PAGENO="0001" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY HEARINGS BEFORE THE SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE NINETY-FIRST CONGRESS SECOND SESSION ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 16 FEBRUARY 24, 25; MARCH 3 AND 4, 1970 ORAL CONTRACEPTIVES (VOLUME TWO) (H Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 40-471 WASHINGTON : 1970 For sale by the Superintendent of Doeuments, U.S. Government Printing Office Washington, D.C. 20402 - Price $1.50 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS [Created pursuant to S. Res. 58, 81st Cong.] ALAN BIBLE, Nevada, Chairman JACOB K. JA\ ITS, 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. 5311T11, Staff Director and General Counsel JAMES P. DUFFY III, .ifinority Counsel SUBCOMMITTEE ON MONOPOLY GAYLORD NELSON, Wisconsin, Chairman JOHN SPARKMAN, Alabama MARK 0. HATFIELD, Oregon RUSSELL B. LONG, Louisiana ROBERT DOLE, Kansas THOMAS J. McINTYRE, New Hampshire MARLOW W. COOK, Kentucky ALAN BIBLE,* Nevada JACOB K. JAVITS,* New York BENJAMIN GORDON, Staff Economist ELAINE C. DYE, Clerical Assistant *Ex officio member. JOHN SPARKMAN, Alabama RUSSELL B. LONG, Louisiana JENNINGS RANDOLPH, West Virginia HARRISON A. WILLIAMS, JR., New Jersey GAYLORD NELSON, Wisconsin JOSEPH hI. bIONTOYA, New Mexico FRED R. HARRIS, Oklahoma THOMAS J. McINTYRE, New Hampshire MIKE GRAVEL, Alaska II PAGENO="0003" CONTENTS Pagų Statement of- Anderson, I-Ion. Glenn, A U.S. Representative from the 17th Con- gressional District of the State of California 6660 Ball, Dr. Philip, specialist in internal medicine, 2600 West Jackson Street, Muncie, Tad 6492 Carrington, Dr. Elsie R., professor and chairman, Department of Obstetrics and Gynecology, Woman's Medical College, 3300 Henry Avenue, Philadelphia, Pa 6654 Connell, Dr. Elizabeth B., associate professor of obstetrics and gyne- cology; director of research and development, Family Planning Services, International Institute for the Study of Human Repro- duction, Columbia University, 630 West 168th Street, New York, N.Y 6502 Cutler, Dr. Max, Department of Surgery, Cedars of Lebanon and St. Johns Hospitals, Los Angeles, Calif.; and Director, Beverly Hills Cancer Research Foundation, 436 North Roxbury Drive, Beverly Hills, Calif 6663 Draper, Gen. William H., Jr., honorary chairman, Population Crisis Committee, 1730 K Street, NW., Washington, D.C.; accompanied by Mrs. Phyllis Piotrow, secretary and member of the board of directors, Population Crisis Committee 6684 Edwards, Dr. Charles C., Commissioner, Food and Drug Administra- tion; accompanied by 1)r. John Jennings, Director, Bureau of Medicine, Food and Drug Administration; William W. Goodrich, General Counsel, Food and Drug Administration; and Dr. John Schrogie, Food and Drug Administration 6779 Goodrich, William W., General Counsel, Food and Drug Administra- tion; accompanied Dr. Charles C. Edwards, Commissioner, FDA~ 6779 Guttmacher, Dr. Alan F., emeritus professor, Mount Sinai School of Medicine; lecturer, Maternal Health, Harvard School of Public Health ;formerly clinicalprofessor, Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University; and president, Planned Parenthood/World Population, 515 Madison Avenue, New York, N.Y 6561 Jennings, Dr. John, Director, Bureau of Medicine, Food and Drug Administration; accompanied Dr. Charles C. Edwards, Commis- sioner, FDA 6779 Kane, Dr. Francis J., Jr., associate professor of psychiatry, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, N.C 6447 Lane, Dr. Mary E., clinical director, Contraceptive Service, Margaret Sanger Research Bureau, 17 West 16th Street, New York, N.Y~_ 6640 Lewison, Dr. Edward F., surgeon; and chief of the Breast Clinic, Johns Hopkins Hospital, 550 North Broadway, Baltimore, Md~. 6648 McCain, Dr. John R., private practice of obstetrics and gynecology, 384 Peachtree Street, NE., Atlanta, Ga 6470 Meier, Paul, Ph. D., professor of statistics, Department of Statistics, University of Chicago, 1118 East 58th Street, Chicago, Ill 6548 Peterson, Dr. William F., Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, 110 Irving Street NW., Washington, D.C 6758 Piotrow, Mrs. Phyllis, secretary and member of the board of directors, Population Crisis Committee, 1730 K Street NW., Washington, D.C.; accompanied Gen. William H. Draper, Jr., honorary chair- man, Population Crisis Committee 6684 III PAGENO="0004" Iv Statement of-Continued Page Ratner, Dr. Herbert, public health director, Box 31, Oak Park, Ill__ 6716 Ryan, Dr. Kenneth J., chairman, Department of Reproductive Biology, Case Western Reserve University, 2065 Adelbert Road, Cleveland, Ohio 6540 Schrogie, Dr. John, Food and Drug Administration; accompanied Dr. Charles C. Edwards, Commissioner, FDA 6779 Schulman, Dr. Harold, associate professor, Department of Obstetrics and Gynecology, Albert Einstein College of i\'Iedicine, Yeshiva University, 1300 Morris Park Avenue, New York, N.Y 6768 Southam, Dr. Anna L., lecturer, Department of Obstetrics and Gyne- cology, College of Physicians and Surgeons, Columbia University, New York, N.Y. (written statement) 6682 EXHIBITS Bibliography of references submitted by Dr. Francis J. Kane, Jr., associate professor of psychiatry, Department of Psychiatry, University of North Carolina School of i\'Iedicine 6459 Article, "The Pill On Trial: Adverse Reports Lead Many Women To Switch Birth-Control Methods-No Fresh Medical Evidence Seen in Senate Hearings, But Users Express Alarm," from the Wall Street Journal, Feb.2, 1970 6462 Article, "Pregnancies Follow Birth Pill Publicity," by Jane E. Brody, from TheNew York Times, Feb. 15, 1970 6464, 6698 Article, "Bad Publicity and `The Pill'," by Wrhayne Eisenman, from the WashingtonPost, Feb. 21, 1970 6465 Chart, emotional or psychiatric problems 6480 Chart, centralnervous system symptoms 6481 Chart, altered menstrual cycle after omission of pills 6481 Chart, infections 6481 Chart, abnormal changes in pelvic organs 6481 Chart, vascular accidents 6481 Chart, miscellaneous complications 6482 Chart, major complications associated with the oral contraceptive pills - 6482 Curriculum vitae of Dr. Elizabeth B. Connell, associate professor, Depart- ment of Obstetrics and Gynecology; director of research and develop- ment, International Institute for the Study of Human Reproduction, College of Physicians and Surgeons, Columbia University 6502 Letter, dated Nov. 18, 1969, to Dr. Edwin Ortiz, Director, Division of Marketed Drugs, Bureau of Medicine, Food and Drug Administration, from Dr. Paul Meier, professor of statistics, University of Chicago 6555 Brochure, "Methods of Contraception in the United States," a publication of the Medical Committee of Planned Parenthood-World Population, revised in 1968 by: George J. Langmyhr, i\I.D., medical director, and George C. Denniston, M.D., associate medical director 6573 List of contraceptive products prepared by the Medical Department of Planned Parenthood-World Population, August 1968 6592 Brochure, "Modern Methods of Birth Control," a publication of Planned Parenthood-World Population, revised 1968 under the direction of George J. Langmyhr, M.D., medical director 6596 Letter, dated Feb. 26, 1970, to Hon. Jacob K. Javits, U.S. Senate, from Donald G. Harris, Marketing Administration, Mead Johnson Labora- tories 6614 Letter, dated Jan. 12, 1970, to "Dear Doctor," from Dr. Charles C. Edwards, Acting Commissioner, Food and Drug Administration, Department of Health, Education, and Welfare, with accompanying revised oral contraceptive labeling 6621 Article, "Poll on the Pili-18 Percent of U.S. Users Have Recently Quit," from Newsweek, Feb. 9, 1970 6627 Statement of Senator Gaylord Nelson with accompanying press release of the American Association for Maternal and Child Health, Inc., dated Apr. 29, 1970 6638 Article, "The Gallup Poll-Pill's Safety Is Doubted by Women," by George Gallup, from the Washington Post, Mar. 1, 1970 6659 PAGENO="0005" V Biography of Dr. Max Cutler, surgical staffs, Cedars of Lebanon and St. Johns Hospitals, Los Angeles, Calif.; and director, Beverly Hills Cancer Page Research Foundation 6661 Letter, dated Feb. 24, 1970, to the Subcommittee on ~\`Ionopo1y, Select Committee on Small Business, U.S. Senate, from Dr. Edward T. Tyler, medical director, Family Planning Centers of Greater Los Angeles 6673 Chart, maternal mortality rates by color: United States, each division, and State, 1965-67 (3-year average) 6695 Booklet, "The Medical Hazards of the Birth Control Pill," Dr. Herbert Ratner, editor, December 1969 (excerpts) 6719 Excerpt of article, "Oral Contraception Dropout Rate," by Dr. Herbert Ratner, from Science 155, 951, Feb. 24, 1967, with accompanying answers by Norman B. Ryder, Department of Sociology, University of Wisconsin, and Charles F. Westoff, Department of Sociology, Princeton University 6755 Bibliography of references submitted by Dr. Herbert Ratner 6757 Curriculum vitae of Dr. Herbert Ratner, public health director, Oak Park, Ill 6757 Statement, "What You Should Know About Birth Control Pills (Oral Contraceptive Products)"-FDA proposed language for a reminder leaflet of uniform content which will be placed by the manufacturer into each package of oral contraceptives produced 6800 Wright committee reports on Enovid, dated August 4 and September 12, 1963, excerpts 6809 Letter, dated June 3, 1970, to Hon. Gaylord Nelson, chairman, Subcom- mittee on Monopoly, U.S. Senate, from M. J. Ryan, Acting Director, Office of Legislative Services, F1)A, with accompanying correspondence of Drs. Irving S. Wright and Leonard Schuman 6819 Letter, dated June 3, 1970, to Hon. Gaylord Nelson, chairman, Subcom- mittee on Monopoly, U.S. Senate, from M. J. Ryan, Acting Director, Office of Legislative Services, FDA, re number of cases of thrombo- embolic phenomena reported to FDA from all sources, 1966-69 6821 Article, "Washington Close-Up-Assessing Blame in `Pill' Confusion," by Judith Randal, from the Evening Star, Jan. 22, 1970 6822 Article, "Birth Pill Warning Is Diluted," by Stuart Auerbach, from the Washington Post, Mar. 24, 1970 6823 Article, "F.D.A. Restricting Warning On Pill-A Draft Revision Indicates Original Is Toned Down," from the New York Times, Mar. 24, 1970 - 6824 Press release, dated Mar. 23, 1970, from the Office of U.S. Senator Thomas J. McIntyre 6825 Article, "Pill Advice Still Unclear as FDA Spurns New Wording-Agency Prefers Short Warning, Despite Protests, by Morton Mintz, from the Washington Post, Apr. 6, 1970 6825 Letter, dated Mar. 27, 1970, to Commissioner Charles C. Edwards, FDA, from Theodore 0. Cron, President, American Patients Association 6826 Article, "HEW Publishes Warning on Pill," from the Washington Post, Apr. 8, 1970 6827 Article, "FDA Moves to Enforce Revised Warning on `Pill'," by Judith Randal, from the Evening Star, Apr. 7, 1970 6827 Proposed Statement of Policy Concerning Oral Contraceptive Labeling Directed to Laymen, by the Dept. of Health, Education, and Welfare, FDA, from the Federal Register, Vol. 35, No. 70, Apr. 10, 1970, pp. 5962-5963 6828 Letter, dated May 7, 1970, to The Hearing Clerk, Department of Health, Education, and Welfare, from Hon. Gaylord Nelson, U.S. Senator 6830 Article, "FDA Goes to the Consumer," from Science News, Mar. 14, 1970 6830 Article, "AMA Opposes `Pill' Warning," by Morton Mintz, from the Washington Post, May 11, 1970 6831 Article, "AMA Pledges All-Out Fight Against Birth-Pill Warning," by Victor Cohn, from the Washington Post, June 24, 1970 6832 Article, "The Pill and the Public's Right to Know," by Morton Mintz, from The Progressive, May 1970, pp. 25-27 6833 Article, "Washington Close-Up-'Pill' Raises Issue of Right to Know," by Judith Randal, from the Evening Star, Mar. 13, 1970 6836 PAGENO="0006" VI HEARING DATES February 24, 1970: Page Morningsession 6447 Afternoon session 6508 February 25, 1970: Morning session 6561 March 3, 1970: Morning session 6659 Afternoon session 6715 March 4, 1970: Morning session 6779 NoTE-Appendixes to Part 16 (Oral Contraceptives-Volume 2) have been printed in Part 17 (Oral Contraceptives-Volume 3). PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition In the Pharmaceutical Industry) TUESDAY, FEBRUARY 24, 1970 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to notice, at 9 :35 a.m., in room 4221, New Senate Office Building, the Honorable Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson, Javits, Dole, and Hatfield. Also present: Benjamin Gordon, staff economist; Elaine C. Dye, clerical assistant; James P. Duffy III, minority counsel; and Denni- son Young Jr., associate minority counsel. Senator NELSON. We will resume hearings at this time. Our first witness this morni~'ig is Dr. Francis Kane, Department of Psychia- try, University of North Carolina Medical School, Chapel Hill, North Carolina. Dr. Kane, we are pleased to have you take the time to appear this morning. Did you submit to the committee some biographical data? STATEMENT OF DR. FRANCIS I. KANE, IR., ASSOCIATE PROFESSOR OF PSYCHIATRY, DEPARTMENT OF PSYCHIATRY, UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE, CHAPEL HILL, N.C. Dr. KANE. No, I was not asked to. Senator NELSON. Would you wish to state briefly your medical credentials for the record, or, if you wish, to submit it later, what- ever you wish. Dr. KANE. I am an associate professor of psychiatry at North Carolina University Medical School. My principal job is as director of psychiatric in-patient services. I have also done research related to the area upon which I am going to comment for a number of years. I possess a medical degree from New York Medical College. Will that be sufficient? Senator NELSON. Fine. Go ahead, Doctor. Your statement will be printed in full in the record. You may present it in any way you desire. If you wish to elaborate on anything you have said in your statement or exteii porize on it, feel free to do so. I assume that if (6447) PAGENO="0008" 6448 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY some questions occur to the committee, you do not mind being inter- rupteci. Dr. KANE. Fine. Senator NELSON. Thank you very much. Doctor. Dr. kANE. Mr. Chairman, members of this committee, I have been asked by this committee to present a report oil one of the newer entries to the "diseases of medical progress," a term used to describe illnesses newly generated by our potent therapeutic agents. The earlier studies on oral contraceptive agents, as I will document later, seem to indicate little problem in this area. However, in view of the large literature on mood and behavior alterations in relation to sexual hormone variation in women, such reactions should come as no surprise. Psychiatric reactions. especially depression, in the early postpreg- nancy period are commonplace in the practice of obstetricians. We from our department. recently reported that 28 percent of a group studied of normal women reported subjective symptoms of anxiety and depression in the postpregnancy period, confirmed by psycholog- ical test materials. Somewhat more surprising, however, was the fact that this figure was less than half that of the changes reported in the last 3 months of pregnancy. These are normal pregnant women. These are not psychiatric patients. While rates of psychosis among pregnant women are below those rates expected in nonpregnant women. in the early postpregnancv period milder forms of illness become less frequent and major psychoses, which many psychiatrists feel are unusual in their clinical phenomenology. dramatically increase in incidence. The fact. that 80 percent of these psychotic epi- sodes occur within the first 30 days after delivery suggests a rela- tionship to the diramaticall altered endocrine state occurring at. the endi of pregnancy. The menstrual cycle is also associated with alterations in mood and behavior, especially immediately prior to and during the menses. A number of studlies have documented the markedily increasedi incidence of psychiatric illness dlurmg this periodi, incliid- ing slucidles, suicidle attempts. homicides. and adlmmssions for a cute psychosis. Some have attributed this to the decline in hormones taking place dhlrmg this time. The relief of premenstrual symptoma- tology by the oral contraceptive agents is striking in some studies andl ma be related to the shortening of the period when there are low levels of hormones. Another period of major psychosocial endocrine change for a woman is the menopause. which also is associated with a marked increase in incidence of major and minor psychiatric illness. The incidence of such illness, especially so-called involutional psychotic reactions, is more than 3 to 1 in favor of women. The use of steroidi hormones for treatment of various conditions has also been associated with notable mood and behavioral change in a certain number of people receiving these drugs. A variety of stud- ies have reported mildi to moderate euphoria and increased well- being as well as tiredness. depression. and increased irritability. Frank manic and depressjve psychotic episodes with higher dosages of steroids are not unusual. Animal and human studies would also PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6449 predict alterations in sexual behavior as a result of hormone use. I shall now review my own work and that of others bearing on the frequency and severity of emotional disturbance associated with oral contraceptive agent use. It must be borne in mind that almost all of the studies to be reported here refer to combination oral con- traceptive agents with little data of a systematic kind being avail- able on sequential hormonal agents.' Glick surveyed the available literature on the use of oral contra- ceptive agents. Nineteen studies, mostly by obstetrician-gynecologists, revealed sporadic reporting of emotional distress, with a 5 percent incidence of depression being the highest reported. There were more favorable comments reported, though these comments, like the others, were likewise largely anecdotal. A similar scattering of reports from the same clinical material showed increased "libido," increased satis- faction with sexual relations, increased control of menstrual pain, and decreased premenstrual tension. Changes of adverse kind were much less frequent, but they were reported for all except premen- strual tension symptoms. Several not following this pattern Wearing reported, with a 16-percent incidence of depression in 62 patients, and when it occurred, the depressioii became more prominent the longer the patient remained on drug. Moos reported a questionnaire survey of women asked to rate a variety of symtoms separately for menstrual, premenstrual, and mter1nenstrual phases of their most recent cycle and for their worst cycle. He reported that almost 80 percent reported slight decrease in menstrual symptoms, while 10 percent had a significant increase and 10 percent a significant decrease in menstrual symptoms. Sequential hormone users reported more symptoms of water retention a.nd nega- tive feeling than the combination drug group. Bakke reported a double blind crossover study of an estrogen-pro- gestin mixture, estrogen, and placebo in a menopausal group. In other words, there were three groups of treatments. Each patient took each treatment, but they did not know which they were taking. Twenty of 27 women preferred either estrogen or the oral contracep- tive agent, which is to be expected in this age group. Complaints of moodiness, being cross and tired, alterations in sexual drive, weight gain. eden'ia, and insomnia were commonest in the group using the estrogen-progestin group. Twelve women reported increased sexual drive. Six women who enjoyed the increase in drive continued on the drug, while six rejected the drugs because of this same change. Scott and Brass reported their experience in the use of massive doses of norethynodrel in the treatment of endometriosis on 20 patients. Daily dose varied from 40 to 100 mg. of norethynodrel. They com- mented that "mood and behavior changes were noted in all patients, and three developed moderate depressions that responded to antide- pressant drugs. One patient also developed a tremendous increase in libido." Senator JAVIT5. Mr. Chairman, could we ask the witness, so we can appraise what he is testifying, whether there is any standard term of use of the pill by the people about whom he is testifying? I-low long had they used it? 1 NoTE-Bibliography at end of statement. PAGENO="0010" 6450 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Dr. KANE. Well, these are documented in the studies. I do not remember offhand. The Scott and Brass study--- Senator PJAVITS. I am told it was 30 days or less. Is that true? Dr. KANE. Oh. that is-I am sorry? Senator PJAVITS. That is, the use of the pill was only for 30 days or less of all of the cases that you are reporting. Is that true? Dr. KANE. Are you talking about some of my own work or the work I am reporting? Senator ~JAVITS. What you are reporting. Dr. KANE. I have not reported any of my own work as yet. Senator JAvITs. Will you let us know, if it is not contained in your testimony, submit a list as to how long each of the patients that you are describing had used the pill before you came to your conclusions in these cases? Dr. KANE. You are getting sort of ahead of the game. Let me state it this way. WThat, you are referring to represent cold metabolic studies. To my knowledge, I think I probably studied only 10 patients, all of whom had taken it for a month. That refers only to studies on neurohor- mone excretion. In many of the studies which have been reported here, the patients had been using the drugs for a considerable period of time. Senator JAVITS. All I want to know is in each case, how long was the pill used. You have already told us that in your 10 cases, it was a month, right? Dr. KANE. Senator Javits. I think it is very difficult. I have given the references to the committee and those can be found, generally speaking, in the studies being reported~ especially the clinical studies and some of the studies I will report in some detail later, generally the women were using them every month, the clinical studies. The kind of studies I was doing had a different purpose. We were really not studying it so much-we were studying biological alterations and we were not interested, really, in a number of other things. Senator JAvIT5. In the 10 cases you have described, it was a month? Dr. KANE. The 10 cases on which certain conclusions are based only. Senator JAVITS. That is what I wanted to know. Dr. KANE. Yes. In these other studies I have reported, these people were using the drug regularly.. We first became int.erested in this when we observed a patient who had a psychotic episode upon withdrawal of a large amount of Enovid used to control endometriosis. The patient experienced relief of her psychotic behavior with drug replacement and intensification of her psychosis when we withdrew the drug once again. We have seen four additional women since that time who have suffered psy- chotic episodes coincident with the use of oral contraceptive agents. In two instances these were associated with the use of the combined agents and in two with the use of sequential hormone combinations. One patient noted change with both, although she became hospital- ized while using the sequential agent. Three of these women gave a history of postpregnancy disturba.nce in the past and one was receiv- PAGENO="0011" COMPETITIVE PROBLEMS IN ~PHE DRUG INDUSTRY 6451 ing psychotherapy for a character disorder. One patient tolerated sequential agents very well for a year but suffered psychotic episodes with only 1 month of combination drug use on separate occasions before and after the use of the sequential agents. This would seem to raise a question as to whether there is not some increased risk in using these drugs in persons with known psy- chiatric illness. There have been two additional reports of psychotic reactions in the world literature. Idestrom reported another case of psychosis upon withdrawal of drug; in this case, norethindrone. Sturgis reports recurrence of psychosis in a patient participating in the prospective study of drug effects. The frequency of a prior psychiatric history among those who had psychosis prompted us to undertake a study comparing normal women with psychiatric patients as regards their reactions to regu- lar use of the pill. In this situation, we were comparing women who were regular users on a retrospective basis. We were asking them questions about their previous use. One hundred and thirty-nine married women who had never had psychiatric care were compared with 64 women who had previous history of psychiatric care. These were private patients attending clinics at the North Carolina Memorial Hospital, while the psychiat.- nc patient.s were private patients hospitalized on our wards. Among those without previous psychiatric care, 64 perceiit of the 139 women reported feeling different than their previous selves. Depression 34 percent, irritability 29 percent, a.nd lethargy 24 percent were most often seen. About 10 percent of these women had increased well- being only, meaning they felt more peppy and had increased vigor. In other words, 10 percent of the users stated in some instances they felt better than they ever had before. Another 2 percent reported an increase in sexual pleasure only. Thus, 52 percent of the entire sample reported undesirable consequences of using the pill. Decreases in sexual desire or capacity for sexual pleasure were found far more often than an increase. When those with symptoms were compared with those without symptoms on a variety of back- ground figures, factors usually associated with neuroticism, such as disability of the menses and significantly decreased frequency of sexual intercourse and capacity for sexual pleasure were found to discriminate the two groups. In other words, the people who had reactions seemed on history to be psychiatricly more loaded. About 15 percent of these women who complained about the effects of the drug stopped the medication for this reason, while another 10 percent reported they had wanted to but had been dis- suaded from doing so by their physician. Perhaps the most extreme of these was the wife of a member of the health professions who complained to her husband that she had become depressed and was having suicidal ideas. She had never felt this way before and won- dered if the oral contraceptive medication might be involved. He assured her that this could not be so because such complaints were not included in the list of side effects on the package insert which accompanied the medication. Senator NELSON. May I ask what date was that? PAGENO="0012" 6452 COMPETITIVE PROBLEMS fl~ THE DRUG INDUSTRY Dr. KANE. That was prior to the listing of these. This was in 1966 or 1967. The lady in question, her husband was a druggist. After reading the package insert, he decided it couldn't be, and she experi- enced relief of the symptoms when she stopped the medication. Senator NELSON. But the package insert now includes even mental depression as a side effect? Dr. KANE. Yes. it does. Senator JAVITS. As I recall your figures, you spoke of 52 percent.. Dr. KANE. Right. Senator JAVITS. You accounted for 25 or 27 percent. What hap- pened to the others? Dr. KANE. The symptomology is such, and this is borne out in a number of other studies. The symptoms are, in some, of fairly mod- erate intensity. These seemed to be the women who stopped the drug. As I will document for von later, the Swedes seemed to have some- what. the same experience. Their principal reason for stopping the drugs was psycl~iatnc. The others sort. of say, well. they are choosing between t.he lesser of two evils. They would prefer feeling a. little tired and a little irritable to being pregnant. Senator JAVITS. Don't von think that has to be compared to the effects of not using the pill and getting pregnant, in terms of mental depression? Dr. K~\xE. This is often so, Senator Javits. but I think it should not be compared with not. using the pill or being pregnant and using another form of contraception. Senator JAVITS. If they would use it. It also must t.ake into account, must. it not. whether or not. the other would be resorted to as frequently. That is a factor. isn't. it? Dr. KANE. That is a problem. again, one of a kind of informed consent. I think as long as the patient knows she is taking risks of this type. I have tall:ed to wives of my colleagues who have felt badly w-hile taking the medication and they have chosen to stay on it.. They have saicL well, I will come back and see von if I feel worse, which I think is fine. They are making a choice for them- selves based on the information there at hand. That is fine, I think. People can choose as long as the have the information. Senator JAVIT5. Now, this work that you discussed, has that been done on any prepondera1~tly economic group, mididlle class or lower class? I am not. trying to characterize people, just. da.t.a. Dr. KANE. Well, my own was. My own was principally, I guess von would call it., white lower to upper midldlle class patients in the university hospital. The Swedish studlies, I think, are more representative. One was clone-both were clone in university hospitals. I think again with some of the lower socio-economic groups, my experience has been, in talking with the ward patients in the hospital, that the pill has a ba.dl name, quite frankly. I couldn't report you a studly. Senator JAVITS. That. is not. clinical research. Now you are talking about hearsay, is that right? Dr. KANE. Of course. I am talking about why we don't see many of these people. I have no explanation for this. PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6453 Senator JAVITS. Well, the only reason I am asking you these ques- tions is because I have the impression that these hearings have given the impression that this, was all bad or a good deal bad and it scared a lot of people. I think that if we really want to do a responsible job in so critical au area, especially with people who really have unwanted children, and I am speaking mainly of numerous families who are the subject of poverty, I think we have to be extremely careful that we know what we are talking about. I hope very much that those who testify, and I am delighted to see that our witness from New York, Dr. Connell, who is doing precisely that, will bear that in mind. WThat's said here can have an enormous effect. And it is having an enormous effect. It is not just a hearing on camera. It is vitally important that a ba]ancedl picture be presented by everyone who testifies. I understand that certainly yoti want the truth and the facts, but we want balance, too, I should think. For men as eminent and able as the witness, it seems to me that it would be extremely helpful if they bore that in mind, that we are dealing with millions of human lives. It is very easy to scare and thus it may be very regressive, or I can see situations where it may be entirely appropri- ate. I think we should have a very balanced picture of social and economic status, with broad saniplings, with understanding in detail of what's afoot, and not an a priori effort to prove the case. Senator NELSON. Let me say I am the only one of the committee who has sat through all the hearings. We have called on the most distinguished witnesses we can find in the country. I think they have given their honest interpretation of the effects of the use of the pill. I do not know of anyone who has appeared who has not done so. They have their differences, but I do not see how we could have secured a more qualified list of witnesses, nor a more balanced group. Go ahead, Doctor. Dr. KANE. Among the psychiatric patients, frequency of morbid- ity was even higher. Eighty-five percent of the psychiatric patients perceived change, most of these being adverse reactions. Here again depression, irritability, and lethargy were most frequently reported. Time psychiatric patients were different in that it seemed to enhance both their sexual desire and capacity for sexual orgasm. They also showed much more sensitivity to stopping the drug every month, indicating some withdrawal effects. While this figure of morbidity with the pill seemed high to us, andi concerned us considlerably, because this was higher than anybody else had reported before, a Swedish study reportedi by Nilsson andl his colleagues supported our findings. They reported on a questionnaire study of 344 women who had received oral contraceptives during the year 1964 at the Univer- sity department in Sweden. They had a 91-percent response to their questionnaires. Of 138 women who stopped using the medication, weight gain and emotional disturbances were the most frequently reported, 26.1 percent and 23.9 percent. Forty-nine percent reported either worsening of previously existing symptoms or a development of new symptoms. In women without a previous psychiatric history, 45 percent reported new symptoms of emotional distress. Fifteen percent of these had five to 10 symptoms. The results of their survey PAGENO="0014" 6454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY suggested side effects of a psychiatric nature are almost as common as purely somatic symptoms and that in many cases the intensity of the side effects is sufficiently great to motivate earlier cessation of oral contraceptive treatment. Senator JAVITS. Doctor, are we to assume that the pill remains the same from 1964 to date? Dr. KANE. No. Senator JAVITS. I mean that there have been no changes or refine- ments or developments, either in the administration or in the medi- cation itself? Dr. KANE. You raise a great problem, Senator Javits. I would not argue with it at all. We do not have enough information. Senator JAvvrs. I do not know. Dr. KANE. There is not enough medical research. If you want to make a pitch for that, I could not agree more. Senator JAvITS. I do not make any pitch. I want to know, is there a difference in administratioii or medication? Dr. KANE. I do not know. There has not been enough research. Senator JAVITS. But is there a different pill, is it differently administered? What's the fact? Dr. KANE. I would say there are no studies available. Senator JAVITS. But is it the same pill? Do they take the same thing, is it administered the same way? You should know that. Dr. KANE. I think there are differences. I am not an obstetrician. Senator JAvITS. Do you not think that has a very material effect on your conclusions, that they use the same thing? You are giving us a `fact that you say is evidence now. Dr. KANE. I think you are making an assumption that I think has no basis in fact. Senator JAVITS. I am not making any assumption. I am asking you a question: Is it the same pill, is it administered the same way? Dr. KANE. I don't think so. I think your assumption is that it is going to be different. Senator JAVITS. I don't assume a thing, sir. I am asking you. You are a doctor. I am only a senator and a lawyer. I am not a researcher. I do not know anything about it. Dr. KANE. Fine. Senator JAvITs. All right, go ahead. Dr. KANE. Among the individual symptoms, those of a neures- thenic-fatigability, emotional lability, irritability-or depressive character-feelings of depression, sleep disturbance, inferiority feel- ings, difficulty in starting work-were the most commonly encoun- tered. The frequency of psychiatric side effects is not related to age, parity, marital status, or social class. Those more likely to develop problems of an emotional nature with oral contraceptive agents were: (1) women with a previous history of psychiatric symptoms; (2) women who have experienced emotional problems or severe nausea or vomiting in earlier pregnancy; (3) women who were sig- nificantly overweight prior to the start of treatment, which is in itself usually associated with an underlying susceptibility to psychi- atric illness. Impaired sexual desire was reported by 25 percent of those using the pill, while almost 50 percent reported their sexual PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6455 adjustment to be improving. Eighty percent of this total related to an increasing security regarding pregnancy rather than an increased sexual desire. Actually 10 times as many women reported decreased sexual desire. In this study, as in our own, 9 percent reported only beneficial effects and fewer symptoms of emotional disorder. In 1968, Nilsson and his colleagues reported a prospective psychiatric and psychological investigation of 169 women during pregnancy and the postpregnancy period, comparing 54 women who were prescribed oral contraceptives during the postpregnancy period with 104 women who used other contraceptive methods. There were no differ- ences between the two groups with respect to psychiatric symptoms and psychological or social factors before medication. Senator NELSON. May I ask, during~ the Nilsson studies, were they using a sequential or not? Dr. KANE. No, as I commented earlier, almost exclusively what I am reporting are the use of combination agents. Senator Javits raised the question as to whether sequential agents do not make a difference. I think there is no information. There simply is no research in this area and there are no answers. Senator NELSON. So these were all fixed combination? Dr. KANE. Right. Almost everything I say has to do only with combination agents. There is simply no information on sequentials. Senator NELSON. Did you recite, did you identify in your bibliog- raphy the Nilsson study? What was the date of that? Dr. KANE. 1967 or 1968. You have the bibliography. I do not have mine here. Senator NELSON. Did they identify the brand of drug they were using? Dr. KANE. I think they did. Senator NELSON. So then if they identify the brand, anybody can find out how many micrograms of estrogen are in the drug? Dr. KANE. Right; that is correct. Senator NELSON. Then, of course, that identifies the synthetic agents and how many iriicrograms- Dr. KANE. Correct. That is all contained in the body of these ref~ erences. Senator NELSON. The studies would reflect the effect of that drug, whether it be 100, 75, or 50 micrograms, and everybody would know that it was that level of estrogen content that was involved in the study and not another level? Dr. KANE. Yes; correct. In this study during the postpregnancy period, a significantly higher frequency of psychiatric symptoms was found in the oral contraceptive group as regards both the total number of psychiatric symptoms and individual symptoms of a neuresthenic and depressive nature. They felt these to be related to the medication. In June of 1969 another study was reported by Lewis and Hog- hughi in the British Journal of Psychiatry. This was a study of 50 pill-takers in a working class general practice in England. Of the 62 women who were known to be taking oral contraceptives, 50 were agreeable to answering questions. A clinical assessment to their mood/state was made by a psychiatrist, and objective rating scales of PAGENO="0016" 6456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY depression were also used. Information about previous depressive episodes and previous mental illness were also collected. They were compared with 50 married women of childbearing age who had not used oral contraceptives. There was no difference in socioeconomic status and very little difference in age. While there was no difference in history of past depressive episodes in either group, the clinical assessment of depression revealed that 14 of the pill sample, or 28 percent, had depression of mild to moderate proportions, while only three of the control group reported this. A comparison of the depression rating scores showed the pill sample to have distinctly higher scores, meaning greater depression than the non-pill-takers. As with the other studies reported, when the intensity of depressive symptoms were analyzed, scores for the pill groups were particu- larlv high for guilt., self-absorption, and loss of energy, but sleep disturbances were not noticeable. Two suicicla.l attempts in the pill sample were found. which had not been disclosed to the general practitioner. Since completing the study. another depressed pill- taker had made a serious suicidal attempt. They comment, and this is my experience also, that while many of these women were aware of the depression as a side effect., they were prepared to tolerate it rather than risk further pregnancies. Loss of interest in sex was very general in both groups. Their data also showed that those with a history of previous depressive illness had much higher scores on the depression test than those who cud not have a positive history of emotional illness. In other words, the results strongly suggest that women predisposed to depressive breakdown react more adversely to any psychiatric side effect the oral contraceptive may have. There is also a trend toward higher scores with lengthening periods of medi- cation and with increasing progestin content of the steroid. This latter comment here may answer, at least in part, one of the questions Senator Javits raised, which was, "Is there any evidence tha.t there may be less or more with other kinds of pills?" There is some suggestion from this study and one other that if you decrease the progestin in the pill, this may have a lesser effect on depression. However, there have been no clinical studies that I know of, and the area remains one for research. Again, as I said ~n my paper, unfortunately, when I asked my col- leagues about this, the sequential agents are in low repute as antifer- tility agents. I report that only as again being a factor that bears upon this. Mr. GORDON. Dr. Kane, why is that? Dr. KANE. They just don't feel it is as effective as the other drugs, there is more risk of pregnancy with these audi they are reluctant to use it for other reasons. Again, this is out of my area of expertise. I am not an expert in this. But just in asking my colleagues about their responses audi what their impression hadl been, this is what they toldi me, that they would prefer to use the combination dirugs still, themselves. In an attempt to elucidlate further the mechamsm underlying these changes, we have studied 10 experimental subjects to date, especially with reference to neurohormone metahohite excretion in urine. In addition to behavioral changes similar to those reported in PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6457 other studies (fatigue, tiredness, lethargy, mild to moderate depres- sion, and loss of sexual desire), there has also been an alteration in neurohOrmone metabolite excretion. There also seems to be some var- iation in neurohormone excretion relative to size of dose of the pill. Again, I think, this would bear somewhat on the question Senator ~Javits made. At the present time, these studies are very preliminary, and number of patients studied must be increased before we may draw very many final conclusions from the data available. In another very interesting study, Morris and TJdry demonstrated that the general 1h3~sical activity level of women taking oral contracep- tive pills is lower than that of women not taking pills, as measured by the use of a peclometer, which was used daily for a 90-clay period. Dr. Morris commented in this study that these women did not complain of depression and had not had a great deal of difficulty with the pills. I-lie pointed out that if there were any bias in the study, it would be on the side of women who had experienced the least side effects. Now, this is very similar to the running activ- ity, depression of running activity that one sees in animals, and this is precisely why they did the study this way, a general lowering of the physical activity of animals, if you study them in running cages. In summary, the studies I have discussed in some detail with you are in substantial agreement on a number of points. First, there is a considerable incidence of mild to moderate psychiatric morbidity associated with the use of combination oral contraceptive agents. The principal manifestation of this morbidity is in the form of feel- ings of depression, sleep disturbance, feelings of inferiority, and dif- ficulty in starting work. Neuresthenic symptoms in the form of fatigability and increased emotional lability and irritability are also extremely common. In three of the four studies, there seems to be agreement that those who have required psychiatric care in the past will be more at risk for the development of morbidity, including psychosis. One study also suggests that there may be some increase in depth of ilh~ess the longer the medication is taken. The study of Doctors Morris and TJdry with regard to the decline in activity would also seem to be in support of the clinical picture described. This would also seem to be compatible with the clinical phenomena generated when other drugs which affect neurohormone n'ietabolism are used. These agents, too, have been associated with a 10- to 15- percent incidence of depression serious enough to warrant discontin- uance of medication. These medications would be anti-hypertension agents such as Rauwolfia drugs and so on. The clinical phenomena accompanying the pseudopregnancy induced by the pill are similar in kind and frequency to those seen during normal pregnancy. There is one significant difference, how- ever, and that is the length of the pseudopregnancy may be much longer than the natural event. The psychotic reactions seen after withdrawal of medication also resemble the clinical phenomena seen in the psychotic reactions at the termination of pregnancy. With regard to the effects of combination oral contraceptives on sexual functioning in the human, the expression of sexuality is less closely tied to hormones, but the evidence does indicate that there is 40-471-70-pt. 16-vol. 2-2 PAGENO="0018" 6458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY some general relationship between the two. The agreement on changes in sexual desire and capacity for orgasm are less well agreed upon b all the investigators. There does seem little doubt that it impairs the desire and capacity for sexual pleasure in 10-15 percent of women who use these medications for any significant period of time. A somewhat smaller percentage seem to have an increase in desire and capacity for pleasure: and this seems espe- cially marked in psychiatric patients, which, I think, underscores the inner relationship between biological and psychological factors in this area. There have been two reported cases of nymphomania, one of whom I saw. From the patient's subjective report and the medica- tion she was using, my guess is that she was responding to this as to a male hormone testosterone, to which the medication she took is related chemically. The clinical picture was very similar to that seen with women who have used male hormones for treatment of other conditions. One problem we became aware of in trying to assess changes in sexual behavior in women taking the pill was that the women often did not notice it themselves, but their husbands com- mented on it. This phenomena has been noted by other investigators, but has not been fully exploited from a research standpoint. While the research available in this area with reference to the emotional problems generated by hormone use is not inconsequential, I think all investigators would agree there is much to be done. There are not, as I have told you, any studies of any consequence on sequential hormone users. There has been extremely little in the way of research done on the possible mechanisms underlying these emo- tional changes in the human. For example, our longest study involves only 1-month use of drug. While we were able to demon- strate change during this period of 1 month, we do not know whether there is a return to normalcy with prolonged use in some women. while others who become depressed may not so change. For example, our longest study involves only 1 month of drug use. Senator NELSON. You say there have not been any study of any consequence on sequential pills? Dr. KANE. In reference to behavior. Senator NELSON. Have you reviewed all the published literature on the psychiatric effects or depression effects of the use of- Dr. KANE. I think I am pretty current. Senator NELSON. Do you have a bibliography? Dr. KANE. I have submitted to you, I think, the salient biblio- graphic items you would need, which refer to- Senator NELSON. Referring to the studies that you include in your statement. Dr. KANE. Right. Senator NELSON. How many studies have there been, offhand, on this subject? And when did they start? Dr. KANE. There are actually only four studies that are really at all systematic in their evaluation of behavioral change. The bibliog- raphy I presented to you has to do with the- Senator NELSON. I see the earliest one appears to be Keeler and Daly and Kane, "An Acute Schizophrenic Episode Following Abrupt Withdrawal of Enovid," and so on-1964. Then the next one appears to be 1966, the next one 1967- PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6459 Dr. KANE. The latest is 1969. Senator NELSON. 1967, 1968, and 1969. This bibliography pretty well covers the published literature? Dr. KANE. That is right. Senator NELSON. So in fact, the scope of the study is pretty well limited? Dr. KANE. Very modest, very modest. There are many women who pay a certain price for their infertil- ity and know it. They realize they feel somewhat less well than they did before and may be more irritable and tired, but feel that this price is not too much to pay for avoiding another pregnancy. We do not know at the present time whether continued use of medication in this situation has ultimate deleterious effects. We also do not know what the long term effects of these drugs are, and in this respect the situation is much like it is for the evaluation of cancer. It will be some time before we know whether women who use these medica- tions for years at a time run any greater risk of psychosis than those who use other methods of birth control, even though these may be somewhat less effective. It is only by large-scale epidemiologic studies that these data can be generated. (The attachment to Dr. Kane's statement follows:) BIBLIOGRAPHY 1. Morris, N. M., and Udry, J. R.: Depression of Physical Activity by Contra- ceptive Pills, Am. J. Ob-Gyn 104: 1012-1014, August 1, 1969. 2. Lewis, A., and Hoghughi, M.: An Evaluation of Depression as a Side Effect of Oral Contraceptives, Brit. J. Psychiat., 115: 697-701, 1969. 3. Glick, I. D.: Mood and Behavioral Changes Associated with the Use of Oral Contraceptive Agents, Psychopharmacologia 10: 363-374, 1967. 4. Grant, E. C. G., and Pryse-Davies, J.: Effect of Oral Contraceptives on Depressive Mood Changes and on Endometrial Monoamine Oxidase and Phosphatases, Brit. Med. J. 3: 777-780, 1968. 5. Idestrom, C. M.: Reaction to Norethisterone Withdrawal, Lancet 1: 718, 1966. 6. Kane, F. J., Treadway, R., and Ewing, J.: Emotional Change Associated with Oral Contraceptives in Female Psychiatric Patients, Comp. Psy. 10: 16-30, 1969. 7. Kane, F. J.: Psychosis Associated with the Use of Oral Contraceptive Agents, South. Med. J. 62: 190-192, 1969. 8. Kane, F. J., Daly, R. J., Ewing, J., and Keeler, M.: Mood and Behavior Changes with Progestational Agents, Br. J. Psychiat. 113: 265-268, 1967. 9. Keeler, M. H., Daly, R., and Kane, F. J.: An Acute Schizophrenic Episode Following Abrupt Withdrawal of Enovid in a Patient with Previous Postpartum Psychiatric Disorder, Amer. J. Psychiat. 120: 1123-1124, 1964. 10. Marcotte, D., Kane, F. J., Lipton, M., and Obrist, P.: Psychophysiologic Changes Accompanying Oral Contraceptive Use, Brit. J. Psychiat. 115: 1969. 11. Moos, R. H.: Psychological Aspects of Oral Contraceptives, presented Annual Meeting American Psychosomatic Society, New Orleans, April 13-15, 1967. 12. Murawski, B. J., et al.: An Investigation of Mood States in Women Taking Oral Contraceptives, Fertil & Steril 19: 50, 1968. 13. Nilsson, A., Almgren, P. E.: Psychiatric Symptoms During the Postpartum Period as Related to Use of Oral Contraceptives, Brit. Med. J. 2: 453-455, 1968. 14. Nilsson, A., Jacobson, L., and Ingemanson, C. A.: Side Effects of an Oral Contraceptive with Particular Attention to Mental Symptoms and Sexual Adaptation, Acta Abst. and GynecoL Scand. 46: 5~7-556, 1967. PAGENO="0020" 6460 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Are any long-term studies under way at the present time that you are aware of? Dr. KANE. I really do not know. I have heard Dr. Hertz speak when he was at the NIH of studies with the Kayser group. I do not know whether they are looking into behavior very systematically. They were monitoring for cancer mostly. Whether there are system- atic studies of this sort behaviorially, I do not know. I am not aware of any, but that does not prove anything. The National Institutes of Mental Health could probably furnish you this information. Senator NELsON. Would you know whether all. none, or part of these studies were underwritten by NIH? Dr. KANE. I do not think any of them were. Senator NELSON. You do not think any of them were? Dr. KANE. No. The two Swedish ones were not, mine was not, and neither was the British study. Senator NELSON. Do you consider it important that such studies be conducted, sponsored by NIH and- Dr. KANE. I do not think there is any question about it. I think it should have been done when the pills came out. At some point, we ought to do a prospective study with some of the new drugs, at least now, much ill the model of the Swedish study. and compare these with other contraceptive agents, because this is the only meaningful comparison we can have. Senator NELSON. Thank you very much. Senator Dole, do you have questions? Senator DOLE. Do I understand perhaps in summary that there has been no real valid conclusion reached. Do I interpret correctly, that there are certain areas where there is considerable evidence of mild neurotic psychiatric morbidity associated with the oral contra- ceptive? But are there any other areas ill which you have reached a valid conclusion? These seem to be very inconclusive. Dr. KANE. I think the clinical studies are in very good agreement. I think where I would be very hesitant is to look, say, at the n'ieta- bolic studies we have been doing, because these are based only on 10 patients. I think the fact that all four of the other clinical studies pretty much agree that about half the women feel poorly- Senator DOLE. You are referring to mental depression? Dr. KANE. Right. I am referring only to behavioral effects. There is fairly good agreement that somewhere between 20 and 50 percent of the women are adversely affected and that 10 to 15 percent of the group are going to discontinue medication because of it, I think this can be agreed upon. Whether this will change with other medica- tions, we do not know, because there is simply no information. The information we have clearly indicates that the combination agents, as specified in these studies. and they were specified, do provoke this. There is some evidence suggesting that lower levels of progestin in the pill will give you less trouble. I think again, that remains to be seen. I think more study has to be clone. As these pills come along,. they must be evaluated for this. I am prepared to be convinced that this will change. For instance, when the steroid hormones came out originally, they had a great deal of trouble because excessively large doses were used.. PAGENO="0021" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6461 When they scaled the doses down, they had less trouble. I am pre- pared to suggest this for this, too, but we do not know. Senator DOLE. Since the hearings started-about a month, now, since the last hearing-there has been some stirring in the air that perhaps we may have caused more problems than we are going to solve. But I would like, Mr. Chairman, at this point in the record, to put in some stories in the Washington Post, the New York Times, and the Wall Street Journal which indicate the alarm among thou- sands and perha~s millions of women in America resulting from some of the statements made here. Dr. Kane, the point is, after reviewing all these studies, what con- clusion can be reached about the pill itself? Do you think the risks or the behavioral symptoms would indicate that the pill should not be taken, or- Dr. KANE. I certainly think that there is an indication that patients with a history of prior psychiatric illness should use the pills with caution and should be observed by a psychiatrist or some- body for possible adverse effects. It seems clear from all the studies that psychiatric patients are most at risk. Unfortunately, there are probably a fair number of users among this group because of the stresses of pregnancy and what have you. Senator DOLE. The risk of taking the pill, is it greater for those people than, say, an unwanted pregnancy? Dr. KANE. The comparison can't be with an unwanted pregnancy. You are assuming they are going to become pregnant. There are acceptable other modes of contraception. I think it should be coin- pared with other means of contraception. Senator DOLE. Are you familiar with other studies? Dr. KANE. There is only one, the Swedish study. That indicates that there is more psychiatric morbidity among those using the pill than using other contraceptives. Senator DOLE. But you have done none yourself? Dr. KANE. No, that is the only one that has ever been done. Senator DOLE. 1-Tow many people participated in that study? Dr. KANE. 169, something of that order. Senator DOLE. You did indicate in your last sentence that perhaps without a long-range study, there is no conclusion that can be relied upon by those who should be making a decision. Dr. KANE. I think there are some things, yes. Psychiatric patients are more at risk, that anywhere from 30 to 50 percent of the women are going to feel different and they should be aware of this. Senator DOLE. Does that mean they should not take the pill? Dr. KANE. I did not say this. I say they should be aware why they are feeling different and if they do feel different, they should talk it over with their doctor, and he should be aware of this so if the symptoms get worse, lie should discontinue the pill. Some women tolerate these things reasonably well, but they ought to be observed a little more carefully. I say those who are going to become depressed should be observed a little more carefully. Perhaps they should take two medicines, a birth control pill and an anti-depres- sant pill, rather than becoming pregnant. I think that could be their choice so long as they know this is going on. PAGENO="0022" 6462 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator Doi~. With reference to your own study, that involved 10 women? Dr. KANE. That is quite a different order of business. We were trying to look at the underlying mechanisms, the changes in neuro- hormonism, which I think must be studied. There are changes which seem to vary pretty much with dosage. Beyond that, I think we still have a lot of work to do. Senator DOLE. Thank you, Mr. Chairman. If there is no objection, I would like to insert in the record these stories that I have referred to. Senator NELSON. Sure, we will be glad to have them in the record. (The news articles referred to follow:) [From the wall Street Journal, Feb. 2, 19701 THE PILL ON TRIAL: ADVERSE REPORTS LEAD MANY WOMEN To SWITCH BIRTH- CONTROL METHODS-No FREsH MEDICAL EVIDENCE SEEN IN SENATE HEARINGS, BUT USERS EXPRESS ALARM-IUD'S, DIAPHRAGMS IN DEMAND `It's horrible," says a Pittsburgh obStetrician-gynecologiSt. "The phone has been ringing off the wall. Even people who aren't our patients have been call- ing." Something like that has been happening in a number of doctors' offices. The callers are anxious women with questions about "The Pill." Via newspapers, television or word of mouth, they have learned of health hazards attributed to the oral contraceptive in Senate subcommittee hearings called by Sen. Gaylord Nelson, Wisconsin Democrat. The publicity has been intense. Interviews in the past few days with gyne- cologists and other practitioners in several major cities confirm that many of the approximately 8.5 million women using the birth control pill are alarmed and distraught. The interviews suggest that a Sizable proportion of women are asking their physicians hard questions about the pill and its hazards, and a number of them are changing to other methods of contraception. But there is evidence that many women who genuinely worry about side effects of the pill are deter- mined to continue using it nevertheless. IRRITATED MD'S A number of physicians are irritated about the furor. They say that the hearings haven't elicited any new medical evidence. There are charges that the subcommittee witnesses have included a disproportionate share of pill foes. Most physicians queried had made up their minds long ago about whether or not to prescribe the pill, and the hearings haven't changed their minds. Some, however, are taking new pains to inform patients of the pill's possible hazards. The controversy reflects a problem common to many drugs. "There's no per- fect way to thwart nature," says a general practitioner in Cleveland. "When- ever you alter the natural process, there is some hazard." The decision as to who uses the drug becomes a complex one involving the patient, the physician and the Government. The Federal Food and Drug Administration, which passes on the safety and efficacy of drugs and certifies them for marketing, indicated last Wednesday that it was considering unusual measures for the pill. The agency said it might require pill makers to include in each package of pills printed matter outlining the possible health hazards. But the FDA said it wouldn't move to take the pill off the market. ANXIETY QUOTIENT What concerns Dr. Milton Perloff, a general practitioner in Philadelphia, is the anxiety that the health reports have created. "Most of my patients have gotten quite apprehensive," says this physician. "Women like the pill." Dr. Perloff says. "It gives them control over a function they think should be under their control in the first place. Most are seriously interested in restricting family growth. Now they're told the pill is PAGENO="0023" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6463 dangerous, and even though the family doctor thinks it's safe, they're left with question marks. They end up with an underlying worry and anxiety about whether taking the pill is right, and this is sure to be reflected in their every- day life." The hearings produced testimony associating the pill with above-average incidence of blood clots and strokes, and one witness said that hormones used in the pill can cause malignancies in laboratory animals when given in large dosages. There also was evidence that use of the pill might speed the develop- ment of some existing malignancies. Dr. Mabel Brelje, a Denver gynecologist, thinks that most of the testimony at the Nelson hearings so far "is based on inadequate documentation and sometimes outright misrepresentation." The scientific debate continues-the hearings are to resume later this month-but the evidence that many women already have responded sharply to the testimony is widespread. ONLY HALF A5 MANY The Planned Parenthood Center of Pittsburgh tallied its calls during the first few days of the hearings. On the first day, there 34 callers expressing concern about the pill, and about 25 daily for several days thereafter. More than that, there has been a change in the preferences of the women asking for birth-control help. "In the past several days, only half as many women are choosing the pill as had made that choice prior to the hearings," says Mrs. Ellenjane Donahoe, an official of the center. The women shunning the pill are choosing intrauterine devices (IUDs) and diaphragms instead, she says. Many of the callers, Mrs. Donahoe says, "are seeking reassurance." Many physicians find that to be the case with the vast majority of patients who have inquired. Dr. Alfred L. Vassallo, a Dallas gynecologist who sees more than 5,000 women a year, says that only one of each 200 using the pill has asked to be switched to other methods. Dr. Clinton Hathaway, another Dallas gynecologist, finds many patients determined to continue taking the pill despite the uncertainty. "Most of my patients are younger women who just tune out on the criticism," he says. "They handle the emotional conflicts the best way they can." When a woman in turmoil calls him, Dr. Hathaway says he tells her, "Look, you've had no complaints about the pill, you're having no side effects. "I try to equate the dangers," he says. "It's safer taking the pill than having a baby every year." Other physicians who prescribe the pill use equally basic reasdning to reas- sure their patients. "I ask them if they drive a car," says one Cleveland gyne- cologist. "They say yes. I say is it dangerous, and of course it is." The anxious callers aren't always the females taking the pill. "I'm getting all kinds of calls from mothers asking whether their daughters ought to continue on the pill," says Dr. Abraham Rakoff, a Philadelphia gynecologist. Dr. Robert C. Stepto of Chicago says one of his patients recently switched from the pill to an IUD, at the insistence of her husband. Dr. John Arey, a gynecologist in Concord, N.C., offers a reminder that there always have been side effects associated with birth-control pills. He has made a point of explaining them. "I still follow the same procedure I always have," he says. "I tell the patient both sides of the issue and let her make up her own mind." Several other physicians indicated that they now plan a new emphasis on having patients make up their own minds. Dr. Perloff, the Philadelphia GP, says, "It's hard to tell a patient the pill is safe with this controversy going on." He now deals with his patients in this fashion: "I explain that they're only getting one side of the story and that there are many competent physicians who believe the pill's benefits greatly outweigh its dangers. I also tell patients that there is no medication that is without some inherent danger but that in this case the potential danger is relatively small." Dr. Sang B. Rhee, a Cleveland gynecologist, says recent information about the pill and its side effects has caused him to be more selective about prescrib- ing it. "I'm more careful of family history and background now," he says. "I don't give it to any patient where there's a history of blood clot or stroke." PAGENO="0024" 6464 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Another Cleveland practitioner has a new worry. "I don't like the medical-le- gal aspects of this thing," he says. "This is the thing that's going to catch up with all of us." This physician foresees a growing number of malpractice suits from women who suffer serious illnesses. "And they're apt to find a lay jury pretty sympathetic," he says. Some physicians prescribing the pill now limit prescriptions to six months. Then they require the w-oman to stop taking the pill for a monthly cycle or more. "By making the patient go off the pill for a month, you allow normal body processes to return to an undepressed state for a while," says Dr. John Isaacs. a Skokie, Ill., physician. "It's like starting afresh. The prolonged use of any drug without interruption is more dangerous than using it with periodic interruptions." The minority of physicians who have staunchly opposed use of the pill since its introduction are more firm than ever now in their opposition. "I'm switch- ing women from the pill when I can," says a doctor in Cleveland, "and the adverse publicity has made it easier." There have been other related developments. The Planned Parenthood Center in Pittsburgh reports an increasing number of calls inquiring about vasectomy. This is a relatively simple operation for male sterilization in which sperm ducts are closed off. Some druggists are hurrying to broaden their inventories of birth-control devices. For instance, Speices Drug Store in Chagrin Falls Ohio, discontinued the sale of diaphragms two years ago, for lack of customer interest. Now the store stocks them again. [From the New York Times, Feb. 15, 1910] PREGNANCIES FoLLow BIRTH PILL PUBLICITY (By Jane E. Brody) Doctors across the country say they are beginning to see the first round of unwanted pregnancies among women who stopped using birth control pills after adverse publicity in the last few months. "I'm now looking for some one to abort a 14-year-old who panicked," said a New York obstetrician who specializes in family planning among the poor. Another New York physician, a Park Avenue obstetrician, said a patient of his who dropped the pill after reading a "scare report" is in London this weekend to get an abortion. In California, Dr. R. Elgin Orcutt, president of the San Francisco Planned Parenthood Association, reports that "many are coming in for therapeutic abortions, many are going to England and many others are getting criminal abortions." These women, who stopped the pill in a panic and are now trying to deal with an unwanted pregnancy, are experiencing "the most serious side effect," Dr. Orcutt remarked. Dr. Orcutt and about a score of other birth control experts interviewed last week said that they expect the number of unwanted pregnancies to soar in the next few weeks and months among women who have recently given up the pill in favor of less effective contraceptive methods and, in some cases, no contra- ception at all. "We regularly see a crop of unwanted pregnancies-a disturbing number of them-after each hatch of bad publicity," commented Dr. Selig Neubardt, a New Rochelle obstetrician who is the author of "A Concept of Contraception," a popular book on family planning. A Gallup poll taken during the first week of this month for Newsweek mag- azine, revealed that largely because of recent reports of suspected health haz- ards. 18 per cent of women have stopped taking the pill and 23 per cent more said that they were giving serious consideration to doing so. Most of the adverse reports on the pill grew out of the Senate hearings on oral contraceptives held last month by the monopoly subcommittee of Senator Gaylord Nelson, Democrat of Wisconsin. Testimony at the hearings linked the pill to a long list of disorders, includ- ing blood clots, strokes. heart attacks, diabetes. high blood pressure, cancer and arthritis. PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6465 Many physicians in the family-planning field have charged that the hearings were heavily stacked in favor of pill critics who overemphasized the health hazards that are at best speculative. Just prior to the hearings, the long-simmering debate about the pill's safety became intensified with the publication of several books and lay articles and the presentation of broadcasts proclaiming the pill to be dangerous. SOME REACTIONS TO REPORT5 "Unfortunately," Dr. Orcutt said, "many women who heard and read these reports stopped the pill without calling their doctors and without using any other form of contraception." Interviews with obstetricians in various parts of the country disclosed that, of the women who did call their doctors, many decided to stay with the pill after being told that the Senate hearings had produced no new evidence of health hazards. But a far greater number of women, these physicians said, were so dis- turbed and upset by the reports that they decided to switch to other methods of contraception. l\Iany doctors reported "a run on diaphragms" and, to a lesser extent, on intrauterine devices (IUD's). A check of pharmacies in and around New York disclosed a small but significant increase in the sales of contraceptive foams, jellies and creams and condoms, and a definite falling off in sales of oral con- traceptives. Dr. Nathan Chaste, a Providence, II. I., urologist, said he has had a tripling in requests for male sterilization procedures (vasectomies) since the Senate hearings. Several doctors interviewed said that the turn away from oral contracep- tives would not cause too many problems among middle-class and upperciass women who, for the most part, are highly motivated to use other contraceptive methods effectively and who could support another child or obtain an abortion should an unwanted conception occur. "But among clinic patients, who cannot afford another child and cannot back up a contraceptive failure with abortion, the defection from the pill to less effective methods could be disastrous," a spokesman for Planned Parenthood of New York said. Dr. Edwin Daily, director of the city's Maternal and Infant Care program, said that the percentage of new patients who requested and received oral con- traceptives dropped from 68 per cent in December to 47 per cent during the last week in January. Dr. Daily pointed out that, except for sterilization, the pill is the most effec- tive contraceptive currently available. {From the Washington Post, Feb. 21, 197O~ BAD PUBLICITY AND "THE PILL" (By Whayne Eisenman) NEW YoRK-Druggists across the country say recent testimony against birth control pills has alarmed many women but sales of the pill have not lagged significantly yet. Some pharmacists reported, however, that demand for other contraceptives is up. Results of an Associated Press sampling indicate it may be too early to assess the impact of scientists' claims before a Senate subcommittee last month that oral contraceptives may be harmful to health. "Most women buy three-to-six-month supplies, so we wouldn't see an instant drop," noted a spokesman for a Los Angeles pharmacy. The pill usually comes in batches for a month or more. "We've had no decline . . . but people have been asking whether or not the pill is safe," said a Little Rock, Ark., pharmacist in a typical comment. Some druggists reported a decline in new prescriptions for the pill since the subcommittee hearings. But they said most women who were taking the pill before the hearings continued to refill their prescriptions. PAGENO="0026" 6466 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The pill was named at the hearings as a possible factor in blood clots, cancer, heart disease and other ailments. Robert H. Finch, secretary of health, education and welfare, advised doctors to alert women to possible risks but he also cautioned against "over reacting." Last Sunday Surgeon General Jesse Steinfeld said a growing amount of evi- dence would indicate other forms of contraception would be safer for some women. However, he said, "I think the pill has saved more lives than it has cost." To some women, he indicated, the possible risk of taking the pill may be less than complications such as miscarriages and hemorrhages. Some doctors say they have noticed an increase in unwanted pregnancies which they attribute to women forsaking the pill. Meanwhile, big money hangs in the balance. Some nine million women last year bought $100 million worth of oral contraceptives. Will the sales eventually decline? A Gallup poll shows that 18 per cent of women surveyed who used oral con- traceptives in the last three months have stopped using them, largely because of the adverse publicity from the hearings. But two-thirds of the 895 women between 21 and 45 years of age surveyed believe the advantages of the pill outweigh the risks, the poll said. Many druggists questioned by the associated Press reported concern among pill users. "Some customers seem very upset," said Dick Berg, owner of the Loop Phar- macy, one of the largest in the Minneapolis-St. Paul area. Berg checks with doctors before refilling old prescriptions and of those he said he had talked to since the hearings, not one had withheld a prescription, he said. Obstetricians interviewed in Albany, N.Y., said they are being asked to rec- ommend alternatives to the pill more frequently as a result of adverse public- ity. One said 10 to 15 per cent of his patients on the pill have requested other forms of contraceptives. "We are selling more intrauterine devices in the last two months than we ever have." said J. Vinson Riley, manager of four drugstores in various sec- tions of Atlanta. "The pills have dropped by a small amount. Senator ~ELSOX. I might say that as to the concern of people around the country hearing different things. I would guess that the fact is that if the doctors had told them in the first place, what are the known side effects and the contraindications, then they would not have been frightened when they heard it. As the Newsweek arti- cle stated. two-thirds of the women in the country had heard noth- ing about the side effects and when they read it in the paper, they became disturbed about it. That is not the fault of the testimony here. that is the fault of the physicians in not advising the patient, and the press failure to publish the FDA committee reports. Thank you very much, Doctor. Senator Hatfield? Senator HATFIELD. Dr. Kane, in most studies of this type their validity is related directly to the number of people involved and the time over which the study is made. These two are factors in judging the merits of the study. What do you believe to be the time factor necessary to draw conclusions from such a study as yours and what number do you think is a sufficient base for making such studies? I know you alluded to this. but. I would like to have you reiterate it at this point. Dr. KANE. There are two kinds of studies one could do. One involves the prospective studies comparing use in large populations- PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6467 comparing, say, a pill-using group with a non-pill-using group; in other words, people who use other forms of contraception-and merely studying other rates of incidence of mental illness in the entire group. The other is a more retrospective thing. That is com- paring rates of psychosis in hospitalized patients who have used drugs for a long period of time; in other words, an expose facto type of study. I think probably there are people-I have not been involved with studies of this kind and I am sure you could get better experts than I from, say, the National Institutes of Mental Health to give you information on this. Senator HATFIELD. Let's take your study. Has the prospective study been based upon what you would call a sufficiently broad patient population? Dr. KANE. Probably not. The two Swedish studies were excellent. Senator HATFIELD. You do not feel, then, that your study actually had sufficient numbers to make their application- Dr. KANE. Their numbers are not important. Their randomness is the critical factor. Mine was not an entirely random population. Senator HATFIELD. As a layman, may I interrupt? Correct me if I am mistaken. We are told by certain experts, according to the testi- mony in this hearing, that, taking breast cancer as an example, we have a Corfman-Siegel report that indicated that in order to get an accurate projection of a twofold increase, let's say, in breast cancer, they would have to have a number of 80,000 cases or 80,000 people. There is a relationship here between numbers and validity of study or what you can draw as conclusions from such a study. Now, going back to your study, what's the number or what's the basis upon which we can draw certain conclusions from your study? Dr. KANE. There are two things here. I think perhaps psychosis is similar to cancer. `We have symptoms here, for instance-you can draw conclusions from 10 patients, studied very carefully, about acutely occurring symptoms. In other words, if you give them a med- icine or a blank and compare their reaction on this, you will then be able to gauge their reaction to the medicine for even a 1 month period. We have done this. They are balanced studies. Senator HATFIELD. You can draw a medical fact `from that? Dr. KANE. Oh, yes, you can, for certain kinds of things, certain kinds of acute symptoms. If you give, for example, LSD, the changes you would expect from LSD, at least behaviorally, would be mainly occurring within a 2- to 4-hour period from certain doses. I think you can have that study. Then you can have the longer term study for, say, effects of hor- mones on genes over a longer period of time. Senator HATFIELD. Let's come back to your study again. Do you feel that your study and the conclusions that you have drawn have incorporated sufficient numbers of people that we can draw a medi- cal fact from them? Dr. KANE. Yes, with regard to the more acute changes, I think so. With regard to the risks for development of psychosis, I think there is much less information. I think that is in the same `ballpark as the figures for cancers. You must have large numbers. PAGENO="0028" 6468 COMPETITIVE PROBLEMS IN TIlE DRLTG INDUSTRY Senator HATFIELD. So we really have to focus upon what we can draw as conclusions from your study and that which we caimot draw. Dr. KANE. Right. Senator HATFIELD. Let me ask about the time factor. We are told by many that there are certain effects that are going to appear in the first 30-day usage, but then some of these will level off at a cer- tam point and reduce. What about the time factor in your study and its relevance to this matter of short-term and long-term use? Dr. KANE. Well, again, with regard to the neurohormone studies, there was only 1 month and I think one can draw a 1 month conclu- sion there. With regard to the others, these were questionnaire types where people had been using the drugs for a certain time, 6 months, a year. So these were not acute changes. Almost all tile studies reported, my own included, involved people who had been using tile drugs for 6 months to 2 years. In other words, these were fairly chronic differences that they noticed in themselves. Senator HATFIELD. In other. words, those conclusions you draw from a 30-day study would not necessarily be tile same conclusions you would draw from the same group of people perhaps over a 60-, 90-, or perhaps 120-day period or longer? Dr. KANE. We simply do not know. Senator HATFIELD. We should be careful in this committee, should we not, between drawing conclusions from short-term use and what might be long-term side effects and such? Dr. KANE. I do not think tilere is any information on long-term side effects. Senator HATFIELD. We silould not apply tile short-term to possible long-term, should we? We cannot ignore the time factor, can we? Dr. KANE. No, I tilink it is an area for further researcil. This sort of thing, tile fact that psyciloses seem to occur at all, it seems to me, is something we ougilt to be concerned about. Tile question of how many in other words, I think we do not know tile answer to the question, if a woman takes a. given pill for 2 or 3 or 4 years, is she somewhat more at risk statistically to develop a psycilosis at that time. We do not know the answer to tilat one. Senator HATFIELD. Even for some of those who might develop this psychosis characteristic in the first 30 clays, is tilere not a possibility tilat they might, too, level off and not have an intensity of such a tiling after 30 days? Dr. KANE. I would be unprepared to risk that. I think they siioulcl try sometiling else. Senator HATFIELD. Then turning it round, shall we assume that because they have such characteristics during the first 30 clays, silould we assume they will retain those over tile longer period? Dr. KANE. No, there would be every expectation that they would recover if you stopped the medicine. Senato HATFIELD. How about if you continued to use it? Dr. KANE. I know of no one who would suggest such a course. Senator HATFIELD. In Otiler words, there could be a differentiation drawn between those who use them for 30 days and others who use them for 60 days? Dr. KANE. I don't think you will ever find out. PAGENO="0029" COMPETITIVE PROBLEMS IN: THE DRUG INDUSTRY 6469 Senator HATFIELD. Why can't you, if you have such a controlled group as you can develop in this study- Dr. KANE. If they develop psychosis, who is going to be willing to continue the drug? Senator HATFIELD. But you indicated these were patients who already primarily, in their own makeup, were probably aggrevated or accentuated or drawn out by the use of the drug, if I understand your testimony. Dr. KANE. At least in part. Senator HATFIELD. Then I understood you to say that, perhaps with long-term usage, there could be differences or changes that occurred in a person's characteristics from that of the 30-day per- iocl alone. Dr. KANE. Well, now, I think you are extrapolating something from where it does not belong. I was referring really to metabolic changes and this, you know, is a speculation. I think if someone did develop psychosis while taking the pill, they probably would not take it again. Senator HATFIELD. Well, then, retrospective studies do not have the medical validity of prospective studies, is that correct? Dr. KANE. Oh, absolutely, yes. And there is only one of those. Senator HATFIELD. And you could not say we could generalize from 10 women to apply, say, to 10 million? Dr. KANE. No, but I think you can generalize from 169 women. Senator HATFIELD. To apply to 10 million? Dr. KANE. Yes. Senator HATFIELD. How many more than 10 million? Dr. KANE. Again, I think more important, perhaps, than numbers here, would be different kinds of pills. I think the point Senator Javits raised is a good one: Are there some pills that are safer to use than others. I think I would rather approach it that way. You could certainly have larger numbers and that would be nicer, but I do not think they would give you much difference in the way of data. ~Seiiator HATFIELD. Dr. Kane, one last subject. You are familiar with the 12 primate centers we have in the NIH across this country? Dr. KANE. Yes. Senator HATFIELD. And you are aware that some of them are devoted exclusively to the subject of reproductive physiology. Are you aware of the studies that are going on or what kinds of studies could be conducted in any of these primate centers relating to the effects or side effects of the pill? Dr. KANE. I think that people at Emory are doing something of this sort. I know there was one chap there who was looking at the behavioral effects of the pill on chimpanzees, I think. I have never seen any of his data published, but I think he is doing something on this. Senator HATFIELD. Do you think that where they can accelerate the generational effect on the use of drugs of particular kinds in the strain, particularly the rhesus, that there could be, say, some benefits derived from such studies within this strain of monkeys? Dr. KANE. I think animal studies are fine. They can allow you to do certain kinds of things, for instance, but there are certain kinds PAGENO="0030" 6470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of animal studies we have planned that can only be done in animals. However, looking at these effects on behavior, I would prefer to see it done on humans, because they are not naturally occurring in humans. My preference would be for human studies. Senator HATFIELD. Does it need to be "either or"? Dr. KANE. As I say, there are some things that you can do better in animals-for instance, studying brain mechanisms, how many changes can you get in the metabolism of the brain. I don't think you are going to get many humans. Senator HATFIELD. Especially the study of generational effects over a period of time, as different from human generations? Dr. KANE. I would say yes, I think so. Senator NELSON. Thank you, Doctor. Our next witness is Dr. John McCain, in the private practice of obstetrics and gynecology, Atlanta, Ga. Dr. McCain, we are very pleased to have you appear to present your view. Your statement will be printed in the record, or you may proceed in any way you desire. STATEMENT OF DR. JOHN It. MeCAIN, IN THE PRIVATE PRACTICE OF OBSTETRICS AND GY~ECOLOGY, ATLANTA, GA. Dr. MCCAIN. Senator Nelson, Senator Dole, gentlemen: Just by way of introduction, I took my medical school training at Emory University, my residency training at the Grady Memorial Hospital in Atlanta. I have the academic rank of clinical professor in the Department of Gynecology and Obstetrics at Emory University. 1 might say my view is personal and not representing the view of the department, which may be different from my own. Senator NELSON. Which school is that? Dr. MCCAIN. Emory. Senator NELSON. Do you teach at the department now? Dr. MCCAIN. The clithca.l professor title means that you teach without pay. Senator NELSON. Go ahead. Dr. MCCAIN. The development of the oral contraceptive pills has been one of the major achievements of modern medicine. The availa- bility of the contraceptive pills and the publicity associated with them have stimulated a. concern for the worldwide population explo- sion. The pills have also provided a method by which this rapidly increasing problem can be controlled. As one considers the use of the oral contraceptive pills in private practice, it is well to remind ourselves as physicians that our pre- scriptions of pharmaceuticals to patients are usually for the treat- ment of specific illnesses. Virtually all medications, even those as simple as aspirin, carry the possibility of danger to some individu- als. Physicians are accustomed to evaluate the risk of the medication against the risk of the disease and then to decide whether or not the drug should be prescribed. The usual woma.n who does not desire children does not have any disease. If the contraceptive pills do carry some risk to the patient, the physician should prescribe them PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6471 with caution to the individual woman. If the contraceptive pills do involve risks, the physician should be even more cautious in advising their use on a population wide basis. On the other hand, the risks of an unwanted, unplanned preg- nancy must also be considered. Even though the patient herself may have no illness, she is exposed in such a pregnancy to all of the risks it involves. The infant, all too frequently, faces major socioeconomic problems which will seriously limit a child's development in our society. It is my opinion that the risks of such a pregnancy are definitely greater than the risks of the oral contraceptive pills. If the patient does not find other methods of contraception acceptable on the basis of economic, social, moral, or religious reasons, I believe that she should have the contraceptive pills prescribed for her pro- tection, and I have done so. The theoretical ideal must be balanced against the practical reality. Just to illustrate this point, back some 5 years ago, when I was first becoming interested and was preparing to speak on the subject of the oral contraceptive pill, around the Sunday dinner table, I made the comment that I was preparing to give a talk about the oral contraceptive pills. My 84-year-old father said, "you know, the best oral contraceptive is `No'." My wife immediately answered, "But that is not practical." So I think it would be that the remain- der of my statement will attempt to consider both the ideal and also the practical. For the usual private patient a considerable range of contracep- tive procedures is available. Through the years I have found for my private patients that the use of the condom by the husband or of the diaphragm by the wife have been effective and satisfactory methods of contraception. During the 20 years of my private practice I do not believe that I have had over a dozen patients become pregnant if they were using a diaphragm as directed. Needless to say, pregnan- cies have occurred among those who occasionally omitted the dia- phragm at coitus. As I initially considered the use of the oral contraceptive pills, I was concerned regarding their possible effects upon the anterior pituitary gland. The contraceptive pills are potent steroid hormones. Alterations of the anterior pituitary function are produced by them. Investigations have been made regarding the effects upon the ante- rior pituitary, but the potential endocrine and systemic disturbances are almost unlimited. The effects produced through the anterior pituitary may be so indirect that years may elapse before a correla- tion is established between the abnormality and the administration of the contraceptive pills. In May 1964 I encountered two patients whose complications were so dramatic that my theoretical concern regarding the potential com- plications of the pills changed. Since that time I have tried to record all of the complications occurring in my patients which appear to be related to the use of the contraceptive pills. A patient whom I saw on May 1, 1964, was a 26-year-old woman with the findings of an acute surgical abdomen. At operation the only pathology which could be found was the presence of two free appendices epiploicae in the cul-de-sac. Appendices are small finger- PAGENO="0032" 6472 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY like projections of fat attached to the colon. The cul-de-sac is the lower portion of the abdominal cavity, the oniy explanation which would be reasonable for such a finding is that the vascular supply to the appendices had become thrombosed, followed by a separation of them from their attachment to the colon. The patient had been on Enovid for 6 months as a contraceptive measure. On the next. day. May 2. 1964. a 32-year-old patient telephoned me that for over a week she had been dreaming of killing herself and that she was terribly afraid she would commit suicide. She had been on Enovicl, 10 lug. daily, for 14 clays in an attempt to control a. men- strual irregularity. I advised that. she omit the Enovicl. After the two patients omitted the contraceptive pills, they have had no additional problems. At about the same time one of my colleagues in Atlanta had a patient. die shortly after being placed upon a. contraceptive pill. The death occurred in a 20-s-ear-old patient who had been in apparently normal health before she was placed upon Ort.ho-Novum as a contra- ceptive. I might state that I am usmg the trade names. This, of course. is tecimicallv. perhaps. not. correct, and inent~on will be macic later that there is no particular implication of one versus another as far as my experience has been concerned. She had taken Ort.ho-Novum, 2 lug. daily, for 7 days hut wa.s then advised to discontinue the pills because of nausea and vomiting. The nausea persisted and a. mild diarrhea developed the next day. The patient became acutely ill on the 12th clay after she had begun the Ortho-Novum and died in 4 hours. Tile only specific pathology found at a complete autopsy, ~ncluciing tile brain, was tile presence of intracardiac mural throinbi of recent origin. No emboli were found. Since May 1, 1964. I have seen patients with 52 complications wilich seem to me to be significant and wilicil may be related to the contraceptive pills. I prescribe tile pills for contraceptive purposes to relatively few patients. but I do advise them fairly frequently ill tile treatment of diysfunctional uterme bleeding. Many of t.ile patients included in t.ilis study were adivisedi to use the pills by other physicians and I saw them later. All of the patients were taking tile pills on a cyclic basis. Tile complications ilave been arranged according to the type of the abnormality which developed. (Tile frequent complaints of patients taking pills, such as breakthrough bleeding, mild-to-moderate nausea and vomiting, or fluid retention are not included as complications.) For the past 2 years, my record of complications have been curtailed. My a.ssocia- tion witil tile complications as a pill ilave been somewhat publicized and I am afraid has probably influenced the patients that I see in practice. So, in fairness, I do not think tile patients that I see would be on an unselected group with regard to the complications of the contra- ceptive pills. Complications: Tile emotional or psychiatric problems are listed ill table 1.1 `See information beginning at p. 6480. PAGENO="0033" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6473 The emotional or psychiatric problems are the complications which seem to me to have the most serious potential danger. Three patients have stated that they were desperately afraid that they were going to kill themselves. Two of them had been on the pills 14 days or less. The third patient lived out of town and later told of her depression and fear of suicide beginning 4 months after she started taking the pills. These three patients are the only ones in the author's experience who have ever told so dramatically of their fear of suicide. After the pills were omitted, the depression and suicidal fears of the three patients disappeared, as did the depression of the other patients in table 1. Now, rather than go through the points of the report that I gave, which do not deal specifically with the emotional or psychiatric problems, skipping over, then, to the discussion on page 8 of the report which I submitted formally: A study of the complications of the report indicates that it might be possible to make suggestions regarding the use of contraceptive pills in selected types of patients as well as some general sugges- tions. Suggestions for specific patients: The possibility of depression or of other emotional disturbances suggests that caution would be advisable if contraceptive pills are to be prescribed for individuals who already have these conditions. Such patients should be kept under close observation for a possible aggravation of their disturb- ance if they are to be given the pills. All physicians prescribing the pills should be aware that emotional disorders can occur and persist until the pills are discontinued. Similar precautions should be observed in prescribing the pills for patients with conditions such as migraine headaches, or with symptoms such as vertigo. Just for example, one patient that is not included in this study called me at 12 :30 a.m. Sunday. She had had previous psychiatric therapy, had been placed on a contraceptive pill for gynecological reasons, had had them omitted during the preceding week because of an aggrava- tion of the psychiatric disturbance, had called seeking some emer- gency sedation for an acute emotional reaction. So I have not included all of the complications which I have seen in the last 2 years. Skipping on then to page 11 with regard to general suggestions: The emotional or psychiatric changes seen in some of the patients of this report suggest that additional study should be given to such complications. If the patients reported here were willing to discuss their problems without any invitation to do so, one is concerned regarding other patients who may not have discussed similar prob- lems. It is disturbing to consider the patients on the pills whose depression may have ended in suicide and/or homicide with no rec- ognition of any association with the contraceptive pills. Investiga- tions would seem advisable to determine the possibility of such a correlation. Personality changes could be a factor in other conditions such as automobile accidents and divorces. It is my opinion that the changes that one encounters on an emotional basis correspond rather closely to those that are associated and described as premen- strual tension. The correlation is probably not absolute, but. I think 40-471-70-pt. 16-vol. 2-3 PAGENO="0034" 6474 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY there is a great similarity and the risks involving emotional and psychiatric disturbances for prolonged, continuous use, in my opin- ion part~cularly with the combination drugs, c,arry a greater risk of involvement of the emotional disturbances. Investigations are desirable to determine the possible correlation of the contraceptive pills with the individuals involved in these cir- cumstances. This report includes 16 major complications-they are listed in the last table of this report.. I will not go over them individually. They should be classified as major ones associated with the contra- ceptive pills (table VIII). Through the years the author has attempted to keep accurate records on his patients. A system of IBM punchca.rds has been used during his practice to analyze and cross- index the records of the g~mecologic and of the obstetric patients. The 16 major complications associated with th.e contraceptive pills are considerably more numerous than have been encountered from all of the other medications combined which have been prescribed during the time of the report. In considering the complications of the pills it is also possible that additional problems may develop in these and in other patients from as yet unrecognized abnormalities produced by altered anterior pituitary gland functions or by other endocrine or systemic changes. If satisfactory contraceptive methods are available which do not carry the possible risks of the contraceptive pills, they deserve con- sideration. If other methods of contraception are not available or acceptable for the patient. the pills are valuable contraceptives, espe- cia.llv if given under careful medical supervision. The patients for whom the pills may be the contraceptive method of choice will include those who find other methods unacceptable for moral, religious, social. or economic reasons. The indigent patients constitute a fairly large group of individuals for whom the pills may be the advisable contraceptive. The hlTsbands of these patients do not use condoms reliably. The medical facilities for the patients ma not permit the individual fitting of diaphragms and individual directions as to their use. The medical care available for the indigent patients in our coun- try is in the process of considerable modification. It appears that, under the title XIX of the Social Security Act, perhaps by 1975 all indigent patients will have medical care available for them by the private physicians on the basis of the physician's usual and custom- ary charges. If this change takes place for the indigent patients, all patients will then have available the methods of conception control which are now available from private physicians by the individual instruction of each patient. The most important factor in the success of almost any of the rec- ommendedi contraceptjve methods is the motivation not only of the patient but also of the physician. The enthusiasm of the physician for the specific contraceptive method which lie is recommending will determine to a large degree the patient's and her husband's accept- ance and utilization of the method. The physician's enthusiasm is important for the success of the contraceptive method whether he is advising it for a private patient or for the women of a large clinic PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6475 for whom he is responsible. From a practical standpoint, from a knowledge of my colleagues and their opinions and relationships in practice, from a practical standpoint, I do not believe that most physicians will take the time to effectively iiistruct their patients in the use of the diaphragm or of condoms. I am not sure that these physicians can motivate their patients adequately for a diaphragm or for condoms to be used successfully. By way of conclusion, then: 1. No method of contraception at the present time is completely safe and at the same time practical as determined by popular accept- ance and utilization. 2. The population explosion is: of overwhelming worldwide impor- tance. It threatens the very foundations of national existence. Unless the explosion is moderated, radical methods of population control, rather than family planning, may be required. On the basis of my best judgment, in the light of these two state- ments, I should like to recommend as effectively as I can: 1. That the Government proceed as rapidly as possible to provide effective methods of family planning to all who desire them. The best methods of contraception now available, as determined by their safety and by their practicality, should be employed. The program should have fully adequate funds for its effective operation. On a dollar for dollar basis, the funds appropriated for family planning will produce far greater social and economic benefit than can be achieved by any other investment of money. 2. That the Government intensify the research beiiig undertaken to develop safer and more effective methods of contraception. (The complete prepared statement of Dr. McCain and attachments follow:) STATEMENT By JOHN R. McCAIN, M.D., IN THE PRIVATE PRACTICE OF OBSTETRICS AND GYNECOLOGY The development of the oral contraceptive pills has been one of the major achievements of modern medicine. The availability of the contraceptive pills and the publicity associated with them have stimulated a concern for the worldwide population explosion. The pills have also provided a method by which this rapidly increasing problem can be controlled. As one considers the use of the oral contraceptive piUs in private practice it is well to remind ourselves as physicians that our prescriptions of pharmaceut- icals to patients are usually for the treatment of specific illnesses. Virtually all medications, even those as simple as aspirin, carry the possibility of danger to some individuals. Physicians are accustomed to evaluate the risk of the medi- cation against the risk of the disease and then to decide whether or not the drug should be prescribed. The usual woman who does not desire children does not have any disease. If the contraceptive pills do carry some risk to the patient, the physician should prescribe them with caution. If the contraceptive pills do involve risks, the physician should be even more cautious in advising their use on a population wide basis. On the other hand, the risks of an unwanted, unplanned pregnancy must also be considered. Even though the patient herself may have no illness, she is exposed in such a pregnancy to all of the risks it involves. The infant, all too frequently, faces major socioeconomic problems which will seriously limit a child's development in our society. It is my opinion that the risks of such a pregnancy are definitely greater than the risks of the oral contraceptive pills. If the patient does not find other methods of contraception acceptable on the basis of economic, social, moral or religious reasons, I believe that she should have the contraceptive pills prescribed for her protection and I have done so. PAGENO="0036" `6476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY For the usual private patient a considerable range of contraceptive proce- dures is available. Through the years I have found for my private patients that the use of condom by the husband or the diaphragm by the wife have been effective and satisfactory methods of contraception. During the 20 years of my private practice I do not believe that I have had over a dozen patients become pregnant if they were using a diaphragm as directed. Needless to say, pregnancies have occurred among those who occasionally omitted the `diaphragm at coitus. As I initially considered the use of oral contraceptive pills, I was con- cerned regarding their possible effects upon the anterior pituitary gland. The contraceptive pills are potent steroid hormones. Alterations of the anterior pituitary function are produced by them. Investigations have been made regarding the effects upon the anterior pituitary, but the potential endocrine and systemic disturbances are almost unlimited. The effects produced through the anterior pituary may be so indirect that years may elapse before a cor- relation is established between the abnormality and the administration of the contraceptive pills. In May 1964 I encountered two patients whose complications were so dra- matic that my theoretical concern regarding the potential complications of the pills changed. Since that time I have tried to record all of the complications occurring in my patients which appear to be related to the use of the contra- ceptive pills. A patient whom I saw on May 1, 1964, was a 26-year-old woman witl1 the findings of an acute surgical abdomen. At operation the only pathology which could be found was the presence of two free appendices epiploicae in the cul- de-sac. The only explanation w-hich would be reasonable for such a finding is that the vascular supply to the appendices had become thrombosed, followed by a separation of them from their attachment to the colon. The patient had been on Enovid for 6 months as a contraceptive measure. On the next day, May 2, 1964, a 32-year-old patient telephoned me that for over a week she had been dreaming of killing herself and that she was terri- bly afraid she w-ould commit suicide. She had been on Enovid, 10 mg. daily, for 14 days in an attempt to control a menstrual irregularity. I advised that she omit the Enovid. After the two patients omitted the contraceptive pills, they have had no additional problems. At about the same time one of my colleagues in Atlanta had a patient die shortly after being placed upon a contraceptive pill. The death occurred in a 20-year-old patient who had been in apparently normal health before she was placed upon Ortho-Novum as a contraceptive. She had taken Ortho-Novum, 2 mg. daily, for 7 days but was then advised to discontinue the pills because of nausea and vomiting. The nausea persisted and a mild diarrhea developed the next day. The patient became acutely ill on the 12th day after she had begun the Ortho-Novum and died in 4 hours. The only specific pathology found at a complete autopsy, including the brain, was the presence of intracardiac mural thrombi of recent origin. No emboli were found. Since May 1, 1964, I have seen patients with 52 complications which seem to me to be significant and which may be related to the contraceptive pills. I pre- scribe the pills for contraceptive purposes to relatively few patients, but I do advise them fairly frequently in the treatment of dysfunctional uterine bleed- ing. Many of the patients included in this study were advised to use the pills by other physicians and I saw them later. All of the patients were taking the pills on a cyclic basis. The complications have been arranged according to the type of the abnormality which developed. (The frequent complaints of patients taking pills such as breakthrough bleeding, mild to moderate nausea and vom- iting, or fluid retention are not included as complications.) COMPLICATIONS The emotional or psychiatric problems are listed (table I.). They are the complications which seem to me to have the most serious potential danger. Three patients have stated that they were desperately afraid that they were going to kill themselves. Two of them had been on the pills 14 days or less. The third patient lived out of town and later told of her depression and fear of suicide beginning 4 months after she started taking the pills. These three PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6477 patients are the only ones in the author's experience who have ever told so dramatically of their fear of suicide. After the pills were omitted, the dépres- sion and suicidal fears of the three patients disappeared, as did the depression of the other patients in Table I. The central nervous system symptoms (table II.) of severe vertigo, headache or nausea and malaise have been encountered in four patients. The symptoms were disabling until the pills were omitted. Since then the symptoms have sub- sided. An alteration of menstrual function after the pills have been omitted has been reported occasionally by other authors. Five patients with this complica- tion are included (table III.). (One of the five patients is listed on a later chart with miscellaneous complications.) Four of the five patients have had a return to apparently normal menstrual function after intervals of up to 6 months. The patient with persisting metrorrhagia is a 20-year-old individual with no history of previous menstrual irregularities. She had taken Enovid-E for 6 months. Since she omitted the medication she has had metrorrhagia for 1 to 2 weeks before her nienses for 24 months. So far she has not returned for any specific diagnostic or therapeutic studies. The infections of the vagina and of the vulva have been encountered fairly frequently. The most frequent infection has been a inonilial vulvovaginitis. In this report 11 patients are listed (table IV.). The monilial infection has been seen so often that no attempt was made to record all of the cases. All of the infections, including the nonspecific vaginitis and the furunculosis, responded rapidly to treatment after the pills were omitted. The most frequent change in the pelvic organs (table V.) has been that of a pseudodecidual reaction of the cervix. The reaction has been encountered so often that the cases listed here represent only a few of the ones which have been seen. The reaction of the cervix has been so severe in some patients that the gross appearance simulated that of a malignancy. The benign nature of the lesion can be proven by a Papanicolaou smear and cervical biopsies. It has not been possible to clear the pseudodecidual reaction by local therapy as long as the pills were continued. The cervical changes cleared, or responded readily to treatment, after the pills were omitted. The two patients with leiomyomas had the uterus enlarge to twice its pre- vious size during the 6 months of treatment with the pills. After the pills were discontinued the leiomyomas and the uterus decreased to approximately the size which had been present before the pills were prescribed. It is possible that unexpected pelvic pathology may be associated with pill therapy. The endocervical polyps were removed by curettage. The pathologist at his examination suggested that the polyps may have developed as a result of tIme Enovid stimulation. Another unexpected finding was that of a patient with recurring attacks of cystitis. After the contraceptive pills were omitted, the bladder infection was cleared by the same medication which she had been using previously. The vascular accidents, together with the emotional or psychiatric changes, have been the most serious complications in my experience (table VI). The patient with the three pulmonary emboli was a 37-year-old woman, 62 inches tall, weighing 121 pounds, who had been placed upon cyclic therapy with Ortho-Novum, 2 mg. daily, for dysmenorrhea with mild pelvic endome- triosis. She was in good general physical condition. As she began her third cycle of Ortho-Novum in November 1965, she developed the first pulmonary embolus, apparently from her pelvic veins, with no other clinical evidence of disease. In the next 2 weeks, in spite of anticoagulant therapy, she developed tw-o more pulmonary emboli. After her recuperation from the emboli, she has had no other abnormality develop. The subarachnoid hemorrhage occurred in a 31-year-old patient who was apparently normal and who had been prescribed Enovid-E as contraceptive pills. After three cycles, the patient developed a subarachnoid hemorrhage. A rupture of an aneurysm of an anterior cerebral artery was suspected but could not be identified in spite of carotid artery angiography performed twice. The Patient's findings slowly cleared and she now has no neurologic residual. The two patients of special interest among the miscellaneous complications (table VII.) are the patient with the visual disturbance and the patient who twice attempted the criminal abortion. The patient with the visual disturbance PAGENO="0038" 6478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY was diagnosed as having vitreous bodies in the posterior chamber of the eyes. The visual change developed 6 days after she had begun 0-Quens. The vitreous bodies still have not cleared 6 months after the pills were omitted. The patient who twice attempted the criminal abortion was an unmarried girl who had an amenorrhea for 3 months after omitting the pills. After she missed her second period she was told by her family physician that she was pregnant and was referred to an abortionist. A French catheter was inserted into the uterine cavity on two occasions, but no bleeding occurred. The patient was referred to the author because of her lower abdominal and pelvic pain. The examination revealed a moderate pelvic cellulitus but no evidence of any pregnancy. The cellulitis cleared on antibiotic therapy. The patient had a fairly normal menstrual period 4 months after she omitted the pills. DISCUSSION The material presented in this paper has included information regarding the type of the contraceptive pill and regarding the duration of its use before the onset of symptoms. The frequency with which one type or another of the con- traceptive pills is included in the study probably indicates the relative fre- quency with which it has been prescribed in the Atlanta area. The study prob- ably does not indicate that one preparation is either more or less dangerous than another. The length of time varied widely from the start of the contraceptive pills until the appearance of the complication. Some of the dramatic complications began w-ithin a few days. Other patients had apparently uneventful courses for several months before the onset of the complications. The menstrual irregulari- ties did not appear until after the pills were discontinued. The complications cleared completely and did not recur for almost all of the cases. The exceptions include the patient who died, the patient with persisting visual difficulties and the patient with persisting metrorrhagia. A study of the complications of the report indicates that it might be possible to make suggestions regarding the use of contraceptive pills in selected types of patients as well as some general suggestions. ~Suggestions for specIfic patients: The possibility of depression or of other emotional disturbances suggests that caution would be advisable if contracep- tive pills are to be prescribed for individuals who already have these condi- tions. Such patients should be kept under close observation for a possible aggrevation of their disturbance if they are to be given the pills. All physi- cians prescribing the pills should be aware that emotional disorders can occur and persist until the pills are discontinued. Similar precautions should be observed in prescribing the pills for patients with conditions such as migraine headaches, or with symptoms such as vertigo. The menstrual abnormalities which were observed in some patients when the pills were discontinued suggest the possibility that a major disturbance of the menstrual pattern can occur in an occasional individual. Such a change would be especially unfortunate if the patient were a young person who might later want to have children. For the young patient it seems advisable to omit the pills at fairly frequent intervals for two to three months to be sure that normal menstruation resumes. For the older patient who has completed her family the pills might be continued for longer intervals of time. Some of my colleagues have told me that the menstrual irregularities after omitting the pills seem to be more severe if the menstrual pattern had been that of dysfunctional uterine bleeding before the pills were prescribed. If these patients are to be given the pills, it would also seem wise to omit them fairly often for two to three months to permit the resumption of normal menstrua- tion. Tf a period of amenorrhea develops after the pills are omitted, it does not necessarily indicate that the patient is pregnant. It is true that pregnancy is the most frequent cause of secondary amenorrhea, but, as illustrated by the patient who twice attempted a criminal abortion, pregnancy is not the only cause of secondary amenorrhea. The menstrual irregularities after omitting the pills are not as serious a problem now as they were in the past. Since clomiphene citrate (clomid) has been released for use, adequate treatment is now available for most patients who have an infertility associated with the menstrual irregularity. PAGENO="0039" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6479 The monilial vulvovaginal infections have been very difficult to clear in many patients as long as they continue the pills. The monilial infections seem to be more frequent in my experience among patients taking the combination type pills than among those using the sequential type. Either type of pill should be prescribed with caution if a patient has an existing medical disease, such as diabetes mellitus or a cardiac lesion requiring continuous chemother- apy, which is more favorable for the development of a monilial infection. Other types of vulvovaginal infections may be associated with the pills. The most frequent of these is a trichomoniasis. The trichomonas infections have not been a significant problem, however, because of the effectiveness of metron- idazole (Flagyl) in their treatment. Occasional non-specific types of vaginal infections may be associated with the pills. The non-specific infections in this study have cleared if the pills were omitted. The pseudodecidual reactions of the cervix have been encountered very fre- quently with the combination type of pills and somewhat less frequently with the sequential type. At times the gross appearance of the lesion may be dis- turbing from the standpoint of a malignancy. The maintenance of the cytologic changes at the external os of the cervix suggests on a theoretical basis that it might predispose the area for a later malignant change. The theoretical dan- gers are probably more than offset by the close observation given patients who are taking the pills. The recent "Survey of Experience with Oral Contraceptive Pills" by the American College of Obstetricians and Gynecologists in October 1967 reported that 98.9 percent of the patients on the pills were being re-exam- ined at least once a year. It is advisable to prescribe the pills cautiously to patients with leiomyomas of the uterus. If the leiomyomas enlarge or become symptomatic, the pills should be omitted. The possible relationship of endocervical polyps and other pelvic pathology to the pills should be remembered. If abnormalities occur, consideration should be given to the omission of the pills. l~Tascular accidents in association with contraceptive pills have been reported with relative rarity. Two patients in this study had serious vascular accidents and two had less serious ones. The frequency is disturbing. The only ophthalmologic complication has been the one with vitreous bodies in the posterior chamber of the eyes. It is slowly clearing since the pills were omitted but it has been a considerable problem for the patient so far. Genei-al suggestions: The emotional or psychiatric changes seen in some of the patients of this report suggest that additional study should be given to such complications. If the patients reported here were willing to discuss their problems without any invitation to do, one is concerned regarding other Patients who may not have discussed similar problems. It is disturbing to con- sider the patients on the pills whose depression may have ended in suicide and/or homicide with no recognition of any association with the contraceptive pills. Investigations would seem advisable to determine the possibility of such a correlation. Personality changes could be a factor in other conditions such as automobile accidents and divorces. Investigations are desirable to determine the possible correlation of the contraceptive pills with the individuals involved in these circumstances. This report includes 16 complications which should be classified as major ones associated with the contraceptive pills (Table VIII.). Through the years the author has attempted to keep accurate records on his patients. A system of I.B.M. punch cards has been used during his practice to analyze and cross-in- Ocx the records of the gynecologic and of the obstetric patients. The 16 major complications associated with the contraceptive pills are considerably more numerous than have been encountered from all of the other medications com- bined which have been prescribed during the time of the report. In considering the complications of the pills it is also possible that additional problems may develop in these and in other patients from as yet unrecognized abnormalities produced by altered anterior pituitary gland functions or by other endocrine or systemic changes. If satisfactory contraceptive methods are available which do not carry the possible risks of the contraceptive pills, they deserve consideration. If other methods of contraception are not available or acceptable for the patient, the pills are valuable contraceptives, especially if given under careful medical supervision. The patients for whom the pills may be the contraceptive method PAGENO="0040" 6480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of choice will include those who find other methods unacceptable for moral, religious, social or economic reasons. The indigent patients constitute a fairly large group of individuals for whom the pills may be the advisable contracep- tive. The husbands of these patients do not use condoms reliably. The medical facilities for the patients may not permit the individual fitting of diaphragms and individual directions as to their use. The medical care available for the indigent patients in our country is in the process of considerable modification. It appears that, under Title XIX of the Social Security Act, perhaps by 1975 all indigent patients will have medical care available for them by the private physicians on the basis of the physi- cian's usual and customary charges. If this change takes place for the indigent patients, all patients will then have available the methods of conception con- trol which are now available from private physicians by the individual instruc- tion of each patient. The most important factor in the success of almost any of the recommended contraceptive methods is the motivation not only of the patient but also of the physician. The enthusiasm of the physician for the specific contraceptive method which he is recommending will determine to a large degree the patient's and her husband's acceptance and utilization of the method. The phy- sician's enthusiasm is important for the success of the contraceptive method whether lie is advising it for a private patient or for the women of a large clinic for whom he is responsible. CONCLUSION No method of contraception at the present time is completely safe and at the same time practical as determined by popular acceptance and utilization. The population explosion is of overwhelming w-orld wide importance. It threatens the very foundations of national existence. Unless the explosion is moderated, radical methods of population control, rather than family planniBg, may be required. On the basis of my best judgment, in the light of these two statements, I should like to recommend as effectively as I can: (1) That the Government proceed as rapidly as possible to provide effective methods of Family Planning to all who desire them. The best methods of contraception now available, as determined by their safety and by their practicality, should be employed. The Program should have fully adequate funds for its effective operation. On a dollar for dollar basis, the funds appropriated for Family Planning w-ill produce far greater social and economic benefit than can be achieved by any other investment of money. (2) That the Government intensify the research being undertaken to develop safer and more effective methods of contraception. TABLE I-Emotional or psychiatric problems Complications: caus Severe depression: 5 With fear of suicide: (Orthonovum, 2 mg./d., for 8 days) 1 (Enovid-E for 9 months) 1 (Enovid, 10 mg./d., for 14 days) 1 With personality change (Enovid for 6 months) 1 "On verge of nervous breakdown" (Enovid for 3~ years) 1 Severe hysteria with psychiatric treatment for 2 years (Enovid for 3~ years) 1 Divorce (proceedings instituted 2 months after patient began Enovid) - 1 Loss of libido (on Enovid) 1 Total 8 PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6481 TABLE 11.-Central nervous system symptoms Complications: Gases Severe vertigo: 2 With hospitalization for 1 week: (Enovid, 5 mg., for'5 months) 1 (Enovid, 5 mg., for 1 cycle) 1 Severe headache (Orthonovum, 2 mg., for 4 months) 1 Severe nausea and malaise (C-Quens for 10 days) 1 Total 4 TABLE Ill-Altered menstrual cycle after omission of pills Complications: Cases Metrorrhagia for 5 months (Enovid for 29 months) 1 Metrorrhagia for 24 months (Enovid-E for 6 months) 1 Oligo-amenorrhea for 3 months (Enovid for 9 months) 1 Amenorrhea for 6 months (Enovid for 3 years and then C-Quens for 6 months) 1 Total 4 TABLE IV.-Infections Complications: Vaginal: Monilial vulvovaginitis resistant to treatment until pills omitted Gases (Enovid, 8 pts.; others, 3 pts.) 11 1\'Iembranous vaginitis (C-Quens for 4 months) 1 Nonspecific vaginitis (Enovid for 33~ years) 1 Systemic: Furunculosis, severe (Enovid for 14 months) 1 Total 14 TABLE V-Abnormal changes in pelvic organs Complications: Cases Pseudodecidual reaction of cervix (Enovid 8 pts., Norlestrin 1 pt.)~ 1 9 Enlarging leiomyomas of uterus 2 (Enovid, 5mg., for 6 months) 1 (Orthonovum, 2 mg. for 6 months) 1 Multiple endocervical polyps, pathology report suggested "as a result of Enovid" (Enovid, 5 mg., for 18 months) 1 Repeated episodes of cystitis (Enovid for 3~4 years) 1 Total 13 TABLE VI.-Vascular accidents Complications: Cases 2 free appendices epiploicas found at surgery (Enovid for 6 months) - - I 3 pulmonary emboli (Orthonovum, 2 mg., for 2 months) 1 Thrombosis of vein of vulva (Oracon for 18 months) 1 Suharachnoid hemorrhage (Enovid-E for 3 months) 1 Total 4 1 This change was seent n many additional patients not included in this table. PAGENO="0042" 6482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE Vu-Miscellaneous Complication: Cases Chloasma 2 (Enovid, 5mg., for 6 months) 1 (C-Quens for 9 months) 1 Peptic ulcer, radiologically clear 2 months after pills omitted (Enovid for 3h years) I Vitreous bodies in posterior chamber of the eyes beginning 6 days after onset of pills (eyes still not clear 6 months after pills omitted) (C-Quens for 2 months) 1 Attempted criminal abortion twice when 3 months amenorrhea occurred after pills omitted (Enovid for 6 months) 1 Total TABLE VIII.-Major complications associated with the oral contraceptive pills Type: C~ases Emotional or psychiatric problems 7 Central nervous system symptoms 4 Vascular accidents Ophthalmologic changes 1 Attempted criminal abortion 1 Total 16 Senator NELSON. Thank you. Doctor. What's your view of the question of informed consent? Dr. McC~~~x. This. I think, is almost impossible to give in a satis- factory manner. If one were to take virtually any medical therapy and were to go down the list of all of the possible complications that can be involved, from even as we mentioned in tile first of the paper, even such a si~nple thing as aspirin, we cannot fairly say a patient carries no risk. i call give what in my opinion would be a generally satisfactory explanatIon to the patiellt of the risks involved. Blow- ever. I think that v~rtually any such statement can be challenged. aildI perhaps successfully, as not being satisfactory informed consent in the various courts of the country. Senator ~ELSox. Would you agree that tile situation is somewhat different in the case of a pat.ient suffering from serious disease of some kind or other which would indicate tile use of some potent drug ill which the doctor has to make a. judgment whether a patient is better off taking the risk of some side effect or not take any drug at all? In other words, this is a. medical judgment about a situation involving a disease. Does that not differ from tile situatioll in which, for the first time in history in t.h~s country, 8i/~ million healthy people. with some exceptions-a small percent age-are receiving a very potent drug? Are not. those two Sitilat.iollS quite different.? Dr. MCCATX. I thmk von, are right.. I thmk there is a difference. I was ~~ving what. I would consider an overall opinion of informed consent. Variations are certainly qu~te ~n order. I think, in giving a statement to a patjent: and I will be frank in my statements here. that when I am speakuin w~t1l doe5ors. I will give a little different interpretation, of my on~.nion regarding the risks of contraceptive PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6483 pills than when I am speaking to indigent patients. I think this is fair. The indigent patient has circumstances and situations such that I think if one considers the overall risk involved, the choice of con- traceptives as compared with the risks of pregnancy puts that indi- vidual in a separate category. From the standpoint of attempting to determine medical complications on a medical background, I think that the physicians should be cautious and concerned about rela- tively infrequent complications unless the situatioii justifies the use of this specific medication. Senator NELSON. Well, you referred to indigent patients. Of course, I think you would agree that there is as high a percentage of indigents with the capacity to understand as well as those who inherited some money. If a person could understand, would you con- sider it a responsibility of the physician to explain the various alter- native methods of contraception and the risks that are involved in each, and the side effects that may occur from each of them, includ- ing the oral contraceptives? Dr. MCCATN. I think that there are limits. I was speaking of the indigent as one particular group. Obviously, there is no real group. Obviously, there are individuals in all economic walks of life for whom this can fairly apply as well. But there are social, I suppose, would be maybe a better word-there are social areas in which one can anticipate that contraceptives of a mechanical nature can be, will be utilized inadequately by a husband or by a wife or by both. For that reason, then, one is not saying that the oral contraceptive is more dangerous than the mechanical method of contraception. One has to compare the risks of the oral contraceptive against the unwanted pregnancies that will occur if that mechanical method is not uniformly employed. Senator NELSON. What I am getting at is should the user be told anything? Dr. MCCATN. Yes, I think, so. But the point that I was trying to make is how much should one tell? Now, you see, I am enthusiastic again for the mechanical methods of contraception. I enjoy teaching. To me, I consider it somewhat of a challenge to be able to present the advantages of the mechanical methods of contraception. The actual number of patients for whom I prescribe the oral contracep- tives initially is about three tenths of 1 percent of my gynecological practice. I do prescribe it, as I have indicated here. With the infor- mation that I give, the motivation which I would hope I could stim- ulate within the patients whom I treat, they can utilize the mechani- cal methods very effectively. From the standpoint of other physicians who do not have this motivation that I might feel with regard to the field, I do not believe, as I have indicated, that they will effectively motivate their patients. As to where one draws the line, there is the responsibility for information for the patient, there is the responsibility on the doctor for the outcome of unwanted pregnancies and all that they carry for the physicians. As to where one draws the line, it is a responsibility. It is a most difficult responsibility as far as tue-I am speaking as the clinician, the person who is a clinician. For the person who is caring for the indiv~diial patient, it is a most difficult responsibility for the care of the individual patient as to what can be done. PAGENO="0044" 6484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Well, if the user is going to use the oral contra- ceptive, should the user be told that if you experience certain reac- tions, side effects, migraine headaches, swollen legs or erythema, should not the patient be told the various signs to watch for which are listed in the package insert so that, if she discovers this kind of a reaction, she would then have enough information to realize that she ought to consult her doctor? Should she be told that? Dr. MCCAIN. This is very difficult to give a completely satisfac- tory answer. Now-. you see, as I am motivating the patieilt to utilize mechanical methods, I like to take a Physician's Desk Reference, which has nearly a page of-well, really, it is about 2 pages, I believe, of all the information that is required by the Food and Drug Administration listed in the Physician's Desk Reference. There is about one column in that of the complications and to visu- alize all the risks involved, this is effective to the patient. Whether this can be clone effectively to the patient who does not have the background, or the physician who does not have the motivation that I feel I have, I am not sure. Then there is also the question of the suggestion to the patient of the possibility of complications and the concern of the patient then for even the slightest little bit of difficulty or discomfort that she may experience, which may be entirely unrelated to the pill itself. For example, just an ordinary sinus headache, for example, will be a matter of grave concern, perhaps, and it would be, to many patients if the physician had cautioned h~r against the possibility of head- ache, had I listed in detail the complications that are listed in the Physician's Desk Reference. Senator NELSON. You do not think, then, that if a person is on the pill, she should be told that if she experiences a very strong head- ache, migraine, temporary loss of vision, swelling of the legs, she should get in touch with you? You do not think you dare tell them that so they will call you and consult with you? Are you saying that on balance, they are better off to suffer the possible risk of throm- boembolism or something else than they would be to call the doctor and consult? Dr. MCCAIN. No, the question is how far down the list of compli- cations-I have not counted tl~em. There must be 75, I suppose, that are listed. It is a long column of complications that are listed in the Physician's Desk Reference. As one takes the ones that would be perhaps the most serious, and you have listed the ones, I believe, that would be the most serious, it would be very fair to go over with the patient these individual precautions. Senator NELSON. This is the point I am getting at. There seems to be quite a division in tile profession. The Commissioner of the FDA sent out a~ letter dated January 12. 