents in fertility control is exceptional and approaches unity. The more recently introduced sequential preparations are also highly effective in reducing the incidence of pregnancies although with not quite the same degree of certainty as the prog~ta- tional compounds. Regarding other uses, the effi- cacy is less certain. Most studies lack control and followup data and, consequently, it is difficult to determine whether drug treatment resulted in a significant departure from the course expected from the natural history of these frequently self- limiting disorders. Consistently the phenomenon "Cyclic withdrawal bleeding" is confused with menstrual period which is unwarranted. Pelvic endometriosis and hypermenorrhea, how- ever, represent notable exceptions. In these dis- orders, prolonged therapy appears to offer excel- lent palliation and an occasional cure. 45 40-471 O-70--pt. 17-9 PAGENO="0130" 6962 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY bibliography 1. Clinical Reports to Ortho Research Foundation based on 80 U.S. Private Practice studies. 2. Clinical Reports to Ortho Research Foundation based on 25 Canadian Private Practices. 3. Clinical Reports to Ortho Research Foundation submitted by: Planned Parenthood Clinic, Las Angeles, Calif.; S. J. Behrinan, M.D., Ann Arbor, Rich.; W. P. Hutcherson, M.D., Chattanooga, Tenn.; A. P. Satterth, M.D., Puerto Rico; Mt. Sinai Hospital, New York, N.Y.; Detroit Planned Parenthood Clinic, Detroit, Rich.; J. W. Goldzieher, M.D., San Antonio, Tex. 4. LIVINGSTON, N. The use of Medroxyprogesterone Acetate and estrogen to inhibit fertil. ity, Internat. 1. FertiL, 8: No.3, July-Sept., 1903. 5. asoomsi, K. The use Of Provera Ethinyl Estradiol in conception control, Internat. 1. FertiL, 8: No. 3, July-Sept., 1963. 6. GoULD, s Control of ovulation with Medroxyprogesterone-estrogen, Internat. 1. Fertil., 8: No.3, July-Sept., 1903. 7. sr&auuus, a. a., ET Al.. Report to the Research Division, Department of Clinical Investi. gation, Parke Davis & Co. 8. GOLDZIEHES, 5. W., MOSES, I.. E., AND ELLIS, L. T. A field trial with a physiological method of conception control, in Research in Family Planning, Clyde V. Riser, ed., Princeton University Press, 1962. 9. GOLDZIEHER, J. W., MARTINEZ-MANAUTOU, 3., LIVINGSTON, N. B., JR., MOSES, L E., AND SOCE-WRAY, E. The use of sequential estrogen and progestin to inhibit fertility, West. J. Surg., 71: 187, 1963. 10. Clinical data on file, Eli Lilly & Co. 11. o0LszIEHEB, ~. w., ET Al. Study of norethindrone In contraception, J.A.M.A., 180: 359-361,1902. 12. COWAN, I.. Norethindrone and Mestranol tablets for endometriosis and other condi- tions. A clinical study of 98 caseS, International Symposium on Ortho Novum 1st- Toronto, Canada, 1964. 13. LAPOINTE, a. Therapy of cyclic dysfunction, Applied Therapeutics, 0: 518-519, 1964. 14. Clinical data on file, Ortho Research Foundation. 15. TOMI'KINS, Sf. i. ProgeStins and the uterus, Applied Therapeutics, 6: 523-525, 1964. 16. BIVA, H. I.., WILSON, r. H., AND KAWASAXI, D. K. Erect of Norethynodrel on endometriosis, Am. J. Obst. & Gynec., 82:109-118,1961. 17. KISTNEB, a. ~v. The treatment of endometriosis by inducing pseudopregnancy with ovarian hormones, Fertil. and Steril., 10: 539-556,1959. 18. GOODMAN, a. S., AND OILMAN, A. The Pharmacological Basis of Therapeutics, MacMillan, 1905, p. 1560. 19. A.M.A. New Drugs, 1965, p. 343. 20. BRATJN, T. E. Progestatlonal agents in clinical obstetrics and gynecology, Am. 1. Med. Sci., 247: 133/739-141/747. 2L GOLD, 3. 3., BORU5HECK, S., SMITH, L., AND SCOMENGA, A. Synthetic progestins: A review, Internat. 1. Fertil., 10: 99-114, 1965. 46 PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 696~i special reports 47 PAGENO="0132" 6964 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Appendix 5 An appraisal of certain problems involved in the use of steroid compounds for contraception ROT HERTZ, M.D. The growing acceptance of various steroid com- pounds as contraceptive agents has been attended by extensive controversy. Such controversy has been mainly concerned with the nature of the immediate and delayed ef- fects of these preparations. This communication aims to identify certain questions which merit con- sideration and to appraise the currently available data bearing on these problems. Such a discussion becomes all the more impera- tive because of piece-meal and inadequate treat menc~i~emnttuin hr-the la and scientific ress and in official statements of responsi e govern inintal agencies. Meanwhile, the distributi~ii~T steroid compounds as contraceptives has become an accepted function of numerous public health agencies despite the lack of appropriately designed epidemio1~ic studi~i concerning~pany of their ~l~tiiiUpotentiai effects. e oTh3~ing are s~l~d for discussion: 1. Will the prolonged use of steroid contracep fives affect the incidence or the pathogenesisRf such mai~iinnt tumors as cancer of the ~ endometrium, or chr~ix? - ~DoThein~ubstances increase the frequency or~redispose to the occurrence of thrombophie- 3. DoeiTF~ prolonged exposure of the ovarian *ova~lsaerelr~u~iveorgenet~ t~pes of steroid contraceptive regimens are currently employed: (a) Estrogen-progesto- gen combinations given cyclically; (b) estrogen and progestogen given in sequence on a cyclic basis, (c) progestogens given continuously. According- * The author is greatly indebted to Dr. John C. Baliar III for many of the statistical calculations presented here; however, he accepts sole responsibility for the Interpre- tations offered. ly, it is imperative that we consider the properties of each of these classes of compounds when admin- istered both singly and in combination. For example, certain effects of the estrogen-pro- gestogen combinations constitute characteristic re- sponses to estrogen. These include: (a) A rise in thyroxin-binding and cortisol-binding protein in the plasma, (b) a tendency to fluid retention as manifested by varying degrees of weight gain and edema, (a) alteration in bromsulphthalein clearance by the liver (4a), (b), and (d) the sub- jective symptoms of nausea and malaise (1-4) and fullness of the breasts. These effects are not pro- duced by even massive doses of progestogens and are readily reproducible with all varieties of nat- ural as well as synthetic estrogens. Such effects clearly indicate that the estrogen administered ex- ceeds normal endogenous estrogen production de- spite the presumed drug-induced suppression of endogenous estrogen formation. Moreov~,j~v~ ~j~kdata concerning normal `~strogen secretion rates in women (5, 6) show that tiihtotal endogi~ ~.gnous estrogen would not e ual in biolo ical activ- - for man the estrogenic doses contained in cur- rently employed contrace tive mixtures (Ca). ence the net biochemical and biological effect of such combinations is characteristic of hyperes- trinism. It is therefore highly pertinent to consider what is known about the relationship between the levels of endogenous and exogenous estrogen and various neoplastic processes both in man and in animals. First, however, certain salient features of the carcinogenic response in man must be described. Of ma~or im ortance is the fact that all known uman carcinogeq~q~hibit a prolonged latent ______ Table I lists most of the agents whièh can be considered with some certainty to be capable of producing malignancies in man. Itisespecially 49 PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6965 ,i~oteworthy. that most of these effects involve a latent period of about a decade. In most instances no detectable objective basis for anticipufj~~g~he ultimate carcinogenic response is apparent during~ ~en~d of latency. It is also noteworthy that all known carcinogenic ~ ~ hence coqimon pathogenetic factors are clearly involved in the developp~p~f hàncer in mafii lnani~ng~~ ~ cannot ignore the reg~yl observed length of ~~pc and ~ parallelisms in the gen~ of cancer in man and animals in evaluating what -~------------------,-----.,-----,.-. is known to date about the carcinogeipqp~tentiai ~~~steroid substances under discussion. Estrogens and Breast Cancer Ovariectomy induces remissions in 30 to 50 per- cent of young women with breast cancer (7). It is generally agreed that this ablative procedure exerts its favorable effects through a reduction of estrogen formation in the body (8). Moreover, urinary excretion studies show that the amounts of estrogen involved must be measured in micro- gram quantities (8). Less direct evidence indi cates that in some woilrii estrógen itduiiihistration ~iidines comparable to those contained in the cur ~i~l~rnarketed ~ will tran siently stimulate the metabolic activit - ste ic reas cancer, ut such stimulation is notal ~~ea to ái~mpairment in the clinical course ~7V~tty~ AccorctingIy~it I iiiiversiil clinical practice to prohibit the use of such materials by. young women with a known breast cancer. Para- doxically, this restriction is not applicable to older women with breast cancer since a substantial pro-V portion of such older women, and less commonly certain younger women, experience regression of a preexisting breast cancer when given estrogens (ii, 18, 29). Jt is therefore clear that both ep42~ enous and inogenens estr~en will modj~y_~ ~fTVTt3~ of estaMished cancer inworne~~ ~The proponents of the use of these agents state ~ ~iii~"Breast caTilcer. such an inference is unt~i ~ fa~ tOer maligiiancies in women such as cancer of the cervix and endom~ `ll~iTffi1nu~e a pi-olunged~piet~p~jj~ ~llilliany~ears.nfortunately,wehaven~ ~ or pathogeneti~ hase of breast cancer in young ~p~peq~ nor do ~e ~ upon ~ 50 p~cess. Indirect evidence from mammography iEiI~ies inctiëates hìowever, that the p~~e~ic pj~ase can occupy several years (12cc). ~~pcej~ - seems reasonable to consider whether or not the re- peated indihlion of a ~ any risk of excllIrbation of this occult phase of ~ alter the established diseasp pr~ess in so~ women. It is frequently stated that although estrogens have been employed clinically for 25 years, the incidence of breast cancer in women has not ma- terially changed and that only an extremely lim- ited number of cases of breast cancer in women have been reported to be specifically associated with estrogen therapy (18-17). These generaliza- tions ignore some serious limitations in our epi- demiological knowledge over the past 25 years. Firstly, past clinical experience relates almost entirely to the use of estrogens for the control of symptoms in women of menopausal or post- menopausal age. In addition, a very limited number of younger women suffering from artifi- cially induced menopause, ovarian insufficiency, menstrual disorders, and other gynecological prob- lems have also been treated. ~ from differences in response of established breast ~~ëltiogen the Ili older women as con traste wit at seen in menstruating women that it is not valid to equate a past experience in predominantly older patients with what should i~tidi~~in~ounger women, especially with ~~Iittö breasFcancer. This difference in re ~E~ilbarly~ in the remarkable in- crease in estrogen-induced regressions in breast canc~ir with i~creasing age (18). The study of Kennedy on the dual effects of estrogen on breast cancer in women aged 35 to 54 also emphasizes the critical role of both age and dosage in determining whether the response of breast cancer to estrogen administration will be exacerbation or regression (11). _____________ states: "In premenopausal women with breast can ~in patients in whom castratiiin produced a regressioiT~i~, there is no doubt that small ~oiogi~iItc1~ses of estrogeilic h~inone mp~y ~p~piate th~g~Uh~if cancer," and furt er: "It might, therefore~be~postulated that the rogemc hormone huh dual actiort; st~mpla~ion of cancer cell growth by small doses, and a more potent in 1ilb~ft~ ~ l~g~qy~~dn l~gp~" (11). Secondly, cause of the absence of specific data PAGENO="0134" 6966 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY as ~o the duration of estrogen exposure of most o~ the women treated during the past 25 years, and because the relatively small number of younger women have with few exceptions received com- paratively short courses of therapy, we have no basis for a direct evaluation of the current ap: proval f~ inilTTr~&or4 ears or more. hus, we were a e to find only four studies in the world literature in which the actual incidence of breast and genital tract malignancies during prolonged estrogen therapy is recorded (19-21, 2/a). These studies respectively include 120, 292, and 304 and 206 women. Two of these studies included respectively 58 and 27 women un- der 40 years of age and in the remaining study, all women studied were over 40 years of age. ~ .!~li~!e~~lata on cancer incidence available for the age group presently under consideiiitiofls limited to 85 patients. Such limited data fill to an adequate epidemiologic basis for the ~i~inulgation of a new public health practice a! lug rnilliiivi ofitomen. course, iddT~luiiil duta reside in the in- dividual clinical records of numerous institutions7 and private offices. ~o~w~ever~ offhand gcnerali- zation from such uncontrolled clinical experiç~pe4 fl~itappropri~fe followup is notoriously mis-I ~vellt~~tl'o~En-f ical account renotte~iiv~J ~ I veloped epiderniological data. Op~jnndeqnate~ knowled e concernin the relationship of estro- gens to cancer in women is corn ara le with what was ownaoutthe association between lungç3p~ ~E.~~iarette smoking before extensive api- I demiologic studies delineated this overwhej~pg ~iificant statistical relation~~. In the absence/ of similarly ~ of exogenous estrpgens on the incidence of br~J cancer in women we are ill-advised to igno~~ej~l~ mass of observations clearly ~ ~ii~d~xogenous estrogen to the pathogenesi ~`thTidT~i~e Iiflldfllman and amma s. Endometrial Cancer Endometrial cancer should also be considered in evaluating the conrequences of steroid therapy. Thus, the observations of Hertig and Somers and of Gusberg clearly define the pathogenetic rela- tionship between adenomatous hyperplasia result- ing from excessive endogenous or exogenous estro- gen and the ultimate development of adenocar- cinoma (22-25). It is a1so clear from retrospec- tive studies of successive endornetrial biopsies that endometrial cancer mey reqnite_many ve~~ys4or ~ *In addition, a~number of cases of endometrial cancer are reported ~o have been ~ protracted estr~g itdministrat~p(23, 27,19,28). ~i~i~em in part fróiiifiie frequent natural setting in which estrogens have been often utilized and in which endornetrial carcinoma is uncovered, namely, in the older women with excessive menstru- al bleeding of undetermined origin. The chance association of these two clinical features is to bean- ticipated in patients recently initiating treatment. However, when endometrial cancer arises follow- ing long-term estrogen therapy, the potential pathogenetic effect of the administered hormone sl1ould be considered. For example, Wallach and Henneman in presenting a statistical analysis of the long-term effects of estrogen administration for the treatment of osteoporosis in 290 women state: ~ ip.cidence of ~ this group of patients is many times the normal in ~~pce."(l9) (table 11). Similarily, Mustillfihi and Gordan (20) found two cases of endornetrial hyperplasia among 120 estrogen-treated osteopo- rotic women, and such hyperplasia is regarded by Gusberg (24) and by others as premalignant. Os- tergaard (28) similarly describes 18 cases of corpus cancer following prolonged estrogen therapy among a series of 123 patients with this disease. To attribute any statistical significance to such scattered reports would be highly fallacious, but such observations do clearly indicate the necessity ~ yroblem. Moreover, such clinical data as we have are not directly applicable to what is to be expected in younger women. Marked age differences in endo- metrial response are readily ndted. For example, the relative infrequency of estrogen-withdrawal bleeding in older women, namely 40 percent as op- posed to more than 98 percent in normal younger women (29) clearly reflects this notable age differ- ence. Hence one may anticipate such differences in the immediate and long-term endometrial re- sponse of the great numbers of menopausal women treated in the past, as compared with that of the normal younger women now being treated with contraceptive agents. Kelly and Baker have reported that metastatic endometrial carcinoma will undergo regression under intensive treatment with progesterone (50). 51 PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6967 In addition, Kistner has described the marked regression of the glandular elements of the endo- metrium in patients with endometrial hyperplasin or "carcinoma in situ" treated with various forms of progestationally active preparations (31) In evaluating the relationship of this finding to our immediate problems, we must recall that practi- cally all k~own carcinolytic agents, such as X-ray and certain alkylating agents, are also carcino- genic. ~ cethese findi~s further implicate the steroid hormones in tbs patho~enesis of endome trial cancer and_underline the serious limitations of our knowledge of the actual role of these factors li~~Iie atho enesis of these disease processes. One ms,y therefore reasona y question the ad visability of unnecessary derangement of such en docrinological relationships in completely normal young women. - These considerations become even more per- tinent when one reviews the highly distinctive his- tological effects of the estrogen-progestogen mix- tures on the endometrium. Notable among these effects ~g idularatroh(1_4). This appears ~_pfogressiveor cumulative effect attsimng ~~ipil~ee ffcr_several months of cyclic medication (1-4). This change is reflected in progressively decreased menstrual flow during the initial months of therapy and in the failure of bleeding on withdrawal in 1 to 2 percent of the cycles during therapy. - Such atrophic changes represent d~-inducedpatholo~ since no such phenomena are observed in the endometria of nor- i~wome2~ This glandular atrophy is accompanied by vary- ing degrees of stromal modification and in some instances by active decidua formation, a phenom- enon not normally observed in the absence of a recently fertilized ovum. Nor are such stromal changes an expected response to the naturally oc- curing progestogen, progesterone, unless accompa- nied by the stimulus of nidation. The degree of such decidualization varies substantially with the various dosage and temporal regimens more re- cently developed. Nevertheless, such tissue is not found in the uterus of a healthy, young, regularly menstruating woman. Its presence in the non- gravid uterus is a distinct drug-induced abnor- mality. Although the endometrium reverts to anentirelj normal-appearing structure after cessation of ther- ~~flis provides little anceas to the jnetrial elements which persist in situ-namely the epithelium and the stroma of the basal layers of thè endometrium from which the more suj~fi~ial l~ers are to bei sequently regenerated through iiiitthe remaining life span. Duringthe pr~gqd latent eriod of the * nc e carcinogens in man, such as radioactive ores, ~ histological changes detectable ~ An instructive lesson regarding the importance of this silent, prolonged, latent period can be learned from studies of the effect of 19-norproges- throne on the ovaries of the mouse. Lipschutz and Iglesias (31a) described completely normal fer- tility after removal of pellets of 19-norproges- terone from Baib A mice after the pellets had been in place for 108 days. However, in a subsequent report these authors described ovarian tumors in 8 of 14 animals which had previously been reported to have had entirely normal ovarian function (31b). We have already emphasized that a prolonged ~ 1~i~iin~of most known carcinogens in man (33,33). ~ ~Fiiiccntraceptives is 9 years and the greatest bulk of observattons is for very much shorter pei~i~T Tithe and only a fink years have elapsed since~T1~ ~ effects areasyet available. Estrogens and Cervical Cancer The relationship of steroid hormones to the pathogenesis and progression of cancer of the cer- vix in man is poorly understood. However~.th9 secretory and mitotic activity of the ~çqryjc~,l ~jE~thelium i~ clearly responsive t~_~q~lic ithgeiin ovarixn hth~mone ou~put~swelLas ~tç. exogenous steroid administration. Hence, altera- ~ITi~i1i these cellular functions are readil in- uce y t eora contraceptivn~gçp~s. ~ tinvifore, universally considered essential that the the presence of malignant and r e e initially eva uated and closel followed. In t is connection, it is to be emphasized tliat when initial screening by Papanicolaou smear of a given population is subsequently repeated, the number of positive smears found on rescreening will be a small fraction of the number found initially. Thus, Christopherson et al. (34) work- ing in Louisville showed that for carcinoma in future behavior f the previously altered endo~ 52 PAGENO="0136" 6968 COMPETITIVE PROBLEMS IN THE DRUG INDUSTI'RY situ a yield of 3.7 per 1,000 on initial screening fell to 0.03 per 1,000 on the second annual screening of the same women. For invasive carcinoma the cor- responding figures were 2.8 and 0.52. This spon- taneous reduction on rescreening reflects the ex- pected difference between prevalence and incidence figures and should not be confused with a presumed favorable effect of any intervening medication in such studies. It would, of course, bee~p~tedth~) all women started on oral contraceptives would( have been givinthe benefit o1~ a prior elvic ox-) amina ion an a ansco aou smear. Hence, thej n ings in such a population of prescreened women cannot be compared with the findings in the population group from which they are initially selected. The prolonged pathogenetic period for cancer of the cervix is estimated to be from 7 to 10 years on the basis of the difference in the age distribu- tion of carcinoma in situ versus invasive carcinoma ~(13, 34). Hence studies of the effect of any medi-1 cation osfT~his pr~l ~at1ocrenetic rocess s ou ce am y exceed in duration t~p~asp~ flindevelopment of cerviedi~ancer. Obspry~4iop,a pf this duration in significant numbe~ are not at Pincus and Garcia (35) have recently summa- rized their availa)ble data on the occurrence of in- vasive cervical cancer and certain associated cyto- logical phenomena in a limited sample of women using either oral contraceptives, vaginal spermi- cides or intrauterine devices. They state: "The data give practically identical figures for the pres- ence of carcinoma, anaplasia or negative tissues in the Enovid and vaginal contraceptive users." Also: "Obviously far more extensive data are re- quired for definitive determination, but with an enlarged population for study we hope to have adequate information on carcinoma incidence." We agree that the-data reported provide no sound statistical basis for assurance on this vital point. More recently, Wied et al. (35a) among others have offered data indicating no significant effect of certain preparations on the course of initial cervical dysplasia over a 1 to 2 year period. Such data provide some assurance as to immediate of- facts on the initial phases of the pathogenetic proc- ess, but have only an indirect bearing~ the ulti- mate response to chronic exposure to medication ~ ~ and after more prolonged exposure are clearly Statistical Considerations A substantial change in the incidence of certain diseases such as cancer, may be difficult to detect even with very large samples. For example, in a study of breast cancer incidence with 4-year fol- iowup of women aged 20 to 39 years, a sample of about 15,000 to 20,000 women, or 60,000 to 80,000 person-years, would be required to have a reason- able (i.e., 90 percent) chance of detecting (at the 95 percent probability level) a two-fold increase in risk. Changes in the incidence of cervical cancer could be detected with samples of about the same size; changes in the incidence of endometrial cancer would require samples about six to eight times as large as those for breast cancer. proaching this magnitude have been re orted. On t e contrary, the initial approval of the. adininis- ~ to oung women was initially based on a 4- ear experience in 400 cases proper y oc~mented~ laboratory studiesJ~). Since du~r~iqp - o~ ~ posure is so critical a factor, only those wome~ exposed fp~, t~ej~~lly appspve~ ~i~d of ~ years provide any experience ertinent to this evaluation. Certai y, it is to be reasonabl ox- pecte t at a newpu he health practice wouldbe predicated on a more soundly developed epidemlo- Thrombophlebitis Thrombophlebitis and thromboembolic phenom- ena following the use of oral contraceptive agents have been reported. Accordingly, in January of 1963 an "ad hoc" committee was established by the Commissioner of the Food and Drug Adminis- tration to determine if the use of one of the oral contraceptive preparations (Enovid) resulted in an increase in incidence of deaths from throm- boembolic conditions. This committee concluded that: "on the basis of the available data * * * no significant increase in the risk of thromboembolic death from the use of Enovid in this population group has been dem- onstrated" (37). J~n concluding their report this Committ~~4 ed: "Any firm reliance on the risks as calculated ~ mittee recommends that a carefully planned an 53 PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6969 controlled prospective study be initiated with the more significant than comparable data in mice, ~j~ciiv~foaining more coii~fiuiiiiiin~regard- rats, rabbits, and hamsters. ing the incidence of thromboembolism and death The vast amount of experimental data concern- T~in such conditions in both untreated ferna~es an~ ing the vital role of estrogens in the pathogenesis those under treatment of this type amongthe,p~- and progression of cancer of the breast, uterus, and tinent age gro~ps" ~37). ~ cervix in numerous species is considered by some icattered observ to have little or no pertinence to comparable pro- superficial inter~ation of the clinical an~~ cesses in man. This view stems largely from the reso ved prob Pi~F~ffiationofthis ~p~t of the stu.~yof aemiological ~b~vations of the past 25~y~~ oi~f~ntraceptive preparations must therefore be `iilready di~di~e. Afso, disproportionate empha ~ ~ inch no malignancies were obs Studies of Carcinogenesis in Laboratory Animals monkeys treated for p~dinnged periods with estro- The initiation and current development of oriii ~ contracepe are almost entirel based on ~ studies, which ~ ranged in duration from 3 months to 10 years, -.------~--_ 47, 48). It is therefore pertinent to consider the involved a total of 25 Maccacus rhesus monkeys results of extensive animal studies concerning the in all, with only 4 of the monkeys treated for 4 role of these and similar agents, in experimental ~. years or more. ~ltliougls, no, i~9~p~l~maligna1cie carcinogenesis and in relation to other endocrino- I were described, these mon~evs almost unifo~ly~ did exhibit profound metaplastic changes in th,~ logical functio~. &~rvix and end~~riu~and one of them showed The major significance of animal data has been recently emphasized by the finding of neoplastic ~ changes in the breasts of dogs following the pro- longed ingestion of Ethynerone, and this finding ~. Estrogen administration readily leads to a wide led to the officially approved cessation of clinical variety of neoplasms under varying experimental trials with this estrogen-progestogen mixture. conditions in several species. These include tu- The estrogenic component, mestranol, is chemically mors of the breast, cervix, endometrium, ovary, identical with that contained in most marketed pituitary, testicle, kidney, and bone marrow pro- mixtures. The progestogen content of this prepa- duced in either rats, mice, rabbits, hamsters, and ration differs from the marketed mixtures in spe- dogs (4.9). These experimental effects are easily cific chemical structure. However, all prior and uniformly reproducible and, in view of their studies in this family of progestogens indicate that multiplicity, do not represent bizarre or rare bio- such structural variations provide only quantita-~ logical effects. Rather, they are the readily re- tive biological differences, unlike the qualitativo producible responses seen in practically all suffi- changes induced by such structural changes in ciently tested species of appropriate genetic con- the corticoid series (48a). Hence it is clearly in- stitution. However, the human population is so consistentto consider the animal data with the new genetically heterogenous, that the role of the1 mixture to be of more significance than the huge 1 genetic factor in man's respgnse to such agents ii~ body of preexisting animal findings with a wide thus far unknown. From what is known experi variety of synthetic estrogenic compounds in nu- ~ ho~ iatiohe frep~q~y merous species of animals, including the dog of response in different genetic ~oupsLbroughout (48b). Either the presently marketed prepara- \the world is not improbable (50). tions are also to be condemned ontli.e1~&sin.oLa1. A considerable part of what has been stated ~ or above relates to estrogens when applied alone. Ethynerone should not have been condemned. However, we have also already considered the The essential consideration is whether or not unique histological effects on the endometrium of ~ ~ togen combinations presently the estrogen-proges ~ employed as contraceptives. The question natu- ~ is no validity in rally arises as to whether or not the combined use considering the recent results in dogs to be any of these two hormonally active agents does not PAGENO="0138" 6970 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY alter what is to be expected from either agent alone. Extensive experimental observations in- dicate certain interactions between estrogen and progestogens. These phenomena include syner- gistic as well as antagonistic effects of these two agents on the endometrium, on deciduoma forma- tion, on premalignant metaplastic changes in the cervical glands, on fibroid tumor formation in the uterus, on carcinogen-induced endometnial car- cinoma, and on many other biological end-points (51-54). The complexity of these interactions, varying as they do with different dosage ratios and with the critical effects of the timing of the administration of each agent creates many as yet poorly understood features of the tissue responses obtained. Moreover, the naturally occurring substance, progesterone, as already noted, when given either following estrogenization of the endometrium or when given simultaneously with estrogen only rarely induces the degree of stromal change ob- served in the uteri of women given estrogen-pro- gestogen mixtures. Such tissue effects in women are supplemented by extensive observations con- derning the unique and anomalous qualitative ef- fects of these compounds in animals as compared with progesterone (47, 48). Hence, it seems in- advisable to presume that the interaction of estro- gen with these newer progestogens will necessarily parallel that which has been previously observed for progesterone itself, and the ~tentiality f~r substantially different long-term effects must be ~ Effects on Germ Cells An unequivocal abnormality produced by estro- gen-progestogen combinations is the suppression of ovulation itself. It is only reasonable to con- sider the ultimate fate of the ovum that would have been normally released from the ovary. We do not know whether this ovum dies or survives. If it survives, is it altered in any way? The only information we now have in this regard is that subsequent fertilization of some ova from the same ovaries readily occurs and that a limited number of newborn derived from such pregnan- cies appear normal at birth (1-4). The number of such infants thus far described in t e literature is a minute fraction o that req~uired to determine nificant ediatric followu of these children is yet. available. Statistical and clinical consi era ions ndicate that for an adequate analysis of this prob- lem a population of 100,000 children would be required. Moreover, the delayed clinical m~pj~- festations of man con enital abnormalities re- quires that these children be follow for 6 to 9 years in order to corn letel a raise an ossib e ect u on the . It seems unustified to assum at the suppression of the normal ovulatory mac anism~filTh~va~ for a 4-year eriod ma not b re ected in the quality of the ova subsequentl~ç lëiii~Tev~from an ovar in which - ogical findings appear to be n~~,,~tterpre GIi~no~ such findings after years of deferral of pregnancy would, of course, have to include a full appreciation of the spontaneous increment in the frequency of congenital abnormalities with ad- vancing maternal age. The foregoing considerations have been brought together to direct the attention of the medical pro- fession to these aspects of our knowledge as well as of our ignorance `cchinh seem pertinent to~p evaluation of some of the risks involved in the use of estrogen-progestogen combination for purposes ~ nnrrnal,iiealtlly, y'~ornan over a 4- ear nod. ach physician must evaluat~these risks with as~ appreciation of, the many et~rminq~1 sac: tors involved and vith dpe regard foy the j~~rits of alternative methods available to him and to his patients. In view of the serious limitations in our knowl ~g~of the potential long-term effects of estrogeii~ progestogen combinations it is mandato that further c mica? experience be ained under ro - ery contro a Table I-Latent period of some known carcinogens in Carcinogen Site of concer Range of latency (years) X-rays Skin 10-30 Radioactive paints Bone iO-30 Radioactive ores Lung 5-20 Thorium dioxide Liver 10-25 Ultraviolet exposure Skin 10-40 Aromatic mines Bladder 2-20 Coal tar (shale oil) Skin 10-25 Soot (chimney sweeps)_~~~ Scrotum 11-17 _______________ ___________________ Physispathology of Cancer." Hooker-Harper. New York, 1559. 55 PAGENO="0139" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6971 Table 11.-Estrogens and breast cancer Ant hors Number of patients Number of menopausal patients Number of patients 20-40 years old DuratIon of treatment Breast cancers Genital tract cancers Expected cancers 1 Geist et al Mustacchi et al Watlach et al Wilson et al 206 ~ 120 292 304 Most 94 234 304 Few 26 58 0 to 53/~ years 5 5.1 7.8 Not observed -- 0 0 0 None `0 47 0 Not stated. 5 or 6. Not Btated. 20. `As stated by authors. 25 with carcinoma efimlnnted from study; others wilh osleoporosis. S Endometrtal hyperplastata 2. `04 had had genital organ removal. 56 PAGENO="0140" 6972 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY bibliography 1. ROCK, j., GARCIA, C. B., AND PINCUS, a. Synthetic Progestins in the Normal Human Menstrual Cycle, Ree. Progr. in Hormone Res., 13: 323,1957. la. PINCTJS, 0., GARCIA, C. B., BOCK, J., PANIAOUA, K., PENDLETON, A., IABAQUE, F., NICOLAS, B., BOBNO, a., AND PAEN, v. Effectiveness of an Oral Contraceptive, Science, 130: 81, 1959. 2. GOLDZIEHEB, 3. W., BICE-WRAY, E., SCHULZ-CONTBEBAS, K., AND ABANDA-BOSELL, A. Fertility Following Termination of Contraception with Norethindrone, Am. J. Obst. and Gynec., 84: 1474,1962. R TYLER, Si. T., AND OLSON, n. .s. Fertility Promoting and Inhibiting Effects of New Steroid Hormonal Substances, J.A.M.A., 169: 1843, 1959, and Tyler, E. T., Current Status of Oral Contraception, J.A.M.A., 187: 562, 1964. 4. RICE-WRAY, E., LcHULZ-CONTBERAS, SI., GUERREBO, I., ARANADA-BOSILL, A. Long.Term Administration of Norethindrone in Fertility Control, J.A.M.A., 180: 355, 1962. 5. MORSE, W. s., CLARK, A. F., AND MACLEOD, a. C. Size and Production Rate of Oestradiol and Oestrone Miscible Body Pool of a Healthy Woman, 1. Endocrlnol., 26: 25, 1963. 6. GUBPIDE, E., ANGERS, K., VANDE WIELE, B. L., AND LIEREBMAN, S. Determination of Secre- tory Rates of Estrogens in Pregnancy and Nonpregnant Women From the Specific Activities of Urinary Metabolites, J. Clin. Endocrinol. and Metab., 22: 935, 1962. 7. REATSON, 0. T. On the Treatment of Inoperable Cases of Carcinoma of the Mammae, Lancet, 2: 104,1896. S. COrSaIR, A. B. (Cf. numerous authors) In Endocrine Aspects of Breast Cancer; Con- ference at University of Glasgow, 1957. Llvlngstone Ltd., London, 1958. 9. PEARSON, 0. IL, WEST, C. D., HOLLANDEB, V. P., AND TBEVES, N. E. Evaluation of Endocrine Therapy for Advanced Breast Cancer, J.A.M.A., 154:234,1954. 10. HALL, ~. c. Biological Activities of Steroids in Relation to Cancer, Pincus, G., and Voilmer, E. P., eds., p.487, Academic Press, 1960. U. KENNEDY, B. 5. Massive Estrogen Administration in Premenopausal Women With Metastatic Breast Cancer, Cancer, 15:641,1962. 12. DUNN, 5. e. The Relationship Between Carcinoma In Situ and Invasive Cervical Carcinoma, Cancer, 6: 873,1953. 12a. 0EBSHON-COHEN, 3., AND BORDEN, A. 0. Ann. N.Y. Acad. Sci. 114: 783, 1964. 13. LIEDEGOTr, a. Mammacarcinom beim Mann rach Follikelhormonbehandlung, Kiln. Wchnsh., 26:599, 1948. 14. ALLABAN, a. a., AND OWEN, 5. E. Adenocarcinoma of the Breast Coincidental With Strenuous Estrogen Therapy, J.A.M.A., 112: 133,1939. 15. AuCmNCLoss, n., AND HAAGEMAN, C. n. Cancer of the Breast Possibly Induced by Estro. genie Substance, J.A.M.A., 114: 1517,1940. 16. LONREJAC, A. K. Cancer de la Mama en la Mujer y Folliculina, Bol. Soc. cir. d. Uruguay, 15:28,1944. 17. PARSONS, w. N., AND MCCALL, E. F. The Role of Estrogenic Substances In the Produc- tion of Malignant Mammary Lesions With Report of a Case of Adenocarcinoma of the Breast, Surgery, 9: 780, 1941. 18. SE NosAQuo, N. Ancirogens and Estrogens in the Treatment of Disseminated Mammary Carcinoma, J.A.M.A., 172: 1271,1960. 19. WALLACH, s. AND HENNEMAN, e. H. Prolonged Estrogen Therapy in Post-Menopausal Women, J.A.M.A., 171: 1637,1959. 20. MUSTACCHI, c. AND GORDON, 0. s. Frequency of Cancer in Estrogen-Treated Osteoporotic Women. Second Biennial Louisiana Cancer Conference, New Orleans, pp. 163-169; Mosby, St. Louis, 1958. 2L WILSON, B. A., BREVETTI, is. E., AND WILSON, ~. A. Specific Procedures for the Elimination of the Menopause, Western J. Surg. Obst. and Gynec., 71: No. 3, May-June 1963. 21a, GRIST, S. N., WALTER, B. I., AND SALMON, V. 3. Am. J. Obst. and Gynec., 41: 29, 1941. 57 PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6973 22. HERTIG, A. T., AND SOMMERS, s. c. Genesis of Endometrial Carcinoma. I. Study of Prior Biopsies, Cancer, 2: 946, 1949. 23. OUSIERO, S. B. Precursors of Corpus Carcinoma, Estrogens, and Adenomatous Byper- plasia, Am. J. Obot. and Gynec., 54: 905, 1947. 24. GUSBEIIG, s. ii., AND KAPLAN, A. L. Precursors of Corpus Cancer, Am. J. Obot. and Gynec., 86: 662, 1963. 25. SPEEIIT, H. Cancer of the Endometriurn in Young Women, Surg. Gyn. and Obst., 88: 332, 1949. 26. TE LINDE, is. VT., JONES, H. w,, JR., AND GALVIN, o. A. What Are Earliest Endometrial Changes To Justify Diagnosis of Endometrial Cancer, Am. J. Obst. and Gynec., 66: 953, 1953. 27. PIIEMONT-SMITH, H., MEIGS, J. V., GRAHAM, B., AND GILBERT, H. Cancer of the Endometrium and Prolonged Estrogen Therapy, J.A.M.A., 131: 805,1948. 28. Ø5TERGAARD, E. Estrogens in the Etiology of Cancer of the Corpus Uteri, Proc. Tnt. Congr. of Gyn. and Obst., Geneva, Switzerland, July 26, 1954, pp. 222-228. 29. KENNEDY, B. J., AND NATHANSON, I. T. Effects of Intensive Sex Steroid Hormone Ther- apy in Advanced Breast Cancer, J.A.M.A., 152: 1135, 1953. 30. SILi.LEY, B. H., AND BAKER, W. H. Clinical Observations on the Effect of Progesterone in the Treatment of Metastatic Endometrial Carcinoma. Biological Activities of Steroids in Relation to Cancer, pp. 427-439, Academic Press, New York, 1960. 31. KISTNER, R. w. Treatment of Carcinoma in situ of the Endometrium, Clin. Obst. and Gynec., 5: 1166, 1962. ha. LIPSCHUTZ, A., AND IGLESIAS, B. Recovery of Fertility After Protracted Steroid-In. duced Sterility in Slice. Nature, 190: 174, 1961. 31b. LIPSCHUTZ, A., IGLHSIAS, R., AND SALINAS, S. Ovarian Tumors Induced by a Sterilizing Steroid, Nature, 190: 948, 1962. 32. HUEPER, w. c. Environmental Cancer, ch. 24, p. 919 in Homburger-Fishman, "Physi. opathology of Cancer," second edition, Hoeber-Harper, New York, 1959. 33. HUEPER, w. c. Occupational Tumors and Allied Diseases. Chas. C. Thomas, Baltimore, 1942. 34. CHRISTOPHERSON, W. H., PARKER, J. E., AND DRYE, J. c. Control of Cervical Cancer; Pre- liminary Report on Community Program, J.A.M.A., 182: 179,1962. 35. PINCUS, IL, AND GARCIA, C. B. Preliminary Findings on Hormonal Steroids and Vaginal Cervical, and Endometrial Histology. International Union Against Cancer; Mexico City, Feb. 5, 1964 (manuscript available through courtesy of the authors). 35a. WIED, 0. L., DAVIS, H. E., FRANK, B., SEGAL, P. B., MEtER, P., AND ROSENTHAL, is. Obst. and Gynec., 27: 327, 1966. 38. Official correspondence with Dr. Arthur Ruskin, Acting Director, Division of New Drugs, Bureau of Medicine, Food and Drug Administration, Washington. D~C., Feb. 4, 1964. 37. WRIGHT, I. S., ET A1 The Final Enovid Report. Journal of New Drugs, 3: 201, 1963. 38. HERTZ, B., TULLNER, W. W., AND RAFFELT, K. Progestational Activity of Orally Admin- Istered 17-alpha-ethinyl-19-nor testosterone, Endocrinology, 54: 228,1954. 39. SANDERS, F. J., COLTON, F. B., AND DRILL, V. A. Progesterone-like Activity of a Series of 19-nor-testosterone, Proc. Soc. Exper. Biol. and Med., 94: 717, 1957. 40. TULLNER, w. w., AND HERTZ, B. Progestational Activity of 19-nor-progesterone and 19-nor-ethisterone in the Rhesus Monkey, Proc. Soc. Exper. Biol. and Med., 94: 298, 1957. 41. OVERHOLSER, H. P., AND ALLEN, i. Ovarian Hormone and Traumatic Stimulation of Monkey's Cervix to a Condition Resembling Early Cancer, Proc. Soc. Exper. Biol. and Med., 30: 1322, 1933. 42. HARTMAN, c. G., GEOCHICKTER, F., SPEERT, u. Effects of Continuous Administration in Very Large Doses, Anat. Rec., 79: Supp. 2, p.31,1941. 43. PFEIFFER, C. A., AND ALLEN, is. Attempts To Produce Cancer in Rhesus Monkeys With Carcinogenic Hydrocarbons and Estrogens, Cancer Research, 8: 97, 1948. 44. ENGLE, E. T., KRAKOWER, C., AND HAAGENSEN, c. n. Estrogen Administration to Aged Female Monkeys With No Resultant Tumor, Callcer Research, 3 858, 1943. 45. OVERHOLSER, H. B., AND ALLEN, E. Atypical Growth Induced in Cervical Epithelium of Monkey by Prolonged Injections of Ovarian Hormone Combined With Chronic Trauma, Surg. Gynec. and Obst., 60: 129,1935. 46. CBOSSEN, B. J., AND SUNTZEC.ITF, V. Endometrial Polyps and Eyperplasia Produced In an Aged Monkey With Estrogen Plus Progesterone, Arch. Path., 50: 721, 1950. 58 PAGENO="0142" 6974 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 47. PINCU5, a., CHANG, H. C., ZARROW, H. x., aes-Ez, E. a., AND MERRILL, A. Studies of the Biological Activity of Certain 19-nor-steroids in Female Animals, Endocrinology, 59: 695, 1956. 48. PINCU5, 0., ET AL. Effects of Certain 19-nor Steroids on Reproductive Processes in Animals, Science, 124: 890,1956. 48a. DJERA5SI, c. Science, 151: 1,055,1966. 48b. J~.soB&, ~. Aust. 1. Exp. Biol., 40:139,1962. 49. GARDNER, W. V., PFEIFFER, C. A., AND TRENTIN, 3. 3. Hormonal Factors in Experimental Carcinogenesis, cli. 6, p. 152, in Honiburger-Fishman "Physiopathology of Cancer," second edition, Hoeber-Harper, New York, 1959. 50. LITTLE, c. c. Genetics of Neoplasia. Cli. 5, p. 127, in Homburger-Fishman `Physiopath- ology of Cancer," second edition, Hoeber-Harper, New York, 1959. 51. LIPBCHDTZ, A. Steroid Hormones and Tumors, Williams and Wilkins, Baltimore, 1950. 52. ORIFFITH5, C. T., TOMIC, M., CRAIG, 3. H., AND KISTNEB, a. w. Effects of Progestins, Estro- gens and Castration on Induced Endometrial Cancer in the Rabbit, Surg. Forum, 14: 399, 1963. 53. HI5AW, F. L., AND LANDBTJM, i' c. Squamous Metaplasia in the Cervical Glands of the Monkey Following Estrin Administration, Endocrinology, 20: 228,1938. 54. TOtING, w. c. Sex and Internal Secretions (Alien), Williams and Wilkins, Baltimore, Md., 1963. 55. BEBTZ, a., wmx~, j. H., AND THoMAs, L. B. Progestational Effectiveness of 19-nor-ethinyl- testosterone by Oral Route In Women, Proc. Soc. Exper. Bioi. and Med., 91: 418, 1956. 59 PAGENO="0143" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6975 Appendix 6 Review of the Procedures and Reports of the Pharmaceutical Companies Concerned With the Manufacture and Sale of the Oral Contraceptives. 8. 0. KOHL, M.D. During February and March of 1966 the seven pharmaceutical manufacturers marketing oral contraceptives were visited at the request of the Advisory Committee of the Food and Drug Ad- ministration. The charge was to collect and analyze the deaths in patients taking oral contra- ceptives which had been reported to the manu- facturers and investigated by them. A further charge was to "look into how they keep records and conduct investigations of adverse reactions." This combination of a specific and general charge made the visits easy to arrange and instructive to carry out. All visits were arranged through the medical di- rectors of the manufacturers. In almost all in- stances the chief medical officer of each manu- facturer was interviewed. Some of the detail work was carried out with his subordinates who were di- rectly responsible for the activities in question. An observation concerning these physicians and medical scientists is unavoidable. I believe these men, almost without exception, to be competent and interested in their work. I am impressed that they are truly concerned about the safety of the medica- tions their firms produce and/or market. They wish to "do a good job." They are aware of the potential dangers of prolonged usage of potent medications and they wish to discharge this re- sponsibility in an intelligent and scientific man- ner. They appreciate the shortcomings of their present methods of surveillance. The "medical departments" of the manufactur- ers are quite variable. Some are very sophisticated in approach and personnel and one occupies a "basement office" and is quite restricted in person- nel and outlook. These characteristics are de- tailed in the attached reports which describe the procedures followed by each manufacturer. Standardization of Records It was anticipated, prior to the visits, that there would be a degree of uniformity in the records and investigations of reported deaths. This was not the case. The variability was marked and so was the feeling of responsibility and involvement. Some of the investigations of deaths were asso- ciated with repeated visits and telephone calls to physicians whose patients had died. Other in- vestigations were quite cursory and reflected con- siderable concern over the company's image with the physician. "He cannot be irritated-it's bad for our business relationships." I was surprised that there are no standard forms in use. This is true for the reporting of both deaths and adverse reactions which do not result in death. Thus com- pilations, tabulations, and analyses are made un- necessarily difficult and awkward. Some physicians and hospitals hesitate to re- lease patient information to a commercial organi- zation. In fact some refuse to do so. It is of more than passing interest to note that the U.S. Naval Hospital at Bethesda replied that they had filed a report with FDA and would release no informa- tion to the manufacturer. This action is in spite of the fact that FDA charges the manufacturer with responsibility for carrying out an investiga- tion. FDA has supplied no report to the manu- facturer on this death. My own hospital has re- fused to release data to manufacturer without the consent of the Corporation Counsel of the city of New York. I am not anxious to undertake the chore of pushing this request through the Depart- ment of Hospitals and the Corporation Counsel's Office~ In this general area, I submit the following rec- ommendations: 1. Adverse reactions should be reported on a standard form, rather than in memoranda, to a 61 PAGENO="0144" 6976 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY single office in FDA. These should be in the form of an initial alert on a postal card perhaps, and followed by the completed form when the investi- gation has been completed or carried on as far as possible by the manufacturer. 2. If copies of these reports are to be distributed to several branches of FDA. this distribution should be by FDA and not by the manufacturer. 3. The present FD 1639 form is not adequate for the analysis of oral contraceptive adverse reac- tions. 4. The initial request for information in the in- vestigations of an adverse reaction should be from FDA on official stationary and signed by a re- sponsiblé medical officer. If followup and collec- tion of data is to be the responsibility of the medi-~ cal department of the manufacturer, the initial request should so inform the recipient. 5. The medical officers of the FDA responsible for monitoring adverse reactions, the medical per- sonnel of the pharmaceutical manufacturer having similar responsibility and the appropriate mem- bers of the Advisory Committee should evolve adequate forms, requests, and standard procedures to be followed. At present each unit acts inde- pendently and with varying interpretations of what is required. 6. Such an organization would make pooling and exchange of information an easy and rewarding experience. An instrumentality for "feedback" would be in existence. Such activity is imperative if reliable and continuous scientific data are to be "fed-in". 7. The pharmaceutical manufacturers' medical departments are enthusiastic about the possibility of working with the Advisory Committee, for whom they have great respect. Perhaps some of the "police activities" required by statute, can be efficiently carried out through the Committee's scientific and consultative activities. Investigational Patients Each manufacturer has a number of "investiga- tional patients" who have been under observation for a known period of time or are continuing under observation. These groups include several thou- sand patients, perhaps as many as 15,000-20,000. The records of adverse reactions are, in general, quite complete. These patients might give more adequate known numerators and denominators for study. The medical people at the manufacturers have indicated to me that they would consider pooling these data for analysis on an anterospec- tive basis. At present, this is awkward because each drug has a different form for the registration of the patient and the collection of followup data. These records are quite variable. Some are very detailed and some are "skimpy." The followup procedures are variable in the rigor demanded in the collection of data. A basic uniform record which was precoded for easy machine handling might be of advantage to both the investigators and FDA. Additions mightbemade to such abase record to satisfy the individuality of manufac- turers and/or investigators. 1. A working group similar to the one suggested in the previous section, could be established to create a basic investigational registration and fol- lowup record. These basic forms would be utilized for all oral contraceptive drugs under study. Ad- ditions might be made to the basic records to sat- isfy individual desires of manufacturer and/or investigators. 2. A manual should be prepared containing "guidelines" for the selection of investigators and patients in future studies to be undertaken. This manual should contain standard terms and defini- tions as well as instructions for completing the various forms. Again single copies should be transmitted to FDA and duplicated by the Agency for internal distribution. 3. There is no uniformity in the procedures to be followed in "closing a case." These should be developed. A decision is needed on the effort to be expended upon patients who "stop coming to the clinic." At present the efforts to follow such pa- tients vary from "nothing" to rather extensive, time consuming, and expensive effort to keep the patient under followup. An important oversight is the lack of followup of patients who are dropped because of pregnancy. This group presents an op- portunity for the collection of considerable data. These data might be of importance in both medical and epidemiological areas of interest. Almost without exception, there is a dearth of data on pregnancy outcome in patients who become pregnant while on oral contraceptive therapy. No single investigator has many such patients but the "pool" would make several hundred available for analysis. 4. A computer program, perhaps patterned after the one in use by Eli Lilly & Co., should be established for the recording, storing, and analysis of these data. A program should also be evolved 62 PAGENO="0145" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6977 for analysis of "adverse reactions," if this activity is to be continued. In as much as each of these manufacturers has computer facilities available, their medical and computer people might be able to add to the program development. The pro- grams evolved could be implemented in their own organizations and perhaps replace some of the naive statistical analysis now carried out. Surveillance of Patients Under Oral Contracep- tive Therapy Conversations with Advisory Committee mem- bers, medical personnel of the manufacturers and FDA personnel revealed considerable concern over the long-range effect of these medications. A woman with three children who begins oral con- traception therapy at age 28, may use the drug for 20 years. Modern epidemiological and biostatisti- cal methodology make possible the surveillance of such patients so that adverse chronic reactions may be detected at the earliest possible point in time. Such surveillance is rarely necessary be- cause rarely have so many patients taken so potent a drug, for so long a period of time. Whether true or not, one gets the impression that certain ad- verse reactions may be time related. It seems imperative that the answers to this type of ques- tion be available. I believe that the costs in- volved in this type of surveillance are peculiar to the drug and its mode of use. Therefore, it seems to me that the cost of such surveillance is an in- /tegral part of the total cost of production and distribution of the medication. At the present time these medications cost the private patient about $25 per year. Because of the large number of patients under therapy, a fractional increase in the cost would supply ample funds to carry out the indicated epidemiologic surveillance. As suggested by Dr. Louis M. Heliman, certain "captive groups" might be enlisted for study. Ex- amples are: Wives of armed service personnel; clients of the Indian Service; patients of the Kaiser Medical Group; H.I.P. and the Family Un- ion Medical Plan of the Hotel Industry of New York. In order to have a representative sample of the population at risk, patients in Family Planning Clinics of various kinds and private patients should be included. The FDA, its Advisory Committee, and the in- dustry should set up a conference with capable epidemiologists and biostatisticians to investigate the feasibility of such a program and the planning thereof. An organization may need to be estab- lished, an existing agency may be able to take on the responsibility or the activity may be con- tracted to one or more of the Schools of Public Health for maintenance of the surveillance. Such an organization could serve as a model for future similar projects or for the maintenance of investi- gational studies in the drug industry. The Food and Drug Administration I have carried out no investigation of the Food and Drug Administration. My only contact with FDA or its personnel was at the committee meet- ing on April 7, 1966. Therefore any observations about FDA are hearsay or are related to what I have seen at the pharmaceutical manufacturers. 1. There appears to be little feedback to the manufacturers of the data which they are required to collect and transmit to FDA. Some pooled data might be very helpful and useful in main- taining a high level of scientific and epidemiologic interest. It might stimulate such awareness where it does not now exist. 2. One is struck by the lack of "guidelines" as to how investigational activities are to be carried out. The FD 1649 form is a cogent example. One manufacturer did not know of its existence. The form had been required for about 6 months and they had never filed a single one. The responsible FDA branch should have corrected this short- coming. The FD 1639 form is completed by manu- facturers' personnel in some cases, by treating physicians in other cases and in still other cases is not filed at all. The manufacturer, in each case, quote conversations with FDA personnel as au- thority for their routine. Who is responsible for this situation is unimportant. The need for in- structions and guidelines is clear. Some of the memorandums filed are voluminous and burden- some to handle because the manufacturer is "afraid" to leave anything out. Others use their own judgment and inasmuch as they hear no com- plaints, it is assumed that their procedure is ac- ceptable. One manufacturer files a list of adverse reactions and elaborates only on those cases which his representative believes merit elaboration. An- other manufacturer files copies (triplicate) of every piece of paper including notes on telephone conversations with "detail men." 3. Intraagency communication seems to be faulty. The 110 deaths examined and tabulated in this report were taken solely from the duplica- 63 40-471 0-70-pt. 17-1O PAGENO="0146" 6978 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tion of material already submitted to FDA. This total, I am told, is at considerable variance with the number of deaths presented to the Advisory Committee by FDA. 4. The expressed desire of cooperation in carry- ing out the provisions of statutes and regulations should be accepted. It may be that enforcement will be easiest and most complete when the indus- try participates in policing itself. The medical personnel, recruitable by FDA and the medical departments of the manufacturers, will be im- proved by cooperation. This will permit the in- sinuation of scientific activity into the usual expending or receiving effects of the required "police activity." Report of Deaths in Patients Taking Oral Con. traceptives A series of tables is appended to the report which lists the 110 deaths found in the files of the manufacturers. The tables also show a sec- ond listing of 65 deaths judged to be due to "idio- pathic pulmonary embolus." These 65 deaths were from the total of `tS deaths caused by pul- monary embolization. For the following reasons 10 deaths were deleted: Rheumatic heart disease with valvulitis. Pancreatitis, hypertension, and renal disease. Thrombophlebitis in a previous pregnancy (three patients). Thrombophiebitis 3 months before therapy. Postoperative cholecystectomy. Postoperative hysterectomy (two patients). Postoperative radical mastectomy. The collected data were abstracted onto 80-col- umn punchcards which have been turned over to the Committee. The coding was performed in accordance with the attached code sheet. The IBM facilities of the Downstate Medical Center were employed to prepare the punchcards and to sort them for the preparation of the tabulations. It is not possible to draw statistically valid con- clusions regarding deaths in association with fhe taking of oral contraceptives. There is no reason to believe that these reported deaths are either a complete or an incomplete recording. They are more likely to be incomplete. The fact that most of the deaths occurred within the first 4 months of administration may reflect the larger number of patients taking the drug for this period of time as opposed to any later time period. It may re- flect the fact that if a patient dies after taking a drug for a short period of time, it is more likely to be associated as a possible causative factor and reported. It may reflect the impression of the physician that the drug taken for a long period of time is not likely to have an etiologic relation- ship with a death. It may even be that a drug taken for a long period of time is ignored in getting a medical history. Another unusual finding is that over 80 percent of the deaths were known to have been submitted to autopsy. This suggests that the association with the oral contraceptives may be an after thought suggested by the pathologic findings. I surely agree with the position taken by the Committee members who feel that the present study has added little to our knowledge of the relationship of oral contraceptives to death in the population at risk. I have detailed the type of data needed to cast light on the presence or absence of such relationship. I wish to thank the Advisory Committee for having given me the opportunity to carry out the investigation. The medical departments of the pharmaceutical manufacturers were forthright and cooperative and they made copies of reports available and in some cases prepared special tabu- lations and listings. The study could not have been completed or even begun without the ap- proval and support of the Commissioner and his staff. It was a rewarding experience for your reporter. Respectfully submitted, SCIIITYLER G. Kosan, M.D. Oral Contraceptive-Death Report 1. Searle 2. Ortho 3. Upjohn 4. Parke Davis 5. Mead Johnson 6. Eli Lilly 7. Syntex 2-3 Case number 12-13 Age at death 4-8 Manufacturers identification 14 Race number 0-White 9 Month of death 1-Negro 10-11 Year of death 2-Yellow 3-Unknown 64 PAGENO="0147" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6979 15 Autopsy 0-No 1-Yes 2-Yes, no report 3-Partial report 16-17 Months of use prior to death 18 Full term 19 Premature 20 Abortion 21 Living children 22 PrevIous vascular disease (prior to medication) 0-No 1-Yes 23 0--None 1-Enovid 10 2-Enovid 5 3-Enovid 2.5 4-Ortho 10 5-Ortho 2 6-Provest 7-Norinyl 8-Norlestrin 9-0-Quens x-Oracon 24 (Other Contraceptive drug used) Same as Column 23 25 Cause of death 0-None listed below 1-Pulmonary embolus 2-Pulmonary thrombosis 3-Cerebral embolization 4-Cerebral hemorrhage 5-Heart disease 6-Thronibocytopenla 7-General thrombosis 8-Leukemia 9-Welch bacillus infection i-Peritonitis 26 Cause of death (2) 27 Other diseases 0-None listed 1-Diabetes 2-Pancreatitis 3-Murder 4-Sarcoma 5-Hodgkins 6-Carcinoma 7-Pneumonia 8-Alcoholism 9-Asphysia (Aspir) s-Renal disease 28 Associated diseases (1) 0-None below 1-Peripheral thrombosis 2-Pelvic throboals 3-Varicose veins 4-Varicose vein ligation 5-Mesenteric thrombosis 6-Hypertension 7-Arteriosclerosis 28 8-Carcinoma of the breast 9-Leukemia i-Psychiatric y-Carcinoma of the uterus 29 Associated dIseases (2) 30 Source of report 0-Not stated 1-Detail man 2-Private physician 3-Hospital clinic 4-Patients family 5-FDA 8-AMA 7-Medical examiner 8-Family planning clinic 9-Other pharmaceutical manufacturers i-Investigator 31-32 State of Residence New England: Maine 01 New Hampshire 02 Vermont 03 Massachusetts 04 Rhode Island 05 Connecticut 06 Middle Atlantic: New York 11 New Jersey 12 Pennsylvania 13 East North Central: Ohio 21 Indiana 22 Illinois 23 Michigan 24 Wisconsin 25 West North Central: Minnesota 30 Iowa 31 Missouri 32 North Dakota 33 Nebraska 35 Kansas 36 South Dakota 34 Unknown State Canada South Atlantic: Delaware 40 Maryland 41 District of Columbia 42 Virginia 43 West Virginia 44 North Carolina 45 South Carolina 46 Georgia 47 Florida 48 East South Central: Kentucky 51 Tennessee 52 Alabama 53 Mississippi 54 West South Central: Arkansas 61 Louisiana 62 Oklahoma 63 Texas 64 Mountain: Montana 70 Idaho 71 Wyoming 72 Colorado 73 New Mexico 74 Arizona 75 Utah 76 Nevada 77 Pacific: Washington 81 Oregon 82 California 83 Alaska 84 Hawaii 85 33 Hospital care 0-None 1-University 2-Affiliated 3-Voluntary (not affiliated) 4-Proprietary 5-U.S. Navy 6-U.S. Army 7-U.S. Public Health Service 34 Physician 0-None 1-M.D.-G.P. 2-M.D-Oh. 0. 3-M.D-Other specialist 4-DO. a-Clinic 35 FD 1639 0-None 1-Treating physician 2-Other physician 3- 4-Mfg.-MD. 5-Mfg-Non M.D. y-Unknown 36 Thrombo-embolic death 9-No 1-Yes 2-Unknown 37 Size of place of residence 0- 1-1,000,000 or more 2-500,000-999,000 3-100,000-499,999 4-50,000-99,999 5-25,000-49,999 6-10,000-24,999 7-5,000 or fewer y-Uakaown residence 65 PAGENO="0148" 6980 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 38 Medical examiner case 0-No 1-Yes 2-Unknown 39 Oral contraceptive death 0-No 1-Yes 2-Not sure 40 On drug at time of death 0-Yes 1-None for 1 month 2-None for 2 months 3-None for 3 months 40 4-None for 4 months 5-None for 5 months 0-None for 6 months 7-None for 7 months 8-None for 8 months 9-None for 9 months or more x-None for less than 1 month y-Unknown 41 IndIcation for drug use 0-Contraception 1-Pregnancy test 41 2-Dysmenorrhea 3-Menorrhagia 4-EndometriosiS 5-Irregular menses 6-Premenstral tension 7-Habitual abortion 8-Ulcerative colitis y-Unknown 42 Obese 0-No 1-Yes 2-Border line y-Unknown Cause Less thus 1 1-4 1-0 9-12 13-10 19-24 25-36 37-40 10 tO Us- bssws Totsi None listed 1 3 1 1 3 1 1 11 Pulmonary embolus Cerebral embolization 7 38 1 17 2 3 8 75 1 Cerebral hemorrhage Heart disease 1 3 1 1 1 1 1 3 1 6 Thrombocytopenia Generalthrombosis 2 1 1 1 3 2 Leukemia 1 1 Peritonitis 1 1 Unknown I ---- Race Age AU Number Percent T.E. Number Percest White Nonwhite Unknown Total 66 60.0 17 15. 5 27 24. 5 43 66.2 6 9. 2 16 24. 6 110 65 All Number Percent T.E. Number Percent 15-19 3 2.7 2 3. 1 20-24 34 30. 9 24 36. 8 25-29 19 17.3 10 15.4 30-34 19 17.3 12 18.5 35-39 19 17.3 9 13.9 45-44 7 6.4 4 6.2 45 and over 4 3. 6 3 4.6 Unknown 4.5 1 1.5 Total 110 65 Range 18-50 18-50 Average 30.2 28.5 66 PAGENO="0149" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6981 Number o 17 1 12 2 18 3 ii 8 6 6 5 8 0 2 10 or more 0 Unknown 30 Total 110 17 _________________________ 12 18 No drug i~ Enovid-lo mg 10 Enovid-5 mg 6 Enovid-2.5 rug 4 Ortho-lO mg 2 Ortho-2 rug 2 Provest 0 Norinyl - 0 Norlestrin - 30 0-Quens Oracon iio Unknown Parity FT. Prrm. Abort. L. CbIId. Current Medication All Number Percent 78 2 0 0 0 0 0 0 0 0 0 30 110 Ta. Number Percent 63 11 1 0 3 2 0 0 0 0 0 29 110 6 21 37 6 1 16 3 3 8 7 0 2 5.5 19.1 33.6 5.5 .9 14.5 2.7 2.7 7.3 6.4 0 L8 1 11 27 5 0 11 3 2 2 2 0 1 1.5 16.9 41.6 7.7 0 16.9 4.6 3.1 3.1 3.1 0 1.5 110 65 Months of Use All T.E. Number Percent Number Percent Less than 1 month 1-4 5-8 9-12 13-18 19-24 25-36 37-48 50 60 Subtotal Unknown Total 11 49 19 4 4 4 2 1 1 1 96 14 110 11. 5 51. 0 19.8 4.2 4. 2 4.2 2. 1 1.0 1.0 1.0 100. 0 12. 7 5 35 16 2 2 0 0 0 .0 0 60 5 65 & 3 58. 4 26.7 3.3 3. 3 100. 0 & 3 Nulligravidae-15. Parity Number F.T. Prem. Abort. Lv. Ch. 0 1 2 3 4 5 6 7 8 lOormore Unknown Total 13 7 13 6 2 5 2 1 0 1 0 15 49 1 0 0 0 0 0 0 0 0 0 15 43 5 1 0 1 1 0 0 0 0 0 14 13 7 13 6 4 s 1 0 1 0 0 15 65 65 65 65 Nulllgravldue-ls. 67 PAGENO="0150" 6982 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Manufacturer On Drug at Report AU Number Percent T.E. Number Percent Searle Ortho Parke Davis Eli Lilly Syntex Upjohn Mend Johnson Total 73 17 8 7 3 2 0 110 66. 3 15.5 7.3 6.4 2.7 1.8 46 11 2 2 2 2 0 65 70.7 16.9 3. 1 3. 1 3.1 3.1 Year of Report AU Number Percent T.E. Number Percent 1959 1961 1962 1963 1964 1965 1966 Unknown Total 1 6 27 23 27 20 1 5 110 0.9 5. 4 24.5 20. 9 24. 5 18.2 .9 4. 5 0 5 13 16 15 13 1 2 65 0 7. 7 20.0 24. 6 23. 1 20.0 1.5 3. 1 Residence AU Es- pected T.E. Number Ex- pected All T.E. Number Percent Number Percent Yes None-less than 1 month_ None for 1 month None for 2 months None for 3 months None for 6 months None for 9 months or more Unknown Total 73 17 1 4 1 1 1 12 66. 4 15. 5 0.9 3. 6 . 9 . 9 .9 10.9 47 10 0 1 0 0 0 7 72.3 15.4 1. 5 10.8 110 65 Obesity AU T.E. Number Percent Number Percent No Yes Borderline Unknown Total 60 19 11 20 54.5 17.3 10.0 18.2 35 14 5 11 53.8 21.6 7.7 16.9 itO 65 Indication for Drug Use Alt T.E. Number Percent Number Percent Number New England Middle Atlantic East North Central West North Central South Atlantic East South Central West South Central Mountain Pacific Unknown Canada 7 6.1 14 19.7 26 20.7 7 8.6 20 15.5 2 6.9 6 10.0 6 4.3 17 13.2 4 110 105 4 5 15 5 15 0 3 3 9 0 4 65 3. 5 11. 5 Contraception 79 12. 1 Menorrhagia 6 5. 0 Endometriosis 5 9. 0 Irreg. menses .4 4. 0 Premenst. tension 2 5. 8 Habit. abortion - 1 2. 5 Ulcer. colitis - 1 7. 6 Pregnancy best 1 Dysmenorrhea 1 Unknown 10 61 Total 110 72. 0 5. 5 4-5 3. 6 1.8 .9 .9 -9 -9 9. 0 49 2 4 3 .0 0 4 75. 3 3-3 6.2 4-5 1.5 1.5 1.5 6.3 65 68 PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6983 All T.E. Number Percent Number Percent All Number Percent T.E. Number Percent Yes No Unknown Total 21 78 11 110 19.1 70.9 10.0 ~6 52 7 65 9.2 80. 0 10.8 H.C.V.D.4; RH. Fev..l; Varlmse VeIn Llgnt..l. Associated Diseases (1) All Number Percent Tx. Number Percent Peripheral thrombonin Pelvic thrombosis Hypertension Mesenteric thrombosis Varicose veins Arteriosclerosis Diabeten Psychiatric Cancer of breast Cancer of uteruse 22 36 11 5 4 4 4 3 2 2 20. 0 32. 7 10. 0 4. 5 3. 6 3. 6 3.6 2. 7 1. 8 1. 8 18 31 4 3 3 2 0 2 1 0 27. 7 47. 7 6. 2 4. 6 4. 6 3. 1 0 3. 1 L 5 0 Autopsy All Number Percent T.E. Number Percent Not done Complete Yen-no report Partial report Unknown Total 4 58 7 26 15 110 3.6 52.8 6.4 23. 6 13.6 0 43 2 16 4 65 0 66. 2 3. 1 24.6 6.1 Alt Number' Percent T.E. Number Percent Yes No Unknown Total 21 81 8 110 19.1 73.6 7.3 12 51 2 65 18.4 78.6 3.0 F.D. 1639 Number All Percent T.E. Number Percent None Treating physician Other physician Manufacturer-medical doctor Manufacturer-nonmedical doctor Total 87 9 0 0 14 110 79. 0 8. 2 12. 8 50 6 0 j~ 9 65 76.6 9. 5 13. 9 Source of Report All Number Percent T.E. Number Percent Detail man Private M.D. Hospital clinic Family FDA AMA Medical examiner Family plan. clinic Other manufacturers Investigator Unknown Total 30 32 5 3 8 1 6 8 2 9 6 110 27. 2 29.1 4.5 2.7 7. 3 .9 5. 5 7. 3 1.8 8. 2 5.5 23 20 3 2 4 0 5 4 2 0 2 65 35. 3 30.7 4.6 3.1 6. 2 0 7. 7 6. 2 3.1 0 3.1 Thrombo-Embolic Etiology Medical Examiner's Case Yes No Unknown Total 75 30 68. 2 27.3 4. 5 65 0 0 100. 0 110 65 Vascular Disease Prior to Drug 69 PAGENO="0152" 6984 COMPETITIVE PROBLEMS IN THE DRUG INDUS~~RY Appendix 7 Pilot Study To Test Feasibility of Obtaining Valid Case and Control Data in Idiopathic Throinboenibolic Disease P. E. SARTWSLL, M.D., A. T. MASI~ M.D., AND J. W. LONG, M.D. An epidemiologic pilot study was designed and conducted under contract with the Food and Drug Administration at the Johns Hopkins School of Hygiene and Public Health, Department of Epi- demiology. A report of the completed pilot study and specific recommendations for the major study follows. The primary objectives of the pilot study were: (a) To define the problems inherent in test- ing the hypothesis that oral contracep- tives serve as a causative factor in thromboembolic diseases in women not otherwise predisposed to these diseases. (b) To develop the methods and procedures that could best meet the needs of the study performance. (c) To test the validity and practicality of these methods, and to coordinate them for maximum yield of pertinent data. (ci) To evaluate the feasibility of the study design in its entirety. (e) To interpret the results of the pilot phase and form conclusions upon which ap- propriate recommendations can be based for a definitive study if indicated. Copies of the clinical record abstraction form and interview questionnaire which were developed during the pilot study and tabulations of the re- sults follow. Design of the Study A. Final diagnosis of all patients discharged alive from the Johns Hopkins Hospital from 1963-65 were obtained. B. After careful review, cases of idiopathic thromboembolism in married women were selected. C. These were controlled with twice the num- ber of carefully matched patients selected from a group whose discharge diagnoses would not remotely be related to throm- boembolic disease. D. Each of the selected patients was exten- sively interviewed with the objective to obtain in a casual but accurate fashion data regarding oral contraceptives. Summary and Conclusions This pilot study has demonstrated that the study design is feasible and can be expected to furnish valid case and control data necessary to achieve an acceptable answer to the hypothesis stated in the study proposal, and to do so within practicable limits of time and cost. It was possible to obtain satisfactory completion of interview question- naires on all cases and controls selected. It is desirable that the initial case selection for analysis be somewhat broader than the limited few that would be designated restrictively as "purely idiopathic"; the final case selection should be the result of deliberate and searching appraisal under supervision of the principal investigators. It is desirable to consider the opinions of an advisory group regarding the criteria to be used to define "idiopathic." Such a group should include experts in the fields of cardiovascular disease, peripheral vascular disease, hematology, endocrinology, and metabolic disease. It is presently considered that if a main study is to be done it should draw cases and controls from approximately 20 large hospitals (the size of Johns Hopkins Hospital or larger), which it is estimated should yield about 200 cases and an equal number of controls. Such a study could possibly be completed in 2 years. The basis for this esti- mate is that the Johns Hopkins Hospital yielded 10 idiopathic cases, constituting about 1 case per 10,000 discharges for all cases, or 10 percent of the 71 PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6985 total discharges that were medically reviewed. The scope of the main study can and should in- clude the opportunity for the use of epidemiologic methods to add to the knowledge of the natural history of thromboembolic disease, especially its "idiopathic" varieties; and, in so doing, to suggest direction for potentially fruitful research into some of the many clouded aspects of this problem. The experience gained in a study so oriented can serve to good advantage not only the immediate problem but future investigations involving other drugs and the application of similar epidemiologic methods to other possible instances of drug re- actions. PAGENO="0154" 6986 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Johns Hopkins Hospital-Food and Drug Administration Thromboembolism Pilot Study (Cooperating Hospital Thromboembolism and Controls Study) Name S M SEP W D (Last) (Middle) (Marital status-circle) Age last Maldenname - - birthday (Last) (First) (On admission) Race Birthdate - Birthplace - - (W, NW) (Manth, Day, Year) (City/County) (State/Country) Addrees on Imission - - Telephone - - (Street): (City/County) (State/Country): Next of kin or Relationship responsible friend --- --- orfriend (Last) (First name) (M. I.). (Specify) ~ddress ----- - (Street) (City/County) (State/Country) Business Name of spouse Employer telephone Business address (Street) (Clty/County) (State/Country) Social Patlentemployed:No____Yes -_ - - securityNo. (Employer) Business Businessnddress telephone Hospital Hospital record No. (Name) (Code number) Dates: Adm. Disch. Blue Cross: No __ Yes (Specify number) If transferred to Admission service __~_ other service - - (Specify) Attending physician ~_ Telephone Address - - (Street) (City/County) (State/Country) At last observation: Living Dead (If dead, complete other side) Reviewer Date form completed *If moved, enter new address below: Last known address * ----- - Date - - (Street) (Month, Day, Year) (City/County) (State/Country) Hospital code No. Patient series No. 1!3 PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6987 Religion: Not specified Catholic Jewish Protestant Other (Circle) (Specify) Welfare: No (Specify No.) Pay status: Private Semiprivate Ward/staff (Circle) Discharge diagnoses: (Prlmsry) (Secondary) ua~e of death (Month, Day, Year) Placeofdeath (Hospital name or etheri (City/County) (State/Country) Cause of death If autopsied, No. Death certificate No. Attending physician Telephone (Street) (City/County) (State/Country) PAGENO="0156" 6988 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY MASTER CODE SHEET 1 Detailed Birthplace or Residence Code Other than United States 00 Not specified 01 Far and Near East 02 Africa 03 Russla/Slavic/Baikan 04 Greece/Italy/France/Spain/Portugal 05 ScandinavIa/Germany/other continents 06 England/Ireland/Scotland/Australia/New Zealand 07 South and Central America 08 MexIco/Puerto Rico 09 Canada United States New England: 43 Missouri West South Central: 11 MaIne 44 North Dakota 71 Arkansas 12 New Hampshire 45 South Dakota 72 LouisIana 13 Vermont 46 Nebraska 73 Oklahoma 14 Massachusetts 47 Kansas 74 Texas 15 Rhode Island South Atlantic: Mountain: 16 Connecticut 51 Delaware 81 Montana Middle Atlantic: 52 Maryland 82 Idaho 21 New York 53 District of Columbia 83 Wyoming 22 New Jersey 54 VIrginia 84 Colorado 23 Pennsylvania 55 West Virginia 85 New Mexico East North Central: 56 North Carolina 86 Arizona 31 Ohio 57 South Carolina 87 Utah 32 IndIana 58 Georgia 88 Nevada 33 IllinoIs 59 Florida Pacific: 34 Michigan East South Central: 91 Washington 35 Wisconsin 61 Kentucky 92 Oregon West North Central: 62 Tennessee 93 California 41 MInnesota 63 Alabama 94 Alaska 42 Iowa 64 MIssissippi 95 HawaiI MASTER CODE SHEET 2 Centimeter-Inch Conversion Centimeter Inch Centimeter Inch Centimeter Inch 150 59 164 65 178 70 151 59 165 65 179 70 152 60 166 65 180 71 153 60 167 66 181 71 154 61 168 66 182 72 155 61 169 67 183 72 156 61 170 67 184 72 157 62 171 67 185 73 158 62 172 68 186 73 159 63 173 68 187 74 160 63 174 69 188 74 161 63 175 69 189 74 162 64 176 69 190 75 163 64 177 70 PAGENO="0157" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6989 MASTER CODE SHEET 3 Kilogram-Pound Conversion Kilog:nm Pound Kilogram Pound Kilogram Pound 40 088 74 163 108 238 41 000 75 165 109 240 42 093 76 168 110 243 43 095 77 170 111 245 44 097 78 172 112 247 45 099 79 174 113 249 46 101 80 176 114 251 47 104 81 179 115 254 48 106 82 181 116 256 49 108 83 183 117 258 50 110 84 185 118 260 51 112 85 187 119 262 52 115 86 190 120 265 53 117 87 192 121 267 54 119 88 194 122 269 55 121 89 196 123 271 56 123 90 198 124 273 57 126 91 201 125 276 58 128 92 203 126 278 59 130 93 205 127 280 60 132 94 207 128 282 61 134 95 209 129 284 62 137 96 212 130 287 63 139 97 214 131 289 64 141 98 216 132 291 65 143 99 218 13 293 66 146 100 220 67 148 101 223 134 29~ 68 150 102 225 135 298 69 152 103 227 136 300 70 154 104 229 137 302 71 157 105 231 138 304 72 159 106 234 139 306 73 161 107 236 140 309 PAGENO="0158" 6990 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Name Reviewer Last First Middle Date: Time: Start Finish Hospital record No. Csl. 1-3 Hospital code number 1 2 3 4-5 Patient's series number in hospital 4 5 6-7 Month of onset 6 7 8 Year of onset 0-1960 1-1961 2-1962 3-1963 4-1964 5-1965 9 Hospital pay status 0-N.S. 1-Private specified 2-Semiprivate specified 3-Attending service 4-Ward or resident service 10 Discharge status 0-N.S. 1-Alive 2-Deceased-no autopsy 3-Deceased-autopsy 11-12 Age on admission (last birth- day) 11 12 13 Race or ethnic groups 0-N.S. 1-White 2-Negro 3-American Indian 4-Puerto Rican 5-Asian (Oriental) 6-Polynesian, Hawaiian 7-Other (specIfy) 14 Marital status O-N.S. 1-Single 2-Married 3-Separated 4-Divorced 3-Widowed 15 Religion 0-N.S. 1-Catholic 2-Jewish 3-Protestant Csl. Ccl. 15 4-Other 21 (specify) 16-17 Birthplace (code as per master code sheet No. 1) 16 17 18 Residence at time of onset 22 0-N.S. 1-Baltimore City 2-Maryland, other 3-U.S.A., other 4-Latin America 5-Russia/Slavic/Balkan 6-Mediterranean/France! Romance 7-Scandinavia and other Europe 8-Commonwealth/Ireland 9-Orient/Africa 19 Occupation 23 0-N.S. 1-Housewife 2-Secretary/office asst. 3-Store clerk/saleswoman 4-Teacher/supervisor/pro- fessional 3-Nurse/dental assistant! laboratory technician 6-Beautician/waitress 7-Seamstress/laundry/clean- er.presser/domestic 24 8-Light machine operator (other than 7) 9-Other (specify) 20 Number of pregnancies 0-N.S. 1-1 pregnancy 2-2 pregnancies 3-3 pregnancies 4-4 pregnancies 5-5 pregnancies 6-fl pregnancies 7-7 pregnancies 25 8-S or more (specify) 9-Never pregnant 21 Pregnancies aborted/miscar- ried (less than 6 months) 0-N.S. 1_Abortion/miscarriage 2_Abortions/miscarriages 3__Abortions/misearriages 4-Abortions/miscarriages 5-Abortions/miscarriages 6-Abortions/miscarriages 7_Abortions/miscarriages 8-Or more (specify) 9-Never aborted/miscarried Delivery of stillborn or living Infant, 6+ months gestation 9-N.S. 1-1 delivery 2-2 deliveries 3-3 deliveries 4-4 deliveries 5-S deliveries 6-6 deliveries 7-7 deliveries 8-8 or more (specify) 9-Never delivered Living children 0-N.S. 1-1 living child 2-2 living children 3-3 living children 4-4 living children 5-S living children 6-6 living children 7-7 living children 8-8 or more specify) 9-None Interval from last delivery to 0-N.S. or D.N.A. 1-Pregnant, undelivered 2-0 to <3 months 3-3 to <6 months 4-6 to <12 months 5-i to <2 years 6-2 to <3 years 7-3 to <4 years 8-4to <5 years 9-5+ years History of allergy 0-N.S. 1-Negative 2-Skin (eczema, anglo-edema, urticaria) 3-Respiratory (Al. Rain. Asthma, AL Bronch) 4-Drug (include biologicals) 5-2+3 6-2+4 7-3+4 77 PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6991 Cat. 25 8-2+3+4 9-If none of the above, but other (specify) 26 History of minor conn. tissue disease 0-N.S. 1-Negative 2-Arthralgia, synovitis cap- sulitis 3-Bursitis, tendonitis, epicon- dylitis 4-Myalgia, myositis, fibrositis 5-2+3 6-2+4 7-3+4 8-2+3+4 9-If none of the above, but other (specify) 27 History of previous T-E dis- ease O-N.S. 1-Negative 2-Pulmonary embolism/in- farction 3-Other arterial (CNS, coro- nary, etc.) 4-Venous 5-2+3 6-2+4 7-3+4 8-2+3+4 9-If none of the above, but other (specify) 28 Nsn-thrombo-embolic vascular disease 0-N.S. 1-Negative 2-Hypertensive vascular dis- ease 3-Peripheral arterial V.D. (C.T.D., diabetic, etc.) 4-Peripheral venous V.D. (varicosities, hemorrhoids, etc.) 5-2+3 6-2+4 7-3+4 8-2+3+4 9-If none of the above, but other (specify) 29 Pelvic or vascular surgery 0-N.S. i-Negative 2-Surgery causing infertility (tubal 11g., oophorect., hysterect) 3-Other pelvic surgery Cot. 29 4-Varicose vein procedure/ hemorrhoidectomy, other vascular 5-2+3 6-2+4 7-3+4 8-2+3+4 9-If none of the above, but other (specify) 30 Past use of cigarettes (code maximum possible) 0-N.S. 1-Never smoked 2-Smoked once in a while 3-Less than % pack a day 4-~ to <1 pack a day 5-1 to <2 packs a day 2-2+ packs a day 31 Current use of cigarettes (code maximum possible) 0-N.S. 1-Never smokes 2-Smokes once in a while 3-Less than ~/2 pack a day 4__1/~ to <1 pack a day 5-1 to < 2 packs a day 6-2+ packs a day 32 Current use of alcohol O-N.S. 1-Never used 2-Occasional drink 3-1 or 2 beers/cocktail, whis- ky/wine a day-moot days 4-i or 2 beers/cocktail, whis- ky/wine a day-almost every day 5-3 drinks a day-frequent 6-3 drinks a day-constant 7-4+ drinks a day-habitual 33 Hormone intake within 2 months of onset O-N.S. 1-Negative 2-Insulin/thyroid 3-Steroids/acth./estrogen 4-Oral contraceptives (spe- cify trade name) 5-2+3 6-2+4 7-3+4 3-2+3+4 9-If none of the above, but other (specify) 34 Other drug intake within 2 months of onset 0-N.S. i-Negative 2-Sedatives/tranquilizers 3-Anorectics/diuretics 4-Antibiotics plus chemo RX Csl. 34 5-2+3 6-2+4 7-3+4 3-2+3+4 9-If none of the above, but other (specify) 35 Postural influence within 1 month of onset 0-N.S. i-Negative 2-Prolonged bed rest 3-Prolonged sitting/stooping/ standing 4-Limb splint, cast/strap/ brace 5-Use of crutches 6-Use of traction 7-Strenuous calisthenics 3-Other than above (specify) 5-Combinations (specify) 36 Infection within 1 month of onset 0-N.S. 1-Negative 2-Local infection at throm- bus site 3-Organ/system infection 4-Generalized infection (bact., viral, ricket.) 5-2+3 6-2+4 7-3+4 3-2+3+4 9-If 3 or 4 positive code col. 37 37 Infection specified O-N.S. 1-CNS 2-Respiratory tract 3-C-I tract 4-Hepatic/biliary tract 5-C-U tract 6-Skin 7-Viremia/bacter./septicem. 3-Other (specify) 9-Combinations (specify) 38 Hemodynamic/fluid imbalance within 1 month of onset 0-N.S. 1-Negative 2-Acute blood loss 3-Hypotension/syncope shock 4-Dehydration 5-2+3 6-2+4 7-3+4 3-2+3+4 PAGENO="0160" 6992 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (752. (752. aol. 38 9-If none of the above but 43 1-Negative 47 8-2+3+4 other 2-Arrythmlas, significant 9-If none of the above but (specify) 3-Decompensation other 39 Minor trauma within 1 month 4-Recent myocardial luij. (specify) of onset 5-2+3 48 Thyroid disease/liver disease! 0-IfS. 6-2+4 malignancy 1-Negative 7-3+4 0-IfS. 2-Thermal (burns, chill) 8-2+3+4 1-Negative 3-Contusion/strain/sprain 9-If none of the above but 2-Hypothyroidism or (no skin break) other Hypcrthyroidism 4-Laceration/abrasion/bite (specify) (skin broken) 44 Major conn. tissue dis. (specify) 5-2+3 3-Liver disease 6-2+4 1-Negative 4-Malignancy - - 7-3+4 2-I~heums.toid arthritis 8-2+3+4 3-S.L.E. 5-2+3 9-If none of the above but 4-P-A. nod. 6-2+4 other 5-Scleroderma 7-3+4 (specify) 6-Derniatomyositis 8-2+3+4 40 Minor surgery within 1 month 7 9-If none of the above but of onset 8 other 0-N.S. 9-Combinations (specify) 1-Negative (specify) 49 Postop/postpartumjmajor 2-Excisions/extractions 45 Metabolic disease trauma within 1 month of 3-Instrumentation 0-IfS. onset 4-Oauterlmtion 1-Negative 0-N.S. 5-2+3 2-Obesity, mild 1-Negative 6-2+4 3-Obesity, moderate 2-Postop. (major surg.) 7-3+4 4-Obesity, severe 3-Postpartum (pregnancy re- 8-2+3+4 5-Diabetes, mild lated) 9-If none of. the above but 6-Diabetes, moderate 4-Major trauma other - 7-Diabetes, severe 6-2+4 (specify) 8-Gout 5-2+3 41 Non-T-E CNS disease 9-Combinations 7-3+4 0-N.S. (specIfy) 8-2+3+4 1-Negative 46 Hematologic disorders 9-If none of the above but 2-Intervertebral disc. syn- 0-N.S. other dromes 1-Negative (specify) 3-Epilepsy/convulsion 2-RBO abnormalities, slgnif- 50 Interval between delivery, op- 4-Stupor/coma icant (anemias, polycythe- eration, or trauma and onset (specify cause) mis) 0-IfS. 3-WBC abnormalities, slgnlf- 1-Less than 7 days 7 Icant (leukemia, lymphoma) 2-7-13 days included 8 4-Bleeding/coagulation dis. 3-14-20 days included 9-Combinations orders 4-21-27 days included (specIfy) 5-2+3 5-1-<2 months included 42 Predisposing heart disease 6-2+4 6-2-<3 months included 0-N.S. 7-3+4 7-3-<12 months included 1-Negative 8-2+3+4 8-1+ years 2-Congenital 9-If none of the above but (specify) 3-Rheumatic th 51-52 Height in inches (see Master 4-Primary myocardopathy (specify) - Code Sheet Number 2) 5-Coronary art. H.D. 47 Pelvic disease 6-Luetic H.D. 0-N.S. 51 52 7-Conu. tissue H.D. 1-Negative If N.S. use 00 8-Other 2-Ovarian Cyst(s) 53-55 Weight in pounds (see Master (specify) 3-Endometriosis Code Sheet Number 3 for 9-Combinations 4-Fibromyomata kgm. to lb. cony.) 43 Precipitating cardiac events 5-2+3 within 1 month of onset 6-2+4 53 54 55 0-N.S. 7-3+4 If N.S. use (8)0 PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6993 OoZ. Ool. 005. 56 B.P. categories at time of ad- 60 7-360-399 Case categories (cole. 68-74) mission 8-400--439 (if controls, skip to cole. (74-75)) O-N.S. 9-More than 440 68 Idiopathic arterial 1-Normal <140/90 61 Bill bin total thrombosls/embolism/ 2-Systolic 140-159 0-Not do e hemorrhage Diastolic <95 1-<1 0 0-Nonidiopathic 3-Systolic 160+ 2-1 to 14 1-Cerebral hemorrhage Diastolic <95 &-i s toi ~ 2-Cerebral thrombosis! 4-Systolic <160 4-2.0 to 2:4 embolism DiastolIc 95+ 5-2 5 29 (specify) 5-Systolic 160+ ° . 3-Other CNS thrombosis/ Diastolic 95+ + embolism LABORATORY (Cole. 57-67) 62 Ceph. Floe. (secclty) 57 Admission 0-Not done 4--Retinal art. thromb/em. Hematocrit or HemoglobIn 1-1+ 3-Coronary art. thromb/em. (Code one test only) 2-2+ 6-Pulmonary art. thromb/ 0-Not stated s-3+ em. .7Tcmatocrit: 4-~+ 7-Mesenteric art. throinb/ 1-Below 25-Spec 9-Negative em. 2-25-29 63 Transaminase 8-Extremity art. thromb/ 3-30-34 0-Not done em. 4__35_39 1-<20 9-Other 5-40+ Spec 2-20 to 34 I.f embolism (specify) Hemoglobin: 3-35 to 49 -- 6--Below 7.5 Spec 4-50 to 64 5-OS to 79 69 Idiopathic venous 8-10.0-12.4 6-80+ thrombosis 9-12.5+ Spec (specify) 0-Nonidiopathic 58 Platelet count (Code one value 64 LDH 1-Cerebral vein only) 0-Not done 2-Intracranial venous sinus 0-Not stated 1-<20 3-Retinal vein Counts 2-200-399 4-Va cava 1-Less than 50,000 3-400-599 5-Pelvic vein Specify 4-600-799 2-50-99,999 5-800-999 6-Upper extremity vein 3-100-199,999 6-4,000-1,199 7-Lower extremity vein, 4-200-299,999 7-1,200-1,399 superficial 5-300-399,999 8-1,400-1,599 8-Lower extremity vein, 6-400,000+ 0-1,600+ deep (specify) (specify) 0-Other or combination Smears: 65 Blood type 7-Low on smear 0-N.S. (specify) 8-Normal on smear 1-0 negative 70 Pulmonary embolism! 0-Increased on smear 2-A negative infarction-clinical 59 Blood test for syphilis 3-B negative presentation 4-AB negative 3-0 ppsitive 0-~egative 1-Reagin-type test negative 6-A positive 1-Presenting and idio. 2-Reagin-type test positive, 7-B positive 2-Presenting and embolic T.P.L sr F.T.A. negative 8-AB positive from pulmonary art. 3-Reagin-type test positive, 66 Chest X-ray examinations 3-Presenting and embolic PP.1. or F.T.A. positive 0-Not done from heart 4-Reagin-type test positive, 1-Negative 4-Presenting and embolic no further tests done 2-Positive (Sp~ify) from idiopath. von. 60 Cholesterol throm. 0-N.S. 5-Presenting and embollc 1-Less than 160 67 Electrocardiogram from nonidio. yen. 2-160 tO 199 0-Not done thromb. 3-200-239 1-Negative 6-Complicating plus No. 2 4240-279 2-Positive (specify) 7-Complicating plus No. 3 5-280-319 8-Complicating plus No. 4 6-320-~359 9-Complicating plus No. 5 80 40-471 O-70--pt. 17-11 PAGENO="0162" 6994 COMPETITIVE PROBLEMS IN THE DRUG INDU~TRY Cal. Cal. Cal. 71 Nonldiopathic arterial 72 7-Lower extremity vein, 74 0-Indeterminate thromb./embolism/hemorr. superficial Idiopathic 0-Idiopathic 8-Lower extremity vein, 1-Arterial 1-Cerebral hemorrhage deep 2-Venous 2-Cerebral tbrombosis/ 9-Other or combinations a-combination embolism - Nonidlopathic (specify) (specify) 4-Arterial 3-Other CNS thrombosIs 73 Thromboembolic episodes 5-Venous embolism (Idlopath. plus nonidlo.) (ijiecify) 0-Does not apply 6-Combinations 4-Retinal art. throm/em Idiopathic (Jontrol categories (cola. 75-76) 5-Coronary art. throm/em 1-One episode, one ~ individual diagnoses to be speot/led 6-Pulmonary art. throm/em 2-One episode, multiple on a master list 7-Mesenteric art. throm/em sites 8-Extremity art throm/em 3-Recurrent, one site 00-09 Operatloni for acute 9-Other or combinations 4-Recurrent, multiple conditions sites 10-19 Acute self-limited tIRI's (specify) 72 Nonldlopathlc venous Nonldlopitthlc 20-29 Acute pneumonitls and thrombosis 8-One episode, one site bronchitis 0-Idiopathic 6-One episode, multiple 30-39 Acute enteritis 1-Cerebral vein sItes 40-49 Other acute G.I. disorder 2-Intracranial venous 7-Reinirrent, one site 50-59 Sprains and simple fracture sinus 6-Recurrent, multiple 60-69 Head Injuries without skull 3-Retinal vein sites fracture 4-Vena cava 9-Indetermlnste 70-79 6-Pelvic veIn 74 Thromboembolic disease 80-89 6-Upper extremity vein category 90-99 Column Comments 81 PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6995 COVER SHEET Date of Interview ____________________________ Time started Time terminated Dates of return calls Respondent's name Address Phone No. Date of Hospitalization Hospital Record No. Series No. Letterhead Interviewer 82 PAGENO="0164" 6996 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Interview Questionnaire 5-31-66 INTRODUCFION TO RESPONDENT Hello, Mrs. Smith, my name is Miss _________________ from Johns Hopkins. You will recall that you received a letter from us last week regarding this interview, and we arranged this time in our telephone conversation. We appreciate your allowing us a few minutes of your time to ask you some questions. Before we start, however, let me explain a little of what we are studying. Actually, we have two purposes in mind: First, we want to learn more about the kinds of medica- tions women are taking, and secondly, we would like to see how the general health of married couples influences their family planning. As you know, new medicines are being introduced all the time, and we would like to learn how some of these have been used over the pastS years. Your name was chosen from a list of all women who were hospitalized at Johns Hopkins Hospital since January 1963. We will be talking to a number of women through- out the Baltimore area, and afterward all the information we receive will be put into computers. This way, we will know the results of the study, but no individual can be singled out nor will any names be known. We'd like to again assure you that all the information you give us will be absolutely confidential to this office, and that your name and identity will not at any time be revealed. Do you have any questions? Fine. Let's then, start with a few general questions about your health. 83 PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6997 Page 1 DRAFF QUESTIONNAIRE Our records show that you were hospitalized at Tohns Hopkins Hospital In _________ (month and year) 1. Before your hospitalization, have you ever had any of the chronic conditions listed on this card which have bothered you over a period of several months? (Show Cord No. 1) Yes_____ No_____ Which conditions are they? Conditions__________ 2. Have you found It necessary to take medicines of any kind over long periods of time Inthepast? Yes_____ No_____ Whatkind of medicines were these? Medications used _________ In this study we are mainly Interested In certain groups of medicines. Some of these can be bought In the drugstore without a prescription; others require a prescription from your doctor or can be given to you at a clinic. We are Interested primarily In the period of your hospitalization and about 2 years before, and we would like your answers to the next questions to relate to that time. This is just to give us a time period to look at, and these questions don't necessarily have to do with any treatment or medication that you required as pact of your hospitalization. 84 PAGENO="0166" 6998 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 2 3. During the 2 years before and leading up to the time of your hospitalization, were you using any medicine for relieving pain, such as for headaches, arthritis, rheumatism, or similarconditions? Yes______ No (skiptoQ-4). (INTERVIEWER: Use Table 1 for multiple medications.) (a) For how long a time before your hospitalization had you been taking this medicine? Irregularly 1-6 months _______________ Less than 1 week 6 months-i year 1-2 weeks ____________________ 1-2 years 2-3 weeks Over 2 years 3-4 weeks Don't remember (b) Do you recall the name of the medicine(s) I Yes_____ No_____ (a) Why were you taking thin medicine? (ci) Did you obtain this medicine: With a prescription. Without a prescription (skip to 1). At a clinic (skip tot). T.usi.z 1 Ties prlsr ts hsspltollsstisa Medlestisa Indicatioss Rs/ellnlc (a) (b) (c) (d) 85 PAGENO="0167" COMPETITIVE PROBLEMS IN. THE DRUG INDUSTRY 6099 Page 3 (e) Do you recall the name of the pharmacy where you bought this medicine? Yes _______ No _______- (f) Do you recall the name of the doctor (or clinic) that prescribed this medicine? Yes - No _______ (g) Did you stop taking this medicine for any reason? Yes _______ No _______ (is) Was anothermediclne snbstltutedfor the discontinued one? Yes _______ No _______ T~BLE 1 Nanio efpharinacy Doctor or clinic prescribing Reason for stopping Medication substituted Ce) (I) Ce) (h) 86 PAGENO="0168" 7000 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 4 4. During the 2 years before and leading up to the time of your hospitalization, were you using any kind of tranquilizers, medicines to calm your nerves, or to help you sleep? Yes_____ No (sklptoQ-5). (INTERVIEWER: Use table 2 for multiple medications.) (a) For how long a time before your hospitalization had you been taking this medicine? Irregularly Less than 1 week 1-2 weeks _________________ 2-3 weeks 3-4 weeks 1-6 months 6 months-i year 1-2 years Over 2 years Don't remember (b) Do you recall the name of the medicine(s)? Yes________ No. ________ (c) Why were you taking this medicine? (d) Did you obtainthis medicine: With a prescription. Without a prescription (skip to f). AtacUnic (akiptof). TeaLs 2 Tions prlsr ~ to hospitalization Medication Indications Ba/clinic (a) (b) (c) . (d) 87 PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7001 Page 5 (e) Do you recall the name of thepharmacy where you bought this medicine? Yes_____ No_____ (1) Do you recall the name of the doctor (or clinic) that prescribed this medicine? Yes_____ No_____ (g) Did you atop taking this medicine for any reason? Yes _______ No (sklptoQ-5). (1&) Was another medicine substitutedfor the discontinued one? Yes_____ No_____ T~nLE 2 Namoof pharmacy Doclor or clinic prescribing Reason forstopping Medication substituted ~ (e) (I) to) (h) 88 PAGENO="0170" 7002 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 5. What Is your present weight? lbs. Page 6 0. What Is the most you have ever weighed when you weren't pregnant? _____________ lbs. When was this? (year). 7. What is the least you have ever weighed since you were 21 years old? lbs. When was this? (year). 8. Did you follow a plan to lose weight within 6 months of your hospitalization? Yes _______ No (skip to Q-1O). (a) Whenwasthis? (INTERVIEWER: Use table 3). (b) What method did you use? (SHOW CARD No. 2). (C) How many pounds did you lose? (d) How long did It take you? 1st time 2d time 3d time TABLE 3 nhea Method Peusdo lost Time period (mosths) (a) (b) (c) (d) (Mo.) (Yr.) (INTERVIEWER: If B. Indicates having used methods 4,5,6, and 7 from card, within time period, ask question 9. If not, SKIP to question 10.) 89 PAGENO="0171" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7003 Page 7 9. If you followed a plan that included medicine to reduce your appetite or to get rid of water In your body during the 6 months before your hospitalization, do you recall the name of the medicine? Yes _____ No (INTERVIEWER: Use table 4 for multiple medications.) (a) For how long a time before your hospitalization had you been taking this medicine? Irregularly ~ 1 to 6 months Less than 1 week 6 months-i year 1 to 2 weeks _________ 1 to 2 years --_____________ 2 to 3 weeks Over 2 years -__________________ 3 to 4 weeks ___________ Don't remember (b) Name of medicine(s)? (c) Why were you taking this medicine? (4) Did you obtain this medicine: With a prescription. Without a prescription (skip to 1). At a clinic (skip to!). TABLC 4 Ttme prtsr to hsspitalizattss Medication Isdications Rn/clinic (a) (b) (c) (d) 90 PAGENO="0172" 7004 COMPETITIVE PROBLEMS IN THE DRUG INDUS~TRY Page 8 (e) Do you recall the name of the pharmacy where you bought this medicine? Yes _______ No (f) Do you recall the name of the doctor (or clinic) that prescribed this medicine? Yes _____ No _____ (g) Did you stop taking this medicine for any reason? Yes ________ No (skip to Q-1O). (h) Was another medicine substituted for the discontinued one? Yes ______ No_____ TABLE 4 Noose of pharmacy Doctor or effete prescribing Remus forstopploag Medicatisa substituted (e) (j) (g) (h) 91 PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7005 Page 9 10. During the two years before and leading up to the time of your hospitalization were you using any kind of medicine for high blood pressure or for a heart condition? Yes _____ No _____ (INTERVIEWER: Use table 5 for multiple medications) (a) For how long a time before your hospitalization had you been taking this medicine? Irregularly 1-0 months __________________ Less than 1 week ______________ 6 months-i year 1-2 weeks 1-2 years 2-3 weeks Over 2 years 3-4 weeks Don't remember _______________ (b) Do you recall the name of the medicine(s)? Yes _______ No _______ (c) Why were you taking this medicine? (d) Did you obtain this medicine: With a prescription. Without a prescription (skip tof). At a clinic (skip to f). T~saz,z 5 Time prior Is hsspltallzatlsa Medlcatlsn Indications Rn/nUde (a) (b) (C) (d) 92 PAGENO="0174" 7006 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 10 (e) Do you recall the name of the pharmacy where you bought this medicine? Yes _____ No _____ (f) Do you recall the name of the doctor (or clinic) that prescribed this medicine? Yes _______ No _______ (g) Did you stop taking this medicine for any reason? Yes _______ No _______ (is) Was another medicine substituted for the discontinued one? Yes ________ No _______ Tsara 5 Name of pharmacy Doctor sr clinic proscribing Reason forslopplng. Medication substituted (e) (I) (g) (5) 93 PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7007 Page 11 11. During the two years before and leading up to the time of your hospitalization, were you using any of the following hormones which I will mention? Yes ________ No. (skip to Q-12). (INTERVIEWER: Use table 6 for multiple medications.) (a) For how long a time before your hospitalization bad you been taking this medicine? Irregularly Less than 1 week ____________ 1-2 weeks ________ 2-3 weeks ________________ 3-4 weeks ___________________ 1-6 months ________________ 6 months-i year 1-2 years Over 2 years Don't remember _____________ (b) Do you recall the brand name of the medication? Yes______ No______ (c) Why were you toking this medication? (ci) Did you obtain this medicine: With a prescription. Without a prescription (skip tot). At a clinic (skip to f). TABLE 6 Time prior ts hospital- motion (a) Medication (5) lndicatlon't (C) Ri/clinic (d) Thyroid. Cortisone or related. Insulin. Tablets for diabetes. Female hormones (2) (Estrogens and Progestins).' If yes, show card for identification. 2 (INTERVIEWER: SHOW CARD #4 of O.C. tablets for positi cc ldentltcatlon.) 2 (SHOW CARD #3 of Indications for use.) 94 PAGENO="0176" 7008 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 12 (e) Do you recall the name of the pharmacy where you bought this medicine? Yes ________ No ________ (/) Do you recall the name of the doctor (or clinic) that prescribed this medicine? Yes_____ No_____ (g) Did you stop taking this medicine for any reason? Yes _______ No (skip to Q-12). (Fo) Was another medllcne substituted for the discontinuedone? Yes ________ No -~ TABLE 6 Name of pharmacy (e) Doctor orchlaic prescribing if) Reason for stopping (o) Medlmtion substituted (h) 95 PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7009 Page 13 Now I would like to ask you some questions about your health and your husband's health since you have been married. Our records show that you were married at the time of your hospitalization at Johns Hopkins Hospital in - Are you still married? (Month and year) Yes _______ No_______ 12. Had you ever been married before? Yes ______ No (skiptoQ-14). How many times had you been married before? Number of previous marriages When did your first marriage begin? Year of first marriage 13. When did the marriage at the time of your hospitalization begin? Year of marriage 14. When were you born? Date of birth ________ 15. How many pregnancies have you had altogether? Number of pregnancies (IF NONE) Did you and your husband plan to have any children? Yes~~ No (sklptoQ-19). 16. How many of those were miscarriages? Number of miscarriages 40-471 O---70-~--pt. 17-.12 PAGENO="0178" 7010 COMPETITIVE PROBLEMS IN THE DRUG INDU&PRY Page 14 Total number of live births?-_-- Total number of children in thishonsehold? 18. DId you and your husband plan to have any more children at the time of your hospital- ization? 19. Was your hnsband In good health at the time of your marriage? Yes______ No (skiptoQ-21). 20. Has his health remained good? Yes ________ No_~- 21. What serious illnesses has your husband had within the year that you went to the hospital? That is, illnesses which caused him to seek medical attention repeatedly or go to a hospital? HOSPITALIZATION Illness Year Yes No Name of bs~pita1 Now we would like some Information about each of your pregnancies, starting with the first. 17. (a) Did your first (2d, 3d, etc.) pregnancy end In a live birth, or did the baby die beforedelivery? (b) About how long were you pregnant? (c) When was the baby born? or When did the pregnancy end? (d) Is that child now living here in this household? 1st 2d 3d 4th 5th 6th 7th a. Live-birth, miscar- riage, still-birth. b. Length of preg- nancy. c. Date of termination month and year. d. Living here? 97 PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7011 Page 15 22. Were you in good health at the time of your marriage? Yes _______ No (skip to Q-24). 23. Has your health remained good? Yes_____ No_____ 24. What serious illnesses have you had since you were married? That is, illnesses which caused you to seek medical attention repeatedly or go to a hospital? You don't have to repeat any hospitalization for pregnancies. HOSPITALIZATION fInesses Year Yes No Name of hospital 25. Have you or your husband felt that any of these illnesses were serious enough to post- pone having children or to prevent pregnancy at the time? Yes _______ No _______ 26. Have you ever had an operation that made it impossible to have any more children? Yes _______ No _______ When was this? What kind of operation was it? Kind ________________________ 27. Has your husband ever had an operation or injury that made It Impossible to have any more children? Yes______ When was this? 1)sl-a No _________ 98 PAGENO="0180" 7012 COMPETITIVE PROBLEMS IN THE DRUG INDUS7PRY Page 16 28. Sometimes for health reasons and sometimes for economic reasons, married couples will decide to space their children and plan their pregnancies to their best advantage. Have you or your husband used any method to prevent pregnancy in the past? Yes _______ No........._ (skip to Q-31). 29. What type of method(s) of birth control have you used within the two years before your hospitalization? (SHOW OARD No. 5) Just read me the letter which corre- sponds to the method if you like? (INTERVIEWER: If R. does not indicate 0.0., use Table 7) (NOTE: If B. does not indicate 0.0. or appears vague and indefinite, ask:) Have you evcr used birth control pills for family planning? (If NO, skip to Q-31) - TABLE 7 Methods of contraception indicated A. _________ __________ B. ____________ H. _____________ C. _______ ________ D. ________________ J. __________________ H. ____________ K. _____________ F. ________ *(INTERVIEWER: If R. does indicate 0.0. use Table 8) (a) When did you begin using this form of birth control? (PROBE for exact year and month.) (b) When did you discontinue this type of method? (PROBE for exact year and month.) (c) Do you recall the brand name? (IF NOT) Do you remember if the tablets looked like any of these? (SHOW CARD No. 4) (d) Why did you discontinue its use? 99 PAGENO="0181" COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY 7013 Page 17 TABLE 8 O.C. Use-Time Periods Used (a) When started (b) When stopped (c) Brand name (d) Reason stopped lot time Id time Id time 4th time 30. Did you consult your doctor orgo to a clinic for advice on birth control pills? Yes_____ No_____ Do you recall the name of the Doctor or clinic that prescribed this medicine? 31. About how many cigarettes a day were you smoking just before your hospitalization: Occasionally. Less than % pack. 1h-1 pack. 1-2 packs. Nonsmoker. 32. Were you working just before your hospitalization? Yes _______ No_______ What kind of work were you doing? 33. Was your husband working at that time? Yes _______ No_______ What kind of work was he doing? PAGENO="0182" 7014 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Page 18 34. What was the highest grade of school you completed? Elementary 1 2 3 4 5 6 7 8 High School 1 2 3 4 College 12345+ 35. What was the highest gradeof school your husband completed? Elementary 1 2 3 4 5 6 7 8 High School 1 2 3 4 College 12345+ 36. Is your religious preference Protestant, Catholic, Jewish, or what? Religion 37. Is your husband's religious preference Protestant, Catholic, Jewish, or what? Religion 38. What was your total family income at the time of your hospitalization? (SHOW CABD No. 6.) Ju8t tell me the letter which corresponds to the income if you like. Income 39. How much of the totalfamily income was earned by your husband? Income PAGENO="0183" 1. Asthma. 2. Any allergy. 3. Tuberculosis. 4. Chronic bronchitis or lung infections. 5. Emphysema. 6. Rheumatic fever. 7. Hardening of the arteries. 8. High blood pressure. 9. Heart trouble of any kind. 10. Stroke. 11. Trouble with varicose veins. 12. Hemorrhoids or piles. 13. Gall bladder or liver trouble. 14. Stomach ulcer. 15. Chronic intestinal or colon trouble. 16. Kidney stones or kidney trouble. 17. Arthritis or rheumatism. 18. Menstrual difficulties. 19. Cyst on ovary or tumor of womb. 20. Diabetes. 21. Thyroid trouble or goiter. 22. Epilepsy or convulsions. 23. Mental or nervous trouble. 24. Serious anemia or blood disorders of any kind. 25. ChronIc or repeated infections. 26. Tumor or cancer. 27. Repeated miscarriages. 28. Unable to become pregnant. 29. Paralysis of any kind. 30. Hirth defects. 31. Repeated back or spine trouble. CARD #2 1. Reducing diet (cutting down on sweets and starches; counting calories). 2. Reducing diet and exercising. 3. Cutting down on liquids (along with dieting and/or exercising). 4. Also took medicine to keep from getting hungry (bought at drugstore, no prescription). 5. Medicine from doctor (or clinic) to control appetite. 102 6. Medicine (pills or shots) to remove water from body. 7. Thyroid pills. CARD #3 i. To help regulate menstrual periods (make them come on time). 2. To cut down on heavy flow (make menstrual flow lighter). 3. To prevent painful cramps with period (make period more comfortable). 4. To prevent headaches, nervousness and bloating be. fore periods. 5. To prevent pain in between periods. 6. To improve chances of becoming pregnant (to help have babies). 7. To treat condition called endometriosis. CARD #4 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7015 Page 19 INTERVIEWER-FILL IN Respondent is: White Nonwhite _____________ Respondent's cooperation was: Very good Good ___________ Fair ________________ Poor _________________ NOTE ANYTHING ELSE ESSENTIAL TO THE INTERPRETATION AND UNDER- STANDING OF THIS INTERVIEW: CARD #1 Enovid 10 Enovid 5 Enovid E Ortho.Novum 10 Ortho-Novum 2 A. Rhythm.f B. Abstinence. C. Rubber, c~ndom, safe. D. Withdrawal. E. Diaphragm. F. Douche. A. Under $1,000. B. $1,000-$1,999. C. $2,000-$2,990. B. $3,000-$3,999. E. $4,000-$4,999. F. $500045090. C.Quens Norinyl Oracon Norlestrin Provest CARD #5 G. Birth control Pills. H. Suppositories. I. Foam tablets. J. Sponge, tampon. K. Jelly, creams. L. Another method not on this card. CARD #6 G. $6,000-$6,999. H. $7,000-$7,999. I. $S,000-$S,909. J. $9,000-$9,999. K. $10,000-$14.000. I.. $15000 pins. PAGENO="0184" 7015A COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Table 1.-Female patients discharged from Johns Hopkins Hospital, 1963-65, with diagnoses of conditions selected for study . Discharges in 3 years White Nonwhite Total Records fotand Acceptable and con- sidered "Idiopathic" Number Percent Final case series Thrombophiebitis extremity Thrombopbiebitis and pulmonary embolism Pulmonary embolism (?source) Cerebral artery thrombosis.~ Cerebral artery embolism Retinal vascular lesion Myocardial infarction Arterialthrombosis, other - Total 22 7 3 6 2 3 2 6 25 8 7 6 0 3 5 0 47 15 10 12 2 6 T 6 36 13 8 9 2 5 7 5 7 2 1 2 0 2 0 0 19 15 12 22 40 4 1 1 2 2 51 54 105 85 14 16 Patients who weremarried, sad record review did not provide evidence of sterility or olpredisposieg conditions. 10 Nuns- her in silo Nuns- her sought Number found and matched Tonsillectomy and adenoi- dectomy 230 25 Acute appendicitis and appen- dectomy 49 44 Acute cystitis 46 6 Infectious hepatitis 36 21 Acute gastroenteritis 22 15 Pilonidal cyst 19 19 Elastosis seniis 10 6 Sprains and strains of sacroiliac.._ 8 8 Fracture upper extremity- closed 5 5 Contussion 3 3 Fracture clavicle-closed 1 1 Total 429 153 20 6 2 Religion (Catholic, Prot- estant, Jewish) Hospital pay status Cases Controls Number selected from printout of dis- charges Records found 105 85 226 127 Excluded because of: Marital statue 29 Sterility 21 Other diagnoses on index sheet Predisposing condition on record 51 107 review 67 Acceptable Interviewed 10 7 20 19 Questionnaires mailed and self- administered 3 1 Table ~ which yielded control subjects Table 3.-List of attributes on which matching of paired controls to cases was done (in addition to sex, marital status, hospital and time period, which were common to cases and controls) Race Age (within 5 years) Table 4.-Cases selected, exclusions, and results of attempt to obtain interview I Control diagnoses which were selected for study but did nut yield any matches with the cases are-omitted. 103 PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7015B Table 5.-Selected findings from interview schedules Cases (10) Number Percent Controls (20) Number Percent Race: White 8 80 16 80 Nonwhite 2 20 4 20 Ages: 18-19 0 0 20-24 1 10 3 15 25-29 3 30 6 30 30-34 2 20 5 25 35-39 2 20 5 25 40-44 2 20 1 s Religion: Catholic 2 20 3 15 Protestant 8 80 17 85 Income: Under $5,000 3 30 3 15 $5,000-$10,000 6 60 11 55 Over $10,000 1 10 5 25 Education: Elementary 1 10 1 5 High school 5 50 10 50 College 4 40 9 45 Parity: 0 2 20 1 5 1 1 10 4 20 2 1 10 9 45 3+ 6 60 6 30 Children in household: 0 2 20 1 5 1 1 10 4 20 2 1 10 8 40 3 3 30 4 20 4+ 3 30 3 15 Birth control practiced 8 80 15 75 Smoker 8 80 11 55 Serious illness: Husband 0 3 15 Wife 0 4 20 Chronic conditions 6 60 14 70 Past medications 3 30 5 25 104 PAGENO="0186" PAGENO="0187" APPENDIX III DEAR DOCTOR LETTERS DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., January 12, 1970. DEAn DOCTOR: I am enclosing revised labeling for oral contraceptives to reflect the latest findings on safety and efficacy, as reported by the Obstetrics and Gynecology Advisory Committee in August 1969. An American study con- firms previously reported studies in Great Britain which show a relationship between the use of oral contraceptives and the occurrence of certain throm- boembolic diseases. These carefully designed retrospective studies show that users of oral contraceptives are more likely to have thrombophiebitis and pul- monary embolism than non-users. Studies in Great Britain also show increased risk of cerebral thrombosis and embolism in users of oral contraceptives. A British study found a hospitalization rate (an index of morbidity) in women age 20-44 to be 47 per 100,000 in users compared to five per 100,000 in non- users. The American study, although not designed to evaluate differences between products, also suggests there may be an increased risk of thromboembolic dis- ease in users of sequential products. This difference in risk cannot be quanti- tated, and further studies are needed to confirm the observation. The British Committee on Safety of Drugs recently advised practitioners in that country that only products containing 0.05 mg. or less of estrogen should normally be prescribed because reports of suspected adverse reactions indi- cated there is a higher incidence of thromboembolic disorders with products containing 0.075 mg. or more of estrogen than with products containing the smaller dose. This finding has not been confirmed by other studies. The FDA is planning studies that will determine, among other things, the thromboembolic effect of various products. You will be kept informed as results become available. Other aspects being investigated in separate studies underway or pending are cervical cytology, carbohydrate metabolism, serum lipids, urinary tract function, blood coagulation, effects on endocrine function in adolescents, breast pathology, outcome of pregnancy, and cytogenetic effects. In the United States during 1969 an estimated 8.5 million women took oral contraceptives monthly. The unsurpassed clinical efficacy of these products is well established. Although reported pregnancy rates vary from product to product, the effectiveness of sequential products appears to be somewhat lower than that of the combination products. I strongly urge you to familiarize yourself with the labeling, particularly with the cautionary material contained in the sections headed Contraindica- tions, Warnings, Precautions, and Adverse Reactions. As the prescribing physi- cian, you are in the best position to determine the extent of your discussion of this material with your patient. In most cases, a full disclosure of the poten- tial adverse effects of these products would seem advisable, thus permitting the participation of the patient in the assessment of the risk associated with this method. I also request your assistance in continuing our assessment of the safety of oral contraceptives. Your reports of adverse reactions will help us to do this. A supply of the standard reporting form (FD 1639), shown in facsimile below, may be obtained from the Bureau of Medicine, Food and Drug Administration, Washington, D.C. 20204. Sincerely yours, CHARLES C. EDWARDS, M.D., Acting Commissioner of Food and Drugs. Attachment: Revised labeling (7017) PAGENO="0188" I, D ~ r~ o~r II) ~ 1 At NI ` 1 Tt~LJ~LLC ~ ~ --~~ Sf~.pItAl, ~l) (N~m. 11 ?.pAlIANt j'lo~t. "o J' A 4 QI I~AI4' ç (Ill. .41'."I, &It~, ig~., .~I 7.!,, 1'&"I..) ~-~---~~` - - * . I ~çN'.~' ~.. 4 wn J !SZ4~0V~#44 4' r,I~A (O1I'# i1~ , , 01111114 0~ `111111',C4014 (M"I"I"~'"~ II NI/A "1~ ~N'.) NANOrACTUfl1~IIS i1(AIAIfl. I OUT I. A/.)'IA `1,U4 Co OL Q I( $U,11L~~UAUY ` fl 0 . U I ~-~H~-- ) ~ ~ - ron rcA usC OMLY h/Il MPG 0511 UNLN ~ ~"`~ - 1 ,.4IVP1ACIIC,14 OP IWO 011 ,l(,I1P All AOl I IUIU/4 IlL'? LIII I~ ACCAI1IIINU 10 LA1~1LI11~ 111,011 OIJ/11A 11141 111141 14141 4II1)3Al~I' I'll//Il II II 14.1' 1 ~` IA/Ill 14Lll~$* 11*114 1141' 1111/Il ~1 III. II Illl$lU Vll%*114/ ~11 141411 PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7019 ORAL CONTRACEPTIVE LABELING DESCRIPTION This section includes generic name, amount, chemical name and the struc- tural formula of each active ingredient. ACTIONS Combination oral contraceptives: The mechanism of action is inhibition of ovulation resulting from gonadotropin suppression. Changes in cervical mucus and endometrium may be contributory mechanisms. Sequential oral contraceptives: The mechanism of action is inhibition of ovulation resulting from gonadotropin suppression. SPECIAL NOTE Oral contraceptives have been marketed in the United States since 1960. Reported pregnancy rates vary from product to product. The effectiveness of the sequential products appears to be somewhat lower than that of the combi- nation products. Both types provide almost completely effective contraception. An increased risk of thromboembolic disease associated with the use of hor- monal contraceptives has now been shown in studies conducted in both Great Britain and the United States. Other risks, such as those of elevated blood pressure, liver disease and reduced tolerance to carbohydrates, have not been quantitated with precision. Long term administration of both natural and syn- thetic estrogens in subprimate animal species in multiples of the human dose increases the frequency for some animal carcinomas. These data cannot be transposed directly to man. The possible carcinogenicity due to the estrogens can neither be affirmed nor refuted at this time. Close clinical surveillance of all women taking oral contraceptives must be continued. INDICATIONS The Obstetrics and Gynecology Advisory Committee considered the following indications acceptable: contraception, endometriosis, and hypermenorrhea. These indications may be used in the labeling when efficacy has been demon- strated in each case. Any other claims will be evaluated on the basis of efficacy data available to support each. CONTRAINDICATIONS 1. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these conditions. 2. Markedly impaired liver function. 3. Known or suspected carcinoma of the breast. 4. Known or suspected estrogen dependent neoplasia. 5. Undiagnosed abnormal genital bleeding. WARNINGS 1. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Retrospective studies of morbidity and mortality in Great Britain and stud- ies of morbidity in the United States have shown a statistically significant association between thrombophlebitis and pulmonary embolism and the use of oral contraceptives. There have been three principal studies in Britain `~ lead- ing to this conclusion, and one' in this country. The estimate of the relative risk of thromboembolism in the study by Vessey and Doll3 was about seven- 1Royal College of General Practitioners: Oral Contraception and Thromboembolic Dis- ease. J. Coil. Gen. Pract., 13 :267-279. 1967. ~ Inman, W. H. W. and Vessey, M. P. Investigation of Deaths from Pulmonary Coro- nary and Cerebral Thrombosis and Embolism in Women in Child Bearing Age, Brit Med J, 2 :193-199, 1968. 3Vessev. M. P. and Doll. R. Investleation of Relation between Use of Oral Contracep- tives and Thromboembolic Disease. A Further Report. Brit Med J, 2 :651-657, 1969. 4 Sartwell, P. E.. Masi, A. T.. Arthes, F. G.. Greene. G. R.. and Smith, H. B., Throm- boembolism and Oral Contraceptives: An Epidemiological Case-Control Study. Am. J. Epidem. 90 :365-380, (November) 1969. PAGENO="0190" 7020 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY fold, while Sartwell and associates in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo throm- boembolic disease without evident cause as non-users. The American study also indicated that the risk did not persist after discontinuaton of administration, and that it was not enhanced by long continued administration. The American study was not designed to evaluate a difference between products. However, the study suggested that there might be an increased risk of thromboembolic disease in users of sequential products. This risk cannot be quantitated, and further studies to confirm this finding are desirable. Retrospective studies in Great Britain have shown a statistically significant assOciation between cere- bral thrombosis and embolism and the use of oral contraceptives. This has not been confirmed in the United States. 2. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medi- cation should be withdrawn. 3. Since the safety of * * * in pregnancy has not been demonstrated, it is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. If the patient has not adhered to the prescribed schedule the possibility of preg- nancy should be considered at the time of the first missed period. 4. A small fraction of the hormonal agents in oral contraceptives has been identified in the milk of mothers receiving these drugs. The long range effect to the nursing infant cannot be determined at this time. PRECAUTIONS 1. The pretreatment and periodic physical examinations should include spe- cial reference to breasts and pelvic organs, including Papanicolaou smear since estrogens have been known to produce tumors, some of them malignant, in five species of subprimate animals. 2. Endocrine and possibly liver function tests may be affected by treatment with * * ** Therefore, if such tests are abnormal in a patient taking * * ~, it is recommended that they be repeated after the drug has been withdrawn for 2 months. 3. Under the influence of estrogen-progestogen preparations, pre-existing uterine fibromyomata may increase in size. 4. Because these agents may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation. 5. In breakthrough bleeding, and in all cases of irregular bleeding per vagi- nam, nonfunctional causes should be borne in mind. In undiagnosed bleeding per vaginam, adequate diagnostic measures are indicated. 6. Patients with a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. 7. Any possible influence of prolonged * * * therapy on pituitary, ovarian, adrenal, hepatic or uterine function awaits further study. 8. A decrease in glucose tolerance has been observed in a significant percent- age of patients on oral contraceptives. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving ~ * * therapy. 9. The age of the patient constitutes no absolute limiting factor, although treatment with * * * may mask the onset of the climacteric. 10. The pathologist should be advised of * * * therapy when relevant speci- mens are submitted. 11. Susceptible women may experience an increase in blood pressure follow- ing administration of contraceptive steroids. ADVERSE REACTIONS OBSERVED IN PATIENTS RECEIVING ORAL CONTRACEPTIVES A statistically significant association has been demonstrated between use of oral contraceptives and the following serious adverse reactions: Thrombophiebitis Cerebral thrombosis Pulmonary embolism PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7021 Although available evidence is suggestive of an association, such a relation- ship has been neither confirmed nor refuted for the following serious adverse reactions: Neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis The following adverse reactions are known to occur in patients receiving oral contraceptives: Nausea Vomiting Gastrointestinal symptoms (such as abdominal cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea during and after treatment Edema Chloasma or melasma Breast changes: tenderness, enlargement and secretion Change in weight (increase or decrease) Changes in cervical erosion and cervical secretions Suppression of lactation when given immediately postpartum Cholestatic Jaundice Migraine Rash (Allergic) Rise in blood pressure in susceptible individuals Mental depression Although the following adverse reactions have been reported in users of oral contraceptives, an association has been neither confirmed nor refuted: Anovulation post treatment Fatigue Premenstrual-like syndrome Backache Changes in libido Hirsutism Changes in appetite Loss of scalp hair Cystitis-like syndrome Erythema multiforme Headache Erythema nodosum Nervousness Hemorrhagic eruption Dizziness Itching The following laboratory results may be altered by the use of oral contra- ceptives: Hepatic function: Increased Thyroid function: Increase in sulfobromophthalein retention PBI, and butanol extractable and other tests protein bound iodine and Coagulation tests: Increase in decrease in T3 uptake values prothrombin, Factors VII, Metayrapone test VIII, IX, and X Pregnanediol determination DOSAGE AND ADMINISTRATION This section includes routine administration and specific instructions on han- dling problems such as breakthrough bleeding, amenorrhea, etc. CLINICAL STUDIES (AN OPTIONAL SECTION) If any clinical data are included, the following paragraph must be used: Different pregnancy and adverse reaction rates have been reported with the use of each oral contraceptive. Inasmuch as these rates are usually derived from separate studies conducted by different investigators in several popula- tion groups, they cannot be compared with precision. Furthermore, pregnancy and adverse reaction rates tend to be lower as clinical experience is expanded, Possibly due to retention in the clinical study of those patients who accept the treatment regimen and did not discontinue due to adverse reactions or preg- nancy. In clinical trials with * * * patients completed * * * cycles, and a total of * * * pregnancies was reported. This represents a pregnancy rate of * * * per 100 woman years. Please see the SPECIAL NOTE in this labeling. PAGENO="0192" 7022 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., June 28, 1968. DEAR DOCTOR: Since 1960, when the first oral contraceptive was marketed in the United States, these drugs have been prescribed in a volume which may exceed that of any other potent medication. According to current estimates, more than six million American women now use oral contraceptives. As the drugs have been used more widely, adverse reactions, not known at the time of original Food and Drug Administration approval, have become evident; the labeling of the drugs has been revised from time to time to include this new knowledge. The most recent data developed in studies conducted in Great Britain con- firms what had been suspected: there is a definite association between the use of oral contraceptives and the incidence of thromboembolic disorders. New labeling, which will be in use by July 1, 1968, contains excerpts from the Brit- ish reports and appropriate revisions of prescribing information. The labeling is uniform for all drugs in this class, and is in the standard format recom- mended by the FDA for all drug labeling. A copy of the revised uniform labeling is attached. We urge you to give careful consideration to the information under the various cautionary headings in the labeling. We ask, too, for your assistance in monitoring adverse reactions by report- ing all such reactions to the Food and Drug Administration. A supply of the standard reporting form (FD 1639), shown in facsimile on the reverse of this letter, may be obtained by writing to: Bureau of Medicine, Food and Drug Administration, Washington, D.C. 20204. Sincerely yours, JAMES L. GODDARD, M.D., Commissioner of Food and Drugs. Attachment: Revised uniform labeling UNIFORM SECTION OF ORAL CONTRACEPTIVE LABELING CHEMISTRY This should include generic name, amount, chemical name and the structural formula of each active ingredient. MECHANISM OF ACTION (As presented in current package insert.) INDICATIONS The Obstetrics and Gynecology Advisory Committee considered the following indications acceptable: contraception, endometriosis, and hypermenorrhea. These indications may be used in the labeling when efficacy has been demon- strated in each case. Any other claims will be evaluated on the basis of efficacy data available to support each. CONTRAINDICATIONS 1. Patients with thrombophlebitis, thromboembolic disorders, cerebral apo- plexy, or with a past history of these conditions. 2. Patients with markedly impaired liver function. 3. Patients with known or suspected carcinoma of the breast. 4. Patients with known or suspected estrogen dependent neoplasia. 5. Undiagnosed abnormal genital bleeding. WARNINGS 1. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7023 Studies conducted in Great Britain and reported in April 19681, 2 estimate there is a seven to tenfold increase in mortality and morbidity due to throm- boembolic diseases in women taking oral contraceptives. In these controlled retrospective studies, involving 36 reported deaths and 58 hospitalizations due to "idiopathic" thromboembolism, statistical evaluation indicated that the dif- ferences observed between users and non-users were highly significant. The conclusions reached in the studies are summarized in the table below: COMPARISON OF MORTALITY AND HOSPITALIZATION RATES DUE TO THROMBOEMBOLIC DISEASE IN USERS AND NON-USERS OF ORAL CONTRACEPTIVES IN BRITAIN Category Mortality rates Hospitaliza- tion rates (morbidity) Age 20-34 Age 35-44 Age 20-44 Users of oral contraceptives Nonusers 1. 5/100, 000 0. 2/100, 000 3. 9/100, 000 0. 5/100, 000 47/100, 000 - 5/100, 000 No comparable studies are yet available in the United States. The British data, especially as they indicate the magnitude of the increased risk to the individual patient, cannot be directly applied to women in other countries in which the incidences of spontaneously occurring thromboembolic disease may be different. 2. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medi- cation should be withdrawn. 3. Since the safety of * * * in pregnancy has not been demonstrated, it is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. If the patient has not adhered to the prescribed schedule the possibility of preg- nancy should be considered at the time of the first missed period. 4. A small fraction of the hormonal agents in oral contraceptives has been identified in the milk of mothers receiving these drugs. The long .range effect to the nursing infant cannot be determined at this time. PRECAUTIONS 1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as a Papanicolaou smear. 2. Endocrine and possibly liver function tests may be affected by treatment with * * ~`. There, if such tests are abnormal in a patient taking ~` * `~, it is rec- ommended that they be repeated after the drug has been withdrawn for 2 months. 3. Under the influence of estrogen-progestogen preparations, pre-existing uterine fibromyomata may increase in size. 4. Because these agents may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation. 5. In breakthrough bleeding, and in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In undiagnosed bleed- ing per vaginum, adequate diagnostic measures are indicated. 6. Patients with a history of psychic depression should be carefully observed anc~1 the drug discontinued if the depression recurs to a serious degree. 7. Any possible influence of prolonged * *- * therapy on pituitary, ovarian, adrenal, hepatic or uterine function awaits further study. 8. A decrease in glucose tolerance has been observed in a significant percent- age of patients on oral contraceptives. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving * * * therapy. 1 Inman, W. H. W. and M. P. Vessey, British Medical Journal 2 :193-199, 1968. 2 Vessey, M. P. and R. Doll. British Medical Journal, 2 :199-205, 1968. 40-471 O--70-pt. 17-13 PAGENO="0194" 7024 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Nausea Vomiting Gastrointestinal symptoms (such as abdominal cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea during and after treatment Edema Chloasma or melasma Breast changes: tenderness, en- largement and secretion Anovulation post treatment Prementrual-like syndrome Changes in libido Changes in appetite Cystitis-like syndrome Headache Nervousness Dizziness Hepatic function: Increased sulfobromophthalein and other tests Coagulation tests: increase in prothrombin Factors VII, VIII, IX and X Pulmonary embolism Neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis Change in weight (increase or decrease Changes in cervical erosion and cervical secretions Suppression of lactation when given immediately post-partum Chloestatic Jaundice Migraine Rash (Allergic) Rise in blood pressure in susceptible individuals Mental depression Fatigue Backache Hirsutism Loss of scalp hair Erythema multiforme Erythema nodosum Hemorrhagic eruption Itching Thyroid function: increase in PBI, and butanol extractable protein bound iodine and de- crease in T3 values Metyrapone test Pregnanediol determination ANIMAL STUDIES This should include results of acute, chronic toxicity and reproduction stud- ies using the compounds present in the product. Significant laboratory and pathologic findings should be mentioned. Endocrine and metabolic screening. State results on dose per weight basis. 9. Because of the effects of estrogens on epiphyseal closure * * should be used judiciously in young patients in whom bone growth is not complete. 10. The age of the patient constitutes no absolute limiting factor, although treatment with * * * may mask the onset of the climacteric. 11. The pathologist should be advised of * therapy when relevant speci- mens are submitted. ADVERSE REACTIONS OBSERVED IN PATIENTS RECEIVING ORAL CONTRACEPTIVES A statistically significant association has been demonstrated between use of oral contraceptives and the following serious adverse reactions: Thrombophlebitis Although available evidence is suggestive of an association, such a relation- ship has been neither confirmed nor refuted for the following serious adverse reactions: Cerebrovascular accidents The following adverse reactions are known to occur in patients receiving oral contraceptives (Consult the clinical section.) Although the following adverse reactions have been reported in users of oral contraceptives, an association has been neither confirmed nor refuted: The following laboratory results may be altered by the use of oral contra- ceptives (see sections on clinical laboratory) PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRIJG INDuSTRY 7025 CLINICAL DATA Efficacy-This should include the number of cycles completed. Breakdown by number of patients completing a specific number of cycles should also be men- ioned. State number of pregnancies in number per 100 woman years. Pearl's formula or life table technique should be used. The following statement is per- mitted if applicable: "Virtually 100% effective when used according to direc- tions." Adverse Reactions Clinical Laboratory Results-This should include liver, thyroid, renal functions, coagulation tests, endocrine function as well as rou- tine hematology and cytology. DOSAGE AND ADMINISTRATION This should include routine administration and specific instructions on han- dling problems such as breakthrough bleeding, amenorrhea, etc. AVAILABILITY BIBLIOGRAPHY Reference, not a complete bibliography. May 10, 1968 / Food and Drug Administration / U.S. Department of Health, Education, and Welfare / Washington, D.C. 20204. PAGENO="0196" APPENDIX IV ARTICLES [From The New York Post, February 14, 1970] SURVEY LINKS THE PILL TO CANCER (By Barbara Yuncker) A "significantly higher" number of very early cancers of the cervix has been found in a study of New York women who use oral birth control pills, com- pared with similar women who use diaphragms, The Post learned today. The still-unpublished report, involving nearly 35,000 women, stresses that the finding provides no proof of cause and effect. Other factors, particularly involving patterns of sexual behavior, may be as likely as causes, if not more so. But this is not expected to avert a new, major debate on the pill's safety. The details of the study have been presented privately to the contraceptive advisory committee of the Food and Drug Administration which has found "nothing to confirm or refute" a theory that "The Pill" might cause such cell changes. It has not suggested any new FDA warning on the basis of this or other related reports, and FDA Commissioner Ley and other officials are understood to concur in this view at this time. EARLY FORM CURABLE When "Pap smear" tests were done on all 35,000 (who were clients at Planned Parenthood clinics) and fohlowup biopsies were done on suspicious cases, 266 "carcinomas in situ" were found. (This is the earliest, most curable form of cancer of the female reproductive organs.) i~Iatching the users of the two methods for age, ethnic background, child- bearing history and economic status, the researchers found about twice as many cases of early cancer among the pill-users. Because they outnumbered those using diaphragms by about four to one, they were matched in one/one, one/two and one/three groupings, with slightly different results, but a consis- tent pattern. A principal reason why cause-and-effect cannot be assumed from this study is that earlier research, cited in this report, has shown that cervical cancer is higher in women with early sexual experience on frequent intercourse or many partners, or repeated pregnancies. It is rare among nuns, relatively high among prostitutes. But because of the kinds of women involved and the fact that they were volunteers from the clients of Planned Parenthood, it was not considered appro- priate-or even particularly revealing-to investigate earlyest sexual experi- ence or number of partners, beyond what could be deduced from marital and pregnancy histories. VIRUS A CAUSE? Another lively area of cervical cancer research, suggesting that a virus may be a causative factor, is not directly involved in this study but is given sugges- tive support because the diaphragm could be a barrier against such infection. It could also be a barrier if simple lack of hygience is involved, which other studies have indicated as a possibility. The study was directed by Dr. Myron R. Melamed, pathologist at Memorial Sloan-Kettering Cancer Center, and Dr. Hilliard Dubrow, obstetrician and cancer research adviser to Planned Parenthood of New York City. He is on (7026) PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7027 the staff at Lenox Hill Hospital and is director of obstetrics and gynecology at Doctors Hospital. Dr. Melamed could not be reached for comment. Dr. Dubrow would not dis- cuss details of the report, on which statistical analysis was guided by com- puter experts from IBM, but acknowledged its existence and general outlines. He said he * * * "until it has appeared in a medical journal where other phy- sicians, may evalute it in full. AN EARLIER STUDY It is tentatively scheduled for publication within a month in the Journal of the American Medical Assn. It and three parallel studies are referred to in an issue of Medical World News, a magazine for physicians, being distributed today. That story cites a study by Dr. George Wied of the University of Chicago which reported an occurrence of this same early cervical cancer six times above expectation in a screening done in Chicago of a similar-sized group. But Dr. Wied's paper has been withdrawn, by him, from planned publication in a research journal to review statistical analyses. An important technical point about the New York study is that it studies "prevalence" not "incidence." Using the same women plus those using other contraceptive devices the same team is also studying "incidence", but the figures are not due for at least a year. ("Prevalence" means how many have a disease at a certain point in time. "Incidence" refers to how many will get it over a period of time. They diverge widely in epidemic diseases but are closer in figures and importance in chronic diseases like cancer.) Cervical and other uterine cancers hit 44,000 women a year in this country and are fatal each year to about 13,000. But carcinoma in situ is so early a stage that it is nearly 100 per cent curable. All cases found in the Melamed-Dubrow study have been treated and are apparently cured. In fact Dubrow regards a frequent examination and Pap smear, as is recommended procedure with oral contraceptives, as more likely to pick up early cancer than diaphragms changed only after childbirth or at other long intervals, unless women getting them also get annual vaginal exami- nations. Fifty-three per cent of the women in the study were Negro, 23 per cent white, 22 per cent Puerto Rican or of other "Spanish" background, and just under 2 per cent were of other racial groups. They ranged in age from the teens to the 40s with nearly two-thirds between 21 and 30. The group were predominantly low-income. Each woman had made her own choice of contra- ceptive method. The study report clearly suggests that the personality and sex pattern may control the choice of contraceptive. But despite the possibility of other factors and the fact that the FDA and physicians like Dubrow still approve The Pill, a storm of debate is expected upon official publication of these new studies. [From the New York TImes, January 17, 19701 EDITORIAL-THE PILL PROBLEM Disturbing questions about the pill and its possible consequences for the mil- lions of women taking it have been raised in Washington this week. Up to the present, most concern about this form of chemical contraception has focused upon the fact that a tiny fraction of users have developed blood clot problems. Now some doctors and scientists are raising the possibility that the pill may be responsible for causing cancer, damaging genes, and harming the children of women who have conceived after they have ceased to use the potent hor- mones that prevent pregnancy. Such unresolved questions as to the long-term effects on human beings of an extraneous influence are not confined to use of the pill, or to drugs for that matter. In modern man's increasingly synthetic environment, the air he breathes and the food he eats contain ever more additives about which similar questions can be raised. What is the long-term impact of the air pollutants to PAGENO="0198" 7028 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY which urbanites are exposed daily or of the antibiotics in meat, just to men- tion two of the most obvious examples? Proponents of the pill-of whom there are many-tend to minimize the short- and long-run dangers described by its opponents. Those who favor the pill point to its high efficiency as a contraceptive, and argue that the potential gains outweigh the potential perils from the pilL It is useful, however, that questions about the pill are being ventilated in public, and that responsible Government officials and the medical profession are being forced to face them. In the present era of widespread concern over the population problem, the utility of the pill is indubitable. But more answers are needed than are yet available about the societal and individual costs that may yet have to be paid for the convenience and near certainty of contraception the pill provides. [From Family Health, January 1970, pp. 36-38] COMMON5ENSE ADVICE ON CONTRACEPTIVES Dr. Louis M. Heilman, one of the nation's leading experts on birth control, answers questions by senior staff writer Judith Ramsey. Dr. Heliman, who heads the Food and Drug Administration's blue-ribbon advisory committee on oral contraceptives, is also chairman and professor of the department of obstet- rics and gynecology at Downstate Medical Center, Brooklyn, N.Y. Judith: It's generally agreed that there's no one contraceptive method suitable for everybody. How can a woman decide which is best for her? Dr. Heliman: Her personal physician can help her make that decision. First, she must identify her own special needs. Does she want a temporary method until she and her husband are ready to have children? Is she undecided about whether she wants more children? Is her family completed? Then she must weigh the benefits and risks of each method. How safe is it? How convenient? Are there any specific risks for her? A contraceptive method is only effective and safe when properly used by a woman who can tolerate it. Judith: Let's talk about some individual but typical cases. For e~rample, what contraceptive method would you recommend for a woman in her mid-twenties who has had two children? She has years of fertility ahead of her, but she and her husband don't know whether they'll want another child. They definitely feel they can't afford one for at least two ye~ars. Dr. Heliman: This woman is an ideal candidate for the Pill, provided that she doesn't have adverse reactions to it. Some women react with irregular vaginal bleeding, weight gain, headaches, or dramatic mood changes. Judith: Could she safely take the Pill for an indefinite period of time? Dr. Hellman. Ohiefly, the problem with oral contraceptives is an increased, though still small, risk of thrombophiebitis, or clots in the vein. A survey of records from more than forty American hospitals shows that the risk of blood clotting is almost four and a half times greater among pill users than among other women of childbearing age who don't use the Pill. Unfortunately, at present there is no test to determine which women on the Pill will have clot- ting problems. Of course there are some clear early warning signs: headaches, visual symptoms, excessive weight gain. If these occur, a woman should stop taking the Pill immediately. Weighted against the small risk of the oral contraceptives are their large benefits. They are nearly a hundred percent effective when taken as pre- scribed; they are very easy to use; and they don't intrude on the relationship between husband and wife. These are the reasons why about eight and a half million American women are now on the Pill. As for the length of time a woman should stay on the Pill, there is no evi- dence that she can't continue as long as she wants. However, she should have a periodic checkup, including a Pap smear and breast examination every six months to a year. Judith: What about a wife who wants to take the Pill but wonders whether it is worthwhile? Her husband is a salesman and is away for many months of the year. They have infrequent seccual relations. Should she take the Pill, and if so, all the time or just before her husband comes home? PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7029 Dr. Heilman: This problem is more common than you would suppose. I see no point in her taking the Pill, since she doesn't need the continuous protection it affords. She could very well use the diaphragm or perhaps the intrauterine device (IUD). If she does take the Pill, however, she must take it all the time. Judith: Then there is the woman with the opposite problem. She and her new husband have frequent sexual intercourse. But they are both in their early twenties and want to wait a few years before having children. Dr. Heilman: The Pill is ideal for her, since it is difficult to insert an intra- uterine device into a woman who has not had a baby. Judith: Does the fact that this woman has frequent sexual intercourse influence the type of oral contraceptive you would prescribe for her? Dr. Heliman: Not at all. The combined pill-which contains two powerful drugs, estrogen and progesterone-is a little bit safer if a woman forgets and skips a pill. But the sequential pill-which consists of a series of pure estrogen followed by several tablets of estrogen and progesterone-is considered safe if taken according to instructions. I, myself, give some of my patients the sequential pill because its effect comes closer to the natural female menstrual cycle and does not diminish the monthly period, which is worrisome to certain women. However, the latest gov- ernment report on the Pill suggests that the sequential form may be associated with a slightly higher risk of blood clotting. This remains to be proved. Judith: What about the woman who has been using a foam preparation for three years since the birth of her second child? Her friends keep telling her about the advantages of the Pill, but she is afraid of its side effects. Should she change methods? Dr. Heliman: If the foam has worked well for her for the past three years, the chances are that it will work well for another three years. If she's satis- fied with the method she is using, there is no reason for her to change. Judith: What about Mrs. 0.? She is twenty-five years old. She has two chil- dren and would like to have two more spaced over a period of four to six years. Is the Pill going to interfere with her fertility? Dr. Hellman: There is no evidence that it does. But before trying to get preg- nant, she would be wise to go off the Pill for a few months and in the interim use another method. Some doctors think that the first few ovulations off the Pill may not be completely normal. Judith: Here are women with special problems. What contraceptives would you recommend for them?.. Mrs. F., aged twenty-six, has just got married. She and her husband want to wait two years before having a child. A routine gynecological checkup revealed that she has fibroids. Dr. Hellman: She's making a mistake from the beginning. There's always a chance that the fibroids, which are benign tumors of the uterus, will grow larger and require surgical removal. She should have her family right away. If she still wants to wait, it would be advisable for her to use a diaphragm. The Pill is not recommended for women with fibroids. The estrogen that it contains tends to make them grow. The IUD would also be suitable in certain cases. Judith: What are the other complications that can be caused by the ITJD? Dr. Heilman: The problem is that it doesn't always work very well. The IUD can bring on cramps and also bleeding. Sometimes it is expelled. In a few instances, it has perforated the uterus. It has also caused peritonitis. The death rate from complications caused by the IUD in the United States is prob- ably around two per hundred thousand-close to that of the Pill. Judith: Tho next case involves a very delicate situation. You are consulted by the parents of a sixteen-year-old girl who is promiscuous. Her parents have tried to be firm. They have even punished her, with no success. She is now seeing a psychiatrist, but she is still sexually promiscuous. Her parents are desperately afraid that she will get pregnant, but they don't want, to do any- thing that will encourage her sexual activities. PAGENO="0200" 7030 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. Hellman: By all means, she should be given contraceptive aid. A preg- nancy would just worsen an already troublesome situation. Unfortunately, the type of girl who is promiscuous is apt to be forgetful about the Pill. She cer- tainly cannot be relied on to use a diaphragm, and her multiple partners are not to be trusted to do anything to prevent pregnancy. I would try to fit this girl with an IUD. The insertion would probably have to be done under anesthesia, since insertion is likely to be painful. I might have to try one of several IIJDs-which come in different shapes and sizes-to find one that fits satisfactorily. Judith: Suppose this girl develops cramps and bleeding or one of the other problems you said were associated with the IUD. Would you give the Pill to someone that young? Is there any chance that it will stunt her growth? Dr. Hellman: No, it does not. In the first place, the growth spurt takes place in the tenth to twelfth years among American girls. In the second place, the amount of estrogen necessary to inhibit growth is far larger than that con- tained in the Pill. The Pill certainly will have less effect on growth at this age than a pregnancy would have. However, I should point out that there is one potential problem in giving the Pill to sixteen-year-old girls. In the early years of menstruation, the Pill can interfere with the establishment of the regular menstrual cycle. This is another reason why I would recommend the intrauterine device for this partic- ular girl. Judith: How would you prescribe for Mrs. IL, whose maternal grandmother has diabetes? Is it all right for her to take the Pill? Dr. Heilman: As long as she doesn't have diabetes. Some women may have heard that the Pill can cause a rise in their blood sugar. This is true, but the elevation disappears as soon as they stop taking the Pill. Of course, any woman who has diabetes in the family should have her blood and urine checked as part of the physical checkup she undergoes annually. Judith: Would you give the same advice to a woman whose mother and aunt both had cancer? Dr. Heilman: No, I would not, for this reason: although there is no evidence that the Pill causes cancer in women, it is possible that the estrogens contained in the Pill could speed up the growth of existing cancers. If a woman has a well-established family history of cancer, she would do better with another form of contraception. This case underscores the need for a complete medical checkup by a gynecologist. The woman should be sure to tell her doctor about any diseases she may have as well as any family history of diseases like dia- betes or cancer, especially if several relatives have been affected. Judith: How would you advise a woman who decides that after the birth of her second child by cesarean section that she doesn't want any more children? Dr. Heliman: For those women whose childbearing is definitely completed, even without complications such as cesareans, the ideal method of contraception is tubal ligation, or tying off, which is both safe and permanently effective. A small incision is made in the abdomen while the woman is under anesthesia. Then the fallopian tubes are tied off so that no more eggs can pass into the uterus. Women who have bad previous cesarean operations and are due to have another one are often asked by their obstetricians if they plan to have more children; if not, the obstetrician can easily perform the tubal ligation at the time of delivery. I prefer the term tubal ligation to sterilization because nothing is taken out. It doesn't alter a woman's hormonal balance or menstrual cycle. Most of my patients who have undergone tubal ligation have felt greatly relieved after- ward. They were free of the threat of pregnancy and were able to enjoy sexual re'ations even more. Naturally, a woman should not undergo this operation unless she's pretty sure that she doesn't want another baby. The tubes can be untied, but only thirty to fifty percent of these women are able to conceive afterward. If the woman doesn't want to undergo tubal ligation, I would recommend the Pill, the IUD, the diaphragm, or a condom for her husband-in that order of decreasing effectiveness. PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7031 Judith: Mrs. I., aged thirty-five, has five children and lives in a crowded apartment in the ghetto area of one of our large cities. She and her husband share their bedroom with their five-year-old daughter. Dr. Heliman: The diaphragm would be difficult to use in such crowded condi- tions. Moreover, with all her responsibilities, she might be forgetful about the Pill. An IUD would probably be the best contraceptive, although, with five children, she really ought to consider having her tubes tied. Judith: Are there any final words you'd like to say about the choice of contra- ceptives available? Dr. Heliman: The ladies usually have the last word. Nine out of ten of them have a preconceived notion of what is best. Unless there's a medical reason not to, I try to give them what they want in the first place. [From Good Housekeeping, January 1970, pp. 64-65, 123-127] CONTROVERSY OVER "THE PILL" (By Bill Surface) When Betty Jo Black died suddenly in 1965, doctors blamed it on the flu. But her husband, convinced that oral contraceptives had caused her death, challenged the diagnosis in court. This is what triggered the current contro- versy over The Pill. Almost daily there are disputed accounts that oral contraceptives-popularly called the Pill-can somethimes cause impaired vision, jaundice, cancer, strokes or fatal blood clots. As a result, 135 suits are pending against manu- facturers of the Pill for allegedly causing death or serious side effects, and some insurance companies now advise doctors not to prescribe it unless a patient signs a statement admitting "awareness of the serious risks involved." The Black vs. Searle case that was tried in May, 1969, is a microcosm of the controversy over a product that is used by approximately 8,500,000 women. Raymond Black, a tall, bespectacled engineer, had just returned from a busi- ness trip. He was surprised that Friday evening when his mother-in-law, but not his wife, greeted him at the door of his two-story, colonial home in South Bend, Indiana. He hastened into the front bedroom, where Betty Jo, his attractive, 29-year-old wife, lay ill from an apparent case of the flu. Her mother was there to attend to the couple's five daughters. As Betty Jo tossed restlessly in bed, she told her husband that their doctor, Bernard J. Dolezal, had treated the children's colds and, though he'd given her an injection of pen- icillin, she continued to "feel worse." Early the next morning, Black drove his wife to St. Joseph's Hospital where, Dr. Dolezal reported, a chest X-ray and tests of her blood and urine indicated nothing more serious than an "influenzal type of bronchitis." Told to take antibiotic capsules every six hours, Betty Jo returned home, only to twist in bed throughout the day because of what she called a "burning feeling in my chest and back." Suddenly, around 8:40 P.M., Betty Jo clutched her chest, gasping: "I'm having trouble breathing-get an ambulance !" In a call to Dr. Dolezal, Black was told that the hospital would have a "Code Blue"- a team of specialists-waiting by the time he arrived with his wife. Perspiring heav- ily, Betty J0 coughed and convulsed until the ambulance's siren could be heard, then collapsed. "All of a sudden her chest heaved up and she groaned," Black recalls. "Her eyes went back in her head and she passed out." As the ambulance driver instructed, Raymond Black held an oxygen mask over his wife's face and massaged around her heart until they reached St. Joseph's Hospital. Noticing Betty Jo's pupils were dilated from a lack of oxygen to her brain, one internist pushed a tube down her windpipe, a second injected Adrenalin into a heart muscle, while other physicians and nurses pressed on her breastbone 70 times a minute to simulate a heartbeat. But, after almost two hours, an electrocardiogram showed that her heart still was not beating. Looking puzzled, Dr. Dolezal led Black into a vacant emergency room. "It looks real bad," he said. "She's just not responding." Minutes later, at 10:55 P.M., Black saw a nurse shaking her head as she spoke to Dr. Dole- zal and realized that Betty Jo was being pronounced dead. PAGENO="0202" 7032 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Black's confusion almost matched his grief on this Saturday evening, Sep- tember 18, 1965. How could a cold or the flu that had only mildly affected his children, he asked, suddenly kill a young woman with no history of rheumatic fever, high blood pressure, allergies or broken bones and who was, as another doctor stated, "considered to be a young, healthy female-healthy enough to have more children"? Aside from routine prenatal examinations, Black recalled, Betty Jo's only previous medical treatment during their eight years of marriage had been for two sore throats and irregular menstruation. Although Catholic, his wife, Black said, had obtained their priest's approval a year earlier to use Enovid, a pink birth control pill prescribed by her obste- trician-gynecologist to obtain regularity in her menstrual cycle. She had stopped taking it in mid-February and looked forward to regularity and an ability to lose the twenty pounds gained during her last pregnancy. The hoped-for regularity of her menstrual cycle did not occur, however-she failed to get her period for over 50 days. Enovid was represcribed by Dr. 0. Norman Forrest, one of her three obstetrician-gynecologists in a group practice. Five months later she was dead. Dr. Dolezal ordered an autopsy. Betty Jo was found to have died from pul- monary embolism, a large, solid blood clot that had formed in her right ovarian vein and passed through the heart before lodging-and closing-the pulmonary artery leading to the lungs. Particles of the same type of clot, believed to have formed at least two weeks before Betty Jo had died, also were clinging to veins extending from the right ovary to the lungs. After learning that the Pill's principal function is \to prevent a fertilizable egg from leaving the ovaries, Black wasted little time. After Betty Jo's funeral, he tried to connect her blood clot and the Pill. It was a complicated project for the 31-year-old, soft-spoken engineer. First of all, he was busy as supervisor of the Bendix Corporation's contract to ascertain that the LM (Lunar Module) capsule would not topple upon landing. When he finished work, he had then to care for his five daughters, all under seven years old. Of equal importance was the fact that, at this time in 1965, there had been almost no public challenge to the general belief that the Pill was completely safe. But Black soon found a doctor in South Bend who looked at the autopsy report and, Black maintains, said that he personally knew of two similar types of deaths and one near-fatality that he believed had been caused by the Pill. He said he could not testify in any suit, however, for fear of being sued for contributing to his patients' deaths. Undaunted, Black began searching for pharmaceutical companies' newsletters -including Searle's-to doctors and found one dated nearly two years before Betty Jo was prescribed Enovid. The newsletter revealed: "As of this date in the United States there have been reported to us 272 cases of thromboembolic disease [clotting of blood in circulatory veins] in Enovid users. In these reports are 31 fatalities." Yet Black did not become infuriated, he recalled, until after reading another newsletter, one indicating that women with tilted uteruses might be "predis- posed to thrombosis" if they used the Pill. Betty Jo's uterus was tilted, he thought, but her only warning was a sentence in the manufacturer's two pam- phlets, For Your Information and Planning Your Family, stating that Enovid might cause such temporary side effects as nausea and breast tenderness. By this time, Black was convinced that pharmaceutical companies were under- reporting to physicians the Pill's possible risks; in turn, doctors were minimiz- ing the hazards to patients. He immediately sought the advice of two attorneys, only to be cautioned about the improbability of winning a suit. Articles are considered "hearsay" in court unless the author testifies, while many drug companies can call upon countless physicians or medical researchers (some of whom are supported by their research grants) to affirm a medication's safety. "I don't care if I win the case or not," Black fumed. "I want this under- reporting out in the open." On the second anniversary of Betty Jo's death, Black filed suit for $750,000 in damages against G. D. Searle & Company, a Skokie, Illinois, pharmaceutical firm that manufactures Enovid, on counts that Searle: 1. was "negligent"; 2. had "breached the implied warranty of its product"; and 3. was "strictly liable" for the Pill's known hazards that caused his wife's death. PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7033 When the trial opened on May 13, 1969, in a courtroom in South Bend's post-office building, there was no shortage of equally reputable physicians will- ing either enthusiastically to support-or dispute-Black's accusation and, in the process, capsulize the medical profession's division of opinion toward all 22 brands of the Pill. The doctor called by Black's attorney who was perhaps the most blunt was John F. Hillabrand, director of obstetrics and gynecology at St. Vincent's Hos- pital in Toledo, Ohio, and chairman of the National Commission of Human Reproduction and Rhythm (which advocates the rhythm method of birth con- trol). A tall, distinguished-looking critic of the Pill, Hillabrand nodded slightly while being asked if he could be "medically certain" about a connection between Enovid and Betty Jo Black's death. "My opinion is that this [Enovid] was directly related to the cause of her death," he testified. "I believe that there is a very definite, positive, chemical statistical and biological effect of all of the oral contraceptive pills in predisposing to the formation of blood clots and thrombi and embolism." As Hillabrand answered carefully worded questions, he theorized how the Pill might have caused Mrs. Black's blood clot. Physicians, he said, still don't know exactly what keeps normal blood from clotting inside the body but, when necessary, they will cause it to clot and thereby prevent an injured person from bleeding to death. Physicians do know, Hillabrand insisted, that the Pill artificially slows down the blood's circulation and enlarges the veins in the genital organs and chest so that the blood congeals, much the same way that water freezes in a leisurely flowing stream. Mrs. Black's flow of blood simi- larly decreased until it clotted, Hillabrand said, and it was not necessary to rely upon other physicians' articles to reach such a conclusion. "I have seen and followed many cases like this," he testified. "I have seen enough deaths under similar circumstances where an autopsy will reveal evidence which is almost carboncopy evidence of this and in which no other apparent cause of death is available, and then with all of the side effects you have described . and knowing that this pill can affect the coagulability [clotting] of the blood -finding a clot in the ovarian vessel and finding an embolism [clot that blocks a vein] in the pulmonary artery-to me this is a straightforward association." Rising slowly from his chair, James Pankow, one of Searle's attorneys, attempted through questions to characterize Hillabrand as someone who had not written enough medical articles to formulate a creditable opinion. After naming journals that had published his articles, Hillabrand crossed his legs and emphasized: "You see I've not been identified with a medical school which gets grants and does research projects and which publishes to stay in business. In the private practice of obstetrics and gynecology, I have delivered eight thousand babies and not lost a mother and I kind of like to keep it this way." Under further cross-examination, Hillabrand conceded that the Pill could be useful in treating disease and he had prescribed it "repeatedly in the treat- ment of various disordered conditions." Before Pankow could rest after that seemingly incongruous statement, Hillabrand added: "But here we are dealing with healthy people when we use it contraceptively . . . [For them], it is a risk that isn't justified." Pankow countered by saying that the risks attributed to the Pill were simi- larly unjustified. He emphasized that several doctors reported, for example, that the blood of women using the Pill doesn't congest. Hillabrand was no less adamant about that contention. "I reserve the right to violently disagree with that," he rebutted, "because had you been in the operating room with me on any number of occasions when you tried to perform major surgery-~ither vaginal or abdominal-on some of these people, you will have the most excit- ing time trying to control bleeding because of the dilation [expansion] of these vessels. It doesn't take you long to get the message that this isn't a very good procedure. I would take them off the Pill and let them simmer down for a while. I have had this experience and I don't like it." The reply led to a series of answers that many doctors also won't like. "Obviously," Hillabrand was asked, "you will admit that there are compe- tent gynecologists and obstetricians who prescribe the Pill for contraceptive purposes." "No, I will say they do it," Hillabrand replied, "but to the extent they do it, in my opinion, their competence should be questioned." "Let me say they are board-certified," the attorney retorted. PAGENO="0204" 7034 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "Well, look, I'm sorry," Hillabrand answered. "In Toledo we have a lot of people who got their boards and haven't opened a book since they got them twenty years ago. And they drive Cadillacs." As opinionated as Hillabrand may have seemed, an even stronger indict- ment of the Pill came from Dr. Herbert Ratner, his classmate at the Univer- sity of Michigan Medical School (1934), now director of the Department of Public Health in Oak Park, Illinois, and editor of Child and Family (a quar- terly journal that reprints articles about traditional concepts of family life). A graying crusader against "pill promoters and profiteers," Dr. Ratner stated, in a deposition introduced as evidence, that the same dosage of Enovid that had been taken by Mrs. Black can produce fatal blood clots and, from his view- point, would continue to do so. "The medical profession has not been given, for a variety of reasons, the objective story of this [the Pill]," he said, "and the patient has been less exposed as to the objective story. They could not deter- mine whether there was or was not a causal relationship [between the Pill and blood clots]." Ratner said his conjecture was based on the theory that the Pill simulates pregnancy by increasing the blood supply in order to prevent conception but, unlike a genuine pregnancy, does not simultaneously expand the uterus: "It's different in the sense that, during pregnancy, blood is now ciculating through the enlarged uterus, which therefore makes the blood supply noncongestive. If blood is brought there by mimicking a natural process in which the enlarged uterus is absent, then the blood has nowhere to go but remain in its own area and this is what produces the congestion. . . ." Ratner's testimony, like that of subsequent witnesses, fell into a predictable pattern. Black's attorneys continued to call upon anti-Pill physicians, such as Paul E. Haley, a retired surgeon from South Bend and veteran of 400 autop- sies. Asked if he was "medically certain there was a causal connection between Enovid and Mrs. Black's death," he testified: "It had a causal rela- tion to it. They [the Pills] can be fatal to a few women." Searle's attorneys contradicted the theory that Enovid could cause blood clots by presenting such pro-Pill physicians as Dr. Celso Ramon Garcia, a member of the Searle-sponsored research team that tested an earlier form of the oral contraceptive on women in Puerto Rico. Now professor of obstetrics and gynecology at the University of Pennsylvania, Garcia testified: "There is no evidence whatsoever that there is any correlation with the thromboembolic phenomena [clotting] in the use of oral contraceptives. I have no hesitancy in prescribing this to any member of my family and, as a matter of fact, I have done so and am doing so." Searle, meanwhile, continued to build its defense with testimony from physi- cians who had demonstrated, to their personal satisfaction, that the Pill has no known hazards. Initially, no such physician seemed more familiar with Enovid than Dr. Robert W. Kistner, a gynecologist in Brookline, Massachu- setts, and member of the Harvard Medical School's faculty. Widely known for his positive articles and book* about the Pill, Dr. Kistner stated that he had used the Pill to treat infertility in women for four years before it was approved for general use by the Food and Drug Administration and sent his reports to Searle so that the company might conduct tests which "were about as extensive, if not the most extensive, that I have ever considered." Dr. Kist- ner testified that he continues to prescribe Enovid, dismissed reports of nausea, depression and bleeding by women using the Pill as minor effects and not hazards, then emphasized: "I have seen no patients who developed throm- boembolic disease, including pulmonary embolism, in over three hundred patients upon whom I have operated [and] who received estrogen-progestin combinations [used in the Pill] prior to and subsequent to surgery." Dr. Kistner's `conclusions, though, were challenged in questions about an acquaintanceship with Searle's medical director (to which he responded: "I work closely with a number of companies"). Earlier in the trial, moreover, Dr. Kistner had been depicted in Dr. Ratner's deposition as being less than objective about the Pill. Asked if Dr. Kistner is "well recognized as an authority and expert," Dr. Ratner replied: "He is well known." Asked if he accepted Dr. Kistner as an expert on the Pill, Ratner answered: "I accept him as a biased person in this area. . . . I find he is not * See GOOD HOUSEKEEPING, February, 1969. PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7035 authoritative. If a person is biased, you can't consider him competent and I will give you a good example. A detail man from Searle showed a colleague of mine a letter that Kistner wrote attacking . . an article calling attention to the relationship of thromboembolism. He said that was without foundation. He has been proven to be wrong." Kistner did little to correct Ratner's impression. At one point, when an attorney contradicted his testimony, Kistner offered no meaningful clarifica- tion. The attorney first quoted this excerpt from Dr. Kistner's book: "There is some evidence of increases in both tendencies toward varicose veins and the increase of blood clot disorders among Pill users." He then quoted from Searle's 1969 bulletin to physicians: "A statistically significant association has been demonstrated between the use of oral contraceptives and the following serious adverse reactions: thrombophlebitis and pulmonary embolism." The attorney then asked Dr. Kistner if the latter sentence appeared in Searle's publications and Dr. Kistner replied: "It must be. You just read it." Dr. Herbert S. Sise, who also practices in Brookline and frequently writes about blood clots, paralleled Dr. Kistner's testimony by stating, "I just don't believe there is any relationship," between the use of the Pill and either blood clots or "the elevation of coagulation factor." (He admitted, under questioning, that his opinion was based on blood tests of only five women using Enovid for one month.) Dr. Sise, similarly, was sharply questioned about a possible rela- tionship with Searle. When asked if he was being paid to testify he replied, "I hope so," but Judge Robert Grant told him he need not answer a question about "how much he normally charges" for testifying on the Pill. Thereupon Sise was handed a letter quoting a study completed in 1968 in Britaint that reported the prevalence of blood clots to be seven and a half times higher among women between 20 and 34 using the Pill than among those who did not. Dr. Sise, responding to a question, read the statistics but inter- jected: "That's what it says here . . . I'm not saying that." "Do you still feel," asked Arthur May, one of Black's attorneys, " . . . that the use of Enovid does not in any way increase the person's risk of having a thromboembolic disease?" "That's right, yes," Sise replied, then added, in response to another question, that the study could "clearly" be wrong because "the diagnosis of pulmonary embolism is one of the most difficult ones." May was unable to challenge Sise's supposition since the U.S. *Food and Drug Administration's Advisory Committee on Obstetrics and Gynecology had not then released its report somewhat supporting the British study by showing that American women using the Pill suffered 4.4 times as many fatal blood clots (or three deaths per 100,000 women) as did those not using it. But the attorney then asked Sise if he had read the 1969 Physicians' Desk Reference, in which the editors, using manufacturers' information, stated that "a statisti- cally significant association has been demonstrated between the use of oral contraceptives.. . and thrombophiebitis and pulmonary embolism." "If I told you that this was the information put out by G. D. Searle," May asked, "would you say this would be inaccurate then ?" "I wouldn't fully agree with it, no," Dr. Sise answered, subsequently adding: "This is a statement which is put in there to satisfy the needs of people who want to be careful about prescription of the drug." "Oh," 1~Iay said sarcastically, "this is just put in to require people to be careful." May had not been too careful about dates. His questioning of Sise proved to be technically useless when Judge Grant told the jury to only "consider fac- tors" about the Pill that Searle "knew or should have known" before Mrs. Black's death in 1965. By contrast, Searle was able to imply that Mrs. Black's blood clot could have been caused by either inflammation or injury to a vein. Dr. Chris A. Pas- cuzzi, a pathologist at the South Bend Medical Foundation, stated that slides of Mrs. Black's tissues showed that she had a viral inflammation and there- fore was a "candidate for thrombosis." Even if Mrs. Black's influenza was unrelated to the thrombosis, attorneys asserted, the clot also could have been caused by a minor automobile accident 1- See The Better Way, page 129, In this issue. PAGENO="0206" 7036 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (in which neither she nor any of her five children suffered apparent injuries or required medical treatment). "I am going to ask you to assume that a twenty-nine-year-old woman was a passenger in an automobile," Dr. Charles Proudfit, a gynecologist from South Bend was told, "when that car was struck from the rear . . . that approximately four hundred dollars worth of damage was done to the . . . bumpers, lights . . . trunk . . . and grill. Assume that this same woman died on September eighteenth [two months later] . . . there was found a thrombus or blood clot in the right ovarian vein . . . I'm going to ask you... whether the thrombus could have been caused by the accident ?" "I couldn't state that that thrombus was caused by the accident," Dr. Proud- fit said. "I think there might be a slight possibility." When asked by Searle's attorney if Enovid was connected with Mrs. Black's blood clot, Dr. Proudfit replied: "I don't feel that you could say Enovid caused that lady's death when you had the other contributing factors that we know may cause an embolism." Told by Black's attorney that, "You cannot say that . . . Enovid medication did not cause this hypothetical woman's death," Proudfit answered: "No, I can't say that and I can't say that it did." Testifying for Black, Drs. Haley, Hillabrand and Ratner felt that they could emphatically say that the accident did not cause the clot. As Hillabrand volun- teered while pointing to his pelvis: "The veins in there adjacent to the uterus are the best protected machinery there is in the human body. You are sur- rounded by thus huge, strong pelvic girdle of bones here, and in order to damage something [there], you would have to have a crushing blow to the pelvis to do that. The automobile accident had nothing to do with it." The Pill also had nothing to do with Betty Jo's blood clot, Searle's attorneys concluded, because few if any drugs have ever been so thoroughly and continu- ously tested for possible hazards, including blood clots. After a large box said to contain duplicate records of Searle's investigations was set before the jury, Dr. Irwin Winter, Searle's supervisor of medical affairs, described tests that were required to obtain the FDA's permission to sell Enovid, recited favorable articles about the Pill or its research (which Black's attorneys called "selec- tive opinion"), and emphasized how his department held an inquest on the death of anyone using Enovid. "We sent an investigative team, one of whom was myself, to the area," he said. "We had to go to hospital admissions, to private surveys on how many people went to see a doctor for what reason. . There was nothing to indicate the Enovid had anything to do with these [deaths]." After reiterating that Searle's team voluntarily investigated every such death that is reported, Dr. Winter was asked: "Isn't it true that the first knowledge your company had of the death of Elizabeth Black . . . [was] only after this lawsuit was filed ?" "I can't answer that," he said, "it could be." A complicated medical question that physicians couldn't resolve after seven days of testimony was left to twelve people who, though they initially seemed piqued at being summoned as prospective jurors, were not disinterested in the Pill. Earlier, there had been such strong opinions about the Pill that selection of the jury was delayed when Judge Grant asked if anyone who experienced or knew about any "unanticipated results from the Pill' would raise a hand and follow him into a conference room. He then dismissed one woman who said that she "fainted once a month while on the Pill and my doctor advised me to stop taking it": another young woman who maintained that her sister "lost her baby because of it"; a man who revealed that "both my sister and wife's best friend in college had quite a bit of trouble with the Pill"; and a woman who claimed that her cousin "got real heavy and violently ill and dizzy" after taking the Pill. But there turned out to be enough people profess- ing no opinion or pharmacological knowledge about the Pill for the judge ulti- mately to approve, as jurors: a female department-store clerk; wives of a jan- itor, house painter and farmer; plus a salesman, plumber, insurance agent, press operator; and employees in an auto body shop, computer plant, real estate company and an airmen's club. By law, verdicts in cases like this one must be rendered by jurors previously unacquainted with the rudiments of the issue. The jurors' difficulty in interpreting the conflicting medical testimony soon became evident once they began discussing it. During the time Black and the PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7037 attorneys awaited a verdict, the jury was far from unanimous about any of the three counts .in question. The first votes tabulated by Leroy Skodinski, the lumber salesman who had been elected jury foreman, were about evenly divided for the plaintiff and defendant. Members of the jury talked, argued and voted fourteen times during the next four hours without approaching unity, except, informally, on the fact that many of them really didn't know whether Enovid had or had not caused Mrs. Black's death. Skodinski was even moved to remark at one point, "Wouldn't this be interesting if twelve doctors were on this jury ?" Several expressed opinions seemed to correspond with Skodinski's contention. "The company was giving some warning to the doctors," he said, "but four years ago-when this woman died-most of the doctors weren't warning the people at all." As three or four jurors nodded in agreement with this state- ment, one woman interjected: "I don't think any of those things are safe, but -this one is about as safe as any of `em. Trouble is, they didn't give enough specific facts in those little books." By 5 :45 P.M., suppertime for most people in the area, eight jurors favored absolving Searle of Mrs. Black's death while four others, not necessarily because they wanted to uphold Black's accusation of negligence, argued that they would not accept any verdict that didn't compel Searle explicitly to warn women-and not just physicians-about the Pill's hazards. After most of the jurors either agreed or offered no objection, Skodinski passed out paper for everyone to write his own secret decision. The time for discussion was over. At 6:05 P.M., after the judge and participants had returned to the court- room, Skodinski nervously rose and read from a piece of paper: "We the jury find for the defendant G. D. Searle on Count I (negligence) . . . on Count II (breach of implied warranty) . . . on Count III (strict liability) ." But as attorneys instinctively turned to indicate that the case had ended, they were surprised to hear Skodinski continue to read: "Further, it is the recommendation of this jury that, effective immediately, G. D. Searle & Company, in instruction literature both to doctors and patients, advise the dangers of the possibility of phlebitis, thrombotic and embolic phe- nomena." Staring sternly, the white-haired judge told the jury of a legality they evi- dently had not known: Their stipulation that Searle warn users of the Pill about its risks could not be enforced. The jury legally exonerated Searle of all liability for Betty Jo Black's death but, by attaching a rider to its verdict, demonstrated that it was clearly dubious about the Pill's purported safeness. More important, the jury's deci- sion was theoretically based only upon facts that were known in 1965. Although inadmissible as evidence, the disclosure during the trial that pharma- cological companies concede that the Pill can cause fatal blood clots proves that an increasingly stronger case is developing against the Pill. Therefore the jury, in general, must still be considered "out" on all brands of the Pill. [Prom Good HousekeepIng, January 1970, pp. 129-131] THE BETTER WAY-WHY THERE Is GRowING CONCERN ABOUT THE SAFETY OF "THE PILL" Of the various contraceptive techniques available, the Pill is considered the most effective. It is also the most controversial in terms of health. Since oral contraceptives came on the market in 1960, the response by American women has been overwhelming. Today, an estimated 8.5 million take some form of birth control pill. There is no debating the efficiency of these pills; obstetri- cians and gynecologists maintain that, when taken according to directions, they are virtually 100 percent reliable in preventing pregnancy. For some women, however, a regimen of birth control pil1~ may be danger- ous. Medical researchers have, in recent years, shown a correlation between these pills and a higher incidence of thromboembolism, a blood-clotting disor- der. (See Controversy Over "the Pill," page 64.) Reports here and abroad have appeared to demonstrate the Pill's link with a variety of other diseases, including eye disorders, migraine headache, diabetes and cancer. As a result of PAGENO="0208" 7038 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY these and other findings, some physicians contend that the hazards of hor- monal contraceptives in family planning outweigh the advantages. They argue that a woman who wants to space her children could better protect her health by using some other form of contraception, such as a diaphragm or intrauter- ine device (IUD). How safe, then are birth control drugs? In order to find out, a government medical-research group-the Advisory Committee on Obstetrics and Gynecology of the U.S. Food and Drug Administration-undertook a major study in 1968. Last September, the FDA released its findings in a 200-page document titled the Second Report on Oral Contraceptives. The report provided new, definitive evidence of a health risk associated with Pill-taking. However, the committee concluded that: "When these potential hazards and the value of the drugs are balanced, the ratio of benefit to risk (is) sufficiently high to justify the desig- nation safe. . . ." However, it was a qualified statement. "No drug that is potent or effective can be absolutely safe," declares Dr. Louis M. Hellman, committee chairman and professor of obstetrics and gynecology at New York's Downstate Medical Center. Despite the designation "safe," data contained in the report confirmed that a cause-and-effect relationship does exist between oral contraceptives and fatalities from thromboembolism. This data showed that the risk from blood- clotting disorders is 4.4 times greater for Pill-users than for nonusers. (In comparable British studies, the risk was found to be seven to ten times greater for Pill-users than for non-Pill-users.; Nevertheless, the report showed that the mortality rate of women on the Pill, who suffered from this blood- clotting disorder, was low-about three per 100,000 cases. Further, it was determined that prolonged use of the Pill does not increase the risk, and the risk disappears once the Pill is discontinued. Moreover, the subcommittee looking into thromboembolism found a somewhat higher degree of risk for users of sequential birth control pills than for users of combination pills. Each pill of the combination type (there are twenty prod- ucts of both types on the market) contains two synthetic chemical hormones: estrogen and progestogen. The primary effect of these hormones is the inhibi- tion of ovulation. Combination drugs, the more popular of the two types of pills, are taken once a day for 20 or 21 days, beginning the fifth day after the onset of menstruation. The regimen is different with sequential pills. Sequen- tial pills containing only estrogen are taken for the first fifteen or sixteen days, then progestogen for the next five days. Some scientists believe that the higher levels of estrogen during the earlier phase accounts for the greater hazard of the sequentials. Some gynecologists feel that birth control pills should not be prescribed for women who are able to use some other form of contraception. Such side effects as skin and hair changes, weight gain and fluid-retention have been noted. "We have known for several years that oral contraceptives are not without danger," Dr. Alan F. Guttmacher, - president of the Planned Parenthood Feder- ation, says. "However, the degree of danger is relatively slight, as the FDA report makes clear, and we are still going to prescribe the Pill in more or less unrestrained fashion." Dr. Guttmacher added that the Pill has special applica- tion for women who lack motivation to use other contraceptive devices. Meanwhile, additional evidence that Pill-takers should proceed with cau- tion continues to increase. At Stanford University Medical Center in Califor- nia, researchers say they have found a link between contraceptive pills and high blood pressure. At the University of Buenos Aires, scientists reportedly have discovered liver-cell changes in women who had taken the Pill for more than a year. Then there are those authorities who maintain that the report is too "hard" or too "soft" on the Pill-health question. One pharmaceutical manufacturer, for example, G. D. Searle & Co., a major supplier of birth control pills, has reser- vations that Pill-taking and thromboembolisms are connected. PAGENO="0209" This chart compares the limitations of birth control methods and their effectiveness. It was prepared for Good Housekeep- ing by Dr. Christopher Tietze, associate director of the Blo-Medical Division of the Population Council, a private organizä- tion concerned with human fertility and its control. IUD (intrauterine device) 0 0 0 ? *** Diaphragm with jelly or cream 0 0 0 0 00 Condom *0 00 0 - Temperature rhythm 0 00 0 0 `~ Calendar rhythm 0 00 0 0 Chemicals (foams, etc.) 0 0 0 , Withdrawal - 0- 000 * I . I Oral pills * Douche ~- 0_ ~O0 PAGENO="0210" 7040 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. Irwin C. Winter, vice-president for medical affairs, said: "Thromboem- bolism and other disorders appear in women who are not taking the Pill as well as in those who are." He said he did not believe that retrospective studies such as the Sartwell report-the blood-clotting investigation team was headed by Dr. Philip E. Sartwell, professor of epidemiology at Johns Hopkins-proved that a causal relationship existed. "I disagree that there is proof, although many may think so," Dr. Winter said. He emphasized that he was giving his opinion as a scientist rather than as a representative of the company. Dr. Winter said that medicine is attempting to pinpoint the woman who is predis- posed to blood-clotting conditions so that she may be warned off the Pill, if necessary, by her physician. Ortho Pharmaceutical Corporation, another lead- ing Pill-maker. takes a more cautious view. "The report gives millions of women and their doctors welcome, new assurance about the Pill," it says. However, "for the woman for whom another birth control method may be pre- ferred, she still has a number of alternatives." A third supplier, Syntex Laboratories, urged that both the British and American studies "be kept in perspective," noting "that a woman has a much greater risk of death associated with pregnancy than by preventing it with the Pill." Another line of investigation was whether an association existed between the Pill and cancer of the uterine lining, breast and cervix. The verdict of the committee's experts, under the direction of Dr. Roy Hertz, an associate direc- tor of the Blo-Medical Division of the Population Council, was that no link could be proved or disproved. However, because observations concerning cervi- cal cancer were inconclusive, Dr. Hertz called for a "major effort" for further studies. A recent study made by Memorial Sloan-Kettering Cancer Center and Planned Parenthood of New York City has disclosed a slightly higher preva- lence of a precancerous condition of the cervix among Pill-talkers than dia- phragm users who attended Planned Parenthood centers. The authors called the difference "small, but statistically significant." The reason for the differ- ence was not obtainable from the data, they said. What health factors militate against taking oral contraceptives? According to Dr. Heliman, the Pill is contraindicated for women with a cancerous or pre- cancerous condition, for those who have a family history of cancer, diabetes, abnormal bleeding during the menstrual cycle, weight problems, thromboembo- lism or a history of thromboembolism. Dr. Hellman said he was aware of a number of anti-Pill books that had been published or were about to be pub- lished, as well as those which take a stand favoring the Pill. "Many of these books are unduly alarmist or unduly optimistic," he said. "In my view, the position they present, both for and against the Pill, tends to be exaggerated. While there are potential risks cited for the Pill-thromboembolism, metabolic and cancer-only the risk of embolism has been clearly defined." Meanwhile, scientists continue to search for ways to improve the Pill and make it safer. Researchers report a number of promising leads in this direc- tion, including the following: Mini-Pill. Dr. Elizabeth B. Connell, associate professor of obstetrics and gynecology at The New York Medical College, reports this low-dose pill has shown a 98 percent effectiveness rate in clinical tests conducted here and abroad involving several thousand women. This pill contains no estrogen and only one half milligram of progestogen, which is about half the amount found in most current Pills. It is taken daily. Dr. Connell says that the mini-pill does not seem to produce the metabolic or endocrine changes that sometimes occur with present oral contraceptives. If there is a thromboembolic risk from the Pill, says Dr. Connell, then the mini-pill "could conceivably be less hazard- ous." However, in clinical trials of this preparation, about 25 percent of the PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7041 women had irregular menstrual cycles or abnormal bleeding, and one quarter of this group was switched to a different form of contraception. Once-a-month treatment. At Harvard Medical School, scientists are experi- menting with a pill that would be taken once a month, instead of daily or every 20 or 21 days, and Dr. Melvin Taymor, assistant professor of gynecology, reports this pill is being well tolerated by women in a pilot study which began six months ago. Dr. Taymor and Dr. Somers H. Sturgis, professor of gynecol- ogy, recently completed trials on a monthly injection contraceptive method which would provide a like immunity. The dosage consists of a birth control drug in combination with an oil emulsion, which is injected into the muscle. Both the pill and the injection slowly release the material into the blood- stream, thereby giving longer-lasting protection against pregnancy without the need for daily motivation. A frequent cause of pregnancy in women on the Pill is that they forget to take it. With a once-a-month pill, the assumption is that there would be less chance for error. Another injection technique, also experi- mental, gives protection for up to three months. Said to be 100 percent effec- tive, it is being put through trials by Dr. Edward T. Tyler, President of the Family Planning Association of the Americas, a new scientific research organi- zation. Morning-after Pill. Birth control pills currently obtainable by the public, and the vast majority undergoing experimental testing, are pre-coital--that is, their action takes place prior to sexual relations. A tablet which could arrest conception after intercourse could be useful. Dr. John McLean Morris, profes- sor of gynecology at Yale University Medical School is currently working to perfect such a pill. To date, Dr. Morris has reported that it has prevented pregnancy in well over 100 cases. In this technique, massive doses of natural or synthetic estrogen-up to 50 times the amount contained in present pills- are given from one to five days after sexual relations. At a recent conference of the International Planned Parenthood Federation, he also reported that side effects were those commonly associated with the Pill. Vaginal ring. A possible substitute for the Pill is the vaginal ring, on which trials are being run by Dr. Daniel R. Mishell, Jr., professor of obstetrics and gynecology at the University of Southern California Medical School. The device, worn internally, is made of silicone rubber impregnated with medroxy- progesterone, a progestogen. The chemical is leaked into the bloodstream through the vaginal wall at a slow, constant release rate. Preliminary studies have been very promising, Dr. Mishell says. An important advantage of the ring is that, after insertion, no daily precautions are necessary. One ring could provide protection for as long as one year, at which time the wearer would return to her physician for renewal. As with conventional pills, there is spot- ting. Regardless of future developments, however, the Pill may never be consid- ered the best method of preventing conception for everyone. At the same time, as an effective brake on the world's tremendously increasing population rate, the Pill is considered a potent weapon. But for the individual? As Dr. Hell- man wrote in his summary to the FDA's report: "In the final analysis, both the physician and the layman must evaluate the risks of hormonal contracep- tives in comparison with other methods of contraception, or no contraception at all." Most authorities agree, however, that users of the Pill should certainly be under medical supervision while they are taking oral contraceptives. PAGENO="0212" 7042 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY /From Archives of Patho1o~r, Vol. 89, No. 1, January 1970, pp. 1-8/ Original Articles Vascular Lesions in Women Taking Oral Contraceptives Nelson S. Irey, MD; William C. Manion, MD; and Herbert B. Taylor, MD, Washington, DC 1 Distinctive vascular lesions in association ~ ~ ora contraceptives. These lesions were char- f~iz~Tstru~tural and hisfochemical changes in the inlima and media. Occlusive thrombi were associated with relatively small organized bases, the age of the latter mea- sured in days to weeks. Nonocclusive and possibly earlier lesions were dominated by endothelial proliferation with minimal throm- bus formation. If is postulated that this endo- thelial and intimal hyperplasia may be related to the steroids received and that it parallels similarly induced hyperplasias that have been found in cervical gland epithelium, in leio- myomas, and in a variety of mesenchymal derivatives under experimental conditions. Furlher control and experimental studies are required to clarify the possible relationship between these vascular lesions and oral con- traceptives. A.. LTHOUGH the clinical aspects of thromboembolism in women taking oral contraceptives have been reported in de- tail,"2 remarkably little attention has been paid to the pathologic findings in these patients. In the course of reviewing 20 examples of thromboembolism associated with the use of oral antiovulants, definite histologic changes in both arteries and Accepted for publication Sept 3, 1969. From the Armed Forces Institute of Pathology, Washington, DC. Read in part at the Ninth Annual Lectures, Armed Forces Institute of Pathology, Washington, DC, March 27, 1969. Reprint requests to Armed Forces Institute of Pathology, Washington, DC 20305 (Dr. Irey). veins were identified. These alterations are quite distinctive and have not been found in patients with thromboembolism who were not taking oral contraceptives. This paper describes the clinical and pathologic findings in a study of these 20 patients, with particular emphasis on the vascular lesions and their possible histogenesis and significance. Material and Methods The 20 examples forming the basis for this study were contributed to the Registry of Tissue Reactions to Drugs during the years 1936 to 1968. The available clinical data were tabulated, and routinely stained sections were reviewed. Histo- logic study was supplemented by preparation of additional slides from available formalindehyde solution-fixed tissue. The blood vessels were also studied with the following special status: Mas- son's trichrome stain; Wilder's reticulum stain; Movat's pentachroma stain; PAS reagent, with and without predigestion with diastase; and the colloidal iron technique for acid mucopolysac- charides (AMP), with and without predigestion with hyaluronidase. Twenty-two examples of thrombosis or thromboembolism in women in the same age range were utilized as controls. Clinical Findings The 20 patients ranged in age from 18 to 41 years, with a median age of 29 years (Table). Fifteen were white and five were Negro. None had clinical or pathologic evidence of any concurrent disease that would predispose to thrombosis or throm- boembolism. The indications for the use of oral con- traceptives were known in 14 patients: Contraception in nine; dysmenorrhea in PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY VASCULAR LESIONS AND CONTRACEPTIVES-IREY ET AL 7043 three; irregular periods in one; and menorrhagia in one. The duration of oral contraceptive medication ranged from five weeks to 13 months, and averaged five months. Other drugs were being taken by nine of these patients, including tran- quilizers, anorexiants, and thyroid extract. One patient was receiving cortisone ace- tate for ulcerative colitis. Symptoms associated with the terminal episode varied. Pain was the most fre- quent, occurring in the chest in six, in the leg in three, in the abdomen in two, and in the rectum and shoulder in one patient each. Dyspnea was noted in six patients, syncope in four. Tachycardia, apprehen- sion, palpitation, sudden blindness, and cold sweats were each described in a sin- gle instance. Ascites was the initial finding in one patient with hepatic vein throm- bosis (Budd-Chiari syndrome). Most patients were taking a combina- tion type preparation, but a sequential product was used by two. The estrogenic component in 16 cases was mestranol and in one case was ethinyl estradiol. The progestins included norethynodrel, nor- ethindrone, chlormadinone acetate, and ethynodiol diacetate. All of these are 19- nortestosterone compounds except chlor- madinone (6-chloro-progesterone [17 a] acetate). In terms of the relative effect of the constituents as evaluated by Dickey and Dorr,3 most agents used were of inter- mediate estrogenic and progestational ef- fect, but five patients received products with strong progestational effect and weak estrogenic effect, and the sequential agents Clinical Data on 20 Cases of Vascular Lesions Associated With Oral Contraceptives Interval From Case Type of Indications for Time on Other Initial Symptoms No. Age Antiovularit Antiovulant Antiovulant Medications Symptoms to Death 1 26 Norethynodrel and mestranol Dysmenorrhea 31/2 mo ... Pain in shoulder 5 days 2 27 Dysmenorrhea 13 mo Cortisone Dyspnea 10 days 3 23 Contraception 37 days ... Apprehension, syncope, tachycardia 3 days 4 41 Contraception 51/2 no Thyroid extract, tranquilizer Pain in leg 3 wk 5 40 Menorrhagia 2 no ... Dyspnea, syncope, cold sweats 7 days 6 36 ... 12 mo ... Blindness, right eye ... 7 34 ... 2 mo ... Pain in leg 5 days 8 18 Mestranol and norethindrone ... ... Anorexiarit, tranquilizer Died unexpectedly at home ... 9 25 ... ... ... Chest pain 5 days 10 33 Contraception 6 no ... Died unexpectedly at home 11 24 Contraception 6 wk ;.. Dyspnea, syncope, palpitation 3 days 12 24 ... 41/i no ... Chest pain 9 days 13 22 Contraception 3 no Tranquilizer Chest pain, leg pain, dyspnea 5 hr 14 27 Mestranol and norethindrone Contraception 6 wk Anorexiant Syncope, abdominal pain 7 days 1520 Mestranol and Irregular menses 3 no ... Rectal pain 12 days - chlormadinone 16 41 Mestranol and ethynodiol Contraception 71 days Thyroid extract Abdominal pain 11 days 17 26 Norethindrone and ethinyl estradiol Contraception 9 no Anorexiant Chest pains, dyspnea 1 day 1829 Type unslated Dysmenorrhea ~ 12 mo Tranquilizer Swelling abdomen (ascites) 2 mo 19 30 Contraception ... Tranquilizer Chest pains 3 wk 20 34 ... .. .. Chest pains, dyspnea 7 days PAGENO="0214" 7044 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY taken by two women had strong estro- genie and weak progestational effect. There was no apparent relationship be- tween the type of oral contraceptive taken and the development of thromboembolism. Pathologic Findings Gross.-Thrombi and associated lesions of the vascular wall were widely distrib- uted in these patients. They were found in the pulmonary, systemic, and portal circu- lations, in arteries and veins, and in ves- sels of large, medium, and small caliber. Thrombi were limited to the pulmonary artery in nine patients; in eight, they were found in the pulmonary artery and in the pelvic, iliac, hypogastric, or leg veins. They were limited to the mesenteric vein, temporal artery, and hepatic vein in one patient each. Microscopic. - Vascular Changes. - Three types of intrinsic vascular lesions were identified in these patients: 1. Three-layered thrombi with under- lying structural and histochemical changes in the vessel wall, found in 19 instances. 2. Endothelial proliferation and intimal thickening, with no changes in the media or adventitia, found in four patients. 3. Focal nodular thickening of the in- tima, media, and adventia, found in only one instance. In the first type (Fig 1 to 4), the throm- bi usually included three layers: an ad- herent and organized base with revascu- larization, collagenization, and in some instances hemosiderin-laden macrophages; over this a zone of fibrin with ingrowth of fibroblasts; and a superficial layer of re- cent laminated thrombus without evidence of organization. The latter usually formed the bulk of the intraluminal mass and was Fig 1.-Pulmonary artery. Organized and vascularized base of thrombus in lower field. Organizing com~ ponent above center of this base. Remainder of thrombus is laminated, recent (AFIP Neg 69~1713; Movat, reduced from x 13). Fig 2.-Higher magnification of portion of Fig 1. Organized, collagenized, and vascularized base of thrombus above arterial wall. At top center darker area of organizing layer. Top left, fresh and unorganized portion of thrombus (AFIP Neg 69.1725; Movat, reduced from X 42). PAGENO="0215" 4 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7045 VASCULAR LESIONS AND CONTRACEPTIVES-IREY ET AL Fig 4.-Higher magnification of portion of Fig 3. Note intimal thickening flanking fibrous base (Al. Hemosiderin deposits in base. Cellular rrasses lBl extending from base to right and left. Fresh and unorganized laminated ttirombus (Cl (AFIP Neg 3714-1; Movat, reduced from X 56). Fig 3.-Pulmonary artery. Base of thrombus (A), small and nodular, with organization and vasculariza- tion. Cellular extension (B) from base. Occlusive masses of fresh, laminated thrombus (Cl (AFIP Neg 3708-1; Movat, reduced from x 17). PAGENO="0216" 7046 COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY VASCULAR LESIONS AND CONTRACEPTIVES-IREY ET AL responsible for most of the encroachment on the vascular lumens. Beneath the. thrombi, the intima was often thickened by fibrous tissue, and the media showed thickening or thinning, with fibrosis and disruption of the muscu- lar, elastic, and fibrous components. The ~ elastica in these areas was variously thickened, fragmented, duplicated, or ab- sent. AMP-positive material was usually present in the organized basilar portions of the thrombi and also in the underlying intima and media. Digestion with hyalu- ronidase removed most of this AMP ma- terial. As judged by the degree of vasculariza- ~ tion and collagenization, as well as by the presence of hemosiderin-laden macro- ~ phages, the basilar portions of the thrombi were estimated to be of at least a week's ~ duration, and probably longer. There was ~ no evidence in any patient of underlying Fig 5.-Pulmonary artery branch. Intimal thickening atherosclerosis, and in only one instance above. Left center, papillary proliferation of endothelial was an acute inflammatory reaction noted cells. Dark streaks and masses in center and to right, . fresh thrombus formation IAFIP Neg 69-4034; Movat, lfl the wall of the blood vessel or in the reduced from X 45). adventitia. Fig 6.-Higher magnification of portion of Fig 5. Intimal thickening on left above internal elastica. Endothelial papillations center and right. Darker material in upper field represents recent thrombus formation IAFIP Neg 69-4035; Movat, reduced from X 135). PAGENO="0217" The second type of vascular lesion was found in smaller pulmonary vessels and consisted of endothelial and intimal pro- liferation characterized by formation of slender to broad papillary projections (Fig 5 to 8). These projections often formed anastomosing plexiform networks that in some instances almost filled the lumen of the vessel. Recent thrombi were some- times found in association with this type of change. The intima beneath the en- dothelial proliferation was often thickened, and hyaluronidase-sensitive, AMP-posi- tive material was present in the inter- stices. The underlying media and adventitia were unaltered. The third type of lesion was found in only one patient, in a small branch of the pulmonary artery. It consisted of a focal nodular, fibrous thickening of the intima, media, and adventitia, with no associated endothelial proliferation or thrombosis (Fig 9). Other Tissues-Sections of one or both ovaries were available from nine patients. Corpora lutea were absent in all instances. Multiple cystic graafian follicles were noted in the ovaries of one patient, but the theca interna was not well developed, and there was no luteinization~ The pau- city of developing graafian follicles and absence of corpora lutea made the cortical and medullary stroma appear relatively more prominent than usual for women in this age group, but there was no evidence of actual stromal hyperplasia. Clear-cut decidual transformation of the endometrial stroma, together with in- active-appearing endometrial glands, was found in two patients. Similar changes were probably present in four others but were obscured by the degree of postmor- tem autolysis. The endometrium was in COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY 7047 Fig 7.-Pulmonary artery branch. Endothelial prolif. eration, lower two thirds. Thrombus formation, lower right (AFIP Nag 69-3717; Movat, reduced from X 115). Fig 8.-Small pulmonary artery branch. Intimal thick. ening, upper and lower portions of vessel. Endothelial proliferation in upper portion (AFIP Neg 69-3438; hema- toxylin and eosin, reduced from x 180). Fig 9.-Small pulmonary artery branch. Above, focal fibrous thickening of intima, media, and adventitia. Internal elastica not demonstrable in this fibrous area (AFIP Nag 69-1630; Movat, reduced from X 145). PAGENO="0218" 7048 COMPETITIVE PROBLEMS IN THE DRTJG INDTJSTRY the menstrual phase in one patient and in the early proliferative phase in three others. Two women had uterine leiomyo- mas. One of the myomas was quite cellu- lar, with marked nuclear hyperchromasia but negligible mitotic activity. This pic- ture has been associated with the use of oral contraceptives.4 In the myometrium of one patient, there was a rather pro- nounced thickening of blood vessel walls. Marked chronic inflammation was present in the cervix of three patients, but no epithelial change or glandular hyperplasia was evident in the available sections. Sections of breast were available from five patients. In three, no particular lobu- lar development or other changes were noted. Lobular development was evident in the other two. It was relatively slight in one, but quite marked and associated with secretory activity in the other. The degree of lobular hyperplasia and lacta- tional change in this patient appeared greater than usually seen in women tak- ing oral antiovulants, although there is considerable variability. Controls The diseases associated with thrombosis and thromboembolism used as the control group are listed in the following tabula- tion: Disease or Condition No. of Cases Rheumatic heart disease 5 Postoperative status 4 Postpartum 2 Pulmonary hypertension 2 Bacterial endocarditis 2 Aortitis with congestive failure 1 Congenital heart disease 1 Lupus erythematosus 1 Myocarditis with mural thrombosis 1 Pregnancy 1 Pulmonary arteritis and pneumonitis 1 Renal disease with anasarca 1 Total 22 In only one patient, intrinsic vascular le- sions were observed resembling those in patients taking oral antiovulants. This one exception was a woman with pulmonary hypertension associated with congenital heart disease in whom pulmonary arterial branches showed circumferential intimal thickening associated with foci of foam cells. In addition, one artery presented a focal nodular thickening of the intima resembling the focal lesion found in one patient in the oral contraceptive group having a lesion of the third type (Fig 10). Further inquiry disclosed that she had taken an antiovulant for six weeks prior to death. Fig 10.-Small pulmonary artery branch. Focal fibrous intimal thickening on left. Elastica sterna intact. No evident medial or adventitial changes IAFIP Neg 69-3120; Movat, reduced from x 1001. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7049 Comment The present study has shown (1) that in many instances vascular occlusion re- sulted from locally formed thrombi rather than from embolization, and (2) that the lesions developed over a period of several days or weeks, with only the final occlu- sive event representing an acute phe- nomenon. Changes in walls of blood yes selswereini~bl found at the site of attachment of* the thrombi, and vascular ~ present in four patients, strongly suggest Thj~hat th~h ~ were jrimary. These changes-endothelial pro- ~ were not found in the control atients. I~yperp asia of various tissues, including endothelium, has been produced experi- mentally by administration of steroids.5 Endothelial hyperplasia in blood vessels has been described in the endometrium and other sites in women receiving oral contraceptives.6 Hyperplasia of endocer- vical glandular epithelium has been asso- ciated with the use of oral contraceptives by several investigators,7~'° as has in- creased cellularity in uterine leiomyomas.4 These observations provide support for postulating a causal relationship between the intimal hyperplasia and ingestion of the steroid hormones. It is obvious, however, that not only are detailed studies of additional examples necessary to clarify the possible relation- ship between the vascular lesions and the use of oral antiovulants, but that parallel studies on control groups of women with thromboembolism who were not taking exogenus hormones, and on women taking these agents who died of unrelated causes, are equally essential, as are additional ex- perimental studies. Nonetheless the con- sistent findings of these characteristic ~ ~ ~mboll~he absence of comparable changes in women with thromboembolism who were not taking these agents, and the apparent specificity of the histologic al- ~ exists, and that further studies are, there- Dr. Irey is Registrar of the Registry of Tissue Reactions to Drugs, which is jointly sponsored by the American Medical Association, the Food and Drug Administration (under contract FDA 67-53), the Pharmaceutical Manufacturers' Association Foundation, and the National Institute of General Medical Sciences, National Institutes of Health (under contract PH-43-66-966), under the auspices of Universities Associated for Research and Educa- tion in Pathology, Inc., Bethesda, Md. Nonproprietary and Trade Names of Drugs Norethindrone-Noriutin. Chlormadinone acetate-Lormtn. 1. Tausk, M.: "Oral Contraceptives and the In- 6. Blaustein, A.; Shenker, L.; and Post, R.C.: The cidence of Thrombosis," in Meyler, L., and Peck, Effects of Oral Contraceptives on the Endometrium, H.M. feds.): Drug-Induced Diseases, New York: mt J Fertil 13:466-475 (Oct-Dee) 1968. Excerpta Medica Foundation, 1968, vol 3, pp 183-209. 7. Candy, J., and Abell, MR.: Adenomatous Hy- 2. Ask-Upmark, E.: "The Relationship between perplasia of the Uterine Cervix, JAMA 203:323-326 Thrombophiebitis, Thrombosis, Embolism and the (Jan) 1868. Use of Oral Contraceptive Agents," in Meyer, L., 8. Taylor, H.B.; Irey, N.S.; and Norris, H.J.: and Peck, H.M. (eds.): Drug-Induced Diseases, Atypical Endocervical Hyperplasia in Women Tak- New York: Excerpta Medico Foundation, 1168, vol ing Oral Contraceptives, JAMA 202:636-639 (Nov) 3, pp 2l~*-217. 1967. 3. Ditkey, R.P., and Dorr, C.H.: Oral Contra- 9. Govan, A.D.T.; Black, W P.; and Sharp, J.L.: ceptives: Selection of the Proper Pill, Obstet Gynec Aberrant Glanoular Polypi of the Uterine Cervix 33273-287 (Feb) 1969 Associated With Contraceptive Pills: Pathology and Pathogenesis, J Cliii Path 22:84-89 (March) 4. Fechner, R.E.: Atypical Leiomyomas and Syn- 1969 thetic Progestin Therapy, Amer J Chin Path 49: ~ Kyriakos, M.; Kempson, R.L.; and Konikov, 697-703 (May) 1968. N.F.: A Clinical and Patholosic Study of Endo- 5. Lipschutz, A.: Stero:d Hormones and Tumors, cervical Lesions Associated With Oral Contracep- Baltimore: The Williams & Wilkins Co., 1950. tives, Cancer 22:99-110 (July) 1968. 8 VASCULAR LESIONS AND CONTRACEPT1VES-IREy ET AL References PAGENO="0220" 7050 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From The New York Post, December 22, 1969, p. 3] RESEARCHER PREDICTS BAN ON THE Pu~L (By Barbara Yuncker) A total ban on The Pill within two or three years is predicted by an English endocrinologist whose research contributed to recent strong official warnings in Great Britain about many forms of the oral contraceptives. Dr. Victor Wynn of the University of London Medical School believes all forms of The Pill will be withdrawn "when we start to get the first clinical cases of cancer which can be linked to oral contraceptive use in women," he said. Such links have been made in test animals. Senate hearings on Pill safety and the adequacy of warnings given women users are to begin Jan. 14, Sen. Nelson (D-Wis.), chairman of the monopoly subcommittee of the Senate Small Business Committee, announced today, con- firming an earlier story in The Post. Public sessions are set for Jan. 14, 15, 21, 22, 23, 28 and 29. In making the announcement, Nelson said, "It appears evident that a sub- stantial number of users are not advised of any of the health hazards or side effects by their doctors." Wynn, a vociferous Pill critic for at least six years, because of the various body-system and cell changes it produces, was interviewed during a visit here for conferences at the federal National Institute of Health which helps sup- port his research. He said his top research associate, Dr. John W. H. Doar also conferred with members of Nelson's staff, before returning to London over the weekend. Wynn's strongly-voiced opinions that possible cumulative effects leading to cancer and heart disease are not measurable and that women need far strong warnings of Pill effects, led him to a dramatic on-camera blowup with the dean of U.S. birth-control spokesmen, Dr. Alan Guttmacher, president of Planned Parenthood-World Population. The incident occurred during a taping of the David Frost show for next Monday on which Wynn had been invited to explain why the Pill use alarms him and Guttmacher had been invited as one of several discussants. When Wynn challenged the statistical and scientific arguments that the Pill was rea- sonably safe, Guttmacher lost his temper and strode out of the studio. "He undertook to lecture me . . . on my alleged lack of understanding of the medical literature," Guttmacher, who is a distinguished obstetrician, said after the incident. Guttmacher accused Wynn of inaccuracy in his interpretation of some of his research findings and of misleading women by "never mentioning that these 3hanges he finds so alarming are reversible when women go off The Pill. That's a dishonest omission." Guttmacher's position is that The Pill is acceptably safe in contrast to the risks of unwanted pregnancies and if women and their physicians are ade- quately alerted to side effect dangers. "Im not sure The Pill is the safest thing ever invented," he said. "But it's not the lethal thing that this character and Barbara Seaman would have you believe." (Mrs. Seaman, who was also a discussant on the same show, is author of a new book "The Doctor's Case Against The Pill.") The research of Wynn and Doar has to do with changes in how the body handles carbohydrates and fats when The Pill is used; they interpret these changes as similar to those that precede diabetes. Nelson, in announcing his hearings, cited British studies indicating one in every 200 women on The Pill suffer blood clots serious enough to require hos- pitalization and that the clots are fatal to one in 67,000 women between 20 and 34 and in one in 25,000 between 35 and 44. Although drug companies are required to put into the package of the drugs as shipped a warning of serious possible dangers, Nelson said, many doctors did not get or read these package inserts and "it appears evident that a sub- stantial number of users are not advised of any of the health hazards or side effects." Nelson charged that Pill manufacturers in their pamphlets for distribution to patients, "make light of the minor dangers and do no even mention the major dangers of The Pill." PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7051 His hearings are expected to explore the possibility that the Pill is doing or can do damage to genes which would not show up until future generations. The Wynn-Doar research deals with how the body handles carbohydrates and fats and the changes in blood levels of these substances when The Pill is used. They interpret the changes they find as like those which precede diabetes and circulatory disease which leads to heart attacks-and therefore frighten- ing. Wynn rejects the argument that The Pill is just a relatively small dose of hormones natural to women in child-bearing years. "The Pills are not hor- mones," he says. "They are synthetic drugs with hormonal action . . . and their effects are equivalent to the last trimester of pregnancy and more." [From the British Medical ~Tournal, November 15, 1969, pp. 380-381] ORAL CONTRACEPTION AND DEPRESSION Delay in the recognition of serious side-effects of new drugs is commonplace in psychiatry. The addictive potential of barbiturates and amphetamines and the hypertensive crises found with monoamine oxidase inhibitors are three examples, and it was a long time before serious depression caused by long- term medication with chiorpromazine was seen to be a much commoner and more troublesome side-effect than either jaundice or agranulocytosis. It is no surprise, therefore, in a different context to find that the effect on mood of oestrogen-progestogen mixtures is displacing thromboembolic episodes at the focus of disquiet about oral contraceptives. Though as far back as 1961 T. B. Lebherz and C. D. Fobes (1) noted that I out of 112 patients being treated for endometriosis showed emotional distress, and that two of them became severely depressed, the general tenor of impressionistic reports until recently has been sanguine. From 5-30% of women complain of such symp- toms as irritability, tension, and depression, but many have had premenstrual symptoms before they started on the pill, and in any case those who complain are balanced by the 10-20% who experience relief of premenstrual tension and an increased sense of well-being. High rates of depression appear to be associated with pills with a high progestogen content (2, 3), and depression diminishes with change to a more oestrogenic pill. When massive doses of the progestogen norethynodrel were given to 20 patients with endometriosis J. W. Scott and P. Brass (4) reported mood changes in all of them. Three developed depression of moderate severity, but it responded to antidepressant drugs. A. Lewis and M. Hoghughi (5) have recently compared the depressive side- effects in 50 women taking oral contraceptives with 50 well-matched controls from the same group practice. Of the "pill" group 13 were mildly and 6 severely depressed, compared with only 2 and 1 respectively of the controls. Two of the severely depressed women had made suicidal attempts unknown to their general practitioners. The patients with a previous depressive history were significantly more depressed than those who had not-a finding that con- firms earlier reports (6, 7). Two other trends emerged but did not reach the level of "significance": there was more depression with the more strongly pro- gestogenic pills: and the longer a patient had been on the pill the more likely she was to be depressed. This last observation has been made before (8). It seems, then, that the pill can precipitate depression in predisposed women of child-bearing age. But need these women, and others who become depressed out of the blue on such medication, be denied the undoubted benefits of oral contraception? Recent work suggests that prevention of this iatrogenic depres- sion may be possible. Steroids, including cortisol and oral contraceptives, appear to influence trypotophan metabolism (9-12). The net effect seems to be to create a functional deficiency of pyridoxine, a coenzyme in the conversion of tryptophan both to nicotinic acid ribonucleotide and to 5-hydroxytryptamine. There is evidence that premedication with pyridoxine prevents the disturbance of tryptophan metobolism by cortisol (12), and some evidence, too, that a very few cases of "pill"-induced depression have responded to pyridoxine (13). A contraceptive pill incorporating pyridoxine has already been marketed in Spain (14). NoTE-Numbered references at end of article. PAGENO="0222" 7052 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Last year K. J. Dennis and J. d'A. Jeffrey (15) commented that "At present it is probably true to say that depression and reduced libido associated with the administration of oestrogen-progestogen mixtures cause more women to dis- continue oral contraception than any other single cause," and other workers agree that depression is the most distressing, though not the commonest, side- effect (8). R. H. Moos (16) believes that up to 25% of the women who start on the pill soon abandon it, and H. Ratner states that there is gross under-re- porting of side-effects (17). If the pill is to remain man's best hope of control- ling the population explosion its side-effects should be eliminated wherever pos- sible, and the value of pyridoxine in treating depression should be studied further. Meanwhile doctors should be careful about prescribing oral contracep- tives for anyone with a clear-cut history of depression. References 1. Lebherz, P. B:, and Fobes, C. D., American Journal of Obstetrics and Gynecology, 1961, 81, 102. 2. Grant, E. C. G., and Mears, B., Lancet, 1967, 2, 945. 3. Nilsson, A., Jacobson, L., and Ingemanson C.-A., Acta Psychiatrica Igcandi- navica, 1968, Suppl. No. 203 p. 259. 4. Scott, J. W., and Brass, P., American Journal of Obstetrics and Gynecol- ogy, 1966, 95, 1166. 5. Lewis, A., and Hoghughi, M., British Journal of Psychiatry, 1969, 115, 697. 6. Daly, R. J., Kane, F. J., and Ewing, J. A., Lancet, 1967, 2, 444. 7. Kaye, B. M., Journal of the American Medical Association, 1963, 186, 522. 8. Wearing, M. P., Canadian Medical Association Journal, 1963, 89, 239. 9. Dewhurst, W. G., Nature, 1968, 218, 1130. 10 Winston, F., Lancet, 1969, 1, 1209. 11. Price, S. A., and Toseland, P. A., Lancet, 1969, 2, 158. 12. Rose, D. P., and McGinty, F., Clinical Science, 1968, 35, 1. 13. Winston, F., Lancet, 1969, 2, 377. 14. Otte, J., Lancet, 1969, 2, 498. 15. Dennis, K. J., and Jeffery, J. d'A.. Lancet, 1968, 2, 454. 16. Moos, R. H., Archives of General Psychiatry, 1968, 19, 87. 17. Ratner, H., Science, 1967, 155, 951. [From OB-GYN News, November 15, 1969, pp. 2, 46] OCs CAN DEEPLY ALTER GLUCOSE METABOLISM Niagara Falls, Ont.-Some oral contraceptives alter glucose metabolism so extensively that, after long-term use, 80% of the women demonstrate abnor- malities in glucose tolerance, Dr. William N. Spellacy told a district meeting of the American College of Obstetricians and Gynecologists here. Dr. Spellacy, associate professor of obstetrics and gynecology at the Univer- sity of Miami, predicted that contraception in the 1970's may no longer in- volve the types of pills and steroids now on the market. He foresees new, highly potent progrestogens administered parenterally by injection or through small semipermeable implanted plastic capsules. These agents would not alter the woman's metabolism nor inhibit ovulation. Con- ception would possibly be prevented by blocking the capacitation of sperm. Dr. Spellacy has collected data on 32 women from across the country who have used sequential or combination type oral contraceptives for longer than 10 years. Unfortunately, there are no data on the metabolism of these women prior to the use of the pills. However, Dr. Spellacy believes it is highly unlikely that many had abnormal glucose tolerance prior to pill use. Glucose tolerance abnormalities are present in 80% of the women using combination agents for longer than 10 years and 25% of those using sequential agents for longer than 10 years. Twelve of the total group of 32 women exhibit significant abnormalities. The high incidence of abnormal glucose metabolism in these long-term users of combination agents may represent an exhaustion phenomenon, Dr. Spellacy said. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7053 Abnormal glucose tolerance is not always reversible. Many women continue to demonstrate abnormalities for months after discontinuing the pills. It is not known whether the abnormalities will resolve with longer follow-up since none of the women at the time of the study had been off the pills for more than 9 months. Dr. Spellacy's hypothesis of the mechanisms leading to these abnormalities in glucose tolerance seems to argue against improvement in all individuals. The investigator stressed that not all pills and not all steriods cause the same effects on metabolism. In his studies of growth hormone, insulin, and glucose, he found that norethyriodrel caused very significant alternations while chlormadinone caused slight alterations. Since many of the agents studied use the same estrogen, the metabolic alter- ations may reflect the action of the various progestins. The higher incidence of abnormalities in women using combinations pills indicates that the mechan- ism is probably dose-related. The alterations in both carbohydrate and lipid metabolism which are induced by oral contraceptives are different from the alterations seen in pregnancy, Dr. Spellacy said. During pregnancy, all major lipids are elevated including the nonesterified fatty acids. In women using oral contraceptives, triglycerides are the most significantly elevated, probably as a result of slower breakdown and increased synthesis. The nonesterified fafty acids are not affected by oral contraceptive use. Lysolecithin, a phospholipid which may affect platelet agglutination in the clotting mechanism, is significantly elevated in pill users. "We can't tell what this means for the individual woman using oral contra- ceptives," Dr. Spellacy said. "The changes are similar to those which are cautioned against by the cardiovascular specialists." Dr. Spellacy and his associates attempted to answer five questions concern- ing the effect of oral contraceptive agents on carbohydrate metabolism: Does the pill alter carbohydrate metabolism? What are the mechanisms involved in carbohydrate alterations by the pills? Do all pills affect this metabolism to the same degree? What are the ulthnate risks? And could women at risk be selected prior to the administration of oral contraceptives? Studies were carried out in women who had never used oral contraceptives but who desire to do so. These women were followed during use of oral con- traceptives and following termination of the drugs. In addition to lipid, growth hormone, and other metabolic determinations, Dr. Spellacy recorded family history, weight changes, previous big babies, babies with birth anomalies, and stillbirths in an attempt to profile a high-risk group. A preliminary investigation indicated that hormonal alterations in the normal menstrual cycle do not affect carbohydrate metabolism. Abnormal glu- cose levels were seen after only 19 days of contraceptive use. Dr. Spellacy found that, after 6 months of therapy, women using combina- tion or sequential oral contraceptives had compensated to bring their glucose levels to normal values, but their insulin levels were increased by 33%. After 1 year, there was a discrepancy between the two groups of women. Those using a combination agent had slightly elevated glucose levels. In sequential users, glucose levels at 1 year were similar to levels at 6 months. In both groups of women, the insulin levels are still significantly elevated at 1 year. By 24 months, 4% of the women had abnormal glucose tolerance tests and by 36 months, 12% had abnormal glucose tolerance tests. "These studies indi- cate that the agents do alter carbohydrate metabolism," Dr. Spellacy said. He explained that oral contraceptives appear to act on the hypothalamus, perhaps by inhibiting an inhibiting factor to growth hormone. The result is an increase in human growth hormone release which leads to an increase in blood glucose levels. The increased glucose level stimulates the beta cells of the pancreas to release more insulin. Initially this sequence compensates for the glucogenic effects of the increased growth hormone. However, there is eventually a failure to compen- sate. Dr. Spellacy believes that the beta cells eventually, and perhaps perma- nently, become exhausted. While this is a probable mechanism for the metabolic alterations seen, it is not the only possibility, he said. PAGENO="0224" 7054 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The elevation of free active cortisol seen during estrogen therapy and during pregnancy may be responsible for some of these changes. Estrogen administration also results in alterations of tryptophan metabolism with an increase in the precursors of nicotinic acid. One of the precursors (xanthurenic acid) is capable of binding and inactivating insulin in the peripheral circulation. The liver dysfunction which has been noted in some women using oral con- traceptives may further contribute to altered carbohydrate metabolism. "In explaining the metabolic alterations, a single casual mechanism will probably not be found," Dr. Spellacy said, "it may be a combination of factors which give this particular pattern." In assessing the data collected prior to administration of oral contraceptives in the light of metabolic alterations developing during therapy, some factors did stand out. These characteristics-high parity, older age, excess weight gain, previous large babies, and family history of diabetes mellitus-are the same found in the gestational diabetic or the prediabetic individual during pregnancy, he noted. However, these high risk women do not account for the total number who develop abnormalities while using oral contraceptives. Dr. Spellacy noted that there is a significant increase in the incidence of monilia infection in women using oral contraceptives. The incidence is 7% in women using sequential agents and more than five times that (37%) in women using combination drugs. Monilia infection may reflect elevated blood glucose levels, he said. [From The St. Louis Globe-Democrat, November 5, 1969, p. 5A] WHY WOULD THE U.S. BAN CYCLAMATES AND NOT THE PILL? (By Morton Mintz, Globe-Democrat-Washington Post News Service) WA5HINGT0N.-A few days after the government learned that the artifi- cial sweeteners called cyclamates caused bladder cancer in rats, it ordered an immediate halt to production of soft drinks and foods containing the chemi- cals. But the oral contraceptives cause a wide variety of tumors in five species of experimental animals, including rats-and yet remain on sale with the blessing of the Department of Health, Education and Welfare. The question for today is, does this make any sense? The short answer is that the situation makes little if any sense medically and scientifically, even if it makes legalistic sense under the anomalies of the food and drug laws. In 1958, Congress enacted legislation, sponsored principally by Rep. James J. Delaney (Dem.), New York, requiring the government to stop production of any food treated with a chemical additive that causes cancer in laboratory animals. The basic idea of the law, which was invoked recently by Robert H. Finch, secretary of HEW-when he told a press conference of his order on the cycla- mates-is that no additive makes a contribution to a food product so impor- tant as to outweigh the possibility that it could cause cancer. Now cyclamates are expected to be handled as drugs. The main result will be that they will be available not to everyone but to patients with diabetes and high blood pressure who buy them on the advice of a physician. In acting against cyclamates, Finch invoked not only the law, but also the importance of following "a prudent course in all matters concerning public health." Is "a prudent course" being followed in the case of the pill? Dr. Herbert L. Ley Jr., commissioner of the Food and Drug Administration, told the news conference that the cyclamates, classified as drugs, will be "in an entirely comparable position" to the pill. The use of the pill, he said, "is limited, the benefits are significant, and med- ical supervision is exercised." Let's take these points one at a time. A few weeks ago, users of the pill were estimated by the FDA's outside experts-the Advisory Committee on Obstetrics and Gynecology-to number 8.5 million in the United States and 10 million elsewhere. These figures excluded additional millions of women who have used the pill but do so no longer. This is "limited" use? PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7055 Dr. Ley termed the benefits "significant." He didn't say for whom. He might, for example, get an argument from those women-or their survivors-who got a disabling or fatal blood clotting disease and who would not have taken the pill had they been warned by their physicians or, for that matter, by the FDA, about these and numerous other hazards. Many private patients and most clinic patients are not told about the haz- ards." In the preface to "The Doctors' Case Against the Pill," a new book by science writer Barbara Seaman, this cultivated ignorance is characterized as "a public scandal" by Dr. Hugh J. Davis, director of the Contraceptive Clinic of Johns Hopkins Hospital. As to "medical supervision" of women on the pill, that indeed has its uses. But it is irrelevant to the question whether the piii does, or does not, cause cancer. In a 200-page report last month, the FDA's advisory committee said there is much data suggesting indirectly that steroid hormones such as those used in the pill, particularly estrogen, "may be carcinogenic"-cancer causing-in humans. The report went on to say: "These data are derived from experiments on laboratory animals in which long-term administration of estrogen resulted in cancer in five species. Although all physical and chemical agents that are carcinogenic in man pro- duce malignant tumors in experimental animals also, evidence of the carcino- genicity of estrogen in other species cannot be transposed directly to man. "Suspicion lingers, however, that the results in laboratory animals may be pertinent to man." Surely this conclusion is as troubling for a healthy woman on the pill who could reliably use another form of contraception as the discovery of cancer in the organ of rats given artificial sweeteners is for a healthy woman who could drink a beverage sweetened with sugar instead of one sweetened with a cycla- mate. And certainly the advisory committee was deeply troubled, because its very first recommendation to the FDA said that whether oral contraceptives induce cancer in women "is the major unsolved question . . . funds to investigate this relation are urgently needed." Most of the advisory committee's report is a catalogue of cause-effect rela- tionships with the pill that have been established, such as blood clotting, hair loss, skin blotching and liver disease, or those that have not been established or disproved but are suspected as possibilities. In this category are not only cancer but also the effects on the offspring of users and on every organ system of the body. Yet at a press conference in which the report was released, Dr. Ley was able to pronounce it "favorable." That, of course, was a legal judgment When Finch met with reporters about the cyclamates, the subject of the pill was raised, to the amazement of almost everyone, by Dr. Robert 0. Egeberg. The assistant secretary of HEW for health and scientific affairs, be was affec- tionately introduced by Finch as "the nation's top health officer, the world's most reasonable man," and the speaker who would "put things in perspective." Dr. Egeberg's perspective proved to be one that would make many a scien- tist shudder. For one thing, he said that the synthetic sweeteners "have proba- bly saved and prolonged a tremendous number of lives the last few years by helping people keep their weight down. . . There is no medical evidence that the cyclamates have saved lives. It turned out that there isn't even significant medical evidence that they help people keep their weight down. Dr. Egeberg finally conceded that his claim was based on nothing more than personal experience in losing 30 to 40 pounds after giving up cigarettes. In short, his claim was a testimonial. Bringing his perspective to the pill, Dr. Egeberg said that it has "draw- backs . . . but if you think of the number of young girls who are killed each year or were killed through aseptic abortion, you have something to balance there, too." Dr. Egeberg's approach is one that views women as a monolith, which they are not. There is nothing in his "perspective" for the woman, say, whose con- cern is merely with postponing her family, not with avoiding an abortion. Besides, fatal blood clotting on the pill kills about as many as die from crimi- nal abortions. 40-471 0-70-pt. 17-~----15 PAGENO="0226" 7056 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. John Rock preceded Dr. Egeberg as a prime source of confusion. His proposition was that the pill is a "natural" form of contraception. He couldn't sell this at the Vatican, and he shouldn't be able to sell it anywhere else. In a new book based on a workshop on the pill sponsored by the National Institutes of Health, three professors of medicine-Drs. Hinton A. Saihanick of Harvard, David M. Kipnis of Washington University and Raymond L. Vande Wiele of Columbia-said that the oral contraceptives are "not natural sub- stances . . . their effects cannot be equated with phases of the menstrual cycle, pregnancy or psuedopregnancy . . . we believe that semantic oversimplification which equates the pharmacological state induced by contraceptive steroids with biological states such as pregnancy should be abandoned." More seriously misleading have been the pamphlets on the pill prepared by the various makers and put by doctors in their waiting rooms-the point of sale. The booklets have touted the pill in ways that, at best, understated the risks and, at worst, engaged in downright falsehood. One pamphlet, for exam- ple, claimed that the brand it was pushing had been "proven safe." No brand has been "proven safe." As if all of this weren't serious enough, now we have Dr. Egeberg talking about "balance" and Commissioner Ley rating the advisory committee report "favorable." What may be most useful is to require the manufacturer to include in every package received by the user a fair, factual summary of the risks-in plain English. Of course, the FDA and organized medicine will oppose such an idea. Their principal reason is that doctor knows best. But doctor was handing out the pill like candy when he didn't know beans about its safety. The opposition should not prevail. The risks are too great, not only to the users, but possibly, eminent scientists warn, by the offspring of users. Again, there hasn't been the testing to determine if there is, or is not a genetic risk. On Oct 20 in Milwaukee, Sen. Gaylord Nelson (Dem.), Wisconsin, chairman of the Senate Monopoly subcommittee, said he is considering holding hearings. "Women using the pill are not being told of the possible side effects," he said. Concerned as he is with "balance," Dr. Egeberg ought to be the first to cheer Nelson on. [From the Journal of Medical Education, Vol. 44, Part 2, No. 11, November 1969, pp. 64-68] CHAPTER 7-IMPLICATIONS OF CONTRACEPTION- A. METABOLIC EFFECTS OF ORAL CONTRACEPTIVES (By Philip A. Corfman, M.D.*) The use of oral contraceptives has been associated with a wide variety of metabolic effects and for this reason a brief review of this topic must be selec- tive. This review will demonstrate, however, that oral contraceptives appear to have a multitude of effects in many women, that we do not yet fully under- stand the implication of these effects, and that much more investigation must be carried out before the significance will be ascertained. The content of this review is based in large measure on the proceedings of a conference held in December 1968, supported by the National Institute of Child Health and Human Development (1). Several other recently published reviews also cover this topic (2-6). All demonstrate that this subject is unusually complex and that oral contraceptives and allied agents have a multitude of effects. Their ubiquitous effects are related to their high degree of contraceptive effectiveness, which is brought about through interference with at least three reproductive processes. The primary effect appears to be inhibition of gonado- trophic hormones; the estrogen in oral contraceptives inhibits (1) Follicle Stimulating Hormone (FSH) release and the progestogen inhibits the Luteiniz- ing Hormone (LII) peak with. occurs at ovulation. In addition, it is thought that oral contraceptives may induce a dysrhythmia between FSH and LII. The second major anti-fertility action of oral contraceptives is on the endometrium. The progestogen acts as an anti-estrogen, causing alterations in * Director, Center for Population Research. National Institute of Child Health and Human Development, National Institutes of Health. NoTE-Numbered references at end of article. PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 7057 endometrial glands, and, like progesterone, a pseudodecidual reaction. Both of these effects serve to make the endometrium unable to support implantation. The third contraceptive effect, which is on the cervix, prevents alterations in cervical mucus that normally occur at ovulation, permitting the ascent of sperm into the uterine cavity. When oral contraceptives are taken, the cervical mucus remains thick and apparently inhospitable to the transmission of sperm. Also, oral contraceptives may affect tubal motility and alter the local ovarian response to gonadotrophic hormones. When considering the metabolic effects of oral contraceptives, it must be remembered that there are many different formulations of these agents and that data derived from the study of one formulation may not be relevant to another. It is useful to identify the variables upon which the effects may depend: 1. the specific agent(s) employed; 2. the absolute amount of each agent; 3. the proportion between the two agents, if more than one is used; 4. the route of administration, which is usually oral or parenteral; 5. the length of time the patient has used the agent; and 6. the age of the patient. Recent attention to the importance of these six variables has been expressed in several articles (7, 8) which suggest that a physician should select a spe- cific agent according to the hormonal balance of the specific patient. These observations are based primarily on clinical impressions but they indicate important considerations which warrant further study and examination. One of the best known metabolic effects of oral contraceptives is their abil- ity to modify carbohydrate metabolism. Although earlier studies demonstrated that estrogen alone may lower the fasting blood sugar levels as much as 20 percent, and that individuals with maturity-onset diabetes may require less insulin with such medication, more recent work with oral contraceptives (9-16) indicates that glucose tolerance is decreased in a significant proportion of normal women on these agents and that diabetic women who take them may require more insulin. Such alterations in glucose metabolism are similar to those which are observed in normal pregnancy but to a smaller degree. In addition, the effect appears to vary according to the specific formulation used. For instance, some recent investigations with progestogens alone, taken continuously, show very moderate effects. These variations in response depend on the chemical struc- ture of the compound, the amount administered, and the sensitivity of the individual patient. Increased insulinogenesis occurs with both short-term and long-term use of oral contraceptives and may be related to a parallel effect on growth hormone levels (17, 18) and to increases in blood pyruvate and lactate (19). These effects are more pronounced with combined rather than sequential regimens, and less with formulations which contain no estrogen. Whereas glucose toler- ance tests return to normal shortly after the cessation of therapy, insulin levels may remain elevated for some time, suggesting that the hyperinsulinism which occurs with the use of oral contraceptives may serve as a compensatory mechanism for the maintenance of glucose homeostasis. This raises the ques- tion of long-term deleterious effects of such agents on pancreatic islet cell function. Although the functional state of the thyroid gland appears to be essentially unchanged with the use of oral contraceptives and the concentration of free thyroxin is normal (20), it is well known that the PBI is commonly elevated about 20 percent above pretreatment levels with these agents. This effect is thought to be due to the increased protein binding induced by the estrogen. The progestogens in oral contraceptives do not appear to have this effect on PBI levels when administered alone (21). Thyroid tests return to normal 2-4 months after cessation of treatment, while the basal metabolic rate, cholesterol levels and 1-131 uptake remain within normal limits throughout the treatment period. Contraceptive steroids increase the levels of plasma cortisol and decrease the clearance rate of its urinary metabolites (22). These effects, thought to be due to the estrogen, are accompanied by the increased protein binding of aldoste- rone and cortisol. This later effect on cortisol may relate to alterations in glu- cose metabolism seen with these agents. PAGENO="0228" 7058 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Moderate changes in liver function tests are seen in many women on oral contraceptives who are symptom-free. Bromosulfophthalein excretion is dimin- ished in a significant portion of women with almost all formulations and this effect appears to be dose-dependent (23); the dye is retained in the plasma primarily as a conjugate. Elevated BSP levels are related to a concomitant alteration in bile transport, an effect shared by all steroids which have an alkyl group at the 17-alpha position. These agents inhibit the glucuronyl trans- ferase system which participates in the transfer of conjugated bilirubin from the liver cell to bile. Another alteration in liver metabolism which is commonly observed is an increase in transaminase values in up to 20 percent of patients (24, 25), and a small proportion of subjects experience a slight elevation in alkaline phospha- tase levels. After cessation of treatment, all of these values return to normal over a period of time. Jaundice occurs in about 1 woman in 10,000 on oral contraceptives. In such patients, nausea, malaise, and itching precede clinical jaundice by several weeks. Liver function tests show increased bilirubin and moderately elevated transaminase levels; liver biopsies demonstrate canalicular and bepaticocel- lular bile stasis. Patients with such jaundice appear to fall into three major groups (26). The first group is women who have recurrent cholestasis of preg- nancy; their livers seem unusually sensitive to contraceptive steroids. The second group are those who have cholestasis without evidence of hepato-cellu- lar damage: this effect is similar to the jaundice produced by anabolic steroids and probably results from a direct effect on bile secretory apparatus. The third group shows frank hepatocellular injury or hypersensitivity. Oral contraceptives affect a variety of enzyme systems (27) and produce increases in beta-glucuronidase and isocitrate dehydrogenase and decreases in lactic dehydrogenase, alkaline phosphatase, and transaminase. One author (28) describes alterations in serum naphthylamidase isozymes as one of the most sensitive indicators of disturbances in liver function and another (29) estab- lishes a correlation between increases in glutamic oxalacetic transaminase levels and histological demonstration of liver cell damage. This latter effect is thought to be due to the progestogen rather than the estrogen in oral contra- ceptives and represents one of the few examples of the implication of the pro- gestogen. In most studies of the effects of oral contraceptives on liver function, estrogen is considered to be the active agent. Another effect on enzyme systems is the decreased ability of the liver to extract cortisol from the blood (31). The related elevation in trariscortin levels produces an increase in unbound cortisol. As already stated, such an effect on cortisol levels is probably related to the effects of oral contraceptives on glu- cose metabolism and raises concern over the possible effect of these agents on pituitary function. It has been observed recently (30) that oral contraceptives appear to partici- pate in the development or enhancement of hypertension in certain women. This effect may be related to the fact that estrogens increase serum-renin sub- strate levels, through the stimulation of the hepatic biosynthesis of related enzymes. Oral contraceptives also increase aldosterone levels. These effects may compromise the ability of the renin-angiotension-aldosterone hormonal system to respond to normal physiological stimuli. Another class of effects of oral contraceptives relates to lipid metabolism. Several studies (32, 33) show that these agents increase plasma levels of nonesterified fatty acids, and produce increases in phospholipids and triglycer- ides. They have a particular effect on low density lipoproteins, changing the proportion between high density and low density lipoproteins to stimulate the proportion observed in adult males. Since lipid synthesis requires the presence of insulin, observed changes in lipid levels may be mediated through the effect of estrogens on plasma concentrations of insulin. Although no specific clinical alterations have been attributed to these changes in lipid and lipoprotein levels they are appreciable and warrant close observation and study. In summary, oral contraceptives have a variety of metabolic effects in many women who use them. Considerable attention has been placed in recent years on their effects on glucose and lipid metabolism, liver function and blood pres- sure. It is not possible at this point in time to state with certainty which iilterations in function, if any, have a permanent effect on the health of PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7059 women; and it will be sometime until we can, as such questions require well- designed and carefully conducted epidemiological studies. Presently available ora.l contraceptives are indisputably effective and undeniably important to the practice of fertility regulation. For some women they are the most acceptable and effective method available. Nevertheless, their use should be monitored and restricted to women who cannot use other methods effectively. References 1. Metabolic effects of gonadal steroids and contraceptive agents: A confer- ence report. Harvard University Press, 1069. 2. Advisory committee on obstetrics and gynecology, Food and Drug Adminis- tration: Report on oral contraceptives, 1969. 3. DICZFALUSY, EGON. Mode of action of contraceptive drugs. Am. J. Obst. and Gynec., 100:136, 1968. 4. World Health Organization. Hormonal steroids in contraception. Wid. Hith. Org. Techn. Rep. Serv., 386:1968. 5. JEFFERY, J. D'A. AND A. I. KLOPPER. Steroid contraceptives: A review. J. Reprod. Fert. Suppi., 4: 81, 1968. 6. LAURITZEN, CHRISTIAN. On endocrine effects of oral contraceptives. Acta Endoerinologica, Suppl., 124: 87, 1967. 7. DICKEY, RICHARD P. AND CLYDE H. iDoon, II. Oral contraceptives: Selection of the proper pill. Ob. and Gynec., 33: 273, 1969. 8. BEHRMAN, S. J. Which `pill' to choose? Hospital Practice, 34, 1969. 9. JAVIER, Z., GERSHBERG, H. AND HIJLSE, M. Ovulating suppressants, estrogens and carbohydrate metabolism. !i[etabol., 17: 443, 1968. 10. GERSHBERG, H., JAVIER, Z. AND HULSA, M. Glucose tolerance in women receiving an ovulatory suppressant. Diab., 13: 378, 1964. 11. WYNN, V. AND D0AR, J. W. H. Some effects of oral contraceptives on car- bohydrate metabolism. Lancet, 2: 715, 1966. 12. PETERSON, W. F., STEEL, M. W. AND COYNE, R. V. Analysis of the effect of ovulatory suppressants on glucose tolerance. Am. J. Obst. d~ Gynec., 96: 484, 1966. 13. SPELLACY, W. N. AND CARLSON, K. L. Plasma insulin and blood glucose levels in patients taking oral contraceptives. Ani. J. Obst. d~ Gynec., 95: 474, 1966. 14. POSNER, N. A., SILVER5TONE, F. A., POMERANCE, A. AND BAUMGOLD, D. Oral contraceptives and intravenous glucose tolerance. I. Data noted early in treatment. Obst. d~ Gynec., 29: 79, 1967. 15. POSNER, N. A., SILVERSTONE, F. A., POMERANCE, W. AND SINGER, N. Oral contraceptive and intravenous glucose tolerance. II. Long-term effect. Obst. d~ Gyncc., 29: 87, 1967. 16. GOLD, E. M., CARVAJEL, J., RUDNICK, P. A. AND GERSZI, K. E. Insulin pro- duction in overt (maturity-onset) diabetes: Absence of hyperinsulinenmia despite hyperglycemia induced by contraceptive steroids. Salhanick, H. A., Ed., Conference on metabolic effects of gonadal hormones and contra- ceptive steroids. Dec. 1-5, 1968. 17. SPELLACY, W. N. The effect of ovarian steroids on glucose, insulin, and growth hormone. Salhanick, H. A., Ed. Conference on metabolic effects of gonadal hormones and contraceptive steroids. Dec. 1-5, 1968. 18. GERSHBERG, H., ZORRILLA, E., HERNANDEZ, A. AND HULSE, M. Effects of medrozyprogesterone acetate on serum insulin and growth hormone levels in diabetics and potential diabetics. Obst. ct~ Gynee., 33: 383, 1969. 19. DOAR, J. W. H., WYNN, V. AWl) CRAMP, D. G. Studies of venous blood pyru- vate and lactate levels during oral and intravenous glucose tolerance tests in women receiving oral contraceptives. Saihanick, H. A., Ed., Con- ference on metabolic effects of gonadal hormones and contraceptive ste- roids. Dec. 1-5, 1968. 20. GOOLDEN, A. W. G., GARTSIDE, J. M. AND SANDERSON, C. Thyroid status in pregnancy and in women taking oral contraceptives. Lancet, Jan. 7, 1967, p. 12. 21. HOLLANDER, C. S., GARCIA, A. M., STURGIS, S. H. AND SLENKOW, H. A. Effects of an ovulatory suppressant on the serum PBI and red cell uptake of radioactive triiodothyronine. N. Eng. J. Med., 269: 501, 1963. PAGENO="0230" 7060 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 22. DODEK, 0. I. AND KOTZ, H.. L. Syndrome of anovulation following the oral contraceptives. Am. J. Obst. f Gynec., 98: 1065, 1967. 23. KLEINER, GEORGE J., KRESCH, LEONARD, AND ARIAS, IRWIN M. Studies of hepatic excretory function: II. The effect of norethynodrel and mestranol on bromsulfalein sodium metabolism in women of child~ bearing age. N. Eng. J. Med., 273: 420, 1965. 24. EI5AL0, A., JARVINEN, P. A. AND LUUKKAINEN, T. Liver-function tests during intake of contraceptive tablets in premenopausal women. Br. J. Med., 1: 1416, 1965. 25. LARSSON-COHN, U. The 2 hour sulfobromophthalein retention test and the transaminase activity during oral contraceptive therapy. Am. J. Obst. c~ Gynec., 98: 188, 1967. 26. SCHAFFNER, FENTON. The effect of oral contraceptives on the liver. JAMA, 198: 1019, 1966. 27. PULKKINEN, MARTTI 0. AND WILLMAN, KALLE. The effect of oral contracep- tives on serum enzymes. Acta. Obst. et Gynec. &,andinav., 46:525, 1967. 28. ARTURSON, G., BECKMAN, L., AND PERSSON, B. H. Alterations in serum naphthylamidase isozymes during treatment with oral contraceptives. Nature, 214: 1252, 1967. 29. STOLL, BAsil A., ANDREWS, J. T., AND MOTTERAM, R. Liver damage from oral contraceptives. Br. Med. J., 1: 960, 1966. 30. LARAGH, J. H., NEWTON, M. A., SEALEY, J. E., AND LEDINGHAM, J. G. G. Oral contraceptives and high blood pressure: Changes in plasma renin, renin substrate and aldosterone excretion. Salhanick, H. A., Ed., Conference on metabolic effects of gonadal hormones and contraceptive steroids. Dec. 1-5, 1968. 31. SANDBERG, A. A., ROSENTHAL, E., AND SLAUNWHITE, JR., W. 11. Certain meta- bolic effects of estrogens. Saihanick, H. A., Ed., Conference on metabolic effects of gonadal hormones and contraceptive steroids. Dec. 1-5, 1968. 32. BRODY, S. KERSTELL, J., NiLssoN, L., AND SVANBORG, A. The effects of some ovulation inhibitors on the different plasma lipid fractions. Acta. Medica. Scandinav., 183: 1, 1968. 33. WYNN, V., DOAR, J. W. H., AND MILLs, G. L. Effect of oral contraceptives on serum lipid and lipoprotein levels. Lancet, 2: 720, 1966. [From The Lancet, October 11, 1969, pp. 783-7841 METABOLIC EFFECTS OF ORAL CONTRACEPTIVES Oral contraceptives are now being used by about 18.5 million women through- out the world (1) ; and it is possible that the metabolic changes associated with this treatment (2) may modify biochemical processes in all body-tissues. More than fifty metabolic changes have been recorded and they include: altered carbohydrate and lipid metabolism (2) ; raised circulating levels of serum iron, copper, cortisol, thyroxine, insulin, and growth hormone (2) ; raised serum-transaminase levels and increased retention of bromsulphthalein (2) raised renin-substrate levels and increased aldosterone secretion (2) ; de- creased serum and urine magnesium (3) and plasma-zinc levels (4) ; increased urine excretion of cl-aminolaevulic acid (5) ; low serum and red-cell folate levels and abnormal urine FIGLU excretion after histidine loading (6) ; altered platelet behaviour, similar to that found in atherosclerosis, (7) and increased circulating levels of certain blood coagulation factors, including factors VII, IX, and fibrinogen (2); and a disturbance of tryptophan metabolism suggestive of vitamin-B6 depletion. (2) These changes are unnecessary for contraception and their ultimate effect on the health of the user is unknown. The evidence suggests that many of the metabolic changes in women receiving oestrogen- progestagen combinations may not arise with low-dose progestagen treatment. (2) Unfortunately, however, a disturbing incidence of menstrual irregularity and pregnancy has been recorded during trials of these latter compounds. It is clearly important to determine the proportion of women affected by these metabolic changes, and the two papers from the Simpson Laboratory at St Mary's Hospital. London, which we publish this week examine the effects Norz.-Numbered references at end of article. PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7061 of oral contraceptives on carbohydrate and lipid metabolism. The findings of Professor WYNN and Dr. DOAR in general confirm their observations of im- paired oral and intravenous glucose tolerance, raised blood-pyruvate levels, and increased serum lipid and lipoprotein levels in previous cross-sectional studies (8, 9). The present longitudinal observations provide additional information. Firstly, relative impariment of glucose tolerance was common, being observed in 78% of oral and intravenous glucose-tolerance tests respectively. Plasma- insulin levels were raised and 13% of women had chemical diabetes mellitus during treatment. Fasting serum-triglyceride levels increased in 95% of women tested before and during therapy. Secondly, the impaired oral and intravenous glucose tolerance and the raised seurm lipid and lipoprotein levels returned towards normal after contraceptives were stopped. Thirdly, no characteristic, such as age, parity, degree of obesity, or family history of diabetes, was de- tected which correlated significantly with the changes in glucose tolerance or serum-lipid levels. It seems that the oestrogen component alone of the combined oral contra- ceptive can produce most of these metabolic changes, (2) though further work on the effects of oestrogens and progestagens given singly is clearly required. Earlier WYNN and DOAR (8) proposed that the raised plasma-glucose and blood-pyruvate levels during glucose-tolerance tests in subjects receiving com- bined oral contraceptives might be "steroid diabetes" caused by high plasma- cortisol levels secondary to the oestrogen component, rather than a primary effect of either the oestrogen or progestagen. This view is supported by the finding of increased non-protein-bound plasma-cortisol during oral contracep- tive therapy (10) and also by the fact that protein-bound plasma-cortisol ex- erts biological activity in certain tissues with protein-permeable vascular beds, such as the liver. (11) While circulating growth-hormone and thyroxine levels are also increased during the taking of oral contraceptives, (2) the patterns of plasma-glucose and blood-pyruvate levels during treatment do not resemble those associated with increased levels of these hormones (12, 13). We have recently discussed (14) possible mechanisms for the increase in serum- triglyceride levels during the administration of oral contraceptives. Although changes of glucose tolerance and serum-lipid levels were observed in most of the women, WYNN and DOAR were unable to find any correlation between the changes of various indices of carbohydrate and lipid metabolism in individual subjects. The clinical significance of these findings is unknown, but clearly they can- not be ignored, since they raise the possibility of irreversible structural changes, such as atherosclerosis, after ten or twenty years on oral contracep- tives. Both raised serum-lipid levels and chemical diabetes mellitus are asso- ciated with an increased incidence of occlusive vascular disease (15, 16). The risks of venous thrombosis, pulmonary embolism, and cerebral thrombosis have already been shown to be increased in women taking oral contraceptives (17, 18). It is too early to say whether the incidence of clinical diabetes mellitus and the rate of development of atherosclerosis will be increased by years of treatment with oral contraceptives, and, as an F.D.A. report (1) em- phasises, the safety of long-term use of these drugs cannot be predicted (1). Prospective studies of morbidity and mortality in women taking oral contra- ceptives have only lately been started by the Royal College of General Prac- tioners in Great Britain and the Kaiser Permanente group in the United States, and their results may not be conclusive for twenty or forty years. The risk of potential carcinogenicity of synthetic gonadal steriods will be equally difficult to determine. In view of these doubts, the wisdom of administering such compounds to healthy women for many years must be seriously ques- tioned. References 1. Second Report on the Oral Contraceptives by the Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, U.S.A. Aug. 1, 1969. 2. Metabolic Effects of Gonadal Hormones and Contraceptive Steroids. Edited by H. A. SALHANICK, D. M. KIPNIs, and R. L. VANDE WIELE. New York. Plenum Publishing Co. 1969. Pp. 762. $27.50. 3. Goldsmith, N. F., Baumberger, J. P. Lancet, 1967, ii, 567. 4. Haisted, J. A., Hackley, B. M., Smith, J. C. ibid. 1968, ii, 278. PAGENO="0232" 7062 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 5. Koskelo, P., Eisalo, A., Toivonen, I.Br. med. J. 1966, i, 652. 6. Shojania, A. M., Hornady, G., Barnes, P. H. Lancet, 1969, i, 886. 7. Bolton, C. H., Hampton, J. R., Mitchell, J. B. A. ibid. 1968, i, 1336. 8. Wynn, V., Doar, J. W. H. ibid. 1966, ii, 715. 9. Wynn, V., Doar, J. W. H., Mills, G. L. ibid. p. 720. 10. Burke, C. W. Br. med. J. 1969, i. 798. 11. Keller, N., Richardson, U. I., Yates, F. E. Endocrinology, 1969, 84, 1. 12. Doar, J. W. H., Stamp, T. C. B., Wynn, V., Audhya, T. K. Diabetes, 1969, 18, 633. 13. Doar, J. W. H., i~Iaw, D. S. J., Simpson, R. D.., Audhya, T. K., Wynn, V. J. Endocr. 1969, 45, 137. 14. Lancet, Aug. 2, 1969,. p. 256. [From ScIence, September 19, 1969, pp. 1203-1204] (Letters) "FAMILY PLANNING AND PUBLIC POLICY: WHO Is MISLEADING WHOM ?" In their article (25 July, p. 367) Harkavy, Jaffe, and Wishik are, in effect, defending their own effort to influence the federal government regarding popu- lation policy. Harkavy and Jaffe are executives with organizations that pro- mote "family planning" (the Ford Foundation and Planned Parenthood), and Wishik is a director of a university-based family planning program. Their past influence is not only directly visible in their consultants' report criticizing HEW's population program for not pushing family planning more aggressively, but it is indirectly evident in the authors' presence (one, two, or all) on com- mittees and hearings concerning population, each appearing to give "independ- ent". but somehow unanimous advice to government agencies, Congress, and the President (1). My questioning of the alleged facts and logic supporting their advice has led them to charge me with statements I never made, nonuse of data they have carelessly overlooked in my article, and failure to include unpublished materials to which I had no access. In their anxiety to discredit my analysis, they even deny their own erstwhile goal of population control. They begin by using over 1000 words to accuse me of claiming that there is "a consensus on U.S. population stability," or "zero population growth," as a goal. I made no such claim. I said that "action to limit population growth is virtually unchallenged as an official national goal," a statement implying neither zero increase nor popular consensus. If anyone doubts that population limitation is endorsed, and endorsed officially, he may consult President John- son, John W. Gardner, the Republican National Platform and, recently, Senator Tydings' 8 May 1969 speech introducing S. 2108 (2). These endorsements have gone unchallenged-that is, until Harkavy et al, suddenly disavowed them. Although every major proposal for federally supported family planning is phrased in terms of the need to stem population growth, my three critics now say that "the federal program has been advanced, not for population control, but to improve health and reduce the impact of poverty and deprivation." This constitutes the first explicit admission by family planning leaders that their interest in contraception is not to be equated in any way with population "planning," "control," or "policy." If this is really their view, it contradicts their past role in this field. If the federal program is to improve health and reduce poverty, as my crit- ics now claim, is it wanted and needed by the prospective recipients? The doc- uments I criticized claim that the poor prefer fewer or no more children than the well-to-do, but the facts I cited show that this claim is not true and that it exaggerates the demand for birth-control services among the disadvantaged. This evidence comes principally from national polls, but it comes also from the only two national fertility surveys (1955 and 1960) available in print, w-hich my critics falsely say I "ignored." In trying further to discredit the evidence, the authors' unfamiliarity with the literature leads them to cite criticisms of a question (the ideal size for the average American family) which was not asked on the polls I used. They also darkly impugn respondents' own state- ments of ideal family size, they prefer number of children "wanted" or Nors.-Numbered references at end of article. PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7063 "desired." Yet the National Fertility Study of 1965 shows, for whites, very close agreement among ideal, desired, and intended family size: the average "ideal" is 3.24, "desired" is 3.29, and "intended" is 3.16 (3). In further misun- derstanding of the surveys the authors make the amazing statement that* "almost all low-income parents" have an "expressed preference for less than four children." They confuse an average with a proportion. Actually, although the average preference is for fewer than four, approximately 40 percent of the women with incomes "under ~3000" said in 1960 that they wanted four or more children (4). As for the categorical claim that Negro couples desire smaller families than do white couples, Table 1 of the authors' own article shows that this claim is true only for well-educated Negroes. Poorly educated ones want more children than comparable whites, except for white Catholics. Continuing to dispute the evidence, the authors object to opinion polls as * against "in-depth" studies on birth control. The "in-depth" question from the 1965 study that they claim I ignored (the results were, in fact, not published) runs as follows (5) : "Most married couples do something to limit the number of pregnancies they will have. In general, would you say you are for this or against this ?" If this question is superior, why are the results, tabulated by educational level (Table 2 of the Harkavy article), essentially the same as the polling data? Both sources show the least approval of birth control among respondents with only a grade school education. Defending their idea of a great "need" for government assistance in family planning, Harkavy et al. turn to the overworked and ambiguous concept of "excess fertility." The concept, as applied to couples, was carefully defined when first used in the 1960 Growth of American Families Study. It was con- cerned with whether the respondents "really wanted" another child at the time of the last conception. If the respondent said that she, her husband, or both had not wanted another child, this was defined as "excess fertility." But the authors of the 1960 study emphasize that in 50 percent of such cases one spouse "really wanted" another child. The original authors also caution that "many wives who said that they had not `really wanted' another child before the last conception also said . . . that if they could have just the number they wanted and then stop, they would have the same number they bad and even more" (5, p. 236). As defined in the actual studies, "excess fertility" obviously cannot be equated with "unwanted" pregnancies; yet such an equation has been a principal argument favoring a federal program. The estimate of the five million women who "want" and "need" contracep- tion is grossly overstated. It includes sterile women, birth control users, objec- tors, and women seldom or never having intercourse. Our reestimate, correct- ing for the errors just mentioned, shows that the number is substantially fewer than two million. This estimate does not imply that the women need federal services, but merely that they need contraception. Harkavy and his colleagues are right that family planning for the poor is not a means of population control. It is not even a "first step" to that goal. But until now this has not been clear; the government has been sold a risky program as part of a population-contol package. This program invites charges of genocide, dissemination of dangerous drugs, and subversion of moral stand- ards-ironically, it now appears, for the purpose of "health" and a dubious welfare goal. The insensitivity to such risks, as well as the paradoxical confu- sion of goals, is exemplified by Senator Gruening's support of the statement that (6) "...whatever might be the long-range adverse effects of the pill women prefer to take their chances. They would risk any possible ill effect rather than become pregnant" JUDITH BLAKE Department of Demography, University of California, Berkeley 94720 References and Notes 1. The principal documents under discussion are: 0. Harkavy, F. S. Jaffe, and S. i\'I. Wishik. Implementing DHEW Policy on Family Planning and Popu- lation (1967, mimeographed; available from the Ford Foundation. New York) ; Report of the President's Committee on Population and Family Planning: The Transition from Concern to Action (Government Printing Office, Washington, D.C., 1968); and Hearings on ~. 1676, U.$. Senate Subcommittee on Foreign Aid Expenditures (17 volumes of testimony con- cerning "the population crisis"). PAGENO="0234" 7064 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Statement by President Johnson at the 20th anniversary of the United Nations at San Francisco, 25 June 1965, and swearing-in ceremony of John W. Gardner as Secretary of Health, Education, and Welfare, 18 Aug. 1965 [Congr. Rec. 113, 6494 (14 Mar. 1967)]. The complete text of the 1968 Republican platform appears in Uongr. Quart., 9 Aug. 1968; the reference to population is on p. 213. "Family planning: A basic human right," speech of Senator Joseph P. Tydings, Uongr. 11cc. 115, S. 4848 (8 May 1969). 3. N. B. Ryder and C. F. Westoff, "Relationships Among Intended, Expected, Desired, and Ideal Family Size: United States, 1965." An occasional paper published by the Center for Population Research, National Institute of Child Health and Human Development, March 1969, no pagination. 4. Tabulation from basic data cards of the 1960 study. 5. From the interview schedule used in the 1965 National Fertility Study. Kindly supplied to me by Charles F. Westoff of Princeton University. 6. Hearings on 2. 1676, U.S. Senate Subcommittee on Foreign Aid Ewpendi- tures, 90th Congress, 1st session (2 Nov. 1967), p. 62. [From the British Medical Journal, July 26, 1969, pp. 195-200] PAPERS AND ORIGINALS-PREVALENCE RATES OF UTERINE CERVICAL CARCINOMA IN SITU FOR WOMEN USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS* (By Myron R. Melamed,t M.D.; Leopold G. Koss,t M.D.; Betty J. Flehinger4 Ph. D.; Richard P. Kelisky4 Ph. D.; Hilliard Dubrow,~ M.D.) Summary: Study of the prevalence rates of uterine cervical carcinoma in situ among women attending centres of Planned Parenthood of New York City, Inc., showed a small but statistically significant difference between the popula- tion choosing and using the diaphragm and the population choosing and using oral steroids for contraception. This can be attributed either to a decreased prevalence rate for women using the diaphragm or to an increased rate for women using oral steroids. The reason for the difference is not apparent from these data. INTRODUCTION In the autumn of 1965 a systematic long-range study of uterine cervical car- cinoma in women using contraceptives was begun by Planned Parenthood of New York City, Inc., in conjunction with the Memorial Hospital for Cancer and Allied Diseases and the Sloan-Kettering Institute for Cancer Research. The study was designed primarily to determine whether various forms of con- traceptives exert any influence on the development of cervical carcinoma. Two major statistical evaluations were proposed. The first, based on prevalence rates of the disease as found in an initial survey, was to compare matched populations of women who had been using the diaphragm with women using oral steroids. The second was planned as an incidence study of cervical carci- noma and related epithelial abnormalities as they develop in matched popula- tions that are initially found to be free of the disease and are using the dia- phragm, an intrauterine device, or oral steroids. The study of incidence rates will require several more years before it is complete. This report is concerned with an analysis of the prevalence rates. DATA COLLECTION The prevalence rates are for clinically occult cervical carcinomas and, except for a single case, they were all carcinomas in situ or carcinomas in situ with micofocal invasion. They were detected by cytology and confirmed by cervical * This study was supported in part by USPHS Grant 3421 to Planned Parenthood of New York City, and National Cancer Institute Grant CA 08748 to Sloan-Kettering Insti- tute. t Department of Pathology and the Cytology Service, Memorial Hospital for Cancer and Allied Diseases, and the Division of Pathology. Sloan-Kettering Institute. ~ Biomathematics Division, Graduate School of Medical Sciences. Cornell University and Sloan-Kettering Institute, and IBM Thomas J. Watson Research Center. § Planned Parenthood of New York City, Inc. Requests for reprints should be sent to Dr. Melamed, Memorial Hospital, 444 East 68th Street, New York, N.Y. 10021. PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7065 biopsy or conization. Overt carcinoma of the uterine cervix was not found in this population, probably because of three factors: (1) this is a generally young population who would not be expected to have advanced disease, (2) the virtual absence of women with advanced cervical carcinoma probably reflects the effect of cancer screening programmes on the general population attending many different health facilities in New York City, and (3) it is probable that women with symptoms seek medical attention at hospitals or physicians' offices and do not think of Planned Parenthood centres as a treatment facility. Routine annual examinations of cervical and vaginal cytology specimens were begun on all women at the onset of this study in October 1965, and the initial cytological screening was completed by July 1967. Previous to that cyto- logical screening at Planned Parenthood centres had been performed routinely only for those women who wished to wear an intrauterine device. For this reason the analysis of prevalence rate data could not include the latter group. Only those women using the diaphragm and those using oral steroids for con- traception were compared. Collection of cytology specimens The cytology specimens were obtained with cotton-tipped applicators, one from the cervix and endocervix and another from the vaginal pool; each was smeared on a separate glass slide and both slides were fixed immediately in 95% ethyl alcohol. The slides were taken by messenger to the Memorial Hospi- tal, where they were stained, screened, and evaluated under the direction of two of us (M.R.M. and L.G.K.). Reports of the examination were mailed back to the centre. Collection of clinical data Clinical data necessary for this study, including a detailed record of the con- traceptive method(s) used, were taken from each woman's chart at the Planned Parenthood centre when the cytology specimen was collected. In the case of new patients this information was contained in answers to specific questions on an initial history form that was filled in by trained interviewers who see each new applicant. This form also contains the examining physician's notes and prescription or recommendation, and a carbon copy accompanies the cytology specimen. In the case of women who had been attending the centre before the start of the study an abstract was prepared from their chart and from a special sup- plemental question form filled in by the interviewer when the first cytology specimen was taken. For all of the women subsequent cytology specimens were always accompanied by a carbon copy of the interval notes that had been recorded in the chart. Questions were included concerning five factors that were chosen as the most reliable and most important of those known to influence the prevalence rate of cervical carcinoma: age, ethnic origin, age at first pregnancy (as a reflection of early sexual experience), number of children born alive (as a reflection of the number of pregnancies), and net weekly family income (as a reflection of socio-economic status) (Lombard and Potter, 1950; Wynder et al., 1954; Jones et al., 1958; Haenszel and Hillhouse, 1959; Terris and Oalmann, 1960; Rotkin, 1962; Rotkin and King, 1962; Boyd and Doll, 1964; Christopher- son and Parker, 1965). It was felt that answers to direct questions about sexual experience, particularly age at first coitus, frequency of coitus, and number of different sexual partners would not be reliable, and that in this population the number of marital partners for each woman could not be esti- mated by the number of legal divorces and marriages. In order not to discour- age unmarried women from attending Planned Parenthood centres, a direct question about marital status was not included. Indirectly this was obtained during the course of the interview by requesting the husband's first name. Twenty per cent of the women coming to the centres failed to supply the hus- band's first name and these at least were thought to be unmarried. This was considered as a possible sixth factor, but most of these women were young and, after correcting for age, there was no association between choice of con- traceptive or the prevalence of cervical carcinoma in situ and failure to supply a husband's first name. Information regarding circumcision status of their marital partners, avail- able only in interviews with the women, was considered to be too unreliable to be used. PAGENO="0236" 7066 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY At the initial interview the various forms of contraception were described to the applicant, who then made the choice of method. Unless there was medical contraindication, the chosen method was prescribed. The oral steroids pre- scribed at all centres were of the combination type and in the manufacturer's recommended dosage. A deliberate effort was made to fairly represent all of the commercially available products among those prescribed. Detailed records of the contraceptives prescribed and used are maintained as a continuing part of the chart for each woman at the centre she attends. Our tabulation of contraceptive use in each case was taken from these records; thus the data always reflect known minimum periods of time during which the contraceptives were used. For this study we were unwilling to accept infor- mation about contraceptive use previous to attendance at one of the centres of Planned Parenthood, and so disregarded it. Thus the new patient was always coded as a contraceptive user of zero time length, according to the method she chose, even though this might be a continuation of the same method she said she had been using before coming to the Planned Parenthood centre. Recording of data Each day the clinical data collected were transferred to IBM key-punch cards. After cytological examinations were complete the diagnoses were added. The data were then transferred from cards to a 1316 disc file on the IBM 360/40 computer at the Computation Center of Cornell University Medical Col- lege and Sloan-Kettering Institute. The individual cytological reports were printed on prepared forms by the computer at rates of up to 600 lines per minute, thus making it easily possible to return a separate report for each woman. FOLLOW-UP OF CYTOLOGICAL ABNORMALII'1E5 When cytological evidence or suspicion of carcinoma was found cervical biopsies were recommended. The woman was recalled and re-examined by one of the several gynaecologists working with Planned Parenthood and specifically concerned with this study. Another cytological specimen was obtained, followed by Schiller's iodine test. Biopsy specimens of any suspicious or non-staining areas were taken or, if the cervix appeared normal, specimens were taken of several different representative sites. All biopsy specimens were processed in the department of pathology of Memorial Hospital, and the histological diag- noses were those of two of us (M.R.M. and L.G.K.). Treatment.-Women who required further treatment were referred to a phy- sician of their choice or to one of the hospitals of the City of New York. For those who wished it, hospital care has also been made available in the gynae- cological ward service at Lenox Hill Hospital.1 Surgical procedures carried out at this latter hospital have been under the direct supervision of one of us (H.D.), and a report on the surgical techniques, complications, and results in over 200 cases is now in preparation. All pathological specimens from surgery performed on the women at Lenox Hill Hospital were examined by two of us (M.R.M. and L.G.K.), and pathological material from surgery performed else- where has been obtained for our review. Final histological diagnoses and the type of surgery performed were recorded on punched cards and added to the patient's data file on the disc. CRITERIA F~R SELECTION OF DETERMINANT CASE5 In order to achieve prevalence rates as nearly accurate as possible the fol- lowing criteria were established. Total population All women who had been examined at least once in one of the centers of Planned Parenthood and had had a technically satisfactory cytological speci- men taken and submitted for our examination, with complete clinical data, were included in the study. Fewer than 25 cases from over 40,000 originally entered were excluded because of incomplete information; 450 were excluded because the initial cytological specimen was unsatisfactory and the women failed to return. Of the remaining 39,954 women, 27,508 selected oral steroids for contracep- tion and 6,809 selected the diaphragm. This analysis is concerned with the 1 We are indebted to Dr. Hugh Barber, Director of Obstetrics and Gynaecology at Lenox Hill Hospital, for his support. PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7067 34,317 women in these two groups. For reasons explained above, the intrauter- ine device users could not be included in this prevalence study but will be con- sidered in subsequent incidence studies. There were too few women choosing other methods (condom, foam, etc.) to warrant their inclusion (Dubrow et a!., 1969). Cases with carcinoma or carcinoma in situ For determination of prevalence rates it was important to identify those patients who could be reasonably assumed to have had carcinoma or carci- noma in situ of the cervix at the time they entered the study. We required that they have (a) cytological evidence of carcinoma, or suspicion of it, on ini- tial examination or on repeat examinations carried out within eight months; or (b) that in those patients with a significant but non-diagnostic abnormality on initial cytological examination there be definite evidence of the disease on the first repeat cytological specimen. Cytological specimens reported as unsatisfactory for evaluation were counted as no specimen, and the first satisfactory specimen was regarded as the initial specimen. The arbitrary eight-month period was selected to include all patients who had repeat cytological examinations for any reason before their routine annual smear. By selecting cases in this manner we were confident that the patients with lesions actually present at the time of first examination, but inadequately represented in the first cytological sample, were included. Those patients who had cytological evidence of the disease when they entered the study, as defined above, and then had histological diagnoses con- firmed by us of carcinoma in situ, carcinoma in situ with microfocal invasion, or invasive carcinoma (one case only) were accepted for determination of prevalence rates. There were some patients with abnormal cytological findings who failed to return or refused biopsy examination. As is shown below, the loss from such cases was random, and did not affect statistical evaluation. Cases of carcinoma in situ that have subsequently appeared in patients with- out initial cytological evidence of the disease, as defined above, are not consid- ered in this report. Cases with lesser degrees of epithelial abnormality are also not included, but are being followed, and will be the subject of subsequent communications. Our criteria for the cytological diagnoses and for the histological diagnoses of carcinoma, carcinoma in situ, and related lesions, based on a long prospec- tive study of this disease, have been described in detail and amply illustrated in previous publications (Koss et a!., 1963; Koss, 1968). We are aware that some of the lesions we diagnose as carcinoma in situ may be named "precan- cerous metaplasia," "anaplasia," "dysplasia," "atypical hyperplasia," - "siguifi- cant epithelial abnormality," "cervical intraepithelial neoplasia," and a variety of other terms by some other pathologists. Any of these lesions may be precur- sors of invasive cervical carcinoma, and though there is controversy about which particular patient with which particular lesion will develop invasive cervical carcinoma, and when-something we cannot predict-there is evidence that invasive carcinoma can be prevented if all women with these precursor lesions are treated (Marshall, 1965). All cytological and histological examinations were performed without refer- ral to clinical data collected for statistical evaluation and without knowledge of the contraceptive used or contemplated. METHODS OF DATA ANALYSIS The initial data analysis compares prevalence rates of carcinoma in situ (including carcinoma in situ with microfocal invasion and the one case of clin- ically occult invasive carcinoma) in all of the women choosing and using dia- phragms with those choosing and using oral steroids, according to docu- mented minimum duration of use. Then, for women using these contraceptive methods for at least one year, prevalence rates are compared according to each of the five factors that were selected because of their known influence on the rate of the disease. As pre- viously noted, these are age, ethnic origin, age at first pregnancy, number of children born alive, and net family income. Finally, in order to eliminate bias which might be introduced by the known association between these five factors and the method of contraceptive chosen (Dubrow et a!., 1969), three separate random matching programmes have been PAGENO="0238" 7068 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY carried out. Each compares groups of women who have been using their con- traceptive method at least one year, and who are matched in regard to all five factors listed above. In order to carry out these last matching programmes, each woman was provided with a five-digit vector that represented her classification according to each of the five factors. Age at the time of the first cytological examination was indicated by the first digit and divided into five groupings: 20 years or less, 21 to 25 years, 26 to 30 years, 31 to 35 years, and 36 years or older. The second digit indicated which of four ethnic groupings was applicable: White, Negro, Puerto Rican (or Spanish-speaking), or other (mostly Oriental or Indian, and accounting for only about 1.5% of the population). Relatively few Jewish women attended centres of Planned Parenthood, and they have not been separately identified. The third digit referred to age at first pregnancy and included three categories: never pregnant, first pregnant at age 19 or ear- lier, and first pregnant at age 20 or later. The fourth digit referred to number. of live births an~I comprised two categories: zero to two, and three or more. The fifth digit referred to net weekly family income and consisted of two cate- gories: less than $75/week, and $75/week or more. About half the population attending Planned Parenthood centres report a net weekly family income of less than $75. Every woman who had been using a diaphragm or contraceptive steroids for at least one year was identified by her five-digit vector (200 such vectors being possible, rather than 240, since women who were never pregnant would necessarily fall into the zero to two category for number of live births). A random computer search was then made for one, two, or three steroid users with identical vectors to each of the diaphragm users, without regard to the cytological o~r pathological reports on these women. The reason for using three different match ratios is discussed later. This process produced a large number of pairs, triplets, or quadruplets, a small percentage of which were positive- that is, contained cases of carcinoma or carcinoma in situ. If it is assumed that the prevalence oi~ the disease had no association with method of contra- ception, then the positive members of these positive pairs, triplets, or quadru- plets would be roughly one-half, one-third, or one-fourth diaphragm users. Deviations from these ratios may be used to test for a significant association between method of contraception and the prevalence of carcinoma and carci- noma in situ. RESULTS Of the nearly 40,000 women who have been seen in the 11 centres of Planned Parenthood since this study began (Dubrow et a!., 1969), 27,508 chose to use oral steroids for contraception and 6,809 chose the diaphragm. During the first year after their initial visit there was a relatively large drop-out rate. but continued attendance thereafter was fairly good. Within the population choosing either the diaphragm or steroids were one case of clinically occult invasive epidermoid carcinoma (stage 1A), 14 cases of carcinoma in situ with microfocal invasion, and 192 cases of carcinoma in situ. The raw data for all women choosing either the diaphragm or steroids are compared in Table I, according to the known minimal length of time each method was used. TABLE I-UNCORRECTED PREVALENCE RATES OF CERVICAL CARCINOMA IN SITU FOR ALL WOMEN USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS, ACCORDING TO KNOWN MINIMAL PERIODS OF USE Know n minimal eriodof co ntraceptive . use (years) 0+~ 1+ 2+ 3+ 4+ 5+ Diaphragm: No. of cases Ca. in situ 26 16 16 13 12 11 Total No. of cases 6, 809 3, 874 3, 519 3, 178 2, 830 2, 533 Raw prevalence rates per 1,000 3.8 4.1 4.5 4.0 4.2 .4.3 Oral steroids: No. of cases Ca. in situ 181 62 36 18 5 2 Total No. of cases 27, 508 6, 331 3, 814 1, 931 596 147 Raw prevalence rates per 1,000 6.6 9.8 9.4 9.3 8.4 f 14 *Total, including women who had just chosen this contraceptive method at their first visit. The number of women in each column using either contraceptive for a given minimal period of time is cumulative in that it includes all women in subsequent columns known to have longer minimal periods of use. tit is necessary to point out that this figure is based on only two cases with carcinoma in situ. PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 7069 The higher prevalence rates of carcinoma in situ 2 among steroid users is not explained by a difference in age between them and the women using dia- phragms; in fact, the women using steroids are generally younger than those using the diaphragm (Dubrow et al., 1969). Age-specific prevalence rates are given in Table II, and compared for the populations of women who are known to have been using their respective contraceptives for a minimum of at least one year previCus to the initial cytological examination. Similar comparisons can be drawn between the women using diaphragms and those who use oral steroids, according to ethnic origin (Table III), age at first pregnancy (Table IV), number of children (Tables IV and V), and net family income (Table VI). In all, there is consistently a higher prevalence rate of carcinoma in situ among the women who chose and used oral steroids for contraception com- pared with those who chose and used the diaphragm. 2 Hereafter, the term "carcinoma in situ" is used in the text and tables in a techni- cally inaccurate sense, for the sake of convenience, to include the few cases of carci- noma in situ with microfocal invasion and the one case of clinically occult invasive car- cinoma. TABLE lI.-PREVALENCE RATES FOR CERVICAL CARCINOMA IN SITU COMPARED ACCORDING TO AGE IN WOMEN KNOWN TO BE USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS FOR ONE YEAR OR LONGER Age (years) «=20 21-25 26-30 31-35 36-1- Total Diaphragm: No. of cases Ca. in situ 0 Total No. of cases 29 Prevalence rates per 1,000 2 341 5.9 2 653 3.1 4.0 6 787 7.6 6 2,064 2.9 16 3.874 4.1 Oral steroids: No. of cases Ca. in situ 0 Total No. of cases. 183 Prevalence rates per 1,000 13 1,914 6.8 21 2,227 9.4 24 1,301 18 4 706 5.7 62 6,331 9.8 TABLE 111.-PREVALENCE RATES FOR CERVICAL CARCINOMA IN SITU COMPARED ACCORDING TO ETHNIC ORIGIN IN WOMEN KNOWN TO BE USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS FOR ONEYEAROR LONGER Ethnic origin - Puerto Rican! White Negro Spanish Diaphragm: No. of cases Ca. in situ 1 12 3 Total No. of cases Prevalence rates per 1,000 Oral steroids: 1.305 0.9 2,053 5.8 487 6.2 No. of cases Ca. in situ 4 46 12 Total No. of cases Prevalence rates per 1,000 724 5.5 3, 884 12 1.666 7.2 PAGENO="0240" 7070 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE IV.-PREVALENCE RATES FOR CERVICAL CARCINOMA IN SITU COMPARED ACCORDING TO AGE AT FIRST PREGNANCY AND NUMBER OF LIVE BIRTHS IN WOMEN KNOWN TO BE USING THE DIAPHRAGM OR CONTRA- CEPTIVE ORAL STEROIDS FOR ONE YEAR OR LONGER Age at first pregnancy Never pregnant <19 years 20 years+ Diaphragm: Number of cases Ca. in situ 0 7 9 Total number of cases 208 1, 106 2, 560 Prevalence rates per 1,000 6.3 3.5 Number of live births 0-2 3+ 0-2 .3+ Number of cases Ca. in situ 3 4 3 6 Total number of cases 357 749 1, 365 1, 195 Prevalence rates per 1,000 8.4 5.3 2.2 5.0 Age at first pregnancy <19 years 20 years+ Oral steroids: Number of cases Ca. in situ 1 29 . 32 Total number of cases 414 2,991 2,926 Prevalence rates per 1,000 2.4 97 11 Number of live births 0-2 3+ 0-2 3+ Number of cases Ca. in situ 6 23 16 16 Total number of cases 1,033 1,958 1,595 1,331 Prevalence rates per 1,000 5.8 12.0 10.0 12.0 TABLE V.-PREVALENCE RATES FOR CERVICAL CARCINOMA IN SITU COMPARED ACCORDING TO NUMBER OF LIVE BIRTHS IN WOMEN KNOWN TO BE USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS FOR ONE YEAR OR LONGER Number of live births 0-2 3+ Diaphragm: Number of cases Ca. in situ 6 10 Total number of cases Prevalence rates per 1,000 Oral steroids: 1,722 3.5 1,944 5.1 Number of cases Ca. in situ 22 39 Total number of cases Prevalence rates per 1,000 2, 628 8.4 3, 289 12.0 TABLE VI.-PREVALENCE RATES FOR CERVICAL CARCINOMAS IN SITU COMPARED ACCORDING TO ECONOMIC STATUS IN WOMEN KNOWN TO BE USING THE DIAPHRAGM OR CONTRACEPTIVE ORAL STEROIDS FOR ONE YEAR OR LONGER Family net income <$75/week >$75/week Diaphragm: Number of cases Ca. in situ 11 5 Total number of cases Prevalence rates per 1,000 Oral steroids: 1, 441 7.6 2, 433 2.1 Number of cases Ca. in situ 34 28 Total number of cases Prevalence rates per 1,000 3, 310 10 3, 021 9.3 PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7071 TABLE VII.-RESULT OF SIMULTANEOUS MULTIFACTORt RANDOM MATCHING OF WOMEN USING THE DIAPHRAGM AND WOMEN USING CONTRACEPTIVE ORAL STEROIDS LONGER THAN 1 YEAR Match ratio diaphragm! Steroid user Number of women successfully matched Number of pairs Number of pox. pairst Diaphragm pus. pairs/Steroid pos. pairs~ Critical values for Expected Observed 5% significance level 1:1 1:2 1:3 4,702 5,493 5,884 2,351 35 17:18 or 18:17 12:23 12:23, 23:12 Number of triplets Number of pos. tripletst Diaph. pox. triplets/Steroid pox. triplets~ Critical values for Expected Observed 5% significance level 1,831 52 17:35or18:34 9:43 11:41,24:28 Numberof quads Numberof quadst Diaphragm pos. quads/Steroid pos. quads~ Critical values for Expected Observed 5% significance level 1,471 58 14:44or15:43 8:50 9:49,21:37 * Age, ethnic group, age at first pregnancy, number of live births, and economic status were all matched simultaneously. Positive pairs, triplets, or quadruplets refers to a matched group of women that includes one with carcinoma in situ. In two separate instances, two women with carcinoma in situ fell into one quadruplet; in both cases the two women were steroid users and each quadruplet was counted as one. Diaphragm positive pairs, triplets, or quadruplets refers to matched groups in which the patient with carcinoma in situ was using a diaphragm; steroid positive pairs, triplets or quadruplets refers to matched groups in which the patient with carcinoma in situ used steroids. It is obviously desirable to correct simultaneously for as many of the known factors influencing the prevalence of this disease as is possible, particularly because these factors are themselves interrelated in varying ways. This was done by the method of vector assignments to each patient, as already described, randomly matching individual patients with identical vectors by computer. As in the previous tables, the women who are matched have all been using their respective contraceptive methods for a minimum of one year. Again, it must be emphasized that the prevalence rates of carcinoma in situ are determined by the number of women with the disease who had cytological evidence of it on entering the study, and subsequent histological confirmation by cervical biopsy or conization. The results of these matched comparisons are indicated in Table VII, for ratios of diaphragm users to steroid users of 1:1, 1:2, and 1:3. The three different ratios were investigated because the number of women from each group that can be matched varies according to the ratio. The over- all number of women using steroids longer than one year is nearly twice the number using a diaphragm for a similar minimum period, hence the 1:2 ratio seems most reasonable. The diaphragm users, however, tend to be older than the women using steroids (Dubrow et al., 1969), and many of the older women using diaphragms and younger women using steroids cannot be matched at a 1:2 ratio. Matching at the additional ratio of 1:1 included more of the older women using diaphragms; and matching at a ratio of 1:3 included more of the younger women using steroids (Table VIII). At all ratios a consistently higher prevalence rate for cervical carcinoma in situ was found among the steroid users (Table VII). TABLE VIII.-VARIATION IN AGE OF MATCHED POPULATIONS OF DIAPHRAGM USERS AND STEROID USERS ACCORDING TO THE MATCH RATIO (SEE TABLE VII) Match ratio diaphragm/steroid user Number of wom en in each age group successfu Ily matched Age (years) <20 21-25 26-30 31-35 36+ Total 1:1 1:2 1:3 48 63 64 682 1,008 1,280 1,270 11,358 11,779 1,632 `2,068 1,608 1,344 1,011 864 4,702 5,493 5,884 I Median age. 40-471 0-70-pt. 17-16 PAGENO="0242" 7072 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We also examined the matched populations to determine whether the differ- ence in prevalence rates could be explained by a systematically greater failure to obtain recommended biopsy specimens from the diaphragm users. The number of cases in each group that should have had biopsy examinations but did not is indicated in Table IX. Biopsy failure were completely random and do not explain the difference in observed prevalence rates between diaphragm users and steroid users. TABLE IX.-COMPARISON OF NUMBER OF WOMEN IN EACH SUCCESSFULLY MATCHED GROUP WHO HAD CYTO- LOGICAL SUSPICION OF CERVICAL CARCINOMA BUT IN WHOM RECOMMENDED BIOPSY SPECIMENS COULD NOT BE OBTAINED Match ratio. Diaphragm user/Steroid user Number of women with biopsy specimens not obtained. Diaphragm user/Steroid user 1:1 5:6 4:7 1:2 2:6 1:3 DISCUSSION AND CONCLUSIONS A study of the prevalence rates of uterine cervical carcinoma in situ among women attending centres of the Planned Parenthood of New York City is reported. There is a small but significant difference between the population choosing and using the diaphragm and the population choosing and using oral steroids for contraception. It can be attributed either to a decreased prevalence rate for women using a diaphragm or to an increased rate for women using oral steroids. The difference is consistently present in subsets corrected for each of five factors known to influence the prevalence rate of cervical carcinoma: age, ethnic origin, age at first pregnancy (as a reflection of early sexual experi- ence), number of live births, and family income (as a reflection of socio-eco- nomic status). When corrections for all five factors are carried out simultane- ously there is still a signiflcantl~ higher prevalence rate for cervical carcinoma in situ within the population choosing and using steroid contraceptives. The reason for the difference in prevalence rates is not clear. One could postulate some still unknown factor (s) in the makeup, behaviour, or habits of a woman that would alter her probability of developing cervical carcinoma and at the same time impel her to choose a particular contraceptive. In several different studies a lower rate of cervical carcinoma was found for women who had used barrier contraceptives (diaphragm or condom), compared with women using no contraceptive (Terris and Oalmann, 1960; Boyd and Doll, 1964; Aitken-Swan and Baird, 1965). Though not confirmed by all investi- gators (Lombard and Potter, 1950; Wynder et al., 1954; Jones et a!., 1958: Rotkin and King, 1962), this finding, if true, could well account for the differ- ences we found. Experimental animal studies can be cited to show that human smegma is carcinogenic in suspectible mice (Pratt-Thomas et a!., 1956), thus providing a rationale for the concept that barrier contraceptives such as the diaphragm and condom are protective. Also, there is an increased rate of cervi- cal carcinoma in prostitutes (Rç5jel, 1958), an incrased frequency of coitus among women who develop cervical carcinoma (Terris and Oalmann, 1960; Boyd and Doll, 1964), an increased probability of carcinoma in women who first experience coitus at an early age (Rotkin, 1962), and virtually no cervical carcinoma in nuns (Gagnon, 1950). On the other hand, the cervicovaginal epithelium is a known target organ for steroids, and it is considerably altered by oestrogens and progestogens (Taylor et at., 1967; Koss, 1968). There is experimental evidence that pro- longed administration of large doses of oestrogens can cause uterine cervical carcinoma in mice (Allen and Gardner, 1941). The constancy of prevalence rates in Table I does not suggest that we are seeing this kind of direct hor- monal effect, but it must be remembered that the data in Table I are not cor- rected for any of the known factors that affect prevalence rates of this dis- ease. Table I must not be interpreted as giving incidence rate information, since it results from initial examinations only (as is true of all data in this PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7073 report), and there is a presumed loss of some cases due to diagnosis and treat- ment elsewhere. The opportunity for loss of this kind increases with increasing time in attendance at the centre previous to the initiation of this study, and would be expected to mask any trend in Table I. A study of the incidence rates of uterine cervical carcinoma in matched pop- ulations of women using various contraceptives is now in progress and should help to clarify some of the questions raised. First, it is essential that the dif- ferences noted in prevalence rates be confirmed by incidence rates before we can be entirely sure that these differences are not artifactitious. Data from the population of women who are wearing an intrauterine device will be particu- larly useful, since there is neither a barrier effect nor a hormonal effect with this particular contraceptive. Clearly, the long-term well-being of many women is involved in these ques- tions, and the health of women attending centres of Planned Parenthood of New York City has been of primary concern to us. During the course of this study every effort has been made to find and treat the women with cervical carcinoma or carcinoma in situ and related epithelial abnormalities while the lesions are still early enough to be cured in 100% of the cases. All women attending centres of Planned Parenthood are assured of prompt and proper treatment, regardless of choice of contraceptive. Preliminary data from centres of Planned Parenthood, unrelated to this report, show a sharp drop in the number of cases of invasive carcinoma of the cervix after establishing the policy of searching out and treating all women with carcinoma in situ. It is our conviction that death and disability from cancer of the cervix in any pop- ulation can be greatly reduced, regardless of the method of contraception used, if a programme of routine yearly cytological examinations is established and all cases of carcinoma in situ are treated. So long as regular visits to a physi- cian are mandatory for women who are using the steroid contraceptives in order to obtain a prescription there is a possibility for them to have better medical care, with less danger from cancer of the cervix, than any other group of women. We wish to acknowledge the programming assistance received from Mrs. M. A. K. Angell and Mrs. Jane Meikle. Mrs. Joyce Washington was responsible for the efficient manner in which this study was carried through at all of the separate centres of Planned Par- enthood of New York City, Inc. We thank Mr. Alfred F. Moran, executive director of Planned Parenthood of New York City, Inc., and Dr. Sherwin A. Kaufman, medical director, for their assistance and support. Dr. ChristOpher Tietze critically reviewed much of the data with us and con- tributed many helpful suggestions. The many centre directors, physicians, nurses, and particularly the dedicated young women who helped collect and record data deserve special commenda- tion for their role in this study, and we regret that they cannot be individu- ally recognized. References Aitken-Swan, J., and Baird, D. (19(35). British Journal of Cancer, 19, 217. Allen, E., and Gardner, W. U. (1941). Cancer Research, 1, 359. Boyd, J. T., and Doll, R (1964). British Journal of Cancer, 18, 419. Christopherson, W. M., and Parker, J. B. (1965). New England Journal of Medicine, 273, 235. Dubrow, H., Melamed, M. R., Flehinger, B., Kelisky, R., and Koss, L. G. (1969). Obstetric and Gynecological ~$urvey. In press. Gagnon, F. (1950). American Journal of Obstetrics and Gynecology, 60, 516. Haenszel, W., and Hillhouse, M. (1959). Journal of the National Cancer Insti- tute, 22, 1157. Jones, E. G., MacDonald, I., and Breslow, L. (1958). American Journal of Obstetrics and Gynecology, 76, 1. Koss, L. G. (1968). Diagnostic Cytology and Its Histopathologic Bases, 2nd ed. Philadelphia, Lippincott. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, B. (1963). Cancer (Philadelphia), 16, 1160. Lombard, H. L., and Potter, E. A. (1950). Cancer (Philadelphia), 3, 960. Marshall, C. B. (1965). Cancer (Philadelphia), 18, 153. PAGENO="0244" 7074 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY Pratt-Thomas, H. R., Hems, H. C., Latham, B., Dennis, B. J., and Mclver, F. A. (1956). Cancer (Philadelphia), 9, 671. Rçbjel, J. (1953). Acta Pathologica et Microbiologica Scandinavica, Suppl. No. 97, p. 66. Rotkin, I. D. (1962). Journal of the American Medical Association, 179, 486. Rotkin, I. D., and King, R. W. (1962). American Journal of Obstetrics and Gynecology, 83, 720. Taylor, H. B., Irey, N. S., and Norris, H. J. (1967). Journal of the American Medical Association, 202, 637. Terris, M., and Oalmann, M. 0. (1960). Journal of the American Medical Asso- ciation, 174, 1847. Wynder, B. L., Cornfield, J., Schroff, P. D., and Doraiswami, K. R. (1954). American Journal of Obstetrics and Gynecology, 68, 1016. [From Science, July 25, 1969, pp. 367-3731 FAMILY PLANNING AND PUBLIC POLICY: WHO Is MISLEADING WHOM? (By Oscar Harkavy, Frederick S. Jaffe, Samuel M. Wishik*) Federal policies on family planning services and population research are cur- rently under review as a result of the report of the President's Committee on Population and Family Planning (1). Judith Blake's article, "Population policy for Americans: Is the government being misled?" (2), which is presumably intended to influence this review, contains numerous errors of fact and inter- pretation which it is important to clarify. To support her position, she knocks down several straw men; ignores the bulk of serious demographic research on U.S. fertility patterns in the last 15 years, as well as research on differential availability of health care and the relative effectiveness of various contracep- tive methods; and cites opinion-poll data in a manner that distorts the overall picture. The article's methodological limitations alone are sufficient to suggest that the question raised in its subtitle may more appropriately be turned around and asked of the article itself. The article is based on six principal propositions. 1) That the reduction of U.S. population growth-indeed, the achievement of "population stability"-is "virtually unchallenged as an official national goal." 2. That, in pursuit of this goal, the "essential recommendation" by official and private groups has been a program of publicly financed family planning services for the poor. 3) That this program of family planning for the poor will not achieve the goal of population stability. 