19T0. to 318,000 doctors. It says: In most cases, a full disclosure of the potential adverse effects of these prod- ucts would seem advisable, thus permitting the participation of the patient in the assessment of the risks associated in this method. Do you disagree w-ith Dr. Edward's letter to tile medical profession? Dr. McCAIN. Of course, you cannot disagree. Senator NELSON. Well, you can. PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6485 Dr. MCCAIN. Well, I mean I could, but it is not feasible to disa- gree with the director in such as that, because complications might happen and you would be in a very difficult position to say I am dis- agreeing with the statement that has come out in that manner. But from the standpoint, you say, of full disclosure-what's meant by full disclosure? This is where I initiated my comments at the onset. What is meant by full disclosure? I-low full does it have to be to be classified as full disclosure? Actually, if you took one single complication and really gave full disclosure, this would involve the essentials of a course in medicine aud of a residency training and of the experience, in my case, of some 25 years of practice. Senator NELSON. Do you think that is what Dr. Edwards meant? l)r. MCCAIN. I don't think so. But the interpretation is what does "full" mean? I think I might, and I do go into considerable detail as I talk with the individual patient that I see. But from the stand- point of how full it is going to be with actual use of these prepara- tions and the large number of the patients that are being seen by family planning that is involved, this is where the difficulty arises. Senator NELSON. I am satisfied that you conscientiously go into great detail. Your statistics on your patients run counter to all the rest. I think there are about 81/2 million on the pill and about one million on the IUD. Interestingly enough, in Dr. 1-lellman's clinic- Dr. Hellman was chairman of the FDA's Advisory Committee on Obstetrics and Gynecology-around 55 percent use the ITJD and about 40 percent use the pill, which indicates that some educational process is going on. I happen to be very concerned and would endorse the statement you made about population. I think the most critical matter facing humankind is the overpopulation of the planet. I have friends who feel that way and think, therefore, you had better not tell anybody about the side effects because one of the benefits of the risk-benefit ratio includes the question of overpopulating the planet. I have never understood that to be the responsibility of the physician, to make a sacrifice of a patient for purposes of some wider sociological gain. But this is the attitude of many people who have talked to me, including many of the doctors that I have talked to. Their posi- tion is that disclosing the concern of the profession and the facts about the pill threatens the cause of birth control and limitations in population growth. They apparently feel, and some of them have in fact conceded to playing the part of "Big Brother" to all the rest of the women in the world. They conclude that population control is so important that no one should be informed about the pill for fear they will not use it. I think that is a very dangerous posture to assume and defend. But that is the position that many of them do take. Let me ask you this question: It has been suggested by Dr. Ley. I think it is under consideration by the Food and Drug Administra- tion now. It has been suggested by a number of witnesses here and elsewhere that there ought to be some informative, understandable piece of literature inserted in the package that the user gets, which is simple and direct and indicates circumstances under which they PAGENO="0046" 6486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ought to consult the doctor, and tells them something about the pill. Would you agree or disagree with that? Dr. MCCAIN. I think that would be a fine idea. May I make a comment with regard to your previous statement about the problems of world population and the risks that are involved in the pill? I became initially concerned because of the fact that there was no statement being made with regard to the fact that pills had any risks. I believe that it has been established that there are risks that are present. The question is how much. I would hope that, certainly from the investigation that is being made here, from the informa- tion that is available, intensive research, or the research can be intensified regarding not only the risks of the pills that are cur- rently available, but additional methods of contraception that can carry less risk or preferably no risk. This is tremendously impor- tant. Senator NELSON. Let me say I certainly agree with you. That is one of the reasons for having the hearings. The fact is we have been unable to get the kind of research support for studies in all methods of contraception and moneys for family planning, which are very important. The battle has been fought for years with hardly any progress. My own view is that, as a result of these hearings, we are going to see a substantial increase in the research moneys allocated for the improvement of the oral contraceptives, and research into other methods of contraception. I think all those I have talked to who have been working in the field would agree that tile oral contraceptive now on the market is a sort of crude, first generation contraceptive and that we have not done enough research including dose response studies, we do not know whether 25 micrograms of estrogen would inhibit pregnancy or 10. We just know that if we give pills containing 100 or 75 or 50 micrograms of estrogen in the tablet, they are effective. We have not made studies to find out 110w far we can go. We have not made ade- quate studies to find out how much tile reduction of the use of these agents reduces tile side effects. So I am hopeful that out of all this, we will get a substantial increase, as I think we will, in research funds. On the question of what people know and are aware of, and in reference to the news stories and the attacks on the hearings on the grounds that people are being frightened by the truth, I doubt whether there is one person, one doctor in a thousand in this country who is aware that Dr. Louis Hellrnan himself, as the chairman of the FDA study, said, "Now, in discussing the chairman's report, the second report to the committee, I said to them that a more forth- right statement has to be made. We cannot just hide behind rhetoric. We are going to have to say something, and we have an option; that these are not safe, and then the Commissioner might have to take them off the market if he believes this. We can say these are safe and our scientific data did not really permit that kind of statement." Yet Dr. Hellman was quoted in the media and in a large number of articles distributed widely to doctors that the oral contraceptives are safe, period. The FDA report did not say they were safe, period. It said they were safe within tile FDA's present interpretation of PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6487 the meaning of the law, which was a law passed in 1938 and did not contemplate this sort of situation where a potent drug~is widely pre- scribed for a healthy user. But the fact that this is disclosed to the public, the truth of what the chairman of the committee said, upsets all kinds of people. I happen to be one of those who believes that we lie in a free country and that if we give people all the facts, they will make the right decision and if they do not, it is better than having somebody take the responsibility to decide what people should know or should not know. Any questions, Senator Dole? Senator DOLE. Dr. McCain, on the bottom of page 1 and on page 2, you indicate that the risks of a pregnancy are definitely greater than the risk of the pill, and also that you have prescribed the pill for protection in your practice. You have practiced for about 25 years. I do not know how many patients you have had in that period of time. How many patients have you seen in the 25 years- of course, you have not had the pill that long. How many patients have you prescribed the pill for? You have said three-tenths of 1 percent? Dr. MCCAIN. This would be the patients within the child-bearing years. As one matures, our patients grow older also. It would run about 1,000 women a year. They would be gynecology patients within the reproductive years. Now, it is hard to modify what one must feel with what's consid- ered generally immediately acceptable. Patients who have been placed on the pills by other physicians, unless they ask my opinion, and unless they are having complications, I do not volunteer the interruption of their method of contraception which has been selected by medical advice. Of these individuals, about 10 percent of the patients I see are continued on contraceptive pills. I have about 10 percent of the patients that are on the contraceptive pills for gynecologic purposes, not contraceptive purposes. In other words, that makes about 12 percent of my patients that I place on them, 12 and a fraction percent. Senator DOLE. For how many. do you prescribe the pill for contra- ceptive purposes? Dr. MCCAIN. That I prescribe them for, about three-tenths of 1 percent, which would run-that would be about three or four a year, something like that. That I initiate the prescription for, for contra- ceptive purposes. Senator DOLE. On these case studies which you have referred to, you have a total of what, 16 different major complications? What are we talking about in numbers? You have seven cases of emotional or psychiatric problems, four of central nervous system symptoms, attempted criminal abortion, one. Are these all patients of yours? Dr. MCCAIN. Most of these were patients that have been put on them by some other physician. For example, the attempted criminal abortion was one that had been seen in another State and the abor- tion had been attempted in another State. Then she was seeii by me in Atlanta as a result of the complications which are described. Let me come back to your comment about the first page there. My statement that the risks of pregnancy are definitely greater, that was PAGENO="0048" 6488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY not an unqualified statement. This was the concluding statement of this paragraph. It is my opinion that the risks of such a pregnancy- in other words, these are the patients who have an unwanted, unplanned pregnancy, and the risks that the infant faces, the socio- economic situation in which the patient may find herself. Now, in such a pregnancy, under those circumstances, under those economic conditions, I think the risk of a pregnancy for mother and for infant carry a definitely higher risk than the pills would have been in that particular individual. It is not an overall endorsement. Senator DOLE. I irnderstand that. As far as your own judgment is concerned, then, based on your own practice, your own experience and your own observation, the pill has a very low priority? Dr. MCCAIN. It does. But yet I know my colleagues pretty well, too, and their response to the figures that are presented is not the same as mine, obviously. With ~ million women on it, obviously it is not the same. Then one tries to consider what's really fairest for the patient, for the women of our country. As one weighs what I know the senti- ments of the medical profession are, what I know as far as my own interpretation of risks are concerned, my conclusion would be the points that I made there. Senator DOLE. On pa ~e it under the heading of "General Sugges- tions," you say, "It is disturbing to consider the patients on the pills whose depression may have ended in suicide and/or homicide with no recognition of any association with the contraceptive pills." I am not certain I understand what you are saying. Dr. MCCAIN. This is one of the things that is very disturbing. i-low many people that see a murder that is. where the woman is a murderer. check to see whether or not she has had the pill? How many studies have been made of women who have killed themselves? Is she taking the pills? Senator DOLE. Are you saying there is some relationship? Dr. MCCAIN. There may be. When I have seen these patients who have come in and without any hint or question on my part tell me of their depression, these three patients very specifically of their sui- cidal impulses, then one gets to be, if you are going to be fair, it seems to me~ you should be very concerned about studies that would really investigate suicides, homicides. divorces. automobile acci- dents-all of these involve emotional disturbances and no studies are made. it would have to be done fairly, because with the number of women that are on the pill. obviously, many of these would he on the pill, but not necessarily the result of the pill. Senator DOLE. You do think there may be some relationship between the taking of the pill and driving off a cliff somewhere? Dr. McCAIN. I do. At least, I am disturbed about the possibility that there may be~ and there is no study undertaken at all with regard to this possibility. Senator DOLE. You base this conclusion on conversations with patients and what they have told you about the pill and the depres- sing effect it has had, but are you speculating here or stating a con- clusion based on evidence? PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6489 Dr. MCCAIN. Well, now, for example, Ofi this patient that I quoted specifically about the divorce, she told me that she was get- ting ready to separate from her husband. She had been on the pill. I told her, why don't you try leaving off the pill? She said, I am not about to. She would rather be divorced than stop taking the pill. Well, was it really because of the pill? I am not prepared to say. On the documentation regarding premenstrual tension, and all the things involved, in the criminal institutions, some 62 percent of all women who are in criminal institutions had their crime committed during this stage of premenstrual tension. Senator DOLE. They were not all taking the pill? Dr. MCCAIN. No, but this is by way of inference. I mentioned in my discussion that it seems to me that the emotional reaction of the patients while they are on the pill correlates very closely with what we have always been accustomed to recognize as premenstrual ten- sion. Now I am taking the emotional problems of premenstrual ten- sion and their wide range of applicability and implying then that it should not be ignored. It may not be this severe, but I am afraid that there may be some correlation. Senator DOLE. You are suggesting, then, that there be some inves- tigation to see if there is a correlation. When a woman runs a stop sign, you do not ask her, "Are you taking the pill ?," but somewhere in the course of investigation, you raise this question to see if there is any relationship based on this medical point which I do not understand clearly. Dr. MCCAIN. I am not sure that I do, but at any rate, the investi- gators ought to work it out and work it out exactly. Senator DOLE. Thank you. Senator NELSON. Senator Hatfield? Senator HATFIELD. Dr. McCain, I would like to go back a little bit to try to understand more clearly in my own mind what kind of profile we are trying to draw from these tables that you have pre- sented to us. I assume that table 8 is an extrapolation of the first seven tables? Dr. MCCAIN. That is correct, the cases that I would consider the maj or complications. Senator HATFIELD. But they are all part of 52 that I believe you referred to in the first part of your testimony? Dr. MCCAIN. That is correct. Senator HATFIELD. This is 52 out of how many? Dr. MCCAIN. This is why I have not reported this as a strictly sci- entific report. This is my experience in private practice. This is the difficulty that it does not bear up as far as it being a scientifically accurate paper. This is my personal experience. I can give you some estimate, as I have done, about the patients that I have seen on the pills, but some of these, you see, I did not have on the pills. I did not prescribe the pills for them. I saw them as a result of their com- plications. So~ it is not a fair presentation. Senator HATFIELD. So you are not really presenting these figures to us as a scientific investigation? Dr. MCCAIN. This is my concern based on my experience, actually, from 1964 through 1967. 40-471-70-pt. 16-vol. 2-4 PAGENO="0050" 6490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator HATFIELD. Could you indicate to us the number of patients you have seen who are not on the pill who have had some of these same side effects that von list for us in these seven tables? Dr. MCCAIN. Probably the one that would be the most frequent that we encounter is with regard to the vascular accidents. Now, I have seen three patients in the period-actually, this carries on up from 1964 to the present time, so it is really no longer that the period that is involved in the report, who had thrombophlebitis. These three patients, two of them were postoperative within 2 weeks, one of them was postpartum within 1 week, this is the time or inter- val in which we fairly frequently encounter this, but this was not because of any medication. This is one of the hazards of surgery or delivery, as I would interpret it. Senator HATFIELD. So in a period of time, you had three cases which were not on the pill and you had four cases which were on the pill from which you drew these conclusions relating to table 6, is that right? Dr. MCCAIN. That is correct. Senator HATFIELD. What about infections? In table 4, you list var- ions complications resulting from infections. I assume it is possible for women to have these infections who are not on the pill? Dr. MCCAIN. Actually, the correlation of a monilial vulvovagini- tis-this is commonly called a yeast infection, it is called. Thrush in babies and infants-is far more frequent than I have indicated here. It is so frequent that I did not even count the tabulation of the cases because of the changes, apparently, in the physiology of the vaginal secretions, making them more favorable as changes are true in preg- nancy and it is a very common complication of pregnancy. It is a nuisance. If it is combined, as is indicated in the part of the paper that I did not read, with diabetes or with cardiac conditions requir- ing the use of continuous antibiotics-either of those two conditions make the monilial infection much more frequent. To add to that, then, the increased likelihood under the pills, should be borne very specifically in mind. It is a very frequent prob- lem. Senator HATFIELD. But it could happen in nonpill users? Dr. MCCAIN. Oh, it does. Senator HATFIELD. In other words, table 8, then, is it possible for all of these effects that you have observed in pill users to take place in nonpill users on listings of table 8, the more complicated ones? Dr. MCCAIN. This is true, except that these that are listed are ones who were treated with the ordinary methods of treatment and failed to respond until the pills were discontinued, and then improved and cleared rather quickly under the same treatment that they had been on previously. Senator HATFIELD. I accept the fact that you have identified this as a nonscientific study, but ill a scientific study, would it not have to be in juxtaposition to what might be a profile of nonusers? Dr. MCCAIX. It would have to work out in considerably more detail with a considerably large number of cases to make it valid from a statistical standpoint. PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6491 Senator HATFIELD. Are we then, as laymen on this committee, merely to draw from this testimony that you have a question as to whether certain problems might result with the use of the pill, but you do not really present us with any basic scientific study to prove it? Dr. MCCAIN. This would be true. Now, as I mentioned during one of the moments of the discussion, at the time this was begun, the general opinion was that there was no risk involved associated with the use of the contraceptive pill. Senator HATFIELD. You were talking about the necessity of long- term studies, and I certainly would agree with you. In fact, I have felt for a long time that we ought to have long-term studies on all drugs. You mentioned the question about the possibilities, because of a lack of study to prove otherwise, of a relationship between pill users and various violence or homicides and so forth and so on. Are there such studies, or could we draw a correlation between that and, say, other uses of drugs such as~ Dr. MCCAIN. Tranquilizers would be one of them. Senator HATFIELD (continuing). Fluoridation of water? I mean these are certain things that are used. Should there be such studies in relation to other uses of other drugs? Dr. MOCAIN. You are out of my field in fluoridation. I would have to say only what my opinion is as I have understood from the expressed opinion of the American Dental Association and from the American Medical Association, from those whose opinions I respect, that they have found no trouble. Senator HATFIELD. Well, the John Birch Society and other groups certainly raise some questions about this, but they are not the Dental Society. Dr. I~s'IcCAIN. I raise some question-certain studies should be borne in mind, and long-range studies, when one is considering health hazards, because it is true, the immediate recognized dangers should be considered. But there are long-range possibilities and fluor- idation would be-well, for that matter, chlorination of the water, too. This would be a very fair consideration. Any time that we are adding a chemical to our environment, it should be kept under- Senator HATFIELD. You are not singling out, necessarily, the pill, but you would apply this same concern to all drugs that people take that might have some impact, either short-term or long-term, for the human physiological system? Dr. MCCAIN. Well, I would carry a concern, but not the same con- cern. Senator HATFIELD. Because it is outside your specialty? Dr. MCCAIN. No, because I think that from my experience and from the reports which I have encountered, which I think are valid, there is significantly more risk involved in the use of this particular medication as compared with some of these others. All medication carries some risk and should not be accepted without consideration. On the other hand, the amount of concern, I think, would have to be evaluated against the evidence of risks that are being encountered. Senator NELSON. Thank you very much, Doctor. Dr. MCCAIN. Thank you. PAGENO="0052" 6492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. We appreciate your taking the time to come here. Our next witness is Dr. Philip Ball, an internist from Muncie, md. Dr. Ball, we are pleased that you took the opportunity to come here today. Your statement will appear in the record. If you desire to read it or simply to submit it and speak extemporaneously, you may do so. STATEMENT OP DR. PHILIP BALL, SPECIALIST IN INTERNAL MEDICINE, MUNCIE, 11Th. Dr. BALL. Mr. Chairman, Senator Dole, Senator Hatfield, this statement comes from the original grassroots, President Nixon's heartland of the United States, the ultimate sampling community, the statisticians' paradise, the standard of American town life, the hub of mid-America; a place semi-out in the boondocks, the typical American city, the Middletown of Lynd's famous sociology work, namely, Muncie, md. I am 28 years in the business of doctoring, first in Chicago's giant Cook County Hospital, later in the Navy three wars back; in pri- vate general practice; and in the Mayo Clinic and in a small clinic; and by myself in solo practice of internal medicine in my hometown. The letters sent out by the Food and Drug Administration to phy- sicians in the United States dated June 18, 1968, and January 12, 1970, list some 40 to 50 adverse reactions that may be caused by con- traceptive pill administration. I have seen most of them-and others not listed by the FDA letters. Several near-tragic examples of thromboembolism caused me to slow up my prescribing of contraceptive medication 6 years ago, and finally to cease totally prescribing the birth control pill some 4 years ago. Even though I have not prescribed the medication in some years, a procession of symptomatically unhappy women taking birth con- trol pills continues to flow into my office. I have seen women with thrombophlebitis, skin pigmentation, edema, weight gain, nausea, irritable bowel syndrome, backache, cancer of the breast, rheumatoid arthritislike syndrome, monilial vaginitis, uterine fibroids, erythema nodosum, temporary and alarm- ing hypertension, and women with abnormal thyroid and liver func- tion tests. But more than any other problems, I have seen women who are chronically tired, or depressed, or lacking in libido, or complaining of frequent migrainelike headaches, often of incapacitating nature. These symptoms may occur singly or apparently rather -frequently together in the same woman. I wrote an article concerning some of these cases in 1966 and after rejection notices by three or four medi- cal journals, the article was first published in January 1968, in The Journal of the Indiana State Medical Association. I summarized my experience with these "side effects of depressive symptoms, malaise, fatigue, tension, lack of libido, acceleration of vascular-type head- aches during the administration of these pills" and stated that I PAGENO="0053" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6493 thought these problems were more common than usually believed and pointed out that they should be looked for and warned that the symptoms could be incapacitating and symptomatically severe. I also stated "it is not considered reasonable that there be any mortality or morbidity in a pill used purely for contraception purposes. Medical research has got to offer something better than this. Physicians will probably look back on the contraceptive pill era of the past 5 years with some embarrassment." Since writing this article, I believe I have seen at least 200 of such types of problems and every week brings one to several more to me, and I have had no reason to change or moderate my attitude toward the birth control pill. These are adverse effects that are happening to women, that have happened, that do happen. They are not just future risks or maybe's. One of the first of the type of patient that I have written about was seen initially on February 13, 1965. This was a 24-year-old mar- ried school teacher who complained of headaches of severe throbbing nature accompanied by nausea, vomiting, and visual disturbances. She also complained of depression and tension and difficulty with adjustment to her marriage. All of these symptoms had been present for some 3 years, i.e., the years that she had been married and been on birth control pills. This girl was advised to discontinue her birth control medication and given advice concerning a different contra- ceptive technique. She did these things and was seen a few months later. She stated that the depression, tension, and migrainetype head- aches seemed to abate promptly when the birth control pill was stopped. She added that she had formerly felt that perhaps she had made a mistake in her marriage and married the wrong man, or that perhaps marriage was not for her, and now she was so happy. The marriage was wonderful and she had no idea that married life could be this wonderful. I have seen such newlywed problems on many occasions since and consider this one of the unkindest prescriptions of all. These unhappily newly married women do not know if it is the wrong man, the wrong town, the wrong job, the wrong year, the wrong apartment, or yet something else, when it is really many times the wrong pill. One of the last cases of this syndrome of unhappy womanhood I have seen came into my office 2 weeks ago. This was a 25-year-old housewife with one child, aged 4. She had been married 6 years and had either been pregnant or on birth control pills all but 2 months of her married life. She complained of being increasingly depressed for several years and she stated that she had never been depressed prior to her marriage, and apparently was inclined to blame her mood on this state-that is, the state called marriage. Her husband stated that he did not know her to be depressed prior to their marriage, but it had been increasingly a problem ever since. She complained of being tired, tense, complained of the gain- ing of some 40 pounds during the recent years and also complained of increasingly severe incapacitating headaches accompanied by vomiting. She also stated that she had been losing sexual desire during the past many months and in fact had beeen increasingly unable to achieve a climax during intercourse. Her blood pressure was found to be as high as 212/142 mm. of mercury. This compares PAGENO="0054" 6494 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY with what would be a normal pressure for this woman of perhaps 130/80 mm. of mercury. She was hospitalized for investigation and treatment.. But with discontinuation of the birth control pills, her symptoms and problems have been rap~dl subsiding within recent days. Why can't I give you accurate statistical numbers about the per- centage of patients placed on birth control pills who develop the symptoms of fatigue, depression. et cetera, that are my particular interests? First of all. I have no idea from what numbers of women on the pill in m localit my Particular statistical sample comes. Furthermore, even though I keep excellent office records which are typed, chronologic and bear face sheets listing major diagnoses and drug allergies. I cannot in my solo practice of internal medicine, seeing all types of problems. set up a complex cross reference or cross indexing system. I do not specialize in birth control problems. Hence. my information about the series of problems that I have reported had to come first. from a flash of insight that I was seeing a new "syndrome." and then a laborious attempt to recall from memory some past patient's names and then keep a list of new patients seen with these problems. Don't ask me or most solo physi- cians for st.a.t.istics regarding symptoms, disease or problems that they see in their office pra.ctice. I take time out to congratulate Dr. McCain on having IB~s1 punchcards. This is, I am sure, unusual in most practices. Many of the women that have come to me with problems resulting from birth control pill administration had the pill prescribed by a gynecologist., or I should say any one of a. number of genecologists in my community. He then has usually carefully examined the woman in reference t.o any pelvic problems resulting from the pill but has expressed disinterest, doubt or denial concerning any side effects not in his field of interest.. The American patient is often par- titioned out among his physicians and this can lead t.o doctors being blind to aspects of people's problems that they see which may fail into other fields. In my experience most of the women that have seen me because of adverse effects from the pill have not been warned by the prescribing doctor that the pill can cause important side effects. In fact., many have been told after their side effect symptoms began, that the pill could not do this, and in fact, their doctors have often denied the obvious evidence even when discontinuing the pill resulted in elimination of the woman's problems. The sale and prescribing of contraceptive medication during the pa.st 10 years or so has been a massive, double-blind, uncontrolled experiment with very little possibility of good mass statistical analy- sis. The doctor is blind (and also sometimes deaf and dumb) ; the patient is blind. The years of administration of birth cont.rol pills t.o millions of women have also. I believe. been a drain on the Nation's medical dollar expenditure. by causing excessive need for medical care at a time when doctors have been in short sul)ply. If all women placed on birth control pills are checked as carefully and as often as pres- ent regulations and prudence advise. there might. not be enough doc- tors to get the job done. These women should actually have careful, PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6495 expert interrogation for all possible side effects, and complete physi- cal examination, with very careful examination of the breasts and pelvic organs, and Pap smear at least every 6 months. This would be all extremely expensive package of medical care if done for all women on the pill. Also then, inasmuch as in my experience, many of these women are going to be ailing after the pill is started with any one of a variety of symptoms-they are going to be utilizing a lot of doctors' time for the care of their side effect problems. I find that many of the women on birth control pills have had prescribed to them multiple medications needed to counteract the adverse effects of tile birth control pills. These women may have additional pre- scriptions given by other physicians for appetite depressants, or diuretic fluid eliminators, or hypertension medication, of antidepres- sant medication, or tranquilizers, or drugs to soothe gastrointestinal side effects or antimigraine medications, or ordinary headache pills,. vaginal suppositories and creams to stop itching, et cetera, et cetera.. All of these medications are costly, of course, in terms of dollars and many of then-i have their own side effects that lnllst in turn be looked for. I have found it easier to suggest to women that they stop birth control pills and let their side effects disappear spontaneously. The birth control pill has been held almost sacred, or at least until the past yea.r or so, it has been held sacred. Why is this? There are many reasons. The medical profession hates as a group to admit that it has been wrong. But we have been wrong. We were wrong in the 1950's in widely using cortisone for very simple cases of rheumatoid arthritis. We eventually stopped this. Now we use it only in excep- tiomial cases. WTe have been wrong, I think, in widespread use of appetite depressants, and their use is not so popular now. And I think we have been wrong about birth control pills. Further, because it is so simple for a doctor to prescribe it, the pill has been popular. But if a doctor carefully instructs his patients in the side effects and dangers and makes the checking exams that are necessary, the birth control pill is not so simple. Another sacred thing about the pill has been its presumed 100-percent effectiveness if used properly and continued. But it is really not accurate to say it is 100 percent effective in mass use, because many women do not con- tinue with these pills over long periods of time for various reasons. Hence, if only 60 percent are taking the pill at the end of 2 years, the' pill is really only 60 percent effective. Furthermore, a woman that becomes ill because of the pill is 100 percent ill. The pill also has been held sacred because it has been the fad or "in" thing to do- that is, for both patient and doctor, I believe. The sacred birth con- trol pill has also had the halo of being the drug that would control the massive social problems of a burgeoning population. It could be used on the poor, ignorant, illiterate woman who scarcely knew what birth control was all about. Doctors' reluctance to leave the birth control pill also comes because, having once prescribed the holy vision of 100 percent effectiveness, what doctor likes to turn around and offer his patient only a 90 percent to 95 percent technique? I believe that we physicians are so used to administering very potent medications to very serious disease problems, we have not really yet learned it is a totally different circumstance to administer PAGENO="0056" 6496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY powerful but nonessential drugs chronically to healthy young women, as is done in contraceptive pill administration. It is of no relevance to say that the pill causes less trouble than cigarette smok- ing-doctors do not prescribe cigarettes. In fact, I take women off tobacco also. It is not sensible to say that birth control pills are safer than pregnancy-we don't prescribe pregnancy. The question is simply, are the pills safer than the diaphragm or safer than the foams or rubber prophylactics? And the answer is clearly no. We have had much talk in our land about preserving our environ- ment or improving our quality of life or preventing pollution of our country. The administration of birth control pills, in my opinion, prejudices a woman's internal environment. It may be termed an internal pollution by chemicals and it will sometimes definitely interfere with a woman's quality of life. Is there perhaps a sexual double standard or sex discrimination that works in this seeming insistence of our medical profession to force the pill on women rather than men? Is the pill safe enough for women b~~t a male contraceptive pill is not safe enough for men? The simple fact that women have the babies should not mean that they should be discriminated against by being the only ones sub- jected to chemical contraception. Is there anyone here that would guess how many men would take a male sterility pill if the list of possible side effects were made known in advance, and this list equalled 40 or 50 items. and the frequency of periodic exams were explained to the men? My recommendation is a declared moratorium on all birth control pills for some 5 years. During this period of time women leaving the pill would be able to see what chronic symptomatology they might have slowly fading away. Doctors would find out which of their birth control pill patients no longer needed their medical services. The American physicians could try to come up with an honest retro- grade evaluation of the pill era-and carry out further testing of the women who were on the pill in the 1960's to see what yet unknown problems they may develop. And the American health pro- fessions could start a concerted effort. to find a new means for birth control. Certainly if all the time and money and words and thoughts and minds that are now spent on arguing the safety or danger of birth control pills were put into constructive new avenues of research, it is probable that a solution could be found for the prob- lem of a cheap, safe, simple. casually usable, esthetically acceptable contraceptive technique. Thank you, Mr. Chairman. Senator NELsoN. Thank ou very much. Dr. Ball. I was glad to see your endorsement of the idea that we certainly need to expand our research substantially in the field of family planning and improving whatever contraceptive devices we can, or discovering new ones. I think it is necessary and a critically important step that we could be asked to take. Did you have any questions, Senator Dole? Senator DOLE. Senator Hatfield has to leave. Maybe he would want to ask some questions first. Senator HATFIELD. Mr. Chairman, I just want to ask Dr. Ball a question or two. PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6497 I have before me the Indiana State Medical Journal of January 1968, entitled, "Some Apparently Common Problems in Patients taking the Pill," which I believe you authored. Again, I am both- ered by perhaps a problem of semantics. Let me quote from one par- agraph of introduction to your case reports: This article was based on an unscientific sample of some 30 cases recalled "out of thin air" from an internist's, office practice. The symptoms concerned were intangible enough that they would not be well identified in a mass survey, particularly if this were of a population of a backward test country or a population group that was only casually or superficially surveyed. It is also true that the symptoms are common enough in any case so that perfect truth of relation of symptoms to contraceptive medication is not easy. The author has also seen several cases of- I do not know if I can iroiiounce this- thromboembolic- Dr. BALL. You are doing wonderfully so far, Senator. Senator HATFIELD (continuing) thromboembolic disease and erythema- Is that right? Dr. BALL. Very good. Senator HATFIELD (continuing) nodosum, on contraceptive pills and feels these are infrequent problems com- pared to those which are of concern here. My basic problem is that I appreciate your frankness, both in tes- timony here this morning and in this article which you have published in the Indiana State Medical Journal. I would like to ask you this question, Dr. Ball, again as a layman. We are here trying to come to some kind of conclusions or some sort of generalizations. I think the question is, "are these valid to do other than raise danger signals," these observations of yours? Because you say they are nonscientific. Secondly, if they are only to raise danger signals, what do we do in terms of getting to the real heart of the matter in reference to the scientific base of data on which we coulcL perhaps, make recommendations? Dr. BALL. Well, sir, I thank you for reading my words from my article, and I agree with the words as heartily now as I did when I wrote that article, which was, I think, 31/2 years ago. I am not a statistician; hence, I cannot give you accurate informa- tion as to how to carry that out. But I feel that evidence presented today by Dr. Kane bears out my initial warning, and that is what I stated this was, a warning. I felt that it had not been adequately warned about. I felt that I was seeing a large number of these women. at that time, 30. before I finished compiling my lists and I kept a list for a while, perhaps for 6 months after that article and I had 70 on the list. Since that time I have estimated 200. My secretaries told me I am wrong, it is probably 400. These are common problems in my practice. I do not have accu- rate statistics. The British studies indicate 30 percent, Dr. Kane as much as 50 percent. These are not adequately warned about. It is PAGENO="0058" 6498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY implied that it. is uncommon, or maybe it happens, or maybe it does not.. But. I say it happens and it happens commonly, and I feel that the statistical boys who have done work on this, particularly the British, perhaps, agree that it is one of the most common problems-. depression, fatigue, lack of energy, lack of motivation-these problems. Senator HATFIELD. Do I understand that you draw certain medical conclusions from these observations which lead you to say in your testimony today pretty strong words about getting off the pill? Dr. BALL. These are observations of mine-as I say, I have had no reason to change mv viewpoint. Further evidence in the literature, American literature. British literature, further evidence that I have had in my practice has convinced me that these observations are as factual today as they were then. Senator HATFIELD. So for the purists in our society who think all things are done on a. scientific basis, with scientific data, this does not necessarily follow, does it? Dr. BALL. Right. Senator HATFIELD. There are other conclusions drawn from obser- vations, as you indicate, that may not be drawn from things that are scientific but may lead von to draw conclusions? Dr. BALL. Right. Senator HATFIELD. Would you suggest others should draw such conclusions based on your observations-I gather you suggest that here today? Dr. BALL. That others would? Senator HATFIELD. That others should. Dr. B~\LL. I feel they should. Senator HATFIELD. Thank von. Senator DOLE. Has this article in the Indiana State Medical Jour- nal appeared in other medical publications? Dr. BALL. I believe that it has appeared in about 12 State journals and the OB-GYN News. I am not sure how many others, but in those. Senator DOLE. I knew it appeared in the State Medical Journal and on the front page of tile article there, it states that the article is based on an unscientific sampling of some 30 cases, recalled out of thin air. Do you think this is an accurate sampling? At least, it is enough for you to call off the pill in certain instances-in fact, all instances. ~1ou do not prescribe it at all? Dr. BALL. I do not prescribe the pill, that is right. Senator DOLE. And you have not since 1966? Dr. BALL. Right. Senator DOLE. Had you before then? Dr. BALL. I had before then, yes, sir. Senator DOLE. In many cases? Dr. BALL. A large number. Senator DOLE. In these same cases you prescribed the pill; then you not.icedl the symptoms andi removed them from the pill? Dr. BALL. The nnmber that were my prescriptions at the time of this original article was probably high. But lately on referred patients with medical problems, problemns that fall within tile internists' province, tile prescriptions are by other practitioners. PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 6499 Senator DOLE. All the instances of who gain weight, of dizzy spells, were not totally attributable to the pill, right? Dr. BALL. That is so. Right. But on the other hand, the evidence that I had was, here were women in large numbers ailing, coming to an internist with problems, and if you removed the pill, they were better. That is pretty good evidence. Senator DOLE. It may very well be. You suggest that perhaps there is a double standard for men and women. As I understand from earlier testimony, there is work being done now on a male pill but I am not certain what stage it is in. Dr. BALL. I know no facts about it. I read in medical journals occasionally that there are such medications that are being tried out. Senator DOLE. If there is such a pill available in say a year or two, then, of course, we can make a judgment whether we would ask men to accept the same hazard as you say we ask women to accept. Would you prescribe the pill in any event now? Dr. BALL. I have not, no. In fact, for treating problems like endometriosis and abnormal bleeding and so on that fall more into the gynecologist's line, the doses used are often higher and it has been my experience that the problems are greater, being somewhat dose-related. Senator DOLE. As Dr. McCain pointed out, he places the pill in a low priority category. You do not place it in any category at all? Dr. BALL. No category at all, that is right. But I practice very well without it. Senator DOLE. You conclude that the risks far outweigh the bene- fits and therefore, you suggest a 5-year moratorium on the pill itself to discover whether the symptoms are lasting? Dr. BALL. That is right. I feel that the vast majority of this 8.5 million women are being basically unsupervised in their taking of the pill; that is, as far as any accurate statistical analysis. Senator DOLE. I detect from your statement that you are as criti- cal in a proper sense of the doctors as you are of the pill. Can I in-fer that if doctors were well-versed in the use of the pill and they were supervising their patients as they should be, then perhaps the pill could be given with some certainty or safety? Dr. BALL. In my opinion, this would be better than it is now. For instance, if, as Senator Nelson suggested, perhaps a list of side effects were dispensed with the pill, this would be of some bene- fit-not, in my opinion, enough; but it would be Qf some benefit. There is one other problem about this depression, fatigue, and so on of these women. Many times you can ask a women and she might not either know it or say it. Therefore, to interrogate her, to ques- tion her, will do you little good. You would miss a good percentage of them. In fact, in a fair number of these women, the husband will call me separately, and say, "My God, do something about my wife, she has just turned into a bitch." So in other words-or the 1nother or the mother-in-law. I never particularly listen to mothers-in-law, but these problems are often stated by other members of the family who have observed a total change in personality. Senator DOLE. Do you have a standard response when you get those calls? PAGENO="0060" 6500 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. BALL. Yes, a physicians' careful courtesy-yes, yes, you know. Senator ~ELSOX. What do you advise the husband whose wife ends up that way and is not on the pill? Dr. BALL. Probably refer him to another practitioner. Senator DOLE. Dr. McCain mentioned earlier that perhaps we should start an investigation of divorces and all accidents and sui- cides and homicides to see if any relationship exists between inges- tion of the pill and the commission of some act. Dr. BALL. Well, that, of course, would only be a fraction of the problem, and I am not sure that would be the best way to get at it. For instance, I guess some have gone to psychiatric units and deter- mined how many with depressions have been on the pill, and I think they have found some answers there. Senator i-IATFIELD. I have another question. Dr. Ball, I presume that all of your objections are purely medical Dr. BALL. Yes, sir. Senator HATFIELD. If there were no medical characteristics that you have observed over this experience of yours, would you have felt that the pills should be equally available to those who are married and those who are unmarried? Dr. BALL. I would consider this immaterial. Senator HATFIELD. Whether it was dispensed from University health centers or whether it was not? Dr. BALL. To me, this is no medical consideration. Senator HATFIELD. And you would not have any viewpoints on that particular pilase of the use of the pill if there were no medical problems involved? Dr. BALL. Mv antagonism is totally medical. In other words, I believe that anybody who is in the situation of needing a contracep- tive should get it, but not the pill. Senator NELSON. Let's suppose further, that if through additional research, an oral contraceptive was developed that seemed to have no significant side effects and was at the same time effective, you then would favor the use of that kind of a device? Dr. BALL. Yes, sir. rUle problem is, we talked about changes in dosage over the years and so on. Each time we change the dose or the chemical, you have a whole new ball game statistically, and then a long period of time has to go by for evaluation. Again, is it going to be just this unscientific, hand-out-the-pills-and-see-who-gets-sick- business, which I say is wrong and which has been done. Each time there is a new pill, there is a new problem. We doctors in private practice are very poor people to be evaluat- mg this. I mean, I am talking about. drug problems. May I add one other tiling? As far as statistical sampling, again, I do not want to appear to be Ilacking away hard at American medi- cine, but ~fl tile statistics on thromboembolic disease that tile FI)A Ilands out, tile statistics that are considered valid, and I think about tile only ones that are considered validi are from tile British. In other words, a 7-fold increase over those ilot on tile pill in tile same age group. Senator NELSON. I think the British study is seven; aildi I tllink the American study is 4.4. Dr. BALL. ies. PAGENO="0061" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6501 Mr. GORDON. Dr. Ball, it has been estimated that perhaps around 10 percent of the adverse actions which result from the use of drugs, pharmaceuticals, are reported. I do not know how accurate that 10 percent is, but let us assume it is a small percentage. Would you say the adverse reports of the pill fall into that cate- gory also? Dr. BALL. I am sure it does. Of course, you could be very direct and say how many have I reported to the FDA. Well, when the pill was first on the market and in general use, I reported to the FDA several cases of erythema nodosum and several cases of thromboem- bolic diseases, one life threatening and the other can be quite an ill- ness. So I reported those. I am an internist. The reporting of those is rather a complicated bit of paperwork and there was no feed- back. In other words, the paper went in and I heard nothing back from it. So from then on, I have not reported any further on the pill. There has been plenty of literature, there have been plenty of sta- tistical studies, presumably going on, and in fact, I considered it a closed subject in my mind in 1966. Mr. GORDON. You do not report the adverse effects that you see? Dr. BALL. Since that time, no. Mr. GORDON. So the 10 percent, as far as you are concerned- Dr. BALL. Is wrong. It is too high. It might be like .5 percent, I do not know. But it is probably very small. Mr. GORDON. So you really do not know the occurrence, the per- centage of occurrence of thromboembohic disorders or any of the other disorders? I)r. BALL. Out in the boondocks, we do not. Senator NELSON. I am now looking at the experience report on the reporting form that you get. Does it have all the information neces- sary? Dr. BALL. Senator Nelson, as I say, it has been several years since I made out one of those blanks, but it required a quite a bit of secre- tarial time. It seemed to me it was not excessive but it took time to do it. If I had reported all of these I had seen, I am afraid the paperwork for the blank would have been greater than the history form I had on the patient. It has been quite a problem, a physical problem. Senator NELSON. Thank you very much, Doctor. So that everyone will notice the balance in the record that is talked about so much, you are the first practicing physician who has recommended aban- doning the pill. We have had no other such witness; they have all been pro to one degree or another. Our next witness is Dr. Elizabeth Connell, associate professor of obstetrics and gynecology, director of Research and Development, Family Planning Services, International Institute for the Study of Human Reproduction, Columbia University, New York City. The committee is very pleased to have you take the time to appear here today and present your statement, Dr. Connell. You may pre- sent your statement-it will be printed in full in the record. You may present it in any way you desire. PAGENO="0062" 6502 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY If you wish to extemporize at any time on anything in your state- ment, please feel free to do so. (The biographical sketch of Dr. Elizabeth Connell follows:) CURRICULuM VITAE OF ELIZABETH B. CONNELL, M.D. College: University of Pennsylvania, 1943-47. Degree: A.B. Medical school: University of Pennsylvania, 1947-51. Degree: M.D. Internship: Lankenau Hospital, Philadelphia, Pa. Rotating: 1951-52. Residencies: Lankenau Hospital, Pathology and Anesthesia, 1952-53. Gradu- ate Hospital of the University of Pennsylvania; Gynecology, 1958-60. Mount Sinai Hospital, New York City; Obstetrics, 1960-61. Fellowship: American Cancer Fellowship, Kings County Hospital, State Uni- versity of New York, 1961-62. Board certification: Obstetrics and Gynecology, 1965. Practice: General Practice and Anesthesia, Blue Hill, Maine, 1953-58. Academic Appointments: Associate Professor of Obstetrics and Gynecology, New York Medical College, New York, 1962-69. Director, Family Planning Center, New York Medical College, Metropolitan Hospital Medical Center, New York, 1964-69. Associate Professor, Department of Obstetrics and Gynecology, College of Physicians & Surgeons, Columbia University, 1970 to present. Direc- tor of Research and Development, Family Planning Services, International Institute for the Study of Human Reproduction, Columbia University, 1970 to present. Appointments: Medical Advisory Board, Planned Parenthood, New York City, 1964. Executive Committee, American Association of Planned Parenthood Physicians, 1968. National Advisory Council, Center for Family Planning Pro- gram Development, Planned Parenthood World Population, 1968. Consultant on Family Planning, New York City Department of Health. Family Planning Project Consultant, Human Resources Administration. Committee on Medical & Public Health, Executive Committee, Association for Voluntary Sterilization, Inc. Professional societies (Membership) : American Medical Association, Ameri- can College of Obstetricians and Gynecologists, American College of Surgeons, American Public Health Association, American Association of Planned Parent- hood Physicians, American Fertility Society, American Medical Women's Asso- ciation, Inc., Medical Women's International Association, Public Health Asso- ciation of New York City, The Society for Scientific Study of Sex, Inc., New York Academy of Sciences, Medical Society of the State of New York, Popula- tion Crisis Committee. STATEMENT OF DR. ELIZABETH B. CONNELL, ASSOCIATE PROFES- SOR OF OBSTETRICS AND GYNECOLOGY; DIRECTOR OF RESEARCH AND DEVELOPMENT, FAMILY PLANNING SERVICES, INTERNA- TIONAL INSTITUTE FOR THE STUDY OF HUMAN REPRODUCTION, COLUMBIA UNIVERSITY, NEW YORK CITY Dr. COXXELL. Mr. Chairman, I would first like to thank you for your kind invitation to appear before von today. I fully recognize the tremendous importance to all of us of the course and the out- come of these hearings. Upon the receipt of such an invitation, one has a moment of introspection-first, why me. and then, what should I talk about ~ After much thought, I decided there were four areas in which I might possibly be able to make some small contribution based on my own personal experience. First and foremost, I am a physician. I was a general practitioner in rural Maine for 5 years and I am now a specialist in obstetrics and gynecology in New York City. It has been my privilege to care for some of the wealthiest people in our PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6503 country. I have been even more greatly privileged to care for thou- sands of our most grossly deprived citizens. I have delivered women of their babies under ideal circumstances-in aseptic, brightly-lit hospital delivery rooms. On a bitter, cold night, I also delivered one woman of her child by moonlight on the front seat of an ancient pick-up truck, surrounded by her distraught husband and her seven fascinated children. Having cared for many patients-men, women, and children-from all sorts and varieties of backgrounds, I hope perhaps to bring to this situation something of a clinical flavor based on a long and varied experience. Second, I started, developed, and ran a family planning clinic in Spanish Harlem in New York City. This led to the third area which I presume may have prompted this appearance, that of a research investigator. I have worked in the actual development of newer contraceptive techniques, have car- ried out studies related to patient motivation and behavior, a.nd have been increasmgiy involved in programs for the training of commnu- nity women. Not only do such programs supply much needed paraprofessional help, but they also give these women an opportunity to learn, to hold responsible jobs, and to help support their families. For many of them, this is their first opportunity to get off the welfare rolls and become happy and productive members of society. Finally, I would be naive and less than perceptive if I did not recognize that a fourth additional factor might be operative here- that I happen to have been born a female and have five sons and a daughter. Thus, I realize that I represent a group not previously heard by this committee and I certainly cannot in any sense be con- sidered to be opposed to the perpetuation of the species. I shrink from approaching my testimony in such a highly personal manner, but after carefully reviewing the situation, it seemed to me that only in this way might my combined areas of experience be of some value to you. In looking at a subject with as many ramifications as the oral con- traceptive, all of us who deal with individual patients as well as major programs face many difficulties. On the one hand, we appre- ciate the obvious necessity for finding contraceptive methods which are 100 percent effective and 100 percent safe-this is not entirely the province of the academic purist. The thought that any method which we currently employ may fall short of this ideal is intensely disturbing to doctors. At the other end of the scale, we see the tragic results of unwanted pregnancies and the growing twin horrors of overpopula- tion and pollution. Those of us who live and work between these two extremes understandably find ourselves in a somewhat schizoid situa- tion. To date, these hearings have not made our lives any easier. It seems to me that much of the previous testimony has been rather like a bikini; what it has uncovered has been interesting, but what it has left concealed is vital. To my mind, one major misfortune has been the artificial and totally erroneous creation: of two camps of doctors, the pro-pill and the anti-pill. Except for a few extremists among us, such an arbi- PAGENO="0064" 6504 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY trary division is not only totally unrealistic but also most regretta- ble. I believe that I speak for the overwhelming majority of physi- cians when I state most emphatically that I do not belong to either group. Senator ~EL5ON. May I interrupt you for a moment? Dr. CONNELL. Surely. Senator NELSON. I would think that perhaps all but two witnesses would put themselves in your category. There may have been reports and stories written which characterized witnesses as pro-pill or anti-pill. I read one national magazine that said that this week, the hearings were loaded seven to one against the pill. I could find about four of them who did not address themselves one way or another, pro or con the pill. But the hearings have not been aimed at either campS and I do not think that more than one or two of the witnessed who have already appeared would put themselves in the category of anti-pill. Some of them have been pro and others have simply expressed their concern about certain aspects of it. But today, Doctor Ball was the only doctor who has testified that he was opposed to using the pill at all. Dr. CONNELL. I was not speaking here only of physicians testify- ing before you. I was speaking of physicians at large who are now being classified by their patients and their confreres as being either pro- or anti-pill. This is what is happening outside of these hear- ~ngs. I firmly believe that no thinking objective doctor can be totally pro-pill or totally anti-pill. WTe all recognize the tremendous contri- bution made by these agents to medicine and society, and we use them with the same judgment and the same respect we ~ to any powerful drug. In this respect, we are pro-pill. We also recognize that there is an element of risk in all potent medications, and so for partic~ilar patients, we are anti-pill. How- ever, to be forced daily by current pressures to declare ourselves as belonging to either the far left or the far right on this question is not only increasingly annoying but is actually incredibly destructive. Segregation of docrors into opposing camps is of value to no one, least of all the women we are all dedicated to serving. I would like to look first at what has come out of the preceding days of testimony. as viewed by a self-styled moderate. First of all, virtuall nothing has been presented in these hearings that those of us working in this field have not heard many times over. When I examined the vintage of the testimony to date. I discovered that some is relatively new, much is several years old, and a few pearls of information were in print long before I started in medical school. It has been frequently asserted that the hearings, thus far, have been slanted, one-sided, and unfair. Objective consideration suggests that in one sense, this criticism may indeed be valid. The bias which I feel has been noticeable on previous days has been the bias of posi- tive results. No scientist of experience would question the capability and integrity of almost all the previous witnesses. Their work has been meticulous and their results are not in question. What is dis- turbing is the fact that such a great percentage of time has been PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6505 devoted to two areas-first, experimental work carried out by com- petent men in excellent laboratories, but far removed from patient care and its implications; and second, to side effects which occur in a very small percentage of the patient population. What has been missing to date and what I think is needed to maintain an overall proper balance and perspective is a better look at the vast majority of women who can and are taking oral contraceptives safely and effectively. As a physician who began to practice before the advent of the pill1 I am constantly aware of the immense difference it has made to the lives of women, to their families, and to society as a whole. The look of horror on the face of a 12-year-old girl when you confirm her fears of pregnancy; the sound of a woman's voice cursing her newborn and unwanted child as she lies on the delivery table; the absolutely helpless feeling that comes over you as you watch a woman die following criminal abortion; the hideous responsibility of informing a husband and children that their wife and mother has just died in childbirth-all these situations are deeply engraved in our memories1 never to be forgotten. Since we have had more effec- tive means of contraception, the recurrence of these nightmares has blessedly become less frequent. The thought that we may once again be forced to face these disasters on an increasing scale because of the panic induced by these hearings strikes~ horror into the hearts of all of us who have lived through this era once before. A great deal of very positive information was presented here last month. Aside from the obvious personal, social, and economic advan- tages of planned pregnancy, we were told of lowered prenatal loss, fewer abnormal babies, and lessened maternal risks. Unfortunately, the general public was not always made aware of this type of information to the same degree that they were made painfully aware of the frightening speculations and the diversity of professional opinion. Senator NELSON. Might I interrupt you for a minute? Dr. CONNELL. Surely. Senator NELSON. What would be your conclusions about that? That Dr. Hellrnan, who headed the FDA task force, should not have testified, or that Dr. Hertz should not have testified or that Dr. Davis of Johns 1-Iopkins should not have testified? Should not what qualified doctors and scientists were saying about the pill have been made public? Dr. CONNELL. I would certainly in no way suggest that any of this evidence should not have been given, but I would suggest that similar prominence should have been given to other equally credible evidence that was of an extremely positive nature. I do not think that this latter information came through to the general public to the same or with the same intensity. The statement ~as not made in criticism of anything that was presented here; it was simply in crit- icism of balance. Senator NELSON. Of balance of what? Dr. CONNELL. Of the overall balance of impact of the very posi- tive aspects of some of the testimony as opposed to the more sensa- tional, not so positive, aspects. 40-471-70-pt. 16-vol. 2-5 PAGENO="0066" 6506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Are you talking about what was testified to here, or what was reported? Dr. CONNELL. I am talking about what was testified to here, out of which came reporting. I am talking about both of these aspects. Senator NELSON. What. I am trying to clarify in my own mind is whether your criticism is that these distinguished people testified as to their view about the pill. Some of them have reservations, some of them presented scientific, accumulated scientific knowledge. Do you think all the facts are not being presented, or that in reporting the facts in the press, some of this has been lost? That is what I am trying to get at. Dr. CONNELL. I think that timewise and balancewise, we have seen more emphasis placed on the disturbing negative aspects of what medical evaluation has unearthed than on the positive aspects of the benefits, which have also been described here. It is a matter of bal- ance. Senator NELSON. Do you not think that may appear to be so, because the news for 10 years has been an almost unqualified endorsement in the 1ev pi~ess, and suddenly. for the first time, reports are being made by distinguished authorities expressing reser- vations. and therefore, it. is not. news to report that the pill is per- fectly safe, as has been reported for several years, but it. is news that distinguished scientists are expressing their reservations and concern about. it? Is that. not, the case? Dr. CONNELL. That may possibly appear to you t.o be the case, but I have heard these same distinguished scientists report precisely this same information for veers. Therefore. I do not see wherein the newness necessarily arises. I have been hearing these same men and many others present similar data. at meetings for many years. There- fore, to me. this does not. represent. anything new. Senator NELSON. I think some of it may probably be 2 years old. It is sort of like chloramphenicol. For years. the American Medical Association warned against the misprescribing of chioramphenicol. When Dr. Goddard came in and testified that, "I am at wit's end on how to dissuade the medical profession from prescribing chloram- phenicol for non-indicated cases," it became news. When Dr. Dame- shek a.npearecl from Mount Sinai Hospital to testify. tha.t in his opinion, 90 percent of the pat.ient.s were receiving chloramphenicol for non-indicated cases, it became news. I received all kinds of let- ters from doctors then, saying, you are driving a good drug off the market. You are disturbing my patients. The reason they were dis- turbed was that they were finding, from the best medical evidence, that 90 percent of the pat.ients were getting chlorarnphenicol for non-indicated cases. Now you have the situation where all the news has been positive and rosy about the pill, with little or no reporting on known side effects from the pills for years. But now even Dr. Hellman, chair- man of the FDA committee is sa.ying, "I have reservations." He cannot say it is perfectly safe. He says, "I am uneasy" about the pill. I would think it ought to be news when the man who directs the report for the FDA says, I am uneasy about the pill; we cannot say PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6507 positively that it is safe. That was never reported before. When the FDA report came out, I scoured through everything I could find in the press. All they said was, the report says it is safe. It did not include the reservations in the report or the reservations that Dr. Hellman had himself, or reservations that Dr. I-Iertz had. I think the problem is that this is the first time that the reserva- tions about the pill by scientists are being aired in public, and the. 1)ublic has heard about them for the first time. Dr. CoNxI~LL. I think perhaps this is a matter of perspective.. Obviously, you and I go to different kinds of meetings. I have heard much reporting of data on side effects for many years. How much of this gets into the media that the average individual sees and reads is perhaps our point of difference. I can only say that none of this information is new to those of us who are involved in patient care and research who have reported these findings who have been talked to and quoted by reporters, who have been involved with multiple. presentations of this material at all types of meetings over a period of years. So maybe it is a matter of perspective from where we sit. Senator NELsON. I am sure that those who are professionally engaged in the field such as yourself- Dr. CONNELL. We have written about these things for a long time. Senator NELSON (continuing). And have done studies of your own for a long time, so it is not news. I would guess that it is news to probably most of the medical. profession, though, those who are not directly involved, that Dr. Philip A. Corfman, of the NIH, writes an article, in which his concluding sentence is: "Nevertheless, this use"-that is the pili-"shoulcl be monitored and restricted to women who cannot use other methods effectively." I doubt whether 10 percent of the doctors in America know that that is Dr. Corfman's view. You no doubt do, if you have followed the literature. Dr. CONNELL. I have read this statement. Senator NELSON. But the public does not know that, and most of the doctors do not know this. I think the fact is that for the first time, this kind of information is being given to the public and, of course, it is upsetting and it is news because it is contrary to the general news for 10 years which has flatly asserted the pill is safe, that there are no problems. Dr. CONNELL. This is not what we have been saying and writing. Senator NELSON. So this is being widely spread. And suddenly, the user of that pill discovers there are some serious side effects. I would guess it would be upsetting. My view, then,. is that every- body who used the pill, if she knew or was. advised in advance, maybe she would not take the pill, or if she did, she would not get concerned about the facts being brought out here. Dr. CONNELL. I could only say in response to your quotation of Dr. Corfman's statement that this obviously represents his personal opinion, and does not necessarily represent the views of all physi- cians in active practice. Therefore, to present his opinion as a fait accompli and something new is, I think, a little bit out of context. Senator NELSON. I was saying I am sure you knew about it, but I doubt whether the public or the medical profession knew about Dr. PAGENO="0068" 6508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Heflman's statement or about Dr. Corfman's. That is all I am saying. Those within the profession, those who are keeping up, know, but much of the medical profession and the public does not. That is why it is news. You are saying the news has been negative. That is the reason, because that is news. That it is safe has not been news, because that had been aileged in the news for 10 years. That would be my guess as to why, when it is written about, that is the way it is written. I would much prefer that we put it in total balance. I would think that would be much better. 1)r. CONNELL. I could not agree with you more. Senator NELSON. However, it is not. Dr. CONNELL. I can only say that as an objective observer of the impact of the hearings to date. that I would not consider the balance at the moment. to be quite dead center. This is obviously only my opinion. Senator NELSON. Sure. Senator DOLE. I would like to add that, as you said, it depends on where we are seated. We see it one way, we listen to the testimony of experts. You are out in the field. I would suppose that many doc- tors have learned a lot about these hearings, and they have had a lot of phone calls based on what has been said in these hearings, and they have probably studied a little more about the pill than they had studied before. I think we are gett.ing balance in the hearings, and I think your presence here will be very helpful in assuring this balance. There has been a great amount of concern expressed across the country because of these hearings. As you point out later in your statement, we are just now begin- ning to realize that there will probably be some unwanted pregnan- cies because of the publicity generated by these hearings. Senator NELSON. I am very sorry; we shall have to interrupt you. That is a rollcahi vote. Maybe everybody could grab a little bit of lunch and return at 1 :30 p.m. Does that interfere with any plans you may have? Dr. CONNELL. No, I think it is a marvelous idea. (Whereupon. at 12 :30 p.m., the hearing recessed until 1 :30 p.m. February 24, 1970.) AFTERNOON SESSION Senator NELSON. May we have order, please. Doctor, I apologize for interrupting your testimony. STATEMENT OP DR. ELIZABETH B. CONNELL-Resumed Dr. CONNELL. That was perfectly all right, Mr. Chairman. Senator NELSON. Please go right ahead. Dr. CONNELL. I think we were at the point of discussing the posi- tive and the negative information as I saw it. I would like to go back to the statement that the relevance and the ultimate signifi- cance of both the positive and the negative data were not always PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6509 presented in such a way that it could be easily understood by the average individual. From a purely scientific point of view, much of the information displayed thus far, can be likened to the relation- ship between the drunken man and a light 1)05t-it has been used more for support more than for illumination. Even the most violent of critics under questioning conceded the limitations of his data, and stated that many of his conclusions were based on unsubstantiated speculation and would not bear the scrutiny of an objective statisti- cal analysis. Mr. GORDON. What page are you on? I)r. CONNELL. I am summarizing. I am not reading my entire tes- timony. are already unfortunately beginning to reap the rewards of the publicity coining out of the January hearings. Most reporting, happily, has been both objective and accurate, but even so, it has created vast uneasiness and unhappiness. This was clearly foreseen and predicted by all physicians working closely with family plan- ning at the grassroots level. I can speak most accurately about the results as I have seen them in New York City, but I know from many personal contacts that this experience is being mirrored throughout this country and abroad. We are just now beginning to see the first of the pregnancies of women who panicked in January, stopped their pills and did not seek or use another means of birth control. These women will not be here to testify, but they now bear within their bodies mute testi- mony to the effectiveness of induced fear. Quite parenthetically and most tragically, they also help to dispel the dire predictions made here of prolonged and widespread sterility following the use of oral contraception. I have repeatedly heard the statement made that middle and upper class women might be upset by the adverse publicity, but that this would not be the case with her culturally deprived sister in the ghetto. Nothing could be further from the truth. Clinic personnel have told me that the mass media reaching low-income women in New York City were among the most active in reporting these hear- ings. Clinic staffs, a~s well as private physicians, have been innun- dated with telephone calls and visits by disturbed women seeking answers and reassurance. It would be nice to think that out of this intense activity has come the needed and neglected patient consultation and instruction about which we have heard so much. Unfortunately, most of this was the purposeless activity of women who already have been properly instructed and cared for, had made their decisions and previously had been entirely satisfied with their contraceptive method. It is obviously too early to detect illegal abortions and deaths occurring as a result of these pregnancies. but it is axiomatic that they will occur in increasing numbers. We might get some idea of the impact thus far by observing what has happened across the country in different localities. Let us look at the experience in planned parenthood clinics from January 14 to February 13 in such diverse areas as Detroit, Houston, and New York City. In Detroit, where approximately 10 requests for dia- PAGENO="0070" 6510 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY phragms have previously been made per month, 118 patients asked to discontinue the pills and be fitted with diaphragms. Senator NELSON. May I interrupt there? Dr. CONNELL. Surely. Senator NELSON. The best statistics that we have had presented here are that the diaphragm, properly used, is about as good as the pill, is it not? 1)r. CONNELL. I think you will find, Senator Nelson, if you look at comparative data on use-effectiveness that we must talk about two different things here. I do not believe that you would find the use- effectiveness of the diaphragm in large studies to be as good as the pill. When you say "properly used" you are talking of total effec- tiveness for individual well-motivated intelligent women who use a diaphragm every time: this is one thing. But one must look at use- effectiveness, must look at the prevention of pregnancy for large groups of women over prolonged periods of time. When one does this one does not find the same order of efficiency and effectiveness. Senator NELSON. Do you not have to, if you are going to start using these figures. include in your statistics the fact, and the testi- mony varies a. little bit-that. 40 to 50 percent of the women quit using the pill after a number of months or in other testimony that over half quit after two or three years? That is a much more impor- tant statistic than the 6 percent of the-that is, the one-third of the 18 percent in the survey made by Newsweek, who say they were going to quit because they have been concerned about the testimony. In other words. Newsweek did a survey in which 18 percent of the women are now quitting the pilL 6 percent on account of what they have read in the papers about it. That is the smallest factor involved in that iS percent. The 50 to 60 percent that quit after a. yea.r or two or three. according to one study. and the 30 to 40 percent that quit * after a few months according to another study, are much more cira- matic statistics than the 6 percent, are they not? Dr. CONNELL. Here you are talking of use-effectiveness and you are also talking about the use of a method which are two different things. A patient who stops usin.g a particular method cannot be used in the statistics for that method. Senator NELSON. But the percentage of women who have quit using the pill for one reason or another has been dramatically higher by six or eight or 10 times than those who have quit because of reading something in the ~Japer. Dr. CONNELL. I think most of this data remains to be collected. We have some concept of the numl)er who are switching, the number who have gone off pills. But. we have no ideaS there has not yet. been time t.o measure the actual importance of these figures. Therefore, I think it. wouldi be dangerous to generalize today as to what the ulti- mate result. of all this is going to be. I think it is a little premature. Senator NELSON. All I am pointing out is-audi I don't have it before me-that one study indicates that. 50 t.o 60 percent of women, after a period of time, quit on their own. Dr. CONNELL. I am familiar with this. Senator NELSON. Another 30 t.o 40 percent quit, in another study. after 6, 7, or 8 months. So you have large numbers quit.ting, and all PAGENO="0071" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6511 you are talking about here is six percent who quit the pill on account of publicity out of the 18 percent that said they were quit- ting in the survey, and of that 6 percent, many are switching to the TUD and the diaphragm. So that again reduces substantially the percentage who are seriously exposed to becoming pregnant. My view is that dramatic statements that I have been reading by some physicians around the country about how effective the pill is, simply ignore the statistics on how many quit voluntarily. I)r. CONNELL. I think this may very well be true, but again, I think it is too early to draw any long range conclusions. Senator NELSON. That is what I am saying. I think the doctors have been premature in drawing their conclusions. Dr. CONNELL. I think that doctors are seeing their patients and are reporting that some have stopped taking pills and that some are pregnant. This is factual. The final outcome of all this, I agree with you, must remain speculative for the moment. Also, we are looking at two different groups here, the women who stop a particular type of therapy because they have developed symp- toms and the women who stop simply because they are afraid. I think these are two identifiable groups in both of which we are be- ginning to build numbers. Therefore, when you talk of 50 percent going off, as was testified here before, which group or groups are you talking about? Again, I think one has to know a little bit more about what the numbers mean. Otherwise, it is statistical gamesmanship. Senator NELSON. That is what I think has been going on. I have not been making many statistical observations, because I do not think anybod has any sta.tistics yet. Dr. CONNELL. I think they are coming. I think we will soon be able to do this. Senator NELSON. Well, that may be. 1-lowever, I have read dra- matic statistics recited by doctors the day after the hearings, that this will mean 100,000 pregnant ladies. What I do not see is statistical support. Certainly they would not use that kind of scientific evidence or unscientific evidence to make a diagnosis of a physical condition. They should not make such a diagnosis of a social situation. All of these dramatic statements on the front pages all over the country are probably contributing in their own way to people quit- ting the pill. Dr. CONNELL. What I am presenting here is not speculation if I may be permitted to go ahead. The numbers are factual. I do not intend to speculate. Senator NELSON. You have your 118 patients that you mentioned quitting the pills and going to diaphragms. Dr. CONNELL. That is a factual statement. Senator NELSON. They are on a birth control device. I-low many of those are you now predicting are going to be pregnant against their will. Dr. CONNELL. I would not predict this. The only way you could estimate this is to look at the use-effectiveness data for diaphragms for the particular patient populations involved. PAGENO="0072" 6512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator ~NELsON. So the number of people who have switched from the pill to the diaphragm, as advised by many doctors, does not indicate a single pregnant patient. Dr. CONNELL. This may be true, but I think it is significant that in one month, you have 118 requests, whereas normally you have only 10. I think this is significant behavior. It indicates significant change in behavioral patterns, if you will. Senator NELSON. That. is what I mean. I)r. CONNELL. This is all I am saying. Senator NELSON. It does not indicate pregnant women I)r. CONNELL. Not yet.. no. Senator NELSON. AU I am saying is that you state if they go off the pill, they must become pregnant. You are stating that they went off the pill and went to the IIJD or diaphragm, and that is what many physicians recommend at present as a matter of practice. Dr. CONNELL. I am not. saying that. all women stopping the pill will become pregnant just because they have changed to less effective methods of contraception. All I am pointing out is what we have observed statistically over a 2- to 4-week span of time, which I think is significant. Senator NELSON. You say it. is significant.. WTe have had a. number of doctors who testified that. that is just. what they would advise for their patients. I)r. CONNELL. This is perfectly true. and they are certainly enti- tled to their medical opmion. Senator NELSON. I thought the argument was made. the comment. was made that. this adverse publicity in the papers was causing a great ca.t.astrophv. and to prove it. you then cite the statistics of how marty switched. Dr. CONNELL. I am saying it has had an undeniable impact.. The ultimate impact I would certainly not discuss. I do not think any- body is capable. I am simply pointing out that in certain centers across the country~ there has been a. change in patient behavior which I think is a perfectly fair statement of objective evidence. Sena.tor NELSON. I think so. We have a. number of doctors who would be very pleased. Dr. CONNELL. I presume that there might be some who would be delighted, but there are also many who feel quite the opposite. Senator NELSON. I am sorry; we have another roll call. It will be 10 minutes. (A brief recess.) Senator DOLE (presiding). Dr. ConnelL you may proceed with your statement. The Chairman has gone to vote and will be back. In the meantime, do proceed. Dr. CoxxELr~. We were discussing the change in patient behavior in a variety of cities. the first. one being I)etroit. Where before, a t.ota.l of 60 IUD's have been inserted per month. 107 were inserted, 45 in patients who had switched from pills. There have been 100 requests for sterilizationS both male and fema.le~ which represents a marked increase over previous requests. In Houston, 50 pill patients switched to ITJD's and 10 to dia- phragms. An additional 2 hours per nurse per day has been needed to cope with the extra activity. PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6513 In New York City, 25 percent of the patients who were taking oral contraceptives requested consultation when they returned to the clinic, and 18 percent were then given ITJD's or diaphragms. Acceptance of pills by new patients went from 70 percent the first week in January down to 47 percent in the first week in February. All of these Planned Parenthood Centers reported that women were frightened, that the number of phone calls had doubled over the number previously coming in and is remaining at this level and that much additional time has to be spent conferencińg and reassur- ing pat~ent5. Objective data coming from the clinics in New York City also bear omit the subjective impression of patient fears and subsequent behavior. In the OEO-funded clinics, approximately 80 percent of the new patients asked for the pill during the 3 to 4 months prior to January 15, 1970. Since that date, this has dropped to approxi- mately 60 percent, and these clinics report that many patients have discontinued using pills for nonmedical reasons, unrelated to the development of symptoms. In the Maternal and Inf ant Care projects in* New York City, approximately 65 to 70 percent of their patients asked for pills in 1969. During the 4 weeks of ~Tanuary, percentages of their 1,200 new patients were 63, 62, 58, and 47, staying at this new low level in early February. A search for factors other than the adverse public- itv did not reveal anything else that could account for this precipi- tons drop. I am sure that such information will be most gratifying to oppo- nents o-f the pill. However, I can only say that it strikes profound fear in the hearts of those of us who deal daily with women and population problems. Despite what has been stated here, I do not know of anyone with wide experience who feels that at this moment, there is any alternate method or combination of methods of contra- ception which can immediately and completely replace the oral con- traceptive. The statement is frequently and glibly made that IUD's and tra- ditional methods can and should be used in place of the more dangerous pill. To anyone who has dealt with large groups of patients, such an assertion is not only untrue but is patently ridicu- lous on several scores, and therefore dangerous. First of all, the fact that the IUD carries its own burden of side effects and deaths is frequently glossed over. Second and much more important is the fact that we have all seen that women will not uni- versally accept and use these alternate and less efficient methods. It is very easy to talk loosely about patient education and motiva- tion. However, studies have been done in this area which point out that education alone will not provide the answer today, tomorrow, or anywhere in the immediate or foreseeable future, even with unlimited funds. In my opinion, and in the opinion of many other physicians, there is at this moment no panacea for the loss of the pill. I would like to look at a few points raised here last month, as seen through the eyes of someone actively and vitally interested in con- traceptive programs. In January 1964 I started and developed a PAGENO="0074" 6514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Family Planning clinic in Metropolitan 1-lospital, which is one of the larger municipal institutions in New York City. In addition, I am clinical consultant in family planning to the New York City Department of Health, project consultant to the family planning unit of the Human Resources Administration. I am a member of the Medical Advisory Board to Planned Parenthood of New York City, and have personal knowledge of most of the remaining large clinics in the New York City area. Criticism has been leveled here at such clinics, saying that patients are not offered free choice of methods, that they are not told of possi- ble side effects and warned to return immediately if certain unto- ward symptoms occur, and that follow-up care is inadequate. I can say with the assurance of direct~ knowledge that such asser- tions are far from true. In point of fact. the care received by Patients attending these facilities is not only good. but it frequently represent.s the only medical attention that these women get. Most of them have previously received only "crisis" care. The family planning clinics in New York City, therefore, have great ublic health importance, because for the first time, Patients now receive continuous medical sul)ervislon. To say that all patients, both service and private, receive superlative care in its broadest asnects would. of course. be foolish. However, to allow the impression to prevail that most. patients, Particularly those in the lower socio-economic groups. receive deficient medical care in these clinics is equally foolhardy. Many clinic facilities are dingy and overcrowded, patients are forced to wait much too long to receive care. needed ancillary services are inadequate, but the contraceptive care per se is good. 1-laying suffered through the birth and development, of a clinic. I feel very deeply the great. handicaps under which we have had to work. Family lannin is a field which only recently has gained status and a minimum of support. Inadequate space. lack of personnel, the failure of city. State. and Federal aovernments to provide sufficient funds for this purpose has hampered all of us. In my testimony is a small section of a paper which I presented in 1966 and which was published in the "American Journal of Public Health" in 1967. It expresses the frustration felt by many people in those years. points out the problems we faced and the solu- tions that we found for some of them. Inevitably, I also became vitally interested in the evaluation of current methods of contraception and the development of improved techniques. Senator DOLE. Dr. Connell. I think it might be well to clarify something, since the quotes will be part of the record. You do state that you had obtained grants and the clinic has been sustained in part by grants from pharmaceutical companies, which might be taken to indicate some bias in your testimony because of that rela- tionship. I wonder if you might expand on the nature of the grants and what, if any, effect this relationship with the pharmaceutical compa- nies may have on your testimony. PAGENO="0075" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6515 Dr. CONNELL. I think one has to look at this fact in context. One of the reasons that I put this particular quotation in, quite obviously, was that I felt that this question was inevitable. I think it is quite safe to say that if you examine the history of most major clinics throughout this country, you will find that this type of financ- ing has been necessary for the actual service and care of patients in these clinics. We have never had sufficient funding. It has been the practice of iuedicine to accept funds from the private sector in order to run programs, in order to make developments possible, in order to evalu- ate new and better methods. Therefore, I, as practically every other practicing physician who has been before you, have been involved in contraceptive research, in return for which, of course, we receive fimds. This is how medical technology has been advanced in this country. Therefore, I am not unique. I think it would be almost impossible to call any authority on the pill before this committee who is not in a similar situation, who has not done drug e~ `tlu'thon Th1s is simply the wa~ rnedic'd pr'tctice in this country has been carried out. Therefore, I am representative, again, of a very large group of individuals. This is how data are collected. This is how we learn. I also do research on intrauterine devices. I also have trained stu- dents for the I)epartment of Labor. I also have accepted funds from OEO. I also have accepted funds from I-JEW, from Planned Parent- hood, from a variety of sources; frankly, anywhere I could get money to run my clinics. Therefore, I do not feel my personal obli- gation to be any greater to any drug company than to the Depart- ment of Health, to OEO tha.n to Planned Parenthood, to HEW than to the U.S. Public Health Service. Again, I think I represent probably the majority of people who have been here before you. All of us who do research, almost with- out exception, have been in a similar situation. I do not believe th~tt any of us feels a greater obligation to any one funding source than to any other. I have personally felt no bias. I have said some drugs are excel- lent, I have said some are very poor. This is part of the reporting of an objective research investigator. Senator DOLE. It is well to have the fuller explanation in the record, because there are some who may believe that because of the relationship, you could not be objective or would not criticize. Dr. CONNELL. I think we all do criticize. Again, if one looks at the medical literature, one will see that those of us who investigate drugs have been reporting that there are difficulties, there are prob- lems. These preparations are not the panacea; they are not 100 per- cent perfect. We have said so. Senator DOLE. You do not share the conviction of Dr. Ball, who said earlier this morning that there should be a 5-year moratorium on oral contraceptives? Dr. CONNELL. No; I t.hink this would be extremely unfortunate for many, many reasons. Senator DOLE. Sorry to have interrupted you. PAGENO="0076" 6516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. CONNELL. That is all right. I am glad to have this clarified, because I do not feel that my soul is owned by any drug company, an more than it is by any Government agency. Like most of the practicing physicians who have appeared before you, I have conducted research programs because I recognized that our existing information was inadequate and our current methods imperfect. One of the areas in which I have worked for the past 4 years is the evaluation of eye findings in patients receiving oral con- traceptives. I presented a paper on this material at the Annual Meeting of District II and IlL American College of Obstetricians and Gynecologists, in New York City, on September 23, 1967, and it was published in "Obstetrics and Gynecology" in 1968. It points out the need for background information so that the discovery of abnor- malities in a retrospective study does not lead to erroneous and dam- aging conclusions. The accusation has been repeatedly made during these hearings that physicians engaged in research were either unaware of or delib- erately disregarded the problems connected with oral contraceptives. Even worse, we have been charged with the actual suppression of data relating to these problems. In a paper which was published last year in "Advances in Planned Parenthood," I described the changes in blood coagulation factors which we have observed in our patients. Hundreds of such papers have been published by me and by many other doctors over the last ~ to 10 years. Thus it is hard to fathom how anybody who makes even the slightest attempt to keep abreast. of current medical literature could say that doctors involved in drug evaluation have not been reporting the abnormalities that they see. Senator NELSON (presiding). May I interrupt at this point? Dr. CoNxELr~. Surely. Senator NET~sox. I just cannot recall the testimony-I am wonder- ing what testimony specifically you are referring to when you say the accusation has been repeatedly made during these hearings that physicians engaged in research are either unaware of or deliberately concealing the problems connected with oral contraceptives. I do not remember that. Can you tell me whose it was? Dr. CONNELL. Dr. Williams', as I recall. I do not have his testi- mony with me, but it is my distinct impression that this was the sum and substance of it. As I recall, he discussed misstatements of facts b prominent physicians promoting the pill, suppression of adverse data from Puerto Rico, and failure to carry out proper research. Senator NELSON. Then you say the accusation has been repeatedly made. I do not remember Dr. Williams' testimony. - Dr. CONNELL. Dr. Kassouf, alsp. I believe, mentioned this. Senator NELSON. What did he say? Dr. CONNELL. The implication, again, was that a great deal of information had been suppressed by a variety of people, including the clinical investigators. I believe that he used the Drill-Calhoun PAGENO="0077" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6517 paper on thromboembolic disease as an example. 1-le also accused the AMA of suppressing information by refusing to publish papers on patients developing strokes and cervical cancer. Senator NELSON. On the oral contraceptive? Dr. CONNELL. Right. Senator NELSON. I guess I shall have to look into the record. Dr. CONNELL. This is my recollection. Senator NELSON. Suppressed by whom? Dr. CONNELL. The individuals doing the work, Committees reviewing the results, pharmaceutical companies, and editors of med- ical publications. Senator NELSON. If you remember, would you give us the names of whoever it was? Dr. CONNELL. Of course. Senator NELSON. I would like to check it. Dr. CONNELL. I would be happy to do this.1 In the interests of time, and at the risk of beating a horse that perhaps should be dead, I would like to mention without further comment the problems of obtaining adequate and reliable data, the difficulties in evaluation of side effects, the relationship between dosage variations and results in both animals and humans, the total inadequacy of most studies to date-all of these and many other critical and vital topics have been brought to your attention. I do not excuse our present lack of knowledge, but only point out that our areas of ignorance are known, are deplored, and are cur- rently receiving all the attention that time and money at the moment will permit us to give. Senator NELSON. I did not understand that sentence. You say you only point out that "our areas of ignorance are known, deplored, and currently receiving all the attention that time and money will permit us to give." You are not saying, are you, that we do not need additional research? Dr. CONNELL. What I am saying is that the funds we have avail- able are insufficient to do the job properly. Within the confines of our present capability, we are doing the best we can, but we need a great deal of additional help in order to do the job more adequately. We acknowledge the inadequacy of many of our studies, the paucity of numbers. We have not done as much as we could have, because we have not had the support to do it. Senator NELSON. The meaning that you intend to convey there is that with the limited money you have, all that can be done is being done, Is that what you are saying? Dr. CONNELL. I think we are attempting to do, with limited funds, as much as possible. We all accept the fact that we could do a great deal better and we are not satisfied at all with what we have been able to accomplish to date. Senator NELSON. And if there were substantially increased amounts of research funds in this field, it could be usefully used now? 1 This information was not supplied by Dr. Connell. PAGENO="0078" 6518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. CONNELL. I think this is quite correct. I think there are many programs that many of us would like very much to do but they would take additional funds. I think the problems have been made very clear, the enormity of the study, the enormity of the problem, and what one would have to do to get some answers to these ques- Lions. I think this has been testified to many times here. `\\Te do not know all the afiswers we need to know, and we need support to find them. Senator NELSON. I was just interested in ascertaining whether your statement ~neant that we have all the money that we need? Dr. CONNELL. No. I meant that what we have is inadequate. Before I leave this topic, I would like to emphasize three points, all made before by others. First, with the single major exception of thromboembolic disease, there has been no proven re'ationship between any of the alterations reported here and the production of permanent damage. Second, it has been repeatedly pointed out that most of these changes are either preventable or are detectable with good medical care, and usually disappear after cessation of treatment. Thus, even the accepted complications might be decreased with an acceleration of research and an augmentatibu of services. Third, one of the stated aims of these hearings has been to deter- mine the current level of patient training and information, and to find out whether those women who elect to use the pill do so with full knowledge of pO55~l)1e side effects. As both a clinician and a researcher, I see many problems in this area. There is absolutely no question in my mind that as substantiated data on adverse reactions become available, they should be comnninicatecl to patients. However, to present the list of possible side effects as outlined in the present package insert to the average patient would serve no useful purpose, and would have many foreseeable and disastrous effects. WTe have been told here that almost all of these are still con- jecture, not proven fact. A patient cannot reasonably be expected to make a profound pro- fessional judgment-she is not a doctor. We have seen that even indi- viduals with wide knowledge and experience are in disagreement. How can we ask or expect informed decision1uaking from these women based on such debatable information? Senator NELSON. May I ask a question? Dr. CONNELL. Yes. Senator NELSON. On page 10 of your statement, you say criticism was leveled here at such clinics, saying that patients were not offered free choice of methods, that they were not told about possible side effects, were not warned to return immediately if certain untoward symptoms occurred, and that the followup care was inadequate. I take it you are saying here that in your clinic, all these things are done? That is, that the patients are warned of possible side effects, warned to return immediately if certain untoward symptoms occur? Dr. CONNELL. I think I speak for more than my clinic. As I men- tioned here, I am a consultant to many of the major clinics in New York City. Therefore, I am involved in the training and supervision PAGENO="0079" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6519 of personnel. I supervise and approve the written material which is given to patients. Therefore, I think I can speak with a certain amount of concrete objectivity about what is actually told to patients, what is actually given to patients, what they are informed of, what they are told to watch for. I also know about the availabil- ity of personnel, to answer questions in person or by telephone, bilin- gual personnel in our situation because of our very large Puerto Rican population. I think I can speak of my own knowledge of a large segment of New York City clinic PoPulations. I believe that the vast preponder- ance of these women are informed in a way that most people would find quite satisfactory. Senator NELSON. I was not referring to that. It seemed to me to be somewhat in conflict with what you are saying on page 14. You say on page 10 that the patients are offered a free choice of methods, that they are told of the possible side effects, that they are warned to return immediately if certain untoward symptoms occurred. rfhlen over here on page 14, you seem to be saying, to present a list of side effects, possible side effects, as outlined, and ~o forth, would not serve any pimipose. Tell me specifically, what you do tell them about side effects. \~rhat untoward symptoms could occur? What physiological upsets do you advise them of? Under what conditions should the patient call you? Dr. CONNELL. Our personnel are trained to tell them that there is concrete evidence that in a small percentage of patients there is a causal relationship between the existing oral contraceptives and thromboeinbolic disease. I think the majority of physicians will agree that this is accepted fact. I think that this fact has been clearly brought forth here. I think that above and beyond this, it has not been clarified here, or in any medical meeting which I have attended, that there is a scientifically proven and accepted cause and effect relationship in any other area. There are certain symptoms, certain signs, which I think are warning signals. rfhese have also been mentioned here. rfhis is the sort of thing I think you should tell a normal, healthy patient. You do not tell her that she has a very statistically small chance of getting diabetes or of getting a variety of other things. I think it is unfair to produce fears in patients when we do not know whether these factors are true or not. If she has a swollen leg, if she develops a fever, if she has chest pains, if her varicosities get worse-these are the things we should and do tell the patient. I certainly do not think every patient should take the pill. One of my in'imediate family called me at midnight last year and described symptoms she had developed while taking an oral contraceptive. I told her that she should immediately stop her pills. She is one of the small percentage of women, I feel, who should not take the pill. Senator NELSON. Just to get this straight, you say on page 10 that you tell them of the possible side effects. You cite one, thromboein- bolism. Is that the only side effect you tell them about? Dr. CONNELL. No. As I said, we tell them certain symptomatic PAGENO="0080" 6520 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY things to watch for-t.hese would include swelling of the legs, ten- derness of veins, headache-these are symptoms. Senator NELSON. These are the things you are referring to when you say certain untoward side effects-certain untoward symptoms, is that right? Dr. CONNELL. That is right. Senator NELSON. What is the whole list-in other words, is there a uniform thing that everybody who advises the patient advises them exactly the same in your clinic ? Dr. CONNELL. I would rather doubt it. I do not think one can advise all patients in precisely the same way. I think one can give them all certain concrete information like that on thromboembolism, for instance. Senator NELSON. Would you not give them all the same informa- tion if- Dr. CONNELL. I would give them the same information. I might couch it in a little different language for different types of patients, but I would certainly give them all the same information. Senator NELSON. On what basis would you distinguish one patient should be told if she has a swelling of the leg and others might not be told- Dr. CONNELL. I am saying that they are all told. Senator NELSON. What patients do you tell as on page 10, and are all patients told the same? Dr. CONNELL. Yes, precisely. Senator NELSON. I thought you said no. Dr. CONNELL. I thought we were talking about the form in which the information was transmitted. Senator NELSON. No. You are saying that you uniformly, in the clinic, tell each patient. that if certain untoward symptoms occur, they are to call the doctor? Dr. CONNELL. That is right, or come to the clinic. Senator NELSON. Are these symptoms-how many of these symp- toms are there that they are told about in the clinic? Dr. CONNELL. Maybe half a dozen or so that I think are impor- tant. I think the problem here is that if you look at the most recent letter to physicians which was discussed earlier this morning, there are a huge number of adverse reactions listed. My statement here is simply that the average individual could not be handed this list, realistically. I think they would neither understand it, nor do I think that we are justified in telling them to patients as proven, since these are admittedly still in the area of unproven scientific information. If they are scientifically proven, as in the case of thromboembolism, I think we can, we should, and we do transmit this information to patients. Senator NELSON. When you tell a patient about these half dozen untoward symptoms which should cause them to call the clinic, to call a doctor, are these untoward symptoms listed for them in writ- ing? Dr. CONNELL. In many instances. Each variety clinic has its own technique of patient instruction. PAGENO="0081" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6521 Senator NELSON. In your clinic, are they? Dr. CONNELL. In my clinic, they are all taught by a conference nurse. They are given an outline of methods with the advantages and disadvantages of each. Senator NELSON. I mean, is the listing of the half dozen untoward symptoms which you say all patients in your clinic are advised about, is that given to them in writing? 1)r. CONNELL. In some climcs in New York, it is. In others, it is a verbal transmission at a clinic training session. Different clinics elect do this in different ways but they are given in some form or other. Senator NELSON. Suppose you have a patient who is on the pill for a year or two. If they do not have it in writing, how can you expect them to recall the untoward symptoms that were given to them in a clinic the first time they went? Dr. CONNELL. I am not sure that giving it to them is necessarily going to mean that they will keep it and use it a year from now. I think we are talking in the area of continuing patient education, which happens to be a great interest of mine. I think you do not give any patient anything and then abandon hei'. Within our programs, we have the capability of continued patient ~~n~act_reconferencing, reexamination, reevaluation. I think this is the essence of good medical practice. Therefore, I think as new things come along, they can be transmitted to patients. This is part of continuing good medical care. Senator NELSON. WThat is your opinion of Dr. Ley's statement, plus a number of others who have testified, that the user of the pill ought to receive in the package some simple statement of what the, as you put it, untoward symptoms are so they can look at it every month? Dr. CONNELL. I think, in essence, this is what many of us have been doing when we convey information to patients both orally and written. Everything in my clinic, for instance, was translated into both Spanish and French so that we could most effectively communi- cate with patients. Senator NELSON. I was getting to the question of whether or not a reminder of the possible untoward side effects should be in a pack- age insert they would go to the user. Dr. CONNELL. As I said, I think many of us already do essentially this. Senator NELSON. I am sure you, in your clinic, do, but the fact is that the Gallup survey in Newsweek magazine found that many women were never told anything. Dr. CONNELL. I cannot say anything about what Newsweek maga- zine found-I do not know how they determined this. I can only tell you that it goes on in clinics. Senator NELSON. I understand that. I am asking you whether you think it would be useful to have a package insert in the package that they get. Dr. CONNELL. I do. As I said, I have written such things for patient instruction. Senator NELSON. I am just asking whether you consider what Dr. Ley is suggesting, and others, would be valuable. 40-471-----70-Pt. 16-vol. 2-6 PAGENO="0082" 6522 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1)r. CONNELL. I think so. As I say. I have given you a~ very con- crete answer as to the fact that I think it is valuable in that I have already done it. Senator NELSON. I am not talking about what is done in a good clinic or by a conscientious doctor. Obviously, two-thirds of the women. according to the survey, were not told anything. It might be well. therefore. to have in their hands a listing of the side effects. I am not at all convinced that an ordinary person can carry around in his head the half dozen or eight or nine different precau- tions or cautions of side effects or indications for calling the doctor. It seems to me he ought to have it in his hand where he could see it. Dr. CONNELL. I think that it is perfectly reasonable that a patient be told svmntoms reciuiring medical consultation. Senator ~ELSON. Do you agree. then. with the FDA Commission- er's statement in his letter of January 1~ to 318.000 physicians, in which he says that: "In most cases. a full disclosure of potential adverse effects of these products would seem advisable, thus permit- ting the participation of the pat~ent in the assessment of the risk associated with this method." Dr. CONXELL. I think within the context that I mentioned in my testimony, which does not include a total listing of the items on the back page of the document from which on are reading, within the confines of what I said before. I think this is an excellent idea.. Senator NELSON. Thank von. (~o ahead. Dr. CONNELL. Finally. I would like to make just a few comments on the part of the heretofore silent. majoritv-women. The fact that I have chosen to pursue an active and exacting career while at the same time electing to Produce six children, should be my most potent evidence for my overwhelming belief in the larger role to which women should aspire. I know personally the excitement of feeling new life moving within my body: I have known the never-to-be-equalled thrill of seeing my own firstborn child; I know the private dreams and fears that all women have as they watch their children growing up. These joys andi sorrows are the right of all women audi should be denied to none. However. I am equally aware of the happiness and fulfillment that comes with being part of the larger world, of making some con- tribution, no matter how small, to society as a whole, as well as to my immediate family. With the advent of effective contraception. women, for the first time in history, have been able to plan their lives, space their chil- dren, and look to their futures with confidence. How vividly I can recall the countless women whom I have seen in the course of my career-active, creative, productive for the first time in their lives, cut down by an unwanted pregnancy, either because of lack of or failure of contraception. This is always a tragic thing to see. Such a misfortune can per- haps be considered partially tolerable when it happens to a woman from the middle or upper class. When it befalls, as I have seen so often, the woman who has just begun to establish her identity as a PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6523 human being in her own eyes and the eyes of her family, only to be returned to the depths of the ghetto, to carry and bear her unwanted child-such a tragedy has far-reaching implications and ramifica- tions that can escape only the most obtuse and unfeeling human mind. If unplanned pregnancies increase, as we are beginning to suspect that they will because women have become frightened and turned to less effective methods of birth control, or worse, no method at all, it can only again widen the gap between groups of women. For many years, adequate means of family planning have been the primany prerogative of the private patient who knew that such help was available and could afford to pay for it. During the past few years this care was increasingly being made available to the poor women as well. Today, once again, we have created two groups, the haves and the have-nots. When a woman of means finds herself pregnant and wishes not to bear her child, a safe, clean abortion is within her reach. When one of my clinic patients finds herself in the same situ- ation, she usually has one of three choices: She may bear the unwanted child, she may attempt to abort her- self, or she may have a cheap, dangerous, dirty, illegal abortion. No matter what her decision, such a. woman, her family, and society in general will be the ultimate losers. A similar disparate and unfair situation unfortunately obtains when sterilization proce- dures are examined. The private patient with three or four children who wishes to terminate her child-bearing finds it infinitely easier to do so than does her clinic counterpart with nine or 10. This double standard of medical practice is a gross miscarriage of justice. Hopefully, legislative and legal measures now under consideration will free the hands and minds of doctors who abhor the situation in which they currently find themselves, disturbed, fearful, and help- less. There has been much discussion here of the use of women for experimentation and their "internal pollution" with oral contracep- tives. I would like to submit that the larger and far more critical and lethal experiment is underway-what happens to these women and society as a whole if we continue our present relentless march to inevitable doom via overpopulation and pollution? What will happen if individuals and nations are deprived of their ability to control their population size, whether by law, ignorance, or fear? These are obviously rhetorical questions to which we all know the answers. The unplanned pregnancy, the unwanted baby, the battered child, delinquency, illegitimacy, crime, drug abuse, the endlessly repeated chain of events encircling our society at all levels is only too apparent. Opponents of oral contraceptives always talk in terms of the treatment of "healthy women." Those of us who have to~ treat women who are pregnant with an unwanted baby do not feel that she can be considered to be healthy. Tile World Health Organization has declared that, "Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." PAGENO="0084" 6524 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Looked at in these terms, we are currently facing a major epi- demic. Evidence documenting the panic regarding the pill mounts daily, both here and abroad. If this panic continues, the problems resulting from these fears will be severe in the United States, but the problems abroad may be catastrophic. Many developing countries where the poverty, maternal deaths from abortion, and all the consequences of the population explosion are most critical have been turning to the pill as part of the solution to their incredibly difficult situations. Our nation has been accused before of a double standard of medical care, of sending abroad, via our foreign aid programs, second class care. For multiple reasons, oral contraceptives are widely and increas- ingly used in these countries. If the pill is discredited here, will we again be faced with the problem of appearing to supply something to women of other nations which is too dangerous to give to our own? The ultimate implications of the fear which is also growing abroad are terrifying to contemplate. If no answers are found, we may well be damning and ultimately damned by future generations. Before closing, I would like to look at what can be done to channel all the energies that have been released into constructive pathways. One of my favorite quotations from Aristotle goes as follows: It is easy to fly into a passion-anybody can do that-but to be angry with the right person and to the right extent and at the right time and with the right object and in the right way-that is not easy. We might do well to consider this ancient advice. There are a number of obvious ways out of our current dilemma. First of all, it lies within our scientific capability to answer many of the questions raised at these hearings, given sufficient funds and direction. Some programs designed to obtain valid answers are underway, others are awaiting support, and many remain to be written. The need for expanded research to find new contraceptive methods and the means to make them widely and rapidly available is too patently obvious to pursue further. Much of this progress, of necessity, lies somewhere ahead of us. What can be done today? Remove all the archaic legislation on abortion and sterilization. This would free both women and their physicians and correct the current social and financial inequality of care. Then, support the programs needed to implement the demands which will immediately and inevitably arise as a result of these reforms. Pass legislation dealing with population problems and their solutions. Provide funds for the training of people to work in these programs at the professional level, but, much more importantly, at the paraprofessional and community levels. It would be unrealistic to think that immediate solutions could be found to all the many and varied problems that we now face, even with unlimited funds. However, many paths are open to us today. and I feel that our next steps are clear. (The complete prepared statement submitted by Dr. Connell fol- lows:) PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6525 STATEMENT OF ELIZABETH B. CONNELL, M.D., ASSOCIATE PROFESSOR, DEPARTMENT OF OBSTETRICS AND GYNECOLOGY; DIRECTOR OF RESEARCH AND DEVELOPMENT, INTERNATIONAL INSTITUTE FOR THE STUDY OF HUMAN REPRODUCTION, COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY Mr. Chairman, thank you for the invitation to appear before you today. I fully recognize the tremendous importance of the course and outcome of these hearings and believe that there are four areas in which I may be able to make some small contribution based upon my personal experience. First and foremost, I am a physician. I have been a general practitioner in a small town and a specialist in Obstetrics and Gynecology in New York City. I have been privileged to care for some of the wealthiest people in our coun- try; I have been even more greatly privileged to care for thousands of our most grossly deprived citizens. I have delivered women of their babies under ideal circumstances-in aseptic, brightly-lit hospital delivery rooms. On a bitter, cold night, I also delivered one woman of her child by moonlight on the front seat of an ancient pick-up truck, surrounded by her distraught husband and her seven fascinated children. Having cared for many patients, men, women, and children from all sorts and varieties of backgrounds, I hope, per- liaps to bring to this situation something of a clinical flavor based on a long and varied experience. Second, I started, developed, and ran a family planning clinic in Spanish Harlem in New York City. This led to the third area which I presume may have prompted this appear- ance, that of a research investigator. I have worked both in the actual develop- ment of newer contraceptive techniques and the equally important peripheral programs related to patient motivation and behavior. Concurrent with the de- velopment of the clinic, I worked in the allied and critical area of training of community women to fulfill multiple needs in the health professions. Finally, I would be naive and less than perceptive if I did not recognize that an additional fourth factor might be operative here-that I happen to have been born a female and have five sons and a daughter. Thus, I realize that I represent a group not previously heard by this Committee and I cer- tainly cannot in any sense be considered to be opposed to the perpetuation of the species. I shrink from approaching my testimony in such a highly personal manner, but after carefully reviewing the situation, it seemed to me that only in this way might my combined areas of experience be of some value to you. In looking at a subject with as many ramifications as the oral contraceptive, the problem of gaining a full and accurate perspective is indeed a most difficult and troublesome one. Those of us who have dealt with problems relat- ing to individual patients, as well as major programs, are bound to see such a topic in a variety of aspects; On one hand, we can appreciate the obvious necessity for finding methods which are 100% effective and 100% safe-this is not entirely the province of the academic purist. The thought that any method which we currently employ falls short of this ideal is intensely disturbing to doctors. At the other end of the scale, we see the tragic results of unwanted pregnancies and the growing horrors of over-population and pollution. Those of us who live between these tw-o extremes understandably find* ourselves in a somewhat schizoid situation. The nicety of proper balance is not always easy to achieve. To date, these hearings have not made our lives any easier. I think much of the previous testimony has been rather like a bikini-what it has uncovered has been interesting, but w-hat it has left concealed is vital. One major misfortune to my mind has been the artificial and totally erro- neous creation of two camps of doctors, the "pro-pill" and the "anti-pill". Except for a few extremists among us, such an arbitrary division is not only totally unrealistic, but also most regrettable. I am quite sure that I speak for the overwhelming majority of physicians when I say that I do not belong to either group. Not to condemn the pill does not automatically make one a chamimpion of oral contraceptives. Nature does not construct all things black or white, yellow or blue. She makes them in shades of grey and green. I believe that thinking, objective physicians are neither pro-nor anti-pill. We recognize the tremendous contribution made by these agents and we use them with the same judgement and with the same respect that. we pay to any powerful drug. In this sense, we are "pro-pill". We also recognize the element of risk inherent in all potent medications and so for particular patients we are "anti-pill". However, to be forced daily by current pressures to declare ourselves as PAGENO="0086" 6526 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY belonging to the far left or the far right on this issue is not only increasingly annoying, but actually very destructive. Segregation into opposing camps is of value to no one, least of all the women we are all dedicated to serving. I w-ould like to look first at what has come out of the preceding days of tes- timony, as viewed by a self-styled moderate. First of all, except for one coy allusion to privy and unpublished information on coronary artery disease, nothing has been presented here that those of us working in this field have not read or heard many times over. When I examined the vintage of the testimony to date, I discovered that some is relatively new, much is several years old, and a few pearls of information w-ere in print long before I started in medical school. It has been variously asserted that these hearings have thus far been slanted, one-sided, and unfair. Objective consideration suggests that, in one sense, this criticism is indeed valid. The bias w-hich I feel has been noticeable on previous days is the bias of positive results. No scientist of experience would question the capability and integrity of almost all of the previous wit- nesses. Their work has been meticulous and their results are not in question. What is disturbing is the fact that such a great percentage of the time has been devoted to tw-o areas, (1) experimental w-ork carried out by competent men in excellent laboratories, but far removed from patient care and its impli- cations, and (2) to side effects. in most instances, the latter occur in a tiny proportion of the population. What has been missing and w-hat is needed to maintain an overall proper balance and perspective is a better look at the vast majority of w-omen who can and arc taking oral contraceptives safely and effectively. As a physician w-ho began practice before the advent of the pill, I am con- stantly aware of the immense difference it has made to the lives of w-olnen, their families, and to society as a w-hole. The look of horror on the face of a 12-year-old girl when you confirm her fears of pregnancy, the sound of a w-oman's voice cursing her newborn and unwanted child as she lies on the delivery table, the helpless feeling that comes over you as you w-atch women die following criminal abortion, the hideous responsibility of informing a hus- band and children that their wife and mother has just died in childbirth-all these situations are deeply engraved in our memories, never to be forgotten. With the advent of more effective means of contraception, the recurrence of these nightmares w-as becoming blessedly less frequent. The thought that we may once again be forced to face these disasters on an increasing scale because of the panic induced by these hearings strikes horror into the hearts of all of us w-ho have lived through this era once before. A great deal of positive information w-as presented at your hearings last month. Aside from the obvious personal, social, and economic advantages of planned pregnancy, w-e were told of lowered prenatal loss, fewer abnormal babies, and lessened maternal risks. Unfortunately, the general public w-as not always made aw-are of this type of information to the same degree that they became painfully aw-are of the ruminations and speculations and tIme diversity of professional opinion. They heard about triploidy found after stopping pills; they did not hear that there was no evidence that this w-as repeated in subse- quent pregnancy. The spector of abnormal infants w-as raised; this was not countered by the knowledge that this situation has not occurred, or that there is no reliable data on mutations related to the new-er oral contraceptives. They w-ere not told that much of the criticism being leveled now, in 1970, at work done around 1900 w-as via the retrospectoscope, using information and tech- niques only recently availal)le to scientists. Nor w-as it made clear that data obtained from human males and laboratory animals cannot, with total impun- ity, be transferred and considered applicable to w-omen. On occasion, with a single testimony, curious dicotomies could be observed. Profound fears of the induction of malignancy were expressed. These w-ere based on an assumption of 20 years of administration of the present oral contraceptives. In the same breath, we were told that the pill u-as a poor method of contraception because it w-as discontinued by more than half of all u-omen in less than one year. From a purely scientific point of view, much of the information displayed thus far can be likened to the relationship between a drunken man and a light post-more for support than illumination. Even the most violent of critics has been forced to concede the limitations of his data, and to state that many of his conclusions are based on unsubstantiated speculation and u-ill not bear the scrutiny of an objective statistical analysis. PAGENO="0087" PAGENO="0088" PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6529 Public Health" in August, .1907. The following quotation from this report, I believe, expresses the frustration felt by many people in those years. "In spite of the fact that, by. city policy, freedom has been granted to prac- tice almost unrestricted contraception, the financial means and personnel to carry out this new policy have not been similarly freed. Although hospital space is l)rovided for the clinic and some physicians services are covered, sufficient personnel to staff the clinic is not available through general city sup- port to clinics. Nursing service is only minimally supI)lied and clerical services are entirely unavailable. "It has been necessary, therefore, to find means to support tile majority of the clinic personnel during the early stages of the growth and development. This has been done by obtaining multiple grants from pharmaceutical houses and social agencies. It would seem, however, that since this is an approved municipal Ilospital clinic, financial support should be available from the cit~. As general recognition of the necessity of contraceptive services to this popula- tion spreads, support should be granted on as firm a basis as to other medical areas." Inevitably, like many other doctors who developed clinic programs, I also became vitally interested in the evaluation. of current methods of contraception and tile development of improved techniques. Like most of the practicing phy- sicians who have appeared before you, I have conducted research programs, recognizing that our existing information is inadequate and our current meth- ods imperfect. One area in which 1 have worked for the past four years is the evaluation of eye findings in patients receiving oral contraceptives. The follow- ing quotation from a paper which was presented at the Annual Meeting of District II and III, American College of Obstetricians and Gynecologists, New York City, September 23, 1907 and published in "Obstetrics and Gynecology" in April, 1968 points out tile lack of necessary background information and time need for large and continued programs of evaluation. "No extensive studies have ever been conducted with the purpose of deter- mining the incidence of visual abnormalities in. women of childbearing age, probably for at least. 2 reasons: first, because women of this age seldom con- sult an ophtllalmologist except for, obvious visual difficulty . . . and second, because such evaluations would have served no particular purpose in the past. Tile current situation of a vast number of women in a restricted age group undergoing therapy witll tile same or similar drugs, and w-ith the same objec- tive-contraceptioll-is unique.. Tile raising qf questions concerning possible side effects of the use of oral contraceptives makes it imperative that scientifi- cally conducted investigations be carried out. "Tile results of this study clearly indicate tile laFge nuniber of ophthalmo- logic abnormalities present in the control group. They also demonstrate the close correspondence of. such ocular changes in the groups undergoing therapy The vast majority of the data shown abo~e does not indicate pathologic conditions in the sense timat visual damage has occurred. However, time discov- ery of such `abnormalities `in a retrospective study `could easily lead to erro- neous conclusions . . . because of the . . . lack of information concerning time incidence of such conditions in the general population." Tile accusation has been repeatedly. made during these hearings that physi- cians engaged in research were either unaware of or deliberately disinterested in the problems connected with oral contraceptives. Even worse, w~ have been charged witil the actual suppression of data relating to tllese problems. Again, \vithl your indulgence, I would like to quote from a paper which I presented to the American Association ,of Planged Parenthood Physicians, in San Antonio, Al)ril 16, 1968, and which was published the following year in "Advances in Planned Parenthood". It described changes in blood coagulation.' "Over 4,000 patients have been given oral contraceptives Ct the Family Plan- ning Center during the past 4.5 years. To our knowledge no tllrornboernhohic episode. has. yet, occurred, a . situation wilich correlates with the experience of many other investigators. Tills fact suggests that, if damage is produced by these agents, it must be very infrequent. In fact, tile incidence may be so very low that it may not be possible to establish it even with the use of large Iwo- spective studies. Possible elements of bias are numerous and very difficult to determine and evaluate, whether the attempt be prospective or retrospective.. It would appear that the final answer to this most `perplexing problem ~vill not be found until reliable rates of the various thromboembolic phenomena are deter- PAGENO="0090" 6530 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mined in the general and specific populations, laboratory tests and results are standardized, common definitions of terms are agreed upon, records made uni- form, comparable data-processing techniques are developed, and a large stable IJol)ulation found which can be subjected to meticulous multiphasic, long-range analysis. In the interest of time, and at the risk of beating a horse that perhaps should be dead, I w-ould like to mention w-ithout further comment a few areas w-hicli have been touched on by previous w-itnesses and in which we are all working. The problems of obtaining adequate and reliable data, the proper and objective evaluation of side effects, the relationship between dosage variations and results, in both animals and humans, the total inadequacy of most studies to date, the difficulty or impossibility of obtaining accurate control information and the need to establish not only use, but use-effectiveness data-all of these and many others have been brought to your attention. I do not excuse our present lack of knowledge, but only point out that our areas of ignorance are known, deplored, and currently receiving all the attention that time and money w-ill permit us to give. Before I leave this topic, I would like just to emphasize three points, all made before by others. First, w-ith the single major exception of thromboem- bolic disease, there has been no proven relationship between any of the altera- tions reported here and the production of permanent damage. Secondly, it has been repeatedly pointed out that most of these changes are either preventable or are detectable w-ith good medical care, and usually disappear after cessation of treatment. Thus, even the accepted complications might be decreased with an acceleration of research and an augmentation of services. One of the stated aims of these hearings has been to determine the current level of patient training and information, and to find out whether those women who elect to use the pill do so w-ith full knowledge of possible side effects. As both a clinician and a researcher, I see many problems in this area. There is no question that as substantial data on adverse reactions becomes available, it should be communicated to patients. How-ever, to present the list of possible side effects as outlined in the present package insert to the average patient serves no useful purpose. First of all, w-e have been told here that almost all of these are still conjecture, not proven fact. Secondly, a patient cannot rea- sonably be expected to make a profound judgement-she is not a doctor. We have seen that even those w-ith wide knowledge and experience are in disagree- ment-how can we ask or exi)ect informed decisionmaking from these women? Finally, I w-ould like to make just a few comments as a member of the here- tofore silent majority-w-omen. The fact that I have chosen to pursue an active and exacting career w-hile at the same time electing to produce six chil- dren, should be my most potent evidence for my overwhelming belief in the larger role to w-hich w-omen should aspire. I know personally the excitement of feeling new life moving w-ithin my body: I have know-n the never-to-be- equalled thrill of seeing my own firstborn child; I know- the private dreams and fears that all women have as they watch their children growing up. These joys and sorrows are the right of all w-omen and should be denied to none. I am equally aw-are of the happiness and fulfillment that comes with being part of the larger w-orld, of making some contribution, no matter how small, to society as a whole, as well as to my immediate family. With the advent of effective contraception, w-omen, for the first time in history, have been able to plan their lives, space their children, and look to their futures w-ith confidence. How vividly I can recall the countless women whom I have seen in the course of my career-active, creative, productive for the first time in their lives, cut down by an unw-anted pregnancy, either because of lack of or failure of con- traception. This is always a tragic thing to see. Such a misfortune can perhaps be considered partially tolerable when it happens to a w-oman from the middle or upper class. When it befalls, as I have seen so often, the woman who has just begun to establish her identity as a human being in her own eyes and the eyes of her family, only to be returned to the depths of the ghetto, to carry and bear her iinw-anted child, such a tragedy has far-reaching implications and ramifications that can escape only the most obtuse and unfeeling human mind. If unplanned pregnancies increase, as we are beginning to suspect that they will because w-omen have become frightened and turned to less effective meth- ods of birth control, or w-orse, no method at all, it can only again widen the gap between groups of women. For many years, adequate means of family PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6531 planning have been the primary prerogative of the private patient who knew that such help was available and could afford to pay for it. During the past few years this care was increasingly being made available to the poor woman as well. Today, once again, we have created two groups, the haves and the have-note. When a woman of means finds herself pregnant and wishes not to bear her child, a safe, clean abortion is within her reach. When oiie of my clinic patients finds herself in the same situation, she usually has one of three choices: she may bear the unwanted child; or she may attempt to abort her- self; or she may have a cheap, dangerous, dirty, illegal abortion. No matter what her decision, such a woman, her family, and society in general will be the ultimate losers. A similar disperate and unfair situation unfortunately obtains when sterilization procedures are examined. The private patient with three or four children w-ho w-ishes to terminate her childbeariiig finds it infinitely easier to do so than does her clinic counterpart with nine or ten. This double standard of medical practice is a gross miscarriage of justice. Hopefully, legislative and legal measures now under consideration will free the hands and minds of doctors who abhor a situation in which they currently find themselves, disturbed, fearful, and helpless. There has been much discussion here of the use of women for experimenta- tion and their "internal pollution" with oral contraceptives. I would like to submit that the larger and for more critical and lethal experiment is under- way-what happens to these women and society as a w-hole if we continue our inevitable march to doom via overpopulation and pollution? What will happen if individuals and nations are deprived of their ability to control their popula- tion size, whether by law-, ignorance, or fear? These are really rhetorical ques- tions to which we all know the answers'. The unplanned pregnancy, the unw-antecl baby, the battered child, delinquency, illegitimacy, crime, drug abuse the endlessly repeated chain of events encircling our society at all levels is only too apparent. In a recent paper presented by Dr. Charles F. Westoff of Princeton University's Office of population Research, it was pointed out "the average animal number of unwanted births during those six years (1960-1965) was between 370,000 and 445,000 among the poor and near-poor, and between 410,000 aiid 540,000 among the mion-poor." Opponents of oral contraceptives always talk in terms of the treatment of "healthy women". Those of us w-ho have to treat women who are pregnant with an unwanted baby do not feel that she can be considered to be free of disease. The World Health Organization has declared that, "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." Looked at in these terms, we are currently facing a major epidemic. Anything that unnecessarily escalates this unhappy situation can only be deplored. It is already clear that this is beginning to occur both here and abroad. Evidence documenting the panic regarding the pill mounts daily. If this panic continues, the problems resulting from these fears will be severe in the U.S.A., but the problems abroad may be catastrophic. Many developing countries w-here the poverty, maternal deaths from abortion, and all the consequences of the population explosion are most critical have been turn- ing to the pill as part of the solution to their incredibly difficult situation. Our nation has been accused before of a double standard of medical care, of send- ing abroad, via our foreign aid programs, second class care. We have been told that some of the IUD programs were viewed in this light-the IUD was less expensive and good enough for them, but American women were getting the pill. For multiple reasons, oral contraceptives are widely and increasingly used in these countries. If the pill is discredited here, will we again be faced with the problem of appearing to supply something to women of other nations which is too dangerous to give to our own? The ultimate implications of the fear which is also grow~ing abroad are terrifying to contemplate. The pebble has been dropped in the 1)001, and all the concentric circles are going out. If 110 answers are found, we may well be damning and ultimately damned by future gemierations. Assuming that the damage we see is not irrevocable, what can be done to channel all the energies that have been released into constructive pathways? One of my favorite quotations from Aristotle goes as follows: "It is easy to fly into a passion-anybody can do that-but to be angry with the right person and to the right extent amid at the right time and with the right object and in the right way-that is not easy." PAGENO="0092" 6532 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY We might do well to consider this ancient advice. There are a number of obvious ways out of our current dilemma. First of all, it lies within our scien- tific capability to answer many of the questions raised at these hearings, given sufficient funds and direction. Some programs designed to obtain valid answers are under way, others are awaiting support, and many remain to be written. The need for expanded research to find new- contraceptive methods and the means to make them widely and rapidly available is too patently obvious to pursue further. Much of this progress, of necessity, lies soinew-here ahead of us. What can he done today? Remove all the archaic legislation on abortion and sterilization which would free both women and their physicians and correct the current social and financial inequality of care. Then, support the programs needed to implement the demands which w-ill immediately and inevitably arise as a result of these reforms. Pass legislation dealing with population problems and their solutions. Provide funds for the training of people to work in these pro- grams at the professional level, but, much more importantly, at the paraprofes- sional and community levels. It would be unrealistic to think that even with unlimited funds immediate solutions could be obtained to the many and varied l)roblems we face, but the next steps are clear. Senator NELSON. Thank von very much. Let me say that one of the reasons stated for calling the hearings was specifically to get additional research funds into this field. One of the great tragedies is that the pill has been on the market for 10 years and neither the medical profession nor NIH, nor anybody else has outlined, in detail, the Protocol of studies that ought to be made, and come to the Congress with requests for funds for it. I would think that very possibly, out of these hearings, that is what. the result.s would be. You refer a number of times in your presentation to the pamc. and so forth, caused by these hearings. We still have a number of witnesses to go. Planned Parenthood and a number of other groups. is it your opinion that the American Public should not know the fact.s that have been developed in these hearings? Dr. CONNELL. Absolutely not. They should be publicized, I agree, As I said. before, the only thing that I disagree with here is the matter of balance. Senator NELSON. Balance in what way? Dr. CONNELL. Of the total impact. the total time devoted to par- ticular topics. I think that most. of what has been said here about tJ~e oral contraceptives is absolutely correct. But as I say in my tes- timony, I do not think anybody has looked concretely at the millions who are faking them happily and safely and what will happen to them if, for any reason, they could not continue to do so. This is what, as clinicians, we are beginning to see. Senator NELSON. Of course. we have not completed the hearings. Dr. CONNELL. I realize that. I said to date. Senator NELSON. I suppose on the first clay of the hearings. von could have made criticism that was much broader. I was pointing out that you cannot. hear everybody on the same clay. We have Dr. Kenneth Ryan. chairman of the Department of Reproductive Biology of Case Western Reserve University appear- ing today; we have Dr. Paul Meier. of the University of Chicago; we have Dr. Alan Guttmacher, president of Planned Parenthood, who will be accompanied by Dr. Mary Lane. staff physician, Mar- garet Sanger Research Bureau, on our list for tomorrow. We have PAGENO="0093" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY *6533 Dr. Edward Lewison; we have Dr. Elsie Carrington, professor and chairman of obstetrics and gynecology at Womens' Medical College in Philadelphia. We shall have Dr. Max Cutler on March 3; Dr. Anna Southam of the Department of Obstetrics and Gynecology at the College of Physicians and Surgeons at Columbia; we shall have General Wil- ham Draper, Jr., and Mrs. Phyllis Piotrow, secretary and member of the board of the Population Crisis Committee-I would assume that the case that you are talking about will be made by these people. Dr. CONNELL. I know most of these people and I respect their capabilities. I am sure that what they will tell you will help to give more precisely the balance that we need. All I am pointing out is that in my testimony I am talking of the effects to date. Therefore, I can only talk of testimony to date. This is the only equivalency I have. Senator NELSON. So you are talking as of today. Dr. CONNELL. As of today, I think we have a lack of balance, and I think we can see the effects of this as we see patients at clinics. Senator NELSON. Are you satisfied that when we hear from this list I have present today, including Dr. Edwards, Commissioner of the Food and Drug Administration, that the viewpoint you are con- cerned about will be presented. Dr. CONNELL. I am sure it will be presented. Senator NEL~ON. So your criticisth is' of the order in which the witnesses have been called? Dr. CONNELL. No, my only criticism has been as an observer of the impact and an observer of what I believe to be imbalance to date. This is all I am saying. As a practicing clinician, along with many other practicing clinicians, I can only report that we are observing certain things. This is all I am reporting. I think these are valid observations. Senator NELSON. I just want to be sure in my mind. You are sat- isfied, then, that after Dr. Guttmacher and General Draper and these various people are heard, the balance you are talking about will be- Dr. CONNELL. This is a very hard question to answer. This has not transpired. I think you are asking me to make a judgment about what will happen over the next few weeks, which I find it very dif- ficult, even impossible, to do. Senator NELSON. We have tried to present a balanced viewpoint. We have publicly stated that anyone who is knowledgeable and has a suggest,ion to make, we shall be glad to put on as a witness. I am just trying to get at the criticism. If we put in all the people I mentioned first, and then we came up with people who had some criticism later, then would you be saying that it was unbalanced if a lot of that appeared in the paper because it appeared at the end of the hearings and obscured what was testified to earlier? Dr. CONNELL. Again, I am not quite sure I follow what you are saying. Senator NELSON. I am trying to figure out precisely what you mean. You are saying that the hearings have not been balanced, and I am saying now that we are trying to present every viewpoint. PAGENO="0094" 6534 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY You are saying to date it has not been balanced. I am asking would you prefer that we had presented Dr. Guttmacher and all those peoPle first, and then had those who had something critical to say last, so that the last impression around the United States would be only of these people who were critical of the pill, instead of the last impression being of those people who were in favor of the pill I)r. CONXELL. It is not my position to say. Senator ~ELSOX. Well. all right. Senator DOLE. There has been a decline in the number of people taking the pill as a result of publicity; is that correct, Dr. Connell? Dr. CONNELL. This fact is beyond the area of speculation. This is documented. Senator DOLE. You have observed this trend yourself in your own clinic? Dr. CONNELL. Considerably more than that. I have observed this through the eyes of statistians who collect clinic data and through the eyes of patients. Senator DOLE. Perhaps some of it was a wise movement on the part of the person stopping the pill? Dr. CONNELL. I am not being judgmental. I am simply giving you numbers. Senator DOLE. I am not certain what will happen after all wit- nesses testify and I do not know what they may say. I think the pomt is that the hearings have had some impact, for good or bad, I do not think we can judge. Perhaps they should have been in executive session, because they are dealing with rather a highly tecimical and important subject matter. But if we are now experiencing some unwanted pregnancies and other things, they may not have provided the service we intended. Dr. CONNELL. This, to an extent, is obviously my persuasion, based on what I see. My own observation of patients who are coming back pregnant-this is irrefutable. When a patient comes in and says, "I stopped my pills because I was scared," and she is preg- nant, this, to me, is the most positive information one can get. Increasingly, we can count these women in the various clinics in New York City, and PeoPle I know in other clinics in the country can begin to count. The numbers are beginning to be of such magni- tude that you can titrate what is going on across the country. I think these are statistics that, again, the ultimate impact-the number, what will happen, how these people will ultimately solve their problems, what will come out of this-I would not even hazard a guess on. This wouldi be pure specuiation. The only thing I can report is that there are, pregnancies; there are women already looking for abortions as a result of induced fear. This, I see; this, I know. I would hesitate to speculate beyond this point. Senator JAVITS. Would the Senator yield for a question? Senator DOLE. Yes. Senator JAVITS. I would like to uinclerstand your conclusions, Doctor. I gather that you feel that, scientifically, there has been inadequate proof to reverse the proof upon which these pills were first allowed to be used. Is that not right? PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6535 Dr. CONNELL. Again, I think it is rather difficult. You are dealing with a preparation which was placed on the open market in 1960. I think I make the point in my full testimony that a great deal of the criticism of the 1960 data is actually based on 1970 knowledge. This is a very tenuous scientific approach, to look at any one era in time through the eyes of a different time. It is sort of like being a knight at King Arthur's Court. I am not sure one can or should do this. Senator JAvITs. But nonetheless, as I read your testimony, you say on page 8 that no factor other than adverse publicity could be found to account for this precipitous drop in use of the pill. That excludes, therefore, adverse scientific information sufficient to override the sci- entific information upon which this was macic available for public use, does it not? 1)r. CONNELL. I believe so. Senator JAVIT5. That is the fact. And that is really a judgment, is it not? Dr. CONNELL. I would say so. Senator J1wrrs. In other words, you are continuing to prescribe the pill, are you not? Dr. CONNELL. Unless I have a definite contraindication. I do not feel the pill is the universal pill for all women. I think anyone with good medical judgment knows that there are some people who should not be on the pill. Senator JAvITS. But certainly, you advise a.gainst it being taken off the market. Dr. CONNELL. Most emphatically. Senator JAvIT5. What do you understand to be the purpose of these hearings? Dr. CONNELL. I think the stated purpose was to explore the area of informed consent. I think this was the primary Irpose. It was also my understanding, reading about the hearings at the end of last year, that they were to determine how much women knew on what basis they were accepting or rejecting the oral contraceptive. This is what I read; this is my understanding. Senator JAVIT5. Now, I noticed with interest the statement on page 9, where you say that the IUD carries its own burden of side effects and deaths. I have noticed that that is said and then dropped. Second, but much more important, is the fact that we have all seen-this is in your statement-that women will not universally accept and muse these alternate and less efficient methods. Now, is there any scientific evidence that IUD has its own burden of side effects and deaths? Dr. CONNELL. Oh, yes, surely. You can find this if you look at the data that Dr. Tietze, who has been quoted here many times has col- lected in his international IUD statistical cooperative through many years. This has been done to an extent that you can actually quanti- tate for any particular IUD the adverse effects of that device in terms of perforation, pregnancy, bleeding. This is well documented. The other study that I think has also been mentioned here before is a study done by the American College of Obstetricians and Gyne- cologists, where there is actual data collection on the side effects of PAGENO="0096" 6536 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the TED's, and in the course of this, there were deaths reported. So I think this is on a reasonably good statistical basis. These problems do exist. They are in print, and have been, again, for qmte some time. Senator JAms. Now, you have made your decision. Your decision is to continue to prescribe the pill. Dr. CONNELL. Properly, for the correct patient, yes. Senator JAvIT5. Enless you have an affirmative belief that it would be deleterious in a given case. Dr. CONNELL. And this exists. As I have said, there is no question that not everybody can take the pill. Senator JAVIT5. Have you learned more as a doctor as a result of these hearings about deleterious effects? In other words, have these hearings contributed to your education as a doctor? Dr. CONNELL. No, because we are exploring a field in which I talk, I write, and I read extensively. No, I cannot honestly say that I have learned anything. Senator JAvITS. Is there anything that you have learned new? Dr. CONNELL. There has been no major new medical evidence that I am aware of that has been presented thus far. Senator JAVITS. On this question of balance, about which you have testified, is it not a fact that no matter what the committee did, the sensational testimony would get the headline? In other words, the testimony, the fact that it is bad rather than good, would get the headline; is that not true? Dr. CoNxEi~L. Again, I am not being critical of the fact that there has been honest publication of the data that were presented here. I am simply talking, as a doctor, of the overall effect. I think this is above question. Senator JAVITS. Well, I shall not ask you about your opinion as to how we could have done it better. But I gather from what you say at the bottom of page 12 that we might have done it better. What you say at the bottom of page 12 is: Thirdly, one of the stated aims of these hearings has been to determine the current level of patient training and information, and to find out whether those women who elect to use the pill do so with full knowledge of possible side effects. As both a clinician and a researcher, I see many problems in this area. There is absolutely no question that as substantial data on adverse reac- tions becomes available, it should be communicated to patients. However, to present the list of possible side effects as outlined in the present package insert to the average patient would serve no useful purpose. First of all, we have been told here that almost all of these are still conjecture, not proven fact. Secondly, a patient cannot reasonably be expected to make a profound judgment-she is not a doctor. We have seen that even those with wide knowl- edge and experience are in disagreement-how can we ask or expect informed decision making from these women based on such dubious information? Now, what else could we do to meet this problem? What else could we have done once we went into the subject, assuming we decided to do it, other than what we did? As Senator Dole says, do you think we should have had hearings in executive session-in other words a nonpublic hearing-and issue a report or something like that? What do you think we could have done to avoid what you consider the unfortunate effects? Dr. CONXELL. I am not sure you could have avoided it under any PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6537 circumstances. I think this is the nature of human beings and the nature of the society in which we find ourselves. Again, this is far outside my role. I really rather hesitate to answer this. I think you could very well, perhaps, have presented, had people who would talk about such things as the relative number of deaths from criminal abortions, pregnancy hazards and maternal mortality statistics. We have heard a certain amount about these subjects, but they have been a small percentage of total time. It is not really so much what has been said and what has not been said, but the per- centage of the time which has been allotted to the data on adverse effects of the particular preparation in a small group, rather than the predictable and known aspects of no contraception or somewhat less effective contraception in large groups. I think this is the only bias. Senator JAvIT5. Dr. Connell, you have been very, very helpful, certainly, to my thinking. I have not, because of other problems, though I am the ranking member of this committee, been as close to these hearings as I should have. I shall take pains to check up on how they have been structured and do my utmost to use what influ- ence I have in that regard. I have been very much helped and edu- cated by your views on it. Dr. CONNELL. Thank you. Senator JAVITS. I have one last question to you as a doctor. Can you make any suggestions about FDA's allowing this medication to continue to be widely distributed, sold, and prescribed? Is there any change that you would recommend, or would you recommend the continuance of the present practice? Dr. CONNELL. First of all, I think I would have absolutely no question that these should be allowed to be continued to be used. I think the alternative in terms of other methods or no methods at all, the medical alternatives are such that, in my own mind, there is no question that these should be allowed to stay on the market. In terms of perhaps getting better information to patients, I think this is quite possible, provided it is done within the context of what the patient can understand and within the context of what we feel to be accepted reality in terms of good medical practice. Senator JAVITS. Could we ask you to do a little job for us in view of your general attitude, which is a sympathetic one to the pills? Would you be good enough to put in writing any changes that you think should be made in the way in which this Government control over these compounds is now administered, if you think any changes should be made, or confirm that present practices are adequate? This would mean that you would actually have to look into what is being done. But I do think it would be very valuable to have somebody with your point of view comment upon the present gov- ernmental operation in this field. Dr. CONNELL. I would be delighted.' Senator JAVIT5. I ask unanimous consent that whatever Dr. Con- nell presents be made a part of the record. Senator NELSON. Certainly. 1 This information was not supplied by Dr. Connell. 40-471-70-pt. 16-vol. 2-7 PAGENO="0098" 6538 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. CONNELL. I can oniy say that it is our sincere hope and our prayer to come out of all this with some answers, with the support of the people on the committee and elsewhere, to do what we are competent to do if we are supported. Senator JAVIT5. I am told that it is a fact that this committee does not have legislative oversight over the Food and Drug Administra- tion. Dr. CONNELL. I am aware of this. Senator JAvrrs. But we do, as a Small Business Committee sub- committee, have the ability to recommend legislation to the Small Business Committee, which may then forward these recommenda- tions to the appropriate legislative committee. It so happens I am also the ranking member of the appropriate legislative committee. Dr. CONNELL. I am happy to know this. Senator NELSON. We have had only one witness who has recom- mended that the pill not be used. Everybody we have had has been propill, some with reservations, some without. But only one has rec- ommended that they be removed from the market. I expect that will be the next attack I shall get. We have been attacked for being propill, for being antipill, so I feel comfortably balanced, in the middle. Senator JAvIT5. The Senator is too experienced a Senator to suffer from that. Senator NELSON. I want to thank you very much for your capable contribution. I thank you for taking time from your busy schedule to come. Would you wait just a moment? Senator Dole has some questions. Dr. CONNELL. Certainly, Senator DOLE. On page two, you made an interesting point. Your rationale might be of some interest to the committee. You say that the pill gives a woman opportunity to learn, to hold responsible jobs, and so on. Many indicate that this is their first opportunity to participate in these roles and to become, as you describe them, happy and productive members of society. Do you care to elaborate on that statement? Do you find this to be true from your own experience? Dr. CONNELL. Yes, this is a more recent area of interest of mine, and one which I think is increasingly important as we look at the problems of cities. We have been involved in the last few years in the actual training of these individuals. There is a program in New York City, to which I am consultant, which takes women from the ghetto, and trains them as family planning counselors. These women are now actually working in mcst of the major hospitals in New York City in actual patient training and recruitment. They are highly effective people. I have also been consultant to the Talent Corps, which is a Department of Labor-funded group, which for several years has been active in the training of these paraprofessional people, and the vast majority of these women do come from ghetto communities. Many from welfare rolls. It has been one of the most exciting things, actually, that I have ever been involved in, to see these women come out of abject poverty. Many have never been creative PAGENO="0099" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6539 or constructive before. To train these people and see them enter the larger society-it is really a terribly exciting, as well as a very valu- able thing to see. I think this is very important. We need these people; they need our support. They need training, This, I think, is extremely impor- tant. Senator Don~. How many patients have you seen personally with reference to the pill? We have talked with numbers of other wit- nesses. Some have seen as many as 10, or at least based studies on that small number. Others have seen hundreds, some thousands. Do you keep any record of the number of patients you have had contact with? Dr. CONNELL. I am in the thousands category. Senator DOLE. And, of course, you have been practicing on up from the sort of prepill days through the postpill days. Dr. CONNELL. I hope not. Senator DOLE. Maybe not post, but at least during the introduc- tion and beginning of the pill. Do you see any changes now, any dif- ferences that you might comment on between women now who take the pill and women before the pill was available? Dr. CONNELL. I think socially there is just no comparison. The feeling of confidence that women have, the lack of fear of preg- nancy, the improved relationships with their husbands, with their children, all these things have made a tremendous improvement in their entire outlook on life. They also have the assurance of knowing that they can sign up for training and they can assume that they are going to be able to finish it and help to support their families. They can only do this because they have effective contraception. In this sense, I think we have made a major contribution to the enlarging role of women, in which I very obviously believe. I think this is very important. Senator DOLE. At the same time you have indicated that not every patient should be a user of the pill. Dr. CONNELL. I have patients to whom I say, you should never take the pill. You have a contraindiction to the pill and it would be dangerous for you to take the pill in its present form. Senator DOLE. Plus some that may start the pill, and you take them off the pill? Dr. CONNELL. Of course. This is the essence of good medical prac- tice; to select properly, to follow properly, and to live up to one's knowledge to the best of one's ability. I think that is what a good doctor is. Senator DOLE. We all share the same concern. I certainly appreciate your testimony. You are the first of your sex to testify before the committee. There were others here earlier this year who were available for testimony, but you are the first scheduled witness. You have been very helpful. I would hope if there has been reduction in the use of the pill because of publicity, that the apprehension which has been generated would be balanced as to whether the pill is good or bad. Such is the `determination that must be made. PAGENO="0100" 6540 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I think it is better if it is made on the basis of a doctor-patient relationship rather than on a Senator-patient relationship. I do not know if you can blame all these babies that are born on the members of the committee or not. Dr. CONNELL. Perhaps all of us have to accept a portion of the blame for the unfortunate events which are producing these babies. Senator DOLE. I do appreciate your testimony. As Senator Javits and Senator Nelson have pointed out, you have been most helpful. Dr. CONNELL. Thank you. Senator DOLE (presiding). The next witness is Dr. Kenneth Ryan, chairman, Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio. Dr. Ryan, you can either read your statement in its entirety or summarize. It will all be made a part of the record. Proceed in any way you wish. I apologize for the lateness of the hour, but we have had some interruptions on the floor. STATEMENT OP DR. KENNETH 3. RYAN, CHAIRMAN, DEPARTMENT OP REPRODUCTIVE BIOLOGY, CASE WESTERN RESERVE UNI- VERSITY, CLEVELAND, OHIO Dr. RYAN. Thank you very much, Senator Dole. If I may, Iwould like to read my presentation. It is quite concise and it says exactly what I want to express. Senator DOLE. Mr. Gordon may have questions during the reading of your statement or I may have questions. Dr. RYAN. Thank you. I would like to preface this by saying by way of basis or qualifi- cation for testifying before the committee that I have had 20 years of experience in research as a steroid chemist. We have known about these hormones for only 40 years. In addition to that, I do partici- pate in the practice of n~edicine. I am neither an unrestrained advo- cate nor an unqualified critic of oral contraceptive medication. It seems to me we have just heard that in the previous testimony. As with all medical therapy, the advantages of curing or preventing the disease should outweigh the risks of the drug used. It is no better to cure an ailment and then lose the patient from a toxic medicine than to have a patient die without treatment or the wrong form of ther- apy. With the pill, the object of therapy is pregnancy prevention. Fortunately, the risks to life and limb from both disease and drug are low. Pregnancy is supposedly a physiological or normal process but carries a 0.04-percent mortality rate. An unwanted pregnancy is a recognized "disease" state with additional challenges to life, health of the mother, to her psyche and society. The pill has acknowledged hazards and its effectiveness in preventing pregnancy must be bal- anced against safer, less reliable means of family planning and pregnancy itself. The relative risks are calculable for groups of people but unfortunately not for the individual patient trying to make up her mind which course to follow. The patient can make decisions only with adequate information PAGENO="0101" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6541 from her physician, drug package inserts, and other reading mate- rials. Unfortunately, I would agree with Dr. Connell that public pronouncements on the pill, either pro or con, are known more for their rhetoric than for their objectivity, often leaving both physician and patient misinformed or confused. Acting as chairman of a department of obstetrics and gynecology, I can testify to the fact that many physicians are as confused as their patients in this respect. Since these hearings will aid in the dissemination of information, I appreciate the opportunity tO present a perspective on the pharma- cological properties of the medications. That is what I would like to talk about now, what we know about some of these oral agents, what we can predict about the side effects, and so on. Most oral contraceptives, whether of the sequential or combined type, contain a synthetic estrogen used in sequence or in combination with a synthetic progestin. I will describe each in turn. Synthetic estrogens have been available since 1937 when Dodds first described diethylstilbesterol which is a synthetic as potent as the natural estrogen, estradiol, but unlike the native hormone is active by mouth. Since then, two other synthetic orally active estro- gens have been produced-ethinyl estradiol and mestranol. I bring these up because these are the two compounds which are used in most of the contraceptives. They are of almost equivalent potency to one another but some 10 to 25 times as active as diethyistilbesterol. The latter two compounds are the ones most frequently used in con- traceptive medication. All of these active estrogens, whether it be estradiol or mestranol, have a comparable spectrum of biological properties and like the native hormone have actions on the reproductive tract as well as broad metabolic effects. The observation written in the FDA report and publicized that contraceptive pills containing these estro- gens have extensive metabolic effects on many tissues of the body is neither novel nor surprising to any student of estrogen physiology. This is a normal consequence of estrogen action, and no particularly unique activity, of any of the synthetic estrogens has yet been described. In any case, synthetic estrogens have been in extensive clinical use for 30 years. Very high doses have been used in men with prostatic cancer, for instance. There has never been a documented case of induction of cancer in the human by these agents and no serious sequelae have been reported save for their current implication in the embolism and phlebitis associated with pill usage and this is reported with a high dosage. If you recall, the British experience and the recent American experience, that thromboembolism seems to be less frequent in the patients taking the smaller dose, the prepara- tion having the smaller dose estrogen. I notice that you have the book on the metabolic effects of these contraceptives in the human and I know it says in there that you cannot equate one drug to another, nor can you equate it to the native hormone. But I know of no information that indicates that the biological properties of the estrogens used in the contraceptive pill are any different than stilbesterol for which we have at least 30 PAGENO="0102" 6542 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY years of clinical experience or, for that matter, different than the natural hormone, estradiol, which circulates in the blood. In other words, we have no data that they are more dangerous than the native hormones at comparable levels of potency. They may be proven to be more hazardous, but there jusf isn't any evidence for this as yet. Even natural estrogens are toxic to laboratory animals when given in excessive dosage. Then the important thing is the rel- ative amount that is given to the patient and how it is given. Information on the amount of hormone produced in the normal cycle indicates levels of 50 to 200 micrograms of estradiol per day. The oral contraceptive medications contain a dose on a potency basis some four to five times the peak levels of the cycle, clearly providing amounts outside the physiological range. I think the current recom- mendations to lower the estrogen dosage and indications that com- plications are fewer with less estrogen would be in keeping with soimd pharmacological principles. It is obvious that we need more studies with the lower level medication in terms of their efficacy in preventing pregnancy as well as in the production of side effects. But I would clearly make a plea for studying the possibility of using drugs with lower estrogen in them. Now, - so much, then, for the estrogen. I could summarize it by saying we have had 30 years of experience and there is not much that has come out. with the newer preparations that we have not seen already, that has not been known and has not been written about at one time or another. It might be related to dose potency, but there is no other iuformation of unique character of the estrogens used in the pill. \T\Then you come to the progestational agent used in these oral medications, they are different from the estrogens. There are more marked qualitative and quantitative variations in biological effects and we don't have the same number of years of clinical usage. Rather than 30 years of experience, it is closer to 15 years with these agents. Experience with some of these progestins is longer than with others and the dosage has varied some tenfold since the first pills w-ere introduced. It is not fair to talk about the side effects produced with the higher dose medication today, because the higher dose med- ication is usually not used. It is, therefore, not possible to bring to bear the same clinical experience as with the estrogens, and there is even less certainty about equating biological properties within this class of compounds. Clearly more information is required for cur- rent dose levels and types of hormone. With a given side effect, we still may not know whether it is the estrogen or progestin compo- nent or both which are responsible. For instance, we have some thoughts on this. but we do not have enough information as yet- again a plea for more research in this area. Now, the synthetic estrogens have been used with the progestin because the two together can usually prevent pregnancy more effec- tively and prov1de a more natural artificial cycle at a lower dosage level than either alone. That is why they are used together, either in the combined pill or sequentially, one followed by the other. Now, the combination of estrogen with progestin, unfortunately, produces effects which are different than the sum of their individual PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6543 properties and experience with the estrogen alone or the progestin alone cannot be equated to the combined medication. The best model for the biological effects of the pill is still pregnancy. Again in your reference books, you will see that many physicians and scientists rightly object to an oversimplistic comparison of the pill's effect to the pregnant state, however, there are still useful analogies to be made with respect to the metabolic alterations and health risks involved. It is just as wrong to say we cannot con~ipare them as it is to say the comparison is complete. Just about all of the side effects and metabolic alterations produced by the pill were first observed years ago as complications of pregnancy, including thromboembol- ism, blood clotting disorders, hypertension, liver disorders, altera- tions in fat and carbohydrate metabolism, pigmentation, hair loss, and post-pregnancy infertility, just to name a few problems shared by pregnant women and pill-takers. I am not trying to equate the two conditions, but the similarities are striking. Mr. GORDON. Dr. Ryan, may I interrupt you? Dr. RYAN. Yes. Mr. GORDON. Do you know any studies to show what the lowest effective amount of estrogen would be? Dr. RYAN. For what purpose? Mr. GORDON. For oral contraception? Dr. RYAN. There have been some studies conducted to test- Mr. GORDON. Who is the sponsor? Dr. RYAN. There have been studies to test the minimal dose of mestranoL which will inhibit gonadotropic release. These have not been the characteristic dose response curves that people would like to see. The reason that the higher estrogen has been used is that they can with more certainty prevent the release of the gonadtrophin with the higher dose-0.02 mg., for instance, of mestranol will not con- sistently stop gonadotropic release, where as 0.05 in many cases does, and 0.08 certainly does. Mr. GORDON. We have 0.05-mg. pills, do we not? Dr. RYAN. In a combination pill. Mr. GORDON. You have considered it effective? Dr. RYAN. Yes. Mr. GORDON. We also have higher numbers, too, don't we? Dr. RYAN. Yes. Mr. GORDON. If we have 0.05 in the market and it is effective, why do we need the higher dose, the higher amounts? Dr. RYAN. This becomes, again, very complicated. There are two prohiems. One is the effectiveness and the other is the ease and con- trol in breakthrough bleeding and other of the less serious side effects, what you might call nuisance side effects in the management of the woman's cycle. It has been that kind of balance that the phar- maceutical industry has become involved in this trying to come out with a pill that is acceptable to woman, which will provide her with the most natural artificial cycle and still prevent pregnancy. The other relates to the red tape, the problems they have in trying to go through the red tape in getting a pill on the market. They did facilitate the medication with the new doses on the market much faster than would ordinarily be the case. PAGENO="0104" 6544 COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY Getting back to the pregnancy question, it has often been the changes that we have seen in pregnancy that provides leads to meta- bolic alteration that were subsequently demonstrated for oral contra- ceptives. This doesn't make the complications more acceptable, just less frightening since one is mimicking changes seen in nature. As a matter of fact, I can think of no complication, described for the pill, that recently received so much publicity, actually no alteration, meta- bolic side effect of the pill, which has not already been reported in pregnancy at a higher incidence, including alterations in the cervix that mimic carcinoma-in-situ. Of the many side effects of the pill, the risk of thromboembolism appears to be significantly increased and dangerous. We still have to remember that these are retrospective studies, not prospective stud- ies. These are still going on. The combination of thromboembolic phenomena is shared with pregnancy but fortunately occurs at a lower level of incidence with the oral contraceptives. It will be important to try to determine whether lowering the estrogen compo- nent of the pill will reduce or remove this hazard. The risk of inducing cervical or breast cancer with the pill cannot be predicted at this time. However, I think it has been the publicity about this which has frightened many patients, not only those taking the pill for contraceptive purposes, but women who are on estrogens, for instance, for replacement purposes in post-menopausal period. There are no convincing data for or against this possibility and only careful study will provide a definitive answer. Aside from suspicions of the relationship of animal models to man, these were mentioned in the FDA report and quoted by, I believe, Dr. Davis in this committee, there is no evidence for steroid induction of breast cancer in humans or primates. Long-term clinical experience with estrogen thus far provides no obvious cause-and- effect relationship, but this is no substitute for careful epidemiologi- cal studies. There just is not any information on the subject one way or the other. The reports indicating increased carcinoma-in-situ of the cervix in pill-users cannot be evaluated as yet since the patients did not rou- tinely have cancer screening prior to being put on the contracep- tives. Earlier short-term careful prospective studies did not demon- strate in-situ carcinoma, as a consequence of pill use and only carefully controlled additional investigation will resolve these con- flicting reports. The pregnant state with which pill use has most often been com- pared does not in itself predispose to the cancers in question, and while experiences with estrogens in the past and Imowledge of the effects of pregnancy cannot be equated with the current contracep- tive medications, this does provide in my opinion a tempering bal- ance to the cancer fears which can ultimately be resolved only by more study. Finally, the occasional infertility that follows stoppage of the pill can fortunately be effectively treated in many cases with ovulation inducers. but it still presents a problem. I would like to conclude these observations by saying that the on-going public drama of the pill should tell us more than anything PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6545 else that we need more research into the biological effects of these agents and certainly more research to develop alternate methods of fertility control. In the meantime, the patient and her physician are left in a quan- dary and still must make the right decisions with insufficient infor- mation. For the patient who desires family planning and cannot or will not use other methods, the pill still offers a healthy 15-to-i odds advantage over pregnancy mortality risks which are already quite low. At the present time, there is actually little more which can be said. Senator DOLE. Dr. Ryan, thank you very much. First of all, in the statements you make based on personal observation, based on your own practice, and again, knowing that numbers are not solely mean- ingful, how many patients have you had over the years? Dr. RYAN. Well, I have a limited personal private practice, but I am director of one of the largest hospitals in the State of Ohio that has a large indigent patient population and a large private practice population, so vicariously, I would say my patient experience is quite large. I also participate as much as I can in the planned par- enthood groups within the City of Cleveland, so again the experi- ence is quite large, though not all of it is personal in the rendering of care to individual patients. Senator DOLE. Then in your own experience, direct and indirect, you pointed out at least some areas of possible danger. I assume that there are persons you would not recommend use of the pill to and probably others, as Dr. Connell has stated, that once they have taken the pill, they can be taken off the pill because of something that may develop. We had testimony earlier this morning of 16 different major symptoms from taking the pill. You mentioned that perhaps one area where we needed more information was knowledge provided to the patient. You are not just suggesting that you give the patient a laundry list with each pill prescription of all the things that might possibly happen? Dr. Connell indicated earlier that maybe if they were advised in writing or maybe orally, but not given every possibility that might happen. Do you share generally this view? Dr. RYAN. We are treading on very, very narrow ground when we determine how much information to give our patients. I think they should be informed as much as possible, because they in fact are the ones that are taking the risk. Senator DOLE. Does that mean to say in a printed circular, "this may cause thromboembolism," would not be meaningful to most patients? You may as well recite a nursery rhyme as far as the mes- sage he receives? Dr. RYAN. This is right. I think the patient should receive not only written information which she can read, she should receive interpretation of this by her physician, and she should receive, as Dr. Connell already mentioned, careful follow-up, because you do not give medication to a patient and let her turn to her own devices and ask her a year later what you said or gave to her in a written PAGENO="0106" 6546 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY presentation. I think from the questions we ask of our patient, they know what we are after, when we ask have you had headaches, have you noted these symptoms or those-the patient very quickly learns the areas of consideration to us. I think it is important to inform the patients. I do not want to be privy to information that the drug was potentially harmful and not disclose as much of this informa- tion to the patient as possible in a meaningful way without fright- ening the patient, and not with minutiae. But we don't very often tell the patient when we give an injection of penicillin that they may drop dead from an anaphylactic reaction. Nor should we. We as physicians know this occurs, we know as physicians that the patient should be asked if he is sensitive to the drug. I think an apparent analogy could be made to the pill. We know those signs, symptoms, complications of the pill which are apt to be most serious and for which the patient is taking the greatest risk. The patient should be informed about these. Senator Dory. As I understand, in some of the clinics and some of the planned parenthood groups, the information is disseminated on an informal basis, in a group-like atmosphere, of perhaps 30, 40, 50 or more women, where the pill is discussed. It is not all clone on a person-to-person basis, is it? Dr. RYAN. It is done in two ways ordinarily. It is done very often in group indoctrination and then on a one-to-one relationship there- after, or in combination with the group-sometimes with film, some- times with strip films and so on-to introduce the patient to just exactly what's going on in relationship to their bodies, to the types of medication which are available, to the types of family planning which are available. Senator DOLE. Do you have any questions? Mr. GORDON. Am I correct that you prescribe the pill for those patients who, one, desire it for family planning, and, two, who cannot or will not use other niethods? Dr. RYAN. Yes. Mr. GORDON. Am I correct in assuming that if the patient is will- ing or is able to use other methods, you do not as a general rule Pre- scribe the pill? Dr. RYAN. I hate to make generalities. I think that the only other method which I would customarily discuss with the Patient on a parity with the pill, based on a patient's motivation, would be the diaphragm. Mr. GORDON. But if the motivation is there? Dr. RYAN. If the motivation is there, I think it is a reasonable approach, and certainly safer. I know of no complications from that form of family planning. I dlon't think anyone would quarrel with that. Senator DOLE. Have you noticed any change in the pill habits of your patients because of the wisdom emanating from this commit- tee? Dr. RYAN. Again, just from personal experience, when I go down to the lunch room in the hospital now, physicians stop over and say, what do you think we ought do? What's your latest feeling on the pill. I have had several patients call up and ask about the cancer PAGENO="0107" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6547 question, some of them not taking these medications for contracep- tive purposes, but for others. I have had several patients who decided not to use the pill in the light of the publicity associated with these disclosures. Senator DOLE. I am not saying we should not have held the hear- ings but am trying to determine what your own experience has been to the reaction? Dr. RYAN. I might say this is not too different from the kinds of experiences we have had over the last 4 or 5 years every time a new article comes out in any of the lay press. As I said in my introduc- tion, public pronouncements always seem to come out with more rhe- toric than objectivity. It is extremely difficult to get the balance in for a patient. In general, it is not the most ideal way for the patient to be informed about her decisions in health matters concerning her- self. I think it can give her information which she can then use in discussing it with her physician or clinic. Senator DOLE. At least she is alerted to some of the potential problems or speculative problems. Did you have a question? Mr. GORDON. Yes. As I understand it, you do not think there is anything wrong with people asking questions about it, do you? Dr. RYAN. Absolutely not. Mr. GoRDoN. Does it not take the physician off the hook, in a way, when people start asking questions? Dr. RYAN. Practicing physicians very seldom, in a sense, get off the hook. We cannot, you know, delegate some of the responsibilities we assume in patient care. I think well-informed patients are a pleasure to deal with. Mr. GORDON. And also you mention the fact that when you go down to the lunchroom, doctors ask themselves, well, what do you think, what shall we do, and so forth? Don't you think that is good? Dr. RYAN. I think it is, yes. I was not making judgments on the propriety of whether or not people should ask questions or whether or not they should be informed. There is no question in my mind that most of the public pronoui~ceinents on the pill have involved rhetoric and scare because they come out with, the pill causes cancer or something, as the snap headline. Then, if you are industrious enough to read the whole article, you will get down to the bottom and see that there were animal models or something of this nature that were involved. This has been going on in relationship to the pill, as I say, almost from the time it has been on the market, and the rhetoric for and against it has been of equal quality in terms of informing people. Senator DOLE. A lot of it may depend on who is asking the ques- tions. If you were sitting up here and another doctor were the wit- ness, you could probably ask very meaningful questions. Maybe Mr. Gordon has not had that problem. Maybe he is an expert in this area. Mr. GORDON. Thank you. Senator DOLE. The basic weakness probably is that we lack the expertise and we may, therefore, unintentionally present an improper picture. PAGENO="0108" 6548 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. RYAN. I was sitting through the prior discussion and I think that on balance, the committee hearings will have the opportunity to hear from people of all interests, experiences, and persuasions. And I think this is all to the good and I appreciate the opportunity to express my own in this respect. I think out of this we would hope would come an awareness that there are problems and patients should be so informed, that we need more information and that we hope that the support for that type of research will come from the Federal Government, because jt is involved, with long-range type of observations of patients. Senator DOLE. Have you observed any shortcomings with refer- ence to the pharmaceutical companies themselves? Are there areas where you feel they can improve communication of information? Dr. Rvxx. Really. I have very little comment about this. I think that the interchange between the regulatory agency-that is, the FDA and the pharmaceutical agency-the interchange between them I believe provides the physician with the kinds of information he needs. Senator DOLE. That, is all. Thank von very much. Doctor. Dr. Meie.r. Dr. Meier is professor of sta.tistics at the University of Chicago. You may handle your statement any way you wish. You may sum- marize or read the entire text. It will all be made a part of the record. Proceed in any fashion you wish. STATEMENT OF PAUL MEIER, PH. D., PROFESSOR OF STATISTICS, DEPARTMENT OF STATISTICS, UNIVERSITY OF CHICAGO, CHICAGO, ILL. Dr. METER. I imde.rstancl that. Senator, thank you. A decade ago, the first oral contraceptives were made available and shown to be highly effective and widely acceptable. Side effects were noted from the start, but. oral contraceptives have become increasingly accepted nonetheless. Many of these side effects are transient and disappear after a time. and many occur in some users and not in others. Other possible side effects are potentially very serious and occur seldom enough that. an individual physician cannot hope to make judgments about them on the basis of his own experi- ence. It is this latter class of side effects with which I shall be con- cerned. There are two aspects of public policy with respect to such effects which I believe require clear identification. There is, first., the right, of an informed individual to elect to take a reasonal)le risk in order to achieve some goal which he believes desirable. I make several trips a year from Chicago to Washington. Purely for convenience I travel by air and not by rail. I am one of the few who have examined the available information on risk in the two modes of travel and I judge that I am accepting a non-negligi- ble risk in choosing the convenience of air travel, but I do it quite deliberately. On the other hand, I no longer smoke cigarettes, although I was once a regular smoker. The benefits were in that case PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6549 outweighed for me by a number of serious disadvantages. I am a strong believer in the freedom of the informed individual to decide for himself how to balance benefits and risks which primarily con- cern him, and I include here the right of the patient, consulting with her physician, to elect to accept some risk in return for the benefits of oral contraceptives. To me, the role of government in this area is clear-it is to be sure that both physicians and patients are as well-informed about the state of knowledge on the benefits and risks or oral contraceptives as it is reasonably possible to make them. A second aspect of public policy is of comparable importance. It is to protect the public from clearly unreasonable risks, both by seeing that the risks are adequately studied and understood and, in some cases, by eliminating them from the environment. In some respects the level of concern by government should be much greater than that of even a prudent individual. For example, an increase in the level of ionizing radiation over the United States due, perhaps, to building nuclear power stations, would increase the risk that I might get leukemia. If the increase were small, I might reasonably ignore it, as an individual. The governm~nt, however, must weigh the combined risk to all of us against the benefits which additional nuclear power plants might provide. In either case it must be emphasized that reasonable judgments are only likely to arise out of a weighing of risks and benefits. It is common to hear that "even one avoidable death is too many," or that the "only acceptable level of pesticide residue on food products must be zero." Neither as governments nor as individuals do we in fact behave this way, and the refusal to weigh risks against benefits often results in the blind acceptance of risks which analysis would show to be unreasonably high. I believe, for example, that the almost disas- trous errors made in the program of safety-testing for the Salk vac- cine in the midl9SO's resulted from an unwillingness to accept the notion that there might be a measurable risk and to seek to evaluate its magnitude. A typical example of a known risk which we accept in return for benefit is the requirement of smallpox vaccination for schoolchildren. A small but definite number of children die as a result of being vaccinated. WTe accept such costs as necessary to achieve a greater benefit. How one weighs the benefits and risks is strongly conditioned by his background and general outlook. Since 1957 I have been a pro- fessor of statistics at the University of Chicago. One of the areas of applied statistics in which I have been most interested is the design and evaluation of clinical trials for new therapies. I have served on numerous review committees for the National Institutes of Health. I am currently a member of the Heart Special Project Committee of the National Heart Institute, and I served also on the National Heart Institute's Diet-Heart Feasibility Study Review Committee. For the past 15 years I have done occasional consulting for pharma- ceutical firms, although never for a company which was a manufac- turer of oral contraceptives. My interest in the problems of population growth and conception control is of long standing, but my direct involvement is recent. I participated in the preliminary analysis of data gathered at the PAGENO="0110" 6550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY University of Chicago which, it was hoped, might shed some light on the question of the risk of cervical cancer which might be associ- ated with the use of oral contraceptives. It was the judgment of those involved that this particular set of data is unsuitable for that purpose, and further work is now being carried out. In the course of this effort, I had occasion to review papers dealing with other stud- ies, particularly those dealing with thromboembolic phenomena. As a result, also, I was asked to participate in a. conference on side- effects sponsored by Planned Parenthood of Los Angeles and other groups. Last November I was asked by a medical director in one of the firms which manufactures an oral contraceptive to review the Sart.well report-the American study of possible association between thromboembolic phenomena and use of oral contraceptives-and to attend two meetings held between company representatives and staff of the Food and Drug Administration. (A letter to Dr. Ortiz of the FDA, summarizing my remarks at these meetings, is attached.) 1 I agree with those who see population pressure as both a short- range contributor to many problems, such as poverty and environ- mental pollution, and a. long-range potential disaster. Of course, in the long run population size will be controlled by Malthusian forces, such as war and famine, but I believe that no humane individual could wish us to be left to the mercy of those forces. I believe that motivation to limit family size is of first importance, but I feel that the contimiing improvement of a still unsatisfactory technology for achieving conception control is also essential. I expect that American society, along with many others, will insist on effective means of conception control and, since I regard abortion as at best a necessary evil, I place a high value on the search for other means of limiting population growth. This does not mean that I favor continued dis- tribution of the pill, no matter what effects it may have. If the level of risk associated with it. should prove unacceptable, existing alter- natives will have to substitute until better methods are found. The current evidence is this. There are a number of side effects which are less than life-threatening and which, because they occur with fairly high frequency, are more easily studied and on which there are many reports. I have not reviewed these studies and I have no further comments to make on this class of side effects. More difficult problems are associated with potential side effects which are relatively rare, but of utmost seriousness. Substantial attention has been given to two such diseases-thromboembolic dis- ease, and cervical cancer. The evaluation of the effect of a drug on the incidence of a relatively rare disease is a very difficult problem. Thromnboembolic disease and cervical cancer are not unknown among young women, quite apart. from use of the pill, so that. case reports, while suggestive, cannot provide convincing evidence of a causal relationship. The direct or prospective approach, although demand- ing, is far and away the most. satisfactory method of study. If we can periodically examine a large group of women taking the pill, say five to 10 thousand, and an equivalent group using some other method of contraception, over a period of years, any difference in 1 See p. 6555. PAGENO="0111" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 6551 disease or death rates large enough to be of concern to us should become manifest. Ideally, subjects should be offered different contra- ceptive methods in accordance with a randomized allocation scheme. In some circumstances the random allocation procedure may be impractical and one must try to achieve relative comparability of groups in other ways. There are likely to be other difficulties as well -losses from observation, refusal to continue with periodic examina- tions, and the like-but none of these difficulties is insuperable and none, in my opinion, justifies the very nearly complete absence of such studies in this field. In fact, one of the earliest studies initiated on oral contraceptives was a controlled prospective study. After initial exploration, start- ing in 1960, established the very nearly complete effectiveness of the pill, Dr. Gregory Pincus and others initiated such a study in Puerto Rico in 1962. Although sound in design, the study was beset with a number of administrative difficulties and, after the death of Dr. Pincus, it has come to be regarded in some quarters as a lost cause. The study is noneth&ess still on-going and it represents the only long-term prospective controlled study of the pill in existence. Early reports from this study were highly favorable to the pill, but these reports also have been subjected to unfavorable criticism and the study is not at present accepted as a substantial contribution to our knowledge on the problem of safety. Regarding thromboembolic disease. Early case reports led to the suspicion that the use of oral contraceptives might be leading to an increase of thromboembolic disease, and the pill has correspondingly been considered as contra-indicated in cases of circulatory disorder. However, until quite recently no important studies of this problem were carried out in this country. Last year two British studies were reported (Inman and Vessey; Vessey and Doll) and, at the request of the FDA advisory committee, a similar study was carried out in this country under the supervision of Professor Philip Sartwell of the Johns Hopkins University. In addition, vital statistics related to thromboembolic disease were reviewed. The British studies have been hailed as models of clinical study design and appear to have been taken in most quarters as incontro- vertible evidence of a pill-induced increase of thromboeinbolic disease. The Sartwell report, similar in design and at least equal in thor- oughness and care in execution, indicates an increased risk of hospi- talizable, nonfatal thromboembolic disease. Let me interpolate that it was an interview study post-hospitalization, and therefore, of necessity was concerned only with nonfatal diseases. This conclusion is widely accepted and perhaps prudence requires us at least to take it as a working hypothesis, and to evaluate the seriousness of the implied increased risk. (The risk of excess mortality due to throm- boembolic disease is estimated from other studies to amount to approximately three deaths per 100,000 per year.) However, for the reasons indicated in my letter to Dr. Ortiz-see attached-I find this type of evidence to be far from convincing. Suspicions about oral contraceptives and thromboembolism have long been current and could readily have led to somewhat different hospitalization rates for women suffering similar disorders according to whether or not PAGENO="0112" 6552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY they were known to be on the pill. Differences in choice of contra- ceptive methods by women of different demographic characteri st.i cs also contribute to the difficulty of drawing firm conclusions from such evidence. The uncertainties of interpretation are given emphasis when we consider the disparity between the conclusions of the Sartwell report and those of a recent prospective British study reported by Ellen Grant. The Sartwell report, in addition to implicating oral contra- ceptives generally, concludes that sequential preparations are more hazardous in this regard than are the combination products. The Grant study, on the other hand, suggests that combination products with high estrogen content show a greater hazard than other prepa- rations. She found relatively less hazard with the usual sequential formulations. Mr. GORDON. Excuse me, Doctor. You talk about the Grant study and the Sartwell report? Are they mutually exclusive? Dr. METER. Well, I do not intend any preference for one or the other in the language. The Sartwell report is a part of the FDA Advisory Committee report and it is commonly referred to by those involved in it as the Sartwell report. It is a study and in general terms, a highly meritorious study, every bit as good quality as the Grant study, as far as I know. The Grant study is one carried out in Britain, the Sartwell one carried out in the United States. Mr. GORDON. Do they conflict? Dr. METER. They do conflict, yes, quite flatly. The testimony of vital statistics is also ambiguous. This was first noted by Drill and Calhoun, whose report has been criticized on var- ions grounds. However, the far more intensive analysis of vital sta- tistics rates in the Sartweil report seems also to lead to an ambigu- oiis conclusion. The rates of mortality from thromboembolic conditions have increased over recent years, but this has occurred in most age groups and in men as well as women. A somewhat greater increase is found in women aged 25-34. although the difference is not statistically significant. The interpretation given in the Sartwell report is as follows: 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. I do not disagree with this cOncTus~On. but I would add that if we consider it a.t all likely that the diagnosis of thromboembolic death in young women may have been influenced to some extent by a heightened index of suspicion in the case of pill users, one might also argue that the vital statistics results are consistent with the hypothesis that oral contraceptives have not produced an increase in mortality from thromboembolic disease. I turn now to information on cervical cancer. The possibility that long term administration of hormones might give rise to one or another form of cancer has been a concern from the start. The possi- bility of an effect which might be long delayed makes it one of the most potentially difficult problems to study and, correspondingly, one for which continuing studies should have been initiated PAGENO="0113" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6553 promptly. Early reports from the Puerto Rican study were highly favorable, but again the evaluation of long-term results from this study is in question. There exist almost no other clinical studies which purport to deal in a serious way with the cancer risk. The study in Chicago in which I participated was initiated as a supplement to a cytology screening program. No appreciable demographic information was recorded and there was considerable uncertainty about the validity of some of the data. No attempt has been made to randomize or oth- erwise control the choice of contraceptive methods and, as indicated earlier, it was judged that no useful results could be obtained from the material at hand. A study initiated in New York City is liable to some of the same difficulties and it has not so far contributed information on incidence among patients under continuing observa- tion. Finally, a prospective study has been initiated at Kaiser-Per- manente, but this has just begun to get underway. At the present time, then, we appear to have very little useful evidence on the ques- tion of possible carcinogenic effects. The main point I have been trying to make is that, in the area of low incidence-high fatality diseases which might be related to use of the pill, we are deplorably ignorant. Why should that be so? It is easy to lay the blame on the manufacturers, and they cer- tainly deserve their share. It is in my view a major responsibility for the manufacturer and distributor of any product to investigate and to inform the public about the consequences of its use. At the same time, I take it for granted that manufacturers in general- whatever their line of effort, and whatever their rhetoric-are pri- marily concerned with making money, and that they will undertake to fulfill such responsibilities only to the extent that custom, pres- sure, or regulation require. Of far greater concern to me is the failure of our governmental agencies to exercise their responsibilities in seeing to it that appro- priate studies were carried out. It seems to me that the reasons are complex, but I think it is worth our while to consider some of them and to consider how the defect may be repaired. I spoke on this point at a conference a year ago, and my next remarks are a para- phrase of what I said then. I think what has happened is that we have been overcome by a lack of appropriate organizational structure. It is only recently that we have begun to take responsibility for monitoring such effects as these, and we are not very experienced in this role. After all, which agency really had the responsibility? The Food and Drug Adminis- tration, even in those periods when it has enjoyed some fraction of the administrative and political support that I think it merits, does not ordinarily take on-going responsibility for long-range studies of a drug or food additive, once it has been judged that the product is reasonably safe. Certainly it has never had the staff or the budget- ary support to justify such ventures. The National Institutes of Health, while budgetarily better equipped, has not seen this kind of activity as coming within its scope. One might have expected the NIH research grant mechanism to fill the gap. It has not, and I think there are obvious reasons why it 40-471-70-pt. 16-vol. 2-8 PAGENO="0114" 6554 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY has not. Frankly, the required research, although important, is not especially appealing to scientists. It is not fundamental and it is not exciting. It is difficult, it is expensive, and it is fraught with the risk of attack from all sides. Who would willingly prepare himself for such a study, make an application to be weighed competitively with others on scientific merit, and risk the loss of support halfway through the study when a review committee with different views or priorities comes to consider renewal of support, when he stands to gain so little in scientific recognition or otherwise? Evidently, for whatever reasons, there is no sound body of scien- tific studies concerning these possible effects available today, a situa- tion which I regard as scandalous. If we proceed in the future as we have in the past, we will continue to stumble from one tentative and inadequately supported conclusion to another, always relying on data, which come to hand, and which were not designed for the pur- ~ The planning of better studies is difficult, and the recruitment of investigators willing to commit their efforts to these purposes may be more difficult still. I believe both are possible and essential to the public welfare. The situation has become a little better recently, but not much. One or two studies executed in the manner which appears most suit- able to those directing them will not provide us with the broad- based kind of information that we need. Appropriate studies can be generated only if a capable advisory group, proceeding in the know-ledge that its recommendations will be acted upon, can outline in some detail the work that is needed and advise on the resources available and on appropriate sources for funding and management. I speak primarily of prospective studies with concurrent and proba- Mv randomized controls. I know it has been taken as a truism that such randomization is impossible with well informed volunteers. The same was said during the planning of a field trial for the Salk polio vaccine, but it proved to be very feasible once the determination to undertake such studies was firm. Recommendations: Are there steps we can take to remedy the admittedly deplorable situation? I believe there are, and I have some views on what we should do now. 1. In view of the pressing problems of overpopulation which we face, we badly need to maximize the number of options for concep- tion control which are open to us. With respect to the potentially most serious hazards of the pill we are basically ignorant but, at least with respect to thromboembolism and cancer, the pill has not been shown to be associated with unacceptable risks. I believe it would be tragic if, on the present evidence, it were t.o be removed from the market. 2. Both as a matter of principle and as a matter of sound public health policy, the fullest possible information about what is and what is not known should be given the widest possible distribution. This includes technical information for the physician and informa- tion in understandable language for the patient. Of course, it is all too easy for such information to be given in a way which either minimizes or exaggerates its significance. Here an unavoidable ele- ment of ]udlgment comes in, but the key should be an intention to inform rather than to persuade. PAGENO="0115" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6555 3. Although I understand that the 1962 Puerto Rican study has been given up as a lost cause by its foundation supporters, I am not at all convinced that the case is hopeless. In view of the uniqueness in design and duration of this study, a federally supported review of the history and present circumstances should be undertaken with a view to possible renewed effort on it. 4. A committee including experts from Government, the academic community, and industry should be convened to consider the design of suitable short-term and long-term studies and to recommend ways in which they might be funded and carried out. It may be that the National Academy of Sciences could contribute to the process of naming a suitable committee. A commitment is needed both from the Congress and from the administration to full support for such a committee's recommendations. Without such assurances, the proposed committee would be simply one more in a long list of advisory groups which have operated in the knowledge that their advice in support of further studies was most unlikely to be acted upon. 5. A final recommendation of broader scope concerns the role of the Food and Drug Administration. It must develop the capacity to deal effectively with problems of the type before us. As it is orga- nized at present, this is an unrealistic expectation. This agency, which has so critical a role in the public interest, needs a great expansion of Federal support, both in terms of budget and in com- mitment to its role. That completes my statement. (Attachments to Dr. Meier's prepared statement follow:) THE UNIVERSITY OF CHICAGO, DEPARTMENT OF STATISTICS, Chicago, Iii., November 18, 1969. Dr. EDWIN ORTIz, Director, Division of Marketed Drugs, Bureau of Medicine, Food and Drug Administration, HEW, Washington, D.C. DEAR DR. ORTIz: I write in response to your invitation at the time of our meeting on November 4. As you recall, I discussed with you and your col- leagues sonie of the limitations which, I feel, are inherent in the interpretation of the findings in retrospective studies-in particular as these apply to the Sartwell report on the possible relationship between the use of oral contracep- tives and the occurrence of thrombo-embolic phenomena. As you know, my professional work brings me into close contact with a number of public health problems, such as the evaluation of the Diet-Heart Feasibility Study Report, and, more particularly, the study of undesirable effects following from the use of oral contraceptives in the studies undertaken by Professor George Wied of the University of Chicago. I read the British studies which provided the early evidence of the possibility of a relationship between oral contraceptives use and thrombo-embolic phenomena with great interest and with concern that the suggestive evidence provided there be fol- lowed up with more convincing studies-particularly large scale prospective studies. I came to see you at the request of Dr. William Govier of Mead Johnson. I knew Dr. Govier when he was employed at Warner-Lambert pharmaceutical Co. where I was (and am) a statistical consultant. Late in the previous week Dr. Govier called to ask if I would be willing to read the Sartwell report and send him my comments. On Friday be asked if I would be willing to be pres- ent at the Tuesday meeting. The report had been in my hands only since Sat- urday. I should add that although Dr. Govier and his colleagues evidently feel that my view is helpful to their case, I have no connection other than the one I have described with Mead Johnson and I have no special interest in their PAGENO="0116" 6556 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY position in this controversy. I have no view on what should or should not be included in the package insert for their product. I do, of course, have a view of what conclusions can reasonably be drawn from the evidence provided by the Sartwell report. Summary of my position I should say first that I think that the study reported by Sartwell and his colleagues appears to have been done with great care and thoroughness and that it appears to be representative of the best work of this kind. The report- ing is especially careful and meticulous, both in respect of the description of methods and in detailed reporting of the results. The study, standing alone, or taken together with the British studies, raises serious questions about the pos- sibility of a casual relationship between the use of oral contraceptives and thrombo-embolic phenomena. At the same time, this study is subject to the same kinds of limitations which afflict the British studies, and these limitations, which are mostly una- voidable, are of a kind which are not mitigated by replication of more studies of a similar kind. On account of the meticulous reporting in the present study it is possible to document some of these limitations from the evidence provided in the report itself. I hold that none of these reports, nor all of them taken together, can be con- sidered to provide conclusive evidence on the possibility of a casual relation- ship between the use of oral contraceptives and thrombo-embolic phenomena. Even less do they provide a satisfactory basis for discriminating degrees of risk due to different products. l~etrospective studies Before I deal with the evidence of the report itself, let me mention by way of hypothetical examples the kinds of difficulties which arise in retrospective studies. Because the population at risk is dealt with only indirectly, it is entirely possible for important subgroups of afflicted individuals to escape observation altogether, or for incidental associations between use of a drug and exceptional incidence of the affliction in some particular stratum of the population to emerge as an apparent increased risk due to the drug. It is ordi- narily far easier to recogiiize such situations in prospective studies and to cor- rect for their effects. It is frequently difficult even to recognize them in retrospective studies, and often impossible to correct for such effects, even if they can be recognized. As an example of a case in which an important segment may be entirely unavailable for observation in a retrospective study, consider an affliction which in an appreciable fraction of cases results in sudden death. A study which depends on post hospitalization interview must necessarily miss this seg- mnent entirely. If the effect of the drug is to modify such cases in a helpful way, so that they survive to be diagnosed and treated, the result of a retrospective study would be a finding of increased risk due to the drug-the exact opposite of the situation that would in fact obtain. A second example is the following. Suppose we are dealing with an illness which tends to afflict those who engage in sedentary occupations and that the drug is expensive and used for minor conditions. It might happen. then, that professional individuals would tend to have a higher frequency of drug use, and a higher incidence of the disease. In a retrospective study where occupa- tion was not one of the matching variables, the result would be to show an increased risk associated with the drug. There is, in fact, no great problem when the relevant characteristic is recognized and used as a matching variable in setting up the study. The problem is serious when, as is usually the case, there are many possible relevant variables, and matching is possible only for a few of those recognized-not to mention those of which we are unaware. Aspects of the Sartweil study-data acquisition As is clearly set forth in table 1, p. 66, over 2600 records of patients with thrombo-embolic phenomena w-ere abstracted, but over 85 per cent of these were eliminated because of possibly predisposing conditions. The report makes the valid point that the concern is with the population of subjects for whom prescription of oral contraceptives would be expected. Despite the claim, how- ever, that few women actually using oral contraceptives would be subject to PAGENO="0117" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6557 these conditions, no evidence on the point is provided. In fact, one could and, I think, should have undertaken to interview a sample of ostensibly normal women to form some estimate of the extent to which this very high level of selection might eliminate some proportion of oral contraceptive users in the population. A priori it seems likely that an appreciable fraction of ostensibly normal women might fail to pass such a test. The result of such heavy selec- tion could be serious. An inadvertent bias which might have only a minor effect were the selection less rigorous could have a profound effect when such a high rate of rejection is employed. Further unavoidable ~~lection-reducing the case-control pairs from 261 to 175-resulted from failure in some instances to obtain interviews from the case or either control. Again, it is entirely possible that availability for inter- view may be correlated with characteristics which are related to use of oral contraceptives, or to liability to thrombo-embolic phenomena. (The potential effect of such relationships could be studied from the data on the abstracts for all the abstracted cases and controls. I understand that this data can be and will be made available. I should welcome the opportunity to review it.) A final note on selection, and the possible bias which may be entailed: The report notes that among prospective controls those matching the demographic characteristics of the case in the record room index, it was sometimes neces- sary to review over 100 cases to obtain a suitable match. (see p. 50). Any inadvertent bias, say having a tendency to exclude oral contraceptive controls because of incidentally related characteristics, could be overwhelmingly magni- fied in the presence of such extreme selection as was exercised here. Unfortunately, the commendable effort to exclude all cases from non-relevant strata of the population tends to open the door to other biases of comparable magnitude. There is no ideal middle ground, and this problem is one of the inherent difficulties faced by retrospective studies. Evidence of possible bias From the careful reporting in the study itself it is possible to see evidence of relevant population strata which are not equally represented in the two groups. Table 5 (p. 70) shows the distribution of cases and controls on a number of factors which were not used as matching variables. There is some evidence that Catholics are less represented among the cases than among the controls, substantial evidence that the less well educated are likewise less represented among the cases, and marked evidence that patients connected with medical settings are better represented among the cases. If, in fact, non-Catholics, better educated, and medically connected people tend more often to be oral contraceptive users, the disproportions in these variables between cases and controls could represent a serious bias. A dramatic example of the difficulties which beset studies of this type is Provided by the situation of the student nurses (p. 60). It is concluded that such individuals are more subject to hospitalization for thrombo-embolic phe- nomena than are others, and it is suggested that there may even be an ele- vated true rate of thrombo-embolic phenomena among hospital employees who niust stay on their feet for considerable periods. One need only add the possi- bility that hospital employees may have readier access to oral conceptives than do most control patients, and the possibility for spurious association between oral contraceptives and thrombo-embolic phenomena is evident. (In fact, the number of admitted oral contraceptive users in this group was only two, and they do not contribute substantially to the evidence. The point is that there may be other more significant relationships of a similar kind. In part these may be elucidated by study of the individual case-control data). Comments on specific conclusions in the report Although most favorably impressed with the evident care and thoroughness in the conduct and reporting of this study, 1 disagree with a number of time assertions and conclusions drawn. p. 45-The report says that the retrospective approach was appropriate and criticises the prospective approach as "difficult, costly, and slow." In view of the impossibility of obtaining convincing results from more retrospective stud- ies, this affirmation seems to me misguided. Both in the fact that this method is suggested for study of possible effects on cancer incidence and in the fact that the committee makes no recommenda- PAGENO="0118" 6558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tion for further study of the problem of thrombo-embolic phenomena, I find vastly more cause for concern than is represented by the use of this method in arriving at the present position. I emphasize that the method does not approach the reliability of a well conducted prospective study and is not a suitable basis on which to draw firm conclusions in a case such as the present one. p. 49-The choice of two controls for each case is described here-the pur- pose being to have a second chance if the first control were unavailable for interview. It is a truism in sample survey practice that such substitution can often lead to highly disturbing selection biases. The rate of unavailability was non-negligible (it appears to be in the neighborhood of 20 per cent), but this potential contribution to bias is not discussed in the report. p. 53-A dozen lines are devoted to the affirmation of a difference in risk between sequentials and combinations. Prof. John Fertig has calculated an over-all chi-square for the 12 different products and gets a cu-square of about 15 (11 d.f.) which does not approach significance. The decision to group the sequentials together (15 :0) but to leave Enovid E (14 :1) with the other group requires explanation, and none is given. Without additional input to justify it, there is no evident ground from the data itself to justify this separation into the two groups presented. A description of the results, based on the data, would certainly take note of the situation of Enovid E. (Significance levels, based on selected comparisons do not have the unequivocal interpretation of those related to a single predetermined question.) p. 60-It is suggested that the possible. bias due to oral contraceptive users being more likely to be hospitalized for equally severe thrombo-einbolic plie- nomena than non oral contraceptive users is satisfactorily tested for by com- paring the situation for severe and mild cases. This is certainly one coinpari- son worth making, but it is by no means justifies a firm judgment on this point. p. 61-The issue of religion is dealt with in a short paragraph which I believe misses the major point. The point discussed is the possible effect of the correlation between pairs in religious background. No special point need be made about religion in this regard. If the matching is at all effective, many variables which were not ascertained will be similarly associated. The impor- tant point-for which this one might be mistaken-is that discrepancy in reli- gion between cases and controls-for which there is some evidence-could introduce an apparent risk where there might be none. This very serious P101)- lem is not discussed. p. 62-It is claimed here that "most of the women in the population w-ho use oral contraceptives have none of the predisposing conditions." Evidence on this point could have been obtained by additional interviews, but no evidence is given. Rather mild predisposing factors led to exclusion, and the point is an important one. p. 72-The data in table 7 are used to justify the conclusion that discontinu- ance of oral contraceptives leads to prompt elimination of risk (p 51). I have no judgment of the relative likelihood of alternatives, but it should be pointed out that table 7 is equally open to the interpretation that the physicians pre- disposition to hospitalize is higher for current oral contraceptive users than for others, but that this predisposition does not exist for those no longer using oral contraceptives. Appendia~ 2B The conclusion stated is that the vital statistics "are consistent" with an increase in thrombo-embolic phenomena among women due to use of oral con- traceptives. They are at least equally consistent with the opposite. S'urn mary In sum, I feel most strongly that the problem of risks associated with use of oral contraceptives are too important to be assessed solely by means of retrospective studies. As I suggested in the meeting on November 6 with Dr. Ley, I believe that prospective studies are feasible and should he initiated without delay. I should welcome the opportunity to contribute to the planning of such studies. Sincerely yours, PAUL MEIER, Professor of Statistics. PAGENO="0119" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6559 Senator DOLE. Dr. Meier, could you summarize the letter to Dr. Ortiz which is attached to your testimony. Dr. MElEE. Yes, I will be glad to try to do that. The critical issue is the lin'iitations of inferences that one can draw from a retrospective study. The burden of this letter is to try to bring into sharp relief the reasons for some of the limitations. Perhaps the most significant comment in the Sartwell report that led me to feel it was important to meet with the FDA people was the suggestion which I hope I can find that the retrospective study is really an ideal method for carrying out investigations of this kind. I do not find that statement. If you do, I would appreciate it. In any event, the kind of limitation that arises comes from the two sources in my direct statement, primarily from those two sources. One is that you have no opportunity to see anything about the population which did not wind up in the hospital, which did not wind up with the relative designation on the death certificate if you are doing a mortality study. Information was not gathered on these subjects with a view to evaluating the pill. It may be true as in the hospital studies that you are interviewing the patients and thus gathering information directly related, but that information is gath- ered after the event of thromboembolism and in the presence of a large body of information that pills may be implicated. In consequence, as I indicated in the direct testimony, it may very well be the case that a doctor having a patient whose symptoms might suggest thromboen'ibolic disease might be more likely to press ahead and make that diagnosis if he knew the patient were on the pill than he might otherwise be. If he is not dealing with that patient in the context of a study in which he has a regular protocol to follow in evaluating the patient, this could introduce a very serious bias. The other major limitation which comes in in considering retrospective studies is that there may well be associations which were not allowed for in the plan for the studies, and one such of small magnitude shows clearly in the Sartwell report. There were a number of student nurses who had thromboembolic disease and they had a very high rate of pill use. Well, it is not in the least surpris- ing that student nurses, (a) might be more liable to thromboembolic disease, being on their feet more than most of us are; it is not in the least surprising that they should be on the pill, because they are in the place that the pill might be more accessible. If we have any reli- ability at all for a causal mechanism for showing the relationship, it might be difficult to disentangle these. It is much more likely one will be able to see anything that is going on in any sort of prospec- tive study. As I have indicated, the only kind of satisfactory study is one in which you have concurrent control. It is the point closest to my heart that despite repeated assurances from one expert to another that it is not possible to carry out such studies in the United States, I strongly believe that it is possible to carry out such studies and that it is very important that we should do so. Senator DOLE. On page 15 of your statement, you state the pill has not been shown to be associated with unacceptable risks as far as thromboembolism and cancer is concerned. That is contrary, of course, at least in part, to some of the testimony we have had from PAGENO="0120" 6560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY some of the experts who have appeared before our committee. But again, yours is based on a statistical study of some magnitude. Can you elaborate on this one point? This is the one area where we have found some general agreement among witnesses. Dr. METER. Yes, I am sorry to disturb the general unanimity of all parties, but I must stick to my conviction that on these retrospective studies, although important, and as I say, prudence may require us to assume that they mean what they appear to mean, still for the reasons I detailed in the letter and alluded to earlier are not consid- ered by me to be convincing evidence that the relationship exists. In this statement, I have said that the pill has not been shown to be associated with unacceptable risks, and that incorporates what I have just said, that it has not in my mind been proved that the pill causes thromboembolic disease. It also embodies some assessment of judgment that I read on the part of many people that if, as has been estimated. there are three thromboembolic deaths per hundred thousand women on the pill for a year, this rate, although regretta- ble, is low compared to many other risks and comparable or lower than some risks, which we take for comparable reasons of conveni- ence, even if that risk is real, it is not necessarily an unacceptable risk. Mr. GORDON. How about the morbidity rate of one in 2,000? Wrould you consider that- Dr. METER. That certainly would have to be weighed, and here, although I have been ready to state opinions on almost everything, I must admit that I am not ready to state an opinion on that, whether that is or is not. an unacceptable risk. Mr. GORDON. Well, whether it is acceptable or unacceptable would depend on the patient, would it not? Is not the patient entitled to know that one in 2,000 women develop blood clots serious enough to be hospitalized? Dr. METER. Emphatically, as I tried to indicate in my testimony, I feel very strongly that the patient has a right to know and I would like to see further steps taken to insure that that right is accommo- dated. Senator DOLE. Thank you very much. The bell indicates that we have to go. We appreciate very much your testimony. The hearing is recessed until 9 :30 tomorrow morning in this room. (Whereupon, at 4 :15 p.m., the committee adjourned until 9 :30 a..m., Wednesday, February 25, 1970.) PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRuG IND1JSTRY (Present Status of Competition In the Pharmaceutical Industry) WEDNESDAY, FEBRUARY 25, 1970 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS Washington, D.C. The subcommittee met, pursuant to notice, at 9:45 a.m., in Room 4221, New Senate Office Building, Hon. Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson, Javits, and Dole. Also present. Benjamin Gordon, staff economist; Elaine C. Dye, clerical assistant; James P. Duffy III, minority counsel; and Denrn- son Young, Jr., associate minority counsel. Senator NELSON. The hearings will come to order, please. Our first witness this morning is Dr. Alan Guttmacher, president, Planned Parenthood/World Population; emeritus professor, Mount Sinai School of Medicine in New York City; lecturer on Maternal Health at Harvard School of Public Health, Boston; formerly clinical pro- fessor in Obstetrics and Gynecology at the College of Physicians and Surgeons, Columbia University. Dr. Guttmacher, we are very pleased that you took the time to come here this morning and give us your views. Your statement will be printed in full in the record. You may extemporize from it or present it in any way you please. If at any time you desire to add to the statement extempora- neously, feel free to do so. I assume you have no objections to questions being asked as we go along? STATEMENT OP DR. ALAN P. GUTTMACHER, PRESIDENT, PLANNED PARENTHOOD/WORLD POPULATION, NEW YORK, N.Y. Dr. GUTTMACHER. Not at all, Mr. Chairman. Senator NELSON. Very well. Dr. GUTTMACHER. Thank you very much, Mr. Chairman. I appre- ciate very much the opportunity to appear before you in these hear- ings on the birth control pill. I probably have one of the largest birth control practices in the world, since my organization in 1969 served approximately 350,000 women in 525 centers, in 130 cities of this country. I assure you that this is a responsibility which neither (6.561) PAGENO="0122" 6562 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I nor my organization, particularly the National Medical Committee and its capable medical staff, takes lightly. I assume that the primary consideration for these hearings is the health of the American female. I interpret your more specific goals to be twofold-to have potential users of the pill forewarned of its risks; and to make the medical profession more cognizant of their responsibility in its Prescription. Senator NELSON. May I interrupt for just a moment to add that one of the other stated reasons is to attempt to get knowledge and understanding of the whole issue so that we may get from Congress larger appropriations for further needed research in the field of birth control devices and family planning. Dr. GUTTMACHEIi. I applaud that, sir. Unfortunately, I assume that you share my apprehension that there have been undesirable side effects from these hearings, and as you know full well, they have created a sense of great alarm. Cer- tainly, nothing fundamentally has changed in respect to hazards from the pill since these hearings began, and well-informed physi- clans found nothing revealed by the hearings which was not pre- viously recorded in a published literature or presented at scientific meetings. The Second Report on the Oral Contraceptives, issued by the Obstetrical and Gynecological Advisory Committee of the Food and Drug Administration was published just 6 months ago. It was based on 189 references to the current literature and covered the same data covered in the January hearings of this body. In many instances these data were written by many of the wit- nesses who appeared before you. Now, I need not extol the competence of the Food and Drug Administration Advisory Committee, because I think you know full well that it was picked from the most representative and competent l)eople in this whole area. It is made up of very respected physi- cians, other scientists, and statisticians, and no doubt you know, but I would like to emphasize once more, their final statement in their recent report., which says when these potential 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. In mid-January, the American College of Obstetricians and Gyne- cologists made the statement that it "considers that the oral contra- ceptives are accepted therapeutic methods~" and they deplored the inaccurate and sensational reports concerning the drugs. At the January 28th meeting of my own very distinguished medi- cal committee, which forms the National Medical Committee of the Planned Parenthood Federation, our physicians went over the data and they came up with the report. that the committee continues to recommend the prescription of oral contraceptives. Of course, the reason I quote these authorities is not to whitewash the pill, but. I have a compelling interest to Place this matter in lroler perspective, in the hope, which I am sure you will agree with, of stemming unwarranted and dangerous alarm. The pill, in my opinion and that of my colleagues, is an important prophylaxis, perhaps the most important, against one of the gravest PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY 6563 sociomedical illnesses extant. That, of course, is unwanted preg- nancy. I would like to tally the results of unwanted pregnancy, a con- dition which is tragically common in our country. First, experts estimate that between 200,000 and 1,000,000 illegal abortions are performed each year in this country, with a death rate estimated to be 100 per 100,000 illegal operations when performed by nonmedical Persolis. I would like to add at this point that there is a large, general municipal hospital in the Harlem area of New York City, the 1-lariem Hospital. The Chief of Obstetrics and Gynecology, Dr. Donald Swartz, kindly furnished me data at my request. Like most city hospitals, the aftermath of illegal abortion has been one of their worst scourges. Dr. Swartz opened an intrauterine contraceptive clinic late in 1963 and until January 1, 1965, employed oniy the ITJD in a relatively few patients. In 1964, Harlem in the ghetto, had 3,857 deliveries and 1,291 abor- tion complications cases with five abortion deaths. With the introduction of the pill in 1965, the birth control clinic rapidly expanded and in 1969 there were 2,226 deliveries, 1,631 (42 percent) fewer than 5 years before; there were 507 abortions, 784 (61 percent) less than in 1964 and zero abortion deaths, five less than in 1964. The Harlem Hospital prescribes five methods of contraception from which each patient may choose. Sixty-seven and six-tenths per- tent preferred the pill, that is, until these hearings made headlines. I am afraid to estimate the Harlem Hospital figures for 1970, but it is fair to assume that the proportion of birth control pill users will decline acutely, abortion admissions will rise, abortion deaths will go up, and in 1971, I am sure that they will exceed the 2,226 deliveries which they had in 1969. Senator NELSON. May I interrupt, Doctor? Dr. GUTTMACHER. Yes, sir. Senator NELSON. You do not have a single statistic to support that. This is, as you stated, just your assumption? Dr. GUTTMACHER. Mr. Senator, we have noticed at Kings County; Metropolitan 1-lospital; Harlem Hospital, that when they have established an active, vital birth control clinic, the abortions in all of these institutions have gone down significantly, and in all of these clinics, the primary method of birth control which patients choose is the birth control pill. Now, it seems to me that it is not accidental that abortions have gone down among their clients. There is nothing that happened in the social picture which would change this. The thing that has changed it is a very active birth control clinic which saturates the peripheral community aroimd these great hospitals. Now, if patients depend primarily on the pill-certainly 67.6 is lower than I thought; in most of our institutions, 75 percent take the pill. To me it is pretty obvious that the pill has made a deep impact in these areas, in ghetto areas, on the horrid and undesired illegal abortions which take up so many beds and cost so many lives. Senator NELSON. I would not quarrel with that. All I am saying is that all that you have said is based upon, as you Put it, "1 PAGENO="0124" 6564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY assume" in 1970 there will be more abortions, more unwanted births. It is an assumption without a single statistic to report as of this date, is that not correct? Dr. GUTTMACHER. Well, I think it is too early to make a factual statement. I think I can create a hypothesis, but I do not think I can prove the hypothesis until the year has run out. Senator NELSON. One of the interesting things in Dr. Connell's testimony yesterday was that in one certain period, whatever it was, a week or two weeks, 118 of their patients quit the pill but went to the diaphragm. Statistics are being thrown around as though, if people quit the pill, they did not go to some other birth control device, whether it be ITJD or the diaphragm.' Dr. GUTTMACHER. I certainly would not argue the fact that some are going to. I would certainly argue the fact that all are going to. This is an assumption, again. You may not say that I can declare it as a fact. And also, we have had such rich experience with the diaphragm with the class of patients that people our great hos- pitals, we now know how relatively unsatisfactory this has been. We have had long tradition of the use of the diaphragm and I think, in certain elements of the population, it is a very effective method of contraception. But I would not say we have had uni- formly good results with the diaphragm in our clinic populations. I think I get to that a little later in my testimony, sir. Senator NELSON. I just point out that I think it is rather interest- ing that Dr. Hellman, who headed the Department of Obstetrics and Gynecology in his own clinic, stated that more people were using the ITJD than were using the pill. Dr. GUTTMACHER. Of course, that depends a great deal upon the interest of the chief of service and the research he is carrying out. He is carrying out research with the Majzlin spring device, which is one of the new IIJDs. It has been my experience that the man in charge of the clinic largely dictates the contraceptive used within that clinic. Now, as you know, they have an excellent clinic at Kings County. I know it very well, I know the people working there. But they are particularly anxious to see the merits and demerits of this particular IUD device. Senator NELSON. Is this a lower-income group? Dr. GurmIAciiER. Yes. Senator NELSON. Does it not indicate, in any event, that those who say they cannot persuade people to use the diaphragm or the IUD are refuted by the statistics of Dr. Hellman's own clinic? Dr. GIJTTMACHER. Certainly the IIJD is used by patients of the lower-income group and quite widely, in certain types of patients. May I go on, sir? Senator NELSON. Go ahead. Dr. GUTTMAcTTER. I was attempting to tally the, to me, tragic sociomedical results that occur as the aftermath of unwanted preg- nancy. I think I made my pomt. At least one out of six U.S. brides is pregnant when married; half of the brides are pregnant when the couple are teenagers. 1 See statement of Senator Nelson, p. 663S. PAGENO="0125" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6565 No less than 300,000 illegitimate children will be born in the United States during 1970, based on the experience of the past decade. A recent study shows that at least 75O,000~ children born each year were unwanted at the time of their conception. We refer to the study of Westoff and Bumpass of the Princeton group. Now, with all this evidence of social pathology associated with unwanted conception, I believe it is inaccurate to belittle the impor- tance of the contraceptive pill by stating it is a potent drug given to healthy women. What is omitted from such a statement is the fact that the pill is the most effective means yet known to prevent a very serious affliction, unwanted pregnancy. It is a serious afihiction for the parents, but far more for the children. Now, I should like to attempt to separate fact from conjecture concerning the safety of the pill. Most of this data has been pre- sented to this committee. I am strongly of the belief that the pill does cause thromboembolism. I am strongly of the belief that the British data confirmed by American studies prove to us that there are approximately three deaths per one hundred thousand pill users per year. I think that this data, to me, is completely convincing. I need not go into greater detail about the incidence of the effect of age on this and so forth, because this has all been given before this committee. On the other hand we have, of course, the risk of pregnancy which, in 100,000 women who are pregnant outweighs the risk of danger from the pill many fold. Now, it is obvious that not all women who discontinue the oral contraceptive are going to get pregnant, but since it is by all means the safest method of contraception and, from our experience, the most acceptable, I have a feeling that pregnancy is going to rise rather precipitously. Again I think the Senator would take issue with my assumption, but nevertheless I hold to that assumption. Senator NELSON. May I interrupt you? Dr. GUTTMACHER. Surely. Senator NELSON. In April, 1969, Dr. Heilman, whom you know, of course, and who directed the FDA study on obstetrics and gynecol- ogy, wrote an article in Redbook magazine, in which he said- We can say that the risk in taking the pill is less than the risk in having a baby. I suppose this is a legitimate statement. But the risk in having a baby is not the same for all individuals. A healthy young girl runs a very negligible risk, hut someone who has serious heart disease or is older, or who has hyper- tension, runs a real risk in having a baby. To say that the risk of taking the pill is less than the risk of having a baby doesn't make sense. What do you think of Dr. Heilman's statement? Dr. GUTTMAOHER. Well, I like Dr. Hellman, but I don't agree with his statement. I think you run a risk in trying to judge mortal- ity in ordinary pregnancy. Obviously the risk goes up with increas- ing parity, with increasing age; we know the figures moderately well. We know that the risk is considerably more among the economi- cally-deprived segments of the population. We have a higher mortal- ity among lower-income groups, among Puerto Ricans, among blacks- we know those facts. I unfortunately have seen death occur to an PAGENO="0126" 6566 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY obviously very healthy woman and so has Hellman. I think that that. statement does not present my point of view very accurately. I think that pregnancy, in good ha.nds-t.hat means excellent facil- ities, in a well-nourished woman who has had excellent prenatal care- carries with it a relatively minimal risk. But I think that anyone would state that if you took a thousand women-you would have to take them in terms of 100,000 women-who were so fortunate as to have this type of care, this type of nutrition, I think you would find you have a higher maternal mortality of more than 3 per 100,000. It may not be the 20 that we find in our American white population; it. may not be the 30 which we find in our American black population.. But it certainly would be a mortality higher than 3, and I think Heilman would be the first to admit this, because he knows the facts as well as I do; but whether it is eight or 12, I cannot argue that point. But I am certainly not willing to accept that mortality, even among our most preferentia.l pregnancies would be less than 3 per hundred thousand, sir. Now, in addition to the danger from thromboembolism which has~ been described to this committee on several occasions by several wit- nesses, I think that there are other dangers for the pill. I think that there are other serious adverse side reactions, or bad effects, which may occur in an occasional patient. The more common have been certainly detailed to you, such as high blood pressure, headache, depression, interference with vision,. and so on. Fortunately these serious side effects are reversible, and most dis- appear if contraceptive pills are discontinued. I certainly recognize that there are very profound metabolic changes in some patients on. the pill. I also know that there has been nothing in the literature and nothing before this committee that these changes are or will be. harmful. Senator NELSON. Is it not also true that it has not been demon- strated that they will not be harmful? Dr. GUTTMAOHER. I suppose that is true. I suppose you are asking whether these changes, if they exist long enough, will cause perma- nent deterioration of body systems. This is a possibility. I am cer- tainly not going to whitewash the pill by saying we know all the answers. We do not; just as you say in your statement that we need~ more resea.rch, I would underscore that 20 times. I agree with you. completely and utterly. There is no problem about that. Senator NELSON. On the question of the metabolic changes-I. have here a book. Dr. GUTTMACHEJ~. That is Dr. Salhanick's volume. I can see it. here. It is an excellent book. Senator NELSON. I a.lso have a pamphlet that discusses a particu-. lar oral contraceptive. The cover says, "So Close to Nature." Dr. GUTTMACIIER. "So Close to Nature," sir Senator NELSON. Yes, that is the title of the pamphlet. Dr. GuTT~IAduER. I do not think Salhanick wrote that. Senator NELSON. Oh, no; it is the pamphlet of one of the drug~ companies, explaining the use of the drug to doctors. Dr. GUTTMACIIER. I see. I was concerned- PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6567 Senator NELSON. So there it is, a slick little piece, and it says: So close to your natural feminine pattern. Your doctor has prescribed this newest kind of fertility-control tablet for you. Unlike others available for the same purpose, this preparation follows the principles and system of nature itself. Its actions closely resemble those of your natural menstrual pattern, and it works without upsetting the delicate balance of your normal body function. Would you agree with that statement? Dr. GUTTMACIIER. No, sir; I do not. Senator NELSON. This is the literature that is being given to the users, the only piece that is beii~g handed out to them, since there is no package insert. Would you think that this ought to be stopped? Dr. GUTTMACIIER. Well, of course, I have not read the whole thing, sir, but from what you have read, I do not agree. It is obviously not stating facts. These are different drugs than the nor- mal-occurring estrogens and the normal progesterone. I do not think one can say that the way you read it. I would disagree with it. Senator NELSON. The sentence at the end, "and it works without upsetting the delicate balance of your normal body function," do you agree with that? Dr. GUTTMACIIER. I would say it may work without upsetting; yes. There are some women who obviously do not have the chemical changes and some women have no side effects. But I think certainly the way it is written is inaccurate. Senator NELSON. Well, this is one of the reasons for the hearings, the fact that all the data included in the FDA-sponsored study has not been widely disseminated. Although it has been published, it does not go to the user. Instead, the information in this pamphlet is what goes to the user. This is the sort of thing being widely run in women's magazines, with an exception or two. Now, do you think that the patient who gets this, or even the doctor, is aware of the Salhanick report on "Metabolic Effects," etc.; this is the one from the workshop spon- sored by NIH. Do you think the women of America are aware of what is said there? In fact, do you think that most of the doctors-I would like the answer to both of those questions-I mean doctors who are not pro- fessionals in this field, such as you are, the gynecologic phase of it- do you think doctors are aware of what this report says? I shall read to you from it. This is the preface of the volume on page 9: Until recently the metabolic effects of the sex steroids have been inade- quately investigated or ignored. These accumulated data and others suggest that no tissue or organ system is free from a biological, functional and/or mor- phological effect of contraceptive steroids. Many of these changes appear to be reversible after short periods of treatment, but it is impossible to form judg- ments on the reversibility of some of the changes resulting from prolonged administration. This question becomes more important daily for the many patients who have already had long-term contraceptive steroid treatment. Further clown on the same page: Nevertheless, the consistency of such reports on such findings reject the pos- sibility that they are of no consequence and require that certain questions be answered. PAGENO="0128" 6568 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Does the user of the pill in America know this? Dr. GUTTMACHER. No, sir; she would not get much if she read that, either. That is the difficulty. I have been in active practice for 25 years as a private practitioner, and in addition, a full-time chief of service for 10 years. I have had contact with thousands of patients in my long medical life. Unfortunately the physician has to make the decisions for patients. You may discuss this with the patient at considerable length, and usually, when the discussion is over and you are talking about a particular therapy or operation, the Patient will look at you and say, "What shall I do ?" Now, I do not think that you are going to be able to educate the American woman as to what she should or should not do with regard to the pill. I think you can educate the American doctor. He is educatable. I think that the average doctor certainly has not read this volume of Salhanick. and I think that much of the information which is in there might be new to the American physician. I think on the other hand the American physician is a conscien- tious man. I do not think that he willfully threatens the life of his patient. I think he probably is so overwhelmed by his medical prac- tice and the normal activities of making a living that he tries to get his medical information in capsule form and he is very likely to take the particular throwaway literature which comes across the desk, not seldom, from the pharmaceutical firms. Senator NELSON. Not seldom? Dr. GUTTMACIIER. Not seldom, from the pharmaceutical firms. Now, I certainly feel that the more we can instruct the American physician about the intricacies of the birth control pill, the wiser the effort. My feeling is that when you attempt to instruct American womanhood in this, which is a pure medical matter which I am af raid she has not the background to understand, you are creating in her simply a panic reaction without much intellectual background. And this is what I think has been unfortunate. I do not accuse these hearings of any diabolical purpose, but I must say that the reaction of the American public, parading this across the news media, particularly with the news media picking out those portions which are inflammatory, have done a great deal of harm. I think educating the American physician is absolutely commend- able and important and necessary, and I think perhaps the Ameri- can physician has been remiss in not trying to educate himself about the intricacies of the pill. I feel that in our own clinics, Planned Parenthood, as I say in my testimony-but it appears at this point we ought to depart from it- I think in our own clinics we have been extremely vigilant, cer- tainly in instructing our clinicians in the United States on what is considered to be a good practice in regard to examinations, Papani- colaou smear, breast examinations, and so forth, with the pill. As you see in my testimony, we had a directive on January 26, 1966, which is more than 4 years ago, in which we stressed this to the physicians working in our clinics. PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6569 `We have tried to keep our physicians working in our clinics- there are thousands of them-intimately apprised of all of the charges made against the pill. All of the evidence-certainly any doctor working in Planned Parenthood knew about thromboemo- lism and the results of Vessey and Doll and that group. They knew it certainly within a week after publication. Now, whether one can do a similar job to the larger medical profession, I have some uncer- tainty. But I think that the committee has served a useful purpose in making the doctor more careful in regard to this and making him keep up to date with what is going on in the literature. On the other hand, I have the reaction that unfortunately the layman has tried to share this, and the layman is a terribly confused person. Senator NELSON. The literature which are distributed by the man- ufacturers of the pill read quite similarly, deemphasizing any seri- ous side effects, substantially deemphasizing them in a way which I think would be considered inaccurate. Do your clinics give out any of these? Dr. GUTTMAOHER. As far as I know, no, sir. We have our own publications in which we describe the pill, and we do go into some of the difficulties. Senator NELSON. Now, since this literature comes out to doctors' offices, and this is what the doctor is reading, I assume that if he thought it were inaccurate, he would not give it to his patients. So we have a situation in which thousands of doctors are handing out the promotional literature of the drug companies, which you agree `is not accurate. Does that not necessitate somehow or other ventilating this problem, so that the doctors themselves will become aware, so that the public and the woman who uses the pill will know that the statement I read from the pamphlet, as Dr. Guttmacher says, is an unsupportable statement? Dr. GUTTMACHER. I think it is unfortunate that in educating the doctors, you have to confuse the public. This apparently is a byproduct which seems necessary by this technique. `Whether the doctor could be educated in a way which would not expose the public to this panic and this fear reaction and distrust, I think is open to debate. Now, I am not a politician and I know nothing about running Senate hearings, but I think there is a tremendous amount of undi- gested pabulum which comes out in the daily press. I think the press is trying to be fair, but witnesses have been adverse in the main. There has been a tremendous amount that becomes terribly undi- gestible to the average layman. This is my problem, and I am sure it is your problem. I do not think you are trying to panic the Ameri- can female. Certainly, she has taken the pill for several years with tremendous satisfaction in most instances, and I think still will, until we get a better contraceptive method, and I hope that we will get a better contraceptive method through immense increase in research efforts. I think until we do, I still think the pill has a tre- mendous and very important indication, and I would hate to see 40-471 0-70-pt. 16, vol. 2-9 PAGENO="0130" 6570 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY American women in good health give up the pill simply because they do not understand what is going on here. Senator NELSON. I might say in reference to your comment about panic-I do not know whether that is the right word or not-some doctors were quoted in the paper 2 weeks after the hearings started that they were now seeing the first pregnancies from the hearings. Dr. GUTTMACHER. That is a rapid pregnancy. Senator NELSON. You have to be pretty panicky to get pregnant in 2 weeks, I think. In fact, yesterday, Dr. Connell testified, and I think it was instantly called to her attention-we heard testimony from Dr. Con- nell, a very distinguished gynecologist, who runs a clinic in New York- Dr. GUTTMACHER. Dr. Connell? I helped train her, so I think she is great. Senator NELSON. Now, we received her testimony on the 17th of February. The hearings opened on the 14th of January. Her state- ment had to come through the mail and she also had to prepare it in advance. So, in less than a month, she was able to say, "Several pregnancies ascribed to stopping the pills because of fear have been seen." So you have a situation in which doctors were supposed to have reported pregnancies before 30 days go by. Does that not give you a little pause about panic statements of the doctors themselves? Dr. GUTrMAOHER. This is a misinterpretation, I think, Mr. Sena- tor. What has happened, of course, is that there have been a tremen- dous number of scare articles in the lay literature, quite sometime before these hearings were scheduled. \Ve found that in some of our clinics, patients were not using the pill. The Margaret Sanger Research Bureau, which is one of the great institutions of the United States, noticed in 1969 a 9-percent drop in pill-users, and they have thousands of patients. This was, of course, a reflection of a lot of the scare literature which got into the Ladies Home Journal and other volumes. So I do not think Dr. Connell or anyone else is insinuating that your hear- ings have impregnated women. I think the thing which has impreg- nated women is the scare literature which anticipated your hearings by several months. I think this is the difference, sir. Senator NELSON. That is the first explanation I have heard. I sup- pose we shall get some credit for people having dropped the pill 3 years ago. Senator DOLE. Mr. Chairman, some of my own doctor friends have indicated that we might better be doing something else for the world. As a member of this committee, of course, it has been very interesting. Our own promotion of these hearings started in Decem- ber, so we have had, really, more than 30 days. There has been a great amount of publicity everywhere in Amer- ica, including my own State, Kansas, concerning the hearings and PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6571 the comments of some of the witnesses. I would suppose everyone who has appeared has been properly motivated. But on the other hand, when the headline reads, "Pill May Cause Cancer," it certainly is disquieting to the woman who may be taking the pill. Perhaps testimony such as yours, that I and others who have had practical experience with great numbers of people, can lay to rest some of the panic that has been caused and created-not, of course, purposely by the committee, but as a direct outgrowth of committee hearings. I am not certain how many babies are going to result from the hearings, but you have indicated that there is some evidence there has been a reduction in the taking of pills. It is fair to assume that some of this has resulted directly from the hearings and the reports of the hearings, but hopefully, with your testimony and the testimony next week, we can have a balanced record to present the American people. Dr. (iUTTMACEIER. Of course, I think that is very important, Sena- tor Dole, to have a balanced record. I think that the hearings have done some good, and I also think, of course, they have done a great harm. I think the great harm is done because the American woman does not know how to evaluate all this. The pill has some strong advantages in certain situations. In pre-~ marital sexual situations, the pill: is an extraordinary medicament. If we want to live with the facts of life in America, there is an extraordinary change in our sex ways, our sex mores. We know that we have to give protection to unmarried adolescents, because a preg- nancy unwanted is a tragedy in an older woman, but it is twice the tragedy in a child. This kind of thing, I think, is going to be very, very dangerous. It is interesting that Dr. Hugh Davis, who castigated the pill so severely in your hearings here, in a very interesting project which Planned Parenthood is conducting in the city of Baltimore, which Dr. Davis is responsible for, in very young teenage children giving birth control to them, some before they have had their initial sex experience, of the 40 patients whom he has served, he gave 26 the pill and 14 the ITJD. So even Davis, who seems to have great distrust for the pill, rec- ognizes that in certain indications it is a terribly important tech- nique. I think in early marriage, while couples- Senator NELSON. May I say something on that subject? This is referring to Dr. Davis. Dr. Davis' testimony was that he would pre- scribe the pill not to exceed 2 or 3 years for the specific purpose of spacing pregnancy. He would hope that they might be persuaded to use another device. So lie did not testify here that he would abolish the pill. He was for limiting the extended use of it. Dr. GUTTMACHER. I recognize this, but I should imagine these young children would have to have extended use of the pill at the age at which they start.. So despite the fact that he would like to PAGENO="0132" 6572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY carry this out, whether he is going to be able to in this group, I cannot say. Senator DOLE. Doctor, we all recognize that you indicate it is dif- ficult to inform the patient by setting forth a list of the possible risks involved. Is the pill in this respect different from any other medication? Is there anything different about the pill and hundreds of other medications? Is there anything about oral contraceptives where the problem of communication is any greater? Dr. GIJrrMACHER. I suppose not. Certainly, when it comes to aspi- rin, we know that we have gastric hemorrhages for aspirin. We have fatal cases of aspirin, even in people who are not taking a vast amount. But I feel that the pill probably is a pretty special kind of medicament. Of course, other drugs have reactions. Certainly, we know of death from penicillin, one of the most widely used drugs, or vir- tually any drug you can name. Wrhether the rate from penicillin is higher than from the pill, I cannot answer; I do not know that. On the other hand, as Senator Nelson has pointed out, this is a drug given to women who are in a state of good health. My reaction to those remarks is that this is a powerful combination of drugs given to women to prevent a most serious illness, and that is unwanted pregnancy. From my point of view, it is justified. Now, you asked me whether special things should be done in, I suppose, packaging and labeling. I have the feeling that most patients do not read what is put into their pill packages or medi- cines, and if they do, they have some difficulty understanding it. Again, my thesis goes back to the fact that your target should be the education of the American physician and that he has to take the responsibility of whether or not to prescribe the pill for Mrs. A or Miss B. This has to be his judgment. I would like to give him, equip him with all the knowledge possible so that he can make his judg- ment correctly and authoritatively. I am all for educating the American medical profession. I have rather dim enthusiasm for attempting to educate the recipients of therapy. I think that the dispenser of the therapy is the person who must be educated and not the recipient. Senator DOLE. We have an obligation to communicate the dangers to the dispenser, as you say. He should be aware, and then some- where along the line, there should be a judgment based on the doc- tor-patient relationship made whether to use the pill, or whether, after having started the pill, to drop the use of the pill. It might be well to have a copy of the information that is made available in your clinics for the record, to see how you approach the problem, what you may give the patient. Dr. G1YrTMACHER. Yes, I am sure we can furnish that. (The material above-referred to, follows:) PAGENO="0133" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 6573 A Publication of the Medical Committee of Planoed Parenthood-World Population For Professional Use Methods of Contraception in the United States C o C C C C 0 C C C C C C C C C o C 0 0 C C o C o C e C 0 C C C o o C e C c 0 * C C C C 0 0 c C C o C C 0 C C 0 0 0 0 C C C C C C o 0 0 C C C C C 0 C C * C C 0 0 C * C C C C * * C C C C * * 0 0 C o * S C 0 C * * * C 0 * * * * C C * * * * C * * * * * C * I * * S * * S * * * * * * * * * S I * I S * * * I I * * * * I * * * * S I * * * * * * * * * * * * * * * I S * * * * * * * * * * * * I * I * * * * * * S * * * * * 0 * * * * * * * S * * * * * S * * * * * * * * * * * * I * * * * * S * * * * * * * * *. * * * * * * * * * * * * * S C * * * * * * * C * * * I 0 5 I C * * * * * S S I * * * * * S C C * * I * C C C I * * * * S C C C * * S C 0 I C 0 * S * 0 0 0 0 C * * S 0 0 0 0 C * * C C C C C C * C C C C I S C * C C C I 0 C C C C C C C C C 0 C ~ C C C C C C C * C C 0 C OCC C S C C C C C 0 0 I C S 0 C C 0 C C C C 0 C 0 0 0 C 0 0 0 o a o C C C C C S C C 0 C C 0 0 C C C C C 0 0 0 C C 0 C C C C C 0 0 C 0 C C C C 0 0 0 C C C I 0 * C 0 C 0 C C C PAGENO="0134" 6574 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Planned Parenthood-World Population is a member of: American National Council for Health Education Council of National Organizations for Adult Education National Citizens Committee for the World Health Organization National Conference on Social Welfare National Health Council George N. Lindsay, Chairman Alan F. Guttmacher, M.D., President Medical Committee Seymour L. Romney, M.D., Chairman Richard D. Amelar, M.D. Richmond K. Anderson, M.D. C. Lee Buxton, M.D. Philip A. Corfman, M.D. R. Gordon Douglas, M.D. Henry L Freedman, M.D. Fritz Fuchs, M.D. John L. S. Holloman, M.D. Sherwin A. Kaufman, M.D. Sophia J. Kleegman, M.D. Kermit Krantz, M.D. Ernest W. Kulka, M.D. Vaughn C. Mason, M.D. John MacLeod, Ph.D. Rowland L. Mindlin, M.D. George J. Moore, M.D. John M. Morris, M.D. Gordon W. Perkin, M.D. Anne B. Pierson, M.D. Duncan B. Reid, M.D. Mortimer W. Rodgers, M.D. Joseph J. Rovinaky, M.D. Edward R. Schlesinger, M.D. Sheldon J. Segal, Ph.D. William A. Silverman, M.D. Aquiles J. Sobrero, M.D. Stuart Shelton Stevenson, M.D. Christopher Tietze, M.D. Winslow T. Tompkins, M.D. Samuel M. Wishik, M.D. George J. Langmyhr, M.D.. Medical Director George C. Denniston, M.D., Associate Medical Director Prepared 1965, by the following subcommittee: Robert B. Halt, M.D. Gordon W. Perkin, M.D. Arthur R. Sohval, M.D. Donald P. Swartz, M.D. Christopher Tietze, M.D. Aquiles J. Sobrero, M.D., Chairman Revised in 1968 by: George J. Langmyhr, M.D., Medical Director George C. Denniston, M.D., Associate Medical Director PAGENO="0135" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6575 Methods of Contraception In the United States Table of Contents Page 3 Criteria for Choice of Methods 3 Methods Requiring Pelvic Examination and Prescription 3 Oral Contraceptives 5 Intrauterine Devices 8 Diaphragm with Contraceptive Jelly or Cream 9 Cervical Cap 9 Methods not Requiring Pelvic Examination or Prescription 9 Condom 9 Chemical Contraceptives 9 Vaginal Foams, Jellies, Creams 10 Vaginal Foaming Tablets 10 Sponge and Foam 10 Vaginal Suppositories 10 Coitus Interruptus 10 Rhythm 11 Postcoital Douche 12 Policy Statements, Medical and Health Organizations 14 Bibliography Planned Parenthood-World Population 515 Madison Ave., New York, N.Y. 10022 PAGENO="0136" 6576 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Copyright © Planned Parenthood Federation of America, Inc. 1965, 1968 2 All Rights Reserved PAGENO="0137" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6577 Methods of Contraception in the United States Contraception is accepted by the medical profes- sion as one of the standard techniques of preven- tive medicine. (See policy statements p. 12) The methods presently used in the United States include: hormonal steroid contraception (of which oral contraceptives are the only products currently approved by the Food and Drug Admin- istration); the intrauterine devices; the diaphragm and cervical cap; the chemical contraceptives (foams, creams, jellies, foaming tablets, supposi- tories); the condom; coitus interruptus, and the rhythm or safe period technique. Contraception is differentiated here from surgical sterilization and: from induced abortion. Criteria for Choice of Methods Safety The device or product must have undergone ade- quate laboratory and clinical testing to have been proved safe for short and long-term use. Acceptability Acceptance by the patient is most important. A method of high theoretical effectiveness may fail because the patient dislikes it and uses it incon- sistently or not at all. Therefore, the physician must assess whether or not the patient is likely to employ a given method conscientiously, and should insist on adequate follow-up interviews so that he may learn whether the method is satisfac- tory for the couple. For example, if the diaphragm is to be prescribed, the physician must consider carefully such factors as the ability of the woman to use it correctly, possible hidden fears about its loss" within her body, proper choice between spermicidal jelly or cream, depending on the, pa- tient's esthetic needs and preference, her attitude regarding the amount of self-manipulation neces- sary, the probable regularity of her use of the method, and the attitude of her husband. Such factors as level of education, degree of available privacy and sanitary facilities, and basic attitudes about fertility and sexual practices undoubtedly play decisive roles in the successful use of all methods. Sensitivity to the psychological make-up of the patient and her husband as a biological unit will thus be crucial in the physician's selection of methods offered for their choice. Effectiveness Comparative figures for effectiveness of contra- ceptive methods are difficult to obtain. Some effort has been made by several investigators to differ- entiate patient failures" from "method failures." This is difficult, for the cause of failure is often im- possible to establish: semen may reach the female genitalia by post-ejaculatory spill from a condom as the flaccid penis leaves the vagina; a diaphragm that is either too small or too large may allow de- position of semen at the os; or a woman may un- intentionally omit an oral pill on several critical days of the cycle. It is likewise impossible to estab- lish or even to estimate the errors of omission that occur when couples decide not to bother with a contraceptive "just this once" and yet do not admit or even realize their responsibility for the "failure." In helping a couple to choose a method, it is most important that the method is one the couple prefers, understands and therefore uses. The fol- lowing basic principles must be borne in mind: Methods of birth control vary markedly in effec- tiveness, but the best method for any couple is the most effective method that the particular couple will use consistently. Acceptability is therefore as critical as theo- retical effectiveness in the practice of successful birth control. Best results are obtained when couples are made to feel free in their choice of methods, and free to change or to use more than one method. Methods Requiring Pelvic Examination and Prescription 1. Oral contraceptives. 2. Intrauterine devices. 3. Diaphragm with contraceptive jelly or cream. 