4) That advocates of this policy contend that the poor have been denied access to family planning services because of "the prudery and hypocrisy of the affluent." 5) That the poor desire larger families than higher-income couples do and are significantly less inclined to favor birth control. 6) That the estimate of 5 million poor women as the approximate number in need of subsidized family planning services is exaggerated. With the exception of proposition 3, each of these statements is seriously misleading or in error. Let us examine the evidence on each point. A CONSENSUS ON U.S. POPULATION STABILITY? If the United States had as a national goal the reduction of its population growth and the achievement of population stability-and if the program of publicly funded family planning services for those who cannot afford private medical care had been advanced as the principal or only means of achieving population stability-Judith Blake's contention that the government is being misled would have much validity. However, neither proposition is sustained by the evidence. * Dr. Harkavy is program officer in charge of the Population Office, Ford Foundation, New York; Mr. Jaffe is director of the Center for Family Planning Program Development, New York, and vice president of Planned Parenthood-World Population, New York; Dr. Wishik is director of the Division of Program Development and Evalua- tion, Columbia University International Institute for the Study of Human Reproduction, New York. N0TE.-Numbered references at end of article. PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7075 We have individually and jointly been associated with the evolution of public policy in this field for more than a decade. To our knowledge, there has never been an official policy regarding the virtue or necessity of reducing U.S. population growth, much less achieving population stability. Nor has there emerged among Americans generally a "virtually unchallenged" consensus on what should constitute an official U.S. population policy. The clearest statement of official U.S. domestic policy is contained in Presi- dent Johnson's 1066 Health Message to Congress (3) "We have a growing concern to foster the integrity of the family and the opportunity for each child. It is essential that all families have access to in- formation and services that will allow freedom to choose the number and spacing of their children within the dictates of individual conscience." Neither in this or in any other statement did the President cite stabilization of U.S. growth as the objective of federal policy. Nor has such a goal been articulated by Congress or the federal agencies. In 1066, Secretary Gardner of the Department of Health, Education, and Welfare (HEW) stated (4) that the objectives of department policy are "to improve the health of the people, to strengthen the integrity of the family and to provide families the freedom of choice to determine the spacing of their children and the size of their fami- lies." In 1968 he reiterated (5) that "the immediate objective is to extend family planning services to all those desiring such services who would not oth- erwise have access to them." It is clear that the federal program has been advanced, not for population control, but to improve health and reduce the impact of poverty and depriva- tion. GOALS OF FEDERAL FAMILY PLANNING POLICY Given this unambiguous framework for federal policy, it is inexplicable how Blake could arrive at the statement that population limitation has become our national goal and that the "essential recommendation" for reaching this goal has been to extend family planning services to the poor. She attributes this "misleading" recommendation to a 1965 report by the National Academy of Sciences (6), a 1967 consultants' review of HEW programs written by us (7), and the report of the President's Committee (1), despite the fact that each of these reports clearly distinguishes a family planning program for the poor from an overall U.S. population control program or policy. For example, the National Academy of Sciences report- stated explicitly (6, p. 6) that U.S. popu- lation growth "is caused more by the preference for larger families among those who consciously choose the number of children they have than by high fertility in the impoverished segments of the population. The importance of high fertility among the underprivileged lies not so much in its contribution to the national birth rate as in the difficulties that excessive fertility imposes on the impoverished themselves." The 1967 HEW review sought to determine how well the department's stated policy was being implemented. It found the department's efforts lagging and recommended higher priority in staff and budget for family planning services and population research programs. It also distinguished this effort from an overall U.S. population policy and progam (7, pp. 23-24) "While study should be given to the present and future implications of the growth of the Nation's population as a whole-perhaps through a series of university studies sponsored by a Presidential commission-the Federal govern- ment should at present focus its family planning assistance on the disadvan- taged segments of the population. The great majority of non-poor American couples have access to competent medical guidance in family planning and are able to control their fertility with remarkable effectiveness. The poor lack such access and have more children than they want. It should be the goal of Fed- eral policy to provide the poor with the same opportunity to plan their fami- lies that most other Americans have long enjoyed. Public financing of family planning for the disadvantaged is clearly justified for health reasons alone, particularly for its potential influence in reducing current rates of maternal and infant mortality and morbidity. Additionally, there are excellent humani- tarian and economic justifications for a major directed program to serve the poor." The President's Committee did not concentrate on family planning alone but made numerous recommendations for short- and long-term programs of domes- PAGENO="0246" 7076 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY tic and international services, research, and education. Its recommendation on domestic family planning services again was justified, not in terms of popula- tion control, but as a health and social measure (1, pp. 15-16) "Excessive fertility can drive a family into poverty as well as reduce its chances of escaping it. rfhe frequency of maternal deaths, the level of infant mortality, and the number of children who are chronically handicapped are all markedly greater among the poor than in the rest of the population. One of the most effective measures that could be taken to lower mortality and mor- bidity rates among mothers and children would be to help the poor to have the number of children they desire." As for immediate programs to further reduce the incidence of unwanted pregnancy among the rest of the population, the committee recommended (1, p. 15) expansion of biomedical research for improved contraceptive techniques and expansion of social research; increased education in population dynamics, sex, and human reproduction, and improved training programs for physicians and other relevant professionals. It stated explicitly (1, p. 37) that these rec- ommended programs "are only one of the important factors that influence pop- ulation trends," and called for a Presidential Commission on Population to, among other things, "assess the social and economic consequences of popula- tion trends in the U.S. . . . [andj consider the consequences of alternative pop- ulation policies" (1, pp. 37-38). These reports only reiterate what has been the basic justification for pub- licly funded family planning services for the poor for more than a decade. The leaders of the U.S family planning movement have not advanced this program as a means of achieving population stability, because it has been evident that the poor and near-poor, who constitute only about one-quarter of the U.S. pop- ulation, are not the major contributors to U.S. population growth, despite their higher fertility. Blake believes the U.S. policy should aim toward a zero rate of population growth, as is her right. But she has rio right to accuse family planners of mis- leading the public into believing that extension of family planning to the poor would bring about such population stability-a claim they have never made. Of course, any reduction in births, wanted or unwanted, will result in less nat- ural increase and, other things being equal, less population growth. Elimina- tion or reduction of unwanted pregnancies among the poor and near-poor would thus reduce somewhat the rate of population growth, though not elimi- nate it entirely (8). PRUDERY-OR POLITICS? Another straw man erected by Blake is the assertion that denial of birth cdntrol services to the poor has been attributed by advocates of family plan- ning to the "prudery and hypocrisy of the affluent, who have overtly tabooed discussion of birth control and dissemination of birth control materials." As proof that this has not been the case, she cites opinion polls going back to 1937 showing majority support for making birth control information available to those who desire it. The proof is irrelevant in two major respects. First, the issue is not infor- mation about birth control, but availability of services (a distinction which Blake obscures throughout her article). And second, the operative factor in regard to the poor has not been generalized approval or disapproval, but the policies in regard to provision of contraceptive services of public health and welfare institutions on which the poor depend for medical care. As she notes, it was evident as long ago as the 1930's that most Americans approved of birth control and practiced it in some form (although it was not until the late 1950's that the mass media began to carry relatively explicit birth control material). But this public-opinion base did not control the policies of public institutions or the attitudes of political leaders. In most tax-supported hospi- tals and health departments there were explicit or implicit prohibitions on the prescription of contraceptive methods and materials, and many states had leg- islative restrictions which were enforced primarily in public agencies. To change these policies required protracted campaigns, which began in the New York. municipal hospitals in 1958 (9), continued in Illinois, 1~iaryland, Pennsyl- vania, and other states in the early 1960's, and culminated in legislative actions in 1965 and 1966 in at least 15 states and congressional action in 1967 in the Social Security and Poverty legislation. PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7077 The family planning movement has not ascribed the denial of birth control services to the poor to a generalized "taboo" but, rather, has ascribed it to concrete prohibitions on provision of services which stemmed from fear on the part of political leaders of the presumed contoversial nature of the subject. The fears were perhaps exaggerated, but nevertheless real. The result was that very few poor women received contraceptive guidance and prescription in tax-supported agencies at times in their lives when it would have been of most importance to them-at the premarital examination and after the birth of a child, for example. It was not until the years 1964 to 1966 that several hundred public hospitals and health departments began providing family plan- ning services, and it was not until 1967 that as much as $10 million in federal funds became available to finance identifiable family planning programs. FAMILY SIZE DESIRED BY THE POOR Judith Blake contends that her data show that the poor desire larger fami- lies than the non-poor. She bases her assertion on responses to opinion polls and ignores the three major national studies conducted since 1955, covering larger and properly structured random samples of the U.S. population, which have probed these issues in depth. Even when the poll responses are accepted at face value, it is of interest to note that the "larger" family said to be desired by those in the lowest economic status group was larger by as much as 0.4 of a child in only 2 of the 12 years cited (10). Also of interest is the fact that Blake treats responses to questions on ideal family size as evidence of the number of children the poor want. At various points in the text she refers to the data she cites as demonstrating "desired or ideal" number of children or "preferred family size," or states that the poor "say they want larger families" (emphasis added). The dubiousness of this methodology is revealed by the very different treatment of responses on ideal and wanted family size in the 1955 and 1960 Growth of American Families Studies (11, 12) and in the 1965 National Fertility Study (13, 14-16). In the 1955 study, Freedman and his co-workers stated that the question on ideal family size "was not designed to discover the wife's personal ideal but sought a picture of her more stereotyped impressions on what family size should be" (11, p. 221). "The more realistic question about desired . . . family size," they concluded, "is that regarding the number of children wanted at the time of the interview" (11, p. 224). They found that the stereotyped "ideal" generally was higher than the number wanted. In the 1960 study, Whelpton and his colleagues came to the same conclusion (12, p. 37). In the 1965 study, Ryder and Westoff expressed "profound reservations" about the usefulness of the "ideal" question and found that it "lacks face validity . . . is relatively unreliable and has a small variance" (13). The poll responses cited by Blake appear to show that ideal family size varies inversely, among non-Catholic white women, with education and eco- nomic status. Responses to detailed surveys on wanted family size, however, either show insignificant differences between lower- and higher-status non- Catholic white respondents or reverse the direction. The data for 1960 show no difference in the number of chilren wanted by highest-status and lowest-status non-Catholic whites, and the data for 1965 show a very small increase in the number wanted by the group with only grade school education. (The pattern for Catholics was, of course, different.) Other measures of socioeconomic status show either no difference in the number of chilren wanted or, in the case of the measure of income, a smaller number for those w-ith income below $3000 than for those with income above $10,000 (Table 1). Judith Blake also uses opinion-poll responses, rather than the results of in- depth studies, to measure approval of birth control in the different socio-eco- nomic groups. The result is, again, an overstatement of the differences between the highest and lowest social groups. In Table 2 are given excerpts from find- ings for 1960 and 1965 on approval of the practice of fertility control (including the rhythm method). The only deviation from the near-universal approval of fertility control is in the group with only grade school education, which is rapidly becoming a smaller proportion of all U.S. women and is hardly coterminous w-ith the poor and near-poor. [Among all poor and near- poor women aged 18 to 44 in 1966, only 26.1 percent had grade school educa- tion or less ; ~31.9 percent had completed from 1 to 3 years of high school, and PAGENO="0248" 7078 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 42.1 percent had been graduated from high school; some of the latter had attended college (17).] Even in the grade-school group, however, more than four-fifths of white women approved of birth control in both 1960 and 1965-a proportion bettered by nonwhite grade-school women in 1965-and all other groups were nearly unanimous in their approval. It is extremely difficult, in the face of these data, to conjure up the notion of great hostility to fertility control among the poor and near-poor (17a, 18). TABLE 1.-NUMBER OF CHILDREN WANTED, BY EDUCATION, COLOR OR RACE, INCOME, AND OCCUPATIONAL STATUS OF RESPONDENTS, AS SHOWN BY STUDIES MADE IN 1960 AND 1965 Education, income, and occupational status 1960 White* Non- whitet 1965~ Total White Non- Catholic Catholic Negro Total Protes- tant Catholic Education: College High school (4 yr) High school (1-3 yr) Grade school High school (1-3 yr) or grade school Husband's income~: >$10,000 $7,000-9,000 $6,000-6,999 $5,000-5,999 $4,000-4,999 $3,000-3,999 <$3,000 Occupation II: Upper white-collar Lower white-collar Upper blue-collar Lower blue-collar Farm Other Total 3. 3 3. 2 3. 3 3.5 3. 3 3. 2 3. 3 3. 3 3. 4 3. 4 3. 2 3. 3 3. 3 3. 3 3. 3 3.5 3.0 3.3 3. 1 3. 0 3.2 3.1 3.1 4. 8 3. 9 3. 6 4.3 4.0 2. 4 2. 7 2. 7 3.5 ~ 2.9 3. 22 3. 21 3. 46 3.29 3. 03 3. 01 3. 30 3.11 3. 86 3. 65 3. 83 3.74 2. 70 2. 89 3. 48 3.21 * From 12, Table 54. t From 12, Table 189. From 13, Table 4. § Unpublished data from the 1960 "Growth of American Families Studies," made available by A. A. Campbell. From 12, Table 71. TABLE 2.-PERCENTAGES (BY EDUCATION AND COLOR OF RESPONDENTS) OF WOMEN WHO FAVORED FERTILITY CONTROL, AS SHOWN BY STUDIES MADE IN 1960 AND 1965.* White Nonwhite Education 1960* 1965t 1960f 1965t College 97 97 97 94 High school (4 yr.) ~ 97 90 94 High school (1-3 yr.) 93 94 78 90 Grade school 82 82 67 84 * Data from 12, Table 102. t Data from 17a, Table 7. For purposes of policy determination, the most salient questions relate, not to all poor and near-poor persons, but to those who are in their prime child- bearing years-that is, less than 30 years old. Presumably it is this group which would be most affected by public programs and whose attitudes policy makers would consider most significant. Data from the 1965 study, presented in Tables 3 and 4, permit direct comparison, for farm and non-farm women below 30 in four income groups, of the number of children wanted and the proportion of women then using, or expecting to use, some form of contracep- tion. The conclusion is clear: younger wives in the "poor" and "near-poor" cat- egories want as few children as wives in higher income groups-or want fewer PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7079 children than the higher-income wives-and have used or expect to use some form of contraception to a similar degree. Despite the fact that 70 percent of poor and near-poor women regarded as in need of subsidized family planning services are white (19, Blake frequently terms the recommended federal effort a "ghetto-oriented family planning pro- gram." She also described the charge of "genocide" which has been leveled by some black militants as "difficult to refute." However, the desire of black cou- ples for smaller families than are desired by whites-and for smaller families than they are now having-was clearly demonstrated in the 1960 study (12, pp. 41, 38) (see Table 5). TABLE 3.-NUMBER OF CHILDREN WANTED BY WHITE AND NONWHITE WIVES UNDER 30 YEARS OLD, BY INCOME AND FARM RESIDENCE OF RESPONDENTS, AS SHOWN BY A 1965 STUDY' Residence Family income >$8,000 $6,000-7,999 $4,000-6,999 <$4,000 Now living on farm Once lived on farm 3. 97 3. 08 3. 12 3. 13 3. 25 2. 99 3. 21 3. 19 Never lived on farm 3.13 3.21 3.12 3.06 1 Unpublished data fro.m the 1965 National Fertility Study, made available by C. F. Westoff. TABLE 4.-PERCENTAGES (BY INCOME AND FARM RESIDENCE OF RESPONDENTS) OF WHITE AND NONWHITE WIVES UNDER 30 YEARS OLD WHO HAD EVER USED, OR EXPECTED TO USE, ANY FORM OF CONTRACEPTION, AS SHOWN BY A 1965 STUDY 1 Residence Family income >$8,000 $6,000-7,999 $4,000-6,999 <$4,000 Now living on farm Once lived on farm 84 91 100 97 85 95 89 88 Never lived on farm 95 96 93 92 1 Unpublished data from the 1965 National Fertility Study, made available by C. F. Westoff. TABLE 5.-NUMBER OF CHILDREN WANTED BY WHIT E AND NONWHITE WIVES, AS SHOWN BY A 1960 STUDY Couples Number of children wanted Percentages wanting 2 children or less Minimum Maximum Minimum Maximum White Nonwhite 3.1 3.5 2.7 3.0 41 29 55 46 Data from 12, tables 15 and 16. Substantially the same pattern emerges from the 1965 study, as shown in Tables 6 and 7: significantly higher percentages of nonwhites continue to prefer a family of two children or less, and the proportion of nonwhites approving and using, or expecting to use, some method of fertility control is indistinguishable from that of whites, especially in the prime child-bearing ages. EXCESS FERTILITY Serious demographic research has thus documented the disappearance of the traditional socioeconomic and ethnic differentials in fertility aspirations and in attitudes toward fertility control. "Clearly," as Westoff and Ryder have stated, "the norm of fertility control has become universal in contemporary America" (17a, p. 394). Yet within this general pattern the studies also reveal that PAGENO="0250" 7080 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY many couples do not achieve the degree of control they wish. Some have more children than they want and can be classified in the "excess fertility" cate- gory; others fail to have their children when they want them and are described as "timing failures." More than half of U.S. couples reported one or another type of failure in 1965; 21 percent of all respondents acknowledged that at least one of their children was unwanted (15). (This must be regarded as an underestimate, since the questionnaire required that respondents charac- terize specific children already born as either wanted or unwanted.) TABLE 6.-DESIRED FAMILY SIZE, BY RACE AND BY FERTILITY PLANNING STATUS, AS SHOWN BY A 1965 STUDY~ 1 Desired number of children Percentages of respondents who regard their fertility as completed Percentages of respondents who more children desire Total White Negro Total White Negro 0-2 36. 2 35. 4 44. 0 27. 1 25. 7 41. 0 3 23. 6 24. 5 14. 8 28. 8 29. 2 24. 3 4 40. 3 40. 2 41. 2 44. 2 45. 0 34. 1 D ata from 13, table 7. TABLE 7.-PERCENTAGES (BY AGE AND COLOR OF RESPONDENT) OF WOMEN WHO APPROVED OF FERTILITY CONTROL (INCLUDING THE RHYTHM METHOD) AND WERE USING OR EXPECTED TO USE SOME FORM OF CONTRA- CEPTIVE, AS SHOWN BY A 1965 STUDY.' Respondents Percentages b y age group 20-24 years 25-29 years 30-34 years 35-39 years Approved of fertility control: White 95 97 95 ~3 87 Nonwhite 92 93 90 Were using or expected to use contraceptives: White 94 93 88 84 Nonwhite 96 90 84 `Data from 17a, tables 8 and 14. While excess fertility is found among all socioeconomic groups, it is more acute among the poor, among nonwhites (the majority of whom are poor or near-poor), and among those with higher parity and less education. In spite of the similarity in family-size preferences in all socioconomic groups, the poor and near-poor had a fertility rate from 1960 to 1965 of 152.5 births per 1000 women aged 15 to 44, as compared to 98.1 for the non-poor (20). And in spite of the expressed preference of almost all low-income parents for less than four children, nearly half of the children growing up in poverty in 1966 were mem- bers of families with five or more children under 18; moreover, the risk of poverty increased rapidly from 9 percent for one-child families to 42 percent for families with six or more children (21). In terms of poverty, the most sig- nificant demarcation appears to be at the three-child level-the average family size wanted by low-income as well as other American couples: more than one- quarter of all families with four or more children were living in poverty, and four out of ten were poor or near-poor. Their risk of poverty was two-and-a- half times that for families with three children or less (Table 8). The 1965 National Fertility Study provides data on the percentage of unwanted births for each birth order, ranging from 5.7 percent of sixth and higher-order births. Application of these percentages to actual births, by birth order, in the years 1960 to 1965 yields an estimated average of 850,000 unwanted births annually in all socioeconomic groups. Combination of these data with Campbell's calculation of differential fertility rates shows that approximately 40 percent of births to poor and near-poor couples were unwanted by one or both parents in the years 1960 to 1965, as compared to 14 percent of births to non-poor couples (22). [This result appears consistent with the 1960 finding of an inverse relation between education and excess fer- tility, with 32 percent of white, and 43 percent of nonwhite, grade-school-edu- cated wives reporting more children than they wanted (12, p. 364).] PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7081 TABLE 8.-RELATION OF POVERTY TO SIZE OF FAMILY, AS SHOWN BY A 1966 STIJDY.1 All U.S. The poor The poor and near-poor Number of Number of families (in thous- Number of children ands) families (in thous- ands) Percentage of all U.S. families families (in thous- ands) Percentage of all ll.S. families 1 9,081 843 9.3 1,276 14.1 2 8,491 869 10.2 1,323 15.6 3 5,416 694 12.8 1,152 21.3 Total for parity 1-3 22,988 2,406 10.5 3,751 16.3 4 2,923 543 18.6 904 30.9 5 1, 396 387 27. 7 593 42. 5 6or more 1,286 541 42.1 747 58.1 Total for parity 4+ 5, 605 1, 471 26. 2 2, 244 40. 0 1 Data from 21, Table 4. EQUALIZING ACCESS. TO EFFECTIVE METHODS~~ It is precisely the reduction or elimination of this involuntary disparity between the poor and non-poor which has been the objective of publicly sup- ported family planning service programs. Given the essentially similar prefer- ences of the two groups concerning family size, programs which equalize access to modern methods of fertility control should also help to equalize the incidence of unwanted pregnancy for the two groups. Blake can regard this as a "fantastic . . . blanket decision" imposed by the family planners only if she ignores (i) the evidence on the type of birth control methods on which the poor rely, (ii) the evidence on the relative effectiveness of different contracep- tive methods, and (iii) the response of poor persons to organized programs which offer them a complete range of methods. The data on contraceptive practice cited above measure the combined use of all methods, including those methods known to be least effective in preventing conception. The cited studies also show that couples of higher socioeconomic status who can afford private medical care tend to use the more reliable medi- cal methods, while low-income couples depend more on less reliable, nonmedi- cal methods. Among white Protestants in 1960, for example, half as many wives with a grade school education as college graduates used the diaphragm and twice as many relied on withdrawal (12, p. 281). Published and unpub- lished findings for 1965 on methods employed by whites and nonwhites reveal the same picture. Three times as many nonwhites as whites relied on the douche (16) and on suppositories (23, p. 2), and twice as many relied on foam (23). When the condom is classified among effective methods and rhythm is omitted from the analysis because of the different proportions of whites and nonwhites who are Catholic, we find that half of nonwhite users of contracep- tives rely on the least effective methods, as compared to about 30 percent of whites (16). These findings are significant in two respects: (i) the methods on which the poor rely most heavily have considerably higher failure rates and thus would lead to a higher incidence of unwanted fertility; and (ii) the overwhelming majority of poor persons accept the best methods science has been able to develop when they are given the choice. The relative rates of failure with the different methods range from 1 to 3 failures per 100 women-years of exposure for pills and I1IJD's to 35 to 38 fail- ures for rhythm and douche, with the numbers for the condom, the diaphragm, and withdrawal clustering around 15 (24). RESPONSE TO FAMILY PLANNING PROGRAMS It is difficult to understand how the greater reliance of the poor on nonmedi- cal methods can be attributed to their personal preferences in view of the con- siderable research demonstrating that the poor have little access to medical care for preventive services (25). When access to modern family planning services offered with energy and dignity has been provided, the response of PAGENO="0252" 7082 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY poor and near-poor persons has been considerable. The number of low-income patients enrolled in organized family planning services under both public and private auspices has increased from about 175,000 in 1060 to 850,000 in 1068, as hospitals and public health departments have increasingly offered services which provide the new methods not associated with the act of coitus (22). In virtually all known programs offering a variety of methods, 85 to 90 percent of low-income patients voluntarily choose either pills or intrauterine devices (IUD's), the most effective methods currently known. In 1965, a Chicago study found that three-fourths of patients continued to use the pills regularly 30 months after first coming to the clinic an astonish- ingly high retention rate for any procedure requiring continuous self-medica- tion (26). A carefully planned program which introduced the first subsidized services in New Orleans, begun in 1967, has already enrolled nearly two-thirds of the target population, three-fourths of whom had not practiced birth control or had used nonprescription methods before attending the clinic. When given a genuine choice, 82 percent chose either pills, or IUD's, while only 17 percent selected a nonprescription method (27). In the rural Louisiana parish where this program was first tested the birth rate among the indigent decreased by 32 percent in the first year after the clinic was opened, as compared to a decrease of only 6 percent in four surrounding control counties where no orga- nized family planning services were available. The illegitimacy ratio in the county in question dropped from 172 per 1000 live births in 1066 to 121 in 1967, as compared to an increase in the control counties from 162 to 184 (28). FIVE MILLION WOMEN Judith Blake challenges the estimate that there are 5 million poor and near- poor women who comprise the approximate population in need of subsidized family planning services. This estimate has been arrived at independently by Campbell (20) and the Planned Parenthood Federation Research Department (19), on the basis of Census Bureau tabulations of the characteristics of the poor and near-poor (17). Campbell estimated a total of 4.6 million, while Planned Parenthood estimated 5.3 million. The difference stems from the use of slightly different assumptions in analyzing the data available for obtaining a "need" figure which defines all women who are (i) poor or near-poor; (ii) not currently pregnant or wanting to become pregnant; (iii) fecund; and (iv) exposed to risk of pregnancy. The differences in the assumptions and results are not regarded as significant at this point, when fewer than 1 million low-in- come patients are reportedly receiving family planning services. There exists, of course, no data base from which to define precisely women who have the characteristics listed above. Both estimates have been presented as approximations which reasonably interpret available information. It is important to note that 5 million represents a residual number of potential patients at any given time, after subtraction, from the total of about 8 million poor and near-poor women aged 15 to 44, of an estimated number of those who are sterile, those who are pregnant or seeking to become pregnant (allowance being made for the fact that poor couples say they want three children, on the average), and those who are not exposed to the risk of pregnancy (20) (Table 3). The estimate does involve the policy assumption that all others should have available competent medical advice on regulating fertility-even if they choose to practice the rhythm method, or if they are less than normally fecund, or if they have sexual relations infrequently-since such advice will tend to make their family planning practice more effective. Whether or not all 5 million women would avail themselves of the opportunity remains to be seen. Until the poor are offered a genuine choice, there is no way to determine how many would actually prefer nonmedical methods. Nor is there any way to judge whether low-income Catholics will voluntarily choose methods officially proscribed by their Church to a degree equaling or possibly exceeding the 53 percent of all Catholics who reported in 1965 that they have already used methods other than the rhythm method (23, Table 3). It is interesting to note that Judith Blake does not cite the one factor which might be a significant limitation on these estimates-namely, the proportion of low-income women who have been able to secure competent guidance in fertil- ity control from private physicians. There exists no adequate information on PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7083 this question, perhaps because most researchers have been singularly uninter- ested in the processes through which fertility control techniques are diffused. Fragmentary data from several state Medicaid programs suggest that, at most, the proportion of poor and near-poor persons receiving family planning serv- ices from private physicians is no higher than 10 percent of the population in need. In sum, then, the 5-million estimate has been presented as a reasonable approximation, based on the inadequate data that are available, of those who need subsidized family planning services and for whom wise social policy would attempt to develop programs. POPULATION POLICY Judith Blake's article, hopefully, will stimulate responsible and dispassionate study and discussion of population policy in the United States. The scholarly community has thus far given little attention to this question, leaving the dis- cussion largely to polemicists. Her message is loud and clear: Our society should not waste its resources on family planning for the poor but should seek ways to restructure the family, reconsider male and female sexual roles (29), and develop satisfying nonfamilial roles for women, if it is to achieve population stability in the long run. `We regard the first part of this proposition as erroneous and misleading. The second part, however, needs thoughtful examination as to its feasibility and the costs and bene~1ts to society. The development of voluntary family planning in the immediate future is in no way antithetical to such realistic consideration of population policy for the long run. It would be useful if Judith Blake were to develop proposals for specific programs to advance the objective of encouraging women to seek satisfaction in careers outside the home. It would be particularly interesting to see whether those programs do not subsume, as a necessary first step, the exten- sion of effective fertility control measures to all women who want and need them-which we believe is the immediate objective of federal policy on family planning. References and Notes 1. President's Committee on Population and Family Planning, Population and Family Planning-The Transition from Concern to Action (Government Printing Office, Washington, D.C., 1968). 2. J. Blake, Science 164, 522 (1969). 3. L. B. Johnson, Message to Congress on Domestic Health and Education, 1 March 1966. 4. J. IV. Gardner, Statement of Policy of the Department of Health, Educa- tion and Welfare on Family Planning and Population Programs, 24 January 1966. 5. , Memorandum to Heads of Operating Agencies on Family Planning Policy, 31 January 1968. 6. "The Growth of U.S. Population," Nat. Acad. Sci. Nat. Res. Counc. Publ. 1279 (1965). 7. 0. Harkavy, F. S. Jaffe, S. 1~I. Wishik, "Implementing DHEW Policy on Family Planning and Population-A Consultant's Report," Dept. Health Educ. Welfare Publ. (19f~7) (available from the U.S. Department of Health, Educa- tion and Welfare). 8. Calculation of data on unwanted births from the 1965 National Fertility Study yields an estimate of an annual average of about 850,000 unwanted births among all classes in the period 1960-65 [see F. S. Jaffe and A. F. Guttmacher, Demography 5, 910 (1968) J; This figure must be regarded, for methodological reasons, as a minimum estimate of unwanted births. It amounts to about 40 percent of the excess of births over deaths in the 6-year period under study. Prevention of unwanted births among the poor and near-poor could have reduced the overall excess of births over deaths by slightly more than 20 per- cent, while prevention of unwanted births among the non-poor could have reduced it by slightly less than 20 percent. These approximations show the orders of magnitude of what might be expected from the extension of modern family planning to the poor and near-poor and from improved efficiency of fer- tility control for all Americans. They do not, of course, add up to a zero rate PAGENO="0254" 7084 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of growth, but they appear to offer the promise of more immediate progress toward reduced growth rates than any other proposed or currently feasible program of equivalent cost (or, for that matter, any cost). 9. See J. Rock, The Time Has Come (Knopf, New York, 1963), chap. 11; A. F. Guttmacher, Babies by Choice or by Chance (Doubleday, New York, 1959), chap. 8. 10. We are indebted to Dorothy Nortman of the Population Council for this observation. 11. R. Freedman, P. K. Whelpton, A. A. Campbell, Family Planning, Sterility and Population Growth (McGraw-Hill, New York, 1959). 12. P. K. Whelpton, A. A. Campbell, J. E. Patterson, Fertility and Family Planning in the United States (Princeton Univ. Press, Princeton, N.J., 1966). 13. N. B. Ryder and C. F. Westoff, "Relationships among intended, expected, desired and ideal family size: United States, 1965," Population Res. (~`Iarch 1969) (available from the Center for Population Research, National Institute of Child Health and Human Development, Washington, D.C.). Their full state- ment of the limitations of the "ideal" question follows: "We asked the ques- tion to correspond exactly with the wording employed in many previous inquir- ies, despite profound reservations about its usefulness. The question can be interpreted as the respondent's opinion as to what she considers to be ideal for the average American family, or what the average American family considers ideal for themselves. In the second place, the wording prompts the further question, `Ideal for whom?' That might be answered from the standpoint of the respondent, or of the average American family, or even of the total popu- lation-since it must face the consequences of the behavior of the `average American family.' Thirdly, the question calls for a statistical judgment of the characteristics of the average American family, a judgment probably beyond the reach of most respondents and varying in relation to their own character- istics. In the fourth place, there is ambiguity about the scope of the term `ideal': Does it means the ideal parity considering the circumstances as well? Finally, there would seem to be a substantial risk with a question so worded that the respondent thinks she is being asked about the actual average number of children in an American family. In our opinion, the sole justification for including this question in o~ur inquiry is to eceplore statistically the validity of this very common but very dubious question [emphasis added]." 14. Convergence is also demonstrated when actual behavior is examined, rather than attitudes. See C. F. Westoff and N. B. Ryder, in Fertility and Family Planning: A World View, S. J. Behrman, L. Corsa, Jr., H. Freedman, Eds. (Univ. of Michigan Press, Ann Arbor, 1969), Tables 13 and 15. In 1960 and 1965, by any measure of socio-economic status, three-fourths to five-sixths of the lowest income groups had used or expected to use some form of fertility control (including relatively ineffective ones). As would be expected of a prac- tice which has diffused down through the class structure, there is a lower level of practice in the lowest groups (which may also be a function of less availability of services). 15. N. B. Ryder and C. F. Westoff, "Fertility planning status of American women, 1965," paper presented before the Population Association of America, April 1968. 16. Unpublished data from the 1965 National Fertility Study, made available by C. F. Westoff. 17. Special tabulation by the Census Bureau of the characteristics of women living in poverty and near-poverty in March 1966. 17a. C. F. Westoff and N. B. Ryder, in Fertility and Family Planning: A World view, S. J. Behrman, L. Corsa, Jr., H. Freedman, Eds. (Univ. of Michi- gan Press, Ann Arbor, 1969). 18. Blake has much to say about the responses of white men and women of lower education and economic status to a poll question. "Do you think birth control pills should be made available free to all women on relief who are of childbearing age?" She ignores the ambiguity of the question, which would appear to require of the respondents judgment on at least four issues: (i) pills; (ii) the public assistance system ("welfare handouts") ; (iii) the morals of women on public assistance; and (iv) the distribution of pills without medi- cal supervision. If we were asked the question in this form, our answer would probably also be in the negative: "Not unless the distribution was under medi- cal supervision and the assistance recipient wanted pills." PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7085 19. G. Varky, F. S. Jaffe, S. Polgar, R. Lincoln, Five Million Women-Who's Who Among Americans in Need of Subsidized Family Planning Services (Planned Parenthood-World Population, New~ York, 1967), a publication based on the Census Bureau tabulation cited in 17. 20. A. A. Campbell, J. Marriage and the Family 30, 236 (1968). 21. M. Orshansky, "The shape of poverty in 1966," Soc. Security Bull. (March 1968). 22. F. S. Jaffe and A. F. Guttmacher, Demography 5, 910 (1968). 23. C. F. Westoff and N. B. Ryder, "United States: Methods of Fertility Control, 1955, 1960 and 1965," Studies in Family Planning No. 17 (1967). 24. C. Tietze, in Manual of Contraceptive Practice, M. S. Calderone, Ed. (Williams and Wilkins, Baltimore, 1964), Tables 3 and 4. 25. See, for example, A. F. Yerby, Amer. J. Public Health Nat. Health 56, 5 (1966). 26. R. Frank and C. Tietze, Amer. J. Obstet. Gynecol. 93, 122 (1 Sept. 1965). See also S. Polgar and W. B. Cowles, Eds., "Public Health Programs in Family Planning," supplement to Amer. J. Public Health Nat. Health 56 (Jan. 1966) ; S. Polgar, "U.S.: The PPFA Mobile Service Project in New York City," Studies in Family Planning No. 15 (1966); D. J. Bogue, "U.S.: The Chicago Fertility Control Studies," ibid.; G. W. Perkin, "A family planning unit for your hospital ?," Hosp. Practice 2, 64 (May 1967). Grover Tape 20-GPO-Senate -36236 Mach 6-NITE 6-11-70 pps. 3481-3500 - 27. J. D. Beasley, Family Planning Perspectives 1, 2 (Spring 1969). 28. and V. W. Parrish, "Epidemiology and prevention of illegitimate births in the rural South," paper presented before the American Public Health Association, November 1968. 29. We confess that we do not comprehend how a society which has as much difficulty as Blake alleges ours does with regard to contraceptives for unmar- ried persons engaging in heterosexual activities can be expected to legitimate sexual deviancy as an antinatalist measure. PAGENO="0256" 7086 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Reprinted from THE JOURNAL OF REPRODUCTIVE MEDICINE: LYING-IN July, 1969 Volume 3, Number 1 Copyright © 1968 by the Chicago Lying-in Hospital PRINTED IN lISA. THE ASSOCIATION OF MORTALITY FROM THROMBOEMBOLIC DISORDERS AND ORAL CONTRACEPTIVE USE DANIEL G. SEIGEL, Sc. D. Epidemiology and Biometry Branch, National Institute of Child Hea1th and Human Development, National Institutes of Health, Bethesda, Maryland 20014 My own interest in mortality data was motivated by the studies conducted in Great Britain on the association between oral con- traceptives and thromboembolism and I should like to review these findings. Inman and Vessey [1] reported their re- sults in the British Medical Journal in April 1968. Their study consisted of an inves- tigation of deaths in England, Wales, and Northern Ireland during 1966 in women age 20-44 with certificates mentioning "thrombosis or embolism of the pulmonary, cerebral, or coronary vessels, or other syn- onymous terms" (Table I). I should like TABLE I PREDISPOSING CoNDITIoNs IN DEATHS Pulmonary Embolism 26 Coronary Thrombosis 84 Cerebral Thrombosis 10 Snssrce: Inttsnn&Ves,ey(1) Ptedi~posing Csnditiont (A) Ab,ent (B) Pre,ent 49 110 16 to make a very simple but very important point with regard to the method used in this study and in the next that I shall de- scribe. The method used is that of a case- control study: the approach is to compare cases and controls on the frequency with which their histories are positive for the agent of interest. This reverses the question of real interest, whether the disease occurs with different frequency in those using the Present data on trends in mortality rates from throm' boembolic causes have been analyzed in collaboration with Dr. Robert Markush of the National Institutes of Health. The data have been described in two papers one of which appears in The American Journal of Public Health (2), the other of which will appear in The Amer- ican Journal of Epidemiology (4). agent and those not. In spite of this reversal, the inferences that are developed are in the forward direction and are often expressed in terms of the relative risk, the ratio of risk in users of oral contraceptives and in those not using the contraceptive. I offer this by way of explanation, not criticism; the method is an old and useful one. Certain exclusions were made from these deaths: those not married, those in which the diagnosis was poor, or where the throm- bosis or embolism was a terminal event to some other medical condition. Interviews were conducted with the physi- cians and information obtained on the woman's oral contraceptive usage and med- ical history. Living controls were selected from these same physicians' files who were also 20.44, and information was obtained from the physician respecting their parity. One to one matching was not done. The pool of controls was used to provide es- timates of the expected frequency of oral contraceptive usage. Two classes of cases were identified, Class A patients, with no known predispos- ing conditions and Class B patients, who had known predisposing conditions. This is an important distinction. No one knows the extent to which persons with conditions re- garded as predisposing to thromboembolic events are given oral contraceptives by physicians. If an evaluation is sought of the relationship between oral contraceptive use and death from thromboembolism in women with a history of predisposing con- ditions, then a control series of women who did not die of a thromboembolic cause but had such a history is required. No such Volume III, Number 1 / July 1q69 Editorial Page 44 PAGENO="0257" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 7087 TABLE II DEATHS B~ CAUSE AND ORAl, CONTRACEPTIVE HISTORY Ns~'U~~ss Pulmonary Embolism Coronary Thrombosis Cerebral Thrombosis 16( 4.2) 18(11.4) 5( 1.5) 10(21.8) 66(72.6) 5( 8.5) For all three conditions there is a greater number of oral contraceptive users among the cases than the control experience would lead one to expect. Except for coronary thrombosis, the numbers are not large. There are only ten cases of cerebral throm- bosis. Two of these contrasts are described as statistically significant; that for coronary thrombosis is described as nearly so. I would like to take this opportunity to raise only one methodologic question that I have not seen discussed. Inman and Vessey say of the cases, "Questions were also in- cluded about any drugs, including oral contraceptives, which had been taken by the patient at the onset or at any time dur- ing the six months preceding the terminal illness." Of the controls, reference is made to "the current use of oral contraceptives." This is analogous to comparing a period prevalence to a point prevalence, and can represent a source of bias. It is the only potentially serious question which I am aware of that is not mentioned in an other- wise thorough discussion. It should be pointed out that Table II provides an estimate of the relative risk for pulmonary embolism by the product of 16/4.2 times 21.8/ 10 or roughly 8. That is, we can infer the risk of death from pul- monary embolism in oral contraceptive users to be 8 times greater than in persons not using the drugs. The study by Vessey and Doll [5] ap- pears in the same issue of the British Med- ical Journal, and describes data on patients ages 16-40 admitted in the years 1964.66 to 19 general hospitals for venous throm- 45 Editorial Page US,,, N~'U~ Venous Thromboenbolism 26(5) 32(53) Coronar Cerebral y Thrombosis Thrombosis 0(1) 5(1) 13(12) 4( 8) 5~~s: Vo~y & DClI (2) Not,: N tb,ss is pttm~Ihssst ~~ttp~tted ~It~s frttttt s~tttttl bosis or pulmonary embolism (Table III). Exclusions were made here as well, of the non-married, of those with predisposing conditions, pregnant, postmenopausal, ster. ilized, and those suffering only superficial thrombophlebitis. The same exclusions were made in the controls. For each affected pa- tient two controls were selected who had been diagnosed as suffering from an acute medical or surgical condition or had been admitted to hospital for an elective opera- tion and who matched the affected patient in regard to hospital, date of admission, age, and parity. In this study, patients them. selves were interviewed, something quite impossible in the mortality study. Informa- tion was sought on oral contraceptive use in the month prior to the start of the episode for which they were admitted. For reasons not stated in their paper, cases of cerebral thrombosis and coronary thrombosis were also obtained, but no matched controls were selected for these cases. Hence, estimates of expected oral contraceptive use in these cases were taken from the controls selected to match the venous thrombosis and pulmonary cases. As in the mortality data there is a striking discrepancy between expected and observed proportions of the various thromboembo. lism cases that had been oral contraceptive users. Experience regarding cerebral throm- hosis is limited, but similar to the mortality experience. In the case of coronary throm- bosis no association is evident. The relative risk suggested by the data in the first row, for venous thromboembolism is about 8. The manner in which Vessey and Doll pre- sent their data does not permit separating the cases that had no previous thrombo- embolic episodes. They do say that the frequency of oral contraceptive use in cases with and without a history of previous The Journal of Reproductive Medicine controls were available,, and there is really TABLE III very little that can be done with Class B CASES B~ DIAGNOSIS AND ORAL CONTRACEPTIVE HISTORY cases. Table II presents the result of this study. S~sss,: Ittst~s&Vestey(l) N,t,: Nstsbs~t is ~ t~d tslsst frost totsttol 40-471 O-70--pt. 17-17 PAGENO="0258" 7088 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY thromboembolism was similar. No such in. formation is provided for the coronary and cerebral thrombosis. There is much to learn from their methodology. Histories of chronic diseases that alter sexual practices or the probabil- ity of contraceptive prescription are a real problem in case-control studies of oral con- traceptive effects. Parity presents~ an in- teresting example of the problems that arise. Parity affects oral contraceptive use, which argues for matching it, but oral con- traceptive use affects parity, which argues against matching it. The two studies for venous thromboem- bolism and pulmonary embolism suggest a relative risk of about eight times for women using the oral contraceptive compared to women who are not. Ryder and Westoff {3] estimate 15 per cent of the U. S. mar- ried population in 1965 of reproductive age were using the oral contraceptive. These two pieces of information lead one to ex- pect a large impact on mortality rates. Table IV illustrates how this couki work. TABLE IV IF NO INCREASED RISK DEATHS 15 Users die at rate 8 R 15 R 85 Non-Users at Rate R 85 R 100 Population 100 R IF RELATIVE RISK OF 8 DEATHS 15 Users die at rate 8 R 120 R 85 Non-Users at Rate R 85 R 100 Population 205 R If the oral contraceptive users experienced no increased risks, the total number of deaths that would be seen in a population of 100, 15 of whom were using the drug, would be equal to 100 R. If the women who used the medication had a risk of death 8 times that of other women, then a total of 205 R deaths would occur. It is important that such large changes in mortality are conceivable because the analysis of mortality trends is not a sensi- tive technique. There are significant limita- tions to the analysis of mortality data. These include a) the inherent difficulty in select- ing an underlying cause, especially when more than one disease process is present, b) the complex of factors that lead to unre- liable death certificate diagnosis such as certifiers who are unfamiliar with the med- ical history of the decedent, c) the bias that physicians may bring to the diagnosis of a condition in a young woman who has been using oral contraceptives, and d) changes in other factors occurring simultaneously that may also affect mortality data. Markush and Seigel [2] reviewed mortal- ity trends from several rubrics of the Inter- national Classification of Disease, notably lCD categories 420, arteriosclerotic heart disease including coronary disease; 332. cerebral embolism and thrombosis; and 460-468, diseases of veins and other dis- eases of the circulatory system. The num- ber of deaths in each of these categories is given in Table V. We attempted to determine whether death rates from these causes in recent years in women of reproductive age have been great- er than one would expect. Estimates of ex- pected rates were derived from a) the ex- perience of women in the years prior to the marketing of oral contraceptives, 1957. 1961, and b) the experience of men in re- cent years 1962-1966. Table VI shows the differences between the observed annual per cent change in mortality (by age, for whites and non.whites) and the per cent change estimated from each of these com- parison groups. Entries that are positive signify that the observed rates are increas- ing relative to the expected rate of change; those that are negative indicate a rate of change in recent years that is less than would be expected. Neither lCD 332 nor lCD 420 shows a consistent pattern of rela- tive increa5es in women of reproductive age. For lCD 460-468, on the other hand, each five-year age group from 20 to 45 shows some relative increase (with one exception), both in white and non-white. Outside these ages, moreover, negative changes occur. Furthermore the increases are not trivial. The mortality data were also used to estimate the relative risk of death from lCD 460-468 [4] for women in each age group. These are given in Table VII. By relative risk we mean the ratio of mortality rates in Volume III, Number 1 / July 1969 Editorial Page 46 PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7089 TABLE V SEVENTH REVISION INTERNATIONAL CLASSIFICATION OF DISEASES CATEGORIES INCLUDED IN REPORT; NUMBERS OF U.S. 1965 DEATHS B~ BROAD AGE AND SEX GROUPS Nombeet of U.S. D Age, 15.44 lCD Ito. lCD Title Meo Wotoett esth, is 1965 Aget 45.64 Mes Wooeo I. 332 Cerebral embolism and thrombosis 226 168 4,130 2,811 II. 341 Phlebitis and thrombophlebitis of intracranial venous sinuses 2 4 6 9 III. 420 Arteriosclerotic heart disease, including coronary disease 11,873 2,616 10,972 5,346 IV. 454 Arterial embolism and thrombosis 30 33 240 119 V. 4608 Diseases of veins and other diseases of circulatory system 421 587 1,971 1,452 A. 460 Varicose veins of lower extremities 4 15 28 55 B. 461 Hemorrhoids 6 3 9 5 C. 462 Varicose veins of other specified sites 30 9 111 37 D. 463 Phlebitis and thrombophlebitis of lower extremities 48 60 203 185 E. 464 Phlebitis and thrombophlebitis of other sites 34 69 182 147 F. 465 Pulmonary embolism and infarction 200 279 757 693 G. 466 Other venous embolism and thrombosis . 72 117 342 244 H. 467 Other diseases of circulatory system 24 35 138 79 I. 468 Certain diseases of lymph nodes and lymph channels 3 0 2 7 VI. 570.2 Mesenteric infarction 41 45 313 250 TABLE VI U. S. MORTALITY, WOMEN AGES 15.64, B~ COLOR AND FIVE.YEAR GROUP DIFFERENCE BETWEEN OBSERVED ANNUAL PERCENT CHANGE AND EXPECTED BASED ON Two COMPARISON GROUPS lCD 332 Ceeebeol lCD 420 lCD 450.8 E,obolits sod Theo,sboti, A. S. H. D. Di,es,e, of VeSt, Cotopseitos 1 Cotopseitos 2 Cotopseitos 1 Cosepseitos 2 Costpseitoo 1 Cotspsei,os 2 Roce Age White 15.19 + 2 -33 +45 +11 - 5 - 7 20.24 -17 -29 +14 + 8 +12 + 1 25.29 +6 +9 +1 -1 0 +12 30.34 +3 -10 +2 -3 +9 ±9 35.39 -15 -5 +3 +2 +8 +6 46).44 0 -1 0 +1 +16 +9 45.49 +1 +3 -1 +1 +1 +5 50.54 -7 -2 0 0 +4 +8 55.59 -7 +1 -1 +3 -4 60.64 -4 -2 -1 -1 -2 -2 Non- White 15.19 -34 -32 -17 -47 0 - 4 20-24 -37 +48 +14 - 9 ±12 + 5 25-29 ±16 ±17 + 2 -10 ± 4 ± 5 30-34 +17 +22 +12 + 1 +17 + 3 35.39 -15 -26 + 6 - 2 +15 + S 40.44 +2 -3 +6 +1 45.49 ._9 -6 +9 0 +17 +10 50.54 -5 -1 -2 -2 +3 55.59 ±3 -3 ±6 -9 fifJ.64 -5 -2 -7 -3 -6 0 Note: Cotsps,4tos geottp 1 it woosets 1957-61 Compaei,ott gesop 2 is toes 1962-66 Soueee: Maekush sod Seigol (4) 47 Editorial Page The Journal of Reproductive Medicine PAGENO="0260" 7090 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE VII ESTIMATED RELATIVE RISKS IN 1966 FOR DISEASES OF VEINS, ETC., (lCD 460-468), B~ AGE AND COLOR Observed ~ Expected Deaths Assumption 1 Assumption 2 Assumption 3 Assumption 4 Excess Deaths Assumption 1 . 75 Assumption 2 72 Assumption 3 61 Assumption 4 . 56 Average of Estimates of Excess 66 314 325 341 345 349 315 324 346 351 360 328 355 393 414 438 333 363 406 431 458 97 151 220 320 98 146 214 309 67 99 151 231. 59 86 134 211 80 121 180 268 Ag, 20.24 25.29 30.34 35.39 4044 White 4 5 6 8 22 Non-white 4 3 9 17 6 women using the oral contraceptives and tion of estrogens to pre.menopausal women those who are not. It should be clear that became more common at about the same mortality rates were not available sep. time as the oral contraceptive began to be arately for these two groups. The estimates used, and has increased in medical prac- were made using the information on the tice. One can speculate that there is a much proportion of the population using these broader base of hormonal use in women drugs and the excess in mortality that ap. over age 40 than is indicated by surveys of pears to be present. The relative risks family planning practice. range from 3 to 9, with the exception of Another way to use the mortality data to whites age 40 to 44 and non.whites 35 to indicate the relationship between oral con. 39. These values are not directly compar- traceptive usage and mortality from lCD able to the estimates yielded by the British category 460.468 is in the form of estimat- studies, which included women without a ing excess numbers of deaths (Table VIII). prior history of thromboembolism, and The expected number of deaths for each were concerned with thromboembolic dis. five.year age group was computed sep- ease appearing anywhere on the death cer- arately for non.whites and whites using four tificate. It is impressive then that the values different assumptions as to what these rates are of the same order of magnitude as those should have been. Two assumptions were yielded in the case-control analyses, in that the slope of rates of women in 1962.66 which a relative risk of eight times was should be that of men in the same time demonstrated. The very high value of rela. period or that of women 1956-61. The tive risk for whites age 40 to 44 arises from other two assumed that the relative slope, allocating the increased mortality at that that is the slope divided by the mean rate, age to low estimates of oral contraceptive should be the same as the relative slope in use. It has been suggested that administra. these same two groups. Finally the expected TABLE VIII ESTIMATED EXCESS DEATHS, B~ YEAR, FOR COMBINED AGES 20-44 FROM DISEASES OF VEINS, ETC., (lCD 460-468), WITH FOUR A5SUMPTI0N5* FOR EXPECTED DEATHS 1062 1963 1964 1965 1966 jeat.nas 389 422 492 565 669 `Enpeoted tlnpe of tnnetnlity entet in wotnen 196266 gOons by: A,,nmptinn 1: Slope of ,nontality eaten in wntoea, 1957-61. .kttntoption 2: Slope of tnontality nate, in ,ootoen, 1957-1961, maltiplied by natis of mean of nate' in women, 196266 nod mean of nate, in women, 1957-1961. A,,sn,ption 3: Slope sf monaality estet in men 1962.66. A,totnpaion 4: Slope of montality natea in men, 196266 multiplied by natis nf mean nf natet in women, 106266, and mean of entet in men, 1962.66. Volume II!, Number 1 / July 1969 Editorial Page 48 PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7091 deaths were summed over the ages 20 to 44 and compared with the observed deaths. In each case there was an excess in the ob- served number of deaths, the excess in- creasing with each year. By 1966 from a third to a half of all deaths were in excess of what one would expect. The means of these estimates of excess deaths is also pro. vided. They increase to a level of 268 deaths in 1966. I should like to make reference to the fact that Vessey and Weatherall [6] have analyzed mortality trends in Great Britain in an article which appeared in The Lancet in July, 1968, and conclude "that there has been an increase in the mortality from ven- ous thromboembolism in young women in recent years of a magnitude compatible with the existence of a casual relation be. tween the use of oral contraceptives and death from venous thromboembolism." SUMMARY In summary the mortality data from women in the United States in recent years are compatible with the finding of the British case.control studies in that area where they are themselves most striking, venous thromboembolism and pulmonary embolism. REFERENCES 1. INMAN, W. H. W. and VESSEY, M. P.: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Brit. med. 1. 2:193-199, 1968. 2. MARKU5H, R. E. and SEIGEL, D. G.: Oral contra- ceptives and mortality trends from thromboembolism in the United States. Amer. J. pubi. HIth. 59:418- 434, 1969. 3. RYDER, N. B. and WESTOFF, C. F.: The United States: The pill and the birth rate, 1960.1965. Studies in Family Planning. The Population Coun- cil No. 20, 1-3, June, 1967. 4. SEIGEL, D. G. and MARKU5H, R. E.: Oral contra- ceptives and relative risk of death from venous and pulmonary thrombsembslism in the United States. Amer .1. Epid. (In press). 5. V~sss~, M. P. and DOLL, R.: Investigation of re lation between use of oral contraceptives and throm- boembolic disease. Brit. med. J. 2:199-205, 1968. 6. VE5SEY, M. P. and WEATHERALL, J. A. C.: Venous thromboembolic disease and the use of oral contra- ceptives. A review of mortality statistics in England and Wales. The Lancet 11:94-95, July 13, 1968. 49 Editorial Page The Journal of Reproductive Medicine PAGENO="0262" 7092 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Science, May 2, 1969, Pp. 522-529] POPULATION POLICY FOR AMERICANS: Is THE GOVERNMENT BEING MISLED?- POPULATION LIMITATION BY MEANS OF FEDERALLY AIDED BIRTH-CONTROL PROGRAMS FOR THE POOR Is QUESTIONED (By Judith Blake, Chairman, Department of Demography, University of California, Berkeley) Pressure on the federal government for "action" to limit population growth in the United States has intensified greatly during the past 10 years, and at present such action is virtually unchallenged as an official national goal. Given the goal, the question of means becomes crucial. Here I first evaluate the par- ticular means being advocated and pursued in public policy, then I present alternative ways of possibly achieving the goal. The prevailing view as to the best means is remarkably unanimous and abundantly documented. It is set forth in the 17 volumes of congressional hearings so far published on the "population crisis" (1) ; in "The Growth of U.S. Population," a report by the Committee on Population of the National Academy of Sciences (2) ; in a statement made by an officer of the Ford Foun- dation who was asked by the Department of Health, Education, and Welfare to make suggestions (3) ; and, finally, in the "Report of the President's Com- mittee on Population and Family Planning," which was officially released this past January (4). The essential recommendation throughout is that the gov- ernment should give highest priority to ghetto-oriented family-planning pro- grams designed to "deliver" birth-control services to the poor and uneducated, among whom, it is claimed, there are at least 5 million women who are "in need" of such federally sponsored birth-control assistance. By what logic have the proponents of control moved from a concern with population growth to a recommendation favoring highest priority for poverty- oriented birth-control programs? First, they have assumed that fertility is the only component of population growth worthy of government attention. Second, they have taken it for granted that, to reduce fertility, one sponsors birth-con- trol programs ("family planning"). Just why they have made this assumption is not clear, but its logical implication is that population growth is due to births that couples would have preferred to avoid. Furthermore, the reason- ing confuses couple control over births with societal control over them (5). Third, the proponents of the new policy have seized on the poor and unedu- cated as the "target" group for birth-control action because they see this group as the only remaining target for a program of voluntary family planning. The rest of the population is handling its family planning pretty well on its own: over 95 percent of fecund U.S. couples already either use birth-control methods or intend to do so. The poor, on the other hand-at least those who are fecund -have larger families than the advantaged; they not only use birth-control methods less but they use them less effectively. The family-planning move- ment's notion of "responsible parenthood" carries the implication that family size should be directly, not inversely, related to social and economic advantage, and the poor are seen as constituting the residual slack to be taken up by the movement's efforts. Why are the poor not conforming to the dictates of respon- sible parenthood? Given the movement's basic assumptions, there are only two answers: the poor are irresponsible, or they have not had the opportunity. Since pressent-day leaders would abhor labeling the poor irresponsible, they have chosen to blame lack of opportunity as the cause. Opportunity has been lacking, in their eyes, either because the poor have not been "educated" in family planning or because they have not been "reached" by family-planning services. In either case, as they see it, the poor have been deprived of their "rights" (2, p. 22; 6). This deprivation has allegedly been due to the prudery and hypocrisy of the affluent, who have overtly tabooed discussion of birth control and dissemination of birth-control materials white, themselves, covertly enjoying the benefits of family planning (7). So much for the logic underlying recent proposals for controlling population growth in the United States. But what is the evidence on which this argument is based? On what empirical grounds is the government being asked to embark on a high-priority program of providing contraceptive services to the poor? Moreover, what, if any, are some of the important public issues that the sug- NOTE-Numbered references at end of article. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7093 gested policy raises-what are its social and political side effects? And, finally, is such a policy, even if appropriate for the poor and even if relatively unen- cumbered by public disapproval, relevant to the problem of population growth in America? If demographic curtailment is really the objective, must alterna- tive policies be considered and possibly given highest priority? Turning to the alleged need for government-sponsored birth-control services, one may ask whether birth control has in fact been a tabooed topic among the middle and upper classes, so that the less advantaged could be said to have suffered "deprivation" and consequently now to require government help. One may then question whether there is a mandate from the poor for the type of federally sponsored service that is now being urged, and whether as many as 5 million women are "in need" of such family-planning assistance. HAS BIRTH CONTROL BEEN A TABOOED TOPIC? The notion that the American public has only recently become willing to tol- erate open discussion of birth control has been assiduously cultivated by con- gressmen and others concerned with government policy on population. For example, Senator Tydings credited Senators Gruening and Clark and President Johnson with having almost single-handedly changed American public attitudes toward birth control. In 1966 he read the following statement into the 28 Feb- ruary Congressional Record (8). The time is ripe for positive action. Ten years ago, even five years ago, this was a politically delicate subject. Today the Nation has awakened to the need for Government action. This change in public attitude has come about through the efforts of men who had the courage to brook the tides of public opinion. Senator Clark is such a man. Senator Gruening is such a man. So is President Johnson. Because of their leadership it is no longer necessary for an elected official to speak with trepidation on this subject. A year later, Senator Tydings reduced his estimate of the time required for the shift in public opinion to "3 or 4 years" (9, p. 12; 10). Senator Gruening maintained (11) that the "ninety-eight distinguished men and women" who testified at the public hearing on 5. 1676 were "pioneers" whose "names com- prise an important honor roll which historically bears an analogy to other famous lists: the signers of the Declaration of Independence, those who rati- fied the Constitution of the United ~States and others whose names were appended to and made possible some of the great turning points in history." Reasoning from the continued existence of old, and typically unenforced, laws concerning birth control (together with President Eisenhower's famous anti- birth-control statement), Stycos, in a recent article (12), stated: The public reaction to family planning in the United States has varied between disgust and silent resignation to a necessary evil. At best it was viewed as so delicate and risky that it was a matter of "individual consci- ence." As such, it was a matter so totally private, so sacred (or profane), that no external agents, and certainly not the state, should have anything to do with it. Does the evidence support such impressionistic claims? How did the general public regard government sponsorship of birth control long before it became a subject of congressional hearings, a National Academy report, and a Presiden- tial Committee report? Fortunately, a question on this topic appeared in no less than 13 national polls and surveys aconducted between 1937 and 1966. As part of a larger project concerned with public knowledge and opinions about demographic topics, I have gathered together the original data cards from these polls, prepared them for computer processing, and analyzed the results. The data are all from Gallup polls and are all from national samples of the white, adult population. Here I concentrate on adults under 45-that is, on adults in the childbearing age group. The data of Table 1 contradict the notion that Americans have only recently ceased to regard birth control as a tabooed topic. As far back as 30 years ago, almost three-quarters of the women questioned in these surveys actively approved having the government make birth-control information available to the married. By the early 1960's, 80 percent or more of women approved over- coming legal barriers and allowing "anyone who wants it" to have birth-con- PAGENO="0264" 7094 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY trol information. The figures for men are similar. The question asked in 1964 -the one question in recent years that did not mention illegality-brought 86 percent of the women and 89 percent of the men into the category of those who approved availability of birth-control information for "anyone who wants it." Furthermore, in judging the level of disapproval, one should bear in mind that the remainder of the respondents, in all of these years, includes from 7 to 15 percent who claim that they have "no opinion" on the subject, not that they "disapprove." TABLE 1-PERCENTAGES OF WHITE US. MEN AND WOMEN BETWEEN THE AGES OF 21 AND 44 WHO, IN VARIOUS NATIONAL POLLS AND SURVEYS MADE BETWEEN 1937 AND 19641, EXPRESSED THE OPINION THAT BIRTH-CON- TROL INFORMATION SHOULD BE MADE AVAILABLE TO INDIVIDUALS WHO DESIRED IT. Year Men % N Women % N 1937 66 1038 70 734 1938 1939 1940 1943 1945 1947 1959 1961 67 74 72 67 64~ 76 78 82 1111~ 1101 1127 628 714 353 301 336 72 73 ~ 73 70 75 79 81 548 630 618 866 879 405 394 394 1962 1963 85 78 288 323 80 79 381 373 1964 89 324 86 410 1 The questions asked of respondents concerning birth control were as follows. In 1937: Do you favor the birth control movement? In 1938, 1939, 1940, 1943, 1945, and 1947: Would you like to see a government agency (or "government health clinics") furnish birth-control information to married people who want it? In 1959, 1961, 1962, and 1963:1 n some places in the United States it is not legal to supply birth-control information. How do you feel about this-do you think birth-control information should be available to anyone who wants it, or not? In 1964: Do you think birth-control information should be available to anyone who wants it, or not? An important difference of opinion corresponds to a difference in religious affiliation. Among non-Catholics (including those who have "no religion" and do not attend church) approval has been considerably higher than it has been among Catholics. Among non-Catholic women, over 80 percent approved as early as 1939, and among non-Catholic men the percentages were approxi- mately the same. The 1964 poll showed that 90 percent of each sex approved. Among Catholics, in recent years about 60 percent have approved, and, in 1964, the question that mentioned neither the government nor legality brought opin- ions of approval from 77 percent of the women and 83 percent of the men. Clearly, if birth-control information has in fact been unavailable to the poor, the cause has not been a generalized and pervasive attitude of prudery on the part of the American public. Although public officials may have misjudged American opinion (and may have mistakenly assumed that the Catholic Church "spoke for" a majority of Americans, or even for a majority of Catho- lics), most Americans of an age to be having children did not regard birth control as a subject that should be under a blanket of secrecy and, as far back as the 1930's, evinced a marked willingness to have their government make such information widely available. It seems unlikely, therefore, that poorer sectors of our population were "cut-off" from birth-control knowledge primarily because informal channels of communication (the channels through which most people learn about birth control) were blocked by an upper- and middle- class conspiracy of silence. What has happened, however, is that pressure groups for family planning, like the Catholic hierarchy they have been opposing, have been acting as self- designated spokesmen for "public opinion." By developing a cause as righteous as that of the Catholics (the "rights" of the poor as against the "rights" of a religious group), the family planners have used the American way of influenc- ing official opinion. Now public officials appear to believe that publicly sup- ported birth-control services are what the poor have always wanted and needed, just as, in the past, official opinion acceded to the notion that such services would have been "offensive" to certain groups. Nonetheless, the ques- tion remains of whether or not publicly supported services are actually appro- PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7095 priate to the attitudes and objectives of the poor and uneducated in matters of reproduction. Is the government responding to a mandate from the poor or to an ill-concealed mandate from the well-to-do? If there is no mandate from the poor, the provision of birth-control services may prove a convenience for cer- tain women but is likely to have little effect on the reproductive performance of the poor in general. Let us look at the evidence. IS THERE A MANDATE FROM THE POOR? The notion that the poor have larger families than the affluent only because they have less access to birth-control information implies that the poor desire families as small as, or smaller than, those of the well-to-do. The poor are simply unable to realize this desire, the argument goes, because of lack of access to birth-control information. The ?~ational Academy of Sciences Commit- tee on Population stated the argument very well (2, p. 10). The available evidence indicates that low-income families do not want more children than do families with higher incomes, but they have more because they do not have the information or the resources to plan their families effec- tively according to their own desires. The committee, however, presents none of the "available evidence" that "low-income families do not want more children than do families with higher incomes." Actually, my data supply evidence that runs counter to the state- ment quoted above, both with respect to the desired or ideal number of chil- dren and with respect to attitudes toward birth control. I shall begin with the preferred size of family. A number of national polls, conducted over some 25 years, provide data concerning opinions on ideal family size. In addition, I include tabulations of data from two national sur- veys on fertility (the "Growth of American Families Studies"), conducted in 1955 and 1960 (13, 14). My detailed analyses of the results of these polls and surveys are given elsewhere (15) and are only briefly summarized here. Table 2 gives mean values for the family size considered ideal by white, non-Catholic women, according to education and economic status. TABLE 2.-MEAN NUMBER OF CHILDREN CONSIDERED IDEAL BY NON-CATHOLIC WOMEN, ACCORDING TO EDUCATION AND ECONOMIC STATUS, FOR SELECED YEARS BETWEEN 1943 AND 1968 Level of education * Income or Total re- economic statust spondents Age Col- High Grade ______________ Date range lege school school 1 2 3 4 X N 1943 20-34 2.8 2.6 2.6 2.9 2.7 2.7 2.5 2.7 1983 1952 21+ 3.3 3.1 3.6 3.3 3,3 3.3 3.3 723 19551 18-39 3.1 3.2 3.7 3.2 3.1 3.2 3.5 3.3 1905 19551 18-39 3.3 3.4 3.9 3.4 3.3 3.4 3.7 3.4 1905 1957 21+ 3.4 3.2 3.6 3.3 3.2 3.5 3.3 448 1959 21+ 3.5 3.4 3.9 3.5 3.5 3.6 3.5 472 19601 18-39 3. 1 3.2 3. 5 3. 1 3.2 3.3 3.2 3.2 1728 19601 18-39 3.2 3.4 3.6 3.2 3.3 3.5 3.4 3.4 1728 1963 21+ 3.2 3.4 3.5 3.3 3.3 3.5 3.5 3.4 483 1966 21+ 3.1 3.3 3.7 3.2 3.2 3.4 3.7 3.3 374 1967 21+ 3. 1 3,3 3.4 3.3 3. 2 3. 1 3.4 3.3 488 1968 21+ 3. 2 3.3 3.7 3. 2 3. 0 3,4 3.6 3.3 539 * Level of education is measured by the highest grade completed. f Levels 1 to 4 for economic status range in order from "high" to "low". I Minimum ideal (results from coding range answers to the lowest figure). § Maximum ideal (results from coding range answers to the highest figure). The data lend little support to the hypothesis that the poor desire families as small as those desired by the middle and upper classes. Within both the educational and the economic categories, those on the lower rungs not only have larger families than those on the higher rungs (at least in the case of non-Catholics) but say they want larger families and consider them ideal. This differential has existed for as long as information on preferred family size in this country has been available, and it persists. It thus seems extremely haz- ardous to base a major governmental effort on the notion that, among individ- uals (white individuals, at least) at the lower social levels, there is a wide- PAGENO="0266" 7096 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY spread and deeply held desire for families as small as, or smaller than, those desired by the well-to-do. No major survey shows this to be the case. Not only do persons of lower socioeconomic status prefer larger families than the more affluent do, they also generally favor birth control less. Tables 3 and 4 show the percentages of white men and women who expressed approval of birth control in surveys made between 1937 and 1964, by educational level and economic status, respectively. Looking at the educational differential (Table 3), one finds that, in general, the proportion of those who approve birth control drops precipitately between the college and grade school levels. As far back as the early 1940's, over 80 percent of women and 75 percent of men with some or more college education approved government action on birth control. By 1964, over 90 percent of both sexes approved. By contrast, only 60 percent of men and women with an ele- mentary school education approved in the 1940's, and, despite a rise in approval, there is still a differential. When non-Catholics alone are considered, the educational difference is even more pronounced in many cases. Turning to economic or income status (Table 4), one generally finds the same results. The high proportions (close to 100 percent) of women in the highest and next-to-highest economic brackets who, in recent years, have approved birth-control efforts is noteworthy, as is the fact that approximately 80 percent of women in these brackets approved such efforts as far back as the 1930's. On the other hand, men and women in lower income brackets have been slower to approve birth-control policies. TABLE 3.-PERCENTAGES OF WHITE U.S. MEN AND WOMEN BETWEEN THE AGES OF 21 AND 44 WHO, IN VARIOUS NATIONAL POLLS TAKEN BETWEEN 1943 AND 1964, EXPRESSED THE OPINION THAT BIRTH-CONTROL INFOR- MATION SHOULD BE MADE AVAILABLE TO INDIVIDUALS WHO DESIRED IT. THE PERCENTAGES ARE GIVEN BY LEVEL OF EDUCATION 1; THE NUMBERS IN PARENTHESES ARE TOTAL NUMBERS OF RESPONDENTS IN EACH CATEGORY. Men Year High College school Women Grade High school College school Grade school 1943 75(184) 68 (284) 56 (157) 82 (216) 74 (442) 60 (207) 1945 74 (202) 62 (360) 58 (140) 83 (216) 68 (434) 56 (207) 1947 91(84) 72 (199) 67 (66) 81(89) 74 (228) 72 (81) 1959 88 (89) 76 (163) 65 (49) 91(55) 79 (279) 68 (41) 1961 88 (102) 81(188) 67 (46) 84 (81) 81(265) 78 (50) 1962 91(93) 85 (171) 61(23) 84 (79) 82 (258) 66 (44) 1963 86 (105) 79 (178) 53 (40) 81(80) 78 (251) 81(42) 1964 92 (107) 88 (188) 83 (29) 94 (79) 86 (293) 74 (38) iThe level of education is measured by the last grade compleded. TABLE 4.-PERCENTAGES OF WHITE U.S. MEN AND WOMEN BETWEEN THE AGES OF 21 AND 44 WHO, IN VARIOUS NATIONAL POLLS TAKEN BETWEEN 1937 AND 1964, EXPRESSED THE OPINION THAT BIRTH-CONTROL INFOR- MATION SHOULD BE MADE AVAILABLE TO INDIVIDUALS WHO DESIRED IT. THE PERCENTAGES ARE GIVEN BY ECONOMIC STATUS (LEVELS 1~41); THE NUMBERS IN PARENTHESES ARE TOTAL NUMBERS OF RESPONDENTS IN EACH CATEGORY. Men Year 1 2 3 4 Women 1 2 3 4 1937 78 (112) 70 (406) 61(520) 67 (69) 78 (293) 64 (372) 1938 65 (125) 74 (453) 62 (521) 80 (51) 73 (232) 70 (259) 1939 78 (116) 75 (432) 73 (553) 71(68) 77 (260) 71(302) 1940 79 (131) 75 (443) 68 (553) 80 (49) 78 (258) 71(311) 1943 76 (80) 72 (219) 62 (330) 80 (90) 79 (272) 68 (500) 1945 73 (67) 66 (286) 62 (352) 83 (75) 77 (264) 64 (531) 1947 86 (42) 77 (123) 72 (188) 92 (38) 71(119) 73 (237) 1959 83 (101) 76 (120) 73(79) 83 (139) 82 (152) 72 (95) 1961 93 (42) 85 (80) 87(103) 69 (111) 88 (41) 80 (97) 80 (76) 81(138) 1962 82 (45) 89 (71) 86 (94) 80 (74) 82 (51) 80 (75) 84 (110) 77(140) 1963 88 (60) 84 (79) 76 (96) 61(97) 87(67) 79 (107) 79 (98) 75 (100) 1964 90 (67) 87 (26) 93 (82) 85 (79) 96 (90) 90 (87) 85 (104) 78 (120) iLevels 1 to4for the years 1961-64 range from income of $10,000 and over down to incomes under $5,000. Prior to 1961, levels 1 to 3 represent `upper," "middle," and "lower" income brackets. PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7097 * Despite the inverse relationship just described, I may have overemphasized the lesser approval of birth-control programs on the part of persons of lower economic and social status. After all, in recent years approval often has been high even among people at the lowest social levels. Among women with only a grade school education, the percentage of those favoring birth-control programs averaged 73 percent in polls taken between 1959 and 1964; among men at the lowest educational level, the corresponding average was 66 percent. Yet it is undeniably true that, throughout the period for which data are available, the people who needed birth-control information most, according to recent policy pronouncements, have been precisely the ones who were least in favor of a policy that would make it widely available. The truth of this conclusion becomes more evident when we move to an analysis of a question asked on the 1966 Gallup poll: Do you think birth-con- trol pills should be made available free to all women on relief who are of childbearing age? This question presents the public with the specific issue that is the focus of curt~ent policy-namely, birth control especially for the poor. A summary of the replies to this question is given in Table 5, together with average percentages of people who, in the five surveys made between 1959 and 1964, replied that they approved birth control generally. TABLE 5.-PERCENTAGES OF WHITE U.S. MEN AND WOMEN BETWEEN THE AGES OF 21 AND 44 WHO, IN A 1966 POLL, EXPRESSED APPROVAL OF FREE DISTRIBUTION OF BIRTH-CONTROL PILLS FOR WOMEN ON RELIEF, AND AVERAGE PERCENTAGES OF INDIVIDUALS IN THIS AGE GROUP WHO, IN POLLS TAKEN BETWEEN 1959 AND 1964, EXPRESSED APPROVAL OF BIRTH CONTROL PERCENTAGES APPROVING AND NUMBERS OF INDIVIDUALS INTERVIEWED ARE GIVEN AS TOTALS AND ALSO BY EDUCATION AND ECON&MIC STATUS OF THE RESPONDENTS. Men . Women 1966 1959-64 1966 1959-64 Item % N (average %) % N (average %) Total 65 264 82 71 385 81 Education: College High school Grade school 82 58 38 98 142 24 87 82 66 75 70 59 197 392 32 87 81 73 Economic status: 1 79 80 89 70 110 87 2 69 75 84 76 99 82 3 59 65 83 70 91 80 4 39 41 74 67 76 78 It is clear that the overall level of approval drops when specific reference to a poverty-oriented birth-control policy is introduced. The decline is from an average of approximately 80 percent for each sex during the period 1959-64 to 65 percent for men and 71 percent for women in 1966. Of most significance, however, is the fact that the largest proportionate drop in approval occurs among members of the "target" groups themselves-the poor and uneducated. In particular, there is a remarkable drop in approval among men at this socio- economic level. There is a 42-percent decline in approval among men who have had only a grade school education and a 29-percent drop among those with a high school education. Among the college-educated men the drop in approval is only 6 percent. The results, by income, parallel those by education: there is a 47-percent drop for men in the lowest income group but only a 9-percent drop for those in the highest income bracket. Even if the tabulations are restricted to non-Catholics (data that are not presented here), the results are essentially the same. If the ghetto-oriented birth-control policy urged on the federal government meets with limited public enthusiasm, how does the public view extension of that policy to teen-age girls? This question is of some importance because a notable aspect of the pressure for government-sponsored family-planning pro- grams is advocacy of making birth-control information and materials available at the high school level. The Committee on Population of the National Academy of Sciences urges early education in "family planning" in order to prevent illegitimacy (2, p. 13). PAGENO="0268" 7098 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY * . . government statistics show that the mothers of approximately 41 percent of the 245,000 babies born illegitimately in the United States every year are women 19 years of age or younger. Thus a large proportion of all illegitimate children are progeny of teen-age mothers. To reduce the number of such chil- dren born to teenage mothers, high-school education in family planning is essential. Katherine B. Oettinger, Deputy Secretary for Family Planning of the Depart- ment of Health, Education, and Welfare, importunes us not to "demand the eligibility card of a first pregnancy before we admit vulnerable girls to family planning services" (16). The Harkavy report states (3, p. 29) Eligibility requirements should be liberal with respect to marital status. Such services should be made available to the unmarried as well as the married. Eligibility requirements should be liberal with respect to the age of unmar- ried women seeking help. This will undoubtedly pose some problems, but they may not be insurmountable. Some publically supported programs are already facing them (for example, in Baltimore). Representative Scheuer from New York has berated the federal government for not "bringing family planning into the schools." He has cited the "desper- ate need for family planning by unmarried 14-, 15-, and 16-year-old girls in school [which] is so transparently evident that it almost boggles the imagina- tion to realize that nothing has been done. Virtually no leadership has come from the federal government" (9, p. 18). Obviously there is little recognition in these statements that such a policy might engender a negative public response. Yet such a possibility cannot be discounted. The results of the 1966 question "Do you think they [the pills] should be made available to teen-age girls ?" suggest that a policy of pill distri- bution to female adolescents may be viewed by the public as involving more complex issues than the mere democratization of "medical" services. These results, tabulated by social level, are shown in Table 6. TABLE 6.-PERCENTAGES OF WHITE U.S. MEN AND WOMEN WHO, IN A 1966 POLL, EXPRESSED APPROVAL OF MAK- ING BIRTH-CONTROL PILLS AVAILABLE TO TEEN-AGE GIRLS. PERCENTAGES APPROVING AND NUMBERS OF INDIVIDUALS INTERVIEWED ARE GIVEN BY AGE GROUP, BY EDUCATION, AND BY ECONOMIC STATUS Item All religions Non-Catholics Men Women Men Women % N % N % N % N Age: Under 30 29 86 17 149 34 65 19 7 102 169 30 to 44 19 172 8 238 20 Education: 13 71 College High school Grade school Economic status: 1 2 32 18 13 33 20 98 142 24 80 75 15 9 11 11 13 100 264 35 113 105 36 19 6 35 24 110 17 58 58 9 14 11 14 5 180 28 75 72 64 3 19 65 7 94 18 50 14 66 4 - 13 41 16 82 15 33 It may be seen that, in general, a proposal for distribution of pills to teen- age girls meets with very little approval. There is more disapproval among women than among men. Even among women under the age of 30, only 17 per- cent approve; among men in this age group, 29 percent approve. At no age does feminine approval reach 20 percent, and in most cases it is below 15 per- cent. Furthermore, restriction of the results to non-Catholics does not raise the percentages of those who approve the policy. Most noteworthy is the socioeco- nomic gradient among men. Whereas 32 percent of college-educated men approve distribution of pills to young girls, only 13 percent of men with a grade school education do. Thirty-three percent of men in the highest income bracket approve, but only 13 percent in the lowest bracket do. Clearly, the extension of "family planning" to poor, unmarried teenagers is not regarded simply as "health care." Individuals may approve, in a general PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7099 way, a wider availability of birth-control information without approving fed- eral expenditure to facilitate a high level of sexual activity by teenage girls. One suspects that explicit recognition and implied approval of such activity still comes hard to our population, and that it comes hardest to the group most involved in the problems of illegitimacy and premarital conception- namely, the poor and uneducated themselves. The extreme disapproval of a policy of pill distribution to teen-age girls that is found in lower-class groups (particularly among lower-class men) suggests that a double standard of sexual behavior is operative in these groups-a standard that does not allow open toleration of the idea that the ordinary teen-age girl requires the pill, or that a part of her junior high school and high school education should include instruction in its use. CAN "FIVE MILLION WOMEN" BE WRONG? The most widely publicized argument favoring federal birth-control pro- grams, and apparently the one that elected officials find most persuasive, is the claim there there are approximately "five million" poor women "in need" of publicly subsidized birth-control help (17). I list below some of the principal assumptions upon which this estimate is based-all of which introduce serious upward biases into the evidence. 1) It is claimed that women at the poverty and near-poverty levels desire families of 3.0 children. While this may be true of nonwhite wives at this eco- nomic level, it is not true, as we have seen, of white women, who comprise a major share of the "target" group and who, on the average, desire a number of children closer to 4 (especially if Catholics are included, as they are in the "five million"). 2) It is assumed by the estimators that 82 percent of all poor women aged 15 to 44 are at risk of conception (that is, exposed sexually), in spite of the fact that only 45 percent of poor women in this age group are married and living with their husbands. In arriving at the figure of 82 percent, the estima- tors assumed that all women in the "married" category (including those who were separated from their husbands and those whose husbands were absent) were sexually exposed regularly, and that half of the women in the "non-mar- ried" category-that is, single, widowed, and divorced women-were exposed regularly. Information is scarce concerning the sexual behavior of widows and divorced women, but Kinsey's data on premarital coitus leads one to believe that the assumption of 50 percent for single women may be high. Among the women with a grade school education in Kinsey's sample, 38 percent had had coitus at some time between the ages of 16 and 20, and 26 percent, at some time between the ages of 21 and 25. Moreover, as Kinsey emphasizes, these encounters were characteristically sporadic (18). 3) The proportion of sterile women among the poor is assumed to be 13 per- cent, although the Scripps 1960 "Growth of American Families Study" showed the proportion among white women of grade school education to be 22 percent (14, p. 159). 4) No allowance is made for less-than-normal fecundity, although the Scripps 1960 study (14, p. 159) had indicated that, among women of grade school edu- cation, an additional 10 percent (over and above the 22 percent) were subnor- mal in their ability to reproduce. 5) It is taken for granted by the estimators that no Catholic women would object, on religious grounds, to the use of modern methods, and no allowance is made for objection by non-Catholics, on religious or other grounds. In other words, it is assumed that all women "want" the service. Yet, in response to a question concerning the desirability of limiting or spacing pregnancies, 29 per- cent of the wives with grade school education who were interviewed in the Scripps 1960 study said they were "against" such limitation or spacing (14, p. 177). Among the Catholic wives with grade school education, the proportion "against" was 48 percent, although half of these objectors were "for" the rhythm method. Similar objections among the disadvantaged have been revealed by many polls over a long period. 6) Perhaps most important, the estimate of 5 million women "wanting" and "in need of "birth-control information includes not only objectors but women who are already practicing birth control. Hence, in addition to all the other biases, the estimate represents a blanket decision by the estimators that the PAGENO="0270" 7100 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY women require medical attention regarding birth control-particularly that they need the pill and the coil. In the words of the Harkavy report (2, attach- ment A, p. 19): "This may be considered a high estimate of the number of women who need to have family planning services made available to them in public clinics, because some of the couples among the poor and near poOr are able to exercise satisfactory control over their fertility. However, even these couples do not have the same access as the non-poor to the more effective and acceptable methods of contraception, particularly the pill and the loop. So, simply in order to equalize the access of the poor and the near-poor to modern methods of contraception under medical supervision, it is appropriate to try to make contraceptive services available to all who may need and want them." Yet the 1960 Scripps study found that, among fecund women of grade school education, 79 percent used contraceptives (14, p. 159). The 21 percent who did not included young women who were building families and said they wanted to get pregnant, as well as Catholics who objected to birth control on religious grounds. As for the methods that women currently are using, it seems gratui- tous for the federal government to decide that only medically supervised meth- ods-the pill and the coil--are suitable for lower-income couples, and that a mammoth "service" program is therefore required. In fact, the implications of such a decision border on the fantastic-the implications that we should sub- stitute scarce medical and paramedical attention for all contraceptive methods now being used by poor couples. In sum, the argument supporting a "need" for nationwide, publicly sustained birth-control programs does not stand up under empirical scrutiny. Most fecund lower-class couples now use birth-control methods when they want to prevent pregnancy; in the case of those who do not, the blame cannot simply be laid at the door of the affluent who have kept the subject of birth control under wraps, or of a government that has withheld services. As we have seen, opinion on birth control has been, and is, less favorable among the poor and the less well educated than among the well-to-do. In addition, the poor desire larger families. Although it may be argued that, at the public welfare level, birth control has, until recently, been taboo because of the "Catholic vote," most individuals at all social levels have learned about birth control informally and without medical attention. Furthermore, the most popular birth-control device, the condom, has long been as available as aspirin or cigarettes, and certainly has been used by men of all social classes. When one bears in mind the fact that the poor have no difficulty in gaining access to illegal narcotics (despite their obvious "unavailability"), and that the afiluent had drastically reduced their fertility before present-day contraceptive methods were available, one must recognize and take into account a motivational component in nonuse and inefficient use of contraceptives. Indeed, were relative lack of demand on the part of the poor not a principal factor, it would be difficult to explain why such an important "market" for birth-control materials-legal or illegal-would have escaped the attention of enterprising businessmen or bootleggers. In any event, any estimate based on the assumption that all poor women in the reproductive group "want" birth-control information and materials and that virtually all "need" publicly supported services that will provide them-including women with impaired fecundity, women who have sexual intercourse rarely or not at all, women who object on religious grounds, and women who are already using birth-control methods-would seem to be seriously misleading as a guide for our government in its efforts to control population growth. Moreover, the proposal for government sponsorship takes no account of the possible advantages of alternative means of reaching that part of the "market" that may not be optimally served at present. For example, competitive pricing, better marketing, and a program of advertising could make it possible for many groups in the population who are now being counted as "targets" for gov- ernment efforts to purchase contraceptives of various kinds. When one bears in mind the fact that an important reason for nonuse or lack of access to contra- ceptives may be some sort of conflict situation (between husband and wife, adolescent child and parent, and so on), it becomes apparent that the imper- sonal and responsive marketplace is a far better agency for effecting smooth social change than is a far-flung national bureaucracy loaded with well-mean- ing but often blundering "health workers." The government could doubtless play an initial stimulating and facilitating role in relation to private industry, PAGENO="0271" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7101 without duplicating, on a welfare basis, functions that might be more efficiently handled in the marketplace. WOULD THE POLICY HAVE SIDE EFFECTS? The possible inadvisability of having the government become a direct purve- yor of birth-control materials to poverty groups becomes more clear when we consider some of the risks involved in such a course of action. Even if the goal of reducing family size were completely and widely accepted by the poorer and less well educated sectors of the population, we should not assume that the general public would necessarily view a policy con- cerned with the means and practice of birth control (in any social group) as it views ordinary medical care-that is, as being morally neutral and obvious- ly"desirable." Birth control is related to sexual behavior, and, in all viable societies, sexual behavior is regulated by social institutions. It is thus an over-simplification to think that people will be unmindful of what are, for them at least, the moral implications of changes in the conditions under which sexual intercourse is possible, permissible, or likely. An issue such as distrib~ tion of pills to teen-age girls runs a collision course with norms about premari- tal relations for young girls-norms that, in turn,~ relate to the saliency of marriage and motherhood as a woman's principal career and to the consequent need for socially created restrictions on free sexual access if an important inducement to marriage is not to be lost. Only if viable careers alternative to marriage existed for women w-ould the lessening of controls over sexual behav- ior outside of marriage be unrelated to women's lifetime opportunities, for such opportunities would be independent of the marriage market and, a for- tiori, independent of sexual bargaining. But such independence clearly does not exist. Hence, when the government is told that it will be resolving a "medical" problem if it makes birth control pills available to teen-agers, it is being misled into becoming the protagonist in a sociologically based conflict between short-run feminine impulses and long-run feminine interests-a conflict that is expressed both in relations between parents and children and in relations between the sexes. This sociological conflict far transcends the "medical" issue of whether or not birth-control services should be made widely available. Actually, the issue of sexual morality is only one among many potentially explosive aspects of direct federal involvement in family-planning programs for the poor. Others come readily to mind, such as the possibility that the pill and other physiological methods could have long-run, serious side effects, or that racial organizations could seize on the existence of these programs as a prime example of "genocide." Eager promoters of the suggested programs tend to brush such problems aside as trivial, but the problems, like the issue of sexual morality, cannot be wished away, for they are quite patently there (9, p. 62). There are risks involved in all drug-taking, and it is recognized that many of the specific ones involved in long-term ingestion of the pill may not be discov- ered for many years. No one today can say that these are less than, equal to, or greater than the normal risks of pregnancy and child-birth. Equally, a class-directed birth control program, whatever its intent, is open to charges of genocide that are difficult to refute. Such a program cannot fail to appear to single out the disadvantaged as the "goat," all the while implying that the very considerable "planned" fertility of most Americans inexplicably requires no government attention at all. POPULATION POLICY FOE AMERICANS It seems clear that the suggested policy of poverty-oriented birth-control pro- grams does not make sense as a welfare measure. It is also true that, as an inhibitor of population growth, it is inconsequential and trivial. It does not touch the principal cause of such growth in the United States-namely, the reproductive behavior of the majority of Americans who, under present condi- tions, want families of more than three children and thereby generate a growth rate far in excess of that required for population stability. Indeed, for most Americans the "family planning" approach, concentrating as it does on the distribution of contraceptive materials and services, is irrelevant, because they already know about efficient contraception and are already "planning" their families. It is thus apparent that any policy designed to influence repro- PAGENO="0272" 7102 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ductive behavior must not only concern itself with all fecund Americans (rather than just the poor) but must, as well, relate to family-size goals (rather than just to contraceptive means). In addition, such a policy cannot be limited to matters affecting contraception (or even to matters affecting gestation and parturition, such as abortion), but must, additionally, take into account influ- ences on the formation and dissolution of heterosexual unions (19). What kinds of reproductive policies can be pursued in an effort to reduce long-term population growth? The most important step toward developing such new policies is to recognize and understand the existing ones, for we already have influential and coercive policies regarding reproductive behavior. Further- more, these existing policies relate not merely to proscriptions (legal or infor- mal) regarding certain means of birth control (like abortion) but also to a definition of reproduction as a primary societal end and to an organization of social roles that draws most of the population into reproductive unions. The existence of such pronatalist policies becomes apparent when we recall that, among human beings, population replacement would not occur at all were it not for the complex social organization and system of incentives that encourage mating, pregnancy, and the care, support, and rearing of children. These institutional mechanisms are the pronatalist "policies" evolved uncon- sciously over millennia to give societies a fertility sufficient to offset high mor- tality. The formation and implementation of antinatalist policies must be based, therefore, on an analysis and modification of the existing pronatalist policies. It follows, as well, that antinatalist policies will not necessarily involve the introduction of coercive measures. In fact, just the opposite is the case. Many of these new policies will entail a lilting of pressures to reproduce, rather than an imposition of pressures not to do so. In order to understand this point let us consider briefly our present-day pronatalism. It is convenient to start with the family, because pronatalism finds its most obvious expression in this social institution. The pronatalism of the family has many manifestations, but among the most influential and universal are two: the standardization of both the male and the female sexual roles in terms of reproductive functions, obligations, and activities, and the standardization of the occupational role of women-half of the population-in terms of child- bearing, child-rearing, and complementary activities. These two "policies" insure that just about everyone will be propelled into reproductive unions, and that half of the population will enter such unions as a "career"-a life's work. Each of the two "policies" is worth considering. With regard to sex roles, it is generally recognized that potential human variability is greater than is normally permitted within each sex category. Existing societies have tended to suppress and extinguish such variability and to standardize sexual roles in ways that imply that all "normal" persons will attain the status of parents. This coercion takes many forms, including one- sided indoctrination in schools, legal barriers and penalties for deviation, and the threats of loneliness, ostracism, and ridicule that are implied in the una- vailability of alternatives. Individuals who-by temperament, health, or consti- tution-do not fit the ideal sex-role pattern are nonetheless coerced into attempting to achieve it, and many of them do achieve it, at least to the extent of having demographic impact by becoming parents. Therefore, a policy that sought out the ways in which coercion regarding sex roles is at present manifesting itself could find numerous avenues for relieving the coercion and for allowing life styles different from marriage and parenthood to find free and legitimatized expression. Such a policy would have an effect on the content of expectations regarding sex roles as presented and enforced in schools, on laws concerning sexual activity between consenting adults, on taxation with respect to marital status and number of children, on residential building policies, and on just about every facet of existence that is now organized so as exclusively to favor and reward a pattern of sex roles based on marriage and parenthood. As for the occupational roles of women, existing pressures still attempt to make the reproductive and occupational roles coterminus for all women who elect to marry and have children. This rigid structuring of the wife-mother position builds into the entire motivational pattern of women's lives a tend- ency to want at least a moderate-size family. To understand this point one must recognize that the desired number of children relates not simply to the wish for a family of a particular size but relates as well to a need for more PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7103 than one or two children if one is going to enjoy "family life" over a signifi- cant portion of one's lifetime. This need is increased rather than lessened by improved life expectancy. Insofar as women focus their energies and emotions on their families, one cannot expect that they will be satisfied to play their only important role for a diminishing fraction of their lives, or that they will readily. regard make-work and dead-end jobs as a substitute for "mothering." The notion that most women will "see the error of their ways" and decide to have two-child families is naive, since few healthy and energetic women will be so misguided as to deprive themselves of most of the rewards society has to offer them and choose a situation that allows them neither a life's work out- side the home nor one within it. Those who do deprive themselves in this fash- ion are, in effect; taking the brunt of the still existing maladjustment between the roles of women and the reproductive needs of society. In a society oriented around achievement and accomplishment, such women are exceptionally vulner- able to depression, frustration, and a sense of futility, because they are being blocked from a sense of fulfillment both at home and abroad. In sum, the problem of inhibiting population growth in the United States cannot be dealt with in terms of "family-planning needs" because this country is well beyond the point of "needing" birth control methods. Indeed, even the poor seem not to be a last outpost for family-planning attention. If we wish to limit our growth, such a desire implies basic changes in the social organization of reproduction that will make nonmarriage, childlessness, and small (two- y families far more prevalent than they are now. A new policy, to achieve such ends, can take advantage of the antinatalist tendencies that our present institutions have suppressed. This will involve the lifting of penalties for antinatalist behavior rather than the "creation" of new ways of life. This behavior already exists among us as part of our covert and deviant culture, on the one hand, and our elite and artistic culture, on the other. Such antinatalist tendencies have also found expression in feminism, which has been stifled in the United States by means of systematic legal, educational, and social pres- sures concerned with women's "obligations" to create and care for children. A fertility-control policy that does not take into account the need to alter the present structure of reproduction in these and other ways merely trivializes the problem of population control and misleads those who have the power to guide our country toward completing the vital revolution. References and Notes 1. Hearings on 5. 1676, U.S. Senate Subcommittee on Foreign Aid Ewpendi- tures (the 1965 and 1966 Hearings each comprise seven volume; the 1967-1968 Hearings, to date, comprise three volumes) (Government Printing Office, Washington, D.C.). 2. "The Growth of U.S. Population," Nat. Acad. Sci.-Nat. Res. Council Pub. 1279 (1965). 3. 0. Harkavy, F. S. Jaffe, S. S. Wishik, "Implementing DHEW Policy on Family Planning and Population" (mimeographed, 1967; available from the Ford Foundation, New York). 4. "Report of the President's Committee on Population, and Family Plan- ning: The Transition from Concern to Action" (Government Printing Office, Washington, D.C., 1968). 5. K. Davis, Science 158, 730 (1967) J. Blake, in Public Health and Popula- tion Change, M. C. Sheps and J. C. Ridley, Eds. (Univ. of Pittsburgh Press, Pittsburgh, Pa., 1965). 6. In the words of the Committee on Population, "The freedom to limit family size to the number of chilren wanted when they are wanted is, in our view, a basic human right . . . most Americans of higher income and better education exercise this right as a matter of course, but . . . many of the poor and uneducated are in fact deprived of the right." 7. W. J. Cohen, Family Planning: One Aspect of Freedom. to Choose (Gov- ernment Printing Office, Washington, D.C., 1966), p. 2. Cohen, former Secretary of Health, Education, and Welfare, says: "Until a few years ago, family plan- ning and population problems were considered `hush-hush' subjects. Public dis- cussion was curtailed not only in polite soceity, but in the legislative and executive branches of the government as well." 40-471 0-70-pt. 17-18 PAGENO="0274" 7104 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 8. Hearings on 5. 2993, U.S. Senate Subcommittee on. Employment, Man- power, and Poverty, 89th Congress, Second Session, May 10 (Government Printing Office, Washington, D.C., 1966), p. 31. 9. Hearings on S. 1676, U.S. Senate Subcommittee on Foreign Aid Ea~pendi- tures, 90th Congress, First Session, November 2 (Government Printing Office, Washington, D.C., 1967), pt. 1. 10. Senator Tydings (D-Md.) said at the Hearings on S. 1676 (see 9): "As recently as 3 or 4 years ago, the idea that Federal, State or local governments should make available family planning information and services to families who could not otherwise afford them was extremely controversial. But in a brief period of time there has been a substantial shift of opinion among the moral leadership of our country, brought about in large measure by the vigor- ous efforts of the distinguished Senator from Alaska, Ernest Gruening, the chairman of this subcommittee." 11. E. Gruening, "What the Federal Government is now Doing in the Field of Population Control and What is Needed," speech presented before the U.S. Senate, 3 May 1967. 12. J. M. Stycos, in World Population and U.S. Government Policy and Pro- grams, F. T. Brayer, Ed. (Georgetown Univ. Press, Washington, D.C., 1968). 13. R. Freedman, P. K. Whelpton, A. A. Campbell, Family Planning, Sterility and Population Growth (McGraw-Hill, New York, 1959). 14. P. K. Whelpton, A. A. Campbell, J. E. Patterson, Fertility and Family Planning in the United States (Princeton Univ. Press, Princeton, N.J., 1966). 15. J. Blake, Demography 3, 154 (1966); Population Studies 20, 27 (1966) ibid. 21, 159 (1967) ; ibid., p. 185; ibid. 22, 5 (1968). 16. Family Planner 2, 3 (1968). 17. The estimate (by Arthur A. Campbell) under discussion here may be found in the Harkavy report (see 3, attachment A, pp. 4-19). Another esti- mate has been circulated by the Planned Parenthood Federation in a brochure entitled Five Million Women (Planned Parenthood, New York). 18. A. C. Kinsey, W. B. Pomeroy, C. E. Martin, P. B. Gebhard, Sea~ual Behavior in the Human Female (Saunders, Philadelphia, 1953), pp. 291 and 337. 19. K. Davis and J. Blake, Econ. Develop. Cult. Change 4, 211 (1956). 20. I make grateful acknowledgment to the Ford Foundation for support of the research presented in this article and to the National Institutes of Health (general research support grant 1501-TR-544104) for assistance to Statistical Services, School of Public Health, University of California, Berkeley. I am also indebted to Kingsley Davis, whose critical comments and helpful sugges- tions have greatly advanced my thinking. The Roper Center and the Gallup Poll kindly supplied me with polling data. PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7105 Reprinted from AMERICAN JOURNAL OF PUBLIC HEALTH, Vol. 59, No. 3, March, 1969 Copyright by the American Public Health Association, Inc., 1740 Broadway, New York, N. Y. 10019 Mortality trends in the United States are consistent with British case-control studies which have indicated an association of oral contraceptive usage with venous thromboeinbolisin and possibly coronary thrombosis. The trends, however, do not reflect the reported association with cerebral thrombosis. ORAL CONTRACEPTIVES AND MORTALITY TRENDS FROM THROMBOEMBOLISM IN THE UNITED STATES Robert E. Markush, M.D., MPH., and Daniel G Seigel, S.D. Infroducflon I N the United States about 15 per cent I of married women under 45 years of age were using oral contraceptives in 1965, four years after the drugs were released to the general market.' Three case-control studies in England, two of morbidity2'3 and one of mortality,4 have suggested that women using oral con- traceptives have an appreciably in- creased risk from superficial phlebitis, pulmonary embolism, deep vein throm- bosis, and possibly cerebral thrombosis. The large relative risks reported in the British studies combined with the ex- tensive use of oral contraceptives in the United States would lead one to expect increases in selected categories of mor- tality. Trends in national mortality sta- tistics provide a readily available source of data to determine whether these in- creases have, in fact, occurred. Although there are major problems in the use of mortality data for the study of etiologic relationships, they are not the same set of problems as those which beset case- control studies. This report, therefore, supplements the case-control studies with an analysis of US mortality trends since 1951 for underlying causes of death that are related to thrombosis or thrombo- embolism. Method The categories of the International Classification of Diseases (lCD), Seventh Revision, included in the re- port (see Table 1) represent 7 per cent of all 1965 US deaths of women age 15-44. The selection of cause of death categories which represent the thrombo- embolic disorders is somewhat arbi- trary.3 Not included are causes of death, such as those involving surgery and trauma, in which factors other than disorders of the clotting mechanism probably have an overwhelming influ- ence on incidence and survival. The analyses were based on pub~ lished and unpublished data from the US National Center for Health Sta- tistics.6 For the cause of death categories involving small numbers, only data on the numbers of deaths since 1960 are included in this report. Analyses on the three larger groupings, 332, 420, and 460-8 are based on mortality rates from 1951 through 1966 (Table 2). The 460-8 lCD group includes several categories not directly related to throm- bosis or embolism: 460, 461, 462, 467.0, 418 VOL. 59. NO. 3. A.JP.H. PAGENO="0276" 7106 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM 468, and parts of 467.1 and 467.2. How- ever, less than 13 per cent of 1965 US deaths in the broad 460-8 group of women in both the 15-44 and 45.64 age groups were in the irrelevant categories. The largest proportion of 460.8 deaths- 48 per cent in both 15.44 and 45-64. year-old women-was from pulmonary embolism and infarction, category 465. Of the individual lCD categories that involve stroke, only 332 is included in this report. This category represents only 6 per cent of the 1965 stroke deaths (lCD 330.4) of women in the 15.44 age group and 20 per cent of those in the 45-64 age group. Though 331 is the lCD category to which "cerebrovascular acci- dent" is coded, a large part of this cate- gory nevertheless consists of nonthrom. botic diagnoses, and consequently is not included.7 For the years in this report prior to 1958, the Sixth Revision of the Interna- tional Classification of Diseases was used in coding cauCes of death; since 1958, the Seventh Revision has been in use. The effect of this change is negligible for the causes covered in this report. Its effect is small in relation to the amount of variability in the trends; fur. thermore, it causes only a single break in the curves, i.e., in 1958. Table 4 pre- sents available ratios of the number of deaths in specific categories according to the Seventh Revision, divided by the comparable number coded by the Sixth Revision.8 Most of the ratios are close to 1.00. The following steps were used to de- termine the relative change in mortality since 1961 for women in each five-year age group between ages 15 and 64, both Table 1-Seventh Revision International Classification of Diseases Categories Included in Report; numbers of US 1965 deaths by broad age and sex groups Numbers of US deaths in 1965 Age 15-44 Age 45-64 lCD No. lCD Title Men Women Men Women I. 332 Cerebral embolism and thrombosis 226 168 4,130 2,811 11. 341 Phlebitis and thrombophiebitis of intracranial venous sinuses 2 4 6 9 III. 420 Arteriosclerotic heart disease, including coronary disease 11,873 2,616 10,972 5.346 IV. 454 Arterial embolism and thrombosis 30 33 240 119 V. 460-8 Diseases of veins and other diseases of circulatory system 421 587 1,971 1,452 A. 460 Varicose veins of lower extremities 4 15 28 55 B. 461 Hemorrhoids 6 3 9 5 C. 462 Varicose veins of other specified sites 30 9 111 37 D. 463 Phlebitis and thrombophlebitis of lower extremities 48 60 203 185 E. 464 Phlebitis and thrombophlebitis of other sites 34 69 182 147 F. 465 Pulmonary embolism and infarction 200 279 757 693 - G. 466 Other venous embolism and thrombosis 72 117 342 244 H. 467 Other diseases of circulatory system 24 35 138 79 1. 468 Certain diseases of lymph nodes and lymph channels 3 0 2 7 VI. 570.2 Mesenteric infarction 41 45 313 250 MARCH. 1969. 419 PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7107 white and nonwhite, and for each of the three large diagnostic groups: a. For the mortality rates for each time period, 1951-1956, 1957-1961, and 1962-1966, we fitted a straight line by the method of least squares. b. The mean annual per cent change in mor- tality rate was estimated by dividing the slope for the time period by the mean mor- ~tality rate. c. The mean annual change for women during 1962-1966 was compared with four different expected values. The comparions were: Comparison (1), with women during 1957-1961. The annual per cent change for women during 1957-1961 was subtracted from that for 1962-1966. Comparison (2), with women during 1957.1961, adjusted for corresponding changes in men. The mean annual per cent change for men during 1957-1961 was subtracted from that for men during 1962-1966. This difference was subtracted from the difference obtained in Comparison 1. Comparison (3), with women during 1957-1961, adjusted for changes between 1951-1956 and 1957-1961. The mean annual per cent change for women during 1951-1956 was subtracted from that during 1957-1961. This difference was then subtracted from the difference obtained in Comparison 1. Comparison (4), with men during 1962-1966. The mean annual per cent change for men during 1962-1966 was subtracted from that for women in the same period. The comparisons, for cerebral throm. bosis are presented in Table 5; for ar- teriosclerotic heart disease, in Table 6; and for diseases of the veins, in Table 7. Table 2-Mortality data included for each cause of death category in report lCD (7th Rev.) Cause of death category Period covered Kind of data prcsented in report Location in report 1. 332 1951-66 Estimated % annual change for women 1962-66 Fig. 1 II. 341 1960-66 Numbers Table 3 III. 420 * 1951-66 Estimated % annual change for women 1962-66 Fig. 1 IV. 454 1960-66 Numbers Table 3 V. 460-8 A. 460 B. 461 C. 462 D. 463 E. 464 F. 465 G. 466 H. 467 I. 468 1951-66 1960-66 1960-66 1960-66 1960-66 1960-66 1960-66 1960-66 1960-66 1960-66 Estimated % annual change for women 1962-66; graphs of rates Nttmbers Numbers Numbers Numbers Numbers Numbers Numbers Numbers Numbers Fig. 1 Figs. 2-9 Table 3 Table 3 Table 3 Table 3 Table 3 Table 3 Table 3 Table 3 Table 3 \TJ 570.2 1962-66 Numbers Table 3 420 VOL 59. NO. 3, A.J.P.H. PAGENO="0278" Cli -3 C~ ~ C~ C\ Cli ~ p co -i cji ~ - A 00 ~ z~ z~ z~ ~ z~ z~ z~ 0 H `C,) - ~ - ~ ~ c - ~ - ~ - ~., 1'~) ~-3 - - co t-~ Cl3 ~ 0~ 0~ \0 co Cl3 -4 Cli Cl3 ~O Cli ~ ~ - t-3 ~ t-~ Cli ~ 0 C13 I) - \0 Cl3 -3 ~ -4 0 0 t~3 ~ V0 o r -~- -- -~ 0~ ~ ~ ~ ~ ~0Cl30\~ 0~Cl33~) Cl#-~--1~ 0Cl)~-~ H ~ ~Cl~0 Cl3CJi~-~ ~ ~ 0~0 ffl * d -- a ~3~3 ©~-~ ~ -~ z 01~)0 ~ ~co~ ~3-4--3~ 0Cl~Cl~ ~ 0 0 ~ ~03~ c~o~-4~ co-co ~c~ci Cl3C~3~ co~c~c~ PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7109 The results of the four different com- parisons were then averaged for each five-year age and color group for each diagnosis. These means are presented as bar graphs in Figure 1. The mortality trends from which these statistics are de- rived are presented in Figures 2-9 only for lCD 460-8. Results I. Cerebral Embolism and Throm- bosis, lCD 332-Figure 1 indicates that death rates for most five-year age groups of women ages 15 through 64 have been decreasing for both the white and the nonwhite in relation to the four comparison groups used. The four siz- able exceptions are: (1) a 6 per cent mean annual per cent increase for the 25-29-year-old white; (2) a 2 per cent increase for the 45-49-year-old white; (3) a 16 per cent increase for the 25-29- year-old nonwhite; and (4) a 25 per cent increase for the 30-34-year-old non- white. All but one of these increases are based on an average of less than 20 deaths per year. Table 5 indicates that each of the four increases occurred with each of four comparison groups. ii. Phlebitis and Thrombophlebitis of the Intracranial Venous Sinuses, lCD 341 (Table 3)-There have been few deaths of women age 15-44 in this cate- gory, and no apparent tendency since 1962 for the numbers to increase. III. Arteriosclerotic Heart Disease, in- cluding Coronary Disease, lCD 420-In Figure 1 all five-year age groups from 15-39 of white, and all nonwhite five- year age groups from 20-49, show at least some relative increase. Most of these increases, however, are either small or based on relatively small numbers of Table 4-Available comparability ratios for thromboembolic causes of deaths: ratios of numbers of deaths by Seventh Revision of the International Lists over those by Sixth, by age and sex, when available8 Decedent age group Color and sex 15-24 25-34 35-44 45-54 55-64 All ages I. Prevalence by color, age, and sex A. Vascular Lesions of Central Nervous System, 330-4 White men 1.05 0.92 0.93 0.97 1.00 1.00 White women - 1.00 0.89 1.00 0.99 1.00 Nonwhite men - - 0.91 0.97 1.00 1.00 Nonwhite women - 093 0.89 0.95 100 097 B. "Other Diseases of Circulatory System," 451-68 White men - - 0.90 1.05 1.03 1.01 White women - - 100 0.98 1.06 1.08 Nonwhite men - - - - 1.05 L04 Nonwhite women - - - 1.19 - 1.08 C. Arteriosclerotic heart disease, including coronary disease, 420 White men - 1.01 1.01 100 1.00 0.99 White women - 1.00 1.02 0.99 0.98 0.97 Nonwhite men - 100 0.99 0.99 0.98 0.97 Nonwhite women - - 0.94 0.94 0.94 0.95 II: Ratios not available specific for age, sex, or color A. Cerebral embolism and thrombosis, 332 B. Diseases of the veins and other diseases of the circulatory system, 460-8 1.02 1.15 C. Mesenteric thrombosis, 570-2 1.17 422 VOL. 59. NO. 3 A.J.P.H. PAGENO="0280" 7110 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM deaths. The exceptions are: (1) an 8 per cent mean annual increase for white 20-24; (2) a 4 per cent increase for white 35-39; (3) a 10 per cent increase for nonwhite 30-34; and (4) a 4 per cent increase for nonwhite 35-39-. Table 6 indicates that all but the last of these were positive with respect to all four comparisons. IV. Arterial Embolism and Throm- bosis, lCD 454 (Table 3)-As in lCD 341, there is no evidence of an increas- ing trend since 1962 in this relatively small category. V. Diseases of Veins and Other Dis- eases of Circulatory System, lCD 460-8 -Figure 1 indicates that all five-year age groups between 20 and 54 for both white and nonwhite have relative in- creases. Table 7 indicates that the relto- tive increases among the white for age groups 30-34, 35-39, 40-44, and 50-54, and among the nonwhite for age groups 30-34, 35-39, and 45-49, occur in each of the four comparisons used. Data for 1960-1966 mortality were available for the individual causes of death constituting 460-8. Categories 463-6 make up the majority of these deaths. a. Varicose Veins of Lower Extremi- ties, lCD 460 (Table 3)-There is no increasing trend for either men Or women in this small category. Table 5-US mortality from cerebral embolism and thrombosis (7th Revision lCD Category 332) Women, ages 15-64, by color and five-year group Annual per cent change during 1962-66, based on four comparisons Comparison 2 Comparison 3 Comparison 1 Comparison 1 Comparison 1 Comparison 4 Expectation adjusted for adjusted for Expectation based on rates analogous analogous based on rates for women, changes changes, for men, 1957-61 for men 1951-56 1962-66 White 15-19 +2 -13 +4 -33 20-24 -17 -17 + 1 -29 25-29 +6 +8 +1 +9 30-34 +3 -7 +4 -10 35-39 -15 -16 -26 - 5 40-44 0 -1 +1 -1 45-49 +1 +4 +1 +3 50-54 -7 -7 -11 - -2 55-59 -3 -5 +1 -7 60-64 -4 -3 -4 -2 Nonwhite 15-19 -34 -43 -53 -32 20-24 -37 +53 -90 +48 25-29 +16 +12 +18 +17 30-34 +17 +32 +30 +22 35-39 -15 -29 -25 - -26 40-44 -7 +9 -2 -3 45-49 -9 -11 -5 - -6 50-54 -4 +2 +1 -5 55-59 -9 -13 -6 -5- 60-64 -5 +2 +6 -2 MARCH. 1969 423 PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7111 +20 - Cerebral Embolism and Thrombosis CD ~-7th Rev.) 332 Expected' I I I I I I 5 202530354045 5055 6065 AGE - WHITE LU +40 ~ ArterLosclerotic Heart Disease IC D (7th Rev.) 420 +30 ~ +20 +10 * Expec~d - - _______ Li_i 11111111111 ,.s.,IIIIII II 520253035404550556065 1520253035404550556065 AGE -WHITE . AGE-NONWHITE. C,) Li_i Diseases of Veins, etc. 420 lCD (7th Rev.) 460-468 uPec~Jhlu1m~~ - 15 2025303540455055 6065 .15 2025 30 35404550556065 AGE - WHITE AGE - NONWHITE * Mean number of deaths less than 20 per year in either /962-66 or 1957-6/ Figure 1-Difference between observed and expected annual change in mortality for US women ages 15-64 during 1962-1966 for three underlying causes of death, by sex, color, and five-year age group. I I II 3035404550556065 AGE- NONWHITE 424 VOL. 59. NO. 3, A.J.P.H. PAGENO="0282" 7112 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM b. Hemorrhoids, lCD 461 (Table 3) -This small somewhat irrelevant cate- gory also shows no increase. c. Varicose Veins of Other Specified Sites, lCD 462 (Table 3)-This cate- gory, which has been used mainly for deaths of men, shows no increasing trend. d. Phlebitis and Thrombophiebitis 0/ Lower Extremities, lCD 463 (Table 3)- Deaths for 15-44-year-old women have increased consistently from 34 in 1960 to 70 in 1966, while deaths for men in- creased during the comparable period from 33 to 50. The increase for men was confined to the white, whereas the in- 1.5 .0 0.5 - Women Ages 25-29 0 0 0 0 C w a- Cl) Lu I- `5 >- F- -J 0 1.0 0.5 20-24 0.5 0 r r--i--i'rT,,~-m-"F-m 1519 1951 `52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 2-.-.US mortality 1951-1966 from diseases of veins, etc. lCD (7th Rev.) 460-8, by sex and five-year age group, white, ages 15-29. -Women Ages 3539 2.0 g 0,) ~ /1 0.5 0- 2.0 F- ~ `.5 F- cc .0 0.5 30-34 1951 `52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 3.-US mortality 1951-1966 from diseases of veins, etc., lCD (7th Rev.) 460-8, by sex and five-year age group, white, ages 30-39. MARCH. 1969 425 PAGENO="0283" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7113 crease for women occurred in both color age 15.44 have increased consistently in groups. both white and nonwhite. In 1960 there e. Phlebitis and Thrombophiebitis oJ were 45 deaths of women age 15.44, Other Sites, lCD 464 (Table 3)-As in whereas in 1966 there were 82. No trend the previous category, deaths of women was apparent among 15.44-year-old men 5 Ages Women ~ 1951 `52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 4-US mortality 1951-1966 from diseases of veins, etc. lCD (7th Rev.) 460.8, by sex and five-year age group; white, ages 40-49. 20 Ages -Women is -- Men 60-64 0 I I a- ~3 5 ~ 10 ..----~ 55-59 I I I I I I I 0 :[ 1951 `52 `53 `54 55 ~6 `57 `58 59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 5-US mortality 1951-1966 from diseases of veins, etc. lCD (7th Rev.) 460-8, by sex and five.ycar age group; white, ages 50.64. 426 VOL. 59, NO. 3, A.J.P.H. PAGENO="0284" 7114 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM who had only 25 deaths in 1960, reached a peak of 36 in 1962, and decreased to 28 in 1966. f. Pulmonary Embolism and In/arc- tion, lCD 465 (Table 3)-Females age 15-44 increased from 177 deaths in 1960 to 335 in 1966. For whites the increase was especially prominent-from 113 in 2.0 ~: ~ 1951 52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 6-US mortality 1951-1966 from diseases of veins, etc. lCD (7th Rev.), 460-8, by sex and five-year age group; nonwhite, ages 15-29. 6.0 Ages 35-39 - Women -- Men Ages 0 0 0 0 2 I. Lu a- (I) Lu ~ 3.0 >- i- 2.0 -j I- .0 cc 0 ~ C 1.0 0.0 o 8.0 0 0 cc 6.0 0 ~ 4.0 a- ~2 2.0 r >- I- -J I- cc 0 4.0 2.0 30-34 1951 `52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 7-US mortality 1951-1966 from diseases of veins, etc. lCD (7th Rev.) 460.8, by sex and five-year age group; nonwhite, ages 30-39. MARCH, 1969 427 PAGENO="0285" 2.0 10.0 8.0 0 8 6.0 0 2 4.0 cc Ui ~ 2.0 (I) cli I- cc 0.0 -J `- 8.0 cc 0 6.0 4.0 2.0 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7115 - Women -- Men Ages 45-49 40-44 195 52535455 `56 57 58 `59 `60 `61 `62 `63 `64 `65 `66 YEARS Figure 8-US mortality 1951-1966 from diseases of veins, etc., lCD (7th Rev.) 460-8, by sex and five-year age group; nonwhite, ages 40-49. Ages 64 40 30 20 0 !~ `~ 30 20 tO F- cc o `~ ,, 55-59 ~E ~ 1951 52 `53 `54 `55 `56 `57 `58 `59 `60 `61 `62 `63 64 `65 `66 YEARS Figure 9-US mortality 1951-1966 from diseases of veins, etc., lCD (7th Rev.) 460-8, by sex and five-year age group; nonwhite, ages 50-64. 428 VOL. 59. NO. 3. A.J.P.H. PAGENO="0286" 7116 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM 1960 to 226 in 1966. Males in the same age group increased from 124 in 1960 to 211 in 1966. g. Other Venous Embolism and Thrombosis, lCD 466 (Table 3)- Among females age 15-44 the numbers of deaths increased from 72 in 1960 to 141 in 1966, the increase occurring in both color groups. No such increase was apparent for males, who had 65 deaths in 1960, a peak of 82 in 1964, and 73 in 1966. h. Other Diseases of Circulatory Sys- tem, lCD 467 (Table 3)-This category includes hypotension, hemorrhage not otherwise specified, and a miscellany of other conditions; a few, such as capil- lary thrombosis and phlebosclerosis, might be pertinent. Neither males nor females age 15-44, however, showed any noteworthy trend during the 1960-1966 period. Females ranged from a low of 16 deaths in 1960 to 35 in both 1962 and 1965, with 32 in 1966. Males had a peak of 36 in 1963. i. Certain Diseases of Lymph Nodes and Lymph Channels, lCD 468 (Table 3)-This category has been used for Table 6-US mortality from arteriosclerotic heart disease (7th Revision lCD Category 420) Women, ages 15-64, by color and five-year group .Annual per cent chance durinsr 1962-66. based on four comparisons Comparison 1 Expectation based on rates for women, 1957-61 Comparison 2 Comparison 1 adjusted for analogous changes for men Comparison 3 Comparison 1 adjusted for analogous changes, 1951-56 Comparison 4 Expectation based on rates for men, 1962-66 White 15-19 +45 +39 +63 +11 20-24 +14 +5 +5 +8 25-29 +1 +3 -2 -1 30-34 +2 +1 +4 -3 35-39 +3 +5 ±4 +2 40-44 0 +1 -3 +1 45-49 -1 +1 -3 +1 50-54 0 +1 -1 0 55-59 +1 0 +2 -1 60-64 -1 -1 -1 -1 Nonwhite 15-19 -17 -17 + 1 -47 20-24 +14 -3 +21 -9 25-29 + 2 0 +10 -10 30-34 +12 +7 +20 +1 35-39 +6 +5 +8 -2 40-44 -f-2 -1 +4 -3 45-49 +9 +5 +15 0 50-54 -1 0 0 -2 55-59 +3 -2 +8 -3 60-64 -7 -6 -8 -3 MARCH~ 1969 429 PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7117 very few deaths throughout the 1960- 1966 period. VI. Mesenteric Infarction, lCD 570.2 (Table 3)-Only data since 1962 were available. For females age 15-44 the year 1962 showed a maximum-58 deaths - whereas a minimum was reached in 1964-44 deaths. In 1966 there were 45. Discussion In this paper we have evaluated ex- cess mortality in women in the repro- ductive ages during 1962-1966 with a relative rather than absolute measure. The recognized limitations of underlying cause mortality statistics5'9'10 prevent de. tection of absolute changes that are not proportionally large. Furthermore, the case-control studies have provided data suggesting that the influence of oral con- traceptives on mortality is, in fact, pro- portional. Inman and Vessey report4 that, "Irrespective of age, the risk of death from pulmonary embolism or cere- bral thrombosis was increased seven to eight times in users of oral contracep- tives." For expected mortality, the four com- parison groups we selected seemed most Table 7-US mortality from diseases of veins, etc. (7th Revision lCD Category 460-8) Women, ages 15-64, by color and five-year group Annual per cent change during 1962-66, based on four comparisons Comparison 1 Expectation based on rates for women, 1957-61 Comparison 2 Comparison 1 adjusted for analogous changes for men Comparison 3 Comparison 1 adjusted for analogous changes, 1951-56 Comparison 4 Expectation based on rates for men, 1962-66 White . 15-19 -5 -33 -22 -7 20-24 +12 0 +5 +1 25-29 0 +10 - 8 +12 30-34 +9 +11 +9 +9 35-39 +8 +21 +15 +6 40-44 +16 +7 +18 +9 . 45-49 +1 0 -1 +5 50-54 +4 +3 +7 +8 55-59 +3 -3 +3 -4 60-64 -2 -2 -2 -2 Nonwhite 15-19 0 +2 -4 -4 20-24 +12 -4 +6 +5 25-29 +4 +13 -19 +5 30-34 +17 +13 +26 + 3 35-39 +15 +13 +20 + 5 40-44 +6 0 +1 +1 45-49 +17 +8 +1 +10 50-54 -2 +5 -9 +3 55-59 +6 0 +13 -9 60-64 -6 -14 -18 0 430 VOL. 59. NO. 3. A.J.P.H. PAGENO="0288" 7118 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM reasonable. Rates for Comparisons 2 and 3, however, particularly the latter, have* large variances because they are linear combinations of several estimates of an- nual per cent changes in mortality. Comparisons 1 and 4 may, therefore, be more useful indicators. The expected value used in the final summary statistic, mean per cent change in mortality rate (Figure 1), puts greatest weight on mor- tality for women during 1957-1961, less on mortality for men during 1962-1966, and still less on mortality for women during 1951-1956, and men during 1957- 1961. We used the per cent changes in mor- tality in comparison groups as measures of expected per cent changes in mortal- ity for women in the reproductive ages during 1962-1966. That is, the assump- tion was made that the effects of most factors that influence mortality trends, such as diagnostic fashions, are propor- tional to the level of mortality. Vessey and Weatherall11 made essentially the same assumption in their analysis of mortality in England and Wales when they extended straight regression lines plotted on a logarithmic scale from rates that were observed in the years prior to the introduction of the oral contracep- tives. In addition to the four comparisons incorporated in the derived statistics, two less formal contrasts provide evidence about whether the mortality changes for women in 1962-1966 are consistent with the pattern of oral contraceptive usage in the United States. First, any excess mortality from oral contraceptive use should be confined to the reproductive ages, although concurrent increases in hormone therapy for menopausal symp- toms may make this pattern less precise. Second, the greater use of oral contra- ceptives among the white suggests that the impact on mortality should be greater for this portion of the US popu- lation. On the basis of the above criteria, we believe the results indicate an associa- tion of the oral contraceptives with an increase in mortality from lCD category 460-8, but not from categories 332 or 420. The positive association for 460-8 is generally true for all four comparison groups The relative increases, further- more, occur to only a minor extent out- side the childbearing years of age, par- ticularly in the white population. In contrast, the results for categories 332 and 420 do not meet the criteria we have set for a positive association with oral contraceptive use. For 332, the only age group among whites with increased mortality by all four compatisons was 25-29. Consistently elevated mortality was also found for this age group of nonwhite, where the next older age group was also consistently positive. The negative results in the white groups 30-44, given the limitations of the data and analytic method, suggest that there has been no effect of oral contraceptives on cerebral thrombosis mortality. We do not feel that our analysis has sufficient power to conclude that there has been an effect confined to the 25-29 or 25-34 age groups. The data for category 420 are equivocal; although there are several small to moderate relative increases in both white and nonwhite reproductive age groups, they are neither so large nor so consistent as those occurring in category 460-8. A relation of oral contraceptives to venous thromboembolism, but not to cerebral or coronary thrombosis, may derive from basic differences between venous and arterial circulation. Throm- bosis and embolism in rapid circulation is probably determined by a different set of factors from thrombosis in the veins of the lower extremities, where varicosi- ties, trauma, pregnancy, infection, and the degree and nature of physical activ- ity are fairly well recognized factors. Extensive publicity on adverse effects of oral contraceptives may have led MARCH, 1969 431 PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7119 physicians to use thromboembolic diag- noses with increasing frequency. Fur- thermore, since pulmonary embolism is primarily an autopsy diagnosis,12 changes in autopsy rates which follow a pattern in trend by age, sex, or color similar to that for oral contraceptive use would also distort trends in mortality for lCD 460-8. Since the lCD 460-8 cate- gory accounts for only a small propor- tion of deaths of US women 15.44 (1.2 per cent in 1965), an increasing tend- ency for physicians to use these diag- noses could cause large increases in the 460-8 category along with imperceptible decreases in a variety of other cate- gories. If knowledge that a patient used oral contraceptives increases the likeli- hood of an autopsy and the diagnosis of pulmonary embolism, case-control studies would also be afTected. The lCD category 460-8 is particularly susceptible to a second kind of distor- tion, possible changes in the tendency to be selected as the underlying cause of death when several diagnoses are listed on a death certificate. US multi- ple-cause mortality data for 1955 indi- cate that there were seven times as many diagnoses of 460-8 listed on the death certificates of 15-44-year-olds as were coded as the underlying cause of death.6 Even if biases are not occurring in mortality statistics for the underlying causes being considered, studies which depend on temporal correlations cannot distinguish among agents which have similar distributions in the population. This especially concerns thromboembo- lism, whose determinants are poorly un- derstood.5 The strength of determinants for thromboembolism can be inferred from the marked geographic variation in the prevalence of thrombosis among autop. sied deaths.13'14 The powerful factors responsible for this geographic variation may also be increasing in US females in recent years at the same time that oral contraceptive usage is increasing. For example, cigarette smoking, which has some influence on blood clotting,15 has increased more rapidly in US fe- males than in US males in recent years.'6 Another such example is suggested by experimental work indicating that pul- monary embolism may be a relatively normal clinical occurrence which be- comes pathological only in the presence of cardiac or respiratory diseases.12"7 Increasing mortality from pulmonary embolism among younger women, there- fore, could result from a relatively greater recent increase in the prevalence of pul- monary disease among females, which in turn may be. a result of the relatively greater increase in cigarette smoking in women than in men during recent years. The large amount of unreported chronic respiratory disease present at death, particularly among females, makes it difficult to interpret the rela- tively greater increases for females in the United States in their rate of death from chronic respiratory diseases.18 Inman and Vessey4 reported a case- control study of deaths in the year 1966 in England, Wales, and Northern Ire- land, where thrombosis or embolism of the pulmonary, cerebral, or coronary vessels (or other synonymous terms) were mentioned on either the first or second part of the certificate. They found a strong relation between the use of oral contraceptives and death from pulmonary embolism or cerebral throm- bosis in the absence of predisposing con- ditions. For coronary thrombosis, their results were suggestive but not statis- tically significant. They studied 26 deaths from pul- monary embolism without known pre. disposing conditions, too few to permit detailed examination for such charac- teristics as age and parity. They present a breakdown of the pulmonary embolism deaths, however, that leads them to con- clude "that the excess of users of oral 432 VOL. 59. NO. 3, A.J.P.H. 40-471 O-7~---~pt. 17-19 PAGENO="0290" 7120 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM contraceptives among those women who died was present within broad age and parity groups." The British case-control data indicat- ing a relationship between pill use and mortality from cerebral thrombosis are based on only ten deaths. Similar re- sults were obtained, however, on a small sample of hospitalized cases compared with a matched control series reported by Vessey and Doll.3 The US mortality data do not show an increase for this category that is consistent with the Brit- ish studies. This discrepancy may stem from problems inherent in the case-con- trol and trend studies; from the limited numbers of cases with cerebral throm- bosis in the British case-control studies; from differences between the United States and Great Britain in diagnostic and statistical coding practices; or from real US-British differences in the rela- tionship between the oral contraceptives and disease. The British investigators discussed in detail the potential sources of error in their results. For the most part, the potential sources of error in interpreting correlations between trends in mortality and oral contraceptive usage are both different and more serious. Mortality trends for lCD. categories 463-6 in England and Wales are similar to those for lCD category 460-8 in the United States in that British women age 20-34 have experienced increased mor- tality during 1962-1967, relative both to women during 1953-1962 and relative to men.'1 For age group 35.44, how- ever, the British pattern is somewhat less consistent in that a mortality increase in women has been accompanied by a similar increase in men. Summary Since the introduction of oral contra- ceptives in the United States, underlying cause of death mortality rates for venous thrombosis and pulmonary embolism have increased at a greater rate for US women age 20-44 than the rates for such women in previous years or rates for men in comparable age groups. No such relative increase has occurred in deaths from cerebral embolism and thrombosis, phlebitis and thrombophlebitis of the in- tracranial sinuses, arteriosclerotic heart disease including coronary disease, ar- terial embolism and thrombosis, or mesenteric infarction. The US mortality trends are consist ei~~~h Biitish reportiiü estin~[hui te use 0 ora contraceptives is asso ciated wTi5'~increas~d risk from~~ ~floT~embolism.Like the Britisi i~ôrts, US mortality trends for coronary thrombosis are equivocal. US mortality, however, has not shown the association with cerebral embolism and thrombosis suggested by the British case-control studies. REFERENCES 1 Ryder, N. II., aad Wrttuff. C. F. The lJeit,d States: The Pill aad the Bi,th Rtte. 1960.1965. 5tudir, itt Fatally Plsaaiag. Pub!. Ne. 25. Nrtc Yark. N. Y. Paptlstiaa Caaacil (Jeer) 1967. pp. 1-3. 2. Sabcacutuittce af the Medical Research Caattcil. Belt. M. 3. 2:355-359 (Mty 6), 1967. 3. ~ M. P., ted Dull. R. Iarettigetiaa af Rels. tire Bettccce Use af Oral Caattctcrpti'rrs aed Thrattt' buee,buiic Di,eatr. Ibid. 2:199-205 (Apr. 27). 1968. 4. !ataae, W. H. W.. ted vrttey. M. P. Ittuestigttiae af Deaths frata Pultuaaery. Curaaary. cad Cer,brtl Thcumbetis ted Etubulisre Ia Wum,n af Child- hrtciag Age. thid. 2:193-199 (Apr. 27). 1968. 5. Schutaae. L. H. The Epidetalalugy af Thrasts' burathulic Ditucdrrs: A Reeirw. 3. Chrattir Die. 18:815-845 (Aug.). 1965. 6. vital Statistics uf the Uait,d States, ttttsaal, 1951- 66: Natiuttal Office af Vittl Statistiat (1951.58), Nutiucul Vital Stttittict Dieitiua (1958.62). Ns- tiaaal Crater fat' Health Statistics (1963.66). Wssh- iagtua, D. C.: Drptcttarat af Hrtlth. Edacatiac. ted Wrlfacr. 7. Keller, L. Ccecbrucutculac Diteate Marttlity Aaauag Baltircurc Residrata Aged 20.64. A.J.P.H. 57:2089- 2183 (Dec.). 1967. 8. Pratt, M. H.. sad Dahaaa. A. B. Cusepacability af Mactality Statittict far the Siath aad Sereatb Re- rieiaat: Waited States, 1958. Vital Statittics.Sprcisl Rep. 51. Na, 4, DHEW, 1964. 9 Markash. R. E.; Schaaf, W. E.; sad Saigel, D. C. The lafiaearr af the Death Certifier an the Retells uf Epidrtaialagic Stadirt. 3. Nat. M. A. 59:105-113 (Mar.). 1967. 10. Marbath, R. E., sad Scigrl. D. C. Prerslessce st Death. I. A New Mrthad far Drriaiag Drash Rstes far Specific Diseaars. A.J.P.H. 58:544-557 (Msr.), 1968. 11. Vrt,ry. M. P., sad Wratherall, 3. A. C, Vraaat Thrusabartahulic Ditcasr aad the Use af OrsI Cat- sracepticrt, A Rrui,w af Murtality Statistics is Eaglaed sad Wales. Ltacrt 11:94-85 (Jaly 13). 1968. MARCH 1969 433 PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7121 12. SoloS, L. A. Acute Pulmonary Embolism. Reciecc. Am. Heurt 3. 74:710-724 (Nov.), 1967. 13. Morac. M. Editorial: Low Incidence of Polmonucy The boembolism in Jupan. hp Heuet J. 8:105-106 (Mur.), 1967. 14. Thomus. W. A.; Davies, J. N.; O'NenI, R. M.; and Dimukulnngen, D. A. Incidonce of Myocuedini in. Inaction Coeroluted with Venous and Polmonuey Thrombosis and Embolism. A Geographic Study Bused Upon Autopsies in Uganda. E. Africu, and St. Louis U.S.A. Am. 3. Caediol. 5:41 (Jan.), 1960. 15. Public Heulth Service Publicution No. 1696-The l-leolth Ccnteqoeocen of Smoking. Wusbiogton, 0. C.: DHEW. 1960. 16. Hummond, E. C., aod Guefinkel. L. Changes in Cigucctte Smoking. 1959-1965. A.J.P.H. 58:30-45 (Jun.), 1968. 17. Allison, P. R.; Duanill, M. S.; and Marshall B. Poltoonury Embolism. Thoruta 15:273-283 (Dec.); 1960. 