4. Cervical cap. Oral Contraceptives (See attached product list and p. 14 for related readings.) Oral contraceptives consisting of a syn- thetic progestin combined with a small amount of an estrogen have been extensively tested over the past ten years. The attached product list indicates oral contraceptives which have received approval of the U.S. Food and Drug Administration for use as contraceptive agents. Dosage schedules vary with different products. The physician is advised to read the product brochures carefully as to administration, and advise his patient as to the specific regimen prescribed. With all oral contra- ceptives however, not a single day should be omitted, for with interrupted administration the effectiveness has been shown to drop signifi- cantly. If a daily dose is omitted it should be taken as soon as it is remembered and the next tablet taken at the regular time-even if this means taking two in one day. If a tablet is omitted on more than one day the patient should be advised to continue taking the tablets and to use another contraceptive for the remainder of the cycle. If breakthrough bleeding occurs the medica- tion should be continued for the remainder of the cycle. There is no convincing evidence that in- 3 PAGENO="0138" 6578 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY creasing the daily dose is of value in controlling the bleeding. If a menstrual period is missed com- pletely the patient must resume the medication seven days after taking the last tablet. When the oral contraceptive is discontinued it is important to advise the patient that her first menstrual period may be delayed as long as two or three weeks after the expected date. The patient should re- main accessible to medical supervision for control of any side effects. Further reductions and modifications in dos- age schedule are being introduced. One variation is sequential therapy-administration of an estro- gen alone for 15 or 16 days followed by the pro- gestin-estrogen combination for the remaining five days of the 20 or 21 day schedule. Another regi- men which consists of taking a pill every day, is now also available. Under this regimen a "com- bined" pill is taken for 21 days and a placebo for the remaining seven days. Not yet approved by the FDA for other than research in this country (but already marketed in several countries abroad) are two new methods, the so-called "minipill," consisting of a minute dose of a progestin only, and taken every day of the month and the once-a-month, and once-every- three-month injectable. The once-a-month injec- tions consist of the same estrogen-progestin combination as are contained in the combined pill, injected intramuscularly so that the ingredients are only slowly released into the system. The once- every-three-month injectables, like the minipill, consist of a progestin only. Neither of the pro- gestin-only contraceptives appears to consistently suppress ovulation in most cases. Their contra- ceptive effect is thought to depend primarily on the production of a hostile cervical mucus and effects on the endometrium. Mechanism of Action The mechanism of action of the currently approved oral contraceptives is primarily that of ovulation suppression. Other mechanisms which may con- tribute to the effectiveness of this method include an acceleration of endometrial development, alter- ation of tubal factors, and the production of a hos- tile cervical mucus. According to the World Health Organization, ". . . it seems likely that different types of compound, or even the same compound at different dose levels, may act in different ways, and that the individual compounds and their com- binations may exhibit multiple mechanisms of action. There is also evidence to suggest that the mode of action of contraceptive steroids in the first one or two cycles of use differs from that in later cycles... Inhibition of ovulation is not essen- tial to the antifertility effect of steroids. For ex- ample, the continuous administration of low doses 4 of progestogens does not consistently inhibit ovu- lation, although it offers a very high degree of pro- tection against conception. The way in which fertility is inhibited in the presence of ovulation is incompletely understood Effectiveness Taken according to instruction the combination oral contraceptives now available are virtually 100 per cent effective. The report of the Advisory Com- mittee on Obstetrics and Gynecology of the FDA, August 1, 1966, states: "The efficacy of the com- bined agent is exceptionally high. The more re- cently introduced sequential regimens are also highly effective in controlling fertility although to a slightly lesser degree. Present evidence indi- cates that the frequency of pregnancies occurring with the patients on sequential medication remain unchanged over the two and one half year period, thus supporting the contention that tolerance to or escape from the medication probably does not occur." Acceptability Clinical studies have demonstrated that patient tolerance of this method of contraception varies somewhat with the different products and dos- ages, and is also dependent upon other factors such as culture, motivation, income, and level of education. In general, the pills have been found acceptable to between 70 per cent and 90 per cent of patients. Secondary benefits of the oral method have also been reported. The menstrual cycle is regulated in practically all women and is accom- panied by a decrease in the amount of menstrual flow and an improvement, in many cases, of pre- existing dysmenorrhea. According to the 1965 National Fertility Study, conducted by Professor Charles F. Westoff of Princeton and Professor Norman B. Ryder of the Univer«=ity of Wisconsin, the overall dropout rate from the pill among all U.S. women for all reasons is about three to four per cent a month over the first three months, and one to two per cent in sub- sequent months. About 80 per cent continue with the pill for at least one year; and, the study found, some two-thirds of women who had started with the pill in 1960 were still using it five years later. Rates of discontinuance appear to be higher among women of lower educational attainment, Most who discontinue drop out because of side effects such as nausea or intermenstrual bleeding. A Population Council report indicates that about 13 million women are using oral contraception as of July, 1967, 6.5 million of them in the U.S. (repre- senting nearly one-fourth of married women of childbearing age). The report found drop-out rates for the pill considerably higher in developing coun- tries studied than in the U.S. In half the countries studied more than half of those women initially ac- PAGENO="0139" discontinue the use of the pill should thrombo- phlebitis, cerebro-vascular disorders, pulmonary embolism or retinal thrombosis occur or be suspected. Masculinization of the female fetus causing partial fusion of the labia and/or hypertrophy of the clitoris has been observed in cases where pro- gestins were given in large doses during preg- nancy for the purpose of preventing threatened Side Effects abortion. No fetal masculinization has been re- The most common side effects include nausea, ported resulting from the contraceptive use of break-through bleeding, weight gain, headache, these compounds. bloating and breast tenderness. These side effects generally disappear by the fourth cycle and ap- Intrauterine Devices pear to be significantly reduced with the lower (See attached product list and p. 15 for related doses of the compounds currently available, Fer- readings.) The recent development (1959) of new tility is promptly restored following cessation of intrauterine devices has reawakened medical in- the medication. No causal relationship between :terest in this method of conception control. the current oral contraceptives and any type of The early intrauterine devices, such as the malignancy has been reported. However, the Grafenberg ring, fell into disrepute because of the World Health Organization declares it is accepted fear of complications. The development of new practice to withhold oral contraceptives contain- and relatively inert materials such as plastic and ing estrogen from pre-menopausal women with stainless steel along with the urgent need for a diagnosed breast cancer. simple, inexpensive, effective method to prevent Because in occasional cases pre-existing conception, independent of coitus and not requir- fibromyomata have been observed to enlarge dur- ing sustained motivation, was responsible for the ing administration of these drugs, the medical revival of interest. Intrauterine devices have re- Committee of Planned Parenthood Federation of ceived the most careful and extensive clinical America has recommended that pelvic examina- evaluation of any contraceptive method to date. tion be done before the initiation of treatment and Statistics from the National Committee on Mater- again six months later. nal Health are currently available for over 27,600 The question of a possible causal relation- women with a record of use in excess of 477,000 ship between the use of oral contraceptives and; woman-months. On the basis of these results the the occurrence of thrombo-embolic phenomena Medical Committee of Planned Parenthood Fed- has been raised. Three recent responsible British eration has found the present "open" devices are studies have shown a slight increase in thrombo- both safe and highly effective. embolic accidents and fatalities among users of oral contraceptives. In one of these British studies it was found that the risk of incurring thrombo- embolic disease was increased nine times for pill users from five per 100,000 to 47 per 100,000. An- other study found that the risk of mortality from pulmonary embolism or cerebral thrombosis among women 20-34 increased from 2 per mil- lion to 15 per million. Among the age group of 35-45, however, the risk is increased from 5 per million to 39 per million. The World Health Organi- zation, taking note of these studies, points out that the risk among pill users of incurring thrombo- embolic disease, or dying from it, "appears to be small in comparison to the overall risk incurred by planned and unplanned pregnancy." Nevertheless, the World Health Organization cautions that a his- tory of thrombo-eThbolic disease should be con- sidered "a contraindication to the use of steroid contraceptives," and the Food and Drug Adminis- tration recently required that all Pill manufacturers revise their labeling so as to inform U.S. physi- cians of the British findings, and advise them to COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6579 cepting the pills discontinued by the end of the sixth cycle and the mean of continuance after one year is 68 per cent. Acceptance rates vary enor- mously from country to country; in Ceylon, a study found 76 per cent continuing after a year, and in Bombay over 71 per cent. These were roughly the same continuation rates reported from developed countries. Insertion Insertion of the plastic and some stainless steel devices into the uterine cavity is accomplished by loading the device into a slender plastic tube which is then introduced through the cervix. A plunger is inserted into the tube and the device is pushed into the uterine cavity. The tube is with- drawn, leaving the device in the uterus, where it rapidly resumes its preinsertion shape. The stain- less steel ring is inserted by being stretched over a forked instrument. With most patients cervical dilation is not required for insertion of either the plastic or stainless steel devices. [Osertion during the last one or two days of a menstrual period is preferred because introduction is easier at this time, an existing pregnancy is not threatened, and post-insertion spotting, which occurs in a signifi- cant percentage of patients, is less likely to alarm the patient. Another favorite time for insertion is at the post partum examination, It was previously be- lieved that intrauterine contraception was more suitable forthe parous than the nulliparous women. 5 PAGENO="0140" 6580 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 0 Hall-Stone Ring Closed device, not generally recommended Gynecoil New design, not widely tested Old design, with beads, not generally recommended Birnberg Bow New open design, not widely tested Birnberg Bow Closed design, not generally recommended PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRuG INDTJSTRY 6581 New evidence suggests that unless the woman ex- general, therefore, the closed devices can no periences pain or syncope in the first day after longer be recommended. If perforation is known insertion, and must have it removed, devices can to have occurred with a closed device, the device be used with equal success in the nulliparous. should be surgically removed without delay. If per- All patients should receive a complete pelvic foration occurs with an open device, removal will examination, including visual inspection of the depend on the judgement of the attending physi- cervix, and a Papanicolaou smear prior to inser- cian, after consultation with the patient. tion of an intrauterine device. Where pelvic dis- In no instance has the IUD been shown to ease is suspected or diagnosed, patients should produce a neoplasm in either the cervix or the be referred for definitive diagnosis and treatment. endometrium of women, and available reports n- Early examination following the first or second dicate no effect of the device on the course of menstrual flow after insertion offers the best : preexisting dysplasia. chance of detecting an expulsion not noticed by If pregnancy occurs with the intrauterine de- the patient before pregnancy has occurred. Good vice in situ, and proceeds to full term, the device medical practice requires that all women be seen is found to be outside the membranes or occa- annually for a complete pelvic examination and: sionally beneath the placenta. The limited num- Pap smear. bers of infants so far available for study do not have a greater than expected incidence of pre- Side Effects maturity or malformations. Chief among the minor side effects of intrauterine On the few occasions when pregnancy does devices are irregular bleeding and uterine cramps occur with the device in place, ectopic gestation or pelvic pain. They occur commonly during the occurs about once in 20 pregnancies. Although first two or three months after insertion and tend this ratio is 10 times the normal rate, it is attributed to disappear with continued use. to the relatively greater reduction in the number More serious is the occurrence or recru- of intrauterine pregnancies. In other words, IUDs descence of pelvic inflammatory disease (PID). prevent intrauterine pregnancies more effectively The incidence of PID in women using IUDs has than they prevent ectopic pregnancies. been reported to be about 2.5 per cent during the first year, falling to about 1.5 per cent during the second. The rates are highest during the first month after insertion. An advisory committee of the Food and Drug Administration believes that even this low rate of infection can be reduced by use of sterile pre-packaged devices with dispos- able inserters. The use of pre-packaged, sterile devices is recommended. If these are not used, it is recommended that a 1:2500 solution of aqueous iodine be used. (2 cc tincture of iodine, USP. In 100 cc water, soak for 5-10 minutes; if Betadine is used, 1.5 cc in 100 cc water.) There are also indi- cations that antiseptic cleansing of the vagina and cervix reduces infection. Acute or subacute pelvic inflammatory disease, however, is considered a contraindication, as are large fibroids, especially those causing distortion of the uterine cavity. Perforation of the uterus following insertion is extremely uncommon and often unnoticed by the physician. Its incidence, from 1 to 4 per 10,000 insertions, is probably the result of trauma caused by the introducer during insertion. The FDA be- lieves that the incidence of perforation can be re- duced by careful sounding of the uterus before insertion to ascertain the depth and directiąn of the uterine cavity, and by routine use of a tenacu- Ium to maintain the uterus relatively straight. With the closed devices there have been reports of in- testinal obstruction following perforation. Perfora- tion of the uterus with intestinal obstruction has not been reported, however, with open devices. In Mechanism of Action The exact mechanism of action of the intrauterine devices in humans is yet to be determined. IUDs have an anti-fertility effect in every animal that has been tested, but the mechanism is different in dif- ferent species. It is thought that the action takes place sometime between ovulation and implanta- tion. The suggestion that the device acts in hu- mans by increasing tubal motility has not been proven, according to the FDA, but needs further study and confirmation. Effectiveness In terms of use effectiveness in clinic patients the IUDs have proved far more reliable than the tra- ditional methods of contraception and slightly less reliable than the oral compounds. Theoretically, however, the IUDs are less reliable than oral con- traceptives given according to the combined or the sequential regimen, and are probably not more effective than the diaphragm or condom, if the conventional forms of contraception are used cor- rectly by highly motivated patients. Unlike other forms of contraception, however, the IUD5 use- effectiveness approaches theoretical effective- ness, since the method requires neither daily nor periodic medication nor any manipulation before, during or after intercourse. The FDA points out that the careful woman can, however, increase her chances of protection by inspecting her menstrual pads or tampons to see whether the device has 7 PAGENO="0142" 6582 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY been expelled; or, if the device has a transcervical appendage, by examining herself periodically. In the United States the most successful IUD5 are associated with a pregnancy rate of from 1.5 to 3.0 per 100 women during the first year of use. These rates tend to decline during the suc- cessive years and in general the rates vary in- versely with the size of the device and with the age of the patient. Acceptability Among clinic patients in the United States the FDA finds that rates of continuation have been much higher for the IUD5 than for traditional contracep- tive methods. Experience of family planning pro- grams in developing countries has been similar. Fragmentary evidence suggests that in the lowest socioeconomic group with the most minimal edu- cation, rates of continuation are higher with IUD5 than with the oral compounds. But adequate infor- mation comparing rates of continuation of lUDs with oral compounds for non-clinic patients is unavailable. About 80 per cent of women will continue to use lUDs for the first year after insertion; 70 per cent for the second year and, from limited data available, about 50 per cent of women are still using the IUD at the end of the fifth year. The inci- dence of involuntary expulsion varies widely among different types of IUD5. The great majority of expulsions occurs in the first year of use; about one half of the total within four months after inser- tion. More devices seem to be expelled with the menstrual flow than at any other time, If an IUD is re-inserted after an expulsion the chance of re- expulsion is two or three times as high as the chance of expulsion after the first insertion of the same type of IUD. Nevertheless, about one half of all women who experience a first expulsion even- tually retain the device after one or more re-inser- tions. Expulsion rates for all types of IUDs tend to decline steeply with increasing age of the woman and less steeply with parity. Expulsion rates are very high following insertion during the first few days after childbirth. They are lower following in- sertion five to 12 weeks after childbirth and the lowest following insertion at three months or later. For all lUDs, voluntary removal at either the doc- for's or the wearer's initiative, is the most impor- tant cause of discontinuation and may exceed the combined effect of pregnancies and expulsions at a ratio of 2 to 1 or more. The most common rea- sons for removal are bleeding and pelvic pain and account for about 60 per cent of all removals, ex- cluding those for planned pregnancies. Like the expulsion rate, the removal rate is highest in the first month after insertion. Some 6-8 million of these devices are now in 8 use, perhaps one million in the U.S. As results are confirmed, it is likely that contraception with the intrauterine device will assume even more impor- tance in the future. Diaphragm with Contraceptive Jelly or Cream (See attached product list and p. 16 for related readings.) The medical profession has found the diaphragm and jelly/cream method very effective among intelligent and highly motivated patients. However, in many population groups a disturbing proportion of users of the diaphragm is known to abandon this method rapidly. The appropriate size and type of diaphragm (supplied commercially in various types from 60 to 105 mm. in diameter) must be selected by trial fitting during pelvic examina- tion. The diaphragm when properly in place lodges in the posterior vaginal fornix, completely covers the cervix, and fits snugly behind the pubic sym- physis. The largest size which can be worn com- fortably and is unnoticed by husband and wife should be prescribed. Various types are available, some of which are more effectively held in place in the presence of a cystocoele or mild prolapse. The size and type of diaphragm needed may change following delivery, pelvic surgery, weight gain or loss, and particularly after the honeymoon period. Once the appropriate size has been deter- mined, it is essential that the patient be instructed carefully in the method of insertion and be given an opportunity to demonstrate her proficiency during this instruction period. Effectiveness The diaphragm, used in combination with jelly or cream, offers a high level of protection, although occasional method failures may result from im- proper placement or displacement during coitus. A rate of 2-3 pregnancies per 100 women per year would seem to be a generous estimate for "per- fect users." If motivation is poor, much higher pregnancy rates should be expected. Patient Instructions Approximately one teaspoonful (5 ml.) of a contra- ceptive cream or jelly (see attached product list) shoulrf be placed on either side of the diaphragm; some is spread around the rim, and the diaphragm inserted with the cream or jelly side uppermost, The diaphragm may be inserted up to six hours prior to intercourse and may be left in place for as long as twenty-four hours, It must remain in place at least six hours following the last ejaculation. Douching should not be permitted during this in- terval. If intercourse is repeated, the diaphragm should not be removed, but additional cream or jelly should be inserted vaginally prior to each coitus. The patient may go to the toilet at any time, The diaphragm is easily removed by hooking the PAGENO="0143" finger behind the symphysis, grasping the dia- phragm and withdrawing it. At removal, douching is unnecessary. The diaphragm should be washed in warm, soapy water, dried, powdered with corn starch, and kept in a closed container. Periodic checking of the condition of the diaphragm by holding it to a light is recommended. With care the diaphragm may be used for several years without replacement. Cervical Cap (See attached product list and p. 16 for related readings.) The cervical cap is a method widely and successfully used in Great Britain and Central Europe, but less well known in the United States. It may be used in a manner similar to the dia- phragm; those made of plastic may be left in place for several days or even for the entire intermen- strual period, in which case renewal of the chemi- cal contraceptive is unnecessary and douching is undesirable. Studies have shown that the cervical cap has a use-effectiveness rate in the same range as that of the diaphragm and that this effective- ness in all probability relates more directly to the mechanical barrier of the cap itself than to the spermicidal action of the product used with it. Some physicians think the effectiveness of the cervical cap may be lowered by the possibility of displacement, but this rarely occurs when pa- tients are carefully and properly chosen for this method. In any event, the woman should be in- structed to feel for the position of the cap before intercourse. It is essential with the cervical cap, as with the diaphragm, that the patient be thoroughly trained in the technique of insertion and removal. Methods Not Requiring Pelvic Examination or Prescription 1. Condom. 2. Chemical contraceptives. a. vaginal foams, jellies, creams alone. b. vaginal foaming tablets. c. sponge and foam. d. vaginal suppositories. 3. Coitus interruptus. 4. Rhythm. 5. Postcoital douche. Large-scale distribution of simple contraceptive methods may be made pdssible only with elimina- tion of the pelvic examination. The Medical Com- mittee of Planned Parenthood Federation of America nevertheless recommends that a yearly pelvic examination, including a Papanicolaou smear, be done on every adult female whenever feasible. Condom (See attached product list and p. 16 for related reading.) The condom, rolled over the erect penis, is ordinarily highly effective without the use of additional chemical contraceptives. Certain couples, however, demand a more absolute sense of security. For such couples it is recommended that, in addition to the consistent use of the condom by the man, the woman should, prior to intercourse, place an applicator filled with jelly, cream or foam (see attached product list) :in the vagina. A contraceptive cream, jelly or foam is not only useful for vaginal lubrication where such is necessary, but in case of breakage or slip- ping of the condom, it eliminates the necessity for a douche. Chemical Contraceptives (See attached product list and p. 16 for related reading.) Laboratory Testing The Fertility Research Laboratory of the Margaret Sanger Research Bureau in New York, official test- ing center of the Planned Parenthood Federation of America, conducts a spermicidal testing pro- gram on all vaginal chemical contraceptive prod- ucts manufactured in the U.S.A. For the laboratory assessment of the effi- cacy of chemical topical contraceptives, the Eval- uation Subcommittee of the International Planned Parenthood Federation has evolved a test for spermicidal action in vitro. Known dilutions of the contraceptive product are mixed with human semen of excellent quality, and the time required for immobilization of the sperm is measured. It is universally agreed that an in vitro test of spermicidsl effectiveness is no substitute for clini- cal experience, but many factors have militated against adequate clinical testing of vaginal con- traceptive products. These include the mobility of the American population, and the reluctance of physicians to place their patients at possible risk of pregnancy. Vaginal Foams, Jellies, Creams Alone These are introduced into the vagina by means of a plastic applicator. After being filled from the container, the applicator is inserted to the depth of the vagina and its contents expelled. The vagi- nal foam is associated with minimal complaints of messiness and has a high acceptance. Insertion may be performed within an hour prior to coitus. If a longer period elapses or coitus is repeated, an additional applicatorful should be introduced. Douching is forbidden until six hours following the last coitus, although the patient may go to the toilet at any time in the interval. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6583 9 PAGENO="0144" 6584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Vaginal Foaming Tablets Vaginal foaming tablets are presently used exten- sively outside of the United States and occasion- ally in this country. Because of their simplicity and low cost they are suitable for mass distribution. A rather common complaint is persistent burning following insertion due to the foaming action. Their use is simple: a tablet is slightly moistened with water or saliva and inserted deep into the vagina not less than five minutes nor more than one hour before coitus. If more than one hour has elapsed before coitus, a second tablet should be used; another tablet should be used before each subsequent coitus. Douching is prohibited until six hours after coitus. The patient may go to the toilet at any time. Although the foaming action is initi- ated upon moistening and insertion, the tablet is not completely dissolved until ejaculation, when the foam generated releases the spermicidal in- gredients. To protect from atmospheric moisture, vials of foam tablets must be kept tightly stop- pered. After prolonged storage a tablet should be tested by dipping in water. Foaming action can be seen and heard if the tablet is fresh. Sponge and Foam This method is one of the simplest and least ex- pensive and, because of its simplicity, is highly acceptable to certain population groups. A syn- thetic or natural sponge of convenient size (i.e., 2 inches square by 3/~ inch thick) is moistened and partially squeezed out, then a spermicidal foam liquid or foam powder is worked into it until a foam is formed. The sponge is then pushed high into the vagina to be left in place until six hours after intercourse. Douching should not be permit- ted until the sponge has been withdrawn. Vaginal Suppositories These are widely available and probably rank with the vaginal foaming tablets in effectiveness, al- though studies of this method are not numerous. Suppositories are removed from the foil wrapping and inserted into the vagina without moistening a few minutes before intercourse, and otherwise used in the same manner as vaginal foaming tab- lets. Their stability may be affected in hot cli- mates, but if packed individually in stiff, shaped foil they may be re-solidified by cooling if liquefied before use. Patients should be warned that sup- positories advertised and sold "for feminine hy- giene" may not be effective for contraception. Effectiveness of Chemical Contraceptives The effectiveness of chemical contraceptives used alone is believed to be lower than that of the dia- phragm used with a chemical, or the condom. Nevertheless, significant reductions in pregnancy 10 rates may be obtained by the use of these simple methods. Among the various forms of chemical contraceptives the vaginal foams appear to be most effective, followed by the jellies and creams. Foaming tablets and suppositories are less effec- tive. No statement can be made on the sponge- and-foam method. Coitus Interruptus (See p. 16 for related reading.) This is an ancient technique. It has particular advantages: it requires no devices or chemicals, and is thus available under all circumslances and at no cost. The couple proceeds with coitus in any manner ac- ceptable to both partners until the moment of ejaculation, when the male withdraws so that emission takes place completely away from the vagina or the external genitalia. Most couples using this method are able to develop their own technique so that the woman as well as the man derives full satisfaction. Some couples are unable to use coitus interruptus at all; others find it en- tirely satisfactory and preferable. Studies showing adverse effects among users are lacking. Effectiveness While coitus interruptus has been responsible for many failures of family planning, it is also the principal method by which the historical decline of the birthrate in Western Europe was achieved from the late 18th Century onward. Statistical studies suggest a level of effectiveness similar to that associated with mechanical and chemical methods. But should ejaculation begin before with- drawal, the possibility of pregnancy is as great or greater than if no birth control method was used, since the early part of the ejaculate contains the greatest concentration of active spermatazoa. Phy- sicians will rarely have occasion to recommend coitus interruptus, but if the method has been practiced successfully for a number of years, with full sexual satisfaction for husband and wife, it would be unwise to insist on a change. For occa- sional use when other methods are not available it has its unquestioned place. Rhythm (See p. 16 for related reading.) Rhythm, also called "temporary abstinence" or "periodic continence," is the only method besides total continence pres- ently accepted by the Roman Catholic Church and some other Churches as licit for the regulation of conception. According to Ogino, the first poten- tially fertile day is determihed by subtracting 18 from the number of days in the shortest menstrual cycle observed during a period of one year, and the last fertile day by subtracting 11 days from the longest menstrual cycle. If, for example, a woman has observed cycles ranging from 26 to 29 days, her potentially fertile period (period of abstinence) PAGENO="0145" COMPETITIVE PROBLEMS: IN THE DRUG INDUSTRY 6585 will extend from the 8th day (26 minus 18) through Effectiveness the 18th day (29 minus 11). Correctly taught, correctly understood, and cor- Because very few women have absolutely : rectly practiced, the effectiveness of the rhythm regular menstrual cycles and most women do not : method may be comparable to that of mechanical remember their irregularities, the computation of : and chemical contraceptives, especially if women the fertile and infertile days of each cycle should with grossly irregular menstrual cycles are ex- be made from a written record of menstrual cycles cluded. However, such successful use implies preferably extending over at least a year. If the: periods of abstinence longer than most couples rhythm method is prescribed on the basis of a find acceptable. Self-taught "rhythm," haphaz- menstrual record kept for a period shorter than ardly practiced, is one of the most ineffective one year, the fertile period should be calculated methods of family planning. According to the according to the complete details provided in The World Health Organization, pregnancy rates range Safe Period booklet (see page 17). It is not advis- from 0.8-1.4 per 100 women-years for women using able to estimate the fertile period on the basis of basal body temperature alone; 3.2-8.0 per 100 the patient's statements concerning her menstrual women-years for women using basal body tem- cycles without a written record, especially if she perature plus calendar, and 14-40 per 100 women- claims "perfectly regular" cycles. years for women using the calendar method only. According to the World Health Organization, bio- BBT Method logical variation, failure to understand the method, The use of a basal body temperature (BBT) chart and unwillingness to abstain from coitus all con- may be useful to the woman who is sufficiently tribute to failures. The lowest pregnancy rates, of motivated to learn how to take a truly basal tern- course, are obtainable only by intelligent, highly perature (immediately on awakening before any motivated women. activity whatsoever), and to interpret the chart correctly. A drop in temperature followed by a rise Postcoital Douche (usually around 0.7~F.) indicates that ovulation has (See p. 16 for related reading.) The postcoital occurred. It is not known whether ovulation takes douche is considered to be a poor method of con- place just before or at the time of this rise in tem- traception because sperm enter the cervical canal perature. The higher level is then maintained for within seconds after ejaculation. Statistical studies the remainder of the cycle, and sexual relations have confirmed this low level of effectiveness. The may safely be resumed on the evening of the third only value of the douche is in an emergency, such day of sustained higher temperature. One must as following the breaking or slipping of a condom. make sure, however, that the woman understands what her basal body temperature is. Any slight in- disposition makes it unreliable to depend upon this method since even a mild upper respiratory illness can cause a slight rise that might be mis- interpreted as the post-ovulatory rise. The temperature record can be used to indi- cate only the end of sexual abstinence; it cannot be used to determine when the period of absti- nence should begin. To calculate when abstinence should start, the woman should refer to her short- est cycle figure minus 18. On that day, when absti- nence begins, she should begin also to take her temperature on awakening and carefully record it each day until relations are resumed on the third day of higher temperature. For those couples who want minimal risk of pregnancy, or for women whose menses are too short or too irregular, total abstinence may be advisable from the beginning of menses until the third day of higher temperature. The presently available methods Uf deter- mining the time of ovulation by means of Ohemical tapes have not proven reliable. While not generally accepted, chloride determination of the cervical mucus has been advocated by some wOrkers for women whose BBT curve is abnormal. 11 40-471 0-70--pt. 16-vol. 2-10 PAGENO="0146" 6586 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Policy Statements of Medical and Health Organizations World Health Organization Health Aspects of Population Dynamics, 1968 The Twenty-first World Health Assembly, having considered the report of the Director-General on health aspects of population dynamics; Noting with satisfaction the development of activ- ities in reference services, research, and training, and the provision of advisory services to Member States, on request, on the health aspects of human reproduction, of family planning, and of popula- tion dynamics... Emphasizing the concept that this programme requires the consideration of eco- nomic, social, cultural, psychological, and health factors in their proper perspective... Recognizing that family planning is viewed by many Member States as an important component of basic health services, particularly of maternal and child health and in the promotion of family health and plays a role in social and economic development; Reiterating the opinion that every family should have the opportunity of obtaining information and advice on problems connected with family plan- ning including fertility and sterility; Agreeing that our understanding of numerous problems related to the health aspects of human reproduction, family planning and population is still limited . . .Requests the Director-General (a) to continue to develop the programme in this field. ..including also the encouragement of re- search on psychological factors related to health aspects of reproduction; (b) to continue to assist Member States upon their request in the development of their programmes with special reference to: the integration of family planning within basic health services without prejudice to the preventive and curative activities which normally are the re- sponsibility of those services; appropriate training programmes for health pro- fessionals at all levels; (c) to analyse further the health manpower re- quirements for such services and the supervision and training needs of such manpower in actual 12 field situations under specific local conditions... American Medical Association Policy on Human Reproduction, Including Population Control, 1964 The Board recommends adoption of the follow- ing four-point statement of policy: 1. An intelligent recognition of the problems that relate to human reproduction, including the need for population control, is more than a matter of responsible parenthood; it is a matter of respon- sible medical practice. 2. The medical profession should accept a major responsibility in matters related to human repro- duction as they affect the total population and the individual family. 3. In discharging this responsibility physicians must be prepared to provide counsel and guidance when the needs of their patients require it or refer the patients to appropriate persons. 4. The A.M.A. shall take the responsibility for dis- seminating information to physicians on all phases of human reproduction, including sexual behavior, by whatever means are appropriate. Policy on Dissemination of Birth Control Information at Tax-Supported Institutions There should be no restraints on the physician concerning the dissemination of birth control in- formation, and, as with other forms of quality medical care, such information should be equally available to both private and clinic patients. It is recognized, however, that in some areas restraints do exist for both physicians as purveyors and patients as recipients of such information... It is recommended that the prescription of child-spacing measures should be made avail- able to all patients who require them, consistent with their creed and mores, whether they obtain their medical care through physicians or tax or community-supported health services... American Academy of Pediatrics Policy Statement on Family Planning, 1965 The American Academy of Pediatrics recognizes that an intelligent program of total health care of children should include considerations of family PAGENO="0147" planning. Pediatricians should become informed about the social, health and demographic prob- lems associated with prolific child bearing. They should work with parents and with teachers in edu- cational activities designed to give young people a proper sense of responsibility about sexual mat- ters, marriage and parenthood. When the needs of their patients require it, pediatricians should be prepared to discuss conception control in a man- ner consistent with the creed and mores of the individuals concerned, or to refer their patients to appropriate persons for such advice. The Ameri- can Academy of Pediatrics further believes that federal, state and local governments should in- clude family planning as a part of their health programs. American Public Health Association Policy Statement on Population, 1964 In the United States, an increasing number of official health and welfare agencies have instituted programs of family planning to reduce the inci- dence of unwanted pregnancies, illegal abortions and maternal and perinatal mortality and morbid- ity. Governing bodies, from the Congress of the United States to town councils, have voted to make family planning information and services available, but millions of Americans are still denied such help as a part of the health or welfare services pro- vided them for tax funds. Although both tax and private funds are sup- porting research on reproduction related to birth and population control and remarkable advances in contraceptive technology are emerging, the National Academy of Sciences has clearly indi- cated how great are the unmet needs in research and training. Governments of developing nations are offi- cially recognizing rapid population growth as a serious deterrent to improved well-being of their people. Increasingly, they are adopting national policies and initiating national programs of family planning. To implement these programs, many seek technical assistance which remains difficult to obtain from governmental sources. These events call for added leadership by the public health profession in understanding act- ing upon public health implications of rapid popu- lation growth. The American Public Health Asso- ciation, therefore, believes it important to reaffirm its 1959 policy statement, dedicates itself to inten- sified study and action on population problems and urges that: 1. Federal, state, and local governments in the United States include family planning as an integ- ral part of their health programs, make sufficient funds and personnel available for this purpose, and insure such freedom of choice of methods that persons of all faiths have equal opportunities to exercise their choice without offense to their consciences. 2. Federal and state governments, foundations, universities, and other research institutions give higher priority to the need for more research and training on all aspects of population problems. 3. The United States expand its technical assist- ance in population programs to those nations re- questing it and urge efforts by the World Health Organization and other appropriate international agencies to do likewise. American Nurses' Association Statement on Family Planning, 1966 .The American Nurses' Association, the pro- fessional organization of nurses concerned with the health and welfare of individuals and families, feels that it is the responsibility of all registered nurses: 1. To recognize the right of individuals and fami- lies to select and use such methods for family planning as are consistent with their own creed and mores 2. To recognize the right of individuals and fami- lies to receive information about family planning if they wish 3. To be responsive to the need for family planning 4. To be knowledgeable about state laws regard- ing family planning and the resources available 5. To assist in informing individuals and fami- lies of the existence of approved family planning resources 6. To assist in directing individuals and families to sources of such aid. Because nurses have a real and enduring interest in the well-being of people, the American Nurses' Association endorses efforts to promote under- standing of family planning methods and supports positive and realistic programs designed to cope with the implications of unchecked population growth. COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6587 13 PAGENO="0148" 6588 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY Bibliography Textbooks 1. Calderone, M. S. (ed.) Manual of Contraceptive Prac- tice. Baltimore: Williams & Wilkins, 1964, pp. xxi, 295. 2. International Planned Parenthood Federation. Medi- cal Handbook, Contraception, 2nd ed. 1965. General 3. AmerIcan Association of Planned Parenthood Physi- cians, Advances in Planned Parenthood, Vol. It, Pro- ceedings of the Third and Fourth Annual Meetings of the AAPPP, Chicago, Ill. May 1965 and Denver, Cob., April 1966. Excerpts Medica Foundation International Congress Series No. 138, 1967. 4. AmerIcan Association of Planned Parenthood Physt. clans. Advances in Planned Parenthood, Vol. lIt, Pro- ceedings of the Fifth Annual Meeting of the AAPPP, Atlanta, Ga., April 1967, Excerpts Medics Foundation International Congress Series No, 156, 1968. 5. Eastman, N. J. "Current trends in population control," Fertility and Sterility, 15:477-484, Sept.-Oct. 1964. 6. Hlmes, N. E. Medical History of Contraception. New York: Gamut Press, 1963, pp. liii, 521. 7. Houghton, V. "International Planned Parenthood Fed- eration: its History and Influence." Eugenics Review, 53:149-153, Oct. 1961 and 53:201-207, Jan. 1962. 8. InternatIonal Planned Parenthood Federation. Pro- ceedings of the Seventh Conference, 10-16 February 1963, Singapore. Amsterdam: Excerpts Medics Interns- lionat Congress Series No. 72, pp. 748. 9. InternatIonal Planned Parenthood Federation. Pro- cedlngs of the Eighth International Conference, 9-15 April 1967, Chile, 10. Johnson, V. E., Masters, W. H. "Intravsginst Contra- ceptive Study: Phase I. Anatomy," Western Journal of Surgery, Obstetrics and Gynecology, 70:202-207, July- Aug. 1962. 11. Johnson, V. E., Masters, W. H. "Intravaginal Contra- ceptive Study: Phase It. Physiology," Western Journal of Surgery, Obstetrics and Gynecology, 71:144-153, May- June 1963. 12. Klser, CV. (ed.) Research in Family Planning, Prince- ton: Princeton University Press, 1962, pp. xv, 662. 13. Potter, R. G., Sage, P. C., Westoff, C. F. "Some Ne- glected Factors Pertaining to Fertility Control," Fertility 14 and Sterility, 13:259-264, May-June 1962. 14. RaInwater, L And the Poor Get Children: Sex, Con- traception and Family Planning in the Working Class. Chicago: Quadrangle Books, 1960. 15. Rock, J. The Time Has Come. New York: Alfred A. Knopt, 1963, pp. xvi, 204, xii. 16. Sptvack, S.S. "The Doctor's Role in Family Planning," Journal of the American Medical Association, 188:152- 156, 13 Apr. 1964. 17. Tietze, C. (ed.) Selected Bibliography of Contracep- tion: 1940-1960. New York: National Committee on Ma- ternal Health, Inc., 1960, pp. iv, 76. 18. Tietze, C. (ed.) Selected Bibliography of Contracep- tion Supplement 1960-63. New York: National Committee on Maternal Health, Inc., 1963, pp. iii, 59. Oral Contraceptives 19. Behrman, S. J. "Norethindrone, 2 mg.: an Evalua- tion." Obstetrics and Gynecology, 24:101-105, July 1964. 20. British Medical Research Council, A Subcommittee. "Risk of Thromboembolic Disease in Women Taking Oral Contraceptives," a preliminary communication to the Medical Research Council. British Medical Journal, pp. 355-359, Vol. II, 6 May 1967. 21. Editorial. "Oral Contraceptives and Thromboembo- lism," British Medical Journal, pp. 187-188, 27 April 1968. 22. Flowers, C. E. "Effects ot New Low-Dosage Form of Norethynodrelmestranol: Clinical Evaluation and Endo- metrial Biopsy Study," Journal of the American Medical Association 188:1115-1120, 29 June 1964. 23. GarcIa, C.-R., Pincus, G. "Ovulation Inhibition by Progestin-estrogen Combination," International Journal of Fertility, 9:95-105, Jan-Mar. 1964. 24. Goldzleher, J. W., Moses, L. E., Ellis, L. T. "Study of Norethindrone in Contraception," Journal of the Ameri- can Medical Association, 180:359-361, 5 May 1962. 25. Gotdzleher, J. W. and Rice-Wray, E. Oral Contracep- tion and Management, Charles C. Thomas, 1966. 26. Goldzleher, J. W., Becerra, C., Gust, C., Livingston, N. B., Maqueo, M., Moses, L E., Tletze, C. "New Oral Contraceptive: Sequential Estrogen and Progestin," American Journal of Obstetrics and Gynecology, 90:404- 411, 1 Oct.1964. 27. Inman, W. H. W. and Vessey, M. P. "Investigation of Deaths from Pulmonary, Coronary, and Cerebral Throm- bosis and Embolism in Women of Child-bearing Age," British Medical Journal, pp. 193-199, 27 April, 1968. 28. Jennett, W. Bryan and Cross, James N. "Influence of Pregnancy and Oral Contraception on the Incidence of Strokes in Women of Child Bearing Age," Lancet, pp. 1019-1023, Vol. 1, 13 May 1967. PAGENO="0149" 30. Mears, E. (ed.) Handbook on Oral Contraception, Medical Advisory Committee of the International Planned Parenthood Federation, J&A Churchill Ltd., 1965. 31. Pincus, G., Rock, J., Garcia, C.-R., Rice-Wray, E., Panlagua, M., Rodriguez, I. "Fertility Control with Oral Medication," American Journal of Obstetrics and Gyne- cology 75:1333-1346, June 1958. 32. Rice-Wray, E., Schulz-Contreras, M., Guerrero, I, Aranda-Rosell, A. "Long-term Administration of Noreth- indrone in Fertility Control," Journal of the American Medical Association, 180:355-358, 5 May 1962. 33. Rice-Wray, E., Goidzieher, J. W., Aranda.Roseli, A. "Oral Progestins in Fertility Control: a Comparative: Study," Fertility and Sterility, 14:402-409, July-Aug. 1963.' 34. Satterthwaite, A. P., Gamble, C. J. "Conception Con- trot with Norethynodrel: Progress Report of a Four-Year Field Study at Humacao, Puerto Rico," Journal of the American Medical Women's Association, 17:797-802, Oct. 1962. 35. Satterthwalte, A. P. "A Comparative Study of Low Dosage Oral Contraceptives," Applied Therapeutics, 6:410-418, May 1964. 36. Tyler, E. T., Olson, H. J., Wolf, L., Finkeistein, S., Thayer, J., Kaplan, N., Levin, M., Weintraub, J. "An Oral Contraceptive: a Four-year Study of Norethindrone," Obstetrics and Gynecology, 18:363-367, Sept. 1961, 37. Tyler, 8. T. "Oral Contraception and Venous Throm- bosis," Journal of the American Medical Association, 185:131-132, 13 July 1963. 38. Tyler, E. T. "Current Status of Oral Contraception," Journal of the American Medical Association, 187:562- 565, 22 Feb. 1964. 39. Untied States Food & Drug Administration. Ad Hoc Advisory Committee for the Evaluation of a Possible Etiologic Relation with Thromboembolic Conditions. "FDA Report on Enovid," Journal of the American Medi- cal Association, 182:140, 7 Sept. 1963. 40, United States Food & Drug Administration. Advisory Committee on Obstetrics and Gynecology: "Report on the Oral Contraceptives," 1 Aug. 1966. 41. Vessey, M. P. and Doll, R. `Investigation of Relation Between Use of Oral Contraceptives and Thromboem- bolic Disease," British Medical Journal, pp. 199-205, 27 April 1968, 42. Waiiach, E. E. and Garcia, Ceiso-Ramon. "Psycho- dynamic Aspects of Oral Contraception," Journal of the American Medical Association, Vol. 203, No, 11, pp. 125- 129, 11 Mar, 1968, intrauterine Devices 44, Brooks, P. G., Home, H. W., Jr. "Intrauterine Devices in Women with Proved Fertility," Fertility and Sterility, 17:267-272, March-April 1966. 45. Ehrensing, R. H. "The IUD: How it Works; Is it Moral?," The National Catholic Reporter, 20-27 Apr. 1966. 46. Halt, R. E. "A Comparative Evaluation of Intrauterine Contraceptive Devices," American Journal of Obstetrics and Gynecology, 94:65-77, 1 Jan. 1966. 47. London, G. D., Anderson, G. V. "Immediate Post- partum Insertion of an Intrauterine Contraceptive De- vice," Obstetrics and Gynecology, 30:851-854, Dec. 1967. 48. Mlshelt, D., Jr., Reil, J. H., Good, R. G., Moyer, D. L. "The Intrauterine Device: A Bacteriologic Study of the Endometriat Cavity," American Journal of Obstetrics and Gynecology, 96:119-126, 1 Sept. 1966. 49. OppenheImer, W. "Prevention of Pregnancy by the GrBfenberg Ring Method," American Journal of Obstet- rics and Gynecology, 78:446-454, Aug. 1959. 50. Perkin, G. W. "intrauterine Contraception," The Ca- nadian Medical Association Journal, 94:431-436, 26 Feb. 1966. 51. Segal, S. J., Southam, A. L., Shafer, K. D. (eds.) `intra- Uterine Contraceptive Devices," Proceedings of the Sec- ond International Conference, 2-3 Oct. 1964. Amsterdam: Excerpta Medica International Congress Series. 52. Soiish, G. I., Majziin, G. "A New Intrauterine Spring Device," Obstetrics and Gynecology, Vol. 32, July 1968. 53. Ttetze, C. "Effectiveness and Acceptability of Intra- Uterine Contraceptive Devices, American Journal of Public Health, 55:1874-1879, Dec. 1965. 54. U. S. Food & Drug Administration, Advisory Com- mittee on Obstetrics & Gynecoiogy "Report on Intra- uterine Contraceptive Devices," Jan. 1968. 55. Wilison, J. R., Boiilnger, C. C., Ledger, W. J. "The Effect of an Intrauterine Contraceptive Device on the Bacterial Fiora of the Endometrial Cavity" American Journal of Obstetrics & Gynecology, 90:726-739, 15 Nov. 1964. 56. World Health Organization Scientific Group. Techni- cal Report Series No, 332 "Basic and Clinical Aspects of Intrauterine Devices." 1966. COMPETITIVE PROBLEMS,: IN THE DRUG INDUSTRY 6589 29. Jones, G. W. and Mauldln, W. P. "Use of Oral Con- 43. World Health Organization Scientific Group. Techni- traceptives with Special Reference to Developing Coun- `cal Report Series No. 326 "Clinical Aspects of Oral Ges- tries," Studies in Family Planning, The Population togens," 1966; and No, 386 "Hormonal Steroids in Con- Council, No. 24, December 1967. traception," 1968. 15 PAGENO="0150" 6590 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Diaphragm 57. Dickenson, R. L "The Diaphragm," Manual of Con- traceptive Practice, (M. S. Calderone, ed), 154-172, Bal- timore: Williama & Wilkina, 1964. 58. Stone, H. M. "The Technique of the Vaginal Dia- phragm," Human Fertility, 6:97-102, Aug. 1941. Cervical Cap 59. Lehfeldt, H., Sobrero, A. J., Inglia, W. "Spermicidat Effectiveness of Chemical Contraceptives Used with the Firm Cervical Cap," American Journal of Obstetrics and Gynecology, 82:446-448, Aug. 1961, 60. Tietze, C., Lehfeldt, H., Liebmann, H. G. "The Effec- tiveness of the Cervical Cap as a Contraceptive Method," American Journal of Obstetrics and Gynecology, 66:904- 908, Oct. 1953. Condom 61. Tietze, C. "The Condom as a Contraceptive," Ad- vances in Sex Research (H. G. Geiget, ed), 88-102. New York: Hoeber, 1963. Chemical Contraceptives Vaginal Foams, Jellies, Creams 62. MacLeod, J., Sobrero, A. J., Ingits, W. "In Vitro As- sessment of Commercial Contraceptive Jellies and Creams," Journal of the American Medical Association, 176:427-431, 6 May 1961. 63. Pantagua, M. E., Vaittant, H. W., Gamble, C. J. "Field Trial of a Contraceptive Foam in Puerto Rico," Journal of the American Medical Association, 177:125-129, 15 July 1961. 64. Rovinsky, J. J. "Clinical Effectiveness of a Contra- ceptive Cream," Obstetrics and Gynecology, 23:125-131, Jan. 1964. 65, Sobrero, A. J. "Evaluation of a New Contraceptive," Fertility and Sterility, 11:518-524, Sept.-Oct. 1960. 66. Tietze, C., Lewit, S. "Comparison of Two Contracep- tive Methods: Jelly or Cream Alone, and Diaphragm with Jelly or Cream," Proceedings of the VII International Conference on Planned Parenthood, 161-168. Amster- dam: Excerpta Medica International Congress Series No.72, 1963. 67. Tyler, E. T. "Simpler Local Methods of Conception Control," Sixth International Conference on Planned Parenthood, 282-284, 1959. London: International Planned Parenthood Federation. Vaginal Foaming Tablets 68. Dingle, J. T., Tietze, C. "Comparative Study of Three Contraceptive Methods: Vaginal Foam Tablets, Jelly Alone, and Diaphragm with Jelly or Cream," American Journal of Obstetrics and Gynecology, 85:1012-1022, 15 April 1963. Sponge and Foam 69. Whitehili, J. L., Wetzel, P. "The Acceptability and Effectiveness of Foam Powder," Human Fertility, 6:151- 152, Oct. 1941. Vaginal Suppositories 70. Eastman, N. J., Weibeis, R. E. "Efficacy of the Sup- pository and of Jelly Alone as Contraceptive Agents," Journal of the American Medical Association 139:16-20, 1 Jan. 1949. Coitus lnterruptus 71. Sjovsli, E. "Coitus Inferruptus," Manual of Contra- ceptive Practice (M. S. Calderone, ed), 202-206. Balti- more: Williams & Wilkins, 1964. Rhythm 72. Ogino, K. "The Ovulation and Conception Periods in Woman: Their Application for Conception Control," Fifth International Conference on Planned Parenthood, 141- 144, 1955, London: International Planned Parenthood Federation. 73. Rock, J. "The Rhythm or Periodic Continence Method of Birth Control," Manual of Contraceptive Practice (M. S. Calderone, ed), 222-229. Baltimore: Williams & Wilkins, 1964. 74. Tietze, C., Poliakoff, S. R., Rock, J. "The Clinical Effectiveness of the Rhythm Method of Conlraception," Fertility and Sterility, 2:444-450, Sept.-Oct. 1951, 75. Tietze, C., Potter, R. G. "Statistical Evaluation of the Rhythm Method," American Journal of Obstetrics end Gynecology, 84:692-698, 1 Sept. 1962. 76. World Health Organization Scientific Group. Techni- cal Report Series No, 360 "Biology of Fertility Control by Periodic Abstinence," 1967. Postcoltal Douche 77. Sobrero, A. J., MacLeod, J. "The Immediate Post- coital Test," Fertility and Sterility, 13:184-189, March- April 1962, 16 PAGENO="0151" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6591 Literature for Patient Uses Single 100 Modern Methods of Birth Control 15 cents 6.00: Questions & Answers About the Birth Control Pill 15 cents 4.50 Questions & Answers About Intrauter- ine Devices 15 cents 4.50 The Complete Book of Birth Control, A. F. Guttmacher, M.D. 50 cents 35.00 The Safe Period 15 cents 7.50 To be a Mother.. To be a Father 15 cents 7.50 Basal Temperature Chart (instructional) 15 cents 2.50 Basal Temperature Chart (blank) 15 cents 2.50 *Obtainable from Planned Parenthood-World Population, 515 Madison Avenue, New York, N.Y. 10022. Physicians and other professionals may obtain single copies of these publications free of charge except for The Com- plete Book of Birth Control. PAGENO="0152" 6592 COMPETITIVE PROBLEMS IN THE DRTJG INDuSTRY List of Contraceptive Products Prepared by the Medical Department of Planned Parenthood-World Population Products Requiring Prescription: 1 Oral Contraceptives (Approved by the U.S. Food and Drug Administration) Product Available Dosage Composition Progestin Estrogen Enovld 10 mg. 9.85 mg. Norethynodrel 0.15 mg. Mestranol Enovid 5 mg. 5 mg. Norethynodrel 0.075 mg. Mestranol Eriovld-E 2.5 mg. 2.5 mg. Norethynoclrel 0.1 mg. Mestranol Ovuien 1 mg. 1.0 mg. Ethynodiol Diacetate 0.1 mg. Mestranol G. D. Searle & Co. P.O. Box 5110, Chicago, 111.60680 Norinyl 2 mg. 2 mg. Norethindrone 0.1 mg. Mestranol Norlnyl 1 mg. 1 mg. Norethindrone 0.05 mg. Mestranol Noriday 21 tablets 1 mg. Norethindrone 0.05 mg. Mestranol 7 inert tablets Norquen 14 tablets 0.08 mg. Mestranol 6 tablets 2 mg. Norethindrone 0.08 mg. Mestranol Syntex Laboratories, inc. 701 Welch Road, Palo Alto, Calif. Norlestrln 2.5 mg. Norleatrin 1 mg. Parke-Davis & Co. Detroit, Michigan 48232 2.5 mg. Norethindrone Acetate 1 mg. Norethindrone Acetate 0.05 mg. Ethinyl Estradiol 0.05 mg. Ethinyl Estradiol Ovral 0.5 mg. 0.5 nig. Norgestrel 0.05 mg. Ethinyl Estradiol Wyeth Laboratories Box 8299, Philadelphia, Pa. 19101 PAGENO="0153" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6593 Scheuier & Company 110 Fifth Avenue New York, N.Y. 10011 Ortho Pharmaceutical Corp. Raritan, New Jersey Goshen instrument Corp. P.O. BoxlO2 Goshen, New York Glaxo-Allenbury's Can- ada, Ltd., 52 Barton Road Weston, Ontario, Canada Ortho Pharmaceutical Corp. Raritan, New Jersey MaJzlln Spring Anka Research Ltd. 139-01 Archer Avenue Jamaica, New York Julius Schmid, Inc. 423W. 55th Street New York, New York 10019 3 Diaphragm with Contraceptive Jelly or Cream Most of the firms listed as manufacturers of contraceptive jellies and creams (see following-Products Not Requiring Prescription), also manufacture various types of diaphragms suitable for the varying needs of individual patients. 4 Cervical Cap Ortho-Novum 10 mg. 10 mg. Norethindrone 0.06 mg. Mestranol Ortho-Novum 2 mg. 2 mg. Norethindrone 0,1 mg. Mestranol Ortho-Novum 1 mg. 1 mg. Norethlndrone 0.05 mg Mestranol Ortho-Novum SQ 14 tablets : 0.08 mg. Mestranol 6 tablets 2 mg. Norethlndrone 0.08 mg. Mestranol Ortho Pharmaceutical Company Raritan, New Jersey : Provest 10 mg. 10 mg. Medroxyproges- terone Acetate 0.05 mg. Ethinyl Estradiol Upjohn Company Kalamazoo, Michigan : C-Quens 15 tablets * 0.08 mg. Mestranol 5tablets EiiLiiiy&Co. P.O. Box 618, indianapolis, md. 2 mg. Chiormadinone Acetate 0.08 mg. Mestranol Oracon 16 tabiets 0.1 mg. Ethinyi Estradioi 5 tablets 25 mg. Dimethisterone 0.1 mg. Ethinyl Estradiol Mead Johnson Laboratories Div. of Mead Johnson 2404 West Pennsylvania St., Evansviiie 21, nd. & Co. : 2 Intrauterine Devices Blmberg Bow Gynecoil Hail-Stone Stainless Steel Ring Lippes Loop Saf-T-Coil (Double Coil) Mliex Products 5915 Northwest Highway Chicago 31, illinois Day, Baldwin & Co. 1460 Chestnut Avenue Hiiiside, New Jersey PAGENO="0154" 6594 COMPETITIVE PROBLEMS IN THE DRTJG INDTJSTRY Products Not Requiring Prescription 1 Condom Quality control is checked by the U.S. Food and Drug Administration; therefore reliable brands bought at drug stores are generally acceptable. 2 Chemical Contraceptives All of the products listed in this group have been tested at the Margaret Sanger Research Bureau, New York City, for effectiveness against live human sperm. Products under "Vaginal foams, jellies, creams," are listed in descending order of in vitro spermicidal activity as determined by the International Planned Parenthood Federation test, Whenever two or more products have the same in vitro spermicidal activity, they are bracketed and listed alphabetically. The difference in sperm immobilizing ability between neighboring groups in the list is not great, but the difference between those at the top and those at the bottom of the list is considerable. It is not possible to determine what correlation may exist between these in vitro tests and the in vivo effectiveness of the products as observed under conditions of clinical use. An asterisk indicates those products advertised or designed for use without mechanical (occlusive) protection. Vaginal Foams, Jellies, Creams Ortho `Pharmaceutical Corp. Raritan, New Jersey Emko Co. 7912 Manchester Avenue St. Louis 17, Mo. 1 *Delfen cream Ortho Pharmaceutical Corp. Raritan, New Jersey Vogarell Products Co. Los Angeles 7, California Research Supplies Pine Station, Albany3, N.Y. Larré Laboratories Division Gynecic Laboratories, Inc. 474 Nepperhsn Avenue Yonkers, New York Day Baldwin & Co. 1460 Chestnut Avenue Hillside, N.J. Holland-Rantos Co., Inc. 393 Seventh Avenue New York, New York 10001 Ortho Pharmaceutical Corp. Raritan, New Jersey Holland-Rantos Co., Inc. 393 Seventh Avenue New York, New York 10001 Veritas Products Co., Inc. 1460 Chestnut Avenue Hillside, New Jersey Ortho Pharmaceutical Corp. Raritan, New Jersey Veritas Products Co., Inc. 1460 Chestnut Avenue Hillside, New Jersey Vogarell Products Co. Los Angeles 7, California Day Baldwin & Co. 1460 Chestnut Avenue, Hillside, N.J. Ortho Pharmaceutical Corp. Raritan, NewJersey Julius Schmid, Inc. 423 West 55th Street New York, New York 10019 Koromex cream Holland-Rantos Co., Inc. 393 Seventh Avenue New York, New York 10001 5Locorol "D" Jelly Peck & Sterba Division, Inc. International Laboratories, Inc. Rochester 14, New York 8 5Lanesta Gel Esta Medical Laboratories, Inc. 902 Broadway NewYork, New York 10018 Vaginal Foams: *Delfen Vaginal Foam *Emko Vaginal Foam 5 Koromex Jelly Marvosan Jelly *preceptln Gel Jellies and Creams: Verlthol Jelly 2 Certane creme contra Creme 3 Creemoz Creme LactIkol Jelly *Koromex,.A Jelly 6 Certane Jelly Lactlkol creme Ortho Creme 7 ~lmmolln cream-~Jel 4 Ortho-Gynol Jelly PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6595 Day Baldwin & Co. 1460 Chestnut Avenue Hillside, N.J. Larré Laboratories Division Gynecic Laboratories, Inc. 474 Nepperhan Avenue Yonkers, New York Vaginal Foaming Tablets: *Durafoam Tablets Sponge and Foam: Durafoam Liquid Durex Products, Inc. 684 Broadway with Sponge New York, New York 10012 Durex Foam Powder Day Baldwin & Co. 1460 Chestnut Avenue with Sponge Hillside, N.J. 9 *Colagyn Jel The Smith Laboratory, Inc. 811 Wyandotte Kansas City 5, Missouri Lanteen Jelly Eats Medical Laboratories, Inc. 902 Broadway *Zeptabs NewYork, New York 10018 Ramses Jelly Julius Schmid, Inc. 423 West 55th Street New York, New York 10019 10 Bllco Jelly Veritas Products Co., Inc. 1460 Chestnut Avenue Hillside, New Jersey *Cooper Creme Whittaker Laboratories, Inc. 898 Washington Street Peekskill, New York Cooper Creme Gel Whittaker Laboratories, Inc. Jellak Jelly Larré Laboratories Division Gynecic Laboratories, Inc. 474 Nepperhan Avenue Yonkers, New York KemI-Cream Kemi Products Corp. Clifton, New Jersey KemI Jelly Kemi Products Corp. Locorol Jelly Peck & Sterba Division, Inc. International Laboratories, Inc. Rochester 14, New York Marvosan Creme Veritas Products Co., Inc. 1460 Chestnut Avenue Hillside, New Jersey Milex Products 5915 Northwest Highway Chicago 31, Illinois Milex Products Milex Products Veritas Products Co., Inc. 1460 Chestnut Avenue Hillside, New Jersey Vaginal Suppositories: eLorophyn Eaton Laboratories 17 Eaton Avenue Norwich, New York Mllex Crescent Creme Mllex Crescent Jelly *Mllex Jelly B4 ~Verltas Kreme PAGENO="0156" 6596 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6597 Revised 1968 under the direction of George J. Langmyhr, M.D. Medical Director Copyright©1965, 1968 Planned Parenthood Federation of America Inc t~anufactüred in the United States of America All rights reserved Planned Parenthood-World Population 515 Madison Avenue, New York, N.Y. 10022 PAGENO="0158" 6598 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Modern Methods of Birth Control Almost all people wish to decide for themselves how many children to have, and when to have them. Modern methods of birth control, or family planning, allow every couple to do just that-have babies when they want them, and avoid pregnancy when they don't. Pregnancy takes place after sex relations, when the man's sperm or seed joins with the woman's egg and attaches itself to the lining of the womb, where the new baby grows. All methods of birth control are designed to keep this from happening: to keep the new life from starting until the parents want it to. Just as there is no "magic" number of children ideal for all families, there is no one method of birth con- trol that is perfect for every couple. There are a number of different medically approved birth control methods that work differently, and that are safe and inexpensive. You can choose the one you like best. The method you will use regularly is the one that will work best. Your private doctor, or the doctor at a Planned Parenthood center, local health department or hospital family planning center can help you choose. This is the most reliable and safest way to pick your method. Some methods can be gotten only by seeing a doctor first. These usually give better protection against pregnancy than those bought in a drugstore without seeing a doc- tor. This booklet describes both kinds. If you cannot visit a doctor, or must wait for an appointment, see page 7 for a list of products you can buy at the drugstore without a doctor's prescription. "Doctor Methods" of Birth Control Available Only with a Doctor's ExaminatIon and Prescription The Pill Oral Contraceptives The Pill is now being used by about seven million U.S. women. It keeps a woman's body from releasing an egg (ovulating). If there is no egg, she cannot become preg- nant. Pills have to be taken on a regular monthly sched- ule. When the doctor prescribes the Pill, he gives you the schedule. Only the full series taken regularly gives protection. Pills taken just "once in a while" will not help. To be sure, take the pill at the same time every day. The Pill Works Well If you follow your doctor's directions, the Pill has a close to 100 per cent record of preventing pregnancy. One big advantage about the Pill is that it can be taken at a time separate from the sex act. Some women taking the Pill feel a little like women do in the early part of pregnancy. They feel sick at the stomach; their breasts are tender. These side effects usually don't last long. Sometimes spotting or bleeding occurs between periods. Careful scientific studies over the last ten years indicate that the Pills are not safe for all women, and it PAGENO="0159" COMPETITIVE PROBLEMS, IN THE DRUG INDUSTRY 6599 is too soon to be sure that there are no long-term ill effects. Your doctor can tell you if you have a condition which would make it unwise for you to take the Pill. If you are on the Pill, you should have an internal exami- nation from a doctor at least once a year. If you have any problem you don't understand or expect, be sure to call the doctor right away. If you decide you want to have a baby, just stop taking the Pill. Intrauterine Devices IUDs The intrauterine devices (IUD5), are small plastic or metal shapes which the doctor places inside a woman's womb (uterus). They come in several shapes and work very well in preventing pregnancy. lUDs have been tested since 1959 and are very safe. Although not quite 100 per cent effective, they are one of the best methods of birth control. IUDs Need Little Attention Once the doctor has placed the IUD inside the womb (a simple, not painful process), it can be left there for years, protecting you from unwanted pregnancy. It re- quires little attention. During sex, neither the man nor woman can tell it is there. An added advantage of the IUD is that it does not interfere with the sex act. The IUD user should visit the doctor at least once a year for a medical examination. Some women have cramps for a little while after the IUD has been put in by the doctor. Menstrual periods may be heavier, and bleeding or spot- ting may occur betwOen periods. Discomfort usually stops after a few months. Menstrual periods proceed normally. Tampons may be used. If you wish to douche you can, but it is not necessary. Use of the IUD in no way changes your ability to have children. When you want to get pregnant, you go to the doctor and he quickly and simply removes the IUD. Diaphragm with Jelly or Cream A diaphragm is a thin sheet of soft rubber stretched over a metal ring that bends easily. It is placed in the birth canal (vagina) and covers the entrance to the womb (cervix). It does not interfere with sex relations and it will not hurt either sex partner. This was considered the most effective method of birth control by doctors until the Pill and IUD beOame available. It is very effective when used correctly. As with the Pill and IUD, you can put it in at a time other than when you are having sex. The diaphragm must fit between two places in the birth canal, and different women need different sizes. A doc- tor must first examine you to find out what type and shape diaphragm you need. The doctor will also teach you how to put in the diaphragm (which can be bought, according to size, in the drugstore). BeOause women's bodies change, you should return to the doctor once a year to see if your diaphragm is still exactly the right size. PAGENO="0160" 6600 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Jelly or Cream Necessary Diaphragms should always be used with a contraceptive cream or jelly. These chemicals kill any male sperm which may get past the diaphragm, or are still alive after the diaphragm is taken out. About a teaspoonful of con- traceptive jelly or cream is placed inside the diaphragm, with some spread around the rim. Then the diaphragm is put in the birth canal with the cream or jelly side up. This can be done at any time up to six hours before sex relations. If more time has passed or sex relations are repeated later, another applicatorful of the jelly or cream should be put into the birth canal; but don't take out the diaphragm. You should leave the diaphragm in place for at least six hours after the last sex act. However, it can be left in for up to 24 hours. When you take it out, it should be washed and dried. Douching is not necessary. If you want to douche, be sure to wait until six hours after the sex act. Otherwise the douching may weaken the dia- phragm's protectiveness. Birth Control Methods Obtainable without a Doctor Two very effective methods of birth control are available without seeing a doctor. One is for use by the man, the other by the woman. The Condom The condom or "rubber" is made to be placed over the male organ (penis) justbefore sex relations. It keeps the man's fluid (semen) with its sperm from getting into the birth canal. Condoms are safe, reliable and can be bought without a doctor's prescription at any drugstore. Condoms are highly effective and widely used. Some men report that they dull sensation somewhat. The condom must be put on after erection. Hence, its use interrupts the sex act. For couples who find condoms acceptable, the method is highly recommended. There is a slight possibility that the condom may break during use, or slip off after the man "comes" and releases his semen. As a result, the man's fluid may spill into the birth canal. Slipping off can be avoided if the man holds onto the condom as it is taken out of the birth canal. Breakage usually occurs because the condom is dry, and can be avoided by using vaseline or any kind of cream. The government Food and Drug Administration checks on condoms and destroys those found defective or inferior in quality. That is why mostcondoms are of high quality and breakage is rare.-Fbi~reater protection, the woman may use a coj~traO~ptive jelly, cream or foam at the same time t~e-tńan uses a condom. She places these in the blrtt(canal before they have sex relations. (See be~9w1~' information about contraceptive jellies, crea~ts and vaginal foams.) PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6601 Vaginal Foams, Creams and Jellies Special contraceptive creams, jellies and vaginal foams can be bought without a doctor's prescription at drug- stores. For couples who cannot use other methods or for women who can't get to a doctor, these are very good products. They are simple to use and no doctor's exami- nation is needed. Special applicators which measure the right amount come in the box when you buy them. To be effective these must be used each and every time before sex relations. Next to the condom, the contraceptive foams, creams and jellies are the most effective birth control methods you can buy without a doctdr's prescrip- tion. Because the foam is less noticeable, many women prefer it to jellies and creams. (See p. 8 for list of prod- ucts on sale in drugstores.) Chemicals in these foams, creams and jellies quickly kill the sperm. The jelly or cream is squeezed out of the tube into the special applicator, in the case of the vaginal foam, the bottle is first shaken well, then the applicator is placed over the valve at the top of the bot- tle and filled with foam. Not more than one hour before sex relations, the applicator should be placed gently but deeply into the birth canal. Pressing the plunger sends the foam where it provides protection. Each time sex relations are repeated, another applicatorful must be used. Douching is not recommended. If douching is desired, a six hour wait:after the last sex act is a must. Less Effective Birth Control Methods Vaginal Foaming Tablets Vaginal Foaming Tablets, also sold at drugstores, are simple to use. They only work when moist. For this rea- son the tablets are not suitable or effective for some women. The tablet should be, moistened with saliva or water and immediately: inserted deep into the birth canal at least five minutes before each sex act so it can dis- solve. The foam produced as the tablet dissolves coVers the mouth of the womb. A new tablet should be used be- fore each sex act. The tablets lose their effectiveness an hour after insertion. Douching is not necessary. If douch- ing is desired it should be postponed until at least six hours after the last sex act. Vaginal Suppositories The Vaginal Suppository is a small, cone-shaped waxy material containing a sperm-killing chemical. A suppos- itory is inserted into the birth canal 10 to 15 minutes before each sex act so that it has time to melt at body temperature. They are simple to use and can be bought without prescription at any drugstore. However, they have not proven to be reliable enough to be recom- mended generally. Sometimes they do not melt quickly enough, or they may be incorrectly inserted. Like the foaming tablets, if the sex act does not take place within ot~e hour after insertion, they lose their effectiveness. Products advertised for "feminine hygiene" are usually 40-471 0-70-pt. 16-vol. 2-11 PAGENO="0162" 6602 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY worthless for birth control. When i~etter methods are not available suppositories are recommended, since they do give some protection. (See p. 8 for a list of such products.) The Safe PerIod Rhythm it is advisable to consult a doctor familiar with the difficulties of this method if rhythm must be used. This method is based on the fact that a woman can become pregnant only during that part of her menstrual cycle when the egg is released from the ovary-around ovula- tion time. It is hard and time-consuming to determine the ovulation time each month for a particular woman. Only a very few women are'regular every month. A menstrual record must be kept for from eight to 12 months. An exact record of her body temperature, taken each morn- ing before rising, is also usually needed. A series of these carefully kept monthly charts shows a slight rise in temperature after ovulation and helps forecast when a woman will release an egg (ovulate). Also, because the time of ovulation is hard to learn in the menstrual cycle, several days must be added before and after and counted as part of the unsafe period when you cannot be sure you can have sex relations without becoming pregnant. The fertile or unsafe period may last from 7-21 days. if a woman's period is irregular, her safe and unsafe days will also be irregular. For many women, the rhythm method may not be reliable, because they have trouble calculating the time of ovulation. A doctor can help you calculate your safe and unsafe period more effectively. Some women com- bine the safe period method with other family planning methods. They use contraceptives only during their fertile days. For a pamphlet on the safe period, send 25~ to Planned Parenthood-World Population, 515 Madison Avenue, New York, N.Y. 10022. Withdrawal Coitus Interruptus Coitus interruptus, or "talēing care," refers to the with- drawal of the male organ (penis) before the man "comes," so that sperm are not deposited in or near the birth canal. No drug or chemical is needed for withdrawal. This method is not completely reliable. Failures may occur because of poor control, carelessness or because sperm are sometimes released before the man's climax. Besides, worry that withdrawal will not take place in time may lessen the enjoyment of sex relations. Some couples find this method acceptable for regular use. For others it is useful when no otber method is available. Birth Control Methods Not Recommended Sometimes women will use products or methods they think are useful for birth control but which are not. Douches The vaginal douche, taken after sex relations is one of PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6603 the least effective methods. It consists of washing out the birth canal with a solution of one kind or another in the hope of removing the sperm. The sperm enter the womb seconds after the man "comes," and cannot be washed out with a douche, even if taken immediately. This is not a reliable birth control method. Feminine Hygiene Products Many products are sold as aids to "feminine hygiene." In some cases, these widely advertised products hint at "birth control powers" in order to fool buyers. Many women buy these products in the mistaken belief that they will prevent pregnancy. Thea's are not useful for birth-control. The Truth about Birth Control The methods listed in this booklet are the major birth control means known to medicine today. Any of those recommended in this booklet will give some protection from unwanted pregnancy. They must, however, be used regularly, according to the doctor's instructions and the directions provided. Remember, even the least effective method is better than no method. Other facts to be remembered about birth ąontrol are these: Modern methods of birth control do not interfere with sexual enjoyment. BecaUse they remove the fear of un- wanted pregnancy, they often make married life happier. The use of birth control in helping couples to plan their families is supported by nearly all Protestant and Jewish denominations. The Roman Catholic Church approves of birth control by the rhythm method. Birth control does not interfere with life that has already started in the womb. It keeps pregnancy from starting. Sterilization Sterilization is a method of birth control involving an operation on either the husband or wife. Once done, it makes the man or woman unable to have children. Ster- ilization of the man (vasectomy) is relatively simple and may be done in minutes in the doctor's office. Complete recovery from the operation takes only a few days and the man experiences no change in his virility, his sex desire or in his sexual performance. Sterilization of the man in- volves tying off the tubes through which the sperm travels. Sterilization for the woman involves an operation in a hospital. it is often performed just after childbirth. For this reason, if theoperation is to take place, it should be planned several months before the baby is born. Ster- ilization does not involve the removal of any sex gland and it does not change the woman's sexual desire or femininity in any way. Sterilization of.the woman involves tying off the tubes through which the egg travels. Additional information on sterilization may be obtained from any Planned Parenthood Center, from hospitals, private doctors or from the Association for Voluntary Sterilization, Inc., 14 West 40th Street, New York, N.Y. 10018. PAGENO="0164" 6604 COMPETITIVE PROBLEMS IN THE DRUG IT~DUSTRY Birth Control Products Birth Control Products Available oniy with a Doctor's Prescription 1. Orai Contraceptives Tho products for oral contracoption approvod thus far * by tho Food and Drug Administration aro: C-Quens, Enovid, Enovid-E, Noriday, Norinyl, Noriestrin, Norquen, Oracon, Ortho-Novum, Ortho-Novum SQ, Ovrai, Ovulen and Provost. Your doctor will tell you what is best for you. 2. Intrauterine Devices intrauterine devices have .been given extensive testing and are available to physicians. These devices have been given names which describe their shapes: Spirals, loops, springs, bows and double coils. Three are illustrated below. ~44il~9~ 3. Diaphragms Many firms manufacture types of diaphragms suitable for the varying needs of individual patients. Your doctor will prescribe the one best suited to you. Birth Control Products Not Requiring a Doctor's Prescription 1. Condoms Quality control is checked by the U.S. Food and Drug Administration: therefore, reliable brands bought at drug- stores are acceptable. 2. Jellies, Creams and Vaginal Foams All of the products listed in this group have been tested at the Margaret Sanger Research Bureau, New York City, for effectiveness against live human sperm. Products listed first under headings A and B are those which were the strongest in the test tube trials. Products of equal strength are listed under the same number. The differ- ence in sperm-killing ability between products close to each other on the list is not great; but the difference between those at the top and those at the bottom of each list is. in choosing the product that best meets your own special needs, you may wish to try several; ask your doctor for advice. Many of these products are available at your local drugstore: PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6605 A. Vaginal Foams: Delfen Vaginal Foam Emko Vaginal Foam B. Jellies and Creams: 1 Delfen Cream 2 Certane Creme Contra Creme 3 Creemoz Creme Lactikol Jelly Koromex-A Jelly 4 Ortho-Gynol Jelly 5 Koromex Jelly Marvosan Jelly *Preceptin Gel Verithol Jelly 6 Certane Jelly Lactikol Creme Ortho Creme 7lmmolin Cream-Jel Koromex Cream Locorol `D" Jelly 8Lanesta Gel 9Colagyn Jel Lanteen Jelly Ramses Jelly 10 Bllco Jelly Cooper Creme Cooper Creme Gel * Jellak Jelly Kemi-Cream Kemi Jelly Locorol Jelly Marvosan Creme Milex Crescent Creme Milex Crescent Jelly *Milex Jelly B4 * *Veritas Kreme 3. VagInal Foaming Tablets: *Durafoam Tablets Zeptabs 4. Sponge and Foam: Durafoam Liquid with Sponge Durex Foam Powder with Sponge 5. Vaginal Suppositorlis *Lorophyn *lndlcates those products designed for use alone (without a diaphragm). PAGENO="0166" 6606 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Planned Parenthood Regional Offices Western d55 Sutter Street San Francisco, California 94102 Southwest 4928 Burnet Road Austin, Texas 78756 Great Lakes 1111 East 54th Street Indianapolis, Indiana 46220 Midwest 406 West 34th Street Kansas City, Missouri 64111 Southeast 3030 Peachtree Road, N.W. Atlanta, Georgia 30305 Northeast 515 Madison Avenue New York, New York 10022 Mid-Atlantic 1505 Race Street Philadelphia, Pennsylvania 19102 Price: Single Copy 25~ Quantity Rates: 50 Copies $ 3.50 100 Copies $ 6.00 1000 Copies $50.00 (postage extra) Planned Parenthood-World Population (Planned Parenthood Federation of America, Inc.) 515 Madison Avenue, New York, N.Y. 10022 PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6607 Senator DOLE. I agree with Senator Nelson that the little booklet called "So Close to Nature" leaves something to be desired. It may not be very realistic at least in the first few sentences that the Chair- man read from that document. Dr. GUTTMACHER. Of course, this testimony of mine has been so interrupted, I really do not know where to take it up, but we have not discussed two things, I believe. One is that for certain individuals, particularly certain married couples, the pill has emancipated them from the onus and chore of contraception. I think that, I trust that you gentlemen have read these excerpts from this letter which I received, which moved me very much, because I think this woman puts in rather simple Eng- lish statements which I would have difficulty putting in more com- plicated English. To them, to her marriage, the pill is almost a saving factor. Senator NELSON. I want to just finish the discussion of this pam- phlet. One of the issues we are ėoncerned about is informed consent. The question raised here is, as a,: matter of public policy, are we enti- tled to withhold information that is known about a prescription drug which gets the stamp of approval of the Federal agency under a statute passed by Congress? There are all kinds of complicated questions. We debated on the floor of the Senate at great length the antibal- listic missile, which is an incredibly complicated mechanical device, which probably nobody in the Congress could explain from a techni- cal standpoint. Should that be discussed although it is complicated and the public may not be able to understand it, or should it not? This is the kind of question we are dealing with here. Do we have a right not to have public hearings and not to make the information available on the ground that all the press may not carry it the way some people think they ought to carry it? Or that it is too compli- cated for the public to understand? Is this the kind of decision that we have a right to make, to withhold knowledge developed by the Federal Government itself through research and studies and confer- ences like the NIH, or should these matters be made a matter of public knowledge, counting, as it seems we always have to do, upon the ultimate good judgment of the public to come to a reasonable conclusion? Very frequently, in a free country, people do not come to reasona- ble conclusions. That is no reason for substituting an arbitrary system such as you have in other countries, where you tell them what you want them to know, no more and no less. This is one of the risks, it seems to me of having a free society in which there are many risks. This is the fundamental question raised here from time to time. I am one of those who happens to favor planned parenthood. I would like to see the perfect pill. I think the rapidly multiplying intrusion of human beings upon the limited resources of the planet is a catas- trophe already. And I think there is not any question but what, with our present situation, the United States is overpopulated now with 200 million people, because we have demonstrated our incapac- ity to dispose of the waste of 200 million people. What will happen when we have 300 million? PAGENO="0168" 6608 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I believe all those things. I also believe that the public is entitled to have the facts. The facts are being presented by all sides. We have invited witnesses who are qualified to make a contribution to come here. We have invited every drug company to suggest wit- nesses and come themselves. We are trying to see that there is a record presented on all aspects of this problem, on my theory, at least, that the public is entitled to know. Now, that is the fundamental question. If, as a result of the public acquiring knowledge, some of them misunderstand it and some of them panic from it, some of them are disturbed by it, so be it. That is part of the democratic process. These hearings are presenting everything that experts can tell us about this pill. Nobody to this day has questioned the qualifications of the experts who appeared here, though they have had different viewpoints. Now, you raised the point that nothing has been raised in these hearings that has not been in the FDA report. What would your view have been if you had been a lay person? The difference is that the information in the FDA report was not put in the papers and only now is being publicized. I have perused the material. It was in some of the medical literature, although much of that was slanted to the final conclusion that the pill was safe within the meaning of the law, with no explanation of what the 1938 law meant. Now, let us assume that when the FDA report came out, the find- ings in that report had been put on the front page of the papers? Would not your reaction have been about the same as it is now? Dr. GUTTMACHER. I think people would have read it and then come to the final conclusion, which I admit is framed in verbiage which is difficult to define. But at least it is verbiage which does create a certain sense of complacency in the user. I think that if this committee has the power and the wisdom to perhaps issue a state- ment at the end of the hearings to put this whole thing in proper perspective, to grant the fact that the pill has magnificent and neces- sary use for many segments of the population, that there are other birth control methods for some which may be substituted with equally good effect, perhaps this will help a great deal. I think that the American public is leaning on this committee for guidance. My hope is that if you agree with me that there has been a lot of material which perhaps has been misinterpreted and has become inflammatory, you will attempt in an honest and perhaps even cautious way to undo this, I think it would be a great service. I do not know whether I am making my point clear to you, sir. Senator NELsoN. I at least do not have the qualifications to draw up a summary of what the experts have said and cnconsions on it, and present it to the public as a valid position respecting the pill, its side effects, and its uses. I have no such qualifications. That is the reason we have called upon distinguished experts such as yourself and many others to state the case for the record. The problems still remain, if the FDA report, as I said, covered most of the things which have been covered in this hearing, with some exception-some of the material in here has been in much more PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRIJG INDuSTRY 6609 detail than in the FDA report-but if the press and the journals had looked at this and given the same visibility to these grave reser- vations that were expressed, the indications of various effects and the concerns about the long-term use, and if that had been on the front page of all the papers, the result would have been exactly the same as the result from taking the same testimony and having it in this committee. You would be reaching the same conclusion. Dr. GUTTMACHER. Yes, but I think it is pretty obvious that the spoken word is more likely to be paid attention to than the written word. I think that these hearings, of course-as you say, the same materials can be brought out, but when they are spoken with an authoritative voice, it means much more than between the pages of a rather sterile document. The newspapers are likely, obviously, to pay attention to the spoken word, not the written word. This is human nature, sir, and this is no exception to it. Senator NELSON. Does that not still raise the question whether or not the FDA report by a committee appointed by the Government, a committee of distinguished gynecologists and clinicians of various kinds, to evaluate the pill should be a matter of public knowledge? Should it not be disseminated to the people of this country, where we have 8,500,000 women using the pill, 10 million in other coun- tries? Is this not something they ought to have a chance to see and read? Dr. GUTTMAOHER. I think you misinterpret me. I have not attacked the hearings, sir. I do not think I have. I am unhappy about the results on our patients in my clinics. This distresses me because I do not think that anything has changed materially. I think they could wait a little longer, but I think there has been a very sudden kind of stampede. This, of course, I regret. Now, whether the hearings could have been differently tailored so that this was not the result, it is certainly not within not my com- petence to tell you. You are : much more experienced at this than I am. I am not attacking the hearings. I believe in free speech. I believe everybody has a right to be heard. But unfortunately, when it comes to medical matters, the negative is so often more clearly understood than the positive by lay people. This is just the nature of the prob- lem, sir. I have not the solution to it. Senator NELSON. Well, my own view is that this is about the only. solution that there is. My own view, furthermore, is that you will conclude, yourself, after a couple of years that the greatest benefit to the pill and the development of more effective devices, or one of the great benefits, is the effect of these hearings. But what we faced here was a situation in which the drug manufacturer's literature is being promoted, the literature that is promoting the pill. You reject the statement in the literature. But that is what' the users get. What is the responsibility of the Government, which does the studies, licenses the pills, approves the package insert which goes to the druggist and most of the time does not get to the physician because he does not PAGENO="0170" 6610 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY get the package? The literature that is going out is inaccurate. It is misleading 8,500,000 women in this country and it has been doing it for 10 years. It has not been corrected by the Food and Drug Administration, it has not been corrected by the medical profession; it has not been refuted by anybody. Here it stands. You refute it; I reject it. You would not use this in your clinics. Yet it is being passed to women all over the country. At what stage do you consider the women's rights? Dr. GUTTMACIIER. I see your point. Well, I suppose if you had the, if the FDA had the, medical manpower and the budget, they could have submitted such literature, I am sure that if they criti- cized it, the drug company that put this out, I should think would make the changes which are suggested. I think that you probably have no right to impose what should be written in such a pamphlet. But if there were some way of clearing all medical throwaway data with the FDA before publication for their criticism, it might be a very salutary thing. Senator NELSON. I think it would be, but they do not have the personnel, nor, at this stage, so far as I know, the authority which is another thing that ought to be corrected. Dr. QUTTMACHER. That is correct. But I do not think you can impose it. I turn our attention to one other aspect of this situation, and that is what is happening the world over because the impact of these hearings has washed up on the shores of almost every country. Senator NELSON. May I interrupt you? I apologize for interrupt- ing you, but I wanted to get the- Dr. GUTTMACIIER. I am hurrying myself along and you are slow- ing me down. Senator NELSON. I just have one more line of questioning. I read to you the statement of the Salhanick study sponsored by NIH. I suppose each individual has to judge himself, and ybu feel that the statement would not mean anything to women, and I assume you mean men, too. Let me read that once more. I do not think there is anything in there that any average person in America would not understand. I understand it; I have no medicai training. Dr. GUTrMACHER. You are the son of a doctor, sir. Senator NELSON. But you do not get any genes or chromosomes for that. Until recently, the metabolic effects of the sex steroids have been inade- quately investigated, or ignored. These accumulated data and others suggest that no tissue or organ system is free from a biological, functional, and/or morphological effect of contraceptive steroids. Many of these changes appear to be reversible after short periods of treatment. But it is impossible to form judgments on the reversibility of some of the changes resulting from prolonged administration. This question becomes more important daily for the many patients who have already had long-term contraceptive steroid treatment. Nevertheless, the consistency of such reports on such findings rejects the possibility that they are of no consequence and requires that certain questions be answered. Now, that is not any medical statement to cause anybody any trouble. Perhaps the word "morphological" may be difficult but, as a PAGENO="0171" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6611 whole, this is a very, very clearly, simply stated paragraph that gives warning about the long-term systemic effect, which is quite a different thing from what is going to the woman, which says: And it works without upsetting the delicate balance of your normal bodily function. Compare this authoritative statement with the statement going to the woman. Dr. GUTTMACHER. Now, I do not think that statement-I agree with it in part, but I think, for example, it could lead one to the impression that it is universal, that every woman on the pill has such changes. As far as I know, it is 8 percent in one series; 20 per- cent in another. Also, these chemical changes often clear up during the time the patient is on the pill. Also, so many of these changes are reversible when the patient concludes it. I think if this were added to the statement, perhaps-then there are words in there that I just have the feeling that a lot of people do not understand. "Morphological", I dare say if you took that word to half the population in Washington, the number of people who do not under- stand that word would be higher than I anticipate. I think it is fine, but I think it needs a good deal more writing. I think it has to add that it is not universal, that it reverses itself even when patients are on the pill; when they come off, most of these disappear. I think also we need to state in there that so far, we do not see any evidence of sustained systemic damage. There is nobody, I think, that thinks, so far as :1 have been able to read that volume or other volumes-and Dr. Carrington is going to follow me, and she can answer me-that the pill is going to cause diabetes. Nevertheless, it causes changes in sugar tolerance. I just have a feeling that you are trying to oversimplify your message to the American public. It is a complicated message and this does not do it all. Senator NELSON. I did not suggest that. I was just saying, as con- trasted with the comments on metabolic effect here- Dr. GTJTTMAOIIER. Oh, I will buy the book against the pamphlet. There is no problem about that. Senator NELSON. And this statement, save a word or two, which could easily be rephrased, is perfectly understandable by any eighth grader, I think, in the country. That is my point. On One side is the information that the woman is getting; that there are no metabolic effects. On the other side is what a most distinguished comn-iittee has gathered on the metabolic effects. It has summarized all the literature here and elsewhere in the world and here is the conclusion they come to. The woman is being told exactly the opposite. That is why I raise the question, should it not be told? Senator JAvITS. Mr. Chairman, a point of interest to me. The Chair said lie was reading from an official document. What is the official Government document? Senator NELSON. It is an NIH-sponsored conference. This is the book that came from the conference sponsored by the NIH, coiisid- ered to be- PAGENO="0172" 6612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. GUTTMACHER. I think it is an excellent book, Senator Javits. Senator PJAVITS. Do you consider it an official Government docu- ment? Dr. GUTTMACHER. No, I do not. I think it is an excellent study. I think the people who contributed to this are among the leaders in the field. Senator JAvIT5. But as far as you are concerned, it is not an official Government document? Dr. GUTTMACHER. No, that is true. Senator NELSON. It is sponsored by the NIH, held in Boston, Mass., in 1968. According to the witness before us, it is the best com- pilation of authoritative material on metabolic effect of steroid hor- mones any place in the world. Is that not so? Dr. GUTTMACHER. It is the best I know. Senator JAVITS. With all due respect, it is far from an official Government document. I just wanted to know what you meant by those rather heavy words. Senator NELSON. It is quite unimportant, sir. Senator JAvITS. I think what you are saying is that the book "So Close to Nature" is deceptive because it is at variance with an official document. I have no lack of indictment for the little book; however, I think it is very important not to let that impression go abroad, that the United States has found the facts that the Chairman has read. Senator NELSON. Let me read into the record so that the Senator from New York will know what it is about. It has the Library of Congress catalog No. 789792. The workshop upon which this volume is based was held in Boston, Mass., December 1 to 5, 1968, and was sponsored by the National Institute of Child Health and Human Development, in the Center for Population Studies of Harvard Uni- versity School of Public Health. It was conducted pursuant to con- tract No. PH43681456, with the National Institutes of Health, Department of Health, Education, and Welf are. Reproduction in whole or in part permitted only for purposes of the U.S. Government. Senator JAVrFS. Mr. Chairman, I would like to ask the witness some questions, if I may, because I think they ought to come at the same point as the Chairman's questions. May I do that? Senator NELSON. Go ahead. Senator JAVITS. Dr. Guttmacher, please let me welcome you to the committee and let me state my own purposes. I have no preconcep- tion about this matter whatever. I think that Congress has a right to conduct these hearings and the chips must fall where they may. We realize that lots of drug companies are interested in selling this pill but that does not make it bad. Lots of drug companies were interested in Salk vaccine, and antidiabetic material-many, many wonderful medicines. That does not make it bad. It does not make it good, either. Until the United States manufactures all the drugs, we have to run a private enterprise system and we have to regulate the best way we can. . . Now, just a question or two, because you are a distinguished PAGENO="0173" COMPETITIVE PROBLEMS: IN THE DRUG INDUSTRY 6613 expert in this field. One, do you prescribe the pill? It is not sold over the counter, is it, without a prescription? Dr. GUTTMACHER. It is against the law, and I hope this law is very seriously enforced. Senator JAVITS. So you prescribe it? Dr. GTJTTMACHER. We do. Senator JAvrrs. Are you continuing to prescribe the pill in your clinics? Dr. GUTTMACHER. We absolutely are, sir. Senator JAvrrs. Do you distribute any booklet for that? Dr. (}UTTMACHER. We have publications about methods of contra- ception. We include, of course, not only the pill in these booklets, but other methods of contraception to help patients make a rational choice. These are written in very simple English, which we antici- pate the patients understand. As I said before you came, Senator Javits, we plan to furnish the committee with these booklets so they can inspect them. Senator JAVITS. Are they the same booklets to which the Chair- man referred? Dr. GtTTTMACHER. No, sir; we write our own. Senator JAVITS. Do you know anything about the practice of other clinics like your own? Dr. GUTTMACHER. Well, of course, we are a national organiza- tion and we sell these booklets in bulk to various-sometimes the U.S. Army for their hospital uses, and we sell them around the country and around the world. Now, we are not the only; people who write such booklets, but we have a very wide distribution of them. Senator JAVITS. Can you give us any factual light on what part of the market, which the Chairman has said was over 8 million people, what part of the market is filled by your particular organization? Dr. QUTTMACHER. About 275,000, sir. Senator JAVITS. Do you have any idea as to what part of the market is occupied by other~ similar clinics. Dr. GUTTMACHER. Of course, what we are talking about, our group is primarily what we call the medically indigent. As we know, the President, in his message to Congress, said that there were approximately 5 million women of fertile age among the medically indigent group who were not seeking pregnancy currently. Of this group, there are about 800,000 getting effective birth-control advice. Forty percent is given by health departments-county, State. Twenty-seven percent are given advice by Planned Parenthood, and 27 percent are given advice by the great hospitals of this United States. Five percent get their birth control advice from other sources. Now, in addition to that, we assume that perhaps another 100,000 get their birth-control advice through medicaid, so that probably the number of medically indigent getting effective birth-control advice may be in terms of a million people out of the 5 million who need it. Now, whether they get the pill or not depends upon their prefer- ence, but in most of our installations, three-quarters of the patients `choose the pill, and one-quarter other means. Senator JAvIT5. I was particularly concerned about the informa- tion which the Chairman feels they are not getting. PAGENO="0174" 6614 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I was wondering about the extent of the distribution of informa- tion about the pill. How many are getting proper information regarding its use? Dr. GUTTMACHER. In absolute honesty, Mr. Javits, I cannot tell you of the million women in the medically indigent group getting birth control through subsidized sources, what percentage are given actual insight into the potential dangers of the pill. I cannot tell you. We certainly know our doctors are thoroughly instructed in these potential dangers. We assume that in conversation with patients, they pass on this information to them. Certainly, if ques- tioned, they would. If they are not questioned, whether they would point out the dangers, I cannot in all frankness say. Senator JAVITS. Now, do you know whether this booklet to which the Chair referred- Dr. GUTTMAOHER. You mean the Saihanick booklet? Senator JAvrrs. No, the little one, "So Close to Nature." Do you know whether this is still in distribution? I see it is copyrighted in 1965, Meade, Johnson and Co. Dr. GUTTMACHER. I do not know. Senator JAVITS. Mr. Chairman, I would respectfully suggest that a request be made of this company to find out if it is in distribution, or what are the conditions of its distribution, the size of its distribu- tion, and so on, that that may be made a part of the record. Senator NELSON. Yes. I would assume you would want it from all companies, because each of them puts a piece of literature out. I have seen other pieces of literature in doctors' offices myself. (The subsequent information was received and follows:) MEAD JOHNSON LABORATORIES, Evansville, md., February 26, 1970. HON. JACOB K. JAvIT5, U.S. Senate, Old Senate Office Bj.tilding, Washington, D.C. DEAR SENATOR JAvIT5: During the hearings of ±he Senate Small Business Monopoly Subcommittee which were in progress February 25, you asked Dr. Alan F. Guttmacher, President, Planned Parenthood if our booklet, "So Close to Nature" was still being given to patients. Dr. Guttmacher replied that lie did not know. You asked that we inform the committee whether or not the booklet is cur- rently distributed so that information might be placed in the record. We withdrew "So Close to Nature" from circulation in November, 1968. No additIonal copies have been printed nor distributed by us since that time. We do appreciate your interest and hope this letter will answer satisfacto- rily your question to Dr. Guttmacher. Sincerely, DONALD G. HARRIS, Marketing Administration. Senator JAvITs. I think, if I may say so to my own chairman, I think we ought to base this solidly in fact and be sure that the facts support the conclusions which we make. I think the distribution of information is really something of great importance that this com- mittee has a duty to go into, since we have undertaken this investi- gation. It is this committee's duty to give the pertinent information which they develop. Do you agree with that? Dr. GUTTMACHER. We have to separate fact from conjecture, and this is a realm of difficulty. We know the facts about thromboembo- lism. I think this is pretty uncontested. We know the facts about PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6615 development of high blood pressure in a certain small proportion of patients. We know the fact that certain patients get depressed on the pill. These are facts we are all privy to. But when it comes to cancer, for example, you are dealing then with a wholly conjectural structure, because we have no evidence to date that the pill causes cancer in the human. When we talk about chromosomal damage to the ovary and perhaps to the offspring, we are talking about conjecture and not fact. This is the thing that I think has a tendency to confuse the public, because the public does not separate fact from conjecture. When you are talking about cancer in such a meeting, in such a forum as this, they do not take: Dr. Roy Hertz's statement that no cancer that he knows of in either a monkey or in a human being can be attributed to the pill. Dr. Hertz is concerned that the hormone estrogen may cause cancer in two target organs in women on the pill, the breast and the uterus. This is highly inflammatory to the public. Senator JAvITs. The doctor's: first responsibility as to whether he will allow the patient to use the pill and as to what information he w~ill give the patient about the pill is to the patient? That ~s the first responsibility? Dr. GUTTMACHER. Absolutely. Senator JAvITs. And the first responsibility? Dr. GUTTMACI-IER. Yes, sir. Senator JAvIT5. So a patient has a right to assume that the doctor is going to be fair and honest with that patient. Dr. GTJTTMACHER. I hope so. I expect so. Senator JAvITS. That is true of many other medicines? Dr. GUTTMACHER. That is true. If the doctor is going to recom- mend surgery, he has to do ~: it from the patient's point of view, because it is necessary. Senator JAvITS. Dr. Connell's implied criticism-and I think she was rather soft in this-of the hearings was that the presentation should have been very carefully balanced at every stage so that the public does not get hit on the head with a sandbag. This has caused many serious problems, which I understand has resulted in a number of unwanted pregnancies, some of which have been terminated by abortions. What is your comment on that? That was my understand- ing of the implication of her testimony. Dr. GTJTTMAOHER. It would have been certainly preferable, if feas- ible. I am not sure you know how a witness is going to testify before he comes on the stand, and perhaps many of the witnesses were uncertain even when they were called. But I think a balanced picture is very valuable, and unfortunately thus far this has not been a balanced presentation. I do not think it is by design of the chairman; I think it is a matter, perhaps, of happenstance that this has been an overwhelmingly negative type of hearing in regard to the safety of the pill. I do not think that people have emphasized the vast and tremendous importance that the pill has to certain seg- ments of our population. When one says more or less carelessly that other methods of con- traception can be easily substituted, he is really not talking out of PAGENO="0176" 6616 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY fact, he is talking, I think, out of misinformation. It can be in some instances, but certainly not in the vast proportion. The fact that our clinics have grown so magnificently since the pill was introduced, I am sure, is not due to the fact that other social factors have made deep impact. The fact that we now have a product which is extraordinarily acceptable to our type of patient, and if we did not have this product and if we deny them this prod- uct or scare them to death from using it, unfortunately, we are going to revert back to situations which are most unhealthy in America. Senator JAVITs. Has anything happened in the testimony or other- wise to change your view as an authority that this is a landmark and historic development in population control? Dr. GUTTMACHER. I think that the two methods, the pill and the intrauterine device, have been significant contributions. I think we are still in the horse and buggy day of effective contraception. I am optimistic in feeling that in 5 years, we shall have methods that are infinitely superior and safer than either. Senator JAvIT5. I would like to tell you just by way of confirming your own view that Dr. Guy Iman, who has just won the Nobel Prize for medicine, addressed the session of trustees of the Salk Biological Institute of La Jolla. I am a trustee and I heard it. His appraisal was precisely yours, that within 5 years, we should have as marked an advance in this science as we have had up to now. It is very interesting. I thought you might be interested. Dr. GUTTMAOHER. I am happy to be confirmed by such a distin- guished person. Senator JAvITs. Is he not one of the most distinguished individu- als in this field? Dr. GUTTMACHER. Yes, he is. Senator JAvIT5. He is beginning to be a fellow at Salk and under- taking his research there. I noted with great interest in your statement-I do not know whether you have come to it or not in your prepared remarks-but your press release quotes the following: "It is against these risks that the proven annual mortality of three deaths per 100,000 pill users must be weighed," and the risks which you outline, I gather, are the toll, as you put it, of unwanted preg- nancy, between 200,000 and a million illegal abortions a year, with a resulting estimated 100 deaths per 100,000 such abortions. Dr. GUTTMAOIIER. When done by nonmedical personnel. Senator JAVITS. No less than 300,000 illegitimate children born in 1970, based on the experience of the last decade; at least three-quar- ters of a million children born each year are unwanted at the time of birth-conception is your statement. Then you give the international problems which are involved. You say millions of women use the pill in other countries. Now, are those the effects to which you just-as against these risks that the proven annual mortality of three deaths per 100,000 pill users must be weighed-is that right? Dr. GUTTMACHER. That is my feeling, sir. I think that the situa- tion, of course, is quite different abroad because of a maternal death rate in much of Asia and Africa and Latin America which is so much greater than the United States that you won] d probably con- PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRuG INDTJSTRY 6617 trast three deaths from the pill per 100,000 in America against 900 deaths per 100,000 childbirths in Africa. Three against 900 is quite a considerable difference. Senator JAvIT5. Could you give us, Dr. Guttmacher, as part of your analysis of such a situation, the documentation which Planned Parenthood distributes to the taker of the pill? Dr. G1JTTMACHER. I unfortunately did not do my homework; I did not bring it with me, sir. As I have said, I have promised to send it. Senator JAVITS. Good. Dr. GIJTTMAOHER. In my written testimony I went into detail with regard to the rules we impose on physicians prescribing the pill, that they must take an annual Pap smear, they must make an annual breast examination, a pelvic examination, and so on. What I am lacking is the material we give to the patients. We shall cer- tainly submit that. Some of my: staff is here and I am sure they will call up New York and get it. Senator JAvIT5. I ask unanimous consent that that become a part of the record. Senator NELSON. It will be printed in the appropriate place in the record. Senator JAVITS. Now, could you make any recommendations to us- this will take a little time, but I hope you can do it-~as to what must be done in law or at the Food and Drug Administration to more nearly present the dangers and the benefits with the greatest accuracy possible to the patient? Now, the chairman, I think, said that the United States author- ized the pill, or words to that effect. Of course, as I understand the operation of the Food and Drug Administration, it may permit a drug to be distributed, but it does not authorize it in the manner that the chairman uses the word. I do not think we would want to be put in that position. Did FDA approve the pill ? Is that your understanding? Dr. GIITTTMACHER. They approved it after considerable research. Senator JAVITS. For use as a prescription drug. Dr. GIJTTMACHER. As you know, the pill was started experimen- tally in 1956 by Pincus in Puerto Rico, and 4 years later, was approved by the Food and Drug Administration for prescription. Senator JAVITS. Would you give us your recommendation as to whether the approval should:be withdrawn? Dr. GUTmIACIiER. I am 100 percent certain that approval should not be withdrawn. That requires no thought on my part, sir. Senator JAvITs. Therefore, the area in which you can help me-I do not want in any way to speak for the committee-the most is to give me your idea as to any changes, which will, in your judgment, more nearly present the case so that the choice of the individual- because it is choice, even though the doctor is ready to prescribe and even recommend it-is as free as possible? Dr. GUTTMACHER. Well, number one, I would say that the physi- cian should be made to understand and appreciate that unless he can see the patient who is on the pill at least every 6 months, he should not prescribe it for her. I think there is danger in allowing a patient to go for an indefinite period without examination. I think second of all, theY doctor should be sufficiently well 40-471 0-70-pt. 16, vol. 2-12 PAGENO="0178" 6618 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY equipped to answer honestly and authoritatively the facts that have been presented about the pill-not conjectures but facts, and I think that he should be made to recognize the necessity for him to take the time from the busy life of a doctor to answer these questions, and if lie feels that lie cannot do this, then I think lie should not dispense the pill. We must recognize that for many situations, the pill may not be the ideal contraceptive. I have often said, and I would say it again, that I think that nothing can be substituted for the pill when it comes to premarital sexual relations. I think nothing can be substi- tuted for the pill in early marriage, where couples are making a good physical adjustment. But I think after marriage has matured and a good sexual adjustment has been made, then I think the intel- ligent patient should go to an intelligent physician and discuss methods of contraception. She may find that other methods may be quite satisfactory to her. Some couples have become so dependent upon the pill, because to them its great virtues would not permit them to substitute other methods. Since sexual response and satisfaction is so largely psychic and so little organic, it is what one's attitude is that counts. If cou- ples wish to reject other methods of contraception, I think they have the right to. On the other hand, if they can make a trial of other methods and find them entirely satisfactory, I think perhaps other methods should be substituted. Now, of course, I get back to what I told Senator Nelson. The pri- mary responsibility, I think, is to educate the medical public, not the lay public. And this is a tough assignment. Senator JAVITS. I think the Government can play a very signifi- cant role in this. I think, therefore, any additional help you can give us on that score would certainly be welcome, very constructive. Mr. Chairman, I would like to thank the Chair particularly for its indulgence in allowing me to break in with this rather lengthy questioning. Senator NELSON. Thank you, Senator. I have just one minor observation on the question that was raised on the balance of the hearings. For example, we called Marvin Legator, Chief, Biology Branch, and Director of Pharmacology and Toxicology, Bureau of Science, Food and Drug Administration, on the first day, because of the distinguished work he has done. On the second day, we called Dr. Roy Hertz, Assistant Medical Director, Biomedical Division, Population Council, Rockfeller TJni- versity, and a member of the Food and Drug Administration panel and a member who signed the so-called Hellman Report. Dr. Hertz made an important contribution to the FDA report. Dr. Hertz' tes- timony got widespread publicity because lie was critical of many aspects of the pill. But of course, that was his testimony. Then we called Dr. Kistner on the second day because lie is a very distinguished gynecologist, wrote a book on it-a very good book- which I read and in which lie, for all practical purposes, unquali- fiedly endorses the pill. He is a strong proponent, so he was on the second day. On the third day, we had Dr. Hellman, who is the chairman of the Advisory Committee of the Food and Drug Administration. He had very critica.l things to say about the pill. He was chairman and PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6619 he wrote the language, in fact, along with Mr. Goodrich, in which they concluded that the pill was safe within the meaning of the law. Dr. Hellman was widely quoted as being critical of some aspects of the pill. So I would just like to point out to Senator Javits and you that some of the broadest coverage was given to members of the FDA panel. We did not even know what Dr. Hellman would say, but we thought that those who wrote the report for the FDA ought to be witnesses very early. Go ahead, Doctor. Dr. GTJTTMACHER. I think the only influence we have, not covered by question is the influence these hearings are leaving in their path throughout the world. I state in my testimony that Professor Alvarez from Montevideo and Professor LaVergne from Panama actually came to the United States because they are members of the Medical Committee of the International Planned Parenthood, to talk with me and others about these hearings because they are so ter- ribly upset and because patients throughout Latin America' are upset. I received from one of them yesterday- Senator NELSON. Who are these two gentlemen? Dr. GUTTMACHER. Professor Alvarez is Professor of Obstetrics and Gynecology in MontevideO. Professor LaVergne is Professor of Obstetrics and Gynecology in, Panama. You see, we have a world- wide committee of physicians for International Planned Parenthood. Senator NELSON. They came for what reason? Dr. GUTTMACHER. They came to discuss this problem with us here in America. Senator NELSON. What problem? Dr. GTJTTMACHER. The problem of the bad publicity the pill was getting in Latin America, how much was fact and how much was fancy, and because there was panic among their people in Latin America due to publicity which had come from these hearings. Senator NELSON. Are these two gentlemen part of Planned Par- enthood's organization? Dr. GUTTMACHER. They are members of the Central Medical Com- mittee. We have eight physicians throughout the world who are members of this committee, of which I am one. These two gentlemen are two of the other seven. Senator NELSON. I am puzzled as to why they would come to the United States to find what was fact and what was fancy when you have testified that everything that was presented here was in the FDA report. Did they not have that report? Dr. GUTTMACIIER. I am not sure they have had it. As a matter of fact, I received from London an editorial in one of the Pakistan papers, in whiCh the editorial ends with the admonition that they should discontinue the pill in Pakistan. This, of course, is a very serious problem, because I know you, Senator Nelson, are among the great protagonists of world population control. Unfor- tunately, the pill is being depended upon more and more throughout the world for population control, and I feel that this setback has been most unfortunate. Now, I am not blaming you. I think you are taking it for granted that I am trying to levy a certain amount of blame, and I am not blaming you at all. I just cannot help but decry that this has gotten PAGENO="0180" 6620 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY so much adverse publicity in the press. I cannot help but say that nothing really has materially changed. Millions of people were on the pill before the hearings were held, and nothing has happened, really, to their knowledge about the pill. Facts and conjectures have been ventilated to physicians who had less knowledge of the pill and ventilated to a lay public which is allergic to all kinds of scare propaganda. I feel our task is to try to put the thing in perspective so that people realize that the pill is still, to me, a magnificent therapeutic agent which has tremendous necessity, until, as Senator Javits says, this 5-year span can be passed and we have much better and safer methods. Senator NELSON. There is no use going back into that. It is just a question of whether you believe the people of the United States should have all the facts or whether they should not. In my view, I think they should. Many people concerned about the question are concerned that the facts are out; some people may decide not to use the pill and therefore raise the problem about population control. I do not think we ought to use individual persons for sociological pur- poses. Would you agree with the letter sent out by Dr. Edwards, Acting Commissioner of Food and Drug Administration, sent about the 18th of January, in which he states: In most cases, a full disclosure of the potential adverse effects of these prod- ucts would seem advisable, thus permitting the participation of the patient in the assessment of the risk associated with this method. Dr. GUTTMACHER. I am sorry, not admitting the patient? Is that what you said? Senator NELSON. No, I am sorry. The quote I read is that in this letter sent to 324,000 doctors. The last sentence reads: In most cases, a full disclosure of the potential 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. Do you agree or disagree? Senator JAVITS. Do you not think the witness ought to see the letter? Dr. GUTTMACHER. I can evaluate that. I have not seen it, but we have discussed it before. I think it places a great burden on the patient. I think it is impractical, sir. I think the physician has to make the decision. As I have told you, in 35 years of active practice, I cannot pass decisions to patients. Patients pass decisions to me. It is very confus- ing to her when she tries to interpret my testimony and what went before. How is the poor patient to make the decision? I think the doctor has to make the decision. I do not think such a disclosure is going to do much good. I think it is going to do great harm. But if Dr. Edwards wants to do it, I think he has a perfect right to do it. I do not want to build optimism that this is going to solve all our problems, because I think the patient, after she has read all of this, is going to come back to the doctor and say, what shall I do? Senator NELSON. I was just asking for your observation. He sent it to 324,000 doctors. PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6621 Senator JAvIT5. Could that go~: into the record? He said he has not read it. Senator NELSON. It has been in. I assumed, since it was a "Dear Doctor" letter, Dr. Guttmacher had read it. Dr. GtTTTMAOHER. Unfortunately, I do not get all my mail. Senator JAvITS. May I ask unanimous consent that if the letter is not in the record, it be put in the record? Senator NELSON. We can put it in the record at this point in the hearings. (The letter referred to follows:) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, FOOD AND DRUG ADMINISTRATION, Washington, D.C., January 12, 1970. DEAR 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 thrombophlebitis 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. Time 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 time participation of time patient in the assessment of the risk associated with this method. I also request your assi~fance in continuing our assessment of the safety of 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, lYashington, D.C. 20204. Sincerely yours, CHARLES 0. EDWARDS, M.D., Acting Commissioner of Food and Drugs. Attachment: Revised labeling PAGENO="0182" ~UG LX L j A I 1 VI ~ TiTiIi~J5ijii~ijJt~iL~1jj-±EJ- T T~~iT~~IiITi ~iL~ (M 4 II p4 I ~ ~ I ii ,., 4., 1' Al .4 I l'l ) t.n~.CIt~4ed IUbI'IIC'rMO,AUVIIN.K ISKIIC .nq,j A:,1 AN4. poa,. .4I.* A.4'A.:IA 44*44 W4~t4 lIl~ fII11.~.) I4V1,1.v*o I . . *, . I ` `V ,A/n14,,,~, /1 1 4 I 4.I.1L44 ,Ir Ill Al. 1,44 II *1,1*1 *4144 Pl.UW.4.A4. II (, 1 ~ ~`~t ~" r'III~ (41(4. 4.4* , * * 1.4 4444 `IA I'? 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I `~_14_** (l$e*)blII,'sS *P,~~IIl4l4lp~*I)., PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDIJSTRY 6623 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 close 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 hypennenorrhea. 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 oral contraceptives. Your reports of adverse reactions will help us to do this. elflcacy 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 studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis and pul- monary embolism and the use of oral contraceptives. There have been three principal studies in Britain 1-3 leading 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 sevenfold, while Sartwell and associates in the 1 Royal College of General Practitioners; Oral Contraception and Thomboembolic Dis- ease, J. Coll. Gen. Pract., 13 :267-279, 1967. 2 Inman, W. H. W. and Vessey, M. P. Investigation of Deaths from Pulmonary Coronary and Cerebral Thrombosis and Embolism in Women in Child Bearing Age, Brit. Med. J. 2 :193-199, 1968. Vessey, M. P. and Doll, R. Investigation of Relation between Use of Oral Contra- ceptives and Thromboembolic Disease. A Further Report. Brit. Med. J. 2 :651-657, 1969. ~ Sartwell, P. B., Mass, A. T., Arthes, F. G., Greene, G. R., and Smith, H. E., Thrombo- embolism and Oral Contraceptives; An Epidemlological Case-Control Study. Am. J. Epidem, 90 :365-380, (November) 1969. PAGENO="0184" 6624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as non-users. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long continued administration. The American study w-as 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 sig- nificant association between cerebral 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 hoimonal 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 C 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 1)y this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation. 5. In breakthrough bleeding, and in all cases of irregnlar bleeding per vagi- nam, nonfunctional causes should be borne in mind. In undiagnosed bleeding per vaginam, adequate diagnostic measures are indicated. 0. 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 aw-aits further study. S. 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 C therapy. 9. T11e age of the patient constitutes no absolute limiting factor, although treatment with C C 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: Thrombophlebitis Cerebral thrombosis Pulmonary embolism PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6625 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 contraceptives: Hepatic function: Increased sulfobro- Thyroid function: Increase in PBI, and mophthalein retention and other tests butanol extractable protein bound Coagulation tests: Increase in prothrom- iodine and decrease in T' uptake bin, Factors VII, VIII, IX, and X values Metyrapone test 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 populai~ion 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 pregnancy. 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. Senator NELSON. You are going to send us the literature that you distribute? Dr. GtJTTMACHER. That we shall, sir. PAGENO="0186" 6626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. What do your clinics tell the user of the pill? Dr. GUTTMACHER. I think I have said in my testimony that I cannot say, because I do not visit the clinics and see them operate, so I cannot tell you how much time is spent by each physician or nurse who is instructing patients as to the adverse reactions that might stem from the pill. I am moderately certain that if a patient asks questions, they are answered as frankly as the respondent can do it. But at the same time, I think I would be dishonest if I tried to tell you that every time a patient is given a packet of pills, the dis- penser tells the patient about the difficulties. I cannot tell you this. Senator NELsoN. I thought you referred, when the literature was handed out- Dr. GUTTMACHER. I think the literature covers this. This is cov- ered by the literature. I am certain that if a doctor is terribly busy and the patient does not ask questions, he does not pause too long to tell her about the potential dangers. Perhaps he should. Senator NELSON. I really think I should have said what is the patient told, what is the patient given orally, or~ Dr. GUTTMACHER. They are given both oral and written informa- tion. Of course, the oral information helps them choose what method of birth control they are going to select. Senator NELSON. In your own judgment, if a woman decides to use the pill, should she be told anything about the side effects, number one? Number two, should she be advised of any untoward symptoms which should cause her to consult a doctor? Dr. GUTTMACHER. I strongly feel that if you are prescribing a pill to a patient who is not knowledgeable, you have the necessity to tell her that in very rare instances, there are clots formed in vessels which apparently are due to this drug, and that sometimes very dan- gerous situations may develop. I would tell her that this is mathe- matically most unlikely to occur. I would tell her that if there is any departure from her normal health picture, the pill might be responsible for these changes in her feeling of well-being, and that under all such conditions, she should promptly get in touch with the proper medical authority who dispensed the pill. I would not, probably, tell her about cancer, because I think this is totally unproved. I do not think I would tell her about genetic changes, because this is totally unproved. I doubt very much whether I would tell her that her blood lipid are going up or there are going to be changes in liver- Senator NELSON. Would you tell her that the incidence of throrn- boembolism, according to Dr. Lynd's study in England, was 9 times as great? Dr. GUTTMACHER. Oh, yes, I think that is well documented. I am not sure I would use-it is 5 against 45. Senator NELSON. That is right. Now, would you tell her about the symptoms to observe? That is, if she experienced temporary blindness, migraine headaches, ery- thema, swollen legs, all of these things-would you tell her about those symptoms and advise her that, upon the showing of a certain set of symptoms, she should consult a doctor? PAGENO="0187" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6627 Dr. GTJTTMACIIER. I would certainly tell her about the possibility of headache. I would certainly tell her about the possibility of mood changes such as depression. I doubt very much whether I would go into greater detail about other things, but I would try to make her understand that any departure from health should be reviewed by the physician so that he can make the determination whether or not the pill may be responsible for it. Senator NELSON. But do you: think, as the former Commissioner of FDA, Dr. Ley, suggested sOmetime back, and also a number of witnesses have testified, that some literature of this kind indicating what untoward symptoms to look for ought to be included with the pill package? Would you agree with this or disagree? Dr. GTJTTMACHER. I think it might be well to do it. I would prefer to have the doctor do it, but since we cannot depend upon him 100 percent, some literature, assuming it is accurate, might be valuable to put in. I think the patient might read it. Senator NELSON. You are aware, I assume, that in the survey done for Newsweek, two-thirds of the women in that survey stated that they were told nothing about side effects by their doctors? Dr. GUTTMACHER. No. I do not remember that. Senator NELSON. Well, that ~: is in the article. As a matter of fact, the article stated that that is one fact these hearings have dramati- cally demonstrated. Dr. GUTTMACIIER. Yes. (The article referred to follows:) [From Newsweek, Feb. 9, 1970] POLL ON THE PILL-18 PERCENT OF U.S. USERS HAVE RECENTLY QUIT For two weeks last month in hearings that headlines blazoned throughout the U.S., a roster of experts testified on Capitol Hill about the possible haz- ards of oral contraceptives. Most ~: of the headlines were scary-more frighten- ing, indeed, than any balanced perspective of informed medical opinion would justify. But just how scared were the women who are actually taking the Pill? To find out, NEWSWEEK commissioned The Gallup Organization last week to take a reading of the latest attitudes and actions among U.S. women using the pill. The result was an eye opener. Largely because of all the recent publicity, 18 per cent of the 8.5 million U.S. women on the pill-nearly one in five-say they have stopped using it altogether. In addition, 23 per cent say they are giving serious consideratiomi to quitting. What makes the proportion of :w~men who are defecting even more remarka- ble is the fact that many of thein~ also say that they have had entirely satis- factory experiences with the pill. Fully 76 per cent of users say they have been "very satisfied" with oral contraceptives, and another 11 per cent were "fairly satisfied." Moreover, two-thirds of U.S. users continue to believe that the advantages of oral contraceptives outweigh the risks. Forty-one per cent of the women say they have had no side-effects or complications, and 38 per cent attribute their approval of oral contraceptives to their unquestioned effective- ness. "They protect me against something I don't want to happen," said a Grand Rapids, Mich., woman. Quitting the pill-Have you stopped using birth control pills, or are you considering stopping, for any reason? Percent Have stopped 18 Considering stopping 23 Neither 59 PAGENO="0188" 6628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To conduct the NEWSWEEK poll, the Gallup researchers assigned women interviewers last week to telephone a representative national cross section of 895 women between the ages of 21 and 45. About one-fourth of the women reported they had been using the pill during the last three months, and these were interviewed further on their current use of the pill as well as their expe- rience with it and their latest view-s on it. The results are therefore projecta- ble, says The Gallup Organization, to all U.S. women 21 to 45 who have used the pill during the past three months. About 28 per cent of them are college graduates, and 65 per cent hold high-school diplomas. Forty-four per cent are married to men in white-collar jobs with incomes above $10,000. Doubts: Of the total of 41 per cent who have now quit or who are thinking of quitting the pill, a quarter say they have had doubts and anxiety because of side effects they have experienced themselves, or because friends of theirs have had side effcts. A 26-year-old Whittier, Calif., college graduate, for example, told an interviewer of "a girl friend who almost died from a blood clot which was attributed to birth-control pills." A small number of women say they have given them up for no particular reason. But the biggest single group of defectors-roughly a third-said their doubts about the pill w-ere directly related to the hearings of Sen. Gaylord Nelson's Monopoly subcommittee, where some experts testified about a possible link betw-een the use of the pill and scores of disorders including blood clots and cancer. Most of the w-omen who quit because of the hearings were especially alarmed about clotting problems and cancer. A 22-year-old Mission, Texas, housewife quit the pill after five years of use because "I heard that it could cause cancer and heart disease, so I talked it over with my husband and he told me to stop." "I guess with all the talk about clots," said the 24-year-old wife of an East Keansburg, N.J., manual laborer, "I'm beginning to suffer from imaginary symptoms." The influence of the recent bad news about the pill is easy to understand. An astonishing 87 per cent of American w-omen have heard or read about the Senate pill hearings, a degree of awareness rare on public issues or events. And no matter what their ow-n personal reaction, more than a third, on the basis of the reports, are prepared to believe that the pill is linked to cancer, blood-clotting problems, diabetes and heart trouble. There remain, how-ever, a good many w-omen who are not particularly frightened by what they have heard. Twenty per cent of tl1e users believe that the relationship betw-een the pill and cancer, or betw-een the pill and blood clotting, has yet to be estab- lished, and another 14 per cent believe that conflicting testimony has made it impossible to reach positive conclusions about the hazards. "It seems to me most of the people who testified stressed the detrimental effects," said a wary housewife in Morristow-n, N.J. "You could die in childbirth just as easy as taking the pill," noted the w-ife of a Hastings, Neb., laborer. Concern: One of the main purposes of the Nelson hearings was to determine whether w-omen are being adequately informed by their doctors about the sus- pected dangers of oral contraceptives. And in the light of the survey, the sub- committee's concern w-as well founded. A startling two-thirds of pill-taking women say they have never been told about possible hazards by their physi- cians. On the other hand, only 16 per cent of w-omen have taken the trouble themselves to discuss the dangers of the pill with their doctors as a result of the Senate investigation. Most of these w-ere reassured by their physicians that the pill is safe and that they have prescribed it for a considerable time with- out noting serious side effects. An Omaha woman quoted her doctor as saying that he had prescribed the pill "long before they were called birth-control pills and never had any patient get cancer or anything else." Less than 1 per cent of w-omen have found their doctors to be totally against the pill. A Norfolk, Va., w-oman reported that her physician told her oral contraceptives were "not natural." And still other physicians seem evasive to their uneasy patients when asked about the risks of the pill. A 26-year-old Denver woman reported that her physician "couldn't be tied down to an answer." The poll's findings of w-idespread alarm among women who have been on the pill proved consistent with soundings by NEWSWEEK correspondents among leading gynecologists across the U.S. Some said that, unfortunately, they could foresee an increase in unwanted pregnancies. "I've seen three pregnant women PAGENO="0189" COMPETITIVE PROBLEMS : IN THE DRUG INDUSTRY 6629 this week who discontinued the pill about a month ago," said Dr. R. Elgin Orcutt, a San Francisco gynecologist. "Two of the three are applying for a therapeutic abortion." Senator NELSON. Two-thirds of: the women are not being told about side effects. I do not know how you persuade the physician to do it. Do you not think, then, that there is some obligation to see that they are informed? Dr. GUTTMACHER. Yes, I would agree with that. I do not think that is too good a substitute. I would like to get the two-thirds of doctors who are not doing it to do it. Senator NELSON. I would agree with you, but since the fact is that that is what they found- Dr. GUTTMACHER. I think maybe these hearings have created a different attitude among physicians. I think a new Gallup Poll would not give you that figure. Senator NELSON. But about the suspected dangers of oral contra- ceptives, and in the light of the survey, the subcommittee's concern was well founded, a startling two-thirds of pill-taking women say they have never been told about possible hazards by their physicians. This is another reason why, in my judgment, the hearings are nec- essary. Dr. GUTTMACHER. Yes, sir. Senator NELsoN. On these statistics, in the first page, Dr. Gutt- macher, you state that according to a Gallup Poll reported in News- week, February 9, 18 percent of women using the pill had abruptly stopped using it and an additional 23 percent were giving serious consideration to quitting. That would leave the impression that, which I am sure you did not intend, that the Gallup Poll indicated that 18 percent were quitting because of something they had read about these hearings. That was not your intent, was it? Dr. GnTTMACHER. I assumed that was the reason. Otherwise, either these hearings or what they had read in the literature, the Ladies Home Journal and various other publications in the previous 12 months. I do not think they make it quite clear as to the source, but certainly they took the Gallup Poll, because they assumed this was probably going to be the result. I think it is naive to feel that some of this 18 percent, or most of this 18 percent did not stop because of the hearings. Senator NEI~soN. Just going by memory, and I want the record to be correct, my memory is that in the survey 18 percent of the women stopping the pill, 6 percent attributed it to the hearings. So the other 12 percent were quitting it for other reasons. Dr. GUTTMAOITER. I see. Senator NELSON. Of course, I am sure you will agree that that does not mean that that 6: percent, or even that 18 percent, are not going to go to some other method, is that not correct? Dr. GUTTMACHER. A certain proportion will. I do not think you can tell exactly what proportion. I hope the vast number will, but we cannot prove it. I think Dr. Daly found that the prescription of the pill in the tre- iiiendous Health 1)epartment Birth Control Clinics that they have in New York dropped from 67 percent to 47 percent among new patients. That is Dr. Edmund Daly. PAGENO="0190" 6630 CO~ETITWE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. All new patients? Dr. GtTTTMAOHER. All new patients. 