18. Markush, R. E. Nutionul Chronic Respiratory Di,. cute Mortality Study. I. Precalence uad Severity at Death .0f Chronic Retpirntory Ditenses t~n the United States, 1963. J. Chronic Dis. 21:129-141 (June), 5968. Dr. Markush is Deputy Chief, Epidemiology Branch, National Institute of Neurological Diseases and Stroke (Building 36, Room 4A05), Bethesda, Md... 20014. Dr. Seigel is Statistician, Epidemiology and Biometry Branch, National Institute of Child Health and Human Development, Beihesda, Md. This paper was presented before the Epidemiology Section of the American Public Health Association at Ihe Ninety.Sixth Annual Meeting in Detroit, Mich., November 12, 1968. VOL. ~ PlO. 3. A.J~P.H. 434 PAGENO="0292" 7122 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From Medical World News, February 14, 1969, pp. 20-21] PILL EXPERTS PERPLEXED B~ DATA ON PAP SMEARS Investigators studying the cervical epithclium in women taking oral contra- ceptives find themselves on the horns of an anguishing dilemma. They now have data-much of it sketchy and none of it conclusive-suggesting that there is a significant increase in Class III Pap smears and possibly cervical carcinoma in situ in women who have used the pill for several years. The scientists are reluctant to publish their preliminary findings, partly because they don't want fear of the slow-developing, nonlethal in-situ carci- noma to set off unnecessary panic among pill using women. But since the information now on hand is the best available, some of the investigators feel it ought not be suppressed. In Chicago, editors of JAMA have put a bright red "rush" label on a contro- versial report by two Sloan-Kettering cancer researchers who found signifi- cantly more cervical carcinoma in situ among pill users than among diaphra- gam users. JAMA may publish the paper late this month-or not at all. The controversial study, conducted by pathologist Myron Melamed and gynecologist Hilliard Dubrow, is one of at least four independent investiga- tions. One is still incomplete, and one shows no change in incidence between controls and test women. But one, conducted by Dr. George Wied at the Uni- versity of Chicago, reportedly shows a sixfold increase in positive Pap smears among women who have taken oral contraceptives. The Melamed and Wied studies both have the unusual distinction of being branded "inconclusive" by FDA Commissioner Herbert Ley before publication. Dr. Melamed based his study on 35,000 to 40,000 Planned Parenthood clients who had been screened for cervical carcinoma in situ by Pap smears and biop- sies. Excluding the positives, he matched pill takers with diaphragm users retrospectively, on the basis of age, ethnic group, parity, age at first preg- nancy, and family income. Since pill users predominated in the study popula- tion, they were matched with the diaphragm users two to one. After three years, Dr. Melamed reportedly found a statistically significant higher incidence of cervical carcinoma in situ in the pill taking women. Dr. Wied and his colleagues began their study by screening more than 40,000 women at Planned Parenthood clinics for cervical carcinoma in situ by means of Pap smears and biopsies, according to an article published in MWN'S Brit- ish sister publication, WORLD MEDICINE. This yielded them a prevalence rate of three per thousand for the premalignant change. Five years later, when the number of pill users in the study population had dwindled to 509, Dr. Wied found nine cases of carcinoma `in situ among them. Extrapolating from this finding, he reported that the incidence was 18 per thousand-six times the anticipated rate. Dr. Wied denies that he ever released any information about his on-going work except in a confidential memo to a grant-giving agency. "Naturally, I was shocked at this breach in confidence. Moreover, the nine `atypical' smears have to be verified. We are now studying 2,100 women who have been pill users for five years or more. It will take at least three more years before we have any answers." The third study, begun in 1961, is a prospective one with a homologous pop- ulation of 8,000 to 10,000 Puerto Rican women randomly divided into pill users and controls. Dr. David D. Rutstein, chief of the department of preventive medicine at Harvard, designed the study and is analyzing the data. So far, he has not been able to support or refute the hypothesis of a link between the pill and cervical cancer. Dr. Rutstein says the Wied and Melamed papers "have not convinced me because the controls do not permit a precise and comparable measure of the expected incidence of the disease. The expected incidence varies widely, depending on such factors as age at first intercourse, age at marriage, eco- nomic level, number of pregnancies, feminine hygiene practices, and whether the consort is circumcised." Dr. Rutstein believes an adequately controlled study would be very hard to do and would require a prospective approach in which a homogeneous study population was divided randomly into pill users and controls. Discussions with colleagues in Chicago led Dr~ Wied to po~tpoiie hi~ earlier plan to publish his report in the Journal of Reproductive Medicine. At JAMA, PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7123 there was considerable internal debate, but the editors decided to accept Dr. Melamed's paper and schedule its publication-provided some requested changes were made. After a meeting with colleagues and critics in Palm Springs, Calif., last month, Dr. 1~Ie1amed was reported hard at work revising his paper. Because of all the debate, insiders say the revisions will be exten- sive. One quips: "That paper was more finished a month ago than it is today." Queried by ~rw~i, Dr. Melamed denied that he was revising the paper and would say only that he had submitted it to a medical journal and was await- ing word of acceptance. He has persevered under heavy pressure from critics in the birth control and cancer fields, who have urged him not to publish. The situation is so tense that wo weeks ago, the public relations department of Sloan-Kettering denied that any paper had been written by the Melamed- Dubrow team, although at that very moment the authors were discussing the draft submitted to the journal. To complicate the picture even further, Los Angeles pathologist Dean Moyer, who conducted a similar study of his own, finds no change at all in the incid- ence of cervical carcinoma in situ between pill users and nonusers. Dr. Moyer, who is an associate professor of pathology at the University of California at Los Angeles, stresses that his study was set up differently from the others. Instead of having diaphragm users as controls, his study focuses on 25,000 women before and after they began taking the pill. "We found four women with carcinoma of the cervix in situ when we ini- tially screened all the women," he realtes. "And we found four who developed the disease after they were put on the pills. So our incidence is exactly the same in both periods." Moreover, Dr. Moyer finds that oral contraceptives may indirectly help pre- vent invasive carcinoma of the cervix, which is far more dangerous. "We would expect to find about two or three cases for each 10,000 women, but we haven't encountered any at all in our 25,000 pill users. The reason for this is that the pill using women have Pap smears done every year, and we are there- fore able to catch the disease at the dysplasia stage, long before it develops into invasive carcinoma." Another expert, cancer epidemiologist E. Cuyler Hammond of the American Cancer Society, points out that the pill normally creates changes in the cervi- cal epithelium that look like pregnancy. Some investigators, he notes, classify these changes with carcinoma of the cervix in situ. "Maybe they are. But pathologists don't agree on this point, and the reproducibility of results in studies of this nature is very low." He adds that there is no evidence that all cervical carcinomas in situ progress to invasive lesions. ACS publications now describe cervical carcinoma in situ as the earliest, most localized, and most curable form of cancer. The disease, they say, is almost 100% curable, and it is described as "Stage 0" cancer. Moreover, there is somewhat evidence from a study at Boston's Peter Bent Brigham Hospital that dhanges producing positive Pap smears in women on the pill are often-but not always-reversible. Pathologist Tilde Kline in a paper presented last autumn to the American Society of Clinical Pathologists, said she had analyzed Pap smears from 1,221 pill using patients and compared them retrospectively with smears from 16,225 controls. In the medicated group, 2.6% of the smears-or one case in 38-showed dysplastic cells. In non-users, the dysplastic cells occurred only in 0.9% of smears, or one case in every 104 -a threefold difference. In most instances, Dr. Kline believes, the positive smears in her study represent dysplasia, not carcinoma in situ. In 11 of the 32 pill users with positive smears, later smears reverted to "negative"-five without the women having stopped using the drug. In two others, a switch in the pills being used brought reversion to negative smears, and in four others the smears became normal when oral contraception was dis- continued. "There's no question about it," says Dr. Kline, "in some cases these changes were quite obviously reversible." The significance of the Melamed report was hotly debated at a closed meet- ing of an American Cancer Society panel on cervical cancer, where it was first presented in September. According to an account in the Washington Post, whose reporter penetrated the meeting: "Some participants said women on the pill tend to be more sexually active than women using diaphragms and that the greater sexual activity can account for the higher incidence of tissue changes." There is also some suspicion that the disease may be virally trans- mitted from male to female and it has been suggested by Harvard's Prof. PAGENO="0294" 7124 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Robert Kistner that a diaphragm might exert a protective effect against possi- ble penile infection with the virus. Two months later the FDA's committee held its own meeting on the pill and cervical cancer in situ. Following the session, the committee issued a statement saying that "the data now available do not confirm or refute a causal relation between hormonal contraceptives and cervical carcinoma (a precancerous condi- tion) in situ. The committee recommends periodic medical examination of patients receiving oral contraceptives, including repeated examinations of the breasts and regular Pap smears at six- or 12-month intervals." One leading cancer epidemiologist summed up what may turn out to be a consensus. "By itself, neither the Melamed-Dubrow nor the Wied study is con- vincing. But when several studies are all alike, there may be fire. We're wor- ried about it. We don't want to sweep it under the rug, but we don't want to scare women all over the world unless there's something to it." [From Science, February 7, 1969, pp. 553-5551 ORAL CONTRACEPTIVES: GOVERNMENT-SUPPORTED PROGRAMS ARE QUESTIONED (By Marti Mueller) Last year a VISTA volunteer in Alaska watched in dismay as an Eskimo woman being treated in a federally financed birth-control center was handed a sack of oral contraceptives, given no counseling on how to take them, and told to come back in a year. At a time when questions are being raised about the safety of the pill, the federal government has become one of the major distributors of the oral con- traceptive in family-planning programs for the poor. Some doubts have been expressed about how safely these programs are administered. Officials within the Food and Drug Administration (FDA) have suggested in the past, for example, that its parent, the Department of Health, Education, and Welfare (HEW) has been lenient in monitoring side effects and adverse reactions to the pill and in supervising general medical health standards in its own pro- grams. One reason for such shortcomings, if they exist, may be that, while HEW programs are federally financed, many are administered on the local level by states, cities, and private organizations, and, as former HEW Assist- ant Secretary Philip Lee has said, "in many cases we are buying into the existing program." Lee also commented to Science that the quality of care for the poor in the United States is well below what it should be. "We thought we were doing much better than we are doing," Lee said. "The poor were not getting ade- quate care, either therapeutic or diagnostic." Lee who was named this week to be chancellor of the University of California Medical Center, estimates there are 5 million women of child-bearings age at or below the poverty level in the United States. He told Science that giving medically supervised family-plan- ning guidance to the entire 5 million would cost about $30 per woman, or about $150 million in all. (This year Congress appropriated about $50 million for birth control programs for the poor, which now serve about a million women.) Many federal family-planning programs are financed in part by the Office of Economic Opportunity (OEO) and by HEW. Some of these programs are operated under such services as Medicaid, Aid to Families with Dependent Children (AFDC), and maternal and child health services. They operate in the slums of large cities and in economically depressed rural areas where doctors are few and facilities often minimum. Other government agencies also provide family-planning services (the Department of Defense purchases and provides pills for about 200,000 military dependents, and AID provides an estimated 14 million women with contraceptives of all kinds in its programs abroad). But the major domestic effort to reach the poor has been through HEW and OEO. FDA's concern over HEW programs has been focused primarily on HEW's administration of the oral contraceptive. While there is no federal regulatory agency with power to ensure that the pill is dispensed safely, FDA does set distribution standards, and some of its members feel HEW has made "pale" PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7125 attempts to supervise its own programs. "You can't just dump a bunch of things in a lady's hand and say, here take them," one FDA official said. HEW officials deny that a physician has any direct responsibility to HEW to submit a report on adverse drug reactions. Lee sees the problem as a juris- dictional one. He feels, in effect, responsibility for monitoring~ medical prac- tices belongs to the American Medical Association; Lee, a physician, says HEW must rely on the built-in systems of peer review to ensure that physi- clans practice medicine responsibly. Others feel this is an uncertain means of ensuring safety, particularly in governmented-supported family planning. There are still many unknowns about the pill. It has been linked speculatively to a higher incidence of blood clots among users, and some physicians feel that if may cause cancer of the breast and cervix or increase the rate of growth of such cancers. It is still not known to what extent the pill may deter bone growth in physically immature women, or may mask menopause in the mid- die-aged. Recently, two doctors at the National Institutes of Health, Robert E. Mar- kush and Daniel Seigel, linked the pill to a higher incidence of death from vascular diseases among users. Indiscriminate distribution may be equally haz- ardous. Patients with known or suspected cancer of the breast or cervix, a his- tory of blood clots, liver disfunctions, epilepsy, severe heart disease, or other disorders should not be given the pill. A woman who is pregnant may endan- ger the health of her child if she takes oral contraceptives. A woman who has not had adequate counseling may fail to take precautions to keep the pill out of the hands of her children. (FDA has reported that the pill causes almost as many deaths among children as aspirin does.) PROCEEDING WITH CAUTION Recognizing these dangers, an FDA advisory committee on obstetrics and gynecology in 1960 established guidelines for dispensing the oral contraceptive; these were similar to international guidelines established by the World Health Organization. FDA recommended that, before a woman is given the pill, her medical history should be taken; she should be given a complete physical examination, with special attention to the breasts and pelvis; and she should be warned of the possible side effects of the pill. She should have follow-up examinations at intervals of 6 to 12 months. FDA recommended that an obste- trician or gynecologist, rather than a general practitioner, prescribe the pill. The agency also warned that physicians should use caution in prescribing the pill for young women whose bone growth is incomplete. In addition, last spring FDA changed the label on the oral contraceptive, calling further attention to the possible side effects and requesting that all physicians monitor adverse reactions to the pill. Unfortunately, FDA has no authority over the dissemination of contraceptives; it inspects pharmacies and rules that the pills cannot be sold without a doctor's prescription, but it cannot regulate what a private physician or a public health official does in his own office or clinic. HEW became deeply involved in family-planning services after its activity in this area was criticized as inadequate by Senator Ernest Gruening (D-Alaska) in 1966. At a meeting called by John W. Gardner, then Secretary of HEW, an interagency family-planning ad hoc committee was established to explore HEW's role in providing services to the poor. But Theodore Cron, an FDA commissioner of public information at the time of the meeting, who has since resigned from FDA, said that HEW gave little attention at that time to exploring the medical risks involved in programs for distributing birth control information and contraceptives. Cron, who is not a physician, recently com- mented to Science about the meetings: "FDA's input was minimal. We were barely in on the discussions and they treated us as if we were irrelevant." HEW-supported family-planning programs face many difficulties. HEW officials concede that a great problem may be that HEW administers only some of its family-planning programs directly. The indirectly supported programs operate under grants that fall into two categories, formula grants and project grants. The quality of the HEW programs that operate under the project grants-such as the maternal and infant care program-is supposed to be guaranteed by HEW's selection process; grant recipients are chosen on the PAGENO="0296" 7126 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY basis of the quality of the proposals submitted, the competency of the physi- cians, and the reputation of the clinics. But in the case of formula grants, such as Medicaid, where HEW is merely "buying into" the prevailing state or local system, HEW relies on locally administered programs, which are not always operated under satisfactory medical conditions that ensure, for exam- ple, safe distribution of the pill. Under the 1967 child health provision of the Social Security Act, the federal government was authorized for the first time to pay up to 75 percent of the costs of family-planning services for the poor in state, city, and nonprofit private programs. Under this system, HEW provides the money for the programs and, as Commissioner Lee says, "depends on the institution it relates to" to ensure safe standards of distribution. Federally supported family-planning programs are subject to the laws of the states in which they operate, and this presents an additional problem of juris- diction. In Wisconsin and Massachusetts, for instance, only married women are eligible to receive birth control information and contraceptives. For years, Con- necticut had an anti-birth-control law, which prohibited all use of contracep- tives and the distribution of information about their use. Other strong criticism of government-operated family-planning programs has been initiated, both nationally and on a local level, by Roman Catholics who feel that birth control is not within the government's purview. Family-planning programs are also criticized on the ground that inadequate attention is allegedly paid to the choice of qualified supervisers at the clinical level. The FDA recommends that the, physician be a licensed obstetrician or gynecologist. *HEW officials admit that, in many government-supported pro- grams, a general practitioner hands out the pill. Cron commented to Science, "I know of one family-planning program in one of the northern plain states that is run by an Opthalmologist because there is no obstetrician around. It's ridicu- lous, absurd-an example of a misallocation of resources." Opinions vary about whether a specialist is necessary, but a number of physicians and government officials feel that few medical practitioners, including specialists, pay adequate attention to FDA's labeling recommendations. Government-financed family-planning programs are further criticized on the ground that they allegedly discriminate against minority groups. Black mili- tants have recently called federal programs a "fOrm of genocide." They claim that, in effect, the government is saying to their race: there should be fewer of you. HEW programs also have been criticized for not setting an age criterion for women receiving the oral contraceptive. Cron says that about half of all illegi- timate babies are born to women under 20. Consequently, the government places no restrictions on giving the pill to young girls, even to adolescents. Criticism of this practice has been sharpest among physicians who feel that the pill may retard growth and that other contraceptives should be used instead. HEW has nine regional offices. Each has one physician to supervise its field programs, but the difficulty, as Arthur Lesser, a HEW deputy administrator, sees it, is that HEW's limited traveling funds do not permit extensive or fre- quent field visits. But HEW officials are beginning to look more closely at their own programs. Lesser told Science that HEW plans to set up a central information system to maintain complete medical histories of all patients who receive treatment and care in HEW-supported family-planning efforts. While it may be possible for HEW to arrange such a system in programs which it oper- ates directly, it still will have little control in indirect programs, where it can only recommend, not insist, that such a pattern be followed. In the past 2 years the government has almost doubled the size and support of its family-planning programs for the poor. Unless the Nixon Administration takes an unanticipated change in direction, gOvernment-sponsored family-plan- ning programs, which include distribution of the oral contraceptive, will con- tinue and, in all likelihood, increase in' the* next 4 years. Today the traditional taboos against government-financed birth control programs have diminished. But the demands for government assurance that safe medical practices are fol- lowed in the distribution of birth control pills are growing. PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7127 [Reprinted from RADIOLOGY, Vol. 92, No. 2, Pages 231-238, 258, February, 1969.[ Copyrighted 1969 by the Radiological Society of North America, Incorporated Oral Contraceptives and Cerebrovascular Complications' H. THOMAS BERGERON, M.D.,2 and ERNEST H. WOOD, M.D. IN 1957 ORAL Contraceptives were intro- duced under limited production in the United States for investigational purposes. Within three years they had been approved by the Food and Drug Administration and were made available for widespread clinical use. It is now estimated that seven to eight million women are using the agents, more than five million of whom dwell in the United States. This volume of use may well exceed that of any other potent medica- tion (12). During the ten-year period of oral con- traceptive use, numerous reports of adverse effects of the medication, including strokes, have been published. The American Com- missioner of Food and Drugs (10) recently warned all physicians that studies have now confirmed a definite association between the use of oral contraceptives and thromboem- bolic disorders. While many reports of clinical data have been published, relatively few cases having angiographic verification and localization of the cerebrovascular occlusion have been described. The purpose of this paper is to report the radiologic features associated with the neurologic disorders in patients on this medication who have been examined and treated at the Neurological Insitute of New York. Other purposes are to point out the increasing incidence of such cere- brovascular lesions in neuroradiologic prac- tice, the need for all radiologists to be alert to the etiology of occlusions in younger women, and to emphasize the prodromal symptoms that could have warned of an incipient stroke in the group studied. PRIOR INVESTIGATION Thromboembolic phenomena in women receiving oral contraceptives have been Nonocclusive disease Occlusive disease, not hormone-related Occlusive disease, hormone-related 58 1 1 55 1 8 TOTAL 60 64 annotated in the world literature with in- creasing frequency since 1961 (6, 13, 17, 18). The first report of central nervous system involvement was a case of venous thrombosis described in 1962 by Lorentz (14). In 1963, however, an ad hoc advisory committee of the Food and Drug Adminis- tration headed by Wright (25) found in- sufficient evidence to indict oral contracep- tives as causing thromboembolic conditions although recognizing adverse reactions in the presence of epilepsy, asthma, cardiac and renal disease, diabetes, hypertension, and numerous other circumstances and associations such as endocrine disorders, the alteration in growth rate of certain tumors, and psychic depression. Subsequently, reports of arterial throm- botic phenomena involving the central nervous system began to appear in rapid succession (1, 11, 15, 21, 26). In 1965, Walsh and his co-workers (23) at the Johns Hopkins Hospital described 69 cases of neuro-ophthalmologic interest which were associated with the ingestion of contracep- tive agents; 25 of the patients had strokes. Since this time the importance of sudden partial loss of vision, diplopia, and papill- edema as warning symptoms and signs of even more serious neural lesions have been appreciated. The following year Shafey and Schein- TABLE I: ANGIOGRAPHIC FINDINGS IN WOMEN TWENTY TO FORTY-FOUR YEARS OF AoE -No. of Cases-S 1960 1966 1From the Department of Radiology, College of Physicians and Surgeons, Columbia University and the Radiol- ogy Service of the Neurological Institute, Columbia-Presbyterian Medical Center, New York, N. Y. Presented at the Fifty-third Annual Meeting of the Radiological Society of North America, Chicago, Ill., Nov. 26-Dec. 1, 1967. 2 Former Special Fellow in Neuroradiology (Fellowship No. 1F11 NB 1518-01 and 02), sponsored by the Na- tional Institute of Neurological Diseases and Blindness, National Institutes of Health, under the Neuroradiology Training Grant(5TO1 NB 05298-06 and 07) at the Neurological Institute of New York. RADIOLOGY 92: 231-238, February 1969. (M.K.) 231 PAGENO="0298" 7128 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY R. THOMAS BERGERON AND ERNEST H. WOOD Fetaua~y 1969 berg (19) reported 6 cases of neurological disorders coincident with the use of oral contraceptives. In early 1967, Bicker- staff and Holmes (2) described 18 cases of cerebral ischemia occurring under similar circumstances. Later in the same year, Gardner and his co-workers (9) reported 9 similar cases, and Cole (4) described 5 additional cases of stroke among young women using oral contraceptive medication (TABLE I). More recently, Inman and Vessey (12) and Vessey and Doll (22) found a highly significant difference between users and non-users of oral contraceptives through a statistical evaluation of thromboembolism carried out in Great Britain. In women twenty to forty-four years of age the mor: tality rate from thromboembolic disease was seven to eight times higher in patients using oral contraceptives than in non-users. Morbidity requiring hospitalization was almost ten times as common. It is of interest that the mortality rate was not appreciably higher in women between the BY MIGRAINE HEADACHES OR OTHER VASCULAR PRODROMATA Total With Series No. of Prodro- Patients mats Shafey and Scheinberg Gardner el al. N.I.N.Y. series ages of thirty-five and forty-four than in the twenty- to thirty-four-year age group. MATERIAL AND RESULTS During a recent twelve-month period at the Neurological Institute of New York, 8 instances of cerebral ischemia occurring in women taking oral contraceptives were verified by radiologic methods as vascular occlusions. During the same period, a large number of women with similar neurologic disorders occurring under cor- responding circumstances were hospital- ized but not subjected to angiography. Many with milder disorders were seen and treated as outpatients. Cerebral angiography was performed on 232 Fig. 1. Middle Cerebral Occlusion: A 34-year-old woman, who had complained of severe frontal headaches. Sudden paresis of the right arm and leg and aphasia developed. She had been taking oral contraceptives for fifteen months. Both her father and mother died of strokes. The frontal (A) and lateral (B) left common carotid angiograms disclose occlusion of the middle cerebral artery at its trifurcation. 6 9 8 5 9 6 PAGENO="0299" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 7129 a total of 64 female patients in the twenty- to forty-four-year (inclusive) age group. In 55 of these, either the angiogram was normal, or tumors, aneurysms, subdural hematomas and disease processes other than cerebrovascular occlusions were pres- ent. Approximately one-half of the 55 patients had normal angiograms; a number of these had ischemic attacks suspected of being caused by oral contraceptives, but evidence of structural change in the vessels was absent. Arterial occlusions were dem- onstrated in 9 patients, 8 of whom had been taking oral contraceptives. The year 1960 was used as a control (TABLE II). During this twelve-month span, in women in the age group under consideration, there were only 2 vascular occlusions demonstrated by angiography. One of the 2 women suffered a stroke in the Vol. 92 ORAL CONTRACEPTIVES AND CEREBROVA~CULAR CoMPLICATIONS 233 A Fig. 2. Middle Cerebral Brabich Occlusion: A 27-year-old woman had been on contraceptive medication for one year. Bifrontal throbbing headaches developed, together with pain in the back of the neck on the right side and lethargy. For two weeks before admission she experienced blurred vision and for two days had diplopia. Examination disclosed papilledema and paresis of the right sixth cranial nerve. The spinal fluid pressure was el- evated. Clinical diagnosis of pseudotumor cerebri was made. The right carotid angiogram reveals prolonged dense opaciflcation of a segment of the post-rolandic branch of the middle cerebral artery (A through D). At four seconds after completion of the injection (D) the obstructed artery has not emptied, and the dilated (paretic) 1 cm long segment of the vessel is still visible (arrow). PAGENO="0300" 7130 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Fig. 3. Posterior Cerebral Branch Occlusion: In this 26-year-old woman there developed right frontal head- ache and stiffness of the neck a few days before admission. She then complained of impaired vision. The pa- tient had taken oral contraceptives for slightly more than a year. Examination disclosed dysesthesia of the left hand and a congruous left homonymous hemianopia. (Legend continued on opposite page) 234 PAGENO="0301" early postpartum period, and this case is considered to be hormone-related. In the two years compared, the number of young women having angiography was almost the same, the variety and incidence of non- occlusive lesions were similar, and there was only one case of occlusion during each of the years that was not hormone-related. Among the 8 patients observed, the median age was thirty years; 5 patients were in the twenty- to thirty-four-year age group while 3 were in the thirty-five- through forty-four-year age group. The average duration of use of oral contracep- tives was sixteen months. One patient had taken medication for two and a half years; 2 patients had been on medication less than one year, the shortest time being four months. Angiographically, in 5 of the cases the middle cerebral artery was implicated. In all but one, branches of the middle cerebral artery were involved with the main trifurcation occluded in one case (Fig. 1). Interpretation of occlusion was on the basis of visible blockage of an arterial lumen with distal avascularity, localized luminal narrowing with slow arterial filling, and emptying and retrograde filling of branch arterial vessels (Figs. 2-4). In two in- stances the posterior cerebral artery or one of its branches was occluded. One case involved evidence of retrograde opacifica- tion, while in the other there was slow flow from the proximally deformed but opacified channel. In another patient, the pen- callosal branch of the anterior cerebral artery was occluded, and filling of the area occurred by way of collateral channels from the posterior cerebral artery. In one of the cases, a positive mercury-197 brain scan was obtained over the area of the middle cerebral artery two weeks after the onset of hemiparesis and aphasia. A Vol. 92 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND CEREBROVASCULAR COMPLICATIONS 7131 235 Fig. 4. Posterior Cerebral Occlusion Diagnosed by Visualizing Collateral Circulation: A 21-year-old woman, who had a long history of episodic bitemporal headache, had taken contraceptive pills for two and one-half years. Several days before admission she awoke with a headache which continued and became progressively worse. This was then followed by dysesthesia of the right hand and mild dysphasia. She was found to have hyperrefiexia of the right upper extremity, slight blurring of the margins of the optic disks, and a highly congruous right homonymous hemianopia that was more dense in the superior quadrants. The left carotid angiogram disclosed no abnormality in the arterial phase (the posterior communicating and pos- terior cerebral arteries did not fill). In the later phases of the angiogram (A and B), however, there svas retrograde filling of the internal occipital (upper arrow) and temporo-occipital (lower arrow) branches back to their origins from the posterior cerebral artery. Fig. 3 (cont.) A bilateral brachial angiogram revealed a 2.5 cm portion of the parieto-occipital branch (arrow) of the posterior cerebral artery that exhibited irregular margins due to segmental narrowing but showed slight over- all dilatation (A and B). Stasis is evidenced by opacification of the segment lasting into the intermediate and venous phases of the angiogram (C and D). The last film demonstrates filling of small branches and a cloud of contrast material around it. The findings suggest arterial recanalization in this portion of the area of infarction. The frontal films (E and F) show the involved segment of the parieto-occipital branch coursing in its fissure (arrow). PAGENO="0302" 7132 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY R. THOMAS BERGERON AND ERNEST H. WOOD February 1969 follow-up examination nine months later was normal. An unusual case of bilateral middle cerebral occlusion was recently sent to us by a colleague and is illustrated (Fig. 5) but not included in the group of 8 assessed for 1966. DISCUSSION It would appear that there are now more than 100 well established cases of cere- brovascular complications associated with the use of oral contraceptives. That the number represents only a small fraction of the actual complications appears almost certain because, as pointed out by Inman and Vessey, in Britain only 15 per cent of the deaths of women who were taking oral contraceptives were reported indepen- dently as users to the Committee on Safety of Drugs. In the United States, the Food and Drug Administration has suggested that physicians are becoming increasingly reluctant to report adverse reactions be- cause of the risk of litigation. The weight of evidence leads to the inevitable conclu- sion that a relationship can be found between the use of oral contraceptives and disability or death from cerebrovascular occlusion in the absence of any predisposing conditions. It is well known that ovulation may be suppressed by the oral administration of progestogens. Of the substances in com- mon use today, the majority are combined products of estrogen and progestogen taken throughout the entire treatment. More recently, sequential products have been available. In this method estrogen alone is administered for fifteen to sixteen days followed by five to six days of combined estrogen and progestogen. In the authors' experience and in the experience of others (9), cerebrovascular complications occurred with either type. There are conflicting reports on the alterations of clotting mechanisms in indi- viduals who are receiving oral contracep- tives (3, 7, 16, 20, 25). Most of the work involves complex testing technics, but much of the data indicates that the admin- istration of estrogen has an influence on the fibrinolytic enzyme system and tends to decrease the breakdown of fibrinogen. Such a change would permit spontaneous thrombosis to occur at an increased rate, much as in the pregnant state (16). In addition, it has been found that the intra- venous administration of progesterone in- creases the platelet count significantly in human beings and in lower animals (17). Egeberg and Owren (7) reported a marked increase in blood coagulability in women on oral contraceptives, evidenced by a uniform increase in the antihemophilic globulin activity (factor VIII) up to 2 to 3 times the pretreatment level. A slight increase in the proconvertin factor (VII) was also noted, and increases in prothrombin factors IX and X have also been reported (3, 5, 7, 20). There is now general agreement that the pathophysiologic mechanism is an altera- tion in blood coagulability chiefly through an increase in several prothrombin factors. There is no evidence that there are predis- posing conditions in either the veins or arteries themselves (1, 8, 12, 15). In none of the cases coming to necropsy has evi- dence been found that there are inflamma- tory or degenerative changes involving the intima or any other vessel coats that might provoke the formation of a thrombus. * Some authors such as Vessey and Doll, while convinced of the high occurrence rate of cerebral thrombosis as a complication of contraceptive ingestion, have not had the opportunity of establishing with certainty the diagnosis of occlusion. In only 2 of the cases of cerebral ischemia studied by them was there opportunity to obtain angiographic confirmation. The present report provides the objective proof of cerebrovascular occlusion that has left several earlier clinical reports open to criticism. The highly significant increase in hormone-related arterial occlusions in 1966 as compared with 1960 (TABLE I) reveals not only an eightfold increase but shows that one-eighth of all women in the specified age group who came to angiog- raphy for any reason had demonstrable vascular occlusion. More recently an even 236 PAGENO="0303" higher incidence of such occlusions has been observed. It appears quite probable that a number of the patients who had no angiographic abnormality suffered from occlusions of small vessels that could not be appreciated with certainty because of the limitation of the angiographic method. HEADACHE Among the more interesting and impor- tant aspects of recent reports are the inter- relationships between the ingestion of con- traceptives, headaches, visual disturbances, and cerebral ischemic attacks. Walsh and his co-workers observed that in 10 of their 69 patients paroxysmal headaches were either incited or aggravated by con- traceptive medications. Whitty et al. (24) reported 30 such cases. Shafey and Scheinberg described 28 patients with vas- cular headaches who had no previous his- tory of migraine attacks before they were started on oral contraceptives. There were additional patients who had vascular headaches reactivated or exacerbated by the medication. In these groups the head- Vol. 92 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ORAL CONTRACEPTIVES AND CERErIROVASCULAR CoMPLIcATIoNs 7133 237 Fig. 5. Bilateral Arterial Occlusions: A 36-year-old woman who had been taking oral contraceptives for ap- proximately two years. On account of a left hemiparesis that cleared in forty-eight hours, her physician recom- mended admission to the hospital for a complete evaluation. Because the weakness had disappeared, however, the advice was disregarded. Three months later the patient had sudden aphasia and a right-sided weakness that progressed to a right hemiplegia. The left carotid angiogram revealed an occlusion of the left middle cerebral artery at its trifurcation (A and B). Bilateral anterior cerebral filling occurred, and on the left anastomotic branches were outlined, extending from the vertex into the middle cerebral territory (transverse arrows). On the right, a posteriorly extending branch fills rapidly and courses to the angular region (vertical arrows). After "washout" of the right anterior cerebral artery, the collateral circulation to the left middle cerebral region is more clearly seen (C). The patient improved very slowly, but no new neurological symptoms or signs developed. One month after the first angiogram a right internal carotid angiogram (D) showed the sharp arterial occlusion and distal avascularity of the angular area that are thought to have produced the first stroke. (Courtesy of Dr. Arthur Rosenbaum) PAGENO="0304" 7134 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY R. THOMAS BERGERON AND ERNEST H. WOOD February 1969 aches were relieved when the synthetic steroids were discontinued. In another group of 6 patients, however, Shafey and Scheinberg found that in 5 cases the headaches were premonitory to the development of cerebral thromboses. Gardner and his associates strongly em- phasized the danger of women continuing contraceptive medication if they exhibit evidence of craniovascular sensitivity. Among 9 patients in whom strokes devel- oped,~ all had headache as a warning. In the Neurological Institute of New York angiographic series, 6 of the S patients had prodromal symptoms (TABLE II). In the group, 5 had headaches related to taking medication prior to the onset of paresis, 1 patient without headache had transient visual disturbances and dysesthesia of the hand. In 3 of the 5 patients with head- ache, additional warnings included: trans- ient cerebral ischemic attacks, 1 case; transient visual disturbances, 1 case; a family history of both father and mother having died of strokes, 1 case. COMMENT It would appear that, in respect to short- term effects, the oral contraceptives are safe for the vast majority of users. In a certain small percentage, however, the medication carries with it the danger of thromboembolic disease, including cerebral thrombosis. The present report of cases is small in number because a representative twelve-month period was chosen to com- pare with earlier observations during a similar interval of time. Numerous addi- tional cases could now be added. At the present time, the common denominator in almost every case of cerebral arterial occlusion demonstrated angiographically in young women is the contraceptive pill. The majority of women in whom cerebral thrombosis develops from contraceptive medication exhibit prodromal symptoms. The development of headache, visual symptoms, or other signs of transient cerebrovascular insufficiency should prob- ably be interpreted as an indication for the immediate and permanent cessation of oral contraception in such individuals. Even this is no guarantee that the clotting mechanism will revert to normal. Two cases of pulmonary embolism, one fatal, have been observed among the patients in whom medication had been withdrawn for a number of weeks. SUMMARY Eight cases of cerebral arterial occlusion have been added to the growing list of com- plications resulting from the use of oral con- traceptives. The series is unusual in that all cases had angiographic verification of a well established clinical diagnosis, and the patients were admitted to a general neurological service during a twelve-month period. Comparison with figures for a year before the widespread use of oral con- traceptives reveals an eightfold increase in incidence. The majority of patients with cerebral thrombosis developing from con- traceptive medication have some warning, most often significant headache, prior to the onset of the paretic event and presum- ably sufficiently in advance to avert a stroke through the cessation of medication. ACKNOWLEDGMENT: The authors sincerely thank Dr. Arthur Rosenbaum for use of the case illustrated in Figure 5. Division of Neuroradiology L. A. County General Hospital Los Angeles, Calif. REFERENCES 1. BAINES, G. F.: Cerebrovascular Accidents and Oral Contraception. Brit. M. J. 1: 189, Jan. 16, 1965. 2. BICKER5TAFF, E. R., AND HOLMES, J. M.: Cerebral Arterial Insufficiency and Oral Contracep- tives. Brit. M. J. 1: 726-729, March 25, 1967. 3. BRODSKY, I., Lswss, G., JR., AND Ross, E.: Effect of Pregnancy or a Progestational Drug on Blood Coagulation as Measured by the Thrombotest. Obst. & Gynec. 24: 213-217, August 1964. 4. COLE, M.: Strokes in Young Women Using Oral Contraceptives. Arch. mt. Med. 120: 551-555, November 1967. 5. DONAYRE, J., AND PINcus, G.: Effects of En- ovid on Blood Clotting Factors. Metabolism (Suppl.) 14: 418-421, March 1965. 6. EcKSTEIN, P., ET AL.: The Birmingham Oral Contraceptive Trial. Brit. M. J. 2: 1172-1179, Nov. 4, 1961. 7. EGEBERG, 0., AND OWREN, P. A.: Oral Con- traception and Coagulability. Brit. M. J. 1: 220-221, 1963. 238 PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7135 8. EHTISHAMUDDIN, M.: Vertebral-Artery Throm- New England J. Med. 269: 622-624, Sept. 19, 1963. bosis and Oral Contraceptives. Brit. M. J. 1: 921-922, 18. SCHATZ, I. J., SMITH, R. F., BRENEMAN, G. M., April 3, 1965. AND BOWER, G. C.: Thromboembolic Disease Asso- 9. GARDNER, J. H., VAN DEN NOORT, S., AND ciated with Norethynedrol. Report of Six Cases. HORENSTEIN, S.: Cerebrovascular Disease in Young J.A.M.A. 188: 493-495, May 11, 1964. Women Taking Oral Contraceptives. Am. Acad. 19. SHAFEY, S., and SCHEINBERG, P.: Neurological Neurol. Program. Neurology 17: 297-298, March Syndromes Occurring in Patients Receiving Synthetic 1967. Steroids (Oral Contraceptives). ,Neurology 16: 205- 10. GODDARD, J. L. (Commissioner of Food and 211, February 1966. Drugs): U. S. Department of Health, Education and 20. SOBRERO, A. J., FENIcHEL, R. L., AND SINGHER, Welfare, GPO 0-311-464, 1968. H. 0.: Effects of a Progestin-Estrogen Preparation on 11. ILLIS, L., KOCEN, R. S., MCDONALD, W. I., Blood Coagulation Mechanisms. J.A.M.A. 185: 136- AND MONDKAR, V. P.: Oral Contraceptives and Cere- 139, 1963. bral Arterial Occlusion. Brit. M. J. 2: 1164-1166, 21. STEWART-WALLACE, A. M.: Cerebrovascular Nov. 13, 1965. Accidents and Oral Contraception. Brit. M. J. 2: 1528, 12. INMAN, W. H. W., AND VESSEY, M. P.: Inves- Dec. 12, 1964. tigation of Deaths from Pulmonary, Coronary, and 22. VESSEY, M. P., AND DOLL, R.: Investigation Cerebral Thrombosis and Embolism in Women of Child- of Relation Between Use of Oral Contraceptives and Bearing Age. Brit. M. J. 2: 193-199, 1968. Thromboembolic Disease. Brit. M. J. 2: 199-205, 13. JORDAN, W. M.: Pulmonary Embolism. Lan- April 27, 1968. cet 2: 1146-1147, Nov. 18, 1961. 23. WALSH, F. B., CLARK, D. B., THOMPSON, R. S., 14. LORENTZ, 1. T.: Parietal Lesion and Enovid. AND NICHOLSON, D. H.: Oral Contraceptives and Brit. M. J. 2: 1191, 1962. Neuro-Ophthalmologic Interest. Arch. Ophth. 74: 638- 15. NEVIN, N. C., ELMES, P. C., AND WEAVER, J. 640, November 1965. A.: Three Cases of Intravascular Thrombosis Occur- 24. WmTTY, C. W. M., HOCKADAY, J. .M., AND ring in Patients Receiving Oral Contraceptives. Brit. WHITTY, M. M.: The Effect of Oral Contraceptives M. J. 1: 1586-1589, June 19, 1965. on Migraine. Lancet 1: 856-859, April 16, 1966. 16. PHILLIPS, L. L., TURKSOY, R. N., AND SOUTHAM, 25. WRIGHT, I. S.: FDA Report on Enovid: Ad A. L.: Influence of Ovarian Function on the Fibrino- Hoc Advisory Committee for Evaluation of a Possible lytic Enzyme System. II. Influence of Exogenous Ster- Etiologic Relation with Thromboenibolic Conditions. oids. Am. J. Obst. & Gynec. 82: 1216-1220, December J.A.M.A. 185: 776, Sept. 7, 1963. 0 1961. 26. ZILKHA, K. j.: Cerebrovascular Accidents and 17. REED, D. L., AND CooN, W. W.: Thrombo- Oral Contraception. Brit. M. J. 2: 1132-1133, Oct. embolism in Patients Receiving Progestational Drugs. 31, 1964. 40-471 0-70-pt. 17-20 0 0 0 PAGENO="0306" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7136 [From the American Heart Journal, Vol. 77, No. 2, February 1969, pp. 153-157] EDITORIAL-ORAL CONTRACEPTIVES AND THROMBOEMBOLIC DISEASE (By M. P. Vessey, MB., B.S., London, England) The first report in the medical press of a woman developing a thromboem- bolic disorder while taking an oral contraceptive preparation appeared in 1961 (1). In that same year, two young Los Angeles women using oral contracep- tives suffered fatal pulmonary embolisms (2). Since that time hundreds of similar case histories, relating both to fatal and nonfatal illnesses, have been published in medical journals, and thousands more have been reported to the Food and Drug Administration in the United States and the Committee on Safety of Drugs in Great Britain. The majority of these reports relate to deep-vein thrombosis in the lower limbs or pulmonary embolism, but the occurrence of coronary thrombosis, cerebrovascular accidents, mesenteric and other arterial thromboses, and the Budd~Chiari syndrome has also been described. All these conditions also occur in young women who do not use oral contra- ceptives and in themselves the case reports provide no significant evidence that oral contraceptives are a cause of thromboembolic disease. A number of attempts have, however, been made over the years to assess the problem in a methodical way. In 1962 at a conference sponsored in Chicago by G. D. Searle and Co., (3) a comparison was made between the reported incidence of episodes of throm- boembolic disease in users of Enovid and the incidence in the general popula- tion estimated from the results of a number of different studies. The partici- pants recognized the considerable inadequacies of the data available to them, but concluded that there was no evidence that Enovid was a cause of throm- boembolic disease. In 1963, a committee appointed by the Food and Drug Administration (4) reviewed about 350 reports of thromboembolic disease in women using Enovid drawn from their own records and from those of the manufacturer. On this occasion, existing statistics about the morbidity from thromboembolism in the general population were considered to be unreliable, and the Committee con- centrated on reports of death. Among Caucasion women using Enovid, deaths from thromboembolic disease were estimated to be 12.1 per million annually compared with 8.4 per million in the general population calculated on the basis of national mortality statistics. This difference was not statistically significant, but the Committee took into account the limitations of the data and said that carefully planned, controlled prospective studies were necessary before reliable conclusions could be drawn. In 1965, the Committee on Safety of Drugs (5) reviewed their findings in Great Britain for the previous year. Sixteen deaths from thromboembolic dis- ease had been reported among women using oral contraceptives, whereas on the basis of national mortality statistics, about 13 deaths could have been expected if the use of these preparations was unrelated to the disease. The Committee concluded that there was no evidence that oral contraceptives had a thrombogenic effect, but they did draw special attention to the fact that 8 of the 16 reported deaths were from pulmonary embolism whereas only 2 such deaths would have been expected. Quite apart from the absence of comparable control data in any of the investigations just outlined, each one also depends on reported episodes of thromboembolism for the calculation of morbidity or mortality rates in users of oral contraceptives. The assumption is, therefore, that all, or nearly all, of the episodes affecting women using oral contraceptives are reported by the responsible physicians. That this assumption is, in fact, untenable has since been demonstrated both by the Food and Drug Administration and by the Committee on Safety of Drugs. Thus in 1966, the Food and Drug Administra- tion (6) showed that, among the 5 million women estimated to have been using oral contraceptives in the United States in 1965, about 85 deaths from "idiopathic" thromboembohism would have been expected on the basis of the national mortality rates even if the contraceptives had not produced any extra fatalities. In fact, only 13 such deaths were reported. Similarly, in 1966 in the Special investigation of mortality from thromboembolism in young women NoTE-Numbered references at end of article. PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG. INDUSTRY 7137 undertaken by the Committee on Safety of Drugs, (7) only 8 of the 53 deaths found to have occurred in women using oral contraceptives were independently reported to the Committee by the responsible physicians. In 1966, Drill (8) reviewed the results of 6 major clinical trials of oral con- traceptives covering many thousands of woman-years of exposure. On the basis of various morbidity statistics, he calculated . that a total of 105 cases of thrombophlebitis would have been observed among the participants in these studies if oral contraceptives were unrelated to the disease. In fact, only 28 cases were noted and Drill concluded that oral contraceptives had no thrombo- genic effect. Unless, however, oral contraceptives protect women from throm- bophlebitis, an alternative explanation for these results is that such factors as patient selection, losses to follow-up, and the inevitable inadequacy of the data used to calculate expected numbers of affected individuals preclude any definite conclusions. In 1966, American (6) and British (9) groups came independently to the conclusion that the best way to obtain adequate data on the thromboembolism problem within a reasonable length of ti~me would be by means of ease-control studies, and the results of 3 British investigations have now been published. In one study, organized by the Royal College of General Practitioners, (10) 29 family doctors interviewed women aged 15 to 49 who had consulted them for an episode of thromboembolic disease and the results were compared with those obtained from 2 control groups matched for martial status and, broadly, for age and parity. The data were too few for any conclusions to be drawn about cerebral or coronary thrombosis, but the results indicated that the risk of venous thrombosis or pulmonary embolism, ("venous thromboembolism") was increased sixfold in women who were pregnant or in the puerperium and threefold in women who used oral contraceptives. (9) Three quarters of the women with venous thromboembolism suffered from superficial thrombophle- bitis of the legs and the estimates of risk therefore relate principally to this condition. In a study carried out under the auspices of the Committee on Safety of Drugs and reported by Inman and Vessey (7), inquiries were made by the Committee's medical field staff about the use of oral contraceptives by women aged 20 to 44 certified as dying in England, Wales, and Northern Ireland during 1966 from pulmonary embolism, coronary thrombosis, and cerebral thrombosis. The results were compared with those obtained for control women selected from the same doctors' practices as those in which the fatalities occurred. It was found that, irrespective of age, the risk of death from pulmo- nary embolism or cerebral thrombosis was increased about eight times in pre- viously healthly women using oral contraceptives. In absolute terms, however, the mortality rate attributable to the use of these preparations was substan- tially lower among those aged 20 to 34 than among those aged 35. to 44, there being an excess of 1.3 and 3.4 deaths per 100,000 users per . annum, respec- tively, in these. two age groups. The situation in regard to coronary thrombosis was much less well defined in this investigation and the existence of an association with oral contracep- tives has not been established. There was, however, some suggestion . that oral contraceptives might be of etiological significance in coronary thrombosis in women under 35. Vessey and Doll (11) carried out an investigation of married women aged 16 to 40 admitted to hospital during 1964 through 1966 with thrombOembolic dis- case without evident predisposing cause. Control patients matched for age, parity, date of admission, and absence of any factor predisposing to throm- boembolism were selected and all participants in the investigation were inter- viewed in their homes. From these data it was calculated that the risk of hos- pital admission for deep vein thrombosis or pulmonary embolism is about 9 to 10 times greater in previously healthy women who use oral contraceptives than in those who do not. By using national sales data for estimating the frequency of use of oral contraceptives in the general population, it was estimated that about 1 in every 2,000 women using oral contraceptives is admitted to hospital each year with "idiopathic" venous thromboembolism in comparison with about 1 in every 20,000 women not using them. Evidence was also obtained in this study to support the suggestion that cere- bral thrombosis may rarely be caused by oral contraceptives, but no relation- ship was found between their use and coronary thrombosis. PAGENO="0308" 7138 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY All these investigations are, of course, subject to the usual defects of case- control studies, but their statistical inadequacies are very much less than those of the earlier studies already reviewed. Considered together they provide very strong evidence that oral contraceptives are a cause of venous thromboembol- ism. In conjunction with other investigations (12-15), in which physicians have reviewed their total clinical experience over a period of time, rather than merely singling out particular case histories for special consideration, they provide a good indication that these preparations may also be sometimes impli- cated in ischemic cerebrovascular disturbances. The evidence for a causal asso- ciation with coronary thrombosis, however, is weak. Recent reviews of national mortality statistics for the thromboembolic dis- eases in the United States and Great Britain (16, 17) have led to the conclusion that trends among women of childbearing age have been paralleled by corresponding trends among men and that vital statistics do not support the suggestion that oral contraceptives cause thromboembolic disease. Vessey and Weatherall (18), however, have shown that the British vital statistics for the venous thromboembolic diseases are fully compatible with the estimates of the small mortality attributable to the use of oral contraceptives provided by the investigation carried out by the Committee on Safety of Drugs (7). No attempt has been made to apply the same calculations to vital statistics for the United States because the British estimates of risk may be totally inappro- priate when applied to another country where, for example, spontaneously occurring thromboembolic disease may differ in incidence. None of the investigations so far described has provided any valid evidence that the risk of thromboembolism is associated with any particular oral con- traceptive formulation, nor that the risk is associated with duration of use. Dr. Doll and this author hope to have some additional information shortly on both these points as we are at present updating our investigation (11) by including patients admitted to hospital during 1967. Data obtained from clini- cal trials where estrogens have been administered to men with coronary heart disease (19) or cancer of the prostate (20) suggest that the estrogen moiety may be at fault and this idea is supported by the recent observation that puer- peral thromboembolism is associated with the suppression of lactation by estrogens (21). The epidemiological investigations thus strongly suggest a causal relation- ship between the use of oral contraceptives and some kinds of thromboembolic disease, but the case would be greatly strengthened if the physiological or biochemical effects of their use were shown to contribute to some part of the disease process. A vast and bewildering literature has accumulated relating the use of oral contraceptives to changes in various blood clotting factors (8) including platelet function (22). Many investigations have yielded conflicting results which is not surprising when the great variety of preparations tested, the differing laboratory techniques, the varying periods of exposure among the subjects investigated, and in some instances, the small numbers of women studied and the inappropriate controls used for comparative purposes, are taken into account. But even if it is accepted that oral contraceptives do affect blood clotting mechanisms, the significance of any alteration in terms of an increased risk of spontaneous thromlfosis is very uncertain. Other workers (23-25) have demonstrated changes in vessel walls and in venous distensibility and blood flow produced by the administration of oral contraceptives in experimental animals and in man. These findings, which seem to have been neglected by some workers, could be of significance in relation to venous thromboembolism. Although no definite relationship between oral contraceptives and coronary thrombosis has been established, the work done by a number of groups, espe- cially by Wynn and his colleagues (26, 27), on the effect of oral contraceptives on carbohydrate and lipid metabolism provides some basis for suspecting that such a relationship might exist. In addition to any further epidemiological information which may yet be obtained from case-control studies, at least four prospective investigations of women using oral contraceptives and control subjects have been, or are in the process of being established. Of these, two are in Great Britain (one organized by the Royal College of General Practitioners and the second jointly by the Medical Research Council and the Family Planning Association),* one in the United States (organized by the Kaiser-Permanente Medical Care Program) PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7139 and one in Australia (organized by the Australian College of General Practi- tioners). It is likely to be 2 or 3 years at least before any of these investiga- tions has anything useful to add to our knowledge of the relationship between oral contraceptives and thromboembolic disease. ADDENDUM Since this editorial was submitted, an article on the same subject, but with different conclusions, has appeared in the Journal of the American Medical Association (Drill, V. A., and Calhoun, D. W.: Oral contraceptives and throm- boembolic disease, J.A.M.A. 206:77, 1968). Space precludes any discussion of that article here and it must suffice to say that nothing it contains has caused this author to revise the views presented above. References 1. Jordan, W. M.: Pulmonary embolism, Lancet 2:1146, 1961. 2. Tyler, E. T.: Oral contraception and venous thrombosis, J.A.M.A. 185:131, 1963. 3. Thromboembolic phenomena in women, Chicago conference, 1962, G. D. Searle & Co. 4. Final report on Enovid by the ad hoc committee for the evaluation of a possible etiologic relation with thromboembolic conditions, Washington, 1963, Food and Drug Administration. 5. Cahal, D. A.: Safety of oral contraceptives, Brit. M. J. 2 :1180, 1965. 6. Report on the oral contraceptives, Advisory committee on obstetrics and gynecology, Washington, 1966, Food and Drug Administration. 7. Inman, W. H. W., and Vessey, M. P.: Investigation of deaths from pulmo- nary, coronary, and cerebral thrombosis and embolism in women of child- bearing age, Brit. M. J. 2 :193, 1968. 8. Drill, V. A.: Oral contraceptives, New York, 1966, McGraw-Hill Book Com- pany, Inc. 9. Medical Research Council: Risk of thromboembolic disease in women taking oral contraceptives, Brit. M. J. 2 :355, 1967. 10. Royal College of General Practitioners: Oral contraception and thromboem- bolic disease, J. Roy. Coil. Gen. Practit. 13 :267, 1967. 11. Vessey, M. P., and Doll, R.: Investigation of relation between use of oral contraceptives and thromboembolic desease, Brit, I\I. J. 2 :199, 1969. 12. Illis, L., Kocen, R. S., 1~IcDonald, W. I., and Mondkar, V. P.: Oral contra- ceptives and cerebral arterial occlusion, Brit. M. J. 2 :1164, 1965. 13. Shafey, S., and Scheinberg, P.: Neurological syndromes occurring in patients receiving synthetic steroids (oral contraceptives), Neurology 16 :205, 1966. 14. Bickerstaff, E. R., and Holmes, J. M.: Cerebral arterial insufficiency and oral contraceptives, Brit. 1\'I. J. 1:726, 1967. 15. Cole, M.: Strokes in young women using oral contraceptives, Arch. Tnt. 1~Ied. 120:551, 1967. 16. Swyer, G. I. M.: Oral contraceptives, thrombosis, and cyclical factors affecting veins, Brit. M. J. 1:355, 1966. 17. Clinical aspects of oral gestogens, Tech. Report Series, W. H. 0. No. 326, 1966. 18. Vessey, M. P., and Weatherall, J. A. C.: Venous thromboembolic disease and the use of oral contraceptives, Lancet 2:94, 1968. 19. Oliver, M. F.: Thrombosis and estrogens, Lancet 2:510, 1967. 20. Bailar, J. C., III: Thromboembolism and estrogen therapy, Lancet 2:560, 1967. 21. Daniel, D. G., Campbell, H., and Turnbull, A. C.: Puerperal thromboembol- ism and suppression of lactation, Lancet 2:287, 1967. 22. Bolton, C. H., Hampton, J. R., and 1~Iitchell, J. R. A.: Effect of oral contra- ceptive agents on platelets and plasma-phospholipids, Lancet 1 :1336, 1968. 23. Danforth, M., Maralo-Estrella, P., and Buckingham, J. C. : The effect of pregnancy and Enovid on the rabbit vasculature, Am. J. Obst. & Gynec. 88:952, 1964. 24. Goodrich, S. M., and Wood, J. E.: Peripheral venous distensibility and velocity of venous blood flow during pregnancy and during oral contra- ceptive therapy, Am. J. Obst. & Gynec. 90:740, 1964. PAGENO="0310" 7140 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 25. Neistadt, A., Schwartz, R. W., and Schwartz, S. I.: Norethynodrel with mestranol and venous blood flow, J.A.M.A. 198:784, 1966. 26. Wynn, V., and Doar, J. W. H.: Some effects of oral contraceptives on car- bohydrate metabolism, Lancet 2:715, 1966. 27. Wynn, V., Doar, J. W. H., and Mills, G. L: Some effects of oral contracep- tives on serum lipid and lipoprotein levels, Lancet 2 :720, 1966. [From the Columbia Journalism Review, Winter, 1968-1969, pp. 4-10] THE PILL -PRES5 AND PUBLIC AT THE EXPERTS' 1~IERCY EDITORS' NOTE: This article, which will be presented in two parts in the winter and spring issues, is unusual for the Review in that it does not focus entirely on journalism. Rather, it is a case study-and a highly important one, in the editors' opinion-of the insufficiency of the mechanisms now available for monitoring specialist institutions and individuals on the public's behalf. The author, Morton Mintz, has been reporting on The Pill for The Washington Post since late 1965. Mintz won numerous awards for his reporting in 1962 in the Post about the baby-deforming drug thalidomide. He wrote "The Therapeu- tic Nightmare," revised and reissued as "By Prescription Only." The only way that democracy can be made bearable is by developing and cherishing a class of men sufficiently honest and disinterested to challenge the prevailing quacks. No such class has ever apppeared in the United States. Thus, the business of harassing the quacks devolves upon the newspapers. When they fail in their dnty, which is usually, we are at the quacks' mercy. -H. L. Mencken in Minority Report (By Morton Mintz) Twenty days a month, the Population Council estimated in 1967, 6.5 million women in the United States and 6.3 million elsewhere swallow a birth control pill. The women are healthy, not sick, and the pills are powerful chemicals. This is a situation "unique in the history of human therapeutics," the Food and Drug Administration's Advisory Committee on Obstetrics and Gynecology said in a report in 1966. "Never will so many people have taken such potent drugs voluntarily over such a protracted period for an objective other than the control of disease." This massive experiment in drug-taking was founded, of course, on a presumption of safety which now has omnipresent manifestations. In Sea' and the Office, in a chapter on how to manage an affair during the lunch-hour, for example, Helen Gurley Brown counsels, "If you use pills, so much the easier." Jeanine Deckers, the former Singing Nun, composes "La Pilule d'Or" ("The Golden Pill"). "In her fresh, warm voice," McCall's said in May, 1967, "she was singing a hymn of praise to God for inspiring mankind to invent the birth-control pill." And 20th Century-Fox produces Prudence and the Pill, which Renata Adler, in The New York Times, described as "a nau- seating little sex comedy in which somebody is always substituting a vitamin or an aspirin for somebody else's oral contraceptive until everyone gets con- fused or pregnant." Such cultural stigmata show that the presumption of safety is pervasive, not that it is valid. They also illuminate the extreme degree of trust put in experts without whose advocacy the oral contraceptives, which are prescription drugs, would not legally have been made freely available to American women. "Experts . . . at any point in time are frequently considered to be those who espouse the most popular and widely held views of the predominant ortho- doxy," Paul Talakay wrote in 1964 in Drugs in Our Society. "The history of medicine abounds with examples of the perpetuation of totally illogical treat- ments . . . because of the powerful influence of an authoritarian ortho- doxy. . . . The opinion of experts should be subject to challenge by way of a wide variety of media and channels." A severe challenge to the presumption of safety of oral contraceptives was laid down on April 27, 1968, in a report in the British Medical Journal. The FDA responded immediately by summoning the American manufacturers to meet with it a few days later, on May 8, in Washington. The upshot was that the producers agreed to a major revision of the uniform labeling, the FDA-au- PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7141 thorized instructions for prescribing physicians. Starting on July 1, 1968, the manufacturers agreed to include this warning: "Studies conducted in Great Britain . . . estimate there is a seven to tenfold increase in mortality and morbidity due to thromboembolic [clotting in the blood vessels] diseases in women taking oral contraceptives. In these con- trolled retrospective studies, involving 36 reported deaths and 58 hospitaliza- tions due to idiopathic [of unknown cause] thromboembolism, statistical evalu- ation indicated that the differences observed between users and nonusers were highly significant." The principal findings of the British studies, which were conducted by Drs. W. H. W. Inman and M. P. Vessey for the Committee on Safety of Drugs, and by Drs. Vessey and Richard Doll for the Medical Research Council, were sum- marized by the FDA in tabular form. The data emphasized that the highest risk was to women in the 35-to44 age group. Among 1 million such women1 the annual death rate, the FDA said, was 39 for users of the pills, compared with 5 for non-users. Among women in the 20-to-34 age bracket the annual death rate was found to be 15 for users, 2 for non-users. A single age group, 20 to 44, was used to chart thromboembolic episodes-mainly, clots in the leg or pelvis (tlirombophlebitis), in the lung (pulmonary embolism), and in the brain (cerebral thrombosis)-which, while not fatal, required hospital treat- ment and sometimes caused lifelong disablement. For episodes of this kind the labeling reported an annual incidence of 470 per million in users, as against 50 in non-users. The FDA and the manufacturers agreed that a "statistically significant rela- tionship has been demonstrated" between the pills and leg, pelvic, and lung clotting, and that the data were "suggestive of an association" with strokes that was "neither confirmed nor refuted." As to a possible causal connection with heart attacks, the authors of the studies said the data available to them did not "quite" attain statistical significance. Nonetheless, these data impressed the researchers sufficiently that they troubled to report what the clotting death rates would be with the heart-attack figures included: 22 per million per year in women age 20 to 34, and 45 per million per year in women age 35 to 44. But inclusive or exclusive of heart attacks, all of the death rates in the Brit- ish studies were acknowledged to understate the true incidences, "very likely" by about 40 per cent. In explanation, Drs. Inman and Vessey said that a check of factory production figures had revealed a substantial overestimate of the use of oral contraceptives-and, therefore, of pill-caused clotting-in the gen- eral (control) population. The fundamental point made by all of this is that a certainty of significant hazard was established not before, but after almost 13 million women had begun to use The Pill (as I will call it hereafter), not to mention additional millions who used it but then gave it up. The evidence which follows demon- strates, I believe, that this phenomenon was the result of monumental failures in numerous institutions, particularly the FDA, the regulatory agency with power to grant or withhold marketing approval, and the medical profession, which prescribed The Pill. Yet even if the FDA failed in its primary mission; even if a large proportion of physicians performed as un-scientists, as True Believers who did not bother to get the facts (or discern the non-facts) before making the cumulatively momentous decisionS to prescribe routine use of potent drugs by healthy patients, and even if The Pill was destined to emerge as the appetizer on Helen Gurley Brown's menu for a naked lunch-even if all of these things happened the consequences would not have been so staggering but for the fact that all news media had supplied an abundance of non-report- ing, mis-reporting, and mal-reporting. For against the arrogance of misguided experts, which was the mainspring of much of the problem, one of the few protections is a robust press-whether the issue is the Bay of Pigs, the war in Viet Nam, the Supersonic Transport, the pesticides in our crops, the additives in our food and drink or The Pill. DIPLOMATIC IMMUNITY - A few professional publications and a few newsmen-notably, Don Oberdor- fer for Knight Newspapers and John Troan for Scripps-Howard-reported 1 The FDA's calculations were on the basis of 100,000, but 1 million is used here so as to maintain consistency with incidence rates cited later in this article. PAGENO="0312" 7142 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY thoroughly on the reasons for concern about the safety of The Pill. But its social and psychological importance conferred what Dr. David B. Clark, a Uni- versity of Kentucky neurologist, has called "a diplomatic immunity." Over and above such "immunity," Dr. Herbert Ratner, editor of Child and Family,2 has found plentiful evidence of affirmative "propaganda." In general, he said in an editorial last spring, "favorable findings of drug company subsidized physician promoters of The Pill and naive physicians have been encouraged, widely dis- tributed, scientifically inflated, maximized and extolled, whereas unfavorable findings have either been ignored, suppressed, rationalized, minimized or ridi- culed." The net result seen by Dr. Ratner "was that the real users of The Pill, the middle and upper classes of the U.S., were seduced away from well estab- lished and safe means of birth control." ,Qthcr ~ssiblc effectaof!anI.ten~'L5C must ~cbecked. Our stud~l~a~'e involved a num~ b~ of tests vnzying frz~z blood pressure to, liver function, (torn biocd-~hI counts to con. * ~-dctection smears. Thzzs far we have no in.. di~tion of abnormaltry, b~iZ we continue re~. * ular examinations. Winan ~ finish in a few ~rs, these studies w(.i probably constitute * or* of the most thorough long-term observa- tions of female physioTc'~~' yet performed. The ~e of oral contacei~:v~ by millions of * wotr~i in ~econtyearshasi~towidepublicity, * and many ills occurrin~a u~rs have been at. Oibuted to the "piILs.'~ A~nZ them may be * * mentioned excessive ha rncwth and excessive * bssofhahi~, insomnia a~talpiness, excessive * bl~ing and a tendensrrj t~ blood dotting. * When subjected to core ~-3coutiny, all of these * amditions have been fousad~so be unrelated to * tbe use of the contracep~v~.. Expert advice: concIu~ioius on the safety of The * Pill by Dr. Gregory Pir~u~, a pioneer in the crearn * ton of oral contrác~t~ves, in Ladies' Home Journal, June, 1963.. The substance of the Clark-Ratner indictment once was turned against The New York Times by Gershon Rolnick, a reader in Brooklyn, who made a tally of stories on The Pill and found a far smaller emphasis on safety than on such aspects as the happiness of sexually liberated and always ready co-eds, secretaries, and housewives, the pronouncements of clerics, and the alleged therapeutic benefits. Replying, Turner Catledge, then executive editor, told Rol- nick that the Times "has tried to inform its readers about all important aspects of the question of oral contraceptives. It intends to continue to report accurately on all newsworthy events." Well over a year after this exchange, in April, 1968, the Times disposed of the momentous report of the British Medical Research Council with a six-paragraph story on page 86, next to the ship arrivals. Four months earlier, on January 7, 1968, a Times specialist on The Pill, Jane E. Brody, pronounced it nothing less than the "perfect" contracep- tive. This evaluation was made in the first sentence of her article. The second sentence made clear that by "perfect" she meant "foolproof." This is not the exclusive criterion for perfection; shooting the mother might also be a "fool- proof" method of contraception. Miss Brody's enthusiasm for The Pill was shared by Dr. John Rock, one of its principal developers, probably its leading proselytizer and a Roman Catho- lic, whose scientific illogic has been treated by the Times and other news media as seriously as his disputes with the Vatican. In the January, 1968, Family Circle, which about 7 million housewives carried home from supermar- 2 is "A Quarterly Survey on The Family" owned by the National Commission on Human Life Reproduction and Rhythm, Oak Park, Illinois. PAGENO="0313" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 7143 kets, Dr. Rock said that when taken "under the supervision of a competent physician, and directions followed," The Pill "is perfectly safe." Similarly, Dr. Robert W. Kistner, a Harvard Medical School colleague of Dr. Rock, said in the 1~Iarch, 1964, Postgraduate Medicine, ". . . scrutiny of the available data by experts in the field of hematology and vascular disease has completely exoner- ated the drug as the etiologic factor." Such claims are, on their face, scientif- ically untenable. For one thing, Dr. Rock's "competent physician" has no way of detecting, say, a predisposition to clotting in a woman with no indication or history of such disease. For another, it is an axiom that no data about a drug and adverse reactions ever warrant a claim that it is "perfectly safe" or has been "completely exonerated." A scientist properly can assert only a cautious conclusion: that there is a probability of a high or low order that a cause-ef- fect relation with adverse reactions has been demonstrated. Dr. Kistner's claim of complete exoneration was circulated among an influ- ential group of laymen by G. D. Searle & Co., manufacturer of Enovid, the pioneer oral contraceptive, and of Ovulen-21, another such drug. On October 15, 1965, a few weeks before the publication of my The Therapeutic Night- mare, Searle launched an extraordinary campaign by sending to "Book Review Editors and Book Reviewers" an 8-page "Fact Sheet." The headline was, "5EARLE SEEK5 TO AVOID PUBLIC `PANIC' ON ORAL CONTRACEPTIVES/BY ALERTING BOOK REVIEWERS TO `MISINFORMATION' IN MINTZ BOOK". Other cover pages were prepared for other news executives, such as "Science and News Editors." 8 What set off the Searle crusade was a chapter on the facts known up to that time about reasons for concern about The Pill. Coming down hard on the pos- sibility, raised in the book, that The Pill could cause clotting, the "Fact Sheet" quoted Dr. Kistner to the contrary. More celebrated, however, is Dr. Rock. He has told people what they want to hear. This has enabled him to shrug off criticism that was scientifically dev- astating. Consider a claim he made in 1963 in his book The Time Has Come. The claim was that The Pill is a "natural" and "physiologic" contraceptive technique. In The New York Times Book Review Dr. Robert E. Hall of Colum- bia University, an admitted "birth control enthusiast," said, "I would like to dismiss this theory as a harmless euphemism; as a doctor I must aver it is medical fantasy." Dr. Herbert Ratner has told why. The Pill, he said, induces "false pregnancy," which "is a disease, not a normal state." In true pregnancy, "the vascular system of the body adjusts to accommodate a rapidly enlarging uterus," he explained. "In false or Pill pseudo-pregnancy, the pelvic vascular system increases the blood supply, but there is no enlarging uterus to utilize the increase. This results in extensive venous congestion [which] introduces a whole series of factors predisposing to thrombosis and embolic phenomena." How can contraception with The Pill be "natural" when, as Dr. Clark, the pro- fessor of neurology at the University of Kentucky, has pointed out, a woman taking it "is, in effect, pregnant and delivering every month," and has over her child-bearing life "90 times more chances of showing the complications of preg- nancy"? THE LAST CLUES Let us see how the present situation developed. Particularly in the period 1954 through 1965, when the late George P. Lar- rick was Commissioner of the Food and Drug Administration, the agency allowed a great many potent drugs to go on the prescription market. Fre- quently, safety had not been actually demonstrated but merely had been asserted by companies in which the FDA had confidence. In May, 1960, Dr. William D. Kessenich, then director of the Bureau of Medicine, notified Lar- rick that the New Drug Branch of the bureau had "concluded that the evi- dence establishes the safety of Enovid tablets for use in conception control The agency enforced rigid secrecy policies that concealed the nature and I have no evidence on what impact the Searle campaign may have had. With extremely few exceptions, the book was neither mentioned nor reviewed in magazines- but it was extensively (and often very favorably) reviewed in newspapers; and I had, and accepted, numerous invitations to appear on radio and television stations in several cities. PAGENO="0314" 7144 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY quality of "the evidence" from the medical and lay press and public. As a practical matter, there was little choice but to take the decision to allow mar- keting on faith. The assumption was erroneously but widely made that those in authority were observing a standard such as that articulated in August, 1961, by Drs. H. Cook Hale, Clarence~ J. Gamble, and Adaline Pendleton Sattherwaite, all of Harvard, in the American Journal of Obstetrics and Gyne- cology: "No method of pregnancy spacing, even though highly effective, is justi- fiable if it endangers life or health." The assumption also was widely made that the tests of large numbers of women in Puerto Rico were for safety; in fact, these tests were for efficacy. There were times when subcommittees of the House and Senate stripped away the secrecy imposed by the FDA and bared evidence of non-feasance, misfeasance, and malfeasance. Usually, the press responded with non-reporting. Such was the case in early 1963 when a Senate Committee on Government Operations subcommittee headed by then Senator Hubert H. Humphrey, which had been monitoring the agency's performance, published some shocking inter- nal FD~~ documents. One was the memo from Dr. Kessenich which provided the foundation for the decision by the FDA, in 1960, to let Enovid be mar- keted as a contraceptive. The "entire series of clinical cases" on which the conclusion of safety was based, Dr. Kessenich said, included only 66 women who had taken Enovid for 12 to 21 consecutive cycles; only 66 more had taken it for 24 to a maximum of 38 consecutive cycles. "Consecutive" is the crucial word, because sustained use is what must be monitored if reliable information is to be had on the impacts of taking a powerful combination o~ estrogen and progestogen over a long period-almost three decades, in the extreme case of a female who should use The Pill over her entire child-bearing age range of 15 to 44. Yet the number of women who had received Enovid continuously for a year or more was 132. As a basis for presuming safety in long-term use by, ulimately, millions of women, this was scientific scandal. To my knowledge, the sufficiency of the test sample since its exposure has not been publicly and spe- cifically defended-not by the FDA, not by scientists, not by organized medi- cine, not even by the manufacturer. For one thing, 132 is a sm~lller number of women than, this year alone, in the United States alone, will die from clotting induced by The Pill. If the adversary system somehow had reached out to the FDA and com- pelled it to disclose its evidence and non-evidence of safety, the agency would have been laughed out of the courtroom. And had the press not failed to call the attention of the lay and medical public to the figures blind ignorance would not so long have been perpetuated. In October, 1965-two and a half years after the Humphrey subcommittee published the data-the Committee on Human Reproduction of the American Medical Association issued, in the Jour- nal of the AMA, a comprehensive guide to conception control. The Humphrey figures were nowhere mentioned. In an interview, Dr. Raymond T. Holden, the Committee chairman, acknowledged to me that he-and, so far as he knew, the seven members of the committee-had never heard of them. They were, he said forthrightly, "not enough." Also in 1963, a report w-as made by the Wright Committee, a group of con- sultants assembled by the FDA after it had learned of 30 fatal and 242 non- fatal clotting episodes in users of Enovid. At the time the committee was named, December, 1962, Enovid was the only oral contraceptive on the market. The committee investigated the available evidence but found it too full of holes to yield a statistically significant result. Again w-idely and erroneously, this was assumed to mean that Enovid had been found safe. The committee's single recommendation was for a u-eli-controlled, prospective (looking forward) study. This recommendation was of obvious, critical importance, and on a grand scale, to health and life. For years, the FDA did not implement it and did not even seek funds to implement it. This non-performance was non-moni- tored by the Congress. With the exception of The Washington Post, time press failed to call attention to the failures of the FDA and the Congress. Once again, non-reporting served to re-enforce an invalid presumption of safety. PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7145 The possible rol. of these pills in clot formation is mentioned frequently. A group of distin- g~ished obstetrician- gynecol- Ogists evaluated aU.the data and could not confirm or refute the eausative role of these corn- counds. ~ - They also concluded that "if ~iaI contraceptives act as a eauie, they do so very infrequent-. 4y, - relative to. the number of users." In addition there is no proof that they cause cancer or have an adverze effectipori the baby when pregnancy is desired. Moeèxpei~t advice: from a column by Dr. Thea- dora R. Van Dellen, distributed by the Chicago Tribune and printed in the New York Daily News,. Deccmber.4,~ 1966 The same presumption was benefited by misreporting, or worse. The next year brought a memorable example. On July 12, 1964, This Week, the supple- ment circulated to millions in their Sunday newspapers, carried an article which a sub-headline heralded as "authoritative" and which was blessed by the American Medical Association by way of an inset saying, "AMA. Authorized." The writer, Dr. Edwin J. DeCosta, said, ". . . studies do not indicate that the pills cause clots." What studies? The FDA's counterpart of the retrospective British trials was not begun until 1966 and will not be completed until some- time in 1969. The National Institutes of Health did not make its first contract for a prospective study, the kind recommended in 1963 by the Wright Commit- tee, until mid-1967; and the intake of volunteers did not begin until the spring of 1968, or eight years after The Pill went on sale. Dr. DeCosta doubtless was referring mainly to preliminary reports on a highly publicized study of 5,000 women who were given Enovid in 38 Planned Parenthood clinica. When the study was formally reported, in April, 1965, G. D. Searle, the manufacturer, unleashed a major publicity campaign which focused on the claim that the rate of leg and pelvic clotting in the 5,000 users was lower than "we have ever found for incidence of thrombophlebitis in women of a similar age group Few noticed the fatal flaw: the 5,000 participants entered the study only after having taken Enovid for 24 months. Thus the study eliminated a crucial group, the drop-outs who because of unfavorable experience with Enovid quit using it, never entered the study, and therefore were not counted. Because most such unfavorable experience, including clotting episodes, occurs well within the first twenty-four months of use, the study was a scientifically ludicrous basis for a claim such as Dr. DeCosta's that "studies do not indicate that the pills cause clots." Even in 1962, about eighteen months before the This Week article appeared, Professor J. R. A. Mitchell of Oxford and the British Medical Research Council had told a Searle-sponsored conference on clotting, "the patients who drop out . . . are much more important than the patients who stay in In This Week, Dr. DeCosta obscured the fundamental question, whether clot- ting occurs in users of The Pill more often than in non-users, with two devices. One was the diversionary one of noting that clotting occurs not only in women non-users, but also in men. The second was ridicule: "I am reminded of a recent medical meeting where a doctor reported several instances of leg clots occuring chiefly in patients taking the pills. Another doctor promptly arose. His patient too had been given a prescription for the PAGENO="0316" 7146 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pills, and had developed leg clots. But she had forgotten to have the prescrip- tion filled." "AMA-Authorized" humor, vintage 1964. At about the same time, on July 3, there was an FDA-authorized uplift for readers of Life. Dr. Joseph F. Sadusk, Jr., then the agency's top doctor and now a vice president of Parke, Davis & Co., a manufacturer of oral contracep- tives, said, "We are not taking a dogmatic attitude that oral contraceptives are absolutely safe. . . . But the indications so far are they are safe, when given under the supervision of a doctor (`my italics). But what does "absolutely safe"-or even "safe"-mean? This question is elementary. Yet it was seldom asked. Actually, the proper question about any drug is not whether it is "safe," but whether it is relatively safe for a particular patient. Safety is not absolute but relative, varying with the individual, the severity of his con- dition, his age, the available alternatives. Being almost totally effective in inhibiting ovulation, The Pill is relatively safe for a woman in whom concep- tion could have a tragic result-death in childbirth, a mental breakdown, an infant born to starve. The Pill is relatively unsafe for the bride who wants to have children but not at once and who reliably will use alternative forms of conception control, such as a diaphragm (always with spermicidal cream or jelly) or vaginal foam. These alternatives (and intra-uterine devices in women who have been pregnant) involve a very small risk of failure, that is, of con- ception, and failure in a w-oman such as described is not tragic. Reassured by experts such as Drs. Rock, Kistner, DeCosta, and Sadusk; given scant help by news media; predisposed to believe that a beneficient Sci- ence had, in the nick of time, galloped to the rescue and simultaneously pro- vided the answer to population control and a chemical passkey to the New Sexual Freedom-given all of these things, it was not to be wondered that the advice once given by the lat Justice Robert H. Jackson was widely violated. We are, he said, in "a day of synthetic living, when to an ever-increasing extent our population is dependent upon mass producers for its food and drink, its cures and complexions, it apparel and gadgets." He went on to say, "Purchasers cannot try out drugs to determine whether they kill or cure." But they do. [From the Columbia Journalism Review, Spring, 1969, pp. 28-35] THE PUL :-PRE55 AND PUBLIC AT THE EXPERTS' MERCY-SECOND PART Morton Mintz, a reporter for The Washington Post, continues here his exami- nation of (in the words of the note on the first part of this article in the winter issue) "The insufficiency of the mechanisms now available for monitor- ing specialist institutions on the public's behalf." (By Morton Mintz) In 1965 there appeared in medical journals a significant volume of reporting that cast doubt on whether the assumed safety of The Pill rested on solid research footings. The Pill's advocates developed a standard response. This was that The Pill had not been proved unsafe. Rarely if ever mentioned was the scientifically required counterbalance, that neither had The Pill been proved safe. Neither was it noted that since 1938, the Food, Drug, and Cos- metic Act had required a manufacturer proposing to market a drug to demon- strate safety; it had not required the Food and Drug Administration to dem- onstrate lack of safety. In any .case, the argument that The Pill had not been proved unsafe became a litany, often parroted in the press. In addition, proponents made loose statements about such proof, For exam- ple, Gregory Pincus, a co-developer of The Pill, said it had yet "to be proved that there is a cause-and-effect relationship between The Pill and the serious adverse effects suffered by some." Again, there was no acknowledgement that more was required-a disclosure as to specifically what weight of evidence of harm, in the eyes of the. advocates, would add up to proof. Also missing was a recognition that for scientists there is no proof in the black-and-white sense, that all that can be had is evidence in one or another shade of gray, and that it is this kind of evidence-data on relative risks-on which those with a responsibility for the public health must judge the relative safety of all drugs. PAGENO="0317" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7147 In April, 1965, Dr. Joseph F. Sadusk, Jr., then the top physician of the Food and Drug Administration, felt compelled to deal with increasing evidence of an association between The Pill and strokes. "It seems reasonable to conclude at this time that there is no evidence of a cause-and-effect relationship," he assured the public, adding that the "information at hand is to the contrary." There was not proof, but there certainly was evidence-a series of reports dating back to 1962 in the British Medical Journal-and it was not "to the contrary." Today, the new FDA-approved labeling says that data from the British studies are "suggestive of an association." In addition to the FDA, an organization that found itself increasingly on the spot was Planned Parenthood-World Population. On February 17, 1966, the Medical & Pharmaceutical Information Bureau (a division of Science Public Relations, Incorporated, whose clients include Ortho Pharmaceutical Company, a maker of contraceptives) distributed a handout headlined: "ORAL CONTRACEP- TIVE NOT CAUSE / OF THROMBOEMBOLISMS: DR. GUTTMACHER". The text began, "NEW YORK-Fears of thromboembolic involvement in women taking oral con- traceptives have, no basis in proven medical fact, according to Dr. Alan F. Guttmacher, president of Planned Parenthood-World Population." The handout was based on a piece in . a throwaway magazine for general practitioners. As more and more troubling reports came in, however, it became more difficult to dispense such pap. Fifteen months after the article appeared, for example, Dr. Guttmacher was asked for comment on documented reports that in users of The Pill migraine headaches could be a signal of an impending, drug-induced stroke. "I'm sure there is some possible connection," he told The New York Times, "and I don't think we can whitewash it." He did not say, "any longer." In 1966, two reports of surpassing importance were made on The Pill. The first was made by a World Health Organization task force and the second by the FDA' Advisory Committee on Obstetrics and Gynecology. The WHO unit, which met in Geneva, was heavily influenced by Dr. Sadusk, who was repre- senting the FDA. After splitting on what kind of report to issue, the task force issued one that was generally soothing and was widely quoted. In the Ladies' Home Journal for July, 1967, Lois R. Chevalier and Leonard Cohen said they were told by a delegate, who was not named, what happened after six members of the task force favored and five opposed a general endorse- ment: But the people who were concerned about the population problem had already decided that we were going to deliver a whitewash. The delegate from behind the Iron Curtain didn't want to incur disapproval since he liked being invited out to attend conferences in the West. Some of the Western European dele- gates just went home before the meeting ended, so that they wouldn't have to commit themselves on the final vote. I wanted to put in a minority report, but I was told quite firmly that all WHO task force reports had to be unanimous. In the end, I signed. In the report of the FDA Advisory Committee, released in August, 1966, maximum attention inevitably was drawn to the conclusion that there were "no adequate scientific data . . . proving these compounds unsafe for human use." This conclusion, of course, comported neither with the need for a balanc- ing statement that the compounds also had not been proved safe, nor with the law's requirement that safety be demonstrated before marketing, nor `with the finding the FDA had made six years earlier that "evidence establishes the safety" of one of the oral contraceptives evaluated by the committee, nor with the admission in the introduction of the report itself that "any assumptions" about relative safety were "unreliable" because of the paucity of crucial data. Despite all this, the headline in Time was, "The Safe and Effective Pills" and in Newsweek, "Popular, Effective, Safe." The lead paragraphs in the sto- ries in The New York Times and The Wall street Journal said that "no evi- dence" of hazard was found, when what in fact was meant was that no proof had been found. The headline in the AMA News, which the American Medical Association describes as "The Newspaper of American Medicine," was "Oral Contraceptives / Safe, FDA Says." Some newspapers, including the morning ~S'un, passed up stories altogethei~. Although Dr. Louis M. Heliman, the com- mittee chairman, had characterized the report as a "yellow light" of caution, PAGENO="0318" 7148 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Planned Parenthood's Dr. Guttmacher was quoted in the Tinies as saying it gave The Pill "a complete green light." Dr. James L. Goddard, who in January, 1966, had succeeded George Larrick as Commissioner of the FDA, went before the television cameras and, despite determined, incisive questioning by Sander Vanocur, persisted in conveying to the Today audience a far more positive impression of the safety of The Pill than was warranted by the report of his own agency's advisory committee. A year later, Dr. Goddard brought his optimistic approach to a CBS television and radio audience. "Do you still think The Pill is safe ?" Martin Agronsky asked on Face the Nation. "Yes," the Commissioner replied. "I believe it is, provided it is taken under a physician's direction and careful consideration is given to all the factors in the medical history." This was a standard reply-and a misleading one. But when reminded in persistent questioning that, for example, only 132 women had received Enovid for a maximum of 38 consecutive cycles before the FDA let it go on sale, Dr. Goddard inplied strongly that the previous regime may have been negligent. "It was," he said, "my impression . . . that there were large-scale studies car- ried out. . . . Whether today, if the same problem came up de novo, I would make the same judgment that was made then, I can't say [my italics]." From then on, Dr. Goddard, who had inherited a mess when he became commis- sioner, took a hard line on The Pill. So has the man who succeeded him, Dr. Herbert L. Ley, Jr. A serious case of non-reporting and mis-reporting was provided by events of April 4, 1967. In Atlanta, Commissioner Goddard, who was now taking a hard line, went into a veritable lions' den-a meeting of the American Association of Planned Parenthood Physicians-to warn that side effects of The Pill were "grossly under-reported." He said that the lack of adequate data was a "grave issue," that every doctor should report even the "subtlest experiences" in users, and that each patient should be told "carefully . . . about all the possi- ble side effects The Pill may bring on, minor or major." Although the FDA widely distributed copies of the speech, most major news media ignored it. On the same day, in London, Minister of Health Kenneth Robinson disclosed in Parliament that a then unreleased, preliminary report of the Medical Research Council would show "a slightly increased risk of clotting." But he went on to try to minimize the risk by comparing it favorably with the risks of pregnancy. He released mere bits of solid information. The net result was almost total confusion. While the Daily Mail was carrying a very large head- line saying "Pill Clearance," the Guardian was saying, "Risk of Thrombosis." At the same time, the Daily Telegraph was so reassured that it said The Pill "must now be regarded as medically pretty safe" and "argument about it . transferred to other spheres." In an angry editorial, Lancet, the, medical jour- nal, said it did not blame the newspapers for the confusion, for they had had "to make what they could of a statement no one could evaluate," but Robin- son, because he had disclosed the "alarming conclusion" of the Research Coun- cil without giving physicians prescribing The Pill "the facts needed to re-ex- amine their decisions." It continued: "The confusion generated by the inept handling of this situation has obscured the main message-mainly, that for the first time since oral contra- ceptives were introduced an authoritative inquiry has shown that they do carry an increased risk of thromboembolism." The "main message" was nowhere in a Time cover story on The Pill dated April 7, 1967. The theme, "Freedom from Fear," carried a brisk, promotional, propagandistic tone. There is "no evidence that the pills cause clots that might travel to the lungs or develop in the brain," Time said. Eight months later- long enough for many readers to have forgotten that they had been promised "Freedom and Fear"-Time backed down. In a piece on December 29, 1067, headed "The Pill and Strokes," Time admitted that enought cases had been reported "to convince physicians that there is a cause-and-effect relationship." On May 5, 1967, the preliminary report of the Medical Research Council to which the Minister of Health had alluded was released. The New York Times accorded it twelve printed lines. These were the lead paragraphs on wire serv- ice stories received in the United States: PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7149 "LONDON (AP)-The British Medical Research Council says birth control pills may have caused the deaths of 20 women in Britain last year, but riding in a cal~ wouldhave been twice as risky as taking the pills. "LONDON (uPI) -British medical researchers said today birth control pills are not 100 percent safe. But they said the pill is far safer than a walk across a busy street. "LONDON (REuTERS)-A report in the British Medical Journal linked the death of 20 women in Britain last year with the birth control pill, but said the risk was small compared to the number of deaths in childbirth or in traffic accidents." Thus did an effort to put things in "perspective" mute the news-shattering to the almost universal presumption of The Pill's safety-in this key sentence: "There can be no reasonable doubt that some types of thromboembolic disorder are associated with the use of oral contraceptives." Inevitably, such mis-reporting helped to entrench the bizarre notion that traffic fatalities on busy streets provided a rational measure of hazard from The Pill. Although such reasoning is considered scientifically irrelevant by the FDA, it continues to be merchandised to this day. With the imprimatur of the Research Council on it, the comparison was used by, among others, Dr. Sey- mour L. Romney, chairman of the National Medical Advisory Committee of Planned Parenthood-World Population, in a letter "FYI to Science Writers," and in England's Family Planning Association Journal by Lord Platt, a former president of the Royal College of Physicians. Actually, the use of traffic acci- dents to downgrade the hazards of The Pill is an old story. On September 18, 1966, for example, it was used by Joshua Lederberg, who in 1958 won a Nobel Prize, in his column in The Washington Post. But if comparisons with traffic accidents are valid, why is it that propagan- dists for The Pill fail to point out, for example, that in the fifty-nine years in which records have been kept, the annual death rate in the United States from polio has exceeded 20 per million exposed population only twice, while the death rate from clotting among the population exposed to The Pill tentatively put forth by the Research Council was 30 per million, or 50 percent higher? Is it possible to reconcile the pooh-poohing of the importance of clotting on The Pill with the crusade against polio? It may also be noted that the clotting rate of 30 per million about equals the incidence of death in white women of child- bearing age from crimes of violence, including murder, forcible rape, robbery, and aggravated assault. Further, the number of deaths from illegal abortion is approximately the same as the number from clotting on The Pill. Some of the scientists most determined to change the abortion laws dismiss deaths from The Pill as inconsequential. Their perspective is puzzling. "I don't think personally that the way to talk about this risk [of clotting] is in comparison with the things we do every day that we don't have to do," Dr. Louis M. Hellman, chairman of the FDA's Advisory Committee on Obstetrics and Gynecology, said on May 2, 1968, on NBC's Today. "For example, you don't have to ride in an automobile Dr. Hellman and the nationwide tel- evision audience would have been ahead had he stopped there, but he unwisely went on to say, ". . . and yet the risk of riding in an automobile is perhaps ten [times higher than the risk of clotting], maybe even more, than that" Showing considerably more presence of mind than the Government's top out- side consultant, interviewer Barbara Walters said, "I could say, Doctor, that in the course of my daily life, I pretty much have to ride in an automobile. . But I don't have to take The Pill." Although more plausible than comparisons with the risks of crossing a busy street, matching the hazards of The Pill with those of pregnancy, delivery, and abortion, if made on a generalized basis, also is invalid; For a healthy woman assured of first-class medical care, pregnancy is a much smaller risk than for a diseased slum dweller who does not get enough' proper" food, lives in squalor, and is unlikely to get proper maternal medical care, if any at all. For an unmarried girl, the possibility of pregnancy and abortion may be an intolera- ble alternative to use of The Pill-but The Pill is not the only method of con- traception available to her. All of this should be obvious. Yet there persist generalized-and therefore meaningless-comparisons of PAGENO="0320" 7150 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the hazards of pregnancy with the hazards of The Pill. These are based on a statistical fallacy. This can be demonstrated by using figures cited by the Brit- ish Medical Research Council in its preliminary report. As has been moted, the Council tentatively estimated that The Pill caused deaths from clotting at the rate of 30 per million per year. This rate was com- pared favorably with the four-times-greater mortality rate of 120 per million completed pregnancies. Such a comparison, however, is valid only for those women who will use no contraception but The Pill; it is absolutely irrelevant -as irrelevant as traffic accidents-for the large numbers of women (espe- cially in the middle and upper classes) who reliably will use, say, vaginal foam or a diaphragm with spermicidal cream or jelly. Among these women the failure (conception) rate is very low, on the order of 2.5 percent. This is about the same as for the so-called sequential form of The Pill, for which the regi- men is ingestion of an estrogen-only tablet 15 days a month and an estrogen- progestogen tablet 5 days. Thus it is not 1 million out of 1 million such women who face the hazards of maternity, but only the 25,000 or 2.5 percent, who become pregnant. The rate at which mortality occurs in completed pregnancies, 120 per million, consequently must be applieed to 25,000. The computation shows that 3 women will die-27 fewer than if all of the 1 million women had taken the almost totally effective combination (not sequential) Pill. In addi- tion to the statistical fallacy, one must take into account other factors-the higher clotting death rates indicated last May in the Research Council's final report, the failure to allow for the less~than-perfect efficacy of the sequentials, and the distortion made unavoidable by a focus on fatal clotting without regard to the higher incidences of serious-and sometimes disabling-clotting episodes and to the possible range of other associated diseases. By now, having been planted in more places than can be counted, the com- parison with maternal mortality is indelibly inscribed in our medical mythol- ogy. In Birth-Control, a Time-Life book published in 1967, for example, Ernest Havemann said the risks of clotting from The Pill "are far less than those of an ordinary pregnancy." Trying to cool questions in Parliament in the same year, Health 1~Iinister Kenneth Robinson emphasized the greater "total risks associated with pregnancy." In The t~vnday Times of London, Moira Keenan said that although there may be 30 clotting deaths per year among 1 million users of The Pill, "four times this number would die from thrombosis if they became pregnant." On Today on May 2, 1968, Dr. Louis M. Hellman, the Food and Drug Administration's outside expert, said, "The British say the risk is less than having a baby." At about the same time, The New York Times said, "But the British reports noted that the risk attributed to the pills was sub- stantially less than the risk of death from pregnancy." And Newsweek cited the greater "well-established risk of blood-clot complications in pregnancy." Worse than any of this were the efforts, which continued even after publica- tion of the preliminary and final British reports, to deny that The Pill caused clotting at all. In October, 1967, for example, Parents' Magazine carried an article in which Dr. George Langmyhr, medical director of Planned Parent- hood-World Population, cited data purporting to show that The Pill could not be the cause. The data were derived from a book entitled Oral Contraceptives, by Dr. Victor Drill, director of biological research for G. D. Searle & Co., maker of Enovid. This was not disclosed to the readers of Parents'. In addi- tion, the data used by Dr. Langmyhr have been acknowledged even by Searle's Dr. Irwin C. Winter, vice president for medical affairs, to be "very likely a reflection of inadequate reporting." One can only speculate about how much harm has been done by efforts to downgrade the hazards of The Pill, no matter whether such efforts were humanely motivated (as in the case that follows of Dr. Louis M. Hellman, chairman of the Food and Drug Administration's outside consultants) or oth- erwise motivated (as in the case that follows involving G. D. Searle, manufac- turer of Enovid). In January, 1968, Dr. Hellman and the FDA held a press briefing on an Advisory Committee report on intra-uterine devices. However, questions about The Pill were asked. Dr. Hellman disclosed that-on a confidential basis pend- ing publication in the British Medical Journal on April 27-he had been shown PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7151 the final figures on the clotting studies. Much in the manner of British Health Minister Kenneth Robinson, Dr. Heliman admitted that a cause-effect relation with clotting had been "established" but characterized the risk-the risk now found to be seven to ten times greater in Pill users than in non-users-as "very, very small." Not for three months was the actual degree of risk known. In any event, Dr. Heilman's disclosure and acceptance of the existence of a cause-effect relationship was important news. Appropriate emphasis to it was given by, among others, all of the daily newspapers in Washington, The associated Press, and Medical Tribune (but not by The New York Times). Then came a bizarre development. In a story on February 27 by Herbert Black and Carl M. Cobb in The Boston Globe there was a paragraph in which Dr. Hellman seemed to back down: Dr. Hellman has been quoted as seeing a cause-and-effect relationship in the British study. Heilman told the Globe: "The study has demonstrated a very real relationship, but is only suggestive of a cause-and-effect relationship [my italics]." But this repudiation, if that is what it was, was itself repudiated on May 2 when Dr. Heilman told Barbara Walters on Today: Well, Barbara, I think the British data is [sic] conclusive. I think that it proves, and this is a new item, conclusively what we have suspected for some time, that there is a cause and effect relationship between the taking of oral contraceptives and lung clots [my italics]. The Searle firm has been phenomenally profitable, thanks in great part to its oral contraceptive products. In 1964, for example, after-tax net earnings were $12.2 million, or 28.2 percent on sales. In 1967, in the Journal of the American Medical Association and in OB-GYN, a medical specialty publication, Searle published advertisements for Ovulen-21. Because they omitted a change in the FDA-approved labeling, which the company had agreed to, that emphasized the possibility of "serious hazards" from clotting diseases in the legs, lungs, and eyes, the FDA found the ads "potentially misleading." Under threat of more severe action by the agency, Searle on January 26, 1968, apologized in a reme- dial letter to every doctor in the country. The letter admitted that the ads: ". . . failed to include the following side effects which, although causation has not been established, have been reported in users of oral contraceptives: anovulation post treatment premenstrual-like syndrome, changes in libido, changes in appetite, cystitis-like syndrome, backache, nervousness, dizziness, fatigue, headache, hirsutism." All such corrective letters, no matter what the drug, are unarguably news. The Washington Post treats them as such. Other news media do not. They thus withhold the benefits of disclosure, which they regularly praise in other circumstances. In the case of letters such as Searle's, patients are deprived of the possibly vital knowledge that their physician may have been deceived about a drug he prescribed for them. Until the FDA cracked down in the fall of 1967, most of the makers of The Pill had prepared pamphlets for customers at what might be called the point of sale-that is, in doctors' waiting rooms. These pamphlets generated pressure on doctors-sometimes by omitting full information on warnings and side effects, or by phrasing such information in language the patient was not likely to understand. The Searle firm's efforts to build the market for The Pill have taken other paths, too. Through support of something called Interscience Information, Inc., it operates the pro-Pill Women's Medical News Service. It has given annual grants to Dr. J. Ernest Ayre, medical director of the National Cancer Cytology Center, Inc., who has pushed the brand-name Enovid in press releases and interviews. (Dr. Ayre also was medical consultant to the Rand Development Corporation, which in December, 1968, was indicted for mail fraud and stock fraud in connection with its promotion of a purported cancer vaccine.) The Searle Foundation has contributed ($17,000 in 1964, for example) to the Wilson Research Foundation, Inc., headed by Dr. Robert A. Wilson, the author of Feminine Forever. Dr. Wilson claimed that The Pill-he usually mentioned a formulation containing a progestogen used only in Enovid-could make sex more enjoyable "regardless of age." This kind of wild claim, which Dr. Wilson 40-471 0-70-pt. 17-21 PAGENO="0322" 7152 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY made in syndicated newspaper articles and in such geriatrics journals as Look and Vogue, provoked the FDA. In November, 1966, it notified Searle, Dr. Wil- son's research sponsor, that he had "publicized the use of Enovid in lay publi- cations, stating that it is effective in preventing symptoms of the menopause. Our investigational drug regulations provide that neither the sponsor nor anyone on its behalf may disseminate promotional material claiming that the drug has been shown to be effective for the conditions for which it is being investigated. Dr. Wilson has disseminated such information. He is therefore unacceptable as an investigator for `Enovid in the Menopause.'" One of the most troubling questions about The Pill is what relation it may have to cancer. The fact is that the Food and Drug Administration, when it let the first Pill go on sale in 1960, was as ignorant about that relation as it was about an association with clotting. The agency's documented experience as to cancer involved 400 women for four years-a ridiculously inadequate number and much too short a time period, the latency period of all substances known to be carcinogenic in humans being about ten years. As of 1966, pub- lished data on the incidence of cancer in women under 40 who had received The Pill continuously for at least four years involved merely eighty-five women, Dr. Roy Hertz, a member of the FDA's Advisory Committee on Obste- trics and Gynecology, has pointed out. Was the number sufficient, then Com- missioner James L. Goddard was asked in January, 1967, on Face the Nation. "No," he said frankly, "I don't believe it is." The same view was held at the National Institutes of Health. On February 17, 1965, the late Representative John E. Fogarty, chairman of a House Appro- priations subcommittee, had taken up the possibility of a relation between The Pill and cancer. There was this exchange with Dr. James A. Shannon, then director of NIH: Mr. Fogarty. So people are really taking a chance. Dr. Shannon. I believe so. There are a great many studies on experimental animals that indicate that they probably can be taken without hazard, but there has not been adequate human eivploration to be certain [my italics]. The subcommittee hearing containing the exchange was published later in 1965 but the message was largely unreported, despite the authoritativeness and prestige of the source and the significance of the message. In its report of August, 1966, the FDA's Advisory Committee dealt with claims made by various purported experts that The Pill provides probable pro- tection against certain kinds of cancer. Disagreeing, the committee said that "there is not sufficient evidence to support the contention that contraceptive pills may* protect against the development of carcinoma of the cervix," that available data "do not permit any conclusions relative to the effect, either adverse or beneficial . . . on endometrial [uterine] cancer," and that the rela- tion of The Pill to human breast cancer is "unknown."1 On the day in April, 1967, when The New York Times ignored the caution- ary speech given by FDA Commissioner Goddard in Atlanta, it carried from Palm Beach an optimistic, 17-paragraph story by Jane E. Brody. It began: "Oral contraceptives not only seem not to cause cancer, but they also appar- ently prevent at least one type of cancer from developing, a Harvard gynecolo- gist reported there today." The conclusion of the FDA advisers that the evi- dence was insufficient to permit any conclusions was not mentioned. The Harvard gynecologist was Dr. Robert W. Kistner, who in 1964, it will be recalled, had told of experts who "completely exonerated" The Pill as a cause of clotting. And Time, in its "Freedom From Fear" cover story, said, "Despite dark fears, there is not a shred of evidence that the pills cause cancer. In fact, they may even give some protection against it." Again, the FDA advisers were ignored. 1 Charging that Merck & Co. failed to report promptly the discovery of breast cancer in beagles given MK-665, an experimental, oral contraceptive, the FDA in April, 1968, asked the Justice Department to undertake a criminal prosecution. PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7153 On September 13, 1968, Robert Metz reported in his "Market Place" column in The New York Times: Those swinging birth control pill stocks were off pace again yesterday as a rumor got around that there might be a relationship between The Pill and uter- ilie cancer. . The rumor evidently stemmed from discussions at a closed meeting of the American Cancer Society regarding research projects that are in an early stage of development. This was by no means the first time that Wall Street received possibly cru- cial information about The Pill, among other potent drugs, well ahead of doc- tors and patients. But I was unaware of this report when, on the morning it appeared, I went to Cherry Hill, New Jersey, on a tip that reports on studies of cervical cancer and The Pill were to be made at a meeting of scientists sponsored by the Cancer Society. No announcement of the meeting had been made and it was, I found, closed. Indeed, I was urged to leave. During a coffee break, one scientist expressed to me a fear that disclosure of the material under discussion might panic the women of America. No concern was expressed that, in a sense, a large number of women may have been "pant icked" into using The Pill on the basis of a misplaced confidence that its safety had been established. After the meeting, I tried but failed to interview Drs. Myron R. Melamed and Hilliard Dubrow about a study-financially aided by the taxpayers through grants from the Public Health Service-done co-oper- atively by Planned Parenthood of New York City and Sloan-Kettering Memo- rial Hospital. Despite the lack of co-operation and even hostility-the Cancer Society's Dr. Jack Milder told me I had overstayed my welcome-I was able to piece together a story reporting that a higher incidence of cervical cancer had been found in many thousands of women on The Pill, but that there were serious questions about whether the higher incidence did or did not mean any- thing. This was essentially the conclusion of the FDA's Advisory Committee when, on November 1, 1968, it reviewed the incomplete, unpublished Melamed- Dubrow data and issued a statement saying that they neither confirm nor refute a cause-effect relation with cervical cancer. A the very least, a finding from the data that a causal relation had not been refuted was troubling. Yet the Times not only did not report the FDA statement, but also, on December 12, carried a story by Miss Brody which was, once again, marked by a lop- sided emphasis: "There have also been a number of scare reports linking the pill to increased risk of cancer, especially cervical cancer, but none have been substantiated." For years, informed scientists have been concerned about use of The Pill in physically immature girls, because it may prevent them from attaining their full height. Late in 1966, when the Food and Drug Administration announced a new, uniform labeling for all brands of The Pill, it warned that in such girls The Pill "should be used judiciously." In April, 1967, FDA Commissioner Goddard repeated the warning in the speech to Planned Parenthood physi- cians. Almost simultaneously, in its "Freedom from Fear" cover story, Time told about a really with-it mother who "announced that she was already slip- ping The Pill into her daughter's breakfast milk." Time did not bother to point out that by law and good medical practice, The Pill is supposed to be individually prescribed.2 Thirteen months later-on May 2, 1968-Dr. Louis M. Heilman, the FDA consultant, told a Today television audience, "I would not hesitate a bit in prescribing pills for teen-agers." He went on, incredibly, to have this exchange: Barbara Walters: Would you prescribe The Pill to a girl who is a virgin? Dr. Hellman: Well, I think if my daughter were a virgin and came to me as a teenager and we could talk about these things, yes, I'd prescribe The Pill for her. 2 In another area of error, Time cited the "latest" report of Dr. John C. Cobb to dem- onstrate successful use of The Pill in Pakistan. Three weeks later, however, he said in a speech in Denver that The Pill, while "moderately successful for a very few selected women," was "not practical. . . . Something more than contraception was needed." The speech was cited In the winter, 1968, Child and Family. PAGENO="0324" 7154 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Miss Walters: There is no more danger in that case than there is for a mature woman? Dr. Heilman: No, I think that the evidence is that the younger the individ- ual taking The Pill the safer they are. The FDA, which frequently has difficulty in getting help from the medical profession, refused to comment on Dr. Hellman's remarks. "Where experiment or research is necessary to determine the presence or the degree of danger, the product must not be tried out on the public, nor must the public be expected to possess the facilities or the technical knowledge to learn for itself of inherent but latent dangers. The claim that a hazard was not foreseen is not available to one who did not use foresight appropriate to his enterprise." For all of our great enterprises that is a wise instruction. It was given to us by the lat Justice Robert H. Jackson in a dissent (in Dalehite v. U.S.) in the 1952 term of the Supreme Court. In the case of The Pill, foresight appro- priate to the enterprise was seldom shown and rarely heeded. H. L. Mencken might have said that again the press had failed to do its duty-to harass the experts-and the public was left at their mercy. "What was not looked for was not found," Dr. Herbert Ratner has said. "What was not surveyed was not seen. What perhaps happened was ignored." [From SR, November 2, 1968, Pp. 64-69] CAUTION ON THE PILL By Louis Lasagna, M.D.) [Louis Lasagna, born in New York City forty-five years ago, received his M.D. degree from the College of Physicians and Surgeons, Columbia University. He is an associate professor of medicine and associate professor of pharmacology and experimental therapeutics at Johns Hopkins University Medical School, and a consultant to the National Institutes of Health. His cautionary state- ment on birth control pills is taken from Life, Death, and the Doctor, a Borzoi book published by Alfred A. Knopf and copyright 1968 by Louis Lasagna.] The most controversial population-control development of the century has been the oral contraceptive-the pill. From its impeccably scientific beginnings, the pill has become all things to all people, spelling riches and fame for some, sexual security to many, and death for a few. Among scientists, it has inspired both ardent religious zeal and deep suspicion. The original observations were made in the 1930s, when it was found that natural sex hormones inhibit ovulation in animals. In 1954, Carl Djerassi applied a new chemical technique to the synthesis of different steroid drugs that produce secretory changes in the endometrium [lining of the uterus] similar to those produced by . . . [female hormones]. Gregory Pincus tested 200 of these drugs in animals and found three to be very powerful inhibitors of ovulation. A few years earlier, Professor John Rock of Harvard had treated infertility in women with daily doses of [the female hormones] estrogen and progesterone to simulate the hormonal environment of pregnancy. . . . The con- tinuous . . . therapy eliminated menstrual periods, a phenomenon the patients found disturbing. As a result, it was decided to give the hormones only from the fifth day of the cycle to the twenty-fifth day and thus allow menstrual flow. Rock, Garcia, and Pincus proceeded to use this same regimen with the three active compounds mentioned above-but now to prevent conception. In most cases, ovulation was inhibited. . . . Large-scale field trials were begun in Puerto Rico, and the pills were a great success in terms of both con- traception and patient acceptability. A few years later, after additional experi- ence in the United States, the Food and Drug Administration approved the sale of the first contraceptive combination of estrogen and progestogen, Enovid. The mechanism of action of these preparations is still debatable. Inhibition of ovulation is probably the most important effect, but the lining of the uterus is an associate professor of medicine and associate professor of pharmacology PAGENO="0325" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7155 the cervical mucus is maintained in its non-ovulatory, relatively impermeable state. How effective is the pill? The medical and lay literature contains a good many quotations from different scientists to the effect that the pill never fails "if taken according to instructions." Critics of this euphoric assessment point out that failures with the pill tend to be attributed to inability to follow direc- tions even when the women swear that they never forgot a single daily dose. The critics also emphasize that if a technique fails because of human error, it is a failure nevertheless and must be considered part of the risk. It is also disturbing that many women in studied populations drop out of the study; there is no way of evaluating the pill's performance in these possibly disen- chanted women. It is unreasonable to expert perfect performance from the pill. With all drugs, there is variability in response to a given dosage, due to vagaries of absorption, metabolism, excretion, or organ response. What works well for one patient may not work well for another, or even for the same patient at differ- ent times. One method of diminishing such variability is to give everyone a dose that is known to be an overdose for some. This is done with penicillin in the treatment of pneumococcal pneumonia. The reason for not adopting this approach routinely with all drugs is that it also generally increases the chance of producing side effects from the drug. This is not a serious problem with penicillin, but it is with oral contraceptives, and has led to a good deal of manipulation of dosage. As the dosage has been reduced, some side effects have apparently diminished-and, incidentally, the cost of this still-expensive form of birth control has been reduced. It seems predictable that some patients will get pregnant while taking the pills even if they are compulsively careful with their dosage, and this number will probably be higher as the dose per day is reduced to diminish unwanted effects. (There is at present no evi- dence that such pregnancies will produce a greater percentage of malformed babies than will other pregnancies.) Nevertheless, even those who are at least enthusiastic about the pill grant its excellent performance as a birth-control technique. If the risk of pregnancy is not zero when taking daily oral contraceptives, it is very low indeed. Nor is this the only advantage. It is easy to use-just a pill a day. It does not have to be timed to intercourse. Its use does not delay, interrupt, or mechanically impede the sexual act. It is attractive to many men and women who object esthetically to condoms, diaphragms, jellies, and foams. Finally, some Roman Catholics who reject other devices against which church officials and parish priests have been less equivocal in their denunciation are willing to take the pills. From the start it was obvious that the pill had drawbacks. Some women gain too much weight. Others develop acne, nausea, vomiting, or breast tender- ness. More distressing are such things as sporadic breakthrough bleeding, depression, excruciating headache, tension, decreased libido, loss or excessive growth of body hair, skin pigmentation, and belly or pelvic pains. Some lactat- ing mothers stop producing milk and have to resort to artificial feeding for their babies. Newer oral contraceptives have claimed a decreased incidence of these various side effects, but none of them is free of nuisance potential. Most frightening of all, thus far, has been the occurrence of clotting within the blood vessels. In 1961, fatal pulmonary embolism occurred in two young Los Angeles women who had been on oral contraceptives. Next, women on the pill were observed to develop thrombophiebitis [blockage of blood vessels, in the extremities] as well as clots that traveled to the lungs. Since then, all sorts of clotting troubles have been reported in women taking the pills. Throm- bosis of the blood supply to the gut, with gangrene of the intestine, has been seen. Thrombosis of the major arteries in the arm and leg has been reported, requiring amputation. A London physician observed strokes in a twenty-three- year-old airline stewardness and a twenty-six-year-old housewife. His report prompted a Sussex physician to describe two similar cases and to state that he knew of at least three others. A Newcastle physician announced that the autopsy on one of his young women on the pill showed clots in the arteries on both sides of the brain. PAGENO="0326" 7156 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "`That kills my faith in the pill. I think i'll picket the company.' -Victor Millar, father of quadruplets born yesterday in Ottawa [Canada, after Mrs. Millar, 30, had taken birth control pills for about a year]~~~ -The New York Times QUOTATION OF THE DAY, SEPT. 21, 1968. PAGENO="0327" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7157 In April 1965, the Johns Hopkins neurophthalmologist, Frank Walsh, asked his fellow specialists (via the Archives of Ophthalmology) to report to him any cases they had seen with visual troubles similar to those he had observed in women on oral contraceptives. By November he had assembled some sixty cases in this way-seventeen with strokes, twenty-one with eye troubles, and twenty-three with other symptoms, including migraine. Without claiming a cause-and-effect relationship, he nevertheless wished to put the experience on the record and to ask for further study. Meanwhile other physicians continued to report deaths as a result of com- promise of the blood supply to the nervous system. One twenty-six-year-old Englishwomen died of a clot in her vertebral artery after a seven-week illness during which she had paralysis of all four extremities. In Ireland, a twenty- five-year-old patient expired with a large dead area in her brain caused by a clot in the carotid artery. Dr. Sherif Shafey in Miami was at the same time accumulating his own series of thirty-four women, ranging in age from twenty to thirty-nine years and all receiving some form of oral contraceptive, who developed various sorts of neurologic complications, including migraine headache and clots in the arteries and veins of the brain. Next, effects on the heart were reported. In January of 1965 a Norwegian pathologist described the sudden death of a thirty-two-year-old woman who had been taking oral contraceptives for five months. Postmortem examination revealed that the smaller branches of the coronary arteries were plugged with clots of various ages, with resulting death of the heart tissue. This was fol- lowed by a fatal case from England with clots in all of the major arteries of the heart; others have since been noted. Why have these cases been put on record by physicians from various parts of the world? All the complications described are known to occur in people who do not use oral contraceptives. No new diseases have been seen. Why, then, the concern over the possibility of a cause-and-effect relationship? It must be remembered that the suspicion of alert physicians is almost always the first indicator of pharmacotherapeutic mischief. Rarely can the doctor do more than suspect a cause-in-effect relation between drug and toxic effect, since hardly any drug's side effects are unique to that drug. Further, massive pulmonary embolism, strokes, and heart attacks are relatively rare in young women. This is a recurrent theme in the statements of concerned physi- cians, such as the British doctor who wrote: "This cause of death [pulmonary embolism in a twenty-two-year-old woman on oral contraceptives for a few months] . . . in young people is extremely rare. In the few cases I have seen in young women there has always been some underlying explanation. . . . It is this feature which has been worrying me in my examination of an otherwise perfectly healthy woman. My own feeling is that [it] is just too much to be a coincidence. I have never seen a similar case and I have seen many unexpected deaths in young people. This does not amount to proof." Supporting this sentiment was a letter from a Cambridge scientist who dis- closed the following information: "From 9,280 consecutive autopsy reports . . . covering 1946-63, we have col- lected 27 cases [of massive pulmonary embolism] under the age of 70. Of 21. females, only 3 women were under the age of 45, and they were either preg- nant or had recently been pregnant. Thus we have no examples of non-pregnant women. . . ." Other studies are in agreement. The coroner's records of Cuyahoga County in Ohio were reviewed in 1964 to see how often pulmonary embolism and unexpected sudden death occurred in supposedly normal persons between fifteen and forty-five years of age. Sixteen females had died in this manner during an eleven-year period. Five of these were pregnant at the time of fatal embolism, and eight of the eleven non-pregnant females were over forty. Thus, while such unexplained deaths are not unheard of in young women, they are decidedly rare. In Hamburg, Germany, a study was made of fatal pulmonary embolism in a series of 5,200 autopsied cases. Of 500 consecutive cases of pulmonary embol- PAGENO="0328" 7158 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ism, half were in women, but their average age was seventy, and 95 per cent were over fifty. A few cases have shown such unusual autopsy findings as to alert doctors to a generalized clotting tendency. In one case autopsied at the Johns Hopkins Hospital, for example, there were numerous clots in arteries and veins all over the body, without any actual disease of vessel walls. But there are other compelling reasons for suspecting the oral contraceptives as a causative factor in these vascular catastrophes. Many of the scientists who have worked with the pill have compared the endocrinologic state induced by these synthetic steroids with pregnancy. While this view is not universally held, there are at least certain parallelisms between normal pregnancy and drug-induced pseudo-pregnancy. As stated above, pregnancy carries with it a definite risk of clotting difficulties, related in part at least to the hypercoagula- ble state associated with the hormonal alterations undergone by the expectant mother. Both during pregnancy and the taking of oral contraceptives, there is also a reduction in blood-flow velocity in the extremities, which favors the for- mation of sludge in the vessels of the limbs. Although the pill buffs tend to ignore them, a substantial number of studies have now been performed to determine whether oral contraceptives affect the clotting capacity of the blood. They have been conducted in such diverse places as Oslo, Norway, and Manchester, England, and in the United States in Wash- ington, D.C., Minneapolis, Brooklyn, Philadelphia, New York, and Seattle. The majority agree on the fact that there are changes from the normal, even in asymptomatic women taking oral contraceptives. These scientists have not all used the same tests, but in general there have been increases in four blood fractions including fibrinogen (the precursor of fibrin, which eventually forms the clot). Blood platelets, in the two studies focusing on this blood constituent (which helps clots to start), were also increased in number. Only one index of blood clotting-the so-called fibrinolytic system-possibly changes in a direction that might impede normal clotting. AU the other changes are such as to encourage the clotting of blood. There are other reasons for worry. In several studies in men and women who have been given female sex hormones as treatment for atherosclerosis of the brain or heart, or for cancer of the prostate, there have been significantly more deaths in the treated patients than in the control (untreated) patients, with more strokes, heart attacks, or both. Studies of blood fats have shown changes in women on the pill that resem- ble thOse seen in post-menopausal women, who have a higher risk of heart attacks than younger women. One extremely provocative report involved a Mead Johnson oral contraceptive that was under trial in 7,000 American women. Trials were suddenly halted when British workers giving "massive doses . . . daily and continuously for several months" to dogs reported throm- boemboli in the animals. A number of researchers have been intrigued by the relationship between hard-water areas and the decreased occurrence of hypertension and other car- diovascular diseases. It has even been suggested that a diet deficient in magne- sium may be partially responsible for the high incidence of arteriosclerosis in Western nations. In 1966, Doctors John and Naomi Goldsmith reported serum magnesium concentrations to be lower in non-ovulating women and women on Enovid than in ovulating women. The finding calls only for speculation at present, but it supplies another bit of evidence to remind us of the multiple effects of hormonal agents. With such highly suggestive data, how can one explain the unwillingness of many physicians even to consider the possibility of clotting troubles in some women taking oral contraceptives? One major reason for this apathy is the now famous report of the 1963 Advisory Committee asked by the FDA for guidance in evaluating thromboembolic morbidity and mortality. The committee decided to focus only on fatal complications, because of the difficulty in tracking down nonfatal cases. (A patient whose lungs were riddled with clots and who survived only because of heroic cardiopulmonary surgery, or who suffered a disabling but nonfatal stroke, thus did not enter into the committee deliberations.) PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7159 It was necessary to know how many women had died while on Enovid, the drug under investigation. For this purpose, they relied completely on the files of G. D. Searle, the manufacturer. This was the first and most appalling mis- take. No drug manufacturer can possibly have complete records of the deaths occurring among patients taking his drug. To have such complete records would require that every such death be associated in the attending doctor's mind with the possibility of its being caused by Enovid, that he always know whether patients have been on Enovid, and that he report every such case to the manufacturer. All experience is contrary to these assumptions. Even in hospitals where drug reactions theoretically must be reported by the medical staff, and simple cards are provided for such purpose, the true incidence of drug toxicity varies from ten to fifty times the incidence calculated from vol- untary reports. The committee also relied on photostats of death certificates for knowledge of what was occurring in the population at large. Regrettably, death certifi- cates are notorious for their inaccuracies, especially when autopsies are not performed. As Professor L. M. Schuman, a member of the committee, said on a later occasion: "In view of the fact that one of the greatest sources of error in hospital statistics is the glib assignment of a clinical diagnosis to pulmo- nary embolism . . . , epidemiological studies utilizing mortality sources should confine themselves to autopsy . . . [findings]." There was also no clear information on how many women were taking the pills. It was known roughly how many prescriptions had been filled and renewed for Enovid, and after some crystal-ball gazing, it was decided to sub- tract 300,000 (primarily to exclude duplicate prescriptions) from the maxi- mum estimated numbers of users to give a tidy-but possibly inaccurate (guesses on the total number of women using the pill range from 3,800,000 to 6,000,000)-figure of 1,000,000 women. No one on the committee seemed to worry, however, about the fact that it was important to know not only how many women took Enovid during a given year, but also how long they were on Enovid. (A lady on for only one month is obviously not at risk from the drug for the whole year; to assume so is to make the drug look safer than it is.) Next, the committee decided to throw out some of the Enovid deaths, for a variety of reasons. Unfortunately, suc~h selective discarding of cases could be done easily for the Enovid cases, but not for the control group. The latter were studied only by analyzing death certificates, whereas the Enovid files con- tained autopsy reports, clinical information, charts, etc., solicited by the manu- facturer or voluntarily supplied by interested doctors. There were many other assumptions as well, but these are perhaps the most disturbing. What, then, could anyone conclude from such an analysis? Nothing, of course, which is exactly what the report says: "There is a need for comprehensive and critical studies regarding the possi- ble effects of Enovid on the coagulation balance and related production of thromboembolic conditions. Pending the development of such conclusive data and on the basis of present experience this latter relationship should be regarded as neither established nor excluded." Unfortunately, the report also included the statement that "no significant increase in the risk of thromboembolic death from the use of Enovid in this population group has been demonstrated." The FDA, the pill enthusiasts, and most physicians have since then acted as if the report, which is based on incomplete data of dubious quality inappropriately analyzed, actually proved for all time that there was no risk. PAGENO="0330" 7160 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY "Brassiere designers are having to accommodate an everexpanding American bust.. Undergarment makers attribute the increase in bust sizes to improved diet and the hormonal effects of birth control pills." -NEWS ITEM, The Wall Street Journal. PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7161 This attitude has been encouraged by several other factors. The manufactur- ers of Enovid, for example, have periodically informed the world that the cases reported are not in excess of those "anticipated." In 1965, their medical director published a paper with the astonishing news that the thromboembolic morbidity was actually less than a quarter of what might have been expected. He conceded that the discrepancy "is very likely a reflection of inadequate reporting" but concluded with the unequivocal assertion "that massive use of Enovid has not increased the incidence of thromboembolic disease in women." A second source of misconception is the group of experts who for one reason or another have decided that the pill's advantages must not be sullied by any doubts. One argument is that pregnancy is risky, too, and that the troubles women get into on the pill must be balanced against the medical risks of preg- nancy. Such an argument is reasonable, of course, only for those women who cannot possibly use any other effective contraceptive technique. Dr. Erik Ask-Upmark, head of the Department of Medicine at the University of Uppsala in Sweden, reviewing his own and others' experiences with throm- boembolism in women on oral contraceptives, pointed out the highly suggestive recurrence of trouble in several women as they took repeated courses of pills. His report ends: "If any female member of my own family applied to me to get oral contraceptives I would most certainly not dare to give it to her." In 1965, a World Health Organization (WHO) Scientific Group came in with their own report. There was a certain friction in the committee, especially from an American expert who bridled at the need-spelled out in WHO rules -for unanimous recommendations. The report pointed out that incidence of thrombophiebitis is highest not in pregnant women, but right after delivery, when hormonal levels are lowest. This was meant, presumably, to exonerate the pill, which is said to produce a "pseudo-pregnancy." It might be argued, however, that women on the pill have a "pseudo-delivery" once a month, as they suddenly stop the pill in order to menstruate. (Such an argument pre- sumes that the pill produces a menstrual cycle more like pseudo-pregnancy than normal menstruation.) Recent studies also suggest that much of the clot- ting troubles seen after delivery are not "spontaneous" but due to estrogens given to suppress lactation in non-nursing mothers. The report also made an interesting and subtle point: Many doctors will not prescribe oral contraceptives in women with a history of thromboembolic dis- ease. Thus in a sense the pill is being given to healtheir women than the aver- age population, possibly biasing present risk estimates in favor of the pill. The committee concluded that oral contraceptives were extremely effective and that no cause-and-effect relationships had been established for serious adverse effects. Nevertheless, it listed twenty unmet research needs, including the effects of the pill on the pituitary, "higher nerve centers," thyroid, adrenals, carbohydrate metabolism, ovaries, cancer development, genetics, uterus, vagina, lactation, infants, liver, blood, weight, emotions, congenital anomalies, and a variety of diseases! In 1966, the Food and Drug Administration came up with still another report on oral contraceptives. Unfortunately, the expert committee was no more able than its predecessor to make factual statements about serious risks from the pill. It acknowledged that deaths from thromboembolism were of con- cern, and that "the present system of reporting deaths and adverse reactions relies on either the cooperation of physicians or the haphazard filtering of rumors to detail men. The latter route is patently unreliable, and the former not much better. Physicians are becoming increasingly fearful of reporting deaths or adverse drug reactions because of possible legal reprisal." (I know of two deaths in Baltimore-from strokes in twenty-one and twenty-six-year- old girls-unpublicized for this very reason.) The report reiterated that avail- able data could neither confirm nor refute the role of the pill in thromboem- bolic disease. No progress, in other words, since the 1963 FDA report. The committee expressed worry about the carcinogenic effects of estrogen taken for long periods, admitted that long-term studies to tell whether the pill might cause cancer were unavailable, but concluded that no maximum limits should be set for how many years the pill might be taken. Other risks were also discussed, but the important conclusions reached were as follows: "The committee finds no adequate scientific data, at this time, proving these compounds unsafe for human use. It has nevertheless taken full cognizance of certain very infrequent but serious side effects and of possible theoretic risks PAGENO="0332" 7162 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY suggested by animal experimental data and by some of the metabolic changes in human beings. "In the final analysis, each physician must evaluate the advantages and the risks of this method of contraception in comparison with other available meth- ods or with no contraception at all. He can do this wisely only when there is presented to him dispassionate scientific knowledge of the available data." Dr. Roy Hertz, a National Institutes of Health endocrinologist and cancer specialist, filed a minority report for the committee that took a much graver view of the pill-cancer problem. He reminded people that all known human carcinogens show a long latent period-most of them about ten years, but ranging up to forty years-and that in most instances there is no way of detecting this fact during the period when the cancer is "cooking," as it were. Hertz also pointed out that all known human carcinogens are also carcinogens in animals and that therefore animal data are not irrelevant, as some have claimed. (It is ridiculously easy to produce tumors of all kinds in rats, mice, rabbits, hamsters, and dogs given estrogen, and early in 1966 an investiga- tional drug of this class under study by Merck Sharp and Dohme was hastily removed from clinical trial when dogs developed breast cancers after a year of treatment.) He then reviewed the accepted evidence that a young women's own estrogen or estrogen in pill form can make breast cancer worse, and observed that most breast cancers are probably in existence for years before they become clini- cally apparent. Hertz derided the claims that use of estrogens in women over the last twenty-five years had not changed the incidence of breast cancer, because most of the women so treated have not been young women, but were post-menopausal, and there is clear evidence of a difference between these ages in response to female hormones-estrogens are even used successfully to treat breast cancer in older women. He further revealed that the entire world litera- ture on the risk of prolonged estrogen therapy causing breast and genital-tract malignancy is based on a pitifully small sample of less than 1,000 women, of whom only eighty-five were under forty years of age. He then performed a similar analysis of the worrisome situation wiith regard to uterine and cervical cancer, and the possible effects on ova and children ultimately born from the eggs of women who have taken the pill. In none of these situations could Dr. Hertz find reason for complacency. He ended with this unequivocal recommen- dation: "In view of the serious limitations in our knowledge of the/ potential long-term effects of estrogen-progestogen combinations, it is mandatory that further clinical experience be gained under properly controlled conditions of observations and follow-up." The FDA report elicited predictable reactions in the interested parties. Phy- sicians suspicious of the pill saw cause for alarm, and found no reassurance. The drug manufacturers saw the report as an exoneration of the drug. Dr. Louis M. Hellman, chairman of the FDA Committee, said the report was a "yellow" caution light. Dr. Alan Guttmacher of Planned Parenthood read it as "a complete green light." One could only recall the story of the blind men describing the elephant. The British at first .did no better than the Americans. In a country with a highly organized National Health Service with allegedly good record-keeping on drug usage, they relied on voluntary reporting by doctors instead of careful detective work on women in the childbearing years who died of strokes, heart attacks, pulmonary emboli, etc. The results were as inconclusive and unsatisfy- ing as might be expected: "At present the number of deaths [voluntarily] reported is small and does not differ remarkably from expectation . [however] the deaths reported . . . may represent an underestimate . . . no firm conclusion can be drawn . . ." A week earlier, in the British Medical Journal, which carried the above report, a distinguished Oxford professor wrote on "Adverse Reactions to Drugs," pointing out that the actual incidence of toxicity with a new drug with which he had worked was twenty-five times higher than one would guess from voluntary reporting by practitioners, and that one could, temporarily at least, quadruple the reported incidence by sending official requests for informa- tion to all British doctors. Obviously the hazards of under-reporting are uni- versal, as is the likelihood that official government committees and drug manu- facturers will neglect these hazards. In the spring and summer of 1967, however, three independent British studies were reported that finally began to clarify the thromboembolic danger. All delivered an affirmative answer to the question, "Can oral contraceptives PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7163 cause thromboembolism?" In the words of a Medical Research Council Subcom- mittee: "The sum of evidence . . . is so strong that there can be no reasonable doubt." It remains to be seen what impact, if any, these findings have on the prescribing habits of physicians. Although the blood-vessel abnormalities have received the greatest publicity, other potentially serious complications of the pill have been reported. In 1964, some Finnish scientists reported abnormal liver function in seven post-meno- pausal women who consented to take oral contraceptives for a month. Depite dissents from some experts and manufacturers, there has now been convincing confirmation of this phenomenon in different parts of the world, including the United States, and involving women in their twenties as well as older females. Particularly at risk of developing jaundice are those rare women who develop the unexplained "jaundice of pregnancy," which is proba- bly also attributable to hormonal changes. It is not reassuring to learn that mestranol, present in most oral contraceptives, can cause severe liver damage and even liver cancers in rats taking the drug in high doses for prolonged periods. Others have observed decreased tolerance for glucose in some women taking oral contraceptives, with "chemical diabetes," a phenomenon again reminiscent of what occurs during pregnancy. Whether this is related to the changes in blood concentration of adrenal or thyroid hormones that occur in women on the pill is not clear. A few letters have appeared in the British journals describing strange muscle pains or symptoms of neuritis associated with the taking of oral con- poses. The bleeding is thought to be due to overgrowth of the lining of the small intestine. American doctors have seen dilatation of the ureters in women taking oral contraceptives. Gynecologists have occasionally observed severe uterine bleeding in women who have stopped the pill after prolonged cyclic therapy for contraceptive pur- poses. The bleeding is thought to be due to overgrowth of the lining of the uterus secondary to disturbance of normal feedback mechanisms among the ovary, the hypothalamus, and the pituitary. Other gynecologists have been troubled by the development of an "obstinate" form of vaginitis due to the yeast Monilia in women taking oral contraceptives, curable in many cases only after the pills are discontinued. Psychiatrists have been upset by the unpredictable mental effects of the pills. Some women on them claim an increase in sexual desire and pleasure, but others become frigid, a situation reversible by stopping the pills and using mechanical devices. Dr. William Masters, co-author of Human ~e~vual Response, said that when referring physicians or marriage counselors ask him to see a woman for secondary frigidity, his first question is: "Has she been taking the pill?" There has been an increasing awareness of depressive reac- tions, with crying spells or suicidal ideas, in women taking these hormones. Some believe that the pills can make a latent depressive state overt or aggra- vate an existing melancholia. Remission may not follow promptly on with- drawal of the drug~ (However, it must also be stressed that some women such as those who suffer from severe premenstrual tension, may be helped remarka- bly by oral contraceptives.) Fears about the long-range effects of oral contraceptives on fertility have ranged from apprehension about ultimate infertility when the pills are stopped after years of use to the possibility that oral contraceptives, by preventing ovulation, may prolong the period of potential childbearing so that pregnant fifty- and sixty-year-old grandmas will be possible. One Canadian physician has even suggested the possibility of a new specialty of "geriatric obstetrics" to care for such aged parents. There are no convincing data at present to sup- port either notion, although both American and Australian physicians have suggested that some women may suffer long-term interruption of their ovula- tory cycling as a result of the pill, with prolonged failure of menstruation (and infertility) after stopping the medication. Proponents of the pill promptly labeled the reports "misleading" and the conclusions "unwarranted." In view of all the side effects reported with the pill, and the clear evidence that some 10 to 25 per cent of women refuse to go on with oral contraceptives because of dissatisfaction of one sort or another, it is confusing to have their enthusiasts deny such defects. In April 1966, The New York Times ran a "gee- whiz" type of article about the pill entitled "Three Men Who Made a Revolu- tion." In it, Dr. Gregory Pincus commented on the medical advertising for PAGENO="0334" 7164 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY some newer-type sequential and low-dosage pills: "These ads are creating a false emphasis. There may be a minute lessening in side effects, but since all present side effects are insignificant, I see absolutely no advantage in sequen- tials." Such a remark stands in strange juxtaposition to the drug ads. One for Ovulen, for example, reads: "A significant advance over older progestins . . . a new measure of freedom from undesirable effects . . . extremely low incidence of breakthrough bleeding . . - low average weight change . . - extremely low incidence of nausea . . . extremely low incidence of amenorrhea . . ." If these statements do not imply a better performance than with older drugs, what are they saying? And if Ovulen is so remarkable, one wonders why the ad explains, in tiny print to be sure, "the following adverse reactions have been reported with Ovulen: headache, dizziness, depression, breast complaints, amen- orrhea, chloasma, vomiting, allergy, edema, migraine, pulmonary embolism, thrombophiebitis, visual difficulties, nervousness, rash, itching, decrease in libido, tiredness and malaise. A small incidence of causea, spotting and break- through bleeding has been reported." What is a sensible, conservative, scientific attitude toward the use of the pills? On occasions when I have taken a public position emphasizing the possi- ble dangers of their use, it has been obvious that the emotions of both patients and doctors are highly charged when it comes to a discussion of oral contra- ceptives. Doctors have accused me of everything from a Catholic-tainted bias against contraception (I left the Church at the age of twelve) to having canine ancestry on my maternal side. These doctors are understandably annoyed because such discussions upset their patients. But is it really defensi- ble to assure women-as many doctors do-that the pill has been proved as safe and harmless as water? How can a doctor say that he "can think of no condition in which these pills would not be safe to take"? (The FDA labeling warns against their use in certain situations.) How can Dr. Rock, in an article entitled "Let's Be Honest About the Pill !," dismiss those who worry about its dangers as "irresponsible, and uninformed . . . zealots"? Does he really believe that all women who find themselves unable to tolerate any brand of oral con- traceptive on the market are in his words, "guilt-aroused neurotics"? Is it really desirable to produce diabetes temporarily with the pill because this merely unmasks a condition that would have become manifest years later and is there- fore "a prophylactic blessing"? Surely such questions deserve serious discussion, not supercilious dismissal. These pills should certainly not be taken off the market. On the other hand, they cannot possibly be considered the contraceptive technique of first choice for all women desiring birth control. They are not necessarily the best or the only way. The pills are indicated for many women, including those who will not or cannot use mechanical devices because of anatomic, psychological, or religious reasons. Since it is my firm conviction that these pills can kill- rarely, to be sure-and that other techniques, properly used, which do not kill are almost as effective in preventing conception, I believe it bad medical prac- tice not to recommend mechanical contraception to those who can use it. I rec- ognize the tremendous importance of the pills for certain women who appar- ently find condoms and diaphragms impractical despite the great need some of them have for means to avoid pregnancy, and I appreciate the Planned Par- enthood Association's interest in avoiding hysterical condemnation of the pill. But it is ethically and morally wrong to take the decision out of a patient's hands by assuring her that these powerful chemicals are completely free of risk. It has been argued that even if one recognizes some small risk from the pill, its advantages far outweigh the dangers. One Baltimore obstetrician argued that a million women not using any contraceptives would experience 300 mater- nal deaths per year, since most would become pregnant (not pregnant every year, however, a fact ignored in the calculations, which also do not jibe with the more recent British data), and some women die in pregnancy. His guess about oral contraceptives was that a million women taking them would show only one or two maternal deaths, and that a few additional deaths from throm- bophlebitis and related vascular troubles would still be acceptable. A main point of his argument is the assumption that use of the condom or diaphragm would result in fifty maternal deaths per year because of a high failure rate with these devices. How valid is such an argument? Another Baltimore obstetrician, equally PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7165 well known and experienced, pointed out that the failure rate of the condom or diaphragm-properly used-is very low. The higher figure obtains in couples with low motivation-for example, those who have one child and are not quite sure when they want a second. An excellent batting average is seen in highly motivated women-those who have completed their families, for example, and are sure that they don't want another child. In his opinion, most failures "are simply an expression of `I don't care.'" And one thing is reasonably certain- condoms and diaphragms are not going to produce breast cancer, or diabetes, or any of the other ills that are at least a theoretical hazard of oral contra- ceptives, which can affect the whole body, not just the uterus. It would be wonderful if doctors could predict which women would get into trouble from the pill, but at the moment it is possible only to avoid its use in certain women, such as those with obvious vein disease, past or present, and a history of migraine or of jaundice during pregnancy. [From the British Medical Journal, October 5, 1968, pp. 19-25] PtTERPERAL THROMBOEMBOLISM IN RELATION TO THE INHIBITION OF LACTATION BY OESTROGEN THERAPY (By P. N. A. Jeffcoate,* M.D., F.R.C.S.Ed., F.R.O.O.G.; Janine Miller,* M.B, Ch.B., M.R.C.O.G.; R. F. Roos,* MB., Ch.B., M.R.C.O.G.; V. R. Tindall,t M.D., F.R.C.S.Ed., M.R.C.O.G.) SUMMARY An analysis was made of 111 consecutive cases of puerperal thromboembo- lism by the age, parity, mode of delivery, and lactation habit of the women concerned, and the findings were compared with those from control groups. The statistics show that inhibition of lactation by means of ethinyloestradiol is associated with a threefold increase in thromboembolism, although the effect is seen mainly in women who have an operative delivery and who are aged more than 25 years. Among women aged more than 35 years who have an assisted delivery, inhibition of lactation is accompanied by a tenfold increase in the incidence of puerperal thromboembolism. Advancing age and operative intervention (especially caesarean section) are in themselves predisposing causes of deep venous thrombosis and embolism. They can also constitute indications for inhibiting lactation. This makes it dif- ficult to assess whether the relation of thromboembolism to inhibition of lacta- tion or to the administration of oestrogen is real or apparent. Doubts on the interpretation of the findings are raised by the fact that the number of fatal cases of puerperal thromboembolism in England and Wales, and of non-fatal cases in the hospitals under review, has not increased in recent years despite a progressive decrease in breast-feeding. Nevertheless, the evidence suggests that although the administration of ethinyloestradiol is not by itself enough to cause puerperal thromboembolism, it may be a factor which can tip the scales in women who are already predisposed to suffer this condition. Any thromboembolic hazard associated with administration of oestrogens for inhibiting lactation is probably acceptable except in women known to be a special risk by reason of age, operative delivery, obesity, and a past history of thromboembolic episodes. INTRODUCTION It was first suggested by Daniel, Campbell, and Turnbull (1967) that sup- pression (or inhibition) of lactation favours the development of deep venous thrombosis and embolism in puerperal women. From information derived from the Cardiff Birth Survey these workers concluded that the inhibition of lacta- tion in mothers aged 25 and more is associated with a tenfold increase in the incidence of thromboembolism, and postulated that the administration of oes- trogen may play a part in this. Following this, Daniel, Bloom, Giddings, Camp- bell, and Turnbull (1968) showed that the administration of relatively large amounts of diethylstilboestrol increases the coagulability of blood by raising the level of factor IX. In the original Cardiff series the oestrogen used was * Department of Obstetrics and Gynaecology, University of Liverpool, Liverpool 3. t Department of Obstetrics and Gynaecology, the Welsh National School of Medicine, Cardiff. PAGENO="0336" 7166 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY diethylstilboestrol administered in divided doses up to a total of 210-330 mg. during the course of nine days. This dosage, it may be noted, is higher than is usually given, and work carried out many years ago indicated that a total of 45-50 mg. of diethylstilboestrol during four to seven days is generally ade- quate to inhibit lactation (Jeffcoate, Lister, Hargreaves, and Roberts, 1948). There are some who question the efficacy of oestrogen therapy to inhibit lac- tation, irrespective of dosage, and the literature pertaining to this was reviewed by lodge (19G7). Differences in experience and opinion may in large measure reflect the timing of the administration of the hormone. The evidence suggests that the sooner after delivery oestrogen is given the more likely is it to inhibit breast activity. Oestrogens will not suppress lactation which is already established. Whatever be their efficacy, there is no question that oes- trogens are widely used with the object of inhibiting or suppressing lactation, and it is therefore of considerable importance to determine whether all or cer- tain of the preparations available predispose to puerperal thromboembolism, and whether suppression of lactation by itself (without any hormone being administered) has any effect. So many possible agents are concerned in the aetiology of puerperal venous thrombosis and embolism that it is difficult to assess the significance of each. The presence or absence of breast-feeding cannot readily be separated from factors, such as age, parity, difficult delivery, and general health, which may have governed a decision to inhibit lactation. This difficulty is emphasized by an analysis of the hospital inpatient inquiry returns for 1962-4, which was published by Hill and Wilson (1968). After correcting for age, parity, and mode of delivery, they concluded that puerperal thromboembolism occurs twice as often after a stillbirth as after a live birth. Information about the administration of oestrogen in their cases was not available, but lactation must inevitably have been inhibited by one means or another after the birth of a dead baby. This still leaves open the question of whether the circumstances of the stillbirth may in themselves have played some part in predisposing to thromboembolism. In a previous report (Jeffcoate and Tindall, 1965) based on a study of the experience at the Liverpool Maternity Hospital during the years 1953-63, it was shown that of the associated factors examined those most significantly related to the occurrence of puerperal thromboembolism were (1) the age and parity of the patient and (2) the mode of delivery. The incidence was found to be three times higher after caesarean section than after any form of vagi- nal delivery. At the time of the original inquiry, however, the lactation habit of affected women was not studied. When the possible importance of breast- feeding was raised by the Cardiff workers it was decided to re-examine our original material for the years 1956-63, and to add to it (1) the experience of the same hospital during the years 1964-6 and (2) the experience of Mill Road Maternity Hospital, Liverpool, during the years 1958-66 inclusive. Cases of puerperal superficial phlebothrombosis, a condition which presents a differ- ent clinical picture and has other aetiological factors, were not included. METHOD AND CRITERIA The statistics presented here are based on the examination of case records, a method which has the disadvantages attached to any retrospective survey. In this instance it means that only recorded cases of deep venous thrombosis and embolism are included. The condition therefore had to be clinically evident, and the diagnosis, which is always subject to individual clinical opinion, beyond reasonable doubt. Similar diagnostic criteria were in use at both hospi- tals at the times in question. The figures are made more incomplete by the fact that they do not incude those cases in which women, having developed deep venous thrombosis after discharge from hospital, were either treated at home or were referred to another hospital for treatment. Though we have reason to believe there were not many of these, it has to be accepted that the true incidence of clinically evident puerperal thromboembolism is somewhat higher than is here stated. The lack of follow-up studies, however, applies equally to breast-feeding and non-breast-feeding women. To provide control series, a study was made of the records of one out of every 100 consecutive women delivered in the same hospitals during the same period. PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7167 A decision on whether or not a woman was lactating was made according to the situation on the seventh day after delivery, a criterion similar to the one adopted in the Cardiff survey. In assessing parity, pregnancies terminating before the twenty-eighth. week were not counted. Women subjected to caesar- ean section or forceps or breech delivery were classified as having an assisted delivery. These standards were applied to both the affected and the control series. Oestrogen Thera~py.