67 percent were choosing the pill. After the hearings, it went to 47 percent. Senator NELSON. They went to other methods? Dr. GUTTMACHER. Or are not taking, not using anything, I do not know. Senator NELSON. I would just like to~ point out that without any hearings at all, if you surveyed the women who started the pill today, according to this Chicago study of Dr. Franks, 2 months later, 40 percent will have quit the pill. Dr. GUTTMACHER. I do not know that study. I know the study by Frank & Tietze on 15,000 patients of Planned Parenthood. 70 per- cent were still on the pill after 30 months of use. That is a very dis- tinguished study. I do not know this study that you referred to. But that is an excellent study. And the number of people on the pill is surprisingly high in that study. It is the highest continuation rate that I know of, sir. Senator NELSON. Well, this is the testimony of Dr. Hugh Davis: In a Chicago study, Frank found that 40 percent of those patients started on oral contraceptives abandoned the method within two months. Dr. GuTmrAcHEn. Well, I hate to dispute my friend, Hugh, but I would love to see that article. Because if you got out the Frank- Tietze article, it is black and white that 70 percent or 15,000 patients were taking the pill 30 months after they had started it. This, to me, is an extraordinary figure. Senator NELSON. He goes on to say: In the Maryland Planned Parenthood Clinic- Which he knows of first-hand--- half of the pill patients abandoned the method in less than a year. So you have a massive dropout of pill users going on at all times without any reference to these hearings. Dr. GUTTMACHEIi. Overseas you have more losses with the JUD, the patients discontinuing IUD, than pills. This has been the Korean results. Senator NELSON. I just wanted to have it in the record, because most people do not realize that over half the people quit the pill in less than twelve months. Dr. GUTTMACHER. This is true of all methods of contraception. One of the problems which we have is attempting to study the intel- lectual mechanisms that make people enthusiastic about contracep- tion. We give them one or two good methods, then, for some reason or other, they abandon it. It is very strange. We have not solved this problem. But it is true of 11Th, it is true of the pill, it is going to be true of the diaphragm as well. So they are not dealing with any- thing absolutely unique with the pill, sir. I hate to be discourteous, but I have to catch a plane. I wonder whether it is going to be much longer that you wish me to stay. Senator NELSON. You can run out on us any time you want. But I am all through. Senator Dole would like to ask some questions. PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6631 Senator DOLE. I would like to place in the record this Newsweek article with the poll on the pill. Senator NELSON. We just asked to put that in. Senator DOLE. That is fine. The article does point out that a third of the ladies sampled did stop the pill because of publicity about these hearings. Maybe it is a good thing; maybe they should have all stopped, I do not know. But I would hope, Doctor, that a man with your broad experience and expertise would be able to allay the fears of some people, with reference particularly to charges about cancer and some of the more serious side effects. You may have made the point, in my absence, that the pill is not perfect-not 100 percent safe. But you still feel, even after the testimony you have given on cross-examination, that it is still an effective contraceptive device or method. Dr. GUTTMAOHER. I think these hearings are the best argument in favor of the Tydings-Yarborough bill of anything I know. I think the Chairman agrees with me, :because he is the best protagonist of that bill that I know. Senator NELSON. I am happy to hear you say that, because I just testified on that bill, and I think these hearings will be very helpful in getting that bill passed and in getting substantial increases in funds for planned parenthood research. One of the criticisms made in my appearance on the Tydings bill was that I thought the money asked for in the bill was inadequate. Dr. GUTTMACIIER. Thank you, sir. Seilator DOLE. Thank you, Doctor. (The complete prepared statement of Dr. Guttmacher follows:) STATEMENT OF DR. ALAN F. GUTTMACHER, PRESIDENT, PLANNED PARENTHOOD/ WORLD POPULATION; EMERITUS PROFESSOR, MOUNT SINAI SCHOOL OF MEDICINE; LECTURER, MATERNAL HEALTH, HARVARD SCHOOL OF PUBLIC HEALTH; FORMERLY CLINICAL PROFESSOR, OBSTETRICS AND GYNECOLOGY, COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY Mr. Chairman and Members of: the Select Committee on Small Business, I appreciate the invitation to appear before you in the hearings on the birth control pill, the invitation tendered me as a physician of long standing and as President of the Planned Parenthood Federation. In the latter capacity, I probably have one of the largest birth control practices in the world, since in 1969 slightly more than 350,000 women attended 525 centers conducted by Planned Parenthood in 130 cities of this country (1). I assure you this is a responsibility which neither I nor my organization, particularly its National Medical Committee and its capable Medical Staff, take lightly. Senator Nelson, I believe that the primary consideration for these hearings was the health of American women. I interpret your more specific goals to he twofold-to have potential users of the pill forewarned of its risks and to make the medical profession more cognizant of their responsibilities in its pre- scription. Unfortunately, and I assume you `share my apprehension, there have been undesirable side-effects from these hearings. They have created a sense of great alarm. According to a Gallup poll reported in Ncwsweele, February 9, 18 percent of women using the pill had abruptly stopped using it and an add~- tional 23 percent were "giving serious consideration to quitting." Nineteen highly qualified physicians, members of Planned Parenthood's National Medical Committee, described at a meeting at our headquarters on January 28, that the hearings had caused great distress among patients. One is forced to ask why? NoTE-Numbered references at end of statement. PAGENO="0192" 6632 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Certainly, nothing fundamentally has changed in respect to hazards from the pill since the hearings began and well-informed physicians found nothing revealed by the hearings which was not previously recorded in the published literature or presented at scientific meetings. The Second Report on the Oral Contraceptives, issued by the Obstetrical and Gynecological Advisory Commit- tee of the Food and Drug Administration (FDA), completed six months ago and based on 189 references to the current literature, covered the same data as presented in the January hearings of this body. In many instances, these data were w-ritten by those w-ho appeared as witnesses before you. The FDA Advisory Committee, composed of 14 of this country's most emi- nent, unbiased physicians, public health experts, and highly qualified research scientists, all fully cognizant of this same data, concluded its report with the important sentence which I feel has not been given sufficient emphasis: "When these potential hazards and the value of the drugs are balanced, the Commit- tee finds the ratio of benefit to risk Sufficiently high to justify the designation safe within the intent of the legislation." On January 15, 1970, the American College of Obstetricians and Gynecolo- gists, in the name of its 12,000 members, said in its statement that it "consid- ers that the oral contraceptives are accepted therapeutic methods" and deplored inaccurate and sensational reports concerning these drugs. At the January 28 meeting referred to above the distinguished physicians who form the National Medical Committee of the Planned Parenthood Federation issued a memorandum from which I quote the key sentence, "The Committee contin- ues to recommend the prescription of oral contraceptives." Why do I quote the report of the F.D.A. Advisory Committee, the American College of Obstetricians and Gynecologists, aiid the National Medical Commit- tee of Planned Parenthood? Not to whitewash the pill. But I have compelling interest to place this matter in proper perspective in the hope, with which I am sure you w-ihl agree, of stemming unwarranted and dangerous alarm. The pill is, in my opinion and that of many of my colleagues, a prophylaxis against one of the gravest socio-medical illnesses, unwanted pregnancy. Let us tally the results of unwanted pregnancy, a condition tragically common in the U.S.: Experts estimate that between 200,000 and 1,000,000 illegal abortions are performed each year, w-ith a death rate estimated to be 100 per 100,000 illegal operations when performed by non-medical persons (2). At least one out of six U.S. brides is pregnant when married. Half of the brides are pregnant when the couple are teenagers (3). No less than 300,000 illegitimate children will be born in the U.S. during 1970, based on the experience of the past decade (4). A recent study shows that at least 750,000 children born each year were unwanted at the time of their conception (5). Undoubtedly a significant proportion lead to unloved, neglected, and abandoned children. Perhaps even worse, some become abused or battered children, children physically assaulted by parents or parent substitutes. This tragic condition is being reported more and more frequently in the current pediatric and psychiat- ric literature (6). With all this evidence of social pathology associated with unwanted concep- tion, I believe it is inaccurate to belittle the importance of the contraceptive pill by stating it is a potent drug given to healthy women. What is omitted from such a statement is the fact that the pill is the most effective means yet know-n to prevent a very serious affliction, unwanted pregnancy. It is a serious affliction for the parents, but far more for the children. Now I should like to attempt to separate fact from conjecture concerning the safety of the pill. I believe that it has been indisputably proven that patients taking birth con- trol pills are more prone to the formation of blood clots than those not on the pill (7). Nine times as many w-omen-45 per 100,000 women per year-will be hospitalized as a consequence of this complication than women not on the pill. There is a death rate of 3 per 100,000 per year from the fatal clots in the lungs or l)rain, among contraceptive pill users, a rate approximately 10 times that of non-pill users from the same conditions. These rates, established by British research, have been corroborated by American studies (8). The British scientists who presented these data also prepared separate anal- yses for women aged 20 to 34 and 35 to 44 and, to give a frame of reference PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6633 and a perspective to these figures, they compared the death rate from blood clots to deaths from all conditions associated with pregnancy and with deaths from motor acadents. They noted that among the younger women 22.8 of every 100,000 healthy married women would die as a consequence of pregnancy, compared with 1.5 of every 100,000 women who would die as the result of a fatal clot associated with the pill. Among the older group, 57.6 of every 100,000 women would die as a result of pregnancy, compared with 3.9 who would die of a clot associated with the pill. DEATH RATES PER 100,000 HEALTHY MARRIED FEMALES Age 20 to 34 35 to 44 Thrombosis, lungs or brain pill users Thrombosis, lungs or brain nonpill users Pregnancy, all causes Motor accidents 1. 5 . 2 22. 8 4 9 3~ 9 . 5 57. 6 3 9 These data show that the risk of death from clots among the younger group of pill users is about one-fifteenth the risk of death from' j~regnancy and about one-third the risk from auto accidents. I recognize that fact that not all women who will cease the pill will neces- sarily become pregnant. But were all the women to switch to the next two most effective contraceptive methods-the Intrauterine Device (I1JD) and the diaphragm-the pregnancy rates would be two to four times higher with the IIJD and 10 to 30 times higher among users of the diaphragm (9). Therefore, the risk of death would rise proportionately. To further complicate the picture, use of the IUD also carries a risk of death, of about 1 or 2 per 100,000 (10). I should like to point out also that the death rate associated with pregnancy is even higher in the U.S. than in Britain, especially among poor women (11). These are some of the considerations that must be weighed when assessing the safety of oral contraceptives. In my interpretation of the published data, the only other established fact in this area is that other serious adverse reactions may occur in occasional patients. The more common are high blood pressure, headache, depression, interference with vision, and nervousness. Usually, these side effects are reversible and disappear if contraceptive pills are discontinued promptly. These rare adverse affects are well known to physicians and appear in the labelling of the drugs. Now, as to metabolic changes: I recognize that fact that there are extensive changes in the body chemistry of some women taking the pill. But no proof exists in the medical literature, nor has any been presented before this Com- mittee, that these changes are or will be harmful. Furthermore, in some patients the changes revert to normal while they continue on the pill; in others, when the oral contraceptive is discontinued. In addition to these facts, there are conjectures about the pill. In underscore conjectures. First, that it may be carcinogenic, cause cancer. Dr. Roy Hertz has stated before this Committee that to date no case of cancer in either a monkey or in a human being can be attributed to the pill. Many physicians and investigators believe that the fact that cancer can be produced in five species of animals (rodents and one breed of dog) by rela- tively huge daily overdosages with estrogen, comparing their body weight with that of a woman, produces little evidence that the contraceptive pill is likely to cause human cancer. Dr. Hertz is concerned that the hormone, estrogen, a component of the pill, may cause cancer in two target organs in women on the pill: the breast and uterus. This is conjecture, by Dr. Hertz' own testimony. It is of interest, I believe, that the American Cancer Society reports that there has been no increase in breast cancer mortality in the decade since the pill has been in use in the U.S. (12). This does not negate the possibility there may be an increase in the future in breast malignancy from the pill, but I believe the fact cited above deserves mention along side of Dr. Hertz' conjec- ture. 4O-471-70-pt. 16-vol. 2-13 PAGENO="0194" 6634 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY As to cancer of the cervix, the scientists who have done the most extensive study of this problem to date concluded that their findings do not establish that the pill causes the condition (13). And they stated unequivocally, "It is our conviction that death and disability from cervix cancer in any population can be eliminated, regardless of the method of contraception used, if a pro- gram of yearly Pap examination is established and all cases of carcinoma in situ (early cancer) are treated." The scientists concluded with this highly sig- nificant observation, "So long as regular visits to a physician are mandatory for women who are using the steroid contraceptives (the pill) 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 grOut) of women." The American Cancer Society verifies, as a matter of fact, that as a conse- quence of early detection by means of the Pap smear, death from cervical cancer has dropped in the past decade. This is not conjecture, this is fact. The second conjecture I should like to deal with is that the pill, particularly if taken over a long period of time, may in some cases cause irremediable ste- rility. As the FDA report pointed out there is evidence that "resumption of ovulation is usually prompt, within 4 to S weeks in most cases." Some few women, how-ever, have difficulty in becoming pregnant perhaps though not cer- tainly as the result of the pill. Their problem fortunately can be corrected by appropriate therapy. It is strange how the medical pendulum swings; for years it was I)eheved that there was heightened fertility after one stopped the pill. Perhaps this still may be true. A third conjecture is that taking the pill may damage the chromosomes of ova within the ovaries. It may. But if this were true with the millions of American women having stopped the pill to achieve pregnancy, one would expect a sharp increase in congenital abnormalities. This has not happened. I should now like to turn attention to the allegation that physicians do not forewarn recipients of the potential hazards of the pill, nor follow them with sufficient care. This may be true in some few instances: but in my experience physicians have behaved responsibly and with the best interests of their patients in mind. This is certainly true in organized clinic programs where careful attention is paid to the instruction of patients in the use of various contraceptives. th Planned Parenthood clinics w-e have provided careful guidelines for the respon- sible prescription of oral contraceptives since they were introduced in our clin- ics. Earliest notices to our medical personnel regarding the oral contiaceptives called attention to side effects and urged careful medical supervision. We have monitored research findings meticulously and have made these findings avail- able to our Planned Parenthood physicians. More than four years ago, on January 26, 1966, the National Medical Committee of Planned Parenthood issued a directive to all Affiliated centers outlining the following procedures for prescription of oral contraceptives: 1. Initial Examination: Prior to receiving oral contraceptives a patient shall receive a complete pelvic examination including visualization of the cervix, a Papaniėolaou smear, and examination of the breasts. The examination of other systems, including appropriate laboratory investigations, shall be determined by medical history. 2. Follow-up Examination: a. One month following initial prescription: Consisting of an interview for teaching and instructional purposes and for assessing complaints. If the latter are severe or unusual the patient should be seen by the physi- cian. b. Six months following prescription: An interview for assessing com- plaints and a complete pelvic examination. c. Annual examination: Subsequent to the six month examination, all patients should be seen annually and receive a complete pelvic examina- tion, including a Papanicolaou smear and a breast examination. I am proud to say my organization has not deviated from this policy. I also wish to state that new patients attending Planned Parenthood Centers are and always have been offered a wide latitude of choice in the selection of PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6635 a contraceptive method. The several available methods are described to them either in groups or individually, depending upon the volume of patients, by either a doctor or a nurse. Ordinarily, questions are answered freely and hon- estly. Quite frankly, I cannot say whether potential risks of the pill are always I)resented by the discussant or : only in answer to questions. I would assume this varies, depending upon the practice of the individual discussant. After a long career in private, full-time practice of obstetrics and gynecol- ogy, I have little faith in the value of detailing the hazards of a drug, as printed on a label, to a patient. In the final analysis, for all but the most well-informed and intelligent patients, therapeutic decisions are made by the physician. Undoubtedly, in most instances, even after a patient reads a label or a printed insert about risks of the pill, she would turn to her physician and ask, "Is it safe," The physician who has just studied the patient's medical history and com- pleted a thorough physical examination is best qualified to answer her ques- tion in consideration of her special needs. Another area I should like to explore is, How necessary is the pill, I think it is very necessary. Of the 350,000 patients who attended our centers in 1969, 76 percent chose the pills. Its acceptability is mirrored in patient growth figures. The pill was introduced by us in August 1960, but few of the 122,498 women that year who sought our services received it. In the year previous to the introduction of the pill, increase in patients had been 4,000; but in 2 years, 1960-1962, we added 60,000 to our rolls. The number of patients has doubled since 1962. Undoubtedly, the growth is due to multiple factors, but aniong them all I feel quite certain introduction of the pill has been the most important. Why is time pill so acceptable, First, it is so protective against pregnancy- almost as protective as celibacy-resulting in less than one unplanned preg- nancy among 100 women using it for One year (14). This is no small consider- ation. We are all aware that fear of pregnancy can have serious adverse affects on the stability of a marriage. Second, the pill is simple to take, requir- ing little effort on the part of the user. Third, the birth control pill permits wholly spontaneous marital relations, since no contraceptive measures have to be instituted to achieve full protection from impregnation before, during, or after the sex act. This has tremendous psychic advantage to a. host of women and to their husbands. Some witnesses have assumed that some other equally effective contraceptive method can and will be readily substituted and accepted by anyone. I chal- lenge this assumption. In the first place, no other birth control method equals the pill's protection against pregnancy. An IUD (nearest the pill in effective- ness) carried an annual failure rate of 3 per 100 users, while the diaphragm in a clinic population results in approximately 18 unplanned pregnancies per 100 users per year (15). Even among college educated women the diaphragm shows a substantial failure rate. Failures in contraception are of grave impor. tance, particularly since state laws prevent correction through safe, legal abor- tion. In the second l)lace, I am extremely concerned that many women who aban- don the pill through fright will not substitute another contraceptive because no other method has the high degree of acceptability for them. Dr. Philip Sarrel, in his excellent Yale-New . Haven Medical Center studies (16), has shown that recidivism in illegitimacy among high school students can be almost wholly prevented by the combination of humane counselling, education, and careful prescription of the pill. I fear that if these same adoles- cents were to abandon the pill, through fear of the health risk, few would be able to find a replacement method. The pill is to date by far the best contraceptive for sexually active adoles- cents, judged by the experience of private physicians and by physicians in teen clinics in Baltimore, New York, San Francisco, among other places. In my esti- ination no other method compares with it. Apparently even Dr. Hugh Davis of Johns Hopkins who so thoroughly castigated the pill before you in January, agrees with this opinion. Dr. Davis is the clinician for Maryland's Planned Parenthood Youth Relationship Project which, among other services, provides contraceptive services for sexually~ active teenagers, many of whom have not yet become pregnant. He placed 23 on the pill while inserting IUD's in 14. Dr. Arthur Lesser, Director of the Maternal and Child Health Service in the PAGENO="0196" 6636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Department of Health. Education, and Welfar~, estimated that if current national trends continue, during 1910 approximately 70,000 girls under 18 years of age will have a child out-of-wedlock (17). If the pill scare continues unabated. I fear that figure will become a gross underestimate. Nor are the harmful consequences of alarm over the pill likely to be confined to unmarried women. I feel that insufficient recognition is being given to the pill's singular contri- bution to the happiness of married couples and the stability of their mar- riages. Rather than theorize and quote statistics, I should like to read excerpts from a letter received February 3 from a woman living in Alma, Michigan: "Being a voluntary user of the pill for six and one half years, I feel that I should say something in defense of the birth control pill, because I feel it is possible that only those persons who are speaking out against the pill will be listened to. "The men I know of whose wives take birth control pills, my husband included, enjoy their wives more because they don't have to worry about get- ting their w-ives preguimnt each time they make love, or worry about supporting a large family. or worry about not being able to give each child enough indi- vidual love and some of the material joys of life. There is the joy of being able to make love more often, if the couple so desires. `But I feel that just because these pills are harmful to some, they shouldn't be banned from all women. The w-omen I know who have had troubles are few, whereas the women who take them without any difficulty are many. I have discussed the possibilities of dangers with women after the frightening articles in a national magazine, and we all agreed that the best advice anyone could be given is to find a doctor you trust, follow his directions for taking the pill, and have frequent check-ups. "The thought of banning oral contraceptives just because some people cannot take them would be as frightening as banning the use of penicillin or other drugs, just because they are harmful to some. "I truly hope the few people who are fighting the birth control pill will lose their battle. so that the many of us who want to take it and have an easier and safer way of controlling the size of our families, may do so." The third matter I should like to discuss is use of the contraceptive pill abroad. especially in the developing nations. I can speak to this issue from extensive personal experience. As Chairman for four years of the Medical Committee of the International Planned Parenthood Federation, and now as a member of that Committee, I travel three months of every year observing birth control clinics all over the world. Both the IUD and the pill are used abroad. In Singapore, where a signifi- cant reduction in birth rate has been achieved through birth control programs sponsored by the Ministry of Health, the oral contraceptive is used exclusively. In Hong Kong and Egypt the pill and IUD are both employed. In Taiwan and South Korea the oral contraceptive is used as a back-up mechanism in patients who cannot tolerate the IUD. In the birth control clinics of Latin America the pill is used more widely than the IUD. It concerns me that the alarming reports emanating from these hearings have burst the confines of American news media and have gained prominence all over the world. Distinguished physicians from Uruguay and Panama, in behalf of colleagues working in the family planning movement in Latin Amer- ica, have been in consultation with me seeking advice. Should we caution our colleagues to cease prescribing the pill? I answer with a strong, No! We support the use of the pill abroad for the same reasons we support its use here: It is an important preventive health tool. Maternal mortality is hideously high in many of the developing countries- estimated at several hundred maternal deaths per 100,000 birth in Africa and much of Asia and Latin America, for example (18). Infant mortality, too, reaches almost unbelievable figures-in some countries as many as one-quarter of all babies die in the first year of life (19). It is against these risks that the proven annual mortality of 3 deaths per 100,000 pill users must be weighed. Sound programs of maternal and child health are a necessary essential coin- ponent of population control programs. Surely, with world population soaring and bringing in its wake malnutrition and starvation, overcrowding and increasing illiteracy, joblessness and hope- PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6637 lessness, it *ould be foolish to abandon use of this particular contraceptive and other methods such as the IUD, because of the infrequent health risks attendant upon their use. Effective conception control is an important remedial effort the world over. These hearings can have one important, positive effect: To highlight the des- perate need for much more research in the area of contraceptive technology and reproductive physiology. We do not have the perfect contraceptive. Both the pill and the IUD, while vast improvements over older methods, leave much to be desired. In addition to the safety factor, these methods require medical supervision and are therefore costly and unavailable to many women around the world. Sizeable numbers of women cannot use one or another or both. The continuation rate after two years for our best methods is not good enough. What we need is new methods that are sdfe, free of side effects, cheap, require little medical supervision, act over a period of time, and are reversible when a woman wants to become pregnant. A massive research program must be undertaken not only to document the true health status of the present oral contraceptive, to remove the issue of their safety from the current polemic status to the status of incontravertible scientific fact. Research must also be undertaken to develop as rapidly as pos- sible a multiplicity of safe and effective birth control methods to be used either by the female or the male. To carry out such a broad and complete research program two elements are necessary: Talent and Money. Scientific talent is available. But the field of conception control research must be given the same glamour, urgency, and long-term funding now assigned to cancer, stroke, and heart research, to attract first-rate minds to the field. Money has not beemi available from the Federal government in anywhere near the amount needed. Contraceptive research has been the stepchild of med- ical research, starved, ignored. What is required is sizeable, long-term funding of a magnitude that is possi- ble only from the Federal government. The sums thus far allotted have been totally inadequate. For this fiscal year, for example, oniy about $5,000,000 has been requested by Federal agencies for both contraceptive development, and research into the safety and effectiveness of existing contraceptives. Over the years, a variety of voices have raised the issue of adequate fund- ing for contraceptive research. In 1967, a group of experts recommended to the Department of Health, Education and Welfare an expenditure of at least $150,000,000 a year for research in reproductive biology; expansion of support for social research and training in population problems; a family planning and research demonstration fund of at least $10,000,000 a year. Needless to say, these funds were not forthcoming (20). In 1968, the President's Committee on Population and Family Planning rec- ommended that a minimum of $30,000,000 be allocated for biomedical and social science research and training in population in Fiscal 1970 and $100,000,000 in 1971. Needless to say, these sums have not been made available (21). I would like to call to time attention of members of this Committeee action pending before Congress which can change this state of affairs. A bill sponsored by Senators Joseph Tydings and Ralph Yarborough, and co-sponsored by 86 Senators and Representatives from both parties, urges a five-year authorization for "medical, contraceptive, behavioral and program ~mpIementation research in the area of family planning." The cost of this research would range from $35,000,000 in Fiscal 1971 to $100000000 in 1975. It is my strong plea that the distinguished Senators forming this Committee support time Tydings-Yarborough bill when it comes to the floor of Congress. rphjS will be a positive way for you to show your concern for the health and well-being of the women of our country as well as women all over the world- and for the population problem that poses such a threat to the w-ell-heing of all mankind. r(~hank you. REF1mEKcI~s 1. Research Department, Planned Parenthood/World Population. 2. rplefze Christopher, Lewit, Sarah. "Abortion," Scientific Ainerican~ Vol. 220, No. 1. Jan. 1969, p. 23. Tietze, Christopher, Studies in Family Planning, #45, Sept. 1969, pp. 6-8. PAGENO="0198" 6638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 3. Duval, Evelyn M. and Sylvanus. Sex Ways-In Fact and Faith: Bases for Christian Family Policy, Association Press, N.Y. 1961. 4. Ventura, Stephanie J. "Recent Trends and Differentials in Illegitimacy," Journal of Marriage and the Family, Aug. 1969, pp. 446-449. Trends in Illegitimacy, United States-1940-1965, Vital and Health Statistics, National Center for Health Statistics, Series 21, No. 15 (U.S. Depart- ment of Health, Education, and Welfare, Wash., D.C. 1968). 5. Bumpass, Larry, Westoff, Charles. Paper presented at Annual Meeting, Planned Parenthood/World Population, Oct. 28, 1969. 6. Heifer, Ray E., Kempe, C. Henry. The Battered Child, University of Chi- cago Press, 1969. Siever, Larry B., Dublin, Christina C., and Lourie, Reginald S. "Does Violence Breed Violence? Contributions from a Study of the Child Abuse Syndrome," American Journal of Psychiatry, 126.3, September, 1969, pp. 152-55. 7. Inman, W. H. W., Vessey, M. P. "Investigation of Deaths from Pulmonary Coronary, and Cerebral Thrombosis and Embolism in `Women of Child- bearing Age," British Medical Jonrnal, 27 April 1968, pp. 193-205. \T~~5~y, M. P., Doll, Richard. "Investigation of Relation between Use of Oral Contraceptives and Thromboembolic Disease. A Further Report," British Medical Journal, 14 June 1969, pp. 651-657. 8. Sartwell, P. E., Chairman. "Report of the Task Force on Thromboembolic Disorders," Second Report on the Oral Contraceptives, Aug. 1, 1969, Appendix 2. 9. Second Report on Oral Contraceptives, p. 4. 10. "Report on the Intrauterine Contraceptive Device, Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, Jan. 1968. 11. Statistical Abstract of the United States, 1969 p. 55. 12. Private communication to Medical Department, Planned Parenthood/World Population. 13. Melamed. Myron R., et al. "Prevalence Rates of Uterine Cervical Carci- noina in situ for Women Using the Diaphragm-Oral Steroids," British Medical Journal, 26 July 1969, pp. 195-200. 14. Second Report on the Oral Contraceptives, p. 15. 15. Ibid., p. 15. 16. Sarrel, Philip M., Davis, Clarence D. "The Young Unwed Primipara", American Journal of Obstetrics and Gynecology, July 1, 1966, pp. 722-725. Sarrel, Philip M., Klerman, Lorraine V. "The Young Unwed Mother", American .Journai of Obstetrics and Gynecology, Oct. 15, 1969, pp. 575-578. 17. Lesser, Arthur, J. paper delivered Los Angeles, California, Feb. 8, 1968. 18. Africa's Population Problem, Victor-Bostrom Fund. Report #11, Spring, 1969. 19. Population Reference Bureau, 1969 World Population Data Sheet, 20. Harkavy, 0., Jaffe, F., Wishik, S. M. Implementing DHETV Policy on Family Planning and Popnlation, Sept. 1967. 21. Ponulation and Family Planning, Report of the President's Committee on Population and Family Planning, Nov., 1968. (A subsequent statement. submitted by Senator Nelson follows:) STATEMENT BY SENATOR GAYLORD NELSON During the hearings on the oral contraceptives, there was some discussion as to how many women stopped taking the pill as a result of the hearings. Ex- travagant claims were made that a considerable number of women went off the pill, and this would result in many unwanted pregnancies The history of the pill indicates that the vast majority of women would have gone off the pill over the years, hearings or no hearings. Studies indicate that 25% to 50% of women w-ho start to use the pill have over the years stopped its use within 3 or 4 to 24 months. In fact, as far back as April 1, 1963 the Director of Marketing Research for Searle and Company in a memorandum to the firm's medical director stated that: "WTe discovered that as high as 70 to 75 percent of all patients w-ho take Enovid do not continue its use beyond three months." Indications are that a substantial percentage of those who go off the pill do so because of undesirable physiologic reactions they experience. This necessi- tates initiating an extensive research and development program which has been neglected during the last 10 years while the pill has been on the market. A recent survey released on April 29, 1970 indicated a small drop in the use PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6639 of the pill. Whereas a year ago 72% of their patients desiring contraception were using the pill, the present level was about 65%, a drop of 7%. The survey indi- cates, however, that almost all those who have discontinued the pill have gone to other methods of contraception. AMERICAN ASSOCIATION FOR MATERNAL AND CHILD HEALTH, INC. 806, 116 S. MICHIGAN AVENUE, CHICAGO, ILL. 60603 PUBLIC RELATIONS DEPARTMENT-AC 312-782-3618-PREsS RELEA5E FOR APRIL 29, 1970-3 P.M. Since the Subcommittee on Small Business, chaired by Senator Gaylord Nelson of Wisconsin, began hearings on "The Pill," sensational headlines have appeared in newspapers across the country and physicians have been busy handling inquiries from concerned women on the subject of oral contraception. In addition, statements have appeared recently in the public press on the effect of the news reports emanating from the Hearings. Many statements have indi- cated that a significant percentage of users of oral contraceptives were suffi- ciently worried to discontinue this method of fertility controL At the North American Conference on Fertility and Sterility held in late Feb- ruary at Dorado, Puerto Rico, clinicians were again warned that there were possible adverse effects from the use of: The Pill, such as amenorrhea, infertility, and electroencephelographic changes. On the other hand, they frequently cited the lack of objective evidence for cause and effect relationships between The Pill and certain alleged side effects, pointing out that in many cases impressions are being taken as facts. All of these events are of serious concern to the prac- ticing physician. At the February executive meeting of the American Association for Maternal and Child Health, it was decided that the practicing obstetrician/gynecologist could make a valuable contribution to knowledge in this area. Accordingly, the Board of Directors asked the Association's executive secretary, Harold J. Fish- bein, to conduct a survey among the approximately 13,000 obstetrician/gynecolo- gists to determine their attitudes and recommendations concerning birth control methods. There was a high interest in the aims of the survey, and over one fourth of the physicians replied to the lengthy questionnaire. Summarizing the responses, 3,240 (97%) physicians believe oral contraceptives are medically acceptable; 61 (2%) believe they are not, and 51 (1%) are unde- cided. This vote of confidence for The Pill is the result of a careful balancing of the risks and benefits involved. The survey asked physicians to rank contracep- tive modalities, considering pregnancy risk, general user health, and patient convenience. The results of the process appear below: oral contraceptives, with a ranking of 1.6 on a scale of 1 to 9 (where 1 indicates high desirability and 9 indicates low preference), are still the preferred method of birth control. Next, with a ranking of 2.7, was sterilization, followed by the intrauterine devices at 3.0. PHYSICIAN RANKINGS OF BIRTH CONTROL METHODS I J If 2I3~ 41 5! 61 7i~ ~t ~ 1 - Medically Most Desirable 9 - Medically Least Desirable Though practicing physicians continue to endorse oral contraceptive use, many women have reacted to the recent publicity about the safety of The Pill. Obstetri- clan/gynecologists report that new patients asking for oral contraceptives have declined by 20% since the recent publicity. Further, established patients using oral contraceptives asking about safety tripled in the same period. Usually these patients are just seeking reassurance. After a discussion with their physician PAGENO="0200" 6640 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY about the comparative risks and benefits of all the available birth control metis- ocis, 82% elect to remain on The Pill. Despite current observations of a 20% drop in oral contraceptive use among new patients and 18% among especially concerned patients, these physicians report that when all patients under their supervision are considered, the decline in the Pill's use is much smaller. A year ago, 72% of their patients desiring contraception were using The Pill. Now they estimate this level at 65%, a drop of 7%. [In percent] Percent of patients using- Now Last year Oral contraceptives Diaphragms 64.5 6.7 72.0 4.8 IUD 8.9 6.3 Rhythm 39 3.4 Condoms 3.1 2.6 Foams or jellies Sterilization (husband or wife) Douches 5.5 2.3 3 4.6 2.2 3 Coitus interruption No method .6 2.7 . 5 2.7 Apparently physicians have no strong preferences for other modalities than the oral contraceptive. Gains for the other birth control methods, as a result of declined Pill usage, have been across the board. One possible exception noted was that when physicians opt to change a patient from oral contraceptives for health reasons, they tend to avoid giving intrauterine devices. Based upon the findings that practicing physicians consider the oral contra- ceptive to be the most desirable method of birth control, the Board of Directors of the American Association for Maternal and Child Health, Inc. voted to re- lease the findings of the survey at a public press conference at 3 P.M., April 29, 1970, to send the press release to all interested agencies, to present the report to all practicing obstetricians and gynecologists in the United States. through the bi-monthly Newsletter of the AAMCH, and to lay readers through Mothers- to-Be, and the American Baby, Inc., the Association media for parent partici- pant membership. Senator NELSON. The next witness is Dr. Mary Lane, clinical director, Contraception Service, Margaret Sanger Research Bureau. Dr. Lane, I apologize to you and to the rest of the witnesses for having proceeded so slowiv this morning, as sometimes happens in hearings of this kind. We did want Dr. Gntt.macher and everybody else to have the time they need. Now I see we are up against a schedule problem. We have to abandon this room at ~ p.m., and I did not know that before now. STATEMENT OP DR. MARY E. LANE, CLINICAL DIRECTOR, CONTRA- CRPTION SERVICE, MARG'ARET SANGER RESEARCH BUREAU, NEW YORK, N.Y. Dr. LANE. Senator Nelson, I was very happy to have been invited to appear before this committee. I would like to point out that I am responding to an individual invitation to me. I am not simply accompanying Dr. Guttinacher. Senator NELSON. That. is correct. We are very pleased to have you. Dr. LANE. Thank von. Your letter to me sucgestcd that I speak of the pill as I see it from the standpoint of a practicing physician. This is one of the things I like to talk about most, not necessarily the pill, but contra- ception in general arid what my general ideas are about the way con- traceptive care should be given. Mv experience in this field really antedates my appointment to the Sanger Bureau. In my general practice of medicine for some 8 years, I, of course, rendered contraceptive service to my patients. PAGENO="0201" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 6641 For 2 years prior to my going to the bureau, I administered the medical seii~vices for the planned parenthood mobile unit in New York. So my experience with patients in providing personal medical care in the field of contraception to patients, I think, is fairly con- siderable. In rendering contraceptive care to a woman, there is no considera- tion more important than the choice of method. For unless the method is one which is right for her, it is little better than no method at all. If you were to ask me my golden rule for rendering contraceptive care, I would give you this: There is no best method of contraception. Suit the method to the woman. In order to do this, I must evaluate her from the standpoint of her medical history, her physical findings, her sexual history and coital practices, her present social situation into which the use of contraception will now need to fit, to some degree her financial situa- tion, her intellectual capacities, her degree of motivation, the strength and the reality of her desire not to become pregnant, the attitudes she holds about her own sexuality and about various meth- ods of contraception as well as the attitudes of her sexual partner with respect to the same things. My function and responsibility as a physician are manifold. It is to assess all these variables and to help my patient come to grips with them. It is to see that she is knowledgeable about the methods, each sharing equal time with the others, the mechanical with the hormonal. It is also to inform her of what she might expect from each of the methods from the standpoint of effectiveness and of the most common and the more important side effects, to the best of my knowledge. But it is also my responsibility to help her see these pos- sible effects in perspective, to allay irrational fears, certainly not to intensify them or create new ones. In this way, my patient arid I together may arrive at an intelli- gent choice. She has come asking me for advice. She leaves me confi- dent that I have rendered that for which she has asked to the best of my medical knowledge, experience and judgment, and that I have neither made the decision with regard to method for her nor left the decision entirely up to her. A method that is theoretically most effective (that is, the hor- monal agents) will not prove to be the best method for my patient if she is psychologically not disposed to use it through fear, lack of motivation, or what-have-you. She will not use it or will use it poorly, risking pregnancy either way. Just as in'iportant, a mechani- cal method such as the diaphragm for which my patient is unable or tmwifling to assume the responsibility is going to be equally ineffec- tive. In most cases, if contraception is needed at all, it needs to be a method that can be relied upon, given a woman with a particular temperament and given a particular set of circumstances. A nebu- lous potei~tia1 risk of low, almost negligible magnitude measures poorly against the immediacy of remaining not pregnant and what to do with a not wanted pregnancy. This is not to say that all should have the pill, any more than I woul.d feel that all couples wanting to spa.ce their children should use the diaphragm. This is to say only that as a physician, I must PAGENO="0202" 6642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY equate all the known risks involved in an individual situation and let my medical judgment prevail. The same judgment must he brought to bear with respect to the intrauterine device. Not only is it sometimes not possible to insert it, hut it does not afford the complete reliability that is necessary in many cases, and by no means have all the risks of the method been ironed out. For the older but not yet menopausal woman, I have prescribed the pill with great advantage from the standpoint of emotional well-being and the continued (or sometimes new-found) tranquility of her sexual life. The pill is a powerful force. I have seen women undergo a meta- morphosis of appearance, mood, attitude about themselves, and a widening of their horizons on the pill that was never possible for them with the less-efficient forms of birth control. I have seen women go to pieces emotionally when deprived of the use of the pill upon which they have become dependent for their sexual happiness. And I have seen unfortunate and unwanted pregnancies in the inter- val during which they have stopped to give their system "a rest," or to test whether or not they can still ovulate. I recognize that there are no perfect forms of contraception-that they all have medical, physiological, psychological, technical draw- backs of one sort or another. But I handle the pill as I handle all the other methods, prescribing it judiciously, following my patients carefully, and discontinuing it when it is no longer serving a useful purpose or when it is creating discomfort for my patient out of all proportion to its benefits. In fact, is this not the way that any medi- cation is handled by any knowledgeable physician ? Thank von. Senator NELSON. Thank von very much, Doctor. Obviously, you d~scuss the method of contraception in great detail with your patients. What, if anything do you tell them about side effects or symptoms which should cause them to consult you? Dr. L~~XE. I do this personally with my patients, and in addition to this, the nursing staff at the bureau now, and in the mobile unit when I was there, also assumed a great deal of this responsibility. We tell them, by and large, the side effects which they are most likely to encounter. We tell them also, now. "this is the one thing that we know definitely about the risk from the use of the pill, it has to do with the question of thronuboembolic phenomena." And we give them statistics in this respect. However, the nurses usually stop pretty much at that point and say to the patient, "now, it is up to you and the physician who sees you from this point on. The physician is going to very carefully review your medical history, go over all of this with you. There are certainly certain contraclications to your using the pill, but the phy- sician will take of this." This, then, is where we take un the respon- sibility. I go through all of this with the patient before, usually, she has made her final decision. There are certainly certain contraindications which I pay very strict attention to. If these exist, of course, the patient must use some other method. PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6643 But in taking all of these other factors into consideration would have a bearing on the method that the patient chooses, I act to emphasize only those things which I feel are of personal, immediate importance to her. Therefore, I can say that rarely would I go down a list of potential hazards if I am not prepared to state that they are terribly important to her at the moment. Senator NELSON. What do you think the user ought to be advised about the symptoms that may demonstrate problems, then or later? Dr. LANE. Certainly I think she should know what the most common symptoms are of thrombophiebitis. This we not only tell her, but we list as part of our information that we give her in writ- ing. I think also that she should be told about migraine headache, either the occurrence for the first time or an increase in the severity of it or frequency of it. As I previously said, aside from the usual things that a patient just going on the pill will be concerned about, such as nausea, per- haps, mild headaches, perhaps, fatigue, mild depression-this sort of thing-then I do not go any deeper unless there is a particular reason for doing so. Senator NELSON. You do advise them about mild depression and fatigue? Dr. LANE. Yes. Senator NELSON. And that under those circumstances, they ought to consult you? Dr. LANE. Well, of course, we tell our patients in general that if anything at all occurs which they have not been familiar with before, to assume that it might have something to do with their con- traceptive method and let us know about it so that we can be sure, and our patients do this. Senator NELSON. How often do you require all patients on the pill to have a regular physical examination? Dr. IJANE. Absolutely we do. She gets an examination when she chooses her contraceptive method, no matter what it is. She is seen again, no matter what the method is, within a month to 6 weeks. Then, on the pill, she is seen every 4 to 6 months thereafter; usually every 6, but occasionally every 4. Senator NELSON. Do you agree with the statement I read some- time back from the "I)ear Doctor" letter of Dr. Edwards to all the physicians in the country, sent in January? It says: In most cases, a full disclosure of tue potential adverse effects of these prod- ucts would seem advisable, thus permitting the participation of the patient in the assessment of the risks associated with this method. Dr. LANE. I agree with it in principle, and I think in principle, I do this. But I do not feel that it is practical to go down a list of vague complaints with a patient. I myself have noticed in practicing medicine that the more you suggest to a patient, the more she will turn up to complain about. People are suggestible beings. I would like at this point-I think this is a good time to mention it-to say something about the statistics that Newsweek came up with with respect to the number of patients who say that they were no told anything with respect to side effects or possible hazards of the pill. You know, Senator Nelson, I just cannot accept that statis- PAGENO="0204" 6644 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tic as gospel. because I have learned that patients frequently hear what they are prepared to hear, and they reject what thy are not prepared to accept. I can give you a very good example of this. If there is anything that they are very, very careful about when we are informing patients about the ITJD, it is that there is any- where from a 2 to 3 percent risk of accidental pregnancies associated with the use of the JUT). We think that this is extremely important in order for them to decide whether or not. they want to use it. We never omit this in our general lecture to the group of new patients or when the physician sees the patient personally or during the sign-out. the individual sign-out by the nurse. Yet so many times, when the patient does become pregnant, she has never heard that before-"no. you never told me that, or I never would have accepted this method in the first place." Therefore. I cannot. accept necessarily that two-thirds of those women really were not. told anything about the possible side effects. Senator NELSON. Then if that is the case, does that not make the reason all the more compelling that something should be given that is understandable to the patient? Dr. LANE. On the- Senator NELSON. If they cannot remember t.hat they were told that. how can they remember, if they get a migraine headache which they might think is normal, how can they remember 2 or 3 years later to consult tile doctor? Dr. LANE. On the surface, this would seen-i very sensible. Yet I wonder how many of the patients would have this information at hand when they needed it? Our pat.ients lose their appointment cards, they lose tile telephone number of the clinic and the statement of clinic, hours: they lose the thing that we write for them very dili- gently with respect. to how to go about it when they call for supplies or to ask questions and so forth. We give them long, Printed instruc- tions. They are not tedious, but they are long, with respect to the use of every method that we give. They take home with them a copy of the instructions to keep, we do not. care where-in their dresser drawer, on the bulletin board, anywhere. Yet how many times do pat~ent.s call us or come back to t.he clinic and say, well, I had breakthrough bleeding on the pill, what do ~ do? Or they come back and have omitted the pills because they had breakthrough bleeding and were anxious about it and did not take any more until they caine. We say, well, where were your instruc- t.ions? They were very clearh- printed. The answer is, I don't know were they are. Senator NELsoN. Does not Dr. Lev's suggestion avoid all of that, which was to put. those instructions in the pill package so that every 30 clays, the have it when they open the package? Dr. LANE. I do not think they will reacT the pill package. When they come back to us. we encourage them to make telephone calls if the hal-c an problem at. all. We encourage this. We tell them, we are going to follow on to the best of our ability and insofa.r as you will allow us to do so. So we pick up things when they come. When they come back t.o us-I really do not see any useful purpose, either- I might be anticipating your question, but I do not see any real PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6645. advantage in even at that time going down a series of possibIe~ symptoms, 25 or 50 or so, and saying, have you had in the past 6 months this, this, this, or this? Now, we do this, mind you, in the running of our research studies for particular methods, because a pharmaceutical company has to have this information, the FDA has to have this information. But if it is not such a method, what is the purpose of doing all of this? I think I get much more valuable and reliable information from the patient by saying to her in a warm, friendly manner, how are you feeling? How have you been getting along? Is the method still serving your purposes? Do you feel as though you have had any ill effects? And giving her time to answer these questions, rather than suggesting symptoms to her. Senator NELSON. As I understand it, you are suggesting that many people will not remember what you tell them. Therefore, why tell them? Many people would not read the literature, so why put it in the package? All I am saying is, I think there are a large number of very intel- ligent, conscientious women. Why should not those people have available in their hands the information that they themselves can make use of? Some percentage of people, not knowing what the medicine is, will look at it, some of them will not. What I am puzzled about is why the resistance to putting the information where those people who want to use it can use it? Dr. LANE. I am not resisting this at all, Senator Nelson. And I am not denying that most patients, when it comes to their own con- traceptive care, are intelligent and conscientious. I think most of them are, and this cuts across all barriers of financial status, race, ethnic background, educational status, everything. I am not promot- ing the denial of important information to them, and I think we give them important information. But I see no reason to burden them when they are trying to make a choice between methods or when they have already chosen a method, which, from every stand- point, is going to be best for them, to burden them with symptoms which might suggest something nebulous going on which they are going to ask us about anyhow if they have any kind of rapport with us as a clinic or as a medical service. They do ask us. Senator NELSON. But you are talking about a case situation where, if everything is perfect, as it may be in your clinic. What about the women who are told nothing? You say you do not believe they are not informed. Everybody seems to want to believe that part of Newsweek survey that they would like to believe. But let us assume that you are correct, that son'ie people would not remember. Let us assume that two-thirds is a high figure. Let us say it is only one- third. Certainly the poll isn't totally incorrect. Certainly they do not all have very bad memories. One-third is a massive number. Should not there be something in the package that they get, since they are not getting it from their doctor and they are not going to a well- controlled clinic, such as you have. Many, many of them, in fact, are not going back for regular physical exams. Should not the literature say you should have an exam every 6 months at least? PAGENO="0206" 6646 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. L~\xE. Of course, I would expect the doctor to tell her this. But if the doctor does not. certainly she should have some way of knowing it. She should have regular checkups. Senator NELSON. Unless the statistics in the Gallup p011 are totally invalid and not a single one. or not even 10 percent of that two- thirds remember correctly, which I doubt very much, then there is a cornpellmg necessity. it seems to me, to put something in the hands of the user unless it is the position of the medical profession that we know what is best in all these matters and we should not tell the patient anything. Dr. LANE. I think certainly the patient should be told, and I think all our literature attests to that fact, that we do tell them. Senator NELSoN. You hand them literature ? Dr. LANE. As I say, we hand them printed instructions with respect to their method in which we tell them again of the most common side effects which they should look for, which would cer- tainly be worth reporting to us. But we also invite them, in the instance of any question at all, that they should call us and that they should be very careful to keep their appointments. If for some unavoidable reason, they cannot keep their appointments, we tell them they should call for another one-this is all in the written lit- erature. Senator NELSON. You issue pills for what period of time? A supply for what period? Dr. LANE. No more than 6 months' supply. We might give them seven packages at a time, but that is because a package actually covers a cycle, not a month, and we do not want them to run out. Senator NELSON. This is a control factor in the sense that unless they go some place else, they have to come back to the clinic and that gives you the opportunity for physical examination and con- sultation? Dr. LANE. Exactly. We also insist that they get their supplies from us so we can be absolutely sure that they are taking what we told them to take and not what somebody else has suggested that they take. Senator NELSON. Thank you very much, Doctor. Senator Dole, do you have an questions? Senator DOLE. First I want to thank Dr. Lane for an excellent statement. It is based on practical experience dealing with great numbers of people. You feel that the benefits far outweigh the risks of taking the pill? Dr. LANE. Yes. Senator DOLE. It might also be helpful if we could have a copy of the literature that you distribute. It may be different from that that we have found. Dr. LANE. Yes, I can make that available, too. Senator DOLE. The patient is more apt to read it if it is given to her by the doctor and by the clinic than if it comes in a box, though I do not see any quarrel with inserting a circular along with the pills. We must use every means available to communicate with the patient. PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6647 It would be very dramatic and would indicate to the women of America how you view the pill yourself, if you could tell us whether or not you take the pill. I do not want to be impertinent or ask embarrassing questions. It would be most helpful if you have enough confidence in the pill to tell us, have you ever used it your- self? I)r. I~Nr. Yes, I have used the pill. Senator DOLE. And you are aware of all the side effects? Dr. LANE. Oh, indeed. Senator DOLE. You have made a value judgment and determined that it is safe? Dr. LANE. I have precisely. I have three children, all of whom I love very dearly. But I could not tolerate another pregnancy. I hope that I have many fertile years ahead of me. So I feel that with my medical responsibilities, with my career responsibilities, it has been my own choice, the kind of life that I have carved out for myself, that it is absolutely important that I use something which I could have complete faith in. Now, this is not to say that I could not per- Imps have complete faith in one of the other methods-not the HID, because there are accidental pregnancies. I think I could have faith in the diaphragm, but for various reasons, I have decided not to use that method of contraception. I think my reasons are valid. I help my patient to arrive at this sort of judgment, what is going to be best for her. This is a very, very personal thing and has absolutely nothing to do with popula- tion pressures or anything else as far as I am concerned. Senator DoI~E. It is probably very helpful if the patient knows that you have enough confidence in these pills, whatever brand it may be, not only to prescribe it for others but to use it yourself. I)r. LANE. I do not give my patients this information because I do not want to bias them in that respect. I suppose they will all have it now. Senator DOLE. But you are personally aware of some of the side effects and have experienced some? Dr. LANE. Yes, this is a risk that I choose to take. Senator DOLE. Have you experienced any that caused you any great difficulty, any side effects? Dr. LANE. Occasional headache, that is all. I am not even sure that that was due to the pill. I am under much pressure much of the time. Senator DOLE. Your last paragraph indicates that the pill is not significantly different from other medications. It is a delicate ques- tion involving judgment. I imagine most physicians have great respect for their patients and do what they must to protect the patient. I assume on page 1, you neither try to make judgment for your patient nor let them make it without information and assume it is a doctor-patient relationship- Dr. LANE. It is precisely this, a relationship, with a rather deli- cate balance many times. Senator DOLE. You are not trying to push people into using the pill? PAGENO="0208" 6648 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. LANE. No, absohitely not. Senator DOLE. Thank you very much. Senator NELSON. Thank you, Dr. Lane, for our ver thoughtful contribution. \\Te appreciate your taking the time to come before us. Our next witness is Dr. Edward F. Lewison. surgeon. and chief of the breast clinic, Johns Hopkins Hospital, Baltimore Md. Dr. Lewison, we are very happy to have you here today, we appreciate your taking the time to come. Your statement will be inserted in the record. You may read it or summarize from it in any way you wish. Thank you for being so patient. STATEMENT OF DR. EDWARD F. LEWISON, SURGEON; AND CHIEF, BREAST CLINIC, JOHNS HOPKINS HOSPITAL, BALTIMORE, MD. Dr. LEWISON. Senator Nelson, Senator Dole, members of this Select Committee, as a surgeon and breast specialist., I would like to make it clear that I will take the liberty to broaden the topic and conform with the suggestions that you have given me in your letter. I will discuss the pill and estrogens and breast cancer. I am includ- ing estrogens because the two previous speakers spoke of the pill and indicated the hormonal relationships, in my particular type of practice, I find estrogens, given during the menopausal period, as being perhaps one of the most important drugs that I have to con- tend with. Now, cancer of the breast is indeed, the most common single organ site of malignancy in women. It is unfortunately a monstrously destructive disease which has claimed its many victims in all walks of life, at almost every age from adolescence onward and from time immemorial. It is in fact an arrant world affliction whose cellular turmoil shows little predilection for race, country, or geographical area. In the United States alone about one woman in 17-6 percent of the female population-is destined to develop this malign disease and the risk of this possibility increases with each decade of life. A woman of 80 has a better chance of developing breast cancer than a woman of 70 and a woman of 70 a better chance than a woman of 60. There is no point when this disease turns downward in its malev- olent course. More than 300,000 American women will develop breast cancer within the next 5 years and the magnitude of this problem appears to be increasing. Benign breast disease such as chronic cystic masti- tis (cysts) and benign tumors (fibroadenomas) are even more common, occurring in about 25 to 35 percent of all adult women. Thus, it is readily apparent that the breast is indeed a most frequent site of both benign and malignant disease. It is also topical knowledge that the breast is a highly glamorized, hormone sensitive, satellite sex organ. Many years ago it was demon- strated that extracts from the ovary (estrogenic hormones) were remarkably potent growth stimulants for the epithelia.l cells of the female genital tract including the breast. Cancer is the uncontrolled growth of these same epithelial cells. PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6649 There is ample evidence to indicate a close relationship between estrogenic hormones and the breast. For instance, development of the breast begins at puberty with the onset of hormonal activity. Breast cancer has almost never been known to occur prior to the dawn of this horrnoiial secretion. Many women experience cyclic swelling and painf iii engorgement of the breasts related to the periodic hormonal changes which occurs during the month. Some patients with chronic cystic mastitis have noted an increase in the size of their cysts and an aggravation of their pain when taking estrogenic hormones or the pill. Pregnancy causes a marked enlargment of the breasts and this is considered to be predominantly an estrogenic hormonal effect. Breast cancer occurring during pregnancy with its high estrogenic stinmla- tion has a most ominous prognosis. Clinical experience bears said witness to the fact that the coexistence of pregnancy, again with its elevated level of estrogens, and breast cancer carries a most pessimis- tic outlook. Few, if any, of the young mothers have ever survived. Enlargement of the male breast (gynecomastia) by the female sex hormone (estrogen) can be caused by hormonal stimulation in men receiving estrogens for the treatment of certain male diseases. Gyne- comastia has been observed in factory workers making estrogenic hormones (the female sex hormones) and in men with estrogen-pro- ducing tumors. Therefore, it seems quite clear that estrogenic hor- mones and the pill which may contain an estrogen can cause epi- thelial cell changes within both normal and abnormal breast tissue. As noted by Hertz and many others throughout the world, breast cancer can be induced experimentally, and I stress experimentally- in a wide variety of animals by the administration of estrogens. Breast cancer in rats produced by prolonged stimulation with an estrogen will even disappear when the source of this estrogen is removed. Breast cancers in dogs have occurred following prolonged ingestion of an estrogen-progestogen pill. The clinical trial of a mini pill in France, Mexico, and England has been recently suspended because of suspicious "tissues masses" which developed in the mam- mary area of dogs. Senator NELSON. May I interrupt? Dr. LEwIsoN. Yes. Senator NELSON. In your reference to the clinical trial on the mini pill, were not there trials in this country, too? Dr. LEWISON. I really do not know, Senator, I read of these experiments with the mini pill abroad and this is not particularly my area of special interest. I do not lmow whether there were trials in this country as well. Senator NELSON. Thank you. Dr. LEWISON. It seems to me that although there is a wide generic gap between man and mouse, yet most cancer investigators agree that there is a close correlation between those drugs which cause cancer both in animal and in man, also, it is my opinion that per- liaps time and close relationships may be the unknown dimension. I know that some of the witnesses have testified that perhaps in pro- longed use the dose factor may be very important in the pill, and I assume it to be the same with estrogens as well. 40-471-70-pt. 16-vol. 2-14 PAGENO="0210" 6650 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Now, important statistical studies in humans by Dr. Feinleib at 1-larvard have shown that women who undergo an artificial meno- pause early in life liv the removal of their ovaries (for diseases totally unrelated to breast cancer) have a reduced risk (by about 75 percent) of developing breast cancer in later life. In other words, removing the ovarian influence, the estrogenic influence, reduces the risk of breast cancer. Another striking example of the close relationship between breast cancer in humans and estrogenic hormones can be demonstrated by the following clinical results. Women with advanced breast cancer, these are women who acthallv have cancer who have metastasis or advanced disease, if they have their ovaries removed therapeutically, removal of the primar source of estrogenic hormones; namely, the ovary-then these women show a remarkable improvement of their metastatic or advanced breast cancer in about one-third of the cases. Also, I have observed that estrogens taken in small doses unwit- tingly may aggravate a preexisting breast cancer. You must remein- ber, this does not mean that estrogens will initiate a cancer, but they may aggravate or make worse a preexisting cancer, one that has not yet become discernible, either to the patient or the doctor. Stopping the pill or discontinuing the drug will slow the tempo of this type of tumor growth. A recent report in the British Medical Journal describes the trag- edy of two male transvestites both of whom developed breast cancer after long-term estrogen therapy. Therefore, being profoundly aware of these clinical relationships and being a clinical surgeon myself, I am naturally concerned in my day to day practice about the potentially harmful effect of long-term low-dose estrogen admin- istration as occurs in young women taking the birth control pill or middle aged women taking estrogens during the menopause. Whereas, some women take estrogens with the illusion of being "a thing of beauty and joy forever," other women take estrogens during tile menopause for medically sound and legitimate reasons. Although breast cancer is "easy to see" it is "hard to foresee." Prudence, however, requires that certain women with suggestive pre- malignant breast lesions and women with a "high-risk" predisposi- tion for breast cancer should in my opinion avoid tile long-term stimulation of estrogens or the pill. Mr. GouDox. Doctor, is it easy to ascertain who are tile high-risk women? Dr. LEwlsox. Mr. Gordon, in tile next page in this same report, I have outlined the high-risk group and I will read them to you. Whereas indn-iclual sensitivity to hormonal stimulation may vary greatly from person to person and fro1n age to age, yet in my opin- ion it is wiser to be safe than sorry for malignancy makes no mora- torium. Thus, for practical purposes and in m~ own practice I would recommend particular caution in the following categories of women who are known to have a higher than normal risk of devel- oping breast cancer: (1) Women with a strong family history of cancer especially breast cancer, more especially breast cancer. (2) Women having had cancer of one breast. It is perfectly obvious to all doctors that women who have had cancer of one breast PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6651 have a much greater predisposition for developing a second cancer on the other side. (3) Women with recurrent benign breast disease. There are the metastasis and fibroadenomas that I mentioned earlier. (4) Women with lobular carcinoma in situ or other proliferative epithelial breast lesions. These are a specific category of breast lesions where the cells seem to have growth or hyperplastic poten- tial. Senator NELSON. As to item 3, you are saying, I take it, women with recurrent benign breast disease, which I recollect you say on page 2 of your statement, 25 to, 35 percent of the women, you con- clude are more susceptible to the inducement of cancer if they are using estrogens over a long period of time? Dr. LEwIsON. Senator, on page 1, 1 mention the fact that between 25 and 35 percent of the women have been known by anatomical dissection to have chronic cystic metastasis or benign breast tumors. These are not women who have recurrent benign disease, but only have this condition at one time. Now, in this category of the high risk group, I have narrowed this group by saying women who have recurrent cysts and fibroadeno- rnas, not just for tile first time. Senator NELSON. I see. 1-lave there been any studies of any size to indicate the predisposition of those who have recurring benign tumors of one kind or another developing carcinomas subsequently? Dr. LEWISON. Yes, there ar:e a number of studies in text books that have been published on this subject, including my own. There have been studies abroad, monograph reports, and the references of these are available. Most of them agree that the risk of developing breast cancer is three to five times as great in women who have recurrent or proliferative types of benign breast disease. Senator NELSON. Three to five times? The development of cancer is indicated three to five times more frequently in those with benign breast disease? Dr. LEWISON. For the same age range. Senator NELSON. Are there any studies which indicate that for those who do have this high incidence of benign breast disease, that extended use of an estrogen for some purpose or other does produce cancer in a lugher percentage? Dr. LEWISON. These studies, Senator Nelson, are at present on- going. Our own study is one of these studies that are at present in the process of accumulating this very necessary information. It is not yet available. Senator NELSON. So that I understand it in the perspective you intend, is it correct that you are saying that since women who have recurring benign breast disease do in fact develop carcinoma three to five times more frequently than those without it, that you consider it risky to add to that the prolonged treatment for either contraceptive reasons or other reasons, the introduction of estrogen into the system, is that what you are saying? Dr. LEwIS0N. By all means, yes, sir. Senator NELSON. We do not have the facts at this time that that would show an increased incidence? Dr. LEwIS0N. That is correct. PAGENO="0212" 6652 COMPETITIVE PROBLEMS IN THE DRTJG INDIJSTRY The fifth group would be a relatively recent high-risk group, women who are seen by their doctors and referred for a mammo- gram. That is a special type of x-ray study of the breast alone. These women occasionally show up with rather peculiar changes or abnormalities or Suspicious findings within the x-ray, and it would be these women also that I personally would consider suspect and would not be willing to give either estrogens or the pill to. In these women, then, the whispers of nature call for caution and not complacency. In the United States during 1969, as indicated in these hearings, an estimated 8.5 million women took the pill as an oral contracep- tive. The clinical efficacy of these pills as a contraceptive measure is indeed striking and very well established. They have been hailed by many, including my very good friend, Dr. Guttmacher, and others, as a drug of great value in controlling the population explosion. A survey of Prescriptions in the United States suggests that almost as many women also may have taken estrogens for the control of meno- pausal problems during the same time. That such potent drugs should have certain biologic dangers seems almost inevitable in n-ied- icine. Nevertheless, more than 50 metabolic changes which modify important biochemical processes in all body tissues have been reported to be associated with estrogens and the pill. Most of these changes as noted in Lancet "are unnecessary for contraception and their ultimate effect on the health of the user is unknown." The development of newer and more satisfactory contraceptive agents without the possible harmful effects of long-term estrogen adminis- tration would certainly be highly desirable. The ultimate clinical significance of prolonged use of the pill or estrogens in relation to breast cancer will require and I stress this- due to a long latent period-many years of agonizingly slow accu- mulation of epidemiologic data. Our own clinical study of patients at the Johns Hopkins Hospital which is being currently conducted by Dr. Sartwell, Dr. Arthes and myself was started only last year and even preliminary statistical results of this type of cancer and control group are not yet available. However, as doctors, we must practice our art by balancing the known risks with the best known scientific data presently available. The experimental evidence relating breast cancer in animals to estro- gens and the pill is suggestive. The clinical evidence indicating a close relationship between estrogenic hormones, the breast and breast cancer is strongly persuasive. Yet, there is no known clinical evi- dence at the present time indicating that estrogens or the pill will definitely cause breast cancer in human beings. Perhaps as indicated by Dr. Guttrnacher, the benefits of the pill may ultimately outweigh its possibility for harm. Certainly, the pill is at present a proficient and convenient contraceptive agent used by many women the world over. However, as Osler has said, "medicine is a science of uncertainty and an art of probability." In this nego- tiation with nature, I can find no relevant olive branch with which to equate the ban on babies with the bane of breast cancer. While awaiting the tyrant of time to tell us these vital answers, I would favor caution in the clinical use of estrogens or the pill, par- PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6653 ticularly in women who are in a "high-risk" group. To safeguard their health in later years, we must try to see today with the eyes of tomorrow. Thank you. Senator NELSON. Thank you very much, Doctor. Is there any-are you aware of any studies, or do you have them with you, about the potential difference from physiological effect, such as you have mentioned here between, say, the 100 micrograms and a 75 or 50 microgram estrogen or lower? In other words, is the amount of the dosage a factor? Dr. LEWISON. Senator Nelsoii, the amount of the dosage is a factor. We have reasonably good clinical evidence to indicate this. For instance, in my own practice, in my own clinic, we will see women with breast cancer. Now; these are women who actually have breast cancer. By giving them massive doses of estrogen, unphysiol- ogic high doses of estrogen, we can actually suppress or cause a regression of their disease. By giving them small doses, physiologic doses of estrogen, we can cause an acceleration of this same disease. So that it is perfectly obvious that there is a dose-time relationship. Senator NELSON. Are there any studies that indicate the kind of dilemma that occurs when high dosages are used? Dr. Wynn's stud- ies and some TJ.S. studies indicate that the high dosage of estrogens increase the incidence of thromboembolism. Are you suggesting that for, say, a patient who as a predisposition in one of the categories you listed or a recurring benign breast disease, that the higher the dosage of estrogen, the less the chance they will develop carcinoma? Dr. LEWISON. I think these time-dose relationships have to be very carefully worked out in future research. We do know that the very small dose will stimulate or aggravate a breast cancer that is already in existence. We do know that the larger dose of this same estrogen presumably, according to the testimony of Dr. Wynn and others, will aggravate thromboembolic disease. But I am talking about therapeu- tic doses of estrogen for breast cancer that are in the very, very high range. For instance, doses that may be 100 to 200 times the dosage that you are talking about. This is therapy for advanced breast cancer. Senator NELSON. So we do not know whether or not, in that woman with some predisposition, that in fact 100 or 75 micrograms of estrogen are more serious in terms of inducing carcinoma than 50 or 25 micrograms of estrogen? Dr. LEWISON. In that range, we do not know. That is correct. Senator NELSON. Mr. Duffy, do you have questions? Mr. DUFFY. Yes, thank you. Doctor, just one question, if I may. You indicated earlier that the risk of breast cancer increases with age, is that right? Dr. LEWISON. Yes, many cancers show a downturn after the meno- pause, but unfortunately, breast cancer is ever increasing with each decade of life. Mr. DUFFY. You would feel, then, that as a woman ages, she should he more careful if she chooses to use the pill? Dr. LEwIsoN. Yes, I certainly agree with this. And since breast cancer also occurs at the ages of 50, ~0, and 70, I would be even PAGENO="0214" 6654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY more careful about recommending the use of estrogens. These are for women who want to take hormones for the remainder of their days, as I said, to be a thing of beauty and a joy forever. But I would be very, very careful and cautious in the high-risk group in recom- mending hormones to them. Senator NELSON. Thank you very much, Doctor. Our next witness is Dr. Elsie Carrington, professor and chairman, Department of Obstetrics and Gynecology, Woman's Medical Col- lege of Pennsylvania. Dr. Carrington, we appreciate very much your patience in waiting to testify. We appreciate your willingness to come here today and present your views to the committee. Your statement will be printed in full in the record. You may present it as you desire. If you wish to extemporize from it from time to time, please do so. STATEMENT OF DR. ELSIE R. CARRINGTON, PROFESSOR AND CHAIRMAN, DEPARTMENT OF OBSTETRICS AND GYNECOLOGY, WOMAN'S MEDICAL COLLEGE, PHILADELPHIA, PA, Dr. CARRINGTON. Thank you, Senator Nelson. Your committee has invited me to discuss certain metabclic effects of oral contraceptive drugs. A summary of my report as a member of the task forces on endocrine and metabolic effects of oral contra- ceptives for the Advisory Committee on Obstetrics and Gynecology for the Food and Drug Administration will providie the first part of my testimony. I have also been asked to comment on the use of oral contraceptive drugs from the standpoint of my role as professor and chairman of the Department of Obstetrics and Gynecology at the Woman's Medi- cal College of Pennsylvania. This is the second part of my testi- mony. The concerns for maternal health and optimal family life are the same in each but the pressing needs of our women and the responsibilities involved in meeting these needs are more immedi- atelv evident in the latter. I would like to say that I can appreciate our concerns and am most gratified with the fairness in the posi- tions that I have seen expressed this morning from your group. At the time of the first meeting of the advisory committee in November 1965 the number of oral contraceptive users was estimated at about 5 million women. The efficacy of the combined estrogen-pro- gesterone preparations was known to be close to the absolute. Evalu- ation of their safety was recognized as a formidable task. This is so because little enough is known about normal endogenous steroid metabolism. Normal endocrine function depends not oniv upon the secretory activity of a given gland but also upon the feedback effect of one hormone as opposedi to another, the mechanism for transport in the circulation, time response of the target organ and the enzyme activities influencing the cellular response. So we come to a very complicated type of evaluation. The steroids used in oral contraceptives have certain similarities to their natural-occurring prototypes, the estrogens and progester- ones. 1-lowever, modifications in their chemical structure even of a PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6655 minor nature may result in profound changes in biologic activity. Some of the effects of the progestins mimic changes seen in pregnant women. This is not unexpected. During pregnancy the estrogenic hormones are increased 100- to 1,000-fold and progesterone is increased approximately tenfold. Many of the important physiologic and metabolic alterations seen in normal pregnancy are due directly or indirectly to these naturally occurring hormones, and comparisons have been made between these effects and those occurring in response to the synthetic progestins. Secretion of thyroid hormones, for exam- ple, is increased by approximately 25 to 40 percent above prepreg- nancy or pretreatment levels, yet the functional status of the thyroid remains unchanged in either case. The cause for this change is related to the known effect of estrogen in inducing increases in thy- roxine-binding protein. Protein-bound thyroxine is rendered biologi- cally less active. "Free" thyroxine remains within the normal range. Circulating levels return to normal values after pregnancy and after discontinuance of oral contraceptives respectively. Both natural and synthetic estrogens cause an increase in cortisol-binding protein. This is reflected in an increase in adrenal corticosteroid hormone secretion similarly in pregnant women and in women on oral contra- ceptives. Adverse effects on thyroid or adrenal function have not appeared in short-term or long-term use of oral contraceptives. Gonadal steroid hormones are known to modify carbohydrate metabolism. Similarities in the diabetogenic effects of pregnancy and oral contraceptive drugs have been noted, particularly in women with a known genetic predisposition to diabetes. Our work with dia- betic mothers and their offspring over the course of the past 15 years has led us to conclude that pregnancy does not alter carbohydrate metabolism significantly in normal women. In genetically predis- posed mothers diabetes may be temporarily unmasked, or permanent diabetes may be precipitated. In women with pre-existing diabetes the disease is usually aggravated durmg the course of gestation. As a rule insulin requirements which are elevated during pregnancy return to the prepregnancy dosage or approximately that dosage thereafter. It is not yet clear which of the women showing a tran- sient abnormality in carbohydrate metabolism during pregnancy will ultimately develop overt diabetes in later life. Our studies and oth- ers-O'Sullivan in Boston, as well as several prospective and retrospective studi es-would indicate that approximately one-fourth of the group showing reduced glucose tolerance during gestation and improvement after delivery progress to l)ermanei~t diabetes within 5½ years. Far less is accurately known regarding the potential dia- betogenic effects of oral contraceptives despite a very large number of carefully conducted research studies in this specific area. Many of these have shown that glucose tolerance is impaired in genetically predisposed women taking oral contraceptives. Evidence is not as convincmg that the progestins produce abnormalities in glucose tol- erance in the absence of a diabetic diathesis.. On the basis of our own studies of subclinical diabetic pregnancies I can attest to the difficulties in separating these subjects from normals. In the early prediabetic stage, the disease is virtually asymptomatic, histories are frequently poor and laboratory tests are lacking in specificity or sen- sitivity at this particular stage of the disease. PAGENO="0216" 6656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Significant information derived from the best controlled studies of the effects of oral contraceptives on carbohydrate metabolism is as follows: Glucose tolerance may be reduced during short-term or long-term use of the drugs. In the same subjects plasma insulin levels also rise above normal levels in response to a glucose load. In some cases glucose tolerance returns to normal with continued use of the pill. It. is not clear whether or not this is due to the increased amount of circulating insulin. In other cases glucose tolerance remains impaired for several weeks or months after discontinuance of the pill. It then returns to normal if the patient is nondiabetic. Hyperinsulinisni appears to persist for longer periods of time than hyperglycemia after the pill is stopped. I do not know the cause for this except as it may relate to the effects of high doses of circulating insulin in reversing the hyperglycemia effect. Growth hormone is known to have a diabetogenic effect and is also known to be elevated in response to estrogen administration. Increases in this hormone have been noted during oral contraceptive treatment. Lipid metabolism is related to the metabolism of carbohy- drates. Blood cholesterol and free fatty acids are not altered signifi- cantly by oral contraceptives hut the triglycerides are increased and may remain so for several weeks after discontinuance of tkn pill. Senator NELSON. May I interrupt a moment? Dr. CARRINGTON. Yes. Senator NELSON. Just to refresh my memory, you stated that blood cholesterol and free fatty acids are not altered by oral contra- centives, but cholesterol may be increased. Does that square with Dr. Wynn's study? Dr. CARRINOT0N. Yes, it does. Dr. Wynn's original study showed that. blood cholesterol and free fatty acids were mildly increased. His subsequent attempt to reproduce the same effects failed, so that he does not have confirmation of these increases-certainly this is true in free fatty acids, in his free fatty acids study. His triglycer- ides showed consistent increases and this is his particular concern with respect to the effects upon the vascular system. Senator NELSON. I had not remembered. I thought he had said blood cholesterol- Dr. CALIITNGTON. This is a very small factor and is pretty hard to document. A number of investigators have worked in this particular area. The increases in free fatty acids have not been reduplicated. Mr. DUFFY. Excuse me, Dr. Carrington. Did you indicate just a moment ago that Dr. Wynn could not confirm his early findings? Dr. CARRINGTON. On free fatty acid elevations. On triglycerides, he not only confirmed them, but had an almost 100 percent effect, a very high, a very significant effect in the increases in triglycerides imcler the therapy. His blood cholesterol was very controversial. Mr. GonDox. Which are the ones that cause arteriosclerosis? Dr. C~LEINGTON. Blood cholesterol and triglycerides are the main ones here. This is not my particular area of expertise, but I do know that triglycerides are increased and this is of importance to us because. lipid metabolism has an effect upon carbohydrate metabo- lism. I think in the testimony presented to you by Dr. Wynn and by Dr. Spellacy, both of whose work I think is really excellent, will PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6657 document or will give you a much more accurate appraisal of blood cholesterol and free fatty acid changes than I can. There are marked differences in the degree of influence the various chemical compounds used as oral contraceptives exert on carbohy- drate metabolism. For example an etliinyl estradiol component does not produce hyperglycemia as readily as its 3-methyl ether, mes- tranol. Some of the Swedish investigators have shown that various oral contraceptive preparations also differ in respect to their effects on plasma lipids. It is possible that better balanced compounds, more closely approaching established ideals for drugs can be found but a great deal of research remains to be accomplished. This is what Senator Javits and Senator Nelson have alluded to. I think this is a critical part of what I have to say. The necessity for birth control measures for our women and for our society and our concern for their safety should be self-evident. Extension of investigative efforts is mandatory along with fuller recognition of the magnitude and diversity of the problems and the urgency of the need for adequate support for their solution. In the meantime the needs for fertility regulation and family planning must be met. The oral contraceptives provide one impor- tant and effective means of accomplishing these objectives. But they are no~ the only means. It is the physician's responsibility to sort out those individuals for whom other methods of birth control are more appropriate. In practice and in our family planning clinics the patient's his- tory, general physical and pelvic examinations and certain inexpen- sive laboratory examinations, including cervical-vaginal cytology, provide the safeguards necessary prior to treatment. In our experi- ence the motivation for patient visits to the doctor, stemming from the desire for birth control measures, is exceptional and has often resulted in detection of significant preexisting disorders. These have included premalignant and preinvasive. cancer of the cervix for which surgical treatment is curative, metabolic disorders such as dia- betes for which early metabolic control is of great importance, and menstrual disorders frequently associated with anovulation and infertility. If the pill had been prescribed without disclosure of these abnormalities it is likely that a cause-and-effect relationship would be ascribed. The use of oral contraceptive compounds in patients with menstrual disorders, whether for birth control pur- poses or for the treatment of menstrual irregularities, deserves fur- ther comment. In women with families this treatment is useful and effective but in young women who have not borne children evalua- tion of fertility status is well-advised before the pill is prescribed. Infertility rates in apparently healthy women range from 10 to 15 percent. Since normal ovulation-and I disagree with your little brochure intensely-since normal ovulation is dependent upon deli- cately balanced secretion of hypothalamic-pituitary-ovarian hor- mones, it is not surprising that derangement and anovulation are relatively common occurrences in untreated patients. The contracep- tive effect of progestins is due primarily to prevention of ovulation through suppression of the hypothalamic-pituitary system and sec- ondarily to alterations in the uterine endometrium and cervical PAGENO="0218" 6658 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mucus. Recovery of hormonal balance is usually prompt after oral contraceptives are discontinued. Occasionally return of the men- strual cycle is delayed for 3 to 6 months or more. In such instances it is not known which cases represent persistent over-suppression of previously normal ovarian function and which represent preexisting hormonal imbalance and anovulation unless ovarian function has been evaluated prior to treatment. No drugs can be considered completely safe. The risks of penicil- liii in causing serious reaction and death are widely known, yet peni- cillin is prescribed with great frequency by practicing physicians. The physician's knowledge is expected and relied upon to identify individuals sensitive to the drug and to provide an alternate drug for treatment when appropriate. Selection is just as important and feasible for oral contraceptives. The argument that such comparisons are invalid because oral contraceptives are not therapeutic agents or agents used in the prevention of illness is open to criticism. It depends to a large extent upon one's definition of illness. Medical and social benefits of such effective contraceptive agents are undenia- ble. Continuance of their use is warranted and in fact essential for many of our individual patients and certainly for our society. Even in their present less-than-ideal form appropriate selection among different oral contraceptive compounds or selection of entirely dif- ferent methods of contraception when indicated is not only possible for a~ high percentage of patients but should constitute regular medi- cal practice. Senator NELSON. Thank you very much, Doctor, for your very fine testimony. We appreciate your taking the time to come today and having the l)atience to wait. Did von have an questions? Mr. DUFFY. No questions. Senator NELSON. Mr. Gordon? Mr. GORDON. I have none. Senator NELSON. The hearings will resume on March 3 in the Caucus ROom. (Whereupon, at 1~ :55 p.m., the hearing was recessed to reconvene Tuesday, March 3, 1970, at 10 a.m.) PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Conipetition In the Pharmaceutical Industry) TUESDAY, MARCH 3, 1970 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF TIlE SELECT COMMITTEE ON SMALL BUSINESS, Washington. D.C. The subcommittee met, pursuant to notice, at. 9 :45 a.m., in room 4221, New Senate Office Building, I-Ion. Gaylord Nelson (chairman of the subcommittee) presiding. Present: Senators Nelson, Javits, McIntyre, and Dole. Also present: Benjamin Gordon, staff economist; Elaine C. Dye, clerical assistant; James P. Duffy III, minority counsel; and Denni- son Young, Jr., associate minority counsel. Senator NELSON. Our first witness this morning is Dr. Max Cutler, Department of Surgery, Cedars of Lebanon 1-lospital and Saint ,Johns Hospital, Los Angeles. Congressman Glenn Anderson from Los Angeles is here this morning to introduce Dr. Cutler. Congressn'ian Anderson, the committee is very pleased to have you come over from the I-louse to our side of the Capitol which is a rare honor that most House Members will not pay to Senators. They expect us to come over to their side. So we are very pleased to on you here this morning. Senator DOLE. Mr. Chairman, before Congressman Anderson pro- ceeds, might I insert in the rečord the most recent Gallup Poll show- ing the effect these hearings have had on American women? A care- fully drawn sample indicates that the weight of opinion is 2 to 1 on the side that birth control pills are dangerous. This poll was taken since the hearing started in January. It might be helpful to have this in the record. Senator NELSON. We would be pleased to put it in the record at this point. (The article follows:) ~From the Washington Post, Mar. 1, 1D7O~ THE GALLUP POLL-PILL'S SAFETY Is DOUBTED BY WOMEN (By George Gallup) PRINCETON, N.J-The recent hearings on birth control pills have appar- ently had a profound effect on the view of American women regarding the safety of oral contraceptives. A carefully-drawn sample of the nation's female adult population, completed following the hearings which began Jan. 14, shows the weight of opinion 2-to-i (6659) PAGENO="0220" 6660 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY on the side that birth control pills are dangerous to a person's health. These findings represent a near reversal of opinion from that recorded in a survey conducted three years ago. In addition, more women today than in the earlier survey express uncer- tainty about the safety of birth control pills. The doctors and other experts who testified at the Senate hearings were divided in their testimony. Some said the pill may be a factor in causing blood clotting, breast cancer, diabetes, sterility, birth of malformed children and long-range damage to future generations. However, others at the hearings said that "the pill" is safe for most women. The Senate hearings, while apparently having had a marked effect on atti- tudes toward the safety of birth control pills, seem not to have changed opin- ions regarding their effectiveness. In both the latest and the 1967 surveys, a majority of 67 per cent of women think that birth control pills are an effective contraceptive. This question was asked first: Do you think birth control pills can be used safely-that is, without danger to person's health? 1970 1967 _________________ (percent) (percent) Yes 22 45 No 46 30 Unsure 32 25 This question was asked next: JjTould you recommend bim-th control pills to a woman who does not want more children? 1970 (percent) 1067 (percent) Yen No Unsure 48 15 35 12 The question asked next: Do you think these pills are effective--that is, do they work, or not? 1970 (percent) 1967 (percent) Yes 67 67 No 8 Unsure 24 25 Senator NELSON. Congressman Anderson. STATEMENT OF THE HONORABLE GLENN ANDERSON, A U.S. REP- RESENTATIVE FROM THE 17TH CONGRESSIONAL DISTRICT OF THE STATE OP CALIFORNIA Representative ANDERSON. Mr. Chairman and members of the committee. It is a distinct honor and a privilege to present to you Dr. Max Cutler. perhaps the foremost authority on breast cancer in the world. PAGENO="0221" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 6661 I asked for this privilege to present Dr. Cutler because if I have one criticism of him, it is that he is perhaps too modest and too humble, and so I felt maybe to get him off on the right foot-I know he does not need that-I did want to make this presentation. Dr. Cutler received a Bachelor of Science from the University of Georgia. at the age of 18-9 years after he entered the country. He received his medical degree from the Johns Hopkins Medical School in 1922, at the age of 22, and served his surgical internship in the Joims Hopkins Hospital. In 1924, he began his training in cancer research at the Memorial 1-lospital, New York, under a Rockefeller fellowship. In 1930 and 1931 he was the director of the New York City Cancer Institute. Dr. Cutler studied at the Curie Institute of Paris where he worked with Maclame Curie and her staff and became a foreign member of the Curie Foundation. In 1931 he was called to Chicago to found and direct the Tumor Clinic in the Michael Reese Hospital. In 1937 he occupied the chair of visiting professor of surgery in the Peking Union Medical College. During this period, he lectured in Peking, Nanking and Shanghai and acted as consultant to the Chinese Government on the cancer problem. Dr. Cutler founded the Chicago Tumor Institute in 1938. The institute has made significant contributions to the cure of cancer of the throat.. From 1931 to 1946 he served as Consultant Director of Cancer and Cancer Research in the United States Veterans Administration. In addition, he served as a member of the National Advisory Cancer Council of the National Cancer Institute, for a 3-year period. In addition to his work in the public interest, he has authored three books and published over 100 papers on various aspects of cancer. Perhaps his best known work was a book on cancer of the breast where he collaborated with a celebrated English surgeon, Sir Lenthal Cheatle. This book, published in 1931 and revised in 1961, was awarded the Walker Prize by the Royal College of Surgeons of England as the most important contribution in cancer research in the British Empire during the 5-year period of 1926-1931. In 1961 the president of Royal College of Surgeons of England said that the revised edition "will be the standard reference for another 30 years." Dr. Cutler has appeared as an expert witness on cancer before committees of the United States House and Senate. He has also been called as an expert witness to testify in trials involving malpractice by cancer quacks. Dr. Cutler is currently on the surgical staffs of the Cedars of Lebanon Hospital and the Saint Johns 1-lospital in the Los Angeles area. I have a more detailed account for the record. (The information follows:) BIOGRAPHY OF DR. MAX CUTLER B.S. graduate of University of Georgia, 1918. M.D. graduate of Johns Hopkins Medical School, 1922. . Curie Institute of Paris graduate study and Hadiumhemrnet, Stockholm, 1922. PAGENO="0222" 6662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Resident House Surgeon, Johns Hopkins Hospital, 1922-23. Assistant in Surgery, Michael Reese Hospital, Chicago, 1923-24. Instructor In Pathology, Cornell Medical School & Memorial Hospital, 1924-26. First Rockefeller Fellow in Cancer Research, Memorial Hospital, 1926-30. Director New York City Cancer Institute, New York City, 1930-31. Founder & Director, Tumor Clinic, Michael Reese Hospital, 1931-37. Consultant in cancer and Director cancer research, Edward H. Veteran's Hospital & U.S. Veteran's Administration, 1931-46. First President of the Americaii Association for the Study of Neoplastic Dis- eases, 1933-34. Visiting Professor of Surgery (Rockefeller Foundation), Peking Union Medi- cal College, Peking, China, 1936-37. Director of Chicago Tumor Institute, 1938-52. Member of the National Advisory Cancer Council, 1939-42. Member of: New York Academy of Medicine, Chicago Institute of Medicine, American Radium Society, American Association of Cancer Research, Interna- tional College of Surgeons, Johns Hopkins Medical & Surgical Association, American Board of Radiology, Honorary member of Cuban Radiological Society, Radiological Society, Chile, Northern Radiological Society, Scandina- via. Author (with Sir George Lenthal Cheatle) of Tumours of the Breast, 1931, Ua~ieer, Its Diagnosis anć Treatment, Tumors of the Breast, rev. 1962, and approximately 100 contributions to medical journals on various aspects of cancer. STATEMENT OF DR. MAx CUTLER'S C0NTRInUTIONS IN THE FIELD OF CANCER BY BEN SILBERSTEIN, PRESIDENT, BEvERLY HILLS CANCER RESEARCH FOUNDATION Dr. Cutler is a graduate of the University of Georgia. He received his medi- cnl degree from the Johns Hopkins Medical School and served his surgical internship in the Johns Hopkins hospital. He received his basic training in cancer in the Memorial Hospital, New York, where he spent seven years (1924-1931) under a Rockefeller Fellowship. 1-le concentrated most of his studies abroad in the Curie Institute of Paris where he w-orked w-ith Madame Curie and her staff and became a foreign member of the Curie Foundation. In 1929. he spent one year in London, where he collaborated with a cele- brated English surgeon, Sir Lenthal Cheatle in writing a book on Cancer of the Breast. This book, published in 1931 and revised in 1961, was awarded the Walker Prize by the Royal College of Surgeons of England as the most impor- taut contribution in cancer research in the British Empire during the five year period of 1926-1931. (The award is made every five years). In a review-, in the British Medical Journal, of the 1961 revision of the Cheatle-Cutler book, Professor Hedley Atkins, President of the Royal College of Surgeons of England. said in part: "Thirty-one years ago Lenthal Cheatle and Max Cutler published their famous book on Tumours of the Breast, which commanded the admiration of the surgical world" "As w-as its predecessor, this w-ork will be a standard reference for another 30 years and tl1e surgical world is much in debt to its author, etc." Betw-een 1930, and 1931, Dr. Cutler served as Director of the New York City Cancer Institute: and, in 1931, he was called to Chicago, to found and direct the Tumor Clinic in the Michael Reese Hospital. In 1937, he w-as invited by the Rockefeller Foundation to occupy the chair of visiting Professor of Surgery in the Peking Union Medical College for one year. During this period, he lectured in Peking, Nanking, and Shanghai and acted as Consultant to the Chinese Government on the cancer problem. In 1938, he founded the Chicago Tumor Institute, which made a significant contribution to the cure of cancer of the throat. In 1951, it was affiliated with the University of Chicago. For fifteen years (1931-1946), Dr. Cutler served as Consultant Director of Cancer and Cancer Research in the United States Veterans Administration under General Hines. He served as a member of the National Advisory Cancer Council of the National Cancer Institute for a three year period. PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6663 He has written three books and published over one-hundred papers on var- ious aspects of cancer, in local and foreign medical journals. He has appeared as an expert witness on cancer before committees of the U.S. Congress and Senate. He also has been called as an expert witness in some famous trials against Cancer quacks by the American Medical Associa- tion, the State of Illinois, the United States Food and Drug Administration and the United States Post Office Department. He is currently on the surgical staffs of the Cedars of Lebanon I-Iospital and the St. Johns Hospital. Representative ANDERSON. I did want you to know that knowing many of the people who have used the service of Dr. Cutler, it looks like a Who's Who in the theatrical world and the Government world and in the business world, and it gives me a great deal of pleasure to present to you, I think the greatest authority in the field, if there is an authority, Dr. Max Cutler. Senator NELSON. Thank you, Congressman Anderson. Dr. Cutler, we are very pleased to have you here today. Your statement will be printed in the record. You may present it in any way you desire. STATEMENT OF DR. MAX CUTLER, DEPARTMENT OF SURGERY, CEDARS OF LEBANON AND ST. JOHNS HOSPITALS, LOS ANGELES, CALIF.; AND DIRECTOR, BEVERLY HILLS CANCER RESEARCH FOUNDATION Dr. CUTLER. Thank you, Congressman Anderson, for this very unexpected honor and courtesy. Mr. Chairman, members of the subcommittee. I will dispense with reading of the first page and a half of my prepared statement, and will begin on the middle of page 2.1 The statement which I shall present this moFning deals exclu- sively with the question as to whether the protracted use of the oral contraceptive increases the risk of breast cancer in women. In approaching this problem, I have reviewed what I consider to be the most reliable reports in the scientific literature pertinei~t to this sub- ject. I have also studied some of the conflictii~g evidence that has been presented before your committee. Without minimizing the seriousness of the established side effects of the oral contraceptives, such as thromboembolism and certain metabolic disorders, the very nature of breast cancer as a suspected hazard places it in a special category. So cancer-conscious has the public become that mere mention of the word is enough to throw most people into utter panic. In order to understand the complexity of the problem, it is necessary to point out some of the salient fea- tures of cancer of the breast and its relation to the ovarian hor- mones. The intimate relation between the ovaries and breast cancer has been known for many years. Surgical removal or radiation treat- ment of the ovaries results in remissions in about 40 percent of pre- menopausal women with breast cancer. This effect occurs as a result of a dimunition of est-rogen production in the body. In clinical prac- 1 See information at p. 6670. PAGENO="0224" 6664 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tice, we avoid the use of estrogens for fear of increasing the activity of existing disease or stimulating the growth of clinically latent foci of breast cancer. Recent studies have shown that the incidence of breast cancer increases before the age 55 but remains constant beyond this age. These findings suggest that the risk from breast cancer is related to the quality of ovarian function. The incidence of breast cancer in childless women is higher than in women who bear children. Even more important is the recent finding that a woman who has her first child under the age of twenty has a connsiderable protection against breast. cancer. From epiclemiological studies, it would seem that the decade following puberty (13-23) is a critical period in establishing the future risk of breast. cancer. The fact that. breast cancer is common in women who have passed the menopause when the estrogen levels are lower can be readily explained on the basis that those cancers are the end-result of a process which began many years before. The carcinogenic effect in humans and in lower animals is charac- terized by a long latent period of some 10 to 20 years or even longer. A carcinogenic agent exerting its effect over a relatively short period can induce biological changes in cells that progress slowly over a period of many years and end up as clinical cancer. One classical example related to workers in aniline factories who are exposed to the carcinogenic dyes for as short a. period as 1 year and develop cancer of the bladder some 20 years later. Withdrawal of the carcin- ogenic agent did not arrest the progress of the latent lesions. Clini- cal, pathologica.l and experimental evidence support the view that breast cancer follows a similar pattern. Our studies of whole serial sections of the breast supported by ciin~cal experience have shown that cancer of the breast is not a sudden event or an accident. in a previously normal tissue, but rather the end-result. of a series of changes which began many years before. Benign tumors change into precancerous lesions before ending up as fully established cancers. It is not inconceivable that the causative agents that result in breast cancer exert their initial effect at a young age. possibly in that critical postpuberty decade. The tissues of the breast present a highly sensitive target for the ovarian hormones and have a great potential for the development of cancer. In all probability there is no direct etiological relationship between the estrogens and breast cancer. It is more probably that the carcinogenic effect of the hormones is to alter the biological state of the cells and thus render them vulnerable to the action of another agent-possibly, if not probably, a latent virus. Recognizing the possible risk of breast cancer as a side effect of the oral contraceptive, the American Cancer Society, as early as 1961. supported research studies on this problem and a recent report of the Advisory Committee on Obstetrics and Gynecology referred to the need for well designed studies and long-term support for research on the breast and uterus. Senator NELsoN. May I interrupt a moment, Doctor. You are referring to the second FDA report on obstetrics and gynecology? PAGENO="0225" COMPETITIVE PROBLEMS' IN THE DRUG INDUSTRY 6665 Dr. CUTLER. I am not certain,' sir. I did not check back on the original reference, but I have seen this referred to in the literature by several authors. Senator NELSON. Do I conclude from what you have said here that the research in this field has been inadequate? Dr. CUTLER. Very inadequate. Senator NELSON. Are you aware of what on-going research there may be at this time on this specific problem? Dr. CUTLER. Not in detail. I know in a general way that some retrospective studies have begun under the National Cancer Insti- tiite. Senator NELsoN. If this issue was raised by the American Cancer Society as early as 1961, what would be the explanation for our fail- are to proceed with the appropriate protocols for an investigation of this kind? Dr. CUTLER. Your question is why? Senator NELSON. That is 9 years ago. Dr. CUTLER. Yes; I do understand. Senator NELSON. Do you have an explanation as to why we have failed to proceed with adequate research in this field? Dr. CUTLER. MTeli, I think it is probably due to multiple factors. One is the complexity of the problem. Second, the answer must come from epidemiological studies, and those studies can only be of rele- vance when a sufficient time has passed. Actually, not enough time had passed to warrant any conclusions. I would think that those are some of the factors in operation. But it is a sad fact that long-many years go by between the time that a significant observation is made and adequate studies are undertaken. That has been tile rule. Senator NELSON. But are the studies that are being done of ade- quate scope to evaluate tile problems, once they are concluded? Dr. CUTLER. So far as I know, tile studies that are underway are totally inadequate to cope with this very critical situation. Senator NELSON. Thank you; go `ahead, Doctor. Dr. CUTLER. Tile early detection of breast cancer often presents formidable difficulties. Not infrequently when a lump is first felt in the breast, either by the patient or by her physician, it is already in a relatively advanced stage of cancer. This is further complicated by the patient's delay-which now averages about 7 mollths-ill consult- ing her physician for fear of facing a diagnosis of cancer with pos- sible loss of the breast. Periodic biannual examination of the breast helps greatly in early detection and prevention by surgical removal of precancerous lesions. Recent progress in the technique of X-ray examination of tile breasts, known as mammography, has led to the detection of breast cancers that are too small to be felt manually. Users of oral contra- ceptives should have periodic X-ray examinations of tue breast. Women using the oral contraceptives often develop fullness and tenderness of the breasts and in some cases actual enlargement which persists. Microscopic studies of biopsy material from patients who have taken the oral contraceptives show increased cellular activity, reflecting the stimulating effects of tile estrogens. In my own surgi- 40-471-70--pt. 16-vol. 2-15 PAGENO="0226" 6666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cal practice, I have a series of patients who have had two or three breast biopsies. In some, the biopsies were performed before the patient started to take the contraceptive. and a second or third biopsy was performed after the patient had been on the contracep- tive pill for several years. Study of surgical specimens under these circumstances 1Jrese1~ts a. unique opportunity to observe the tissue changes that may be related to the stimulating effect of the estro- genic component of the oral contraceptive. One has to be careful, however, in interpreting microscopic changes in tissues under the influence of hormonal stimi.ilation because such changes can be so pronounced as to be indistinguishable from fully established cancer. I cite the following example: My col- league, the late Sir Lenthal Cheatle of London, removed the breasts of a female infant who had died at birth. He prepared microscopic slides of the breast tissue and without divulging their source submit- ted them to five distinguished pathologists, several of them profes- sors of pathology. Four of the five pathologists reported the tissue as cancer of the breast. The liyperhormonal stimulation of the sensi- tive breast tissues caused by the high estrogen levels in the mother's circulation resulted in an erroneous microscopic diagnosis, by highly sophisticated pathologists. It is important to understand that microscopic changes of this magnitude can be reversible. We know that every 20th woman will develop cancer of the breast sometime during her lifetime. We also know that if the mother, the sister, or the maternal aunt had breast cancer, the risk is at least doubled, so that approximately one woman in ten will develop the disease. It is manifestly imprudent to prescribe oral contraceptives as a first-choice birth control method to patients with a family his- tory of breast cancer. Senator MCINTYRE. May I interrupt you at that point for a. ques- tion. You just said, "it is manifestly imprudent to prescribe oral contraceptives as a first-choice birth control method to patients with a family history of breast cancer." My question is this, does the current. labeling of these drugs or the recent letter from the FDA. contraindicate the use of birth control pills in patients with such a family history? Dr. CUTLER. Senator McIntyre, I cannot answer that question, because having received the letter, I do not recall in detail whether that point is mentioned. Senator NELSON. I might say that it does not. Senator MCINTYRE. Do you have the letter before you? Senator NELSON. This is the package insert for the layman. What it says is under contraindictions, No. 3, "known or suspected carci- noina of the breast." It does not refer to the sister, mother, or aunt. Dr. CUTLER. That would refer to a patient who has had breast cancer or perhaps had a recurrence of the disease; in other words, in the presence of clinical cancer, but it apparently says nothing about family history. Senator NELSON. You would recommend that the information that goes to the physician and the information on the package insert spe- cifically include the contraindication that you have just discussed? Dr. CUmRE. Without question. PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6667 Senator MCINTYRE. Thank you, Doctor. Dr. CUTLER. In this controversy, those who suspect a possible link between the oral contraceptives and breast cancer point to the fol- lowing evidence: (1) Removal of the ovaries in lower animals and in women mark- edly reduces the risk of breast cancer. (2) Breast cancer has been induced in five different animal species by the administration of estrogens. (3) Chemical agents having carcinogenic effects in man also induce cancer in animals-often at the same site. (4) Bilateral breast cancers have developed in two male transsex- ual individuals treated with estrogenic hormones, and (5) The discovery of a high incidence of breast cancer among males, 6.6 percent compared to the general incidence of 1 percent, in certain parts of Egypt where a parasitic infection of the liver inter- feres with the destruction of estrogens. Those who argue against a possible link, point to the lack of con- vincing evidence now available, after some 10 years of use of the oral contraceptive, that breast cancer is caused by the pill. They call attention to the extensive use of estrogens by millions of women for many years in the treatment of menopausal symptoms without definite evidence of a carcinogenic effect, and finally, they are not willing to accept the animal experiments as being applicable to women. With respect to the effect of estrogens on menopausal women, it should be pointed out that here we are dealing with replacement therapy. This cannot be compared to the prolonged addition of estrogens to a young woman's natural hormones. Furthermore, when one considers the prolonged latent period of carcinogenicity, many women in their menopausal and postmenopausal age brackets (late forties and fifties) may not live long enough for the carcinogenic effect to exert itself as clinical cancer. Considering the question of the transferability of animal data to man, it is difficult for me to escape the conclusion that the results are relevant and must be regarded as significant. The difficulty of demonstrating a causative relationship between the oral contraceptives and breast cancer obviously relates to the long latent period between exposure and final effect. A minimum of 10 years is required before reliable results can be expected. TJnfor- tunately, this experiment upon millions of women might prove to be too costly to contemplate. When the oral contraceptives were introduced some 10 years ago, they were hailed as a solution to the world's population explosion and a safe means of preventing birth of unwanted children. The simplicity and effectiveness of the pill have constituted a veritable blessing to millions of women. Unfortunately a broad area of disa- greement as to their safety has developed. Thus a serious cloud has appeared, and the question has arisen as to whether the benefits out- weigh the risks. Although there is no conclusive evidence that oral contraceptives cause breast cancer, the potential hazards involved in their pro- tracted use-and I emphasize protracted-by young, healthy women PAGENO="0228" 6668 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cannot be ignored. Both physician and patient must be made aware of the possible risks and give due consideration to alternative con- tracept~ve methods. I cannot help being greatly concerned for the millions of women who are bound to be frightened by the mere suggestion that in using the oral contraceptives they face a potential risk of breast cancer, and I think it would be utterly wrong to frighten millions of women unnecessarily over a potential risk which can be controlled, mini- mizeci, and perhaps even eliminated. Senator MCINTYRE. May I interrupt you at that point, Doctor. You just told us, "it would be utterly wrong to frighten millions of women unnecessaril over a potei~tjal risk which can be controlled, minimized, and perhaps even eliminated." WTouldl you please tell the committee a little bit more about how this can be accomplished. Dr. CUTLER. By use of the weaker pill, 50 micrograms, instead of the stronger pill. This has been pointed out by the British scientists and is being more and more accepted by the profession in this coun- try. The use of a weaker pill, and second, by its use over a limited period of time. I will explain this point in greater detail, later in my statement. Senator MCINTYRE. Well, all right; thank you. Senator NELSON. May I ask a question. When you say over a lim- ited period of time, what is that period? Dr. CUTLER. I have said in this statement 2 or 3 years. That figure is quite arbitrary. WTe are guessing and compromising. WTe have no definite knowledge. No one can say at what point it becomes a little more or a little less safe. But experimental evidence in animals shows that the carcinogenic- ity is dose-related and time-related. The larger the dose, the more cancers that are produced. The longer the waiting period, the more cancers appear. It is on the basis of this time and dose relationship that we make this estimate, which is purely arbitrary. It could be 3 or 4 years, it could be 4 or 5 years. This is about as far as we can go with it. It is a compromise. Senator NELSON. I would assume from what you previously said, when you refer to minimizing the risk, that you would recommend a 50 microgram of estrogens in the pill, that you would recommend a limited period of use. You also testified earlier in your statement as to need for a regular breast examination. You would include that with these other two; is that correct? Dr. CUTLER. That is right, sir. Senator MCINTYRE. Doctor, in view of this, is there any reason why the high estrogen pills should remain available, in your opin- ion? Dr. CUTLER. I am not certain that I am competent to answer that question because I am not a gynecologist, and actually do not dis- pense the pill. I refer my own patients and friends who come to me to a gynecologist. But in discussing this matter with men who are highly sophisticated and experienced in this area, I get the clear impression that there is no real use for the larger pill. I am not absolutely sure about that. That is my impression. PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6669 Senator MCINTYRE. Thank you very much, doctor. Dr. CUTLER. In the final analysis, we are faced with this dilemma: Do the "blessings" of the pill outweigh its long-range potential haz- ards? The available evidence indicating a relationship between the ste- roid hormones and the induction of breast cancer suggests that this relationship is dose-related and time-related. The higher the dose given and the longer the exposure, the greater the number of cancers produced in animals. It becomes obvious that it should be a matter of good medical practice to use the lowest doses which are effective, and to avoid the chronic use of oral contraceptives altogether. Senator NELSON. What do you mean by chronic use? Dr. CUTLER. I mean over a period of many years. Referring to a couple who had their family at a certain age, 35/36, and are consid- ering the use of the contraceptive pill until the menopause, I think that perhaps should be dispensed with and perhaps another contra- ceptive considered under those čircumstances. The combination type of pill containing 50 micrograms or less of estrogenic component is equally effective contraceptive as pills containing far higher doses and their use should be encouraged. This information I get from the gynecologists who have studied this problem extensively. The chronic use of the pill for many years as a form of chemical~ sterilization is dangerous from the point of view of its potential car- cmogenesis. Other methods of birth control which are strictly local~ in their mechanism of action, such as the diaphragm or the intrau- terine device, provide perfectly adequate means of spacing children. If termination of a reproductive career for medical or other reasons is desired, the option of surgical sterilization should be available. I am told, and I was shocked to learn, that nearly one-half of the States in our country still have archaic laws on the books winch either prohibit or discourage the use of voluntary sterilization. I hold tl~at the fallopian tubes are the property of the woman and not government property. After completing its family, a mature couple should be able to elect other methods of birth control than the pro- onged chronic use of the pill. It has been said that the proven risks of taking the pill are less than the proven risks of pregnancy. No doubt this is true, and would be a valid argument if the sole alternative to the pill were pregnancy. It is also true that the potential long-range hazards of inappropriate chronic use of the pill may be considerably greater than anyone can really assess for another 10 to 20 years. The women who have been taking the pill for 5 years or more are too few and too young to demonstrate any changes with respect to the risks of increasing the incidence of breast cancer. That risk is a potential time bomb with a fuse at least 15 to 20 years in length. I share the hope that the concern about this danger may be unfounded, and that the considerable experimental evidence may be inapplicable to women, but this is a gamble which is difficult to jus- tify because of the large numbers of women at risk. It seems to me that official policy and sound medicine should strongly dictate that the lowest effective doses of the pill be used for child-spacing purposes not to exceed 2 to 3 years, perhaps 3 or 4 PAGENO="0230" 6670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY years, perhaps 5 years; the figure is purely arbitrary. A broad range of effective alternative methods of birth control should be made available, and women should be discouraged from using the pill as a form of chemical sterilization. The pill is neither dangerous enough to condenm it out-of-hand. nor safe enough to prescribe it as a uni- versal panacea. The circumstances of its use should be carefully defined and steps thoughtfully taken to protect women from the con- sequences of slipping into the tabit of taking the pill indefinitely. Senator NELSON. Thank you very much, Doctor. (The complete prepared statement submitted by Dr. Cutler fol- lows:) STATEMENT By Da. MAX CUTLER* Mr. Chairman and Members of the Subcommittee: I am Dr. Max Cutler, Medical Director of the Beverly Hills Cancer Research Foundation and a member of the surgical staffs of the Cedars of Lebanon and St. Johns Hospi- tals in Los Angeles. My interest in cancer extends over a period of almost half a century. I received my early training in cancer between 1924 and 1931 in the Memorial Cancer Hospital, New York, most of it under a Rockefeller Fellow- ship. In 1931. I founded the Tumor Clinic of the Michael Reese Hospital in Chi- cago and served as its director for five years. In 1936, I served as Visiting Professor of Surgery in the Peiping Union Medical College, Peiping, China, under the auspices of the Rockefeller Foundation. In 1938, I founded the Chi- cago Tumor Institute and served as its director for thirteen years. Between 1931 and 1946, I was consultant in cancer to the U.S. Veterans Administration. I was a member of the National Advisory Cancer Council for three years and have served in an advisory capacity to the Food and Drug Administration as an expert witness. In 1929-1930, I was engaged in a research project in collaboration with Sir Lenthal Cheatle at Kings College Hospital, London. Cheatle had developed a new technique for the preparation of whole serial sections of the breast. Microscopic study of these giant sections yielded the first significant informa- tion on precancerous lesions of the breast. The results were published in a monograph. Tumors of the Breast, in 1931 of which I was the junior author. In 1938 we donated approximately a thousand of these historic sections to the Army Museum of Pathology in Washington, D.C. The statement which I shall present this morning deals exclusively with the question as to whether the protracted use of the oral contraceptive increases the risk of breast cancer in women. In approaching this problem, I have reviewed what I consider to be the most reliable reports in the scientific litera- ture pertinent to this subject. I have also studied some of the conflicting evi- dence that has been presented before your committee. Without minimizing the seriousness of the established side effects of the oral contraceptives, such as thromboembolism and certain metabolic disorders, the very nature of breast cancer as a suspected hazard places it in a special cate- gory. So cancer conscious has the public become that mere mention of the word is enough to throw most people into utter panic. In order to understand the complexity of the problem, it is necessary to point out some of the salient features of cancer of the breast and its relation to the ovarian hormones. The intimate relation between the ovaries and breast cancer has been known for many years. Surgical removal or radiation treatment of the ovaries results in remissions in about 40 per cent of premenopausal women with breast cancer. This effect occurs as a result of a dimunition of estrogen production in the body. in clinical practice, we avoid the use of estrogens for fear of increasing the activity of existing disease or stimulating the growth of clini- cally latent foci of breast cancer. Recent studies have shown that the incidence of breast cancer increases before the age 55 but remains constant beyond this age. These findings suggest that the risk from breast cancer is related to the quality of ovarian function. * Medical Director of the Beverly Hills Cancer Research Foundation and Surgical Staffs of the Cedars of Lebanon and St. Johns Hospital in Los Angeles. PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6671 The incidence of breast cancer in childless women is higher than in women who bear children. Even more important is the recent finding that a woman who has her first child under the age of twenty has a considerable protection against breast cancer. From epidemiological studies, it would seem that the decade following puberty (13-23) is a critical period in establishing the future risk of breast cancer. The fact that breast cancer is common in women who have passed the mena- pause when the estrogen levels are lower can be readily explained on the basis that those cancers are the end result of a process which began many years before. The carcinogenic effect in humans and in lower animals is characterized by a long latent period of some ten to twenty years or even longer. A carcino- genic agent exerting its effect over a relatively short period can induce biologi- cal changes in cells that progress slowly over a period of many years and end up as clinical cancer. One classical example relate to workers in aniline facto- iies who are exposed to the carcinogenic dyes for as short a period as one year and develop cancer of the bladder some twenty years later. Withdrawal of the carcinogenic agent did not arrest the progress of the latent lesions. Clinical, pathological and experimental evidence support the view that breast cancer follows a similar pattern. Our studies of whole serial sections of the breast, supported by clinical expe- rience have show-n that cancer of the breast is not a sudden event or an acci- dent in a previously normal tissue, but rather the end result of a series of changes which began many years before. Benign tumors change into precancer- ous lesions before ending up as fully established cancers. It is not inconceiva- ble that the causative agents that result in breast cancer exert their initial effect at a young age, possibly in that critical post-puberty decade. The tissues of the breast present a highly sensitive target for the ovarian hormones and have a great potential for the development of cancer. In all probability there is no direct etiological relationship between the estrogens and breast cancer. It is more probably that the carcinogenic effect of the hormones is to alter the biological state of the cells and thus render them vulnerable to the action of another agent-possibly a latent virus. Recognizing the possible risk of breast cancer as a side effect of the oral contraceptive, the American Cancer Society, as early as 1961, supported research studies on this problem and a recent report of the Advisory Commit- tee on Obstetrics and Gynecology referred to the need for well-designed studies and long-term support for research on the breast and uterus. The early detection of breast cancer often presents formidable difficulties. Not infrequently when a lump is first felt, either by the patient or by her phy- sician, it is already in a relatively advanced stage of cancer. This is further complicated by the patient's delay in consulting her physician for fear of facing a diagnosis of cancer with possible loss of the breast. Periodic biannual examination of the breasts helps greatly in early detection and prevention by surgical removal of precancerous lesions. Recent progress in the technique of X-ray examination of the breasts (mam- mography) has led to the detection of breast cancers that are too small to be felt manually. Tjsers of oral contraceptives should have periodic X-ray exami- nation of the breasts. Women using the oral contraceptives often develop fullness and tenderness of the breasts and in some cases actual enlargement which persists. Micros- copic studies of biopsy material from patients who have taken the oral contra- ceptives show increased cellular activity, reflecting the stimulating effects of the estrogens. In my own surgical practice, 1 have a series of patients who have had two or three breast biopsies. In some, the biopsies were performed before the patient started to take the contraceptive and a second or third biopsy was performed after the patient had been on the contraceptive pill for several years. Study of surgical specimens under these circumstances presents a unique opportunity to observe the tissue changes that may be related to the stimulating effect of the estrogenie component of the oral contraceptive. One has to be careful, however, in interpreting microscopic changes in tis- sues under the influence of hormonal stimulation because such changes can be so pronounced as to be indistinguishable from fully established cancer. I cite the following example: My colleague, the late Sir Lenthal Cheatle, removed the breasts of a female infant who had died at birth. He prepared microscopic PAGENO="0232" 6672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY slides of the breast tissue and without divulging their source subniitted them to five distinguished pathologists. Four of the five pathologists reported the tissue as cancer of the breast. The hyperhormonal stimulation of the sensitive breast tissues caused by the high estrogen levels in the mother's circulation results in an erroneous microscopic diagnosis. It is important to understand that microscopic changes of this magnitude can be reversible. We know that every twentieth woman will develop cancer of the breast. We also know that if the mother, the sister or the maternal aunt had breast cancer, the risk is at least doubled, so that approximately one woman in ten will develop the disease. It is manifestly imprudent to prescribe oral contra- ceptives as a first choice birth control method to patients with a family his- tory of breast cancer. In this controversy, those w-ho suspect a possible link between the oral con- traceptives and breast cancer point to the following evidence: (1) Removal of the ovaries in lower animals and in women markedly reduces the risk of breast cancer. (2) Breast cancer has been induced in five different animal spe- cies by the administration of estrogens. (3) Chemical agents having carcino- genic effects in man also induce cancer in animals-often at the same site. (4) Bilateral breast cancers have developed in two male trans-sexual individuals treated w-ith estrogenic hormones, and (5) The discovery of a~ high incidence of breast cancer among males (6.6 per cent compared to the general incidence of 1 per cent) in certain parts of Egypt u-here a parasitic infection of the liver interferes with the destruction of estrogens. Those u-ho argue against a possible link point to the lack of convincing evi- dence now available, after some ten years of use of the oral contraceptive, that breast cancer is caused by the pill. They call attention to the extensive use of estrogens by millions of women for many years in the treatment of menopausal symptoms without definite evidence of a carcinogenic effect, and finally, they are not u-hung to accept the animal experiments as being applica- ble to w-omen. With respect to the effect of estrogens on menopausal women, it should be pointed out that here we are dealing with replacement therapy. This cannot be compared to the prolonged addition of estrogens to a young woman's natural hormones. Furthermore, when one considers the prolonged latent period of car- cinogenicity, many women in their menopausal and post-menopausal age brack- ets (late forties and fifties) may not live long enough for the carcinogenic effect to exert itself as clinical cancer. Considering the question of the transferability of animal data to man, it is difficult for me to escape the conclusion that the results are relevant and must be regarded as significant. The difficulty of demonstrating a causative relationship betw-een the oral contraceptives and breast cancer obviously relates to the long latent period betw-een exposure and final effect. A minimum of ten years is required l)efore reliable results can be expected. Unfortunately, this experiment upon millions of women might prove to be too costly to contemplate. When the oral contraceptives were introduced some ten years ago, they were hailed as a solution to the world's population explosion and a safe means of preventing birth of unwanted children. The simplicity and effectiveness of the pill have constituted a veritable blessing to millions of women. Unfortunately a broad area of disagreement as to their safety has developed. Thus a serious cloud has appeared, and the question has arisen as to w-hether the benefits out- weigh the risks. Although there is no conclusive evidence that oral contraceptives cause l)reast cancer, the potential hazards involved in their protracted use by young healthy women cannot l)e ignored. Both physician and patient must be made aware of the possible risks and give due consideration to alternative contra- ceptive methods. I cannot help being greatly concerned for the millions of women who are bound to be frightened by the mere suggestion that in using the oral contra- ceptives they face a potential risk of breast cancer, and I think it would be utterly wrong to frighten millions of u-omen unnecessarily over a potential risk which can be controlled, minimized, and perhaps even eliminated. In the final analysis, we aie~ faced with this dilemma: Do the "blessings" of the pill outweigh its longrange potential hazards? PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6673 The available evidence indicating a relationship between the steroid hor- mones and the induction of breast cancer suggests that this relationship is dose related and time related. The higher the dose given and the longer the exposure, the greater the number of cancers produced. It becomes obvious that it should be a matter of good medical practice, to use the lowest doses which are effective, and to avoid the chronic use of oral contraceptives altogether. The combination type of pill containing 50 micrograms or less of estrogenic component is an equally effective contraceptive as pills containing far higher doses and their use should be encouraged. The chronic use of the pill for many years as a form of chemical steriliza- tion is dangerous from the point of view of its potential carcinogefleSis. Other methods of birth control which are strictly local in their mechanism of action, such as the diaphragm or the intrauterine device, provide perfectly adequate means of spacing children. If termination of a reproductive career for medical or other reasons is desired, the option of surgical sterilization should be avail- able. I am told nearly one-half of the states in our country still have archaic laws on the books which either prohibit or discourage the use of voluntary sterilization. I hold that the fallopian tubes are the property of the woman and not government property. After completing its family, a mature couple should be able to elect other methods of birth control than chronic use of the pill. It has been said that the proven risks of taking the pill are less than the proven risks of pregnancy. No doubt this is true, and would be a valid argu- ment if the sole alternative to the pill were pregnancy. It is also true that the potential long-range hazards of inappropriate chronic use of the pill may be considerably greater than anyone can really assess for another ten to twenty years. The women who have been taking the pill for five years or more are too few and too young to demonstrate any changes with respect to the risks of increas- ing the incidence of breast cancer. That risk is a potential time bomb with a fuse at least fifteen to twenty years in length. I share the hope that the con- cern about this danger may be unfounded, and that the considerable experi- mental evidence may be inapplicable to women, but this is a gamble which is difficult to justify because of the large numbers of women at risk. It seems to me that official policy and sound medicine should strongly dic- tate that the low-est effective doses of the pill be used for child spacing pur- poses not to exceed two to three years. A broad range of effective alternative methods of birth control should be made available, and women should be dis- couraged from using the pill as a form of chemical sterilization. The pill is neither dangerous enough to condemn it out of hand, nor safe enough to pre- scribe it as a universal panacea. The circumstances of its use should be care- fully defined and steps thoughtfully taken to protect women from the conse- quences of slipping into the habit of taking the pill indefinitely. Senator NELSON. When you say women should be discouraged from using the pill as a form of chemical sterilization, you are referring to hong-term use? Dr. CUTLFR. Long term, yes, sir. Senator NELSON. Senator Dole. Senator DOLE. Just briefly, Dr. Cutler, Mr. Chairman, I would like at this time to place in the record a statement of Dr. Edward T. Tyler, medical director, Family Planning Centers of Greater Los Angeles. (The document follows:) FAMILY PLANNING CENTERS or GREATER Los ANGELES, Los Angeles, Calif., February 24, 1970. A Report For Senator Gaylord Nelson's Subcommittee. From: Edward T. Tyler, M.D. HONORABLE SENATORS: I have been invited to present my views to your Com- mittee on oral contraceptives and the possible problems related to the use of these a gents, particularly in the United States. While I am not certain it will PAGENO="0234" 6674 COMPETITIVE PROBLEMS IX THE DRUG INDUSTRY be possible for me to apnear personally (since no specific date has been set for my testimony at the time of this writing), I have prepared some remarks that I believe may be pertinent for the record, regardless of a personal appearance. Since, by the time my presentation would have been reached, virtually all of the major scientific data concerning serious side-effects will undoubtedly have already been presented, it would be a waste of this Committee's time for me to attempt to present the same type of discussion. Rather than presenting data concerning our own specific scientific studies which are virtually all in print (and referred to in an attached bibliography), I would prefer to direct my remarks to other issues that have been raised during and perhaps preceding these Hearings. Firstly, in connection with much of the data that has already been presented by the eminent scientific spokesmen who have already appeared, I believe one important point should be emphasized. It w-ould be an insult to these scientists to argue with the facts that may have been stated during these Hearings as derived from particular specific investigations, but I must emphasize that many scientists would have differing views on the intcrpretatIoa of these facts. I doubt that there are any sets of experimental findings or statistics or data of any kind concerning which there would not be varying interpretations by different statisticians. In Sl1ort, it is not the data with which one would reasonably take issue, particularly with reference to reliability, but rather with the question of whether the data merits the conclusions that may have been drawn during these Hearings. In this vein, therefore, I would like to address myself to several important points that may not have been sufficiently discussed during the Hearings. One of the most important of these would involve the question of "public good" served l)y the presentations. Presumably, a basic reason for the initiation of these proceedings was the question of whether users of oral contraceptives were being sufficiently informed of the risks involved in their use. It would obviously be impossible for me to comment on whether or not this has been the case, because I can only relate to our own practices and those of others I know who are also actively involved in this field. Certainly, the knowledgeable physician has likely not been negligent in advising his patients of the potential hazards. On the other hand, no one will deny that a certain percentage of doctors, although possibly a very small percentage, have not been as conscientious about their prescribing of the pills and examination of patients as they might have been. For these physicians, at least, and for their patients undoubtedly this purpose of the Hearings has been accomplished. But an important qiies- tion is: Has this been over-accomplished? It is one thing to make sure women are aware of the statistical risk of thromboembolism, but it is another to frighten millions of women into worrying about a relationship between carci- noma and use of the pills when no such relationship has as yet been estab- lished. On the basis of comments I've heard from patients recently in our family planning clinics. I am convinced that these Hearings have led many women and their husbands to believe that oral contraceptive pills cause cancer. As a matter of fact. I suspect the Hearings have even led many physicians to believe that pills cause cancer. The fact of the matter is that no one knows whether or not pills cause cancer and it will undoubtedly take many years before any one does know, assuming a possible relationship can eventually he proved or disproved. I would like to amplify this area of discussion a little further because I am certain the Honorable Senators as well as millions of people across the comin- try do not really understand the difference between questioning a cause-and- effect relationship between pills and cancer and actually demonstrating that one exists. In the early days of these Hearings, an eminent gynecologist snake about the possibility of the pills causing cancer of the breast. As I recall the testi- mony, he spoke specifically about studies that were done on dogs and then gave the impression that it was reasonable to transpose the drug experiments to humans. Apparently, by mistake he suggested that one could make this assumption on the basis of the fact that all agents that are known to produce cancer in humans will also produce cancer in experimental animals. This state- ment could sound to the lay individual as a direct inference that if an agent PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6675 causes cancer in animals it will also cause it in humans, which is not actually the meaning of the statement. The statement simply indicated that if an agent does knowingly produce cancer in humans, when this agent is given to experi- mental animals, they will also develop cancer. The real question is actually the reverse: Do all agents that produce cancer in experimental animals also pro- duce cancer in humans? The answer to that question is that it is not true that all agents producing cancer in experimental animals can be arbitrarily stated to produce these tumors in humans. As a matter of fact, certain agents may apparently produce cancer or tumors under one set of circumstances in a spe- cific group of animals, even of the same strain or breed, while other groups exposed to the same agent may not develop these lesions. A case very recently in point relates to the production of breast tumors in a group of beagles by one of the hormones present in a particular birth control pill. This agent, known as chiormadinone, was given in one series of experi- ments to a group of dogs (specifically, beagles) and a substantial percentage of these animals developed breast tunors, which, according to interpretation, may have been malignant. Because of these observations, the United States Food and Drug Administration removed this particular chemical from its list of approved experimental compounds for contraceptive study. This was done at a time when chlormnadinone in the sanie dosage, used as a "mini-pill", had already been marketed for some time in England and, I believe, Canada and other countries. It has also been for several years a constituent of one of the major sequential oral contraceptives on the market in the United States. Of great interest here is the fact that on the basis of dosage in a given menstrual cycle, chlormadinone as a mini-pill, given at a dose of 1/2 mg. daily for 28 days (the average length of a menstrual cycle), would require a total of 14 mgs. per cycle. At the same time, chlormadinone in the present compound still on the market would provide 2 mgs. a day for 5 days in a sequential preparation for a total of 10 mgs. per cycle. In addition, the marketed preparation also provides .08 mgs. of mestranol daily for 20 days, one of the estrogens used in many contraceptives and an agent which has been accused by those claiming cancer is related to oral contraceptives as being the agent most likely to pro- duce these tumors. In other words, we have a situation now in which 10 mgs. of chlormadinone may be used commercially per cycle by millions of women while in the experimental preparation which was apparently virtually on the verge of FDA approval, a total mini-pill dose per cycle, with no estrogen at all, was 14 mgs. I was told, when I questioned this, that beagles who had been treated with the marketed sequential product containing the estrogen devel- oped no tumors of the breast. It might therefore be deduced that perhaps the added estrogen which some claim causes cancer, might have actually protected the animals against this. Either that, or the daily dose of a mini-amount of the progestogen was more carcinogenic than the intermittent, every fourth week dose of more concentrated amounts of the hormone along with daily estrogen. Here, again, we have an area where facts were obtained on the basis of experimental observations and these facts required interpretation which, despite their seeming lack of logic, led the FDA to remove the experimental drug from further study and permit the marketed preparation to remain avail- able. Thus far, regardless of one's logic, this may seem purposeful in order to protect the public on the basis of observations that were suspicious. Yet, con- sider one additional piece of information that has just become known. Another company testing a similar hormone for a mini-pill, in addition to using non- treated control beagles also started for its own information another series of what might be termed "controls in therapy" and gave a similar set of their beagles chlormadinone in the same experimental design as described above and which had resulted in withdrawal of chiormadinone from the study. Strikingly, none of the chlormadinone-treated animals in this company's studies developed breast tumors! These facts are important to note, not because they prove anything, but simply to illustrate how extremely difficult it `is to prove anything. I would leave it to pathologists and those experts in veterinary medicine to explain why one group of the same animals under the same investigational conditions developed a substantial percentage of breast lesions while another group of the same animals under the same conditions failed to develop any. I would also w-oncler about the statistical validity of interpretation of positive findings in relatively small groups of animals. PAGENO="0236" 6676 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY So much for animals. Now let's go on briefly to the real issue-the question of the induction of cancer in humans by oral contraceptives. I would like to say at the beginning that I do not know the answer to this question, and I strongly believe that no one knows the answer. For this reason, I believe the entire subject should be treated not with exaggerated headlines and publicity but with a certain degree of circumspection. Unfortunately, this has not been the case. As I mentioned previously, these Hearings have also accomplished dissemination of an unproved fact: that pills are producing cancer. The Hear- ings have also apparently publicized an accusation that there is a vast conspir- acy between drug companies, the American Medical Association, clinical inves- tigators, and possibly practicing physicians, to conceal from the general public and from other physicians the fact that the pills are causing cancer. For example, early in these Hearings there was considerable press coverage of remarks suggesting that a clinical study emanating from a group of Planned Parenthood clinics in New York City and Memorial Hospital bad been sup- pressed in the medical literature. It was suggested that suppression of the report of this study was instigated by the pharmaceutical companies, who because of their vested interests, w-ere afraid that the publicity would result in a considerable drop in sales of birth control pills. As something of an "insider" in this matter, I w-ould like to set the record straight. First of all, studies designed to prove or disprove a relationship between any agent and cancer are extremely difficult to perform and sometimes virtually impossible. With use of tobacco dating back hundreds of years, it was only very recently that the United States Public Health Service felt that it had enough conclusive information to relate cigarette smoking with cancer. (It is my personal opinion that these Hearings might have served a far greater public service by concentrating on cigarettes and cancer, which is a problem of far greater magnitude than concentrating on the subject matter which has been before this committee the past several weeks-but that's a different story!) As far as the New York oral contraceptive study is concerned, this investigation w-as under the direction of Doctors Malemed and Dubrow. If there were any attempts to suppress publication of their report, this uncloubt- edly came from scientific areas and not from commercial interests. About two years ago these investigators accumulated data as a result of collaborative efforts in New York Planned Parenthood clinics. The reliability of the data depended to a certain extent on the veracity of women who were attending these clinics, the records of the clinics, the adequacy of patients' visits to the clinics, as w-ehl as adequacy of comparisons between pill users and non-pill users. Malemecl and Dubrow reported their data at various local medical meet- ings (I believe in the New York area) and, as is usually the case, word got around that there had been an investigation completed which proved that the birth control lills were causing cancer of the cervix. Naturally, this informa- tion also reached the U.S. Food and Drug Administration, a federal agency which has often been unjustly maligned, and one which I believe has really done a remarkable job considering the limitations of its finances, as well as staff. The FDA promptly requested its Advisory Committee, led by Dr. Louis Heilman, who testified at these Hearings, to hold a meeting in Washington, inviting several groups of investigators u-ho have had long-term experience with oral contraceptives in the hope that they would bring their data relative to the pills and carcinoma of the cervix. My understanding is that four grouns of investigators were invited: the Malemed and Dubrow group which had the study in New York: those representing the Puerto Rico study, the first one done anywhere: a group led by an eminent pathologist, Dr. George Wied in Chicago; and our own group from Los Angeles, which has a study dating hack to 1950-the longest in the United States per se. and one which started a short time after the Pincus, Rock and Garcia study in Puerto Rico. All were invited to present their data at the Advisory Committee meeting in the FDA offices in Washington. The only ones who came with data were Doctor Malemned w-ith the material that he had been reporting and Doctor Moyer and me with our data. Present at the meeting were most of the members of the Advisory Corn- inittee along with FDA Commissioner Herbert Ley, as well as several members of his staff. Dr. Malemed presented his data and suggested that the informa- tion implied that women using birth control pills had a substantially increased risk of developing cancer of the cervix. We presented our data and after prior consultation with a number of statisticians as well as with members of the PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6677 National Institutes of Health, we gave the conclusion that despite a substan- tial amount of material and a lengthy period of observation, our data provided no conclusions at all. Word was also received that Dr. Wied had reached a similar conclusion concerning his own voluminous data and therefore had not come to present it. Following the presentations at this meeting, several participants suggested that Dr. Malemed refrain from submitting his report for publication until he had more data himself, or at least until one other group anywhere had con- firmed his conclusions on the basis of their own studies. Dr. Malemed objected to these recommendations and felt that the study should be published at least as a preliminary warning. Following the nģeeting in Washington, it is my understanding that Dr. Malemed submitted his report to tl1e Journal of the American Medical Asso- ciation. As is customary, the J.A.M.A. distributes copies of any submitted arti- cles to several consultants to determine whether it is suitable for publication. My understanding is that the Journal editors were advised not to accept the report for publication, primarily because of major questions concerning the interpretation of the data. Subsequently, the article was submitted to other major medical journals and similarly was not accepted in the United States. Finally, the authors submitted the article to one of the major medical journals in England and it was published in the British Medical Journal although there were significant modifications in the article that was finally published, as com- pared to the one originally submitted in the United States. In short, there was no conspiracy to keep this report from publication, but rather an honest, scientific doubt as to whether the publication of a very pre- liminary and controversial report, in a major medical journal such as the J.A.1\I.A., would lend too much weight to the conclusions drawn. With our present rapid communications and the quick transfer of information published in scientific journals to the press and broadcasting media, conservative scien- tists felt that such a report might cause great hysteria, among women using the pills, as well as their husbands. This, of course, could be acceptable if the conclusions were really definitive but in the absence of combined informed opinion there was little justification in causing such a tremendous scare. While I am on the subject of publication of articles and again referring to the so-called conspiracy between the J.A.M.A. and the drug industry and some physicians; I would like to relate briefly my own experiences with the J.A.I\LA. For many years, I have served with no compensation as a consultant (as have other doctors) to the Journal in reviewing articles that are submit- ted for publication which happen to be in my own particular area of interest. Over the years, I have had a substantial number of reports referred to me for review and recommendation. In looking over my files, I find that beginning about 1960 when oral contraceptive reports began to be prepared in increasing numbers, and I was consulted because of our early studies, I have suggested that the J.A.M.A. publish substantially more articles relating to side-effects than those that related to pro-pill data. Appended to this report will be photo- copies of excerpts of correspondence between the editors and me relating to several reports which were favorably reviewed by me and then accepted by the J.A.M.A., and, when published, related to pill side-effects. Specifically, in reviewing some of these reports I find, for example, that in October 1962, an article was submitted for publication by Doctor David 0. Weiner and associates, of Dallas, Texas, which was entitled "Phlebitis Devel- oping While Under Treatment with Norethynodrel-Mestranol (Enovid). This referred to only a single case report, and my note reads: "I feel that this case report is an interesting one and merits publication particularly in view of the recent (lay) publicity concerning oral contraception and its possible relation- ship to thrombophiebitis." My review sheet states "Accept" and, I believe, this was one of the earliest medical reports to link the pills with thrombophlebitis. The report was accepted for publication by the Journal at that time. In November 1963, there was a report submitted by Doctor Ervin Schatz, from Henry Ford Hospital in Detroit, also relating thromboembolism to oral contraceptives and my recommendation was this article be published with per- haps some slight editorial revisions that appeared necessary. It is my under- standing that this article was also published with subsequent revisions sug- gested by the Journal. Also in November 1963, there was a report submitted by Doctor Charles PAGENO="0238" 6678 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Farris covering changes in the uterine lining under the influence of oral con- traceptives and I again recommended the publication of this report. In 1965, there was a critical article submitted to the J.A.M.A. entitled "Is Fertility Altered by Oral Contraception?" Here again, this article was accepted for I)ublication but as a "Letter to the Editor" since it did not contain a great deal of original data. In addition, in August 1964, there was an article by Robert Burtket of Cin- cinnati General Hospital, which was reviewed and accepted for publication relating to "The Incidence of Idiopathic Thromboembolism in Women." In November 1966, an article was submitted from Scott Air Force Base by Doctor S. S. Resnick describing "Melasma Induced by Oral Contraceptive Drugs." This presented a possible new side effect and I recommended its publi- cation. In addition, more recently, February 1968, there was an article entitled "Ovulation Suppression, Psychological Functioning and Marital Adjustment" and this article was also accepted for publication. These are just a few illustrations of some of the types of articles that were considered acceptable and that primarily dealt with problems of side effects related to use of the pills. On other occasions where there were articles submitted relating to new mod- ifications of present pills which did not seem to present any major scientific advances, and I went on record as suggesting that these not be published and in almost all instances the Editors went along with these recommendations. This, despite the fact, that their publication would have undoubtedly been desired by advertisers. It is, therefore, I am sure most unfair for any statement to remain in the record implying that the J.A.M.A.. had acted in any prejudicial fashion regard- ing publication of reports relating to oral contraceptives. There are other major concerns that I have regarding the government's rela- tionship to oral contraceptives and the lack of a keen interest in them, dating back to the start of these programs. It appears to me that during the several years since the introduction of oral contraceptives, government research funds have been extremely limited in the direction of exploring possible side effects. As a matter of fact, I am certain that the amount of money available from NIH for research into these fields was extremely limited and it was appar- ently felt that the pharmaceutical industry should take care of any other nec- essary studies on these medications even after they were approved for market- fng. This might be to some extent reasonable if one were to assume that there was only limited numbers of women using a very specialized medication. On the other hand, when the numbers became so great that it appeared that only extensive studies on large population groups could provide meaningful informa- tion, this would have been a time for the government to step in and exert its influence as well as provide cooperation to investigators. My impression is that only in the last few years has there been any real government policy toward .encouraging contraceptive research. In addition, The Population Council and Ford Foundation which originally supported limited oral contraceptive research then decided that this was not in their field of interest and also indicated it was the drug industry's concern. I will send you correspondence to verify each of these statements, should you indicate you would like copies. At the time I started this report it appeared indefinite as to whether my tes- timony would be desired in Washington to present a more objective viewpoint than had appeared to date. Since I find that some of the recent presentations have made more sense it is unlikely that it will be necessary for me to come personally. Therefore, not knowing what use will be made of these written remarks, I will discontinue them at this point and simply indicate that if you should care to have more data for the records I would be glad to discuss in writing what I know about the FDA's attitude toward oral contraceptives over the past decade, as well as the WHO, where industry has stood, bow the pres- ent coverage has to some extent been manipulated, how TV has very obviously taken sides and how, in general, this subject has become more of a political football than a matter for objective scientific evaluation. Yours respectfully, EDWARD T. TYLER, M.D. Medical Director, Family Planning Centers of Greater Los Angeles. (Enclosure omitted.) PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6679 Senator DOLE. One of the points Dr. Tyler raises is the need for more funds for research. We are generally in accord on this point on the Committee. In his rather lengthy statement, lie questions whether the hearings really serve a public good. In discussing that, there is a `question I would like to ask. He says that the knowledgeable physician has likely not been negligent in advising his patients of the potential hazards-some of the hazards you have discussed. On the other hand, no one will deny that a certain percentage of doctors, although possibly a very small percentage, have not been as consciencious about their prescribing of the pills and examination of patients as they might have been. For these physicians, at least, and for their patients undoubtedly their purpose of the hearings has been accomplished. But an important ques- tion is: Has this been over-accomplished? It is one thing to make sure women are aware of these statistical risks of thromboembolism, but it is another to frighten millions of women into worrying about a relationship between carci- noma and use of the pills when no such relationship has as yet been estab- lished. Do you agree with the statement that there has been a relationship established between the use of the pills and carcinoma? Dr. CUTLER. No, I said in my testimony there has been no definite evidence of that etiological relationship. Senator DOLE. Dr. Tyler goes on, On the basis of comments I've heard from patients recently in our family planning clinics, I am convinced that these hearings have led many women and their husbands to believe that all contraceptive pills cause cancer. As a matter of fact, I suspect the hearings have even led many physicians to believe that pills cause cancer. The fact of the matter is that no one knows whether or not pills cause cancer and it will undoubtedly take many years before anyone does know, assuming a possible relationship can eventually be proved or disproved. Do you agree with that statement, no one does know if there is a relationship between the use of the pill and cancer? I want to emphasize that point, because the first headline I read about these hearings was "Pill may Cause Cancer." I assume that you agree with that headline, it may or it may conceivably cause something else. But how do we give comfort to some of the people who have been frightened because of what may have been said or not said at the hearings? Is there anyway we can, except through more research? Dr. CUTLER. Yes, of course. I am completely concerned about the fear that can be caused and to some extent has been caused among women with respect to cancer. As I said in my testimony, there is such tremendous fear about the disease itself that the mere mention of it in a newspaper or anywhere will cause alarm. However, I do not agree that because of that we should ignore these hazards. These hazards are very definite. They have a considerable back- ground and there is reason for concern. I hope very much that the news media will fully appreciate the importance of accurate report- ing on this sensitive subject. I would hope that they will state that there is no definite evidence of a causative relationship between the pill and breast cancer, but that there is sufficient reason for concern, and I hope that they will point out that women with a positive his- tory of breast cancer in the family should avoid the pill. PAGENO="0240" 6680 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I should add that patients who have been operated on for removal of so-called benign tumors of the breast, in which the pathologist has been concerned about an overactivity of the cells under the microscope, should be considered in the high risk group. I think we simply have to realize that there is reason for concern and do everything we can not to frighten the public by emphasizing that there has be~n no proof. Senator DOLE. Do you think the physician generally is aware of the point you made in your testimony that where there is a history, family history of breast cancer, that the pill should not be pre- scribecl? Is that general information or is it something new this morning? Dr. CUTLET~. That depends on the gynecologist. Many of my gyne- cological colleagues have called me over the years to ask whether a certain Patient whom we are taking care of mutually should have the pill. I cannot sa how widespread this knowledge is, it certainly is not new this morning, nor is it common knowledge among the profession. Senator DOLE. That is a good point. As far as I know it has not been called to our attention previously, and it is something that should be conve~-ecl at least to the physician, the gynecologist, who prescribes the pill. You summarized quite well-that it is neither a panacea nor should it be condemned out of hand. You also indicate on page 10, that probably the potential risk can be controlled, minimized, or perhaps even eliminated. I assume it is to be inferred from your statement that with more research we can achieve this goal. How do you eliminate the risks? Dr. CUTLER. Only by more research, and there are many avenues, clear cut areas, in which important information can he gleaned even before these many years pass from epidemiological studies. Hope- fully, two things, one is that some information will come along as a result of research within the next few years that will give us some lead as to which way we are going and, of course, the other, hope- fully, is that something altogether new in a contraceptive will come which will be more safe than anything we have now. Senator DOLE. There has been a Corfman-Siegel study. Would additional studies of this type be helpful? Dr. CuTLER. Yes. The Corfman study is extremely helpful and a very important epidemiological contribution. You se~e, epidemiology has become a science only in the last S or 10 years. Before that time, the results of some statistical studies have been quite uncertain. In recent years, epiclemiological studies are far more scientific and more accurate and more reliable. And it is upon these that we really have to base our ultimate conclusions. Senator I)0LE. Thank you, Mr. Chairman. Senator MCINTYRE. Doctor, back on page 6 you point out that recent progress in X-ray techniques have led to the detection of breast cancers that are too small to be detected manually, and for this reason you recommend that users of oral contraceptives have 1)eriodic X-ray examinations of the breast; I take it, along with other recommendations that you are making here about low estrogen content of the pill, trying to control the period for which it is taken, PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6681 along with this indication that a family history of cancer of the breast should constitute a red flag indicating that the pill is not a first-choice contraceptive. Now, on this X-ray of the breast, do you have any idea of the fre- quency with which this is being done now? Dr. CUTLER. It is being done very frequently. X-ray examination of the breast has been known for some 30 years. But it is only in the last 10 years and more particularly, in tli~e last 5 years, where the technique has improved to such a degree and the accuracy of inter- pretation has improved that it has become widely used. Very often, when a doctor does not recommend a mammogram, the Patie1~t will come in and ask for one. It is being widely used and more and more used. And it is still in its relative infancy. There are improvements going on almost every month in the apparatus and technique and interpretation, and we can hope for much more accuracy as time goes on. Senator MCINTYRE. Would you be able to state how frequently it is being done in women who are users of the pill? Dr. CUTLER. Whether it is being done more often with users? Senator MCINTYRE. Yes. Dr. CUTLER. I have no knowledge of that. I do not know. I have recommended that it be used among my patients and friends and colleagues. Senator MCINTYRE. Thank you very much, Doctor. Senator NELSON. Well, for a patient on the sustained dosage of estrogens, how often would you yourself recommend that there be a mammogram done? Dr. CUTLER. I-low often should it be done? Well, I think that it would be very wise if it could be done once a year. That is not too often to be concerned about any exposure to X-rays. And I think it would be very useful. There are many of us who recommend annual mammograms even for those who are not taking the pill. Senator NELSON. So you recommend in your testimony that a user of the oral contraceptive have a regular physical exam, which includes a breast examination. I-low often are you suggesting that the regular exam be given? Dr. CUTLER. Most physicians and much o-f the teaching speak of annual examinations. Now, I have been doing this work for some 40 years and I have always recommended to my patients that they have their breasts examined a minimum of twice a year, preferably four times a year. And I do that because it is not infrequent when I see a patient 6 months after a previous examination, to find a cancer of the breast. Actually, I have currently under my care approximately 1,000 patients who come regularly every 3 or 4 months. I also find that the reassurance that they get from this examina- tion seems to be great, evidenced by the fact that they keep coining back year after year. I do find many early cancers by this method. Senator NELSON. Many what? Dr. CUTLER. I do discover many cancers in their early stages by these frequent examinations. Senator NELSON. I was wondering if you understood my question correctly, when I inquired what the recommendation would be for physical examination which would include breast examination of a 40-471-70--pt. 16-vol. 2-16 PAGENO="0242" 6682 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY user of an oral contraceptive. I do not know whether you are saying this is a routine examination of a patient of yours who is not under oral contraceptive or one who was. All of the testimony, save two witnesses, has said every 6 months. One of them said 6 to 7 or 8 months. One doctor, a specialist in the vascular area, said once every 3 months. Doctor Kistner said once every 12 months. Dr. CUTLER. What is your question, sir? Senator NELSON. My question is, how often would you recommend a physical for somebody on oral contraceptives, you replied, for most people once a year. I was wondering whether you had under- stood my question. Were you simply referring to how often some- body ought to have a breast examination whether or not they are on oral contraceptives? Dr. CUTLER. Yes. The frequency with which a patient should be examined, the opinions of the profession on that question vary widely as you have already indicated, whether they take the pill or not. It is a matter of philosophy as to how often a patient should go t~o their doctor with respect to cancer. Again, in the early part of the century, the American society for the control of cancer, which is now called the American Cancer Society, took the leadership in urging people to have periodic cancer examinations. The British have never agreed to that even to this day. I think that insofar as patients who are taking the oral contracep- tives, and insofar as the breast is concerned, I think that examina- tion of the breast, at least twice a year, would be a logical proce- dure. I think that also depends a little bit on the patient's age. You see, cancer of the breast is almost unknown under the age of 25. They are rare between 25 and 30. So I think the frequency with which such examinations are done, including X-rays, would depend a little bit upon the age of the patient. Certainly, a patient with a positive family history of breast cancer should be examined every 3 months. Senator NELSON. Thank you very much, Doctor. We appreciate your taking your time to come this morning. Dr. Anna Southam, of the Department of Obstetrics and Gynecol- ogy, College of Physicians and Surgeons, Columbia University, called to say she was unable to appear this morning. She requested permission to file along with her statement a supplementary state- ment. That will be printed in full in the record. (The information follows:) STATEMENT BY ANNA L. SOUTHAM, M.D., LECTURER IN OBSTETRICS AND GYNECOLOGY, COLLEGE OF PHYSICIANS & SURGEONS, COLUMBIA UNIVERSITY, NEW YORK, N.Y. I am Anna L. Southam and I testify before this Subcommittee on the writ- ten invitation of Senator Gaylord Nelson. The views I express are my own and not those of the institutions with which I am affiliated. As a member of the faculty of the Department of Obstetrics and Gynecology of Columbia University's College of Physicians & Surgeons, I have been involved in the clinical evaluation of the synthetic steroids used in birth con- trol pills since 1955. I have carefully followed the literature relating to the metabolic and pathologic effects of oral contraception which was reviewed before this Subcommittee during January. Although birth control pills have been used in clinical trials beginning in 1956 and were approved for marketing in the United States in 1960, it is PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6683 impossible to find a group of users who have taken oral contraception long enough to allow for epidemiologic studies or statistical analysis of side effects. Half of all women who start using oral contraceptives discontinue the method before one year of use. In some studies half discontinue in less than six months. The number of women using oral contraception for two years or more has been too small to permit meaningful studies. Hence, the long-term effects of the medication have yet to be determinedand are relevant to few users. Polls taken after the January Nelson Subcommittee indicate that 40 percent of United States women currently using oral contraception have been disturbed because unfavorable comments in the lay press during last month's Senate hearings led them to conclude that the pills were a serious hazard to health. The known side effects and complications of oral contraception are being continually monitored by task forces, groups of experts advising the United States Food and Drug Administration. Two reports, one published in 1966 and one in 1969, report the current state of knowledge and advise specific studies. The reports have been distributed to the medical community of the United States. The World Health Organization has likewise convened groups of experts and distributed technical bulletins to the world medical community. I maintain, therefore, that physicians have been adequately informed and pos- sess the information necessary to make the proper decision concerning the pre- scription of oral contraceptives. The rash of books and articles written by non-medical science writers for the most part tend to be sensational rather than scientific and are a disservice to the consumer, who should depend on her physician for advice. The pharmaceutical industry, I believe, has been conscientious in reporting side effects. There is a need, however, for a systematic and collaborative evalu- ation of the effects of hormonal contraceptive agents. An admirable example of an evaluation of a new contraceptive is the collaborative statistical study of intrauterine devices organized on a world wide basis by a private agency, the Population Council, in 1962. This study led to the rapid accumulation of signif- icant information on the effectiveness, acceptability and risks associated with intrauterine contraception. Hormonal contraceptives are important drugs for the treatment of gynecolog- ical abnormalities. Cyclic administration will control abnormal bleeding and painful menstruation. Continuous administration will prevent the pain due to endometriosis which is usually associated with menstrual periods. There is no evidence that these preparations have a beneficial effect on infertility. They have been used in attempts to prevent threatened or habitual abortion, but convincing evidence of effectiveness is lacking. Oral contraceptives prevent ovulation and do so at the level of the central nervous system. Thus, the entire metabolism of the individual may be affected. We believe the ideal contraceptive should interfere with some peripheral reproductive event such as fertilization or implantation. The need for funds to support research leading to the development of new contraceptives is urgent. Until the time when we have simpler methods, however, I plead with the women of the world to calmly rely on the advice of their physicians concern- ing the contraceptive of choice. I beg the press to report accurately or not at all. No new information was disclosed during the January hearings, and there is no cause for panic. SUPPLEMENTAL STATEMENT OF Du. ANNA L. SOUTUAM The continuation rates quoted apply to foreign users chiefly from Asian countries. Continuation rates in the United States are somewhat better, partic- ularly if medical follow-up is good. The Indian Council of Medical Research has evaluated the reports issuing from the Monopoly Subcommittee on the adverse effect of oral contraceptive pills. Expert consultants in India are not impressed by data that have been presented. They have conducted their own studies and feel that the oral con- traceptives are safe to use. Senator NELSON. Our next witness will be Gen. William H. Draper, Jr., Honorary Chairman, Population Crisis Committee, PAGENO="0244" 6684 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WTashington, D.C.; accompanied by Mrs. Phyllis Piotrow, secretary and member of the board, Population Crisis Committee. We are very pleased to have both of you here before the commit- tee today and we are well aware of the fine contribution to the public that your organization and the peopie in it are making. You may present your statement however you desire. it will be prmtecl in full in the record. STATEMENT OP GEN. WILLIAM H. DRAPER, ER., HONORARY CHAIRMAN, POPULATION CRISIS COMMITTEE, WASHINGTON, D.C.; ACCOMPANIED BY MRS. PHYLLIS PIOTROW, SECRETARY AND MEMBER OF THE BOARD OP DIRECTORS, POPULATION CRISIS COMMITTEE General DRAPER. Mr. Chairman and Senators. My name is William H. Draper, Jr. I appreciate Very much indeed the privilege and courtesy of being invited to appear here today, but before testifying and with your permission, I should like to introduce Mrs. Phyllis Piotrow, who, as you have said, is the sec- retary and a member of the board of directors of the Population Crisis Committee. For the past 5 years and until very recently, she was also execu- tive director of the committee. Prior to that, she had been legislative assistant to two Senators, Senator McGovern and Senator Keating. I should acid that her work as executive director of the Population Crisis Committee has resulted very largely indeed in whatever suc- cess our work has accomplished. She is married, has two children, her husband is Dean of the School of International Service at American University. I think it is particularly appropriate that this important question before this committee be discussed from a woman's point of view. Obviously, whatever risks are entailed because of childbirth or from usmg the pill are not borne by any of us men, and I think that the point of view of a woman, particularly one who is as qualified as Mrs. Piotrow is in this particular field, would be useful to your com- imttee. Mrs. Piotrow. Mrs. PloTnow. Thank you, General Draper. Mr. Chairman, I appreciate your invitation to appear with Gen- eral Draper and comment upon some of the issues which have arisen or may arise in connection with the use of oral contraceptives. My name is Phyllis Piotrow. As indicated, I formerly served as executive director of the Population Crisis Committee, and am cur- rently studying and doing research on a fellowship at Johns Hop- kins University. I have been married for 14 years and have two chil- ciren. The testimony which was presented before this committee during the initial hearings in January, and somewhat later, can be divided into five general categories: 1. There was technical testimony from scientific researchers which indicated a number of specific abnormalities that might be associated with use of oral contraceptives, including delayed return of fertility, PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6685 genetic or teratogenic effects, rheumatoid complications, tliromboem- bolism, liver, blood and metabolic changes. Some of these effects have actually been recorded in a small number of cases, others are merely suspected. Virtually all of these witnesses strongly recom- mended that further research be undertaken to determine whether these apparent associations were real, what the actual hazards might be, and how the vulnerable patients might be identified. 2. There was repetition of the arguments, many of which have been repeated for a decade, that steroids may either cause or prevent cancer. In the absence of any evidence whatsoever of human cancer due to oral contraceptives and in light of the long latent period of development of many cancers, both sides admit that the argument cannot be settled upon existing data and that additional research is needed to answer this most disturbing question raised. 3. There were several witnesses who were critical of the promo- tional material and other activities of drug companies in downgrad- ing certain data or reported adverse reactions to oral contraceptives. 1-lere, too, further research plus full and objective reporting of results is necessary. 4. There were witnesses who spoke more generally, in terms of the broad perspectives of pregnancy, of other contraceptives available, and of the need to weigh benefit and risk in each case. Because little is really known of how oral contraceptives-or most drugs, in fact- actually operate, to weigh a known benefit against an unknown risk is not a simple task-even when the risk is 1iOt demonstrably great. 5. There were, unfortunately, also charges macIc which, although supported by no new data, have in fact aroused considerable new anxiety among the 20 mullion women on five continents estimated to be using oral contraceptives. I would like, if I may, to include fol- lowing this testimony an article from the New York Times of Feb- ruary 15, 1970, reporting an increase in unwanted pregnancies among women who discontinued use of orals because of widely cir- culatécl news stories and reports of possible danger. Senator NELSON. May I ask a question at this stage. rr1~is is an article from February 15, New York Times? Mrs. PIoTuow. Yes, sir, it is. Senator NELSON. What puzzles me is that that is 31 days after hearings started. I wonder how they accumulate these statistics of pregnancy since stopping the pill for such a short period? Mrs. PioTuow. I imagine that as soon as the women think they may be pregnant they go to the doctors rather promptly. Senator NELSON. The story had to be researched, they had to go find some basis for this story, so at best you had a pregnant woman in 20 days or so. It puzzles me the way these stories are thrown around by doctors who have no statistics and no proof, asserting that pregnancies occurred and some of them were asserting it within 14 days after the hearings had started. I think it indicates careless aiid hysterical comments by the medical prOfession. One doctor got out his com- puter and said this will cause 100,000 babies. They did not comment on the fact that, as Dr. Connell said last week, they had 116, 1.. guess it was, requests, to transfer to another contraceptive. PAGENO="0246" 6686 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY You assume because somebody quits an oral contraceptive that she does not go to something else. And to assume everybody who quits is never going to use anything else and therefore becomes pregnant, is a pretty careless piece of reporting, it seems to me. I am puzzled about a New York Times piece that was printed in the paper stating statistics on pregnancies. which they would have had to gather within 20 days after the hearing started. Mrs. PIOTIIOW-. There have been subsequent articles which I would be glad to gather for the record, if you wish, Senator. The subse- quent ones may be based on additional data. You mention the computer. Actually, the estimate of 100,000 births is rather conservative. The figure suggested is that 1.7 million women may have discontinued oral contraceptives, which on the face of it. might look like about 1.7 million births. It is by calculating this downward and by considering the relative effectiveness of var- ious other means of contraceptives that. one arrives at a figure that is no larger than 100,000 when you are dealing with 1.7 million women. I could, if you wish, go into a little more detail as to how that figure is arrived at. It is, of course, an estimate. Only time will tell the exact number. Senator NELSON. WelL what baffles me a bit is that the Newsweek article starts out saying their survey showed 18 percent quitting the pill, and that 6 percent of those said they were quitting the pill because of the hearings. Dr. Guttmacher testifies that 18 percent quit because of the hearings, using the same surve of Newsweek. So, Dr. Guttmacher, whose profession is this field, was misleading the country by three times the percentage that Newsweek had. The people who believe in planned parenthood are being scared to death by statistics which are imagined. I would like to point out that 6 percent of the women are quitting the pill. We do not know how many transferred to a diaphragm or IIJD, but certainly if they were motivated to take the pill, they would go to something else, at least a high percentage would. I would like to have you address yourself to these statistics, if 100,000 people-which I extrapolate from the 6-percent figure- 100,000 are going to have an unwanted baby, which I think is non- sense, but let us assume it is correct-let me quote to you from Dr. Hugh Davis, and then you tell me how many people are getting pregnant by quitting on their own. And that had nothing to do with the hearings. Dr. Hugh Davis quoted from a Chicago study that: "Frank found that 40 percent of those patients started on oral contraceptives aban- doned the method within 2 months." And then, in Maryland's Planned Parenthood Clinic, "Half the pill patients abandoned the method in less than a year." So if you have half of the people in America starting the pill, qiuttmg in a year, how many of them got pregnant because of the hearings? All of this occurred before the hearings. Could we not have for the record the extrapolation of the planned parenthood and population crisis people of the disaster that is occurring because women voluntarily quit the pill? I think it would help put the hear- ings in l)alance, which we have been trying to do here for so long. PAGENO="0247" COMPETITIVE PROBLEMS~ IN THE DRUG INDUSTRY 6687 Mrs. PI0TR0W. I would say two things. First of all, we are extrap- olating now, but with pregnancy, you do not have to extrapolate forever. Within 9 months the figures will be available. So we may have a scholarly dispute at this point as to what the precise figures are. We will know in the fall. It will be possible to determine from the seasonally adjusted birth rates, adjusting for trends and for monthly differences. It will be possible to determine within a fair margin how many babies born, for instance, in the last 3 months of 1970, might con- ceivably be traced to these hearings. So we can argue now, but this is not something we have to wait 10 years to have an answer on. We will have an answer before that. Secondly, I would say that I am not entirely sure how others arrived at their figure of 100,000 births. The way I arrived at it, and I saw later that others had arrived at it, too-was to figure approxi- mately 1.7, 1.8 million women discontinuing pills. Now, we do not even know precisely from the existing data how many women are taking pills now because there is no count of patients. It is only a count of how many pills drug companies think they are selling. There is no actual count of women taking them, so that this amounts to an estimate. But if there are approximately 1.8 million women taking pills who discontinue taking pills because of publicity, and this comes from a survey, whether you rely on survey data generally or not- Senator NELSON. WThat survey was that? Mrs. PIOTROW. That was a Gallup survey that was reprinted in Newsweek. Senator NELSON. What did that survey say? Mrs. PIOTROW. That survey, I believe, indicated that 18 percent of those taking oral contraceptives had discontinued and another 23 percent might discontinue. Senator NELSON. Because of these hearings? Mrs. PIOTROW. Yes. I do not count those 23 percent who might discontinue. I do not know what that means. And I do not know the precise methods by which the survey was conducted. But I think Gallup surveys are fairly well thought of in the survey field. Senator NELSON. This is the point I made a few minutes ago: that the planned parenthood l?eople and population crisis people, by mis- stating the facts, are frightening people who believe in population control. The Gallup survey did not say that 18 percent of the women were quitting the pill because of the hearings. All you have to do is read the article. Dr. Guttmacher apparently did not understand the article either. It was very simple. They said one-third of those surveyed of the 18 percent who said they were quitting the pill did so because of the hearings. That is 6 percent, not 18 percent. I think it is a dangerous business for responsible organizations to exaggerate the statistics. Mrs. PIoTRowr. I have here from the report that appeared in the New York Times giving these figures: "Polls indicate that 18 per- cent of pill users-or about 1.7 million women-have dropped the pill as the result of these adverse reports." PAGENO="0248" 6688 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This is a story by Jane Brody that appeared in the New York Times. Senator NELSON. Was that based on the Newsweek survey? Mrs. PIOTROW. The date of this was February 22, 1970, and it appeared in the medicine section of the News of the Week of the New York Times. General I)1iAPER. May I read into the record, Senator, from News- week, which rel)ortS the Gallup survey. The result was an eyeopener. Largely because all of the recent publicity, 18 percent of the 8.5 million U.S. women on the pill, nearly 1 in 5 say they have stopped using it altogether. In addition, 23 percent say they are giving serious consideration to quitting. This says largely because of the recent publicity. Senator NELSON. Doesn't it say in there that one-third of the 18 percent said ti~ev were quitting on account of the publicity of the hearings? General DRAPER. I do not find it; it may be. Senator NELSON. That is the Newsweek article? General DRAPER. I will read it again. Senator NELSON. WThat is that from? General DRAPER. Newsweek reporting the Gallup poll. New-sweek had the Gallup 1)011 made. "The result was an eveopener. Largely because of all of the recent publicity"-there was publ~cit.y besides the committee hearings, I realize-"18 percent of the 8.5 million U.S. women on the pill, nearly 1 m 5 sax they have stopped using it altogether. In addition, 23 percei~t say they are giving serious consideration to quitting." Senator IcELSOX. May I see that a moment? I am not familiar with that one. General DRAPER. This is a Xeroxed copy of the Newsweek article. Senator DOLE. I do not think they were asked precisely Mr. Chair- man, whether or not the were stopping the pill because of the hear- mgs. There has been some publicity about these hearings. Senator ~ELSOX. Now-. this is the same article I read in News- week. but I am in tile habit, if I am interested, in reading the whole article. It says a small number of women say they have given them UI) for no particular reason, but the biggest single group of defec- tors-roughly oiie-third--saicl their doubts about tile pill were directly related to the hearings. I calculate one-third of 18 w-oiilcl be six. All I am saying is that I thjnk that the public should not be frightened by misrepresenting statistics as newsiapers and reporters and readers have been doing. One-th~rd said their stepping tile pill was related to the hearing. But that is one-third of 18 Percent. I would hope that people who write about it would at least get their facts straight and people whose full-time business it is to be informed about~ this question would be careful enough to come in and recite accurate statistics. I do not think it is unreasonable to expect. General l)riAPER. But, Senator, may I pomt out that long before the hearings were started there were stories and news reports and television programs related to this subject. I do not say that they all PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6689 came from the hearings. It results largely because of the publicity which WaS not only at the hearings. There was a good deal of it before the hearings, as you know, and then it goes on. Senator NELSON. I do not have the total, you know. General DRAPER. I am not blaming anyone, and I have not, nor has Mrs. Piotrow. Senator NEI~soN. But I would like to point out, I think the story is misleading when it says largely due to the hearings, and then they qualify it by saying- General DRAPER. Largely due to the publicity. Senator NELSON. They qualify it by getting down further in the article and saying one-third of the women attribute it to the hear- ings. Let us take that piece of careless reporting, which it is, which states that 18 percent were quitting the pill and then qualify it by saving but only one-third said it was attributed to the hearings. These statistics, then, suggest the following question: How many of that 18 percent and how many of the 23 percent who are thinking of quitting are in the category who quit automatically? According to Dr. Hugh I)avis, in a Chicago study by Frank, 40 percent of those patei~ts started on the pill abandoned the method within 2 months, and then in the Maryland Planned Parenthood Clinic half the pill patients quit in less than a year. These high percenta.ges of drop outs are not related to the hearings. Now, I think von ought to include these statistics on how many pregnancies result from such a situation. When you get 50 percent quitting, that is about 900,000. So there are 900,000 unwanted preg- nancies occurring as a ~resiilt of women volimtariiy quitting before the hearings were ever heard of. Is that right? Mrs. PloTnow. You heard testimony already, I believe, indicating that every year there are something like 750,000 unwanted pregnan- cies, in addition to the ones that may arrive this year, which can be attributed basically. I think, to the hick of reahl adequate, corn- pletelv effective means of birth control, and to the fact that abortion is unfortunately illegal in many States. Women who become preg- nant because of contraceptive failure or because they stop taking pills, or sto}? some other method, because they may be nervous, have no recourse whatsoever. There are admittedly-and I would be happy to eml?hasize this for the record-a very large number of imwanted children because of the failure of one kind of method or another. But I think that the facts-I would be prepared to predict that in 9 months, the facts will show that there will be more unwanted babies in the last 3 months of this :~ear than previously. And whether you want to call these babies "Nelson babies" because they were caused by these corn- mittee hearings, or whether yOu want to call them unwanted babies for some other reason, to me that makes less difference than the tragedy of unwanted children being born altogether. And anything which contributes in any way to unwanted children being born to families that do not want them and do not love them PAGENO="0250" 6690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY and are not able to take care of them, from a woman's point of view that is a tragedy. Senator ~ELSON. What baffles me is that people are so excited about 6 percent quitting but unconcerned and not even reciting the statistics of 50 percent who quit voluntarily. I think there has been a rather great con game played on the American public, that you have a perfectly safe pill, that it works perfectly, and that you were controlling population growth with it when half the people stop taking it voluntarily. Tremendous excitement when 6 percent quit, when they are get- ting some information that they should have had in the first place and if they had had it. they would not be frightened. They would already have known. According to the same Newsweek article, two-thirds of the women said they were told nothing about side effects. Practically every single expert we have had, save for Dr. Guttmacher, have said they ought to be told. informed about the pill. Dr. Edwards sent a letter to 324,000 doctors saying, you should tell them about the pill. Now, if these two-thirds who were never told anything had been told what the other one-third apparently had been told, then when the truth came out the would not have been frightened, would they? sirs. PIoTnow. Senator, you say this excitement is new. I have been excited about this issue for the past 5 years. That is why I am working in this field. Senator NELSON. So have I. ~Irs. PIOTROW-. I have been working in this field for the last 5 years. We have been urging more research, better family planning services, in order to eliminate this large number of unwanted chil- dren. I have been excited about this a long time and I am delighted you are excited about it, too. now. Nothing pleases us more than to see the degree of concern and excitement and despair over this prob- 1cm of unwanted children and unwanted pregnancies. I would cer- tainly hope one of the really constructive results of this hearing would be that the concern over the inadequacy of existing birth con- trol methods would leadi towards additional research and better methods in this field, better than the existing pills, better than any of the existing methods. Mv concern is not that this pill, that these pills were the best method that exist in the worldl and shouldi be taken by women for- ever; my concern is that the situation for women today, with alarm- ing reports in the papers that. are very dlifflcuit to assess, is creating an increase in the number of unw-antedl childiren. Senator NELSON. I understood you to say my interest is sudiden. I might say that for a good many years I have been speaking audI have spoken in over half of the States of the Union, saying that the disaster that is coming is overpopulation. It is a dlisaster right now. America. is overpopulatedi probably by 100 million. We have diemOn- strated our incapacity to preserve a decent environment for 200 inil- lion. andi it will be a catastrophe at 300 million, which is surely commg. PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6691 `What is disturbing to me is to see all of these attacks on the hear- ings upon the grounds that the public is being told what the facts are. The argument seems to be that the public should not have the facts, therefore, we should not have hearings. There are serious problems with the pill and they do not want it publicized because it will frighten people. Some of the facts about the pill are of great concern to individuals, and they ought to be told, and that is one of the things these hearings are about. And if anybody thinks that this pill, which is in about the model T stage in this field, is the solution to the world's population prob- lems, it is nonsense. If we do not get this out in the open and if, unfortunately, some very substantial and serious side effects develop that are not now specifically known, leaving out carcinoma-just say metabolic imbal- ances that create a serious problem for women for the last 20 years in their life-if that occurred-and nobody knows that it will not, and the FDA report is very concerned about it-if it does occur, it will wipe out all birth control pills all over the world all at once. It is a whole lot better to have 6 percent of them fussing and worrying now and get at the business of having the public understand the issue and get the money for the research and do something about expanding studies for planned parenthood and research in this field, than to run around concerned only about the fright which occurred when you start telling the American women the truth-facts they should have been told 10 years ago. That is my view. Senator T)0LE. Mrs. Piotrow, did you say 100,000 even at 6 per- cent? I do not want to take any credit from the Chairman. You referred to them as "Nelson babies" and that is all right with me. I)o you consider that a conservative estimate? Mrs. PIoTuow. I arrive at the figure 100,000 babies on the estimate that two-thirds of the women who had discontinued pills manage to find some other effective method and do not become pregnant. That is a fairly conservative estimate, that two-thirds of the women who stopped taking orals managed to avoid pregnancy some other way. I was only considering on the basis of one-third of those who discon- tinued, which is 600,000 women. One-third of those were then being exposed to pregnancy for a period of 3 months. And again, figuring conservatively, the 600,000 women are exposed to pregnancy for a period of 3 months when the likelihood is about 80 percent -for married women at risk to become pregnant over a 12-month period. Over 3 months, there would be a 20-percent chance of becoming pregnant, so that would be about 120,000 pregnancies. I would assume a considerable number of those would not lead to births, either because of spontaneous miscarriages or, in a great many cases. abortion, even though it is not legal. So when I get the figure down to 100,000 unwanted births in 1970, that is conservative. One could say it was going to he 1.6 million. But I think the figure 100~000 is probably a conservative figure for this particular group that may be the result of these hearings, Nelson subcommittee babies. PAGENO="0252" 6692 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator DOLE. There is no doubt in my mind that the hearings have had a~ profound effect on American women and also some physicians all over the country. There has been a profound impact. and I placed in the record ear- 11cr this morning the most~ recent Gallup poll, and I am not certain what a poll would show today insofar as the number who have stopped usmg the pill. It may be higher than 18 percent for various reasons, maybe lower. There is nothing we can do about what hap- penecl the first few days of these hearings. Since that time the hear- ings have been more balanced, and both pros and cons have been Presented. BT1t the first headline I saw following the January 14 hearing was "The Pill May Cause Cancer." Well, that word, as has been pointed out by Dr. Cutler and others, frightens everyone. You should read tile entire article as the Chairman pointed out, but many people do not-thev read the bold print, they read the headline, and they never read tile balance of the story. But I would hope that when we complete our hearings that we will pubi~sh tile results of tile committee's findings in a balanced way, so we can set tile record straight. General DRAPER. Mr. Chairman, could I comment? I have never attacked tile hearings. My own point of view at this stage of tle hearings is that for the shortrange probably there will be considerable increase in unwanted births. But my own conviction is that the long-range effect of these hearings will 1)e constructive and in the interest of the American ieopie~ because I think for the 1irs~ hme thro~igIioiit the country with adequate publicity, it has been brought home to the American people and I am sure to tile Con press that there has been illadequate research in this field. I tIllilk our Government. both tile executive branch, and I should say the Congress, too. largely because of lack of information and lack of publicity on this problem, have been derelict in not furnish- lug the funds or asking for the funds on tile Part of the executive branch to carry out adequate research and contraceptive sidelights. Seuptor X~nsox. I tilank von very much. General, -for that state- nient. The reason I talk so much he~e is I am about the only one in the T~nitecT States defending the hearings. I might say in retrospect that if we could back up to January 14, I. would start them again, because I flunk it is in the interest of tile public, for which you and I are concerned, and I appreciate ~oiir comment.s on that matter. Mrs. PIOTROW. Shall I continue? From a woman's point~ of view there are several issi~es which stand out m tins controversy and which have not been sufficiently emphasjzed. perhaps because most of the initial witnesses were men. First and foremost, it is a biological fact that all tile mortality associated with human reproduction is borne by the female. There are no male fatalities from pregnancy or childbirth. Yet, every woman - must face this risk in one way or another. For married women, the choice is either to practice some form of birth control or to bear the 10-12 children estimated to be tile natural reproductive capacity of a healthy female married from ages 15 to 45.' 1 Christopher Tietze, "Pregnancy Rates and Birth Rates," Population Studies July 1962, p. 31. PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6693 Until this century, it was natural for women to bear many chil- dren and it was necessary for women to take these risks to assure surviva.l of the human race. It was also considered natural for many, many women to die in childbirth and it was natuia~i for men and women both to have a life expectancy well under 50 years. Even today it is still common to see high mortality from childbirth and relatively low life expectancies in most of the world. In the United States, and in other developed countries, people enjoy the unnatural but great benefits of potable drinking water, immunization, antibiotics, advanced medical care, nutritious diet, well-heated homes, and a variety of modern improvements which have unquestionably produced a greater li-fe expectancy than any previous generation of hun-ian beings has ever enjoyed. If that lon- gevity is in danger today, if it is threatened-as I believe it may be-by increasing pollution of air and water, the basic cause is rapid multiplication of the human race over the last half century. And I would certainly commend the Chairman of this committee for the niany statements he has made recognizing that challenge. He has indeed been a pioneer in that respect. From a woman's point of view then, whether looking at the health and economic needs of her own family or the broader challenges to all of society, the argument that it is natural to l~ave children and unnatural to take oral contraceptives does not seen-i very convincing Actually, women have been looking for an orally administered con- traceptive for thousands of years and there is no doubt at all that the present ones are safer and more effective than any previously available.2 I might add that the greatest biological experiment that most women undertake throughout their whole lives is not contraception but pregnancy itself, and the decision to seek pregnancy is usually made without any consultation with a physician at all. Secondly, and again from a woman's point of view, I am glad to note the genuine and growing concern over female morbidity and mortality, especially during the years when women are most involved in having and raising a family. In this connection, it is appropriate to mention that, among the complications associated with pregnancy and childbearing, it is widely estimated that a major cause of death is abortion-either self-induced abortion or what is currently described as criminal abortion. There may be as many as 1 million so-called criminal abortions every year in the United States-abortions undertaken by women who so desperately want to avoid childbirth that they seriously risk and often lose their lives. In Atlanta, a study showed that 22 per- cent of maternal mortality was associated with criminal abortion. Some cities had rates twice as high-the National Institute of Mental Health suggests-although official vital statistics reveal a B. E. Finch. H. Green, "Contraception Through the Ages," Springfield, Ill., Charles C. Thomas, [963, p. 88. "One of the earliest mentions of a metallic contraceptive origi. nates from the Chinese Book of Changes which dates from 2736 B.C." See also N. Hines, Medical History of Contraception, New York, Gamut Press, 1963, p. 109. PAGENO="0254" 6694 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY rate of 2.4 deaths per 100,000 live births for whites, and 13.2 mater- nal deaths for nonwhites.~ As usual, nonwhites are more often the victims. Throughout the world it has been estimated that there may be as many as 25 million illegal abortions annually. I have here a table on the relative risk of mortality for American females. The figures are derived from the British study, and more or less confirmed by the American one. They suggest that the use of oral contraceptives lead to an excess of maternal mortality of three deaths per 100,000 users of oral contraceptives. Senator NELSON. I do not quite understand that. What is the cause of the death in that case? Mrs. PIoTnow. This is the tliromboembolism studies to date. There have been no other proven causes of death from oral contraceptives at all, to my knowledge, but there are, as indicated, some suspicions. Secondly, complications of pregnancy, childbirth, and puerperium, and excluding abortion, can be estimated at approximately 20 deaths per 100,000 pregnancies. This excludes abortion deaths and the denominator is pregnancies rather than live births. So it is a some- what smaller ratio than the ordinary rate for maternal mortality in the united States. Then the figure for criminal abortions performed out of hospital by lay abortionists is estimated by Dr. Tietze-because these figures cannot be completely solid-as 100 deaths per 100,000 abortions. So the differential risk in taking oral contraceptives, becoming pregnant and having an abortion, I think, stand out as well as one can deal with this kind of admittedly unsatisfactory statistics at this time. Mr. Gormox. May I interrupt at this time? Concerning the 20 deaths for 100,000 pregnancies, complication of pregnancy. childbirth. and puerpernim. have you a breakdown for the income groups on that? In other words, would it be the same for healthy women with good medical attention and good prenatal/postnatal attention? This figure is an average, is it not? Mrs. PI0TR0W. For both mortalities from abortion and complica- tions of pregnancy, there would be probably a considerable differen- tial based on socioeconomic status, which is reflected in the health condition of the woman as well as the services available. I will be glad to provide those figures for the record. Mr. GORDON. I think it would be very good, Mr. Chairman. Senator NELSON. Fine. (The information to be furnished, above-referred to, follows:) Maternal mortality rates broken down exclusively by social and economic status are not available. Maternal mortality by State, broken down by race, give some indication of mortality differences which may be considerably deter- mined by differences in social and economic status. `National Institute of Child Health and Human Development and National Institute of Mental Health, "Abortion: A National Public Health Problem," conference, October 1958, p. 31. PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6695 MATERNITY MORTALITY RATES BY COLOR: UNITED STATES, EACH DIVISION AND STATE, 1965-67 (3-YEAR AVERAGE) Maternal deaths are those assigned to deliveries and complications of pregnancy, childbirth, and the puer- perium, category numbers 640-689 of the Seventh Revision of the International Lists, 1955. Rates per 100,000 live births in specified group, 1965-67. Asterisk indicates rate based on a frequency of less than 20. Maternal mortality rates are subject to sampling error; see Technical Appendixj Division and State Total White Nonwhite United States 29.6 20.3 75.4 Geographic divisions: New England 12.6 10.8 *457 Middle Atlantic 32.4 21.1 94.3 East North Central 26.0 19.3 71.8 West North Central 20.5 18.3 47.9 South Atlantic 36.9 20.2 76.3 East South Central 45.7 24.1 99.2 West South Central 36. 5 27. 0 69. 4 Mountain 24.6 20.4 64.0 Pacific 23.6 20.1 45.0 New England: Maine *53 *54 - Newllampshire *79 *79 - Vermont *4.2 *4.2 - Massachusetts 14.3 12.9 *454 Rhode Island *10.1 *10.6 - Connecticut 15. 3 `~9J 6 *60.0 Middle Atlantic: Nesv York 36.4 22.8 103.7 New Jersey 35. 9 22. 5 105.8 Pennsylvania 23. 6 17. 7 66. 1 East North Central: Ohio 23.6 19.2 59.3 Indiana 23. 6 21. 7 `44 1 Illinois 29. 4 18. 5 76. 1 Michigan 30. 4 22.0 84. 7 Wisconsin 16.7 13.2 *83.5 West North Central: Minnesota 15.3 15.2 *20.0 Iowa 15.0 14.6 `359 Missouri 24.4 19.8 `494 North Dakota *27.6 *26.3 *49 7 South Dakota *23.8 *14.8 *96.2 Nebraska *18.0 *16.3 *48.9 Kansas 27.1 26.3 *359 South Atlantic: Delaware *25.8 *24.2 *32.0 Maryland 30.3 18.0 73.1 District of Columbia 61. 5 *19.9 71.9 Virginia 29.6 16.0 7L5 West Virginia 30. 5 27. 5 *69. 3 North Carolina 36. 0 17. 5 77.0 South Carolina 52.1 23.1 94.1 Georgia 43.6 25.1 77.6 Florida. 33.9 19.6 71.0 East South Central: Kentucky 27.3 26.1 `397 Tennessee 36.2 21.4 87.9 Alabama 54.5 23.9 109.2 Mississippi 69.4 *25.9 108.4 West South Central: Arkansas 30. 5 `13 s 72. 3 Louisiana 47. 3 29. 4 74.2 Oklahoma 25.5 22.0 *42.7 Texss 35.8 29.3 69.2 Mountain: Montana `58 3 `14 3 `59 8 Idaho `230 `210 `1054 Wyoming `33 2 `34 7 - Colorado 21. 5 `18 7 *72.7 NewMexico 35.3 *29.2 *72.2 Arizona 21.2 *15.9 *46.4 Utah *19.1 *13.6 *214.6 Nevada *40.6 *38.6 *530 Pacific: Washington 20. 7 16. 8 *77* 4 Oregon `7.2 `75 - California 26.2 22.4 52. 4 Alaska *30.2 `15. 1 `60. 5 Hawaii *8. 7 - `122 Source: Vital Statistics of the United States, 1969, Mortality, vol. A. PAGENO="0256" 6696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mrs. PIoTuow. That is indeed a factor. Surely these figures bear witness to the desperate search of women for a sure method of fertility control. Unfortunately, today legisla- tion in many States deprives women of the right to a relatively safe hospital abortion except in highly restricted circumstances. At the same time, the lack of adequate research has greatly delayed the development of absolutely safe and effective contraceptives. It should be uotecL of course, that if abortion were readily available in cases of contraceptive failure, as it is, for instance, in Turkey today, it would be easier both to develop and to use less-effective measures of birth control that would probably be safer than measures which have to be near 100-percent effective. If concerui over the morbidity and mortality of women is serious and smcere, attention should be given to the issue of abortion. I believe the day is Past when any woman should be forced to bear a child she does not want. Thirdly, when we speak of any birth-control method, we must be concerned not only with physiological factors but also with psycllo- logical ones. Family planning, unlike many forms of direct medical care, depends very heavily for its effectiveness upon the feelings aild attitudes of tile user. If a woman does not like tile method, she will not use it. Even thougii laboratory researchers may consider diaphragms, or foams, or IUD's, or sterilization to be nearly as good as orals, most women would not agree. The evidence is overwhelming that women who have been offered a choice of contraceptive methods-whether they be high- or low-income, well or poorly educated, United States or foreign-prefer an oral, self-administered method. This preference, I may add, appears to be strongest in their first attempts at family planning. Senator NELSON. May I ask a question Ilere? How important do you think tIle advice and the attitude of the pllysician is in the user's selection of a method? Mrs. PIoTnow. I think it can be extremely important. It can range from tile situation ill certaul countries wilere tile physicians adminis- tering a Government program simply exclude or prohibit use of one method or another, all tile way to the quiet advice that an obstetri- Cifill will give his owi~ patient, to a clinic situatioll wilere, in effect, you migilt have three or four doctors, each of which had completely different choices and, tileref ore, tile woman is given a fairly unbiased accoullt of all methods. It call make a great deal of difference. But as I was going to say, it is mtereStillg to look at tile Government family planning pro- grams around the world, because they are cases where you can docu- mnent what choice is provided. \Ulere there was a clloice, in Hong Kong and Singapore, for example, both of those programs started out witil tile expectatioll that 80 percent of tIle women would want IUD's and tiley were prepared to insert IUD's for most of the women who turned up at tile clinic. As it turned out, for various reasons, some of which I tilink have been- corrected, the women did not- -like the IUD's and started stay- PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6697 ing away from the clinics in droves until the program shifted over to oral contraceptives. And with a shift over to oral contraceptives, new publicity and new enthusiasm generated, the programs reached what might be called the takeoff point, and have gone better since. Those are two interesting examples where attempts on the part of the doctors to put across a method did not work. But, in general, I think an individual doctor can exert quite a considerable degree of influence over the method that is used. Senator NELSON. I thought it was interesting that Dr. I-lellman, who directed the FDA study on obstetrics and gynecology, testified that in his clinic- Mrs. PI0TROW. Yes, I have been there. It is a very fine clinic. Senator NELSON (continuing). The record will speak for itself, but something like 55 percent used IUD's, the balance used the pill or the diaphragm-but here was a case where over half selected the JUT). Now, his testimony was that the doctor operating the clinic very strongly believed in the IUD. But it is interesting to note that because of his feeling about it, he ended up with over half the women using the JUD against the pill and the diaphragm. Mrs. PIoTuow. This can happen. There is another effect that I think perhaps obstetricians do not mention, and that is if women do not like the method being offered in one clinic, they might very well go to another clinic that offers another method. The clinic figures do not always reflect what the women are doing. But I will go on. I reported Singapore and Hong Kong shifted emphasis to IUD's as against the original intent of the administra- tors. Two other programs-Korea and Taiwan-are expanding use of pills because tile existing IUD-oriented programs seemed to have reached a plateau of acceptors. Both India and Pakistan, where the need for birth control is great and maternal mortality high, have re-fused to introduce pills, and at present TUD insertions and other methods are apparently on the decline in both countries. In other words, the preference of the user cannot be ignored if any family planning effort is going to succeed. In light of the fact that women, especially younger women, prefer pills, the recommen- clation of some researchers that women should now use old-fashioned methods instead is unrealistic, and, in fact, even naive. Most women, I believe, would respond, "Well, if you think these pills are not 100-percent safe, then please hurry up and test them more carefully, or develop a new kind of pill that is safe." In that conclusion, I believe the women o-f this country and the responsible scientific community, are fully agreed. Billions of dollars have been spent by the National Institutes of Health in searching for cures to diseases that only a fraction of the population will ever have. Yet every married woman-and apparently many unmarried ones-faces the problem o-f fertility control, and every man and woman and child will face the problems of pollution and overcrowd- ing that will press upon us if population growth is not checked. 40-471-70--pt. 16-vol. 2-17 PAGENO="0258" 6698 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Surely, research to produce more knowledge and better methods toward the control of fertility deserves a higher priority than it has so far received in Government-sponsored health programs. Thank vou~ Senator. (The New York Times article, above referred to, follows:) [From the New York Times, Feb. 15, 1970] PREGNANCIES FOLLOW BIRTH PILL PUBLICITY (By Jane E. Brody) Doctors across the country say they are beginning to see the first round of unwanted pregnancies among women who stopped using birth control pills after adverse publicity in the last few months. `I'm now looking for some one tO abort a 14-year-old who panicked," said a New York obstetrician who specializes in family planning among the poor. Another New York physician, a Park Avenue obstetrician, said a patient of his who dropped the pill after reading a "scare report" is in London this weekend to get an abortion. In California, Dr. R. Elgin Orcutt, president of the San Francisco Planned Parenthood Association, reports that "many are coming in for therapeutic abortions, many are going to England and many others are getting criminal abortions." These w-omen, who stopped the pill in a panic and are now trying to deal with an unwanted pregnancy, are experiencing "the most serious side effect," Dr. Orcutt remarked. Dr. Orcutt and about a score of other birtl1 control experts interview-ed last week said that they expect the number of unwanted pregnancies to soar in the next few w-eeks and months among women who have recently given up the pill in favor of less effective contraceptive methods and, in some cases, no contra- ception at all. "We regularly see a crop of unwanted pregnancies-a disturbing number of them-after each batch of bad publicity," commented Dr. Selig Neubardt, a New Rochelle obstetrician who is the author of "A Concept of Contraception," a popular book on family planning. A Gallup poll taken during the first week of this month for Newsweek mag- azine, revealed that largely because of recent reports of suspected health haz- ards, 18 per cent of women have stopped taking the pill and 23 per cent more said that they were giving serious consideration to doing so. Most of the adverse reports on the pill grew out of the Senate hearings on oral contraceptives held last month by the monopoly subcommittee of Senator Gaylord Nelson, Democrat of Wisconsin. Testimony at the hearings linked the pill to a long list of disorders, includ- ing blood clots, strokes, heart attacks, diabetes, high blood pressure, cancer and arthritis. Many physicians in the family-planning field have charged that the hearings w-ere heavily stacked in favor of pill critics who overemphasized health haz- ards that are at best speculative. Just prior to the hearings, the long-simmering debate about the pill's safety became intensified with the publication of several books and lay articles and the presentation of broadcasts proclaiming the pill to be dangerous. SOME REACTIONS TO REPORT5 "Unfortunately," Dr. Orcutt said, "many women who heard and read these reports stopped the pill without calling their doctors and without using any other form of contraception." Interviews with obstetricians in various parts of the country disclosed that. of the w-omen who did call their doctors, many decided to stay with the pill after being told that the Senate hearings had produced no new- evidence of health hazards. But a far greater number of women, these physicians said, w-ere so dis- turbed and upset by the reports that they decided to switch to other methods of contraception. PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6699 Many doctors reported "a run on diaphragms" and, to a lesser extent, on intrauterine devices (IUD'). A check of pharmacies in and around New York disclosed a small but significant increase in the sales of contraceptive foams, jellies and creams and condoms, and a definite falling off in sales of oral con- traceptives. Dr. Nathan Chaste, a Providence, It. I., urologist, said he has had a tripling in requests for male sterilization prOcedures (vasectomies) since the Senate hearings. Several doctors interviewed said that the turn away from oral contracep- tives would not cause too many problems aniong middle-class and upperelass women who, for the niost part, are highly motivated to use other contraceptive methods effectively and who could support another child or obtain an abortion should an unwanted conception occur. "But among clinic patients, who cannot a~ord another child and cannot back UI) a contraceptive failure writli abortion, the defection from the pill to less effective niethods could be disastrous," a spokesman for Planned Parenthood of New York said. Dr. Edwin Daily, director of the city's Maternal and Infant Care program, said that the percentage of new patients who requested and received oral con- traceptives dropped from 68 per cent in December to 47 per cent during the last week in January. Dr. Daily J)ointed out that, except for sterilization, the pill is the most effec- tive contraceptive currently available. Senator NELSON. Thank you very much, Mrs. Piotrow. Please proceed, General. General DRAPER. As I said, my name is William H. Draper, Jr. For the past 5 years, I have devoted my entire time on a voluntary basis trying to solve population problems here and abroad. I serve as honorary chairman of the Population Crisis Committee, as honorary vice chairman of the Planned Parenthood/World Population in this country, as a member of the governing body of the Internatioiial Planned Parenthood Federation, and as president of the Population Crisis Foundation of Texas, whose entire activities are concerned with contraceptive research. However, I am testifying today as a concerned individual, and not as spokesman for any organization. I first became aware of the problems of too rapid population growth more than a decade ago when President Eisenhower appointed me chairman of his committee on Military and Economic Assistance. Our 10-man committee had a staff of 50 and worked con- tinuously for nearly a year. We visited most of the developing coun- tries, and concluded that their exploding population was in many cases holding back their economic development. We unanimously recommended that the United States should a Esist any of them that wanted such help in dealing with their population problems-in other words, we should help them install birth control programs. In November 1959, President Eisenhower answered us publicly and said, "So long as I am President, this Government will have nothing to do with birth control-this is something for private orga- nizations alone to deal with." Ten years later, almost to the day, in November 1969, President Nixon appointed me the United States Representative on the Popu- lation Commission of the United Nations, thus recognizing officially that the world's population explosion is not only the concern of the United States Government, but of all other governments, and of the United Nations as well. So far have we come in a single decade. PAGENO="0260" 6700 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY in the meantime, President Eisenhower himself had seen the light, und became honorary chairman of the planned parenthood move- ment in this country and had openly declared that governments and private organizations must work together energetically to solve the PoPulation problem or future generations would castigate us. President Kennedy. a Catholic, authorized our Government for the first time to help other nations achieve population limitation. President Johnson stressed its importance in more than 40 speeches~ and last year President Nixon, for the first time, addressed a special message to the Congress asking that family planning facilities be made available to our entire population within 5 years, and that our foreign aid in ti~is field be greatly increased. Nor has the Congress lagged behind. Over the opposition of some in the executive branch 2 :~ears ago, $35 million of foreign aid funds were earmarked for population programs only. Fifty million dollars were so earmarked last veer. $75 million this year, and $100 million have now been earmarked for such use in fiscal year 1971. Appropriations for domestic family planning services and research. while still inadequate. have been keeping pace with foreign aid programs; the budget request totaled $75 million this year. The budget. request for next year adds up to $120 million, despite present fiscal restraint.. And forward-looking legislation is now before both Houses of Congress-the Tvclings. Scheuer. Bush bills-which when enacted, will greatly speed up our own domestic family planning programs. Senator NEJ~soN. May I interrupt. General? General DRAPER. Surely. Senator NELSON. WThat level of funding for family planning and for research would you consider to be. your organization or you per- sonally, the optimum amount we should have and at what stage? General DRAPER. The timing. of course, has a great deal to do with that, because you cannot start these programs overnight. Senator NELSON. Right now. for example~ say for this year, next year, the next 3 or 4 or S :~ears. at. what level could we usefully siDend money on family planning and on research, in your estima- tion? General DRAPER. The Tvdings bill-and I see no real objection to the levels in that-range in the research field from $35 million a year this year, this current year. to $100 million a year in 5 years. Senator NELSON. Do you think that is high? General DRAPER. I do not. think it is high: I think it is probably low. Senator NELSON. That is what I mean, you do not think it is high enough. General DRAPER. However, a. 5-year authorization of that kind is so far beyond anything that has been on the books before, that it would be a. tremendous increase, a tremendous improvement. After a year or two of experience, if the scientists are drawn into the pro- gram. then the programs that are undertaken-not only there that would be carried on by the Federal Government itself with direct laboratory research but also the grants that would be made by Health, Education, and WTelfare, to at least, I would hope, four or PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6701 five contraceptive research centers throughout the country-will develop their own impetus and their own requirements, which may well be beyond what this Tydings legislation now includes. But I believe firmly, because legislation that is already before the Congress has a far better chance of enactment, obviously, than some- thing else, that if this legislation is promptly enacted this session, with the bipartisan support of Democrats and Republicans-and I would hope with full administration support-a beginning of a sub- stantial enough program to assure reasonable success in this country will have been achieved. I was delighted to learn recently that you are now a cosponsor of that legislation. There are something like 90 cosponsors in both the House and the Senate. I know of no direct opposition in the House or Senate, and I would hope that that legislation would become law within the next few months. Senator NELSON. What is our current level? I assume that during those hearings all the background for current expenditures was put into the record? General DRAPER. That is correct. Let me illustrate it without having the exact figures in mind. Over the years, the National Institutes of Health have had increasing appropriations ranging from several hundred million a year and gradually going to almost a billion dollars a year for normal health purposes. The amounts that the National Institutes of I-Iealth had devoted, partly because of their own inclination, I assume, and partly because there were very few specific appropriations for both basic research in iniman reproduction and direct. operational research looking toward finding better contraceptives, have been in the neigh- borhood of 4 or 5 or 6 million a year. rplie~T got up this past year to something like 10 or 12 million. The administration recommeuded~ based on the old Johnson appropria- tions, something like 15 million but they were cut down in the I-louse by 2 or 3 million. Through Senator Tydings' championing, at least the restoration of that 2 or 3 million on the Senate Floor was accepted by the conference committee. So it is now somewhere around $15 million. On the service side, there has been considerably more than that made available, starting about 3 years ago. And that has been divided between the Office of Economic Opportunity, OEO, which really under our present Ambassador to France, who was then head of OEO, showed more courage in this then-controversial field, than any other executive officers, I believe. Anyway, OEO started out about 4 years ago with a. small but active program which has increased. I-JEW has started also through its offices to fund programs. and I would estimate the total figures for the last 3 or 4 years are something like $25 million, increasing to $30 or $40 million, and then about to about $60 million last year, and maybe $70 or $75 million this year, and the range of something around $100 million or a little more, if the present requests of the administration are approved. These are very minor, minimum figures, as compared to our national requirement and the tremendous effect on our national life- PAGENO="0262" 6702 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY on the envlronment, on the 1)ollut~on of the air and water, on all of the other things that too many people too quickly bring to our country, aside from the povert -the race problems and the c~ity core problems that are brought about by overcrowding. I believe, along with many others. that the population Problem now in this country is one of the two or three most difficult and threatening problems that we face, It will directly affect our own children and grandchil- dren unless we as a nation-it cannot be done by a few people-real- ize that smaller families are better able to provide more education, more care, better housing. better clothing, and all that goes with the smaller family. For the Xo~ion as a whole, it represents the only way we are going to solve in the end our question of resources, of rising incorws. of environment, of polhition. of health, and of national stability. I)oes thn~ answer your riuestion sufficiently? Senator )~ETSO~. Yes. sir. Thank von. General T)n~prr~. Shall I l)roeeed? Senator Nrr~sox. Go ahead, General. General T)n\P'n. Fortunately, those responsible in the executive branch for carrying out both our domestic and our foreign popula- tion and famil planning programs are sincerely concerned them- selves, and are giving the highest priority to this problem. T have talked with all of these gentlemen and I am sure I am stat- ing the fact. Secretary Robert Finch. Assistant Secretary Roger Egberg, and I)enuty Assistant Secretary Louis Hellman, in the Department of J-Tealth. Education. and Welfare, and Mr. Donald Rumsfeid. of OEO. are lo~all~ devoted to carrying out President Nixon's 5-year program. ATD Administrator .Tohn B. Hannah and his Deputy~ Rutherford Poats, and those more directly responsible for population activities in the developing world, ~Toel Bernstein andl Dr. Reimert Ravenholt, are carrying on a~ magnificent worldwide program of growing size and effectiveness. And that program is because the Congress has ear- marked the money and they have then gone loyally to work. Even the man in the street andi the bogs and girls on our college campuses are fast becoming concerned. For the first time they see that our own environment is being ruined, and that the much adlmired American "quality of life" is gradually being destroyed. They see that it is people and more and more people who are rap- idly using up the earth's limited resources, and who are polluting its air and its water. They begin to see that the population explosion is no longer far off in either space or time. It is no longer only a problem, say, in India, nor a problem that is years off in the future. The population explosion is here in the United States, and it is here today. Fortunately, the American people are beginning to realize that we must reduce our rate of population growth-and very soon-or our children and grandchildren will pa~T a horrendous price. The decade of the sixties has been the decade of comprehension. The decade of the seventies must become the decade of all-out action. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6703 No longer can we listen complacently a~s the demographers tell us that if present rates continue the 31/2 billions of men and women on earth today, the resultant of tens of centuries of growth, will now double in only three decades-30 short years-and then to 28 bil- lions, and then to 56 billions and then to what? Over a hundred bil- lions? Standing room only? We know it can't and won't happen. The only question is, when it starts happening, whether we, the people of the world, are going to stop this madness ourselves by using our God-given intelligence and our own will power, or whether we will let nature stop it by her own time-honored, effec- tive, but brutal weapons-malnutrition, disease, and then mass star- vation. And as that starvation grows~ I can see man helping nature along by political conflict and war to lust start the thing going faster. It is true that we in this country have made some progress. During the past decade, motivated toward small families, and with the help of the nmch maligned pill, and other contraceptlves, we have cut our rate of natural increase in half-from nearly 2 percent to less than 1 percent. Eight and one-half million American women have been taking the pill-nearly one-quarter of our women of child-bearing age. Senator NELSON. We had our lowest birth rate in history during the depression, did we not? General DRAPER. No, sir, we passed that last year. Senator NELSON. Last year? General DRAPER. Yes, sir. The year before, 1968. Senator NELSON. 1968? General DRAPER. We got lower, that is right. Senator NELSON. I had in my head an old statistic. General DRAPER. It was lower for a long time on account of the depressuon. Senator NELSON. Up until 1968, the lowest birth rate was during that period in the depression, the thirties? General DRAPER. That is true. Senator NELSON. That was before there was any pill. Does that not really indicate that a critically important factor in the whole business is motivation? General DRAPER. It is the most critical factor, it is more important than the pill or any other contraceptive or anything else. If the people of this country or of any country decide-and it is not the legislators or the government-if the people of this country decide that they want smaller families, by and large they will find a way to have it come out. But these various contraceptives, methods, are improved greatly over the past, and should be greatly improved again to help that along when there is the right motivation. Senator NELSON. But it does, does it not, demonstrate something very significant, when you consider- General DRAPER. Let me point out that in France and Italy where contraception has been illegal, they have perhaps the lowest birth rates in the world. And it probably is not all done by prayer. PAGENO="0264" 6704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. I think it is interesting to note that even though the pill has been on the market for six years up to 1968, without any pill at all, well motivated people during the depression had a lower birth rate in this country than afterwards, which ought to tell us something about those who are worried about the fear caused by the hearings. General DRAPER. It has some bearing. Senator NELSON. Please continue. General DRAPER. A few million others have been using other but less effective methods. As a result-and I ought to add their motiva- tion, although I mentioned motivation just before that-our growth rate has been steadily declining almost a tenth of 1 percent a year, although 1969 for the first time saw a slight upward turn in the number of births and in the birth rate itself. That. is l)robably the result of the baby boom after the end of the war with those babies now coming of fertile age, and adding to the number of babies born, though not necessarily to the percentage. Senator NElsoN. When you are using a percentage figure here, it is a percent of the total population, is it not? General DRAPER. That is right. Senator NELSON. So it is still 2 percent birth rate with 100 million people. is it not? General DRAPER. Equivalent of 1 percent with 200 million. Senator NELSON. One percent with 200 million. So, since we do have 200 million, even the increase at this rate is a very serious matter. Now, what is the increase that you estimate would result in zero population increase? General DRAPER. About slightly over two children per family would bring that about. Senator NELSON. Are you using percentages here, on say we have gone~ General DRAPER. Well, zero percentage rate would be zero. Zero growth rate means simply that. Senator NELSON. Zero indicates increase in population, I am talk- ing about that. General DRAPER. I am, too. Senator NELSON. But the birth rate? General DRAPER. The birth rate would have to be approximately, under present death rate conditions, approximately seven-tenths of 1 percent. The last 2 or 3 years, the death rate has been approximately nine-tenths of 1 percent. Now, we have to take into account the fact that we do have some immigration into this country. We have about two-tenths of 1 percent immigration a year. So to have a~ zero growth rate, we would have to have at present seven-tenths of 1 per- cent birth rate, as compared to approximately 1.8 percent at the present time. Birth rate, I am talking about. That is birth rate. Senator NELSON. Maybe I do not understand this. General DRAPER. Under present conditions, seven-tenths of 1 per- cent birth rate would be offset by nine-tenths of 1 percent death rate and two-tenths of 1 percent immigration rate, and would result in a net zero growth rate. Senator NELSON. You said, at what percent birth rate? PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6705 General I)RAPER. Seven-tenths of 1. percent. Senator NELSON. That is seven-tenths of 1 percent of what? General DRAPER. Of the total population. We have 200 million people. We have now approximately 3 million, six births in this country, and approximately 1 million, eight deaths a year. So that we would have to bring 3 million, six births down to about 1i/2 mil- lion, which would be approximately offset by a million, 800,000 deaths and 400,000 immigrations, and practically result in a net zero growth rate for this country. Senator NELSON. I w-ifl examine those figures later. Go ahead~ General. General DRAPER. What long-run effect the widely publicized testi- mony of these hearings may have is hard to say. One. Gallup poll- we have been all over that this morning, but I will repeat it-has recently indicated that 18 percent of women taking the pill were abandoning it-I don't say why- and that 23 percent more were considering doing so. This, I believe would be a disaster. I am hopeful enough to believe that most of these women, after they and their doctors have weighed the relative risks of taking or of not taking the pill-and I will go into that a little more later- will gradually resume its use until equally effective but better and safer contraceptives are available. Broadly speaking, there seems to have been very little, if any, new information disclosed that was not already known to the Food and Drug Administration and to the special Advisory Committee on whose advise the pill was found sufficiently safe for continued use under medical supervision. I understand that this position has been reaffirmed after much of the testimony before this committee has been recorded. The hearings have certainly showed that some doctors disagree as to the seriousness of the pill's acknowledged side effects, and as to possible other dangers. Like any drug, the pill has some drawbacks and some dangers, but the benefits are very great indeed for those women wishing to limit or space their families, and for society as a whole. As one witness put it, "The pill is safe. It is safer than preg- nancy, but not as safe as continence." I believe that it is now clear that- (1) The pill is virtually a 100-percent effective contraceptive if taken regularly, and is more effective than any other known method of contraception; (2) It has side effects which are sufficiently serious for a small percentage of women so that it should be used only under appropriate supervision. That would normally be medical super- vision; (3) Many of the feared side effects, such as developing or bringing on cancer, have not been proved for women using the pill, as brought out again this morning; (4) While metabolic alterations affecting the liver and other organs do result from use of the pill, there is no evidence at this time that they pose serious hazards to health; (5) The most serious known threat is blood-clotting or throm- boembolism; taking the pill appears to increase the risk of death from this cause from one-half per hundred thousand to PAGENO="0266" 6706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY three or four per hundred thousand, although less estrogen con- tent may reduce this risk; (6) However, if unwanted pregnancy results from discontinu- ance of the pill, mortality rate associated with pregnancy and child-bearing, excluding abortion in the United States today, is some 20 per hundred thousand for white women and more than three times as high for non-white women; (7) When an unwanted pregnancy caused by discontinuance or any other reason is terminated by an induced illegal abortion, performed by a layman outside of a hospital-it is estimated on a theoretical basis, these are not hard figures, the risk of death increases again to at least 100 per hundred thousand;' (8) The relative risks of taking the pill, of discontinuing its use, or alternatively of using some less effective contraceptive, should be kept in proper peispective by those women who wish to avoid pregnancy, and by their doctors; I think that is the most important conclusion that I could reach about this, but the relative effectiveness and relative risk should be known-this committee's hearings have certainly made the risk of the pill known, but the relative risk should be kept in mind as decisions are made; (9) For the American people as a whole, the lesson brought home conclusively by these hearings is the fact that neither the pill nor any other known contraceptive method is ideal or with- out drawbacks and dangers, and that only through a greatly increased program of contraceptive research can either the many questions raised in these hearings, or the population explosion itself here and abroad be satisfactorily solved. Certainly, since a present lack of data is admitted by all witnesses, future large- scale studies are very necessary to determine much more definitely the effect of using the pill on both the present and future generations: also research designed to produce better con- traceptives is of equal or even greater importance. Mr. Chairman, these hearings have had the news headlines for days on end in every town and village in this country. They have been reported on every radio station and every television chain simply because the American people-a~1most all of them-are inter- estecl in reducing or limiting the size of their own families, that is the motivation you spoke of yourself, Mr. Chairman, and are grop- ing for *a sure and safe method of accomplishing this by avoiding unwanted pregnancies. At least 15 million women in this country who use some contraceptive method, and including those whose hus- bands use the condom, must represent, together with their immediate families and close relatives, a clear majority of the people of this country. This means that 100 million Americans, more or less, are directly interested in improving present contraceptive methods. This committee has clearly proved that we need better methods of preventing conception. This committee can perform a great l)ubhc service if it will adopt and equally publicize the broad conclusion that the scientific community, whose medical miracles have reduced 1 C. Tietze, "Mortality with Contraception and Induced Abortion," Studies in Family Planning, September 1969, pp. 6-8. PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6707 death rate and brought about the population explosion, must now concentrate on making new contraceptive breakthroughs and so bringing the birth rate back into balance. Senator JAvIT5. Would the witness mind interruption? General DRAPER. Not at all. - Senator JAvITs. This has been charged by others, but I think our Chairman has taken it very, very seriously. Could you make any practical suggestion, now or later, as to how something could be done to give a complete balance to the picture in the eyes of the public, which you intimate was not given? Now, bear in mind that the Chair feels he has done his best to try to add balance. Therefore, if you do have some suggestion, General, which could help us to do what you say, I am sure that our Chairman and I am sure that the committee would give it the utmost consideration. General DRAPER. Senator Javits, I said before you came in, in the interplay of conversation with the Chairman, that the effect of these hearings short-range would be to bring about a certain number-and I do not know what the number is, nobody else does either-a cer- tain number of unwanted pregnancies greater than there were before because of the scare headlines. I also believe that the long-range effect of these hearings is going to be most constructive, because I do believe that the hearings have brought about a consciousness of this problem and the need for better contraceptives, that this country never would have gotten in any other way, or the Congress perhaps either. And it will result, I certainly hope, in freely increased contracep- tive research, both basic, human reproduction research and looking for specufic, better contraceptives. Senator JAvITs. Thank you. General DRAPER. On your specific question, I believe that the coun- try perhaps without quite realizing it is awaiting whatever conclu- sions this committee itself may arrive at. Now, no one can blame the Chairman for headlines that come because you had to call all of those interested in this problem, the doctors for and against the pill. rFhe newspapers are just like life itself, there is no news in some- thing that agrees with what is going on. The newspapers and the television cameras naturally are going to Pick up the spectacular, the sensational, and that is what they have done. I believe though that there has been enough on the other side, and some of it publicized, so that the public realizes there are two sides to the question. And I would believe that if the Chairman and the committee, when as I hope they will, they reach some conclusions that they can publish in due course, after appropriate consideration, and if those conclusions are as you suggest and I believe they would be, balanced and appropriate, and suggesting the need for greater contraCel)tive research, I believe those will get great publicity amid I think they will do a great deal of good. Senator JAvITs. Thank you, Mr. Chairman. Senator NELSON. Another witness made a similar suggestion to the committee, but I would just say for myself that I do not have the qualifications for evaluating the conflicting testimony. PAGENO="0268" 6708 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY General DRAPER. Somebody has to. Senator NEI~sox. And then drawing the conclusion to Present to the public. and the scientific community, that c.omniunity itself being sharply divided. I think anybody who reacTs the testimony does not have any difficulty reaching a conclusion, that certain things are clear, one, we are not able to specifically predict whether or not there will be serious consequences to a user over a short period or long period. It is a matter of concern we do not yet have any answer for. However, all of these things are pretty much agreed to. The physician will say "I am satisfied, having used it over the years, and on balance vis-a-vis the problems the user may have psychologically or ~hysiologically and otherwise, we ought to use it, and I have no reservations." And another one, looking at the same patient, will say, `~I think my reservations are such that I would recommend, as one witness did today, that. it. should not be used for longer than 2 or 3 years without. interruption." I think it is a pretty simple matter for anyone reading the hear- ings to come to a conclusion about what. people have said but not for a. committee to draw a conclusion unless somebody has a clearer insight into what the committee can say, more so than I have. Maybe somebody does. General DRAPER. After all, the scientist and the doctor-of course, they are divided on this point-after all, they are only witnesses, they are each of them testifying. That happens on every bill we have before Congress. There are technical w-itnesses on any subject. But the Congress and the committees then with the evidence before them, and the American l)eople, and the women that we are talking about, all have to come, each to their own conclusion. All I am urging is to take the varied testimony as it has been, as you have read and heard it, as all of the committee will read it, and then the committee deciding what the upshot of all of this means, and no one can do it as well as you and your committee, in my Opin- ion. And if that conclusion, that deduction tha.t you take from the varied testimony and the weight that you give to each is carried out, as I am sure it. would be, in a balanced way, that gives to the Amer- ican people the conclusions that this committee has reached as a result of all of the testimony heard, and then ending up on a note that is not in controversy at all, mainly that the proof of the hear- ing has certainly been that there are not good enough contraceptives available and that. a great deal of research is needed. I believe this won Idi have a tremendous effect on the future of the human ra.ce. Senator NEI~sox. It might very well be possible. Senator J~~vrrs. Would the Chair vieldi? What you are calling for is a report by this committee. General DRAPER. Yes, sir. Senator JAvrrs. And that is precisely what. I want, a report by this committee. I do not think that you can just leave this up in the air and I shall do my utmost. to bring such a report about. Another thing I would hike to ask you is this: The figures are important, that is, if there is a risk, X testifies to a risk, Y testifies to no risk, there is still a residual question, a risk to how many out of how many. PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6709 General DRAPER. There is not so much difference in the figures, Senator. Senator JAVITS. No, let us not get to the difference. General DRAPER. There is a difference in the conclusion sometimes. Senator JAvITs. The point is when you speak of risk, you do not speak of it up in the air. General DRAPER. That is right. Senator JAVITS. You speak of an actuarial proposition. General DRAPER. That is correct. Senator JAVITS. And the question that has to be balanced, as against the admitted risk, even by the most extreme commentator, what is the proportion who are adverse; is that correct, sir? General DRAPER. That is correct, and what are the benefits from those taking the risk. Senator JAVITS. Right. Senator NELSON. Please proceed. General DRAPER. This committee has clearly proved that we need better methods of preventing conception. This committee can per- form a great public service if it will adopt and equally-and I use the word "report to the public", that is what I had in mind-equally l)lihlicize the broad conclusion that the scientific community, whose medical miracles have reduced death rate and brought about the population explosion, must now concentrate on making new contra- captive breakthroughs and so bringing the birth rate back into bal- ance. The scientists must be told this quest is so important that they must go all out; the sky is the limit. After all we have been spend- ing a billion dollars a year in research to reduce the death rate; we can afford whatever it takes for research now to help bring down the birth rate. rJlhis committee has attracted the attention of the ears and the eyes of the American people. If it will now champion the need for better contraceptives publicly and here in the Congress the necessary increased appropriations for more contraceptive research can and will be made available. This is something necessary for the future welfare and perhaps even the survival of the people of this country, and for all the people of the world, as well. Scientific contraceptive research is not a controversial issue. It is not a political issue. It should, and I believe will, have complete bipartisan support. President Nixon in his message last year to the Congress on popu- lation gave contraceptive research a very high `priority. He said, "First, increased research is essential. It is clear that we need addi- tional research on birth control methods of all types * * Senator Tydings in the Senate and Congressmen Scheuer and Bush in the House of Representatives have introduced proposed leg- islation to this end, with some 90 cosponsors from both parties. Sen- ator Jacob Javits and Representative Steiger have introduced an administration bill on family planning which, hopefully, can be combined by some administrative adjustments with the Tydings bill and should then receive general bipartisan support. I congratulate the chairman on his recent sponsorship and testi- mony on behalf of the Tydings bill and hope that the entire subcom- PAGENO="0270" 6710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY mittee will join in this support. I hope that its members from both parties will give the strongest possible support to the program for ~greatly increased contraceptive research during the coining 5 years as proposed in the Tydings bill. It has been estimated that during the past decade, about 20 per- cent of all births in this country were unwanted. The parents either did not have contraceptive services available, or they failed in use. This would indicate that more than 600,000 births-somebody esti- mated before this committee, 750,000, somewhere in that range-last year were not planned or wanted. If these estimates are correct, and if improved effective contraceptives actually become avail able and are used successfully by the parents involved, so that broadly speak- ing, unwanted children have become relics of the past-and I hope that they will soon come-our present rate of growth of 1 percent per annum-eight-tenths of 1 percent natural increase, plus two- tenths of 1 percent immigration-would drop to seven-tenths of 1 perceiit-fi~e-teiitIis of 1 percent natural increase plus two-tenths o-f 1 perceiit immigration. And, of course, we cali control the immigration if we find that that is necessary. WThiie this could not all happen immediately, obviously, the trend with better contraceptives would be in that direction and would have a profound effect on our national future. It would help mate- rially to continue the declining growth rate trend-line of the past decade, and could greatly reduce the 100 million people which Presi- dent Nixon estimated in his message would be added to our popula- tion in the next 30 years. The future hoped-for improved contraceptives, whether an annual shot in the arm, a. once-a-month pill, a morning-after pill, or what- ever they may be, would accomplish a great humanitarian good by reducing the numbers of unwanted children, so many of whom now lack the loving care and the economic and social opportunities to which every hiunan being should be entitled. I should like to refer again to the risks of induced abortion. It is estimated that as many as a million illegal abortions may take place in this country each year and that about 400 of these women may be dying each year to avoid childbirth. That is that theoretical 20 to 1OO,000 now. This shows what terrible risks women are taking today to avoid unwanted children. How much better if they had only taken the pill, with all its reported risl~s or used some other contra- ceptive. But let us look at the situation from society's standpoint. If these abortions had not taken place, and if a million more human beings were being added to our population each year, our growth rate would be back to 11/2 percent, and no longer 1 percent as now. We would add nearly 150 millions rather than 100 millions to our popu- lation in the next 30 years, and so compound our problems of educa- tion, of deteriorating enviroment, of urban breakdown, and of air and water pollution. Despite the ethical and religious issues involved, our society owes these million women each year a great debt indeed. Again, better contraceptives can be a God-send to these million PAGENO="0271" COMPETITIVE PROBLEMS TN TUE DRUG INDUSTRY 6711 women each year by helping them to avoid the very high risks of illegal abortion and still keep down the rate of population growth. But there is still another approach. The courts in California and also here in the District of Columbia have recently thrown out overly restrictive abortion laws as unconstitutional. Sooner or later the Supreme Court will. have to decide whether or not a woman can be forced by society to have a child she does not want. Many States have liberalized or are considering liberalizing their laws on abor- tion, as Great Britain has already done, and as India is debating. Legal abortions, if performed under hospital conditions during the first 2 or 3 months of pregnancy involve only nominal risk. A newly perfected suction method-which came, I believe from Hungary, where it is legal-and perhaps a new abortive drug may make sur- gery unnecessary. ~Japan cut its population growth in half during the 10 years fol- lowimig the war by legalizing abortion. They also had motivation. Senator NELSON. Aren't they now to six-tenths of 1 percent? General DRAPE1m. No. five-tenths of 1 percent, during the year of the 1-lorse, which in Japanese mythology, I suppose you would call it, means that any child born in that year cannot become pregnant and the rate went lower than it had ever been to about one-half of I percent growth rate, and then it went up the following year to seven-tenths. It is a little less than ours. It came down between 1948 and 1958, or 1960, some 2 percent to 1 percent, and then kept on dropping. Senator NELSON. Is this annual growth rate, you are talking about? General DRAPER. Annual growth rate. I am not talking birth rate; annual growth rate, which is the net of the births and deaths. Worldwide, there is little doubt that legal abortion, as in Japan and in many East European countries, and criminal abortion else- where, even now prevent more births than all methods of contracep- tion combined. That is, I am sure, a fact, and it is one I do not think is realized in many quarters. If greater leeway is given to the medical profession to perform legal abortions by liberalizing or eliminating present laws, many rel- atively safe abortions may well supplement the improved contracep- tion that can hopefully be anticipated. I have been discussing the continental United States and its seri- ous population and environmental problems. You, Mr. Chairman, who have proposed a constitutional amendment guaranteeing every American "an inalienable right to a decent environment," under- stand very well the difficulties of bringing this about. Your proposal fortunately is leading to the environmental teach-in on college cam- puses and high schools throughout the country next month. I feel sure these campus discussions will help greatly to bring the youth of this country face to face with future realities, and above all to a clear understanding that our national environment cannot be saved for posterity unless our population growth is curbed. However, the situation in the developing nations of Asia, Africa, and Latin America is far more terrifying. Their 21/2 billion people are expanding two and a half to three times as fast as we are in this PAGENO="0272" 6712 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY country. They have far less resources with which to cope with the education, health, economic, social, and political problems inevitably raised when their populations almost double with each new genera- tion. Increased poverty, disease, and starvation certainly lie ahead, and the threat of turmoil and political chaos. Many of them have very little time left to turn the demographic clock around. Fortunately, the interested private organizations-and particu- larly the International Planned Parenthood Federation with its 64 member associations in 64 different countries-have been persuading government after government to announce policies calling for lower population growth rates and to adopt national population and family planning programs. In the past 3 years nearly 30 govern- ments have made such a beginning. And only 6 weeks ago the Commonwealth of Puerto Rico announced a governmental islandwide birth control program. On January 15 Governor Ferre in his State of the Commonwealth mes- sage announced "a vigorous and ample program of family plan- ning." He called Puerto Rico's rapid population growth the "great- est obstacle to the realization of the Great Task which we have set before us." He went on to say, "All the jobs which we are able to create will not be enough; all the moneys spent to improve education and health will not be sufficient; we will not be able to construct enough homes; nor construct enough aqueducts; nor pave enough streets; nor equip enough hospitals. "In other words, the Great Task will be impossible. By the year 2000 we will have 5,600,000 inhabitants"-they have about 2.7 mil- lion, something like that now-"and we will have doubled our popu- lation density." And 3 weeks ago, in an historic announcement by Archbishop Luis Aponte Martinez the Catholic bishops of Puerto Rico-and there are seven of them-stated publicly their approval and support of the government's family planning program, provided only that there is no coercion and the decision as to family size and the use of contraceptives is left freely to the conscience of each couple. This example-both the government's decision and the supporting statement by the Catholic bishops-points the way for many Latin American Catholic countries which also find too rapid population growth the greatest obstacle to their economic and social develop- ment. It illustrates very well indeed how well the world's leaders everywhere are beginning to understand the meaning of the popula- tion explosion, and how governments on every continent are starting to take the necessary action to head it off. Better contraceptives would also help the Puerto Rico program. Speaking of Puerto Rico, last Saturday I was in Puerto Rico, in Sail Juan, and called Oil Governor Ferre to extend to him at the suggestion of Dr. Moynihan in the White House, tile White House congratulations a1ld offer of help Oil this program in any way possi- ble, and he is very hopeful, with tile support of tile Catholic bish- ops, and generally of tile population of Puerto Rico, in which this population problem is probably as serious as anywhere iil tile world, to have a successful program there. But I am sure he would appreciate better contraceptives. I should add, Mr. (Thnrrn~r~ fh~ fT~ `~~`Lftt. ~ ~orw~rd ~n ~ PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6713 marks the culmination of over 30 years of devoted effort begun by your distinguished colleague, former Senator Ernest Gruening, when in 1935, representing President Franklin D. Roosevelt, he opened the first Birth Control Clinic in San Juan, P.R. I might add that the following year, when the election was on, and there had been some complaints in this case from the Catholic bishop, Jim Farley told him to call it off. And he did. Almost at the same time that the Puerto Rican Governor made an announcement, a Catholic governor in Asia also spoke out. On Janu- ary ~9, 1970, President Marcos of the Philippines in his State of the Nation message said, c~WTe are faced by a population crisis. It is time that we take steps to arrest a population growth which, unless checked, threatens to compound our problems in the years ahead. "I have decided to propose legislation making family planning an official policy of my administration." He told me last June when I talked with him in Manila, along with General Romulo, the former president, who is now the foreign minister, he told me then that if he were reelected in November, which he was, he would announce this policy, which is now done. I quote from him further: The meaning of the population explosion is human misery-a deprivation of the basic necessities for sheer physical survival. This is the rightful concern of the Church for above all else it is committed to man as man. I, therefore, invite the church to join in a common enterprise to alleviate suffering-to help as its sister churches have helped in many lands where the population explo- ~ion is a persistent, an urgent, and above all an intensely human problem. On the Population Commission which I met with in Manila about the same time last June, one of the Catholic bishops there, a very liberal and fine man, is also a member, and I am sure that his plea to the church was made with full knowledge of those to whom it was addressed. I might add that the better contraceptives we must find will cer- tainly help President Marcos also carry out his new official family planmng program. And only a month ago-a lot has been happening in these last ~ or 3 months-U Thant and Paul Hoffman initiated an active United Nations population and family planning program to help all member countries who wished such help. Paul Hoffman appointed Rafael Salas, a Filipino who had been the right hand man to Presi- dent Marcos, as director of the Population Fund for the United Nations. They set a $15 million program for this year as a starter, a large part of which will be carried out by the World Health Orga- nization, which obviously can offer help to many countries where a bilateral program from the United States would be unwelcome. This historic action followed 5 years of discussion and debate which has now committed the entire United Nations family to help bring down the world's rate of population growth. U Thant himself has laid out an important and growing role for the United Nations, including WHO, ILO, UNICEF, UNESCO, FAO and the World Bank-we all know how Mr. McNarnara as president of the World Bank has taken up this issue in the last year-and lie hopes-that is, U Thant, and believes that during the decade of the seventies we will be finding a humanitarian solution to the world's population problem. 