-At both hospitals it was the routine practice, when it was decided to inhibit lactation, to administer ethinyloestradiol by mouth, beginning as soon as possible after the woman's delivery was complete. This was given two or three times daily in gradually diminishing amounts for seven days. The dose on the first day was 0.35 mg., and this was reduced by 0.05 mg. daily. So the total dose administered to each woman was 1.4 mg., which is reckoned to be equivalent in activity to 50-70 mg. of stilboestrol (Jeffcoate et at., 1948). PRESENTATION OF RESULTS The control cases were analysed by age, parity, mode of delivery, and lacta- tion habit1 to give a picture of the hospital community at the time and to show how many women fell into each of the groups. By breaking down the cases of thromboembolism into similar groups it was then possible to calculate the incidence of thromboembolism per 1,000 women in each category. The figures shown in Table I, which represent a breakdown by age alone, illustrate the method employed. If for any group there were no control patients an inci- dence could not be calculated, and no figure appears in the Tables. If any group contained fewer than five (equivalent to 500) control cases, the calculated incidence is regarded as unreliable, and the figure in the Table is marked with an asterisk. TABLE l.-LIVERPOOL MATERNITY HOSPITAL (1956-66 INCLUSIVE) Age in years <25 25-34 35+ Total Sample of control deliveries (1 in 100 cases) Calculated total control deliveries Cases of thromboembolism Incidence of puerperal thromboembolism per 1,000 deliveries___ - 119 (35.7%) 11,900 14 1.2 179 (53.8~3') 17,900 29 1.6 35 (10.5%) 3,500 29 8.3 333 133,300 72 2.2 I The actual number of recorded deliveries in the hospital was 33,627. FINDINGS AT LIVERPOOL MATERNITY HOSPITAL The number of women delivered in this hospital during the 11-year period 1956-66 was 33,627, and 91 of these suffered deep venous thrombosis or embo- lism, or both. The incidence of recorded thromboembolism was therefore 2.70 per 1,000 births. The vascular accident occurred during pregnancy in 19 cases and during the puerperium in 72. The incidence of puerperal thromboembolism was therefore 2.14 per 1,000 births. Of the 72 women with puerperal thrombo- embolism 26 were lactating on the seventh day. The number of control patients studied was 333, a figure which is three fewer than one-hundredth of the total recorded deliveries. This slight discrep- ancy is explained by the fact that, at this particular hospital, control case sheets were abstracted for each year separately. Of the control women 212 (almost 64%) attempted breast-feeding, and 121 had lactation inhibited. From this it can be calculated that 46 of the 62 women who developed thromboem- bolism should have been lactating, whereas, as mentioned previously, the actual number was 26. This overall picture is confirmed by the calculated incidence of thromboembolism, which is 1.2 per 1,000 among lactating women and 3.8 per 1,000 among those who had lactation inhibited. For parity groups 1, 2, and 3 the comparable rates are 1.0 and 3.4 per 1,000. It is next necessary to examine the influence of other factors, and the break- down of our cases by age, parity, and mode of delivery is shown in Tables II and III. Consideration of these suggests the following conclusions. 1 The weight of the woman Is another factor of some importance in the aetiology of thromboembolism, but the records were not sufficiently complete to permit a study of this. 40-471 0-70-pt. 17-22 PAGENO="0338" TABLE 11.-LIVERPOOL MATERNITY HOSPITAL (1956-66 INCLUSIVE). NUMBER OF CASES OF PUERPERAL THROMBOEMBOLISM AMONG LACTATING WOMEN AGAINST THE NUMBER OF CONTROL CASES IN EACH CATEGORY (E.G., 5/40). THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES Parity Age in years 1 2and3 4and More Total 8 ~ ~ -~ ~ -~ L~1 N.D. Ass.D. N.D. Ass.D. N.D. Ass.D. N.D. Ass.D. All Deliveries <25 5/40 (1.3) 2/19 (1.1) 0/14 (0.0) 0/4 (0.0*) 0/0 (-) 0/1 (0.0*) 5/54 (0.9) 2/24 (0.8) 7/78 (0.9) 25-34 2/17 (1.2) 2/23 (0.9) 3/50 (0.6) 2/9 (2.2) 2/16 (1.3) 0/2 (0.0*) 7/83 (0.8) 4/34 (1.2) 11/117 (0.9)119/134 35+ 0/1 (0.0) 0/4 (0.0)* 1/5 (2.0) 1/3 (3.3*) 4/3 (1.3*) 2/1 (20.0*) 5/9 (5.6) 3/8 (3.8) 8/17 (4.7) j(1.6) Total 7/58 (1.3) 4/46 (0.9) 4/69 (0.6) 3/16 (1.9) 6/19 (3.2) 2/4 (5.0*) 17/146 (1.2) 9/66 (1.4) 26/212 (1.2) ~d ~ ~ ~ ~ ~ w ...~ ~ Deliveries: 11/104 (1.1) 7/85 (0.8) 8/23 (3.5) 26/212 (1.2) All 18/189 (1.0) N.D. 11/127 (0.9) Ass.D. 7/62 (1.1) In this and the following tables: ND-Normal delivery. Ass. D.=Assisted delivery. *Figure calculated on fewer than 5 (equivalent to 500) control cases. TABLE 111.-LIVERPOOL MATERNITY HOSPITAL (1956-66 INCLUSIVE). NUMBER OF CASES OF PUERPERAL THROMBOEMBOLISM AMONG WOMEN WHO HAD LACTATION INHIBITED AGAINST THE NUMBER OF CONTROL CASES IN EACH CATEGORY (E.G., 1/12). THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES -~ ~ ~ ~ Parity 1 2 and 3 4 and More Total N.D. Ass.D. N.D. Ass.D. N.D. Ass.D. N.D. Ass.D. All Deliveries <25 1/12 (0.8) 4/10 (4.0) 1/13 (0.8) 1/6 (1.7) 0/0 (-) 0/0 (-) 2/25 (0.8) 5/16 (3.1) 7/41 (1.7) 25-34 4/9 (4.4) 3/6 (5.0) 6/36 (1.7) 3/6 (5.0) 1/5 (2.0) 1/0 (-) 11/50 (2.2) 7/12 (5.8) 18/62 (2.9) 139/80 35+ 0/2 (0.0*) 7/1 (70.0*) 2/5 (4.0) 5/2 (25.0*) 4/7 (5.7) 3/1 (30.0*) 6/14 (4.3) 15/4 (38.4*) 21/18 (11.7)ç(4.9) Total 5/23 (2.2) 14/17 (8.2) 9/54 (1.7) 9/14 (6.4) 5/12 (4.2) 4/1 (40.0*) 19/89 (2.1) 27/32 (8.4) 46/121 (3.8) Deliveries: 19/40 (4.8) 18/68 (2.6) 9/13 (6.9) 46/121 (3.8) All 37/108 (3.4) N.D. 14/77 (1.8) Ass.D. 23/31 (7.4) PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7169 Among lactating women (Table II) age has little effect until the borderline of 35 years is reached. After this the incidence of thromboembolism mounts steeply in all parity groups, being increased five times overall. A similar trend is shown among women who did not lactate (Table HI). In Table III there are subgroupings by mode of delivery, but, disregarding this factor, the inci- dence among non-lactating women is 1.7 per 1,000 for those less than 25 years and 4.9 per 1,000 for those older. Again, however, 35 years is a more significant divisional point. The incidence for women aged 25 to 34 is 2.9 per 1,000, whereas for women aged 35 and more the figure rises to 11.7 per 1,000 (almost seven times greater than that for women less than 25 years of age). A similar picture is presented by studying the effect of age irrespective of parity, mode of delivery, and lactation. Thus, in Table I it will be seen that considering all cases of thromboembolism, the incidences for the three age groups are 1.2, 1.6, and 8.3 per 1,000 respectively. Parity The figures in Tables II and IV, and to a less extent those in Table III, suggest that, irrespective of lactation habit and mode of delivery, the incidence of thromboembolism increases with high parity. However, as was suggested previously (Jeffcoate arid Tindall, 1965), the having of many babies generally means older age, and the latter factor is likely to be the more important. Leaving aside "grand" multiparity, the breakdown of our cases suggests that 1-paras are rather more likely than 2- or 3-paras to develop puerperal throm- boembolism (Table IV). This may reflect a higher incidence of operative deliv- eries in that group (see below). TABLE V--LIVERPOOL MATERNITY HOSPITAL (1956-66 INCLUSIVE) Parity: 1 2 and 3 4 and more Total Sample of control deliveries (1 in 100 cases) ~ Calculated total control deliveries Cases of thromboembolism Incidence of puerperal thromboembolism per 1,000 deliveries_ 144 (43.2%) 14,400 30 2.1 153 (46.0%) 15, 300 25 1.6 836 (10.18%) 3,600 17 4.7 333 33,300 72 2.2 1.9 Mode of delivery The analysis of our series, unlike that published by Daniel et a!. (1967), indicates that mode of delivery is very significantly associated with puerperal deep venous thrombosis and embolism. Among lactating women the incidences for spontaneous and assisted delivery are similar, but among women who had lactation inhibited the chance of thromboembolism is increased four times by operative delivery. Moreover, comparing Tables II and III, it will be seen that for women less than 25 years of age inhibition of lactation has no effect unless the delivery is assisted, when the risk rises three times. This is different from the experience of the Cardiff workers, who concluded that inhibition of lacta- tion in women less than 25 years of age had no effect, irrespective of mode of delivery. Disregarding age, when women delivered normally do not breast-feed the incidence of thromboembolisln is only doubled; among those who have assisted delivery inhibition of lactation is associated with a six times increased risk. For the oldest age group of women failure to lactate considerably increases the risk if they have a complicated delivery, whereas it has virtually no effect if their delivery is normal. The importance of operative intervention may be even greater than is indicated by the statistics presented here because a few of the women who suffered puerperal thromboembolism and who are classified as having a spontaneous delivery had other operations such as manual removal of the placenta under general anesthesia or tubal ligation in the puerperium. To avoid complicating the presentation these were not put in separate categories. Another disadvantage of accepting the classification "assisted delivery" with- out qualification, which was done to conform with the original Cardiff study, is that it gives no idea of the severity of the operative intervention. Thus an PAGENO="0340" 7170 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY easy low-forceps extraction under anaesthesia involves little more trauma than spontaneous delivery, whereas caesarean section is a procedure of an entirely different order. A young woman of low parity is likely to have a minor procedure, whereas an elderly primigravida is prone to have a more difficult vaginal operation or even caesarean section. Table V shows that primiparae who developed puerperal thromboembolism are more likely to have had an assisted delivery than are multiparae. Assisted delivery among older women developing thormboembolism was unusually fre- quent, and often involved more extensive surgical intervention. Of the 58 women aged 25 years or more 41 were para 1-3, and 23 of these (56%) had operative deliveries. The incidence of operative delivery among the correspond- ing control group was only 30%. Twenty-nine women who suffered thromboem- bolism were aged 35 years or more, and 18 of these had an assisted delivery. TABLE V-LIVERPOOL MATERNITY HOSPITAL (1956-66 INCLUSIVE). ACTUAL NUMBER OF CASES OF PUERPERAL THROMBOEMBOLISM BY AGE, PARITY, AND MODE OF DELIVERY Age in years -- Parity Total - 1 2 and 3 4 and more ND. Ass. D. ND. Ass. D. N.D. Ass. D. N.D. Ass. D. <25 6 6 1 1 0 0 7 7 25-34 6 5 9 5 3 1 18 11 35+ 0 7 3 6 8 5 11 18 Total 12 18 13 12 11 6 36 36 The interim conclusion drawn from a study of the experience of the Liver- pool Maternity Hospital is that, although women who have lactation inhibited show a greater incidence of thromboembolism, any effect is considerably modi- fied by the more important factors of age and method of delivery. In illustra- tion of this it may be noted that among the 72 cases of thromboembolism there were eight cases of pulmonary embolism. The ages of the patients concerned were: less than 25 years in one, 25 to 34 in one, and 35 or more in six. Two of the women died from embolism. Both had had lactation inhibited with ethinyl- oestradiol, but they had been delivered by caesarean section and were aged 39 and 41 years respectively. Moreover, the older one suffered from diabetes mel- litus. FINDING5 AT MILL ROAD MATERNITY HOSPITAL During the nine years 1958-66 there were 30,833 deliveries in this hospital, and 65 cases of thromboembolism were recorded. Three of the women con- cerned were admitted to hospital on account of deep venous thrombosis, having been previously delivered at home. Excluding these, the incidence of throm- boembolism was 2.1 per 1,000 hospital births. In 26 of the cases (42%) throm- boembolism occurred during pregnancy, leaving only 39 puerperal cases for analysis. In 21 (54%) of these lactation had been inhibited by means of ethi- nyloestradiol; this is approximately double the expected number calculated on a known breast-feeding rate of 73% for the hospital community on the seventh day. The total number of records of control patients studied, abstracted as indi- cated previously, was 308. Based on these, the incidence of thromboembolism by age, parity, mode of delivery, and lactation habit was calculated to give the findings shown in Tables VI and VII. The figures from this hospital are too small to draw many firm conclusions, but they go to confirm the experience at the Liverpool Maternity Hospital. Overall, the incidence of thromboembolism was increased three to four times when lactation was inhibited. The effect of not lactating was manifested mainly in women aged more than 25 years and in those who had an assisted delivery (especially if they were of low parity). Among lactating women, however, the mode of delivery did not influence the incidence of thromboembolism except possibly in those aged 35 and more. A rising incidence of puerperal thromboembolism with age is apparent only in non-lactating women. PAGENO="0341" TABLE VI.-MILL ROAD MATERNITY HOSPITAL (1958-66 INCLUSIVE). NUMBER OF CASES OF PUERPERAL THROMBOEMBOLISM AMONG LACTATING WOMEN AGAINST THE NUMBER OF CONTROL CASES IN EACH CATEGORY (E.G., 5/54). THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES. Ageinyears ND. Parity Total c~ 0 ~ ~ 1 2and3 4and more - Ass. D. ND. Ass. D. N.D. Ass. D. N.D. Ass. D. All Deliveries <25 5/54 (0.9) 25-34 0/12 (0.0) 35+ 0/2 (0.0*) 1/9 (1.1) 1/8 (1.3) 0/1 (0.0*) 3/39 (0.9) 4/39 (1.0) 1/6 (1.7) 0/1 (0.0*) 0/3 (0.0*) 0/1 (0.0*) 0/7 (0.0) 2/35 (0.6) 0/15 (0.0) 0/0 (-) 0/0 (-) 1/1 (10.0k) 8/100 (0.8) 6/86 (0.7) 1/23 (0.4) 1/10 (1.0) 1/11 (0.9) 1/3 (33*) 9/110 (0.8) 7/97 (0.7)19/123 2/26 (0.8)~(0.7) Total 5/68 (0.7) 2/18 (1.1) 8/84 (1.0) 0/5 (0.0) 2/57 (0.4) 1/1 (10.0*) 15/209 (0.7) 3/24 (1.3) 18/233 (0.8) Deliveries: All N.D Ass.D 7/68 (0.8) 8/89 (0.9) 15/175 (0.9) 13/152 (0.9) 2/23 (0.9) 0 L~i TABLE VlI.-MILL ROAD MATERNITY HOSPITAL (1958-66 INCLUSIVE). NUMBER OF CASES OF PUERPERAL THROMBOEMBOLISM AMONG WOMEN WHO HAD LACTATION INHIBITED AGAINST THE NUMBER OF CONTROL CASES IN EACH CATEGORY (E.G., 0/16). THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES. Parity 1 2and3 Age in years N.D. Ass. D. N.D. Ass. D. 4end more Total - N.D. Ass. D. N.D. Ass. D. All Deliveries <25 0/16 (0.0) 1/6 (1.7) 1/9 (1.1) 0/3 (0.0*) 1/1 (10.0*) 0/0 (- ) 2/26 (0.8) 1/9 (1.1) 3/35 (0.9) 25-34 1/7 (1.4) 2/0 (-) 4/10 (4.0) 3/1 (30.0*) 4/12 (3.3) 0.3 (0.0*) 9/29 (3.1) 5/4 (12.5*) 14/33 (4.2)118/40 Z 35+ 0/0 (-) 1/0 (- ) 0/3 (00*) 0/0 (-) 2/3 (6.7*) 1/1 (10.0*) 2/6 (3.3) 2/1 (20.0*) 4/7 (5.7)ç(4.5) Total 1/23 (0.4) 4/6 (6.7) 5/22 (2.3) 3/4 (7.5*) 7/16 (4.4) 1/4 (2.5*) 13/61 (2.1) 8/14 (5.7) 21/75 (2.8) Deliveries: 1 5/29 (1.7) All N.D Ass.D 3/58 (0.5) 18/233 (0.8) 8/26 (3.1) 13/55 (2.4) 6/45 (1.3) 7/10 (5.0) 8/20 (5.0) 21/75 (2.8) I, PAGENO="0342" 7172 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TOTAL LIVERPOOL EXPERIENCE Combining the findings in the two hospitals offers a study of 111 cases of puerperal thromboembolism and of 641 control cases. The overall incidence of evident puerperal thromboembolism was 1.7 per 1,000 deliveries. The incidence by age, parity, mode of delivery, and lactation habit is shown in Tables VIII, IX, and X. Examination of these strengthens the conclusions drawn from the experience of the individual hospitals. They can be summarized as follows: (1) The incidence of puerperal thromboembolism is three times higher in those women whose lactation is inhibited by administering ethinyloestradiol than in those who breast-feed their babies (3.4 as against 1.0 per 1,000). The difference is seen mostly among those who have an assisted delivery. The incidence is only doubled (2.1 compared with 0.9 per 1,000) when the delivery is spontaneous, but is increased six times (7.6 compared with 1.3 per 1,000) when the delivery is complicated. (2) The incidence of thromboembolism rises with age irrespective of parity, mode of delivery, and lactation habit (Table X)~ It is especially high in women aged 35 or more. The rates are 1.0, 1.6, and 5.1 per 1,000 deliveries respectively for the three age groups under consideration. (3) There is a slight suggestion of a rising risk with high parity, the respective incidences being 1.6, 1.5, and 2.5 per 1,000 deliveries for each parity group. This is more apparent in non-lactating women, but any association is probably indirect, being accounted for by concomitant advancing age. (4) Of all the factors under consideration the most significant, as can be Inferred from conclusion 1 (above), is mode of delivery. Thus in women less than 25 years of age, inhibition of lactation has no effect unless they have an assisted delivery, when the incidence is trebled. In young lactating women of low parity, operative intervention does not influence the incidence of throm- boembolism, probably because the intervention is minor. In women aged more than 25, however, assisted delivery raises the incidence twofold if they are lac- tating, and almost sixfold if they are not. Indeed, the woman aged 35 or more, having had an assisted delivery, has a 10 times greater chance of thromboem- bolism if her lactation function is inhibited than if she breast-feeds her baby. In this respect if has to be recognized that the severity of the operative inter- vention, together with age and general condition, may determine the decision to inhibit lactation. (5) The highest incidence of thromboembolism among women of low parity is seen in those who have an assisted delivery and who do not breast-feed. For parity groups 1, 2, and 3 combined the incidence in lactating women is 0.9 per 1,000 deliveries for normal delivery and 1.1 per 1,000 for assisted delivery; in non-lactfiting women the comparable figures are 1.6 and 7.3 per 1,000. If advan- cing age is added to the three factors already under consideration here, then the risk of puerperal thrombosis is probably very high (possibly 40-45 per 1,000), though the figures available to us are too small to be statistically sig- nificant. DISCUSSION The statistics on which this communication is based can be handled in sev- eral ways, each being attended by difficulties of one type or another. Irrespec- tive of the approach, however, they confirm the overall conclusions of Daniel et al. (1967) to the effect that puerperal thromboembolism is seen more fre- quently among women in whom lactation is inhibited than among those who breast-feed their babies. But the difference between the two groups of patients is not so great in our series as was reported from Cardiff. For all women the incidence of thromboembolism was three times greater when they did not lac- tate. For low-parity women aged 25 and older inhibition of lactation was asso- ciated with a fourfold increased risk, whereas in Cardiff there was a tenfold increase. If the administration of oestrogens plays a direct part in predispos- Ing the puerperal woman to thromboembolic episodes, it might be argued that the difference between the two centres could be attributed either to our employment of a much smaller dose of hormone for inhibiting lactation or to the use of ethinyloestradiol rather than stilboestrol. The results of our study also differ from those in Cardiff in that they indi- cate that age, and especially mode of delivery, are of equal if not greater importance than inhibition of lactation in determining the risk of puerperal PAGENO="0343" TABLE VIII.-TOTAL LIVERPOOLSERIES. INCIDENCE OF PUERPERAL THROMBOEMBOLISM AMONG LACTATING WOMEN AGAINST THE NUMBER OF CONTROL CASES IN EACH CATEGORY (E.G., 10/94) THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES Parity Total 2 Age in years 1 N.D. Ass. D. 2 and 3 4 and more N.D. Ass. D. N.D. Ass. D. N.D. Ass. D. All Deliveries <25 10/94 (1.1) 3/28 (1.1) 25-34 2/29 (0.7) 3/31 (1.0) 35+ 0/3 (0.0*) 0/5 (0.0) 3/53 (0.6) 0/5 (0.0) 7/89 (0.8) 2/12 (1.7) 2/11 (1.8) 1/4 (2.5*) 0/7 (0.0) 4/51 (0.8) 4/18 (2.2) 0/1 (0.0k) 0/2 (0.0*) 3/2 (15.0*) 13/154 (0.8) 3/34 (0.9) 13/169 (0.8) 5/45 (1.1) 6/32 (1.9) 4/11 (3.6) 16/188 (0.8) 18/214 (0.8)) 28/257 10/43 (2.3)J(1.1) 44/445 (1.0) Total 12/126 (1.0) 6/64 (0.9) 12/153 (0.8) 3/21 (1.4) 8/76 (1.1) 3/5 (6.0) 32/355 (0.9) 12/90 (1.3) Deliveries: 18/190 (0.9) N.D Ass.D 33/364 (0.9) 15/174 (0.9) 24/279 (0.9) 9/85 (1.1) 11/81 (1.4) 44/445 (1.0) TABLE IX.-TOTAL LIVERPOOL SERIES. INCIDENCE OF PUERPERAL THROMBOEMBOLISM AMONG WOMEN WHO HAD LACTATION INHIBITED AGAINST THE NUMBER OF CONTROL CASES IN EACH ~ CATEGORY (E.G., 1/28). THE CALCULATED INCIDENCE PER 1,000 DELIVERIES IS SHOWN IN PARENTHESES Parity Age in years 1 2 and 3 N.D. Ass. D. N.D. Ass. D. Total 4 and more N.D. Ass. D. N.D. Ass. D. All Deliveries <25 1/28 (0.4) 25-34 5/16 (3.1) 35+ 0/2 (0.0*) 5/16 (3.1) 5/6 (8.3) 8/1 (80.0*) 2/22 (0.9) 10/46 (2.2) 2/8 (2.5) 1/9 (1.1) 6/7 (8.6) 5/2 (25.0*) 1/1 (10.0~) 5/17 (2.9) 6/10 (6.0) 0/0 (-) 1/3 (33*) 4/2 (20.0*) 4/51 (0.8) 20/79 (2.5) 8/20 (4.0) 6/25 (2.4) 12/16 (7.5) 17/5 (34.0) 10/76 (1.5) 32/95 (3.4) ~57/120 25/25 (10.0)S(4.8) ~1 Total 6/46 (1.3) 18/23 (7.8) 14/76 (1.8) 12/18 (6.7) 12/28 (4.3) 5/5 (10.0) 32/150 (2.1) 35/46 (7.6) 67/196 (3.4) Deliveries: All f ND 1 Ass.D 1 24/69 (3.5) 50/163 (3.1) 20/122 (1.6) 30/41 (7.3) 26/94 (2.8) . 17/33 (5.2) 67/196 (3.4) PAGENO="0344" 7174 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE X.-TOTAL LIVERPOOL SERIES. INCIDENCE OF PUERPERAL THROMBOEMBOLISM IN RELATION TO AGE AND PARITY REGARDLESS OF LACTATION AND MODE OF DELIVERY PER 1,000 DELIVERIES IN EACH CATEGORY Age in years Parity 1 2 and 3 4 and more Total <25 1.1 0.7 1.1 1.0 25-34 35+ 1.81 735 * 1.61 4.05 1.41 5.35 * 1.6 5.1 * Total 1.6 1.5 2.5 1.7 1.6 thromboembolism. Indeed, for women who have spontaneous delivery, inhibi- tion of lactation by administering a moderate dose of ethinyloestradiol does not increase the incidence of thromboembolism if they are less than 25 years of age, and only doubles it if they are older. Our evidence suggests that any dramatic increase in the occurrence of thromboembolic disorders is related to the severity of any operative intervention and also to age. It may well be that major surgery and advancing years often underlie both the decision to inhibit lactation and the associated increased risk of thromboembolism~ The same may well be true of obesity, but the weights of the patients in these series were not studied. Apart from the fact that the findings reported here reveal an interplay of several probably more important factors, there are some general considerations which raise serious doubts about any direct effect of inhibition of lactation, or of administering oestrogens for the purpose, in determining puerperal throm- boembolism. Though the Reports on Confidential Enquiries into Maternal Deaths in England and Wales (Ministry of Health, 1957, 1960, 1963, 1966) show that venous thrombosis and embolism constitute a leading cause of death, the actual number of deaths per annum from this cause did not increase during the period 1952-63 despite a rising number of births. Indeed, the number of fatal puerperal cases showed a fall over the years, the total figure being kept constant by a gradual rise in the number of fatal episodes occurring during pregnancy. The national decrease in the number of fatal puerperal cases occurred despite a general trend away from breast-feeding.2 Between 1951 and 1957, and in England and Wales, the proportion of women who attempted breast-feeding fell from 85% to approximately 78%, varying a little as between domiciliary and hospital deliveries and from one part of the country to another (Ministry of Health, 1957a; Dykes, 1957; Burns, 1957). Since then the percentage has fallen but the extent is unknown. Reports from the Simpson Memorial Pavilion of Edinburgh Royal Infirmary (1965) indicate that the incidence of breast-feeding among mothers at the time of discharge from that hospital fell from 70% in 1955 to 26% in 1965. At the Royal Mater- nity Hospital, Glasgow, during the years 1962 and 1963 the percentage of breast-feeders varied from 6.2% for "grand" multiparae subjected to caesarean section to 42% for primiparae having a normal delivery (Garrey, Paterson, and Evans, 1964). Throughout Scotland as a whole, and in 1965, only 31% of mothers ever attempted breast-feeding (Arneil, 1967). Whether Scottish practice is a measure of the trend in England and Wales as a whole is uncertain. But lactation habits certainly changed among the women delivered in the two hospitals on which this study is based. Up to 1959 and 1960 the incidence of lactation on the seventh day of the puerperium among the control women was 80-90%. After 1960 the incidence fell progres- sively to approximately 60%. Yet the annual incidence of thromboembolism remained static throughout the whole period. The number of cases did not sig- nificantly rise despite the fact that ultimately 40% of all puerperal women received ethinyloestradiol and did not breast-feed. So far as can be ascertained 2 Comments in the reports suggest that during the years under review there had been no significant increase In the use of anticoagulants to explain fewer puerperal deaths. PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7175 there was no other change in obstetric management which could have operated to keep the figures static. At both hospitals, from the beginning to the end of the period under review, there was an intensive campaign to recognize and correct pregnancy anaemia; the third stage of labour was managed actively and the incidence of postpartum haemorrhage kept to a low constant figure; all patients were ambulant and practising physiotherapy from the first day of the puerperium onwards; and very few women were discharged home before 8 to 10 days after delivery. The fact that thromboembolism is now occurring relatively often during pregnancy, whereas formerly it was rare before delivery, is of some interest. In England and Wales during the period 1961-3 there were more deaths from embolism during pregnancy than after caesarean section, an operation known to carry an unusually high risk. In the period 1952-4 only 3% of the obstetric deaths from thrombosis and embolism in England and Wales occurred before labour; by 1961-3 the figure had risen to 29%. Our local experience confirms the country-wide trend. At the Liverpool Maternity Hospital antenatal thromboembolism accounted for almost 21% of all cases during 1956-66. At the Mill Road Maternity Hospital 42% of the thromboembolic episodes occurred before delivery, a remarkably high figure difficult to explain. The only obvious difference between the practice of the two hospitals is that the Mill Road Maternity Hospital deals mainly with women drawn from the poorer socioeconomic groups, whereas the Liverpool Maternity Hospital caters mainly for the middle classes. During pregnancy there are high levels of oestrogen and progesterone in cir- culation. One or other or both of these hormones almost certainly play some part in predisposing women to thromboembolism during pregnancy, as they do women who take oestrogen/progestogen preparations for purposes of contracep- tion (Inman and Vessey, 1968; Vessey and Doll, 1968). But pregnant women have always been exposed to this influence, and it is difficult to accept that this is a prime cause of thromboembolism occurring during pregnancy, since it would appear that it did not operate until the last 15 to 20 years. In this context it is not irrelevant to mention that, during the period 1952-66, 59 pregnant women attending our clinical department were treated empirically with large doses of oestrogen on account of a past history of unex- plained recurrent abortion. Of these, 43 were given stilboesterol in amounts which were gradually increased from 45 mg. daily in the first trimester to 135 mg. daily between the thirty-second and thirty-sixth seeks. The other 16 women were given ethinyloestradiol, beginning with 2.25 mg. daily and increas- ing to 6.75 mg. daily. Not all these women carried their babies to term, but those who did each received a total of 75,000 mg. of stilboestrol or 3,750 mg of ethinyloestradiol. None of the women concerned, irrespective of the time of delivery, suffered thromboembolism before or after labour. All these considerations make it necessary to question whether the undoubted association between inhibition of lactation with puerperal throm- boembolism is direct or indirect, and, if the former, whether oestrogen therapy is responsible. It has to be reckoned that inhibition of lactation by any means, even the avoidance of suckling and fluid restriction, could be the operative factor. This aspect of the problem was not examined by us because all the non-lactating women in our series received ethinyloestradiol. There is a need for a controlled study in this field. Meanwhile there is now so much ancillary evidence to indicate that the administration of oestrogens in other circumstances can favour the develop- ment of deep venous thrombosis and embolism that it seems justifiable to con- clude that probably they play some part in determining any increase in the incidence of puerperal thromboembolism among women who do not breast-feed their babies. But our findings suggest that their role is a secondary one. They appear merely to contribute one more factor to many other factors already operating. Thus ethinyloestradiol administered in reasonable doses for the pur- pose of inhibiting lactation has no effect in young women having a normal delivery. If, however, the factor of advancing age is already present then its PAGENO="0346" 7176 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY administration appears to raise the incidence from approximately 1 to 2 per 1,000 deliveries. Again, women having an operative delivery already carry a relatively high risk of thromboembolism; ethinyloestradiol given to them may have a summation effect to increase the risk six times. Fundamental determin- ing factors to puerperal thromboembolism are combinations of relative late age and traumatic delivery and there may well be others such as obesity and hypertensive states complicating pregnancy. It still remains uncertain how often it is these which prompt the administration of oestrgoens to inhibit lac- tation. At this stage of knowledge it may be concluded that, provided oestrogens have the inhibitory effect on breast activity which is credited to them, and which our observations lead us to accept as genuine, their administration does not increase the risk of puerperal thromboembolism to an unacceptable degree. This is true for women at low risk, but for those who are advanced in years and who are subjected to operative delivery involving considerable trauma there is some reason to hesitate to add one more predisposing factor, even if it be a minor one. Obesity and a past history of thromboembolic disorders might also sometimes be considered to be contraindications to the administration of oestrogens in the puerperium. When oestrogens are given, however, it would seem wise to use the lowest dose compatible with efficient inhibition of lactation. A firm conclusion about the role of therapeutic doses of oestrogen in predis- posing to puerperal thromboembolism may not be possible without controlled prospective studies, and these are already in progess. Because the incidence of clinically evident disease is relatively low, this will take time. Meanwhile, the results of this retrospective study are reported to add to the evidence which needs to be collected from many sources. References Arneil, G. C. (1967). ~S!cottish Health S1ervice Rtudy, No. 6. Edinburgh. Burns, D. (1957). Med. Offr, 98, 205. Daniel, P. G., Campbell, H., and Turnbull, A. C. (1967). Lancet, 2,287. Daniel, D. G., Bloom, A. L., Giddings, J. C., Campbell, H., and Turnbull, A. C. (1968). Brit. med. J., 1, 801. Dykes, R. M. (1957). Lancet, 2, 230. Garrey, M. M., Paterson, 1~I. M., and Evans, J. M. (1964). Lancet, 2, 1057. Hill, G. B., and Wilson, W. A. (1968). Med. Offr, 119, 147. lodge, C. (1967). Lancet, 2, 286. Inman, W. H. W., and Vessey, M. P. (1968). Brit. med. J., 2, 193. Jeffcoate, T. N. A., Lister, Ursula M., Hargreaves, Betty, and Roberts, H. (1948). Brit med. J., 2, 809. Jeffcoate, T. N. A., and Tindall, V. R. (1965). Aust. N.Z. J. Obstet. Gynaec., 5, 119 Ministry of Health (1957, 1960, 1963, 1966). Reports on Confidential Enquiries into Maternal Deaths, England and Wales. H.M.S.O., London. Ministry of Health (1957a). Annual Report of the Chief Medical Officer. H.M.S.O., London. Simpson Memorial Pavilion (1965). Annual Medical and Clinical Report. H.M.S.O., London. Vessey, M. P., and Doll, R. (1968). Brit. med. J., 2, 199. [From the British Medical Journal, Oct. 5, 1968, pp. 1-2] THRoMBosIs AND INHIBITION OF LACTATION An association between oral contraceptives and thromboembolism has now been the subject of many reports, with oestrogens rather than progestogens incriminated as the likely cause of it (1, 2). Moreover, puerperal venous N0TE.-Numbered references at end of article. PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7177 thrombosis and embolism occur more commonly in mothers who are in the higher age and parity groups or who have had an operative delivery or a stillborn baby. Such women are less likely to breast-feed and more likely to have lactation inhibited. So it should not have occasioned great surprise when it was reported from Cardiff last year that the administration of stilboestrol to inhibit lactation favoured the development of thromboembolism, to the extent of a tenfold increase in incidence in mothers aged 25 or more (3). This week Professor T. N. A. Jeffcoate and colleagues at Liverpool report in the B.M.J. at page 19 a careful analysis of 111 consecutive cases of puerperal thromboembolism in two maternity hospitals during 1953-66. They found that in women whose lactation was inhibited by oestrogens the incidence of puer- peral deep venous thrombosis and embolism was increased, threefold over all the cases and sixfold when delivery was operative, as compared with similar mothers who breasfed their babies. Increasing age of itself brought increasing hazard, with newly delivered women of 35 or more carrying the highest risk. And assisted delivery further increased the chances of thromboembolism, more so if lactation was inhibited, so that a woman of 35 or over delivered opera- tively had a ten-times greater risk if her lactation was suppressed with oestro- gens than if she breast-fed. These are weighty statistics, but there are some noteworthy discrepancies between the Cardiff and the Liverpool figures. At Cardiff the increase in puer- peral thromboembolism imputed to oestrogen suppression of lactation was more than double that reported from Liverpool, where, however, the routine dosage of oestrogens was much lower. In the Cardiff series the inhibition of lactation in women under 25 who had operative deliveries entailed no extra risk, but in the Liverpool series it did. Indeed the Liverpool analysis suggests that increas- ing age and major operative intervention at delivery are at least as important as the hormonal suppression of lactation in increasing the chances of throm- boembolism. This view is supported by the fact that despite a national decline in breast-feeding the incidence of puerperal thromboembolism and the number of fatalities from it are not rising. As well as differences between results from the two cities there are some between the two hospitals in the Liverpool series. In one the incidence of puerperal thromboembolism was less than two- thirds what it was in the other; and, while in one hospital an incidence rising with age was found only in non-lactating women, in the other increasing age had an adverse effect on both breast-feeders and non-breast-feeders. Further inquiries into these important questions are clearly needed, and it is good to know that controlled prospective studies have already begun. As well as taking note of age, parity, previous thromboembolic attacks, and operative delivery the studies should also examine hypertension, obesity, smoking habits, and whether the patient received general anaesthesia after delivery (for exam- ple, for manual removal of the placenta) or in the puerperium (for example, for tubal ligation). Furthermore, some women develop thromboembolism either after discharge from a maternity hospital or after delivery outside hospital. Compulsory notification of puerperal thromboembolism, at least in localities where these studies are being made, would result in much more reliable statis- tics; failing which, figures from general hospitals containing maternity units will be more comprehensive than those from maternity hospitals. Secondly, research should be continued into the effects of different dosages of different oestrogens, synthetic and natural, not only on the blood factor IX (4) and plate- lets (5) but also on other factors concerned with blood coagulation, espe- cially in newly delivered women. Thirdly, the efficacy and acceptability of other, non-hormonal, methods of inhibiting lactation (6, 7) should be examined and confirmation sought on whether the absence of lactation of itself increases PAGENO="0348" 7178 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the chances of puerperal thromboembolism. In addition, the several benefits of breast-feeding might be more widely publicized in the press and on television. Meanwhile all who practise obstetrics might consider it advisable to use the minimum effective dosage of oestrogens for the inhibition of lactation, and to pause before prescribing them at all for any new mother with a considerably greater-than-average chance of thromboembolism because of a past history of it, or because she has had an operative delivery, or, especially, because she is 35 or over. References 1. Inman, W. H. W., and Vessey, M. P., Brit. med. J., 1968, 2, 193. 2. Vessey, M. P., and Doll, R., Brit. med. J., 1968, 2, 199. 3. Daniel, D. G., Campbell, H., and Turnbull, A. C., Lancet, 1967, 2, 287. 4. Daniel, D. G., Bloom, A. L., Giddings, J. C., Campbell, H., and Turnbull, A. C., Brit. med. J., 1968, 1, 801. 5. Elkeles, R. S., Hampton, J. H., and Mitchell, J. R. A., Lancet, 1968, 2, 315. 6. MacDonald, D., and O'Driscoll, K., Lancet, 1965, 2, 623. 7. MacDonald, D., and O'Driscoll, K., Lancet, 1967, 2, 472. [From the British Medical Journal, Sept. 28, 1968, pp. 777-780] EFFECT OF ORAL CONTRACEPTIVES ON DEPRESSIVE MOOD CHANGES AND ON ENDOMETRIAL MONOAMINE OxIDA5E AND PHO5PHATASES (By Ellen C. G. Grant,* M.B., Ch.B., D.Obst.R.C.O.G.; John Pryse-Davies,t M.D., MC. Path.) Summary: Significant variations in the incidence of depression and loss of libido were found with the various types of oral contraceptives. The highest incidence occurred with stongly progestogenic compounds (especially with those containing a small amount of oestrogen) which have high monoamine oxidase activity for most of the cycle. The lowest incidence was found with the stongly oestrogenic sequential regimens which have weak monoamine oxi- dase activity for most of the cycle. INTRODUCTION Mears and Grant (1962), Pullen (1962), and Goldzieher et a!. (1962) re- ported that premenstrual tension improved in women taking progestogenic/ oestrogenic oral contraceptives. 1\Iears and Grant (1962) also reported changes in libido which they suggested might be due to psychological factors. How- ever, it became clear that depressive changes were more troublesome with some products than with others. It was therefore decided to study the effect of the various types of oral contraceptives on the histochemistry of a selected group of enzymes in the endometrium. Monoamine oxidase, which was also measured biochemically in some cases, was of special interest because mono- amine oxidase inhibitors are used for treating depressive states. Alkaline and acid phosphatase were chosen as marked enzymes with known variations in the normal cycle. McKay et a!. (1956) described a decrease in alkaline and an increase in acid phosphatase during the late secretory phase. Cohen et a!. (1964) demonstrated an alteration in the staining for endometrial monoamine oxidase in the latter part of the menstrual cycle, and Southgate et a!. (1967) showed that in vitro there may. be as much as a tenfold increase in biochemi- cal activity of monoamine oxidase in the late secretory phase of the normal cycle. * Council for the Investigation of Fertility Control, 27-35 Mortimer Street, London w.1. t Bernhard Baron Memorial Research Laboratories, Queen Charlotte's Maternity Hos- pital, London W.6. PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7179 METHOD Full clinical histories, including details of premenstrual tension and previous mental illnesses, were obtained from volunteers attending the central clinic of the Council for the Investigation of Fertility Control. A total of 797 women received one or more of 34 oral contraceptives (Tables I and II), giving a treatment experience of 1,217 women. The incidence of depression, loss of libido, tiredness, and irritability occurring with the various formulations was observed over six years. Endometrial biopsies were obtained, at all stages of the cycle, before treat- ment and thereafter during routine six-monthly examinations. The 137 biopsies studied were obtained at random from women taking the products being tested during a one-year period. The various products have been grouped according to endometrial effect and break-through bleeding incidence (Grant, 1967) as strongly progestogenic, strongly oestrogenic, and intermediate compounds. They have been further subdivided according to oestrogen content (Table III). The specimens were examined without previous knowledge of clinical details. Cu- retted fragments were frozen immediately after removal, and sections were pre- pared and examined as described by Southgate et at. (1967). Monoamine oxi- dase activity was demonstrated by the method of Glenner et at. (1957). Alkaline and acid phosphatase were demonstrated by an azo dye coupling method, Fast Red LTR (Pryse-Davies et at., 1961). CLINICAL RESULTS Tables I and II show the percentage of women complaining of depression and loss of libido on the individual preparations. These are grouped according to hormone balance and type of oestrogen in Table IV. The incidence of depression and loss of libido ranged from 28% of women on strongly progesto- genie preparations containing ethinyloestradiol to 7% of women on the strongly oestrogenic sequential regimens containing ethinyloestradiol and 5% on the sequentials containing mestranol: these figures differ significantly (P<0.01) from the average incidence of 16% for all women in Table IV. Thus the incidence of depression and loss of libido are greatest with the strongly progestogenic oral contraceptives containing a small dose of oestrogen. Two of the 136 women taking Anovlar (norethisterone acetate 4 mg.~ethinyloestradiol 0.05 mg.) became sufficiently depressed to attempt suicide. Though Lyndiol (lynoestrenol 5 mg.~mestranol 0.15 mg.) is strongly progestogenic (break- through bleeding 2%) it also contains a high dose of mestranol and has a low incidence of depression and loss of libido, whereas Volidan (megestrol acetate 4 mg.~ethinyloestradiol 0.05 mg.) is less progestogenic (break-through bleeding 10%) but contains a low dose of ethinyloestradiol and has a high incidence of depressive change. Other mood changes noted were tiredness, irritability, aggression, and increased libido. These could not be related to hormone balance but may be influenced by vascular changes. Aggression was particularly noticeable with norethisterone acetate 1 mg. and ethinyloestradiol 0.075 mg., which had a marked effect on the development of both arterioles and sinusoids in the endometrium. Premenstrual tension, which was a common complaint before the trial, especially in older women, almost invariably improved. Only a few women discontinued the tablets because of mood changes in the early cycles, but over the period of the trial 40% of those withdrawing for side-effects had at least one mood complaint. HISTOCHEMICAL RESULTS Fig. 1 shows the activities of the three enzymes according to the day of the cycle. In the untreated groups (I and VI) the late secretory phase is also indi- cated. PAGENO="0350" 7180 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I PRE-TRIAL. CYCLE Ac.P. o Late secretory phase Alk.P. *~IO 20 30 II STRONGLY PROGESTI AlL?. M~~1 0 20 30 0 20 30 GENIC COMBINED TABLETS (BIB. 0-3°/a) Act. MAO. Strong Moderate Weak Strong Moderate Weak ______________________ Strong Moderate Weak _________ ___________ Strong Moderate Weak _________________________ Strong Mode rate Weak AIk.P. Strong L .. Moderate Weak 00000 0 20 30 to 20 30 0 20 III SEOUENTIALS te. strongly oestrogenc 30 . AIk.P. Ac.?. MAO. . 0 20 30 ~ 20 30 tO 20 30 IV COMBINED TABLETS WITH E.O. (B.T.B. 40/0 or more) AILP. Ac.?. MAO. **: i..: ***.. **. ..~* *~ * 0 20 30 V COMBINED TABLETS 0 20 30 WITH MESTRANOL (BIB. 0 20 4°/o or more) 30 Alk.?. Ac.P. - . . I MAO. * F ..: *.: 0.:.. * ~ * **0 *** .*.s. ** * VI POST-TRIAL CYCLE . Ac. P. 0 20 30 o Late secretory phase MAO. ~oooooo 10 20 30 10 20 30 * Grap~is illustrating alkaline phosphatase, acid phosphatase, and monoamine oxidase activity in the menstrual cycles of untreated and oral-contraceptive-treated women. PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7181 Untreated cycle Alkaline phosphatase activity was strongest in the late proliferative phase in the glandular and superficial epithelium, decreased in the latter half of the cycle, and disappeared in the late secretory phase. Activity was considered strong when more than two-thirds of the epithelium showed activity, moderate when about half the epithelium stained, and weak when less than a third showed evidence of activity. Alkaline phosphatase was also seen in capillary and arteriolar endothelium throughout the cycle, but arteries showed little or no activity. Acid phosphatase showed a more generalized activity in both epithelium and stroma. Early in the cycle there was weak staining of all elements, in mid- cycle staining became heavier in the epithelial cells, while in the latter secre- tory phase there was a further increase of staining in the epithelium these three degrees of activity, were regarded as weak, moderate, and strong respectively. Monoamine oxidase activity in the first half of the cycle was seen as dark granules or fine droplets scattered in the stroma and epithelium with no selec- tive vascular staining. In the late secretory phase a purple-blue colour devel- oped diffusely in the glandular epitheliurn, especially the luminal border. As a result of parallel biochemical studies by Southgate et al. (1967) it was found that the diffuse blue stain was associated with high monoamine oxidase activ- ity in vitro and the granular stain with weak activity. Biopsies from 20 untreated and 24 treated patients in this series were also examined biochemi- cally for monoamine oxidase activity; the results corresponded with the histo- chemical findings in each case, ranging from 1,000 to 20,000 units. Enzyme activity in the cycles one month before and one to six months after treatment (Fig. 1, VI) was more closely related to the histological pattern than the exact day of the menstrual cycle. This accounts for the overlapping of results at 20 to 25 days, which depend on variations in time of ovulation. Flowers et al. (1966) found that while alkaline and acid phosphatase and diphosphopyridine nucleotide diaphorase enzyme activity was below normal in the second months after Ovulen therapy, normal activity was found during the third recovery month. PAGENO="0352" 7182 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY TABLE I-Oral Contraceptive Compounds Containing Mesiranol Progestagen Ic Smr~ng Cycles Cy-ks Women with °ibido and Ethynodioldiacc- talc 2 .. 01 Metrulen 25 525 ~2 20 1 .. 01 Ovuien 30 629 13 05 .. 01 19 202 5 21 025 01 25 287 40 8 01 .. 01 11 140 25 9 Norethynodrel 5 0075 Conovid 27 515 16 22 25 01 Conovjd E 28 678 20 10 Norethisterone 2 01 Orthonovum 55 965 `2 20 Lynoestrenol 5 015 Lyndiol I 28 969 `3 3 25 0075 Lyndiol 25 34 576 4 26 282 5483 - Sequential preparations Mestranol (mg) Women I Cycles j Lib.- + B.~.B. Depression 1. l4daysM.0l+7davsM.01+ chlormadinone 15 mg .. 11 93 1 1 2 2.15 days M. 008+5 days M. 0OS + chlormadinone 2 my. 62 j 860 4 1 3. 11 days M. 01 + 10 days M. 01 + chlormadinone 2 cog. 27 275 05 1 2 100 1,220 5 Strongly progestogcnic compounds, including I.yndiol, which is strongly TABLE 11.-Oral Contraceptive Compounds Containing Ethinyl Oest radio! Women with E.hLnyl w B.T.B. Loss of (mg )g n d `\ rn St ~ I CycI Cyl s L bd nd ______ ____ (%) Norgestrol 3 0-05 9 96 00 44 2 ~.. 0-05 12 117 `1 25 1 .. 005 28 430 `2 29 05 .. 0-05 29 349 03 13 025.. I 0-05 31 183 10 10 01 .. 005 20 145 40 10 Norethisterone acetate 4 005 Anovlar 136 1,925 *2 30 25 005 Norlestrin 32 833 6 25 1 005 21 139 26 10 1 0075 31 194 8 20 1 009 27 225 4 22 Megestrol acetate Si 01 57 515 8 11 3 01 3-i 322 20 2 ~ 005 Volidan 85 1,510 10 34 Lynestrenol 3 005 . 13 110 4 30 2 005 68 810 6 30 634 7903 Sequential preparations: Women Cycles Lib.- + 13.T.B. Depression 1. 11 days EQ. 0-05 mg. + 10 days EQ. 0-05 mg.+chlormadi- none 1 mg 24 140 S 1 2. 11 days 5.0. 005 mg + 10 days EQ. 0-05 mg. + chlormadi- none 2 mg 25 137 3 4 3. 16 days EQ. 01 mg.+5 days EQ. 0-1 mg.+megestrol acetate 5 mg. .. .. 84 1.249 Oi 6 4. 16 days 5.0. 0075 mg. + 5 days E.0.005mg. + megestrolace- tate 4 mg 49 375 4 3 5. 8 days EQ. 005 mg. + 12 days 0.0. 01 cog. +5 days EQ. 015 cog. + 5 days medroxy- progesterone acetate 10 mg (l'rovcra) 19 171 0 1 0 201 2,275 14 * Compounds classified as strongly progcstogenic. PAGENO="0353" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7183 TABLE III.~-Number of Biopsies Obtained from Women in Various Groups No. of Biopsies Group I. Pretreatment. No previous oral contraceptives . . *. 19 Group It. Strongly progestogenic compounds (B.T.B. 2-3%): Lynoestrenol 5 mg. ± mestranol 01 mg. .. .. 3 Norgest.rol 1 aug. ± etlsinyloestradiol 0-05 mg 6 19 Norgestrol 0-5 aug. ± ethinyloestradiol 0-05 aug. .. 3 Norcilsisterone acetate 4 mg + ethinyioestradiol 0-05 mg 7 Group III. Sequential fornsuiations (B.T.B. 0-5%) .. .. 18 Group IV. \Vcakcrprogcstogenic compounds + ethinyloestradiol (13.T.B; Norcthistcronc acetate 2-5 aug. cthinylocstradiol 005 mg 1 1mg. ,, .0-05 ,, 1 1mg. ,, 0-075,, 20 1mg. ,, 009 ,, 7 ~37 Norgestrol 0-25 aug ,, 0-05 ,, 3 Megestrol acetate 4 mg. ,, 005 ,, 3 2mg. ,, 01 *,, 2J Group V. Weaker progestogenie compounds +mesteanol (B.T.B. 4-40%): lithynodiol diacetate 1 aug. mestranol 0-1 aug. .. 7 0-5 aug. ,, 01 aug. .. 2 ,, 0-25 mg. ,, 0-i rug. .. 4 Lynoestrenol 25 mg. ,, 0-075 mg. .. 6 Norethynodrel 5 aug. ,, 0-075 aug. .. 1 25 mg ,, 0-1 aug. .. 2 Group VI. Posttreatment-from 1 to 6 months 21 - 137 TABLE IV.-Percentage of Women with Mood Changes Ethinyloestradiol Mestranol ~ LI _________ / zi 1. Strongly progesto. genie combined tab. (break. 214 28 8 5 108 17 10 3 tisrough bleed- ing 0-3%) 2. Intermediate combined tab. (break-through 420 20 11 9. 174 16 8 2 bleeding 4% or more) 3. Strongly oestro- genie se~uentiaIJ. 201 7 8 5 100 5 8 5 Treated cycles Grant (1967) described the histology of the normal and oral-contraceptive- treated endometrium. Strongly Progestogenic Combined Tablets (Break-through Bleeding 0.3%).- The high dose of progestogen allows only a short growth and early secretory phase from day 7 to 11, which is followed by a prolonged post-secretory phase or atrophic phase, when the small glands have a single layer of low columnar cells. The enzyme pattern showed changes typical of a late secretory phase as early as day 12 (Fig. 1, II). Alkaline phosphatase was weak from day 10 and acid phosphatase strong from day 12. 1~Ionoamine oxidase was strong from day 12 even from very small fregments of atrophic endometrium. The overall incid- ence of depression and loss of libido on these preparations was 28% with ethinylestradiol but only 17% when combined with larger doses of mestranol. Sequential Tablets (break-through Bleeding 0-5%).--By contrast the strong oestrogen stimulation in the sequential regimens produces accentuated growth and early secretory phases and allows no definite secretory changes as late as day 26 (Fig. 1, III). There was a low monoamine oxidase level throughout the cycle. The incidence of depression and loss of libido on these preparations was 6%. Weakly Progestogenic Combined Tablets (Break-through Bleeding 4-40%).- These have more prolonged proliferative and early secretory phases, the length of the latter being proportional to the incidence of break-through bleed- 40-471 0-70-pt. 17-23 PAGENO="0354" 7184 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ing. A tablet with a 4% incidence has a modified early secretory phase from days 8 to 12, while one with 40% incidence of break-through bleeding may be secretory from days 10 to 20. (a) Containing 0.05-0.09 mg. Ethinytoestradiol: An intermediate picture was seen in this group with a gradual decrease in alkaline phosphatase and early increase in acid phosphatase activity (Fig. 1, IV). The post-secretory low columnar or cuboidal glands showed a weak, moderate, or strong monoamine oxidase activity from day 17 onwards. (b) Containing 0.075-0.1 rng. Mestranot: Alkaline phosphatase was stronger and acid phosphatase weaker during the cycle than with the corresponding ethinyloestradiol tablets. Though most specimens were from Ovulen and Lyn- diol 2.5 (break-through bleeding 4%) which produce a post-secretory atrophic endometrium from day 13 onwards, only two biopsies showed a strong mono- amine oxidase activity (Fig. 1, V). The day 24 specimen giving a strong reaction was from the Ovulen-treated endometrium of a woman complaining of loss of libido. The other strong reaction was given after several months' continuous therapy with Lyndiol 2.5, when the patient was complaining of depression and abdominal distension: cyclic therapy, discontinued because of menstrual head- aches, was then restarted at the patient's request. DI5CU55ION In the normal cycle there is a dramatic rise in the monoamine oxidase activ- ity of the endometrium in the late secretory phase. At this time endogenous oestrogen levels fall and premenstrual tension is common, especially among older women. With a strongly~ progestogenic combined oral contraceptive tablet the rise in endometrial monoamine oxidase occurs early in the cycle at day 12, at which time the woman is receiving constant amounts of exogenous oestro- gen. If the amount of oestrogen is low some women may notice a depressant effect on mood or libido. Though a strongly progestogenic combined tablet such as Lyndiol has strong monoamine oxidase activity early in the cycle, the high dose of oestrogen in the tablet seems to protect against the depressant effect. However, Ferin (1966, personal communication) found that some ovariecto- mized women taking Lyndiol became depressed and treated them with mono- amine oxidase inhibitors. With the strongly oestrogenic sequential regimens the amount of oestrogen is high, the monoamine oxidase activity low, and fewer women complain of depression. With the intermediate compounds monoamine oxidase varies in activity and may even be weak in post-secretory glands. It is interesting, in view of our finding in women, that Michael et at. (1967) showed that progesterone inhibited sexual receptivity in female rhesus mon- keys. As the endometrium is especially sensitive to variations in oestrogens and progestogens the changes in monoamine oxidase activity may reflect simi- lar changes occurring in other sensitive areas of the body such as the hypo- thalamus. Cyclic changes in the rat hypothalamus have been reported by Kuwa- bara et at. (1967), who found that monamine oxidase and biogenic amine activity reached a maximum at pro-oestrus. In women, plasma monoamine oxi- dase has been found to double at the end of the cycle, and significantly higher values were recorded in amenorrhoeic women (Klaiber et at., 1967). These find- ings support the hypothesis that progestogenic stimulation causes generalized changes in monoamine oxidase metabolism which may be a factor in the occurrence of depression and loss of libido in susceptible women. Kane et at. (1967) described mood and behavioural disturbances in women who were using a variety of oral contraceptives, while Daly et at. (1967) reported two cases of psychosis associated with the use of sequential regimens. In our series many women had mood disturbances and vascular side-effects at the same time. It seems possible that susceptibility to mood changes may be affected by vascular reactivity (Grant, 1968). We are grateful to Dr. Eleanor Mears and Dr. Hilary Hill for their interest and encouragement in this project, which was supported financially by the Council for the Investigation of Fertility Control and the Labor Foundation. We should also like to acknowledge the help of Dr. Barbara Schooling and Sister Barbara Lamb, the technical assistance of Mr. Keith Napier, and the advice on statistical analysis of results by Mrs. Ann Davis. PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7185 References Cohen, S., Bitensky, L., Chayen, J., Cunningham, G. J., and Russell, J. K. (1964). Lancet, 2, 56. Daly, R. J., Kane, F. J., and Ewing, J. A. (1967). Lancet, 2, 444. Flowers, C. E., Vorys, N., Stevens, V., Miller, A. T., and Jensen, L. (1966). Amer. J. Obstet. Gynec., 96, 784. Glenner, G. G., Burtner, H. J., and Brown, G. W. (1957). Histocheni. Gyto- chem., 5, 591. Goldzieher, J. W., Moses, L. E., and Ellis, L. T. (1962). J. Amer. med. Ass., 180, 359. Grant, E. C. G. (1967). J. Obstet. Gynaec. Brit. Uwith, 74, 908. Grant, E. C. G. (1968). Brit. med. J., 3, 402. Kane, F. J., Daly, R. J., Ewing, J. A., and Keeler, M. H. (1967). Brit. J. Psy- chiat., 113, 265. Klaiber, E. L., Kobayashi, Y., and Brooverman, D. M. (1967). 49th Meeting of the Endocrine Society, Miami Beach, Florida. (Abstract.) Kuwabara, S., Russfield, A., Weisz, J., and Lloyd, C. W. (1967). 49th Meeting of the Endocrine Society, Miami Beach, Florida. (Abstract.) McKay, D. G., Hertig A. T., Bardawil, W. A., and Velardo, J. T. (1956). Obstet. and Gynec., 8, 22. Mears, E., and Grant, E. C. G. (1962). Brit. med. J., 2, 75. Michael, R. P., Saayman, G. S., and Zumpe, D. (1967). J. Endocr., 39, 309. Pryse-Davies, J., Dawson, I. M. P., and Snape, I. M. (1961). J. Path. Bact., 81, 197. Pullen, P. (1962). Brit. med. J., 2, 1016. Southgate, J., Grant, E. C. G., Pollard, W., Pryse-Davies, J., and Sandler, M. (1967). Biochem. Pharmacol., 17, 721. [From the British Medical Journal, Apr. 27, 1968, pp. 187-188] ORAL CONTRACEPTIVES AND THROMBOEMBOLISM The two reports published on pages 193 and 199 give the most recent infor- mation on the association between oral contraceptives and thromboembolic dis- ease. Almost exactly a year ago the B.ZJI.F. published a report to the Medical Research Council which gave the preliminary results of three investigations into this association (1). One study in general practice showed that the use of oral contraceptives increased the risk of thrombosis three times. The second showed that 38% of women admitted to hospital with venous thrombosis had been taking oral contraceptives, while only 8% of control women admitted to the same hospital for reasons other than thrombosis were taking them. The third investigation, carried out by the Committee on Safety of Drugs, sug- gested that there was a relationship between the use of oral contraceptives and death from pulmonary embolism. It was estimated that fatal pulmonary embolism was caused by oral contraceptives in three out of every 100,000 users per year. The present reports are the completed work on the second and third investi- gations. They confirm the association between the use of oral contraceptives and deep-vein thrombosis and pulmonary embolism. The figures in the larger series are more impressive than in the preliminary report. M. P. Vessey and R. Doll found that 45% (26 out of 58) of patients admitted to hospital with deep-vein thrombosis or pulmonary embolism had recently been taking oral contraceptives, while only 9% of controls who were admitted for reasons other than thromboembolism were taking the drugs-a figure very close to the national average for the proportion of the female population at risk of preg- nancy who take them. Doll and Vessey took great care to see that their con- trols and the patients admitted with thrombosis were comparable, and there seems little doubt that their conclusion that oral contraceptives are a cause of non-fatal deep-vein thrombosis and pulmonary embolism is correct. It is also probable that these pills may cause cerebral thrombosis. On the other hand, an association between oral contraceptives and other thrombosis on the arterial side, notably coronary thrombosis, remains unproved. W. H. Inman and Vessey, NoTE-Numbered references at end of article. PAGENO="0356" 7186 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY expanding the preliminary findings of the Committee on Safety of Drugs, were unable to show a definite association between coronary thrombosis and oral contraceptives, though such a possibility cannot be ruled out on the present evidence. When deaths rather than illness from venous thrombosis were considered Inman and Vessey found a strong relation between the use of oral contracep- tives and death from pulmonary embolism and cerebral thrqmbosis, especially in older women. Vessey and Doll investigated the different preparations used by the patients in their series, but were unable to show any marked difference between var- ious contraceptives. The oral contraceptives incriminated in venous thrombosis contain a number of very different progestogens, while only two very similar oestrogens are used in drugs marketed in Britain. There is other evidence that oestrogens may have an effect on blood clotting (2, 3). These findings suggest that it is the oestrogen rather than the progestogen which is responsible for the thrombosis, and if this is true there are three practical conclusions. Firstly, the sequential types of oral contraceptive may be more dangerous, since they contain more oestrogen than the combined pills. Secondly, the contin- uous-low-dose-progestogen technique (not considered in the trials reported), using such compounds as chlormadinone acetate (4), requires no use of oestro- gen and may afford a means of avoiding thromboembolic effects. This tech- nique is not free of disadvantages but it seems to be well worth careful evalu- ation with respect to the danger of thrombosis. Thirdly, the administration of oestrogen for any purpose-not only contraception-should be regarded as carrying a definite risk if the oestrogen is given for a long time or in high dosage. The use of oestrogens to reduce blood cholesterol in patients with coro- nary insufficiency or to suppress lactation (2) are particular cases in point. The occurrence of thromboembolic disease in one out of every 2,000 women on the pill each year is disquieting. Should a doctor give a healthy young woman a prescription for an oral contraceptive if it may lead to her death? The picture must be seen in the perspective of the effect on the whole popula- tion. Other forms of contraception-apart from male and female sterilization -have high failure rates. The risk of death in ~pregnancy, even from thrombo- sis alone, is greater than that of taking oral contraceptives for the same length of time, though how many pregnancies would result from changing to other forms of contraception than the pill is speculative. So, while there is no cause for panic about the possible consequences of widespread use of the pres- ent types of oral contraceptives, neither is there room for complacency. No chair in clinical reproductive physiology exists in Britain, but co-ordinated interdisciplinary research in this field is urgently needed. The goal must be effective contraception, free of all risk, and psychologically fully acceptable. Women would give high priority to such research. References 1. Subcommittee of the Medical Research Council, Brit, med. F., 1967, 2, 355. 2. Daniel, D. G., Campbell, H., and Turnbull, A. C., Lancet, 1967, 2, 287. 3. Oliver, M. F., Lancet, 1967, 2, 510. 4. Martinez-Manautou, J., Giner-Velasquez, J., Corts-Gallegos, V., Aznar, R., Rojas, B., Guitterez-Najar, A., and Rudel, H. W., Brit. med. F., 1967, 2, 730. [From the British Medical Journal, Apr. 27, 1968, pp. 193-199] PAPERS AND ORIGINALS-INVESTIGATION OF DEATHS FROM PULMONARY, CORONARY, AND CEREBRAL THROMBOSIS AND EMBOLISM IN WOMEN OF CHILD-BEARING AGE* (By W. H. W. Inman,t M.A., M.B., B.Chir.; M. P. Ves~ey4 M.B., B.S.) The use of oral contraceptives in the United Kingdom has increased progres- sively during the past seven years and it is estimated that between 10 and 15% of married women were regularly using this method of contraception in * A report to the Committee on Safety of Drugs. t Senior Medical Officer, Committee on Safety of Drugs, Queen Anne's Mansions, London S.W.1. ~ Medical Research Council's Statistical Research Unit, University College Hospital Medical School, London W.C.1. PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7187 1967. During these years numerous accounts have been published in the medi- cal and lay press of individual or small groups of patients who developed thromboembolic disorders while taking oral contraceptives. In the three-and-a- half-year period ending 31 December 1967 the Committee on Safety of Drugs received 1,024 reports of thrombosis or embolism occurring after the use of oral contraceptives or similar preparations. Eighty-eight of these reports referred to a fatal episode. The Food and Drug Administration (1963) in the U.S.A. reviewed some 350 reports of thrombosis or embolism in women taking Enovid (a mixture of norethynodrel and mestranol, marketed in the United Kingdom as Enavid). As no information was available about the morbidity from these conditions in women not using oral contraceptives, the Food and Drug Administration con- fined its attention to reports of death. The mortality from thromboembolic dis- ease among users of oral contraceptives was estimated to be 12.1 per millilon women per year, compared with 8.4 per million in the general population, and this difference in mortality rates was not statistically significant. In 1966 the Food and Drug Administration showed that among the five million women esti- mated to have been taking oral contraceptives in the United States in 1965, 85 deaths from "idiopathic" thromboembolism would have been expected on the basis of natiOnal mortality statistics, whereas only 13 such deaths were reported. It was suggested that physicians in the United States were becoming increasingly fearful of reporting adverse reactions because of the risk of litiga- tion. In the same year the Committee on Safety of Drugs was informed of 19 thromboembolic deaths among the 400,000 women who were estimated to have been using oral contraception in the United Kingdom. Ten of the 19 women had no recognized predisposing conditions. In November 1965 the Committee on Safety of Drugs (Cahal, 1965) pub- lished its findings up to the end of August 1965. In the preceding 12-month period 16 deaths from thromboembolism had been reported among users of oral contraceptives. Thirteen deaths would have been expected on the basis of the Registrar General's statistics, and the Committee did not regard the difference as clear evidence of a thrombogenic effect. They did point out, however, that, whereas only two cases of pulmonary embolism would have been expected, eight had been reported. The Committee therefore decided to enlarge the scope of its investigation to include all deaths from thrombosis or embolism in women of child-bearing age recorded by the Registrars General in England and Wales and Northern Ireland in 1966. Protocols for the investigation were con- sidered by the Committee during the last quarter of 1965, and the study began on 1 January 1966. During 1966 and early 1967 studies were also undertaken by the Royal Col- lege of General Practitioners of patients with thromboembolic disease seen in general practice and by the Medical Research Council's Statistical Research Unit of women admitted to hospital. In April 1967 the results of these two studies, together with those of the Committee on Safety of Drugs, were consid- ered by a subcommittee of the Medical Research Council under the chairman- ship of Lord Platt, and a preliminary report to the Council was published in May 1967. Though two of the investigations were at that time incomplete it was concluded that there could be no reasonable doubt that some types of thromboembolic disorder were caused by oral contraceptives. From the prelimi- nary results of the investigation by the Committee on Safety of Drugs it was estimated that the risk of death from thromboembolism among women who used oral contraceptives might amount to an excess of three deaths per 100,000 women per year over the corresponding mortality in non-users. The Royal College of General Practitioners has published a full report of its investigation elsewhere (Royal College of General Practitioners, 1967), and that of the Medical Research Council's Statistical Research Unit appears else- where in this issue (Vessey and Doll, 1968). The present communication describes the final results of the investigation of deaths undertaken by the Committee on Safety of Drugs. SELECTION OF DEATHS FOR STuDY Transcripts of 499 death certificates relating to women aged 20 to 44 who died in England, Wales, and Northern Ireland during 1966 were obtained by special arrangement with the Registrar Generals. They included certificates PAGENO="0358" 7188 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mentioning thrombosis or embolism of the pulmonary, cerebral, or coronary vessels or other synonymous terms in either the first or second part of the cer- tificate. Certificates relating to deaths attributed to venous thrombosis at peripheral sites but in which pulmonary embolism was not specifically men- tioned were also included.' Eighteen certificates indicated that the thrombosis or embolism was a termi- nal event in the course of some other fatal disease such as cancer, and these deaths were not further investigated. Forty-nine certificates relating to spins- ters were also excluded. Strenuous efforts were made to identify and interview the general practitioners who had cared for the remaining 432 patients. Twenty- seven women, however, were either not registered with any doctor or the coroner, hospital, or local executive council could not identify him. In another 16 instances, though the doctor was identified, arrangements could not be made to interview him within one year of the patient's death. Four doctors refused an interview because they felt they would be unable to be of any assistance. The remaining 385 deaths were all investigated by the Committee's medical field-officers and a further 51 patients were subsequently excluded for a vari- ety of reasons. One patient's age was found at interview to be 47 (not 41 as certified). Eighteen were widowed, divorced, or separated and living alone (women "living as married" were retained). Investigation showed that throm- bosis or embolism was a terminal event in the course of cancer in three patients and in one with subacute bacterial endocarditis; two patients with thrombosis of the superior vena cava were also excluded. Twenty were excluded because the cause of death was not as certified. In a further six patients there was no post-mortem examination and the history and clinical features of the terminal event were too obscure to support the certified cause of death. The remaining 334 deaths provide the basis for this report. Ninety-five were attributed to pulmonary thrombosis or embolism, 209 to coronary thrombosis or myocardial infarction, and 30 to cerebral thrombosis or embolism. It is thought that the great majority of deaths from pulmonary embolism and cononary thrombosis that occurred in 1966 have been included in this investigation. The Registrar General for England and Wales, however, has informed us that, because of the widely varying terminology used by certifying physicians, the deaths attributed to cerebral thrombosis or embolism (I.C.D. List No. 332) may not represent all those that occurred from this cause. PROCEDURE Thirty-five members of the Committee's staff of medical officers took part in the field work in this study. During the investigation of each death one of them completed a questionary as fully as possible with the aid of the general practitioner and any other docotrs who had attended the patient during her terminal illness. Since the general practitioner's records had usually been returned to the local executive council after the patient's death, he was asked to retrieve them before the medical officer called to interview him. These major sources of information were often supplemented by hospital case notes, family planning clinic records, post-mortem reports, and court depositions sup- plied by a coroner. As a matter of policy no attempt was made to obtain infor- mation direct from the patient's relatives. The deaths of eight users of oral contraceptives had been notified independ- ently to the Committee before the summaries of the corresponding death certificates had been received. This information was withheld from the field- officers to avoid possible bias. The questionaries asked about the patient's (1) age and marital status, (2) obstetrical, gynaecological, medical, and family histories, and (3) terminal ill- ness and post-mortem findings. Questions were also included about any drugs, including oral contraceptives, which had been taken by the patient at the onset 1 The great majority of these deaths would be assigned to the following list numbers In the International Classification of Diseases (I.C.D.) : 332 (cerebral thrombosis and embolism), 420 (arteriosclerotIc heart disease, Including coronary disease), 463, 464 (phlebitis and thrombophlebltls), 465 (pulmonary embolism and infarction), 466 (other venous embolism and thrombosis). Deaths assigned to list numbers 648 (other complica- tions of pregnancy) 682, 684 (puerperal phlebitis and pulmonary embolism) were not considered. PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7189 or at any time during the six months preceding the terminal illness. Check- lists of the proprietary names of the various preparations used as oral contra- ceptives were provided. In addition to providing details concerning the fatal case each general prac- titioner was also requested to give information for comparative purposes about the age, marital status, parity, and current use of oral contraceptives of certain other women in his practice. It was thought that, since considerable demands had already been made on his time, close age and parity matching between the dead woman and these control subjects would not be possible. An extensive search of the practice records would often be involved, in particular when the woman who had died had borne many children. The procedure for obtaining controls was therefore very simple. Each doctor was asked to locate in his files the position which would have been occupied by the late patient's records and which was usually still occupied by records relating to other members of her family. Moving first forwards and then back- wards from that position, the doctor selected the first two sets of case notes encountered relating to women aged 15 to 44 years. Irrespective of whether or not the doctor had all the necessary information about these subjects, they were accepted as controls. Subsequent experience showed that this procedure of selecting two controls at each interview was yielding too few subjects of high parity. Therefore for interviews concerning patients who died after 1 July 1966 four to six controls were obtained at each interview and the selection was also limited to women who were married. In this way information about 1,133 married control subjects aged 20 to 44 years was collected.2 Of these, 17 were known to be pregnant, 28 were of unknown parity, and there was no record of whether or not a further 90 were using oral contraceptives. These 135 controls were omitted from the analysis. ASSESSMENT Many conditions such as prolonged immobility, recent surgery, hypertension, and diabetes mellitus must be regarded as predisposing towards some types of thromboembolic disease. Each case history was therefore carefully examined for evidence of the presence of these or other conditions which might have contributed to the terminal illness. On receipt of each completed questionary the data concerning the patient's age, parity, and drug history were separated from the remaining information to avoid any bias in the subsequent assess- ment. Each case history was then considered independently by three assessors and placed in one of the following categories: Class A.-Patients with no known predisposing conditions. Class B.-Patients with known predisposing conditions who were neither pregnant nor in the puerperium. Class 0.-Patients who were pregnant or had been delivered during the month before the onset of the terminal episode. At subsequent conferences it was found that major disagreement between the three assessors was unusual, and in every case it was possible to reach agreement on classification. RESULTS IN CONTROL SUBJECTS Table I shows the pattern of use of oral contraceptives by the 998 control subjects retained in the analysis, classified by age and parity. Among women aged 20 to 24 years there was a steady rise in the proportion using oral con- traceptives from 9% of those who had never borne children to 44% of those who had borne three or more. The pattern was similar for women aged 25-34 years, though at a slightly lower level throughout the parity range. Among those aged 35-44 none of the 40 nulliparous women were using oral contracep- tives and the proportion among those who had borne fewer than four children was uniformly low. 2 Controls aged 15-19 years were discarded, as none of the deaths studied occurred In that age group. PAGENO="0360" 7190 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-USE OF ORAL CONTRACEPTIVES BY CONTROL SUBJECTS IN RELATION TO AGE AND PARITY Parity Age 20-24 Age 25-34 Age 35-44 All Ages No.* %t No.* %t No.* %t No.* %f 0 1 2 3 4 or more 45 46 32 9 7 8.9 15.2 34.4 1438 S 52 91 172 85 52 5.8 8.8 25.0 30.1 28.8 40 88 141 68 70 0.0 10.2 9.9 11.8 22.9 137 225 345 162 129 - 5.1 10.7 19.7 22.8 27.1 All parities 139 20.9 452 21.0 407 11.5 998 17.1 *Number of women studied. Percentage of women using oral contraceptives. RESULTS IN FATAL CASES Twenty-five deaths occurred during pregnancy or the puerperium (class C). These are not considered in this communication. Fifty-three (17.2%) of the remaining 309 patients were using oral contraceptives at the onset of the ter- minal episode. Five of these 53 women had obtained their oral contraceptives from a family planning clinic, three from a gynaecologist, 39 from their gen- eral practitioner, and six from another general practitioner when their own had declined to prescribe for them. Pulmo~iary embolism (77 deaths) Class A.-Of the 26 patients in this category, only one did not have a post- mortem examination. The standard of diagnostic accuracy is therefore high in this class. Nineteen of the death certificates were signed by a coroner, four by a hospital doctor, and the remaining three by a general practitioner after post-mortem examination. Sixteen of these patients had been taking oral con- traceptives at the onset of the fatal illness Table II). The corresponding number predicted from the experience of control women of like age and parity is only 4.2 and this great disparity in the use of oral contraceptives between the dead women and the control women is statistically highly significant (P'(0.001). Table III shows that the excess of users of oral contraceptives among those women who died was present within broad age and parity groups. No women in this class had been taking any other type of sex-hormone prepa- ration before becoming fatally ill. Class B.-Fifty-one patients who had the following predisposing conditions were allocated to class B: recent surgery (17), prolonged immobilization due to a variety of medical conditions (12), previous thromboembolism (9), car- diovascular disease (8), blood disease (3), and diabetes mellitus (2). Even though many patients had suffered prolonged ill-health, post-mortem examina- tions had been carried out on 43 of them and 20 death certificates were signed by a coroner. It was uncertain whether two of these patients had been using oral contraceptives at the onset of the terminal episode, but nine of the remaining 49 had been doing so (Table II). The corresponding expected number calculated from the control data is slightly smaller (6.8), but the dif- ference between the experience of the study and control groups is not statisti- cally significant. If classes A and B are combined a highly significant excess of oral contra- ceptive users among the women who died is still found (Table II, P'(O.OOl). Errors in the assessment of predisposing conditions cannot therefore be respon- sible for the strong association between death from pulmonary embolism and the use of oral contraceptives. ~ Throughout this report the expected numbers of women using oral contraceptives have been calculated from the data shown for control subjects in Table I. In making any calculation the first step was to classify the dead women, irrespective of known oral contraceptive use, into the same age and parity groups as those shown in Table I. The expected number of oral contraceptive users in each cell of the table was obtained by multiplying the cell total by the corresponding percentage in Table I and dividing the result by 100. The individual cell expected numbers were then summed to give the overall expected number. For tests of significance, the control data shown in Table I were reclassified In nine subgroups by combining adjacent cells containing similar percentages, and the method of Mantel and Haenszel (1959) was applied. PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7191 Coronary thrombosis (205 deaths) Class A.-Post -mortem examinations were carried out in 74 of the 89 patients (83%) in this class, and diagnostic accuracy is therefore likely to be high. Sixty-one death certificates were signed by a coroner, 14 by a hospital doctor, and 14 by a general practitioner. Details of oral contracptive use or parity were unknown for five patients, who have been omitted from the analy- sis shown in Table IV. Of the remaining 84 deaths 18 occurred in users of oral contraceptives while only 11.4 such deaths would have been expected from the experience of the control series. This difference does not, however, quite attain statistical significance (P=O.O~i). Fifteen patients in this class were known to have been obese. None had being using oral contraceptives. The assessors were reluctant to include obesity as a predisposing condition, because body weight and height had not been recorded for all the women who died and for none of the controls. If, however, these patients are omitted from class A the excess of oral contraceptives users among the remainder attains statistical significance (PO.001. Note-The normal x2 test is likely to overestimate the probability of obtaining such extreme results by change, as it ails to take account of the way in which the affected and control patients were matched. A test suggested by Professor J. Finney (personal communication), in which the results for each `set" of cases are scored separately, gives: t=5.3, =57. P<0.001. able in respect of their country of origin and religion, the social class of their iusband, and the interval between the birth of their last child and the onset f the current episode of disease. Differences were, however, recorded in the requency of previous thromboembolic disease, the distribution of obesity, and he prevalence of smoking. Altogether 26 patients reported previous attacks of superficial or deep vein hrombosis or pulmonary embolism-18 during pregnancy or the puerperiurn nd S at other times when oral contraceptives were not being used. Table VI shows that the proportion of affected patients who reported previous attacks (36%) was significantly higher than the proportion of control patients (4%). Among the affected patients the proportion was approximately the same irrespective of the subsequent use of oral contraceptives. This was unexpected because many doctors regard a history of thromboembolism as a contraindica- tion to the use of this type of contraceptive. One hundred and forty-eight patients had never had a previous attack of thromboembolism, and in these women also the use of oral contraceptives was significantly more frequent in the affected group (17 out of 37, or 46%) than in the control group (8 out of 111, or 7%). In these women the prevalence of varicose veins-determined by the woman's history-was approximately the same in both the affected patients and the controls (19 and 24% respectively), and only 3 of the 17 affected women who used oral contraceptives were aware of ever having had varicose veins. These data therefore contradict Rivlin's (1967) suggestion that oral contraceptives produce phlebitis only when vari- cose veins are present. PAGENO="0372" 7202 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE V.-COMPARABILITY OF PATIENTS WITH VENOUS THROMBOEMBOLISM AND CONTROLS Attribute Number of p Thrombo- embolism atients Control Attribute Number of p Thrombo- embolism atients Control Country of origin: United Kingdom 41 82 Religion: Church of England 35 70 Ireland 7 11 Nonconformist 5 14 Other European Westlndies 3 3 9 6 Roman Catholic Otherornone 13 5 27 5 Other 4 8 Total 58 116 Total 58 116 Social class: Nohusbandl 5 6 Interval since last delivery (completed months): 3-11 7 12 I-Il 7 19 12-23 9 28 III 34 70 24-27 14 23 IV 10 18 48 or more 22 39 V 2 3 Not recorded Not applicable (nulliparae) 0 6 2 12 Total 58 116 Total 58 116 1 Divorced, separated, or living a s married. TABLE VI.-HISTORY OF PREVIOUS VENOUS THROMBOSIS OR PULMONARY EMBOLISM IN AFFECTED AND CONTROL PATIENTS (PERCENTAGES SHOWN IN PARENTHESES) Oral Diagnostic group contraceptives Number of patients previous venou bolic disease with history of s thromboem- All women Present Absent fUsed Thromboembolism ~Not used I Total 9 (35) 12 (38) 21(36) 17 (65) 20 (62) 37 (64) 26 (100) 32 (100) 58 (100) fUsed Control ~Not used Total 2 (20) 3 (3) 5 (4) 8 (80) 103 (97) 111 (96) 10 (100) 106 (100) 116 (100) Comparison between frequency of previous attacks (all affected and control patients): x2=28.5, n=1, P<0.001. Comparison between frequency of use of oral contraceptives (affected and control patients without previous attacks): x2=27.0, n=1, P<0.001. Hospital records were too incomplete to be used as a source of information about physical measurement. The women were therefore asked about their height and weight at the time of the relevant hospital admission, and the stated weight was compared with the standard weight given by Billewicz, Kemsley, and Thomson (1962) for women of the same age and height. Table VII shows the mean difference between the stated and standard weights for the affected and control patients. The control women not using oral contracep- tives were, on average, 3 lb. (1.4 kg) above the standard weight for their height and age, but with the use of oral contraceptives the difference increased to 7 lb. (3.2 kg.). Among the affected women who used oral contraceptives the difference was similar, but those women who were not using oral contracep- tives weighed, on average, nearly 13 lb. (5.9 kg.) more than the standard. This large excess was due to the presence of 10 women (32% of the total) who weighed 28 lb. (12.7 kg.) or more above the standard. In each of the three other groups the proportion of such obese women was approximately 10%. Table VIII shows that the affected patients were, on average, heavier smok- ers than the control patients. The difference, however, is statistically not quite significant, and it will be noted that the proportion of women who used oral contraceptives was greater for the affected patients than for the controls in each smoking category. PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7203 TABLE VII.-AVERAGE DEVIATIONS OF STATED WEIGHTS FROM STANDARD WEIGHTS (NUMBER OF PATIENTS SHOWN IN PARENTHESES) Diagnostic group Average deviation from standard weight (lb.) Oral contraceptives Used Not used All women Thromboembolism Control +7.4 (24) +12.9 (31) +7.1 (10) +3.0 (103) +10.5 1 (53)* +3.4 1 (113) Both groups +7.3 (34) +5.3 (134) +5.7 (168) I Weight not known for 3 patients in each diagnostic group. ABLE VIII.-PREVALENCE OF CIGARETTE SMOKING IN AFFECTED AND CONTROL PATIENTS (NUMBER OF PATIENTS IN EACH CLASS IS GIVEN WITH PERCENTAGES IN PARENTHESES) Oral contracep~ Diagnostic group tives Number of cigarettes smoked at onset of episode 0 1-14 15+ Total no. of patients Mean No. of cigarettes smoked Used hromboembolism Not used___ 8(31) 4(15) 4(54) 11(34) 14(44) 7(22) 26(100) 32(100) 15 7 I Total 19(33) 18(31) 21(36) 58(100) 11 7 7 Used ontrol Not used_ - 3(30) 5(50) 2(20) 49(46) 35(33) 22(21) 10(100) 106(100) Total 52(45) 40(34) 24(21) 116(100) 7 Comparison between affected patients and control s, x2=5.13, n=2, 0.10>P >0.05. The data summarized in Tables VI, VII and VIII provide no evidence that revious attacks of disease, obesity, or smoking could have accounted for the ssociation between the use of oral contraceptives and the development of hromboembolism. They accord with other experience suggesting that the risk f thromboembolism is increased by previous attacks and by obesity (Coon and oiler, 19159b; Fleming and Bailey, 1966) and that the use of oral contracep- ives tends to increase weight (World Health Organization, 1966). ias in~ diagnosis An alternative explanation of the results is that a history of the use of oral ontraceptives led to the recognition of thromboembolic disease which would therwise have been missed. It is easy to overlook the diagnosis of both deep em thrombosis and pulmonary embolism (Coon and Coller, 1959a; Medd and leBrien, 1962; Hamilton and Thompson, 1963; Richards, 1966), and the eports of thrombosis in women who used oral contraceptives, which began to ppear in British medical journals in 1961, will have alerted doctors to the ossibility of its occurrence. If this were the explanation, the strongest association should be found in those patients for whom the diagnosis was least evident, as this group would contain patients whose condition was diagnosed only because they were known to have been using oral contraceptives. We have therefore sought to test this hypothesis by classifying the affected patients according to the confidence placed in the diagnosis. For this purpose we made detailed summaries of the records of all 61 affected patients, omitting reference to their contraceptive practice, and submitted these summaries to a colleague (Dr. Frank Speizer), who classified the diagnoses as "possible," "probable," or "certain." No patient was classified as certainly having deep vein thrombosis alone, because none had been submitted to phlebography or vascular surgery (Haeger, Nilsson, and Robertson, 1967). No patient was diagnosed as possibly having both deep vein thrombosis and pulmonary embolism, as the combination of signs in the leg PAGENO="0374" 7204 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and chest was regarded as sufficiently strong evidence to justify classing the diagnosis as at least "probable." Table IX shows that within each disease category the use of oral contracep- tives was no greater, and was indeed less, when the diagnosis was less certain, and that the proportion of affected patients who had used oral contraceptives was higher among those who suffered from the serious condition of pulmonary embolism than among those who suffered deep vein thrombosis alone. It seems improbable, therefore, that the observed association is due to a greater ten- dency to diagnose thromboembolic disease in women who use oral contra- ceptives. Distribution of affected patients by calendar year Table X shows the number of affected women admitted to hospital each year. No trend with time is evident. The numbers each year are small and the changes, though not providing much positive evidence in support, are statisti- cally compatible with the hypothesis that the incidence of thromboembolism is static in women not using oral contraceptives and is rising in step with the number at risk in women who are. It should be noted, however, that the incidence of thromboembolic disease may have been increasing before oral contraceptives were widely introduced (1~Iorrell, Truelove, and Barr, 1963; Loehry, 1966) and the risk of thromboem- bolic disease may vary with the length of time oral contraceptives have been used and with the characteristics of the women who take them. We have evi- dence from one Family Planning Association clinic to show that women who took oral contraceptives in 1964 were, on average, older and more parous than women who took them in 1966, and these and other similar factors may affect the temporal trend. Type of oral contraceptive used and duration of use The contraceptive preparations last in use before the onset of the relevant episode were known for 23 of the affected patients and for eight of the con- trols. These data were compared with expected distributions calculated on the TABLE IX.-CLASSIFICATION OF CERTAINTY OF DIAGNOSIS OF VENOUS THROMBOEMBOLIC DISEASE BY ORAL CONTRACEPTIVE USE OF AFFECTED PATIENTS (THE NUMBER OF PATIENTS IN EACH CLASS IS GIVEN) Certainty diagnosis Deep vein thrombosis Deep vein Pulmonary thrombosis embolism and pulmonary embolism All types of venous thrombo- embolism Oral Contraceptives Used Not used Used Not Used Not Used used Used Not used Possible Probable Certain 2 7 11 15 1 1 2 3 2 5 3 a 6 3 3 8 15 23 9 3 Total 13 22 6 4 8 8 27 34 TABLE X.-NUMBER OF AFFECTED PATIENTS IDENTIFIED EACH YEAR BY ORAL CONTRACEPTIVE USE: AN ES- TIMATE OF CONTRACEPTIVES SUPPLIED IN ENGLAND AND WALES IN EACH YEAR, MEASURED IN WOMAN-YEARS IS ALSO GIVEN Oral contraceptives 1964 1965 1966 Total Used 5 11 11 27 Not used Total Estimate of oral contraceptives supplied in England and Wales (woman-years) 1 9 16 9 34 14 27 20 61 250,000 400,000 600,000 1,250,000 Based on information provided by Intercontinental Medical Statistics, Ltd. (personal communication, 1967) and the Family Planning Association (Hill, personal communication, 1967). PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7205 basis of known supply figures (provided by Intercontinental Medical Statistics Ltd., personal communication, 1967). No indh~ation was obtained that any one contraceptive formulation is more likely to be responsible for thromboembolic disease than the others, though only a marked effect would have been detecta- ble with a few data. None of the affected women had been using sequential preparations; but this was to be expected as only about 2% of the oral contra~ ceptives consumed during 1964-6 were of this sort. Comparison of the duration of use of oral contraceptives was also handi- capped by the small amount of data. We may note, however, that 42% of the women who developed thromboembolic disease (11 out of 26) bad been using oral contraceptives for less than six months, and the corresponding proportion for the control patients was almost identical (4 out of 10). Family history All affected and control patients were questioned about the illnesses and causes of death of their parents and sibs. No significant differences were found between the numbers of relatives who had died from a variety of causes. There were, however, small differences in the reported frequncy of morbidity from phlebitis among both mothers and sisters. Thus nine mothers and seven sisters of the affected women and nine mothers and two sisters of twice as many control women were reported to have suffered from non-fatal phlebitis. These differences may indicate family predilection for venous thromboembolism or they may be the result of preferential recall by the affected subjects. There was no suggestion that a positive family history might be more common among affected women who used oral contraceptives than among affected women who did not. Estimate of incidence Data provided by the North-West Metropolitan Regional Hospital Board indicates that the hospitals participating in the study include approximately 60% of the Board's female acute general medical and surgical beds. All but one of the affected patients resided within the Board's catchment area at the time of admission to hospital, so that we can reasonably relate our findings to the population of that area. The total number of woman-years at risk can be estimated by reducing the size of the total female population aged 16-40 years for the Board's area in 1965 (Registrar General, 1967) by appropriate factors to allow for the propor- tion of single, widowed, pregnant, and puerperal women, and then multiplying the result by three. No adjustment can, however, be made for the other factors taken into account in this study, such as the number of women with relevant chronic diseases or in the postoperative or postmenopausal state; but the number is unlikely to be large (not more, we would think, than 10% of the population). An estimate of the years at risk for women who took oral contra- ceptives can be made from supply figures for the country as a whole, on the assumption that women resident in the Board's area were representative of the whole population with respect to their use of oral contraceptives; and an estimate of the number of affected patients who did and who did not use oral contraceptives can be obtained by multiplying the observed numbers by 1.67, on the assumption that the study covered 60% of the relevant hospital beds and that the one affected patient who was not resident in the area counterbalanced one affected resident who was treated elsewhere. On this basis the annual attack rate of venous thromboembolic disease, with- out evident cause but of sufficient severity to require hospital admission, is about 5 per 100,000 (or 1 in 20,000) women who do not use oral contracep- tives, and is about 10 times higher (47 per 100,000, or 1 in 2,000) in women of similar marital status who do. If the calculations are limited to women with- out previous venous thromboembolic disease the annual attack rate is reduced to about 1 in every 3,000 women who use oral contraceptives, but the relative risk is not materially altered. The two patients taking Metrulen-M have been omitted from these calculations as the use of this drug is not known for the estimated population at risk. Relative risks can also be calculated directly from the hospital data given in Table IV. From these data the risk among women who use oral contraceptives is calcualted to be about nine times that among women who do not (26/32 divided by 10/106). These two values for the relative risk, which use different PAGENO="0376" 7206 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY sources of material for estimating the use of oral contraceptives in the general population, are in close agreement. II. CEREBRAL THROMBOSIS Women who were treated in hospital for cerebral thrombosis should have been recorded in the hospital diagnostic index under International Classifica- tion of Diseases rubric 332. This diagnosis, however, is difficult to establish accurately and some cases could be classified under other heads. All case notes were therefore examined relating to diagnoses coded under other rubrics for cerebrovascular disease-that is, numbers 331 to 334-for the period 1964-6. A preliminary check showed that patients coded under rubric 330 (subarachnoid haemorrhage) almost always had blood-stained cerbrospinal fluid, and this rubric was omitted. At three hospitals the diagnostic indexes provided incom- plete information about the sex and age of the patients. It was impracticable to review all the notes coded 331 to 334 at these hospitals and our results relate only to patients treated at the other 16. Firstly, all notes excluded relating to women who were single or widowed, postmenopausal, sterilized, pregnant, or puerperal, or had a predisposing condi- tion adequate to account for the development of a cerebrovascular distrubance. Secondly, notes were excluded which related to episodes where there was proof that the diagnosis was one of haemorrhage or which were obviously not due to cerebral thrombosis. Abstracts of the remaining 16 sets of notes were then pre- pared and were reviewed by a neurologist (Dr. Gerald Stern) without knowl- edge of the patients' contraceptive practice. Nine patients were accepted as having had a cerebral thrombosis, but the diagnosis was regarded as certain (angiographic evidence of arterial occlusion at a site which could be related to the focal signs) in only two. The nine patients were interviewed in their homes (five) or completed postal questionaries (four) in the same way as the patients suffering from venous thrombosis or pulmonary embolism. Five (including one in whom the diagnosis was certain) had been using oral contraceptives during the month before they became ill and for periods ranging from one week to four years previously. For comparison we have used the control patients selected to match the women with venous thromboembolic disease. Of these, 10 out of 116 used oral contraceptives (see Table IV), so that the crude number expected among the women with "cerebral thrombosis" would have been less than one (0.8). If account is taken of the age, parity, and year of admission of the women with "cerebral thrombosis" the expected number (1.0) is hardly altered. Even with these few patients the difference between the observed and the expected num- bers of women using oral contraceptives is statistically significant (P<0.01). III. CORONARY THROMBOSIS It was again impracticable to review all the notes coded under International Classification of Disease rubric 420 (arteriosclerotic heart disease, including coronary disease) at three hospitals, because the diagnostic index was incom- plete and our results relate only to patients treated at 16 hospitals during the period 1964-6. All notes were excluded relating to women who were single or widowed, postmenopausal, sterilized, pregnant, or puerperal, or had a predisposing condi- tion; the remainder were classified into three diagnostic groups-angina pecto- ris only, possible coronary thrombosis (only ST or T changes in the electrocar- diogram, but showing progression; serum enzymes either not done or offering no support to the diagnosis), and certain coronary thrombosis (pathological Q waves in the electrocardiogram or only ST or T changes accompanied by sup- porting serum enzyme changes). None of the notes relating to patients in these categories made any mention of oral contraceptives; there was therefore no risk of bias, and the classification was made without reference to others. Sixteen women were accepted as having had coronary thrombosis without predisposing cause. Three had died and were excluded from the study because they could not be interviewed; of the remainder, the diagnosis was regarded as certain in four. All 13 patients were either interviewed (12) or had com- pleted a postal questionary (1), and none had taken oral contraceptives during the month before the onset of their disease. The number expected to have done PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7207 from the experience of the control subjcts selected to match the patients ith venous thromboembolic disease, was 0.7.~ IV. DISCUSSION ulmonary embolism and deep vein thrombosis Retrospective studies of hospital patients are always open to bias, and the esent study is no exception. Both the affected and the control patients were lected from larger groups by procedures that were certainly not random, and formation about the use of oral contraceptives was obtained by inquiry of e patient and so was dependent on the accuracy of her memory. The evi- nce, however, suggests that these sources of bias have not materially ected the results. Firstly, women were selected for inclusion only for objective reasons, and y subsequent decision to exclude them for subjective reasons-for example, e presence of doubtfully significant predisposing disease-was taken in igno- nce of their contraceptive practice. Secondly, the proportion of women with ep vein thrombosis or pulmonary embolism who used oral contraceptives was eater when the diagnosis was firmly established than when the diagnosis as less certain-and the contrary would be expected if diagnosis and referral hospital were biased by knowledge of the women's contraceptive practice. hirdly, the proportion of control women who said they were using oral con- aceptives (9%) was close to the proportion of married women estimated to e them: (1) from knowledge of available supplies (approximately 11% at es 15 to 44 years in 1966~); and (2) from the experience of women of gen- al practice lists (7% at ages 15 to 49 years in 1965-66 4)* Fourthly, the pro- rtion of women treated for pulmonary embolism who said they were using al contraceptives (54%) is close to that recorded among women aged 20 to years who died of pulmonary embolism in England, Wales, and Northern eland in 1966 (62%, Inman and Vessey, 1968). We conclude, therefore, that e method of investigation has not materially biased the results and that the sociation between the use of oral contraceptives and the development of deep in thrombosis or pulmonary embolism is real. Two considerations suggest that the association reflects cause and effect. ~rstly, we have been unable to find any evidence of a third factor which uld account for the association by being related to both. Many factors which use the disease or influence the use of contraceptives were excluded by the sign of the study. Two-previous attacks of thromboembolism and obesity- ere not excluded; both were found more commonly in affected patients, but ither was particularly associated with the use of oral contraceptives. Others ere either unrelated to the disease or the relation was so weak that it could ye had no material effect on the results. Secondly, there is evidence that oes- ogens can cause thromboembolism in other circumstances (Daniel, Campbell, d Turnbull, 1967; Oliver, 1967; Bailar, 1967; Schrogie and Solomon, 1967). Further evidence should eventually be obtained from examining trends in e incidence of the condition and its geographical distribution, particularly as ie use of oral contraceptives has become more common than it was in 1966. he evidence, however, will not be easy to interpret, as the use of oral contra- ptives is only one of many potential causes of thrombosis, and changes in e prevalence of the other factors may mask its effect. If, as we now conclude, the use of oral contraceptives is a cause of venous ~romb6embolism, three questions arise. How big is the risk? Is it concentrated n a particular section of the population? And is it attributable to any one mponent? The results of our study are quantitatively similar to those obtained by the oyal College of General Practitioners (1967) and the Committee on Safety of rugs (Inman and Vessey, 1968). In the first of these studies the data relate mainly to superficial phlebitis, nd it may be noted that the total morbidity from all types of thromboembolic isease was approximately 2 per 1,000 women per year and that the risk of enous thrombosis or pulmonary embolism in women who were taking oral ontraceptives was increased approximately threefold. Only six women aged 15 This number is less than that expected among nine patients with "cerebral thrombo- is" because those with coronary thrombosis were, on average, older. Medical Research Council (1967). PAGENO="0378" 7208 COMPETITIVE PROBLEMS IN THE DRtJG INDUSTRY to 39 years, however, were recorded as having a deep vein thrombosis or pul- monary embolism when neither pregnant nor puerperal (Crombie, personal communication, 1967); three used oral contraceptives and three did not, and two in each category were admitted to hospital. The resultant annual hospi- tal admission rates (approximately 60 per 100,000 women who used oral con- traceptives and 5 per 100,000 women who did not; are subject to large stand- ard errors, but are none the less similar to those calculated in the present study (47 and 5 per 100,000 respectively). In the second study (Inman and Vessey, 1968) the data relate only to deaths and, in the case of pulmonary embolism, women who had suffered a previous thromboembolic episode were classified with women who had other predisposing conditions. Again, however, it may be noted that the relative risk among women who used oral contraceptives was increased about eight times, whereas in our study the relative risk of pulmonary embolism was increased approximately 12 times. In any disease which is as rare as "idiopathic" deep vein thrombosis or pul- monary embolism it is always possible that the condition reflects an idiosyn- cratic reaction due to the patient's genetic constituttion. Our data do not rule out this possibility, but neither do they provide any strong support for it. In particular there is no suggestion, either in this study or in that of the Com- mittee on Safety of Drugs, that venous thromboembolism tends to occur shortly after beginning the use of oral contraceptives-as might be expected if the reaction was idiosyncratic. The data are also too few to give any clear answer to the question of the relative effect of the different combinations of oestrogen and progestogen, but neither study provides any indication that there is likely to be much difference between them. Cerebral and coronary thrombosis Our data contribute little new information relating to the occurrence of cere bral and coronary thrombosis. Only nine previously healthy women who wer married and aged 40 years or under were treated for "cerebral thrombosis" and 16 (including three who died) from coronary thrombosis in 16 large hospi tals in a three-year period. The diagnosis of cerebral thrombosis is difficult to establish with certainty, and it is possible that the majority of patients in our small series suffered from some other intracranial condition. It is notable, however, that five of the nine patients had been using oral contraceptives when their disease began. This finding in itself implies little, but taken in con- junction with the similar findings of the Committee on Safety of Drugs (Inman and Vessey, 1968), of Bickerstaff and Holmes (1967), and of Illis et al. (1965), it justifies the conclusion that oral contraceptives can be a cause of episodes of cerebrovascular insufficiency. Only Jennett and Cross (1967), who studied 26 non-pregnant women suffering from "ischaemia in the carotid terri- tory" during 1961-5, failed to find any evidence of an association. Most of the nine patients in the present study suffered a mild illness fol- lowed by a good recovery. At the time of interview several of the patients complained of minor residual disabilities, but only one was still severely inca- pacitated by a slowly recovering left hemiplegia. She had suffered bilateral internal carotid artery thrombosis in September 1966, demonstrated by angiog- raphy, and had previously taken an oral contraceptive for several months. Despite the fact that changes have been demonstrated in carbohydrate metabolism and the pattern of serum lipids in women taking oral contracep- tives, which might be regarded as conducive to coronary thrombosis (Wynn and Doar, 1966; Wynn, Doar, and Mills, 1966), epidemiological studies have as yet provided very little confirmatory evidence. A few case histories have been reported-for example, Hartveit (1965)-and a number of other studies have shown an excess mortality from coronary thrombosis in men treated with oes- trogens for various reasons (see Schrogie and Solomon, 1967). The study of the Committee on Safety of Drugs (Inman and Vessey, 1968) is compatible with some increased risk under 35 years of age, but the 13 patients with non- fatal coronary thrombosis in our study (only five of whom were under 35 years of age) offer no further support. We conclude that the existence of a risk of coronary thrombosis is not proved. If, as our data suggest, women who use oral contraceptives are somewhat heavier smokers than average, this factor will need to be taken into account in interpreting future findings (Dorken, 1967). PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7209 V. SUMMARY AND CONCLUSIONS Married women aged 16 to 40 years discharged during 1964-66 from 19 rge general hospitals in the North-West Metropolitan Regional Hospital oard area with a diagnosis of deep vein thrombosis or pulmonary embolism ~ithout evident preclisposing cause were identified by means of the hospital iagnostic indexes. They were subsequently interviewed in their homes, when quiries were made about their past medical, obstetric, social, family, and ontraceptive histories. For comparison, married control patients admitted to the same hospitals ith acute surgical or medical conditions, or for elective surgery, and matched ith the affected patients for age, parity, date of admission, and absence of ny predisposing cause of thromboembolic disease, were also identified and ~milarly interviewed. Of 58 affected patients 26 (45%) had been using oral contraceptives during e month preceding the onset of their illness while only 10 of the correspond- g 110 controls (9%) had been doing so. From these data it is calculated that the risk of hospital admission for enous thromboembolism is about nine times greater in women who use oral ntraceptives than in those who do not. If national supply data are used for timating the frequency of use of oral contraceptives in the general popula- on it is calculated that about 1 in every 2,000 women using oral contracep- yes are admitted to hospital each year with "idiopathic" venous thromboem- olism in comparison with about 1 in every 20,000 women not using them These results are not thought to have been produced by bias or by any mmon factor responsible both for the use of oral contraceptives and the pro- uction of thromboembolism, and it is concluded that oral contraceptives are a use of the disease. At 16 hospitals women suffering from coronary or cerebral thrombosis were so studied. Five of nine patients who survived an attack of "cerebral throm- sis" had been using oral contraceptives during the month preceding their ill- ess. Taken in conjunction with other similar findings, it is justifiable to con- ude that oral contraceptives can also be a cause of cerebrovascular sufficiency. Of the 13 women who survived an attack of coronary thrombosis without ident predisposing cause none had been using oral contraceptives. We should like to express our thanks to the many people who have helped ith this work, and especially to Miss Keena Jones, who traced and inter- iewed the patients; to Miss Rosemary Emerson, who gave technical assistance roughout; to Dr. S. Mackenzie, who provided information about hospitals in e North-West Metropolitan Regional Hospital Board; to Dr. F. E. Speizer nd Dr. G. M. Stern, who assessed many of the case histories; to the consul- nts and general practitioners who allowed us to study patients under their re; to the hospital records officers and coding clerks who gave willing assist- nce in many different ways; and to the patients themselves, who gave up eir time to answer our questions. References ailar, J. 0. (1967). Lancet, 2, 560. ickerstaff, E. R., and Holmes, J. M. (1967). Brit. med. ~ 1, 1, 726. illewicz, W. Z., Kemsley, W. F., and Thomson, A. M. (1962). Brit. J. prey. soc. Med., 16, 183. oon, W. W., and Coller, F. A. (1959a). $urg. Gynec. Obstet., 109, 259. oon, W. W., and Coller, F. A. (1959). Surg. Gynec. Obstet., 109, 487. aniel, D. G., Campbell, H., and Turnbull, A. 0. (1967). Lancet, 2, 287. orken, H. (1967). Munch. med. Wschr., 109, 187. lemirig, H. A., and Bailey, S. M. (1966). Brit. med. J., 1, 1322. aeger, K., Nilsson, I.M., and Robertson, B. (1967). Brit. med. J., 3, 493. amilton, M., and Thompson, E. N. (1903). Postgrad. med. J., 39, 348. artveit, F. (1965). Brit. med. J., 1, 60. his, L., Kocen, R. S., McDonald, W. I., and Mondkar, V. P. (1965). Brit. med. J~, 2, 1164. nman, W. H. W., and Vessey, M. P. (1968). Brit. med. ,1., 2, 199. ennett, W. B., and Cross, J. N. (1967). Lancet, 1, 1019 PAGENO="0380" 7210 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Loehry, C. A. (1966). Brit. med. J., 1, 1327. Medd, W. E., and McBrien, D. J. (1962). Laneet, 1, 944. Medical Research Council (1967). Brit. med. J., 2, 355. Morrell, M. T., Truelove, S. C., and Barr, A. (1963). Brit. med. J., 2, 830. Oliver, M. F. (1967). Lancet, 2, 510. Registrar General of England and Wales (1967). Statistical Review of Eng- land and Wales for the Year 1965, Part II. H.M.S.O., London. Richards, R. L. (1966). Brit. med. J., 2, 217. Rivlin, S. (1967). Brit. med. J., 3, 864. Royal College of General Practitioners (1967). J. roy. gen. Practit., 13, 267. Schrogie, J. J., and Solomon, H. M. (1967). J. chron. Dis., 20,675. World Health Organization (1957). Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death. Geneva. World Health Organization (1966). TVld Hith Org. techn. Rep. Ser., No. 326. Wynn, V., and Doar, J. W. H. (1966). Lancet, 2, 715. Wynn, V., Doar, J. W. H., and Mills, G. L. (1966). Lancet, 2, 720. [From Chemical & Engineering News, March 27, 1967, pp. 44-49] RESEARCH-BIOCHEMISTRY OF THE PILL LARGELY UNKNOWN MOLECULAR BIOLOGY AND INTERMEDIARY METABOLISM ARE SLOWLY BECOMING CRITICAL AREAS FOR STUDYING MECHANISMS OF ORAL CONTRACEPTIVES The 5 to 7 million women in the U.S. who practice birth control by oral con- traception have two new versions of "the pill" to choose from: Orthos 1 mg. Ortho-Novum and Syntex's 1-mg. Norinyl-1 (see table). Yet, for all the interest and energy that companies are putting into developing oral contraceptives (the Food and Drug Administration is studying about 30 more possibilities), and for all the efforts tO upgrade safety surveillance, nobody knows fundamentally how the drugs work. For the biochemistry of inhibiting conception by taking drugs remains one of reproductive physiology's more fogbound research areas. And little wonder. Each woman who uses the pill is daily swallowing tablets containing various synthetic formulations of sex hormones of the type she would routinely produce during pregnancy. Being biochemically pseudopreg- nant, therefore, she fails to ovulate. Failing to ovulate, she can't conceive. When faced with comprehending this biochemical interplay of brain, glands, and genitalia, most scientists turn to work that leads to quicker publication- such as extrapolating the results of urine and blood analyses. Fortunately, all is not blood and urine. Molecular biology and intermediary metabolism are slowly becoming the critical areas for studying the mechanisms of both the natural sex hormones and their oral contraceptive counterparts. Work of this type is moving ahead at such centers as the Population Council in New York City; the Universities of Chicago, Wisconsin, and Michigan, and Washington University in St, Louis. Also, to a limited extent, at FDA, the National Institutes of Health, the Worcester Foundation for Experimental Biology, Oxford University (England). San Diego Naval Hospital, and Cana- da's Food and Drug Directorate. Several laboratories are probing the action of estrogens and progesterone at the protein synthesis level. Some are at long last tracing steroidal pathways through the cell with tritiated agents. Other groups are trying to relate neuro- chemical triggering mechanisms to hormone production. Still others are study- ing the effects of estrogens, progesterone, and their synthetic counterparts on the structural chemistry of target tissue such as uterus, ovary, and pituitary. All this activity, though really just beginning, could one day lead to a sort of biochemical systems analysis of steroidal interactions. It also could help to clear up the mass of. confusion over the pill's long-term effects in connection with diabetes, cancer, diseases of the circulatory system, and various interac- tions possibly too subtle to be noticed now. And confusion there is. The chemical manipulation of the woman's sex cycle by synthetic estrogens, synthetic progesterones (progestins), and future non- steroidal contraceptives has posed questions of ultimate effects on her biochem- istry and physiology. Moral questions aside, millions of women, their husbands, and a high percentage of their physicians express qualms over whether several unresolved possible risks outweigh the convenience. PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7211 The World Health Organization lent authority to such apprehension in a port on oral contraceptives about 18 months ago. "There is at present no equate explanation for the oral activity of these compounds or of their fluence on secretion and metabolism. There have been reports of an apparent se in pregnancy rates after cessation of combined treatment, an increase in ucose tolerance (with consequent risks of diabetes mellitus), an increase in agulability of blood, and liver disturbance. All these phenomena need to be vestigated." SYNTHETICS MORE ACTIVE ORALLY THAN NATURAL AGENTS Progesterone is weak when taken orally. The ethynyl and other changes at 17, plus removal of the angular methyl between rings A and B, impart oral .tivity of progestins. Chlorine or methyl at C-6 also adds to oral potency. sition of norethynodrel's double bond lessens possible androgenic action. Natural estrogens are also weak acting when taken orally. Adding an ethynyl C-17 eases passage of the compound from the intestines into the blood stream, e concept holds, allowing low dosages. nthetic progesterones OH Norethynodrel Norethindrone Chiorinadinone acetate C113 C=o ~CH O=OO~ Norethindrone acetate ~CH Ethynodiol diacetate Medroxyprogesterone acetate Dimethisterone PAGENO="0382" 7212 COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY ~atura1 estrogens Synthetic estrogens In contrast, however, clinical data gleaned from observation and research o thousands upon thousands of women point to no apparent relationship betwee contraceptive therapy and cancer, circulatory system blockages (thromboer bolic diseases), thryoid gland abnormalities, and damage to the ovaries, uteru~ or Fallopian tubes. This enormous outpouring of safety data led a special FD panel on oral contraceptives last August to declare the pills "not unsafe" fo human use (C&EN, Aug. 15, 1966, page 19). But it didn't close the door on th possibility of such effects on some particularly susceptible women. Pharmacologists assert that the oral contraceptives occupy a new niche i drug use. Their presence, in many cases for years, affects the sex endocrinol ogy of healthy women during the prime of their reproductive lives. Not onl do they substitute for woman's natural hormonal secretions but, in suppressin ovulation, they also jam the production of her gonadotropic (fertility regulat ing) hormones: follicle stimulating hormone (FSH) and luteinizing hormon (LII), both glycoproteins. Also, they alter carbohydrate metabolism. An chances are that they affect the pattern of cholesterol metabolism, since tha sterol plays such a central and critical role in the synthesis of all body ster oids. In short, the ramifications of oral contraceptive use are immensely wide spread. The problem with studying the pill is that little enough is known abou normal steroid metabolism per se. Progestin function, for example, seems t differ from dose to dose, from animal to animal, and even from ethnic grou to ethnic group, says Dr. Gabriel Bialy of the Worcester Foundation fo Experimental Biology. Moreover, the effects on target tissue aren't clean mapped out. Effects of the synthetic estrogens-mestranol and ethynylestradiol-are a little less fuzzy. These do indeed suppress ovulation, probably via the hypothalamus, by inhibiting production of a protein that triggers secretion of gonadotropin in the pituitary. And they're considerably more powerful than the progestins (see dosages on table). With this background-the question of subtle dangers and the purely aca- demic fascination-specifically what headway are scientists making toward unraveling this complex biochemistry? The story might well begin at the TJni- versity of Chicago's Ben May Laboratory for Cancer Research, in the labora- tory of Dr. Ellwood V. Jensen. Organic chemist Jensen was the first to demonstrate the existence of a sub- stance he calls estrogen receptor in the cells of certain target tissue. He remembers his surprise at the swiftness and intensity with which the receptor Esthiol ~CH Mestranol Ethynylestradiol PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7213 collected and concentrated estradiol in uterine, vaginal, pituitary, and estrogen- dependent tumor tissue. "We studied testo~terone and progesterone, too," he adds, "but found that only estrogen had such remarkable affinity for this material, as well as certain synthetic estrogens such as hexesterol. Estrogens seem to bind to the receptor and exert their action without undergoing chemical transformation." Recent studies by Dr. Jensen and colleague Peter Jungblutt indicate that the receptor is a macromolecule containing protein, phosphorus, ribose, and sulfhy- dryls (which appear essential to the binding). The receptor also seems to be part of the nuclear membrane. As an interesting sidelight, Dr. Jensen recently reported on the interaction between the receptor protein and the oral contra- ceptive estrogen mestranol. It turns out that mestranol itself has little affinity for the receptor, but undergoes demethylation in the liver to form ethynyles- tradiol, which does bind. Dr. Jensen's studies have helped build the base for the work on the cellular dynamics of estrogens being pursued a quick hop away in Madison, Wis. There, Dr. Gerald C. Mueller of the McArdle Laboratory for Cancer Research at the University of Wisconsin is using uterine tissue as a model system for studying Jensen's hormone receptor complex in the broader context of the role of estrogens in protein synthesis. PAGENO="0384" 7214 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Oral contraceptives mimic pregnancy, act at various sites -~ Brain (cortex) May interfere with hi.ogenic amine activity ~-Hypothalamus May block production of gonadotropic releasing factor, a protein ~ Anterior Pituitary Known to inhibit secretion of luteinizing hormone and/or follicle stimulating hormone `(1 May interfere , with ovary 4" response to LH and~jI Acetate ~-.. Cholesterol May change endometriurri to prevent fertilization fertilized egg Ovary Fo1lic~e Cor~uz~~. luteum Estrogens (start Progesterone and May affect growth estrogens cholesterol mechanism in (maintain ~ met~ olisrn by endometrium) endometrium or feedback ppocess healthy ~ pregnancy) thus indirectly rus ~ affect steroid synthesis May render mucus compo sit~lon unfavorable to sperm transport Fallopian tubes ~ Cervix May alter secretion mechanism and affect egg movement PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7215 All of the oral contraceptives now on the market are designed to mimic pregnancy. Since a pregnant woman does not ovulate, there are no subsequent eggs to fertilize and hence no multiple pregnancies. Normally, the female part of the reproductive process starts with physiologically timed stimuli that reach the brain (cortex), which, via the hypothalamus, stimulates the pituitary to secrete follicle-stimulating and luteinizing hormones (FSH and LII). These hormones are involved in the growth of ovarian follicles, rupture of the folli- cle to release its egg, secretion of the female sex hormone estradiol (an estro- gen), change of the follicular cell into the corpus luteum, and secretion of pro- gesterone. Estradiol is involved in the growth of the uterine lining (endometrium) ; progesterone is involved in preparing the lining for implanta- tion and nutritive support of the fertilized egg and in preventing the develop- ment of more follicles and eggs. The natural estrogens and progesterone, secreted by the ovary and later the placenta, inhibit the secretion of FSH and LII during pregnancy and thus prevent ovulation. When a nonpregnant woman ovulates and fertilization does not take place, secretion of progesterone stops, the uterine lining breaks down, and sloughs off. This is menstruation. The entire cycle in the nonpregnant woman takes about 28 days. The synthetic estrogens and progestins in the birth control pills produce the same effects as the natural hormones. Their basic difference is that they are modified chemi- cally so that they can enter the woman's system when taken orally. Two types of birth control pills (and treatments) are on the market: combined and sequential. In combined treatment, each pill contains both estrogen and proges- tin. Generally, the woman takes one pill a day for 21 days, stops for seven days (menstruation period), and resumes taking the pills. In sequential treat- ment, she takes only an estrogen for 16 days, then a combination pill for five or six days (depending on the product). She then stops until the 28th day before resuming. Some months ago, Dr. Mueller and his group showed that estrogen sparked the growth of uterine tissue by direct effect on protein synthesis, through stepped-up production of RNA (ribonucleic acid) in the nucleus. They noticed that there was an increase in RNA polymerase activity-the enzyme which catalyzes the RNA synthesis-just after estrogen was added. But of much interest, in their opinion, is that this higher polymerase activity correlated with the production of protein elsewhere in the cell. In other words, two events were taking place: Protein was being produced somewhere else in the cell; it was affecting the synthesis of RNA via its polymerase. "We interpret this to mean," Dr. Mueller says, "that this other protein is modifying the activity of the polymerase because if we decrease protein we stop the activity of the polymerase." Where does estrogen fit into this process? Mueller thinks that it's either facilitating the manufacture of the other protein or helping to transport it to the polymerase area. As for the receptor protein, it could well be acting as a carrier of the estrogen to the site of action. Progesterone's action is an even bigger mystery. But work by Dr. Walter G. Weist of `~Vashington University (St. Louis) medical school is uncovering some clues. In labeling experiments, he has found that progesterone, like estrogen, also encounters a receptor in uterine cells during the progesterone-dependent proliferative phase of endometrial growth (when the endometrium is being readied to receive the fertilized egg). Studies of the type being done by Dr. Jensen, Dr. Mueller, and Dr. Weist-as well as the related research of Jack Gorski of the University of Illinois and Sheldon Segal of the Population Council-are indeed scarce in endocrinology today because they're at the level of molecular biology. But this is the trend, and rather a necessary one, in the opinion of Dr. Weist. "Steroid distribution studies, too, are a must," he says. "That is, it must be determined where they tend to distribute in the target cell, how and to what they are bound, and their metabolic fate. The big hooker is how you assess the physiological results of cell hormone interaction." Hookers do indeed abound in this field. For example, in vitro studies of ster- oid metabolism could clear away dozens of parameters that muddy results obtained with whole tissue: But all attempts to isolate reaction systems in the necessary lipid environment have meant destruction of one enzymic component or another. Moreover, cell biologists haven't succeeded in growing target tissue outside the cell. Some work along this line is being pursued at Worcester 40-471 0-70-pt. 17-25 PAGENO="0386" 7216 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Foundation, but so far without astonishing success. Needed is a chemical medium that prevents the cells from reverting as they do with maddening rou- tine to a primitive, unrecognizable state. But metabolic studies are beginning to emerge from the what-goes-in-w-hat comes-out stage into the what-happens-inside phase. Dr. Donald S. Layne of Canada's Food and Drug Directorate, Ottawa (a counterpart of the U.S's FDA), is examining changes in the chemical struc- ture of progestins by some inherent action in the tissues that localize them (liver, kidney, and target organs). He has found, in one study, that norethynodrel is peroxidized in the blood stream shortly after administration. "This could implicate the blood as an important site of metabolism of norethynodrel," he reported recently. "Fur- ther," he says, "the hydroperoxy intermediate has recently been shown to be as potent an ovulation inhibitor as norethynodrel itself, although it has little progesterone-like activity. This indicates that classical progestogenic action is not necessary for contraceptive* action." Work on how the steroids affect the structural chemistry of target tissue has come out of the U.S. Naval Hospital in San Diego, Calif., under Dr. Thomas B. Lebherz. His group has found, for example, that the normal buildup of endometrium involves polymerization of acid mucopolysacharides, the so- called "ground substance" material that structurally fortifies living tissue. Such a physical framework is needed to support the thickening web of. blood vessels that bring nourishment to the fertilized egg after implantation. With progesterone, Dr. Lebherz has found, the ground substance depolymer- izes, a sol state ensues, and the softened endometrium (also undergoing a phase of intense secretion) facilitates implantation of the fertilized egg. Dr. Lebherz theorizes that with oral contraceptive progestins, which in low doses apparently prevent implantation, the sol-gel effect via the acid mucopolysac- charides is thrown out of phase so that, before the sol effect sets in, the egg has already arrived and failed to implant. FDA's Bureau of Science (now in the process of redefining its mission) is making modest efforts toward getting at some of the scientific issues that could lead to a deeper insight into mechanisms. But much of this work is pre- liminary and is hindered by FDA's notorious manpower shortage. Anyway, under Dr. Ernest Umberger at the Bureau of Science, scientists are beginning to look into such areas as the effects of steroids on liver enzymes, the role of receptor protein in estrogen and progesterone metabolism, and uptake of estro- gen by the hypothalamus. In a study on hamster ovulation, Dr. Umberger's group has found that monoamine oxidase prevents ovulation at the hypothala- mus level by blocking release of the luteinizing hormone releasing factor. Sev- eral laboratories, incidentally, have tried to characterize this factor but so far can do no better than call it a protein. SEVEN DRUG FIRMS MARKET ORAL CONTRACEPTIVES UNDER EIGHT BRAND NAMES Product Manufacturer FDA clearance Progestin Estrogen Enovid 0. D. Searle June 1960 NorethynodreL - - - 9.85 mg_ Mestranol 0.15 mg. Do do March 1961 do 5mg do 0.075mg. Enovid-E do February 1964 do 2.5 mg do 0.1 mg. Ortho-Novum Ortho pharma- May 1962 Norethindrone~. 10mg do 0.06 mg. ceutical. *Do do October 1963 do 2mg do 0.1 mg. Norinyl Syntex March 1964 do 2 mg do 0.1 mg. Norlestrin Parke-Davis March 1964~~ Norethindrone 2.5 mg -- - Ethynyl-estradioL - 0.05 mg. acetate. Provest Upjohn August 1964~ - Medorxyprogester- 10 mg do 0.05 mg. one acetate. Oracon 1 Mead Johnson~ April 1965 Dimethisterone.~ 25 mg do 0.1 mg. C-Quens 1 Eli Lilly April 1965 Chlormadinone 2.0 mg~.. Mestranol 0.08 mg. acetate. Ovulen 0. D. Searle March 1966..... Ethynodiol 1 mg do 0.1 mg. diacetate. Ortho-Novum Ortho pharma- December 1966 Norethindrone~.... 2 mg do 0.08 mg. SQ.' ceutical. Ortho-Novum-1 do February 1967 do 1.0 mg do 0.05 mg. Norinyl-1 Syntex February 1967 do 1.0 mg do 0.05 mg. 1 Sequential; all others are combination type. PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7217 What appear now to be the future patterns of basic research in the sex steroid-oral contraceptive field? Dr. Gregory G. Pincus of Worcester Foundation thinks ovulation mechanism studies are the vogue-to-be. "The locus of action seems to be the central nervous system but nobody knows where," he told C&EN. Dr. Goeffrey Harris of Oxford University has recently shown in rabbit studies that the primary site of action could well be at a higher level than the hypothalamus. There seem to be connections between such nervous system metabolites as serotonin, noradrenaline, and prostaglandin and the hypothal- amic control of ovulation. One typical idea is that biogenic amines are respon- sible for inhibiting ovulation and that the sex steroids block breakdown by amines, thereby causing suppression of gonadotropin. Dr. Pincus thinks such mechanism studies must be related to all types of ovulation inhibitory agents alone and combined. The overall picture that can be drawn after discussions with individuals in basic endocrinology laboratories, in industry and in Government is lack of agreement on exactly what paths to take in exploring all the ramifications of oral contraception mechanisms. One scientist throws his hands up over the hope of making any immediate headway. The field is too volatile, he says, products are changing, events in the field don't stand still long enough to even set up the proper experiments. Steroid metabolism work is simply confoundedly difficult. Only clinical studies, at least for this era, yield the quick results most investigators in the field seem to want. Adds another scientist from a private research foundation: "The trouble in this field is that aside from purely physiological and pharmacological consider- ations, you know that almost all investigations are done in mutual vacuums. All specify one drug or another; there's little comparative work in the same lab, no unified approach. "Purely independent ~vork is difficult because so much of it is supported by industry. Government takes months to respond to a proposal. Another hin- dance to objective results, and I think this ought to be said, is that too many investigators have too personal an interest in the drugs they work with. All in all I get the feeling that the experimental aspects of this field are so fluid and so controversial that you must be careful over who says what and why he says it." Whether the scientists do indeed prejudge their studies is something nearly impossible to document. But what is needed is better research coordination and improved rapport between biochemists, clinicians, and physiologists. "Another of the troubles in this field," one scientist told C&EN, "is. that many of the big names in steroids frown on basic work on the pill. Those that go ahead with such research immediately get tagged as a toxicologist, or worse yet, a commercial boy. It's ridiculous, but that's the attitude of mind." Many scientists think the Government is the logical place for a coordinated program to understand all aspects of oral contraceptive action. But no such program exists, despite the recommendation of a special advisory committee to establish one a couple of years ago in the National Institute for Child Health and Human Development. The special advisory committee was asked to sug- gest research programs in the then new institute, and among the recommenda- tions was a multidisciplined effort at. unraveling problems connected with con- traception. But the recommendation was turned down by the National Institutes of Health. Research on the metabolism of the pill seems to be run in scattered fashion at NIH. There appears to be little effort to coordinate NICHHD's oral contra- ceptive research with that being pursued in considerable volume at the neigh- boring cancer, heart, general medicine, and allergic and metabolic disease insti- tutes within the organization. The final note, an ironic one, involves the position of industry. Industry has helped find, and has certainly inspired, some of the research on the frontiers of reproductive biochemistry. Yet, the drug industry is the last to be identified with an aggressive search for solutions to problems of biological science as they relate to public issues. This is unfortunate although consistent with a competitive economy. One nonindustry chemist commented to C&EN that "Industry isn't shoving very hard to delve into some of the problems because they know that what's found could work against, as well as for, them. Yet I have to say truthfully that they've been quite generous in the support of my work." PAGENO="0388" 7218 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The feeling persists that several companies do have significant mechanism data in endocrinology but save it for two reasons: It could lead to new prod- ucts or, if publicized, could also lead to disfavor on the part of the Govern- ment. So industry plays it conservatively. In FDA's oral contraceptive report last year, Dr. Schuyler G. Kohl of the State University of New York, Brooklyn, suggested that companies pool some of their money and establish a thorough surveillance program of patients under contraceptive therapy. (Surveillance is the biggest drawback to reliable safety data.) The same suggestion might apply to an interindustry research effort on fundamental problems, perhaps through a special institute of basic studies. The closest approach to this is the Pharmaceutical Manufacturers Asso- ciation Foundation, which, as of now, is a low-key effort of modest support to some investigators. [From The AMA News, Vol. 9, No. 34, August 22, 1966, pp. 1, 6] ORAL CONTRACEPTIVES SAFE, FDA SAYS The U.S. Food and Drug Administration's Advisory Committee on Obstetrics and Gynecology reported that in a comprehensive study it found no proof that oral contraceptives are unsafe. Among the committee's recommendations was one that the time limitation on the use of the drugs be discontinued. But the committee added in its 21-page report that it had "nevertheless taken full cognizance of certain very infrequent but serious side effects and of possible theoretic risks suggested by animal experimental data and by some of the metabolic changes in human beings." "In the final analysis, each physician must evaluate the advantages and the risks of this method of contraception in comparison with other available meth- ods or with no contraception at all," the committee of 13 physician experts said. CHANGE PREDICTED The committee reported the efficacy of current oral contraceptives in fertility control as "exceptionally high," but said they probably will be replaced by others in five or 10 years. "Drugs with even less potentially adverse effect, utilizable in smaller dosage, will undoubtedly be developed through continuing research," the committee said . . . "It would be indeed unfortunate were such research and testing to be stifled by unnecessarily complicated, unscientifically harsh, and inelastic administrative procedures." The committee made 10 recommendations: A large case-control (retrospective) study of the possible relation of oral contraceptives to thromboembolism. Continuation and support of studies such as the ones being carried out by the Kaiser Permanente group in California and the U. of Pittsburgh group in Lawrence County, Pa. Support of additional controlled, population-based prospective studies utiliz- ing groups of subjects that are especially amenable to long-term follow-up, such as married female employees of certain large industries, and graduate nurses. Continuation and strengthening of the present surveillance system of the FDA. Review of the mechanism of storage, retrieval and analysis of surveillance data. A conference between FDA and the respective drug firms concerning uni- formity and increased efficiency of reporting. That priority be given to support laboratory investigations concerning all aspects of the hormonal contraceptive compounds. Uniformity in labeling of contraceptive drugs. Discontinuance of time limitation of administration of contraceptive drugs. Simplification of administrative procedures to allow reduction in dosage of already approved compounds. [Copyright 1966 by American Medical Association] PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7219 [From Good Housekeeping, February 1966, pp. 67-68] SPECIAL REPORT BASED ON NEw MEDICAL EVIDENCE-MUST WE Now BAN THE BIRTH CONTROL PILLS? Are birth control pills safe? Should doctors be more careful and selective in prescribing them? Indeed, should the pills be banned until clearer proofs of safety have been developed? For the second time in less than four years, medical evidence has posed such questions of vital concern to the estimated five million American women using oral contraceptives. In 1962, it was disclosed that blood clotting, fatal in some cases, had occurred among a number of women who, perhaps coincidentally, were using the pills. Now, new fears about the pills' safety have been raised by a medical journal report that detailed damage to eyes and the central nerv- ous system in some women taking the drug. After studying evidence gathered by Johns Hopkins Hospital specialists who prepared that report, the U.S. Food and Drug Administration took these steps last November: It requested all pharmaceutical manufacturers of birth control pills to include a precautionary warning in material supplied to physicians and phar- macists on neuro-ocular side effects. This advises that patients should stop using the pill if there is a sudden onset of severe headache or dizziness, blurred vision, or if examination reveals eye nerve, retinal or vision defects. It appointed a committee of obstetricians and gynecologists to make a full- male review of the safety of birth control pills. At its first two-day meeting in November, the committee, on the basis of preliminary facts, found no evidence of a cause-and-effect relationship between the use of birth control pills and the recently reported neuro-ocular manifestations. Nevertheless, it endorsed the action of the FDA in placing a warning concerning eye problems in the mate- rial sent to doctors. In an attempt to find out whether eye problems occur more in women taking the pills than among women in general, the committee planned a study to compare two groups-one of women who take the pills and the other of women who do not. This study is expected to be completed for the committee's final report, due in March. In 1963, another FDA advisory cdmmittee had concluded there was no statis- tically significant relationship between the use of pills and certain blood-clot- ting conditions. However, the committee strongly recommended further study of how oral contraceptives affect blood clotting. The pills' labeling was also revised to warn that they should not be used by women who have a history of thrombophlebitis or other thromboembolic disorders (the blood conditions stud- ied). Such blood-clotting problems can cause damage to the blood vessels, lungs, heart or brain. At its meeting in November, the new committee evaluated more than 2,200 adverse reactions which the FDA classified as "serious." The total number of reactions studied is expected to reach 12,000, including less serious ones, before the committee's final report. The FDA would not reveal how many deaths are included in the total. Subcommittees have been set up to study thromboembo- lism, carcinoma (cancer) potential and other possible adverse experiences. The FDA will not consider extending its present limit of four years' use of the pill until after all safety and efficacy factors have been reviewed by the committee. A Good Housekeeping article on the pills last September noted that a few ophthalmologists had reported some patients on oral contraceptives had devel- oped papilledema, a condition affecting eye nerves. As a result of these reports, the pill then most recently approved by the FDA for prescription sale to the public had included a warning, in material sent to doctors, against continued use if vision defects were noticed. The FDA said at that time it was studying whether this warning should be applied to the nine other birth control pills it had approved. In November, the report by Dr. Frank B. Walsh and his asso- ciates at Johns Hopkins listed 63 cases of eye and nervous-system damage to women taking the pills. The FDA then acted. The Walsh report detailed cases of 25 women who developed stroke-like symptoms while taking the pins. Five died. Twenty-two women developed eye symptoms, 10 suffered migraine headaches, four had symptoms resembling brain tumors and two had other adverse reactions. Dr. Walsh and his asso- ciates said available data did not prove a direct relationship between birth control pills and the reactions cited in the report, but the physicians con- PAGENO="0390" 7220 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY eluded: "We submit that the evidence we have produced, added to what has been reported previously, supports the conclusion that further study is indi- cated." Dr. Joseph F. Sadusk, Jr., director of the FDA's Bureau of Medicine, says it is hard to evaluate a cause-and-effect relationship from a case history. How- ever, he says, if conditions do appear, a doctor should stop birth control medi- cation to evaluate the effects the drug may have on the trouble. A study on the long-term safety of oral contraceptives is being planned by the National Institute of Child Health and Human Development to evaluate their effects on women and on children later born to those who had used them. Although some studies of oral contraceptives have been under way for as long as 10 years, no studies have covered the usual 25-to-30-year span during which a woman can bear children. It is not known, therefore, what effects 20 or 30 years of use might have. Because in prescribing oral contraceptives a doctor is giving medicine to~ a person who is not ill, some physicians believe a patient is needlessly taking a chance on developing side effects, possibly seri- ous ones. Such physicians admittedly express a minority view, but they say they prefer to prescribe other birth control methods. Since the last GOOD HOUSEKEEPING report, some authorities have indicated the importance of cau~ tion in prescribing the pills, for recognizing uncommon side effects and for fur- ther intensive study of their safety. For example: Dr. Sherif S. Shafey, a neurologist at the University of Miami School of Medicine, *says the most common neurological problem found in patients on oral contraceptives at the school's Cerebrovascular Disease Clinical Research Center is migraine headache. "A number of these patients," he says, "have never experienced in the past such headaches until they were taking the pills." Dr. Shafey says the patients became symptom-free when the pills were discon- tinued. Dr. Shafey says a cooperative study to collect data from different med- ical centers where patients are on oral contraceptives has been organized. Its aim, Dr. Shafey says, is to alert physicians and patients using the pills to the possibility of occurrence of such problems so that, by early detection, serious complications may be averted. Dr. James A. Shannon, director of the National Institutes of Health, told a congressional hearing last year that "there are a great many studies on experi- mental animals that indicate that they (the pills) probably can be taken with- out hazard, but there has not been adequate human exploration to be certain." When asked ifhe believed that people are really taking a chance in using oral contraceptives, he replied: "I believe so." Late last year, a spokesman said that Dr. Shannon's views on the subject remain the same. Dr. John 11. MeCain, professor of obstetrics and gynecology at Emory Uni- versity in Atlanta, said during a recent regional meeting of the American Col- lege of Obstetricians and Gynecologists he would hesitate to prescribe any oral contraceptive for his patients. One area he is particularly concerned about is mental disturbances. He said he has seen seven cases of mental disturbance which started in women taking the pills and ended when the patients stopped taking them. The relationship between taking oral contraceptives and blood clots is under investigation in Europe. For instance, the British Committee on Safety of Drugs reported that in a 12-month period ending in August, 1965, there were 16 deaths due to thromboembolic (blood clot) episodes in women taking oral contraceptives. The committee estimated that 13 such deaths could normally be expected in the same period in a comparable population of women not taking the pills. However, it drew no firm conclusion and urged doctors to continue to report such eases. "In the meantime," it said, "the committee do not feel jus- tifiedin objecting to the marketing of oral contraceptives." [From Good HousekeepIng, February 1966, pp. 68-70] ONE NOTED AUTHORITY SAYS :-"YE5, I'LL STILL PRESCRIBE THE PILLS" (By Dr. Alan F. Guttmacher) As President of Planned Parenthood Federation, I feel a deep responsibility to seven million young women throughout the world who arc using oral con- traceptives to regulate the size of their families. Ever since the pills were PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7221 introduced, I have been concerned by some adverse side effects. These will con- tinue to bear close observation until definitive answers to critical questions are found. 1~iy obligations to society and the medical profession supersede the objectives of the Planned Parenthood Federation. Weighing all factors, however, I would not advise a woman to discontinue the pills unless her personal physician prescribes another method-and no reason is now known why he should, in the absence of certain specific symp- toms. Despite the anxiety aroused by reports that some women taking the pills have experienced strokes, blood clots or impaired vision, present evidence has not established a clear connection between such reactions and oral contracep- tives. Although hundreds of serious complications have been noted by reliable authorities throughout the world since the Food and Drug Administration approved the sale of the pills on doctors' prescriptions six years ago, statisti- cians say this is a negligible incidence of trouble with a new drug that is used 20 times a month by five million American women and two million more women in England, Canada, South Africa, Australia and South America. They further point out that the disorders reported have also been found in women who are not on the pills. All this is true, yet as long as there is a shadow of doubt regarding the relationship between the, pills and some disturbing symptoms, we are watching patients very closely in Planned Parenthood's 276 centers in 128 cities in this country. Birth control pills are not innocuous preparations like aspirin. They are extremely powerful drugs, and it is essential to maintain a critical scien- tific attitude toward them until we are absolutely sure they are safe for the overwhelming majority of women. Proponents of birth control have criticized me for refusing to give an all-out endorsement of the pills in view of the notable success Planned Parenthood has had with them. Approximately 150,000 of the 300,000 women asking our centers for advice have chosen the pills in preference to other methods-the largest single group anywhere in the world-with remarkably few serious com- plications. Yet I cannot overlook the fatalities reported, including the one in the experi- ence of Planned Parenthood. The case was that of a healthy young woman with six children who died of pulmonary thrombosis a few years ago. She had been taking the pills in our Wilmington, `Del., center. Of course, when I think things through, I realize that she might have died of the same cause had she not been taking the pills. At about the same time she died, a distinguished committee, headed by Dr. Irving S. Wright, that had been appointed by the FDA to investigate just such cases reported that there was no causal connec- tion between the fatalities and the pills. Although it would be inexcusable ethically to give the public unwarranted confidence in the pills while some important questions remain unanswered, it is' equally wrong to disregard the pills' positive advantages. First of all, they are foolproof. A special committee of the American Medical Association recently concluded a year-long study of all contraceptive techniques and found that the pills are virtually 100 percent effective. Whenever a powerful drug is administered, there is valid' concern that it may have undesirable after-effects. It can be stated flatly that the pills do not interfere with a woman's ability to bear children when she stops taking them. In fact, her fertility may be increased. Fear of unwanted pregnancy often sets up a psychological block against conception. Conversely, a woman is much more relaxed when she does decide to have children. Every prospective mother is plagued by fear that any drug' taken for an appreciable period will cause her baby to be abnormal. There are no statistics to indicate that the pills have any residual effects on an embryo. There was a good deal of apprehension when the pills were put on the market that they would promote~ cancer. Although it is too early to draw definite conclusions, there is some evidence to suggest that the combination of progestins and estrogens in the pills may even reduce the incidence of some tumors and retard the growth of others. One facet with far-reaching social implications is the ready acceptance of the pills by women who reject other methods of birth control for a variety of reasons-expense, aesthetic aversion, sexual mores or sheer laziness. In Decem- PAGENO="0392" 7222 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ber, 1960, Planned Parenthood launched a pilot project in our Chicago clinics that led to interesting disclosures. The pills were offered to women in economi- cally depressed neighborhoods with soaring birth rates. The "average" user turned out to be a Negro woman in her middle twenties who was raising three children on a family income of $66 a week. A total of 14,365 women, largely attracted by the simple procedure, agreed to try the pills, and three years later 75 percent were still taking them. In North Carolina's Mecklenburg County, the pills were distributed to 690 women on public relief and two years later 74 percent of these women were following the one-a-day schedule faith- fully. These figures contrast sharply with the reactions of women in the same socioeconomic group who were given diaphragms and contraceptive jellies in New York and Cincinnati. Within the first year, the active users dropped to 56 and 64 percent, respectively. Many of my colleagues bitterly assail newspapers for ignoring the estab- lished benefits of oral contraceptives and alarming the public whenever some- one comes up with a bit of inconclusive evidence suggesting an element of danger to a small fraction of women. Lord knows it's difficult sometimes to maintain a detached, philosophic attitude toward such stories, but I really cannot condemn the newspapers. It is their function to alert readers to poten- tial health hazards. My one objection is that they sometimes leave readers with a distorted impression of the overall information. A prime example was the sensational treatment many newspapers gave the report issued last November by Dr. Frank B. Walsh listing eye and nervous- system disorders found in women taking the pills. Fuel was added to the fire when it was revealed that the FDA had ordered manufacturers of the pills to send circulars to doctors and pharmacists warning that patients who have cer- tain eye difficulties should not be put on the pill. Millions of women and their husbands would have been spared a good deal of mental anguish if the papers had told them that warnings by the FDA are standard operating procedure with all new drugs. All antibiotics carry certain warnings on the label, and patients with a history of gout or diabetes are told to stay away from oral diuretics. In the order to the manufacturers of the birth control pills, Dr. Joseph F. Saduck, Jr., medical director of the FDA, stressed that tests had not established "a cause-and-effect relationship" between the~ pills and the "adverse experiences" of some women. But that important detail was buried deep in most of the news stories. I believe the government is pursuing the proper course in keeping oral con- traceptives under close surveillance. Although the number of women stricken with blood clots and eye conditions is small statistically, these conditions require continued study. Pending better explanations than we now possess, several basic checks should be made before the pills are prescribed. A woman sl1ould be given a thorough pelvic examination by a competent physician to determine whether an internal abnormality may preclude use of the pills. Doctors should be most cautions of prescribing them. Patients with case histories of breast tumors, heart trouble, migraine headaches, liver disease, kidney ailments or thrombo- phelebitis (inflammation of veins caused by blood clotting) may have to be given another method of birth control. This may appear to be a rather formidable list, but it applies only to less than five percent of women in the childbearing age group. As a final precaution, a woman should be kept under intense. periodic observation by a doctor to make sure the pills can be continued safely. Patients constantly ask why it isn't possible to determine in advance whether it is safe for them to take the pills. The question is a perfectly rea- sonable one, but, unfortunately, such a test has not yet been devised. The rueful truth is that we still have a great deal to learn about the physiological processes of ovulation and pregnancy. Some studies have demonstrated there are chemical changes in the blood during pregnancy. Somewhat similar find- ings have shown up in the blood of some pill-users, but these findings are so inconclusive that they do not help to clarify the problem. One puzzling observation is that there is no consistency in* the onset of adverse symptoms. They may occur anywhere from 48 hours after taking the first pill to three years of steady medication and even three months after stop- ping the pills. As a rule, reactions to drugs follow a more standard pattern. PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7223 This, of course, adds strongly to the argument that the pills bear no causal relationship to adverse side effects. Questions raised by oral contraceptives can be solved only by conducting a series of tests with large control groups that are divided equally between women who are on the pills and women who are not. Thousands of patients of the same ages up to the menopause and representing a cross section of all racial, social and economic backgrounds should be examined periodically during every stage of the menstrual cycle with careful records kept of various physical reactions for purposes of comparison. The first attempt to tackle this elaborate, expensive and time-consuming procedure was made recently by the FDA when it gave a large appropriation to the Permanent Group of subscrib- ers to the Kaiser Health Plan in California for a study of side effects of all drugs, including oral contraceptives. The FDA will issue a report after study- ing all the data, but this report cannot be expected for several years. Scientists have been searching for a safe, effective and inexpensive contra- ceptive for many years. The second and third conditions of this long-awaited dream are fulfilled by the birth control pills now on the market. We know they are effective, and the cost ($1.50 to $3) a month is reasonable enough for the greatest majority of married couples in industrialized countries. The first-and overriding-requisite still has to be proved with absolute cer- tainty: Are they safe? Yes, they are, for the overwhelming majority of women, but the search cannot be relaxed until doctors can prescribe a pill with com- plete confidence for every patient who wants it. I am positive we will know all the answers eventually. Please believe I am not trying to condone the relatively few fatalities, either falsely or correctly imputed to the use of the pills. Each one is a tragic acci- dent, but the dangers of pregnancy are not insignificant, either. If the five million American w-omen taking the pills were to become pregnant, it is a grim, predictable fact that 1,400 would die in the normal course of confine- inent. That figure would be increased substantially by women desperate enough to terminate an unwanted pregnancy by exposing themselves to the hideous dangers of illegal abortions. If I had to make a decision, I would not hesitate to give the pills to a member of my immediate family. That is the ultimate test of a physician's integrity and judgment. [From Good Housekeeping, February 1966, p. 70] How DoEs THE PILL WORK? Following is an excerpt from an article that appeared in the September, 1965, issue of Good Housekeeping: Oral contraceptives contain synthetic hormones (those manufactured rather than produced naturally) which act in similar fashion to the female sex hor- inones estrogen and progesterone. A woman taking an oral contraceptive expe- riences some conditions usually associated with pregnancy, including the inhi- bition of ovulation. These conditions, some doctors point out, are natural. Women who have had large numbers of children have experienced such condi- tions during most of their childbearing years. During pregnancy, progesterone and estrogen levels are raised. This signals the pituitary gland, sometimes called the body's master gland, that no more egg cells are needed. The pitui- tary withholds stimulation of the ovaries to produce such cells. Oral contracep- tives are believed to accomplish the same responses. A rise in estrogen and progesterone levels-whether during pregnancy or when taking contraceptive pills-also affects other mechanisms of body chemis- try. This is what may cause the side effects some pill users experience. A few physicians do not prescribe oral contraceptives because of their effects on body function. Among oral contraceptives on the market, two types are available. One is a combination of synthetic estrogen and progestin, a synthetic progesterone. Such products include Enovid, Ortho-Novum, Norlestrin, Norinyl and Provest. The other type-approved for sale by the FDA last April-is the sequential oral contraceptive. Two products-Oracon and C-Quens-are sold. In the sequential method, the estrogen component is taken daily for 16 days and then the pro- PAGENO="0394" 7224 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gestin component is added to it for five days. Dr. Robert B. Greenblatt, chair- man of the department of endocrinology at the 1~iedical College of Georgia, says this system more nearly follows the natural production of estrogen and progesterone in the menstrual cycle. The most common side effects Qf oral contraceptives are those also usually seen in pregnancy, such as nausea, weight gain, breast discomfort, swelling of hands and feet and changes in skin or hair. Occasionally spotting or breakthrough bleeding may occur before the men- strual period. Doctors may increase the dosage to control this. In other cases, menstruation or withdrawal bleeding may be missed or absent. [From The Washington Post, December 19, 1965, pp. El, ES] ARE BIRTH CONTROL PILLS SAFE?-SOME DOCTORS DOUBT THAT THE DRUG HAS BEEN TESTED WELL ENOUGH FOR POSSIBLE SIDE EFFECTS (By Morton Mintz, Washington Post Staff Write~r) A small but growing number of physicians, including some in key research posts, have been expressing concern about the scientific quality of the testing done to establish that oral contraceptives do not seriously endanger the women who use them. One of these physicians is Dr. James A. Shannon, director of the National Institutes of Health. When the matter came up at a hearing of a House Appro- priations subcommittee last Feb. 17, Rep. John E. Fogarty (D-R.I.) remarked, "So people are really taking a chance" (in using them). "I believe so," Dr. Shannon replied. "There are a great many studies on experimental animals that indicate that they can be taken without hazard, but there has not been adequate human exploration to be certain." In the same vein are these statements: "Whether serious long-term effects-over a lifetime-can occur will not be known for many years." The Medical Letter, a nonprofit publication that eval- uates drugs for physicians, July 17, 1964. "While I cannot prove it, I am convinced that, women [using oral contraceptives] have died because of clots forming in the vessels of the heart, the brain, the lungs and the intestines."-Dr. Louis C. Lasagna, associate pro- fessor of medicine and pharmacology and experimental therapeutics, Johns Hopkins University School of Medicine, last Nov. S. "I have never seen a similar case . . . and I have seen many unexpected deaths in young people . . . My own feeling is that the association is just too much to be a coincidence."-A British pathologist at the inquest last Sept. 7 on a 22-year-old woman who had been "perfectly healthy," who had been taking pills "since the beginning of the Summer" and who died of a clot that formed in a leg vein and traveled to the lungs. Specialists say that pelvic or leg clots rarely occur spontaneously in healthy young women. "For reasons having to do with cost, the relatively high motivation required to remain on long-term [pill] therapy and our lack of knowledge about the ultimate physiologic consequences of such long-term therapy, reliance at the family planning clinic of the Johns Hopkins Hospital has been largely placed on . . . traditional methods . . . and the intrauterine devices."-Dr. Hugh J. Davis, clinic director, in a monograph now being printed. Women who have reliably used, or can reliably use, what Dr. Davis called "traditional methods" form a significant proportion of the millions who have turned to birth control pills. They have had an almost unquestioning trust that the pills pose no serious dangers. Necessarily, their trust reflects the confidence of a majority-probably the great majority-of the medical profession, because the oral contraceptives are prescription drugs. DRUG MAKERS CONFIDENT The physicians' confidence, in turn, has been furthered by assurances such as these: "If the instructions of the physician are followed in taking . . . the pills, I can imagine no danger whatsoever . . . I can think of no condition in which these pills would not be safe to take."-Dr. Joseph W. Goldzieher, a consultant PAGENO="0395" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7225 to Eli Lilly & Co., in an interview recorded last Nov. 6 by "This Hour Has Seven Days," a Canadian Broadcasting Corp. program. "The effects of birth control pills have been studied possibly more thor- oughly and for a longer continuous time on the same persons than any other drug."-G. D. Searle & Co., manufacturer of Enovid, the first oral contracep- tive. Among critics, there is a growing belief that the confidence of most of the medical profession in the pills is, at least in part, a result of inadequate infor- mation, wishful thinking and questionable scientific and statistical analysis. In the Searle statement, for example, critics say the word "possibly" auto- matically raises questions about the quality of the testing. They also make a more serious objection. (Because the pill studies have not been controlled, the data are less meaningful than that from scientific investi- gations made of other drugs in fewer people over shorter periods. Apart from contraception, the pills are recognized to have purely medical uses for many women, such as treatment for abnormal bleeding not caused by benign or malignant growths. This is one of the reasons why none of the doubters, so far as is known, advocates taking the pills off the market. In addition, the benefit/risk ratio is variable. It is at one level for a mother who may die if she becomes pregnant again and goes to a Planned Parenthood clinic, but who cannot be relied upon to use a mechanical method of contracep- tion. It is different for a woman who is willing to use a diaphragm but has been inspired by popular reports to ask her doctor for a prescription for the pill. The advocates contend that the incidence of harmful effects is extremely low. But the fact remains that they have not established that the rate is low, or that it is even as low as they say it is, or that it is not actually many times higher than they say it is. In addition, there is a widespread, resentful, "don't rock the boat" attitude in the medical profession. Recently, one manufacturer said that if warnings about the pills are widely circulated, "literally millions of American women could be thrown into panic regarding the safety for all oral contraceptives." Dr. Gregory Pincus, co-developer of the pill with Dr. John Rock, says it has yet "to be proved that there is a cause-and-effect relationship" between use of the pill and subsequent ill effects suffered by some. DEGREES OF EVIDENCE This is generally conceded. But those who keep speaking of lack of proof of a causal relation in regard to the pills, and many other drugs as well, fail to specify just what degree of evidence w-ould in their eyes, constitute proof. One such is Dr. Joseph F. Sadusk Jr., medical director of the Food and Drug Administration. The advocates imply that proof can be black or white, that it has a finality that all would concede. Scientists recognize, however, that there is no proof-that evidence is in a gray area, that it is relative, that it boils down to sufficient data on relative risks. This is the kind of data on which persons charged with protecting the public health must judge the relative safety of all drugs. With a small chance of being wrong, they must decide whether the occurrence of adverse reactions is significantly more than would have arisen under normal conditions. To insist upon certainty rather than compelling evidence of lack of safety is to risk the public health. Dr. LeRoy E. Burney, while Surgeon General of the Public Health Service, has said that to wait for "proof" is "to invite disaster, or at least to suffer unnecessarily through long periods of time." CHALLENGE AND RESPONSE In the case of oral contraceptives, it has not been proved, and perhaps never can be, that they can cause, say, painful migraine-a possible indicator of more serious trouble in the bloodways. But some women who had never had migraine get it on the pills, lose it when they go off the pills and get it again when they resume taking the pills. PAGENO="0396" 7226 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY By accepted scientific standards, this kind of challenge (taking a drug a second time) and response (reappearance of a side effect) is overwhelming evi- dence. To demand evidence of this quality for such side effects as lung clots or strokes is to risk lifelong disability or life itself. Inescapably, then, the lack of proof of a causal relation-the standard repeatedly invoked by Dr. Sadusk-requires acceptance of evidence less conclu- sive than that in the migraine situation. These questions, then, arise: Has FDA been adequately protecting the public health-has it been reverent of life and scientifically responsible-in taking the position that it must wait in such problems as clots and strokes for the kind of proof of a "cause-and-effect relationship" that is available for migraine? In the labeling of oral contraceptives, has FDA promptly given physicians full information about all of the known factors in the benefit/risk ratio so they can make informed, intelligent decisions about whether to prescribe the pills? Are women who can reliably use other methods "taking a chance for noth- ing?" as Dr. John R. McCain put it. He is professor of gynecology and obste- trics at Emory University, Atlanta. Last March, Dr. Lasagna of Johns Hopkins disclosed that two of his col- leagues, Drs. David B. Clark and Frank B. Walsh, l1ad collected data on about 20 young women who had suffered strokes-some of them fatal-after using birth control pills. An autopsy on one showed clotting in "practically every artery and vein in her body." Dr. Lasagna said. Yet, he noted, most of these causes had not been reported in American medi- cal literature although there have been reports of similar episodes in the Brit- ish Medical Journal since 1962. Thus, many physicians were ignorant of possi- ble serious and sometimes fatal hazards. Last Oct. 25, the Journal of the American Medical Association published a report on all methods for AMA's eight-member Committee on Human Reprod- uction. None of the authors was an endocrinologist, although the oral contraceptives involve the endocrine system. And the article makes no clear, specific mention of the possibility of strokes in pill users. Dr. Lasagna, asked for comment, said he believed the article, "in its concern for the benefits to be obtained from effective contraception, neglects what I consider to be all too definite warning signals on the horizon in regard to the ability of the oral contraceptives to cause vascular catastrophe." Vascular catastrophe includes serious or fatal clots in the bloodways. Those that block brain arteries are called strokes. Those that reach the lungs are called pulmonary embolisms. In a recent interview, the chairman of the AMA Committee, Dr. Raymond T. Holden of Washington, said frankly of the article, "Maybe it wasn't strong enough . . . It's possible we didn't stress the side effects," although "we thought we were being emphatic." Relying on the theory that the safety of the pills, if used as directed under medical supervision, has been assured by FDA, the article emphasizes their effectiveness ("virtually 100 percent") and says that their acceptability is "of prime importance." Yet on Nov. 16, FDA said that "several months ago"-that is, before the article was submitted to the AMA Journal-it had had a copy in hand of a report on 61 injuries involving blood clotting, including strokes and eye damage. EYE DAMAGE EVIDENCE That report, which was published in the November issue of Archives of Opthalmology, included only those cases disclosed by ophthalmologists re- sponding to an invitation to do so, and was therefore an obvious and large understatement of the reality. Only when asked for comment on the Archives report did FDA disclose that -30 days after deciding to do so-it was just then in the process of asking manufacturers to include an eye hazard warning in the labeling for the pills. Despite the great reliance the medical profession would place on Dr. Hol- PAGENO="0397" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7227 den's committee and its report, it had been told nothing of these things by FDA. Nor, according to Dr. Holden, had the committee been aware that FDA had approved inconsistent labeling for different brands of identical pill formula- tions. This permitted a physician to believe one brand was safer than another, although both brands were chemically the same. About three years ago, a Senate subcommittee headed by then Sen. Hubert H. Humphrey published a revealing FDA document, of which Dr. Holden was- and other members of his committee apparently were-unaware. The document disclosed the situation in 1960 when FDA released Enovid, the first oral contraceptive, for birth control purposes in possibly millions of women. At that time, when the agency recommended a maximum consecutive use limit of two years, the grand total of patients on whom Enovid had been tested for safety for from 12 to maximum of 38 consecutive menstrual cycles was 132. Dr. Holden said the 132 were "not enough." The number of Enovid tests has greatly increased since 1960, but similarly small numbers were involved last spring when FDA released the first sequen- tial oral contraceptives, which employ a different concept of action with a rec- ommended maximum consecutive use limit of 18 months. The number of women who as of last spring had taken Mead. Johnson's sequential product, Oracon, for 18 consecutive cycles was 274, for 24 cycles it was 148 and for 36 cycles it was 16. For Eli Lilly & Co.'s C-Quens, the total for 18 cycles was 445, for 24 cycles it was 180 and for 30 cycles it was four. PAGENO="0398" 7228 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0399" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7229 CONGRESSIONAL WRATH While the kind of faith put in FDA by the AMA Committee has been com- monplace in organized medicine, it has not been held by the chairmen of con- gressional committees that have investigated the agency's performance. Last summer, Rep. L. H. Fountain (D-N.C.) was so disturbed by the findings turned up during his inquiries that he felt impelled to remind top FDA officials that their responsibility is "not to the drug companies, not to the doc- tors, but to the consuming public that may live or die as a result of your deci- sions." The AMA committee report dealt with the troubling question of thromboem- bolism. (A clot that forms in a blood vessel is a thrombus. An embolus is a piece of a thrombus that has broken off and traveled to another site, where it can cause lifelong disability or death by blocking the flow of blood.) "The possible association of thromboembolic phenomena with the use of oral contraceptives has been reviewed by several committees, including one appointed by the FDA," the report said, thus invoking the FDA as a ground for assuming safety. The "several committees" were identified by Dr. Holden as two: the British Committee on the the Safety of Drugs and the special FDA advisory commit- tee headed by Dr. Irving S. Wright of Cornell Medical College. The Wright committee was convened after FDA and the manufacturer of Enovid had received, by late December, 1962, reports of thrombophlebitis-an inflammatory vein-clotting condition-in 272 women who had taken the pills. Thirty died after pieces of the clots broke loose and reached the lungs. By July 1963, the reported total had increased to 400 cases, with 40 deaths. For the moment, the major point about the Wright committee is that it did not eliminate the possibility of a relation between the use of Enovid and the occurrence of clots in the legs, pelvis and lungs. The committee felt that the data it had to work with required it to be cau- tious in drawing conclusions. In the 27 months since the committee made its report, its restraint has not always been mirrored by others, who have tended to assume that there is no reason for worry about a possible relation. Such an assumption has been nurtured in many places. AN AXIOM DEFIED In March, 1964, for example, Dr. Robert Kistner, a Harvard gynecologist, said that "scrutiny of the available data by experts . . . has completely exoner- ated the drug" as the causative factor. This defies an axiom followed by expert statisticians: that no data ever warrant a declaration that a drug has been "completely exonerated." They say that the most that can ever properly be said is that the data permit a cautious conclusion: that there is a high or low probability of a causal relation. Thirteen months after the Kistner exoneration, the FDA's Dr. Sadusk joined in, in a two-step progression. First, he said that it "seemed reasonable to conclude at this time that there is no evidence of a cause-and-effect relationship between strokes . . . and the oral contraceptive drug." His undocumented contention that there is "no evi- dence" is disputed in several reputable quarters, although no one claims that the evidence is conclusive. Then Dr. Sadusk went on to declare that the "information at hand is to the contrary." But numerous cases of stroke reported do suggest the possibility of a causal relation with the pills. They do not prove it, but they are hardly evidence "to the contrary." Within days of Dr. Sadusk's statement, a preliminary report on women pill- users who had strokes was made by Dr. Sherif S. Shafey at Jackson Memorial Hospital in Miami. Last October, a full-dress version of the report was made before the Ameri- can Heart Association by Dr. Shafey, who heads the Cerebral Vascular Dis- ease Clinical Research Center at the University of Miami School of Medicine. He and Dr. Peritz Scheinberg, chairman of the school's neurology department, said that "there is a strong suggestion of an increase in the number of young females suffering from vascular occlusions during the last PAGENO="0400" 7230 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY two years. All the cases diagnosed as such were on the oral contraceptives except one." Instead of the relaxed attitude suggested by Dr. Sadusk, they urged "aware- ness of the possible existence of a causal relationship." Among four stroke patients aged 20 to 29 who had been referred by private practitioners, there had been no previous symptoms of predisposing conditions. A fifth, 39, had had mildly high blood pressure for 23 years. All had been taking oral contraceptives for between six months and three years. A sixth woman, 29, who had been taking the pills for a year, developed a fatal clot in a major vein in the brain, although "without a precipitating factor," this condition "is rare," the researchers said. 10,000 `ADVERSE EXPERIENCES' A few weeks ago, FDA said that a computer was "memorizing" more than 10,000 instances of "adverse experiences" with oral contraceptives. The agency said it had a "crash program" to catalogue every scrap of information con- nected with the pills. Perhaps inadvertently, the agency thus acknowledged that, despite the grav- ity of the problems involved, its surveillance of adverse effects had to be strengthened by a crash program. In explaining the program, FDA said it was about to convene a special Advisory Committee on Obstetrics and Gynecology "to look at broad, overall problems of adverse experiences with all contraceptive drugs," including dis- crepancies in labeling of identical and similar products that the committee is expected to ask be made uniform. In its initial meeting Nov. 22-23, the committee said that its preliminary review "finds no evidence of a cause-effect relationship" between the pills and reports of eye damage, strokes and other injuries associated with blood clot- ting. The committee did not include in its statement the usually expected counter- balance: that it has no evidence that a causal relation does not exist. Yet by adopting a resolution endorsing FDA's request for an interim eye-damage warning in the labeling, the committee clearly indicated that a causal relation might indeed exist. The committee is scheduled to meet again Jan. 20-21 and to issue its final report after a third meeting next March. Its chairman is Dr. Louis M. Hell- man of the State University of New York College of Medicine. Although certain consultants have been enlisted, Dr. Hellman and the six other committee members are all obstetricians and gynecologists. Such relevant specialties as endocrinology, hematology and cardiovascular and blood-clotting diseases are not represented. One crucial problem area in the committee's deliberations is the significance of the 10,000 instances of "adverse experiences" and the wortl1 of such studies as have been made about the safety of the pills. The 10,000 reactions are a potpourri of often sketchy reports in medical lit- erature, of cases from manufacturers' files, of cases reported with uneven pre- cision by private physicians, of cases from a small proportion of hospitals. On Nov. 29, Drug News Weekly said that the committee "reportedly found the data useless-at least in its present form." Another warning, this one about assumptions that computers can provide magic answers, came recently from Dr. John T. Litchfield Jr., a drug industry scientist who spoke at the dedication ceremonies for FDA's new building. In trying to enlist computers, he said, many people in industry are "learning a few hard facts of life. `Gigo' is the word-garbage in, garbage out. Comput- ers cannot improve data." The real fear of some competent, knowledgeable scientists and statisticians is of "garbage results" as a basis for making judgments about the safety of the pills. In addition to being dubious as a sampling of reality, the 10,000 reac- tions almost certainly understate the reality. Underreporting of adverse reactions is a fact of life about drugs recognized almost universally by persons familiar with the situation, including officials of FDA. Especially among private practitioners, underreporting is tremendous. The magnitude of underreporting has probably never been more dramatically illustrated than it was last year at Johns Hopkins, a top-rank teaching hospi- PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7231 tal where there is a reporting system of extraordinary quality. It has been made easy to follow by providing staff physicians~ with reporting cards attached to the patients' charts. Dr. Leighton Cluff, professor of medicine at Johns Hopkins, and three Public Health Service epidemiologists made daily inquiries of doctors and nurses about drug reactions in a 120-bed medical service. They found that those sup- posed to fill out the cards failed so often that fewer cards were filled out for reactions in the entire hospital than the survey found had actually occurred in a 10 per cent sample of the hospital. ENTHUSIASTS TROUBLED If the 10,000 adverse reactions are a shaky foundation for judgments on safety, so are the uncontrolled studies upon which so much reliance has been placed to date. The studies have troubled even such exuberant boosters of the pills as Dr. Joseph Goldzieher ("I can think of no condition in which these pills would not be safe to take"). Citing the "deficiencies in published trials" in an article in the Medical Jour- nal of Australia last June, he said that "much of the current discussion of the incidence of side effects is an exercise in futility." In the British Medical Journal, Dr. Geoffrey Rivett said he had found no circulatory disorders in between 50 and 100 patients on the pills, even though some of them had a history of such afflictions. "But such figures prove nothing," he said. "It would be a great help if an authoritative body would carry out" a valid trial. (See accompanying box.) The FDA's Wright committee did not carry out a valid trial. Its mission was to determine if the incidence of thromboembolic phenomena-clots in the bloodways-is significantly higher in women on the pills than in women in the normal population 15 to 45 years old. The committee found it impossible to get solid, usable data out of cases of nonfatal clots in Enovid users as recorded in the files of FDA and the manu- facturer. For that reason, the committee could shed no light on the incidence of a condition that is nonfatal but can cause lifelong disability. The committee concentrated on fatalities, for which the data were more complete. Even so, the consultants labored under terrific handicaps. The rate of side effects is the product of a fraction. The numerator is the estimated number of persons in whom adverse effects have been reported. The denominator is the population estimated to have taken the drug being studied. If for any reason the numerator is too small or the denominator too large, or if both flaws exist, the incidence is understated. To determine the incidence in the normal female population, the committee divided the population believed to be at risk-the denominator-into the number of cases of fatal lung clots as reported in death certificates for 1962. Death certificates-the numerator-were all that the committee had to go by. But the reliability of these certificates varies greatly. Unless there is an autopsy-and postmortems are held in only 20 to 30 per cent of all deaths-there is, if the cause of death is not obvious, no audit of the cause given in the certificate. Lung clots are often not obvious. For women who had taken Enovid (which in this respect is believed to be no more or no less safe than other oral contraceptives), the committee's numerator again had to be what was available: the number of deaths reported to FDA and by the manufacturer, G. D. Searle & Co. For its denominator, the committee used the number of women assumed to have been using Enovid during 1962. Precisely what that figure was, nobody- the company included-could possibly know. This was dramatically illustrated last Oct. 16 in the British Medical Journal by Dr. Arnold mopper. "An inquiry to leading companies in this country and in the United States . . . produced estimates varying from five million to 20 million women all over the world taking these compounds daily," he said. But if a mere 10 per cent fewer patients took Enovid than the Wright com- mittee calculated, Science magazine has said, "the death rate . . . would come very close to statistical significance for all ages; and if 50 per cent fewer people took it, the rates would be very significantly greater." 40-471 0-70-pt. 17-26 PAGENO="0402" 7232 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The often neglected facts are that the Wright committee, sharply aware of the limitations imposed by the information it had to work with: Concluded only that the available data showed no significant increase in the risk of fatal lung clots in Enovid users. Cautioned that "any firm reliance on the risks as calculated is tempered by the assumptions made." Made one, and only one, recommendation: that carefully planned, controlled studies be started. Although the potential consequences may be immense, FDA has not acted to implement this recommendation in the 27 months since the Wright committee made it. Until the recommendation is carried out, the uncertainties about haz- ards will not be stilled. Nor will the uncertainties be dispelled by what Dr. Irwin C. Winter, Searle's vice president for medical affairs, said a year ago was "undoubtedly . . . the most comprehensive large-scale study in the oral contraceptive field." He referred to a study undertaken by Searle in cooperation with 38 Planned Parenthood Federation clinics. An initial check of a group of 5000 women, he reported, showed an incidence of inflammatory clots among pill users compara- - ble to the minimum rate known in the normal female population. ~ But the usefulness of the study was frankly conceded to be limited even by :Dr. Winter when he said that there was not "an adequate control group" and *that "adequate statistics" on the normal incidence of thrombophlebitis "were not available." A SIGNIFICANT YEAR ~ A further criticism was made by Dr. Herbert Ratner of the Stritch School of Medicine of Loyola University in Chicago, who dealt in an interview with acknowledgements by Dr. Winter that the 5000 women were limited to those who, before entering the study, had been on the pills for at least two years. * This means that the study excluded those women who had started on the pills but dropped out because of side effects-serious or otherwise-or for other reasons in the first 12 months of use. And this initial period, Dr. Ratner said, is the one in which most side effects occur. Therefore, he said, any conclusions drawn from data on the selected group that was able to enter the study are open to question. Today's concern is most intense not about nausea and other such effects associated with pill-induced pseudo-pregnancy, but about afflictions involving the circulatory system: fatal clots, disabling clOts, eye damage. There are, however, other concerns, including a feared possible relation between pill use over several years and cancer. Although his warnings about such a possible relation have been hotly and widely challenged, Dr. Roy Hertz, former chief endocrinologist of the National Cancer Institute, said in an interview that the estrogenic substances used in the pills are known to induce a wide variety of tumors in numerous species of a nimals. "It is, therefore, imperative that their generalized distribution to women of child-bearing age for protracted perids of time be preceded by appropriately comprehensive epidemiologic studies to ascertain whether such effects are to be anticipated in man," he said. "To date, no statistically adequate studies sustained for a sufficiently long I)eriod of time have been reported," Dr. Hertz said, but some are being orga- nized at the National Institute of Child Health and Human Development, of which he is now scientific director. He said that these studies will get follow-up data for prolonged periods of time on users of various methods of contraception so as to ascertain the com- parative effects. These studies are recognized as appropriate for dealing with the questions about a possible serious adverse reaction that, if it would appear at nfl, would not be expected to manifest itself until after many years of pill use. But such studies will not be directed primarily to answering questions about possible adverse circulatory effects that most commonly would appear in the initial months of use. PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7233 UNDERCURRENT OF UNEASE A gap almost as wide as that between Dr. Hertz and his challengers, who say flatly that the pills pose no cancer danger, exists over another possibility: that the pills, under certain rare circumstances involving failure of the user to follow instructions, can masculinize a female fetus. In cases involving other major afflictions-including heart, liver, kidney and, in teen-agers, bone-closure diseases-those who believe the pills safe when carefully and properly used are challenged occasionally, but thus far rarely by solid, meaningful data. Here, too, however, there is an under-current of unease. The pills have not been used long enough-it is only eight years since Enovid was marketed, chiefly for menstrual disorders-for anyone to speak with complete certainty about the effects of continuous use from adolescence to menopause. Dr. McCain, the Emory University obstetrician, has reported that between May, 1954, and October, 1965, he f.ound "disturbingly numerous" complications in 41 patients on the pills. "The psychiatric complications seem to me~ to carry the most serious poten- tial," he told a group of colleagues at the District IV meeting of the American College of Obstetricians and Gynecologists last Oct. 21 in Norfolk. Of the 41 patients, he said, three "have told me that they were desperately afraid that they were going to kill themselves"-two of them after they had been on the drugs less than two weeks, the third after about four months. "The suicidal fears have disappeared in all three patients since omitting the contraceptive pills," he reported. These patients are "the only ones I have ever had that have told me so dra- matically of their fear of suicide," he said, adding that "it is disturbing to wonder how many women on the contraceptive pills have committed suicide and/or homicide." Dr. McCain said that some colleagues have told him of pill users who have become almost euphoric. In either case-depression or euphoria-study of the psychiatric effects is needed, he said. In this area as in others, the uncertainties about the relative safety of the pills can no longer be brushed aside. FDA's new Advisory Committee on Obste- trics and Gynecology acknowledged this after its first meeting. Whether the committee will attempt to remedy this situation by recommend- ing a proposal for a rigorously controlled investigation, such as that in the box with this story, "may well be its single most crucial decision," says the scientist who made the proposal. [From This Week Magazine, ~u1y 12, 1964, p. 13] BIRTH-CONTROL PILLS-HAVE THEY SIDE-EFFECTS ?-AN AUTHORITATIVE ANSWER TO A QUESTION MANY WOMEN ARE ASKING (By Edw-in J. DeCosta, M.D., Attending Obstetrician and Gynecologist, Passarant Memorial Hospital, Ohicago) "But doctor, are they really safe?" No wonder that after the thalidomide tragedy many patients worry about the possible harm from taking the new birth-control pills. And there have been a few medical reports-plus many rumors-of dangerous side effects. Without considering the controversial social or religious aspects of birth control, let us take a look at the medical facts about this important discovery. First, no other method of birth control is as simple. The small hormone pills are taken at bedtime for 20 days each month. Apparently they work by sug- gesting to the body's master gland, the pituitary, that the woman is already pregnant, so the pituitary doesn't instruct the ovaries to produce an egg that month. When the patient stops taking pills after 20 days the lining of the uterus is sloughed and bleeding follows. Then the pills are started again for the next cycle. This simple methpd approaches 100 per cent effectiveness. But . . . and there is always a but . . . there may also be undesirable effects when the pills are used. Generally, these effects are not serious-only nuis- ances similar to those experienced by some women during early pregnancy. They may become, for reasons we can't explain, bloated or nauseated, have PAGENO="0404" * 7234 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY fullness and soreness of the breasts, suffer from headaches or even changes in their personality. Some women also gain weight rapidly, some have disturb- ance of their menstrual flow. Rarely, the menses do not return for some time after the pills are discontinued-which, of course, makes the patient fear she is pregnant. Fortunately, in most instances these complaints disappear within a couple of months, as in pregnancy. But not always. At times, the weight gain, bleeding and personality changes maybe sufficiently disconcerting to warrant discontin- uance of the pills. But these are just nuisance factors. What about the reports of more serious problems? I have heard oral contraceptives accused of masculinizing female babies if taken inadvertently during early pregnancy, of interfering with future fertility, of causing uterine fibroids or even cancer. Most of these charges are palpable nonsence-there is no evidence to support any of them. Indeed, many patients report getting both physical and psychological benefits from the pills. DANGER-LEG CLOTS There is, however, one other widely reported problem connected with oral contraceptives. From time to time women taking them have developed blood clots (thrombosis) in the veins of their pelvis or legs. This can be serious- even fatal-but studies do not indicate that pills cause the clots. Thrombosis also occurs in men, and in women who are not taking contraceptive pills. I am reminded of a recent medical meeting where a doctor reported several instances of leg clots occurring in patients taking the pills. Another doctor promptly rose. His patient too had been given a prescription for the pills, and had developed leg clots. But she had forgotten to have the prescription filled! Do I myself prescribe the pills? I do, whenever I think they are indicated. But to avoid even the most remote risk, I would not prescribe them to women who have had blood clots, varicose veins, heart or kidney disease, or malig- nancy. To sum up, my own answer to anxious patients is yes, there is good reason to believe that oral contraceptives are safe for normal women under their phy- sicians' supervision. PAGENO="0405" APPENDIX V WRIGHT COMMITTEE REPORTS ON ENOVID REPORT ON EN0vID BY THE AD Hoc COMMITTEE FOR THE EVALUATION OF A POSSIBLE ETI0L0GIO RELATION WITH THROMBOEMBOLIC CONDITIONS SUBMITTED TO THE COMMISSIONER OF THE FOOD AND DRUG ADMINISTRATION OF THE DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, AUGUST 4, 1963 For centuries man has been interested in mechanisms and factors affecting the normal menstrual cycle, as well as those believed to be effective in either increasing of decreasing fertility. The artifacts of many civilizations attest to this. Therefore it should arouse no surprise that when a preparation which suppresses ovulation became available in tablet form it should be rapidly accepted and widely used. Such a tablet consisting of norethynodrel with ethi- nylestradiol 3-methyl ether (Enovid) has now been used by well over 1.5 mil- lion women for either contraception or for the treatment of disturbances of gynecologic endocrinology. It is believed that this substance acts* by inhibiting the synthesis of gonadotropin by the anterior pituitary gland and in this manner suppresses ovulation in a high percentage of users. It was soon recognized that Enovid produced a variety of side effects, including nausea and vomiting (sufficient to require discontinuation of the treatment in about 25% of the cases) and there have been reports of edema, weight gain, changes in thyroid or adrenal function, thyroiditis or toxicosis, hair loss or growth, dermatitis, cholestatic jaundice, chloasma, toxemia of pregnancy like syndromes and others. Except for nausea and vomiting the proof that these have been a direct result of the use of Envoid is in most instances open to question and is not within the scope of this report. Beginning in 1961 reports began to appear from numerous sources of throm- boembolic conditions, including thrombophlebitis and pulmonary embolism, occurring in women who had taken or were taking Enovid. Some of these patients died. While the index of Suspicion was raised it was also recognized by the scientific community that a very large number of young and middle- aged females were involved, that such conditions do occur with and without obvious explanation, and that the coincidental factors involved' in such situa- tions are not necessarily etiological. One solution would have been to scrutim- ize carefully each case history in detail, select those which appeared to be idi- opathic in all other aspects, but who had the common denominator of exposure to Enovid, and compare these with a proper sampling from the population as a whole to determine whether there was evidence of an increase in the incidence of thromboembolism and deaths in the exposed series. Unfortunately the incidence of thromboembolism in the United States in this or any other popu- lation group is not known despite efforts in a few areas to obtain such figures. This type of condition is not reportable so that most of the patients which are not hospitalized are never recorded at all or the records remain in the physi- cian's files. Once the attention of the medical profession and the general popu- lation was drawn to a possible relationship with Enovid, reporting of all types and severity of thromboembolic conditions in patients who had taken this drug was inevitably accentuated and comparable statistics became even more difficult. The death rate from thromboembolism in females of a comparable age group during the same period was not known, although this was obtained in * the course of the present investigation. In January of 1963 the Commissioner of the Food & Drug Administration, of the Department of Health, Education & Welfare established an ad hoc Com- (7235) PAGENO="0406" 7236 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mittee to review and analyze this situation and to determine if the use of Enovici resulted in an increase in the incidence of death from thromboembolic conditions. This consitutes a report of the efforts of the Committee to resolve the questions involved. The Committee was composed of representatives with broad interests but especially experienced in the fields of gynecology and obste- trics, vascular diseases, thromboembolism, hematology (especially coagulation), and statistics; and epidemiology. The Committee has not been unmindful of the complexity of the over-all considerations involved in this area. These incude not only the medical impli- cations but also those involving the biological, psychological, social, philosophi- cal and religious aspects. The relationship of all of these to the population explosion must be of interest to all intelligent citizens. Nevertheless these fac- tors were not permitted at any time to cloud the immediate issues which con- stituted the commission of the Committee. Background material was obtained from the Food & Drug Administration and G. D. Searle & Company. The representatives of both organizations were completely co-operative throughout this study. More than 350 case reports of both thromboembolism and death from the files of both sources were reviewed by the members of the Committee together with much additional data. After this it was concluded that because of the impossibility of obtaining solid com- parable statistics regarding thromboembolic complications as they occur in the usual population groups, it was essential to concentrate on deaths where the documentation is more complete and valid. The coagulation balance The possibility of the production of changes in the coagulation balance which might significantly add to the risk of thrombosis or embolism was care- fully considered. The pertinent literature on this point was reviewed and spe- cial studies designed to answer certain questions were carried out in the labo- ratories of member of this Committee. In assuming the responsibility of trying to establish whether the use of Enovid affects blood coagulation adversely to a degree capable of resulting in thromboe~nbolic disease, the Committee, after reviewing the available literature and recent unpublished experiments performed by members of the Sub-commit- tee (attached appendix), accepted the following basic facts: 1. Enovid produces some uterine changes similar to those occurring in preg- nancy. Therefore it was essential that the coagulation changes during preg- nancy be reviewed. The gravid woman develops significantly increased concentrations of the following plasma clotting components: Factors VII (pro- convertin), X (Stuart), VIII (AHF),* IX (PTC), fibrinogen, and platelets. Less definite evidence regarding Factors II (prothrombin) and the fibrinolytic components has been reported. Virtually nothing is known as yet regarding parallel changes in Factors XI (PTA) and XII (Hageman). Factor V (AC- globulin) is unaffected. Although thrombotic phenomena were not searched for or carefully analyzed in the studies during the antepartum period upon which these findings were based, overt thromboembolism was not strikingly impres- sive. This is not surprising since thromboembolism complicating pregnancy occurs 4-6 times more frequently in the immediate post-partum state than during the gravid state. 2. These facts having been established in pregnancy, comparable studies in subjects receiving Enovici were sought. In a small series of subjects, one labo- ratory had reported an increase in Factor VIII activity and lesser increase in Factor VII (1) Less impressive changes in other clotting parameters have also been reported (Rapaport) (2) and Hanstell). (3) Eleven women receiving Enovid and eleven healthy women were studied concurrently. Levels of Factor VIII activity, one stage prothrombin times, plasma recalcification times, and~ platelet numbers were not significantly different in the two groups. (Spittell, Owen, Thompson, and Bowie (Personal communication to the Committee). In order to attempt to determine a possible relationship between elevated levels of Factor VIII and hypercoagulability, experiments were performed by adding semi-purified Factor VII to in vitro clotting systems. Significant shortening of plasma partial thromboplastin times below the normal range was not produced when the levels of AFH ranged between 100 and 850 percent of normal. Nei- * Alexander. B., personal communication with Committee. PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7237 ther was there acceleration of prothrombin conversion or of the clotting of whole blood (Penick, for the Committee) (5) (attached appendix Fig. 1-5. The possibility that as yet unknown Factors or interactions may function under such conditions cannot be excluded. With respect to Enovid, the available data to date do not establish, or exclude, the possibility that the drug produces hypercoagulability as defined by increases in clotting components or acceleration of clotting kinetics. More com- plete and extensive studies in this area are clearly indicated. Moreover, the question of the relationship between the hypercoagulable state as defined above, to clinical thromboembolic disease is still undetermined. Clinical survey In order to obtain information regarding the clinical experience of both phy- sicians and clinics using this drug, a survey was undertaken by Dr. Willard Allen. Acting for the Committee he obtained data giving the age distribution of patients receiving Enovid by means of a letter of inquiry sent to representa- tive obstetricians and gynecologists throughout the United States. The data were obtained from 20 private gynecologists and obstetricians, and from six Planned Parenthood clincis. The details of these data will be found in the Appendix. (tables 1-17). This study included a total of 5,798 cases. (See table 17) This table also gives a percentage distribution. The incidence of reported phlebitis in this total group of cases was 1.55 per thousand. The incidence of pulmonary embolism was 0.34 per thousand (2 cases). There were no deaths in this series of 5,798 cases. This sampling is considered to be representative of the age distribution of patients in the United States who are receiving Enovid, both in private practice and in clinics. Review of data on reported deaths The Committee reviewed and evaluated the clinical records, the autopsy reported the death certificates and other pertinent material of each patient alleged to have died from thromboembolic disease who had taken or was taking Enovid. From the records a list was developed consisting of those patients who were considered to have died of idiopathic thromboembolism. Excluded from this list therefore were those patients whose deaths were not due to thromboembohic disease and those whose deaths from thromboembolic disease were found to be probably due to recognized causes; such as post-oper- ative state, cancer, including leukemia, pregnancy, extreme obesity (500 lbs. plus ), and prolonger dependency edema. One patient was excluded because she had not taken Enovid for 10 months. During the years 1961-1962 there were 14 cases of idiopathic thromboembolic deaths. 13 additional cases were excluded from the series in as much as their deaths were considered not to be idiopathic. There were two cases regarding which the Committee could not agree. Of the 14 idiopathic deaths, 10 occurred during the year 1962, which was then adopted as the year for further analysis because they oc- curred outside the limits of the continental United States, they were beyond the age limits of the study, or they occurred before 1961. There were 10 cases which were unanimously agreed upon as idiopathic. These cases plus two addi- tional cases about which there was lack of unanimous agreement were accepted for the statistical analysis. In the first of these additional cases, on the basis of the obtainable data the Committee was undecided as to whether the explanation of the entire pathology found within the lung was on the basis of pulmonary infarction due to thromboembolism of an idiopathic nature or whether it was explained by an upper respiratory infection which developed into pneumonia and which in turn was the factor in the development of thromboembohism and infarction in the lungs. In the second case the patient died of the effects of mesenteric venous thrombosis, but the details in the case history were not sufficient to justify a determination as to whether this condi- tion was idiopathic or not. Once the selection of patients whose deaths could not be explained by some other known etiological factor had been completed, a statistical evaluation became feasible. It is obvious that the ideal study, to measure a given effect as caused by a given agent, takes on the form of an experiment in which two groups are compared which are identical in all respects except for the presence in one of the independent variable (agent) to be evaluated. On extremely rare occasions nature performs this experiment, but by and large such experiments PAGENO="0408" 7238 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in nature are not available to us in the precise form presented above. Many variables are uncontrollable and two groups in which contrasting effects are to be noted may indeed not be similar in certain factors which may have bearing on the outcome. Thus, in most situations the pertinent characteristics of the groups must be defined, or adjusted for, in order to permit comparison. Although a number of undesirable effects have been reported among users of Enovid and these have created suspicion as to their possible relationship to such use, of the most important serious phenomena brought to the attention of the F. D. A. were those of thromoembolisni in the form of either thrombo- phlebitis, and/or pulmonary embolism. The Committee's principal objective therefore was to assess the significance of the association between Enovid use and these latter phenomena. From to beginning of the Committee's deliberation, it was very apparent that an assessment of the true quantitative values for morbidity from throm- bophiebitis would be fraught with great uncertainties. As suggested above such factors as the broad spectrum of the severity of the disease and hence the seeking of medical care for diagnosis with obvious variation in reporting, diag- nostic acumen, geographic differences in occurrence, and the number of unhos- pitalized and medically untreated cases could contribute in a differential way between groups of Enovid users and non-Enovid users and hence create arti- factural differences which did not in reality exist. Mortality data concern themselves with events which have a finality at which point sufficient clinical and laboratory information is frequently avail- able for reasonable diagnosis. Such deaths must be certified and in spite of the lack of precision sometimes noted in death certificates one can assume a lngher order of completeness of reporting and of certainty as to diagnosis than may be found in morbidity data dealing with this problem. Thus, the Commit- tee elected to expore available information relative to mortality from throm- boembolic phenomena among Enovid users in relation to the occurrence of similar deaths in the general population and to determine whether such an approach might be reliable and provide meaningful information. METHOD Inasmuch as Enovid users as a groups were predominently non-pregnant females it was obvious that such a group would have to be compared with the general population of non-pregnant women in the childbearing age groups. This was particularly necessary in view of the fact that pregnancy per se is known to carry with it a risk of thromboembolic phenomena. See Table VII for a graphic comparison of the two numerators and denominators used in estimat- ing the relative risks of using Enovid. 1. Validity of the numerator counts a. Mortality in Enovid group, first numerator-It is felt by members of the Committee that the cases of death for 1962 from thromboembolic phenomena among Enovid users is almost complete, if not entirely so, because the atten- tion of the medical profession and the public had been focused in 1962 by both the Food & Drug Administration and the manufacturer on the need for docu- menting all events which might conceivably be related to Enovid use. b. Mortality in the qeneral population, second nunierator.-Initially, data on thromnboembolic mortality in the general population were not available. This was obtained upon request and with the cooperation of the National Vital Sta- tistics Division (NVSD) in the National Center for Health Statistics. The Committee requested a tabulation of all deaths from thromboembolic phenom- ena (ISC Codes 463, 464, 465 and 466) and the niffimber of deaths from these entities was obtained for the entire United States for 1961. Inasmuch as final- ized counts for 1962 w-ere not available from NVSD and since the analysis would be necessity be based on only 1962 data, the Committee attempted to obtain such mortality data from 19 states which had shown a majority of the thromboembolic deaths in 1961 in the United States, and represented a good geographic distribution. Sixteen States provided data in time for the Commit- tee study. These 16 states accounted for at least 60% of the thromboembolic deaths occurring in 1961 and their data for 1962 were utilized in an extrapola tion of the expected total number of such deaths in the entire population in 1962. The data provided by the states were actual photocopies of the pertinent PAGENO="0409" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7239 death certificates and included 18 of the deaths of patients known to have taken Enovid. The assumption was then made that the mortality from throm- boembolic conditions in the general population for 1962 was at least at the same rate as in 1961. 2. Characteristics of the numerator counts Only deaths occurring among residents of the United States in 1962 were accepted: Furthermore, patients known to be pregnant at the time of their demise and postoperative thromboembolism cases, were excluded by virtue of the fact that the general population numerator would not include these groups in the codings listed above for thromboembolism. The Enovid numerator had no negro deaths. Inasmuch as it was uncertain whether this lack of deaths among negroes using Enovid, in the data available to us, represented an inadequate population at the risk or not (since total use of the Enovid among negroes was not great and even at "normal" risks of thromhoembolic death one would require a very large population at risk to obtain a single death), it was decided to omit negro females from both denom- inators and the general population numerator. a. Every death reported in patients exposed to Enovid was again reviewed in detail to determine its suitability for inclusion on the basis of any throm- boembolic phenomena irrespective of the underlying cause. These were distrib- uted among the five year age groups into which they fell from 15 to 44 years of age. (For other purposes these were further subdivided into idiopathic and non-idiopathic cases). b. The general population numerator similarly included all deaths from thromboembolic phenomena exclusive of those occurring among pregnant women or shortly after surgery regardless of other antecedent causes. These deaths were also subdivided into their 5 year age groups from 15 to 44 years of age. 3. Validity of the denominator counts a. Inspection of some available data and the experience of members of the Committee relative to the use of Enovid for conception control indicated that the age distribution of the population of Enovid users would be drastically dif- ferent from the age distribution of non-pregnant females in the general popula- tion. Thus, data were sought from a geographically diversified sampling of Planned Parenthood clinics and private practitioners for a cross-section of the age distribution of Enovid users. There were obtained for both white and negro patients. Although for reasons above noted negro patients were excluded from the final analysis of users, their distribution was not remarkably differ- ent from that of the white patients. Further assumptions were herein made: That the sample derived by solicitation was representative of all Enovid users in the United States at least with respect to age; that geographic differ- ences might be accounted for by representation in the sample of data from all l)artS of the country; and that the blending or private and clinic patients occurred in the same proportion as might exist in the general population. Actually, the age distribution of private patients was not significantly different from that of the clinic patients. The most unreliable data to be utilized in the calculation of relative risks resided in the denominator for the Enovid user group. The only data available were furnished by the manufacturer on the basis of prescriptions filled and renewed during each of the quarters of the year of 1962. The maximum esti- mated number of users of Enovid was 1,300,000, but this value contained an unknow-n proportion of negroes and a lesser but still unknown proportion of duplicate prescriptions- On the basis of the best preliminary estimate the corn- inittee could formulate, 300,000 were subtracted, leaving 1,000,000 white users of Enovid. These were then categorized according to the age distribution of the white Enovid user sample- This distribution provided the individual age group denominators which were subsequently used to calculate the thromboem- bolic mortality rates among such users. b. The corresponding denominators for the 1962 general population included the distribution of w-liite females for the same individual age groups. NVSD provided these data and also estimates of the age distribution of white non- pregnant women. For each age-interval denominator the estimated number of PAGENO="0410" 7240 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pregnant women was subtracted. Thus the individual age-interval denominator continued only white non-pregnant women. RESULTS In table VI there is presented a comparison of age-specific mortality rates from the thromboembolic phenomena among white Enovid users and the white non-pregnant United States female population in 1962. The incidence of deaths among all Enovid use was 12.1 per million users. It will be noted that the unadjusted rate for the general population is 7.9 deaths per million. On adjust- inent of the general population for the age distribution of the Enovid user pop- ulation this rate becomes 8.4 (table VII). In either case the difference between the Enovid and population rates is not statistically significant (p=.14) utiliz- ing Poisson probability for small expected rates. However, the larger individual age-interval rates among Enovid users in the 35-39 and the 40-44 year age groups are highly significant (P=.001 and P .0001 respectively). DISCUSSION Inasmuch as the population number for Enovid users estimated from avail- able data is not an exact figure, but based on drug distribution figures, some attempts were made to determine the effect of a 50% decrease in the estimated population of white users to see what effect this might have on the excessive mortality rates among Enovid users in the older groups. This increase reduced the difference between the 35-39 age groups rates to that of a borderline level of statistical significance (P=.09) whereas the 40-44 year Enovid group rate, although reduced, remained highly significant. A 50% decrease in the estimate of users doubles the Enovid rates and would make them very significantly greater for virtually every age-specific group. These ranges of 50% plus or minus represent extreme possibilities rather than probable range and are highly unlikely. However, an over-all Enovid death rate (all ages) based on a 10% decrease in the estimate of users is very close to statistical significance. In summary; on the basis of the available data and if the above outlined assumptions are reasonably correct, no significant increase in the risk of thromboembolic death frdm the use of Enovid in this population group under the age of 35 has been demonstrated. The relative risk, from the available data, of death from thromboembolism does appear to be increased for Enovid users at ages 35 or over. The reasons for this are not clear at this time. There is a need for comprehensive and critical studies regarding the possible effects of Enovid on the coagulation balance and related production of throm- boembolic conditions. Pending the development of such conclusive data and on the basis of present experience this latter relationship should be regarded as neither established nor excluded. Although a detailed study is not within the scope of this report it is recog- nized that in judging the over-all risk from and the values of the use of Enovid, data concerning the risks of pregnancy and induced abortion in each age group would be extremely important. Any firm reliance on the risks as calculated is tempered by the assumptions made. This committee recommends that a carefully planned and controlled pro- spective study be initiated with the objective of obtaining more conclusive data regarding the incidence of thromboembohism and the death from such condi- tions in both untreated females and those under treatment of this type among the pertinent age groups. COMMITTEE, I. S. WRIGHT, Chairman, New York. B. ALEXANDER, Boston, Mass. W. M. ALLEN, St. Louis, Mo. W. CROSBY, Washington, D.C. R. HERTZ, Bethesda, Md. G. D. PENICK, Chapel Hill, N.C. L. M. SCHUMANN, Minneapolis, Minn. J. S. SPITTELL, Rochester, Minnesota C. L. SPURLING, Baltimore, Md. PAGENO="0411" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7241 TABLE I-PLANNED PARENTHOOD CLINICS, WHITE PATIENTS Minne- Balti- Pitts- St. Indian- Percent apolis more burgh Miami Louis apolis Total of total 15to19 99 6 4 14 88 211 8.9 20to24 460 12 35 11 82 326 926 36.8 25 to 29 303 14 42 12 108 227 706 28.1 30 to 34 151 5 21 6 63 139 385 15.3 35to39 90 4 11 3 34 73 215 8.5 40to44 32 1 8 18 59 2.3 45 to 49 11 1 12 .5 50+ Total 1,146 35 115 37 310 871 2,514 100.4 Phlebitis 1 2 3 (1) Embolism `Incidence 1.19/1,000. TABLE I I-PLAN NED PARENTHOOD CLI NICS, NEGRO PAIl ENTS Minne- Indian- Percent of apolis Baltimore Miami Miami' apolis Boston' St. Louis Total Total 15to19 11 2 2 2 36 1 7 61 5.9 20 to 24 20 19 7 19 171 18 45 299 28. 8 25 to 29 25 19 9 27 154 21 52 307 29.6 30 to 34 11 6 2 23 103 8 35 188 18.1 35to39 5 9 5 25 52 1 18 115 11.1 40 to 44 2 3 30 9 1 2 47 4.5 45to49 18 2 20 1.9 50+ 1 1 .1 Total 74 58 25 145 527 50 159 1,038 100.0 Total Percent of total 15to19 19 9 7 4 39 3.5 20 to 24 83 95 55 59 292 26.4 25 to 29 69 124 48 25 266 24.0 30 to 34 54 139 39 27 259 23.4 35 to 39 34 94 19 11 158 14.3 40 to 44 26 46 5 6 83 7.5 45to49 2 4 1 7 .7 50 to 55 1 1 .1 Total 288 511 173 133 1,105 99.9 Phlebitis 2 2=1,81/1,000 incidence. Embolism 1 1=0.91/1,000 incidence. Phlebitis 0 Embolism 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 (2) 0 Not planned parenthood. 2 Incidence 0.96/1.000. TABLE 111.-WHITE PATIENTS, PRIVATE, ST. LOUIS PAGENO="0412" 7242 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~ _~or~_c~, o w~ r~- N- -~u~ - = .~ ~ ,~ ci) ~ C'JNJ,-~ LC) ci) - ~ ~-~HH~ - 0 = H ~ ~ I~L()~ ~ : H ~ * I1III:I: ~ C) ~ C) ~ C) ~ C)It) ~ U) ~LC) *- - ~ E LU PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7243 TABLE V.-SUMMARY Table I Table II Table III Table IV Total Percentoftotal 15to19 211 61 39 70 381 6.56 20 to 24 926 25 to 29 706 30 to 34 385 35to39 215 299 307 188 115 292 266 259 158 351 308 199 133 1,868 1,587 1,031 621 32.22 27.36 17.78 10.72 40 to 44 59 47 83 65 254 4.38 45 to 49 12 20 7 12 51 .88 50to55 1 1 3 5 .09 Total 2,514 1,038 1,105 1,141 5,798 99.99 Phlebitis 3 1 2 3 . 9 =1.55/1,000 incidence. Embolism 0 0 1 1 2 =0.34/1,000 incidence. TABLE Vl.-COMPARISON OF AGE-SPECIFIC MORTALITY FROM THROMBOEMBOLIC PHENOMENA AMONG WHITE ENOVID USERS AND THE WHITE NONPREGNANT U.S. POPULATION, 1962 Age group Enovid users Ge neral population Number of TE deaths Population,l white females Rate per million Number of TE deaths Population, white nonpregnant females Rate per million 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 Total 0 4 2 2 2 2 67, 200 329, 600 268,900 177,100 106, 300 43, 500 0 12. 1 7. 4 11.3 18. 8 46. 0 10 20 30 37 40 66 5, 556, 000 2, 759, 000 2, 861, 000 4,015,000 5, 037, 000 5, 374, 000 1. 8 7. 3 10. 5 9.2 7. 9 12. 5 12 992, 600 12. 1 203 25, 602, 000 2 7 9 `Age distribution is based on Dr. Allen's sampling of clinic and private M.D's and on an assumed total population of white users of Enovid. 2 When adjusted for differences in age distribution this rate equals 8.4 deaths per million. The difference between the 12.1 and 8.4 rates is not statistically significant, but the differences between the Enovid users and general population rates for the 35 and over groups are highly significant. The Enovid rate for ages 20-24 is large enough to be of borderline significance (P=.06). ASSUMPTIONS NECESSARY FOR THESE CALCULATIONS 1. That all users were white. 2. Distribution by age (estimated) is representative for Enovid users. 3. That our 60 percent sample provided a valid estimate of 1962 deaths from TE cases. 4. That all 1962 cases of fatal TE-Pulmonary embolism are known to us. 5. That the proportion of post-operative patients among the Enovid users (in the denominator) is not significantly different from that in the general population denominator. 6. That the proportion of deaths where Enovid was being used for pathologic states (noncontraceptive) is the same as the proportion of Enovid users for such States. TABLE VII.-THROMBOEMBOLIC DEATHS PER MILLION IN WHITE USERS OF ENOVOID AND IN THE GENERAL POPuLATION OF WHITE NONPREGNANT FEMALES The two numerators and the two denominators used in obtaining the comparative death rates are shown below: Envoid users: Deaths (12).-White nonpregnant females; aged 15 to 44; death associated with PE/TE; excludes post-operative cases. Equals 12.1 deaths per million users. Enovid Users (992,000).-White females; aged 15 to 44. Nonusers: General population deaths (203).-White nonpregnant females; aged 15 to 44; deaths classified under ISC codes 463-6; excludes post-operative cases. Equals 8.4 deaths per million users General population (25,602,000) .-White nonpregnant females; aged 15 to 44. PAGENO="0414" 7244 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1001 901 801 : I t50 ~ 40-. ~ 30 20 101 Influence of Excessive Factor ~ on in Vitro Clotting Systems PRQTHROIID/N UTILIZATION RATES .~Y,~'/ure: Z0 ml /iOflfl2l humcn blxd 1.0 nil sd/ne or froclion T~rofir~. 289C % Factor ~ mixture 940 % 765% 100 % 54 % 0 15 30 Ti'ne in MthL//es 45 60 PAGENO="0415" 00 200 300 400 500 600 700 800 900 1000 200 300 % A//F in C/oIling Mix/we Factor 3flI[ Activity in Hemophilic Dog on Daily Dose of 5 mg Enovid -/40 ~ -/30 ~ COMPETITIVE PROBLEMS IN~ THE DRUG INDUSTRY 7245 Influence of Excessive Factor ~UI on In Vitro Clotting Systems WHOLE BLOOD CLOTTiNG TIMES (2nd of huo ttibes/ Mixture: 2.0 ml norn,o/ hun7on i/cod 5 4 `3 2 to 100 90 80 hernophilic r160 -/50 control- 1% 40 30 20 10 0 II I I I I, 5 18 9 20 21 22 23 25 2627 28 29 30 2 4 6 0 12 7 9 March - /20 1/0 ~ 22 24 April PAGENO="0416" 7246 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Influence of Excessive Factor ~ on In Vitro Clotting Systems I 0 - PART/AL TIIROMSOPLAST/N TIME (2 Exp/s.) Mix/o'e: 0.1 ml animal human p/aTtic 100 - 0/ nil saline a, plasma 1,-cc/ion Tempeia/w-e: 28C 2::: ~ ~ 60 50 - ~ -r ~i 0 100 200 3~0 400 500 600 700 800 900 000 % A//F in C/o//thg Mix/ures 140 130 Influence of Excessive Factor 57111 on i~.Yjtro Clotting Systems PARTIAL THROMBOPLASTIN TIMES Mix/we: 0.1 nil hemaphi/ic human p/sinus 0.1 ml saline or plasma fran/ian Tempeic/ux e: 28C 90 0 100 200 300 400 500 600 700 800 900 1000 % A//F in C/o//thg Mixture PAGENO="0417" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7247 FINAL REPORT ON EN0vID BY THE AD Hoc COMMITTEE FOR THE EVALUATION OF A POSSIBLE ETI0LOGIc RELATION WITH THROMBOEMBOLIC CONDITIONS SUBMITTED TO THE COMMISSIONER OF THE FOOD AND DRUG ADMINISTRATION OF THE DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, SEPTEMBER 12, 1963 * * * * * * * (Pages 1 through 13 of the Final Report on Enovid were identical to the Report on Enovid and, therefore, have been omitted. The balance of the Final Report on Enovid follows.) DISCUSSION Inasmuch as the population number for Enovid users estimated from avail- able data is not an exact figure, but based on drug distribution figures, some attempts were made to determine the effects of a 50% decrease and a 10% decrease in the estimated population of white users to see what effect this might have on the mortality rates among Enovid users and the significance of any difference from those in the general population. Any increase in this estimate of users would obviously reduce the user death rates and these rates would approach those in the general population. This would be particularly true if we deducted too many as Negro users, a possibil- ity which remains. A 50% decrease in the estimate of users would double the Enovid rates. This would make the overall rate as well as the rates in the 20-24 and 40-44 year age groups very significantly greater. A 50% decrease in the population estimate represents an extreme possibility rather than a probable estimate and is deemed highly unlikely. A 10% decrease in our user- population estimate (which might represent a reasonable error) would, how- ever, not yield Enovid-user death rates significantly different from the general population rates (total and individual 5-year age groups) at the level of P=0.05. In summary, on the basis of the available data and if the above outlined ass~Tmptions are reasonably correct, no significant increase in the risk of thromboembolic death from the use of Enovid in this population group has been demonstrated. There is a need for comprehensive and critical studies regarding the possible effects of Enovid on the coagnlation balance and related production of throm- boembolic conditions. Pending the development of such conclusive data and on the basis of present experience this latter relationship should be regarded as neither established nor excluded. Although a detailed study is not within the scope of this report it it is rec- ognized that in judging the over-all risk from and the values of the use of Enovid, data concerning the risks of pregnancy and induced abortion in each age group would be extremely important. Any firm reliance on the risks as calculated is tempered by the assumptions made. This committee recommends that a carefully planned and controlled pro- spective study be initiated with the objective of obtaining more concusive data regarding the incidence of thromboembolism and death from such conditions in both untreated females and those under treatment of this type among the per- tinent age groups. References 1. Egeberg and P. Owen-Oral Contraception and Blood Coagnlability-Britain Medical Journal-January 26, 1963 2. Rappaport, S. I.-Coagnlation Factor Analysis. Appendix V-Pg. 154-Proc. Conf. Thromboembolic Phenomena in Women-G. P. Searle & Co. 1962 3. Henstell, H. 11.-Coagulation Studies in Los Angeles Planned Parenthood Center Patients. Appendix VI pg. 156 ibid. 4. Spittell, J. A., Owen, C. A., Thompson, J. H. and Bowie, W. H. J.-Personal Communication to the Committee-1963 5. Penick, G. D.-For the Committee. 1953 COMMITTEE, I. S. WRIGHT, Chairman, New York. B. ALEXANDER, Boston, Mass. W. M. ALLEN, St. Louis, Mo. W. CROSBY, Washington, D.C. R. HERTZ, Bethesda, Md. G. D. PENICK, Chapel Hill, N.C. L. M. SCHUMANN, Minneapolis, Minn. J. S. SPITTELL, Rochester, Minn. C. L. SPURLING, Baltimore, Md. 40-471 0-70--tot. 17-27 PAGENO="0418" 7248 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE 1.-PLANNED PARENTHOOD CLINICS-WHITE PATI ENTS Minne- Pitts- Indian. Percent apolis Baltimore burgh Miami St. Louis apolis Total of total 15to19 99 6 4 14 88 211 8.9 20to24 460 12 35 11 82 326 926 36.8 25 to 29 303 14 42 12 108 227 706 28. 1 30to34 151 5 21 6 63 139 385 15.3 35 to 39 90 4 11 3 34 73 215 8.5 40 to 44 32 1 8 18 59 2.3 45 to 49 11 1 12 .5 50+ Total 1,146 35 115 37 310 871 2,514 100.4 Phlebitis 1 2 3 (1) Embolism - `Incidence 1.19/1,000. TA BLE Il.-PL ANNED PA RENTHOOD CLINICS -NEGRO PATIENTS Minne- Indian- Percent of apolis Baltimore Miami Miami' apolis Boston I St Louis Total total 15to19 11 2 2 2 36 1 7 61 5.9 20 to 24 20 19 7 19 171 18 45 299 28.8 25 to 29 25 19 9 27 154 21 52 307 29.6 30to34 11 6 2 23 103 8 35 188 18.1 35 to 39 5 9 5 25 52 1 18 115 11. 1 40 to 44 2 3 30 9 1 2 47 4.5 45 to 49 18 2 20 1.9 50+ 1 1 .1 Total 74 58 25 145 527 50 159 1,038 100.0 Phlebitis 0 Embolism 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 (2) 0 `Not planned parenthood. 2 Incidence 0.96/1,000. TABLE 111.-WHITE PATIENTS, PRIVATE, ST. LOUIS Total Percent of total 15to19 19 9 7 4 39 3.5 20 to 24 83 95 55 59 292 26.4 25 to 29 69 124 48 25 266 24. 0 30 to 34 54 139 39 27 259 23.4 35 to 39 34 94 19 11 158 14.3 40to44 26 46 5 6 83 7.5 45to49 2 4 1 7 .7 50to55 1 1 .1 Total 288 511 173 133 1,105 99.9 Phlebitis 2 2 =1.81/1,000 incidence. Embolism 1 1 =0.91/1,000 incidence. PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7249 ~ ~~wr-~o~ a~ ~ ~ ~ - co ~ c~z - o ~ - w ~ :U,~::Hr~. = ~ If) LU ~ -j LU I- LI ~ - 2 0. $$ U.) .~ I ~ ~ u~r..Lr)c~4s~ 2 ~ ~ H E fDC~4'~ H H U,©Lt) ~ .0 E ~ 0~LU PAGENO="0420" 7250 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE V.-SUMMARY Percent Tablet Table It Table Ill Table IV Total of total 15to19 211 61 39 70 381 6.56 20 to 24 25 to 29 30 to 34 35 to 39 926 706 385 215 299 307 188 115 292 266 259 158 351 308 199 133 1,868 1,587 1,031 621 32.22 27.36 17.78 10.72 40 to 44 59 47 83 65 254 4.38 45 to 49 12 20 7 12 51 .88 50to55 Total 1 1 3 5 .09 2,514 1,038 1,105 1,141 5,798 99.99 Phlebitis Embolism 3 0 1 0 2 1 3 1 9 2 (1) (3) I Incidence 1.55/1,000. 2 Incidence 0.34/1,000. TABLE Vl.-COMPARISON OF AGE-SPECIFIC MORTALITY FROM THROMBOEMBOL1C PHENOMENA AMONG WHITE ENOVID USERS AND THE WHITE NONPREGNANT U.S. POPULATION, 1 1962 Enovid users General population Popula. tion Number of TE Age group deaths Popula. tion 2 white females Rate per million Number of TE deaths white nonpreg- nant females Rate per million Prob. ability values 15 to 19 0 67,200 0 10 5,556,000 1.8 0.89 20 to 24 4 329,600 12. 1 20 2, 759, 000 7.3 0.22 25 to 29 2 268,900 7.4 30 2, 861, 000 10. 5 0.47 30 to 34 2 177, 100 11.3 37 4, 015,000 9.2 0. 49 35 to 39 2 106,300 18. 8 40 5, 037, 000 7.9 9.21 40 to 44 2 43, 500 46. 0 66 5,374,000 12. 3 0. 10 Total 12 992,600 - 12~ 1 203 25,602,000 1 7.9 0. 14 I When adjusted for differences in age distribution this rate equals 8.4 deaths per million. The difference between the 12.1 and 8.4 rates is not statistically significant (P=0.14), neither are the differences between the rates among the several age groups. 2 Age distribution is based on Dr. Allen's sampling of clinic and private M.D.'s and on an estimated total population of white users of Enovid. 3 Probability from poison distribution. Note-Assumptions necessary for these calculations: 1. That all users are white. 2. Distribution by age (estimated) is representative for Enovid users. 3. That our 60 percent sample provided a valid estimate of 1962 deaths from TE cases. 4. That all 1962 cases of fatal TE-Pulmonary embolism are known to us. 5. That the proportion of post-operative patients among the Enovid users (in the denominator) is not significantly different from that in the general population denominator. 6. That the proportion of deaths where Enovid was being used for pathologic states (noncontraceptive) is the same as the proportion of Enovid users for such States. TABLE VII.-THR0MB0EMB0LIC DEATHS PER MILLION IN WHITE USERS OF EN0vID AND IN THE GENERAL POPULATION OF WHITE NONPREGNANT FEMALES The two numerators and the two denominators used in obtaining the compara- tive death rates are shown below: Enovid users: Deaths (1~).-White females; aged 15 to 44; death associated with PE/TE; excludes post-operative cases. Equals 12.1 deaths per million users. Enovid users (992,000).-White females; aged 15 to 44. Nonusers: General population deaths (~O3).-White females; aged 15 to 44; deaths classi- fied under ISC codes 463-6; excludes post-operative cases. Equals 8.4 deaths per million users. General population (25,602,000).-White females; aged 15 to 44. PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7251 1~'igure I Influence of Excessive Factor ~!U on In Vitro Clottir~ Systems * PRDTHR0~f8/N UTILIZATION RATES iizi~vs: ~O ml ~ ~ Miod IDm/so/ir,.cvf'uC/iCdl T~s,u/ure 28'C \ `\ S FOCtOf ~ `940% 765% \ 100% `.54% ~ ~1~ 0 15 30 45- 60 Tune in /1/mi/os N 100 ~:3o PAGENO="0422" 7252 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Figure II Influence of Excessive Factor ~ on In Vitro Clotting Systems Wht~L( 8LOCt~ CLOTTINC TIMES (2nd of lit' lube:) Mi,lgtt~ 20 ml riojrxI atumcn blood ~J' ~:1, ~ 0 100 200 300 400 500 600 700 800 900 1000 1200 1300 % A/IF in C/oiling Mix/ure Figure III Factor ~IIt Activity in Hemophilic Dog on Daily Dose of 5mg Enovid /60 ~ Ii I ~ 5 8 19 20 21 22 23 25 26 27 28 29 30 2 4 6 10 12 17 9 22 24 tIci'ch PAGENO="0423" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7253 FigurelV Influence of Excessive Factor ~ on jrL~tro Clotting Systems 110 - PART/AL TMR0M~OPLASTIN TIME (2 (ç/~) Miil~rs: 0/ ml axma/ ,timne pIa:n~ 100 - 0/ ml saline ~ plasma f,aclb, Tsmpsvalws: 28'C ~ `60 50 ~ i r ~ I $ I 0 100 200 300 400 500 G00 700 800 900 1000 % AMP in CIo//iri~ M,x/u~es Figure V Influence of Excessive Factor V111 on In Vitro Clotting Systems 258-ps 140-' $30 - PART/AL T/I2OMBOPLAST/M TIMES Mix/we: 0/ ml Aemopáilic huma. p/a~ 4 ~ 80-i 0 1 $ I I $00 200 300 400 500 600 700 800 900 1000 % AMP in C/oiling Mix/urn PAGENO="0424" APPENDIX VI THE LIBRARY OF CONGRESS, LEGISLATIVE REFERENCE SERVICE, Washington, D.C., February 26, 1970. To: Senate Subcommittee on Monopoly, Seleet Committee on Small Business. From: Education and Public Welfare Division. Subject: Study of pharmaceutical advertising and critical reactions regarding oral contraceptives in selected medical journals. This report is in response to a request from the Chairman of the Subcom- mittee asking the Legislative Reference Service to undertake an examination of patterns of pharmaceutical advertising appearing in certain medical jour- nals over a three year period. We were asked to determine the quantity and kind of advertising for oral contraceptives and advertising for other pharma- ceutical products. In addition, it was requested that we examine any critical reviews, correspondence, editorial comment, etc., which seem to draw to the attention of readers some of the potential or actual adverse effects of oral con- traceptive products used by human beings. Due to the limitations of time set by the Committee, we are forwarding here only that portion of the study deal- ing with oral contraceptive advertising. We will, as soon as possible supply information pertaining to reports of adverse effects of oral contraceptives, such as they appear in the journals surveyed. 1. The advertising survey design At the request of the Subcommittee staff, the Legislative Reference Service undertook a study of pharmaceutica1 advertising for oral contraceptive prod- ucts appearing in three medical journals, each of which is published by a dif- ferent professional association of medical practitioners. Following a conference with the staff, three journals were selected for examination: The American Journal of Obstetrics and Gynecology, published by the American Association of Obstetricians and Gynecologists and its affiliated bodies; OF, published by the American Academy of General Practice; Obstetrics and Gynecology, pub- lished by the American College of Obstetricians and Gynecologists. The survey period covered a span of three years for each publication, from January 1967 through December* 1969. Each issue of each magazine was reviewed by the staff. The journals selected were obtained from the collections of the Library of Congress and the National Library of Medicine. As in the case of other advertising surveys previously submitted to this Committee, the information offered in this report was obtained fr6m a review of the advertising pages in each journal and from a review of the advertising indices which each of the journals publishes in each issue. Where the advertis- ing indices were used, careful examination of the particular index was made to assure that the information contained therein accurately reflected advertis- ing copy appearing in the publication. Where the indices were deemed unrelia- ble, a page-by-page review was made of the issues under study. The criteria employed in tabulating the data contained in this survey have been in line with criteria utilized in previous advertising survey reports to the Committee. Only those advertisments for products which specifically represent a product as designed for contraceptive purposes serve as the basis for the data con- tained in this report under the classification or oral contraceptive advertising. Combination hormone products, which are often promoted for other therapeutic purposes such as relief of menopausal symptons, amenorrhea, etc., are elimi- nated from the category of oral contraceptive advertising. Advertising for such products, however, are included in the figures showing total volume of all advertising pages. The advertising copy published in each of the three journals was studied in detail to obtain the following information: 1) the total volume of advertising in each journal 2) the proportion of advertising copy devoted to oral contra- (7254) PAGENO="0425" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7255 ceptives 3) the total number of advertising pages for contraceptive devices other than oral-chemical products. In addition, we were able to compile statis- tics on the advertising patterns of the leading manufacturers of oral contra- ceptives, in order to show ratios between advertising for oral contraceptives and advertising for all other products promoted by these manufacturers in each journal. Summary data which appears in the tables at the end of this report were compiled for each journal. 2. Organization of the report The summary and detailed data given in this report are arrayed by the par- ticular journal surveyed and are computed to give total figures for the entire three~year period, rather than a year-by-year breakdown. OF, which is pub- lished monthly and is the largest of the three publications, in terms of circula- tion and total volume of advertising, is discussed in Section I of the report. Section II is devoted to the American Journal of Obstetrics and Gynecology, which is a semi-monthly specialty journal and ranks second in this survey in terms of advertising volume. Obstetrics and Gynecology, a monthly specialty journal, is discussed in Section III. Each Section in the report begins with summary data covering the entire survey period for each journal studied. The tables also contain a breakdown for each of the seven leading contraceptive manufacturers advertising in the journals. These summaries cèntain information about the total number of oral contraceptive ads sponsored by each manufacturer and the total number of advertisements for all products sponsored by oral contraceptive manufacturers. For the purposes of this report, we have identified as "leading contraceptive manufacturers" only those manufacturers who advertised frequently in the journals studied. In the tables, the leading manufacturers of oral contracep- tives have been organized to show rank order in terms of volume of advertis- ing for oral contraceptive agents. SECTION I. GP, General Practice.1 Oral contraceptive advertising represents 3.5 percent of the total advertising copy in "GP" for the period January 1967 through December 1969. Volume in pages, Years 1967-69: Total pages oral contraceptive advertising 227 Total pages all advertising 6,536 Total pages advertising for other contraceptive devices 20 1 Information based on a review of 36 monthly issues. VOLUME IN ORAL CONTRACEPTIVE ADVERTISING SPONSORED BY LEADING MANUFACTURERS, YEARS 1967-69 Manufacturers Total pages oral contraceptive advertising Total pages firm advertising Ortho Searle Lilly Mead-Johnson Wyeth Syntex Parke-Davis Total all manufacturers 99 58 27 16 15 12 0 164(65) 122 (64) 267 (240) 189 (173) 193 (178) 12 (0) 200 (200) 227 1,147 (920) I Figures in parentheses indicate total pages of firm advertising minus pages devoted to oral contraceptive ads. PAGENO="0426" 7256 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SECTION 11.-The American Journal of Obstetrics and Gynecology.' Advertising, 1967 through 1969. Oral contraceptive advertising represents 17.5 percent of the total advertising copy in "The American Journal of Obstetrics and Gynecology" for the period January 1967 through December 1969. Volume in pages, Years 1967-69: Total pages oral contraceptive advertising 1, 142 Total pages all advertising 6, 512 Total pages advertising for other contraceptive devices 102 1 Information based on a review of 72 semimonthly issues. VOLUME IN ORAL CONTRACEPTIVE ADVERTISING SPONSORED BY LEADIN G MANUFACTURER 5, YEARS 1967-69 Manufacturers Total pages oral contraceptive advertising Total pages firm advertising I Ortho Searle Parke-Davis Lilly Syntex Mead-Johnson Wyeth Total all manufacturers 276 224 168 165 165 91 53 486 (192) 374 (150) 248 (80) 277 (112) 185 (20 172 (81 131 (78) 1, 142 1,855 (713) 1 Figures in parentheses indicate total pages of firm advertising minus pages devoted to oral contraceptive ads. SECTION III. Obstetrics and Gynecology.' Advertising, 1967 through 1969. Oral contraceptive advertising represents 14.1 percent of the total advertising copy in "Obstetrics and Gynecology" for the period January 1967 through December 1969. Volume in pages, Years 1967-69: Total pages oral contraceptive advertising 547 Total pages all advertising 3, 914 Total pages advertising for other contraceptive devices 71 1 Information based on a review of 36 monthly issues. VOLUME IN ORAL CONTRACEPTIVE ADVERTISING SPONSORED BY LEADING MANUFACTURERS, YEARS 1967-69 Manufacturers Total pages oral contraceptive advertising Tota I pages firm advertising 1 Ortho Searle Lilly Parke-Davis Syntex Wyeth Mead-Johnson 144 94 81 ~ 70 ~ 38 250 (106) 199 (105) 117 (36) 145 (70) 82 (12) 104 (59) 102 (64) Total all manufacturers 547 999 (452) 1 Figures in parentheses indicate total pages of firm advertising minus pages devoted to oral contraceptive ads. PAGENO="0427" APPENDIX VII THE LIBRARY OF CONGRESS, LEGISLATIVE REFERENCE SERVICE, Washington~, D.C., March 4, 1970. To: Subcommittee on Monopoly, Select Committee on Small Business. From: Education and Public Welfare Division. Subject: Articles discussing side effects of oral contraceptives. This is in further reply to a previous request from the Staff of the Subcom- mittee asking the Legislative Reference Service to undertake a study of the patterns of oral contraceptive advertising appearing in selected medical jour- nals and a review of any articles appearing in these journals which seem to draw the attention of the reader to potential or actual side effects of oral con- traceptive products used in human beings. We have already forwarded to the Subcommittee the information dealing with oral contraceptive advertising. A description of the number and types of articles discussing the side effects of oral contraceptives is outlined below. 1. Journal sources and methods used in~ preparing this review As requested by the Subcommittee staff, the medical journals to be examined for this review were the following: The American Journal of Obstetrics and Gynecology, published by the American Association of Obstetricians and Gyne- cologists; GP, published by the American Academy of General Practice; and Obstetrics and Gynecology, published by the American College of Obstetricians and Gynecologists. The survey period covered a span of three years for each publication, from January 1967 through December 1969. In order to obtain a complete listing of all articles appearing in these jour- nals dealing with the effects of oral contraceptives, we examined the subject. index for each publication which appears at the end of every volume and lists by various subject classifications of every article appearing in each issue, including articles in the form of a research paper, editorial comment, capsule announcement, or correspondence from readers. For the purposes of this review, we have eliminated any articles dealing with oral contraceptives which. were limited in discussiion to merely a statistical reporting of the relative suc- cess of various contraceptive methods in preventing actual conception. How-. ever, if articles falling into the above-mentioned category also made references to actual reported side effects or adverse reactions to the oral-chemical agents, these articles were included in the information presented here. Also excluded from this report were articles which were concerned only with a technical study of the physiological action or oral contraceptives and which did not con- tain specific reference to potential or actual side effects which might result from the type of physiological action described. The tables which appear at the end of this report summarize, by journal, the total number of articles discussing potential or actual side effects of oral contraceptives. Also, the. data for each journal has been subdivided to show the following: 1. Total number of articles specifically recommending caution in prescribing oral contraceptives for individuals with certain conditions predisposing to adverse side effects. 2. A classification of articles indicating the types of potential or actual side effects under discussion. We have attached a list of the articles examined in this review arranged alphabetically by title under each journal surveyed. There appears to be a con- sensus of opinion in the majority of articles surveyed containing recommenda- tions regarding limited prescribing of oral contraceptives for women with cer- tam medical histories that the advantages of the pill outweigh the potential or actual risks in long-term use in human beings. It might also be pointed out (7257) PAGENO="0428" 7258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY that there was only a very slight increase between 1967 and 1969 in the total number of articles found in these journals discussing the various side effects encountered by users of oral contraceptives. Aside from the articles found in GP, which were mainly in the form of letters from physicians or brief reviews of papers appearing in other medical journals, the majority of the articles sur- veyed were in the form of research papers reporting studies conducted at major hospitals or medical centers. SEcTIoN I. The American Journal of Obstetrics and Gynecology Articles discussing side effects of oral contraceptives, years 1967-69: Total number articles discussing side effects 35 Total number articles specifically cautioning against prescription in certain conditions 9 Breakdown of articles by type of side effect discussed, articles describing: "Usual" side effects 7 Effect on vascular system - - - - 9 Effect on metabolic processes 5 Effect on hepatic system 1 Effect on reproductive system 8 All other side effects 2 5 I Refers to broad spectrum of relatively mild complaints, such as nausea, weight gain, breakthrough bleeding, headache, etc., frequently reported by women on oral contraceptive therapy. 2 Refers to articles discussing all other side effects, including the relationship between oral contraceptive and such things as thyroid function, cancer, intestinal infarction, arthritis, etc. SECTION II. GP, General Practice Articles discussing side effects of oral contraceptives, years 1967-69: Total number articles discussing side effects 7 Total number articles specifically cautioning against prescription in certain conditions 5 Breakdown of articles by type of side effect discussed, articles describing: "Usual" 1 side effects Effect on vascular system 3 Effect on metabolic processes 1 Effect on hepatic system 0 Effect on reproductive system 1 All other side effects 2 2 1 Refers to broad spectrum of relatively mild complaints, such as nausea, weight gain, breakthrough bleeding, headache, etc., frequently reported by women on oral contraceptive therapy. 2 Refers to articles discussing all other side effects, including the relationship between oral contraceptives and such things as thyroid function, intestinal infarction, arthritis, etc. SECTION III. Obstetrics and Gynecology Articles discussing side effects of oral contraceptives, years 1967-69: Total number articles discussing side effects 37 Total number articles specifically cautioning against prescription in certain conditions 13 Breakdown of articles by type of side effect discussed, articles describing: "Usual" 1 side effects Effect on vascular system 2 Effect on Metabolic processes - 7 Effectonhepaticsystem 2 Effect on reproductive system 12 All other side effects 2 5 I Refers to broad spectrum of relatively mild complaints, such as nausea. weight gain, breakthrough bleeding, headache, etc., frequently reported by women on oral contraceptive therapy. 2 Refers to articles discussing all other side effects, including the relationship between oral contraceptives and such things as thyroid function, cancer, intestinal infarction, arthritis, etc. PAGENO="0429" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7259 ARTICLES DISCUSSING SIDE EFFECTS OF ORAL CONTRACEPTIVES A. The American Journal of Obstetrics and Gynecology 1. "Alkaline Posphatase Activity of Polymorphonuclear Leukocytes in Rela- tion to Oral Contraceptives," Mohamed B. Sammour, PROSE, and Samir 0. Hilal, MRCPE. 103 :823-827, March 15, 1969. 2. "Carbonic Anhydrase Concentration in Endometrium After Oral Progestins, Richard A. Nicholls, MD, and John A. Board, MD. 99:829-832, Novem- ber 15, 1967. 3. "Changes in Blood Coagulation and Fibrinolysis in Women Receiving Oral Contraceptives." Johan Ygge, MD, et al. 104:87-98, May 1, 1969. 4. "Comparative Validity of Oral and Intravenous Glucose Tolerance Tests in Pregnancy; a Study of 144 Patients Tested Both During Pregnancy and in the Nonpregnant State," Fred Benjamin, MD, and Donald J. Casper, MD. 97: 488-492, February 15, 1967. 5. "Control of Postpartum Breast Engorgement with Oral Contraceptives," David E. Booker, MD, and Irwin R. Pahl, MD. 98: 1099-1101, August 15, 1967. 6. "Depression of Physical Activity by Contraceptive. Pills," Naomi M. Morris, MD, and J. Richard Udry, Ph.D. 104: 1012-1014, August 1, 1969. 7. "Effect of Estrogen-Progestin Combinations on Clotting Factors," Roger W. Robinson, MD. 99: 163-167, September 15, 1967. 8. "Effect of Mestranol and Chlormadinone Acetate on Urinary Excretion of FSH and LH," Vernon C. Stevens, Ph. P., et al. 102:95-lOS, September 1, 1968. 9. "Effect of Oral Contraceptives on Glucose Metabolism," Marshall B. Taylor, MD, and Martin B. Kass, MD. 102: 1035-1038, December 1, 1968. 10. "Effect of Prolonged Cyclic Therapy with Estrogen-Progestin Combinations on Thyroid Function," R. Ralph Margulis, MD, and Robert Leach, MD. 99: 263-68, September 15, 1967. 11. "Effects of a Sequential Oral Contraceptive on Endometrial Enzyme and Carbohydrate Histochemistry," Lawrence L. Hester, Jr., MD, et al. 102: 771- 783, November 15, 1968. 12. "Effects of a Sequential Oral Contraceptive on Plasma Insulin and Blood Glucose Levels After Six Months Treatment," William N. Spellacy, MD, K. L. Carlson, BS, and S. L. Schade, RN. 101: 672-676, July 1, 1968. 13. "Factors in Oral Contraception Related Hypertension," Max Rosenberg, MD. 104: 1221-22, August 15, 1969. 14. "High Blood Pressure and Oral Contraceptives; Changes in Plasma Renin and Renin Substrate and in Aldosterone Excretion," Michael A. Newton, MD, et al. 101:1037-45, August 15, 1968. 15. "Incidence of Side Effects with Contraceptive Placebo," Ranon Aznar- Ramos, MD, et al. 105: 1144-1149, December 1, 1969. 16. "The Incidence of Side Effects With Oral or Intrauterine Contraceptives," Joseph W. Goldzieher, MD. 102: 91-94, September 1, 1968. 17. "In Vitro Autoradiographic Study of the Endometrium From Women Treated Wtih Low-Dose Chlormadinone Acetate for Contraception," Hector Marquez-Monter, MD, et al. 102: 896-900, November 15, 1968. 18. "Oral Contraception Started Early in the Puerperium," Richard Frank, MD, William M. Alpern, MD, and Dorothy E. Eshbaugh, MD. 103: 112-120, January 1, 1969. 19. "Oral Contraceptive Medications and Headache," A. W. Diddle, MD. Wil- liam H. Gardner, MD, and Perry J. Williamson, MD. 105: 507-511, Octo- ber 15, 1969. 20. "Oral Contraceptives and Carbohydrate Metabolism," C. DiPaola, MD, et al 101: 206-216, May 15, 1968. 21. "Oral Contraceptives and Elevated Blood Pressure," J. E. A. Tyson, MD. 100: 875-876, March 15, 1968. 22. "Oral Pregestational Agents as a Cause of Candida Vaginitis," Helen Walsh, BS, Richard J. Hildebrandt, MD, and Harry Prystowsky, MD. 101: 991-993, August 1, 1968. 23. "Ovarian Morphology Following Cyclic Norethindrone-MestranOl Therapy," William V. Zussman, MD, Donald A Forbes, MD, and Robert J. Carpen- ter, MD. 99: 86-89, September 1, 1967. PAGENO="0430" 7260 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 24. "Patient Acceptance of Oral Contraceptives; 1. The American Indian," Edward B. Wallach, MD, Alan B. Beer, MD, and Celso-Ramon Garcia, MD. 97: 984-991, April 1, 1967. 25. "Patient Acceptance of Oral Contraceptives; 2. The Private Patient," Edward Wallach, MD, Francis M. Watson, Jr., and Celso-Ramon Garcia, MD. 98: 1071-1079, August 15, 1967. 26. "Platelet Adhesiveness and Lipoprotein Lipase Activity in Controls and in Subjects Taking Oral Contraceptives," J. M. Ham, MD, and R. Rose, B. Sc. 105: 628-631, October 15, 1969. 27. "Prolonged Anovulation Subsequent to Oral Progestins, R. Pinkney Rankin, MD. 103: 919-924, April 1, 1969. 28. "Psychiatric Reactions to Oral Contraceptives," Francis J. Kane, MD. 102: 1053-1062, December 1, 1968. 29. "Pulmonary Embolism and Oral Steroidal Contraceptives," Calvin J. Hobel, MD, and Daniel R. Mishell, Jr., MD. 101: 944-996, August 1, 1968. 30 Relationship Between the Oral Contraceptives and Fohc Acid Metabo lism," Frederick W. McLean, MD, et al. 104: 745-747, July 1, 1969. 31. "A Review of Carbohydrate Metabolism and the Oral Contraceptives," Wil- liam N. Spellacy, MD, 104: 448-460, June 1, 1969. 32. "Syndrome of Anovulation Following the Oral Contraceptives," Oscar I. Dodek, Jr., MD, and Herbert L. Kotz, MD. 98: 1065-1070, August 15, 1967. 33. "The Two Hour Sulfobromophthalein Retention Test and the Transaminase Activity During Oral Contraceptive Therapy," Ulf Larsson-Cohn, MD. 98: 188-193, May 15, 1967. 34. "Two Thousand Woman-Years' Experience with a Sequential Contracep- tive," Max C. Karrer, MD, and Edward R. Smith, MD. 102: 1029-1034, December 1, 1968. 35. "Zinc and Copper Levels in Pregnant Women and Those Taking Oral Con- traceptives," James A. O'Leary, MD, and William N. Spellacy, MD. 103:. 131-132, January 1, 1969. B. tiP, General Practice 1. "Blood Coagulation and Oral Contraceptives," in Information Please. 39: 135-137, June, 1969~ 2. "Intestinal Infarction Associated with Oral Contraceptives," in Tips From Other Journals. 39: 137, April 1969. 3. "Oral Contraceptives and Pulmonary Vascular Disease," in Tips From Other Journals, 38: 157, November, 1968. 4. "Oral Contraceptives in the Puerperium," in Tips From Other Journals. 40: 155, October, 1969. 5. "The Pill and Arthritis," in Medigrams. 40: 139, October, 1969. 6. "The Pill and Folic Acid," in Editorials. 40: 77, July, 1969. 7. "Pulmonary Embolism With Oral Steriodal Contraceptives," in Tips From Other Journals, 39: 121, February, 1969. C. Obstetrics and Gynecologij 1. "Achilles Tendon Reflex to Evaluate Thyroid Function During Pregnancy and in Subjects Taking Oral Contraceptives," T. Hilgers, BS, C. Crutch- field, MD, and W. N. Spellacy, MD. 30: 83-88 July, 1967. 2. "Adrenal-Pituitary Responsiveness During Therapy With an Oral Contra- ceptive," Jorge H. Mestman, MD, Gail V. Anderson, MD, and Don H. Nelson, MD. 31: 378-386, March, 1968. 3. "Amenorrhea Following Oral Contraceptives," David R. Halbert~ MD, and C. D. Christian, MD. 34: 161-167, August 1969. 4. "Amenorrhea Subsequent to Treatment With Oral Contraceptives," Robert W. Kistner. 29: 604-605, April 1967. 5. "Anovular Corpus Luteum in a Woman Taking and Oral Contraceptive," Kurt S. Ludwig, MD, and Marshall Horowitz, MD. 33: 696-702, May, 1969. 6. "Biliary Statis After Mestranol-Norethjndrone Ingestion; Report of a Case," G. H. Sabel, Lt, MC, USN, and R. F. Kirk, CDR, MC, USN. 31: 375-377, March 1968. 7. "Cholesterol Content of Menstrual Discharge; Influence of Contraceptives," Leon J. DeMerre, Ph.D, Elizabeth B. Gilbreath, BS, and D. Stanley Pat- tison, MD. 32: 645-648, November, 1968. PAGENO="0431" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7261 8. "Continuous Tablet Therapy for Oral Contraception," Philip J. DiSaia, MD, Clarence D. Davis, MD, and Ben Z. Taber, MD. 31: 119-124, Janu- ary, 1968. 9. `~Contraceptives, GTT, and Insulin Level," William N. Spellacy, MD. 32: 441-442, September, 1968. 10. "Cytolgic Changes Following the Use of Oral Contraceptives," Winifred Liu, MD, et al. 30: 228-232, August 1967. 11. "Effect of an Ovulatory Suppressant on Glucose Tolerance and Insulin Secretion," F. Xavier Pi-Sunyer, MD, and Stuart Oster, MD. 31: 482-484, Arpil, 1968. 12. "Effects of Contraceptive Hormone Preparations on Fine Structure of the Endometrium," Ernst R. Friedrich, MD. 30: 201-219, August, 1967. 13. "Effects of Contraceptives on Glycogen Content of Blood and Menstrual Discharge," Leon J. Demerre, Ph.D, Eizabeth B. Gilbreath, BS, and D. Stanley Pattison, MD. 33: 200-203, February, 1969. 14. "Effects of a Sequential Oral Contraceptive on Endocervical Carbohydrate Histochemistry," William W. Kellett, III, MD, et al 34: 536-544. Octo- ber, 1969. 15. "Estrogen-Deprivation Headaches," Eduard Eichner, MD. 32: 294, August, 1968. 16. "Failure of Mestranol to Prepare for the Generalized Schwartzman Reac- tion," L. L. Phillips, Ph.D, et al in reports of abstracts presented at annual convention of American College of Obstetricians and Gynecolo- gists. 33: 592-593, April, 1969. 17. "Fertility and Contraception After Age 40," Sherwin A. Kaufman, MD. 33: 288-291, February 1969. 18 "Growth Hormone Alterations by a Sequential-Type Oral Contraceptive," W. N. Spellacy, MD, W. C. Buhi, MS, and R. P. Bendel, MD. 33: 506-510, April, 1969. 19. "Hypertriglyceridemia During Treatment With Estrogen and Oral Contra- ceptives," Herbert Gershberg, MD, Mildred Hulse, MA, and Zenaida Javier, MD. 31: 186-189, February, 1968. 20. "Indocyanine Green Liver Function Studies on Women Taking Progestins," Norman K. Takaki, LCDR, MC, USN, and Carter W. Mathews, LT, MC, USN, 30: 220-227, August, 1967. 21. "Insulin and Glucose Studies After One Year of Treatment With a Sequen- tial-type Oral Contraceptive," William N. Spellacy, MD, William C. Buhi, MS, and Richard P. Bendel, MD. 33: 800-804, June, 1969. 22. "Modified Sequential Oral Contraceptives Employing Mestranol With Chlor- madinone," Edward T. Tyler, MD, Eric M. Matsner, MD, and Milton Gotlib, MD. 34: 820-824, December 1969. 23. "Nonpuerperal Galactorrhea and the Contraceptive Pill," Saul W. Rosen, MD. 29: 730-731, May, 1967. 24. "Norgestrel and Ethynyl Estradiol; a New Low-Dosage Oral Agent for Fertility Control," Edris Rice-Wray, MD, Christina Avila, MD, and Juvenal Gutierrez, MD. 31: 368-374, March, 1968. 25. "Norgestrel, a Low Dose, Oral Progestogen for Fertility Control," Maxwell Roland, MD, Max Friedman, MD, and Ralph J. Hessekiel, MD. 31: 637-642, May, 1968. 26. "Ophthalmologic Findings With Oral Contraceptives," Elizabeth B. Connell, MD, and Charles D. Kelman, MD. 31: 456-460, April, 1968. 27. "Oral Contraceptive Medications and Vulvovaginal Candidiasis," A. W. Diddle, MD, et al. 34: 373-377, September, 1969. 28. "Oral Contraceptives During the Immediate Postabortal Period," Jerome W. H. Niswonger, MD, et al. 32: 325-327, September, 1968. 29. "Oral Contraceptives and Intravenous Glucose Tolerance; 1. Data Noted Early in Treatment," Norman Ames Posner, MD, et al. 29: 79-86, Janu- ary, 1967. 30. "Oral Contraceptives and Intravenous Glucose Tolerance; 2. Long Term Effect," Norman Ames Posner, MD, et al. 29: 87-92, January, 1967. 31. "Oral Contraceptives: Selection of the Proper Pill," Richard P. Dickey, MD. 33: 273-288, February, 1969. 32. "The Oversuppression Syndrome," Benson J. Horowitz, MD, Mark Solomkin, MD, and Stanley W. Edelstein, MD. 31: 387-389, March, 1968. PAGENO="0432" 7262 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 33. "Plasma Lipids and Lipoprotein Alterations During Oral Contraceptive Administration," Bernard A. Sachs, MD, Lila Wolfman, BA, Norman Herzig, MD. 34: 530-535, October 1969. 34. "Prescribing Contraceptives for Teenagers-a Moral Compromise?" Ronald J. Pion, MD. 30: 752-755, November, 1967. 35. "Reversible `Cancer' and the Contraceptive Pill," John Graham, MD. Ruth Graham, BS, and Koji Hirabayashi, MD. 31: 190-192, February, 1968. 36. "The Story of Contraceptives," from Editorials. 31: 556-559, April, 1968. 37. "Vaginal Moniliasis in Private Practice," Bernard A. Davis, MD, 34: 40-45, July, 1969. PAGENO="0433" APPENDIX VIII [Planned Parenthood-World Population News Release, June 1965] MASS ORAL CONTRACEPTIVE STUDY FINDINGS RELEASED The findings to-date of a large scale, oral contraceptive research project have been announced by Alan F. Guttmacher, M.D., President, and Gordon W. Perkin, M.D., Associate Medical Director, of Planned Parenthood. The project, known as the "25 Month Club Study", was initiated in 1962 with the full endorsement of the Federal Food and Drug Administration. This massive clinical research program was established to study, and to follow from then on, women who had by then taken an oral ovulation suppressant (Enovid 5 mg.) for two years continuously. The examinations and data collection programs were performed by 38 selected Planned Parenthood Centers broadly distributed acorss the United States. Enrollment for the progam began in mid-1963 and terminated in November, 1964, at which time a total of 11,711 women had received their enrollment examinations (generally in their 25th month of medication-thus the popular pseudonym, "25 Month Club"). Thereafter, all enrollees reported on their phys- ical and mental conditions and were re-examined every six months. It is important to emphasize, Dr. Guttmacher stated, that the intent of this ongoing study is to follow closely women who remain on oral contraceptive medication for extended periods of time. The data do not generally reflect what is to be expected in women who have used the medication less than two years. The women in this study have presently completed over 29,000 years of experience with the medication. TOTAL USE-EXPERIENCE OF ALL ENROLLEES Total number Total number of women of months Initial enrollment exam (25th month) 11, 711 282, 553 First revisit (30th month) 17, 355 46, 159 Second revisit (36th month) 1 2, 776 17, 064 Third revisit (42d month) 1 617 3,712 Total use-experience, in this study, to date (months) 349,488 Total in terms of woman-years 29, 124 1 These are the women who have returned to date, and does not represent dropouts from the study. (7263) 40-471 0-70-pt. 17-28 PAGENO="0434" No. of Womoi~ .1 ~. C~) 03 o ~ ~ CD p. No. of Worn.,, I C, D m -`I I TOI -I 9? ~ri PAGENO="0435" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7265 MENSTRUAL HISTORIES Period of use in percent 25 to 30 31 to 36 37 to 42 months months months Spotting Breakthrough bleeding No withdrawal bleeding 15.6 4. 1 4.9 14.9 4. 1 5. 1 14.7 4. 4 4. 4 Conclusion: Among women who continue to use this type of oral contraceptive beyond 2 years, approximately 15 percent can expect to have some spotting, about 4 percent some breakthrough bleeding, and about 5 percent some "amenorrheic periods". 2,652/11, 711 (22.5 percent) reported irregular menses prior to taking norethy- nodrel w/mestranol; none had similar irregular menses while on the medication, but: 22.4 percent reported spotting at least once, 6.6 percent reported breakthrough bleeding at least once, and 7.1 percent reported no withdrawal bleeding at least once during the first 2 years of medication. PAGENO="0436" * * S * Irregular Menses D Spotting ~ Breakthrough Bleeding ~ No Withdrawal Bleeding 02 First 24 Mo. of Medication 25.30 Mo. 31.36 Mo. 37-42 Mo. Period of Use 25 *L~. Prior to Medication PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7267 DYSMENORRHEA 3,577/11,711 (30.2%) women reported having had a history of dysmenorrhea prior to taking norethynodrel w/mestranol; 7.0 percent reported similar dys- menorrhea during the first 2 years of medication. Period of USC ~ Reporting dysmenorrhea: percent 25 to 30 months 8. 5 31 to 36 months 8. 8 37 to 42 months 8. 9 PAGENO="0438" 100 75 ~ 50 25 Prior to Medication ~ Women Reporting Dysmenorrhea 0 Prior to Medication First 24 Mo. of Medication 25~30 Mo. 31 ~36 Mo. 3742 Mo. Period of Use PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7269 Conclusion: It can be expected from these data that 3 out of 4 women with a history of dysmenorrhea prior to taking the medication will receive persistent relief from dysmenorrhea during the period of medication. LIBIDO AND GENERAL WELL-BEING After 2 years of medication, the women were asked, "How is your sexual desire now as compared to before medication?" Over 60 percent reported "no change," 19 percent-"slight increase," 13 percent-"much increase," 6 percent- "slight decrease," and 2 percent-"much decrease." After each subsequent 6-month period, they were asked, "How is your sexual desire since your last visit?" The responses are shown in the following graph. PAGENO="0440" 100 75 S3 50 25 0 - At 30 Mo; ~ At 36 Mo. ~ At42Mo. 1.2 1.0 1.6 0 0 ~rj CD L~1 0 Slight Decrease Much Decrease No Change Slight Increase Much increase SEXUAL DESIRE PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7271 Similarly, after 2 years of medication, the women were asked, "How are you feeling, in general, now as compared to before medication?" Sixty-seven percent reported "no change," 11 percent-"some better," 17 percent-"much better;" 4 percent-"some worse," and 2 percent-"much worse." After each subsequent 6-month period, they were asked, "How are you feeling, in general, since your last visit?" The responses are shown in the following graph. PAGENO="0442" ~1~~ 100 * 75 . I 25 0 0.7 0.$ ~ ____ * ~ At36MO ,~ AL42Mo. Much `Worse Seme Worse No Change Some Better Much Better PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7273 GENERAL WELL-BEING Conclusion: After 2 years of medication, most women felt no change in their sexual desire or in their general well-being; however, for those who did note a change a greater number persistently said they felt better than worse. Subsequent to the 2-year period, libido and general well-being tend to stabilize. DEPRESSION 1,268/11,711 (10.8%) women reported depression as a common menstrually- related event in their premedication history; 692/11,711 (5.9 percent) reported similar depression during the first 2 years of medication. Period of use in Reporting depression: percent 25 to 30 months (492/7355) 6. 7 31 to 36 months (165/2776) 5. 9 37 to 42 months (40/617) 6. 5 PAGENO="0444" 0 L~i 0) z 0 * 0) 50 25 Women Reporting Depression 0 25*30 Mo. 31.36 Mo. 3742 Mo. Prior to Medication PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7275 Conclusion: Menstrually-related depression was reported by 10.8 percent of the study patients prior to medication. The rate decreased to 5.9 percent during the first 2 years and remained at approximately this level from the 25th to the 42d month on medication. NAUSEA AND EDEMA The following numbers of women reported these reactions at least once during: Period of use i n percent 25 to 30 31 to 36 37 to 42 24 months months months months 7.0 5.7 4.8 4.8 6.2 4.9 5.1 4.7 Nausea Edema PAGENO="0446" 100 EJ Nausea 75 ~.Edema ~50 25 o _...~._iz ~z ______________________________ First 24 Mo. o! Medication 25.30 Mo. 31.36 Mo. 37~42 Mo. Period of Use PAGENO="0447" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7277 Conclusion: The incidence of nausea and edema occurring in these women during 25th to 42d months of medication is slightly less than that reported by the same group during the first 2 years. After 24 months, the incidence appears to stabilize. No patients in the study group dropped out for these reasons. IFigures in percenti Class I Class II Class Ill Classes IV-V At 25 months At 30 months At 36 months 791 (5,208/6,583) (2, 090/2, 402) 79.9 204 (1,343/6,583) (300/2, 402) 20.1 0.4 (26/6, 583) (8/2, 402) 0 0.1 (6/6, 583) (4/2, 40~) At 42 months (1,094/1, 3~) (88/100) (275/1, 3~) (12/100) 0 0 : CERVICAL CYTOLOGY At the time of enrollment, 6,583/11,711 women had recorded Pap smears. Conclusion: The incidence of abnormal cytology was low in those women examined, and was not observed to increase with continued use (25-42 months). THROMBOPHLEBITIS This study was not designed to provide a comparative incidence of throm- bophiebitis. Such an investigation would require more detailed follow-up exam- inations than were feasible in order to establish (1) a positive diagnosis of the condition, (2) the existence of recognized contributing causes, and (3) whether the patient was hospitalized. Satisfying these criteria is necessary to provide any meaningful comparison with the only reliable base-line incidence data for this disorder which is limited to idiopathic, hospitalized cases. However, in an effort to provide a rough check on thromboembolic incidence, the women were asked, "Have you had thrombophlebitis?" at the time they were enrolled in the study (25th month of medication), and at each subse- quent six-month visit. All those answ.ering "yes" to this question are presently being followed-up to verify the diagnosis and hospitalization. When completed, this data will be analyzed electronically to provide a comparison with the exact population-at-risk at the time of each occurrence. The resulting incidence rate will then be released. Of interest is the fact that 116 of the 11,711 women enrolled reported a prior history of thrombophlebitiS; during the first two years of medication 8 reported a recurrence and continued uneventfully on the medication. A total of 58 occurrences (new and recurrent) were reported during the 29,124 woman- years of exposure, resulting in a crude incidence rate of 2 per 1,000 woman- years. This crude rate based on unverified patient-response will undoubtedly be sig- nificantly reduced by verification with each woman's personal physician, and classification as hospitalized and non-hospitalized cases. The crude rate does, however, closely correspond to those comparable estimates of thrombophlebitiS rates which include both hospitalized and non-hospitalized cases.* Conclusion: The crude reported incidence of thrombophiebitiS in women who have been taking an oral contraceptive (norethynodrel with mestranol) for two years or longer appears to approximate that in the untreated population. * Health Insurance Plan of New York: 1.97 cases/1,000 enrollees, both sexes, age 15-44 years. Morbidity Statistics In General Practice (England) : 2.4 cases/1,000 non-pregnant women 15-44 years. PAGENO="0448" 7278 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PROGRESS REPORT ON "THROMBOPHLEBITIS" CASES Of the 58 cases of "thrombophlebitis" which were noted in the 22,460 inter- view and examination reports received to date, careful investigation has revealed that: Twenty-seven were in error (no diagnosis of thromboplebitis). Fourteen cases were doubtful (diagnosis of thrombophiebitis could not be confirmed). Seventeen cases were confirmed as some form of thrombophiebitis. Of the 17 wIth a confirmed episode of thrombophiebitis: Nine experienced some possibly precipitating factor such as surgical opera- tion. Three had some possibly predisposing condition such as obesity. Five could be termed as idiopathic (at least no other information was avail- able). Two of the women had had earlier episodes. There was no pulmonary embolism. subsequent use of enovid: Enovid was continued without recurrence in seven women. Enovid was continued with one recurrence in one woman that cleared while on Enovid. Enovid was resumed, with recurrence, in one woman. Enovid was continued, despite chronic "thrombophlebitis" in one woman. Enovid was stopped in four women. Enovid was stopped 2-3 months before the episode, in one woman. Not known whether Enovid was stopped, in two women. The 17 known cases of thrombophlebitis in the 25-month club study repre- sent an incidence figure of less than 1 per 1,000 and approximates the lowest figure derived to date for a randomly selected population of women of child- bearing age. DROPOUTS To date, 1,063/11,711 (9.1 percent) have dropped from the study. Of these 892/1,063 (83.9 percent) discontinued for nonmedical reasons. Of these, 135 did so because of the desire to become pregnant; to date, 73/135 (54 percent) are known to have conceived. 170/1,063 (16.1 percent) stopped for medical reasons. MEDICAL REASONS FOR DROPPING OUT OF STUDY Reason: Number of women Changein weight 59 General intolerance 30 Thrombophiebitis ~ 24 Changeinskin 19 Change in libido 14 Abnormal Pap smear 13 Change in hair 11 1 170/11, 711 1(1.5 percent) have discontinued for medical reasons, to date. No unplanned pregnancies occurred. PAGENO="0449" 8 -1 - -`1 __ C 25 .. o _ _ [1 ii ~j Change in General Thrombophiebitis Change in Change in Abnormal Change in Weight Intolerance * Skin Libido Pap Smear Hair Medical Reasons fo.r Dropout PAGENO="0450" 7280 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SUMMARY AND CONCLUSIONS Norethynodrel with mestranol 5 mg. was taken by 11,711 patients in 38 Planned Parenthood centers for a combined use experience of 29,124 years. All patients had completed two years on the medication prior to enrollment in the study program. No unplanned pregnancies have occurred. New side effects have not appeared with extended use up to 42 months. Pre-existing dysmenorrhea was relieved in three out of four women. Pre-medication menstrual irregularity occurring in 22% of women was elimi- nated while on norethynodrel with mestranol; approximately 5% of women experienced some amenorrheic periods, 4% some breakthrough bleeding, and 15% some spotting. Libido was reported to be unchanged or improved in 94% to 98% of report- ing women. Similarly, "well-being" was unchanged or improved in 93% to 95% of women receiving medication. The incidence of abnormal Pap smears was low in those women examined, and was not observed to increase with continued use of norethynodrel with mestranol. Menstrually-related depression, reported by 11% of women before medica- tion, was reduced to 6% during the period of the study. Nausea and edema were reported to have occurred at least once during the study by approximately 5% of the women. The crude reported incidence of thrombophiebitis appears to approximate that in an untreated population. * * * Ovulation suppression by physiological means-the simple act of taking a progestogen-estrogen tablet daily during most of the non-bleeding days of a menstrual cycle-is an epoch-making breakthrough in conception control. This study has re-affirmed that this method is 100% effective and is associated with diminishing side-effects in continued use. ACKNOWLEDGEMENTS This collaborative study was made possible through the cooperation and sup- port of G. D. Searle & Co., and the following Planned Parenthood Centers. Planned Parenthood Centers P.P. Assoc. of Phoenix P.P. Clinic of Tucson P.P. Assoc. of Los Angeles P.P. Assoc. of San Francisco P.P. Center of Colorado, Inc. P.P. Assoc. of Chicago P.P. of Evansville, Inc. P.P. Assn. of Indianap- olis, Inc. P.P. Center, Inc. (Louisville, Kentucky) Washtenaw County League for P.P. (Ann Arbor, Michigan) PP. League, Inc. (Detroit, Mich.) P.?. of Minneapolis P.?. of St. Paul PP. Assoc. of K.C., Inc. Ewecutive Director Mrs. Gladys MacLean Mrs. Eileen Strutz Mrs. Janis Davidson* Mrs. B. F. Gardner Mrs. Lucile Wolf* Mrs. Gail Montgomery Mrs. Sheri S. Eberhart Mrs. Jane C. Browne Mrs. Arthur J. Grady Mrs. Gordon McCalment Mrs. W. R. Keys, Jr. Mrs. Dan H. Cooper Mrs. Mildred F. Stern Mrs. Mildred Veerhusen Mrs. Lloyd A. Larson Mrs. Carl B. Benson Gerda E. Klipfel, M.D. Louis A. Brunsting, Jr., M.D. Edward T. Tyler, M.D. Alan J. Margolis, M.D. Harold M. Haugen, M.D. Richard Frank, M.D. Harold H. Davidson, M.D. Robert D. Arnold, M.D. Peggy J. Howard, M.D. Glenn W. Bryant, M.D.* David G. Anderson, M.D. Darrell E. Statzer, M.D. W. H. Bittick, M.D. James J. Swendson, M.D. Daniel Aks, M.D. * Director at time the study was initiated. PAGENO="0451" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7281 Planned Parenthood Centers P.P. Assn. of St. Louis, Inc. P.P. of Southern New Jersey (Camden) P.P. of Bergen County (Hackensack, New Jersey) PP. Assn. of Cincin- nati, Inc. P.P. Assoc. of Youngs- town (Ohio) PP. Center of Pittsburgh P.P. of Rhode Island (Providence) PP. of Dallas PP. Center of El Paso P.P. Center of Fort Worth Mrs. Grace D. Buzzell Mrs. Harold L. Miller Mrs. Agnes Morgan Mrs. Marjorie Kagay* Mrs. Wm. F. Zimmer- man Mrs. Frances Hum- phreys Aquiles J. Sobrero, M.D. Ida Gelber, Ph.D. Mrs. Jeannette L. Nevins Mrs. Benjamin Bowering Mrs. Eleanor B. Levenson Sherwin A. Kaufman, M.D. Charles L. Poskanzer, M.D. Joseph Wrana, M.D. Wilbur M. Dixon, M.D. Executive Director Mrs. Dorothy H. Lynes Mrs. Everett H. Graves Shirley S. Passow Mrs. Corinne L. Buford C. Sachs Martha Paquet, R.N.* Mrs. Anne M. Kinney Mrs. Henry Wise Mr. Edward J. Rydman 1~Irs. Bernadine Thomas i~Irs. Compton Mrs. Dorothy Buxton Seth Wissner, M.D. B. Frank Lovett, M.D. Felix H. Vann, M.D. Robert L. Burket, M.D. K. C. Kunin, M.D. Emilia M. Caprini, M.D. Evelynè L. Slabey, M.D. Warren F. Dixon, M.D. Gray E. Carpenter, M.D. Jack L. Hargan, M.D.* James C. Anderson, M.D Charles Braseton, Jr., M.D.* P. J. Hoovestol, M.D. Jay A. Larkey, M.D. Fred H. Pulver, M.D. Philip L. Ferro, M.D. Dorothy Deitrick, M.D. Aquiles J. Sobrero, M.D. Mrs. Helen M. Burke Mrs. Robert M. Garvin 1~Irs. Shawna Keegan Mrs. Robert T. Williams P.P. Center of Houston PP. Assoc. of Milwaukee P.P. League of Schenectady, Inc. P.P. Center of Syracuse Hudson River Commit- tee for P.P. (Yonkers, N.Y.) Margaret Sanger Research Bureau (New York, N.Y.) P.P. of Manhattan & the Bronx P.P. Assoc. of Albany P.P. of South Suffolk (Babylon, N.Y.) Broome County P.P. Center (Binghamton, N.Y.) P.P. Center of Brooklyn PP. Center of North Suffolk P.P. Center of Southern Westchester (Mt. Vernon, N.Y.) P.P. Center of. Eastern Westchester (Port Chester, N.Y.) * Director at time the study was initiated. There have been many others (nurses, secretaries, social workers, etc. who have worked behind the scenes, but without whose assistance this study would not have been possible). Rebecca Zeiger, M.D. Bruce A. Harris, Jr., i\I.D. Isabel Beck, M.D. Jacob Shragowitz, M.D. PAGENO="0452" APPENDIX IX [Medical & Pharmaceutical Information Bureau of Science Public Relations, Inc. News Release, February 17, 1966] ORAL CONTRACEPTIVE NOT CAUSE OF THROMBOEMBOLISMS: DR. GUTTMACHEII New York-Fears of thromboembolic involvement in women taking oral con- traceptives have no basis in proven medical fact, according to Dr. Alan F. Guttmacher, president of Planned Parenthood-World Population. Writing in The Physician's Panorama ~`, Dr. Guttmacher says that while pos- sible involvement of the orals with embolic phenomena should be kept in mind, medical findings have been negative and he recommends the oral contracep- tives as the best method of birth control for the newly married. Dr. Guttmacher offers this guidance in an article written for the medical magazine which is read widely by general practitioners. "No one has demonstrated that any of the hematological alterations observed in some women on the orals create hyper-coagulability [excessive clotting] of the blood", Dr. Guttmacher states. "And no one has been able to prove that the use of the orals leads to a greater incidence of thromboembolism." When possible, Dr. Guttmacher advises his readers to prescribe the oral con- traceptives for "two cycles before marriage so that the relatively transient, minor effects will have had time to disappear before the honeymoon. Further- more, a bride may remain on the pill throughout the honeymoon, taking one pill each day and thus postponing the menses until a more convenient time." Other counsel Dr. Guttmacher advises physicians to give their patients include: "Don't be in a hurry to have a baby . - . Be sure first to complete all the education you desire . . . Of course, if you are so fortunately situated that you can afford the luxury of having a baby before completing both educations, that is a different situation. But, even so, don't have a baby immediately. First get better acquainted and adjusted." Such advice is especially called for in the case of teenage marriages, he emphasizes. Certainly postponement is better for the baby, Dr. Guttmacher adds, because some 40 per cent of youthful marriages end in divorce. Only when the bride is 25 or past is delay in beginning her family unwise, Dr. Guttmacher writes. "The best ally of pregnancy and birth is youth, and... [this makes it] important for doctors to stress this advantage of youth with each couple for whom we prescribe contraception." Among other contraceptives which Dr. Guttmacher rates as highly effective are the IUCD, or intrauterine device. His article discusses other techniques and devices and evaluates their effectiveness. Panorama is published, primarily for general practitioners, by Sandoz Phar- maceuticals of Hanover, N.J. * February 1966. (7282) PAGENO="0453" APPENDIX X WASHINGTON WOMEN'S LIBERATION STATEMENT ON BIRTH CONTROL PILLS The furor and confusion about the pill which has erupted during the last 2 months has made one thing very clear. Over the past 10 years women through- out the world have been taking a pill about which they knew little or nothing. The idea for Women's Hearings on the Pill grew out of Senator Gaylord Nelson's hearings which were supposed to deal with the pill and informed con- sent, that is, whether or not doctors told women about the possible risks they were taking in choosing the pill as their form of contraception. Weeks before his hearings members of Women's Liberation tried to contact him to talk to him about the organization and content of these hearings. He was at that time, too busy to talk with us, as were his assistants who were doing the administrative and organizational work for the hearings. During the first round of the Nelson hearings members of Women's Libera- tion rose up to question the way in which the hearings were being conducted as well as the issues that were being covered. in spite of the fact that it is women who are taking the pill and taking the risks, it was the legislators, the doctors and the drug company's representatives, all men of course, who were testifying and dissecting women as if they were no more important than the laboratory animals they work with every day. As one of the doctors said "in an age in w-hich preventive medicine has high priority it is distressing to have women exploited as guinea pigs in order to establish the absolute certitude of the causal relationship of the pill to cancer and other complications. Though it must be admitted that women make superb guinea pigs-they don't cost anything, feed themselves, clean their own cages, pay for their own pills and remunerate the clinical observer." The pill has been falsely projected as the only effective safe means of birth control and the answer to the control of the population explosion. We think these projections are misleading. The media, the drug industry and the medi- cal profession has advanced the idea that the pill has lead to the sexual libera- tion of women. But is this really true? Families, they maintain, will be smaller, but the women's place is still in the home. And it is still women who carry the primary burden of contraception and the full responsibility for child rearing. The pill has not significantly lowered the birth rate and it has not become the panacea for population control. The lowest birth rate in this country occurred in the 1930's, long before the advent of the pill, (implying the impor- tance of social and economic factors). Most proponents of the pill, including the FDA's Advisory Committee, say that the benefits outweigh the risks, but the benefits they are talking about relate to the generalized social philosophy of population control and the risks are taken by us, specific individual women. The only countries that have succeeded in controlling their population growth are Japan and Bulgaria, and this through legalized abortion and not the pill. If one takes the time to survey the literature in the field, one can see that most of the positive reports on the pill come from drug company sponsored studies, and those adverse reports, which people like Dr. Guttmacher are doing so much to discredit, come from researchers unconnected in any way with the drug companies. It is not our mission to have all women on the pill discard it and change to another form of contraception. Our mission, if such it can be called, is to rise up, as women, anti demand our human rights. We will no longer let doctors treat us as objects to be manipulated at will. Together we will ask for and demand explanations and humane treatment by our doctors and if they are too busy to give this to us we will insist that the medical profession must meet our needs. We will no longer tolerate intimidation by white coated gods, anti- septically directing our lives. (7283) PAGENO="0454" 7284 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY We are trying to offer the facts so that women can exercise a truly free choice and make decisions for themselves. And we are trying to create a forum here for meaningful discussion of these facts. We are not opposed to oral contraceptives for men or for women. We are opposed to unsafe contraceptives foisted on uninformed women for the profit of the drug and medical industries and for the convenience of men. (Opening statement of Washington Women's Liberation on Saturday, March 7, 1970, at Women's Hearings on the Birth Control Pill.) EXCERPTS FROM TESTIMONY AT WOMEN'S HEARINGS ON THE PILL, MARCH 7, 1970, WASHINGTON, D.C. Barbara Seaman, a medical columnist for two women's magazines and author of "The Doctors' Case Against the Pill" said the pill side effects she found most disturbing were personality changes, depression, irritability and fatigue. She said she was alarmed, too, at reports of broken, sore or distended veins and fatal blood clots. This evidence, plus the possibility that the pill leads to cancer and sterility, makes up too strong a case against using oral contraceptives, she siad. Many women said they were confronted with a blank wall when they complained of side effects to their doctors. Most doctors just laughed and prescribed other medications to counteract the side effects. Mrs. Seaman said when news had got around that she had drafted a book about the suppression of evidence about the pill, the drug industry tried to keep it from being published. Before she had even seen the galleys, she said, five sets had been xeroxed and circulated outside the publishing house. The Searle drug company warned book review editors that they would frighten women if the book was widely reviewed. Investigators quizzed Mrs. Seaman's friends about her private life, and doctors quoted in the book received threat- ening phone calls; one eventually lost his job. Mrs. Seaman also said she was annoyed at the way "American men have turned against the condom," which she said has led to a rise in venereal dis- ease. STUDIES Elaine Archer, of the New York Women's Health Collective, said that by the end of the third year of the original studies of Enovid, which began in 1957, all 857 women who started with the project had dropped out. The final report cov- ered only 132 women who had taken the pill for one to three years. During that time, five of the women died. No autopsies were performed. In 1966, Miss Archer said, the FDA Advisory Committee on Obstetrics and Gynecology checked the pill's relation to breast cancer. One case involving a woman taking oral contraceptives had been reported during 1965. Researchers at the National Cancer Institute felt there should have been 1200 cases, but the FDA found only one. Drug companies admitted they had gathered no data on side effects. Several of these companies had been actively discouraging doc- tors from reporting side effects. In September, 1968, the American Medical Association Journal reported that there had been no increase in the incidence of blood clots among pill users. This came six months after British studies had pointed to a definite relation- ship. The author of the AMA article was a man associated with Searle, the company that manufactures Enovid. The AMA Journal had refused to print another study showing that cancer of the cervix was more. prevalent in women who use the pill than in women who depend solely on the diaphragm. The Journal editors had tried to make the authors revise their study. A British medical journal eventually printed it. DRUG COMPANIES Miss Archer contended that the pill is the greatest source of increased prof- its for most drug companies, and has financed four foreign subsidiaries for Searle. In 1968, more than a fourth of drug company sales were in foreign countries where the Agency for International Development is pushing the use of oral contraceptives. PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7285 RESEARCH Barbara Seaman noted that drug companies spend more on promotion and advertising each year than on research. She said doctors simply are not exposed to adequate information about the pill themselves. Important research by specialists such as neurologists and psychologists rarely reaches many phy- sicians. A research associate with the Population Council, Sarah Tietze, said that with an estimated 18.5 million women in the world on the pill (8.5 million in the United States), new research is needed on conditions now coming to light. At least two large prospective studies-one in the United States, on 12,000 women, and one in Great Britain, with 40,000 women-are under way. THE IUD Further testimony pointed out that with intrauterine devices, used by an estimted 5 to 6 million women, common side effects are bleeding, pain and expulsion. Among the rare complications associated with the IUD are perfora- tion of the uterus and pelvic inflammatory disease (PID). The incidence of perforation, except for the closed, bow type which is no longer used, is about 100 per 100,000 insertions. ABORTION In the United States no accurate figures on mortality due to abortion are available. Sarah Tietze believe the estimate of 5000 to 10,000 deaths each year from illegal abortions is unreasonably high. However the number reDorted for 1966-189 deaths-is certainly too low. More realistic data comes from Euro- pean and Scandinavian countries. In Czechoslovakia and Hungary, between 1957-67, there were 69 deaths among almost 2.5 million women undergoing legal abortion. This is a rate of 2.8 per 100,000 legal abortions. In Japan the rate was 4.1 per 100,000 based on 278 deaths among 6,8430,000 legal abortions for the period 1959-65. In the Scandinavian countries the death rates were higher-40 per 100,000 legal abortions. This may be because a large number are performed after the third month of gestation, unlike practice in the other countries. GENOCIDE Etta Horn, a Washington welfare rights leader, said poor women are being forced by the medical system to seek help from the abortion underground. Officials in the D.C. Department of Public Health are responsible for the death and injury of such women, she charged. Mrs. Horn said social workers are intimidating women on welfare into using birth control pills. She called it a form of "genocide." These women feel there is no alternative, she said: "You don't want to make anyone mad. You're really on your knees." As a result of this kind of coercion, many women on welfare, who are not in good health to begin with, suffer additionally from side effects of the pill, she contended. Concern about the "population explosion" has resulted in considerable public discussion of birth control, and increasing pressures on women around the world to use unproven and potentially dangerous oral contraceptives as a means of limiting population growth. These discussions have generally regarded population control as primarily a technical problem-to be solved by more efficient technology, ie, contraceptives. Standing in the way of a technical solution to birth control, are insufficient or suppressed research on other, more desirable methods than the pill, and a lack of safe and inexpensive abortions on demand. While the development of technically more effective contraceptives is desira- ble, the questions of population control are primarily socio-political, not tech- nological. The solution to problems of over population and hunger lie not so much in effective technology as in the liberation of women and the redistribu- tion of resources. The popular media's portrayal of the liberation of women places great importance on her so-called sexual revolution. This "sexual" revolution is pre- sented as a direct result of "improved methods of contraception-notably the PAGENO="0456" 7286 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY pill. The pill is said to give women the same sexual freedom that men have, as well as the same careers and opportunities. But this portrayal is very misleading as it does *not deal with the total oppression of women and the reasons why women want and have many chil- dren. Alternatives to motherhood do not exist at present. Job situations discrimi- nate against women. Our educational system tracks women into home econom- ics and men into science. Woman's primary role in life is still that of wife and mother. Some are isolated in suburbia, and others are trapped in crowded working class homes. Most live vicariously through their children. As long as women are defined as bodies to produce children; as long as a woman's goal in life is to "meet a man" and have a child, we are going to have kids-no matter how safe and effective the contraceptive devices. There is no other source of. identity given women other than child-rearing and family life. Judith Blake, chairwoman of the Department of Demography of the Univer- sity of California at Berkeley, examined the American population policy in Science, May 2, 1969. She questioned those institutional policies which are pronatalist-that is, which encourage reproduction. Thes policies are most obvious in the family, where both male and female sexual roles are standard- ized in terms of reproductive functions, and in occupational roles which are defined for women in terms of child-bearing, child-raising, and complementary activities. ON POPULATION CONTROL She wrote: "The notion that most women will `see the error of their ways' and decide to have two-child families is naive, since few healthy and energetic women will be so misguided as to deprive themselves of most of the rewards society has to offer them and choose a situation that allows them neither a life's work outside the home nor one within it." When women are allowed greater diversity and freedom to pursue their own lives, then they will not feel it essential to have many children and a more humane system of population control can develop. Population control is a socio-political issue involving the redistribution of world resources. The white middle-class male-dominated West has again tended to view population control as providing technical means to control the population growth of others, ie, Third World or Black. A more realistic solu- tion is the redistribution of the 70% of the world's resources now controlled by 7% of the world's population (the U.S.) but this would mean extensive land reform and possible revolutions in nations where land and wealth are owned by only a few or by U.S. corporations. Such a redistribution of resources would not only help feed overpopulated areas but also create conditions in which people could choose to limit their population growth, if this were seen as advantageous to human interests. In some nations especially socialist ones, human beings are an asset and not a deficit. There are only two choices. One is to take a technical approach which adopts a solution that must be forced on people regardless of their choices, thereby creating an in-humane though controlled society. The other is to work now to change socio-political conditions-to work toward the liberation of women and the redistribution of world resources. RE5TJLT5: WOMEN'S LIBERATION SURVEY ON THE ORAL CONTRACEPTIVES (PREIJMINARY FINDINGS FOR 750 WOMEN IN 35 STATES, 143 U.S. CITIES) The most obvious impression obtained while tabulating questionnaires was the continuing frustrated search by women for a contraceptive that is both medically safe and 100% effective in preventing pregnancy. Unfortunately, that ideal contraceptive is not available. Those women still on the pill have one thing on their mind-avoiding pregnancy. Some have shut their ears to the dangers all together, others see no other alterntive, since other methods are not as reli- able and safe abortion is too expensive and difficult to obtain. Of those women who have gone off the pill, and alarmingly high number, 17%, of literate, finan- cially stable women are using no contraceptive at all or the least effective ones (condoms, withdrawal or rhythm). This seems to indicate that women are gen- erally uniniformed about reproductive biology and birth control. (In addition, PAGENO="0457" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7287 8% of women who have gone off the pill are abstaining). The doctors offer little help. Some women don't even see them, they are afraid (he is an author- itarian figure) of him or they are too modest to submit to a pelvic exam or the answer questions about their sex life. Other women go to the other extreme and follow his suggestions without receiving explanations or asking questions. In the area of prescribing oral contraceptives the doctors are espe- cially guilty of 3 things: 1. Not mentioning other means of contraception. 