40-471-70-pt. 16-vol. 2-18 PAGENO="0274" 6714 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I certainly hope that turns out to be true. I suggest, Mr. Chairman, that your committee, and the entire Con- gress, and the American peo~1e themselves, might usefully begin considering-and from your questions earlier, I see that you already were-what rate of population growth would best serve the future interests of our country. After full discussion and full consideration our people should reach a consensus, if possil)le, and decide on the optimum rate, the very best rate of growth for all of us. Then we should shape our tax laws, our social customs, our subsidies and our educational programs towar(1 achieving that best rate on a voluntary basis as soon as Possible. I, myself, believe that the most favorable rate from all points of view would be a zero growth rate. We have gone down already from 2 percent a year to 1 percent a year, and if we give ourselves 20 to 30 years to go down from 1 percent to zero we would find ourselves with about 250 million people in this country by the year 2000. This should be enough for any of us. WTe would be well on our way to solving our pollution problems, our environment could be saved, and the threat from toa many people would be over. Perhaps other coun- tries would want to follow our example. Finall, I should again like to emphasize that. no single action could so surely speed up efforts in that direction here and through- out the world as a massive and well-financed program of contracep- tive research carried on by our Federal Government.. This committee has demonstrated the overpowering need for far better contracen- tives-I hope, recommend, and respectfully urge that it help in every possible way to bring about the financing and the actual launchin of a inas~ive research program to provide them. I should add as a last word that. many high officials in India and many foreign observers as well fear that India's half billion peoile and its 600,000 villages can never successfully curb its overpowering popi~lat~on growth until new contraceptive methods are found which are much better adapted to the poverty, illiteracy and encrusted social customs that now plague its progress. This may be true in many other countries as well. It. is quite possible, Mr. Chairman, that the fate and the future of the human race is actually at stake. Senator NELSON. General Draper and Mrs. Piot.row, the committee appreciates our taking the time to come here today. It has been a helpful addiition to the hearing recordl. Are there any questions? Mr. DL~FFY. General Draper, I understand someone has been in contact wit.h you on behalf of Dr. Southam, with reference to a correction in her committee statement. General DRAPER. Oh, yes, yesterday I was talking on the telephone with Dr. Ha.rkavy of the Ford Foundation audi he mentioned to me that in Dr. Southam's testimony, which was presented for the record today, that there had been misunderstanding by her or an omission by her, t.o state that the figures used in Dr. Southam's statement were based on the less-developed countries and not on the U.S. figures. Somewhere she had referred to 50 percent going off the pill within a yea.r, or something like that. And I will make available to PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6715 the committee staff the figures, and she is going to correct those anyway. SenatOr NELSON. Are you knowledgeable about the studies that have been made, if they seem to vary some? General DRAPER. On the discontinuance of the pill? Senator NELSON. Yes. Dr. Hugh Davis, quoted from the Frank report, which stated that 40 percent quit in 2 months and then quoted from the Maryland Planned Parenthood Report, which stated that over 50 percent-or about 50 percent-went off the pill in less than 12 months. Now, are there other studies that have been made? General DRAPER. Yes, the one that Dr. Harkavy referred to yester- clay, and the one on which he assumed that Dr. Southam's figures were based, are in a publication of 2 years ago, "Use of Oral Con- traceptives," put out by the Population Council in December 1967. And the one thing I note from their table of figures is just what you pointed out, the studies vary so completely that it is very difficult to fix on one figure. They vary in the foreign countries all the way, after one year, from 56 percent still using, continuation rate; in Puerto Rico, 75 percent; to 12 percent in Turkey; 53 percent in India; 71 in India under another study; 42 percent in rfaiwan Now, for the United States, there are four studies here quoted at that time. And this is after 1 year, continuous rates at that time, 67 percent in one study, 77 in another, 68 in another, and 61 in another. Senator NELSON. Over what period? General DRAPER. After the first year. And then, in a United Kingdom study, 85 percent. Then it gives it after 11/2 years and 2 years. So all you can judge is, it depends on where the study was carried out. Senator NELSON. Thank you very much. Tile hearings will resume at 2 o'clock. Senator McIntyre and Sen- ator Dole will be here. I have an appointment at that time. I will try to get back before the hearings are completed. General DRAPER. Might I just add one word. I would like to give a copy of this to tile staff, this is a booklet that does go into that question ill some detail, "Use of Oral Contraceptives in Developing Countries," by Ravenhoit and Piotrow, who has testified. Senator NELSON. Do you have a copy for the committee? General DRAPER. Will do.1 Senator NELSON. Thank you very much. (Whereupon, at 12 :30 p.m., the committee recessed, to reconvene at 2 p.m., this same day.) AFTERNOON SESSION Senator DOLE. Dr. Ratner, if you will, just take a seat. Senator McIntyre will be here momentarily and Senator Nelson has a com- mitment until about 2 :30. You can either read your statement in full, paraphrase it, or summarize it. It will appear in full in the record. So any way you wish to proceed is satisfactory. 1 The booklet, "Use of Oral Contraceptives in Developing Countries," by Dr. R. T. Ravenholt and Phyllis Piotrow, has been retained in committee files. PAGENO="0276" 6716 COMPETITIVE PROBLEMS IX THE DRUG INDUSTRY STATEMENT OP DR. HERBERT RATNER, PUBLIC HEALTH DIRECTOR, OAK PARK, ILL. Dr. RATxEI~. Senator, I think it is a relatively short statement, and I think it would really save time if I read it, after watching what went on today. Senator DOLE. Go ahead. Dr. IRATXEE. My name is Dr. Herbert Ratner. I am a full-time public health physician and Director of Public Health in Oak Park, 111. I am a former editor of the "Bulletin of the American Associa- tion of Public Health Physicians" and am presently editor of "Child ~ Family Quarterly." For many years I have been chairman of the Maternal and Child Health Committee of the Illinois Association of Medical Health Officers. I am also a member of the Family Planning Coordinating Council of Metropolitan Chicago, Inc., which is hosted by the Planned Parenthood Association of Chicago. Because I believe each witness before this committee should make himself crystal clear on this score, I state, for the record, that I am not indebted to any of the manufacturers of the birth-control pill by virtue of being the recipient of grants, of clinical or research slip- port, of consultant or writing fees, of expense accounts, or funds or favors of any kind. Nor do I own stock in any pharmaceutical firm. Because of my public health training and experience in epidemic intelligence, I first became alerted to the actual dangers of the oral contraceptives-The Pill-early in 1962 when reports of thromboem- bolic deaths associated with the pill first appeared in the English medical literature. Such reports by private physicians following the marketing of a new drug frequently forecast impending trouble. It was on the basis of such reports that the thalidomide disaster was averted in the United States: that the Salk vaccine was recalled for further evalu- ation in 1955: and that numerous drugs have been removed from the market in the past. A prominent example of the latter is MER-29. As a result of this alert, as well as the many theoretical fears engendered by the use of a l)Owerful systemic synthetic chemical, especially one intended to disrupt a major normal physiological process in healthy women, and the fact that the pill was intended as a mass prescription for a major segment of our society-women in the prime of life-the potential and actual dangers of the pill became an immediate professional interest to me and the subject of continuing stud. My first public statement questioning the pill was addressed to the Illinois Public Aid Commission, November 6, 1962. At that time the Commission was contemplating underwriting an extensive birth-control program made possible, they believed, by the availability of what was taken to be an effective and safe birth-con- trol pill. This 11-page memorandum was entitled "Practical and Financial Problems Associated with the Use of Oral Contraceptives in Tax Supported Programs." The conclusion regarding the finances of such a program was that a conscientious observance of precautionary medical procedures PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6717 necessitated by the use of the pill-and we have heard some addi- tional medical procedures this morning in the form of periodic X-ra.ys up to four times a. year. Senator DOLE. Dr. Ratner, are you in the practice of medicine now? 1)o you see patients? 1)r. RATNER. I am in the full-time practice of medicine as a public health physician sPecialist. Senator DOLE. In this area of oral contraceptives? Dr. RATNER. My patients are my community and I have to be con- cerned about everything that affects the health o-f my community. I have a community of 60,000 and we are a medical center. Senator DOLE. How many do ~OU see personally? Dr. RATNER. I do not see patients personally. Senator I)0LE. YOU have not seen any patients for how long? T)r. RATNER. I have not seen patients for at least 10 years, but I am a consultant to physicians, and I am a consultant to the public at large. My primary work is health education. This is the primary w-ork of apublic health physician. Senator DOLE. What do you base your statements on, with refer- ence to the pill? Dr. RATNER. Well, Senator, you know there are about a thousand medical periodicals that are published, and practically each one has an article on the pill each month. I happen to get about 20 periodi- cals in my office, and somebody has to take the time out to read what is being reported. The private practicing physician does not have the time- Senator DOLE. Have you done any research on the pill? T)r. RATNER. No. Senator DOLE. You do not do research; you do not have any patients; you read articles is that your base of expertise? Dr. RATNER. Senator, the reason we have medical literature is for people to keep up- Senator DOLE. `We have had a lot of medical literature in this committee, but I do not know if I have learned anything or not. Dr. RATNER. `We have scientific publications that are intended for physicians who have responsibilities directly to people. And this is the thing that I have as an obligation, as a health officer, to keel) U~ with the medical literature to know what is going on, and this is what leads to epidemic intelligence. On the basis of this I have sent out warnings to my physicians from time to time. So that they are getting the results of my screen- ing of the medical literature. Senator DOLE. They could learn the same thing by reading the same })eriOdicals? - Dr. RATNER. A busy practicing physician hardly has time even to read his own specialty journals. Senator DolE. The point is that you have not done any great research in this field other than reading, you have not seen any patients-I assume you have not personally had any experience with any of the side effects, and I assume you are here as an expert wit- ness with reference to the pill. I just wonder what you base that on. Dr. RATNER. I base this on my expertness as a public health spe- PAGENO="0278" 6718 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY cialist, and I have been invited here to talk about the public health aspects of the pill in that capacity. Now, I would be quite an ignoramus as a Physician if I did not read the medical literature that was coming out pertaimng to this, and the person who reacTs and keeps up with the medical literature is better informed about the pill than the person practicing in his own office, seeing his own patients. which is simply a mirrored image of himself. Half the time, if his patients develop complications from the pill they go to another doctor. As a result, he does not even know what is happening in his own practice. Senator DOLE. Are you board certified? Dr. RATNETi. I am a qualified public health physician. I cannot hold my post unless I am certified by the State as being qualified to handle the Public's health. Senator DOLE. Proceed. Maybe there will be some questions later. Dr. RATNER. Yes, sir. And the treatment of medical complications resulting from the use of the pill, would make this an exorbitantly expensive method of family planning. I pointed out at that time that the pill would result in a~ "sharp increase in expensive, iatrogenic"-which means physician caused disease-ancl that "although medical committees hastily appomtecl by the Government and drug houses have con- chided (in 1962) that these cases (of thrombophlebitis) seemed coin- cidental, one is circumspect in concluding that the last word has not been said." When I became the editor of Child & Family Quarterly late in 1961, we initiated a section entitled, "Recent Setbacks in Medicine" to make clear to our readership that not all recent discoveries in medicine represent advance. In it we abstracted articles from the current medical literature reporting medical complications of the lMll. Appended to these collections of abstracts were editor's comments critically evaluating the status of the pill. The material on the pill from Child & Family was subsequently reprinted in a booklet enti- tled, "The Medical Hazards of the Birth Control Pill" (M.1L), and has just been received from the printer. Because the collection of medical abstracts, editor's comments, the editor's preface commenting on the secondl report of the Heliman committee, and the introdluction by Dr. Louis Lasagna, professor of clinical pharmacology at Johns Hopkins Medical School, is so ger- inane to the subcommittee hearing, a copy of the booklet has been submitted in connection with this statement. Although I dlo not wish to take the time to read them now, I would like the "Preface." "Introduction." and the "Editor's Com- ments" from this booklet to be included as a part of the record of these hearings. Senator DOLE. Who is the editor? Dr. RATNER. I am. Senator DOLE. So the editor's comments you refer to are your comments? Dr. RATNER. Right. PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6719 Senator MCINTYRE. Without :objection, they may be made a part of the record. (rflle document follows:) [Excerpts from Child and Family, December 1969] THE MEDICAL HAZARDS OF THE BIRTH CONTROL PILL PREFACE In answer to the direct question, "Are the birth control pills safe?"-to which the public and the medical profession seek a candid, clear, unambiguous response-Dr. Louis Heilman, in his Chairman's Summary, (1), gives an elu- sive, evasive, equivocal reply. He concludes: "When these potential hazards and the value of these drugs are balanced, tile ratio of benefit to risk (is) sufficiently high to justify the designation safe witlun tile intent of the (Kefauver-Harris) legislation." That one Pill manufacturer promptly distributed free copies of H's summary to American physicians, is not, therefore, a surprise; nor a surprise that another Pill manufacturer utilized: it in a letter to book editors and reviewers to undercut in advance three, current, responsible books documenting tile (lan- gers of Tile Pill for tile public at large. For H. to claim in defense of ills conclusion that "no effective drug can be absolutely safe" is not only irrelevant but a type of sophistry unbecoming to a chairman of a committee with guardianship over tile Ilealtil of IllilliOlls of women In tile prune of life. The fact is that in the treatment of disease where the patient is in a state of imbalance, e.g., hypothyroidism or diabetes, effec- tive drugs such as thyroxine and insulin are safe in proper therapeutic dosage. Tile unique problem with oral contraceptives is tilat powerful drugs are being given to healthy ~vomnen already in a state of balance for which tile term timer- apeutie dose doesn't exist, except as a metaphor. Even Aristotle knew that altilougil effective drugs given to sick people may get them well, effective drugs given to tile healtily are bound to lead to imbalance and disease (2). In a different category we have antibiotics. Some are safe, and some are dangerous. Tile safety of penicillin in respect to toxicity of the therapeutic dose is not questioned, nor is it the subject of Congressional Hearings. Clllor- amnphenicol (chioromycetin), on tile other ilanci, wincil WCS the suh~ect of a Congressional Hearing, is universally recognized among experts as a dangerous drug tha't should be strictly limited in its use. (its lethality Illatciles that of Tile Pill (3). Again, no one questions tile safety of condonls, diaphragms, SpernlatoCideS or rhythm-available alternatives to women interested in family planning. No conlmnittee, meeting over months and years, is necessary to proclaim tills fact. Were I-I. to have pronounced Tile Pill dangerous-and H. admits close to "3 per cent [additional deaths] to tile total age-specific mortality in users," to say nothing of serious morbidities-but justified ill certain, delimited categories of patients (as was done with chioramphenicol) tile air would have been cleared and women and physicians alike would have benefited from Iliglily useful guidelines. H., instead, manages to rationalize the safety of The Pill by an overinfiated estimate of tile current Pill's effectiveness and an overinfiated estimate of the diaphragm's ineffectiveness. Implicit in his comparison is that deatils from dia- pilragm-failure pregnancies, calculated from overall maternal mortality, equal thromboembolic deaths from The Pill, thereby making "the pill . . . as safe (or as dangerous) as the diaphragm." (4) By this gross comparison, H., and Pill enthusiasts emulating him (Dr. Robert Kistner of Harvard is a striking exam- ple) are dangerously misleading women and their physicians. The fact is, as H. knows, "the risk in having a baby is not the same for all individuals. A healthy young girl runs a very negligible risk, but someone who ilaS serious heart disease, or who is older, or who has hypertension, runs a real risk in having a baby. So to say the risk in taking the pill is less than the risk in having a baby doesn't make much sense. (5)" NoTE-Numbered references at end of Preface. PAGENO="0280" 6720 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Furthermore, for women spacing children, the need for maximum effective- ness of The Pill at the risk of serious medical hazards ranging from throm- bophiebitis to sterility is clearly unwarranted, since these women desire another baby anyway. Obviously, their need for effectiveness is different from those w-ith completed families and radically different from those who have high risk vulnerability to the potential hazards of pregnancy. Had H. deline- ated the numerous categories which, in his terms, would have differentiated justified from dangerous usage of The Pill, he would have made a major, edu- cational contribution to the prescribing physician in his task of intelligently advising women and in protecting patients from a wide spectrum of medical complications. Here H. could have benefited from Perkins Guide in Establish- ing Priorities for Contraceptive Care (6). In 1966, the first report of the Hellman Committee concluded that it found "no adequate scientific data, at this time, proving these compounds unsafe for human use." (1) Notwithstanding, H., in press conference, interpreted that report as a yellow- light of caution." (8) Since the 1966 report, more than fifty metabolic changes have been recorded in w-omen on The Pill (9) and its association w-ith thromboembolism, depression, chemical diabetes, migraine, ste- rility, libido loss, hypercholesteremnia, hypertension, jaundice and lesser condi- tions established. In the light of this it seems hardly acceptable three years later for time second report of the same Committee to find "the ratio of benefit to risk sufficiently high to justify the designation of safe." Drug companies and Pill enthusiasts have interpreted this designation of safety as a green light. One w-onders what new' medical hazards have to be unfolded to deepen the yellow in the yellow- light of caution or to change the light to red. Disturbing is the fact that H. chose to be the sole author of the summary of the second report (1969)-that part of the report w-hich receives the prime publicity. He apparently, preferred not to entrust the summary to the Commit- tee as a w-hole w-hich is normal procedure and which w-as an unexplained departure from the first report. According to Medical World News, "There were indications that not all members of the blue-ribbon committee w-ere in agreement with the general con- clusions reached on the relative risks and benefits of the pill." One committee member told MTVIV that the summary was "the chairman's synthesis of committee discussions." (10) Why, then, w-asn't there a committee synthesis? It is know-n that Dr. Philip Corfman, a prominent member of the Committee, and director of the Center for Population Research, National Institutes of Health, held a contrary posi- tion, more in harmony w-ith the recorded facts. At the Family Planning Con- ference of the American Medical Colleges Association, Corfman concluded that The Pill's "use should be monitored and restricted to women who cannot use other methods effectively." (11) This recommendation received no publicity. It seems improper that his assessment of The Pill was ignored, or eliminated, and kept from the ears of those eager to be informed. Because so much is at stake I urge the reader not only to carefully scruti- nize the contents of this booklet, but also other recent books which critically reexamine The Pill. Some excerpts from these appear on the pages preceding the Preface. Perhaps, then, the reader w-ill wonder-as we do-what pressures exist to retain Dr. Hellman as chairman of this important committee when he has failed in making available to us clear directives protective of the health of American w-omen. REFERENCES 1. Second Report on the Oral Contraceptives of the Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, Aug. 1, 1969, Superintendent of Documents, U.S. Government Printing Office, Washing- ton, D.C. 2. ~S~ee The Medical Hazards of the Birth Control Pill, p. 46. 3. R. 0. Wallerstein, M.D. et al. JA]IA 208 :2045. 1969. 4. Louis M. Hellman, M.D. A Doctor's View- of Birth-Control Pills, Redbook Magazine, April 1969. 5. Ibid. 0. Gordon W. Perkin, M.D. Assessment of Reproductive Risk in Non-Pregnant Women, Am. J. Ob. c~ Gyn. 101: 709-717, July 1, 1968. PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6721 7. Report on the Oral Contraceptives. Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration, Aug. 1, 1966. Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. S. Washington Post, Aug. 16, 1966. 9. Metabolic Effects of Gonadal Hormones and Contraceptive Steroids. Ed. by Hilton A. Saihanick, M.D., David M. Kipnis, M.D., and Raymond L. Vande Wiele, M.D. Plenum Press, New York, 1969. 10. illedwal World News, p. 5, Sept. 19, 1969. 11. Philip A. Corfman, M.D. Metabolic Effects of Oral Contraceptives, J. Med. Education Part 2, 44 :67, Nov. 1969. * * * * * * * * INTRODUCTION There are few n1edical controversies that have stirred up as much public discussion as the safety of "The Pill-the oral contraceptives. Why, then, this booklet 1 The answer lies in the history of oral contraceptives. To begin with, these cheiiiicais proved extraordinarily effective in preventing conception, and were hailed (with good reason) as a major advance in individual, national, and global birth control efforts. Second, the convenience and psychological and esthetic advantages of the Pill over older mechanical devices, time rhythm method, etc. rapidly made oral contraceptives popular with women, their sexual partners, and doctors alike, especially since the technical skill required to fit a diaphragm, e.g., was not required of the physician, who could now con- fidently manage the contraceptive needs of his patients by the simple use of his prescription pad. Third, these substances were, although not natural hormones, hormone-like in their actions, and were thus considered by some scientists as somehow less likely to cause mischief than "drugs." (The fact that even true hormones could be catastrophic in their effects, as in hyperthyroidism or the conditions associated with hyperfunction of the adrenal glands, seems to have been over- looked in this argument.) Fourth, the Pill quickly became big business, so that drug manufacturers began to manipulate professional opinion at an early date, stressing the won- ders of the Pill and minimizing its dangers. In this they were aided by medi- cal journalists, who for a long time-with a few exceptions-filed "gee-whiz" stories that tended to condition lay readers to a positive orientatiomi toward oral contraceptives. Finally, the serious side effects of the Pill have been difficult to pin down in conclusive fashion. The various clotting disorders that have been reported are all conditions that occur with a frequency that is not sufficiently ugh to be detected with certainty by anything short of carefully planned studies. Fur- thermore, the voluntary reporting of pulmonary emboli, strokes, etc. has been generally so fragmentary as to make a travesty of several "expert committee" reports prepared for the Food and Drug Administration or the World Health Organization. The possibility of drug-induced cancer of the breast or reproduc- tive system is still in scientific limbo, since the lag time between initiation of chemical insult and the appearance of clinical cancer (if it ever occurs) can be expected to be long. Those who have been struggling for years to alert the public and the I)rOfes- sion to the potential mischief inherent in the prolonged use of these powerful chemicals that affect almost every cell in the body have thus had to combat a host of forces arguing against their point of view. These include the women whose sex lives have been revolutionized by the Pill, the population control experts who sincerely believe that the population explosion is a far greater danger than any harm inherent in oral contraceptives, the pharmaceutical firms that have a substantial financial stake in the Pill's image, and the doc- tors who have been telling their patients for years that the Pill was "as safe as water." Obfuscating the entire picture has been a series of Alice-in-Wonderland rationalizations that smack of science but are really so unscientific as to con- stitute an insult to the intelligent person. The risks of death are contrasted with the risks of pregnancy as if, a) no alternative, safe and effective methods PAGENO="0282" 6722 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY of l)irth control were available, b) oral contraceptives were not going to be taken for year after year. and c) women who don't use oral contraceptives WOUld he pregnant almost continuously. As imprecise as the figures for death from the Pill are, comparison of the relative risks over a reproductive lifetime of oral contraceptives, other effective techniques, and ad lib pregnancies makes the Pill look anything but benign. What is the situation today? In my opinion, the drawbacks of the Pill mount with each passing year, as the annotated bibliographies in this booklet indicate. The whole story of the Pill's mischief has yet to be told. Neverthe- less, oral contraceptives remain one useful approach in the judicious pliysi- clan's management of his patients. There are women for w-hom the Pill must he considered the contraceptive tecimique of choice. But there are many women for whom it is not, and some who should not take these drugs under any circumstances. This booklet should help to weigh the scales so as to achieve a better bal- ance about the Pill in the mind of the reader. It does not attempt to argue the case for the oral contraceptives, so that anyone who has somehow escaped exposure to the sunnyside of the story will end up w-ith a biased point of view. But for most people, the pages that follow should prove informative and useful. provided one believes that a w-ell educated public will make wiser deci- sions about health matters than one that is misinformed. Louis LASAGNA, M.D. The Johns Hopkins University ~ehooi of Medicine. BALTIMORE, M.D.. ~eptem her 19, 1969. * * * * Editor's Comment: To w-ithdraw a drug once on the market is considerably more difficult than to get a drug on the market. FDA originally approved The Pill (Enovid) as safe for marketing on the basis of studies on only 132 women who had taken The Pill consecutively for 12 or more months. (Morton Mintz, By Preser~ption Only, Houghton Muffin Co., Boston, 1907, p. 271.) Since The Pill has been on the market, the number of deaths reported in association with The Pill has far exceeded this number. In fact, it is safe to say that The Pill is the most dangerous drug ever introduced for use by the healthy in respect to lethality and major complications. It is certainly the most talented drug ever intro- ducecl in its ability to produce diverse and varied disease phenomena and sys- tematic abnormalities in normal w-omen. Furthermore, "nobody knows funda- mentally how the drugs work. For the biochemistry of inhibiting conception by taking drugs remains one of reproductive physiology's more fogbound research areas." (Chemical d~ Engineering News. March 27, 1967, p. 44.) Finally, we are ignorant of The Pill's long range effects, particularly as a contributing cause of cancer. This latter concern has led Dr. Hellman, Chairman of the most recent FDA Advisory Committee on Oral Contraceptives, to state, "If I were a young lady these clays and had any fear of cancer, I'd probably use an intrau- terine device." (Oh. Gyn. News, Aug. 1, 1967, p. 14.) To admit mistakes is not characteristic of the American scene. Governmental agencies are no exceptions. In addition, time pressures and manipulations by drug firms-and the people they subsidize-to prevent a drug from being removed from the market can be extraordinary. This is especially true of The Pill. Everyone prefers to believe that The Pill is safe. It is the most psychologically acceptable birth control agent for women because of its separation in time and place from the love act. It is a boon to the physician, because the writing of a prescription is the quickest and sim- plest of medical acts. and because the effects of The Pill necessitate keeping the patient under observation, returning her to the doctor in a continuing exercise of his medical skill and authority. It is a fabulous money-maker. Research workers and social engineers promoting The Pill-at university levels and in birth control clinics-never had it so good in terms of financial support. But there comes a time in the history of a drug when it is imperative to take a sober second look: to compare the drug's initial promise with its subse- quent performance. The issue, obviously, isn't effectiveness. We can all agree with. Guttmacher (Recent Setbacks: Action) that the three fold effect-steril- ization, contraception and ahortion-"a ccounts for the extraordinary success" PAGENO="0283" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6723 of The Pill (provided, however, that o~e can motivate women to use it, or to stay on it, or to take it on 20 consecutive days). The sober second look concerns itself with safety. The extent of the gap between promise and performance is highlighted by the accumulation of con- traindications, precautions, warnings and adverse effects listed above, as well as by The Sampler on The Pill. The latter is only a token of the thousands of articles that have been written, since the introduction of The Pill, questioning safety, reporting deaths or lesser complications, or reporting unsuspected, newly discovered, systemic effects. These reports are written by reputable physicians and are judged to be worthy of publication by editors of leading scientific periodicals. With Eng- land's recent statistical demonstration of a definitive association of The Pill with throinboembolism (Brid. Med. J. 5/6/67), the judgment of individual clini- cians recording this association has been substantiated and has proven supe- rior to the judgment of the four committees appointed to determine safety. (Searle-AMA 0/2/62; Wright 8/3/63; WHO 12/6/65; and Hehlman 8/15/66.) r[~l1e Pill was originally and erroneously introduced as a "natural" and "physiologic" means of birth control and, by implication, safe. (John Rock, M.D., The Time has Come, Alfred A. Knopf, 1963, Ch. 14.) Early investigators, thereby, focussed their greater interest on effectiveness rather than safety. Protocols, as a result, were deficient in medical surveillance. This deficiency accounts for the innocent dismissal as "heart attacks" (author's quotes) of two deaths among the 838 women using The Pill in the Harvard School of Public I-Iealth-Puerto Rican field trials. (A. P. Satterthwaite, M.D. & C. J. Gamble, M.D., Conception Control with Norethynodrel, J. Am. Med. Women's Assoc., 17 :797-802, Oct. 1062.) These women were young, in previous good health, were not seen during their illness l)y staff members conducting time study, and were not autopsied. Subsequent investigations by Puerto Rican phy- sicians (A. M. de Andino, Jr., M.D., et al Informe Preliminar Del Coniite Dc La Assoeiaeion Mediea Dc Puerto Rico Nombrado Para El Estudio Dc Las Reacciones Adversas A La Droga Enovid, Aug. 28, 1902; Ramon Sifre, M.D., Statement on Enovid, April 20, 1963) as well as a representative of the FDA (Heino Trees, M.D., Meeting conducted by Sen. E. Gruening, Aug. 7, 1963), confirmed that thromboembolism and deaths were occurring in association with The Pill, contrary to the denials of the promoters of The Pill in Puerto Rico. Because The Pill had acquired "diplomatic immunity from criticism" (D. B. Clark, M.D.. Annual Meeting, American Academy of Neurology, Philadelphia, 1967), unknown to any other marketed drug, no publicity of these facts was forthcoming. Kiopper (Recent Setbacks) makes clear that The Pill is not natural and physiologic in its action. This theory was also effectively dismissed by Robert E. Hall, M.D., of the Columbia University School of Medicine: "Rock's ration- alization of The Pill is to me a little short of preposterous . . . As a birth con- trol enthusiast I would like to dismiss this theory as a harmless euphemism; as a doctor I must aver it is medical fantasy." (N.Y. Times Book Review Sec- tion, May 12, 1963.) The Pill acquired its diplomatic immunity because it was promoted as the solution to the population problem in undeveloped countries, and to tl~e grow- ing welfare problem in the U.S. Under the thesis that the end justifies the means, imputing danger to The Pill was branded as unhumanitarian. Time fact is that The Pill has not solved the population problem and, with the exception of a few episodic successes, has not received significant acceptance in develop- ing countries and among the poor. This accounts for the subsequent major shift to other contraceptives as a solution to the problem: first to the IUD- the hoop or coil, and following its failure, to new and then to old contracep- tives. The Agency for International Development, for instance, is now shipping condoms to India. When Time went all out for The Pill (April 7, 1967), it referred to the "latest" report of Dr. John Cobb to prove that The Pill was being successfully used in Pakistan. But Time was ignorant of his latest report, from ~rl~ichi I quote: "Enthusiasm was contagiOus . . . But then we began to analyze our data, checking off the women who had received the IUD and other contracep- tives, against our census roster for the village . . . At the most, this would reduce the birth rate from the estimated level of 50 to about 47, a long way PAGENO="0284" 6724 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY froni the goal of reducing the birth rate to 30. . . . Oral contraceptives were moderately sucessful for a very few selected women, but were not practical * . . . Something more than contraception is needed." (John C. Cobb, M.D., MPH., Obstacles to Population Control In West Palcistan, American Associa- tion of Planned Parenthood Physicians, Denver. Colorado, April 27, 1966.) The net result of propaganda which led to pronouncements of Pill safety out of so-called humanitarian considerations w-as that the real users of The Pill, the middle and upper classes of the U.S., w-ere seduced away from w-ell estab- lished and safe means of birth control. To attribute the present reduction of the U.S. birth rate to this seduction is erroneous. r1~he recent decline in birth rate began in 1057, four years before The Pill was on the market, and more years before it w-as used I)opularly. rJ~he lowest birth rate in the history of the U.S. occurred 35 years ago without the benefit of The Pill. Perhaps the most fallacious argument in defense of The Pill is that it pi'e- vents the hazards of pregnancy. How a Pill which places the w-oman in a con- tinuous state of false pregnancy, which in turn reproduces the illnesses of occasional pregnancies, can be considered an advantage is beyond scientific comprehension. The English, in an attempt to w-ater down their finding of 3 deaths per 100,000 w-omen from thromboembolism by alleging that The Pill l)revents 12 deaths per 100,000 from pregnancy, ignore tw-o essential facts. The first is that the alternative to The Pill is not pregnancy but other and safer means of conception control. TIme second is that prior poor health contributes to most of the deaths in pregnancy. Contrasting the death rate of healthy women on The Pill to healthy pregnant women results in an entirely cliffeient coiii parison. There is even a more basic error: viz., the failure to realize that false preg- nancy is a disease, not a normal state. What is ignored in true pregnancy is tIme compensating factor of a growing and developing fetus, and the adaptation of the mother's body to gestation. As far as I know, no one has discussed this. Three examples suffice. In pregnancy, the vascular system of the body adjusts to accommodate a rapidly enlarging uterus. 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 pelvis venous congestion, a condition which has already caused distress to surgeons. Such unnatural congestion introduces a whole series of factors predisposing to thrombosis and embolic phenomena. The second example relates to the hypercoaguable state of pregnancy. This state was described prior to the introduction of The Pill. (B. Alexander, M.D., et al, Increased Clotting Factors in Pregnancy, New Eng. J. Med. 256 :1093-1097, Nov. 30, 1961.) "This (state) provides a means where by rapid clotting may take place at the site of placental separation." (Louise L. Phil- lips, Ch. 12, "Modifications of the Coagulation Mechanism During Pregnancy," in Modern Trends in Human Reproductive Physiology, Ed. H. M. Carey, But- terworths, 1063.) The Pill duplicates the hypercoaguable state. Because it serves no function in false pregnancy, its only contribution is to make time "patient potentially more susceptible to intravascular thrombosis." (Ibid.) Th~ Pill introduces the risk without compensatory advantage. The third example relates to the w-ell know-n protection pregnancy om' embryonic tissue confer against certain induced cancers in the lower animal. In the absence of fetal tissue this protection is not conferred. Projecting this fetal-maternal relationship to human beings, w-e cannot assume in using The Pill contraceptively, via the mechanism of a false pregnancy, that the pi'otec- tion against cancer is present in the absence of the fetus. It would seem that if w-e had any respect for nature's economics, subtleties and the ordering of health, and any humility in respect to our multiple igno- rances of the fetal-maternal relationship, we w-ould more readily recongize that a state of false pregnancy is pathologic and a monstrosity of nature. On the basis of the original norm for safety. "no method of pregnancy spac- ing, even though highly effective, is justifiable if it endangers life or health" (Recent AS'etbacks: Norm for safety), The Pill should have been removed from the market years ago. Since the FDA has failed to follow the original norm, it should inform us of its present norm. How many deaths, how many disabili- ties, how many newly discovered disease conditions associated with The Pill must there be before the FDA, in terms of its regulatory responsibility, feels PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6725 obligated to act? Is it to wait until the dangers become fully apparent to the consumer herself? One out of five women (estimated to be 1,232,000) once having used The Pill, has already decided on her own never to use The Pill again. (Science 153:1109, Sept. 9, 1966; 155:951, Feb. 24, 1967.) Do we wait until all women reject The Pill? Obviously not, since the FDA is supposed to supply expert epidemiologic knowledge in advance of the obvious fact. In the spring of 1955, the government reluctantly removed Salk vaccine from the market, because its dangers became apparent to the man on the street. \Vitli the later Sabin vaccine, and the bitter Salk vaccine experience behind it, the government took a more sophisticated and responsible position. When doubts arose, it was ready to recall the Sabin vaccine if cases of paralytic polio caused by the vaccine exceeded one per million inoculations. It has now been established that The Pill causes 30 deaths per million women from thiromboembolism, to say nothing of severe disabilities from the same condi- tion. Again, we ask, at what point will the FDA act on The Pill? Presumably, The Pill would have been recalled from the market if any of the four committees in considering the association of The Pill to thromboem- bolism found a significant relationship. Is FDA's inaction a preview of things to come? Are we going to witness a series of future rationalizations as associations are established between The Pill and pseudo-carcinoma, chromosome damage, depression, diabetes melhitus, hypertension, liver disease, magnesium deficiency, migraine, sterility, cerebral arterial insufficiency, vaginitis, vision impairment and perhaps cancer? Medicine's ultimate goal is the prevention of disease and the promotion of life. When one takes the incidence of individual adverse effects and calculates the numbers of women suffering from ailments generated by The Pill, the total number of women converted from a state of health to a state of illness is in the hundreds of thousands, if not in the millions. Estimated deaths from thromnl)oembolism now amount to 180 for the six million women on The Pill in the U.S. For as long as records have been kept in the U.S., with the exception of 1916, the incidence of deaths from polio has never reached this level. A major reason for failure to obtain a more objective assessment of the problem, including its public health dimensions, rests with the method of selecting experts for advisory connnittees. Some of the experts chosen are deeply obligated to drug firms for subsidiza- tion of their research and other activities. Chemical and Engineering News quotes a scientist on the latter situation as follows: "Another hindrance to objective results, and I think this ought to be said, is that too many investiga- tors have too personal an interest in the drugs they work with. All in all I get the feeling that the experimental aspects of (The Pill) are so fluid and contro- versial that you must be careful over w-ho says what and why he says it." (Ibid. p. 48.) Such investigators are capable of stating publicly that The Pill "is a per- fectly safe method," (Medical Science, Nov. 1963, p. 47) and again, as late as January, 1968, that The Pill when "taken under the supervision of a compe- tent physician, and directions followed, is perfectly safe." (John Rock, M.D., Family Circle, Jan. 1968, p. 33.) The fact is that perfect safety cannot be attributed to any drug, not even aspirin. The opposite ploy is also used to defend The Pill; e.g., "I think we agree that there is nothing in life that is absolutely safe. `Safe' then becomes a rela- tive term, and we have to consider safer than what, or less safe than what." (Don Carlos Hines, M.D., Director of the Medical Special Services Division of Eli Lilly and Co. on The Open Mind, WNBC TelevisIon, Feb. 6, 1966, "Are Birth Control Pills Safe?") The first committee appointed to study the question of thromboembolism, was sponsored by the manufacturers of Enovid, not the government, and con- ducted by the American Medical Association. (Proceedings of a Conference: Thromboenibolic Phenomena in Women, Sept. 10, 1962, Chicago.) The latter has a well known bias in favor of the pharmaceutical industry. Within several hours of convening this meeting, before participants had an adequate opportu- nity to study and discuss the data presented at the meeting, the Chairman called for a vote that would, in effect, be a whitewash of The Pill. (Ibid. pp. 69. 81, 82.) He commented, ". . . so far there has not been a single shred of evidence that has been presented in any of these figures to suggest that it con- PAGENO="0286" 6726 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY tributes to a greater incidence of this disease . . . Will everyone agree with that?" The Chairman ultimately got the vote he requested. That it was not unanimous is a tribute to Stanford Wessler, M.D., a leading authority on thrombosis, who with courage and perspicacity, was the single dissenting voice. Concerning the selection of experts for committees, the conclusion of a Johns Hopkins conference held in November, 1963, to explore the niajor problems in making safe and effective (Irugs available to the public is pertinent. Time fol- lowing is taken from a section dealing with "experts and decisions" from the summary of the conference. "Experts . . . at any point in time are frequently considered to be those who espouse the most popular and widely held views of the predominant orthodoxy. The history of medicine abounds with examples of the perpetuation of totally illogical treatments or the irrational resistance to significant therapeutic advances because of the powerful influence of an authoritarian orthodoxy Experts should be replaced periodically so that no single orthodoxy exerts a dominant opinion. The opinion of experts should be subject to challenge by way of a wide variety of media and channels." (Drugs in Our Society, Ed. Paul Talalay, Johns Hopkins Press, 1964, pp. 284-285.) If, for reasons of its own, FDA feels it cannot remove The Pill from the market on the same basis as other drugs, we would urge the FDA to appoint another committee. The appointment of experts to this committee should be governed by the conclusion of the Johns Hopkins conference. If the safety of the public is paramount, such a committee should be sympathetic to a long established principle of medicine; viz., to lean toward the worst diagnosis. With all due respect to the concept of statistical safety, there are numerous individual women who are having their lives ruined by The Pill. ("Our Read- ers Talk Back About The Birth Control Pills," Ladies Home Journal. Nov. 1967.) This should be of deep concern to a medical profession dedicated to the personal welfare of the individual patient. CHn~D & FAMILY WINTER, 1008. * * * * * * * Editor's Comment: "To THE EI)IToim: Yesterday I received my first copy of your magazine, with its thorough report on the pill. Yesterday, also, my obstetrician inserted an intrauterine device. I certainly admire and respect the cautious viewpoint of your nmga- zine. Actually cautious really means honesty, and real and consistent honesty is pretty hard to find. Thanks." Honesty among men makes possible a well functioning society. In two areas, in particular, man hungers for "real and consistent honesty": from science, since its goal is truth; from medicine, since its goal is individual w-ell-heing and longevity. In the latter, no hunger for honesty is greater than that of the person w-ho is in the process of making a medical decision about life and health. The number of other readers who expressed appreciation similar to that quoted above testifies that many w-omen of child-bearing age hunger for the facts of The Pill. These w-omen are concerned about risks to life and health: about their responsibilities as wives and mothers. They are concerned about their womanhood and time integrity of their bodies. The younger w-oman is especially concerned about the possibility of subsequent sterility or adverse effects on future babies. For most women, the overriding factor in choosing a method of conception control is safety. Since established safe methods of con- ception control are already available, they resent being seduced from these methods by false assurances of Pill safety. To the frequently repeated ques- tion. `Is The Pill Really Safe', however, scarcely anywhere does the American woman get a knowledgeable or candid answer to help her in her personal deci- sion. Because of the pateint's right to the facts, we have compiled another Sam- pier on The Pill. Most of the articles abstracted have appeared or have become available since the original Sampler (CF 7:80-56 Winter 1968). These articles, for the most part, come from the daily reading of the editor in his capacity as a public health physician. They are not the result of a scrutiny of the litera- ture. The second Sampler confirms the continuing concern of physicians with PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6727 Pill safety. Some of the abstracts confirm earlier reports. Others report addi- tional associations of The Pill and pathology: blindness, uterine cervical lesions, gingivitis, lupus erythematosus reactions, hair loss, cholesteremia, lac- tation suppression, frigidity, hepatic porphyria, pulmonary vascular disease, psychoses, sunlight sensitivity and vascular occlusion of the colon and the liepatic veins (Budd-Chiari Syndrome). Of greatest interest are the final reports of two British studies demonstrating the cause and effect relationship of The Pill to thromboembolic (TE) disease and deaths with special reference to the lungs, brain and heart. (Recent Setbac1~s: TE Disease, Vessey & Doll; Inman & Vessey). These studies definitely resolve a six year controversy in the U.S., a contro- versy in w-hich it seems that every possible effort was made by promoters, pro- pagandists or proponents of The Pill, to minimize the issue and prematurely claim safety. It is sufficient to note at this point that although The Pill was first discovered, researched, clinically tested, marketed and widely used in the U.S., and although the number of women using The Pill in the U.S. far exceeds use in other countries, and although there were four U.S. dominated committees appointed to look into safety, it was not the U.S. with its much vaunted scientific resources and superior health accomplishments that resolved this vital question. It was resolved by England, a medically socialized country whose resources, supposedly, do not compare to ours. Except for the dedicated reporting of Morton Mintz of The Washington Post, these important findings of deel) interest to all women and most physicians received the sketchiest reporting in the mass media and minimal reporting through medical channels. The use of the upper limits of thromboembolic disease (TE) incidence reported by the English, applied to the U.S., results in the following predicted number, of cases: (In accordance with the Ehglish studies, pathology is restricted to hospitalized cases of TE and to deaths from TE in the lungs, brain and heart. Deaths from TE in other parts of the body, e.g., hepatic vein thrombosis resulting in the highly fatal Budd-Chiari Syndrome-see Recent Setbacks: Thrombosis-are excluded. Out of an estimated 6,000,000 women on The Pill in the U.S., The Pill would produce 2,520 hospitalized TE cases annually. Annual predicted deaths from pulmonary, cerebral and coronary TE would range from 242 to 1000. The calculation resulting in the smaller number is based on the assumption that 70% of American women on The Pill are under 34 years of age. If the over-all TE death rate were applied to American pill-users, the number of deaths would exceed 242. The higher figure is based on the English calculation that The Pill accounts for 2% of the total mortality of women in the child-bearing age. It is the current technique of apologists for Time Pill to dismiss the death risk as "very small" (Louis Heilman, M.D., The Today Show, 5/2/68). But sim- ilar numbers of deaths from other causes produce quite a contrary reaction. For instance, deaths from TE correspond to the incidence of deaths from chloramphenicol or dietary pills, both of which were the occasion of congres- sional investigations. The incidence of death in white women of cI1ild-bearing age from crimes of violence which include murder, forcible rape, robbery and aggravated assault is equivalent to the incidence of TE deaths from Time Pill. More pointedly, for this suggests an opacity or lack of perspective on the part of the obstetrician, The Pill, which the obstetrician prescribes contraceptively, causes more deaths-approximately twice the number-than are prevented when the same obstetrician immunizes a pregnant woman against poliomyeli- tis. There are numerous additional lethal diseases in the U.S. to which public health devotes large sums of money and to which physicians devote great energy, in which the incidence of death is less than that caused by The Pill. The final irony, however, is found in a comnparison of time number of deaths from criminal abortion. Reported deaths from abortion in the U.S. in 1963 which were criminal, self-induced or without legal indications only amount to 114 (CF 7 :39 Winter 1968). Christopher Tietze, who favors relaxation of abor- tion laws, estimates deaths from abortion as follows: "According to official sta- tistics, the number of reported deaths from abortion in 1964 was 247 for the entire United States. Doubtless almost all of these deaths were associated with illegally induced abortion. Also without doubt some deaths from abortion were untruthfully or even mistakenly reported under other diagnoses, but I do not believe that the true total of deaths due to illegal abortion, recorded and PAGENO="0288" 6728 COMPETITIVE PROBLEMS IN TI~ DRUG INDUSTRY hidden, can be much larger than 500 per year." (Statistics of Induced Abor- tion, International Conference on Abortion, Sept. 1968, Washington, D.C.) Most of the supporters of The Pill-the same physicians, who are minimiz- ing deaths from The Pill-are in the forefront decrying deaths from illegal abortion as a rationale for relaxation of the abortion law-s. They do this with humanistic fervor. All can lament these deaths, for each human life is pre- cious. But where is their concern for women dying from The Pill, which match in number the deaths from criminal abortion? They dismiss the number of deaths from The Pill as inconsequential, a comment no abortion advocate has yet made concerning deaths from abortion. Incidentally, these same physicians take pleasure in referring to the rhythm method of conception control as Vatican roulette (a term w-hich at best can only be applied to unsupervised calendar rhythm). In Vatican roulette, how- ever, when the w-oman loses, she at least gains a baby, a baby who very quickly becomes a precious asset. With The Pill, the w-oman I)lays real roulette -Russian roulette: w-hen she loses, she loses her life! It seems that Dr. Louis Bellman, who as Chairman and official spokesman of the Committee on Obstetrics and Gynecology of the FDA w-hich w-eighs Pill safety, has become particularly negligent in his public interpretation of the English findings. The Bellman Committee caine into being because of the dissatisfaction of FDA with the reports of previous committees: the Searle sponsored American Medical Association Conference (Sept. 10. 1962), the Wright Committee of the FDA appointed by Dr. Goddard's predecessor (Aug. 4, 1963) and the World Health Organization Conunittee (December 6, 1965). To its credit, the Bellman Committee w-as the first of all committees to introduce a cautionary note. Time ~lIagazine (8/19/68) expressed it as follow-s: "On the key issue of whether the pills are ready safe, the formal report took refuge behind a double negative "The committee finds no adequate scientific data, at this time, proving these compounds unsafe for human use.' A committee spokesman for human use.' A committee spokesman translated `We wanted to put a w-ord of caution, to put a yellow light, not a green light, on the matter.'" The committee's spokesman was subsequently identified by the Associated Press as the chairman, Dr. Hell- man (Washington Post 8/16/66). With subsequent proof of The Pill as a cause of death and serious disease, logic w-ould dictate that Dr. Bellman sw-itch from the yellow light to the red light. His public statements indicate his acceptance-sometimes perhaps w-ith reluctance-of the validity of the English reports :"Discussing risks of birth control pills . . . Dr. Bellman said studies in Great Bi'itain have show-n that the pills have caused thromboembolism. But he said the risks are extremely small." (Chicago Sun-Times 1/22/68). "Dr. Bellman . . . concedes that there is a cause-and-effect relationship betw-een birth control pills and sometimes fatal lung clots . . ." (Science iVemes 2/3/68). According to Herbert Black and Carl Cobb of the Boston Globe. however, Bellman, "has been widely misquoted on his assessment of the British Study." In his statement to the Globe Dr. Bell- man stated: "The study has demonstrated a very real relationship, but is only suggestive of a cause-and-effect relationship" (2/21/68). But, ho and behold. it is not a red light he ha~ "put on the matter" but a green light, as indicated by subsequent public statements: "I think the British data is conclusive. I think 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 clots (but the British figures) should not be taken in themselves as at all alarming. It's a very small risk. The British say the risk is less than having a baby. Perhaps this isn't the proper w-ay to evaluate the risk. I don't think personally that the w-ay to talk about this risk is in comparison with the things we do every day that we don't have to do . . . I think the pill . . . has Proved remarkably safe over the seven or eight years that it has been used . . . I wuuld not hesitate a bit in prescribing it for teenagers . . . I don't think there is anything in the immedi- ate future that w-ill cast any serious doubt on the safety (of The Pill) beyond what w-e know- right now-." (The Today Show. 5/2/68). "There's no sense trying to hide the risk. These very responsible figures show (the) danger . . . The risk of thromboembolism in pregnancy is the same as that from Tl1e Pill. And the over-all risk of death in pregnancy is considerably higher" (Medical World News 5/24/68). PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 6729 Wish-fulfillment may have bettered Dr. Heilman's scientific acumen and may account for his contradictions and unseemly statements. Certainly, it does not become the chairman of a committee investigating safety-a committee that has promised to turn in a report on safety in 1969 (which will not help the women who may be dying in 1968)-to prejudge safety in advance as in his statement: "I don't think there is anything in the immediate future that will cast any serious doubt on the safety (of The Pill) beyond what we know right now." Furthermore, he should make up his mind about comparing deaths from The Pill to deaths from pregnancy. For one thing, the claim that "the over-all risk of death in pregnancy is considerably higher" cannot be substantiated. Even if it could, it would have dubious application. He plainly misinterprets the British when they compare The Pill and pregnancy. (Recent Setbacks: TE. Inman & Vessey, last paragraph). Dr. Hellman, at least for some audiences, accepts the causal relationship of The Pill to TE, a relationship which by his own statement he "suspected for some time." It has not served the public welfare, however, for him to have kept his suspicion from the public. The suspicion belongs to the patient who takes The Pill and risks her life, not to the physician who prescribes The Pill, nor the drug company which profits from The Pill. The physician has the obli- gation to share his suspicion with the patient. Nor is it serving the public for other physician backers of The Pill, writing for the public, to ignore or dismiss the cause and effect relationship. An exam- ple of this is to be found in Today's Health, a lay periodical of the American Medical Association which is found: in most physicians' waiting rooms. The May 1968 issue contains an article entitled, The Pill-Is There a Danger?, which followed the original Sampler on The Pill (CF Winter 1968). The author, Edward T. Tyler, M.D., of Los Angeles Planned Parenthood clinics, a pioneer on oral-contraceptive research, is knowledgeable and, no doubt, has his own suspicions. The article, however, reads like a skillfully written promo- tional piece from a pharmaceutical house. To refer back to the discredited two year old WHO Committee's whitewash of The Pill (Recent Setbacks: Scandal) and to keep silent about the English studies is, to say the least, misleading. To the credit of Dr. Tyler, however, lie handles the question of the teenager and The Pill in conformity with FDA'S recommendation (CF 7:77 Winter 1968) and quite differently from Dr. Hellman who gave carte blanche to the use of The Pill by teenagers over a national network (supra). Dr. Tyler's guarded statement is: "There is no definite known reason why oral contraceptives cannot be prescribed for a normal : girl when she has completed puberty and has reached her full height." Even then many would disagree with its advisa- bility. An earlier example of an article written to offset adverse criticisms of The Pill, and which used irrelevant data, appeared in Parent's Magazine, Oct., 1967. It was written by George L~ngmyhr, M.D., formerly associated with a leading manufacturer of The Pill and presently Medical Director of Planned Parenthood-World Population. He quoted data from a book entitled, Oral Con- traceptives, by Dr. Victor Drill, whom he failed to identify as the Director of Biological Research for Searle & Co., the manufacturers of Enovid. The data purports to prove that since there is less TE reported in Pill users than in non-Pill users, The Pill cannot be the cause of TE. Neither Drs. Langmyhr nor Drill, however, make mention of the gross under-reporting of Pill complica- tions in this country. As Vessey and Inman state in (Recent Setbacks), "The hypothesis that there was no relation between the use of oral contraceptives and fatal thrombosis depended on: the assumption that there has been almost complete reporting of thromboembolic deaths. That this assumption is untena- ble has now been demonstrated." These authors point out that only 4% of the known deaths were reported by the attending physician. There is reason to believe that reporting is even less than that in the U.S. Dr. Drill quotes Dr. Winter of Searle's in support of lac.k of association, but fails to mention Dr. Winter's admission that, "The considerable discrepancy between the reported numbers and the predicted incidence is very likely a reflection of inadequate reporting" (The Incidence of Thromboembolism in Enovid Users. Metabolisms 14:422-431 1\Iarch 1965). A final example of biased interpretation to allay criticism, or in this case, perhaps, innocence, is found in an article by two sociologists, Drs. Charles F. Westhof'f of Princeton and Norman B. Ryder of the University of Wisconsin 40-471-70--pt. 16-vol. 2-19 PAGENO="0290" 6730 COMPETITIVE PROBLEMS IN THE DRUG fl~DTJSTRY (Duration of Use or Oral Contraceptives in the United ~S1tates, 1960-65; Public Health Reports 83 :277-287 April 1968). These authors direct the National Fertility Study under a contract from the Public Health Service. Their bias or innocence is reflected both in the introduction and the conclusion. In their introduction they state that ". . . confidence in (The Pill's) safety has increased with time and accumulation of satisfactory experience." They are obviously opaque to the prolific recording of unsatisfactory experience. In their conclusion they state, "Based on these data, admittedly inadequate for diagnos- tic purposes, there does not appear to be any evidence of serious health prob- lems associated with the use of the pill." Their data, however, belies the con- clusion. Insofar as their data is interpretable and projectable to 6,000,000 users of The Pill, their data yields the following pathology: The Pill results in 1) 3,040 cases of thromboembolism (TE) or a rate of 74 per 100,000 users (which is comparable to the English findings) ; 2) of these cases of TE, 1580 cases are pulmonary emboli requiring hospitalization (naturally, they were not able to record deaths since they surveyed live patients). Of women who remained on The Pill, and whose symptoms were recorded at the time of the interview, 1) 792,000 women complained of weight change, fluid retention, breast tenderness or nausea: 2) 147000 women complained of spotting, hemorrhage, irregularity or cramps; and 3) 198,000 complained of headaches and/or nervousness. If serious disease means imminent death and good health means the proliferation of headaches, nervousness and a variety of female ailments, then these two sociologists are right in their conclusion. All should agree, however, that none of these ailments contributes to either a satisfactory personal life or a harmo- nious relationship with other members of the family, although they do keep the practicing physician inordinately busy. Space does not permit a full exposition of the sophistry and shallow science found in the writings of most promoters of The Pill since serious complica- tions from The Pill were first reported seven years ago. Although promoters of The Pill had the earliest and largest clinic experiences with The Pill, they were not the ones who discovered and reported serious adverse findings. What was not looked for was not found. What was not surveyed was not seen. What perhaps happened was ignored. With rare exception, the clinical researchers ignored the firm warning of Prof. J. R. A. Mitchell of Oxford and the British Medical Research Council, given at the Searle & Company AMA Conference on Throniboembolie Phenomena in Tfomen in Chicago, 1962: "the patients who drop out of the trials . . . are much more important than the patients who stay in them." This was the radical error of the highly touted and highly pub- licizecl Planned Parenthood-World Population study released April 2, 1965. No wonder it never found the deaths and the strokes and the multiple pathologies that caused women to discontinue The Pill-it only studied women who had survived Enovid for at least 24 months. This study was made despite the knowledge that the vast majority of the 132 cases of TE disease and death,- which was the basis for the Chicago Conference-occurred much earlier than the 24 month period and predominantly within the first six months of Pill use. In general, favorable findings of drug company subsidized physician promot- ers of The Pill and naive physicians have been encouraged, widely distributed, scientifically inflated, maximized and extolled whereas unfavorable findings have either been ignored, suppressed, rationalized, minimized or ridiculed. Concerning TE disease and death, the so-called authorities on The Pill in the U.S. have been consistently wrong on the issue of safety. It seems that this demands investigation-if necessary, congressional investigation. It seems, also, that the greatest support should be given the FDA, to protect it from the pressures of the pharmaceutical industry and from foundations, and from gov- ernment and voluntary agencies whose real concern is not individual health but the alleged social health associated with the use of any type of population control, whose scientists and swivelchair physicians tend to view people as sta- tistical numbers rather than as patients and persons. Mass prescription must not displace the individualized therapeutic decision. Here, if we believe in the principle that the state is ordered to the good of the individual, we must agree with Walter L. Hermann, M.D.: *.If widespread and generalized use of these progestins (The Pill) will provide humanity with a first early formula for solution to the population problem, are we not then entitled to think in terms of over-all results, and deviate just one step from the traditional prirnuns nos noccie-first do no harm-of the healing profession? The answer is a very emphatic no." (Introduction to A ~Symposium on Oral Contraception, 1L[etabo- lism 14 :422-431, March 1905). PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6731 Finally, it must be emphasized, in this era of consumer protection, that the woman has a right to protection from manipulation and victimization. No right is more firmly established than the right of the patient to informed con- sent (CF 7:75 Winter 1968) to a prescription directed at his body, whether surgical or medicinal. Knowledge sufficient for enlightened consent is a moral, medical and legal right to which malpractice suits testify. The classic state- ment of this right is found in Plato's Laws (Greek pagination 491) where Plato distinguishes between the physician who took care of slaves, and the one who took care of freemen. Whereas the slave-doctor prescribed "as if he had exact knowledge" and gave orders "like a tyrant," the doctor of freemen went "into the nature of the disorder," entered "into discourse with the patient and his friends" and would not "prescribe for him until he has first convinced him." The reader can determine for himself whether the American woman, as patient, is treated as slave or free person. It is our belief that the decline of responsibility to the individual patient in the area of family planning by groups and individuals working in this field is resulting in a national scandal. CHILD & FAMILY SPRING, 1968. Editor's Comment: The above contrainclications, warnings, precautions and adverse reactions are the `fine print' which are required by law in thug labeling and advertisements of The Pill to the medical profession. These Pill complications have been drawn up by an ad hoc committee of the FDA. No other drug on the market lists as many and such varied complications-testimony to the pervasive and universal action of sex hormones on virtually every cell of the body. Further- more, one must never forget that in the case of the oral contraceptives one deals not with natural hormones but with artificial or synthetic substances capable of abnormal, unpredictable and possibly disastrous effects. Despite the extensive complications enumerated, many believe that the Com- mittee's formulation reflects a partiality favoring the interests of Pill manu- factuiers that the Ad Hoc Committee exhibits a reluctance to share whim the prescribing physician and the patient the deep concern it and others have over the complications arising from the use of powerful synthetic steroids in the normal healthy woman. Information raising doubts about the true safety of The Pill is frequently withheld. Premature reassurances are released to the press in the absence of supporting data. As one might suspect the manufacturers of Time Pill abet this situation. They support research which confirms their bias and furthers their self-inter- est. They seek advocates and promoters. They favor supporters of The Pill with subtle forms of payola: research grants, subsidized trips to national and international meetings, and consultant fees, to name a few. The burden of demonstrating and communicating The Pill's dangers to phy- sicians and the public at large, therefore, fails to those who do not have the official responsibility for the safety of The Pill and who have little source of financial subsidy to pursue unbiased investigations to evaluate safety. This burden is inappropriate for the prime responsibility for the safety of The Pill rests with the Ad Hoc Committee and the FDA. Theirs, however, seems tO be a timid and reluctant guardianship. Once again we remind the FDA of the recommendation of the Johns Hopkins 1963 conference on drugs (CF 7 :93 Winter 1968) that experts appointed to advisory committees "should be replaced periodically so that no single orthodoxy exerts a dominant opinion." An example of deference to the interests of drug manufacturers is the inclu- sion of the paragraph implying that recent British data causally relating The Pill to disease and death from thromboembolism (TE) are not applicable to women in the U.S. Rhetorically, the statement casts doubt on the significance of the British findings for American women. Taken literally, however, the par- agraph discounting the British findings introduces the alternative possibility that TE dangers of The Pill may be greater for American women. Were the Committee concerned more about the health of 6,000,000 American women for whom safe conception control alternatives are available, rather than for the health of the pharmaceutical industry of the social engineering proclivities of sociologists, the importance of the British studies demonstrating unequivocal associations with death and disease requiring hospitalization could not be treated so lightly nor rationalized so readily. Actually, the sophistry of the pharmaceutical industry and those who work with them is apparent. In earlier studies, representatives and allies of drug PAGENO="0292" 6732 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY manufacturers did not hesitate to use foreign data on TE to support conten- tions that The Pill was not a cause of TE in the U.S. Eden Berman, M.D. of the Division of Clinical Research of G. D. Searle & Co., manufacturer of Enovid, and Dr. Robert I. Cien, Searle's Director of \-Iarket Research, utilized Saskatchewan and British Columbia data to support their contention that The Pill was not associated with TE in the U.S. (Proceedings of a Conference: Thromboembolic Phenomena in Women, Sept. 10, 1962 Chicago). Christopher Tietze, M.D. at the same meeting, likened the death rate from non-puerperal thrombophiebitis and pulmonary embolism in American women of reproductive age to the death rate from the same causes in British women: he reported the former as experiencing 7 deaths per million, whereas the Brit- ish experienced 6 deaths per million (Ibid. p. 74). This contradicts the current ~claim that British and American women are not comparable. (Dr. Tietze even -went on to say that "The number of reported deaths among (American) users -of Enovid is . . . almost twice as high as the number of expected deaths. . . .") Dr. Victor Drill. Director of Biological Research for Searle has also utilized statistics on TE from foreign countries to argue for the safety of The Pill in the TJ.S. (Oral Contraceptives. 1966, McGraw-Hill, N.Y.) There, he equates the incidence of TE in England and Wales to that reported by the National Dis- ease end Therapeutic Indea~ for the U.S. The difference is less than 1% (p. - 173). When representatives of the drug industry (and others) advance British sta- tistics as comparable when they serve the purpose of protecting the sale of The Pill to American women, but reject analagous British statistics as not -comparable when they do the opposite, sophistry has pre-empted truth and bias has sabotaged science. Of relevance is the fact that safety studies leading to acceptance of The Pill by the FDA were carried out on Puerto Rican women. If one argues that Brit- ish women are not comparable to women of the United States, a fortiori, Puerto Rican women, in terms of climate, nutrition, ethnic background and activity, are even less comparable. In other words, the FDA's acceptance of the thesis that women of different countries are not comparable negates the original studies allegedly proving the safety of The Pill. It was these studies upon which the approval of the FDA was based. The new labeling requirements continue to reflect a minimalistic approach to the adverse effects of The Pill. In this regard, the FDA seems to demand only what it feels forced to accept in matters critical of The Pill. The benefit of the doubt would seem to favor the use and sale of The Pill rather than the best interests of the woman who may be victimized by its taking. Does this not echo the old Scotch verdict, "Not quilty! But, don't do it again"? The language of the original article by Inman and Vessey, upon which TE warnings required by the FDA were primarily based, is ". . - irrespective of age, the risk of death from pulmonary embolism or cerebral thrombosis was increased seven to eight times in users of oral contraceptives." (CF 7 :179 Spring 1968). Is there not therefore, a glaring inconsistency to be noted when a statistical correlation is admitted for one (pulmonary embolism) and not for the other (cerebrovascular accidents)? To admit the relationship of one finding with no qualification and to downgrade the other, somewhat arbitrarily, to a "suggestive association"? Or, to declare, as explained at length previously, that an English study has relevance to American women in one case but not in another? Could it be that the drug industry, the Ad Hoc Committee and the FDA are playing a specious game? The continuing apparent capitulation of the FDA to interests more concerned with sales than with safety remains most alarming and disappointing. If the practicing physicians, the wives and future mothers of this country cannot look to the FDA in complete trust, to whom can they turn? CHILD & FAMILY SUMMER, 1968. * * * * * * * * * Editor's Connnent: The Third Sampler on The Pill contains abstracts of unusual interest from the scientific literature: 1. Under Blood Coagulation, Poller reports that "clotting changes do not appear to be dose dependent." Accordingly, the new low-dose oral contracep- PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6733 tives cannot be construed to be any less dangerous than the old high-dose orals in respect to thromboembolic phenomena. This is to be expected since what are euphemistically termed "side effects" are in reality "direct effects," as charac- teristic of the oral steroids as contraceptive effects. 2. Under Blood Platelets, Bolton reports that, unlike natural estrogens, the synthetic estrogens used in The Pill produce a "pattern of platelet behavior (which) resembles that of patients with arterial disease or multiple sclerosis." The effect is mediated through an abnormal enzyme produced by the synthetic estrogens. This finding helps elucidate~ the multiple mechanism which accounts for the increased incidence of thrombosis in women on The Pill reported by the English (CF 7 :178-80 Spring 1968). It further exposes the illusion of pro- tagonists of The Pill and the fantasy~ of pharmaceutical advertising that The Pill is a natural and phsyiologic form~ of contraception. Others have been criti- cal of this claim (CF 7 :89 WTinter 1968). 3. Under Carcinoma-in-Situ, Mintz' report of the unpublicized meeting of the American Cancer Society at which secrecy was imposed on a finding linking The Pill with precancerous uterine cervical changes is most disturbing. Secrecy in such matters is completely foreign to medical tradition. The suspicions and findings of clinical medicine belong to the patient and to the prescribing physi- cian responsible for the therapeutic decision.When, under the guise of social engineering, population control or alleged prudence, knowledge is withheld which pre-erninently belongs to the medical profession and public, physician and patient rights are transgressed. Unfortunately, suppression of knowledge associating The Pill with cancer is more prevalent than this isolated report indicates. In certain elite circles it is common knowledge (which until pub- lished cannot be substantiated) that one of the major hospitals in the East is observing a sixfold increase of precancerous cervical changes in women on The Pill. One also hears that grant money has been withdrawn from a study at an Eastern medical school which uncovered breast cancer in monkeys on The Pill. Additionally, one gynecologist has informed me that he has recently seen an increased incidence of cervical cancer in girls in their early twenties who are on The Pill, a phenomenon uncommon to his experience of approximately 3,000 cases of cervical cancer. Furthermore, it is public knowledge that one oral con- traceptive was kept off the market because of breast cancer produced in dogs. In an age in which preventive medicine has high priority, it is distressing to have women exploited as guinea pigs in order to establish absolute certitude of the causal relationship of The Pill to cancer and other complications. Though it must be admitted women make superb guinea pigs-they don't cost any- thing, feed themselves, clean their own `cages,' pay for their own Pills and remunerate the clinical observer-the letter and spirit of the Kefauver Bill was to the contrary: that safety be established before, not after, placing the drugs on the market. 4. Under Depression, Nilssen, in a prospective psychiatric and psychologic investigation of postpartum women on The Pill and not on The Pill, reports a "significantly higher frequency of psychiatric symptoms" in Pill users. This confirms an earlier prospective study on depression (CF 7:171 Spring 1968). If medicine's goal is high-level wellness, using a contraceptive that causes depres- sion in up to 1 out of 4 women is hardly a contribution in that direction, nor can it be much of a contribution to domestic bliss. 5. The findings under Diabetes Mellitus are equally disturbing. Spellacy, for instance, reports that "77% (of women on) the combination type (of oral con- traceptives) have abnormal glucose tolerance curves" after being placed on The Pill. Assuming there are 5 million women in the reproductive years on combina- tion oral contraceptives, close to 4 million are undergoing a detectable altera- tion of carbohydrate metabolism in the prime of their life. This pathologic con- dition is potential to many serious late complications such as stroke, coronary infarction, gangrene and cataracts. Vaginitis Candida, communicable to hus- bands, has already been established as an immediate complication (Supra, TTaginitis;also CF 7 :87 Winter 1968). Four million human guinea pigs at no charge is an attractive gift to physi- cians doing clinical research. One would be happier, however, if these physi- cians displayed more of a puhliė health conscience and raised their voices against a mass experiment proceeding more from ignorance than from knowl- edge. PAGENO="0294" 6734 COMPETITIVE PROBLEMS IN THE DRUG R~DUSTRY 6. A particularly unwarranted threat to the young woman using The Pill to postpone initiation of a family is post-Pill sterility. (Supra SterIlity). There is no greater and more ironic retribution nature exacts than to rob The Pill user of the gift of motherhood she gratuitously takes for granted. 7. Finally, under Pulmonary Embolism, "The gross inadequacy of physician reporting" of adverse reactions to The Pill is reaffirmed (OF 7 :185 Spring 1968). This can only mean one thing: that the actual damage The Pill is caus- ing in the most active years of a woman's life is considerably worse than the Samplers on The Pill indicate. Editor's Comment: The scientific papers abstracted above in the Fourth Sampler testify anew to the inadequacy of the original studies sponsored by the manufacturers of The Pill to detect and uncover the medical hazards of The Pill: and the innocence of its discoverers in promoting The Pill as `natural and physiological." Rather than being natural and physiologic, these scientific articles show that, on the contrary, The Pill produces 1.) significant abnormalties of the intermediate metabolism of glucose in brain and of acetate in the aorta in vivo, 2.) abnor- mality in platelet behavior in the direction of thrombus formation, 3.) altera- tion of the electric activity of the brain as registered by the encephalogram, 4.) iia~reased pathological changes in uterine cervical cells and tissue, 5.) chro- mosomal damage resulting in subsequent spontaneous abortions, 6.) a marked increase in the concentration of serum copper, 7.) changes in monoamine oxi- clase metabolism associated with depression and loss of libido ranging from 7 to 2S% in Pill users, 8.) abnormal alterations in carbohydrate metabolism necessitating special precautions for u-omen with a family history of diabetes or who have a diabetic prednisone glucose tolerance test, 9.) green plasma, an abnormality which is also found in women with rheumatoid arthritis, 10.) a high incidence of endornetrial arteriolar development associated with hyperten- sion and cerebral thrOml)OSiS, 11.) a significant lowering of the cholesterol con- tent of menstrual discharge, 12.) a striking increase in the concentration of plasma angiotensinogen and plasma renin each of which are associated caim- `sally with hypertension. 13.) persistent u-eight gain, 14.) suppression of immune factors, 15.) suppression of lactation even with a new low-dose oral contraceptive. 16.) an increase in psychiatric pathology, 17.) amenorrhea and sterility and 18.) thromboembolic disease and deaths initiated by thrombi in a variety of blood vessels in the body. Can there be any remaining doubts that the steroid components of The Pill have a pharmacologic effect that far exceeds the simplistic and stubborn belief uf the discoverers and promoters of The Pill who limited the significant effects of The Pill to its contraceptive, sterilizing and abortifacient action? It would seem that they should have known better. They could have listened, for instance, to the prophetic words of Dr. Alan Guttmacher, President of Planned Parenthood-World Population, who, in 1959-one year before The Pill was marketed-commented on the essential dangers of the birth control pills: "The steroid pills violate a general medical principle. It is deemed safer to affect a target organ, in this case the uterus, tubes, or ovaries, directly, rather than to tinker with that affect through another organ, particularly when that organ is as important and complex as the pituitary gland. This master gland produces more than a dozen other chemicals and hormones, each regulating a vital body process, such as thyroid activity, water metabolism, and body growth." (Babies By Choice Or By Chance, Doubleday & Co. pp. 66-67). Unfortunately, not even Dr. Guttmacher heeded his basic clinical and physio- logical insight. In his ardent pursuit of population control even he permitted extra-medical considerations to dull his medical acumen. In doing so, he relin- quished his professional obligation to individual patients not to violate "the medical maxim primum non nocere [first do no harm]." (see Common Problems). Markush's paper (see Thron?boernbolic Deaths), which confirms, in American women, the increased incidence of thromboembolic deaths among Pill users reported by the English, should not go unnoticed. It highlights the weakness of the FDA in capitulating to the demands of drug manufacturers that the new warnings on thromboembolism in Pill users contain a modifying paragraph stating (as if the English were a peculiar species physiologically) that the PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6735 English findings do not necessarily apply to American women (see CF 7:274-5). How much longer will the FDA continue to grant The Pill a diplo- matic immunity not accorded any other drug? CHILD & FAMILY FALL, 1968 * * * * * * * * * * Senator MCINTYRE. I want to ask you, doctor, back there on page 2, who sponsored this publication, Child & Family Quarterly? Dr. RATNER. It is a group of physicians who are deeply interested in human life and reproduction, and incidentally, interested in the rhythm method and they have incorporated as a nonprofit organiza- tion. And I am the editor for them, of this quarterly, which has had a long history of concern with things pertaining to maternity and family and child- Senator MCINTYRE. Thank you very much, Dr. Ratner. Dr. RATNER. Right. As a public health physician~ I am deeply concerned with the nar- rowed vision of the private physician and the narrow interests of birth control clinics and clinics restricted to special diseases. It limits them from appreciating what is happening to the health of the country as a whole. We are losing sight of the whole person and we are losing sight of the whole community. We have become insensitive, epidemiologically and ecologically speaking, to our affluent and indulgent approach to medical problems. The following observations, then, are intended to give a broader view and a better insight into the ramifications in our society of the birth control pill. IATRoGE~IO DISEASE I trust that all physicians, including those who have testified at this hearing, would be in agreement that the ultimate goal of medi- cine is not simply the cure or prevention of disease but the promo- tion of optimum health and the achievement of high level wellness. In practice, however, we seem to ignore, or at least fail to accom- plish this goal. Physicians and patients alike tend to be over- enthusiastic about treatment. We have become a pill-swallowing civilization and man a paying animal as if health were a commodity to be bought at the marketplace rather than to be sought through an intelligent respect for nature's norms. ~ add here that when the Center for the Study of Demo- cratic Institutions in Santa Barbara, headed by Robert Maynard Hutchins, did a series, the American Character Series, and it was initiated at the Hotel Shoreham, Washington, in 1962, I was chosen to write a critique of American medicine, which was entitled "The Interview on Medicine." The above thought is to be found in the Interview. As a result it is generally recognized that America is the most overmedicated, most overoperated and most overinnoculated country in the world. This has brought about an increasing prevalence of iatrogernc-physician caused-disease and the medical literature abounds with case studies, review articles and books dealing with this malady. PAGENO="0296" 6736 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY With the widespread use of the oral contraceptives_the pill- iatrogenic disease has hit epidemic proportions. The reason for this is clear. Up until now physicians, for the most part, have only been producing iat.rogenic disease as a byproduct of treating the already sick person. For the first time in medicine's history, however, the drug industry has placed at our disposal a powerful, disease-produc- ing chemical for use in the healthy rather than the sick. In 1969, this made available to the medical profession a target of 81/2 million healthy women in the prime of life. We have had no better target for making obvious our talent for producing iatrogenic disease. How have we made out? The following represent numbers of healthy women who have become diseased as the result of using the pill. The first estimates are based on data from the national fertility study carried out for the Public Health Service by Westhoff, of Princeton, and Ryder, of Wisconsin.' I have listed what they found and I will not spell it out because I think everybody here has a copy. But ~n the day they made this interview they asked people what symptoms they had, which their doctors attributed to the pill. It resulted in 1,603,500 episodes of dis- ease, which is a ratio of about one out of five, which fits in with a lot of other figures we have on the incidence of complications from the pill. (The information follows:) Cases Thromboembolism (total) 4,306 hospitalized cases of pulmonary embolism 2, 238 Of women who remained on the pill, and whose symptoms were re- corded at the time of the interview: Weight change, fluid retention, breast tenderness or nausea, ac- counted for 1, 122, 000 Spotting, hemorrhage, irregularity or cramps accounted for - - - 209, 000 Headaches and/or nervousness accounted for 272, 500 Total 1, 603, 500 Dr. RATNER. Newsweek reported that of the women asked about complication, 51 percent of them said they had complications. It is ~n this basis, since they were healthy to begin with, that one is con- cerned about the extent of iatrogenic disease caused by the pill. Tile following estimates of incidence are conservative and are applied to the 81/2 million women on the pill in 1969. The basis for them can be found in either the Medical Hazards of the Pill or sup- plementary literature. All disease conditions are not represented, nor are most of the more than 50 metabolic abnormalities represented. For instance, in this paper I omitted chloasma, abnormal pigmen- tation of tile skin-usually of a permanent nature-which occurs in 29 percent of the women on the pill. This means that 1,650,000 women end up with disfiguring skin pigmentation, not previously present, brought about basically by mechanisms associated with the adrenal glands. 1 See reference 1 of Bibliography, beginning at p. 6757. PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6737 (The information follows:) Thromboembolic diseases requiring hospitalization, 42 per 100,000; 3,570 cases: Depression (16 percent) 1,360,000 Libido loss (16 percent) 1, 360, 000 Vaginitis (15 percent) 1,275, 000 Chemical diabetes (13 percent) 1, 105, 000 Absolute sterility (1.5 percent) 127, 500 Partial sterility (15 percent) 1, 275, 000 The following are based on an estimate of 1 case per 2,000 users: Migraine 4~ 250 Liver disease 4, 250 Uterine cervical pathology 4, 250 Hypertension 4, 250 Hypercholesteremia 4~ 250 Lupus erythematosus 4, 250 Erythema nodosum 4, 250 Ureteral dilatation 4,250 Hearing difficulties 4, 250 Vision difficulties 4, 250 Hypertrophic gingivitis 4~ 250 Herpes gestationis 4,250 Hair loss 4,250 Dr. RATNER. Without running through all of these conditions and these diseases- Mr. DUFFY. Let me interrupt you for a moment. You use the word "disease" here. Disease to me seems to be a pretty strong word and I am just curious why you would consider weight change to be a disease. Dr. RATNER. You realize that obesity is one of our maj or problems in this country. Mr. Durr~. Weight changes is a bit different, in my mind. If a person simply gains 5 or 10 pounds, is that a disease? Dr. RATNER. The optimum weight for a human being relating to- Mr. DUFFY. Let us move on. Dr. RATNER (continuing). Extension of life is ten pounds under the standard figures. Our No. 1 disease in this country is obesity, because with it comes malfunctioning of organs, and any time you put on 3 extra pounds, which consists of whatever it consists of as long as it is not muscle tissue and things like that, you are begin- ning to introduce a health hazard. Mr. DUFFY. What characterizes a disease? When is a headache a disease? I have a headache right now; is that a disease caused by those bright TV lights we had this morning. Dr. RATNER. Of course, it produces dysfunctions. You are not functioning as well when you have a headache. Mr. DUFFY. I still have very great difficulty in accepting these as diseases. Dr. RATNER. You may have a difficulty with a few of them but you do not have difficulties with migraine and liver disease and you do not have difficulty with uterine cervical pathology, you do not have difficulty with hypertension, you do not have difficulty with hypercholesteremia, you do not have difficulty with lupus erythema- tosus, you do not have difficulty with erythema nodosum- PAGENO="0298" 6738 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. DUFFY. I do not understand that. Dr. RATNER. That is part of the difficulty here. You do not have difficulty with vaginitis. Mr. DUFFY. You say 1,122,000 cases of disease involving weight gain? Dr. RATNER. Say that again? Mr. DUFFY. You say here weight changes account for 1,122,000 cases of disease. Dr. R.ATXER. I am quoting from a study by Westhoff and Ryder. It was directed to what was happening in respect to illnesses among people taking the pill, and they saw fit to list these things. These are not my figures. These are people who are associated with Planned Parenthood. They are working under a grant from the U.S. Public Health Service. They happen to be the official recorders of what is happening at large with the pill. This is their data, so argue with them. But they saw fit in an arti- cle that was published-and I have it here, and I will be happy to show it to you afterwards-in the "Public Health Report" to list these as the complications of the pill. Mr. DUFFY. They did not call it disease, though, they called it complications. Is that what you say? Dr. RATNER. Now we are getting into semantics about what you say are complications and what another person says is a disease. I want to make it clear to you that optimum and high-level wellness consists of neither. And I have already said that the goal of Ameri- can medicine is not simply to prevent disease, it is to promote opti- mum health. This is what good nutrition is all about, and a lot of other things are all about.. And this is what we are concerned about in this country, we are not concerned about making distinctions between disease and complications. Without enumerating them further, to give you just a notion of the extent of disease conditions that the pill is producing, I say here, because I have added it up, that the last group of individual disease conditions caused by the pill total 6,561,500 disease condi- tions in 8,500,000 women. Senator DOLE. You just added everything on page 5 to reach that total? Dr. RATNER. On the latter half of page 5. Senator DOLE. What about the upper half? Dr. R.ATNER. The upper half, I already gave you those figures when I read them to you; 1.600,000. Senator DOLE. If you add those to the other, you get over 10 mil- lion disease conditions in 8 million women? Dr. RATNER. Yes. No, a lot of these are duplicates. You can see they are duplicates. One is headaches and nervousness up above, and the other- Senator DOLE. You get one credit for headache and credit for being nervous? Dr. RATNER. These are conditions that are happening in women. It is not one woman for each condition. Some women, unfortunately, have several conditions. They can have pigmentation, they can have PAGENO="0299" COMPETITIVE PROBLEMS IN TiI~ IJG INDUSTRY 6739 depression, they can have libido loss, they can have vaginitis. This makes them just more of a cripple. Senator DOLE. Are you saying that there are 6,561,500 diseased~ women out of 8,500,000? Dr. RATNER. No, I did not say that. I said diseased conditions iii 8.5 million. Senator DOLE. How many women are you talking about? Dr. RATNER. This would be less than 8.5 million women. I only give you one total figure to give you an idea of the problem. Senator DOLE. You gave a whole page of figures. Dr. RATNER. If you want a clarification at this point, I would point out two things. In terms of the Westhoff and Ryder report,. this constituted 20 percent of the women. In terms of the Newsweek Gallup polL which was referred to earlier, which came out a couple of weeks ago, 51 percent of the women said they had complications~ So this will give you an idea of the amount of women who have complications. They range anywhere from 20 to 50 percent. Senator DOLE. You believe the poll was accurate? Dr. RATNER. Well, it is as accurate information as we have and it supports many other studies, including the Westhoff-Ryder study, which pointed out-I think I am coming to that later-that one out of five women give up the pill, and they say they will never use it again, and the main reason is because of medical complications. That is one datum. OK? Senator DOLE. It is OK with me. I do not add quickly. Dr. RATNER. I did not expect everybody-I thought the least I could do was acid it up for you. Senator DOLE. That is fine. Dr. RATNER. Let there be no doubt about the medical dangers of the pill. I think it sufficient to recognize that we never had congres- sional hearings on the safety of other methods of conception control such as foam, diaphragm, condom, or rhythm. The incidence of death from the pill is of the same order as deaths from chloramphenicol (M.H. pp. 2, 59) and diet pills-and both of these have been subject to congressional investigation by your subcommittee. The deaths from chioramphenicol is three per 100,000, and this is precisely what the pills are, three per 100,000. To place the dangers of the pill in sharp perspective, let me trans- late a mostly ignored conclusion from the "Chairman's Summary" of the "Second (1969) Report of the Advisory Committee on Obstet- rics and Gynecology." Dr. Heilman states that of all causes that kill women annually in their child-bearing years almost 3 percent of deaths in women users of the pill arC caused by the pill. This was in his "Chairman's Sum- mary" of the report that came out in August. Many a voluntary health agency launched to save lives from a particular disease have been launched on an incidence of deaths less than that caused by the pill. To illustrate, the pill which the obste- trician prescribes contraceptively causes more deaths-approxi- mately twice the number-than are prevented when the same obste- trician immunizes a pregnant woman against poliomyelitis. PAGENO="0300" ~674O COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. DUFFY. Do you have a cite for that, Doctor? Dr. R.ATNER. Yes. Mr. DUFFY. Would you supply that for the record? Dr. RATNER. Yes. It is written up in a Medical Hazards and you ~will find it in the index on the policy-I will leave the exact refer- ~ence, OK? Senator DOLE. Leave it with the reporter, please. Dr. RATNER. Yes. The citation is M.H. pp. 44-45. Overlooked is the fact that the incidence of thromboembolic deaths from the pill is equivalent to the incidence of deaths in white women of child-bearing age from crimes of violence which include murder, forcible rape, robbery, and aggravated assault (M.H. p. 49. "Homicide rates for whites of all ages and both sexes is 3.1 deaths per 100,000 people." Statistical Bulletin of the Metropolitan Life Insurance Co., February 1968, p. 5.) Senator DOLE. Do you say they mention the pill in that study? Dr. RATNER. No, sir; I am trying to give you comparable figures so you can have a perspective on what we are dealing with when we admit three out of 100,000 die because of the pill. This perspective is sadly lacking in discussion of the pill. I am obviously talking now as a public health man. Furthermore, deaths from the pill compare to deaths from both legal and illegal abortions. Dr. Connell last week lamented "the helpless feeling that comes over you as you watch women die follow- ing criminal abortions" which she attributes to the nonuse of the pill. The life of a woman dying from a. "therapeutic misadventure" is the English term used as a cause of death on death certificates in England when death occurs from iatrogenic or drug disease. The life of a woman dying from a "therapeutic misadventure" with the pill is equally precious. The helpless feeling of the attend- ing physician in many instances is even worse. Unfortunately, Dr. Connell's chief experience with death relates to obstetrical cases. She doesn't normally see deaths from the pill, since the women in whom pulmonary embolism or cerebral accidents occur don't return to the birth control clinic prescribing the pill for medical care, because birth control clinics do not give total medical care. Therefore, when a woman is getting the pill from the birth control clinic and 3 weeks later has a stroke and is indigent, she goes to the county hospital, and the county hospital takes care of it and there is no followup on these cases in all of the birth control clinics I am associated with professionally. The person instead is seen by an internist or chest surgeon or neu- rologist. This conforms to a medical adage that states: Specialists do not see their own mistakes. Other specialists, however, do see them and for the most part in the case of the pill these other spe- cialists know more about what is happening than obstetricians and gynecologists. The chest surgeon or neurologist can tell more about serious com- plications than the obstetrician. The trouble here is that Dr. Connell is apparently unaware or unmindful of the fact that the number of women dying from the PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6741 pill in the United States is of~ the same order as the number of women dying from legal and illegal abortion combined (M.H. p. 59). A death is a death. Loyalty to one's biases should not elevate the significance of one cause of untoward death over another. Now, to make this point clear here, I mean to make my evidence clear, I am using the estimate of abortion deaths of Dr. Christopher Tietze, who you know is for the pill, and is the leading statistician for the Population Council and many other organizations promoting the pill (M.H. pp. 59-60). According to official statistics, the number of reported deaths from all abortions in 1964 was only 247 for the entire United States. Without doubt, some deaths from abortion were untruthfully or mistakenly reported and therefore underdiagnosed, but, with Dr~ Tietze I do not believe that the true total of deaths can be much larger than 500 per year. Now with the rate of three deaths from the pill per 100,000 pill- users, a conservative figure according to the original English studies, 8.5 million women on the pill resulted in 255 deaths. This is compa- rable to Tietze's estimate of minimum deaths from all abortions, legal and illegal, vis 247 deaths. This is what permits me to place pill deaths in the same numerical category as abortion deaths. So I concluded: A death is a death and that loyalty to one's biases should not elevate the significance of one cause of untoward death over another. We should weep equally for the woman dying from the pill as we weep for the woman dying from a criminal abortion. The huge amount of iatrog~nic disease caused by the pill and the numerous medical examinations and laboratory tests required in order to monitor the patient a~gainst the potential inroads of the pill on the woman's health, raises the question whether the medical care system of the United States can carry this burden. Pill complica- tions are making excessive inroads on limited medical personnel and facilities. The cost of medical care in this country is becoming astro- nomical. Is our nation really in a position to absorb the additional costs brought about by a careless and indulgent use of the pill, with- out doing grave injustices to the more important medical needs of our country? If I had the time in preparing the statement, I would have worked out a cost analysis associated with the medical supervision of the pill such as repeat mammography, glucose tolerance tests, repeat physical examinations, and pap smears. It becomes quite an expensive drain on our limited medical resources. Finally, I would like to say in passing as we move on from the topic of introgenic disease that the scientist in the laboratory has never had it so good in his pursuit of metabolic abnormalities. He has had available to him hordes of experimental animals. Women on the pill are readymade and superb guinea pigs: They don't cost any- thing, they clean their own "cages," feed themselves, pay for their own pills and, in many instances, even remunerate the clinical observer. PAGENO="0302" 6742 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY VICTIMS OF SOCIAL ENGINEERS. The American woman, both rich and poor, black and white, is being victimized by social engineers. Population control rather than the health of the individual has become the new directing force of the family planning movement. The Planned Parenthood Federa- tion's name change in the early 1960's to Planned Parenthood-World Population illustrates this. When preoccupation is with control rather than planning, people are viewed numerically as statistics, and concern for the welfare of the individual, the person, diminishes. An effective contraceptive iather than a safe one becomes the prime consideration and the tech- ~nological achievement replaces the humanistic goal. Were the original Puerto Rican studies equally concerned with safety as they were with effectiveness, we would not have had to wait 10 years later for the committee hearing to bring out the dan- gers of the pill. For the first time in the history of conception control, a dangerous contraceptive remains on the market despite its dangers because the birth control movement in this country has become population-con- trol-oriented rather than family-health-oriented. Despite the fact that we knew in advance that a powerful chemical disruptive of normal physiological mechanisms was being introduced. The pill has been the most poorly tested drug ever approved by the FDA. Mr. Durr~. Do von have a citation for that, Doctor? Your last sentence? Dr. RATNER. I think the evidence is clear cut, that since the pill came out and was put on the market in 1960, we have uncovered 50 metabolic disturbances and thromboembolism, and a whole series of diseases caused by the pill. I have a whole page somewhere and I can give you all of the references, but this would require a book of references alone to record for you all of the things that have been discovered since the pill was originally approved as safe. Now, the spirit of the Kefauver-the legislation inspired by the Kefauver bill-intended that before a drug gets on the market it should be proven safe, not afterwards. It has been the reverse with this drug. If this is not self-evident, you just tell me what you think is nec- essary to make this clear to you and I will be happy to go to work. Actually, I believe my booklet, "The Medical Hazards of The Pill," which has about 140 abstracts of the medical literature, is the documentation. The medical hazards are not to be found in the orig- inal studies allegedly demonstrating safety. This is what I a~m saving. I have listed these hazards in the form of abstracts from the scientific literature. They are indexed and represent. the medical haz- ards discovered since the pill was put on the market in 1960. The booklet is the measure of how inadequate the early studies were. Satisfied? Mr. DUFFY. Proceed, please. Dr. RATNER. Although many other drugs have been removed from the market for lesser reasons, we must wonder why the pill has been retained despite the massive accumulation of medical hazards and PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6743 metabolic disturbances reported from clinical medicine and the labo- ratories. It should be distressing to American physicians that although the pill was first discovered, researched, clinically tested, marketed and widely used in the United States, and although the number of women using the pill in the United States far exceeds the number in other countries, and although there were four United States-domi- nated committees appointed to investigate safety, it was not the United States with its much vaunted scientific resources and supe- rior health accomplishments that resolved the vital question of the association of thromboembolism with the pill. It was resolved by England, a medically socialized country whose resources, supposedly, do not compare to ours. Well, we had 6 million on the pill and now 8.5 million. England never had more than 600,000, but they managed to get the studies done. And I would like to suggest to this committee that the reason we never have gotten good figures on the medical hazards of the pill are that the promoters of the pill, including the drug companies, are not interested in having these figures determined and made available. There is no other way of understanding why over a 10-year period *we have not gotten answers to this. And I think it is near hypercrit- ical for somebody to suggest that the Government spend all kinds of money to determine the hazards, not that they should not be done, but because by the time we hand out enough money, by the time the studies are completed, the pills will be off the market and we will have a new pill to contend with. The fact remains that the question of thromboembolism was resolved by England, a medically socialized country whose resources, supposedly, do not compare to ours. Furthermore, although promot- ers of the pill had the earliest and largest clinical experiences with the pill-and this includes Dr. Guttmacher, who in his testimony last week pointed with pride to the fact that he personally, as presi- dent of Planned Parenthood-World Population had "one of the larg- est birth control practices in the world"-they were not the ones who discovered and reported serious adverse findings. Apparently, what was not looked for was not found. What was not surveyed was not seen. What perhaps happened was ignored. With rare exception, the clinical researchers and promoters of the pill ignored the firm warning of Professor Mitchell of Oxford and the British Medical Research Council given at the Searle-AMA 1962 Conference (M.H. p. 63): "the patients who drop out of the trials * * * are much more important than the patients who stay in them." To ignore the patients who dropped out was the radical failure of the highly touted and highly publicized Searle-Planned Parenthood study, released April 2, 1965, of women who had taken the pill for 25 months. They only studied women who had been on the pill 25 months, which meant that any woman who had died before 25 months was not part of the study, nor were the "51 percent" of the women who dropped out the first 12 months because of complica- tions part of the study. This automatically eliminated all of the "bad eggs" and that is why they had such a good propaganda piece. This study lulled the PAGENO="0304" 6744 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY medical profession into a false sense of security in respect to the safety of the pill. I would like to conclude this section by saying that the social engineers-I am not talking now about people helping women not to have babies in birth control clinics-that the social engineers, i.e., the population control experts, in promoting the pill regardless of safety are practicing chemical warfare on the women of this country- Senator DOLE. What page is that on? Dr. RATNER. I just added this. Senator DOLE. That is an indication? Dr. RATNER. That is a conclusion and the young lady has it down. It is a conclusion to the section on iatrogenic disease, which listed over 6 million episodes of illnesses imposed on 8.5 million women. I call this chemical warfare. And I only hope-and this is a word to the Senators-I only hope that since the Federal Government is tying up aid to developing countries so that family planning and birth control programs must be included, that somewhere along the line developing countries like the Asiatic and Latin American countries do not end up accusing the U.S. of practicing chemical warfare against their women. EFFECTIVENESS OF THE PILL I cannot help but remind you here preliminarily, that when Gen- eral Draper said this morning, "The pill is virtually 100 percent effective contraceptive if taken regularly," that frankly everything is 100 percent effective if done regularly, including abstinence. If you practice abstinence regularly you will have 100 percent effectiveness and the trouble with every birth control device, including the pill, is that there are multiple psychological reasons why none of them are practiced regularly. The effectiveness of the pill in the field is lower than the publi- cized claim of virtually 100 percent effectiveness; furthermore, the acceptance rate of the pill over a period of time is in actuality as low or lower than other birth control methods. 1. Drug companies and enthusiasts promoting the pill consistently compare the effectiveness of the pill determined under advantageous circumstances to the effectiveness of other birth control methods measured under unfavorable conditions. When comparing the pill to the diaphragm, for instance, pill promoters use effectiveness rates of diaphragm users obtained from clinic figures which are approxi- mately 18 times higher than rates in women under private gyneco- logic supervision. The latter constitute the majority of diaphragm users. Although Dr. Guttmacher reported last week that "the pill is simple to take, requiring little effort on the part of the user," he neglected to mention what he has complained about on other occa- sions: The inability of the American woman "to count up to 20" and therefore to take the pill as directed. The failure of patients in gen- eral to take drugs as directed is noteworthy and has been thoroughly documented in numerous studies. Forgetfulness occurs even when it involves serious threats to life. PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6745 Forgetfulness in the area of birth control is particularly striking in women and is attributed to their underlying ambivalence about pregnancy. (Incidentally, leaving the pill out in the open so as not to forget it has led to numerous child poisonings.) Senator DOLE. Do we have some evidence on how many cases you know of? Dr. RATNER. Of accidental poisoning, child poisoning, it was the nmnbcr two cause 2 years ago in Missouri, and it has a high inci- dence in the United States. Senator DOLE. From the pill? Dr. RATNER. Yes-child poisoning. Now, remember, the problem is that the woman does not want to forget to take the pill. And there are underlying psychological reasons why she has ambivalence about taking the pill, so she always keeps it where she can see it, which means the child can see it, and so this became the number two cause of child poisoning reported in the Government literature and reported in the newspapers and it came as a cause- Senator DOLE. Not to hold you up, but have there been numerous child poisonings because of the pill? If you will just insert some evi- dence on that, it would be helpful.2 Dr. RATNER. 2. Presently publicized effectiveness rates are derived primarily from the original pills marketed in the early sixties. These pills are four to 10 times stronger than the reduced dosage pills. In the hope of reducing the so-called side-effects (pharmacologically speaking the so-called side effects are equally the effects of the pill as the desired effects), the antiovulatory effect of the pill has been reduced two thirds. Mr. DUFFY. Would you supply that cite? You left it blank. Dr. RATNER. I would be glad to tend to it.~ Obviously, the latter pill cannot be as effective a contraceptive as the former pill with the high antiovulatory effect. The British Committee on Safety of Drugs, in contrast to those promoting the pill in the United States, has alerted British physicians to the decreased effectiveness of the lower dosage pills (M.IH. p. 84). 3. In field use, effectiveness of the pill is sharply reduced because of the high dropout rate associated primarily with undesirable effects and medical complications. Authoritative national surveys (M.H. p. 44) report that one out of five women who were on the pill and went off it state they will! "never use it again." In the age group 30 to 34, one out of 3.6 users state they will never use the pill again. Overall studies show that because of dissatisfactions, approximately 30 percent discontinue the pill by the end of the first year and about 40 percent by the end of 2 years in this country. The notion, there- fore, that the solution to population growth is the pill is fallacious. Medical complications prevent it from achieving high acceptance rates particularly in undeveloped countries. Although Dr. Gutt- macher, in last week's testimony, singled out Singapore as one for- eign country where "the oral contraceptive is used exclusively" by the health ministry, he was in error. With the Singapore example, he apparently was trying to make the point that the pill is necessary for world population control. The fact of the matter is that in Sin- 2 See reference 2 of Bibliography. See reference 3 of Bibliography. 40-471-70-pt. 16-vol. 2-20 PAGENO="0306" 6746 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY gapore the pill only achieved maximum usage of 61 percent among people offered birth control. Thirty-nine percent of the people used other methods offered by the health ministry. Furthermore, in a study "covering a possible maximum of 18 months use" "the percentage of acceptors of oral contraception still using the method" was 55 perc~nt. "Medical reasons contributed the most to the discontinuation rate in each cycle," and 65 percent of the women discontinuing the pill turned to the condom which was "the most popular alternative method of protection." This casts quite a different light on the Singapore situation. (Studies on Family Planning. Singapore: The Use of Oral Contraceptives in the National Program. December 1969. The Popula- tion Council). TIlE PILL AND POPULATION CONTROL The pill was originally introduced and acclaimed as the solution to the world population problem. The subsequent ascendency of the ILTD as the chief method for population control was silent testimony to the fact that the pill did not live up to its expectations. More recently, we have witnessed the Agency for International Develop- ment shipping condoms to India, and the Ford Foundation granting over one half million dollars to a gynecologist at Mount Sinai Hos- pital, New York, to perfect the much ridiculed rhythm method. The fact is that in no nation of the world, including the United States, has it been demonstrated, that national birth rates have been reduced by virtue of the unique or indispensable properties of the pill as a contraceptive. Some of the reasons for its failure have been suggested above. Actually, when women and couples are serious about controlling conception, they will make any one of a variety of traditional methods work. This was demonstrated in the depression years of the thirties at which time the United States had the lowest birth rate in its history, a birth rate only matched this past year. The low rate of the thirties occurred 30 years before the new dan- gerous contraceptives were introduced. Again it should be remem- bered that the post-war decline in birth rates started in the United States in 1957, 3 years before the pill was approved by the FDA and another 4 years before the pill became popular. So there is no evidence anywhere on a national basis to attribute to the pill a unique contribution to the reduction of birth rates. UNWANTED PREGNANCIES In Dr. Guttmacher's testimony of last week he stated that "The pill is the most effective means yet known to prevent a very serious affliction, unwanted pregnancy." The concept of unwanted pregnancy is one of the most confused, misused concepts ever to enter the vocabulary of the social engineers. To be very candid, let me first state that according to all of the large scale studies made about wanted and unwanted pregnancies in the United States the evidence clearly indicates that most Ameri- cans, and that includes the majority of us in this chamber, are the result of unwanted pregnancies at the time of conception. And I had two references, standard references for you. I won't bother reading them to you.4 ~ See reference 4 of Bibliography. PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6747 Mr. DUFFY. Would that suggest, Doctor, there was contraceptive failure? Dr. RATNER. No, the way they are using the term now is to say, and I am quoting from Dr. Guttmacher-unwaflted pregnancy at the tinie of conception, he reported, 40 percent of the babies are the result of unwanted pregnancies at the time of conception. This was given at the last annual meeting of the planned parenthood in New York. Now, this means that if 2 weeks after the woman becomes pregnant she is happy about it, it is still listed as an unwanted pregnancy. And when this term was originally introduced to mean excessive fertility, it included unwanted pregnancies, even if only one of the partners did not want it. Now, to make this point clear, evolution has been also deeply con- cerned about this problem otherwise we might not have made it here. There are mechanisms in the baby to convert it from being unwanted to wanted. Prior to quickening-the silent period fre- quently associated with nausea and fatigue-a woman may be recep- tive to the idea of an abortion. But once the baby starts kicking suf- ficiently to produce the sensation of quickening the woman's attitude changes. The woman now knows she has a baby inside and her attitude to an abortion radically changes. When the baby first smiles at the end of the first 6 weeks-the smile is actually an atypical facial reflex to colic-from an evolutionary point of view, the smile contributes to the conversion of an unwanted baby into a wanted baby. Evolution has worked out a whole series of events in the baby's life which helps to make him wanted. To be wanted is the most imperative need in this little defenseless human being's life. An authoritative study on unwanted conceptions conducted under the auspices of the Social Science Committee of the Planned Parent- hood Federation of America was published in "Eugenics Quarterly" in 1967 (47 :143-154) under the title, "Unwanted Conceptions: Research on Undesirable Consequences." After an exhaustive study of the literature its author, Professor Edward Pohiman, concluded as follows: There is a contention that unwanted conceptions tend to have undesirable effects. This article has implied some channels whereby such a causal relation- ship is almost completely lacking, except for a few fragments of retrospective evidence . . . at a common-sense level one may feel fairly confident that induced abortions, out-of-wedlock conceptions, and illegitimate births are the results of unwanted conception and produce undesirable effects. But these com- mon-sense observatioliS are available from the armchair. It was the hope of this article to find more convincing systematic research evidence and to give some idea of the amount of relationship between unwanted conception and undesirable effects. This hope has been disappointed . . . the present writer attended a conference at (a) Population Crisis Committee. The writer and others found it somewhat embarrassing to have to confess that there was little clear evidence that unwanted conceptions were in a worse light than other conceptions. So I want to emphasize to this committee that when people assume and imply all of the dire consequences to the unwanted child ~there is little scientific research or data to back this up. PAGENO="0308" 6748 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. Blau also points this out in an article on unwanted children appearing in a population crisis book. He made it clear that "a pregnancy may be unwanted and yet good affectional attitudes may develop after the birth under the influence of the child. Or the reverse may happen-the pregnancy is wanted, and then the baby for one reason or another is rejected."5 There is no evidence to support Dr. Gut.tmacher's contention that unwanted conceptions result in abused or battered children. I have had a lot of experience with battered children since I investigate them in my community. Try to take a battered child away from his mother. It is difficult. She has a certain complex personal relation- ship with that child which she wants to retain. There is no evidence to show that the battered child could have been predicted in advance and prevented by an abortion. It seems to me that we are in a treacherous period in our coun- try's history. People today are bracketed with pesticides as environ- mental pollutants. People in prominent places prefer to limit num- bers of children rather than numbers of automobiles which are a direct cause of air pollution. If a recent governmental figure really wanted to act on air pollution, he would not say "let us limit fami- lies to two children." He would say "let us limit families to one automobile." Reducing automobile traffic by half would immediately reduce air pollution by half. Paul Ehrlich is proclaiming to our nation that the United States would be better off with 100 million less people. It is natural to wonder who they should be. We also have with us the slogan of the unwanted child. I think it should interest you, Senators, that at the world population meeting in Bel- grade about 3 years ago, our American representative, Mr. Lorimer, made the same point: "We have 200 million people now, we will have 300 milhioii by 1980. Wouldn't we be better off with 100 million people less." The Russian delegate's response was, "What is the matter with you Americans, don't you like people?" Here I would like to suggest that the road to social maturity is wanting the unwanted human being and that the road to responsible parenthood is not technology but the inculcation of responsible atti- tudes. As Professor Westhoff pointed out in population: "The Vital Revolution" (Aicline Press)-a.ncl General Draper supports this-for "family planning effectiveness * * * the problem of motivation rather than only information about (birth control)methods appears vital." PANIC AND THE PILL The charge of "panic promotion" has been leveled against these hearings. Such charges should not distract you from the responsibil- ity you have undertaken, the protection of the health of American women. These charges appear to be but one more name calling tech- nique designed to protect and preserve the salvation aura of the pill. There is no evidence to support these charges. Women who have dropped the pill as a result of these hearings are, in all probability, women who were never told of the dangers of this pill prior to going on the pill. See reference 5 of Bibliography. PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6749 Despite Dr. Guttmacher's testimony last week that the majority of physicians acquaint their patients with the complications of the pill, this is not true. The Newsweek-Gallup poll, February 9, 1970, a source which Dr. Guttmacher used to illustrate the "great alarm" caused by these hearings, reported that a "startling two-thirds of pill-taking women say they have never been told about possible haz- ards by their physicians." It is on this basis that Newsweek states that the "subcommittee's concern was well founded, that women were inadequately informed." It is my experience as a public health physician that this is the case. The literature contains many accounts of pill pushing and 6-month prescriptions in both Government and private birth control programs.6 The pill is probably the most casually refilled prescrip- tion ever written. Numerous women are taking the pill who are no longer under medical supervision. And I can show you letters and give you names to support this, because I have been on radio and television, frequently, on the medi- cal hazards of the pill and this is what you constantly hear from women in response, for example that some doctor in Seattle will refill a prescription over the phone for a patient who has moved to San Francisco and the woman never sees a physician again until she develops a complication. The real panic makers are those supporters of the pill who are trying to make the pill appear safe by exaggerating the dangers of pregnancy. They are contributing to panic in three ways: 1. By frightening women about the alleged ineffectiveness of methods of birth control other than the pill. 2. By threatening instant pregnancy for those going off the pill. 3. By portraying pregnancy as a pathologic state with a high incidence of deaths. Such dramatization, I assure you, is no comfort to millions of women in the United States presently pregnant or considering pregnancy. Mr. GoRDoN. How many wOmen died from pregnancy in any given year? Dr. IRATNER. I will have to give you a little- Mr. GORDON. If you do not have the figures, would you please send it to us? Dr. RATNER. Yes, I just have to give you a little background, because I think this is very important. Even the English point out that without the pill-over the last 30 years, this applies to the United States as well-the average number of children the family has is between two and three children. Let us call it three children. That means over a reproductive period of 30 years, they are only having on the average one child every 10 years. Therefore, when you talk about death from the pill, three per hundred thousand, and contrast it to the higher overall death rate from pregnancy per year it is not as if the woman is exposed to the risk of having a baby every year as she is to the pill every year. She just is not having a baby yearly and has not from time immemorial and has had only three to four babies totally on the average since certainly the early part of the century. So there is misunderstand- ° See reference 6 of Bibliography. PAGENO="0310" 6750 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ing here that the average woman is essentially so highly fertile that she has a baby yearly. Mr. GORDON. Could you give us the figure? I would very much like to have it. Dr. RATNER. Okay, I would be happy to. To answer the question of risk of pregnancy by simply giving the gross overall maternal mortality rate only deceives, since the mater- nal mortality rate varies with the characteristics of the women under consideration. Thus, a woman who is white, young, free of serious disease, of low parity, of upper socioeconomic status, undergoing a well-conducted pregnancy has a radically lower mater- nal risk than a woman who is nonwhite, older, seriously diseased, of high parity, of low socioeconomic status and undergoing a poorly conducted pregnancy. The latter rate is radically higher. The relevant scientific question to be answered is as follows: What is the potential maternal mortality rate-the lethal risk of preg- nancy-of women on the pill were they not. using the pill, nor practic- ing birth control of any kind. and were active sexually. To help you understand how one arrives at a scientifically valid answer to such a question I will assume a resulting pregnancy and will proceed step by step in arriving at the estimate. 1. 28.0 maternal deaths per 1.000.000 live births represent the total maternal death rate for all women in the United States. (The data is from the official Vital Statistics of the United States for 1967.) (a) 19.5 is the rate for white women; (b) 69.5 is the rate for nonwhite women. Since nonwhites only constitute approximately 10 percent of the population and since a considerably smaller percent of nonwhite women use the pill than white women. we will assume the rate for white women of. 2. 19.5 maternal deaths per 100~000 live births. According to Ryder and Westhoff (Use of Oral Contraception in the United States. 1965. Science. 153: 199-1204, Sept. 9. 1966) the largest. category of women (married) using the pill are in the age bracket of 20-24. These women according to official Vital Statistics for 1967 have, 3. 11.0 maternal deaths per 100,000 live births. The reproductive risk. however, varies considerably for individual women within this group. See "Assessment of Reproductive Risk in Nonpregnant. Women." A guide to establishing priorities for contra- ceptive care. Gordon W. Perkins. M.D.. formerly medical director of Planned Parenthood-World Population and now of the Ford Foun- dat.ion. Am. J. Obst. &. Gynec. 