2. Not warning of the side effects caused by the pill and if they do, omitting the serious and often fatal ones. 3. When side effects are reported they are unsympathetic and unresponsive. In February, 1970, Washington, D.C. Women's Liberation decided to launch a survey to collect information on women and the pill. The response to our questionnaire has been overwhelming and is just one additional proof of how vital this issue is to women. More responses pour into the office everyday but we decided to start the analysis with 750 questionnaires. (We had to do the tabulations manually, as we did not have money to buy computer time). Should we somehow have access to computer time we will go on with a com- plete analysis of this valuable information. Our questionnaires were mailed to Women's Liberation groups around the country who were asked to reproduce and distribute them. We now have returns from over 35 states and from women representing all classes and ages. Questionnaires were distributed in shopping centers, high schools, colleges, in government offices, just about everywhere women work and live. Three quarters of women responding to our survey were between 21 and 30 years old. About ~ have family incomes above $10,000. (This compares to 44% of the Gallup sample compiled for Newsweek.) 100% of the 750 whose ques- tionnaires we analyzed had had experience with the pill (compared with 25% of Gallup's 895 women). Over half of these women used the pill as their first form of contraception. For women who did use other means of contraception before starting on the pill 1/3 used condoms and slightly fewer used diaphragms. Foams, jellies and creams, were employed by over 20% of women who used another means of con- traception before starting on the pill. The most often mentioned reason for using the pill-listed by more than *half of our respondents was its effectiveness in preventing pregnancy. Women clearly want contraceptive measures which can eliminate all fear of unwanted pregnancy. (Ending in abortions or unplanned for children). Many started on the pill after pregnancies resulting from ineffective methods of contraception (40% of the women asked mentioned the convenience and ease of the pill as a reason for using it. It was aesthetically more pleasing to many. Only 8% of our group started using the pill for medical reasons-usually related to regular- izing menstrual cycle. In spite of this obvious desire for effective contraception, over 40% of the women answering our questionnaire had stopped taking the pill permanently. A shocking 17% who had gone off the pill were using no other means of con- traceptive what ever, and another 8% were using abstinence . . . that is, 1/4 of the women who had gone off the pill permanently were still looking for another means of birth control. Most often women-about 1/s-who had stopped the pill switched to the diaphragm. Most of the women in our survey had the pill prescribed by a private gyne- cologist who did not ask for a medical history, who did give a physical and pelvic exam and who did tell the woman she should return for regular pelvics. But, even among this type of group, we find that only one in every four women ever had any other form of contraception described or recommended to her by her doctor before he prescribed the pill. Over 40% of the doctors never mentioned any possible side effects (this compare with 66% in Gallup sample). Of the 55% of women who were warned of side effects, only the most mild ones were normally mentioned . . . nausea and weight gain alone account for half of all side effects warned against by doctors, cancer accounts for only 2% and thromboembolism or infertility are hardly ever mentioned as possible side effects. 75% of the women in our sample experienced some side effects, but only 42% were `told by their doctor that they should contact the doctor if they developed side effects. In conclusion we find that: (1) Women have not been able to give informed consent to their own use of the pill because they have been grossly ill-informed by their doctors. PAGENO="0458" 7288 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (2) Most women are experiencing serious side effects and many are perma- nently ceasing to use the pill. (3) However, there is difficulty in finding another means of contraception which will meet the desire for safety, effectiveness and convenience of use. (4) Although it is not evident in the figures given here we can tell from the letters and personal evaluations of experience with the pill written in answer to question 25 that women acorss the country are facing a dilemma which is causing extreme psychological stress-there is no contraceptive method avail- able which is proven medically safe and effective. Women feel forced into choosing between taking higher risks of becoming pregnant or high risks of developing cancer, diabetes or other serious side effects. Finally women describe how little information support or understanding they receive from their doc- tors in trying to make these crucial life decisions. Perhaps the best way to conclude this presentation is with a few representa- tive quotes from our questionnaire: 2-27-70 "I cannot honestly say I have had unpleasant side effects from the pill but I have been to many doctors in the last four years in three cities in which we have lived, concerning headaches, and legaches. Each doctor and planned parenthood center assured me that the pill was not causing or contrib- uting to my difficulties, and so I continued to take the pill. Incidently, no one could give me an answer for the pain. "The pain lately has been so severe I decided I would go off them just in case they could cause it. Since my doctors have argued for the pill I don't know or feel its my place to judge them, but I do feel every woman deserves to know the truth, and that will only come when we demand further testing in laboratories instead of the current situation which is that the woman is simply their guinea pig." Mrs. W. Bloomington, md. 2-28-70 "I began using the 1mg. pill in June, 1969. Within a few weeks I began experiencing severe breast swelling and tenderness. After seeing my doctor as soon thereafter as an appointment was available (you really could die while you are waiting), I was assured that it was "nothing" and advised to continue on the pill, which I foolishly did for six months. (It's amazing how we believe and trust doctors and assume they know more than we do). During those months I saw him again about the pain and after an examina- tion he concluded that it was due to wearing a bra that was too tight (you see now how buxom I had become). When I protested that I rarely wore a bra, that become the cause somehow. I was beginning to feel very neurotic. "By the fall, I detected lumps in both breasts, at which point I freaked out and saw a doctor who referred me to a surgeon (more delays). My condition has been diagnosed by him as chronic cystic mastidis, often called "buckshot dis- ease," caused by a hormone imbalance and not unusual in women experienc- ing menopause. I am 27. The surgeon felt this condition was a direct result of Norlestrin. This is my first month off the pill and there is a noticeable improvement in my condition, although there is no assurance that it will ever disappear entirely." .D. S. Washington, D.C. 2-70 "As indicated in question #21 I had many adverse side effects while taking the pill. The headaches I experience were attributed to "tension" as my male OB put it. Nausea is "normal" and something your system adjusts to with the pill. Weight gain too is just one of those things that go hand and hand with this form of birth control. The irritability and breathing difficulties were supposed to be due to tension and were treated with tranquilizers which only served to make me tired along with being irritable and depressed. "When I complained of loss of libido, it was suggested that a psychiatrist would be the one to help me. (no doubt a male psychiatrist who supported Freud would have been recommended had I been fool enough to take the advice). "I finally stopped taking the pill when the chest pains and leg cramps I experienced became excruciating and too frequent to bear. Never once during the 9 months that I was on this medication did the doctor ever suggest that I discontinue the pill or grant the possibility that the symptoms I manifested were pill induced." Syracuse, New York PAGENO="0459" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7289 Of 750 women, the following disease conditions were reported in answer to question No. 21 on the questionnaire. Total number 2070 Response to possibilities listed on questionnaires 1923 Response to "others" category 147 Headache 153 Nausea 213 Skin blemish 54 Bleeding gums 25 Blood clots 23 Infertility 22 Stroke 1 Jaundice 1 Weight gain 329 Epilepsy 1 Swollen breasts 253 Skin discoloration 39 Cervicallestions 14 Cystic ovary 10 Enlarged uterus Cancer of cervix 3 Cervisitis 16 Cancer of breast 0 Cancer of uterus 1 Genetic defects 1 Breathing difficulty 29 Hairloss Depression 186 Irritability 171 Changes in metabolism 46 High blood pressure 19 Changes in thyroid function 15 Chemically induced diabetes 4 Loss of libido 72 Changes in sensory perception 26 Other: Vaginitis 24 Breakthrough bleeding 23 Amennorhia or reduced flow 22 Cyctic mastitis 11 Impaired circulation 13 Chest and or leg pains 10 Hemmorhage Hirsuiteness (hair gain) 7 Allergy Lack of vaginal lubrication 3 Dizziness 6 Uterine infection 3 Shrunken uterus 1 Anemia 2 Rheumatoid arthritis 1 Swollen ovary 1 Other (indigestion, constipation, etc) 13 Positive effects reported in answer to question No. 21 (17): Weight loss 1 Acne cleared up 6 Menstrual regularity 6 Freedom from anxiety 2 Increased libido 2 PAGENO="0460" 7290 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Number Percent Age distribution: Under 20 21 to 30 31 to 40 Over 40 Income distribution: Under $3,000 $3,000 to $6,000 $6,000 to $10,000 Over $10,000 Don't know Used other form of contraception before pill: Yes No Don't know Got pill from: Private doctor Planned parenthood University or student clinic Public health Private clinic/group health Military Other Doctor was: Gynecologist General practicioner Internist Other Asked for medical history: Yes No Don't know Gave full physical: Yes No Don't know Gave pelvic: Yes No Don't know Told to return for regular pelvic: Yes No Don't know Recommended other form of contraception: Yes No Don't know I 147 19 528 72 46 6 15 2 127 17 144 19 178 24 264 35 37 5 340 45 409 54 588 78 69 .09 35 .05 14 .02 8 .01 7 .01 29 .04 478 64 226 30 23 3 23 3 488 65 226 30 36 5 468 62 272 36 10 1 595 79 121 16 34 5 688 81 129 17 13 2 190 25 541 72 19 3 PAGENO="0461" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7291 Number Percent Warned of side effects: Yes- No - Don't know- Contact doctor for side effects: Yes No Don't know Stopped taking pill permanently: Yes No Don't know Now using: Diaphragm ud Foam, jelly cream None Condon Abstinence Withdrawal Pregnancy or nursing tubal ligation hysterectomy Other form of contraceptive used before the pill: Condon Diaphragm Foam jelly Rhythem Withdrawal Started or switched to pill: Effectiveness Convenience Medical Other Side effects mentioned by doctor: Nausea Weight gain Bleeding/spotting Swollen breasts Headache Cancer Sterility/infertility Will have none Other 312 42 339 45 99 13 304 41 426 57 20 2 115 31 52 46 55 35 27 23 133 33 125 31 90 22 36 8 21 5 482 275 75 97 196 26 192 26 75 10 67 9 54 7 17 2 7 1 130 18 423 55 303 41 24 4 PAGENO="0462" 7292 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Recent Senate hearings raised many frightening questions about the safety of The Pill. But no testimony was heard from women, no women sat on the committee, not many women heard about the hearings. ~AR TESTIMOMY FROM WOMEN WHO KNOW: YOU, AND YOUR SISTERS! Bring ques~ on The Pill, on other methods of birth control, on abortion, on the ecology of population control, on information suppression by drug companies, to: ~ ~ PAGENO="0463" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7295 18. Before prescribing the pill, did the doctor recommend or describe any other form of contraception to you? Yes ~J No rJ. 19. Did the doctor warm you of any nossible side effects which minht result from thc pill before he nrescribed it for you? Yes ~j. No ~[. If yes, what side effects were mentioned? ____________________________________________________ Did he tell you to contact him if any of these occurred? Yé~~~j~No ~=j. 20. What kind(s) -- brand name -- of pill have you used? ________________________ 21. Have you had any side effects from the pill? Yes ~ ~ If yes, please check any of the followino which you have had: headache swollen breasts breathina difficulty - nausea - skin discoloration - hair loss - skin blemish - cervicallesions - deoression - bleedino owns - cystic ovary - irritability blond clots - enlarged uterus - changes in metabolism _infertility ___c~%cer of cervix _high blood pressure - stroke ~rvlsitis - changes in thyroid function - jaundice - cancer Of breast - chemically induced diabetes _weiqht oain _cancer of uterus _loss of libido - epilepsy - genetic defects - chan9es In sensory perception. OTHER~ 22. Have you ever stormed takinci the pill for a month or longer and then started taking it again? Yes Ei* No ~. If yes, why? ______________________ Did you co~üTt your doctor? Yes No ~. 23. Have you now stooped takino the pill permanently? Yes No t~3 Did you consult your doctor about the decision to go off the ni 1? Yes ~. No~. If you are NflT now using the pill, what form of contracention. if any, are / *vou using? 24. If you have ever gone off the nill, did you notice any body channes? Yes ~ No ~ jf yes, was it: loss of hair~\. weinht loss~. skin nroblems disappearance of unpleasant side effectst~. OTHER________________ 25. What is your own personal evaluation o~ your experience with the nill? Please use another sheet of paper for your reply, if necessary. Do you have any further comments or sunaestigns? Do you have any ouestions you would like to see raised at the Women's nill hearinns? Please let us know. THANK YOU FOR T~KINr~ THE TPiE TO HELP US IN THIS SURVEY. 40-4'Tl O-70--1pt. 17-30 PAGENO="0464" APPENDIX XI UNITED STATES SENATE, Washington, D.C., March 10, 1970. Mr. BENJAMIN GonuoN, Select Committee on Small Business, Senate Office Building, Washington, D.C. DEAR Mr. Gordon: Enclosed are several newspaper articles concerning oral contraceptives and the recent hearings of the Monopoly Subcommittee. I would appreciate them being included in the record of the Subcommittee hearings. Sincerely yours, BOB DOLE, U.S. Senate. [From The Washington Post, March 5, 1970] HEALTH-IUD HAZARDS (By Morton Mintz) Sen. Gaylord Nelson's hearings on the Pill, which ended yesterday, have awakened women to known and possible hazards they never heard about from their doctors. Thousands have decided to be fitted with an intrauterine device (IUD). Some of these women are going to be injured needessly, because certain IUD designs are unduly hazardous, because of improper insertion by doctors and because of inadequate precautions to assure sterile packaging and insertion. The origin of the problem is that the Food, Drug and Cosmetic Act puts drugs and medical devices in different categories. Since 1938, when the original law was passed, a manufacturer wishing to market a medicine has carried the burden of truth. That is, it has been up to him to demonstrate to the Food and Drug Administration-before marketing can begin-that the product is safe (and also, since 1961, effective) in the uses for which it is recommended. But the maker of a medical device has not been required to get premarket- ing clearance. He is generally free to market what he will. Once a device is on sale, the FDA, if it sees a need to act, must be prepared to assume the burden of proof; that is, to try to demonstrate in court that a device falls short of the claims of safety and efficacy made for it by the manu- facturer. If the FDA should prevail, it will-probably after lengthy proceedings-get an injunction against further manufacture of the questioned device. As a practical matter, however, this cumbersome procedure has severely lim- ited the FDA's potential for protecting the public. In January, 1968, the Advisory Committee on Obstetrics and Gynecology, a consultant group to the FDA, briefly stirred hope for legislative reform. At that time, when an estimated one million women in the United States, Canada and Puerto Rico had been fitted with IUDs, the committee issued a comprehensive report on the devices. IUDs come in two basic shapes. By far the more popular is the "open" shape, of which the best known example is the Lippes Loop. The other is the "closed" shape, of which the better known designs are the "bow," the "Incon Ring" and the "Butterfly." The committee said that in a survey of Fellows of the American College of Obstetricians and Gynecologists 10 deaths were reported among IUD users. A clear cause-effect relation was shown in four of the 10 cases, but not in the others. In addition, the committee estimated that 10 deaths (for a total of 20) had not been reported. (7296) PAGENO="0465" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 7297 (Even the maximum assumed fatality of 2 per 100,000 was well below the 3 per 100,000 demonstrated for the pill from clotting diseases. The pill also has been shown to cause nonfatal but disabling clotting in some women, psychic depression, skin blotching and hair loss.) Aside from fatalities, 369 women were reported to have suffered critical inflammatory infections in connection with IUDs. The committee pointed out that among the fatal and critical IUD cases were an undetermined number of needless victims-women who had been fitted with unsterile or improper devices and insertion techniques. An additional 177 women were reported to have suffered perforation of the uterus. One fact stood out: A high proportion of the 177 victims had been fitted with one of the "closed" IUD designs. Even more striking were cases of perforation that were followed by intesti- nal obstruction. This is a highly dangerous condition which almost always requires surgical removal of the IUD. Of the 15 such cases reported, 13 had been fitted with a "closed" IUD. In the remaining two cases the design was not ascertained. In sum, the committee attributed a significant proportion of all deaths and critical illnesses in IUD users to two factors: First, the use of "closed" designs, and second, the use of nonsterile packag- ing for most IUDs then being sold, the lack of disposable tools with which physicians insert the devices, and inadequate insertion instructions in the labeling. The committee warned that "the safety of the material used, the quality control and its manufacture, and the labeling and packaging of intrauterine devices are at present the sole concern of each manufacturer~" Obviously, the problem is even more urgent today. Not only are more women using ITJDs, but new designs are being developed including two that unlike early ones can be used in women who have not been pregnant Last September Virginia Knauer, the President's consumer affairs adviser, said that defective medical devices were needlessly killing, injuring and exploit- ing people. She cited poorly designed artifical kidney machines; "5,000 to 10,000" diath- ermy machines used to give 20 million heat treatments yearly "that are worth- less for any known medical purpose," and 40,000 ineffective emergency respirators. President Nixon, in his October consumer message to Congress, said "certain minimum standards should be set" for medical devices, with the government being given "additional authority to require pre-marketing clearance in certain cases." Dr. Theodore Cooper, director of the National Heart and Lung Institute, heads a panel studying legislative reform at Mr. Nixon's request. It is seeking a proposal which will protect the public without denying it the benefits of new technology and is scheduled to report by the end of this~ month. Hopeful as this may sound, Presidents Kennedy and Johnson sent six mes- sages to Capitol Hill urging lawmakers to require manufacturers of medical devices to demonstrate before marketing that devices to be implanted in the body are safe, effective and reliable. All were unsuccessful. Members of Congress have introduced a series of bills aimed at that objec- tive. But all such proposals have had less steam behind them than a $500-mil- lion-a-year industry. ______ [From The Evening Star, March 8, 1970] MEDICAL REPORT-PILL' WARNING To SET A PRECEDENT (By Judith Randal, Star Staff Writer) Within the next two or three weeks a notice will appear in the Federal Reg- ister that will set a precedent. Its publication will serve notice to pharmaceutical manufacturers that the Food and Drug Administration intends to insist that the 8.5 million America" women who take "the pill' have access to authoritative information about what the side effects may be. No longer will it be good enough-as it is for the thousands of other pre- scription drugs on the market-merely to inform the physician what transient PAGENO="0466" 7298 COMPETITIVE PROBLEMS IN THE DRUG INDUSTTRY or lasting harm may befall his patient as a result of the medication. Instead, a leaflet written by the government in clear, simple English will be included in every package of oral contraceptives sold. The draft text as printed in the Register will spell out the slight added risk of blood clots (pointing out that few are fatal) ; warn users to see their doc- tors if they experience such symptoms as sudden headaches, leg or chest pain and counsel that people with breast cancer, serious liver disease or. unex- plained vaginal bleeding should not take oral contraceptives at all. The industry will have 30 days to "offer comments." Several months later a final version of the leaflet should begin to become as familiar to women of child-bearing age as "the pill' itself. A recent Gallup poll reports that two-thirds of the doctors prescribing oral contraceptives make no mention to their patients of its possible side-effects. One possible result of the leaflet, then, will be to protect such doctors against possible malpractice suits. Nevertheless, its reception by the medical profession is bound to be mixed. Some physicians probably will construe it as "interference in the private prac- tice of medicine" and the drug companies, too, are hardly likely to be pleased. The way in which the FDA commissioner, Dr. Charles C. Edwards, handled the announcement then must be counted as a master stroke. The last day of the hearings on oral contraceptives conducted by Sen. Gaylord Nelson, D-Wis., as chairman was, of course, a natural forum. But Edwards went beyond merely telling Nelson what in general terms his agency intended to do. He released the provisional text of the brochure to senators and the press, thus assuring that its contents would become widely known. In this way, it should be more difficult than it otherwise would be for the industry to try to bar the leaflet or to water down the language describing, the hazards of con- traceptive drugs. Despite rumblings of dissatisfaction from doctors and industry spokesmen, the FDA's general counsel said he expects no serious opposition and that drug makers will be required to include the leaflets within four months. The point was often made at the Senate Hearings that nothing was dis- closed that was not already available in scientific papers. This is perfectly true. However, what these critics failed to mention was that little of this information had been made known to the public at large. Will the FDA's consumer leaflet be followed by others for other drugs? Per- haps. Drug side-effects increasingly are the cause of death, disability and illness~ and both Edwards and his FDA predecessor, Dr. Herbert L. Ley, Jr. are known to favor the principle of "informed consent" and greater consumer edu- cation. In their view, the patient who knows what he may experience from prescrip- tion medicine is the one who will call his doctor in time to avoid becoming seriously ill. It would not be surprising, therefore, if the oral contraceptive leaflet were the beginning of a trend. [From The Evening Star, March 8, 1970] `PILL' SALES AND STOCKS COOLED BY CONTROVERSY (By Bailey Morris, Star Staff Writer) As the controversy over harmful side effects of the pill has heated up, sales of oval contraceptives and stock prices of their manufacturers have cooled off. Estimates by Wall Street analysts of the number of women who have stopped using the pill since hearings conducted by Sen. Gaylord Nelson, D- Wis., centered national attention on blood clotting and other side effects range as high as 2 million of about 8.5 million users in the United States. The figures are speculative, but they do give substance to comments from four of the nation's eight largest pill manufacturers that soon after the Senate hearings began, the impact on oral contraceptive sales could be detected. BROKERS CONCERNED This negative effect on an oral contraceptive market estimated at more than $95 million in the U.S. alone has set off a dual alarm in the financial commun- ity. It has affected both drug manufacturers worred about public impact in PAGENO="0467" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7299 dollars anid cents terms and financial analysts now jittery about recommending pill stOcks formerly classified as fast-moving or steady-growth purchases. "It's too early to assess the full impact, but from reading the polls we know sales are in a slump, and in a couple of months we'll have a clear picture of drugstore prescription sales," says a spokesman for Syntex, a corporation that controls 54 percent of the oral contraceptive market. "As soon as we find out what's happening, we'll know how to adjust our sales forecasts and promotional efforts," the spokesman said. "Privately, I think sales will slump for a while, then bounce back because too many women have had good results with the pill." SYNTEX STOCK FALLS His optimism was not apparent on Wall Street which last week put Syntex on the American Stock Exchange's most active list closing at 35, down l1/s on volume of 376,400 shares. Syntex, the wonder stock of 1963 when its price soared from 20 to almost 100 in a few weeks, is down about 55 percent from its 1969 high. G. D. Searle and Syntex are the companies most vulnerable to anti-pill feel- ing because they have the largest percentage of total sales in oral contracep- tives, according to a stock broker at Paine, Webber, Jackson & Curtis. "I've seen estimates that if just one-quarter of the women now taking the pill stop, Syntex stock will decrease 30 percent a share and Searle, 15 percent a share," be said. Another drug company included in the top eight pill producers also admitted a sharp decline in sales, but said it is not too worried. FIRM IS CONFIDENT A spokesman at Johnson & Johnson, which through its Ortho Pharmaceuti- cals Division is the only company making every kind of female contraceptive, said: "We're not just in orals and if we lose a large percentage of pill sales we'll probably pick it up in sales of other devices." Asked if there has been increased demand for other devices, he said the response from doctors and drug stores has been so large that Ortho salesmen have been devoting most of their time to showing diaphragms and IUD's (intrauterine devices). Wall Street reaction to the current trial of the pill has been mixed and emo- tional. "Have you seen any figures on how the average woman is reacting?" asked one broker-and from another: "We have to weigh the benefits-to-risk ratio." Several brokers said they think it possible pill hazard warnings may have the same effect as cigarette warnings and that confirmed users will con- tinue to do so but younger people growing up may shy away from it. DEMAND CHIEF QUESTION Six to ten brokers polled said they needed to make a decision on the basic question of whether the American woman will continue to buy the pill despite the fact that the Federal Drug Administration is requiring manufacturers to warn her of excessive bleeding, clotting, arteriosclerosis and other dangers. The consensus for the long term was that women will still buy the pill because it's cheap, convenient and 100 percent effective and newer and safer products are bound to come. But their short term outlook is more cautious and ranges from: "We're not recommending any pill stocks," to "we're waiting to see what happens," to "We're recommending a small number of companies who have either a low percentage of oral contraceptive sales or products with low estrogen content." Estrogen is the substance largely responsible for clotting. PAGENO="0468" APPENDIX XII G. D. SEARLE & Co., Chicago, Iii., January 30, 1963. AF 13-505. NDA 10-976 (Enovid). Enovid medication and increased blood clotting. On January 25, 19(32 an article on Enovid medication and coagulation changes along with Drs. 0. Egeberg and P. A. Owren Medical Paper on "Oral Contraception and Blood Coagulability," Brit. Med. Journal, January 26, 1963, page 220 and 221, was addressed to Dr. Frances 0. Kelsey by Faye Marley, a Science Service Medical Writer, Washington, D.C. There are some deficiencies in this Science Service medical writer's sum- mary, that should be corrected before it is released to the press, etc. First of all-it is not the first time (The report in Brit. Med. Journal-see above) that it has been shown that Enovid medication changes blood coagula- tion factors towards hypercoagulability. Similar and other changes have been already known to certain investigators and published in the Proceedings of a conference: "Thromboembdlic Phenomena in Women," page 154 through 157, copyright 1962, G. D. Searle & Co., Chicago, Illinois. The fact is only that the knowledge of these changes in the coagulation factors has not found its way into the American or World Medical literature nor has the existence of those findings been emphasized in the press releases, therefore they have remained unknown to most of the medical circles and public. Secondly, in September 1962 nine cases (not six) of deaths were discussed at the meeting in Chicago and the reported number of deaths is now increased over 31, as presented in the letter to physicians by G. D. Searle & Co. of December 26, 1962. Finally the statement made by Dr. Lee D. VanAntwerp, Searle's Assistant Medical Director is untrue (if only Faye Marley is quoting him correctly) that American scientists have not been able to find a relationship between Enovid medication and changes in the blood coagulation factors. Those changes towards hypercoagulability have been published in the above mentioned pro- ceedings of the conference and should be known to Dr. VanAntwerp. I recommend that these facts should be made known to the Science Services for appropriate corrections of their review on "Enovid and changes in blood coagulation system." Further since Dr. Owren is internationally known as an expert on coagula- tion, I believe he should be invited to serve in our panel, which is going to evaluate the Enovid medication and coagulation changes. ARTHUR RU5KIN, M.D., Acting Medical Director, IND. HAIM0 TREES, M.D., Division of New Drugs. (7300) PAGENO="0469" APPENDIX XIII STATEMENT OF JOHN R. RAGUE, EXECUTIVE DIRECTOR, AssoCIATION FOR VOLUNTARY STERILIZATION, INC., 14 WEST 40TH STREET, NEw YORK, N.Y., PREPARED FOR THE MONOPOLY SUBCOMMITTEE, UNITED STATES `SENATE COMMITTEE ON SMALL BUSI- NESS, ON THE SUBJECT OF VOLUNTARY CONTRACEPTIVE STERILIZATION AS A MAJOR METHOD OF BIRTH CONTROL Senator Nelson, distinguished members of the Committee-Thank you for this opportunity to talk with you today about voluntary sterilization as a modern method of birth control. The organization I represent, the Association for Voluntary Sterilization, Inc., conducts a program of education, research and service on voluntary sterilization as one valuable solution to family and population problems. In a recent discussion on radio between Dr. R. J. Ederer, a professor of Eco- nomics at State University of Buffalo, and H. Curtis Wood, Jr., M.D., Medical Consultant to this Association, Dr. Wood made this statement: "There is an organization known as the Atmospheric Sciences Research Center, which is under federal grant from the National Science Foundation and the National Institutes of Health. Now, this is a fairly respectable organization, and they said-and I'm quoting them-'Ten to fifteen years from now, every man, woman and child in the hemisphere will have to wear breathing helmets to survive outdoors. Streets for the most part will be deserted. Most animals and much plant life will be killed off. In twenty years, if man survives, he will live in domed cities, and will put on semi-space suits and roam around a deserted, dead country.' We ran out of clean air six years ago, the last being in Flagstaff, Arizona. Pollution is increasing far faster than the air can cleanse itself. So this Atmospheric Sciences Research Center is predicting that in maybe ten or fifteen years from now, if a mother wants to put her baby out- side in the playpen, she'll have to put a gas mask or helmet on him or some- thing." A recent national conference sponsored by the Association for Voluntary Sterilization, Inc., in which leaders of several major national conservation organizations participated, had the following theme: "Conservation and Volun- tary Sterilization-A New Alliance for Progress". This theme was carefully chosen because we believe that voluntary sterilization could be used by a greatly increased number of Americans in order to stabilize our spiraling pop- ulation growth and give anti-pollution efforts a chance to succeed. Dr. Paul R. Ehrlich, outstanding biologist at Stanford University and author of the best-selling book, The Population Bomb, stated at that Conference: "The species we are trying to conserve now is homo sapiens, and ironically the only hope we have is by reducing the numbers of human beings on the Spaceship Earth. Voluntary sterilization should be promoted all over the world-it is one of the best means of conservation available to us." We read today of new types of mass transportation in the planning stage, and of architects' visions of new "omni-buildings"-gigafltic structures which are practically cities in themselves. All this to accommodate and adjust to an expected population increase of 100,000,000 Americans within 30 years-a 50% addition to the current population. Even Secretary of Commerce Maurice H. Stans, in a recent lecture, warned us that by the year 2,000, we Americans will be jammed together in an "ant-hill society" due to continuing migration into "megalopolises" already in formation along the east and west coasts. He rec- ommends, among other measures, construction of new cities away from present urban concentrations. Regarding such new cities, he states candidly that to accommodate the 100,000,000 projected population increase within the next 30 years, by this approach alone, would require building a city the size of Tulsa, Oklahoma, every month until the year 2,000. (7301) PAGENO="0470" 7302 COMPETITIVE PROBLEMS IN THE DRUG INDUS~~RY The tragedy is that nowhere in the thinking of the architects, or in Mr. Stans' attitude, can we discern anything but acceptance of this fantastic popu- lation growth. Where is the understanding of the terrible social and economic strains that it will produce in our country? Where is the determination and will not to merely accept it as inevitable but to do something effective to stop it? Where is the national commitment to programs of education, research and* service that will enable us to steer clear of the "Ant-hill Society" and head off destruction of what is left of the country we love? If we can land men on the moon, we can, with an equal commitment, reduce the population explosion in this nation to zero. Zero, in this case, means a great deal. It means the difference between a reasonably good life and a life of impossible overcrowdedness, vanished recreation space, destroyed wildlife, polluted air and water, and an endless floor of cement and asphalt from Boston to San Francisco. I submit that in both the governmental and private sector, the intellectual and executive leadership of our nation should concentrate now-not 10 or 20 years from now-on the immediate necessity for reducing the U.S. population growth rate to zero, and then to implement programs of information, educa- tion, service and financial incentives which will make such stabilization possi- ble. There is increasing acceptance among the American people of this idea. A new organization called Zero Population Growth, Inc., started hardly a year ago, has burgeoned at an astounding rate, and now has active and enthusiastic chapters in over 60 localities around the country. College students preparing exhibits and speaking programs for "Environmental Action Day", April 22, are well aware of the importance of zero population growth and its corollary, the two-child family. These students, vitally concerned with the destruction of our environment, understand the basic prerequisite of halting population growth in order to reverse this trend. They have already ordered from this Association thousands of lapel buttons saying "Stop at Two", and more orders are coming in daily. Nor has the U.S. government entirely ignored this essential point. At a recent Conference on Environment here in Washington, Secretary of Health, Education and Welfare Robert H. Finch bluntly endorsed the idea of the two- child family as a social and family ideal for all Americans. He termed over- population "a paramount concern that must be dealt with if other environmen- tal problems are to be solved." In like vein, President Nixon's chief Science Advisor, Dr. Lee DuBridge, has called the reduction of the earth's population growth rate to zero "the first great challenge of our time." He said: "Do we need more people on the Earth? We all know the answer to that is `No' . Can we reverse the urges of a billion years of evolving life? We can. We know techniques for reducing fertility. We are not fully utilizing them . . . Can we not invent a way to reduce our population growth rate to zero? Every human institution-school, university, church, family, government and international agency such as UNESCO-should set this as its prime task." Other distinguished men of science and government have also endorsed this concept. Among them is General William H. Draper, Jr., one of the most emi- nent men in the population field. General Draper recently called for a zero population growth rate for the U.S., "by the end of the present century." The Committee on Resources and Man, of the National Academy of Sciences, has also gone on record forthrightly declaring the need for zero population growth by the year 2,000. To these statements, I can only say that the concept is correct, but the time framework is too lenient if we are to save what is left of the quality of life in our country. To accomplish zero population growth in the U.S., the average number of children per family must be reduced from 2.8, where it is now, to 2.2. This, of course, means that most families must limit children to two. In September of 1969, the Board of Directors of this Association unani- mously passed a Resolution on the Desirability of the Two-Child Family, which states in part: "We have resolved . . . that the medical profession should make voluntary sterilization, for both men and women, more freely available to those who want no more children, regardless of the number of chil- dren they already have; and we further resolve that, to prevent over-popula- tion, American parents in general, irrespective of race, economic status, educa- PAGENO="0471" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7303 tional background, or age range, should adopt as a social and family ideal the principle of the 2-child family." Commenting on this, Dr. Paul Ehrlich recently stated: "In view of the seri- ousness of runaway population growth in the United States and in the world as a whole, no informed or patriotic American couple should have more than two children. I congratulate the AVS on its resolution on the desirability of the two-child family . . ." Let us understand clearly that overpopulation is not only one of the main roots of poverty, mental illness and crime in the U.S., but it is also the basic root of the environmental pollution that concerns all of us today. Regardless of the most energetic efforts on the part of scientists and technicians to turn back the tide of pollution, their fight will be lost unless effective population control is made a fact in the very near future. Dr. Allan J. Brooke, an ecolo- gist at the University of Minnesota, said in a recent lecture: "If we want to save ourselves, we must stop putting our heads in the sand, and think about sterilization programs and relaxation of abortion laws. We must achieve a change in all our attitudes. We have got to change to the point where we rec- ognize that it is now socially unacceptable for people to have more than two children." Remember, this man is an ecologist-one who understands far better than most of us what the roots of dangerous environmental pollution really are. Listen to Dr. Wayne H. Davis, who teaches in the School of Biological Sci- ences at the University of Kentucky. He comments as follows: "I define as most seriously overpopulated that nation whose people by virtue of their num- bers and activities are most rapidly decreasing the ability of the land to sup- port human life. With our large population, our affluence and our technological monstrosities, the United States wins first place by a substantial margin. Let us compare the U.S. to India, for example. We have 203 million people, whereas she has 540 million on much less land. But look at the relative impact of people on the land . . . I want to introduce a new term, which I suggest be used in future discussions of human population and ecology. We should speak of our numbers in `Indian equivalents.' An `Indian equivalent' I define as the average number of Indian citizens required to have the same detrimental effect on the land's ability to support human life as would the average American. This value is difficult to determine, but let's take an extremely conservative working figure of 25." Emphasizing that this figure of 25 for an "Indian equivalent" is very con- servative, Dr. Davis adds that it has been suggested that a more realistic figure would be 500. He concludes, therefore, that in Indian equivalents, the population of the U.S. is at least 4 billion, and the rate of growth is even more alarming. We are growing at 1% a year, a rate which would double our numbers in 70 years. India is growing at 2.5%. Using the "Indian equivalent" of 25, our population growth becomes 10 times as serious as that of India. One year's crop of American babies can be expected to use up 25 billion pounds of beef, 200 million pounds of steel, and 9.1 billion gallons of gasoline during their collective lifetime. Even more serious are the demands on water and land for our growing population. We are destroying our land at a rate of over a mil- lion acres a year. We now have only 2.6 agricuiture acres per person. By 1975, this will be cut to 2.2, the critical point for the maintainance for what we con- sider a decent diet. By the year 2,00~Y-if we survive that long-the projection would be 1.2 agricultural acres per person, insufficient to feed Americans. In assessing realistic means of bringing about the acceptance of the two- child family as a social and family ideal in America, we cannot neglect the need for private and governmental education toward a basic change in family attitudes. It has been correctly point out that regardless of available birth control technology, if couples want to have more than two children, they will do so (barring any direct and stringent government action). On the other hand, a broad acceptance of the two-child family ideal among all Americans would still be to little avail unless completely reliable birth control methods, especially sterilization, are readily available to all. As you already know, this is not now the case. What is less generally known is that sterilization is the most reliable method of birth control known today, and is finding increasing acceptance among millions of American men and women. It is estimated that over 2 mu- PAGENO="0472" 7304 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lion living Americans of childbearing age have obtained sterilization, and that each year at least another 100,000 use this method of birth control. (That figure of 100,000, by the way, we consider very conservative; it may be as high as 200,000 per year.) Not only is voluntary sterilization legal in all 50 states, but it is the most appropriate method of birth control for those couples who are sure they want no more children. Properly performed, the operation is vir- tually 100% reliable, is medically accepted, safe, and has no negative after- effects, either physical or mental. The sexual harmony of couples is often enhanced as a result of complete freedom from worry about unwanted preg- nancies, when the sterilization method is used. Studies in the U.S. as well as other countries, have repeatedly shown that a significant proportion of couples do not want any more children. This is as true of the black community as of the white community. It also includes per- sons of a much younger age than might be expected. For example, a woman in her twenties who already has two children may have twenty years of fertility stretching ahead of her. She and her husband may both be sure that they want no more children, and may be urgently seeking completely reliable birth control. The AVS receives applications for help from many such women who are dissatisfied with temporary methods of birth control and fearful of some of them. It seems clear that many such women would be better off with a steri- lization operation than with any other method. It remains for government and private agencies to make the operation far more readily available than at present. Every hospital, whether tax-supported or not, should have a voluntary sterilization clinic or service for both men and women. The operation should be done at low cost or no cost, both for the obvious benefit of the patient and as a sound national policy. Whatever the government spends on providing ster- ilizations would be returned twice over through decreased need for basic chil- dren's services such as education, avoidance of costly environmental pollution, and lower welfare costs in the Aid to Dependent Children areas. Let me empha- size, however, that we do not suggest sterilization merely as a method for the poor. On the contrary, it should be made freely available to all adult citizens, regardless of income, age, number of children or marital status. The male operation (vasectomy) has been called by the Journal of the American Medical Association "safe, quick, effective and legal." It is more simple than that for the woman, and can be done in less than 1/2 hour in a doctor's office. Although possibly 100,000 male sterilization operations are done in the U.S. each year, probably 10 times that number would be performed if wide and favorable publicity and government encouragement in the areas of education and direct service were brought into play. In terms of cost, sterilization for the average person is not expensive com- pared to other methods of birth control, when one considers the cost of the pill or the condom over a number of years, and when the lower rates of reliability of other methods are brought into the equation. In broad economic terms, there is evidence that vasectomies would cost the government considerably less than some other birth control methods promoted through government pro- grams. Voluntary sterilization is acceptable to Americans of all religious faiths. The files of AVS show that among people we help to obtain the operation, one or both spouses in a family are Roman Catholic in about 30% of cases. A recent Gallup Poll showed that 64% of the American people approve of voluntary sterilization for socio-economic reasons. Contrary to common belief, the operation is reversible, in the hands of expe- rienced surgeons, in up to 80% of cases in men and up to 65% of cases in women. Furthermore, the coming use of sperm banks promises a new means of assuring a couple that they can have a child at some future time, even though the man may be sterilized. In relation to the Pill, and the IIJD, it must be acknowledged that steriliza- tion is more reliable than both. Furthermore, it does not interfere with the hormonal system of either the woman or the man, and is a simple operation with a very low degree of medical risk. In a sense, therefore, it can be consid- ered not only more reliable, but less dangerous than some other commonly used methods. You already are well aware of possible dangers of the Pill. You may also know that recent studies reveal the possibility of perforation of the womb, peritonitis, or intestinal obstruction resulting from the use of the PAGENO="0473" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7305 intrauterine device. The overall reliability of the IUD as compared to steriliza- tion is, of course, considerably lower. One estimate, published by Time-Life Books, and using recognized medical sources, puts it this way: The number of likely pregnancies among 100 women using sterilization for one year is .003, whereas for the same number of women using the IUD for one year, the figure is 5. I do not say that sterilization is absolutely safer than either the Pill or the IUD, but it is safer in terms of absence of side-effects and avoiding disturb- ance of the hormonal system. Thus, on all counts of safety, effectiveness, low cost and acceptability, voluntary sterilization scores high. We are in the last inning of a fight for survival of the human race against environmental pollution. The scientists who know most about this threat are telling us that we have only 30 to 35 more years to go. A root cause of the pollution is tOo many people. The time for studies, for committees, is over. What is needed now is action-action on a very large social and financial scale. On this point, John D. Rockefeller, III, has declared: "The problems of population are so great, so important, so ramified and often so immediate, that only government, supported and inspired by private initiative, can attack them on the scale required . . . It is for the citizens to convince their political lead- ers of the need for imaginative and courageous action." The U.S. government should act now, not in 1971 or 1972, but this year, to make government-financed birth control services, especially voluntary steriliza- tion, freely available to every adult in the country who wants them. The public acceptance is there; the medical know-how is there; and the need is most certainly there. The intellectual and financial commitment from the gov- ernment is all that is lacking. On behalf of the Association for Voluntary Sterilization, Inc., I urge the dis- tinguished members of this Committee to help provide that commitment and those funds before it is too late. Thank you. PAGENO="0474" APPENDIX XIV EXCERPTS FROM TESTIMONY IN THE CASE OF RAYMOND BLACK VS. G. D. SEARLE & COMPANY {No~rE.-This case resulted in a jury verdict for the defense. No appeal was taken.] VOL. Ill-MAY 19,~ 1969 (PAGES 421 THROUGH 535) UNITED STATES DISTRICT COURT, NORTHERN DISTRICT OF INDIANA, SOUTH BEND, DIVISION Civil No. 4082 RAYMOND BLACK, As ADMINISTRATOR OF THE ESTATE OF ELIZABETH BLACK, PLAINTIFF V. G. D. SEARLE AND COMPANY, DEFENDANT PROCEEDINGS RESUMED PURSUANT TO ADJOURNMENT Before the Hon. Robert A. Grant, Judge, and a Jury, Monday, May 19, 1969, at 9:30 o'clock a.m. Present: Arthur A. May, Esq., Thomas H. Singer, Esq., James H. Pankow, Esq., William Richmond, Esq. Also present: Mr. Raymond Black and Dr. Victor Drill. * * * * * * * Victor A. Drill, M.D., called as a witness on behalf of the Defendant herein, having been first duly sworn, was examined and testified as follows~ DIRECT EXAMINATION By Mr. PANKOW: Q. Would you state your name, sir? A. Victor A. Drill. Q. And in what capacity are you engaged in your work? A. As a research doctor. I have an M.D. and a Ph. D. Degree. Q. Dr. Drill, where do you live? A. 1620 Meadow Lane, Glenview, Illinois. Q. Where do you work, Dr. Drill? A. The Laboratories of G. D. Searle and Company in Skokie, Illinois. Q. And what is your title or your capacity at the G. D. Searle and Company? A. I am Director of Biological Research for the Laboratories. Q. How long have you been Director of Biological Research there? A. Since December of 1953. * * * * * * * CROSS EXAMINATION By Mr. SINGER (continuing): Q. Your findings for the incidence of thrombophiebitis in users of oral con- traceptives, these are the things that you have gotten together yourself from your own work? A. These are reports, data given to us from clinical studies conducted with our product, Enovid. (7306) PAGENO="0475" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 7307 We haven't gone out and treated their patients. This is the data that comes back to us. Q. But you put all these statistics together, have you not? A. From each of the papers. I took the number of women used in the paper, the number of cycles used, the number of cases of thrombophlebitis, tabulated them for each of the studies in the AMA paper, and arrived at that average. Q. All right. This is a Searle and Company chart, though? This is your chart? A. It is my chart. Q. It is not a Government chart? A. No, it is not. * * * * * * * Q. Right. And you referred, for instance, to the plarmed parenthood study? A. Right. Q. And some twelve to fourteen thousand women participated in that? A. Yes. Q. And they belonged to a little group called the "Twenty-five Month Club"? A. Right. Q. And are the statistics that you have used in your chart taken from women who belonged to the "Twenty-five Month Club"? A. Yes. Q. All right. A. Part of the statistics and that value came from that. Q. Well, fourteen-twelve to fourteen thousand people who belong to the "Twenty-five Month Club" are included in your statistics down here of oral con- traceptive users? A. Right. Q. All right. In other words, Doctor, that meant that a woman had to stay on the pill for twenty-five months before she would ever be included in your statistics from the planned parenthood study? A. Right. Q. All right. So, then, that if a woman got sick on the way or if she died, she wouldn't be included in this "Twenty-five Month Club," would she? A. Yes, they would; she would. Q. Doctor, didn't you tell me that you had to be there twenty-five months before she was included? A. You said if she died or became sick. Q. Well, let's take "sick". A. Yes. Q. Suppose she got sick and went off the pill and didn't continue for twenty- five months. A. Yes. Q. She would not be included in that statistic? A. That's right, if they dropped out because of nausea, if they dropped out to become pregnant; if they mOved out of the neighborhood, they would not be in- cluded in the study. Q. All right. So, in other words, you took for your study, at least so far as the planned parenthood study was concerned, only those women healthy enough or willing enough to survive for twenty~five months, is that correct? A. No, I wouldn't put it that way exactly. Q. Well,- A. These are women Who do give us experience for over two years of use. Q. Right. A. They haven't just received the compound for one week; they have had it continuously for two years, and go beyond two years. Q. All right. A. So this gives us excellent use experience with a large number of women. Q. For women who last twenty-five months, correct? A. For who what? Q. For women who last on the pill twenty-five months? A. For women who continue to receive the pill for twenty-five months or longer. Q. All right. Now, this pill, Doctor, affects some women differently than it affects others? PAGENO="0476" 7308 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A. To some degree. Q. All right. And some women get nauseated when they start to take this pill? A. Right. Q. It is a sign to them that they don't feel good? A. Iwould think so. Q. And some women drop off of the pill at that sigI~ of nausea? A. Right. Q. All right. So the women who either move or want to get pregnant or whose reactions to the pill are such that they don't want to continue with it, are not included in your statistics down here of the oral contraceptive users? A. They are not in that, but they are included in two other studies that I haven't included. Q. We are talking about- A. One study that I have included in there does evaluate the people who dropped out; that's the Frank and Tietze paper. They evaluated-I think they had roughly 11,000 women in the study.. I would have to look it up to be sure, but they evaluated-gosh, if I had the paper I could calculate it-a higher per- centage of women who dropped out; 50 to 60 per cent, because they wanted to check on the point that you are raising, why do women drop out. Well, we know some of the reasons; some have nausea; some move; some want to get pregnant, but they canvassed well over a thousand patients in a fairly respectable percentage, 50 to 60 per cent of the drop-out. None of the drop-outs had developed thronibophiebitis, although some of them said they had dropped out because they said they were scared about getting throm:bophebitis, but none had the disease. Q. Doctor, you are talking about 50 to 60 percent of the drop-outs that they interviewed? A. That's right, of the people that drop out. They did a check by interviewing 50 to 60 per cent-I sty; I'm trying to remem- ber the figure. I can calculate it-just to see if the questions of the type you are raising have any validity, and they did not find any women who had dropped had developed thrombophlebitis. Q. Now, Doctor, the accuracy of your study done here dealing with the users of oral contraceptives, of course, depends upon the reporting of the incidence of pulmonary embolism? A. Right. Q. And if a woman dies of pulmonary embolism and there is no autopsy, you don't know if that is the disease that caused her death? A. I can't be certain. You go by clinical signs and symptons, obviously. Q. Yes. But those signs could account for any number of diseases, as heart attack? It would be symptom of a heart attack that would be almost like pulmonary embolism? A. I agree; it would be better to have an autopsy to be sure. Q. So unless you have an autopsy, Doctor, you don't know how many women on oral contraceptives are dying of pulmonary embolism? You can't tell,can you? A. Well, first off, you have to have some that are dying, and in the study of Frank and Tietze, again, with 11,000 women, there were no deaths, as I re- member it, so I don't * * * * * * * * * Q. All right. And you also know that many of the women who buy Enovid for oral con- traceptives do not complete their medication? `A. Some don't. Q. You had studies in the Seattle area where up to 75 per cent of the women went off the pill? A. There was a certain small study. You must remember, too, that normally some of the studies were done at the ten-milligram dose which did produce more nausea. With the five-milligram and the two and a half-milligram doses, the incidence of nausea and side effects of that type is very much less. PAGENO="0477" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7309 Q. Well, Doctor, talking about the dose response or whether or not this medica- tion is dose-related, women on even the one-milligram pill are still getting nausea? A. The nausea is pretty much at the Placebo level * * * * * * * * VOL. lI-MAY 16, 1969 (PAGES 208-420) Dr. KISTNER. DIRECT EXAMINATION Q. In other words, if there is a kthking, if the uterus tips, and in so tipping backwards, the retroversion, it twists (indicating) and kinks the ligament that carries the vein, then there will be obstruction and diminished blood-flow in that vessel. Now, Doctor, over what period of time have you worked with Enovid? A. I have worked with Enovid since 1957. Q. Up to the present time? A. Up until the present, yes. Q. And have you received literature from the Searle Company regarding Enovid? A. Yes; I have. Q. Insofar as that literature is concerned that you have received from the Searle COmpany, how does it compare with the knowledge that you have acquired from other sources? A. Essentially the same. Q. When you prescribe Enovid, do you have to write a prescription for it? A. Yes. Q. For your patients? A. Yes. Q. What do you tell them about Enovid when you prescribe it? A. Well, my routine is-and I hope I maybe able to give my routine- Q. Surely. A. (Continuing)-is to take a thorough history, to do a complete pelvic examin- ation, a complete physical examination, including a pelvic examination, and then have the patient come back to my office, and if I feel that she should take an oral contraceptive agent, I then describe to her the method of taking the pill, and I also describe to her the most common side effects that she might experience. In addition to this, I will usually give her one of the prepared booklets that all of the pharmaceutical houses have in order to have her better understand exactly what is going on in the physiology, in her basic physiology. I like my patients to know what is going on and how the drug that she is taking is effective in preventing pregnancy. Q. Now then, you are familiar with the package inserts that come with the pill? A. Yes, I am. Q. To what extent do you go over the information with your patients? To what extent do you go over with your patients the information contained in the package insert? A. I don't relate the package insert to the patient. The package insert is related to me. Q. Let me ask you this. When you give Enovid to your patients in the manner which you have pre- scribed, do you discuss with them the reports that appear in this Searle literature? Mr. SINGER. Your Honor, I'm going to object unless this question goes to what this doctor told his patients up `til September 18, 1965. Mr. PANKOW. That's agreeable with me. The COURT. I think it should be so limited. By Mr. PANKOW (continuing): Q. Doctor, my question is directed only to the period of time of September 18, 1965, and before that time. A. Yes. Q. Your routine. A. Yes. Q. Did you tell your patients about the reports that appeared in the Searle literature in the package insert regarding the occurrence of thromboembolic phenomena on takers of Enovid? PAGENO="0478" 7310 COMPETITIVE PROBLEMS IN THE DRUG INDUS~~RY A. Are you asking me whether I initiated the conversation? Q. Yes; whether you told your patients about it, yes, as a part of your routine. A. 1 told her as a reply or initiation of the discussion? Q. Well, as an initiation. A. No, I did not. Q. How would it come up, if it came up? A. If the patient asked me that she had read that there were some protdems with blood clotting, then I would reply to her question. * * * * * * * :1 have seen no patients who developed thromboembolic disease, including pul- monary embolism, in the over three hundred patients upon `whom I have operated who received estrogen~progestin combinations prior to and subsequent to surgery. Q. Doctor, have-can you compare for us the testing that Enovid received, from your knowledge of it, prior `to the time it went on the market as an oral contraceptive? Can you compare the testing itself with the testing received by other drugs with `which you are familiar before they went on the market? A. In my opinion, I think `that the testing that Enovid and all of the other estrogen~progestiu combinations received were about as extensive, if not the `most extensive, th'at `I `have ever considered. For example, when we were doing clinical investigation with estrogen alone, I would `say practically the only studies that `we were doing at that particular time were related to the morphology, the changes in `tissue, but none of the other multiple facets of body function were studied. Q. Now then, will you compare for us, from your knowledge, the extent of the testing and clinical study that has been done of Enovid and the other estrogens and progestins? A. I think I indicated that I think they were, if not the most `extensively studied, as extensively studied as any I h'ave known. Q. My last question went to `before they went on the market as oral contracep- tives. A. Yes. I think I should m'ake this clear, that my work in this field, from 1957 and continuing to 1960, was not with the use of these agents, Enovid as an oral contraceptive, but in the disease processes of endometriosis and the regulation of abnormal bleeding, and the change in the lining of the womb which might be precancerous. My studies were not designated at all-were not designed along the studies as an oral contraceptive would offer. Q. All right. Were you aware of such studies going on? A. Oh, yea * * * * * * Q. All right. How many of the people that you see have such a regular cycle that you have described? A. Not very many, but I am a gynecologist and I see women with menstrual disorders in general. Q. Okay. Doctor, as a result of your knowledge and your experience with Enovid, have you an `opinion, based upon a reasonable medical certainty, as to. whether ~there exists any causal relationship between the taking of Enovid and the occurrence of th'romboembolism or pulmonary embolism? You may answer that "yes" or "no"; you do or do not have an opinion. A. At the present time, I do not believe that there is statistical evidence to prove that there is a definite relationship. Mr. PANKOW. You may cross examine. * * * * . * cRoss ExAMINATION Q. Involves some risk. And the risk being to a healthy female of not using an oral contraceptive, I take it, would be pregnancy? That would be the only risk, wouldn't it? A. No. PAGENO="0479" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7311 Q. If she didn't use the oral contraceptive? A. No. There are other methods of contraceptives. Q. The other methods of contraceptives such as the diaphragm involve no risk of health to the patient or to the female? A. Not the way you stated the question. The diaphragm involves a little ad'di-~ tional risk. Other methods don't. Q. Does the diaphragm involve any risk, Doctor, to the female who uses it? A. No. Q. No risk to her life? A. No. * * * * * * * Q. What are the other ones in not taking the oral contraceptive? A. If you just drive down the street, you have an increased risk of losing your life. If you travel in an airplane, et cetera,-there are risks to everything. The way you are phrasing the question, I can't agree. Q. That's correct, but driving down the street in an automobile has nothing to do with an oral contraceptive, does it? A. No, except for the comparison of risk. Q. And flying in an airplane has nothing to do with whether or not you are taking an oral contraceptive? It doesn't have a thing to do with it, Doctor? A. Except for the comparison of risk, which you are comparing. Q. And when you get in your car, Doctor, you know that there is a risk that you might have an accident? A. That is correct. That's right Q. And when you get `into an airplane, as you d'id to fly out here to South Bend and testify in this case, you knew that there was a risk- A. (Nodding.) Q. (Continuing)-in airplane flight? A. That's correct, yes. Q. But you never tell your patients that there is a risk t'o the use of this oral contraceptive pill? A. No, I do not. Q. Isn't that correct? A. That's correct. Q. All right. So, while the patient knows about the risk of life, `she doesn't know about the risk of this pill, at least from your treatment of your patients, isn't that correct, Doctor? A. Yes. Q. All right. Now, Doctor, you wrote an article recently that was published in ~the Woman's Day magazine? A. Yes. Q. `And did you see that `article before it was published? A. Yea * * * * * * * Q. We talked about it? A. Yes. Q. Did you make this statement in this article: "There is some evidence of in- creases in both tendencies toward varicose veins `and the increase of blood clotting disorders among pill users." Is this a fair statement of what you said in that article? A. Yes. Q. And so, Doctor, you were talking about the risk of a blood clot? A. I said there was some evidence. Q. All right. But when you were talking about the risk, you're talking about the risk that~ some evidence shows that oral contraceptives are related to blood clots? A. Yes. Q. Now, that was one of the facts that you were talking about in this article? A. Yes. Q. It wasn't one of the fallacies? A. No. PAGENO="0480" 7312 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY Q. Isn't that correct? A. This is one of the purported facts, yes. Q. Well, it was one of the facts that you referred to in your article? A. Yes. Q. Correct? A. Yes. Q. And then, Doctor, you went on to finish that statement by saying: ". . . but the risks for a woman who becomes pregnant are considered greater." A. Yes. Q. Is that correct? A. Right. Q. So, again, you were balancing the risk of taking this oral contraceptive medication against the risk of pregnancy? A. That's true. Q. And there are certain risks to pregnancy, are there not? A. Yes. Q. Do you know how many women in this country die in the birth per- A. Per year? Q. (Continuing)-per year per million? A. No, I don't. Q. Well, there are some risks, though? A. There are quite a few, yes. Q. And the risk of blood clots? A. Yes. Q. And the risk of death in childbirth? A. Yes. Q. Now, Doctor, some of the women who die in childbirth do so because they don't have adequate prenatal care? A. True. Q. And adequate postnatal care? A. True. Q. And their babies are delivered in facilities that are not adequate? A. Yes. Q. And sometimes by doctors who are not well trai'ned? A. Yes. Q. Is that correct? A. Yes, these are all correct. Q. So to `the extent that the human female has good prenatal care, good post- natal care, her `babies are delivered in good facilities, she is on a good diet, and she is watched by a good obstetrician, her risk of death lowers in childbirth, isn't that correct? A. That's true. Q. And you are aware of the fact, Doctor, that in South Bend, Indiana, we have good medical facilities, is that correct? A. Yes. Q. And our gynecologists here are well trained? A. (Nodding.) Q. Isthatcorrect? A. Yes. Q. And so a woman in South Bend, Indiana, who has good medical attention, and is delivered at one of our local hospitals, is on a good diet, has good prenatal care and good postnatal care, has a much lower incident of death in childbirth than the women who do not, isn't that correct,just from statistics? A. Yes. I would have to `agree. Q. And that would be true, wouldn't `it? A. Yes. Q. So to the extent, Doctor, that the risk of death from childbirth goes down, as it is in South Bend, Indiana, where you have good facilities and a good doctor, the risk of a blood clot from an oral contraceptive goes up, as you balance the risk's? A. All right. Q. Isn't that correct, Doctor? A. It would have to be, if you diminished the other risks. Q. All right. Now, Doctor, I take it as part of your professional attitude toward your PAGENO="0481" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7313 patients, you do not consider it good medical practice to tell a healthy female about the risk of oral contraceptive medication? A. That is correct. Q. You clon't---~ A. Nor do I tell her about the risk of pregnancy when I see a pregnant woman, that she may die of throinboembolic disease. Q. It doesn't make any difference, then, Doctor; she's already pregnant, Lsn't that correct? A. Yes, but she may be considering pregnancy. * * * Q. All right. So that the patient wants to become pregnant and she doesn't care what the risks are, isn't that correct? A.No. Q. All right. But the oral contraceptive pill, while it involves some risk of a blood clot,, is a risk that you `do not discuss with your patients? A. I do not. Q. And the medical profession- A. Beg your pardon. I do not initiate the discussion. Q. All right. If she inquires about it, you may tell her about the risk of this oral contra- ceptive medication? A. I do if she inquires. 1 do go into length about this discussion. Q. And you and the medical profession certainly aren't going to volunteer this information to her, correct? A. The ` information has already been volunteered and not only volunteered, but has been made widely available to patients. Q. Well, this is a prescription drug, Doctor. Isn't the information that is contained in the package inserts and the doctors' brochures that goes only to the d~ctor, doesn't it? A. You asked me if the patients or the public ha's been in'formed. Q. Has the public been informed about the `risk of :the oral contraceptive medi- cation and i'ts relationship to `blood cints? A. Yes. Q. Were they informed of that in 1964 and 1965? A. I th'ink the initial report was in 1962, and subsequent to that time, there was a good deal of publicity. Q. All right. You are assuming, of course, that everyone has read those articles in the newspaper aren't you, if the patient is to be informed? A. The information was available. * * * * * * * Q. Well, Doctor, haven't you told us that there is some evidence that an oral contraceptive pil'l is related to blood clots? A. Yes. Q. That's number one, isn't that correct? A. There is some evidence. Q. All right. And if we have a woman who has an enlarged uterus that is tipped backward, then there are two more predisposing things to the development of the clot in the right ovarian vein, correct? A. No. If I may- Q. No. A. If I may answer the question? There's no doubt about the fact that the enlarged, retroverted uterus predis- poses to blood clotting, venous sta'tis, because I've seen this. * * * * * * * Q. Well, then, you said if your-I'm sorry. I can't remember it; that you might suggest something to them? A. No. That was in the context wi'th the other questioning about the suggestion of certain symptoms arising as a result of suggestion, but not as a result of sur- gical procedures. Q. Oh, I'm sorry. PAGENO="0482" 7314 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY In other words, when we are talking about medication, if you went through all the side effects or symptoms they might have, they might-those might even be suggested to them in your- A. This has been well documented. Q. All right. Doctor, in all of your experience, have you ever heard of one case where sug- gestion induced the formation of a blood clot? Have you ever heard of one case? A. As diagnosed by what method? Q. Well, Doctor, does suggestion cause blood clotting? It doesn't, does it, Doctor? A. Well, it might. Q. All right. A. It might. There's a possibility through various adrenal factors and by the excitation of some of the blood clotting mechanisms that it might. Q. All right. In other words, you can suggest to somebody if they take this they might get a blood clot and the very suggestion would cause that clot? A. It very frequently causes the symptoms which are exactly the same as blood clotting, and that's the reason I asked about the method of diagnosis, because if it were not precise, the incidence would be higher. Q. All right. Now, Doctor, I'm not talking about symptoms; I'm talking about the existence of a clot. Can you suggest the formation of a clot and have it occur in a human being? A. It might be possible to do so, yes. Q. All right. A. But very rare. Q. Very rare? A. Incidents of fatal blood clots are very rare, anyway. Q. All right. Have you ever seen a document case where somebody made a suggestion that, "You are going to get a blood clot," and then it developed? A. No, I have not. Q. There's not such a case in all the medical literature, is there? A. But you asked me if it were possible. Q. All right. But there has never been a case like that? A. I know of no such cases. * * * * * * * Q. I'm sure he will. A. Yes. Q. You came out here at the request of the G. D. Searle and Company, didn't you? A. Yes. Q. They asked you to come and testify? A. Yes. Q. And you came here thinking that your testimony would be helpful to them, isn't that correct, Doctor? A. No, it is not Q. All right. Doctor, do you know Dr. Drill? A. Yes, I do. Q. Did you know Dr. Winter? A. Yes. Q. And you have worked closely with G. D. Searle and Company over the years? A. I have worked closely with many companies. Q. Many drug companies? A. Many drug companies. Q. And do these drug companies, Doctor, give you research grants? A. Yes. Q. And as a result of the research grants that you get from the drug companies, you write papers? A. Yes. PAGENO="0483" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7315 Q. All right And part of your qualification as an expert witness here today is that you wrote a number of papers? A. ~Not necessarily. Q. Just a minute. Many of them for drug companies? A. The qualification is that I have had experience in this field. Q. All right. And part of your experience comes in working closely with drug companies, isn't that true, Doctor? A. No, I disagree. Q. All right. Doctor, does the Harvard Medical School receive large grants from drug companies to do studies? A. I don't know. Q. You don't know? A. No, I don't. Q. Well, you receive grants from drug companies to do studies? A. Yes. The Boston Hospital for Women, yes. Q. And you are being paid to come out here today and testify? A. I assume my expenses will be paid, yes. Mr. SINGER. Thank you very much, Doctor. The COURT. Now, just a minute. Do you have something by way of redirect? Mr. PANKOW. Yes. REDIRECT EXAMINATION By Mr. PANKOW: Q. Doctor, will you tell us the type of work you do that you have mentioned in connection with your association with drug companies so far as- A. Well, the type of work that I do was to obtain the medication that I de- sired to begin clinical * * * * * * * * Dr. WINTER. CROSS EXAMINATION By Mr. MAY (continuing): Q. Doctor, you know the difference between a prospective study and a retro- spective study, don't you? A. Yes, sir. Q. And a retrospective study is where you look back to see what has happened, don't you? A. That is correct. Q. In other words, in your studies that were conducted of the pill, you went back and you looked at people who remained on the pill for a certain period of time. Am I correct in that? A. I think that is just the other way around; that in our studies which we conducted, we considered them prospective studies. We followed them during the time that they had-they were on the pill from the beginning onward. Q. Now, you had about a 75 percent dropout, didn't you, on the studies that you conducted of persons that started on the pill? A. Well, this varied from study to. study. `I think that's rather high, but eventually, of course, it might reach such a figure. Q. Pardon? A. Eventually, if we carried it on long enough, it might reach such a figure, yes. Q. Well, what would you say would be the dropout rate? A. Well, as `I say, it varied from study to study. Q. Yes. Well, I'm asking you, Doctor, if you are familiar with the memOrandum that was written to you on April 1st, `1963, which says-which is written by Dr. C'hien, Director of Marketing Research for Searle and Company? A. Yes, sir. Q. All right. I will ask you if you do not recall this statement: "Although we, ourselves, have not made any `large-scale study of the dropout rate, a `relatively small number of high volume prescription stores were audited by our personnel in order to discover-in order to follow through the refill pat- tern of Enovid prescriptions. We discovered that as high as 70 to 75 per cent of all patients `who take Enovid do not continue its use beyond three months." PAGENO="0484" 7316 COMPETITIVE. PROBLEMS IN THE DRUG INDUSTRY That's the initial patient dropout rate for the ten-milligram tablet. A. Dr. Chien was referring to- Q. Well, do you recall that statement, Doctor? A. Yes, sir. Q. And would this-was this part of your knowledge that you had hack there in t1963? A. Yes, sir. Q* In any of your studies, did you ever undertake to check on the dropout of the patient, the patients that dropped out? A. Yes, sir. Q. What study was that? A. All of our studies-essentially all of them, at any rate, the ones which we relied on mostly all had what we called dropout forms in which the Investigator was to fill out for women who did not continue with the study. Q. What study was that, Doctor? A. All of them, as far as I know. Q. All of them did? A. I can't answer that exactly. Q. Would that include Dr. Tyler's study in Los Angeles? A. I think they had dropout figures, too. I would have to check to be exactly zure. Q. All right. A. The dropout forms. Q. How many of these reports did you follow through on the people that dropped out, off the pill? A. It was not possible, of course, to follow through into their private life everybody that dropped out of the pill. What we were more concerned with is why they dropped out. Q. And do you have any of those statistics? A. I don't have them with me, no. Q. You don't have those with you and you don't know how many were made or ever checked on? A. I would have to look it up, but a large number certainly were. Q. Yes. Was it the Tyler study? A. The Tyler study was one. Q. And they checked on the dropouts? A. Again, they checked as nearly as was possible to check out why they dropped out. Again, we didn't follow them on for months or years after they had left the study. Q. Now, Doctor, isn't it true that the basis of this statistical data which you relied upon which gave you this feeling of security depended upon the reporting of these cases to Searle and Company by the doctors? A. Yes, sir. Q. Isn't it also true, Doctor, that there are probably a great many cases where people may die of thromboembolic diseases or pulmonary embolisms that are never reported to Searle and Company by users of the pill? A. That's possible, but- Q. All right. Doctor, when did you first become aware of the death of Elizabeth Black? A. Well, I can't answer that exactly. * * * * * * * Q. Doctor, isn't it true that back in 1963 requests were made to the manufac- turers of Enovid, G. D. Searle Drug Company, that they conduct a prospective study on the use of Enovid as an oral contraceptive? A. I don't remember any formal request of that sort. Of course, this was one of the possibilities that had been discussed, and the possibility was considered, yes, sir. Q. Well now, wasn't the suggestion made to them by the Wright Committee? A. It was suggested that such a study be conducted, yes, sir. Q. All right. And wasn't it also suggested in the Chicago meeting of 1962? A. I'm sorry. Q. Pardon? A. I didn't realize you had stopped. PAGENO="0485" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7317 Yes, this was one of the suggestions that came out of that meeting. Q. All right. Were you at that meeting in Chicago? A. Yes, sir. Q. Doctor, I will ask you, at this meeting, and I'm reading from Defendant's Exhibit Q-this statement was not made by Dr. Mitchell at the meeting: "Dr. MITCHELL. Could I come back to this? "As you have referred to anticoagulants, the reason why I am so unhappy about Dr. Tietze's study is that I had the privilege of serving on the Medical Research Council study group on long-term anti-coagulant therapy, and I have seen some of the difficulties that arise. Dr. Tietze makes the point that the answer is wanted two or three months before yesterday. Is it better to get a real answer from a well-planned prospective study taking three years, even though it costs two and a half million dollars, than a rapid answer from not such a well-planned retrospective study, costing much less? Which is going to give the answer? "Surely it is the right answer we want, not the quickest or the cheapest or the most convenient." £ I don't remember the exact words, but I'm willing to accept the fact that he did say it just that way. Q. Well, do you have any question about that statement? A. No, sir. Q. I will hand you Defendant's Exhibit Q. Doctor, and ask you if those words do not appear in the first paragraph on page 66? (Defendant's Exhibit Q handed to witness.) By the WITNESS: A. Yes, sir. This is as read. By Mr. MAY (Continuing): Q. Did you ever obtain any requests of Dr. Sise or any recommendation from a Dr. Sise about the best way to tell about this thing would be a prospective study? A. I don't remember exactly that, but I think everyone agrees that this would be the best way to carry out such a study. Q. All right. And you never carried on a prospective study, as requested by these gentlemen, did you? A. No, sir. Q. I notice in Dr. Mitchell's statements he said the cost would be two million dollars. Would this be an `accurate estimate in your opinion as to the cost of this pros- pective study? A. I really have no way of knowing, but I think it would be probably on the meager side. I think probably it would cost more than that. Q. Well, at that time, during 1963 and 1962, `64, `65, even, G. D; Searle and Company had money to `spend for a prospective study of this type? A. Yes, sir. Q. But `they never spent it? A. Not for that reason, though, no, sir. Q. All right. Okay. Doctor, are you familiar with the recommendations of the Wright Committee or the Ad Hoc Committee tha't was formed in 19-rendered in 1963? A. I read th'em. Q. Okay. I will ask you if this was. not one of the recommendations: "Any firm reliance on the risks as calculated is tempered by the assumptions made. This Committee recommends that a carefully planned and controlled prospective study be initiated with the objective of obtaining more conclusive data regarding the incidence of thromboembolism' and death from such conditions in both untreated females and those under treatment of this among the pertinent age groups." Do you recall that? A. Yes, sir. Q. Did G. D. Searle Company conduct such a study after this recommendation was made? A. We discussed it at great length, but no, we did not. PAGENO="0486" 7318 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Q. Okay. In any of your brochures, "Dear Doctor" letters that were sent out, was there any mention made about the request for these prospective studies? A. Not that I remember. Q. Was there any mention made about the validity of the statistical studies that you had already communicated or that you had already acquired? A. Well, I can't remember the exact wording. I don't think that we ever made the statement that these were 100 percent accurate. Q. Yes. Well, they were far from 100 percent accurate, weren't they? A. (No audible response.) Q. They were far from that, weren't they? A. I don't think we can say that. They were the best we could do. Q. All right. Now, you say this, Doctor. Do you recognize this statement? This was made during the year 1962. "We `have very `little data. As I have said, I have thought we might organize the meeting along some lines `which may seem a little `backward, but I am doing it for a reason; because almost universally `when we talk to people about th'is possibility, the assumption is that young people in their twenties do not have th'rombophle'bitis and never have pulmonary embolism, and, therefore, Enovid is obviously suspect, if these conditions occur in women who are taking Enovid." Do you `recognize that statement? A.No. Q. Doctor, I wonder if I told you that you said that at the Cherry Hills Sym- posium on April 12, 1962, `that that `would be correct? A. 1 wouldn't be at all surprised. That's exactly the `way I felt. Q. But you didn't have the data. You had very little d'ata? A. That's `correc't. Q. So, in `other words, you realized back in 1962 that your data was very little, very incomplete? A. There was very little known by anyone in the medical profession about t'his particular condition at that time. Q. Well, but back in 1962, Doctor, you were getting a tremendous amount of reports `of deaths among users of Enovid of thromboembolism, `weren't you? A. `Not a tremendous number, no, sir; not considering the number of people who were being- Q. All right. Do you remember how many dea:ths you had prior to 1961 from the users of Enovid before it was being used as an oral contraceptive for treatments of disease? A. No. No, I surely don't. You are not `speaking only `of th'romboembolism now? Q. Pardon? A. You are speaking of all deaths? ~ No, I have no way of knowing that. Q. `Do you have any recollection or knowledge, Doctor, about the number of reports of clots or deaths that were reported in users of this medication prior to its use for contraception purposes prior to `1965? A. Yes. I have knowledge, yes. There were none that were `reported to us. Q. There were none? A. No, sir. Q. Wasn't there 27 incidents `between 1957 and 1961? A. Of thromboembolism? Q. Yes. A. Not to my knowledge. (Pause in the proceedings.) By Mr. MAY. (Continuing): Q. I'm reading, Doctor, from this thick document, Defendant's Exhibit P, and I apologize for having you wait I guess I didn't do my home work, as far as the pages went, as much as I thought I did. You are familiar with this exhibit that formed part of your knowledge back in `62? A. Right Q. And under Section 2 you have a summary of cases which were reported up to the date of this document? A. I don't remember exactly everything that's in every page of that book, but I will accept that, yes. PAGENO="0487" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 7319 Q. And I will ask you if a summary of cases reported by date of onset, 1957- 1961, was 27? A. Fatality? Q. No. I said "cases." - A. You said "fatality." * * * * * * * Q. All right. Now, the study also showed, did it not., that the rate per million of thrombo- embolic deaths of users of the pill wa-s 12.1, did it not, Doctor? A. According to their calculations. Q. All right. In any of the literature that you sent out following the Wright Committee re- port, did you include these figures in it? A. The figures themselves? Q. Yes. A. I am not sure. Q. Can you recall any at this time? A. I just don't remember. We may have-I'm sure we referred toithe Wright Committee, but I don't know whether we included the figures. Q. Ail right. Now Doctor, Searle and Company has what is known as "detail men," do they not? A. Yes, sir. Q. And their function is to go around and talk to doctors and discuss the products with the doctors? A. Right. Q. And try to familiarize themselves with it and the medical profession? A. Right. Q. Following the reports of these deaths from Los Angeles, which is the first ones in 1961, I believe it was, was any instruction given to these detail men? A. Not as I remember. There was-there were, of course, more conclusions referred at that time. Our detail men are bound by our official literature, and our official literature didn't call for any such statement. Q. In other words, the detail men are just supposed to tell the doctors what is in your official literature? A. Well, what we do in our promotional brochures, that sort of thing, they can elaborate on it, but they are not to-they are not supposed to go outside of what the official literature says, that's correct. * * * * * * * Q. Okay. And you intended that these be given to the patient for their information on the pill? A. If a doctor so chose, yes. Q. Do you recall, or did you have any practice with your detail men requesting the doctors to give these booklets to their patients? A. No. They were not told to do that. Q. Did you ever know of any instances of them doing that? A. No, sir. Q. But this was intended for the information of the patient? A. That's correct. Q. And you knew that the patient would rely upon this in the use of the pill, didn't you? A. These were intended for the doctor to give to the patient and for the doctor and the patient's convenience. As the doctor gave it to the patient, she would rely upon it in the context with which he gave it to her. Q. Yes. And that was true of both of these- A. Yes, sir. Q. (Continuing)-pamphlets is it not? A. Yes, sir. Q. I think the last one had a calendar in it for the patient to rely upon in keeping her records of the pill? A. That's right. PAGENO="0488" 7320 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Q. So I mean the company knew that when these were given to the patient, the patient would rely upon them in the use of the pill? A. As far as the booklets went, yes.. Q. Now, there's nothing in these booklets, Doctor, that talked about what to do if they had any chest pains, was there? A. No, sir. Q. Or what to do if they suddenly started breaking out in a sweat with chest pain? A. No. Q. Or shortness of breath? A. No. Q. Or other symptoms that have to do with an embolism, is there? A. No, sir. Q. You talk about morning sickness, don't you? A. Right. Q. That's not fatal, is it, Doctor, to most people? A. No. Q. You talk about weight gain? A. Yes. Q. That's not necessarily fatal, is it? A. Not usually. Q. I hope not. You talk about the enlargement of the breasts. Normally, that isn't-in other words, you talk about things that have-can have no real effect upon a person's life? A. These were the ones that were most commonly observed by patients which gave them the most trouble and which took most of the doctor's time to explain. Q. Yes. Well, in this booklet you say some people experience weight gain? A. That's right. Q. Right. Some people experience thromboembolisms, too, don't they? A. We know that that happens, yes. They experience a lot of other things, too, though. Q. Doctor, why is it that you didn't put in these booklets the warnings about this potentially deadly thromboembolism? A. If we put in every possible thing that could happen to a woman, we would have to really give a full course in medicine, and this is almost impossible to do in this short a booklet. These were designed solely for the convenience of the doctor and the patient. They included the common things that we knew that might occur to a woman who took Enovid, and that this doctor would have to explain. These were the symptoms which were similar to those which occurred during pregnancy and which we thought a woman would understand, but if we got intO things, all sorts of reactions which women have, whether or not they are related to Enovid, this would require volumes, and we despaired of trying to break this down to a point where a lay person could understand. We felt and still think that this is better done by the physician. Q. You still think it's better done by the physician? A. Yes, sir. Q. Doctor, I will ask you if you are still putting out these information book-~,. lets for the patient, aren't you? A. Yes, sir. Mr. PANKOW. If it please the Court, I'm going to object. We didn't go beyond `65 with the doctor. I think- The COURT. Well, he's answered. I think the answer may stand. Go ahead. By Mr. MAY. (Continuing): Q. Doctor, you `still put out these information booklets, don't you, for the information of the patient? A. Yes, sir, we do. Q. And in your current literature you are instructing the patient about- Mr. PANKOW. Wait. By Mr. MAY (`Continuing): Q. (Continuing)-thromboembolism? Mr. PANKOW. Wait a minute. The COURT. Now, just a minute. PAGENO="0489" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7321 This goes to the issue of the duty of the manufacturer as of September, 1965, and the question you posed goes to that point, and that objection is sustained, and the question will not be answered. (The following is an offer of proof outside the hearing of the Jury:) Mr. MAY. The plaintiff makes an offer to prove that if the witness was per- mitted to answer the question, he would answer that in their current booklets they are informing the patients as to the symptons of thromboembolism and pul- monary embolisms and instructing the patients to report to the doctors any swell- ings or pains in the legs or chest pains and these things that should be reported promptly. The plaintiff feeLs that this is a proper question and that that is proper evidence, because the doctor in a prior answer to a prior question said that he still believes that the symptoms-these symptoms should not be given to the patient for their information and still presently is of that belief. (Whereupon, the following proceedings were had within the presence and hear- ing of the Jury The COURT. The ruling ofthe Court stands. Mr. MAY. This next question, Your Honor, I'm going to ask is going to the question of causation. The COURT. All right. In that area we are not limited by the September, 1965 date. * * * * * * * By Mr. MAY (continuing): Q. (Continuing)-four hundred-plus incidents of clotting and the users of Enovid, were you? A. In the sense that we couldn't prove a negative, that is correct. On the other hand, we could find-well,- Q. You couldn't find one way or the other, could you? A. Well, we couldn't find any evidence to indicate that Enovid was the cause, and we were not able to prove a negative. That is correct. Q. And at that time, as a result of these committees and these experts that you called in, the Wright Committee advised a controlled prospective study, didn't they? A. Yes, sir. Q. At this meeting up in Chicago, the experts called for a controlled prospec- tive study to give you more additional information, didn't it? A. That's right. Q. The World Health Report called for a controlled prospective study, did it not? A. Yes, sir. Q. And Searle and Company never made a controlled prospective study, did they? A. That's correct. Q. And this information was never reported to the physicians in the "Dear Doctor" letter, was it? A. No, sir. Mr. PANKOW. What information? (Pause in. the proceedings.) Mr. MAY. Mr. Pankow asked what information. I'm speaking about the infor- mation that these studies have been requested by these three committees of experts, and that you had never made such a study. The WITNEss. That's right. By Mr. MAY (continuing): Q. That was not reported? A. That's correct. * * * * . * * * PAGENO="0490" APPENDIX XV U.S. GOVERNMENT MEMORANDUM MAY 11, `1960. To: Geo. P. Larrick, Commissioner of Food and Drugs. From: Bureau of Medicine. Subject: Enovid Tablets-NDA 10-976. The New, Drug Branch has concluded that the evidence establishes the safety of Enovid Tablets for oral use in conception control and has issued a letter on April 22, 1960, `making conditionally effective a supplemental application for this purpose. Because of the considerable general `interest and possible objec- `tions from some quarters with respect to our action in clearing the drug for such use, we are furnishing *the following information concerning the basis for our action. On the basis of the original data and the presently submitted data G. D. Searle and Company have recommended that Enovid be used for contraceptive purposes at a dose `level of one 10-milligram tablet daily starting from day 5 to day 25 of menstrual cycle. Because `the studies did not progress beyond 3 years and in view of the `lack of longer clinical experience, Enovid is proposed to be limited for use `for this purpose to 2 years. This product has always been limited to prescription sale and will continue to be dispensed on prescription. A supplement for this New Drug Application was conditionally filed on Octo- ber 29, 1959. This supplement proposed the use of Enovid Tablets for conception control. The original New Drug Application `was made conditionally effective May 21, 1957, and fully effective June 10, 1957. Enovid `has `been on the market since `that time. However, it was made effective for its progestational activity and has not `been labeled for conception control although `we knew at the ti'me of original `submission that it does inhibit ovulation. T'he initially indicated progestational uses of this product were amenorrhea, primary or secondary, Metrorrhagia, menorrh'agi'a, habitual abortion, the inadequate luteal phase as *a potential cause of infertility, threatened abortion, idiopathic `infertility, endo- metriosis, premenstrual tension, and dysmenorrhea. Because of the short-term nature of the indica'tions it has not been used for more `than 3 or 4 months at a time except in endometriosis in which condition it has been used for periods up to 10 months. The following studies were conducted in support of `this supplemental appli- cation proposing the use of Enovid for conception control. In the initial and subsequent studies it was shown that Enovid does, in fact, prevent ovulation. In April 1956, the first study to investigate the practical usefulness of this agent to control population increases was undertaken. At preseiit, there are 2 studies In Puerto Rico; 1 in Port-Au-Prince, Haiti, and 1 in Rio Piedras section of San Juan, Puerto Rico. The following points were and are being studied: (1) Inhibition of ovulation over long-term cyclic administration. On medication 2.7 pregnancies per 100 woman-years occurred. Gregory Pin- cus, *M.D., `Shrewsbury, Mass., states that the pregnancies that occurred were due to irregular `tablet taking. Edward Tyler, M.D., University of California Medical School, reports 8.6 percent pregnancies (22 pregnancies in 3,082 woman- months), but some of' these patients were on ~other progestational agents such as 17-a'lpha-acetoxy progesterone and 9-alpha-11-ketoprogesterone. Normally, the pregancy rate in normal woman in the reproductive phase of life under conditions of regular exposure is in the range of 75-85 per 100 women-years. Incidentally, the contraceptive efficacy of other devices under normal conditions of use ranges `from 2-10 percent. Therefore, it can be assumed that the product on daily use in efficacious for this `indication and if properly used better than the usual mechanical means. (2) Effect on the menstrual cycle. (7322) PAGENO="0491" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 7323 When the medication is taken in doses of 10 milligrams from day 5 to 25 as directed, the cycle length is unchanged. A condition known as breakthrough bleeding may occur despite regularity in taking the tablets (6 percent on 10 milligrams of Enovid and 18 percent on 5 milligrams of Enovid daily). Break- through bleeding is manifested by the appearance of bleeding sometime in the menstrual cycle other than at the usual menstrual period. The incidence is highest in the first treatment cycle and declines to lower levels by the fifth cycle. After that time, it is a rare occurrence. The amount of bleeding with menses is unchanged although Dr. John Rock of Brookline, Mass., states that after 4 or 5 successive cycles, the duration and amount of flow tends to diminish. (3) Side effects or reactions. Side effects such as nausea, dizziness, vomiting, headaches, and gastralgia occur in from 6.3 to 18.3 percent of the subjects in the various series. However, the side effects last only 2 to 3 weeks at the most. There were no apparent changes in weight, well-being, or libido. Any objection by the patient to the side effects, of course, would result in voluntary discontinuances of the use of the product and therefore are of no serious concern. (4) The effect on fertility when medication stopped. Altogether in the entire series of clinical cases, 897 women representing 801.6 women-years and 10,427 cycles have been studied. However, only 66 patients have taken Enovid for 24 cycles or more to 38 and an additional 66 women have continued medication for 12 or more cycles to 21. In one of the series in San Juan, Puerto Rico, there were 86 women on Enovid from 1-20 months; 83 percent (54) of those not using other contraceptives became pregnant after a mean exposure time of 6 months after discontinuing use of the ~1rug. Dr. Rock did follicle counts on the ovary to be sure that the potential for production of the egg was left intact on 15 women taking Enovid for 2-20 months and found no change from normal controls. (5) Possible malignant changes. Robert Kistner, M.D., Harvard Medical School, administered Enovid to 7 patients; 4 with endometrial hyperplasia, 2 with endometrial carcinoma and one patient with adenocanthoma. Six of these patients were administered daily dosages from 14 to 80 days. The seventh patient with adenocanthoma received 2 other preparations, Delalutin and an estrogen antagonist in addition to Enovid. With one exception, reversal of the malignant endometrial changes occurred and a beginning or fully developed pseudodecidual endometrial response was obtained. The one exception continued to have "carcinoma in situ" remaining. The con- clusion here was that "cystic and adenomatous hyperplastic glands may undergo regression and actively growing stroma may be converted into decidus by the action of potent progrestins." However, this in no way implies that this product would be of therapeutic value for malignancy of the female generative tract. In order to obtain some additional assistance in determining safety for use of this product for this particular indication, conception control, a letter of inquiry was sent to 61 professors and associate professors of obstetrics and gynecology at the medical schools in the United States. We were pleased to re- ceive a 100-percent response. The answers we received were as follows: 14 of the professors felt that they did not have sufficient data to reach a conclusion and said that because of lack of knowledge they did not know whether or not this product should be allowed for this indication; 26 said yes, it should be allowed for contraceptive purposes; 21 of the professors said that even though they could give no specific reason for reaching this conclusion they must say no; however, 2 of the noes were based on religious grounds, and others may have been. Some were based on cost and what was felt to be impracticality so that safety was not a factor. We asked in our letter of inquiry 7 questions of these professors so that we could determine if there were any side effects or potential dangers of which we were not cognizant. The questions were as follows: 1. Do the side effects such as nausea and break-through bleeding proscribe the use of this product for contraception? 2. Would the fertility of women on this product be effected after the medication is stopped? 3. Is there any concern about the possible carcinogencity after longterm use? 4. Would there be any concern about premature menopause? 5. Would abortion be any higher in these women than usual? PAGENO="0492" 7324 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6. Would the offspring of a previously treated mother be affected more than usual? Would congenital abnormalities be greater? 7. Do you feel that Enovid, or Enovid-like product, should be on the market for contraceptive purposes? Most of the professors who answered no to No. 7 stated that, as far as they could tell, there were no dangerous side effects associated with the use of this product. In view of the data submitted, the brochure which limits the use of this product to 2 years and the majority of favorable answers from the professors, we have concluded. the, drug is safe and as indicated above have issued a letter making this supplement conditionally effective. W. H. KE55ENICH. 0 PAGENO="0493" HUMAN RESOURCES PROGRAMS 1101 ones; business location; and effect on competition; and (d) Effects on the stability, level, volume or other aspects of employment, wages, costs, sales, prices, or other phases of economic activity.-As described in the earlier reference "Education and the Atom," the genesis of the atomic energy program stemmed from the academic world. The early history of the atomic energy program describes the impact of institutions such as Columbia University, the University of Chicago, Iowa State Uni- versity, the University of California and many others in the research and production efforts that led to the first atomic bomb. Ever since, educational institutions have carried a leading role in the total re- search and development efforts for military and peaceful uses of atomic energy. The present state of development of the atomic energy industry is in no small part due to this research activity and the parallel manpower productivity of the Nation's colleges and univer- sities. The nuclear education and training program of the AEC has significantly contributed to the rapid growth of college and university nuclear education capability. Due to the complete interrelationship between research and educa- tion and training we find it difficult to separate out in a meaningful way the specific contribution of the DNET activity to economic de- velopment as requested in your questions. We believe your basic purpose is well served by the following material on "Relationship to Employment," reproduced from "Statement of the USAEC on the Impact on Scientific and Technical Manpower of Federal Research and Development Policies." (d) Relationship to employment.- (i) Direct and secondary impact.-With the exception of straight employment statistics, * * * we have no quantitative data to describe the impact of our research and development dollars upon a region. We suspect, however, that professional salaries, family housing needs, and localized laboratory procurements are the main instruments through which the sponsored research and development directly affects the nearby community. Considered solely on the basis of dollar flow into a region, we have no evidence which would lead us to believe that this one phase of governmental spending is in any way a unique or more effective mechanism for stimulating local economies than the many others now in being. There are usually some new small businesses which develop close to our installations and which owe their genesis to the AEC activity. For example, a number of activities have located at Oak Ridge and Albuquerque to take advantage of the nearby technology, people and related sources, or markets. One such firm at Oak Ridge sells science kits, taking advantage not only of proximity to the source of much of the technology but also of the technical information resources at hand. As another case in point, the far-ranging research and development activities of the Los Alamos Scientific Laboratory and the Sandia Corp. have spawned some expansion in Albuquerque of the electronic- support function. At Hanford (Richland, Wash.), where we are attempting to foster and encourage diversification activities, several of the new contractors who are to operate Government-owned facilities have plans to estab- lish private plants or laboratories in the area. Such new private facilities will not necessarily be related to the AEC-supported work there, but the presence of key management personnel, technical PAGENO="0494" 1102 HUMAN RESOURCES PROGRAMS competence, support facilities, etc., are important factors in deciding to locate such facilities at Hanford. With several successful private facilities in existence, the prospects of others being established would seem to be good. (ii) Short-term and long-term regional e~ects.-Aside from the actual flow of Federal funds to support a given research or development. effort, scientific-technological activities have another important in-~ fluence on the economic well-being of an area and its people. The opportunities and facilities for education at all levels usually are markedly improved. Secondary education systems tend to benefit from the presence of scientific personnel in the community. They often show marked interest in establishing high standards for the school system and at times will participate in the development of curriculums in their field of specialization.. If opportunities for higher education do not exist in the community, they are often established. For example, the Tlniversity of Tennessee and the University of Washington now have extension programs in Oak Ridge and in Richiand, Wash., respectively. Further, the existing institutions of higher education in a region, if they are properly motivated, can benefit considerably by the presence of a sizable Federal research and development installation in the area. Cooperative programs between such institutions and AEC laboratories have already been mentioned. One has only to look at the many new industrial concerns that have sprung up about the Harvard-MIT and Berkeley-Stanford complexes. to see the effects which strong centers of education have, on the eco- nomics of an area. We can identify several factors which undoubtedly have contributed to this contribution to local economic growth by educational centers. Faculty members have often been instrumental in initiating local commercial ventures which draw heavily on the scientific competence available on the campus. In addition to such personal participation in industrial development, many faculty mem- bers also serve as consultants to industry. The availability within the local community of such highly competent technical people con- tributes to growth of the area. Further, industry can arrange with nearby universities for extension courses and other educational op- portunities for their employees. Industrial employers often make participation in such educational activities more attractive to em- ployees by adjusting their work schedules. Such additional educa- tion leads to more scientific and technical competence, thereby further strengthening the growth potential of the complex. Thus, the gravi- tation of Government contracts and other enterprises to those areas which have strong centers of graduate education and research is both evident and logical. It is also interesting to note that there is usually a rather pronounced effect upon a community's cultural facilities traceable to research and development personnel. For example, the level of interest in and support of local symphonic activity, community drama, and artistic functions in Oak Ridge, is considerably above that of other communi- ties of comparable size. (iii) Transmission of technology within a region.-We have very httle data about the transmission of specific items of technology to the commercial interests in the same area. Probably the greatest such transmission occurs through the subcontracting prôce~. In the ca~e PAGENO="0495" 819 BIOGRAPHICAL INFORMATION (PUBLIC) Section I Arthur Joseph Gajarsa Page 28 For New York State Industrial Commission Iris A. Steel, Esq. Assistant Attorney General Office of the Attorney General Albany, New York 12207 (518) 431-0247 d) Description: This was an action brought by the New York State Industrial Commission to deny unemployment benefits to certain individual members of the St. Regis Mohawk Tribe, including the members of the Tribal Council. The Commission denied the benefits because the individuals were receiving per diem payments for services to the Tribe. After an administrative hearing, Mr. Ross issued an order denying repayment of benefits and denying further payments. I appealed the decision on behalf of the Tribal Council to the New York State Court of Appeals, Third Appellate Division, which reversed the Commissions order and reinstated the benefits. The Appellate Court did not accept my basic argument that the State Industrial Commissioner had no jurisdiction over Indian reservations due to their unique federal status and because the Tribal Council members were cloaked with the tribal governmental authority while acting in their official capacity. However, the court decided in favor of the Tribe based on a narrow ground involving the interpretation of the statutory term "employment." VIII. 1. United States Small Business Administration, Receiver Taroco Capital Corporation, David Ruey-Chyi Chana, et al., Civil Action No. 94-863 (U.S. Dist. Ct. for the District o~ New Jersey) 2. United States Small Business Administration Southern Orient Capital Corporation, Civil Action No. H-95-4591 (U.S. Dist. Ct. for the Southern District of Texas, Houston Division) 3. United States Small Business Administration jon Civil Action No. 95-5007 (U.S. Dist. Ct. for the District of New Jersey) PAGENO="0496" 820 BIOGRAPHICAL INFORMATION (PUBLIC) Section I Arthur Joseph Gajarsa Page 29 a) Date of Representation: 1991 to present b) Name of court/Judge: U.S. District Court for the Southern District of Texas, Houston Division - Judge Ewing Werlein, Jr. U.S. District Court District of New Jersey - Judge John C. Lif land (Taroco) Judge John W. Bissell (Japanese) c) Attorneys: For Defendants Arthur J. Gajarsa, Esq. Peter J. Wiernicki, Esq. Joseph, Gajarsa, McDermott & Reiner, P.C. 1300-19th Street, N.W., Suite 400 Washington, D.C. 20036 (202) 331-1955 John G. Gilfillan, III, Esq. Carella, Byrne, Bain, Gilfillan, Cecchi Stewart & Olstein Six Becker Farm Road Roseland, New Jersey 07068-1739 (201) 994-1700 For United States Neil R. Gallagher, Esq. Assistant United States Attorney 970 Broad Street, Room 502 Newark, New Jersey 07102 (201) 645-2845 Thomas G. Morris, Esq. Chief - Liquidation Division U.S. Small Business Administration 409 Third Street, S.W., 5th Floor Washington, D.C. 20416 (202) 205-7366 Mark Stephens, Esq. Associate General Counsel, SBIC Litigation U.S. Small Business Administration 409 Third Street, S.W. Washington, D.C. 20416 (202) 205-6860 PAGENO="0497" 821 BIOGRAPHICAL INFORMATION (PUBLIC) Section I Arthur Joseph Gajarsa Page 30 Mark A. Speilman, Esq. Trial Attorney. Office of the General Counsel U.S. Small Business Administration 409 Third Street, S.W., 7th Floor Washington, D.C. 20416 (202) 205-6863 Mark W. Vita, Esq. Administrative Law - Litigation Center U.S. Small Business Administration 633 17th Street, 7th Floor Denver, Colorado 80202-3607 (303) 294-1178 d) Description: In May of 1991, I was retained by the principal share- holders of Taroco Capital Corporation (`TCC"), a small business investment corporation licensed by the Small Business Administration ("SBA") as a minority business enterprise. Although it was headquartered in New Jersey, TCC had been capitalized by the Asian community to finance economic development projects on a national basis for the Asian community. TCC had been placed in liquidation status by the SBA on the basis of certain financial regulatory violations. On February 19, 1991, the United States District Court for the District of New Jersey had granted the SBA's petition to be appointed as the Receiver for TCC. The regulatory violations which were alleged by the SEA were questions relating to the portfolio investments which had been undertaken by TCC within the Asian community in various parts of the country. For many of these investments, TCC had invested for its own account and had also solicited the participation of several other SBA licensed lenders. ~1hen TCC was placed in receivership, it caused the SEA to initiate a review of all the TCC investment portfolios and also those of the participating lenders. Two other participating lenders retained me to represent them in the same proceedings: the Japanese ?~merican Capital Corporation (`JACC"), a small business investment corporation located in Jersey City, New Jersey, and the Southern Orient Capital Corporation ("SOCC"), a small business investment corporation located in Houston, Texas. Like TCC, both companies had been transferred to liquidation status by the SBA. The corporations retained me to negotiate with the SBA regarding allegations of regulatory non-compliance. 40-643 97-27 PAGENO="0498" 822 BIOGRAPHICAL INFORMATION (PUBLIC) Section I Arthur Joseph Gajarsa Page 31 In February of 1994, the SBA, as receiver for TCC, filed suit against numerous officers and directors who were affiliated with TCC, JACC and SOCC. The lawsuit, filed in the United States District Court for the District of New Jersey, asserted that the defendants had breached their fiduciary duties of loyalty and care to TCC; that they were negligent; and that they had converted assets which rightfully belonged to TCC. We have filed an answer and developed a defense strategy for all of the defendants. To date, we have not been required to proceed to trial because all the parties would like to reach a negotiated settlement of these matters. On behalf of Taroco Enterprises (a separate company from TCC), SOCC and JACC, I have preliminarily negotiated a global settlement with the SBA that encompasses the lawsuit filed in Federal Court by the SBA as receiver for TCC. A final settlement is pending. The SBA has also filed for the receivership of JACC and SOCC and we are presently negotiating on their behalf to avoid protracted litigation. IX. United States v. Zaitech Capital Corporation, (not reported) C.A. 94-2537 a) Date of Hearing: July 7, 1995 b) Name of Court/Judge: Federal District Court for the State of New Jersey Judge Nicholas H. Politan c) Attorneys: For Defendant Arthur J. Gajarsa, Esq. Joseph, Gajarsa, McDermott & Reiner, P.C. 1300-19th Street, N.W., Suite 400 Washington, D.C. 20036 (202) 331-1955 John G. Gilfillan, III, Esq. Carella, Byrne, Bain, Gilfillan, Cecchi Stewart & Olstein Six Becker Farm Road Roseland, New Jersey 07068-1739 (201) 994-1700 PAGENO="0499" 475 The Honorable Pete Domenjcj August 18, 1977 page 4 In summary, I believe that federal programs should respond quickly to local initiatives that are fully supported by federally funded programs of technical assistance organized by the states. A single federal official should be authorized to negotiate a comprehensive assistance program with state and local officials immediately upon its presentation. The form of assistance should be extremely flexible to match the un- predictable variety of local situations. The level of federal resources available for state and local use should be set at a level that best approximates the increased costs that would otherwise be passed on to energy consumers if community in- vestments were not made. Since these recommendations match the provisions of the bill, I heartily support it. ~ ~) PAGENO="0500" 476 Senator D0MENI0T. I want to thank you, Senator Randolph, for being with us here in New Mexico. I am certain that the good Senator from West Virginia knows about the growth booms and boom-bust problems, but I think we have added a new dimension to it here. today. I think he will understand that there are probably many parts of the United States that are going to have these kinds of problems and, hopefully, we can work together to do what the Federal Gov- ernment should do ~perhaps to supplement local goveriiment and pri- vate sector and State government for providing a decent living environment in these growth areas. I want to thank you, Mr. Chairman, and I thank the witnesses who have appeared. It has been tremendous for New Mexico and Albu- querque to have you with us. Senator RANDOLPH. Mr. Cook, how much has your firm expended? Mr. CooK. $26 million. Senator RANDOLPH. All private? Mr. CooK. Stockholder money. Senator RANDOLPH. Are you discouraged, encouraged, or what? Mr. CooK. I take the fifth on that, I guess. No; we are not discour- aged, yet we are still pushing. We have hopes. Senator RANDOLPH. I want to underscore what has been indicated here today, but perhaps not stressed enough. New Mexico is first of all our States in uranium production ai~d it exports all of it. You rank fourth in natural gas production and you export 87 percent of it. You rank fifth in the country in oil production and export 80 percent of it. You rank 10th in coal production and export 90 percent of it in the form of coa~I or coal-generated electricity. You are a very unusual State. Senator DOMENIOT. Indeed. Senator RANDOLPH. I doubt if the people of the country generally know the facts that I have just referred to. And this is the place to hold such a hearing as we had today, and I commend you for doing it, and I appreciate what the witnesses have said. Many of them with varying approaches, but all with contributions which will help us when we go back into the Senate itself. I would like to promise those here today listeners as well as partici- pants that this is in no way just a.nother hearing. This hearing will be the informative base by which we can make this bill a better bill. I am gratified that I have been permitted to work with you today, Pete. This is entirely worthwhile. Senator Do~rENIcJ. Thank you very much, Mr. Chairman. The committee will stand in recess. [Whereupon, at 1 :08 p.m., the subcommittee was recessed to recon- vene subject to the call of the Chair.] PAGENO="0501" MATERIAL SUBMITTED FOR THE RECORD BY MR. WELLS City of Grants Building Permit valuation March 1, 1977 to August 1, 1977 Permits issued in 5 months $ 223,294.00 179 Water Utility Connections 6 months ending July, 1977 A 10% increase (Milan Increase 20% Past Fiscal Year) 114 City of Grants General Fund: FY 72 FY 77 % Increase Total Revenues Total Expenditures 525,000 650,000 * 1,433,000 1,660,000 272.4 255.4 Property Tax 15,000 24,000 266.7 Gas Tax 99,000 128,000 129.3 Sales Tax 261,000 826,000 316.5 Utility: Revenue 296,000 848,000 286.5 Water and Sewer Expenditure 259,000 845,000 326.3 1973 1974 1975 1979 1977 July, - 250,782 203 , 34 3 204 ,839 189 ,796 197,238 1977 51,029 (477) 95-826 0 - 77 - 31. PAGENO="0502" 478 Our applications for assistance represent an intensive local effort to timely meet the basic needs of our new residents - both from other New Mexico communities and other states attracted by the earloyment opportunities created by nes. Nazicn~] ~er~~y and of our own basic community. The principal initial need is obviously housing. Private industry will build the housing and furnish its on~site streets, utilities, at no cost to the ~ will and are doin this now. A future tax base is thus being created. This activity then demands its Counterpart: Water: New sources of supply, collection, storage, transmission. (the new areas furnish the distribution and future revenue source). Sewer (collectors furnished by area) interceptors and wastewater treatment plant. Streets: overloaded and hazardous residential streets carrying arterial traffic must be relieved until long- range programs under regular State Highway and Federal Aid Urban Systems can become effective - Possible only after history and statistics can form the bases for financial planning; and, of course, / our ~ problems have not become history, nor statistically useful, nor will they be in time to be currently valuable. TO MEET THIS CHALLENGE, many sources have come to our assistance, but most needs are incomplete and must have immediate serious attention without further and unnecessary delay - after all, State and Local laws and the requi rements of any one Federal Agency arc sore than aclequal:e security - competi ti on 1)ctween them for interpretive nod arb trary acknowl edgement defeats the true law as effecl:ivel y as i f d rect violations were jotciuti ooal ly coami ttcd for persona I gal ii PAGENO="0503" LATER Well, C~'~lector line (well to tank) transmission line (storage, to system): project initiated 1975,.origirial HUB project .~,y'°' CITY OTHER hELL Unable to meet procedural requirements, paid entirely by City WETS Revenue Bond 1976 Fund; (Completed) .`: 49,154.66 2. WELL EQUIPMENT: Unable to obtain assistance in time, 100% City W%S Revenue Bond issue 1976 (Completed) 104,130.00 3 COLLECTOR LINE 6 405,525.23 ~HUD ` 150,000.00 TRANSMISSION LINE: 280,000,00 EDA 280,000,00 Project Total 685,525.23 CITY W6S R. 78,882.00 1976 Comm.Assist(State) 176,643.23 (None of the above is in service until item three is complete) 4. WATER LINE REPLAC1IMENT Main line fire and pressure loop and sizing in existing CAC 154,589.00 system, inadequate with housing infill older areas. critical end costly, to have been financed with funds now to be used in other high priority and matching proj acts, 5. WATER MASTER PLAN - Critical to proper and efficient use of funding, approved and nearing completion Four Corners lIST ` 37,000.10 total 50472.08 CITY EST 13,000.00 244,166.66 $ 79S,232.23 PAGENO="0504" STREET - TRAFOIC SAFETY, minimum immediate: City Other Nimita - Elm - Mesa. Due tb physical land barriers (lava flow, San Jose - Bluewater creek) only two access streets serve major housing areas traffic flow and controllability are severely restricted Project cost $223,000.00 City: $ 34,358.00 NMSHD: $ 34,358.00 CAA: $ 154,284.00 ~ cI~ Mesa - Lobo - Roosevelt Intersection Traffic Safety requirement due to major intersection, complicated by El Paso Natural Gas Co. and Gas Co. of Nc~: Mexico rights of way, local and state roads, including Nimitz - Mesa. Project cost $155,000.00 City $ 30,000.00 CAA $ 135,000.00 Andcrm:tn Crossing provide additional access street, although minor, to relieve other two streets CAA $ 55,000.00 PAGENO="0505" SLWER: Loho Cenyon - Northeast Interceptor; Santa Fe Sewer Transmission. 1 (Milan) ; Zuni Canyon Sower System. 1. Lobe - Northeast interceptor: Orginally applied for Round I SEA Emergency public works. Planning target Round II: Project total $990,160.00 Project key to entire NE residential overload and new housing areas. 2. Sant~i Fe Transmission Sewer - Milan approved project. Delayed pending apparent admin. details with Farmers Adm, and highway permit, the latter near resolution. CAC financing will resolve other, 3. Zuni Canyon sewer system, - Applied for HUE community Development funding of $250,000.00 maximum. In- sufficient points in priority rating, Total *project $270,170.00 Area critical:Health, high cost project due to Railroad, US 66, IS-40 and Lava Barriers City EDA CITY 105,160.00 CAC Four Corners. Reg. CAC other 285,000,00 600,000.00 308,000.00 77,000.00 CAC 270,170.00 PAGENO="0506" CITY OTHER 4, Santa Fe Sewer II Interceptor: Intercept transmission line from Milan Sewer System and deliver to treatment plant, CAC 582,910.00 also portions of Grants. Anticipated.tobecome critical, but full information must be developed under wastewater PLOSOO 201 Phase I Master Study Planning Grant, which Grant is delayed at this stage due to questions (in Dallas) of estimated costs anditems deemed ineligib~lebut. critical to the value of the study. If study could be financed and proceed the interceptor project may well be qualified for Federal and State EIA-EPA aid (87½%); But too late. 3 year estimate of priorities and planning minimum) /this project is the least critical for immediate funding and is superceded by all others submitted. 5. hastewater requirement - 201 EIA EPAbase for all Aid. Total cost $98,523.00 approved, except for delays. FED 50,250.00 CAC approval would release this project and improve STATE 8,375.00 funding assistance from Federal - State on all CAC 39,898.00 sewer requirements, now and future ____________________________ $105,160.00 $2,221,003.00 PAGENO="0507" Industry ~1 188,640 +13% 44~~2('~r~ ~ 7fc~ flzpja~t ,1ce~eX~ PROJECT NEEDS 1. Road from Lobo Canyon area across from Grants Ridge to 53 North. distance of aooro~d.mate1v three (fl m~1ee ~~e't ~ HUD State, Federal, County, Private 2 Ordinance requiring sidewalk and paved parking 3 Rehabilitate the old water pump house on San Jose Drive Property Owners HUD State, Fcdeial - 235 000 ~. 2400 feet 12 inch water line on Santa Fe Avenue; 12' from High to Santa Fe on Nimits; on Santa Fe from Nimitz West Setion line of 32. Will con- nect with the line coming from Lobo Canyon Road via the section line. * S State, Federal - 30,000 12x2400 ~`3% and 10% 5 Water well and storage tank NE of Grants engineering 900 000 6, Water line looping, E. Grants via section line between 20 6 19; 30 6 29; and 31 6 32. State, County, Federal - 7. Proposed 547 By-Pass. Road following same line as above - connecting Lobo Canyon Road to Sante Fe Avenue, 100 feet right-of-way - four (4) lane. * * : * * Federal, State, County - 3,000,000 23% * * 8 Recreation facility - baseball BOR 1 000 000 9 Human Resource Center BOR lots 10 Paving repairs of existing City streets 11 Street Rehabilitation PAGENO="0508" 484 GORDON HERKENHOFF & ASSOCIATES, INC. 302 Eighth Street, N.W. 545-810-77 Albuquerque. New Mexico 67102 (505) 247-0295 June 2, 1977 * Tony Vasilakis, City Manager * City of Grdnts Municipal Building . * Grants, New Nexico RE SEWAGE FLOW FROM MILAN TO GRANTS TREATHENT PLANT In accordance with instructions fran Hr. Don Des Jardin, and based on the attached memorandum front Hr. Vance Vartderhoof, it appears. * * * that the Town of Milan has increased its sewage contribution in the last eight ntonths by about 24.4 percent. * The following is an estimated average flow rate per eight month * period from the Town of Milan. . .* * A. For th~ eight month period from January 1976 through August 1976 the Town of Milan contributed sewage at the rate of 88,612 gpd. This is equivalent to 61.5 gpm of * sewage flow to the Grants Sewage Treatment Plant. * B.. ~or the eight month period £ ran September 1976 through * . . April 1977 the Town of Milan contributed sewage at the rate of 110,100 gpd. This is equivalent to 76.5 gpm of * * * sewage flow to the Grants Sewage Treatment Plant. (76.5 -. * .. . 61.5/61.5) 100 = 24.4 `1, increase. * * please contact this office mis ends. * PAGENO="0509" 485 TABLE 1 TITLE Crentsjuilsn Peculation Projec- SOURCE: Census, COG Estarnates tions and i7llocatic-ns ED/Zone Redden hal ~ PopuJa-I Popula-I Popula tion tion tion Capacity `°70 1676 Popula tion J80.. Popu1a-~ tion J5.5_. Popula- Popula- tion tion ~Jj.5Q.. j.~_.. MILAN - 27 ]~3 3014 693 99 2,426 847 ~Q~0 L22P ~ ~J~Q ~q ~ ~ ~ 28 29 54 1323 645 870 ~j~0 j~ja G+ 193 4,729 50 80 550 L~i~ TOTAL MILAN: 469 11,492 L~2~ GRANTS - 21 170 4,760 ,~ 4,590 4,600 22 63 3~764 1,297 j~0 j~5 ~j~5 23 118 3,304 j~ J~9 ~a~0 ~O 24 142 3,976 j~ 2,250 ~o 25 50 1,400 1~50 ~Q 0 ~S 26 333 8,324~7O4~Q ~0 8,900 ~O C+ -0- -0-- -0-- -0- -0-- -0- -0- -0- TOTAL GRANTS: 876 24,528 J~~Q Jj~j.Q~ ~Q5 21,645 PLANNING AREA - A 57 1,496 30 690 800 ~100 1.050 B 1,066 .A~ iJ~AQ 1LQ29 ._2~~P C ~_. -* ...IcLP c' - - - 175 D 683 J2,2L~ 2QQ 5.Q~ L2.00 E 401 10,526 10 750 ,~) ~3~Q E' 176 5a' LSn .J25 F 56 ~jQ - 260 ,~ F' 35' - ._laQ ._2L0 G ~J~Q Qj~0 21 450 .JQ~ ~L~Q2 2...120 G' 262 j~ 40 325 A25 i~i2.Q J~i~ H 254 j~ - 15 .~9 TOTAL PLANNING AREA .~.a 760 .IL~.Q J.~z1~ TOTALS: MILAN - 469 11,492 ~fl5 6,975 8,975 GRANTS 676 24,520 jj~90 jj~5 18,305 J~Pj PLANNING AREA: LOG] 153,~]~3 760 3~,0 J~0 17.~Rfl Jf~Oc GISANO 5OTAL~ 1JJ~613 J1,76:4 ~~oo ~jro -6- PAGENO="0510" 486 TABLE 3 GRANTE/MILAN PLANNING AREA EMPLOYMENT ANT) POPULATION PROJECTIONS1 1976 - 1995 l970' [ 1976 1980 [ 1955 1990 ~ 16,175 20,800 20,4501 TOTAL EMPLOYMENT 3,800 6,675 9,450 MINING E~JLOYMENT 1,921 3,300 4,875 8,425 10,700 l0,~ POPULATION ~r763 18,800 25,100 37,500 48,100 46,500 1) Population Estimates and Projection Rounded to Nearest 100; Employment Rounded to Nearest 25. 2) Source: 1970 Census, Adjusted Mining employment by residence for the Grants/Milan area was based upon establishment data for areas within the San Juan Basin (Northwest New Mexico), which in turn was derived from state U3O8 production and employment forecasts. The allocation ratios were calculated using information frcm the U.S. Energy Re~earch and Development Administration (EEC), the State Inspector of Mines, and mining companies. Projected mining employment was combined with forecasts for the relatively small manufacturing sector to yield total basic employment. Nonbasic~to-ba5ic ratios were adjusted over time to reflect the degree of change in basic employment scale of the economy, and other factors. Total employment was used to calculate the population in each time period, with the population_to_employment (depen- dency') ratios taken from the U.S. Water Resource Councils OBERS Projections: Reqional Activity in the U.S., which includes data on the State of New Mexico. The New Mexico ratios were modified slightly to reflect the varying impacts PAGENO="0511" 487 THE GOVERNOR'S ENERGY IMPACT TASK FORCE A PRELIMINARY REPORT MANAGING THE BOOM IN NORTHWEST NEW MEXICO PREPARED BY EITF STAFF FUNDED BY EDA UNDER GRANT No, O8-09-0L784 FEBRUARYJ 1977 PAGENO="0512" 488 2. Uranium a. History "It is possible that Indians in Northwest New Mexico used uranium minerals as a pigment for hundreds of yeers however, the discovery ci uranium in New Mexico is credited to a Navajo sheepherder named Paddy Martinez. Martinez was always on the alert for bits of brightly colored or unusual rock, and one day in 1950 he picked up a uranium bearing rock in the vicinity of Haystack Mesa near Grants. When he. took the rock to a friend in Grants to determine what the rock was, the ore was discovered to contain uranium. That chance discovery brought Paddy Martinez a lifetime stipend from the Santa Fe Railway, which owned land in the area, and it led to ma- jor exploration programs that revealed the most prolific uranium production district in the world. The first production of uranium was shipped to the Atomic Energy Commissionts buying station at Monticello, Utah. Later ex- ploration and development of uranium out- crops brought about the establishment of an AEC buying station and limestone treat- ment mill built by the Anaconda Company at Bluewater in 1952. In 1951, a major dis- PAGENO="0513" 489 covery led to the development of the Jackpile Nine, the world's largest open pit uranium mine. In 1955, the discovery of enormous uranium deposits near Ambrosia Lake was made. ifl the same year, a second mill was com- pleted by Kerr-McGee to process the new ore and a boom was on. Early production was supported almost entire- ly by the AEC at the supported prices. Pro- duction reached record levels in 1960, but suddenly dropped when the AEC announced a phasing out of its purchases. Grants/Milan has, since 1950, been influenced by uranium production activities. An analysis of employment by place:of residence reveals that in 1970, ~9% of the residents of the Grants Census County Division were employed by the mining industry. Wholesale and retail trade contribute the next highest employment, identifying Grants/Milan as a trade center for Western Valencia County and as a service center for Interstate t~0 travelers. Com- munity supportive services are the third major employer." "Total two year expansion = 23~5 to 2'460 employees Total five year expansion 3078 to 33'i8 employees PAGENO="0514" 490 aFacility and employees expansion to be operational within two years. `~`Facility and employee expansion to be operational within five years. 1ERB Questionnaries, 1976 2State Planning Office Report, "Grants Mineral Belt", August, 1976 3Navajo Nation Report, 1976 EMPLOYED PERSONS 16 YEARS OLD AND OVER - GRANTS CCD'~ Classification by Indust~y~ Percent Agriculture, Forestry and Fisheries 1 Mining 49 Construction 3 Manufacturing 2 Transportation, Communication, Utilities 4 Wholesale and Retail Trade 17 Finance, Insurance, Real Estate 1 Business and Repair Services 2 Personal Services 4 Entertainment, Recreation 1 Professional and Related Services 13 Public Administration 3 TOTAL 100 SOURCE: 1970 Census of Population and Housing ~Census County Division PAGENO="0515" 491 Grants/Milan `The occupancy rates in both Grants and Milan are near 100%, with only the most dilapidated homes vacant. The lack of availab3e units and the high construction costs, have con- tributed to the significant increase in mobile homes in the Grants/Milan area. The cost of housing construction in the Grants/ Milan area generally ranges from $20 - $26 per square foot, which is comparable to prices in Albuquerque. Rental charges may be as high as $250 - $300 per month for either conven- tional housing or mobile homes. At present, some 100 prefab homes are being constructed in Milan for sale at approximately $25,000 average price. Also at this time, about 80 multi-family units are being built in Grants." City of Grants a. "A serious housing shortage in Grants already exists. As a result, mobile homes have become more common place in the community, over 1000 making up 30% of the housing units. Rehabilitating substandard housing is a number one priority (no cost estimate). b. Construction of rental housing is another priority (no cost estimate)." PAGENO="0516" 402 C. Sewer, Wastewater Systems, and Storm Drainage The sewer systems in Northwest New Mexico share many of the characteristics of the water systems in that all communities have serious problems. The majority of these systems are outdated and were constructed for smaller more centralized communities. The rapid increase in population has initially affected the communities by over- flow of sewage into the street, substandard cesspool systems and leaking sewage ponds, all of which create serious health hazards. Wastewater treatment plants in many communities cannot process the volumes of sewage that are presently transmitted through existing lines. Many improvements are needed. One problem is that of lead time planning. These projects need to be started now before the additional impact occurs." IV. SUMMARY S CONCLUSIONS "New Mexico is entering into an era of rapid energy resource development. Since the recent energy crisis, our nation's leaders have been debating methods for developing adequate energy supplies. Because of the recent natural gas short- ages in the Northeast and Midwest, we can expect some de- cisions to be made in the very near future as to how Project Independence will be achieved. New Mexico will play a key role in these decisions. With ~3% of the nation's uranium production and its large reserves of low sulphur PAGENO="0517" 493 coal, New Mexico will become one of the nation's largest exporter of energy. Wl-iile creating many economic benefits for the citizens of the state, this energy development will also cause some social and economic hard- ~ The purpose of this report has been to determine what those socio-economic effects will be. In order to do this, the Governor's Energy Impact Task Force has first of all summarized the imminent demands that will be placed on Mew Mexico's resources, based on the most current available material. From this review, it is estimated that the coal production in the state will increase four-fold by 1985. The uranium ore production will increase narly five-fold by 1985. One coal gasification plant can be expected to be completed and numerous experimental geothermal wells will be tapped. The next step in the study was to determine what these deve~.opments mean in terms of additional jobs being created. The employment icnrease, due to coal and uranium development, will reach 8,500 by 1981 and up to 18,000 byl985. Some of these workers will be absorbed from the local labor pool; however, many will come from outside the area, either from other p~j~p of the state, or from out-of-state. After reviewing a multi- tude of projections based on similar development in other Rocky Mountain States, the staff derived the following ratios to determine how many new people will actually be coming into a coal or uranium development area; every mineral extraction job will create 2.7 jobs in the service sector, 50% of all jobs will be filled by influx, 80% will bring in families with an average of 3.3 household members. 95-826 0 - 77 - 32 PAGENO="0518" 494 This means that we can expect a total population influx of 21,000 people into the northwest communities by 1981 or 72,000 people by 1985. This averages out to an annual growth rate for the area of 5%, far above our state average of 1%, and in some areas like West Valencia County, the growth rate may reach as high as 8%. This rapid influx of people will place serious burdens on local community facilities. A major part of this study was to catalog the existing community infrastructure and determine, first of all, if it is adequately serving the present population and secondly, if it will service the expected population. Without fail, the researchers found a serious shortfall in present services in relation to the demand. Schools are overcrowded, with emergency portable classrooms handling the crunch for this year, but no plans for tI'e future. Law systems are overwhelmed, with a low officer ration yet a high crime rate. Housing is inadequate, with vast capital improvements needed. Sewage systems are substandard or inadequate with a massive need of expansion and rehabilitation. Health and Social Services are swamped, with one of the lowest doctor ratios in the state and yet the highest demand of need. This shortfall in present services is due to two reasons. First,the area has a high level of need. The communities have already experienced rapid growth impacts in the past and have yet to catch up with the first boom. Secondly, they are mostly rural, isolated, and, have in- adequate planning or funding resources to cope with the demand. These problems become especially critically when we talk about the future requirements to serve the anticipated population. The Task Force staff and Council of Governments spent the last six PAGENO="0519" 495 months researching and evaluating specific project needs that the communities have identified as beingnecessary to meet the present problem, and to cope with the boom. The capital outlay requirements over the next five years for these projects total 119 million, if we consider just local funding requirements, and up to 242 million, if we consider state and federal highways and education. For example, this figure includes $40 million for water systems, $40 million for streets and roads, $27 million for sewer, and $8 million for social services. However, money is not the only solution. WATER SEWAGE, WATERWASTE, S STORM DRAINAGE.. SOLID WASTE HEALTH 6 SOCIAL SERVICES TRANSPORTATION (Local) FIRE PROTECTION... PUBLIC SAFETY RECREATION OTHER (MUNICIPAL BUILD.).. 7138 8224 75 PROJECTED FACILITY REQUIREMENTS: for the region from the various planning bodies in Northwest New Mexico. These figures are approx. and only include projections for the next 2-5 years. MCK. COUNTY 4185 2570 300 ($1000 `s) SAN JUAN COUNTY 18072 5141 250 W. VALENCIA 7653 SANDOVAL COUNTY 405 NW QUADRANT 30315 23073 625 1215 5650 22350 710 720 2230 4269 550 5000 4509 6865 4050 981 31650 92 50 1402 11720 844 263 7846 4841 333 425 5599 SUBTOTAL 119095 U. S. HI-WAYS 6 ST. HI-WAYS 85l60~ EDUCATION 400OO~ PAGENO="0520" 496 IOTALS . Lt0280 ~t8282 20110 10~23 GRAND TOTALS 2LH~,255 State Highway Department DFA Public School Finance (I-~O Costs not Included) In order to avoid the building of sporadic mobile home units, concerted local and regional planning must be done. Planning capa- bilities of the Northwest area need to be augmented to perform this job. Additional technical assistance and cooperation of state and federal planning authorities is also needed to cope with zoning problems, land use, title clearance, and financing problems. Possible incentives that should be investigated and utilized are subsidized construction funds, increased federal funding, tax credits, low interest loans, and rent subsidies. Planning is also needed in the area of health and medical programs. Shortages should be addressed by new and innovative programs. Environmental health problems need more attention. The areas should receive greater priority in the competition for federal and state funds. Emergency funds should continue to be allocated from the state to impacted areas, but more long term solutions need to be explored. School finance formulas should be altered to accommodate the sudden influx of students so as not to penalize individual districts that become overwhelmed. Skill training programs should be set up for local residents in order to gain the skills the expanding industry needs. Higher education and adult night classes need to be expanded. PAGENO="0521" 497 Since there is a long lead time needed for construction of sewer, water, and other utilities, forecasting capabilities in boomtown communities need improvement, in order to project with some accuracy the timetable for initial construction. Public and private utilities should be encouraged and required to develop implementation schedules, which make these utilities available in an orderly manner. Adequate fire and law protection services should be available to the communities and surrounding areas. This will require state and county support. The definition of functions should be made to clearly establish jurisdictional responsibility between city, county, state and tribal officials. In boomtown conditions, social service agencies will experience dramatic increases in caseload, especially in child abuse and drug abuse. Increases in mental health counseling, public assistance and crisis intervention should be planned for immediately. Environmental concerns are also present in the northwest communi- ties. Local and state agencies should focus their attention and increase their capacities to monitor the potential environmental impacts of developments. Finally, local government financing capabilities need to be in- creased to cope with boomtown problems. One of the major conclusions of this report is that the cities and counties cannot pay for the construction of the needed facilities out of their own revenues. The increase in property tax does not come until the boom is on its way. There isa lag of upto five years between the time the people come needing facilities and the time that tax revenues are flowing into the communities to pay for these services. Even if the cities were allowed to raise their mill levies and general obligation bond limits beyond the constitutional limit, their financial ability to pay back the debts would be seriously constrained by ttis lag time and boomtown phenomena.' PAGENO="0522" 498 THE GRANTS URANIUM BELT A REPORT TO THE STATE PLANNING OFFICER MEW MEXICO STATE PLANNING OFFICE DIVISION OF NATURAL RESOURCES PAGENO="0523" Grants Uranium BeL. - 29 - 499 CAPITAL OUTLAY FOR URANIuM BELT BY 1985 Service Water Sewer Solid Waste Fire Library Recreation Health1 Police Streets and Roads Local Government Schools TOTAL GRA~TS/IU LAW Service Water Sewer Solid Waste Fire Library Recreation Police Local Streets (@ $265/Capita) Local Government Service Water Sewer Solid Waste ii re Library Recrea tion Police Local Streets (P $265/Capita) Local Government Low Estimate $1 ,632,480 1,388,145 26,850 235,2 123,510 349,050 161 ,lOO 711 ,525 115,455 $4,744,395 Hi~ Estimate $ 4,190,335 3,563,164 63,920 636,496 317,032 895, 960 413,520 1,826,380 296,356 $12,173,164 Low Estimate IU9h Estimate S 4,893,184 $14,118,976 4,160,816 12,005,774 80,480 232,220 708,224 2,043,536 370,208 1,068,212 1,046,240 3,018,860 434,592 1,253,988 482,880 1,393,320 5,875,040 16,952,060 345,064 903,546 6,438,400 18,577,G00 $24,836,128 $71,663,092 CAPITAL OUTLAY-TWO GROWTH Low Estimate Hi~ Estimate $1,055,488 $2,709,855 897,512 2,304,269 17,360 44,570 152,768 392,216 79,856 205,022 225,680 579,410 104,160 267,420 460,040 1,181,105 74,648 191,651 TOTAL $3,067,512 $7,875,519 GRANTS/MILAN CAPITAL OUTLAY-FIVE YEAR POPULATION GROWTH YEAR POPULATION TOTAL PAGENO="0524" 500 CAPITAL OUTLAY FOR GRANTS/MILAN BY 1985 Service Low Estimate High Estimate Water $2,740,256 $ 7,906,432 Sewer 2,330,119 6,723,068 Solid Waste 45,070 130,040 Fire 396,616 1,144,352 Library 207,322 598,134 Recreation 585,910 1,690,520 Police 270,420 780,240 Local Streets 1,194,355 3,446,060 (@ $265/Capita) Local Government 193,801 559,172 TOTAL $7,963,869 $22,978,068 From the above figures, capital outlay in the Uranium Belt varies from a low estimate of $9,568,886 in two years to a high of $71,663,092 in 1985. Capital outlay for Grants and Milan ranges from $3,067,512 in two years to $22,978,068 by 1985. This is based on a required capital outlay of $3,086 per capita in the Uranium Belt and $1,767 per capita in Grants and Milan. Present operating expenses in Grants and Milan are $150 and $153 per capita per year. This is compared to an average of $221 per capita per year for communities in the Four Corners Region.2 With more growth and new sources of revenue, the operating rests for Grants and Milan could be expected to approach the regional average. The later chapter on revenues will discuss the ability or inability of local governments to meet the costs of the growth gen- erated by the uranium industry. Thus, the local funds that might be available would be about $280,000 in general obligation bonds for Grants, $65,000 in general obligation bonds for Milan, and $500,000 in revenue bonds for Grants. (Done) Any further revenue bond capacity would require study by a bond consultant. General obligation bonding capacity also should PAGENO="0525" 501 ±ncFegse with growth, Grants(Milan could raise about $845,000 through bonds if the existing citizens are willing to pay higher taxes. This compared to the estimated capital outlay required in two years indicates a defecit of $2,222,512 - $7,030,519. If we assume the communities to be com- petitive for state and federal water, sewer, and recreation grants, capital outlay could be further reduced to $746,605 - $3,3l9650.~ Other federal grant money might be available from the Economic Development Administration, Farmers Home Administration or the Four Corners Regional Commission. In any case, it appears unlikely that Grants/Milan will be able to entirely support the uranium impact either by bonding or by competition for grant funds. This leaves the state as the next potential source of funding available to the com- munities through taxation of the uranium industry. These rates are about 15 mills over the state average (about 42.2 from 1970-1975) and about six mills over the median rate paid in Grants and Milan over the past six years.2 It would probably take some salesmanship to carry a general obligation bond issue in Grants and Milan. The following consideration might help sell the bond issue to the voters: 1) the prospect of using increasedrevenues do not increase proportionally from the growth instead of property taxes to meet some of the obligation; 2) about half of the present ob- ligation is expiring in 1978 and almost all of it will be paid off in 1980; 3) as gro~4th brings in more property owners and higher valuati n, tax rates would diminish or else bonds would be paid off more rapidly. According to Grants Mayor E. H. Well, Grants has a $500,000 water and sewer revenue bonding capacity as estimated in the fall of 1975. Issued $500,000 Jr. lien to Farmers Home Administration, 1976. PAGENO="0526" 502 Although it would seem reasonable to assume that present and future residents of Grants/Milan could pay for the operation and maintenance of expanded public facilities, once they are built, there are several problems that go beyond the ability of local communitieS to deal with them: 1. In order for growth to occur in such a way as not to cause a deterioration of quality of life for existing residents to impose unnecessary hardship on newcomers, housing and necessary public facilities should be available as new people arrive. A local community cannot come up with ~ capital outlays before its taxing capacity hn expgnd~ by new people and new buil~q~. 2. The large equipment and improvemefit investments and the pro- duction of the uranium companies are located outside Grants! Milan and not available to these communities as a source of revenue. Though it would seem reasonable that impact costs that are a result of uranium activity should be borne by that. industry and not by the existing residents of Grants! Milan, the industry is beyond the authority of the com- munities to tax that activity. 3. Communities dependent on mineral development are tradition- ally faced with boom and bust situations. Grants grew from 2,250 people in 1950 to lO,27~ people in 1960 and then went down to 8,768 by 1970. Present national energy policy seems to call for a large dependence on nuclear power, but environ- mental concern could change this drastically. If the nuclear industry does develop as the Energy Research and Development Administration predicts, it is likely that the uranium in the Grants Belt will be exhausted by the year 2000. State action could help to mitigate the effects upon Grants! Milan of extreme fluctuations in uranium development. PAGENO="0527" 503 MATERIAL SUBMITTED FOR THE RECORD BY MR. WEBB OF FARMINOTON, NEW MEXICO CITY OF FARMINGTON STATUS REPORT AUGUST 25~1g77 PAGENO="0528" 504 TABLE OF CONTENTS TOPIC PAGE NO. Introduction 1 I. City of Farmington 2 II. Economic Development 2 III. Constraints 8 IV. Current and Project City Budgets 9 V. Bonding Capacities 13 VI. Capital Improvements 1977-1981 VII. Summary of Applications. 15 VIII. Status of Grant Applications i6 PREPARED BY: The City of Farmington PLANNING DEPARTMENT Farsington, Nev Mexico PAGENO="0529" 505 INTRODUCTION Since the early 1970's the northwest part of New Mexico has been identified to receive anticipated major energy resource development im- pacts. The City of Farmington is the major trade and financial center of this area. The City is currently suffering from its inability to adequately meet the needs generated by these on-goingdevelopments. This report briefy documents the City's dilemma and immediate need for assis- tance. Enclosed is a summary of the City's needs and resources. The docu- ment identifies the location of the City of Farrnington, present and anti- cipated economic developments, constraints, projected municipal needs for the short run and long run periods. Also included is a summary of projects that the City must undertake in order to cope with the present population and anticipated growth. A brief synopsis of the City's bond issues and resources is reviewed. Also enclosed is the status of the City's present attempts to acquire State and Federal funds. PAGENO="0530" 506 CITY OF FARMINGTON I. City of Farmington The City of Farmington is situated in the northwest portion of the State of New Mexico. The City is the center of population of Nan Juan County. The municipality is located in the northcentral part of the county, at the junctions of U. S. Highways 550 and 61i. In addition to these major highwayc, New Mexico 371 extends south from Farmington and presently links the City with the Navajo Irrigation Project. This highway will also serve as the major route between the City and the proposed gasification projects. Table No. 1 summarizes population forecasts which were included in the City's Water Master Plan of 19711. The high projection of 35,790 for 19(7 approxi- mates the current population estimate. This represents an increase of better than 60 percent over the 1910 population of 21,979. Graph No. 1 depicts population projections for both Farmington and San Juan- ~-nunty, to the year 1985. II. Economic Developsient San Juan County is endowed with an abundance of natural resources which are, at present, in the early stages of economic development, and ultimately will result in a rapid growth of jobs and population. The evidence points out that the projected population growth will be a long-lasting versus a temporary surge. The economy of San Juan County is well diversified and depends mainly on trade, government construction, oil and gas production, electric power generation and agriculture. -2- PAGENO="0531" 507 TABLE 1 SUMMARY OF FARIIINGTON POPULATION FORECASTS Year 1 Basic ._~orecast El fects of ~ Coal Casjfjcatn Plan's Total PorcnE~IF po~,lauon (Low) With New Town Without New Town (Medium) (IIi~) 1973 1974 1975 1976 1977 1978 1979 26,000 27,340 28,680 29,720 30,760 31,800 32,840 . * 1,680 . 3,730 4,759 6,104 7,328 14680 3,730 5,030 6,978 8,656 26,000 27,340 30,360 33,450 35,519 37,904 40,168 26,000 27,340 30,360 33,450 35,790 38776 41,496 1980 1981 1982 1983 1964 1985 1966 1987 1988 1989 *:~;~ 1991 1992 1993 33,880 34,557. 35,21i9 35,953 36,672 37,1,03 38,152 38,914 39,694 . 40,487 `4~~ 42,12~3 I' 42,967 I 1e3,827 * . ` 7,167 8,lOE 9,918 9,804 9,677 10,042 10,409 9,528 9,132 6,913 8,717 8,493 8,235 8,235 9,279 11,132 13,422 14,016 14,798 15,879 16,606 16,548 16,522 16,628 16 C~ I 16,543 . 16,406 1 J 164061 41,047 42,663 45,167 45,757 46,349 47,445 48,561 48,442 48,826 1~c L,nr, - ~ 50,616 51,202 ~,OG2 43,3.59 45,689 48,671 69,696 51,470 53,282 54,758 55,I~62 56,216 ~ )I, ~JL1 58,666 59,373 Gordon Herkenhoff and Associates, Inc., City of Parmington Water System Master Plan - 1974 .AFuquerque, New Mexico - January, 1974 PAGENO="0532" GRkPH NO. 1'. POPULATiON PR JECT~ONS FC~ CItY of FARM!NGTON & SA~ JUi~N COUNTY. NEW MEXICO 125,000 120,000 110,000- 100,000 90,000 80,000 70,000 60,000 50,000 40,000 ~0,000 20,000 10 ,000 ~-_~ `--I--_ - . * Farmin San Jua ton Industrial Dc~ cloinen Service County, Farmington Nev~ Mexico Populat on Proj 1975 ction for Gordon Herkenh~ff and Aso~. Inc. City c1f Farmi~ gton Wa~r Syster~ Master Plan, Al~uquerquic, ~iuw i~gexico - ~974. - 125,CC0~ 120,C00~ 110,000 100,000i 90,C0C~ 80,000 70,0CC~ 60,000~ 50,000~ 40000 30,000 20,0CC 10,000 Cn. ci~ O~ -... ~- -. C-, *-. c-, -.. c~ - ~. 0 .-.. c~ ..-~ ~3 ci~ .-. c~ -,,. c~ - ~; c-~ ,..__. PAGENO="0533" 509 The tremendous growth is expected during the next five (5) years due to the new economic developments proposed as follows: 1. Development of the $ 300 million Navajo Indian Irrigation Project funded by Congress and administrated by the Navajo Tribe and the Bill. 2. Current and projected expansion of Four Corners and San Juan Generating Stations 3. New drilling and exploration for oil and natural gas. 14~ Construction of two (2) coal gasification plants. 5. Uranium exploration by Exxon in the Navajo Indian Reservation. 6. Public Service Company of New Mexico, generating station ($ 2.5 billion). The growth history of an area can be illustrated with the aid of building permit information. Table No. 2 and Graph No. 2 depict the valuation of both residential and non-residential permits issued in the city of Farmington since 1970. TABLE NO. 2 CITY OF FARMINGTON VALUATION OF BUILDING PEJNITS ISSUED 1970 - 1977 (July) YEAR RESIDENTIAL NON-RESIDFDTIAL 1970 $ 1,253,070. $ 916,100. 1971 1,081,929. 697,530. 1972 3,738,6214. 1,760,335. 1973 3,5614,8145. 14,333,230. 19714 3,785,328. 3,1483,278. 1975 7,250,626. 5,51414,9814. 1976 7,187,096. 8,987,228. 1977(Jan. -. July) 8,577,892. 6,14147,966. 95-826 0 - 77 - 33 PAGENO="0534" 510 C, 0 swilca wrniw ~i ~)JI1~1WA -6-- PAGENO="0535" 511 Table 3 reflects the growth which the county is likely to experience through 1985. While these increases have not been allocated to specific portions of the County, Farmington is certain to be impacted by this growth. TABLE NO. 3 SAN JUAN COUNTY Assessed Valuation Actual 1970 $ 112,152,321 1911 * 181,802,966 1972 238,687,092 1973 270,718,577 1978 320,837,169 1975 396,057,270 1976 396,057,270 1977 853,388,953 cot. Proj ection 1978 $ 8~o,ooo,ooo 1979 890,000,000 1980 510,000,000 1981 530,000,000 1982 550,000,000 1983 s6o,ooo,ooo 1988 570,000,000 1985 575,000,000 SOUBCE: Quinn OCompany, Albuquerque, New Mexico, August, 1977. -7- PAGENO="0536" 512 III. Constraints A. One of several constraints is the land ownership pattern of the County, which is outlined as 59% Indian (Navajo Reservation), 29.2% Federal (BLM), 5.3% State (New Mexico), 0.2% Inland Water, and 5.1~% private land. The County is coaposed of approximately ~,5i6 square miles. * B. The "people" impact on the San Juan Area is resulting, and will continue to result, in an accelerated demand for services. These services arc costly and long-range ones that must be provided primarily by local governments, school districts, health and social service agencies and other special districts. The burden facing these agencies is awesome indeed, even with federal funding assistance and virtually insurmountable without it. C. The City of Farmington is utilizing the property tax for capita] ire- proveiaents through the use of general obligation bond issues. In a period of "boom" or high growth, property values skyrocket, increasin2 the tax base. This may appear then to be a self-supporting situation, however, this is not the case. This is because there is at least a year's lag time in the property tax system and a limitation of bonding capacity. By the time the "boom" is underway, the inflation in local construction costs and land prices tends to offset the increase in property tax values and hold down local financing capability even more. It is difficult to get the old property taxpayers to assume a new bond obligation for the benefit of a wave of newcomers and builders from the outside. Most of the energy related industry will be developed outside of the City of Farmington and this tax base will not contribute to meeting the needs of Farmington. * Source.: Southwest Federal Regiona]. Council Meeting at Farmington, N. N., October 16th and 11th, l97~r (prepared by the San Juan Council of Governments). -8- PAGENO="0537" 513 IV. Current and Projected City Budgets The City of Farmington is forecasted to increase annual municipal budget expenditures from $ 27.6 million in FY 1978 to $ 31~.2 million in FY 1979, an increase of ~5%. Also, assuming that the City increases from 35,790 (1977 popu- lation) to 51~,758 population by 1986, the City is anticipated to invest an estimated $ 77.9million for capital improvements during this time period. Opera- tion and maintenance costa will increase to $ 32.0 million annually by the year 1986. The budgets for FY's 1976 - 1978 are shown on Table No. ~. Table No. 5 and Graph No. 3 depict the projected capital improvement and maintenance coat for Fl's 1979 - 1986. The formula used to arrive at these costs is giver on both the table and the graph. -9- PAGENO="0538" Grand Total FY ~8 TABLO NO. S CITY OF FAICOINGTON FT 78 RUDGOT ru~c~P $27,586,757. Fl i6 FY 7( FY 78 BUDGET C General Fund Recreation Fund Sanitation Fune Airport Fund Golf Fund Fire Fund Lodgers Tax Fund Bevonue Sharing Fund Utility Operating Fund 0. 0. Interest Fund 0. 0. Principal Fund . * $ 1;~i8,517. 6o,ooo. 110,000. 559,9)9. 38,088. 39,000. 21,000. 022,085. 6,~9i,351. 59,218. 205,000. $ 5,161,761. 60,000. 533,603. 116,999. 11,128. 85,000. 25,000. 001,290. 8,993,275. 19,255. 130,000. $ 6,290,600. 70,000. 512,758. 120,818 -0- 28,000. 25,000. 270,000. 11,802,353. 41,325. 130,CO0. Total Budgeted Funds $12,530.638. $15,803,618. $19,291,220. * City Share - Construction City Share - Utility Construction Sub Total - City Share Construction $ 320,151. 3~958,7l2. $ 1,278,866. State and Federal Contribution for Construction $ 0,016,671. PAGENO="0539" 515 TABLE NO. 5 PROJECTED CITY OF FARMINGTON BUDGETS - FISCAL YEAR 1978-1986 2) 3) POPULATION POPULATION FISCAL CAPITAL IMPROVEMENT MAINTENANCE YEARS FROJECTIONS INCREASE BUDGET YEAR COSTS IN MILLIONS COSTS IN MILLIONS 1977 35,790 1978 38,778 2988 1978 $ 12.0 *($l14.o) $ 21.5 *($l3.6) 1979 41,1496 2718 1979 10.9 23.3 1980 143,159 1663 1980 6.7 214.9 1981 145,689 2530 1981 10.1 25.9 1982 148,671 2982 1982 11.9 27.14 1983 49,691 1020 1983 14.0 29.2 19814 51,1490 1799 19814 7.2 29.8 1985 53,282 1792 1985 7.2 30.9 1986 514,758 11476 1986 5.9 32,0 TOTAL: $ 75.9 $ 21314.9 * Actual 1978 Budget for the City of Farmington. 1) Population Projections by Gordon Herkenhoff & Associates, City of Farrsington Water Master Plan, High Projections, Albuquerque, New Mexico, 19714. 2) & 3) Federation of Rocky Mountain States, Inc., Resource City Rocky Mountain Denver, Colorado, 19714. (Note: Capital Improvements cost arrived at $ 14,000.00 per capita for new incoming residents locating within the municipal boundaries and maintenance costs for related City services are arrived by $ 600.00 per capita on annual basis.) Date: August 22, 1977 City of Farmington Planning Department -11- PAGENO="0540" GRAPH. .3 5565 Ct I) Federation of Rocky Mountain States Inc., Cenner, Coin. isyg. (Mote: Capital inprouenents arrisad at $4,7C5. per capita for new residents locating within the nsoitipal boundarins, S costs for related City arriued by $600 par capita on annual 2) Gordon 0.0 eerkeohoff S Oatnr Raster Albuquerque. 1974 N) Fiscal year July 1 ta June 36. Auooet 02/1977 ttty er yua-nnongtea ,01enning Oepea'teest CRY t~ FIIICYRGTCN'S ESTiCYiTED :EDNiiin CL. 1978 -1986 I N 0 0 I. A S S H ru N a 0 I. L A 2 S PAGENO="0541" 517 V. Bonding Capac%~y A. General Obligation Bonds: According to New Mexico law, a community can issue General Obligation Bonds to. a maximum of 14% of the City's assessed evaluation excluding water and sewer improvements. At present, the City of Farmington has a maximum of $ 2,2014,000 General Obligation Bonds excluding water and sewer. Therefore, the remaining amount that the City can issue under the General Obliga- tion Bond category is $ 1,3914,000 excluding water and sewer. B. Revenue Bonds: The City has Revenue Bond Issues which are charac- terized by Utility Bonds and Sales Tax Bonds. Utility Revenue Bonds are employed for electric, water and sewer programs. Sales Tax Revenue Bonds are for public building and parking lots. Currently, the City of Farmington has $ 22,625,000 in Utility Revenue Bonds and $ 3,936,000 in Sales Tax Revenue Bonds outstanding or authorized to be sold. The total Revenue Bond Issues outstanding and authorized for sale is $ 26,561,000. -13- PAGENO="0542" 518 VI. Capital Improvement Program- 1977-1981 At present, the City has over twenty major projects in the areas of water, sewer, fire, etc., which must be undertaken as soon as possible to bring the City in line viththe present population. (Refer to population projections, Table No. 1). These projects are estimated at nearly $ 143 million. The time frame in which these projects should be undertaken is 5 years, to begin in 1977 and be completed by 1981. The following is a summary by major categories: Area of Capital ~pp~~vements Needs 1977-78 1978-81 Parks and Recreation $ 826,300. $ 381,000. Electric Utility 1,650,000. 14,750,000. Public Works: A. Water 3,212,888. 7,980,1400. B. Sewer 1,971,759. 6,273,200. C. Streets 1,6145,600. 2,7140,556. D. Drainage and 100,000. 3,000,000. Storm Sewer E. Municipal Operations 125,000. 14,000,000. Center F. Municipal Airport 200,000. 1400,000. Fire Department 1,001,200. 1,019,01414. Criminal Justice (Police Dept.) 883,832. 8814,880. Civic Center 11,800. 1141,8140. Total $ 11,633,379. $ 31,570,920. GRAND TOTAL $ 143,2014,299.00 PAGENO="0543" 519 SUMMARY OF APPLICATIONS SUBMITTED TO VARIOUS AGENCIES As of August 25, 1977, the City is awaiting the out-come of a number of grant applications. The total value of these projects to be funded by these grants is $ l2,l81~,1466.OO of which $ 2,132,14014.00 are local funds. If the projects are approved, the remaining non-local share will come from the following: ECONOMIC DEVELOPMENT ADMINISTRATION COMMUNITY ASSISTANCE COUNCIL BUREAU OF OUTDOOR RECREATION SAN JUAN COLLEGE FOUR CORNERS REGIONAL COMMISSION ENVIRONMENTAL INPROVEMENT AGENCY TOTAL NON-LOCAL SHARE $ 6,700,573.00 2,089,600.00 50,000.00 25,000.00 86,889.00 100,000.00 $ 9,052,062.00 -15- PAGENO="0544" 520 STATUS REPORT City of Farmington's Applications submitted to various state and federal agencies. APPLICATION MATCH TOTAL STATUS 1. Project City of Farmington Water Line Replacement and Exten- sion (12 inch line replace- ment along N. M. Highway 614.) United States Economic Development Administration 75% $337,500.00 City of Farinington 25% $112,500.00 ~145O,OOO.OO Submitted 2/2/76 2. Project Installation of Water Lines U. S. EDA 60% $508,073.00 City of Farmington 28% $238,716.00 Environmental Improvement Agency 12% *$lOO,000.O0 $8146,789.00 March, 1976 Grantor U. S. Dept. of Commerce * The~se funds allocated to the City ECONOMIC DEVELOPMENT through the Water Supply Construction ADMINISTRATION; Act, August 6, 1976. ENVIRONMENTAL IMPROVEMENT AGENCY -16- PAGENO="0545" 521 APPLICATION MATCH TOTAL STATUS 3. Project Improve the City of Farmington Raw Water EDA Supply 75% 500 , 000 . 00 City of Farxsington 25% $6,000,000.00 August 11, 1976 $1,500,000.00 Grantor U. S. Dept. of Commerce ECONOMIC DEVELOPMENT ADMINISTRATION Project a. Street Construction - construction of Thirtieth Street between Butler Avenue and Sullivan Avenue, and the EDA construction of Sullivan Avenue 100% Submitted between Twentieth and Thirtieth. $676,500.00 $676,500.00 1/11/71 b. Elementary School Parks - entails improvements to recreation areas within four elementary schools; Animas, Country Club, McKinley, and McCormick. All schools are within EDA the Farmington Municipal School 100% Submitted District #5. $200,000.00 $200,000.00 7/11/71 c. Senior Citizen Center Addition - the addition will be linked to the existing facility by an enclosed walk-way. The new facility will have an en1arged~game room, a large EDA kitchen with stoves, refrigeration 100% Submitted serving area `md storage space. $150,000.00 $150,000.00 7/11/77 d. Phase III North Interceptor - the proposed sewer improvements - project consists of 6,500 L. F. EDA of VDP sewer line ranging in 100% Submitted size from 8 to 15 inches. $328,500.00 $328,500.00 7/11/77 Grantor ~ ECONOMIC DEVELOPMENT Total Projects: $ 1,355,000.00 ADMINISTRATION -37- PAGENO="0546" a. Treatment plant expansion, additional storage tank, and inter-system transmission lines. b. Replacement of structures in Farmer's Ditch. Add earthen dikes to increase capacity of Lake Farmington. Install pump station at Lake Faraington. Community Assistance Council - Energy Impacted Mondes STATE OF NEW MEXICO 6. Project Community Assistance Council 63% $1,366,785.00 City of Farmington 37% $802,715.00 Community Assistance Council 63% $ 722,815.00 City of Farmington 37% $ ~21~,5lO.OO Total Projects: $ 3,316.825.00 Recreational Facilities located at the San Juan College New Mexico State University, San Juan Branch and the City of Farmington New Mexico State P?.anning Office - Bureau of Outdoor Recreation San Juan College 25% $ 25,000.00 City of Farmington 25% $ 25,000.00 Bureau of Out- door Recreation 50% $ 50,000.00 $100,000.00 August 1976 APPLICATION 5. Project 522~ MATCH TOTAL STATUS Sutmitted $2,169,500.00 7/15/77 SuBmitted $l,1~7,325.OO 7/15/77 Grantor Grantor -18- PAGENO="0547" 8. Project Surplus and Excess property. Grantor The State of New Mexico and Four Corners Regional Commission. 523 APPLICATION MATCH TOTAL STATUS 7. Project City of Farmington - Drainage Master Plan City of Farmington 25% $ 28,963.00 Four Corners Regional Com- mission 75% $ 86,889.00 $115,852.00 Submitted May, 1977 Grantor Four Corners Regional Commission (The Planning Department anticipates little or no possibility of funding this project through the Four Corners Regional Commission.) On-going project. -19- PAGENO="0548" 524 MATERIAL SUBMITTED FOR THE RECORD Bx STATE SENATOR JOSEPH GANT The city of Carlsbad has experienced a rapid growth in population over the past 3 years as a direct result of energy related activities in the area. The activi- ties include development of oil and gas, the planning of the atomic waste isola- tion pilot research project, the establishment of anhydrous ammonia plants which use natural gas as feedstock, and increased mining of potash. The Carlsbad area is of major importance to every section of our Nation because of several pertinent facts. 1. The energy crisis requires that~ every effort be made to develop new oil and gas sources. The Carlsbad area has led the permian basin month after month in oil and gas drilling activities (exhibit 1) as documented in the weekly rig report published on a weekly basis by the petroleum information corporation, Midland, Tex. These activities need to continue and Carlsbad must keep abreast of the increased populatiOn and need for services caused by these operations moving into the area. 2. The potash mines and anhydrous ammonial plants in the area (exhibits 3 and 4) provide fertilizer throughout our Nation and the free world. The production of these two of the three major elements essential to grow our food and fiber crops are direct factors in our domestic and foreign trade. Any Carlsbad area deficiencies that would cause difficulty in maintaining these in- dustries and encouraging their continued growth would be of great detrimental affect to our Nation. 3. Of equal or greater importance to the above is the waste isolation pilot plant project that is now progressing rapidly in the Carlsbad area. Without a proper, safe and efficient method of storing nuclear waste, our Nation cannot make the strides necessary in solving our energy crises. The people of the Carlsbad area are working with ERDA and Sandia laboratory to assist the orderly progress being made. The impact upon the Carlsbad area as this project materializes (exhibit 2) will be tremendous as detailed in the Larry Adcock and Associates report on the socioeconomic impact analysis of the proposed waste isolation pilot plant. PAGENO="0549" 525 4x4/~ i7' 011616 *)pqor,/CTS 0901 1)111/9 )NOIJSTOTS INC 1/650 G9'W9- 019119 1E9~S 19162 9/5/3333/// MON!)AY, JULY 29, 977 PETROLEUM INFORMATION CORP. Anderson Oil Report WEEKLY RIG EFFORT F/V P. 0. Box 1842 Midland, TX 79702 SECURITY ROCK BIT - WI/ST TEXAS DIVISION OPERATOR LOCATiON CONTRACTOR APPROX PROP ________________________________ DEPTH DEPTH ANDREWS COUNTY Exxon 835 Fullerton Clfk Unit Rod-Ric #3 4695 7300 Exxon 1172 Means San Andres Unit Tom Brown #18 Spud 4700 BORDEN COUNTY Monsanto 1 Good i/es-Tea 1/li 9400 9800 Texaco 3142 Jo Mill Unit 1)-Il 1/8 7000 7500 COCHRAN COUNTY Coline 189 West Level/and Unit litton #1 4800 4950 Coline 190 West Leveliand Unit Sitton i'i 4200 5000 Dyco 20 Hasten "4" Verna #9 TD TD Union Calif. 2 Masten "B' EKA /8 TD 4925 Union Calif. 5 Hasten "J' hal /18 3300 4700 COKE (:OUNTY R. L. Burns 1 Ellwood "20" Fortune #1 6980 7000 Keadrick & Mulligan 1 Hendry Texiand 1/3 6000 6900 CRANE COUNTY Atlantic C-S Block 31 Johnn #8 8140 9100 Atlantic K-6 Block 31 Johnn #8 4250 3,0,500 Getty 3711 North McElroy T. H. Blue #1 1750 34553 Gulf 16 M GEM 112 4320 10,500 Gulf 284 McElroy Tom Brown #2 1426.. 3200 Sabine 2 Glenn Capitan #1 2150 7400 CROCKETT COUNTY Azoarex 1-A Baggett "8" Wes-Tex #9 4150 10,700 Anderson 3-4 J. S. Pierce Wes-Tex 1/10 4975 6450 Anderson 14 Nillspaul "2-A" Wes-Tex #15 2140 5600 Delta 1 Joe Couch "A" Delta #2 9870 12,500 Delta 1 Delta Delta #2 2931 10,500 Delta 2 Friend Delta #60 1145 9000 Gulf 10 Henderson Tom Brown #5 TO 6730 Gulf I Hoover 1)m Brown #6 Fshg - . - H&D Well 7 Shannon 1111) Completing H&W 4 University "9" /1,1/n Wilson #1 600 2400 95-826 0 - 77 - 34 PAGENO="0550" ,CURITY ROCK BIT ge #2 526 7-25-77 CROCKETT COUNTY (/:nt `d) PETROLEUM INFORMATION CORP. Anderson 0/1 Report n 2. Harrison 1 We' lex 111 3981 7000 diem Well. Montgomery "10" Tucker 111 6200 7000 diem V.11. 2 Montgomery "10" iiicki'c 111 2190 7000 diem Well. diem Wells 3Nontgotnery `Montgomery Tucker #5 "C" W,'s-Tex #6 5050 3110 7000 5200 `than. Gas 2 Baggett lIeu- lox 12 6510 10,000 :0112, Wagner 6 Brown 1-8 Hoover "B" U'u-ex 111 3000 9000 Cleo Thompson 2 Bailey W~u -T,'x Pit, 900 5200 xoma 1 Hudapeth CULBERSON COUNtY terican Quasar 1 Meeker Unit Yh.trp I! 5 Basin ft land /12. 15,650 17,200 :lantic 1 Delaware DAWSON COUNTY . 12,000 9600 1 Ails Byrd SItU dl MOE //i ntex 060 DICKENS COUNTY thiend 1 Pike Lh'hbins i~ 5 ECTOR t:itN1 P serada 12 Catlinvilie Nat'i at)' Lnoco 138 E. F. Cowden clsntic 76 3. L. Johnson tlsntic 97 North Foster anoco 106 Gist aillips 4 Cowden an 716 Foster-Johfl~ofl axaco l4-12We,et Jorden Unit ex*cO 15-12 West Jordan Unit GAINES COUNTY merada 2309 SemInole Sadt Ut. merads 2312 Seminole Sadr Ut. merada 2709 Seminole Sadr Ut. merads 2710 Seminole Sadr Ut. ities Service 1 Peters "A" xxon 8002 Robertson C11k Ut. ytech 1 Sherman obil 11 Tom May obil , , . 4 Braddock obil 1 H&J "B" hell 23 Stark exacO 90 Wharton exacO 91 A. B. Wharton "TIGHT" 7600 8260 Spud 7000 10,600 6800 3300 2200 4190 2800 "TIGHT" 3720 "TIGHT" 3457 5181 4915 2354 10,190 6800 4999 "TIGHT" 5115 5480 4649 4306 TO 4840 ttus/li? thin //10 (:ict us #511 cactus //58 it. H. Smith 1151 Paul's #4 IlIlliti (/6 Norwood #1 I/Ill/n #8 Cactus 1)9 Cactus 1159 Cnctu3 063 Cactus 163 tug West `;ii a/_RIo P7 lyid #2 I/illtti #`l Sr ton #4 Norton #4 RI-Rio #2 (`.,ct,,l 11(5 ti:'; #56 .7 550 11,000 9500 4300 4400 4400 4500 4400 3750 3400 540Ô 5400 5400 5400 12,000 7200 5600 5600 5600 5400 4850 4820 PAGENO="0551" SECURiTY ROCK HIT Page #3 527 :,\i/~~ ct -:t ii:iRoJ.tIJ1~ INFORMATION CORP. Anierson Oil Report Amoco Amoco (;ulf love lady Joe Meltoit Sun Texas Pacific Union Calif. l'heeler Properties Amoco Atlantic I). L. Dorland i:nserch Phillips Rendrick-Mull igan Resources Investment Samedat, John L. Cox )unigan tortune ierr-McGee *1 lit 3 ben `A' I Unit- `:1. Edwzt rds 2 S. it. I oth 6 161 lii it 24 011k 2 Chalk 1 Ins El. `k' 1 Field "1129' 7 Murphy I St `14" lions i)rig. 1/3 ley 01 /t.h/sss, `ri~. lu-s ii,' lx litid Ill 1114 ~1? Creuli 1 ty /2 ci se 1 General Crude Maguire Sun P1. R. Young Eaton] Newbourne Oil Tamarack Amoco Amoco Amoco Amoco Inexco I S1 1 `1 I Slaughter lot I `IN" `A Swenson "31' I Spinning CL\~4cocK (11/616 I C. h. Currt 2 Riley 2 Angst (/41.1 (009/3 391 Ancn-l ri sit 011k Ut 365 AnIon-Irish Cl 1k Ut 374 Anton-Irish Cl k II 375 Anton-Irish (11 I Carson (22 C~ttraI N;) i-i 51 2/1 Ii. C. Cr1-i WI_i .1 lIrstitsy 20 tel ra I I I 2 Ci iw~i 109 :6, 9. Sidu~:l. 8301 8500 5200 8500 7300 8500 7500 8300 3435 9700 2835 8100 6386 8000 3200 5600 2000 5600 5600 6300 5200 6300 TO 10,70 .1:) /13 (-1(1(1 1)4 Mt/ti hen /34 let Sledge 1/i Fri-Service #4 `I'm (rows /13 (lift Ill Norton 1/2 (tar tus 1/54 061st /12 NrA 64 /1/i: /1 i--I :t'; It: TO TI) TI) ID 3500 311311 3100 TI) 6900 6800 1000 1000 3000 1000 100 8400 1000 `TICRT" 4075 2891 7986 4900 8200 10,21 4800 5050 5000 5700 6060 8750 2900 2459 10,00i 2900 3250 9600 3250 8100 6800 8000 8100 PAGENO="0552" 528 SiCUKITY ROCK BIT i-:,-,! `ETIl()IEUM INFORMATION CORP. Fags #4 Aod"r',on 011 Report jAN13 (3)0515 ((.0))) A~Oco 390 Anton-IrIsh Cl 16 `1 (h(co 1/3 5600 6300 Fred Olsen I V. C. Hart (N3) `/6 TO 7000 1.04' N~ GUSTY Exxon . 2 Linehery Thompson 115 5050 20,51 ~ Hunt 011 1 ((arrlson "10" (`arker (/86 19,505' 22,5( LURHOCK COUNTY Kewanee 1004 HarrIson Norton 1/] 4900 4900 LYNN COUNTY Kevanei 908 North Welch /t. Norton (1 4900 4900 MARTIN COUNTY Ilytech 2 Mabec Tn-ServIce /3 2412 10,50 MENAR1) CO/ISIS Anada11ko I Sorrells `.5 /~Y 4516 4600 M/ 1)3_ASS (:0151 J. 1. Cox 1 Braun USA (3 "TIGHT" 9500 1 Faskeri "13-A" USA 112 "TIGHT" Mobil 3 C. B. Haley "A" !)rnhaney 11. 11,760' 12,201 MITCHELl. COUNTY I Coleman "A" Incus (/2 1815 1900 Mallard 1 tllwood Est, "6' 0(0//i 6700 7100 Sun 18 McCabe "B" Won-Tex 1112 5300 6450 Sun 19 McCabe "B" W,'s-Tex 1112 3100 6300 Sun 6 Stubblefleld ` Wes-Tex 1114 4000 6430 TIPCO 7 Parks UCO #2 5960 6500 PECOS COUNTY *mariflo 1 DIxel Gas Sharp 1155 18,800 23,000 Merican Quasar 1 Elslnore "65" Warton 113 14,000 16,O0O BTA ç 1 Riggs loffiand 11324 TD 23,000 Exxon 1 MarjorIe Crawirl (`/e'rpson 118 6900 23,500 Exxon 14 John May Sharp 1132 11,0(30 12,000 Catty 1 Montgomery "38" Sharp 11/38 4750 12,000 Getty , 2 Mendel "26" Noble N-17 5200 12,400 G-ty ` 4 Mendel Est. "16" Sharp //36 Fshg 12,000 Gfrd, Mtchl, Wsnbkr I Raymal-Eagie `ar/r,'r 5(5 14,000 22,700 Gulf I Emma Lou ~iarp `Ni Whtpatocking 25,500 Billiard 1 Grant-State `rwo~d /1 5300 5700 Hillin 4 Moore-Gl1mc'o~ tIM / in `,` "TIGHT" 9700 Lovelady 2 Chalkley C-li 13 1400 4150 PAGENO="0553" 529 SECUPITY ROCK BIT J'age #5 :I) `tHIGH INFORMATION CORP. ,`o'l"riion Oil Report l4id-Anerican 4 `l,t'lbv `II 1 11,629 11,500 :onsanto S I)crnic,' Vi 8900 10,800 Monsanto `~ .""~" "Ii" `4 6600 10,800 Monsanto 1 )itlngcr "or 190 14,109 18,000 Northern Natural llt'r';Iooooti "1c~' ."~ 711' 15,110 16,500 Phillips M)tJo'l I S.uj' 9!!, 9450 12,000 Texas Pacific 11 "15 I'. `tl'oi' 115 1000 14,000 IILVA'\ (11:1 I Bill Beach 1 Fr,'czo 05 14 "TIGHT" 4, W. Buchanan 3 Rotor I) "II" I''o Gown "I 2501 7225 4. W. Buchanan 6 R,','k,'r B "1')" c: ii `wit 7) 6331 7400 ,I. W. Buchanan 4 lIoker B "1)" I". `Iwo 11'~ 5950 7500 cities Service I I!u)v'r)ty "St" ~ /115 9915 9950 Gulf 2 No'),) in~rr ii nt /5 8340 8340 iaxon 2 Wo,r),'rl,v "II' :,`, i "TIGHT" 7700 `anarack 3 `L,dvt; Click "5" :` 1r"oc " 6240 7850 .`ay 6 Hills I i'nivr'rsitv "I 1" `H ` I 1020 3300 I. L. Cox I Nil .` ` "TI(;In" TAPCO I ~i. i . .1:'', 961)1) 22,500 dobe 1 .t o `to ~`ti~t'' TI) 13,900 ,nericau (3uaS'IT ,` I Lr';Ii.t:' "I)" ` `i' `7 16,724 17,000 TA ,` /(,t)7 `ci:, ``i `0'S 10,150 16,000 :1,cvron .1 I tI "17- 19" It `IV `0 * 9950 14,500 yco I :Idw'II Sit ., `~ 147 8700 11,200 .nserch I .s~,j it :o:' 0 3180 3300 ;nserch 1 Suit 1 Il I. 3200 3400 xxon I 19'hi) ct' `.` `; 4018 11,000 if / 0. 5. Lip. c' ``` ` 6988 17,600 NC 1 i1'Vr):iit! "0/" 1)0 1 1 9 10,453 18,500 GO ` 1 1,:,!,,' Stui,' `ocr 95 12,800 19,500 ant Now 1,''catlot, `ut Sr /1,1, 4105 18,000 orthern Natural 1 571. "19" .1'".' ` 0) 18,798 19,000 ,`xaco I 1O',v,'c; "91)" 1".' "`c,'.'iOI.' 3100 18,000 `xaco 1 )I~,".'~ `u "III" I' , to .1 `` II) 3400 ,`xaco 9 R,.','v",. ".1" 1',, ``~i VI 0) 18,000 SI 111.1 ~I ~I :t `.1' ,~ 1 St, "1')" `, . 7915 8500 `yer & Ansoc. I Wilt,' `` :`. : ` `11)0 5600 * I. O'Neil 1 )i'Ot,'I,' "5" . 5480 6850 icker 1 W"r:t ``5 300 5800 .`dgco I Irk I Go'.')': `:" ```ti :1', TO 7800 PAGENO="0554" 530 SECURiTY ROCK BIT P.ga ~6 `-[1-li SlERI. IN( (:001 lY I B))T,(3/M INFORMAl ION CORP. A,,'l,'rs',n (Ii I Report C&K Chevron Mobil Resources investment VAL VF:RI'l: (001/1 1 Mobil-Mills 1 Bassett Minet:iI `40" 2 Morrison 1 Mills `18' Stuck 7622 8400 5303 8200 5400 8100 8100 8100 1 Foster-Price "7" 8 Hil,iebrand "18" 4 Sterling "H" Fee 3 Sterling "I" Fee SUTTON (1)1/ITO 1 Cauthorn "15" 2 Kirby "183" 1 Shannon "52" 2 Brown "78" 1 Aidwell "17" 4 Hicks 9 Whltehead 3 Wilson "185" 4 Wilson "188" TERM/Il. 131/N V 3 Banner tsr. 5 Bernice TERRY (3101/ 16 Covington "1/" I IJaughtery "A" I)-)) 01 1/3 C p Stan /11, );;irttan 13 I'rt,~n~' //2 Tm Brown //13 Tom Brown 113 Tom Brown //11 Em Brown /12 Sioux 1/5 /),`lta //61 1)elta //73 lIta //73 /0 liney /14 Ca,' t u' //25 1" ma /1 Dorchester StolEs, Wagner & Brown Texaco Texaco Atlantic 1180 1180 11MG Lively Way & Hill. Wewoka Windsor Windsor Mobil Monsanto Amoco Young Euraf rep Florida Gas John H. Hill Tucker Burns Cotton Pet. Gulf Gulf Gulf Knox North American Royalties Texas Oil & Gas 9500 6150 3870 4985 7100 1073 Fshg Re-Entry 7290 12,300 9100 9550 7050 7000 5300 9400 3750 9300 9000 9000 13.50 12,00 TO 8900 4350 5000 2 McGregor 1 West Pate 1 Field 1 Harper TOM'CRELti OTCiIY Caraway /2 in, /:``r 11 kr 1/i UPTON (3)1/STY 1 McElroy 4 haul 282 Crier-/IeEE `av 993 McElroy 995 McElroy 4 Turner 1 I/ceo Ftc 3 Dancon 6813 5810 6425 5793 8750 5420 3022 1983 3200 6925 3450 "TIGHt" 14,210 19,150 468 4250 7100 6500 7400 6800 14,000 10,100 3900 3900 3400 6950 10,500 15,500 20,000 14,500 15,500 1/ `11/day /`l `n Sledge rf/, :~ l/r'wn / c 1/r,,wn /9 1/.' / 1 / lay / 21 11 I/wa, (/7 /19 Dl). 04 PAGENO="0555" WI NI Ill!; 1)114 V 531 WAlk (11/4 (`0(105 INFORMAT 0111 CORP. A,,'I"r.'an 011 Report BECURITY ROCK JILT Page 07 ~aoco ~TA Forrest Gulf Cull Gui I INC INC. Pfon~aiiLO Shell Texaco Union Texas Clayton Williams Clayton Williams Amini Exxon Gird, Mtchi, Wsnbkr Gfrd, Mtchl, Wsnbkr Gird, Mtchi, Wsnhkr Cfrd, Mtchl, Wrnbkr INC IJ]]Jard 010 Shell Tahoe Shell Shell Shell Shell Texaco Texaco Texaco Texas Pacific ilell Sites .`nadarko Autwel 1 Antwel 1 tlantic last Ic \tlant Ic \t last Ic 5 I")stcllc' lit//ri ~`4 "TIGHT" 8800 I Stallings 1:,,t,s 1/1 15,980 17,00' I CII Si;t W. Cadr',W,;,,! st `/8 Sharp 11S9 800 9100 20,00i 18,15/ 3 1. 1. Prueti ih'nn;"ar, 1/1 17,100 19,80/ 2 Stat "OA" /,,/,~ 74 5500 1 Its' "1 28" 1': kr 1158 TI) 22,000 124 5 11 I `1 `i; ";:" (town i'll 3674 6750 I tic,dg,'rs 1' ,rk,'r 1/87 9100 19,500 1/8 Sely-Smitti V,'r,o, °16 3100 6700 1 Stat, (4,s lii, i "1," `Fhr';'ij'son 1/1 15,445 20, 39C I Scaly "511" tans //5 5780 17,500 2 Svary N'rw'od I/I TO & RU 6800 4 `t'(,mpsor :51 `A" ``1' tan 1/2 5900 6700 1 Scaly-Smith "1/" (IA !1 7900 9200 2 Haley "17" //In/son 113 14,875 18,500 l Capita (I. i/ni tI, /55 1900 3200 1 011th' W,ih/ 1/nit/i 1/51, 1900 3300 11sf/i /`; /, 713 16,984 22,500 1 11,m:n N,,;,. /` ,/r 491 4510 22,500 ./ DaIry "(`1" 1: 774 20,374 18,500 I 5/v :. (,,(,,. ,:` 8700 9300 /,/) ,,ly-l;ii/, .., i,,, `, 8599 9800 I (/`,,,(,iks *..\" I ;/; :15 351/0 4200 `24 lh,,ver It . kr;,.; /h 424(1 5320 5411 I/,,ver Ut, 4'., mr. //2 4210 5250 1716 Denver Ut. V~,n., 119 5250 5300 1717 Denver Ut, Virs, 119 Spud 5300 2127 Roberts (3, 1 t,in //57 3934 5300 3217 Roberts Ut. ( ii': f1(,7 2320 5300 3326 Roberts Ut. C.,, ~i'; IVI 4206 5300 4222 Roberts Ut, Cv, t,,~; 161 2320 5300 274 Rennett lane/i Vt 1-0 7') TI) 5500 8 Am,;;' Fcdi'r. / 3830 ID 1 (vs i;;m 3497 4700 `Onion /1(, M,,,;,;', /7 "`,i,,;.,, li/I 101)5 UI//ISiS 1 (ed-rI Corn 1 lIes;, Arriba I Rio 372 `ii r"..Os; (//1 Umptr; .//;,` ``/`` 141 lri;pir~ ,\(,;; "1" 6412 6880 Logging 2582 TI) & Logging 6180 Spud 12,000 11,600 12,000 6400 6300 6400 64(30 PAGENO="0556" SECURITY ROCK BIT Pap #0 532 7-i,)-'' I'ErRol.IdJM INFORMATION CORP. Ander:,'n Of I Report I:l11)ycl)GNTY ( (``u 3) Atlantic 1 State "BU" Ard /12 10,888 1O,90i Bennett & Ryan i ~ `lrV:,y 114 6305 9000 C~ 1 Carlsbad `12' /hnrp 1/37- 8840 12,00) Exxon I Laguna Crand(' l(,1)a 1/3 1260 12,001 Exxon 2Laguna Grand" l)')t:i 11) 3612 12,001 Exxon 1 NM "CU" State Mirc',m 113 3684 10,501 Gulf 1 North Shug.irt SV'uy /9 9786 12,00) INC I Valdez "5" i;~. Wat vi' /i 8412 13,50 Moncrief S Lechgial 1 Ia any's `rd `1, 7591) 11001 Monsanto I Myers am' 111' ` 118(3 9000 Penroc 5 Ross Draw D't.eiv',dS 8520 8500 Southland I Featherstonc Stat, (iee)u `1 1655 11,3011 Texas Pacific 1 Glenn Farmer Aid 11) 6384 8100 Western 1 Bass MVay 1") 1684 11,50/ Yates 3 Box Canyon `/ ~7 8460 8600 Yates I Dinkus Stat' 7 `ran'a' 119 8912 8900 Yates 4 WillIamson "SC" Mimic 112 3788 11,601. LEA COUNFY American Quasar 2 Brinnlnstool Cactus //3) 13,089 14,50/ Atlantic 1.1 Wlmberly (a ttis //51 7277 7400 Cleary 1 NM Federal "F" (on. (`ar ton 111 14,348 14,10/ Getty 1 NM "2" NCT ((undo //7 6498 ` 8000 Gulf 424 Central DrinkarI MGF /110 6558 6750 Gulf 1 Lea "IL" Stat' MeSsy //10 14,296 16,001 Ledbetter , Leonard Bros. `` 2 Jay Federal 6 Leonard Bros. Cactus #66 Car ttts 1166 2124 250 3700 4000 Maralo 1 Carson Federal (,,rst,'r U's 9391 12,00C Marathon 18 Lou Wurtham (:n't~,m; 1164 7390 7700 Newbourne I State "C" 1c,s ttts PS 4590 13,SOC Oil Dcv. I State "9" li'ndo d5 11,250 12,501 Texas Pacific 1 Feed Federal Cic In'; 1154 3914 5000 Tipperary 1 State "28" Tri-1/,'rvic,' I'h 9591 12,50/ Union Calif. 1 Cinch Stale S,d,in';cr1 (ru-i. /2 10,700 10,70C Yates 1 1, 1). Pow'll "7,1" (vi,) TI) 3750 S/SCUll:) (71(1(1, 1 1 its/cr SFI'RR TransOcean (111am') /11,' PAGENO="0557" 533 `SFLCURlTY ROCK BIT Page (/9 The Following Rigs Are Stacked, RigginG Up, l'~1~G, /1. Torn Brown Torn Brown 1116 Torn Brown Brahaney 116 Byrd /11 Byrd 117 Cactus /19 Cactus //23 Cactus 1130 Cactus /160 ChIco /14 Chleftan //1 Delta //36 FWA 1/4 FWA (/8 FWA (/17 Five P's 1/1 Richard Gray `1 (;if 112 loffland /:2 7 Norwood //] Thompson 14 iliompson 111, Tri-Strvfce 55 Verna /~5 Verna 1/7 Warton /,31 [fig Wt'st /11 Cacti's 1/34 McVay 1/7 lIoranco //6 Rohi flSOfl from Wirton //7 [// 10 1'; / //u/i r~ fOld StackS /`vfns~ / or [bill ips `/ / ir S Sloe/oS / n Ml land Yard tad/cd low 11 11 /1/ for Mobil Nov 1 It~ 1 ii New toe kit St ic I f NOV/did I' Midland Yard St old 51.1/ SI :11/I 10/ 15 I s / Am TiO S/ic/id ii 11ff/land Yard / 1ff' Mv I //,. I //;.ii I'; `i/TROIFlJM INFORMATION CORP. AnOrion 011 Report 1/ .XAS Ni:td /1/S / PAGENO="0558" 534 Larry fldcock and EIssociat~s Economic Consultants SUI'YlARY SOCIOECONOIIIC IIIPACT ANALYSIS OF THE PROPOSED WASTE ISOLATION PILOT PLANT APRIL, 1977 PREPARED BY: LARRY D~ ADCOCK BASIL B WEST PAGENO="0559" 535 STATEMENT OF EXISTING CONDITIONS 1.0 STUDY AREA The proposed Waste Isolation Pilot Plant will be physically located within Eddy County. However, the impact anticipated from that plant will primarily affect both Eddy and Lea Counties. All of the following socioeconomic analysis will be limited to this primarily impacted area, Eddy and Lea Counties. The following analysis will cover the existing conditions, the expected impact and change during the construction phase, and expected impact and change during the operation phase. Given the proximity of the plant to Carlsbad, it is expected that Carlsbad will receive 88 percent of the direct impact, from the plant, both in terms of ln'comes and employment generated. Of those indirect impacts, i.e. those Individuals and dollars connected with secondary and.tertiary Industries, approximately 80 percent will go to Carlsbad, 10 percent will leak off into the surrounding area- inside Eddy County, and the remaining 10 percent will spread to Lea County. PAGENO="0560" 536 STATEMENT OF EXISTING CONDITIONS 2.0 POPULATION CHARACTERIS11~ In 1912 when New Mexico became a State, Eddy County contained approxl. mately 9,600 people. The 1910Census showed 9,684 IndIviduals; by 1920 the population had dropped to 9,116, and population again rose to 15,842 In 1930. With the start of potash mining in 1931, growth between 1930 and 1940 was fairly substantial and showed an increase of nearly 9,000 persons, or a total of 24,311 persons. Between 1940 and 1960 Eddy County continued to grow principally because of the mining operations in the county. By 1960 the population had reached 50,783. However, in 1970 the activity in the mining sector decreased, and the population subseuqently dropped to 41,119. Between 1970 and 1975 this trend was reversed, and the population count of Eddy County again begin to grow. The 1975 estimate released by the Bureau of the Census showed that Eddy County had grown to 42,400--an increase of approximately 1,300 people. In 1917 Lea County was organized from parts of Chavez and Eddy Counties. By the time of the 1920 Census, the area now known as Lea County had 3,545 residents. Oil exploration began in southeastern New Mexico in 1924 which brought substantial growth to the county. Dy 1930 the population had Increased to 6,144, and by 1940 had tripled to 21,154. Continued growth through 1960 reflected a populationof 53,429 at the time of the Census. However, between 1960 and l97D'Lea County sustained a population decrease of approximately 7.3 PAGENO="0561" ~537 2.0 POPULATION CHARACTERISTICS continued 3 percent. Between 1970 and 1975 the population of Lea County increased from 49,554, at the time of the 1970 Census, to 51,200 for mid-1975. Thus, both counties sustained population decreases in the 1960 decade precipitated principally by depressed conditions in the mining sector, the basic industry supporting the economy in both counties. The decrease in the potash mining activity was caused by Canadian potash dumping on national and international markets. Eddy County contains four municipalities: the Cities of Artesia and Carlsbad, and the Villages of Loving and Hope. The largest of these is Carlsbad which recorded a population of 21,297 in 1970. The estimates pre- pared for this study show that the population in mid-1976 has grown to 25,000-- still below the population of 25,541 achieved in 1960. Artesia, the second largest municipality, recorded a 1970 population of 10,300. Again, this was down from ~ 1960 population of 12,000. Both the Villages of Hope and Loving are small. In 1970 Hope registered a population of 90, and Loving had a population of 1,192. In Eddy County some 97.1 percent of the population is white by race, while only 2.2 percent are black by race, with an additional 0.7 percent of racial minority groups other than black. The Spanish ethnic group is fairly large; 25.4 percent of the population is of Spanish origin or descent. Lea County has five municipalities: the Cities of Hobbs, Lovington, Eunice and Jal, and the Town of Tatum. In 1970 these municipalities had respective populations of 26,025, 8,915, 2,641, 2,602, and 982. In Lea County 93.7 percent Of the population is white, while 5.3 percent of the population PAGENO="0562" 538 2.0 POPULATION CHARACTERISTICS continued 4 is black, with 1.1 percent of minority groups other than black. The Spanish ethnic group is somewhat smaller in Lea County than in Eddy; only 10.9 percent of the population are of Spanish origin or descent. In 1970, 76.9 percent of the population of Eddy County resided in urban places, approximately 18.1 percent of the population lived in rural non-farm settings, and 5.0 percent lived on farms. In Lea County the popula- tion was slightly more urban in distribution; 81.1 percent of the population resided in urban areas, while 15.1 percent resided in rural non-farm areas, and the remaining (approximately 3.8 percent lived on farms. PAGENO="0563" 539 5 STATEMENT OF EXISTING CONDITIONS 3.0 GENERAL ECONOMIC CHARACTERISTICS There are three basic industries in the two-county area: in order of importance, they are mining, manufacturing and agriculture. Although government may be considered,in parts of New Mexicc~ a base industry because of heavy federal government activity, this is not the case for Lea and Eddy Counties. Most of the government activity in this area is of normal size and supportive of the area. On the other hand, the retail and services sectors are larger than might be expected from the general activity of the area. Eddy County encounters heavy tourist traffic attracted to Carlsbad Caverns; thus, the average size of the retail sector is somewhat above normal. Trans.. portatibn facilities and the transportation sector within the area are well developed because of the existence of heavy-type industry activity within the area. 3.1 AGRICULTURE In 1974 income figures prepared by the Bureau of Economic Analysis show that the agriculture industry's mainstay in the two-county area was meat animals and livestock. Total agricultural receipts in Eddy County in 1974 amounted to just over $31.4 million of which 59 percent was received from the animals and livestock sector. In Lea County slightly more than $20.9 million in receipts were registered from farm marketings in 1974. Of this amount PAGENO="0564" 540 3.1 AGRICULTURE continued 6 62.4 percent came from meat animals and livestock. In the area of the proposed project the only agricultural activity present is that of cattle grazing. 3.2 MANUFACTURING In 1976 there were 44 manufacturing companies in Eddy County and 47 in Lea County. Employment in manufacturing in Eddy County was approximately 930 in 1976, while employment in manufacturing in Lea County was close to 950. According to the latest information available, income from manufacturing in Eddy County in 1974 was between $8.7 and 8.8 million, while in Lea County income derived from manufacturing amounted to between $10.2 and $10.3 million. In 1974 manufacturing accounted for the second highest amount of income generated from "basic' type industry. 3.3 MINING Mining is the major industry in both Eddy and Lea Counties. In Eddy County in 1976, mining employed approximately 5,200; in Lea County mining employed between 3,400 and 3,500. In both counties, employment in the mining sector was substantially larger than in any other identified industrial sector. In Eddy County, potash mining is the primary mining industry; more than nine out of ten persons employed in mining work in the area of potash mining. Potash from Eddy County supplies a very large portion of total potash production in the United States. While recent figures have not been disclosed, in 1965 potash from New Mexico supplied 90 percent of total potash deliveries in the United States, Canada, and Puerto Rico. At that time point, mining employment in Eddy County was somewhat larger than it is today. PAGENO="0565" 541 3.3 MINING continued 7 However, potash mining remains the principal basic industry in the county's economy. In Lea County, most of the mining activity centers around the oil and gas industry, although other mining operations exist in potash,.sand and gravel, rock, salt and caliche. Total mining employment in those activities other than oil and gas amounted to less than 200 individuals in 1976. There- fore, it is estimated that nearly 5,000 individuals are employed in the mining of oil and gas in Lea County. Personal income from mining was over $36.6 million in 1974, or 21.5 percent of total personal income generated in Eddy County. Personal income from the mining sector in Lea County amounted to just over $59.7 million in l974--26.7 percent of total personal income. This is, by far, the largest industrial sector in the county. 3.4 TRADE AND SERVICES SECTORS The latest available information listing the total number of dollars and number of establishments in the two-county area in retail trade appears in the 1972 Census of Business. This Census shows a total of 1,068 retail outlets. in the two-county area--454 of these located in Eddy County, and 614 of these located in Lea County. Within Eddy County the majority of the locations, some 281, are located in the City of Carlsbad. Total sales volume for all 1,068 outlets in 1972 was about $185.9 mil- don, or just over 8 percent of the more than $2.3 billion in retail sales throughout the State of New Mexico. Although no information is available after 1972, it is obvious that retail sales in the area have increased substantially. 95-826 0 - 77 - 35 PAGENO="0566" 542 3.4 TRADE AND SERVICES SECTORS continued 8 Employment in both wholesale and retail trade has increased from an average of 2,500 in 1972 to approximately 3,000 in 1976 in Eddy County alone. In Lea County, l~72 employment in both wholesale and retail trade was just under 3,600. In 1976, employment in this sector moved close to 4,400 people. Thus, the trade sector in the two-county area has shown substantial increase since 1972. -. There were 835 establishments operating in the area of services-- hotels, motels, barber shops, advertising, business services, repair shops, etc.--at the time of the 1972 Census of Business. In that year these establishments were doing an annual business of just over $32.6 million. The 835 establishments represented just over 10 percent of the total 8,273 such establishments throughout the State. However, their volume of about $32.6 million was only about 4.3 percent of the total volume of such estab- lishments' i'n New Mexico. Therefore, the average size of these businesses is somewhat below the state average. As in the trade sector, activity In the services sector has increased substantially since the 1972 Census of Business. In 1972 service sector employment in Eddy County was just less than 1,900. Preliminary estimates for Eddy County in 1976 put that employment at approximately 2,500, a substantial increase during the four-year period. In Lea County service sector employment is somewhat smaller than that in Eddy County. In 1972 that employment was slightly less than 1,800. Nevertheless, preliminary estimates for 1976 place employment in that sector at approximately 2,300 individuals, a substantial increase. Analysis of the trade and services sectors indicates a steady increase in overall economic activity in Eddy County during the last three or four PAGENO="0567" .543 3.4 TRADE AND SERVICES SECTORS continued 9 years. This suspected boost in economic activity is also supported by information from the Employment Security Coninission which shows 311 report- ing establishments for retail trade in Eddy County through the second quarter of 1976. In the second'quarter 1972 the reporting number was 300. The average number of employees per establishment has increased from just under 7 to over 8 in the four-year period. In wholesale trade, the number of establishments reporting employment increased from 59 in 1972 to 70 in 1976. The average number of employees per establishment in wholesale trade increased from 6½ to almost 8 in the four- year period. In the services sector, the number of establishments reporting employ- ment has increased only slightly from 275 in the second quarter 1972 to 279 in second quarter 1976. Those establishments reported that the number of emp1oye~s has increased from an average of 6.3 employees in 1972 second quarter, to 8.7 employees in 1976 second quarter. 3.5 FINANCIAL RESOURCES In Lea and Eddy County combined there are a total of eight chartered banks--four of which hold state charters, and four national charters. Five of these eight banks are in Eddy County--three state banks and two national banks. As of December 31, 1976, these five banks reported assets totaling about $173 million and total deposits of nearly $161.6 million. In addition to the main offices, there are four branch locations. The main banking offices are lpcated in the two major municipalities in Eddy County--Artesia PAGENO="0568" 544 3.5 FINANCIAL RESOURCES continued 10 and Carlsbad. Carlsbad has three banks--two state and one national--with assets totaling close to $104.3 million, and total deposits of just over $98.6 million. In Lea County the only chartered state bank is located in Hobbs. One of the national banks is also lcoated in Hobbs, and the remaining bank has main offices in Lovington. In addition tothe main offices, there are 13 branches located throughout Lea County. Total assets for the three banks combined are slightly less than $236.9 million, while total deposits are slightly more than $218.9 million. In addition to the banks, other financial institutions within the two-county area include four savings and loan institutions, and three credit unions. Three savings and loan institutions are mutual associations located in Eddy County, and the one capital stock savings and loan institution is located in `Lea County. All four have combined assets of almost $114.7 million. Total savings within the institutions amount to approximately $103.8 million. The three mutual savings and loan institutions in Eddy County have combined assets of more than $95.8 million and total savings of more than $87.1 million. The savings and loan capital stock institution located in Hobbs (Lea County) has total assets of more than $18.8 million and about $16.7 million in total savings. Of the three credit unions in the two-county area, two are located within Eddy County. Both of these credit unions are insured by the National Credit Union Administration. The credit unions in Eddy County are for school employees'--on'e in Carlsbad and one in Artesia. They have combined assets of PAGENO="0569" 545 kirry Adcock ~id (Issociates Economic Consultants 3.5 FINANCIAL RESOURCES continued ii more than $1.8 million, and combined shares and deposits of about $1.5 million. The credit union located in Lovington (Lea County) is insured by the New Mexico Credit Union Insurance Corporation. it has total assets of slightly more than $1 million, and total shares and deposits of $.9 million. Twenty-one small loan licenses are doing business in the two-county area, 11 of which are located in Eddy County and 10 of which are located in Lea County. Distribution of the small loan operations are as follows: Carlsbad, 6; Artesia, 4; and Lovington, 1; and in Lea County, Hobbs, 7; Jal, 1; and Lovington, 2. 3.6 PERSONAL INCOME Combined total personal income in Lea and Eddy Counties was listed by the Bureauof Economic Analysis as $394.4 million in 1974 (the latest available information). Of this amount, residents of Eddy County received $170.4 million and the residents of Lea County received $224 million. The combined two-county area accounts for about 6.3 percent of total personal income generated in the State of New Mexico. Total personal income in Lea County has been showing steady, but gentle, increases in recent years. However, Eddy County has not been as fortunate because of declines in acti- vity of the potash industry in the middle and late l960s. Eddy County sustained a decrease in total personal income in 1968, and in 1969 barely * achieved the level established in 1967. However, since 1968, the total personal income in the county has been increasing--a small gain in the 1970-1971 period, and more rapid gains in the periods since 1971. While recent information is not available, trends in the area and the State would PAGENO="0570" 546 3.6 PERSONAL INCOME continued 12 indicate that total personal income has been increasing at slightly over 10 percent per year since 1974. In both c~o"nt~es mining is the base industry generating the most total personal income. In Eddy County potash mining is the major component, while in Lea County, mining is centered around the oil and gas industry. In 1974 Eddy County's mining sector contributed between $36.6 and $36.7 million to total personal income, or about 21.5 percent of all income generated in the county. In Lea County, mining accounted for more than $59.7 million-- nearly 26.7 percent of the total. In both counties the second major sector contributing a total per- sonal income is retail and wholesale trade--generally viewed as a "non-basic" sector. Other activities which may be identified as basic industries are agriculture and manufacturing, but these contribute very small amounts com- pared tomining, and retail and wholesale trade. Per capita income in the two-county area varies between the counties. For example, Lea County's per capita income in 1977 was $4,480, or approx- imately 8 percent above the $4,139 registered statewide level. In Eddy County, however, the income was near the state average at $4,109, or about 1 percent below the state level. In Eddy County per capita income increased 37.2 percent between 1970 and 1974, while in Lea County per capita income Increased 44.7 percent during the same period. The statewide level also increased 34 percent during the same period; thus, the per capita income for the two-county area is increasing slightly faster than the statewide average. PAGENO="0571" 547 3.6 PERSONAL INCOME continued 13 The Bureau of Economic Analysis reported that statewide per capita income grew more than 11 persent in 1975 and preliminary indications are that it is continuing to rise at a healthy rate. Given thetrends in Eddy and Lea Counties, it can be assumed that per capita income -in these two counties has also grown by at least 11 percent in each of the last two years. 3.7 TOURISM It is important to note that tourism is a substantial portion of the economic activity in Eddy County. While outdoor recreation in the area centers around activities such as hunting, four-wheel driving, camping, etc., the nearby parks--Guadalupe Park, Living Desert State Park, the President's Park in the City of.Carlsbad and others--also attract recreationists and tourists., The main tourist attraction in the area is Carlsbad National Park. In 1976, the total number of visitors to Carlsbad Caverns was 876,490, or more than 43 percent of all visits throughout the State to all 11 national parks and monuments. The effects of these visits and the tourism in the area can readily, be seen in the Employment SecurityCorriiiission statistics for the area. - Retail trade and selected services are most affected by tourism. For ex~ ample, employment in eating and drinking establishments (a part of retail trade) more than triples in the three summer months throughout the county. In the area of services, employment in lodging will increase 60 to 70 percent during the summer months more than employment in the winter months. Additionally, other secondary and tertiary types of services impacted by PAGENO="0572" 548 3.7 TOURISM tourism also show substantial increases. Therefore, tourism is one of the major economic sectors in Eddy County. However, it is highly seasonable due to the nature of visits at Carlsbad Caverns. Such visits fluctuated in 1976 from a high of 185,750 in July to a low of 25,160 in November. This variation illustrates the seasonality of the tourism industry in Eddy County. To support this tourist industry, the City of Carlsbad has a total of 18 motels and hotels with over 900 rooms. While additional facilities are found throughout the county, it is obvious that Carlsbad, due to its proximity to the Caverns, receives the major portion of the impact from this national park. PAGENO="0573" 549 15 STATEMENT OF EXISTING CONDITIONS 4.0 LABOR FORCE Labor force is defined by the Department of Labor as those persons who are employed and those persons who are unemployed and actively seeking employment. The combined total labor force in Eddy and Lea Counties is approximately 40,700. The annual average labor force in Lea County in 1976 was approximately 22,700, while in Eddy County the labor force was about 18,000. In 1976 total employment in the two-county area was 38,500. The combined unemployment rate for the two counties was just over 5.3 percent. However, the unemployment rate varies significantly between the counties. Since 1973, when the economy of both Eddy and Lea Counties began tQ pick up, the total labor force has grown approximately 13 percent, or by roughly 4,700 individuals in the three-year period. Thus, the annual average growth rate in the labor force has been approximately 4 percent. The overall growth of employment in the area for the three-year period was 11.6 percent, which indicates an annual average growth rate in employment somewhat less than 4 percent. Therefore, the number of persons unemployed and the unemployment rate have been steadily increasing for the last three years. 4.1 EMPLOYMENT Examination of employment by sector in the two counties shows that mining 1s by'far, the largest employer of the identified sectors. Manu- facturing and agriculture, other basic sectors in the area, appear to have PAGENO="0574" 550 4.1 EMPLOYMENT continued 16 approximately the same amount of employment. Accurate figures on agricul- tural employment are difficult to obtain and are normally out of date. The latest available credible information on agriculture shows that between 1,900 and 2,000 people were employed in agriculture in the two-county area in 1974. Agricultural employment in the area has been decreasing. Between 1973 and 1974 alone, the number of people working in agriculture dropped by over 5 percent. Today in the two-county area it can be estimated that between 1,700 and 1,900 people are presently employed in the agricultural sector. The manufacturing sector incorporates approximately 1,900 individ- uals within the two-county area. In Lea County approximately 925 individuals are employed in manufacturing, while in Eddy County figures indicate nearly 975 persons. Therefore, the manufacturing employment is fairly equally distributed between the two counties. Those non-basic sectors in the two- county area include contract construction; transportation utilities; trade; finance, insurance and real estate; and services. Additionally, the govern- ment accounts for a significant amount of employment. In the two-county area it is estimated that by-sector employment distribution is as follows: agriculture, 5 percent; mining, 23 percent; manufacturing, 5 percent; construction, 7 percent; transportation utilities, 9 percent; wholesale and ret&il trade, 21 percent; finance,insurance and real estate, 4 percent; services, 15 percent; and government, 12 percent)1 1/ Total does not add to 100 percent because of rounding. PAGENO="0575" 551 17 4.2 UNEMPLOYMENT Unemployment is relatively low in the two-county area. By the end of 1976, the average unemployment rate in Eddy County was 6.7 percent, while in Lea County 4.3 percent was recorded. Unemployment varies significantly from month to month. Higher unemployment rates are generally recorded during the month of June each year, and lower unemployment rates are generally recorded in the late spring or late fall. A review of those individuals applying for work through the New Mexico Employment Security Coimiission revealed a large number of technical occupa- tions available in the area. Many of these occupations were directly con- nected with construction or with mining--the two occupational categories needed for the construction of the WIPP project. Additionally, this infor- mation showed a large number of clerical and secretarial skills available in the area,. 4.3 UNDER UNEMPLOYMENT AND DISGUISED UNEMPLOYMENT The unemployment rate computed by the state and federal governments Is based upon those individuals actively seeking employment. In some cases, an area may experience a defined unemployment rate and have a significant amount of underemployment. Underemployment refers to occupations or jobs that do not take full advantage of an employed individuals potential. Also, disguised unemployment may exist in which case many individuals are actively seeking employment but would take a job ira job were available In the area. These concepts are difficult to measure, particularly at the sub- PAGENO="0576" 552 4.3 UNDEREMPLOYMENT AND DISGUISED UNEMPLOYMENT continued 18 county level where no information is provided by the various Department of Labor programs. Areas witF~ significant underemployment can be identified by considering labor statistics in relation to wages. However, quantification of this rela- tionship remains difficult. A review of the labor statistics and wages in the two-county area indicates that some underemployment may exist due to seasonality, but it does not appear to be significant in the labor market. Disguised unemployment is also difficult to measure. However, a review of labor force participation rates by age groups indicates whether or not an area is experiencing disguised unemployment. In the two-county area the labor force participation rate of males is higher than the state average. On the other hand, it appears that the labor force participation rate for females is lower than the state average. It is assumed that not all females who are ~il'ling to work are actively seeking employment and that the labor force availability for females may be greater than the current labor force statistics would indicate. PAGENO="0577" .553 19 STATEMENT OF EXISTING CONDITIONS 5.0 HOUSING AND LAND USE 5.1 HOUSING PROFILE Vacancy rates for housing in Carlsbad are relatively low due to inactivity in new construction because of population losses experienced between 1960 and 1970. Since 1970, this trend has been reversed, and by the mid-l97Os 200 to 250 new residential units are being produced each year in the City of Carlsbad. The estimated vacancy rate of 2.9 percent implies 263 available units to support new population growth. 5.2 LAND USE PROFILE The zoning ordinance for the City of Carlsbad identifies eight zones for residential and business activity. Except for lands used for multi- family dwellings, development in the area has proceeded in accordance with the zoning classifications used. There are substantial nonconforming uses within the multi-family zone. Substantial vacant land exists within the city for all zoning clas- sifications. For example, it is estimated that 1,446 acres zoned for single-family dwellings is currently available. PAGENO="0578" 554 20 STATEMENT OF EXISTING CONDITIONS 6.0 CARLSBAD COMMUNITY FACILITIES Revi~ of existing conditions on coninunity facilities includes existing conditions for education, ground water, municipal water systems, waste water systems, electrical production, fire protection, law enforce~ ment, medical and dental care, library facilities, coninunication services, and sports and recreation. 6.1 EDUCATION The Carlsbad school district is served by 15 schools at all levels. There are ten elementary, two junior high, one mid high, one high and two private schools. Current enrollment is estimated at 6,812, and capacity is estimated at 9,638 students. This indicates that the school system could absorb an additional 2,826 students at all grade levels. 6.2 GROUND WATER AND MUNICIPAL WATER SYSTEMS The City of Carlsbad currently draws its water supply from Capitan Reef. The reef aquifer is allocated 22,128.51 acre feet of water rights per year. Carlsbad has been exceeding water right withdrawals from the reef aquifer for the last two years. However, Carlsbad has acquired an additional 1,000 acre feet of water per year. Production and transpor~. tation systerirs must be built to exploit these water rights. PAGENO="0579" 555 21 6.3 MUNICIPAL WASTE WATER SYSTEMS AND TREATMENT FACILITIES The City of Carlsbad currently has a collection and treatment capa- bility of approximately 4.5 million gallons per day of waste water. The existing trickling filter treatment system is undergoing Improvements which will result in a design capacity of 6 million gallons per day and substantial improvement in the quality of treated effluent. 6.4 ELECTRICAL SERVICES Electrical services are provided by the Southwest Public Service Company. Current service area demand totals approximately 60 to 80 mega- watts serving 10,667 residential customers, 1,213 comercial customers, and 30 special contract customers. The company requires approximately six months lead time to provide services for a subdivision. Adequate power appears to be available to the service area for anticipated growth. 6.5 FIRE PROTECTION Fire protection services are provided by both city and county govern- ments. The city mans and operates a 24-hour fire protection operation, whereas the county fire services are provided by volunteer departments. The Insurance Service Organization recomends two firemen on a 42- to 56-hour work week per 1,000 population. Carlsbad currently has a ratio of 0.67 per 1,000 population. 6.6 LAW ENFORCEMENT Law enforcement in the City of Carlsbad and Eddy County is provided by local city and county governments. The City of Carlsbad operates its PAGENO="0580" 556 6.6 LAW ENFORCEMENT continued 22 police department with 41.5 persons; the county government provides law enforcement services through its sheriff's department which employs 23 per- sonnel. The FBI guide to manpower requirements recommends 2.5 officers per 1,000 population. Carlsbad had a ratio of 1.1 per 1,000 population. 6.7 MEDICAL AND DENTAL CARE A regional medical center consisting of a 124-bed hospital is located in the City of Carlsbad. There are currently 30 M.D. `S with various spe- cialties and 10 dentists serving the community. There is a 134-bed full- service hospital under construction. The national average of physicians per 1,000 population is approximately 1.53. The City of Carlsbad has a physician per 1,000 population ratio of 1.2. 6.8 LIBRARY FACILITIES AND SERVICES The city government in Carlsbad operates a municipal library with 37,271 volumes. The American Library Association standards recommend two volumes per capita; Carlsbad currently has approximately 1.5 volumes per capita. 6.9 GARBAGE COLLECTION AND DISPOSAL The City of Carlsbad provides solid waste collection and disposal services. Collection services are provided by rear-loading packers and the land fill is a daily trench and fill operation. A refuse collection vehicle in Carlsbad has a production capability of approximately 450 house- holds per day. PAGENO="0581" 557 23 6.10 TRANSPORTATION FACILITIES There are no mass transit systems serving the general population in Carlsbad. However~.transportation services do exist to serve specialized needs. For example, an industrial bus service transports workers from the conviunlty to the potash mines and operates on a daily basis. There are approximately 28 buses with a capacity of 40 passengers each which make these daily trips to the mines A survey of traffic counts at.high volume intersections within the City of Carlsbad indicates that substantial excess capacity exists within the street system. 6.11 COMMUNICATION SERVICE FACILITIES Telephone communication services are provided by GTE. There are approximately 21,450 telephone instruments in service including 1,547 business arid 9,316 residential main lines. GTE is presently implementing an expansion of services in the Carlsbad area which will provide for In- stallation of 1,800 new lines. The planning period for installingthe new lines is approximately 18 months. 6.12 SPORTS AND RECREATION It has been estimated that approximately 1.8 million visitors come to the Carlsbad area each year. These visitors enjoy a variety of recrea- tional activities including fishing, swimming, boating, hunting, and visits to Carlsbad Caverns and the Zoological Botanical State Park. PAGENO="0582" 558 ANTICIPATED IMPACT OF THE WIPP CONSTRUCTION AND OPERATION 1.0 GENERAL ECONOMIC IMPACTS The construction phase for the Waste Isolation Pilot Plant (WIPP) Is expected to begin in 1979 and end about May of 1983. During that time, sub~- stantlal increases in the number of construction workers within the labor market area are expected. In addition to these construction workers, a below- ground construction phase--similar to a mining operation--will also take place concurrently with the above-ground construction phase. As a result of the construction and mining-type activities, those industries serving the population (generally secondary and tertiary industries) and those industrieswhich service other businesses (basically, some manu- facturIng,~ service and wholesale operations).will also experience substantial increases in activity (i.e., dollar volume and need for additional employees). The location of the Waste Isolation Pilot Plant is within Eddy County; however, the socioeconomic analysis assumes that the primary impact will be spread over two counties--Eddy and Lea Counties. The survey of existing patterns indicates the following: approximately 88 percent of the direct impact connected with the plant will go to the City of Carlsbad; 11 percent of the impact will go to areas within Eddy County, but outside of Carlsbad; and approximately 1 percent of the impact will go to Lea County. In terms of indirect impact, 80 percent was allocated to Carlsbad, 10 percent was ~1located to areas outside of Carlsbad withinEddy County, and the rmnaining 10 percent was assumed to spread into the Lea County area. The. PAGENO="0583" 559 1.0 GENERAL ECONOMIC IMPACTS continued 2 operation phase for the Waste Isolation Pilot Plant is expected to begin in 1983. However, the impact from the operational phase is expected to be below average in 1983; it is not until 1984 that t~near-fu11 impact of the operational phase will be felt in the two-county area. During the construction phase nearly $222 million will be directly expended on the two-county economy. In addition, indirect, or spin-off, effects of an additional $117 million will occur. On an annual basis, the greatest amount of economic activity during a single year is expected to be below $90 million which will occur sometime during the period 1980-1982. As the Waste Isolation Pilot Plant construction phase ends and the plant becomes operational, the impact upon the coninunity is expected to change significantly. Beginning in 1983, as the construction is completed during the first four months of the year, operation activity will take over. It is expected that at least $15 million in operating expenditures will occur during 1983. During 1983 indirect impact from the operation phase will amount to just over $8.1 million. Thus, total direct and indirect impact from operation in 1983 will be $23.1 million. Beginning in 1984 some $40 to $52 million in expenditures will be made for the operation phase. However, only about 80 percent of the actual opera- tion cost ($40 million) plus $2 million for continuous construction, will flow into the Carlsbad economy directly. This amounts to some $34 million dollars annually, after full operation phase begins in 1984. It Is anticipated that beginning in 1984, and for an additional 23 years, the economic Impact of the operation, both direct and indirect will amount to $55.7 million annually ($21.7 million indirect expenditures). PAGENO="0584" 560 1.1 EMPLOYMENT AND POPULATION 3 During 1979--the first year of the construction phase--direct employment due to the construction of the Waste Isolation Pilot Plant above ground will result in just.over 400 additional construction jobs. While the above- ground construction phase is being completed, the below-ground operation-- very similar to potash mining operation--will also be occurring which will employ just less than 200 individuals. The nature of the Waste Isolation Pilot Plant requires an additional 19 individuals because of equipment sophistication and construction preciseness in the area for engineering and inspection. Therefore, a total of approximately 6l9~ individuals will be directly employed during the first year of construction in 1979. During the approximate three-year period following 1979, until May l983,* an average of 529 individuals will be. employed in the above-ground construction phase, and 193 workers will be employed in the below-ground operation phase. The inspection and engineering crew will remain at approximately 19. Therefore, an average employment of 741 individuals will be directly attributable to the Waste Isolation Pilot Plant during the years of 1980, 1981, and 1982. Approximately 56 percent of the direct employment during the construction phase will be individuals *not now residing in the area; the remaining 44 percent is assumed to~ be drawn from the labor force in Eddy County, with .a few coming from the Lea County area. Indirect job impact associated with the first-year construction of the Waste Isolation Pilot Plant is estimated to be 1,172 jobs. From 1980 through the end of 1982, it is expected that an annual average of slightly over 1,400 *phasè_~fown is assumed during the first 4 months of 1983; thus the average of 529 employees may not be met. PAGENO="0585" 561 Li EMPLOYMENT AND POPULATION continued 4 jobs will be an indirect result of the construction of the Waste Isolation Pilot Plant. Of those jobs created as an indirect result of the construction phase of the WIPP project, it is estimated that some 46 percent will be filled by newcomers to the area who are attracted by new employment opportunities. During the first year of construction, approximately 1,600 new individ- uals will migrate to the area. In 1980 an additionall,300 will be attracted to the area; in 1981 the impact of the construction phase is expected to be complete with an additional 400 migrants. Thus, in 1982, the final full year of construction, the impact of the Waste Isolation Pilot Plant on the area should be static, with 3,300 total new individuals attracted to the two- county area. It should be noted that during the years of plant construction, the unemp1o~meht rate is expected to drop substantially--to an overall rate of approximately 3.5 percent for the combined two-county area. This, however, is not an unusual unemployment rate for these counties. In 1976, Lea County experienced monthly unemployment rates as low as 3.1 percent and an overall average of 4.3 percent for the year. During the 1960s when economic condi- tions were somewhat depressed in the two-county area, the unemployment rate in Eddy County never rose above 6.9 percent (1963) on an annual basis, and was as low as 4.6 percent (1960). in Lea County during the 1960s the unem- ployment rate was 3.8 percent in 1963, and as low as 2.8 percent in 1968. However, a level of 3.5 percent will essentially constitute an area of labor shortage, given today's unemployment rates and conditions throughout the State and the Nation. PAGENO="0586" 562 1.1 EMPLOYMENT AND POPULATION continued 5 The following table shows the population for Eddy and Lea Counties, the municipality of Carlsbad, and the Carlsbad School District. Population projections are presented for the area with and without the Waste Isolation Pilot Plant. The population figures end in 1985, since it is assumed that the operational phase will be static in terms of impact by that time. The most significant population impact will be felt by the year 1981 when approximately 2,700 individuals will have been added to Carlsbad's population due to the construction of the plant. The impact on the school district is expected to be 2,900 individuals, while throughout Eddy County an additional 3,100 people are estlmated.* In Lea County by 1980 an addi- tional 200 people will be added to the population. After that time, it is assumed that impact of the plant will be essentially static until 1983. As the operation phase begins and construction is completed, population and employ~nent~ characteristics will change significantly. For example, the number of people required during the construction phase is substantially greater than the work force in the operation phase. During the construction phase total employment is expected to be approximately 741 people during the most active years; by 1984 employment directly connected with the operation will total only 427 individuals. Most of these, slightly over 300, will be directly connected with the general operation of the plant, while between 75 and 80 persons will be working on continual mining operations, and approxi- mately 40 individuals will be employed in maintenance and additional construc- tion work. In addition to these jobs directly created by all operation acti- vity, there wlll.be between 950 and 1,000 jobs indirectly created bythe opera- tion phase. * Figures are for concentric geographic areas, and are not additive. PAGENO="0587" 1984 1985 50,700 51,600 31,100 31,700 34,500 35,100 63,100 64,500 POPULATION 8ASELINE POPULATION 1 WITHOUT WIPP PRWECT 1910 1975 1976 Eddy County 1,2 41,119 42,400 43,400 Carlsbad 1,3 21,297 NA 25,000 1977 44,300 26,000 1978 45,300 27,000 1979 1980 46,200 47,200 27,900 28,700 Carlsbad School District 1,3 25,498 NA 28,400 29,400 30,400 31,300 32,100 Lea County 1,2 49,554 51,200 53,000 54,100 55,200 56300 57,400 FOPIJLAT ION WITH WIPP PRO.JECT Eddy County Carlsbad 49,900 31,100 Carlsbad 4 School District 34,700 Lea County 57,600 April, 1976. 1 1970 Census of Population data. 2 l975-T~31ata, .odTfTéFBaER, University of 3 1975-1985 data, new dati for this report. 4 1979-1984 data, new data for this report. New Mexico projactiv~, 1981 1982 1983 48,100 49,400 49,800 29,400 30,~ 30,600 32,800 33,700 34,000 58,800 60,200 61,700 51,200 52,500 52,500 32,100 33,000 33,000 35,700 36.600 36,500 59,000 60,400 61,900 47,700 29,200 32,700 56,400 52,800 33,000 36,500 63 .200 53,700 33,600 37,100 64,600 PAGENO="0588" 564 1.1 EMPLOYMENT AND POPULATION continued 6 Therefore, the total number of jobs both directly and indirectly created through the operation phase will be about 1400. This increased job-level is expecte~i to be achieved duringl984. Between 1982 (the last full year of construction) and 1984 (the first full year of operation) employment adjustments in the quantity of people directly connected to the project, and the types of occupations required by the project will have to take place. During the construction phase some 529 jobs, on an average annual basis, were created directly by construction activity. The continual construction activity in the operation phase is expected to employ only 40 people. Therefore, a loss of slightly less than 500 positions is expected In construction-related trades. The mining effort runs concurrently with the construction phase and the operation phase of the WIPP project. However, during the construction phase 193 `pe~'sons will be employed in that effort while only about 75 people will be employed in the mining effort during the operation phase. Under the operation phase the types of occupations and skills required may dictate that from 150 to as high as 170 jobs will be filled by individuals not currently in the area. The shuffling of population due to losses of construction jobs, mining jobs and increases of operation jobs, will result in a net population decrease of those individuals directly and indirectly connected with the Waste Isolation Pilot Plant project. It is expected in 1983 that the out-migration of slightly more than 400 individuals will occur because of the construction-to-operation shift. In 1984 it is estimated that just less than 300 individuals will migrate out of the area who were either directly or indirectly connected with the Waste PAGENO="0589" 565 1.1 EMPLOYMENT AND POPULATION continued 7 Isolation Pilot Plant construction. It is interesting to note that during the 1982-1984 period the population figures for Carlsbad will remain constant at approximately 33,000, while the other areas within Eddy County will continue a slight growth pattern due to natural increase and other activities in the area. The effect on Lea County of the change from the construction to operation phase is expected to be a net loss of approximately 100 individuals. 1.2 PERSONAL INCOME During the 1979-1982 construction period, it is expected that a total of more than $43.1 million will flow directly into wages and salaries from the construction of the plant. In addition to this amount of money, slightly more than $31 million will be derived in wages and salaries from those businesses indirectly affected by the construction. Personal income derived from interest, dividends and rent is expected to increase nearly $16.4 million during the four-year period. A total of about $90.6 million is expected to be derived both directly and indirectly in the private sector, due to the construction of the WIPP Project during the 1979-1982 period with some spillover into 1983. In the public sector, nearly $11 million in personal income will be derived because of the in- creased activity in the area and additional government employment required for support. Thus, total personal income added to the area during the con- struction phase of the WIPP project is expected to be $101.6 million spread 95-826 0 - 77 - 36 PAGENO="0590" 566 1.2 PERSONAL INCOME continued 8 over a four to five year period. However, net loss from transfer payments will decrease this total to $97.0 million. Carlsbad will receive approximately $82.5 million of the additional. personal income; other areas inside Eddy County, but outside Carlsbad, will receive nearly $10.3 million; and additions to total personal income in Lea County will amount to $4.2 million. During the construction period, it is anticipated that personal income will flow in the following manner: just over 15 percent will be derived in 1979; just less than 25 percent will be derived in 1980, 1981, and 1982; and nearly 11 percent will be derived dur- Ing 1983, the final partial year of construction. The personal income to be derived from the operation of the WIPP pro- ject will be significantly different from that derived in the construction phase. The amount of money flowing directly into the economy during a nor- mal year of `operation will be approximately $34 million, but this figure may vary depending upon expenditure patterns in the operation of the plant. This study uses a constant figure of $34 million as direct expenditures of the plant. This figure is significantly different from total direct expenditures of nearly $52 million annually during the period in which the major portion of construction will be completed. The $34 million estimated annual flow of dollars directly associated with the operation of the plant will mean that: 1) approximately $9.4 million will be allocated to wages and salaries of those individuals con- nected directly with the plant; 2) wages and salaries derived from the in- direct effect on businesses within the area will amount to $5.8 million; PAGENO="0591" 567 1.2 PERSONAL INCOME continued 9 3) government expenditures brought about by additional activity and flowing into personal income will total between $2.2 and $2.3 million per year; 4) new dividend interest and rent is estimated to create approximately $3.4 million in personal income; and 5) just over $0.9 million will flow out of the area via transfer payments for social security. The net result, there- fore, is an increase in total personal income on an annual basis of approx- imately $19.9 million. During the transition between construction and operation in 1983, the total personal income being derived from the operation phase will be sub- stantially less than income during the construction phase. However, In addition to the income generated by the operation phase, the construction phase will continue during the first four months of 1983. Approximately, $7.2 million in total personal income will flow from the operation phase, both diredtly and indirectly, and an additional $10.4 million will flow from the remaining portion of the construction phase. Therefore, in 1983, total personal income from both the construction and the operation phases (i.e., the transition period) will amount to $17.6 million. When the operation phase reaches its full impact, approximately 83.4 percent of the total personal income generated both directly and Indirectly from the plant will go to the Carlsbad area; approximately 10.6 percent will flow to areas outside of Carlsbad, but inside Eddy County; and, the remain- ing 4.0 percent personal income increase will flow into Lea County. PAGENO="0592" 568 10 ANTICIPATED IMPACT OF THE WIPP CONSTRUCTION AND OPERATION 2.0 HOUSING AND 1~AND USE 2.1 HOUSING A total of 2,963 units of housing of all types will be necessary if WIPP locates in the Carlsbad area. If the WIPP project does not locate in Carlsbad, it is estimated that 2,283 housing units of all types will be necessary. The impact of the WIPP project on housing totals 680 units. Timing of delivery and type of demand for housing (i.e., mobile homes, single-family detached, multi-family) varies over construction and operation time periods. For example, the demand for mobile home units reaches a peak of 453 units in 1982 with the WIPP project. In 1985 the demand for mobile home units totals 285 with the WIPP project. The following impacts were identified: 1) An increase in construction capability must occur. It is estimated that the construction industry can produce approximately 75 percent of the housing required over the term of the project. 2) The demand for housing, by type, Is expected to shift over the time period and some types of housing will be oversupplied. This is particularly the case for mobile homes. 3) There are identifiable time lags which may vary from six months to one year for housing production. These time lags are associated with processes required by local ordinances such as obtaining proper zoning, drainage plans prepared by engineers, street design plans prepared by engineers, and utility installation neces- sary for construction to begin. PAGENO="0593" 569 2.2 IMPACT FOR LAND USE 11 The analysis of impacts on land use with and without the WIPP project, included determining: 1) total new land required for residential develop- ment; 2) total new. tand required for multi-family dwellings; 3) total new land required for mobile home parks and subdivisions; 4) total new comercial land required; 5) total new industrial land use; and 6) total new land devoted to public rights-of-way. Based on the analysis of these types of demand it was determined that 604 undeveloped acres would be placed into use. There is adequate undeveloped acreage within the City of Carlsbad for all types of land use required except mobile home parks and mobile home subdivisions. An addi- tional 45 acres must be zoned for mobile home parks and an additional 15 acres must be zoned for mobile home subdivisions if the WIPP project locates in Carlsbad. PAGENO="0594" 570 12 ANTICIPATED IMPACT OF THE WIPP CONSTRUCTION AND OPERATION 3.0 PRIVATE SECTOR The private sector is strong in both Lea and Eddy Counties. However, the economic base in the private sector is rather narrow. Most of the economic activity centers around the mining industry. In Lea County, the oil and gas industry generates more economic activity than any other Indus- trial sector, while in Eddy County, potash mining is the most active sector. In addition to these two basic industry sectors, retail trade and services (normally non-basic sectors) may be considered to be partly a basic industry in Eddy County. This is brought about by heavy tourism traffic in the area of Carlsba'd Caverns. The direct impact from this tourist traffic is felt through the retail trade and services sectors. Other basic industries in the area such as agriculture and manufac- turing have substantially less activity than the mining sector. Fertilizer production, i.e., manufacturing of chemicals, is significant in the two- county area and accounts for a significan amount of employment in the total manufacturing sector. 3.1 INDUSTRIAL ACTIVITY During the construction phase of the WIPP project, certain currently existing industries within Eddy County are expected to receive a substantial PAGENO="0595" 571 3.1 INDUSTRIAL ACTIVITY continued 13 increase in activity. Because of the nature of construction of the WIPP project, and the needs for specific and highly technical equipment, a significant amountS of the construction materials and probably mos-t a-li of the technical equipment will be purchased outside of the area. However, basic materials going into the construction, such as sand and gravel, rock, certain electrical products, concrete, etc., can be purchased In the area. It is anticipated that during the total construction phase approximately $17.5 million in new business will flow through the manufacturing sector in the two-county area. As the Waste Isolation Pilot Plant project moves from the construction phase into the operation phase, the effect on the various economic sectors within the two-county area is expected to change significantly. The oper- ation phase of the WIPP project will be very similar to the warehousing operation,w~th two exceptions: 1) the mining operation will continue, and 2) at the same time approximately $2 million annually in maintenance con- struction is expected. Under the operation portion of the project the impact upon local manufacturing is expected to be minimal. However, those entities that would experience some impact are paints and chemicals, rubber and leather products, and machinery manufacturing. As a result of plant location in the area, impact may be felt indirectly in the food products area of manu- facturing. Impacts to othér&reas of manufacturing will be minimal. Be- cause the operation phase does not produce a product, but in a technical PAGENO="0596" 572 3.1 INDUSTRIAL ACTIVITY continued 14 sense stores a product previously produced, the estimated amount of spinoff to the industrial manufacturing system within the county is minimal. The effect of the mining operation may also be minimal in attracting new industry because potash mining dominates an extremely large portion of the economy of Eddy County. The mining operation of the project represents an addition to this already-existant activity, and therefore the impacts from the mining operation will flow through those industries already established for the most part. In the construction sector, the $2 million allocated per year to the construction sector will generate some activity. However, this amount is not expected to be enough to attract new industry to the area which is directly attributable to construction. 3.2 RETAIL TRADE AND SERVICES One of the most significantly affected sectors outside of those industries receiving direct impact, such as construction and mining, is retail trade. It is expected that the increase in retail sales during the construction period will total nearly $24 million. The heaviest impact (about $5.4 million annually) in the retail sector will come in the years 1980, 1981, and 1982 as employment -- directly and indirectly due to the construction activity -- reaches its peak. Most of this impact is created through increased buying in the household sector with some expenditures made directly by construction-related purchases. Between 15 and 20 percent of household,income goes directly into the retail sector. Additionally, PAGENO="0597" 573 3.2 RETAIL TRADE AND SERVICES continued 15 businesses also purchase from the retail sector. For example, approximately 5 percent of construction expenditures are made in the retail sector. In the services sector, substantial increases are also expected. Nearly $22 million in increased activity, both directly and indirectly, will flow through the services sector. In addition to this amount, approximately $1.7 million per year can be expected from the professional engineering portion (usually classified as a business service) of the construction activity. Thus, $22 million is an anticipated minimum flow which could increase by $6.8 million (4 x $1.7 million) during the four to five year construction period if professional engineering services are included. As a final note, it should be pointed out that this impact assumes that the construction phase demand for goods and services takes advantage of those goods and services available in the area, and that the variety of goods and `services offered in the area receives no substantial change in the construction period. Beginning in 1984 it is estimated that the addition to retail sales in the area will amount to $3.8 million annually. This is, by far, the greatest impact on any identified sector. Therefore, much of the impact in the oper- ation phase will flow into the secondary and tertiary industries, not Into the manufacturing or basic-type industries. This is further justified by the fact that the increase in wholesale trade is expected to be approximately $1.9 million, while the annual impact going to finance, insurance and real estate is expected to be approximately $2.2 million. The services sector will enjoy a'substantial increase also--just over $3.2 million per year annually. PAGENO="0598" 574 3.2 RETAIL TRADE AND SERVICES continued 16 In summary, it would appear that the private sector response to both the construction and operation phases in the two-county area will come in the form of new activity in many of the existing secondary and tertiary industries. It is expected that the operation phase will bring very few new manufacturing firms. However, it is also recognized that small equip- ment manufacturers and fabricated metal operations may be attracted to the area because of the maintenance and construction occurring during the oper- ation phase and the need forcertain repairs to equipment during the opera- tion phase. PAGENO="0599" 575 17 ANTICIPATED IMPACT OF THE WIPP CONSTRUCTION AND OPERATION 4.0 COMMUNITY FACILITIES 4.1 EDUCATION Impact on the educational system was determined by estimating total student enrollment, with and without the WIPP project, for each of the years 1979 through 1985. It was determined that 1,232 students would be enrolled at the high school level with the WIPP project in 1979. This figure will exceed current high school capacity of 1,225 students. This problem is apparent only during the year 1979, and only for high school enrollment; increased enrollment at other levels can be accommodated by existing facili- ties. 4.2 UTILITY SYSTEMS 4.2a Ground Water and Municipal Water Systems Water demand, with and without the WIPP project, was estimated. It was determined that 703 acre feet of additional water would be attributable to primary and secondary population increases associated with the WIPP project. This additional water demand magnifies an existing problem; the City of Carlsbad is currently exceeding its water rights withdrawal capacity from its wellfleld in the Capitan Reef. For example, the total amount of water pumped in 1976 amounted to 9,268 acre feet, 1,426 acre feet in excess of withdrawal rights. It is estimated that the City of Carlsbad will require an additional 2,295 acre feet per year on the average, should the WIPP project PAGENO="0600" 576 4.2 UTILITY SYSTEMS continued 18 4.2a Ground Water and Municipal Water Systems continued become a reality., This amount is In addition to current excess over withdrawal rights. In sumary: 1) The City of Carlsbad will require an additional 2,295 acre feet per year, on the average, should the WIPP project become a reality. Of this amount approximately 703 acre feet per year are directly attributable to the WIPP project. 2) TheCity has adequate water rights to supply additional water. 3) The City has adequate well field to produce additional water. 4) The location of water rights and well field capacity serves as a constraint for production of adequate amounts of water to serve increased population. 4.2b Wastewater Treatment Estitnates were made of the number of millions of gallons per day of discharge associated with the population increase in Carlsbad with and without the WIPP project. It was estimated that an additional flow of 0.175 million gallons per day could be attributed to the population increase associated with primary and secondary employment resulting from the WIPP project. A major capital improvements program for wastewater treatment is antici- pated. Thus, processing requirements of volumes associated with the WIPP project will not be problematic. In 1982, when the new plant is scheduled to begin operation, it will be operating at approximately one-half of capacity. 4.3 LAW ENFORCEMENT AND FIRE PROTECTION Estimat~s were made of the increased personnel in law enforcement and fire protection required to maintain the existing ratio of personnel per PAGENO="0601" 577 4.3 LAW ENFORCEMENT AND FIRE PROTECTION continued 19 i,ooo population in the City of Carlsbad, with and without the WIPP project. It was determined that new police costs associated with location of the plant near Carlsbad could amount to approximately $325,000 over the 1979- 1985 period. Adjusted fire protection costs were estimated at approximately $110,000 for the same period. 4.4 HEALTH CARE Based upon methodology used in a recent health planning report for Carlsbad Regional Medical Center, an estimate was made of the number of beds required to serve the anticipated increased population. These estimates were made for population in the Carlsbad area with and without the WIPP project in order to determine impact of the plant. The facility housed 134 beds, with expansion capability in 1985 to 160 beds. Analysis indicated that capacity of the planned 134-bed facility would be exceeded in 1.980 if the WIPP project located in Carlsbad. It was estimated that a total of 219 beds would be required by 1985 with the WIPP project, or a total of 204 beds would be required without the WIPP project. 4.5 TRANSPORTATION AND COMMUNICATION 4.5a Transportation Traffic flows and volumes within the City of Carlsbad were estimated for certain high-volume locations selected to determine capacity after location of the WIPP project. It was assumed that if capacity remained adequate, no adverse impact could be attributed to the WIPP project. It was determined that an approximate 30 percent increase in number of trips taken would occur PAGENO="0602" 578 4.5 TRANSPORTATION AND COMMUNICATION 20 4.5a Transportation continued in the City of Carlsbad. By 1985 average daily volume and peak volumes could be accorml1odated by existing capacity at each of the selected high-volume locations during peak travel periods. 4.5b Comunication GTE currently has a capital improvements program to provide approximately 1800 new telephone lines. It is estimated that from the present through 1985 approximately 2,963 new households will locate in the Carlsbad area. The tele- phone company has indicated that with approximately 18 months lead time suffi- cient capability can be on-line to acconiiiodate the required increases. 4.6 SPORTS AND RECREATION The total population increase due to the WIPP project location in the Carlsbad'area amounts to 8,600 persons. This population increase represents 0.04 percent of the total number of recreationists and tourists who currently visit the Carlsbad area during the year. It is felt that this visitor increase is insignificant and will not adversely affect the sports and recrea- tion facilities. PAGENO="0603" 579, 21 ANTICIPATED IMPACT OF THE WIPP CONSTRUCTION AND OPERATION 5.0 LOCAL GOVERNMENT There will be a need for local government to expand its service capabilities for police protection, fire protection, garbage collection, and other population-related services. This need for services expansion will contribute to an already-existing problem. That problem has been identified in previous research as a discrep- ancy between the growth rate of revenues and expenditures. Revenues for New Mexico municipalities grow at a rate between 6 and 7 percent per year while expenditures grow at a rate between 10 and 11 percent per year. In addition to placing some pressure on existing capabilities to finance services, the WIPP project will require acceleration of planning processes for certain capital improvements; in particular, deficiencies have been noted in the City's ability to provide water. A water master plan should be prepared to identify how to improve and what kind of improvements should be made by the City of Carlsbad to solve water rights and withdrawal problems. PAGENO="0604" 580 EXIt! ElI 3 ANHYDROUS AMMONIA PLANTS Recently, two an.hydrous ammonia planta have located in the Carlsbad area. Their decision to locate in Carlsbad was based primarily on the availability of natural gas which is the only natural resource used in the production of anhydrous ammonia. The two plants are owned by Baker Industries and N-ReN Southwest. The activities, increased population and service requirements of these plants have added to the energy related impact upon our community. EXhIBiT 4 POTASH ~4INlNG / The seven operating pot'~'h mines in the Carlsbad area have enjoyed a more favorable climate for production and sales over the past few years. This has resulted in a gradual building up of the potash basin employment and increased stability. Potash miners are the largest single group of miners in New Mexico and make up a vital part of our coninunity. PAGENO="0605" 581 FAIRBANKS TOWN & VILLAGE ASSOCIATION FOR DEVELOPMENT -~ INCORPORATED Richard T. Greer Sub-Committee for Regional and Economic Development Suite 4202 Dirksen Senate Office Building Washington, D. C. 20510 Dear Dick: As I promised in Corpus Christi I am sending some materials relevant to the issue of social and economic impact on small communities as a result of mas- sive energy resource development proj ects. I note with interest that Senator Gravel has co-sponsored S. 1493, and assume it is part of the committee's work. I am not sure which of these may be most relevant for the committee's record, but I would suggest either the letter to Mr. Goldman, or the written presenta- tion to the President's Council on Environmental Quality. If neither is ap- propriate, you might give me a call in Fairbanks and we can discuss some of the local research materials that are available on the issue. I feel obligated to emphasize, for your infonnation, that federal agencies played no role in identifying or resolving pipeline related social and eco- nomic impact problems in Fairbanks.. .with the single exception of FDA's plan- ning assistance grant to the Town and Village Association. Unfortunately, the state's role was only minimally more than FDA's role. The whole burden of dealing with the problem - including trying to figure out what the problem was - fell on the people, the municipal governments of Fairbanks, and, as a result of our regional development efforts, on us. Reading the record of this effort raises some provocative questions of public policy, but an outside perspective may be more helpful to you than anything I might say. I thought you might, therefore, appreciate the observation of a delightful New Zealand lady who visited Fairbanks in August of 1976. Phone (907) 452-4761 Ext. 271 October 14, 1977 95-826 0 - 77 - 37 PAGENO="0606" 582 I enjoyed the opportunity to talk briefly with you in Corpus Christi and hope we will have a better opportunity soon. I hate to beat the idea of a trip to Fairbanks to death, but an investigation of our past local efforts with re- spect to the "impact" of the trans-Alaska pipeline, and our current efforts to prepare for gas pipeline construction are relevant to the coninittee `s work. There is no 4uestion in ny mind that a trip up here will give you pertinent information and a unique an4 valuable perspective for the committee's delib- erations. If such a trip is possible I would be pleased to make as many appointments and arrangements as are necessary to give you full access to our accumulated knowledge. Sincerely, Jerry . Smetzer Execu ve Directo JES:rlf cc: Senator Mike Gravel Enclosure: 1. August 1 - letter to Leslie Goldman 2. June 6 - letter to the Council on Environmental Quality 3. December 6 - Research Memorandum, Dr. Evelyn Stokes, University of Waikato PAGENO="0607" 583 August 1, 1977 Leslie Goldman, Coordinator Alaska Gas Pipeline Task Force Executive Office of the President Box NP Washington, D.C. 10641 Dear Mr. Goldman: I appreciate this opportunity to coonent formally on President Carter's forthcoming Sepceeiber I decision relevant to the transportation of natural gas from Prudhoe Bay to hthat we in Fairbanks refer to as `the lower 48 states." Since early 1973 the Association has been actively seeking methods of resolving problems created by .a phenomena commonly referred to as "pipe- line impact." Our work and that of others equally concerned has been limited to a continuous program of date. gathering, analysis, and public dissemination of information on the social and econonic effects of construction of the trans-Alaska crude oil pipeline on Fairbanks and on the 45 isolated villages, towns and settlements which surround Fairbanks in an area the size of the State of Texas. Several years of time and effort have been invested in this work. During this period we have made repeated formal and informal requests to any one of several federal agencies which appeared to us to have clear agency responsibilities for resolving local problems resulting from trans-Alaska pipeline construction. With the single exception of the federal Economic Development Administration, which has indirectly financed this work with annual planning assistance grants to our As- sociation, our efforts to secure federal assistance in resolving local and regional problems related to pipeline construction have produced little in the way of visible federal response. To illustrate this problem, I have attached a copy of our published comments on. the Draft Environmental Impact Statement prepared by the Federal Power Commission with respect to the El Paso-Alaska (CI' 75-96 et al) proceeding. The FPC response which appeared in their FEIS. also appears opposite the relevant paragraphs. PAGENO="0608" 584 Also enclosed is our recently published final report describing problems of pipeline impact in the snail communities scattered throughout the Interior of Alaska. The FPC response was typical of the response we normally receive from agencies of the federal system that we believe should be, or should have been involved in this problem. Our comments, by the way, expressed our best thinking on the role of the federal government with respect to the resolution of adverse social and economic consequences of "major federal actions." We based the comments on the extensive identification and documentation of impact problems during construction of the trans-Alaska oil pipeline through the In- terior of Alaska. During the Anchorage hearings before the Council on Envirorniental Quality on May 16, we repeated those recommendations and, at the request of the Council, recast them in terms of the Alaska Natural Gas Transportation Act of 1976, P.L. 94-S86. Those comments, so far as I know, are part of the CEQ's public hearing record, and remain our best thinking today. Given our long record of frustration in dealing with the federal govern- ment, we decided to prepare this letter only because the CEQ in their official report to President Carter made an accurate reference to the substance of my comments in Anchorage, thus bringing the issue, "out of the closet," so to speak; and because the Canadian National Energy Board in their July 1 approval of the Alcan Gas Pipeline proposal also re- quired that a 200 million dollar fund be established for the resolution of social and economic problems associated with the project north of Canada's 60th parallel. Since I have not read the official NEB decision, I cannot comment on their intent with respect to either the creation or the disposition of these funds, but I believe it is imperative that President Carter in- clude the creation of a similar fund - though the amount and methods of collection and disbursement tray be entirely different - in his September 1 recommendation to Congress ... if, in fact, he recommends that one of the two remaining applicants be authorized to construct and operate the gas pipeline. With respect to distribution of such funds we do not believe that a fund of this sort necessarily needs to be set up on a 100% grant basis except for planning and programming purposes. Obviously, if the project is successful, revenues accruing to nainicipalities and states will be ample to repay loans made to these entities for impact preparations, including essential capital improvements, prior to the project start. PAGENO="0609" 585 I do note with interest that one of the competing applicants has pub- 1 icly condemned the NEB fund requirement as a violation of the recently approved Natural Gas treaty with Canada, and, by implication, a sign of bad faith on the part of the Canadian government. Their assertion is preposterous. The Canadians and the Comnonwealth countries in general have closely watched our experiences and our recording of impact phenomena associated with trans-Alaska pipeline construction. The NEB fund requirement is nothing more, in my opinion, than a recognition of the enormous social costs of these massive energy,resource development projects, and an understanding that the government at the federal level has the ultimate, though clearly not the entire responsibility, to reduce them~ This has been our message to the United States federal government for the past several years. I sincerely hope that with the Canadian NEB precedent in mind that your office and the Office of the President will give serious consideration tosone sort of a federal mechanism for reducing the inevitable social and economic disruption in small commu- nities adjacent to the gas pipeline. I should note in closing that extensive documentation of impact problems in the rural and urban areas of Ltterior Alaska is available and can be supplied on short notice to the appropriate office of the federal gov- ernment. I should also note that the Association's Executive Committee of the Board of Directors has informally taken the position that of the two trans-Canadian gas pipeline proposals the Alcan route proposal is far superior to the Beaufort Sea/~ickenzie River route proposaL Generally we believe that, in line with our concern with the social and economic implications of these projects, an overland route following existing transportation corridors will create less uncertainty during construction and operation of_the-facility, and, therefore, signifi- cantly reduce long term social disruotion. and related social costs~ Sincerely, Jerry Smetzer Executive Director JES:bjs Enclosures: L FPC, FEIS, El Paso Alaska, CP 75-96 et al~ Pages 237 - 290 2 Final Report, Rural Impact Information Program PAGENO="0610" 586 June 6, 1977 Council on Environmental Quality Executive Office of the President 722 Jackson Place, N.W. Washington, D.C. 20006 Dear Members of the Council: I would like to thank you again for the hearings recently conducted by the Council in Anchorage, Alaska on Nay 16 and 17. I sincerely appreci- ated the opportunity to testify on the environmental impact statementS relevant to the transportation of natural gas from Prudhoe Bay to the lower 48 states. During my testimony on the 17th, members of the Council asked me to revise and extend certain of my coraients. It is my pleasure to do so at this tine, though I fully realize they may be received too late in your decision making process to be fairly considered. In order to keep my coennents relevant, the first part of this letter contains our three recoimnendations which were made to the Federal Power Coimnission in Januaxy of 1976 in response to their DEIS and were sub- sequently reported with the FPC response in Volume IV of the Final Environmental Impact Statement. As promised, I am recasting these recoamendatioris in the context of your responsibilities under the Natural Gas Transportation Act of 1976. The Fairbanks Town and Village Association for Development, Inc. wishes to reiterate its position that the Federal Power Conmission, under the National Environmental Policy Act of 1969, have a responsibility and a duty to explore - in the language of established NF.PA procedure - 1) meth- ods of "enhancing the environment" and "mitigating adverse environmental effects" in the social, economic, political. environment with care equal to that displayed for the physical environment; and 2) must, in a re- lated way, develop alternatives~ and discuss the exercise of its respon- sibility to protect the public interest in municipalities and conatu- nities i~ihith will be subjected to significant short and long term effects as a result of construction and operation of an interstate natural gas PAGENO="0611" 587 pipeline. FT/AD believes that several methods should have been explored in the Federal Power Commission's Draft Environmental Impact Statement in order to elicit public comment on these issues prior to the prepara- tion of the Final Environmental Impact Sstatement. These issues were not raised by the Federal Power Commission, and we hope that the federal Council on Environmental Quality will recommend to the President that these issues now be considered and that a resolution of them be part of the final Presidential recommendation to Congress on the disposition of this issue. Those recommendations, as a recast in terms of the Natural Gas Trans- portation Act of 1976, follow: I. That the President of the United States require, by means of an appropriate stipulation or covenant, that the successful applicant immediately establish a grant and loan fund, sufficiently large to provide immediate financing to state, regional and local governing entities, for planning and construction of needed public facilities, and other facilities necessary to mitigate disruptive short term effects on the cooununities as a result of gas pipeline construction and operation. Questions concerning amounts, and the authority and mechanisms for disbursement and loan repayment should be resolved by a special purpose agency of the Executive Branch of the federal goverimlent after consultations with state, substate, regional and local representatives of affected governing interests and those applicants who, if successful, wil] conduct pipeline construction and operations within the jurisdiction of those governing entities. 2 That the same special purpose agency of the Executive Branch ex- plore, with each agency of the federal government having operations in geographic areas affected by pipeline construction and operations; the extent of their authority and the extent of their capability and willingness to provide assistance and/or to perform specialized services at the request of state, substate, regional and local entities responsible for the protection of the public interest and support of pipeline construction at the local level. 3. That .the sane special purpose agency of the Executive Branch re- quire the perfornzrnce of certain essential federal services such as; census counts, costs of living analysis, labor force analysis and such other services uniquely available through the federal govern- ment as training, housing development, social services, financing for essential public and federally sponsored private capital in- prcvcinents, etc.; and that such services be paid for out of the fund proposed in ~`l above; to require and assure the coordination of the federal program activity and policy making in order to provide financial, technical and administrative support to state, regional and local decision making entities. Cur written comments to the Council on Environmental Quality contained more specific recommendations ~along these sane lines. Since they are PAGENO="0612" 588 part of your Anchorage hearing record, I have not enclosed copies. However I have enclosed supporting information on the manpower problems we have experienced during the period of pipeline construction which were not addressed in the FPC FEIS. The second part of my letter has to do with the Council's responsi- bilities with respect to the development of the environmental impact statements. These coianents are of little relevance to your respon- sibilities and authority under the Natural Gas Transportation Act of 1976, but should, nevertheless, be considered carefully in the develop- ment of future regulations guiding the environmental impact information process. Our general recocenendation.s follow: - 1.: The Environmental Impact Statement process which has evolved since NEPA, including the EIS which accompanyied the FL PASO-ALASK~~t case before the Federal Power Commission is too static and too reliant on the acc~xmlation of data and scientific analysis to be of any value in addressing "impact" on the human environment, and specif- ically on social, political and economic institutions at the state, local and substate regional level. We agree that data accumulation followed by expert analysis, evaluation, and publication, is im- portant, per se, in the EIS process. However, this activity has traditionally occurred in a vacuum in terms of its relevance to the general public and their more generalized interest in the subject projects. If, as we beliévéit must, the EIS process is to have relevance to the general public, there must be a clear, concise statement of the policy parameters and probable effects of the "major federal ac- tion~' prior to the beginning of the EIS process. Furthermore, this general statement should be prepared by those officials represent- ing the federal agency with the final decision making authority. In addition to the initial statement periodic revisions in the sane clear, concise manner, should be issued at regular intervals through- out the BIS process in order to assess the effects on policy of new information generated by the process. 2. In order to avoid the "in house" flavor of the FIS generated docu- ments, some federal financing should be made available to existing public, interest organizations involved in activities or questions of policy relevant to the major federal action contemplated. It is our understanding that the Berger Inquiry followed this methodolgy in developing its report to the National Energy Board in Canada on the gas pipeline issue. The methodology of the Berger Inquiry s one that should be carefully reviewed by the Council on Bnviromu~ntal Quality for application to the EIS process. The format here is too confined for extended consideration of this important issue. We have generated a great deal of information on the social and - PAGENO="0613" 589 economic impact on Fairbanks and its surrounding communities as a re~ suit of petrolei~a resomce develoixaent in Alaska. Time and money pennittin~g, we are quite willing to explore this infor- mation with you in more detaiL Thank you again for rage hearings. Sincerely, / Jeri~y Smetzet~ Executive Di~ctor. JES:bjs EncL PAGENO="0614" 590 ,~,tJN1VERSI1Y OF WAJKATO SCHOOL OF SOCIAL SCIENCES HUNTLY SOCIAL AND ECONOMIC IMPACT MONITORING PROJECT RESEARCH MEMORANDUM - Number 9: 6 December 1976 Subject: FAIRBANKS, ALASKA: MONITORING SOCIAL AND ECONOMIC IMPACTS OF THE CONSTRUCTION OF THE TRANS ALASKA PIPELINE Evelyn Stokes* While the literature on social and economic impacts of development projects is beginning to accumulate at a more rapid pace, most studies simply report on results of impact at particular points in time. The Impact Information Center in Fairbanks, Alaska, is one of the few examples of regular reporting of changes in a community over a period of time. The Center was set up in April l97~ (at the same time as construction began on the Trans Alaska Pipeline) and has reported regularly since then. A related programme was organised early in 1975 through the Fairbanks Town and Village Association for Development to report on rural impacts in the region. Although both programmes were set up as community information centres, they have essentially performed the task of monitoring social and economic changes in an extreme impact situation. This report is compiled as an attempt to extract from the Fairbanks experience some ideas that may be of value in monitoring social and economic impacts elsewhere. It is based on a stay of only one week in Fairbanks in August 1976, during which wide ranging discussions were held with Sue Fison, present director of the Impact Inform- ation Center, Him Dixon, a former director, Gene Straatmeyer, Presbyterian Minister, and former chairman of both the Social Concerns Committee of the Fairbanks Council of Churches and the Impact Advisory Committee for the Impact Information Center, Jerry Smetzer, executive director of Fairbanks Town and Village Association for Development which administers development programmes for the much wider area of Fairbanks Economic District, Larry Carpenter, Community Relations Officer for the Alyeska Pipeline Service Company (the consortium formed to construct the pipeline), and various other Fairbanks residents. While I have quoted freely from all these informants, aU interpretations are mine. There was also some variation in ideas about how effectively the Center operated and in attitudes toward impact of pipeline construction on Fairbanks. * Dr Evelyn Stokes is a Reader i~Geograpby at the University of Waikato. Project Co.ordinotor: 1W Fookes MA (Cant) Cert Ekistks (ACE, Greece) DipTP(Auck) MNZPI Fosta~ Address: HunI~ Monitoring Project, Universily of Waikato, Honi}tcn, New Zea~and PAGENO="0615" 591 Background In the 1970 Census Fairbanks North Star Borough (a territorial adminis- trative unit containing both urban and, rural areas) contained 1i5,846 people. The region lies mostly just south of the Artic Circle and the terrain ranges from the wide swampy river flats of the Tanana, a tributary of the Yukon River, to mountainous country. There are large areas of permafrost. The short summers are warm but winters are long and harsh with average December-Janus.ry temperatures around 34 degrees celsius below zero, occasionally reaching 50 below. Ice fog conditions caused by temperature inversion in the Tanana Valley, are common in winter. The main urban centre is Fairbanks which contained 14,771 people in 1970 and functioned as a service and delivery centre for the scattered small communities of the vast interior and northern areas of Alaska. There was also a large military component in the Borough pop- ulation - 15,246 people living on two military reservations outside the city of Fairbanks. The non-military population outside Fairbanks city in 1970 was 15,289, a figure which includes Eskimo and Indian villages as well as European populations. Among the civilian population the ratio of male to female was 113:100 in 1970; when military personnel are included this figure increases to 134:100. Fairbanks in 1970 was a frontier community with a large number of unattached males, a lower than average proportion of old people and the very young. Crimes against property were few but assaults against the person were frequent. There was also a dIsproportionate number of bars and saloons in downtown Fairbanks. Alcoholism was already a problem, exacerbated by long hard winters and high unemployment rates, especially winter unemployment. Alaskan economy has always been shaky and what can be loosely described as a "boom or bust mentality" cam be identified in Fairbanks. Public agencies provided 52 percent of employment in 1970 but the military component was declining from the cold war peak, and the community was moving away from dependence on military spending.. An infusion of Federal and State finance for reconstruction after a serious flood in 1967 helped, but the construction industry was described as "erratic". Housing was already in short supply and very expensive. - twice the price of equivalent housing in Seattle for example. Many of the PAGENO="0616" 592 existing houses constructed in the post second world war boom of military expansion were sub-standard. Mining in the area, in- cluding coal, was on the decline. There was still a good deal of subsistence in rural areas, supplemented by winter trapping for furs and cast~al summer employment when it was available. A high proportion of people employed in Fairbanks city were involved with transport, especially air freight. There had been some increase in tourism and recreation but these were not regarded as major sources of income. Prices and wages had always been high, but stable, and wage and salary differentials were provided to attract people to skilled and professional positions. The discovery of oil on the North Slope in 1968, and subsequent sale of oil concessions for $900 million,was perceived as the economic salvation of Alaska, and the Fairbanks area in particular. The Trans Alaska Pipeline was planned to carry the oil lI~OO kilometres from Prudhoe Bay in the north, past Fairbanks, to a terminal at Valdez on the south coast where tankers would take the crude oil to refineries in Puget Sound, San Francisco, and the Los Angeles area. The oil companies had begun moving in pipe and equipment, and build- ing a series of construction camps along the projected route when an injunction against the pipeline on environmental grounds stopped all further work in 1970. From 1970 to October 1973 when the Trans Alaska Pipeline was approved by the Federal Government, there was a period of uncertainty, and nc preparations were made. Fairbanks citizens, especially businessmen and administrators who had begun to gear themselves to meet the demands of pipeline construction, were trapped. There was no State or Federal Government commitment to help the region cope with any influx of population. There was no commitment from oil companies either. Mobilisation began in April 197I~, when pipeline construction started with Fairbanks city the principal administrative, supply and trans- port centre for construction activities. Peak employment on the whole project reached 23,000 in 1975. Costs have escalated from the projected $6 billion (u.s.) to near $10 billion already, but Alyeska Pipeline Service Co. still hope to begin pumping oil in the PAGENO="0617" 593 autumn of 1977. Actual construction should end by September 1977. The number of people required to operate the line on completion will be between 600 and 700 but only 50 of these will be stationed in Fairbanks. The population of Fairbanks city in 1973 was estimated at near 18,000; the mid 1976 estimate is 36,000 people. The Establishment of the Im3act Information Center Even before construction began, a few people in Fairbanks-were concern- ed about possible social impacts of such an enormous project. In - particular, the Social Concerns Committee of the Fairbanks Council of - - Churches, while discussing impact on churches realised that the impli- cations were much wider and called in other people in the community. At this stage, discussion of impact had been concerned almost solely with "environmental impact" (i.e. physical and ecological) and "economic impact" (i.e. increased income to the region). This small group of concerned citizens organised a one-day Community Forum described by one of the organisers as being "like an old-time town meeting" which met on 23 February 19Th. For most of the participants, this meeting was an information exercise, for few people had much idea what was in store for them. There were strong feelings of apprehension about "the massive army mowing in on us". Others have likened the arrival of Alyeska Pipeline Service Co. and the whole construction organisation to - "a military invasion of a colonial province". (It did not help perhaps that the Alyeska headquarters and a-construction camp were set up at Fort Wainwright, just outside Fairbanks city in military quarters no longer required by the Defence Department). Various issues were discusseft at - this first Forum such as crime, the provision of social services, the role of the churches etc. as well as economic impacts. The chief outcome of the meeting was a strong feeling that the people of Fairbanks needed to know what was going on. Some sort of information center was needed to look at the effects of pipeline construction on the lives of people in the community. The Social Concerns Committee along with other interested individuals organised support for an Impact Information Center as part of the local government services at Fairbanks North Star Borough. The presiding - officer of the Borough Assembly envisioned a centre whose purpose was PAGENO="0618" 594 to collect and disseminate information. "It does not forecast, predict, extrapolate, or otherwise attempt to indicate the shape of the future .... The sole measure of success of the Impact Information Center will be how well it serves the whole community..." The Borough Mayor further refined the idea in outlining three basic purposes for such a Center: (1) to provide the general public vith information relevant -to pipeline activity which "could or will affect their personal, occupational, business, financial and recrea- tional affairs"; (2) to provide the Borough Assembly and administration with "factual data to aid them in conceiving and formulating public policy designed to cope with pipeline impact"; (3) to present information as rationale to support requests for State, and possibly Federal, impact funds or services. The Mayor also recommended that a-broadly based committee be appointed to guide the proposed Information Center. There was some opposition to the idea of an Impact Information Center. The business community were mainly concerned with econ- omic effects and some businessmen labelled supporters of the Center `eggheads". The prevailing business attitude was that the additional money that would flow into the community as a result of pipeline construction would solve many of the community's problems. There was also opposition from "fiscally conservative" individuals who were suspicious of spending Borough funds on such a fuzzy idea as an Impact Information Center. There was a strong move to have the local Chamber of Commerce organise the Center, but this was countered with the argument that the Chamber was a special interest group and therefore could not be impartial. The Social Concerns Committee has argued on similar grounds that as a church group with special interests they could not support it alone, that there had to be broader community involvement. In order to ensure necessary impartiality, it seemed most appropriate that the Borough should run it. This arrangement did not ensure complete impartiality for PAGENO="0619" 595 the comment was also made that there were too many politicians "stick- ing their fingers in" and that the Borough were a little too possessive about their Center. But in the circumstances the best place did seen to be a downtown location associated with the Borough administration. Apart from the occasional interested individual, there was no input from the Fairbanks campus of the University of Alaska at this stage. The comment was made that supporters of the Center did not use the uni- versity as much as they could have or perhaps should have. It was felt that the university could not have run such a center, partly be- cause of the distance from the city, but more particularly the dominant frontier attitude in Fairbanks that "those eggbeads on the hill" were much too removed from the concerns of everyday life. However, researchers in the Institute for Social and Economic Research, Univer- sity of Alaska, have been working on topics related to pipeline impact and some individuals are turning more specifically to impacts in Fairbanks itself. A great deal of data has been collected by the Impact Information Center and social scientists at the local campus are being encouraged to use it. The Institute for Social and Economic Research is also developing proposals to assess impacts of further off- shore oil development and gas line construction. Organisation and Administration of the Impact Infommation Centei On 25 April i971~ the Fairbanks North Star Borough Assembly appropriated $l3,1~5o from the general fund to the Mayor's OffiCe for the purpose of establishing an Impact Information Center and operating it for the ye- mainder of the fiscal year. The Borough Assembly later decided to use a portion of the impact funds received from the State of Alaska and thereby appropriated an additional $1~9,l98 to operate the Center during the fiscal year l971~-75. The original Impact Advisory Committee, appointed by the Mayor, repres- ented a cross section of the community, including the chairman of the Social Concerns Committee of the Fairbanks Council of Churches, the president of the Fairbanks Chamber of Commerce, the Community Relations Officer for Alyeska Pipeline Service Co., the vice president of Doyon Ltd, (the regional native Corporétion), and the Presiding Officer of the Borough Assembly. Later the committee was expanded to PAGENO="0620" 596 include a consumer representative, a representative of the Black community and a representative of the Joint Labour Council. There have been several changes in membership but this broad representation has been maintained. The Center began with a staff of two, a veteran political journalist, Joe La Rocca, as Information Officer, and a secretary. Soon after, an applied anthropologist, Dr. Mm Dixon, joined the staff. Eight months later it was decided that there was a need for a rural impact information programme for the interior of Alaska beyond the area of Fairbanks North Star Borough. By a contractual agreement, Mim Dixon served as consultant to this programme which was organised through the Fairbanks Town and Village Association for Development Inc. At the end of the fiscal year state impact funds lapsed and the Borough Assembly decided to appropriate funds out of general revenue to con- tinue the programme. The State of Alaska added $10,000 to the budget as it was thought the Center was providing valuable information to state agencies. Additional funds were obtained through contractual arrangement with Fairbanks WA for the rural impact programme. Mim Dixon was appointed Director when Joe La Rocca left and the secretarial position was amalgamated into an Information Assistant position with responsibilities for working with the public and assisting with re- search as well as clerical duties. On 31 March 1976 Mim Dixon resigned to work full-time on a book on pipeline impadt. The new director is Sue Fison, an economist with experience both in research at the Institute for Social and Economic Research and working ~n a local government authority. Staff in the Center in mid 1976 comprised the Director, Information Assistant (both full-time) and a part-time secretary. Accommodation was provided in the Fairbanks North Star Borough offices on 2nd Avenue in downtown Fairbanks. The Center functions as an autonomous office within the Borough administration and the Director is respon- sible to the Msyor and the Impact Advisory Committee. Reports are issued at the discretion of the Director. There is no formal vetting procedure although the work of the Center is discussed regularly by the Impact Advisory Committee and all reports are submitted initially to PAGENO="0621" 597 the regular public meeting of the Committee and made available immed- iately to local news media. In April 1976 the Fairbanks North Star Borough Assembly deleted the proposed $62,000 funding for the Impact Information Center from their budget for the 1976-77 fiscal year. A few weeks later the funding was, reinstated but reduced to $31,000. In the final budget session on 27 May the Assembly voted 6 to 5 to fund the Impact Information Center at the amount originally requested. The budget for 1976-77 is as follows: Salaries and benefits 143,365 Office supplies 600 Telephone 600 Mail and distribution 2,000 Meetings, conferences, memberships 2,000 Local transportation 1,200 Copying expenses 12,000 Equipment 532 Total $62,297 Funding for the Impact Information Center is available to 30 June 1977. The future of the Center beyond that date is unknown but there are strong suggestions that some sort of community information center should be retained within the Borough administration. Activities of the Impact Information Center The primary purpose of the Impact Information Center was to collect- and disseminate information about changes in the community that have resulted directly or indirectly from pipeline activities. There was little attempt to establish any formal research design. `Decision on what information needed to be collected arose out of `brain storming" in meetings of-the Impact Advisory Committee and out of issues raised by people in the community. The following summary of methods used to collect data was provided by the Center: 1. A reporting system has been established in which local and state agencies send copies of their regular reports to the Impact Information Center. 95-826 0 - 77 - 38 PAGENO="0622" 598 2. The local newspaper and other major newspapers within the state are reviewed daily and a file of newspaper clippings relating to the community, the impacts of the pipeline, and energy resource development is maintained. 3. Regular market basket surveys, heating oil cost surveys, and surveys of rental prices advertised in the local newspaper are conducted to establish economic indices. In addition, in- formation obtained by the Bureau of Labour Statistics in its Anchorage Consumer Price Index is utilised. A major activity of the Impact Center and its Advisory Committee has been to encourage the re-establishment of a consumer price index in Fairbanks. 1~. Utilising the dockets from the State Superior Court, filed divorce complaints are recorded monthly; and information from previous years is being collected in order that a time series analysis may be possible. 5. Interviews are conducted with local persons to obtain information on a variety of subjects, and local institutions are visited and observed. 6. Public meetings and hearings are attended to obtain both inform- ation and public expressions of sentiments. 7. Formal questionnaires are used occasionally to obtain information on specific problems, (e.g. a survey of high school students to determine their roles within the workforce, a survey of senior citizens to ascertain their pipeline related problems, and a survey of local pipeline-related wOrkers to determine their child care needs). 8. Local university students are encouraged to study impact phenomena. Their work is supervised and co-ordinated through the Impact Center and the Center acquires copies of completed papers. 9. Impact Center staff participate in local groups, give speeches at meetings of various urganisations, are interviewed on radio and televj~siontalk shows and participate in community activities in PAGENO="0623" 599 other ways which help create a positive image and a Sense of trust which facilitates an informal communications network. 10. As the Impact Information Center has become recognised as a community resource, persons in the community or elsewhere with questions, problems, or information contact the Impact Center either by telephone or by going directly to the Center. Persons in the community provide information not only in terms of data, but also by alerting the staff to community concerns. Information collected by the Impact Information Center is disseminated in various ways. People call or visit the Center, some information is exchanged through correspondence, and the staff of the Center give talks to groups in the Fairbanks area. Much information is dis- seminated through news media coverage of the monthly Impact Advisory Committee meetings. Impact Information Center staff were involved in a "Community Con- ference" on 26 April 1975 sponsored by the Social Concerns Committee of Fairbanks Council of Churches and Fairbanks Town and Village Asso- ciation for Development Inc. This forum was described in a brochure as "the day for residents of Interior Alaska to come together to share informaticn and gain a greater understanding of the problems and opportunities which are developing as a result of rapid growth in the interior". The list of topics for group discussion is an indicator of some of the community concerns at this point: Hiring for pipeline jobs - are Alaskans getting enough pipeline jobs? Oldtimers and newcomers - what happens when you don't have a pipeline job? Youth - what is happening to youn~ people? Congestions and hassles - is it getting too crowded here? - traffic jems, phones, getting things. Housing crises - can anything be done? Families - family life under impact - child care, finances, mental health. Business and commerce - does the pipeline mean more profits PAGENO="0624" 600 or more overhead? - firms with and without pipeline contracts. Land and community - is community laRd use planning possible? A walk on the wild side - what's happening that polite people don't talk about? - organised and unorganised crime. Oil and Gas industry - are we getting our fair share? - revenue to the State, access to the product, economic development. The proceedings of the conference were summarised in a publication titled Fairbani~p~ Interi ka: a one day comm~~~t forum on The major form of activities and the major vehicle for dissemination of information is through the publication of regular Pipeline Impact Information Center Reports. In just over two years the Center has. produced 29 regular reports covering a variety of topics and 14 special reports. Reports are distributed to Borough administrators and Assembly members, to others on request, and to persons who have re- quested that their names be placed on the mailing list. Of a total mailing list of 585 in August 1975, 3146 were in the Borough, 127 in Alaska outside the Borough, and 103 outside Alaska. Of the total distribution 39 percent went to private individuals, 35 percent to business or other organisations, 11 percent to university, 10-percent to State and 6 percent to Federal agencies, and 3 percent to the press. A survey of users of Impact Information Center reports completed in March 1976 indicated that the data provided in the reports is being used in a great variety of ways both by people in the local cçmmunity and at regional and State levels of decision-making. Some I~p~cations of the Impact Information Center Ex~eie It is difficult to evaluate fully the operations and achievements of the Impact Information Center. Certainly the financial and political constraints on the Center limited the amount and detail of information that could be collected. While attitudes varied, there was general agreement that it had been worthwhile and as much had been done as could possibly be done in the circumstances, especially cons!dering the innovative nature of the Center. - A number of poInts can be PAGENO="0625" 601 made that have implications for monitorIng social and economic impacts: 1. A regular basis for funding is essential. The shaky fund basis of the Center made it difficult to establish longer term pro- jects beyond regular agreed communications from agencies providing data. 2. A full-time Director with professional qualifications is necessary. Much depends on the individual personality of the Director and each Director has brought different perspectives and emphases to the task. 3. The role of the Advisory Committee can be an importmnt one as a sounding board. Comments on meetings of the Impact Advisory Board ranged from "dull" and "a waste of time" to "emotional" and "too much time placating irate natives" to "intelligent and thought-provoking discussion'. Members were all unpaid and usually deeply involved in community affairs anyway and felt un- able at times to give as much as they might wish. The feeling was also expressed that economic interests tended to dominate and it was difficult to keep social concerns to the forefront. The monthly meetings were public and public attendance varied from about 5 to 20. However, proceedings were veil reported in the local news media. The impartiality of such an information centre or monitoring pro- ject must be preserved. In the supercharged atmosphere of an impact situation there are considerable political pressures. There was a paradox in weighing up the advantages of giving the Impact Information Center "official" status in the Borough ad- ministration and the potential disadvantages of accusations of political interference because it was funded through the Borough. The question of impartiality is particularly import- ant where community trust and involvement is to be encouraged. 5. The whole question of community participation is an important one in a monitoring exercise. While public participation in the Impact Advisory Committee meetings was small, many. individuals did visit the Impact Information Center and made use of inform- ation provided. Many also brought .in comments and queries that PAGENO="0626" 602 served to stimulate further investigation. Ways of encouraging much greater feedback from the community need to be developed. 6. Perhaps the most important observation of all is the need to obtain the most sophisticated, detailed data possible. This of course implies adequate funding and properly trained people to collect and process such material. There are very real difficulties in using data already collected by various govern- ment or other agencies, especially in an impact situation where such agencies are under stress of extra work loads. When such data are collected, it is essential to establish agreements for regular reporting in consistent usable form so that a series of' data can be compared over a period of time. The establishment of such data collecting arrangements can be very time consuming and frustrating but some persistence in the early stages pays off later as a regular file of information begins to build up over time. 7. It is also wise to spread the net of data collection as far as possible. Not all information may seem immediately relevant but in the long term may prove invaluable. Two major gaps in data at the Impact Information Center are concerned with the cost of living and housing. While some information has been collected it is not sufficiently detailad. A special survey on mobile homes has just been completed to help remedy this. There is some concern that too little is known about how the rising cost of living is affecting people. Many people have made money - bank deposits have risen dramatically - but it is now becoming increasingly obvious that the additional income generated by pipeline construction has not flowed evenly through the community. There is real poverty among many old people, especially those who have moved into Fairbanks from more remote communities in order to be closer to medical facilities. One explanation of the inadequacy of the police in coping with increasing crime iS that any policeman with initiative earning $1,000 a month has left the force to work on the pipeline where he can earn $1,000 a week and more. Those on fixed incomes and even middle income people in fixed salary or wage scales are finding it increasingly difficult to live within their incomes. Much more detailed information is required on ~iow the money gen- PAGENO="0627" 603 erated by pipeline construction flows through the local community, how much stays, where it is spent, how much goes out, and so on. Likewise, the effect of high wages on the pipeline in forcing up other wages and prices in non-pipeline related activites needs further investigation. If detailed information on spending patterns and money flows in the community were available over a period of time perhaps some of these longer term effects could have been foreseen, and demonstrated much earlier. It is now obvious that initial predictions that the extra income generated by pipeline construction would only help solve community problems were much too simplistic. More efficient ways of identifying particular groups in a community most likely to be affect- ed by an impact situation must be developed. One commentator remarked that the Impact Information Center should have been started much earlier, but until people perceived the problems, it would not have received any support. The residents of Fairbanks were likened to an army about to be invaded. One obvious course of action was to set up a center for intelligence operations to monitor activities, plan strategies and help allocate resources to deal with the new situ- ation. But the Center did not fully achieve this aim for at least half of the Fairbanks community welcomed the invasion. What was needed was a sort of command post to feed back information, not just as a service to decision-makers, but also as a service to local Oiti- zens to help them understand the processes of change that were being forced upon them. The oil industry was described as a very competent invader because it was well organised. The local people were not. They needed much more help in understanding and coping with social forces and pressures which were bringing so many changes. The ieonle needed to be alerted and educated to the stresses of rapid change that an impact situation produces. q~Implications of the Fairbanks Experience The visitor to Fairbanks is immediately confronted with the impact of the pipeline. The Alyeska Service Desk occupies a prominent position at the airport and handles all pipeline related passenger movements through the airport either to other aircraft or to buses waiting out- side. The airport itself is constantly busy coping with far more flights than would normally be generated by a population the size of PAGENO="0628" 604 Fairbanks. The city itself has exploded out of its original compact cluster of buildings, many of them old style log cabins, ona bend of the Chena River which flows through swampy flats into the Tanana. Many of the new houses are mobile homes; even the permanent structures are strictly functional and not very beauti- ful. In contrast.some very attractive homes have been built on more elevated sites in woodland subdivisions on the outskirts of the city. New office blocks and apartment complexes recently completed or still under construction are dotted about the central area, while further out in the suburbs are large new shopping centres, mostly built by developers from outside Alaska and housing well known national supermarkets, restaurants, and department stores. A large new complex is under construction and some doubts have been expressed as to whether Fairbanks really needs any more such complexes. Very little development in re- tailing has occurred in the downtown area, where narrow streets are congested with traffic in spite of a one way street system. In spite of some substantial new buildings much of the town has the rough, raw untidy appearance of a hastily built camp, rather than a permanent community. And the frontier camp atmosphere is perpetuated by the disproportionately large number of scruffy saloons and bars downtown, mainly but not exclusively on 2nd Avenue, and the equally scruffy collection of people accumulated around them. More telling than the visual appearance of the community is the psychological impact of the pipeline: the way local chronology is perceived in two periods - before and since the pipeline - and the wistful remarks of some that Fairbanks will neverbe the same again. But others say it is a great improvement on what it was. Fairbanks has barely coped with the social and economic impacts o~ the, construction of the pipeline and there is little evidence of overall planning for the impact situation. Some generalisations can be drawn from the Fairbanks experience: 1. It is impossible to keep politics out of the impact of a development project, both the politics of the impact situ- PAGENO="0629" 605 ation itself and the political pressures on the researcher interested in impact. 2. Attitudes of the people involved in and affected by the impact situation are often ambivalent, inconsistent and contradictory. 3. Those who have most to gain, particularly in short term mone- tary terms, are often least sympathetic to the effects of impact, especially negative effects. 4. The longer-term effects, particularly those involving permanent structural changes in the community, are rarely perceived in the early stages of an impact situation. 5. An impact situation will exacerbate existing ills in the corn- munity. 6. The impact situation will often be used as a scapegoat for a variety of problems, thus increasing the difficulty in separat- ing out "normal" from "impact-induced" situations. 7. Individual and group perceptions of impact will change through time. 8. Very few peo~le or administrative structures are geared to-cope with the very rapid social and economic changes that an impact situation demands. Impact can be defined as the stress of a rapidly changing situation. The more rapid the change, the greater the effects of stress. Stress can be personal, institutional, physical, environmental, social, economic. The idea of stress can be related to the concept of carry- ing capacity, that there are certain limits, actual or perceived, to the amount of activity that can be tolerated in a certain area. For example, the Tanana Valley experiences strong temperature inversions in winter in which ice fog conditions occur. The thermal power station (coal-fired) in downtown Fairbanks, auto exhaust fumes and burning oil or wood for domestic heating exacerbate this condition. The influx of more people means more houses with heaters and more PAGENO="0630" 606 vehicles emitting exhaust fumes which may quickly push this natural condition to a point where there is a real hazard to health. Thus human activity has exceeded the physical or environmental carrying capacity of the area in this respect. In the same way there are definite physical limits to the capacities of utilities systems such as water supply, sewerage treatment, telephone networks, all of which were only just adequate prior to pipeline construction. They are now severely overloaded. The idea of carrying capacity. does not necessarily mean that there are simple, finite limits to the stress that can be borne. The physical capacities of utilities systems can be expanded. But there are economic limits in terms of finance available to cope with such expansion, both in terms of actual cash in hand and how much extra the local community, is able or prepared to pay. Local taxes are rarely adequate to pay for the extra facilities required for a sudden influx of population. Thus severe stresses may be placed on local institutions in providing the services they are normally. expected to provide in terms of finance, personnel and expertise. Jerry Smetzer, surveying the economy of the Fairbanks district, the rapid changes brought about by the pipeline and the prospects of continued growth if a gas line is Constructed, commented: These findings clearly suggest that massive public investment in new and vastly expanded public facil- ities must be initiated rapidly in order to meet the quantum leaps in the demand for public services. To defer these public investments means that their costs - which are almost beyond the limits of political acceptance already - will rapidly escal- ate beyond state and local governments' actual financial ability to absorb then. More precisely, given the institutional and political reluctance to confront this problem directly, it is likely that present levels of service will simply deteriorate to the point where the community can no longer guarantee clean' water, public safety, basic health, telephone, electricity, school buildings, roads etc, at a price the average citizen. can afford. Obviously some profound questions of public policy are wrapped up in this issue, and they are not necessarily unique in this case to Fairbanks. PAGENO="0631" 607 Srnetzer likened the Fairbanks situation to the `so-called Boom Town phenomena in the Western United States" and quoted a statement made by the Denver Research Institute: "An annual growth rate of 10 per- cent strains local service capabilities. Above 15 percent seems to cause breakdowns in local and regional institutions." There is a real dilemma that on the one hand the greatest inputs need to be made "at the front end" of the impact situation to prepare for the influx of population. On the other hand, such inputs require accurate pre- diction of impact effects. For example, the Alyeska-sponsored social and economic impact study predicted peak direct project employment levels on the pipeline in 1975 around 6,500; the actual figure in 1975 exceeded 23,000. It was also predicted that school rolls would increase but there was nowhere near the expected increase for the project attracted a large number of single workers and family men left their wives and children behind. Some say it is impossible to plan for impact. However, the comment was also made that it was obvious that there was already pressure on housing, water and sewerage, and telephones in Fairbanks before the pipeline, so that any further influx of people would inevitably cause stress. Larry Carpenter commented: * You ask how to predict problems be?ore they occur - that is a Herculean task. However, as a rule of thumb, you can inventory the existing community problems in the pre-impact period and anticipate that they will be the most serious problems during the impact period. Impact here in Fairbanks simply compounded our existing problems. All the sorts of stresses outlined add up to a great deal of personal and community stress which is expressed in various ways. Decision- makers at all levels are often confronted with impossible work loads. A city attorney arrested earlier in the year for beating up his wife is reported to have commented "The last two years have been the hard- est of my life". Some have profited from higher incomes from the pipeline, have bought new homes, paid off mortgages and gained other material benefits. But some, in the midst of new affluence, have also felt that something was lost. For others the high wages simply meant more regular drinking and better class prostitutes. It is also very difficult to assess the family stresses that have occurred as a result of breadwinners qf a family being away working on the pipe- line for long periods. PAGENO="0632" 608 There ha~ been conflict between the old residents and the newcomers exaressed in local jckes: Happiness is 10,000 Texans moving south with an Okie under each arm" (or vice versa). Another version of the sane theme is: "Put an Alyeska man and a Bechtel man on the top of the Polaris (the tallest building in Fairbanks - 11 floors) and rush then both off. Who would land first? Answer: Who cares?" At one point "Yankee Go Home" was painted on cars with out-of-state number plates. Many Alaskans feel their distinctive lifestyle is being threatened. The sense of separateness is expressed in the phrase "the lower forty-eight" which covers the conterminous United States, (Hawaii is a warn place to the south where one can escape the Alaskan winter for a holiday and is not included in this termin- olo&v). There is a dividedness in the Fairbanks community. Old prejudices are exacerbated. Bacial andethnic tedsions have in- creased. While the pre-pipeline community was not without prejudices, "the people knew where they were at"; they knew andcould cope with existing attitudes and prejudices. A massive influx of newcomers with differing attitudes and prejudices increased existing tensions, as well as creating new ones. While there is no other place quite like Fairbanks, there is much in the Fairbanks experience that should serve as a warning to other com- munities experiencing an impact situation. The social and economic benefits and costs are not fully accounted in Pairbanks and may not be for a very long time. Fairbanks will never be the same again for many of the social and economic changes wrought by the~ impact of the construction of the pipeline are permanent. There is a strong fe~ling emerging that the perpetrators of an impact situation ought to be made to account for the costs to local communities of their development projects. There are also suggestionk that some mechanism for establishing en information centre and ensuring regular monitoring of impacts should b~ built into environmental assessment requirements for development projects. In the meantime, Fairbanks residents are preparing for the "bust" when pipeline construction is over, and at the same time pinning their hopes on construction of a gas line across Alaska. For the social scientist interested in impact analysis it is obvious from the Fairbanks experi- ence that we still do not know enough about the processes of acceler- ated social and economic change induced by a large development project. Still less are we able to educate the communities concerned to cope with the impact stresses produced by such rapid change. PAGENO="0633" 609 REFERENCES The following list includes publications generated by the Fairbanks North Star Borough Impact Information Center and Fairbanks Town and Village Association for Development Inc. Rural Impact Information Program. It is not intended as a complete bibliography of pipeline impact. Copies of all these publications are held by the Huntly Social and Economic Impact Monitoring Project, University of Waikato, Hsmilton, Sew Zealand. A.) Impact Information Center: Fairbanks North Star Borough: Pipeline Impact Information Center Reports Hoe. 1-29, July l97t~ - July 1976. Fairbanks North Star Borough: Pipeline Impact Information Center Special Reports: 1. Rim Dixon and Georgina Herron: Minority Hire and Alaska Hire. on the Pipeline. February 1975. 2. Him Dixon: Senior Citizens: the Effects of Pipeline Construction on Older Persons Living in Fairbanks. June 1975. 3. Rim Dixon etal.: Questions and Answers about the Cost of Living in Fairbanks. December 1975. 1~. Sue Fison: Mobile Home Living in Fairbanks. * September 1976. Rim Dixon: Pipeline Impact, Culture Change in Modern Complex Society. Paper presented at American Anthropological Association 71~th Annual Meeting, San Francisco, December 1975. [Him Dixonj: Fairbanks North Star Borough Impact Information Center: A Case History. [March l976J. Kate Wedexseyer: Impact Information Center. Evaluation. March 1976. PAGENO="0634" 610 B.) Fairbanks TVA: Fairbanks Town and Village Association for Development Inc (TVA): Rural Pipeline Impact Information ~~ram Reports, Nos. l-6, March-September 1975. Fairbanks TVA: Rural Pipeline Impact Information Program Interim Report, June 1975. Fairbanks TVA: Rural Pipeline Impact Information * Program Special Reports: ~port on Interviews in Galena, Kalt~g and Huslia, June 1975. Trade Union Hall Hiring Procedures, September 1975. * Transportation in Interior Alaska, December 1975. Communications in Interior Alaska, March 1976. Jerry Smetzer: The District and its Economy. Part III of a report on Fairbanks Economic Development Dis- trict prepared by Fairbanks TVA for OEDP. Fairbanks and Interior Alaska: a one-d~ycommun~yforuxn on growth. Social Concerns Committee of the * Fairbanks Council of Churches and Fairbanks Town and Village As~ciation for Development Incorporated, April 1975. 0