101: 709-717. July 1, 1968. The author p~nts out. that "maternal risk increases with . . . increasing maternal age above 30": "with each pregnancy beyond three"; with the "presence of specific disease entities which . . . includes the fol- lowing: cancer, cardiovascular renal disease. collagen diseases~ diabe- t.es, epilepsy. psychoses, repeated toxemias of pregnancy and severe anenuia" and with "the poor." Furthermore. maternal mortality is significantly increased by a poorly conducted pregnancy. Since the greatest users of the pill are to be found in the upper classes, since the great majority of them are free from the serious diseases enu- PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6751 merated above, since the bulk of them have available to them compe- tent medical supervision-the bulk of prescriptions written for the pill are prescribed by physicians capable of a well-conducted preg- nancy-maternity mortality is radically reduced in this group. We estimate a 95 percent reduction of maternal mortality in this group. This results in, 4. 0.6 maternal deaths per 100,000 live births. Two further considerations are in order: (a) Many of the women using the pill in this age bracket are taking the pill for' the sake of postponing the first birth. Let us assume this applies to 50 percent of the women. Ten percent of' these women will subsequently discover they are sterile, and accordingly will not undergo the risk of becoming pregnant were they not to take the pill. This results in, 5. 0.57 maternal deaths per 100,000 live births. (b) Finally, it should not be forgotten that since the pill in large part in this age group is being employed to postpone having babies, not to eliminate them, the risk of pregnancy is~ irrelevant since this is the price tag that comes with the joy of having a baby when they do become pregnant. It should be apparent, in conclusion, that the risk of death from pregnancy for the large number of pill users described above is less than the risk from the pill. Furthermore, and this cannot be overem- phasized, the risk of pregnancy is even more sharply reduced by using alternative safe methods of contraception even though alleg- edly less effective. Again one can achieve the effectiveness of the pill without the risk of the pill or of pregnancy by a combination of contraceptives, for example, the condom, diaphragm, jelly, and/or rhythm. To substantiate in a general way that the above calculations corre- spond to reality I have analyzed the actual maternal mortality figures of the Oak Park and West Suburban Hospitals both of which are under my jurisdiction as the Oak Park Public Health Director. The data is from the official "Annual Summary of Hospi- tal Maternal Services" of the Illinois Department of Public Health. The clientele of these hospitals are predominantly middle class and white, and with rare exception have well-conducted pregnancies. They include women of all reproductive ages, of varying parity- numbers of children-and with the usual spectrum of serious dis- eases. The last 5 years for which figures are available-4964-68---show a total of 16,863 deliveries for both hospitals. According to the over- all maternal mortality rate for white women given above for 1967, namely 19.5 the expected number of deaths would be over three. Actually, none occurred. This is confirmatory, in general, of the slight risk to pregnancy to be found among the majority woman users of the pill were they to become pregnant were the pill discon- tinued. I trust this gives the committee a better picture of the reality than that obtained from overall maternal mortality rates which do not correspond to this large segment of pill users. PAGENO="0312" 6752 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY The fact is that today the United States is one of the safest coun- tries in the world in which to have a baby for the vast majority of women. Pill promoters are doing American women a disservice by not differentiating the small handful of women who are at high risk from the great majority of women who are at negligible risk. If they did distinguish, and here I include the failure of the Chairman of the FDA Committee on Obstetrics and Gynecology to make such a distinction in his "Summary of the Second Report, 1969," they would of necessity conclude that for approximately 85 percent of the women on the pill at the time the hearings began, that is, 71/4 of 81/2 million women on the pill, the risk to health from pregnancy is negligible, whereas the risk from the pill is real. It is for this reason that I agree with the position of Dr. Philip Corfman of the FDA Committee-a position which did not find its way into the Chairman's summary report either because it was sup- pressed or ignored-that the pill's "use should be monitored and restricted to women who cannot use other methods effectively." ~ And I do hope the committee will see that Dr. Corfman's sup- pressed or ignored conclusions, because apparently he was not con- sulted in the Chairman's summary, gets publicity. Mr. DnFFY. Did he sign the report, Dr. Ratner? Dr. RATNER. No, the Chairman's summary was written by the Chairman; by nobody else. He signed his own section. Mr. DuFFY. Dr. Hertz did not agree, by the way, he is the new cheirrnan of the committee. Dr. RATNER. You have a reference to support my statement in M.H. pages 3-48. Dr. Guttmacher was again in error in his testi- mony when he attributed the conclusion of the Chairman's summary to the 14 eminent unbiased physicians, public health experts, and highly qualified research scientists. The evidence is that not all the committee members concurred in Dr. Hellman's conclusion (Medical World News, Sept. 19, 1965, p. 5). Now, Mr. Duffy, I would like to point out one thing, perhaps in answer to what you just said. In 1966, when the first report came out with Hellman as chairman, that summary was written by the whole committee. I think somebody should find out why in 1969 the position was switched so that he alone wrote the summary, because it does not seem coincidental that a drug firm immediately had the summary circularized all over the United States. We do not yet live in Orwell's society, although some of our col- leagues in both medicine and Government do not wish to admit this. For Dr. Guttmacher to say, in effect, that the hearings have pro- duced nothing new in regard to risks, that those who are well-in- formed have known these things all along, that they-the well-informed-have balanced the hazards against the values and decided as groups of experts what is best for the less well-informed, the misinformed, and the uninformed is an affront to the principles of good medicine, as well as the foundations of the form of govern- ment under which we live and which you have been elected to uphold. ~ See reference 7 of Bibliography. PAGENO="0313" COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY 6753 I am saying, simply, it is not part of our medical tradition for doctors to make decisions for people without getting informed con- sent. Who is so well-informed, so highly qualified, so distinguished an expert as to decide for someone else what values outweigh the haz- ards of preventable injury, illness, and death? ALLEGED ABORTION OUTBREAK RESULTING FROM THE HEARINGS The alleged unwanted pregnancy-abortion outbreak resulting from adverse pill publicity generated by the committee hearings is a charge that insults the intelligence of the educated person. The charge was first made in Newsweek (2/9) and repeated in a round- up story in the New York Times (2/15) of several Planned Parent- hood physicians and others. In a later New York Times story (2/25) Dr. Elizabeth Conneli was alleged to have stated in Washington that, "New York doctors were performing operations on women who have had undesired pregnancies since the subcommittee hearings started six weeks ago." Two comments are in order: (a) Any woman who, by virtue of discontinuing the pill on Janu- ary 15 when the hearings started, had an abortion because of a sub- sequent pregnancy was operated on by a quack. Senator DOLE. In other words, you are saying it is not possible, then? Dr. RATNER. That is right. No physician could have known this early with requisite certitude that the woman on whom he performed an abortion was actually pregnant. Furthermore, the woman couldn't have known she was pregnant. Mr. DUFFY. You are quite certain about this? Dr. RATNER. I am saying this publicly for the record. Let me make that clear to you. Mr. DUFFY. There is no way you could be wrong? Dr. RATNER. That the earliest possible time you can tell a woman is pregnant, a woman normally suspects she is pregnant when she misses a period 2 weeks after ovulation, and the earliest possible time you can have a test which can determine a pregnancy is 2 weeks later. So you already have 28 days there, so you have to assume it would be possible for the woman to become pregnant 2 hours after she discontinued the pill, which is highly improbable. Mr. DUFFY. Doctor, would you just answer that question. Is there absolutely no way you could be wrong on these particular statements that you are making? Dr. RATNER. Well, now, I am not infallible. I decide on the basis of my medical knowledge. I would not be making such a statement without having medical knowledge backing it up. And I would assume that every obstetrician would agree with me. Now, Dr. Alcock8 was called up by one of my doctor friends. He first said he knew of three abortions-and I think you should look 8 See reference 8 of Bibliography. PAGENO="0314" 6754 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY into this-however, one. a woman was never on the pill but was using a foam contraceptive when she got pregnant and her abortion had nothing to do with the hearings. He was vague about the other abortions. So I think doctors can talk loosely, to New York report- ers, and I do not think we should use the New York Times as an authority for the fact pregnancies and abortions have taken place as the result of these pill hearings because it is virtually impossible, because they only started January 15. General Draper had enough sense to realize that if they occurred it was not. because of the hearings, but because of earlier reports of pill dangers. The need to stimulate propaganda. and I mean this literally-I was a bit shocked when a person who is doing graduate work at Hopkins, who was executive director for a population council, uses as her authority not the original article in Newsweek but a news reporter's version of the Newsweek poll in the New York Times instead. I do not think we should be making charges on the ba.sis of secondhand information. The need to stimulate this type of story by pill supporters should alert. all readers to the characteristic t.ype of propaganda that has been used to promote the pill since its int.roduction. (b) That women become pregnant as a result of being panicked off the pill goes counter t.o the claim of Planned Parenthood person- nel and others that. the physician sees to it. that the client "is knowl- edgeable about the methods, each sharing equal time with the others, the mechanical with the hormonal." This is what Dr. Mary Lane of P1 anned Parenthood-World Population testified to on February 25 before your committee. Furthermore, patients who are capable of pa.nicking off the pill as a result of adverse publicity were obviously not prescribed the birth control method best suited and most acceptable to them. CONCLUSION In bringing my statement to a close, I respectfully suggest that each member of the Subcommittee read Judith Blake's criticism of the social engineers in Science, May 2, 1969. Professor Blake is chairman of the Department of Demography, University of Califor- nia, Berkeley. Her paper is entitled "Population Policy for Amen- cans: Is the Government Being Misled?" And I will quote from her writing-"but llntil now this has not been made clear." Senat.or DOLE. Could you just submit that for the record, we are running out of time. Dr. RATNER. I am at the conclusion, so I will be through shortly, but I think you really want to hear these three sentences. "The Government has been sold a risky program as part of a pop- ulation control package" (namely, that 5 million poor women want birth control. She says it is much less than 2 million.) "This pro- gram * * * invites charges of genocide, dissemination of dangerous drugs, and subversion of moral standards. Ironically, it now appears for the purpose of health and a dubious welfare goal." ~ See reference 9 of Bibliography. PAGENO="0315" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6755 She challenges the claim of Planned Parenthood and others, "that the Government should give highest priority to ghetto-oriented f am- ily-planning programs 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." 10 This latter figure that 5 milliOn indigent people want birth control but can't obtain it is one of the most unscientific estimates ever foisted on the American people~ It becomes the excuse by which the pill is exploited among the indigent. The pill is actually a rich man's contraceptive since it needs so much medical followup and Teady access to a doctor. Life for the poor is miserable enough with- out adding to it the miserable and depressing complications associ- ated with the pill. I have spoken as a public health physician who is deeply con- ~cerned about the current trend: in this country to manipulate, rather than enlighten, people. Mass prescription and misleading slogans are no substitute for honest health education. I am concerned that mon- eyed interests play such an influential role in the whole spectrum of mass education. This is an era of consumer protection. The woman has a right to protection from manipulation and victimization. No right is more firmly established than the right of each patient to informed consent to a prescription directed at her body. Knowledge sufficient for `enlightened consent is a moral, medical, and legal right to which malpractice suits testify. The classic statement of this right is found in Plato's Laws where Plato distinguishes between the physician who took care of slaves, and the one who took care of freemen. Whereas, the slave doctor prescribed "as if he had exact knowl- edge" and gave orders "like a tyrant," the doctor of freemen went "into discourse with the patient and friends" and would not "pre- scribe for him until he has first convinced him." I, therefore, congratulate the committee for treating the American woman as a free person rather than a slave. Senator DOLE. First, I would like to insert in the record an excerpt of a letter which appears written by you and answered by Mr. Ryder and Mr. Westoff, in the February 24, 1967, issue of Sci- ence. Dr. RATNER. Yes. What about it? Senator DOLE. I am going to put it in the record. Dr. RATNER. Thank you very much. Senator DOLE. You read it; in fact, you wrote it. Dr. RATNER. I was modest about putting it in. Thank you very much. (The document above-referred to, follows:) [From Science 155, 051, Feb. 24, 1067] LETTERS-ORAL CONTRACEPTION DROPOUT RATE Because the Ryder-Westoff study of oral contraception usage ("Use of oral ~contraception in the United States, 1965," 9 Sept., p. 1199) is so widely quoted as an index of extensive pill acceptance, the following datum from their report 10 See reference 10 of Bibliography. PAGENO="0316" 6756 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -which for some reason is not commented on despite considerable interpreta- tion of other data-deserves emphasis. One out of five women who have ever used the pill stated that they "will not use [it] again." The ratio runs as high as one out of 3.6 users in the age group of 30 to 34. This is a strikingly high rejection rate for a drug. There is none that I know of which is comparable. It supports the contention of many that the untoward effects of this drug are extensive and that there is gross underre- porting of these effects to surveillance agencies. The dropout is also consonant with the continuing reporting of the dangers of the drug in the medical litera- ture, and the concern expressed in the Heliman report to the Food and Drug Administration.1 The fact that this contraceptive is the most desirable to women psychologi- cally (because it dissociates itself in time and place from coitus) and that its use is initiated in a state of health heightens the significance of this finding. HERBERT RATNER, Department of Public Health, Bos~ 31, Oak Park, Illinois 60303. We did not comment on the admittedly high proportion of women who have used the pill but who have stopped using, and report that they will not use it again, because this measure is totally inadequate as an index of the dropout rate, not to mention the "untoward effects of this drug." The reasons for its inadequacy are: 1) The ratio calculated by Ratner does not take into account the length of time the pill was used; it includes women who have used it for less than a month as well as those who have used it for 5 years. The implications of ter- mination obviously differ by length of use. 2) Our analysis of the use of the pill included women who used it for rea- sons other than contraception. Some of these women have now stopped using it bec~nise it had satisfied (or had proven ineffective in satisfying) the original medical complaint-such as menstrual discomfort. 3) Some women who had used the pill stopped because they no longer needed it; their contraceptive needs vanished with the onset of menopause or sterility. 4) A small group of women used the pill in order to promote fertility, and accomplished this purpose. 5) Some women stopped using the pill because of problems unassociated with side effects-such as questions of morality, or cost, or difficulties in remembering to take the pill. 6) Some women reported stopping because of "doctor's orders." Although part of this may be atributable to the occurrence of undesirable symptoms, it is likely that much of the category represents the doctor's precaution without specific indications. The remaining women who do not intend to resume can be classified as interrupting use because of reported undesirable reactions. Admittedly they constitute a majority of the total group referred to by Ratner, but it is evi- dent that the symptoms they reported cover a wide range from real to imagi- nary, and from significant to trivial. We are currently in process of trying to estimate the dropout rate over time by type of reason, in order to achieve refined estimates appropriate to the question Ratner has raised. NORMAN B. RYDER, Department of Sociology, University of Wisconsin, Madison 53706. CHARLES F. WE5TOFF, Department of Sociology, Princeton UniversIty, Princeton, New Jersey. Dr. RATNER. Since von are putting that in. it should be made clear that I quoted from their work which took cognizance of what I said 1 `Food and Drug Administration Report on Oral Contraceptives" by the Advisory Committee on Obstetrics and Gynecology. FDA. 1 August 1966. Available from the U.S. Government Printing Office, Washington, D.C. 20402. PAGENO="0317" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6757 2 years later and which, in effect, agreed with my February 24, 1967, communication. My statement stimulated them to do what they did and it was from this latter work that I quoted the figures.1' Senator DOLE. It is a very interesting statement. We appreciate it. Dr. RATNER. Thank you very much. (The supplemental information submitted by Dr. Ratner fol- lows:) BIBLIOGRAPHY 1. Charles F. Westhoff, Ph. D & Norman B. Ryder, Ph. D. Duration of Use of Oral Contraceptives in the United States, 1960-65. Public Health Reports. 83: 277-287, April 1968. 2. a. "Birth control pills are secondary to aspirin as the cause of accidental poisoning among children treated at St. Louis Children's Hospital. . ." New York Times. March 19, 1906. b. "Contraceptive pills have become'a major . . . source of childhood poison- ing, the Public Health Service Reports. There were 962 reported childhood poi- sonings due to the pill during 1962 to 1965, according to Mr. Henry L. Ver- huist, chief of the Poison Control Branch of the P.H.S." Modern Medicine, May 9, 1966. p. 28. c. Oral contraceptives are listed among "Products Most Frequently Ingested in 1968." National Clearinghouse for Poison Control Centers Bulletin. Nov.-Dec. 1909. 3. Appendix 1. Report of the Task Force on Utilization, Effectiveness and Current Investigations. S. J. Segal, Ph. D., Chairman. Report on the Oral Con- traceptives. Advisory Committee on Obstetrics and Gynecology. Food and Drug Administration, August 1, 1966. 4. a. Family Planning, Sterility and Population Growth. R. Freedman, P. K. Wheipton & A. A. Campbell. New York 1959. b. The Third Child. C. F. Westoff, R. G. Potter & P. C. Sagi. Princeton, 1963. 5. The Population Crisis and the Use of World Resources. Ed. Stuart Mudd. In the chapter, The Unwanted Child, by Dr. Abram Blau. 6. Oral Contraceptives: Government Supported Programs are Questioned. Science. 163 :553-555, Feb. 7, 1969. 7. Metabolic Effects of Oral Contraceptives. Philip A. Corfman, M.D. J. Med. Education. Part 2, 44:67, Nov. 1969 (M.H. pp. 3-4). 8. Unwanted Pregnancies Follow Adverse Publicity on Birth Pills. Jane E. Brody. New York Times. Feb. 15, 1970. 9. Family Planning & Public Policy: Who is Misleading Whom. Judith Blake. Science, Sept. 19, 1969 pp. 1203-4. 10. Population Policy for Americans. Is the Government Being Misled? Popu- lation limitation by means of federally aided birth-control programs for the poor is questioned. Judith Blake. Science 164 :522-529, May 2, 1969. Curriculum Vitae of HERBERT RATNER, M.D. UNIVERSITY EDUCATION Undergraduate: B.A. University of Michigan, Feb. 1929. Graduate: Bacteriology: 1929-1930 Ibid. Public Health: 1934-1935 Ibid. Professional: M.D., 1935 Ibid. PRESENTLY Public Health Director of Oak Park, Ill. 1949- - Associate Clinical Professor of Family and Community Medicine 1947- - Stritch School of Medicine, Hines, Ill. Editor of CHILD AND FAMILY QUARTERLY 1967- - Secretary Treasurer, National Commission on Human Life, Reproduction and Rhythm. 1964- - Medical Advisory Board La Leche International. 1957- 11 5ee reference i of Bibliography. PAGENO="0318" 6758 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Scientific Consultant, Human Life Foundation 1970- Chairman of the Maternal And Child Committee Illinois Association of Med- ical Health Officers 1960- Registrar of Vital Statistics, Oak Park Health Department 1949- - Board of Directors of The American Council for Medical and Social Legisla- tion 1970- - Fellow of the American Public Health Association. 1947- - FORMERLY Instructor in the Department of Bacteriology and Hygiene at the University of Michigan Medical School 1929-1931. Research Assistant to the Pasteur Institute, University of Michigan 1929-1931. Research Assistant in Hematology, Mt. Sinai Hospital, N.Y. 1933. Research Assistant in the Division of Experimental Medicine and Nutrition in the Department of Internal Medicine of the University of Michigan 1934-1936. Senior Member in Science on the Committee of the Liberal Arts, University of Chicago 1937-1940. 1~Iedical Consultant to the Syntopicon, Encyclopedia Brittanica 1945-1947. Editor of the Bulletin of the American Association of Public Health Physi- cians 1954-1956. MEMBER American Association of University Professors. American Medical Association American Public Health Association And additional associations. Senator DOLE. The next witness is Dr. Peterson. Dr. Peterson, you can either summarize your statement any way you wish, or you can read it in full. It' will be made a part of the record. the complete statement. You may proceed in any way you wish. STATEMENT OP DR. WILLIAM P. PETERSON, CHAIRMAN, DEPART- MENT OF OBSTETRICS AND GYNECOLOGY, WASHINGTON HOS- PITAL CENTER, WASHINGTON, D.C. Dr. PETERSON. Thank you, Mr. Chairman and members of the subcommittee. I am Dr. William F. Peterson, a Clinical Board certified obstetri- cian and gynecologist, with over 23 years of active practice as a member of U.S. Air Force. In this capacity, I have consistently been directly responsible for large numbers of Air Force dependents. Most recently, as chairman of the Department of Obstetrics and Gynecology at. Malcolm Grow IJSAF Medical Center at. Andrews here in Maryland. Over 1,500 deliveries per year in excess of 33,000 outpatients visits yearly, have been mv direct, area of concern and responsibility. Since my recent. retirement from the U.S. Air Force, I have been appointed chairman of the Department. of Obstetrics and Gynecol- ogv at the Washington Hospital Center here in the District of Co- lumbia. I am here today to testify in behalf of the American woman. The problems and responsibilities of reproduction are of necessity being brought from the bedroom to the national scene; but rather than gaining clarity and purpose are becoming more complex and confuisecl. PAGENO="0319" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 6759 The population explosion sincerely troubles learned heads and far- sighted leaders have advocated numerous measures to control the sit- uation-even to altering portions of the tax structure. Worry is evinced as to how to house and feed future generations. Educational facilities are even now bursting at the seams and standards continue to fall in spite of the most intensive efforts. Scarcely a magazine or newspaper can be found wherein this subject has not been discussed- some portraying a rather dismal future for our children-and their children. Abortion has become a burning issue throughout the country and while a few enlightened States have changed their laws, and thus met the problem head-on-instead of losing themselves in theoretical and theological labyrinths, most have not. Even in those permitting termination of pregnancy there is considerable difference of opinion not only from one area to another but from one hospital to another within the same city. We do not have to look further than our own city of WTashington for an all too clear example of this problem. These discussions, studies, and investigations have begun to crys- tallize the problem all too well-but, gentlemen, I fear, at an increasing and unnecessary cost to our women. The past decade or two while bringing improved social and cul- tural liberties to the American woman has in addition brought the light of sexual emancipation-and long overdue it has been. Orgasm is now a polite word and a heritage she has the right to expect. Her physical and emotional needs have been unveiled in order that man can recognize his woman as a sexual partner rather than a recipient. While these changes have brought the opportunity for a bright new horizon to the American woman, they still have not exonerated her from the basic responsibility for pregnancy. No matter what changes may yet occur-the male will still not be able to get preg- nant-and right or wrong, its prevention is generally left to the woman-too often at the last and the most inopportune moment. The male too frequently expects his partner to provide complete contraceptive protection, as long as it does not interfere with his enjoyment or her availability. The introduction of the pill about a decade ago has done much to bring the sexual emancipation of women to fuller fruition. Last minute, hurried, and often unromantic preparations are no longer required and she has been freed to experience the pleasure of sex on the highest emotional plane-content and relaxed in the knowledge that she is completely protected against an unplanned pregnancy. This approach to simple and effective family planning measures has been so successful that millions of American women have requested and have been given this protection. As a recent member of the U.S. Air Force and a senior obstetrician/gynecologist, I was deeply involved in the institution of family planning clinics in the Armed Forces following the DOD directives of late 1967. Senator DOLE. Could you go into detail. I am not familiar with the DOD directive of late 1967. Dr. PETERSON. This was an instance wherein Mr. McNarnara and the Department of Defense authorized the Institution of Family Planning Clinics throughout the Armed Forces in the dispensing of not only the oral contraceptive, but mechanical contraceptive meas- PAGENO="0320" 6760 COMPETITIVE PROBLEMS IN TI~ DRUG INDUSTRY ures through military hospital pharmacies, which had not been pos- sible prior to that time. We were not allowed to dispense any form of contraceptive meas- ures through the pharmacies to any dependents, even though they were authorized that type of care. Senator DOLE. Thank you. Dr. PETERSON. Currently an estimated 258,000 Air Force depend- ents take the pill-by and large most of whom are using it for con- traceptive measures. Each patient is given an appropriate supply of medication after undergoing a breast and pelvic examination, including a Pal) smear. I might add for the record, in response to Dr. Ratner's commen- tary about 6 months' supplies, the Armed Services only gives out 3 months' supply of oral contraceptives at a time. Further supplies are dispensed at appropriate intervals, again only after an examination, as determined by the patiei~t's age and her clinical course. I might also inject further for the record that if the patient is under 30, she is examined yearly; if she is 30 to 35, she is examined every 9 1floflthS; and if she is 35 and over, she is examined every 6 months. In spite of this intensive program-341,644 such visits were reported by the Air Force in 1969-a recent study at the Malcolm C-row USAF Medical Center showed that over 50 percent of the babies delivered over the study period were unplanned. These find- ings are similar to those reported by Ryder and Westoff-Fertility Planning Status: United States 1965 Demography 6 :#4, Nov 1969- on a sample of 4,810 married women who were respondents in the 1965 national Fertility Study. These are dismal statistics if we are truly concerned about the population explosion and its effect on the welfare of future genera- tions. Yet in spite of this most serious situation the American woman, faced with the responsibility of proper family planning, has been consistently exposed to articles in magazines and the national press describing myriads of so-called dangers inherent in the use of the pill-the most effective contraceptive currently available on a national level. They have been led to believe that they will either die of blood clots or if they live will develop diabetes, liver damage, cancer or migraine headaches, and if they survive these perils, may give birth to defective babies-or if avoiding this are placed in an excellent position to become promiscuous or have other psychological prob- lems. The doctors faced with the tasks of supporting these patients find an increasing amount of their energies occupied by repititious reas- surances, thus losing precious time needed for proper followup care* or the management of other problems. The recent hearings conducted by this committee, rather than bringing forth a more enlightened atmosphere, 1~ave precipitated a state of confusion and chaos among a large segment of our popula- tion. Women have been scared so successfully that an estimated 20-odd percent have summarily stopped the pill-many without con- sulting their physician for his opinion-or even advice regarding other means of contraception. PAGENO="0321" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6761 The number of unplanned, unwanted pregnancies resulting from this situation awaits further study-the number of deaths from ille- gal abortion or complications of the pregnancy frightens the imagi- nation. The only group that appears to have benefited is the tele- phone company-if the number of frantic long-distance phone calls I have personally received is an accurate indication. As a clinical gynecologist, meeting the needs of the female on an everyday basis, I am deeply concerned over the position in which our women are being placed. It is now time for someone to stand in their behalf and raise a real sense of concern for their interests and needs-physical and, above all, emotional. Much has been said against the pill-yet little factual information is currently available, and less that has been presented in simple everyday language, upon which each woman or family can base an intelligent decision within their own personal and individual needs. Information has come from England on the incidence of tlirom*- boembolic disease, received wide national attention, and caused seri- ous concern in many quarters because of the death rates reported. Yet it has been based on studies that have been by and large retrospective in nature, and composed of a different patient popula- tion than exists in the United States. Until more accurate prospective data has been collected on a proper scale, in our own country, the exact relationship between the pill and thromboembolic disease will remain exactly what it is not -an impression-and one that may be hazier than suspected. It is not proper to hide factual data nor falsify current findings or impressions from the national eye-nor is it proper on the other side of the coin to magnify incomplete informatiOn into undeserved promiI~ence. Until such time as medical science can accurately diagnose pulmo- nary embolism in all instances-and it cannot do so at this time-it is not possible to even know the usual incidence of this problem in the general population, much less whether a given patient is afflicted with the disease or some other entity. ~Women, if they are to continue to be informed of this disorder in such detailed manner must also be informed of these facts-and told that it is not unknown for a diagnosis to be swayed by the simple fact that she is on the pill. They must also have these findings places iii their proper prospective-rather than be left as simple rates of three or 10 per 100,000. Show how these compare with the risk of smoking, driving a car, living in a city with its polluted air, illegal abortion or simply taking aspirin which has been reported to cause 20,000 deaths a year in the United States. Senator DOLE. I might say there, Doctor, we have just had a wit- ness who has given us reverse analogy, that the pill causes more deaths than murder, rape, several examples. So I assume this is a fair statement to give the other side of the coin, as you say, at the top of the page. Dr. PETERSON. Well, I don't know, you all are running late and I did not intend to go into some of Dr. Ratner's findings. I thought I would just present my side of the coin here. Senator DOLE. Fine. 40-471-70-pt. 10-vol. 2-21 PAGENO="0322" 6762 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Goiwox. Concerning these ostensible deaths, could you tell us, who are the victims? Are they children or~ Dr. PETERSON. I am sure that this is child poisoning to a large extent, yes. Mr. Goiwox. Can you give us the information for the record? Dr. PETERSON. I can give you the reference on this. It came out of an article I recently read and I did not have the reference immedi- ately available when I put this together. Mr. GORDON. Would you send it to us? Dr. PETERSON. I will do my best.' Our women must be given greater consideration and no longer treated like a cockleshell boat in a toy pool to be buffeted about at someone's whim. The potentialities of diabetes have been emphasized out of all pro- portion to the facts. Peterson and Steel in reporting their findings in 61 patients, who had taken the pill for periods ranging from 3 months to 7 years, noted decreased glucose tolerance in 39 percent with 18 percent showing diabetic-type tolerance curves ("Analysis of the Effect of Ovulatory Suppressants on Glucose Tolerance," Peter- son, W. F., Steel, M. W., and Coyne. R. \T._AM J.OB/GYN 95:484, 1966). Six of ten patients whose initial curves were diabetic in nature were restudied over a period of 3 to 28 months. Three returned to normal levels even tough still on the pill. One continued to show a diabetic curve 18 months later while still on therapy even though she had no other stigma of diabetes. Two were taken off the pill and the curve reverted to normal in one without additional measures, while the other was placed on tolbutamide therapy. Since putting this paper together, I have gotten further data on these 10 patients. All of these patients in this group have since had followup evaluations. One is normal, off therapy; three were trans- ferred and are lost to followup; one is still on tolbutamide therapy; and six have normal curves while still on the pill. These results would indicate that while the pill exerts an influence on carbohydrate metabolism, possibly by increased plasma protein binding of insulin, the effect is variable and currently unpredictable. They are, however, not necessarily a reason to avoid pill therapy when appropriate nor a reason to discontinue such medication if an abnormal laboratory result is obtained. As there is no evidence that continued use of the pill will even- tuate in clinical diabetes, the patient should be fully appraised of her findings and carefully followed at appropriate intervals if she elects to continue using the pill as it best meets her individual needs. Much the same situation exists where clinical diabetes is present. Even though the pill may raise insulin requirements in some diabet- ics, this group of patients require meticulous conception control to a higher degree than almost any other group-for their own welfare. To arbitrarily deny them this simple and effective agent is the antitheses of good medical practice and should be deplored by all. A recent report, emanating from these hearings, suggests that all 1 At the time of going to press, iio reference had been received by the committee. PAGENO="0323" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6763 women who have never been pregnant should avoid using the pill until their fertility has been proven. This statement, based on the finding that occasionally women experience difficulty in establishing pregnancy following use of the pill, arbitrarily compromises the majority for a small minority. Consider the plight of the single girl who indulges in sexual activity-in view of a current rate of illegitimacy of about 10 per- cent-or on a larger scale the problem of the young bride-to-be. Are we to return to the centuries-old problem of planmng the wedding' around nebulous menstrual periods or conducting the honeymoon-C with its expected frequency of intercourse-around the 8-hour postcoital mechanical restrictions because a few women may or will have difficulty after pill therapy. Here again romance and freedom has been extended to the young woman, an opportunity to start marital life on the most desirable emotional plane, and then snatched away because of half truths incompletely and improperly reported to the public. Are we to deny the therapeutic benefits of the :pill to those with severe dysmenor- rhea, or profuse and prolonged menses, and subject them to surgical measures, with its more serious risks and increased costs? The facts of the matter are that only a small number of women will have this problem, they are usually those who reflect compro- mised menstrual function prior to instituting pill therapy, and rela- tively simple and effective therapy is available to them. In a recent study of 1,141 women, the incidence and timing of conception was ahnost identical in the group that had taken the pill and stopped in order to conceive, when compared to the control group using other methods, or none at all. Of the pill group, 62 per- cent were pregnant within 3 months as compared to 60 percent of the control group. This, incidentally, did not seem to be altered if the patient took the pill in excess of 24 months. These findings are in accord with those reported by other-Watts et al., Am. J. OB/GYN 90:401, 1964. The potentialities of genetic defects have been repeatedly raised during these hearings leaving a dark cloud hanging over the head of young America. Turning again to the same study for information made available to physicians through the specialty literature last year-and, incidentally, unmentioned by the investigators of this committee, many of the people testifying in front of this committee- it was noted that 9 percent of pregnancies following use of the pill ter- minated in spontaneous abortion as compared to an abortion rate of 8.6 percent among those who had used other measures or nothing at all. Mr. GORDON. May I interrupt here for a moment. I understand you were a consultant to the B. & K. Dynamics pilot study for the Food and Drug Administration. Dr. PETERSON. Yes, sir. Mr. GORDON. In the conclusions, we have the following statement: However, the facts that nine out of 44 births that occurred subsequent to 00 usage were abnormal in some way, indicates further research in this area may be fruitful. The percentage of abnormal births was surprisingly high, however, no procedural sampling technique was found which would account for this fact. PAGENO="0324" 6764 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In other words, there were 20.5 percent, that is nine out of 44 births that were abnormal. Could you give us some more informa- tion about that? Dr. PETERSON. This was a sampling area that they took. This is a very complicated and complex situation. B & K Dynamics was asked to run a pilot study on, I believe, 100 or 200 charts at the hospital, `which they did will'y-nilly in their own fashion, in an effort to determine whether a study on our population at the hospital would be worthwhile and productive. The basic idea behind this was to run a large sample prospective pill study effort. This was to be firnded by the FDA. This is the data that they pulled out of the charts. I had nothing to do with this and I did not consult in that portion of their investi- gation whatsoever. Mr. GORDON. But they found that nine out of 44 births of those taking the pill were abnormal births. Is that correct? Dr. PETERSON. Well, I will not dispute this because I do not kiiow. This was now 3 years or so ago, and I do not recall their original figures because they took this information. We were not apprised of it and they worked with it. Mr. GORDON. One more point. I notice that in the "Results" on page 21, volume 1 of the pilot study we have the following informa- tion: In the course of this study a total recruitment of 321 ever-users was deter- mined with total of 159 present users. Since the OC's were obtainable from private sources, these figures merely reflect the record data, not necessarily the true picture. This represents a total attrition of 162 or 50.5 percent. It is interesting to note that in the report of the Advisory Committee on Obstetrics and Gynecology, FDA report on the oral contraceptives, dated 1, 1966, the assumption is made that 60 percent of ever-users are current users. I am not sure I understand `what this means. Does that mean there was a dropout rate of 51.5 percent? Dr. PETERSON. This data was compiled before the Air Force dis- pensed its medication, sir. So the patients were getting their pills from private sources, or paying for it on their own. It was not available and we had no formal so-called birth control or family planning type clinics in existence at that time. So, in order to give you the information on what the dropout rate was, there is no way for us to know because of the fact the patients were' not getting most of their medication through military channels. Mr. GORDON. Thank you. Dr. PETERSON. It is interesting that you bring that particular study up. The FDA on several differeht `oCcasions stated that the military services are the best study popnlation available' in the United States today. Insofar as population, socioeconomic sampling, racial amid cultural standards. In spite of a willingness of the Armed Forces to `conduct this study, a prospective study to delineate exactly what problems are or are not~ associated with the pill, inasmuch as the study would have been:considerably cheaper to be `done by the armed services, the FDA `for reasons known to itself `decided that they would not do that, but' rather `tOok the money that eventually became available PAGENO="0325" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6765 and sent them overseas for studies to be done in Europe-at a time that we are all involved with "Buy America." And it is a little dif- ficult to understand. To continue, the incidence of congenital anomalies of any degree, as evaluated by qualified pediatricians, in the pill group was 3.7 per- cent-15-of 401 births as compared to 4.8 percent of 641 births in the control group of patients. Since this report was released an addi- tional 4,124 patients have been studied-1,835 of whom had taken the pill prior to conception. The pregnancy terminated in spontaneous abortion in 6.8 percent of those women who had taken the pill and 8.3 percent of those in the control series. The incidence of congenital anomalies of all types in those having been on the pill was 3.9 percent or 68 in 1,711 births. In the control series the incidence was 3.7 percent or 77 in 2,098 births. While all of this new data must await more detailed coin- puter study, it is permissible at this time to state that the use of the oral contraceptive prior to conception does not appear to exert any important genetic affects on that pregnancy. Another problem of relatively minor concern, yet of major dis- comfort to the patient, is that of momlial vaginitis. About 2 or 3 years after the pill appeared on the national scene articles began to appear in the various medical journals stating that the incidence of this disease was higher in those on the pill. Several suggested a cause and effect relationship and the hyperhormonal influence of the pill was given as the probable etiological explanation. This has crept into our teaching and today is a relatively widely accepted concept. A recent unpublished study from the Malcolm Grow USAF Medical Center r~veals that the incidence of positive cultures of monilia is only slightly higer in the pill-taker, as com- pared to a control grup-15 percent versus 12 percent. The study further suggests that the difference is related to the use of mechanical means of contraception rather than any direct influ- ence of the pill, for similar problems are noted in those who have undergone hysterectomy. Gentlemen, it is facts such as those that must be presented to the American women, rather than half-truths incompletely detailed in a sensationalistic manner. We must no longer permit incomplete medi- cal findings to appear in~ the press before they have been made avail- able to physicians who must weigh their importance in the light of each patient's individual situation. Witness to current discussions regarding the low dose estrogen pill -how are we as physicians to answer the patient's inquiries if we have not had an opportunity to properly evaluate the findings iu detail. If it is this committee's purpose to see that the patient is more completely and properly informed then here is an opportunity for it to provide a great service to the patient and physician alike and the Nation as a whole. Let us stop attacking the pill in an indis- criminate manner just because it makes good copy. Let us provide the full picture-develop all of the truths, detail its values, its side reactions and its disadvantages. Yes, and stimu- late every opportunity to find answers wherein they are absent and PAGENO="0326" 6766 CO~ETITWE PROBLEMS IN THE DRuG INDUSTRY questions cloud the horizon. We must not continue this policy of denying the American woman the inherent right to factually, com- plete information. We cannot compromise her ability to select opti- mum family planning measures according to her own individual cir- cumstances and need-abortion after the fact is not a proper answer to the confusion created. Senator DOLE. Dr. Peterson, first, we appreciate your statement and regret that you have had to wait so long. First of all, do you feel through your contact with men in your specialty, and also general practitioners, that most physicians are aware of some of the side effects or complications caused by the pill, and relate them to their patients who take the pill. Dr. PETERSON. I am not clear I understand your question. Senator DOLE. Well, there has been at least some testimony that the pill is very casually given, and other witnesses have said doctors rarely explain the side effects. Dr. PETERSON. I think by and large most physicians inform their patients of the advantages and the disadvantages of this method, and some of the problems that the patients may encounter. Nowa- days. it is a rare patient that you can encounter that does not enu- merate all of the dangers to you and ask you your opinion of every single one of them right down the line. For instance, I had a premarital counseling a short time ago with a young lady and I spent 2 hours with her. Senator DOLE. Dr. G-uttrnacher made the same observation, after reading all of the literature and after some discussion, the patient tunis to the doctor and says. "Is it safe? Dr. PETERSON. This is what the final analysis is, and this is what it boils down to, and the patient is with you as an individual. And I think this is the crux of the whole situation. Each patient is an indi- vidual. her needs are personal, and highly centralized in herself. And only the physician that attends to hei is in the position to help her make the proper decision as to what is best for her. Senator DOLE. That is right. Dr. PETERSON. The pill may be best for Mary and the diaphragm may be best for Sally. And it is the doctor's position and preroga- tive to help them choose the best. Senator DOLE. Do you have any record of maybe the number of patients you have seen about the pill and have told not to take the pill, and use some other device? Is it a high percentage, or do you have any idea? Dr. PETERSON. Most of my personal patients that require contra- ceptive medication are on the pill. I think that there is an awful lot that has not been said about the pill to the American woman, to the family as a unit. If one has to get involved with mechanical meas- ures they lose an awful lot of the closeness that comes in true love. To have to wait until the last minute and then get involved in the last minute preparations is detrimental to romance and the closeness of the family circle. These are the problems that we see when we are seeing patients every day. It is very simple for a surgeon or an internist or a der- matologist or a public health officer to say the patient should not be PAGENO="0327" COMPETITIVE PROBLEMS IN TUE DRTJG INDUSTRY 6767 on the pill, it is not safe. Because they do not have to face the patient as a female with marital problems, marital difficulties, pelvic complaints, coming from inadequate or incomplete sex life. This is our business. And you will find that by and large most men who are gynecologists and have seen the patient or at least seen the patient for gynecological problems, uses the pill in a high percentage of his patients. None of us use the pill 100 percent of the time. The pill is not adapted to 100 percent of the women. Senator DOLE. Dr. Cutler testified this morning that where there was a history of breast cancer in the family that the pill should not be prescribed. Would you agree with that statement? Dr. PETERSON. No, I do not. I can say something for off the record, but I cannot say something on the record. Is that permitted in these hearings? Senator DOLE. Well, probably not. We are trying to make the record. Dr. PETERSON. This was not involving Dr. Cutler or anything else like that. But, many men have come along and said, and I think they have a very well-taken point, that we may well find that this time bomb that the American woman has been scared into believing may occur 20 years hence, as far as breast cancer, may actually turn out to be a boon and that the pill, the chronic pill-taker, may actually have a lower incidence of breast cancer than expected in the normal population because she is being exposed to more consistent lroper levels of ovarian hormones, artificially supplied, than her own body is going to give her. No one ovulates every month. And we know that it is progesterone produced after ovulation, by the ovaries that exerts the modifying influence on the breast. We know also that estrogen stimulates it. But these pills all contain progesterone. Senator DOLE. I inserted in the record this morning a statement of Dr. Edward T. Tyler, Medical Director for Family Planning Center, Greater Los Angeles, and he discusses the same general topic you just discussed in your statement, that it may be a boon. He does not use those exact words, but he did indicate as much. Hopefully the committee will publish objective findings at the conclusion of the testimony. We have had people here whose motives are unquestioned, unas- sailable, who feel that the pill should not be given under any condi- tion, but you indicate some of them have not had contact with the female, they have read many articles, maybe they are in some other area of medicine- Dr. PETERSON. I think that is a very, very important point to make, sir. I have had any number of physicians with whom I am in association, in other specialties, advise patients to stop the pill because of one finding or another. I have talked to them and invari- ably there is not one yet that can give me a specific reason why that patient should come off the pill, except that maybe it will do her some good, or her symptoms will disappear. Hypertension is one of them. Some with migraine headaches, which, incidentally, I have had as many patients benefited by the PAGENO="0328" 6768 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY pill as I have had made worse. I have had patients with rheumatoid arthritis, which has been brought up in this. I have two specifically who are failures to medical therapy, who were put upon the pill, in what we call amenorrheic doses, like a false pregnancy, because pregnancy may be so beneficial temporarily to rheumatoid arthritis. We know those with rheumatoid arthritis who become pregnant often are symptomaticall improved. I had one patient, a doctor's wife, she could not write or sew, which was her love in life. She has better hands than I do. Another one, who was a bed patient-this does not make the pill good for all rheumatoid arthritis, because it is not. But we have to bring these things into proper perspective. It also does not mean that the pill should not be given when a person has rheumatoid arthritis. These facts must be brought out in the proper perspective and they must be detailed by men meeting and handling women, not those that are treating a piece of a woman, a heart, a lung, a kidney, a blood pressure. This is a com- bined thing and it has not been, and it must be if we are to get the real picture. Senator DOLE. Thank you very much. Dr. Schulman, you have a rather brief statement, you can either read it in its entirety or summarize. It will be made a part of the record completely.1 And I apologize, you have been waiting some time, also, and we appreciate very much your taking your time to come here today and testify on a' very important topic. STATEMENT OF DR. HAROLD SCHULMAN, ASSOCIATE PROFESSOR, DEPARTMENT OP OBSTETRICS AND GYNECOLOGY, ALBERT EIN- STEIN COLLEGE OF MEDICINE, NEW YORK, N.Y. Dr. SCHULMAX. Thank von, Senator Dole, and members of the committee. My name is Harold Schulman. I am an associate professor of obstetrics and gynecology at the Albert Einstein College of Medicine in New York City. I would like to present a point of view based upon my position in which I am responsible for teaching obstetrics and gynecology to medical students and residents, as one who is engaged in private practice, and in addition responsible for the supervision and care of women in a large municipal hospital setting. Our hospital-Jacobi Hospital-contains 91 obstetric and gynecol- ogic beds which are filled to capacity most of the time and we see an average of 500 women per week in our outpatient offices. In Senator Nelson's opening statement he indicated a desire to learn if women and physicians are being adequately informed about the merit.s and risks of oral contraceptive pills. I do not believe that the committee has uncovered any data to suggest that there is any information that has been withheld or kept secret from doctors or the public. Furthermore, I do not believe that the committee is qual- ified or should get involved in attempting to determine the validity of a scientific analysis of possible long-range effects of a drug. Sd- 1 See information beginning at p. 6775. PAGENO="0329" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6769 entific information cannot be resolved in a democratic approach, for example, or by a majority vote. I have no reason to believe or even suspect that the two reports of the Advisory Committee on Obstetrics and Gynecology to the FDA and a WHO report are not accurate or reasonable summaries of the state of knowledge regarding the pills and their effects on women who use them-Advisory Committee on Obstetrics and Gynecology report to Food and Drug Administration, Aug. 1, 1969. The members of the I-lehman committee are known to me either personally or through the quality of their published works. I believe the conclusions of this committee are reasonable and moderate and are similar to those arrived at by most gynecologists who have made an effort to survey and keep abreast of the published scientific reports on tile pill. Whether all gynecologists are as fully informed about medical advances as they should be is open to question, but it is clear from several polls that the majority of gynecologists pre- scribe the pill because that is what their patients ask for, and most require annual examinations before renewing prescriptions-Ameri- can College of Obstetricians and Gynecologists "Report on a Survey of Experience with Oral Contraceptives," October 1967. The selection of a contraceptive technique reflects a decision based upon multiple considerations. First and foremost, "How important is it not to become pregnant." I don't believe that the vast majority of physicians understand how the fear of pregnancy can pervade a woman's entire life and activities. A number of years ago the gyne- cologist used to see a fairly common clinical picture which was called the tired housewife syndrome. Characteristically, this was a woman in her late twenties or early tlurties with two or three children who came to the office with multi- ple vague complaints. Physical and laboratory examination did not reveal any physical cause for her complaints. Greater exploration into her social history reveals a woman tied down to raising three children, her husband rarely home because of this critical period in his career development and, therefore, there is very little external social life. She knows that another pregnancy will just add to an already burdensome and frustrating existence. Consequently, the frequency of sexual activity and her ability to respond sexually are considera- bly diminished by her fear of further pregnancy and eventually leads to her psychosomatic complaints as well. The pill has provided her with a form of security she has never had before. The diaphragm has never been a technique which a large number of women have enjoyed using. Many find it distasteful to insert, although it is highly effective when used properly. This dislike for the method leads to the temptation not to use it during certain days of the month. An additional problem is to have to interrupt love play to insert the diaphragm. The intrauterine contraceptive device has far too many local side effects to be widely accepted. The use of the condom is aesthetically unsatisfactory and, finally, intravaginal foam suffers from a high failure rate. In short, if the pill is safe, it bypasses all of the previous men- tioned deficiencies of other methods: namely, a remarkable degree of PAGENO="0330" 6770 COMPETITIVE PROBLEMS IN T}~ DRUG INDUSTRY effectiveness with minimal side effects, some beneficial effects such as reduced menstrual flow and the elimination of premenstrual tension and painful menstruation. Finally, it allows spontaneous, uninhi- bited and uninterrupted loveniaking. The question must be asked then, "Why has the pill been a subject of such hot debate ?" There are at least two major health hazards which are indisputable which have generated much less discussion and virtually no action. I am speaking of the automobile which abruptly kills young and old each year in terrifying numbers. For those spared abrupt death b the automobile, there are the hazards of air pollution. Secondly, cigarettes clearly cause chronic hmg dis- ease and have a striking association with the development of lung cancer. Is the furor over the pill genuinely related to a fear of its unknown effects, such as an ability to produce cancer? Biology does not enjoy the precision of physics or mathematics. One cannot write down a precise formula~ and predict what its effects will be. These effects are determined by experimentation: namely. giving the drug under controlled conditions and observing and recording its effects- Lasagna., L., "The Pharmaceutical Revolution: Its impact on Science and Society." Science: 166 :122~, Dec. 5, 1969. The pills have probably been the most carefully scrutinized medi- cation in medical history, and we have been hard pressed to find any significant permanent or harmful effect from using these agents. At this point, the margin of safety of these tablets certainly exceeds those of penicillin and aspirin. Senator DOLE. That statement is directly contradictory to a state- ment made by an earlier witness. who indicated there had not been anything done. or very little done concerning the safety of these Pills. Dr. ScnUI~IAx. I think it is perhaps a difference of degree. I could not really analyze the amount of investigation which went into the pills or other medication, say, prior to their release, but cer- tainly since their release they have been more heavily scrutinized and I think we have more data-general systematic data on the pill which we do have on almost every other medication we use. It is argued also that 10 or 20 years may be needed to know if these agents will produce breast or uterine cancer. The breast can- cers produced in rats, rabbits, or dogs do not take 10 or 20 years to develop but develop within months. This type of argument accrues from such indirect evidence that people begin smoking in their teens and twenties but don't develop their cancers until they reach 40 or 50. Or excessive X-radiation such as that experienced by the sur- viving Japanese at Hiroshima or Hagasaki has led to increased risk of developing leukemia following a period of 6 years. The time period clearly varies a great deal, and this kind of yardstick cannot be applied irresponsibly for if it were, penicillin would only have been released for usage during the past 2 or 3 years, and thereby have deprived millions of its benefits. `Why the furor then? It is my belief that one of the underlying currents that has not been faced in this meeting as well as in medi- PAGENO="0331" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6771 cal and lay circles is that what we are really talking about is sex. The pill is being taken for sex. Our society has not handled sex well, and in general has imposed a terrible burden on women. For exam- ple, she has been forbidden until she is married to participate in sexual activity, and after this type of santification she may release or attempt to release 20 or 25 years of imposed inhibitions. Some religions may forbid her to use birth control or not allow her to have relations until she has stopped menstruating for one week, so she is being reminded that she may be dirty or kept in her place. If she should become pregnant by accident or out of wedlock, by rape or by indiscretion she is forced to bear the products of this moment or go to London, Japan, or Puerto Rico to obtain help, or go to back alleys, or be preyed upon financially by amoral physi- cians. The pius have been primarily responsible for the blossoming of family planning in our society and up to now represent the choice of approximately 70 percent of our patients. They are a positive source of mental and social health. The average municipal hospital now sees more women for family planning visits than they do prenatal visits. A common sight in municipal hospitals a few years ago were women having somewhere between their fifth and 18th baby. These patients are becoming increasingly rare. The pill is probably doing more to eliminate and diminish poverty and problems of the urban poor than any other political action program devised, by giving women the freedom of only having one or two children and raising them properly. If you look at the critics of the pill you will see that very few of them are gynecologists. Most gynecologists appreciate how important it is for a woman to be able to control when she is to get pregnaiit. Gynecologists are facing the bold facts of sex and sexuality every day and are forced to become comfortable with these issues whereas the vast majority of our society, including physicians, are not nearly as comfortable. When medical students are assigned to work in obstetrics and gyne- cology, we see the highest incidence of psychosomatic illnesses, and in addition we find them reacting very strongly in either a positive or negative way to this area of medicine. There is little doubt that the reporting of these hearings by the press, radio and television has created widespread alarm among women, and many have stopped taking oral contraceptives because of this. Tragically, it is once again the poor who are discriminated against in this type of situation, because they stop their method of birth control, and do not have easy access to a physician to obtain other methods. We have already seen several women seeking abortion because of these developments. If hearings such as this are going to be held, I believe the committee must carefully plan and screen all individuals who are invited to testify as to the content of their testimony. Mr. GoRDoN. Doctor, doesn't that sound something like censor- ship? Are you saying that the testimony of a witness should be examined thoroughly before he be allowed to testify? Dr. SOHULMAN. No, I am certainly not advocating the suppression of minority opinion. PAGENO="0332" 6772 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. GORDON. Or majority opinion? What kind of opinion are you referring to? Dr. SoIIuI~IAx. I think opinion expressed in a responsible way, and I amplify this statement in the remaining paragraph. Mr. GORDON. Who would make the decision whether it is responsi- ble or not? Dr. SCIIULMAN. I think in years past, newspapers and magazines have hired science writers and deliberately trained them so they would have some ability to present information in a way which it does not alarm the public, regardless of what the content might be. Mr. GORDON. You are saying that the committee must carefully Plan and screen all individuals who are invited to testify, as to the contents of their testimony. I)o von think that the content of the testimony of various witnesses should be screened before it is allowed to be presented to the public? Is that what you are saying? Dr. ScI-Iuiz~iAx. I think in an area such as this, I think that is necessary, yes. Because you screen it does not mean you would not allow it to be heard. Mr. GORDON. But the committee, you say, should determine what should be stated publicly? Dr. SCI-IULMAN. No, I think it should determine how it is said publicly. Mr. GORDON. You do not think that is a type of censorship? Dr. SCHULMAN. Well, I do not see it as a type of censorship. It is conceivable that it could be, but if a Committee has broad represen- tation. presumably there would be a majority opinion or at least aiiother opinion expressed where it would not be censorship. The Committee does iiot have a uniform viewpoint towards this issue, either, I would presume. Mr. GORDON. Thank you very much. Senator DOLE. Perhaps the hearing should have been held in exec- utive session because of the somewhat sensational nature of the pub- licity they generated. If we were concerned only with the problem, we may have been able to explore it more quickly and perhaps have a more detailed examination of witnesses in executive session. Certainly, no one here suggests censorship, but it does seem we are dealing with a very delicate medical problem, one we Senators are not at all well qualified to deal with. We can ask questions, we can enlist the witnesses, and we can listen to their statements, but we really do not understand the problem. We have had no experience at all with the problem, except in the work we have done-I cannot speak for Mr. Gordon, because he does have great Imowledge in this area-that is in the record. Dr. SCHULMAN. WTell, I am certainly nQt advocating censorship, but freedom also implies responsibility and I think the minority should be responsibly expressed. As I mentioned, reputable newspapers and magazines have employed science writers to ensure that the public gets accurate information without unduly alarming the public. Furthermore, the committee must use its legal skills to question and deliberately point out to witnesses ~nd the public at the time of testimony when inflammatory statements such as "mass experiment", and a number of others that have been made today, are being used. I think this PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6773 committee now also has an obligation to provide the public with a written statement of its findings. In regard to what the physician should tell the patient, I don't think this is too much a problem. The choice of a contraceptive is a personal decision made by the patient and if she selects an oral con- traceptive the physician should give the patient written pamphlets which describe potential side effects of these drugs. The difficulty of evaluating side effects of a drug was beautifully illustrated in a recent study from Mexico. In this study there were 147 women who had recently experienced a spontaneous abortion and were interested in having further children. 1-lowever, they volunteered to participate in a 1-year study to evaluate a new oral contraceptive. At least, that is what they were told. This new pill was composed of sugar and starch only. And I hope you will agree these are harmless. These patients while taking these tablets developed 31 different kinds of side effects, including percentages of headache, bloating, weight gain, pain in veins, and many others in equal or greater numbers than those which have been attributed to real oral contra- ceptives-Agner-IRamos, IR. Incidence of Side Effects with Contrac- tive Placebos. Amer. J. Obst. & Gynec. 105 :1144, Dec. 1, 1969. In summary- Senator DOLE. Do you have either a summary of that study, or do you have available a copy of the study itself? Dr. SCIIULMAN. I have listed it as reference 2 in my statement. Senator DOLE. We can obtain that. Dr. SCTIULM~N. The Incidence of Side Effects with Contraceptive Placebos. Senator DOLE. Thank you very much. Dr. SCHULMAN. In summary, I would say that continued efforts should be made to continue to study and quantitate the biologic and social effects of oral contraceptives. I would like to add from listen- ing to the discussion today, I think everyone in making this sort of a statement is assuming that something grand is just over the hori- zon and I think this is a very dangerous sort of thinking to get into. I do not think the human body is that easy and there are many maj or medical areas such as cancer where we have had these kinds of promises for 50 or 60 years, we are now getting these kinds of promises for transplantation and the body's ability to reject an organ, and I think perhaps the body is not going to be easily thwarted in terms of conception, either. I believe that for the most part physicians and their patients have been adequately informed and are continually informed about the status of tile known factual information. Thank you. Senator DOLE. Is it possible for a woman to be known to be preg- nant by, say, February 19, as a result of stopping the pill on or about January 14th? That is the day the hearings started. Dr. SCHULMAN. I think she would have to stop it a little bit sooner. I think if she stopped around January 8 or 9, it is conceiva- ble that she could conceive sometime in the next 10 days. That would make it the 19th, and that a pregnancy test could be positive by early or midFebruary. Yes. PAGENO="0334" 6774 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator Doi~. Have you had any contact with patients who stopped using the pill as a result of what they may have read or heard about the hearings? Dr. SGHULMAN. Yes, we have had many. Senator DOLE. You mention inflammatory statements and head- lines, such as, "Pill May Cause Cancer." Were these the overriding concern of those who have contacted you? Dr. SOHULMAN. I think this is the principal problem, the linking of the pill with cancer does present a significant fright to anyone. Mr. GORDON. Doctor, when you say they went off the pill, did they go to another form of contraceptive? Dr. SCHULMAN. No, they did not. These were patients in a munic- ipal hospital setting. Mr. DUFFY. Doctor, just to pursue the line of questioning begun by Senator Dole. Of these patients that you have seen that have left the pill, for whatever reasons, do you know any of them that have become preg- nant at this point? Dr. SOHULMAN. Well, I am aware of three patients, one of which I would think probably stopped taking the pill because of the pre- liminary discussions regarding the hearings, and this patient did receive an abortion in our institution last week. There are two other women who have applied for abortion within the past week, who claim they stopped taking the oral contraceptives on the basis of the information which they heard. Mr. DUFFY. I ask you that question again, and I would like to remind you that a prior witness was quite definite, he said this was just not possible. And in view of that statemetit, is your answer still the same? Dr. SCHULMAN. I think it is possible if a woman had stopped taking the pills the 8th or 9th of January. Then ovulation could easily have occurred 10 or 11 days later, therefore, pregnancy would become apparent toward the end of the first week or the second week of February. These patients appeared in the last week of February with their pregnancies, Senator DOLE. I think it is probably common knowledge now that these hearings have had great impact on American women who were using the pill. Now, since no one knows about some of the side effects, the complications or dangers of the pill, whether this impact may have been beneficial or not, but I think we all agree it has had an impact. We have had letters in our offices and telephone calls and conversations with physicians that we know, and as you say, you have had telephone calls, Dr. Peterson has, and I am certain every other physician who may have prescribed the pill has been con- tacted. But I think you make one good suggestion, which was stressed by Senator Javits earlier today, and that is what we should do now, of ~course, and what we will do is issue a report of our findings and hope that they are widely publicized. As I believe, if we can reach nn agreement, if we are not going to decide the issue of whether or not it causes cancer or any other side effect, as you say, by majority vote, but we can perform a service, I think, by working very hard in PAGENO="0335" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6775 our objective study and reporting our findings and publicizing them very widely. And we will have a chance from the committee, all of us, to review the testimony and come up with some objective findings and release a report at the earliest possible time. I think it is important that it be done very quickly because tomorrow we have our final wit- ness, Dr. Edwards of the FDA.~ Is there anything else that you want to add that you did not men- ~ion in your statement? Dr. SCI-IULMAN. I do not think so. Senator DOLE. Thank you very much. (The complete prepared statement submitted by Dr. Schulman follows:) STATEMENT OF DR. HAROLD SCHULMAN, AssOcIATE PROFESSOR, DEPARTMENT OF OBSTETRICS AND GYNECOLOGY, ALBERT EINSTEIN COLLEGE OF MEDICINE My name is Harold Schulman. I am an Associate Professor of Obstetrics and Gynecology at the Albert Einstein College of Medicine in New York City. I would like to present a point of view based upon my position in which I am responsible for teaching obstetrics and gynecology to medical students and res- idents, as one who is engaged in private practice, and in addition responsible for the supervision and care of women in a large municipal hospital setting. Our hospital (Jacobi Hospital) contains 91 obstetric and gynecologic beds which are filled to capacity most of the time and we see an average of 500 women per week in our outpatient offices. In Senator Nelson's opening statement he indicated a desire to learn if women and physicians are being adequately informed about the merits and risks of oral contraceptive pills. I do not believe that the committee has uncov- ered any data to suggest that there is any information that has been withheld or kept secret from doctors or the public. Furthermore I do not believe that the committee is qualified or should get involved in attempting to determine the validity of a scientific analysis of possible long range effects of a drug. Scientific information can not be resolved in a democratic approach or by a majority vote. I have no reason to believe or even suspect that the two reports of the Advi- sory Committee on Obstetrics and Gynecology to the FDA and a W.H.O. report are not accurate or reasonable summaries of the state of knowledge regarding the pills and their effects on women who use them (1). The members of the Heilman Committee are known to me either personally or through the quality of their published works. I believe the conclusions of this commtltee are rea- sonable and moderate and are similar to those arrived at by most gynecolo- gists who have made an effort to survey and keep abreast of the published sci- entific reports on the pill. Whether all gynecologists ar~ as fully informed about medical advances as they should be is open to question, but it is clear from several polls that the majority of gynecologists prescribe the pill because that is what their patients ask for, and most require annual examinations before renewing prescriptions (3). The selection of a contraceptive technique reflects a decision based upon multiple considerations. First and foremost, "110w important is it not to become pregnant?" I don't believe that the vast majority of physicians under- stand how the fear of pregnancy can pervade a woman's entire life and activi- ties. A number of years ago the gynecologist used to see a fairly common clini- cal picture which was called the tired housewife syndrome. Characteristically, this was a woman in her late 20's or early 30's with 2 or 3 children who came to the office with multiple vague complaints. Physical and laboratory examina- tion did not reveal any physical cause for her complaints. Greater exploration into her social history reveals a woman tied down to raising three children, her husband rarely home because of this critical period in his career develop- mnent, and, therefore, there is very little external social life. She knows that NOTE-Numbered references at end of statement. PAGENO="0336" 6776 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY another pregnancy will just add to an already burdensome and frustrating existence. Consequently, the frequency of sexual activity and her ability to respond sexually are considerably diminished by her fear of further pregnancy and eventually leads to her psychosomatic complaints as well. The pill has provided her with a form of security she has never had before. The diaphragm has never been a technique which a large number of women have enjoyed using. Many find it distasteful to insert, although it is highly effective when used properly. This dislike for the method leads to the tempta- tion not to use it during certain days of the month. An additional problem is to have to interrupt love play to insert the diaphragm. The intra-uterine con- traceptive device has far too many local side effects to be widely accepted. The use of condom is aesthetically unsatisfactory and finally intravaginal foam suf- fers from a high failure rate. In short, if the pill is safe, it bypasses all of the previous mentioned deficiencies of other methods, namely a remarkable degree of effectiveness with minimal side effects, some beneficial effects such as reduced menstrual flow and the elimination of premenstrual tension and pain- ful menstruation. Finally, it allows spontaneous, uninhibited and interrupted love making. The question must be asked then, "Why has the pill been a subject of such hot debate?" There are at least two major health hazards which are indisputa- ble which have generated much less discussion and virtually no action. I am speaking of the automobile w-hich abruptly kills young and old each year in terrifying numbers. For those spared abrupt death by the automobile, there are the hazards of air pollution. Secondly, cigarettes clearly cause chronic lung disease and have a striking association with the development of lung cancer. Is the furor over the pill genuinely related to a fear of its unknown effects, such as an ability to produce cancer? Biology does not enjoy the precision of physics or mathematics. One cannot write down a precise formula and predict what its effects will be. These effects are determined by experimentation, namely giving the drug under controlled conditions and observing and record- ing its effects (4). The pills have probably been the most carefully scrutinized medication in medical history, and we have been hard pressed to find any sig- nificant permanent or harmful effect from using these agents. At this point, the margin of safety of these tablets certainly exceeds those of penicillin and aspirin. It is argued also that 10 or 20 years may be needed to know if these agents will produce breast or uterine cancer. The breast cancers produced in rats, rabbits, or dogs do not take 10 or 20 years to develop but develop within months. This type of argument accrues from such indirect evidence that people begin smoking in their teens and 20's but don't develop their cancers until they reach 40 or 50. Or excessive x-radiation such as that experienced by the sur- viving Japanese at Hiroshima or Xagasaki has led to increased risk of devel- oping leukemia following a period of 6 years. The time period clearly varies a great deal, and this kind of yardstick cannot be applied irresponsibly for if it were, penicillin would only have been released for usage during the past 2 or 3 years, and thereby have deprived millions of its benefits. Why the furor then? It is my belief that one of the underlying currents that has not been faced in this meeting as well as in medical and lay circles is that what we are really talking about is sex. The pill is being taken foi- ser. Our society has not handled sex well, aild in general has imposed a terrible burden on women. For example, she has been forbidden until she is married to partic- ipate in sexual activity, and after this type of sanctification she may release or attempt to release 20 to 25 years of imposed inhibitions. Some religions may forbid her to use birth control or not allow her to have relations until she has stopped menstruating for one week, so she is being reminded that she may be dirty or kept in her place. If she should become pregnant by accident or out of wedlock, by rape or by indiscretion she is forced to bear the products of this moment or go to London, Japan or Puerto Rico to obtain help, or go to back alleys, or be preyed upon financially by amoral physicians. The pills have been primarily responsible for the blossoming of family planning in our society and up to now represent the choice of approximately 70% of our patients. They are a positive source of mental and social health. The average municipal hos- pital now sees more women for family planning visits than they do prenatal visits. A common sight in municipal hospitals a few years ago were women PAGENO="0337" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6777 having somewhere between their 5th and 18th baby. These patients are becom- ing increasingly rare. The pill is probably doing more to eliminate and dimin- ish poverty and problems of the urban poor than any other political action program devised, by giving women the freedom of only having one or two chil- dren and raising them properly. If you look at the critics of the pill you will see that very few of them are gynecologists. Most gynecologists appreciate how important it is for a woman to be able to control when she is to get pregnant. Gynecologists are facing the bold facts of sex and sexuality every day and are forced to become comfortable with these issues whereas the vast majority of our society including physicians are not nearly as comfortable. When medical students are assigned to work in obstetrics and gynecology, we see the highest incidence of psychosomatic illnesses, and in addition we find them reacting very strongly in either a positive or negative way to this area of medicine. There is little doubt that the reporting of these hearings by the press, radio and television has created widespread alarm among women, and many have stopped taking oral contraceptives because of this. Tragically it is once again the poor who are discriminated against in this type of situation, because they stop their method of birth control, and do not have easy access to a physician to obtain other methods. We have already seen several women seeking abortion because of these developments. If hearings such as this are going to be held I believe the committee must carefully plan and screen all individuals who are invited to testify as to the content of their testimony. Reputable newspapers and magazines have employed science writers to ensure that the public gets accurate information without unduly alarming the public. Furthermore the committee must use its legal skills to question and deliberately point out to witnesses and the public at the time of testimony when inflammatory state- ments such as "mass experiment" are being used. I think this committee now also has an obligation to provide the public with a written statement of its findings. In regard to what the physician should tell the patient, I don't think this is too much a problem. The choice of a contraceptive is a personal decision made by the patient and if she selects an oral contraceptive the physician should give the patient written pamphlets which describe potential side effects of these drugs. The difficulty of evaluating side effects of a drug was beautifully illustrated in a recent study from Mexico. In this study there were 147 women who had recently experienced a spontaneous abortion and were interested in having further children. However, they volunteered to participate in a one year study to evaluate a new oral contraceptive. This new pill was composed of sugar and starch only. These patients while taking these tablets developed 31 different kinds of side effects including percentages of headache, bloating, weight gain, pain in veins, and many others in equal or greater numbers than those which have been attributed to real oral contraceptives (2). In summary, I would say that continued efforts should be made to continue to study and quantitate the biologic and social effects of oral contraceptives. I believe that for the most part physicians and their patients have been ade- quately informed and are continually informed about the status of the known factual information. REFERENCEs 1. Advisory Committee on Obstetrics and Gynecology Report to Food and Drug Administration, Aug. 1, 1969. 2. Agner-Ramos, R. Incidence of side effects with contraceptive placebos. Amer. J. Obst. & Gynec. 105 :1144, Dec. 1, 1969. 3. American College of Obstetricians and Gynecologists Report on a Survey of Experience With Oral Contraceptives Oct., 1967. 4. Lasagna, L. The Pharmaceutical Revolution: Its impact on science and society. Science :166 :1227, Dec. 5, 1969. 5. Miller, R. W. Delayed radiation effects in atomic-bomb survivors. Sci- ence :569, Oct. 31, 1969. Senator DOLE. The hearings are adjourned until 9 :30 tomorrow morning. (Whereupon, at 4:35 p.m., the committee adjourned, to reconvene at 9 :30 a.m., on Wednesday, March 4, 1970.) 40-471-70-pt. 10-vol. 2-22 PAGENO="0338" PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition In the Pharmaceutical Industry) WEDNESDAY, MARCH 4, 1970 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to recess, at 9 :35 a.m., in room 318, Old Senate Office Building, Hon. Gaylord Nelson (Chairman of the Subcommittee) presiding. Present: Senators Nelson, McIntyre, and Dole. Also present: Benjamin Gordon, Staff Economist; Elaine C. Dye, Clerical Assistant; James P. Duffy III, Minority Counsel; and Den- nison Young, Jr., Associate Minority Counsel. Senator NELSON. Our witness today is Dr. Charles Edwards, Com- missioner, Food and Drug Administration. Dr. Edwards, the committee is very pleased to have you appear here today. Your statement will be printed in full in the record. You may present it as you desire, and if you wish to extemporize from it at any time, or elaborate on it, feel free to do so. I assume you do not mind if we interrupt with questions as you go along. Dr. EDWARDS. Not at all. Senator NELSON. All right, go ahead, Doctor. STATEMENT OF DR. CHARLES C. EDWARDS, COMMISSIONER, FOOD AND DRUG ADMINISTRATION; ACCOMPANIED BY DR. JOHN JENNINGS, DIRECTOR, BUREAU OF MEDICINE, FOOD AND DRUG ADMINISTRATION; WILLIAM W. GOODRICH, GENERAL COUNSEL, FOOD AND DRUG ADMINISTRATION; AND DR. J~OHN SCHROGIE, FOOD AND DRUG ADMINISTRATION Dr. EDWARDS. Thank you, Senator Nelson, Senator Dole. I would like to begin by introducing my colleagues. On my right, Dr. John Jennings, who is Director of the Bureau of Drugs, and on my left is Mr. William Goodrich, who is the general counsel for the Food and Drug Administration. We certainly appreciate this opportunity to present to the com- mittee the views of the Food and Drug Administration on some of the issues raised during these hearings. The primary issue, as we see (6779) PAGENO="0340" 6780 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY it, has been the relative safety of oral contraceptives and a concern for public understanding of the risks associated with them. We have, needless to say, carefully followed the progress of these hearings. You have heard a wide range of opinion concerning the safety of oral contraceptives. The opinions of these witnesses have been expressed intelligently and sincerely. They certainly merit seri- ous consideration, both by you and by the Food and Drug Adminis- tration. However, the expression of an informed opinion is not the same as making a decision. We, in the Food and Drug Administration, also have expert Opinions; but it is our responsibility to study the avail- able scientific data, consider the advice of our consultants and render a decision on the safety and efficacy of new drugs under the Federal Food, Drug, and Cosmetic Act. At this point I wish to summarize the Food and Drug Adminis- tration's current position. I would like to emphasize "current", because this is a situation that can change from month to month, year to year. However, our position is that the oral contraceptives are an effective and safe method of birth control, but as with other potent drugs there are both contraindications and complications. WToinen whose history and present medical condition include thromboembolic disorders, impaired liver function, known or sus- pected cancer of the breast, estrogen dependent tumors, and abnor- mal bleeding should not take oral contraceptives. Senator NELSON. Doctor, may I ask a question at this point? Dr. EDWARDS. You certainly may. Senator NELSON. On the use of the wOrd "safe" in respect to the oral contraceptives, I think that there is considerable confusion within the medical profession and the public alike as to how the word "safe" was being used when the Heilman committee caine to that conclusion and used the phrase "Safe within tile intent of the law." I would just like to read to you what Dr. Hellman said before the committee, and ask for your comment on it. I shall read out of con- text a couple of excerpts of his testimony. This is Dr. Heliman speaking when he appeared before the com- mittee- It is quite apparent if you read the report, in the first report the committee recognized certain very serious problems with oral contraceptives. They, how- ever, were unwilling, and rightfully, I believe, to say these things ought to come off the market. Now, I skip down further where Dr. Hehlman states: Now, in discussing the Chairman's report, the second report, with the com- mittee, I said to them that a more forthright statement has to be made. We cannot just hide behind rhetoric, we are going to have to say something and we have an option. These are not safe and then the commissioner might have to take them off the market, if you believe this. We can say these are safe, and our scientific data really did not permit that kind of statement. I doubt whether one doctor in 10,000 in the country knows that this was what Dr. Heilman, the Chairman, said and understands the context within which the word "safe" was used in reaching tile con- clusion when the Chairman of FDA's Advisory Committee said "safe within tile meaning of the intent of the law." PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 6781 Would you mind elaborating on that? Dr. EDWARDS. Certainly. In categorizing this drug as safe, I do not want to imply, by any stretch of the imagination, that this is an innocuous drug. It is a very potent drug, and when arriving at this decision to call it a safe drug we had to utilize the same standards we use for all other drugs. As you well know, most of the other "safe" drugs, the powerful drugs, have certain contraindications. There are certain dangers in taking any drug, and they have to be taken under the conditions which are stated very clearly in the labeling. So again, I would like to emphasize that in establishing this clas- sification, we applied the same standards for the oral contraceptives as we have for all other drugs in categorizing them as safe. Senator NELSON. The use in this context, then, was not in the ordinary dictionary use of the word- Dr. EDWARDS. It certainly was not. It was a Food and Drug Administration description of the word "safe", which really is "safe under the conditions of labeling," and which perhaps is a more accurate definition. Senator NELSON. This is a legal question. Dr. llellman mentioned that he discussed the phrasing-do you have Dr. Heilman's phras- ing? In any event, he discussed how it should be phrased with your counsel, Mr. Goodrich. Perhaps you may wish Mr. Goodrich to respond to this. But it raises another question of some significance, it seems to me. Dr. Heliman said: Now, 1 therefore wrote the sentence that has caused you and Mr. Gordon and other people same difficulty. I tahe full responsibility for writing this sen- tence "safe within the intent of the legislation." But I did have consultation in writing the sentence. And so forth, and he refers to your counsel, Mr. Goodrich. If it had been my responsibility, I might have come to the same conclusion, but it does raise a question about the intent of the law and its meaning. In 1938 Congress passed the statute requiring that to market a drug proof of safety must be submitted, adequate proof of safety or proof of safety acceptable to the FDA must be presented. I would just like to ask Mr. Goodrich what he thinks was intended at that time. Let me state it this way: In 1938 there were no oral contraceptives. In 1938, I would assu~ne that the Congress was thinking of a drug for treatment of a specific target organism in a specific disease situation. In fact, it was in re- sponse to a particular safety problem that arose at that time respect- ing sulfanilamide, and maybe Mr. Goodrich will have a different view-and correct me if you do-that Congress was thinking then of a drug in which the issue was, is it safe for the particular disease situation which it is being used for, that is, the drug does have side effects, we are well aware of that; however, under the circumstance the illness of the patient indicates that on balance the risks of the side effects from the use of the drug are far outweighed by the bene- fits that the patient would get from the use of the drug for the par- ticu lar disease situation that exists. PAGENO="0342" 6782 COMPETITIVE PROBLEMS IX THE DRUG INDUSTRY And just to delineate it a little further, let us take the case of chlorarnphenicol on which we had substantial hearings. This is a. very potent drug and everybody knows it. It has in a certain incid- ence, some dramatic side effects involving blood dyscrasias, including aplastic anemia. In today's circumstance, chloramphenicol, according to the National Research Council of the Natonal Academy of Science, is not the drug of choice in any disease. It is the choice only when the target organism is subject to control by chlora.mphenicol, when no other drug will do the job, and when the disease situation is very serious. So clearly, if you had some disease organisms that would not respond to treatment by tetracycline or any other drug, and the patient was seriously ill and the target organism was sensitive to chloran'iphenicol, the drug under that situation is safe within the meaning of the law. However, if the disease is subject to treatment by tetracycline, it is not safe within the meaning of the law or if the patient has a. serious disease or if the target organism is not subject to control by chloramphenicol, it is unsafe. Is that your understanding of what the law means? Mr. GOODRICH. Yes. My understanding is that all safety decisions have to be made in the context of the conditions for which the drug is prescribed, recommended or suggested. Now, going back to what Congress had in mind in 1938 when they focused on an acute episode of poisoning, it happened to be due to the vehicle and not the drug itself. But as soon as we began passing on safety from the very first drug, the sulfanilamides, that were involved there, those drugs were not safe in any absolute sense of the term but they were quite safe in treating infectious disease at that time, because many of those were lift threatening. Now, in that &:iss of drugs, of course, it is relatively easy to bal- ance benefit-to-risk, which is the test here. But there are other types of drugs that we have had to deal with over the years, drugs used for prophylaxis, or that type of drug, and in each instance it is essential that the agency balance benefit to risk, because there are very few drugs that have no side effects whatever, if they do any- thing. There are some inoccuous drugs that do not do anything, but if they are innocuous, then they do not have any benefit or any risk; they are just ineffective. But from the beginning of time we had to dea.l with the sulfa.ni- lamides, first as a. class, with the corticosteroids, and many other classes of drugs that came on the market after 1938. And this was really kind of the beginning of a. new era of chemotherapy that had both b~neficia.l effects and side effects and contraindications that were necessary to be observed in using the drug. Now, you had drugs effective against specific target organisms and effective as prophylactic measures. Senator NELSON. Let me ask this question, though. Is it not cor- rect when using the word "safe" that you do not mean safe in gen- eral, you mean safe for this particular patient who has a particular PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6783 disease situation which the doctor decides that this drug will effec- tively treat, that is, target organism is subject to control by this drug, and on balance it is better that the patient risk whatever side effect this drug has rather than risk letting the disease run its course untreated by any drug. It is an individual case, an individual disease, an individual pre- scription under an individual circumstance; is that not what we mean by "safe"? Mr. GOODRICH. That is the decision for the individual prescriber,. but the decision for the Food and Drug Administration has to take into account different circumstances in which the drug will be used, some in private practice, others in university medical centers. It has to take into account the total experience with the drug in the total prescribing population, and make a judgment there on all of these circumstances, this drug will be reasonably safe, that is, its benefits outweigh its risk under the circumstances in which it enters the market. There have been a few instances in which drugs were allowed to enter the market only for use in university-type hospital settings, but in others the drug is permitted for widespread prescribing in most instance. But the Food and Drug decision has to take into account all of these circumstances in reaching a safety decision. Senator NELSON. Maybe I am not making myself clear. When you say "safe within the meaning of the law" are you not saying that we mean safe for the appropriate use of that drug under an appropri- ate circumstance in a specific disease situation? Mr. GOODRICH. Certainly. Senator NELSON. Now, then, how do we bring the word "safe" to bear in the circumstance here of the oral contraceptive when: (1) There are alternative methods; (2) when, let us say, you are dealing with an intelligent, healthy, well-motivated prospective user? How does the word "safe" apply in that respect? The person has available medical care and a good hospital, has a good physician, has all of the facilities of the medical profession available as contrasted with the situation in which the patient has diabetes, or the patient has a history of high blood pressure, or car- cinoma in the immediate family, something like that. How do you evaluate that specific case, the healthy patient with the finest medi- cal facilities available with respect to the phrase "safe within the intent of the law"? Mr. GOODRICH. As you pointed out, that individual evaluation is for the prescriber, but as I approach it, as I see the responsibility of the Food and Drug Administration, it is to make sure that that prescriber has before him the information that is necessary for the safe, effective use of this drug. Now, the drugs are essentially very effective. They have two classes of side effects, some troublesome, but not serious; some seri- ous. Our role is to make sure that the material going from the spon- ors of these drugs to the prescribers fully discloses both the benefits and the risk and that for the doctor to make a judgment there, after he has taken this lady's history, after he has made the typical exam- ination, the physical examination, and after he has taken into PAGENO="0344" 6784 COMPETITIVE PROBLEMS IN TI~ DRUG INDUSTRY account all of the things that he is warned about, or cautioned about, or precautioned about, or contraindicated about in the label- ing, to make the choice that this is a safe medication for this patient and that this is the one most likely to be effective. Senator NELSON. If the patient is a healthy, well-motivated user, or prospective user, who could afford the best medical care, you do not have a problem of weighing the risk of a baby being born not in a hospital, but in a very poor circumstance. You are not weighing the question of whether the woman has psychological problems or diabetes, or disease; we are aiming at the problem of the perfectly healthy person. Then under those circumstances, where there are alternative meth- ods of birth control and we are dealing with the question of safety, is there any obligation by the doctor to disclose to that patient the benefits and side effects of this contraceptive versus those of alterna- tive methods of contraception? iDr. EDWARDS. I think there is an absolute responsibility of the physician to: (1) Point out the alternative methods of contracep- tion, and the contraindictions to each, and then I think it is a judg- mental consideration on the part of both the physician and the patient in arriving at an approprjate. choice of contraceptive methods. But certainly the physician has a primary responsibility, as we see it, in bringing this information on the safety of this particular product to the Patient. Senator NELSON. To the patient's attention? Dr. EDWARDS. Right. Senator NELSON. Because the situation is quite different if there is no disease problem, when there is no other problem. Dr. EDWARDS. Absolutely. Senator NELSON. The patient is entitled then to know the facts on thromboembolism or other risks, with a right then to decide, along with the doctor, whether she would use an oral contraceptive or another device; is that right? Dr. EDWARDS. Absolutely. And I would again emphasize that in our judgment this is a potent, powerful drug that has to be utilized under the supervision of a competent physician. Senator NELSON. Then does not the Newsweek poll raise quite a dramatic problem nationwide, when it is your position as well as the position of the former Commissioner Dr. Ley, as well as many wit- nesses before the committee, that there should be disclosure to the user? Are we not confronted with a very serious situation wheii the Newsweek poll says that two-thirds of the women interviewed said they were told nothing about side effects? Dr. EDWARDS. I think very definitely, yes. I think that, unfortun- ately, the subject of the oral contraceptive has become somewhat of an emotional one in the eyes of many women, in the eyes of the public generally. I think one of the responsibilities of the Food and Drug Adminis- tratibn is to bring the facts to bear so that they are available to the patient. I think that there have been more women taking the pill than perhaps should have been taking the pill. I am not sure that this number is absolute, but I think it does indicate there is a need to better inform the patient of the potential dangers of the pill and the risks involved. PAGENO="0345" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6785 Senator NELSON. If, as you and many others state, it is important to share the knowledge of the side effects with the user, what do we do about the fact that according to the Newsweek pool two-thirds of the doctors are telling the patients nothing about side effects? Dr. EDWARDS. As I am going to suggest in my prepared testimony, Senator Nelson, I think that the Food and Drug Administration has a responsibility to make sure that these individuals taking the oral contraceptives have received this information, and this is what we are going to propose. This is what we are planning to do immediately, as a matter of fact. Senator NELSON. Excuse me. ~1ou are planning immediately to do what? Dr. EDWARDS. We are going to publish in the Federal Register a patient information sheet that we are proposing be placed in all con- tainers of oral contraceptives. Senator NELSON. That are received by the user? Dr. EDWARDS. By the user, right. Senator NEr~soN. Has that ever been done with any other drug? Mr. GooDRICH. Yes. There have been a few instances in which it was necessary to have the prescribing information with the package. Senator NELSON. What drugs are they? Mr. GOODRIOJI. Well, I think~ back- Dr. JENNINGS. I do not think we have ever required it to the extent that is contemplated in this case. However, we have in at least one recent instance gone contrary to the traditional approach of requiring only the information the doctor wants on the dispense package of a prescription drug. In this instance, we required a warning directed to the patieit in a certain class of drugs, the iso- proterenol aerosol inhalants. The reasons they were somewhat coin- parable to what we are facing today, in that the drugs were pre- scribed in such a way that they could be refilled, the prescriptions could be refilled repeatedly, and the patient therefore had more con- trol over the medication than they would with most prescription drugs. So we did require a warning on the dispensed containers, directed to the patient. Senator NELSON. What did the warning say? Dr. JENNINGS. It simply warned against certain hazards here, associated with overdosage, and that if the usual or desired effect of release of difficult breathing: was not obtained, that the physician should be consulted. That, of course, does not approach in scope what is contemplated with the oral contraceptives. Senator NELSON. So this is the first time that you will be propos- ing that there be a user, so to speak, a user package insert that tells the patient something in detail about the drug? Dr. EDWARDS. Certainly in the detail that we propose this one in, yes. Senator NELSON. Will that be in all packages dispensed to the user? Dr. EDWARDS. We visualize it being in all of the oral contraceptive packages, yes. PAGENO="0346" 6786 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator NELSON. Well, I certainly want to commend YOU for moving in that direction. I had thought maybe there was a legal question, and I had had the counsel draft a bill to accomplish the same purpose, which we introduced yesterday, but which your action will make unnecessary. Is there any legal problem about the authority of the FDA to require a user package insert? Mr. GOODRICH. Not if a finding is made as to the product here that is necessary for the safe use of the drug. The legal point being raised, I suppose, has to do with the ordinary rule that prescription drugs dispensed to the user do not themselves carry the warning of hazards, but. that information is normally directed to the physician himself, and the law requires that the package dispensed contain such warnings as the prescriber requires in his prescription. In this case, upon a finding that this kind of information cannot be safely left to word of mouth, that it must be communicated in a more orderly way, this is a safety factor that enters into the new drug decision and can be required, in my opinion. Senator NELSON. We missed that aspect of the law. I had assumed that it would take some additional legislation, but I am pleased to hear that it does not. Pardon me for interrupting, Doctor. I had another question I might as well ask right now, because. it comes within the next sen- tence of your prepared statement In reading your sentence below, the one we just discussed, 4~WTomen whose history and present medical condition include thromboembolic disorders, impaired liver function," as you were reading it, you inserted a "family history of diabetes." This is not in my text. Dr. EDWARDS. No, I inserted it. Senator NELSON. So it would read "impaired liver function, family history of diabetes"? Dr. EDWARDS. Strong family history of diabetes. Senator NELSON. "Known or suspected cancer of the breast." This is the question we discussed yesterday with Dr. Cutler, in which he would use, I guess, about the same language you would as to diabetes. We asked him this question, whether the package insert which I believe use.s the language "lniown or suspected cancer of the breast," whether that was adequate. He feels, if I recollect his testimony cor- rectly, tha.t it ought to say about what you said, about diabetes, but that if, as he put. it, a sister, mother, or an aunt had cancer of the breast, it should be a contrainclic ation. Would you agree with that? Dr. EDWARDS. No, I would not. I would not be quite that forceful in my statement. I think certainly there is an area that we have to keep a very careful eye on, but at this point in time I do not think that our information, our data, would substantiate a statement of that magnitude. Senator NELSON. So you would not be inclined to even use the words "family history", as you do with diabetes? Dr. EDWARDS. Not at this point in time. Again, this is one of those areas I think we have to watch very, very carefully, and very shortly we might have to add that. PAGENO="0347" COMPETITIVE PROBLEMS IN TUE DRIJG INDTJSTRY 6787 Senator DoLE. Mr. Chairman, we had a subsequent witness yester- day afternoon, Dr. Peterson, who is chairman of the Department of Obstetrics and Gynecology at the Washington Hospital Center, who had much the same indication, that he would not include the family history. I might also say, Mr. Chairman, that later on in the statement we will be apprised fully of the knowledge of the leaflet that will become the insert. Is that correct? Dr. EDWARDS. That is correct, yes. Senator NELSON. Please proceed, Doctor. Dr. EDWARDS. Thank you. The risk of having thromboėmbolic disorders is four to nine times greater for users than for nonusers. Perhaps more accurately stated, the mortality for users-I emphasize mortality-is approximately three women per hundred thousand versus 0.5 per hundred thousand in the nonusers. Consequently a few apparently healthy women taking this drug will be affected. For all women, an understanding of this risk and other less-serious adverse reactions will reduce the possibility of serious consequences. In fact, I must say that the question of the safety of all contra- ceptives which has come out in these hearings can be clarified only through better public education as to what is involved. I believe only one witness thus far has suggested to the subcom- mittee that oral contraceptives be taken off the market. What has been suggested, I think, is that the question of safety is directly related to understanding of risk. I certainly agree and I am pre- pared today to suggest how we can help the physician better inform his patients on the safe use of oral contraceptives. First I would like to review the history of the Food and Drug Administration's action with respect to oral contraceptives. The first oral contraceptive, a combination of mestranol and nore- thynodrel, was approved for sale in this country in June of 1960. During the next few years the Food and Drug Administration received increasing reports that this oral contraceptive was associ- ated with certain thromboembolic phenomena. A committee of experts was formed by FDA to review and analyze available data and to determine if use of this oral contraceptive resulted in an increase in the incidence of thromboembolic conditions. The commit- tee chaired by Dr. Irving S. Wright, reported in September 1963, that in their opinion no significant increases in the risk of throm- boembolic disease had been demonstrated. Less than 2 years later, in April 1965, the first two sequential products were approved. These new products stimulated wider inter- est in birth control through use of oral contraceptives. It was estimated that during 1965 the average number of users of all marketed oral contraceptives in the United States had reached 5 million. Although the Wright committee found no demonstrated increased risk, the Food and Drug Administration continued its surveillance of adverse reactions. An FDA Advisory Committee on Obstetrics and Gynecology was established under the chairmanship of Dr. Heilman. This committee was asked to consider all of the available PAGENO="0348" 6788 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY evidence and to provide the Food and Drug Administration with the best 1)ossible advice. This committee of experts issued their first report in August of 1966. They found no adequate scientific evidence at the time to say that these compounds were unsafe for human use. However, the committee noted their concern for better data and made several rec.- ommenclations which were subsequently acted upon by the Food and Drug Administration. Included among these were the following: First of all, the ftmding of a. retrospective study to determine the possible relationship of oral contraceptives to throinboembolic dis- ease. Second, to support prospective studies utilizing groups of subjects especially amenable to long-term follow-up. Third, the continuation and strengthening of FDA surveillance system. Fourth, review of the mechanism for storage, retrieval and analy- sis of oral contraceptive surveillance data. Fifth, to support laboratory investigation on carbohydrate metab- olism, lipid metabolism, renal function, blood coagulation mec.ha- nisins, and potential carcinogenic effects in animals and man. Sixth, to establish uniform labeling of contraceptive drugs. Seventh, discontinuation of time limitation for administration of contraceptive drugs. Lastly, to expedite approval of low dosage oral contraceptives. The retrospective study was initiated; uniform labeling was achieved; the 2-year limitation was dropped; computer improve- ments were. made in the storage, retrieval, and analysis of surveil- lance data.; bett.er reporting was discussed with the manufacturers; and effects were made to obtain better reporting from hospitals and from prescribers. By 1966 competition in the oral contraceptive market had resulted in exaggerated and misleading claims. Advertising to physicians and some promotion materials attempted to establish ideas of product superiority which in our judgment had no scientific basis. As a result, the Food and Drug Administration's efforts to correct this situation led us to the uniform label approach for oral contra- ceptives. By early 1968, the improved surveillance - system was reporting increasing numbers of thromboemnbolic diseases associatedi with women taking the oral contraceptive. At. about the same t.iine results of epidemeological studies in Great Britain became available. For the first time these studies demonstrated an increased incidence of thromboembolic disease in users of oral contraceptives. The British data., compiled by Dr. Inman, Dr. \Tessey, and Dr. Doll, were reviewed by our experts who also considered the available U.S. data. These experts concluded that there was "a definite association between the use of ora.l contracept.ives and the incidence of t.hromboembolic disorders." Based on this conclusion, in June of 1968, FDA sent a letter to all ph3sicians advising them of the British findings. Senator NELSON. How many cases of thromboembolic disorders PAGENO="0349" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6789 had been reported to the department by the end of 1969? Do you happen to have that information? Dr. EDWARDS. I woufd like to refer that question to Dr. Jennings, or a member of his staff. Senator NELSON. On both deaths and morbidity. Dr. JENNINGS. We have been compiling these on an annual basis for the past couple of years, and as of December 31, 1969, the total number of reported reactions for that period, July 1, to December 31, 1969, included 15 deaths and 28 nonfatal thromboembolic cases. Senator NELSON. Over what period of time? Dr. EDWARDS. From July to December. Is that not correct? Dr. JENNINGS. That is right. That was for that particular year. Senator NELSON. How many~ deaths? Dr. EDWARDS. Fifteen. Senator NELSON. And what was the other, thromboembolic? Dr. JENNINGS. Yes, nonfatal thromboembolic, 28, with about six other miscellaneous adverse reactions. Mr. DUFFY. Doctor, so I can understand these figures now, are these figures that are actually documented? In other words, it is clear that these are pill-related or are these just incidents which have occurred in people who have used the pill? You may or may not know. Dr. JENNINGS. Deaths and the nonfatal. In fact, all of these adverse reactions are ones that we attribute to the use of the drug. Mr. DUFFY. I would assume, then, that if you just looked at the gross number of deaths from thromboembolic accidents of women using the pill, there would be a larger number than 15? Dr. JENNINGS. Yes, I am sure there would. Mr. DUFFY. And you narrowed this down to instances where you could be sure it w'ts pill related ~ Dr. JENNINGS. In attempting to establish a cause and effect rela- tionship in any adverse reaction to a drug, where the adverse reac- tion is one that occurs for other reasons, but the linking of the two. is extremely difficult. I think that we cannot always say with abso- lute certainty that a c~tuse and effect relationship exists. Now, therefore, even in our labeling, the retrospective studies, for instance, that were done, can establish only that; that they do not establish the precise cause and effect relationship. We have here the tabulation that we do on these, and although I do not have handy the figure that I think the Senator was asking for, the total that we have to date, we can tabulate this fairly rap- idly for you, if you want us to do that. Senator NELSON. Do you want to submit it for the record? Dr. JENNINGS. Yes, sir.1 Senator NELSON. I was getting at another aspect of this. We have had witnesses over the past 3 years, distinguished physicians, who deplored the state of reporting on various diseases as being wholly inadequate. By coincidence, last week we had an internist before the committee, who talked about the forms he had to fill out and that he used to religiously report but never got any playback from FDA- this was several years ago-and finally he stopped reporting entirely 1 See p. 682. PAGENO="0350" 6790 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY I would like to ask your view about the status of reporting to the FDA on side effects, which you would like to know about. But first, let me read what Dr. Best said before the committee, about 2 years ago. This is from a statement of William R. Best, chief, Midwest Research Support Center, Veterans Administration, Edward Hines, Jr. Hospital, Hines, Ill. He said: I am not sure how much effect the reporting system would have itself. It would produce a universal reporting system . . that would have a little more meaning than those I have written about that I related to voluntary reporting. In other words, we would have a better feel for what the total number of cases are. I think we still would not have the whole picture. I know that in a recent study in Philadelphia, for example, five of the medi- cal school affiliated hospitals tried to set up their own reporting system to catch all the adverse reactions occurring in all of these hospitals. People being people, the way they are, when they went back to check and see how complete their reporting system was, even though the chief of every service told all of his residents and internes to report every case that came through, I think they reported somewhere in the neighborhood of 5 percent. About 95 percent still did not get reported, even though this was the rule of the particular hospital. This would seem to have been a. case where there was a conscien- tious, specific effort, and according to Dr. Best, about 5 percent of the side effects were reported. Do you think in your experience, in your judgment, that figure is anywhere near in the ball park of any kind of voluntary reporting the FDA gets on side effects? Dr. EDWARDS. I do not think I a*m in a position to give you an absolute figure. I would say without any hesitation our reporting system is poor. As long as we continue to have a reporting system that is voluntary, as it. is right now. where we have very little access to the medical records in both hospitals and in doctors' offices, I think the likelihood of our establishing a really accurate, up to date reporting system is not going to be very encouraging. I think that we have to move in this direction for all drugs, not just for the oral contraceptives. I think a complete adverse reporting system has to be established in this country eventually, if we ar& really going to provide the surveillance for these powerful drugs that is necessary. Senator NELSON. I bring this up just to make the point that if the Philadelphia study and the five hospitals with the chiefs of all the services cooperating produced only a 5-percent reporting result, alf of your reports on the incidence of deaths and other side effects from the pill, would have to be multiplied by 20 to get an accurate figure. Dr. EDWARDS. I have some reservation as to whether this is an accurate figure. I would add if I were chief of the service in a major teaching hospital and if I could not get my residents and internes to do better than that.. I think that maybe I would look at myself, not my staff. I think we can do better than that. I think maybe some do better than this, but I think the situation is generally poor throughout the country. Senator MCINTYRE. Mr. Chairman, you asked the question back there, or called for the figures on the number of reports that FDA PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6791 had received on thromboembolic disease and deaths associated with the pill, and I just want to make sure the answer you gave includes all reports which have been received by FDA from all sources since these drugs came on the market. And if your answer was not inclu- sive as far as that is concerned, would you please supply it for the record? Do I make myself clear? Dr. EDWARDS. Yes, I believe they were, were they not? Dr. JENNINGS. No, they were not, and that is what I pointed out to the Senator and said we would compile the figures I think he wants. Dr. EDWARDS. I was thinking of something else. Senator MCINTYRE. We had a feeling the figures you gave in response to the chairman's questions were only partial and I wanted to make sure. Dr. EDWARDS. The period was from July to December, 1969. We will give you the total compilation of the figures. Senator MCINTYRE. Thank you very much. Dr. EDWARDS. Again, referring to the letter that the Food and Drug Administration sent to all physicians in 1968, the letter expressed the Food and Drug Admistration's conclusion that a definite association had been established-this is between the oral contraceptive and thromboembolic disease, and called their attention to the revised labeling, and asked for their assistance in monitoring adverse reactions. In 1969, FDA's OB-GYN committee made another comprehensive review of the oral contraceptive problem. The second report was published on August 1, 1969. In addition to a comprehensive review of the problem, the report contained the results of a well-defined retrospective study on thromboembolie phe- nomena by Dr. Philip E. Sartwell of Johns Hopkins. The Sartwell study established the association of increased risk of some throm- boembolic disorders, confirming the earlier British studies. Although the committee had also studied the problems relating to carcinogenesis and metabolic effects, they could iiot point to conclu- sive evidence associating these conditions with the use of oral con- traceptives. 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 designation safe within the intent of the legislation." As in their first report, the committee made a number of recom- mendations. First of all, they recommended we investigate the carcinogenic and metabolic effect of oral contraceptives in humans. They recommended we support development of new methods of contraception. They recommended we support the National Fertility Survey in 1970 by the National Institute of Health. They recommended that we improve the present system of report- ing adverse reaction by financially supporting the use of centers to report reactions on oral contraceptives and by strengthening the present surveillance system of the Food and Drug Administration. PAGENO="0352" 6792 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Lastly, they recommended that we sponsor an annual conference of . scientific writers on contraceptive knowledge and accomplishments. The FDA's review of the committee report and the Sartwell study led to a decision that a change in the uniform labeling was neces- sary. Accordingly, on November 14, 1969, we met with industry rep- resentatives to discuss the revised uniform labeling which has been required since January 1 of this year. In December when I became Commissioner, the decision was made to issue a. letter to all U.S. physicians, hospital pharmacists, and hospital administrators. In it., I warned that "carefully designed retrospective studies show that users of oral contraceptives are more likely to have t.hrombophlebit.is and pulmonary embolism than nonu- sers" and I strongly urged physicians to familiarize themselves with the revised labeling. I suggested that "a full disclosure of the potential adverse effects" to patients is advisable, and I also again requested their assistance in reporting adverse reactions to the Food and Drug Administration. In addition, in December of 1969, reports came to our attention of the British annoimcement advising practitioners to prescribe only products containing .05 milligrams or less of estrogen. I indicated then that the Food and Drug Administration would await full data from England and evaluate this and our own data. before making a decision on whether any action should be taken with regard to the oral contraceptives containing high doses of estrogen. I would like to say in this regard, we just yesterday or the day before received a message from the British, inviting us to come to London on March 18 with appropriate individuals from the Food and Drug Administration and the National Institute of Health, to review their data. So this month we will have the British information. Senator NELSON. You will be sending a delegation shortly, did I understand y~u to say? Dr. EDWARDs. That is right. We are to be there on March 18. Senator NELSON. Are you, as Commissioner, going with the dele- gation? Dr. EDWARDS. Yes, sir, I am. Three people from the Food and Drug Administration, in addition to two from the National Institute of Health. Senator NELSON. If their data satisfies you and the group with you that oral contraceptives with more than 50 micrograms of estro- gen do in fact induce a higher incidence of thromboembolism, will it be the decision of the FDA to order from the market all of those in this country that exceed 50 micrograms? Dr. EDWARDS. Obviously, I think it would depend to a certain degree on the quality, or at least our interpretation of the quality of their data. I think we have to continually bear in mind the formulation of these products, and this is certainly one of the alternatives that we have to think about if the data. warrant it such a decision. Senator NELSON. That is what I am getting at. If you and your scientists are satisfied with the quality of the research and conclude that they are correct, that over 50 micrograms increases the incid- PAGENO="0353" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6793 ence of thromboembolism, would you be inclined then to order from the market all of our oral contraceptives that exceed that? Dr. EmvARl)s. Again, I think vce would have to give this very seri- ous consideration. If the data were of the quality that we insist upon in the studies that we currently have ongoing in this country, I think we would have to cons~cler this, yes. Senator Nin~sox. Is there any question of the effectiveness of the So microgram tablet-I am not talking about the side effects-the effectiveness in preventing pregnancy, inhibiting ovulation? Dr. Erw~\riDs. I would like to have Dr. Jennings answer that ques- tion, if I may. I think he perhaps is a little more familiar with it. Dr. JENNINGS. I think that the picture is perhaps not quite as simple as simply a difference between .05 milligrams of estrogen and .08 milligrams. The two commonly used estrogens are ethinyl estra- diol, which is usually present in a quantity of .05 milligrams, and mestranol, which is usually present in the higher dosage. Both of these seem to be effective at those respective levels. There was some indication that a lesser amount of mestranol, the one that is usually present in the higher amount, might not be as effective as manifested by breakthrough bleeding, I believe, and also by preg- nancy rates in some of the studies where this amount was lowered. So I think that in addition to simply considering the two levels of estrogen, a certain difference in the estrogenic strength of the two products, the two compounds, has to be considered. In addition, the products currently on the market all include pro- gesterones, either to be taken in combination throughout the period of medication, or to be taken in sequence. The progesterones vary also in their estrogenic effect. So that this also has some bearing on the potential for the side effects that might be attributed to estro- genic activity. I think all of this will have to be taken into consideration when the British data are available to us. Senator NELSON. Thank you. Senator MCINTYRE. Mr. Chairman, a question. I would like to know if you have received any of the British data as of now. Dr. EDWARDS. No. Senator MCINTYRE. Thank you. Dr. EDWARDS. I think with all due respect, it is a matter of their not having been able to tabulate their information. I think it has been rather substantial. And I think they have had trouble pulling it all together. It has not been because they have been trying to keep it from us, it is just they wanted to get it in order before we had an opportunity to look at it. Senator MCINTYRE. Thank you. Dr. EDWARDS. Another action taken soon after I became Commis- sioner was to convene a meeting of our OB-GYN Advisory Commit- tee. I met with this group on January 21 to re-evaluate available information on oral contraceptives. I believe the advice and counsel of this group is important to our work in this area, and I intend to meet with them every 30 to 60 days. I think this is perhaps an appropriate occasion to announce that Dr. Allan C. Barnes, professor and chairman of the Department of 40-471-70-pt. 16-vol. 2-23 PAGENO="0354" 6794 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Obstetrics and Gynecology at Johns Hopkins University is the new chairman of our advisory committee. replacing Dr. Hellman. Dr. Barnes will chair our meeting next Wednesday when we will review some of our present research projects. I would like at this time to review some of our studies which are now under way. There are several general areas on which the total scope of the Food and Drug Administration's present program is based. Information is being sought on the degree and mechanism of changes brought about. by the oral contraceptive and the indications of these changes. Also, we are trying to determine whether certain of these drugs, or their ingredients, have unique pharmacological properties; whether high risk subpopulations can be identified; and to what degree can findings observed in animals be extrapolated t.o the human population. Clinical and animal studies presently under way and supported by the Food and Drug Administration include: A retrospective study of a cost of $175,000 on the relationship be- tween thromboembolic phenomena and oral contraceptive use con- duct.ecl by Dr. Philip Sartwell at the Johns Hopkins University School of Hygiene and Public Health. Here we are planning to ex- tend this for another year, beginning next month, at a cost of approximately $75,000. We have an investigation going on of the carcinogenic potential, hematologic, and endocrine effects of two experimental oral contra- ceptive formulations using dogs and monkeys treated over a pro- longed period of time. This continuing study by the International Research and Development. Corp., was begun late in 1968 at a cost of $372,000. We have an intensive study of changes in blood coagulation and fibrinolysis in women using oral contraceptives, which was initiated a.t the New York University School of Medicine in May 1969, at an annual cost.of $27,000. Results are expected early in 1971. We have the study of the University of Rochester on the possible effects in women of oral contraceptives on renal, bladder and ure- teral function and the incidence of infection which was initiated in May 1969, at an annual cost of $77,000. We have the study at Temple University on the effects of oral contraceptives on lipid metabolism in sublnunan primates and women of reproductive age. which was initiated in May of 1968 at an annual cost of $118,000. We have a prospective study on the effects of prolonged use of oral contraceptives on carbohydrate metabolism in a large group of women, and this has been underway at the University of Miami since June 1967, at annual cost of $63,000. Lastly, we have a stud a.t Temple University on the effects of oral contraceptives on cervical cytology which was initiated in July of 1969 at a. cost of $95,000. All of these studies are currently costing the Food and Drug Administration $380,000 annually. Senator Doi~. Dr. Edwards, there has been some testimony that additional funds are needed to research oral contraceptive research. PAGENO="0355" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6795 Do you feel additional funds are needed, and if so, in what specific areas? Dr. ErwAiu~s. I think without any hesitation I would say that our research efforts in this whole general field have to be increased, both within the Food and Drug Administration and at the National Institute of Health. Senator DOLE. You indicated on page 10 an increase of $700,000 to in excess of $3 million. Dr. EDWARDS. When I say the 3 million, I am talking a ballpark figure and I am talking about total research. Again I do not mean that we are capable of taking this kind of increase all at once, but I think over a period of several years. I think this is the ballpark figure that we are talking about. Senator DOLE. There are specific areas now with reference to oral contraceptives, where research could be done if you had the money, is that your opinion? Dr. EDWARDs. I think additional research needs to be done in a number of these areas. This whole area of the carbohydrate metabo- lism, lipid metabolism, the possible effect or relationship between the oral contraceptive and carcinogenic effects have to be looked into in much greater depth than we have at this poiiit in time. I am speak- ing oniy for the Food and Drug Administration, of course. Our research funds are extremely limited, and we have had to establish priorities. And as I can assure you, in establishing these priorities, the oral contraceptives have been up at the top of our list. So' we have spent most of our funds on research in the oral contracep- tives. There are other areas, but I think these are certainly some of the main areas where additional research needs to be done. Senator DOLE. Thank you. Senator NELSON. May I pursue that subject a little further? I guess every witness has commented on the question, including General Draper and Dr. Guttmacher, as well as various physicians and specialists who have appeared before the committee. They have all deplored the lack of adequate amounts of research. One of the points raised, I think by Dr. Corfinan of NIT-I, although the record' will correct' me if `it were not he, was that unfortunately there has been no dosage level research done in terms of trying to find out how low a dosage of progesterones and estrogens may be given and still be effective and what reduction in incidence of side effects might occur as a consequence of lower dosages or lower dosages in various combinations. And you know, of course, that the first pills were 150 micrograms of estrogen and were effective, and 100 were effective, and 75 were effective. The British seem to think 50 are effective. Would you consider it an important piece of research to establish some protocol for comprehensive investigation of this aspect of the oral contraceptive? Dr. EDWARDS. Very definitely. I think this is an area in which far too little has been done. I am thinking in terms of the formulation of these products, the minimum amount that will provide the efficacy that we want. ` I think some of this, however, has to also be done' by the industry. PAGENO="0356" 6796 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY And who does what is a rather difficultY question for me. The answer is a difficult one. But I think without. an question this is an area I should have mentioned in greater detail. I think much more has to be done, and I think we have to play an important role in stimulat- ing this research. either we do it or we stimulate industry to do it. But I think without any question this is one of the most impor- tant. areas. Senator NELSON. Again, this is a legal question: `What authority does the FDA have to require drug companies to do additional research after a drug has been placed on the market? In this case dose level studies? Do you have authority to require such data? Dr. EDWARDS. I would like to have Mr. Goodrich answer that. I am not sure about our authority, but after all, in approving new drugs, we have to evaluate and judge the adequacy of the clinical investigations that have led up to the marketing of this drug, and in our judgment, if these are not adequate, then I think we certainly can go back to that particular company and say more study needs to be done in these particular areas; but legally, I would like to turn to Mr. Goodrich. Mr. GooDRIcH. Our legal authority is to require the companies to make either a regular or special report. A report could be called for on any phase of the safety decision. If we attempt to require the research, our ultimate administrative step would be to withdraw approval. `We have legal authority to withdraw approval at any time we find that there is a lack of adequate evidence, either of safety or of effectiveness. So what would have to be done would be to identify with the company those areas in which additional research was needed, some kind of time within which this could be clone, and say that if it were not done, they would be risking the loss of the product by the with- drawal of approval. `We do not have any direct authority to say do this research, but the ultimate withdrawal possibility does facilitate a good deal of research. Senator NELSON. In the specific case at hand, or with any drug, a potent one, anyway, extensive use over a period of years develops information that could not have been developed by FDA, so you have a case here where thromboembolism was proven quite early, and statistics have accumulated to support it. Do you have the authority to say it is pretty clear that a drug could be developed with less dramatic side effects, a lower incidence, therefore you must proceed with some protocol for investigating this possibility? Mr. GooDnIcIl. We think so. But as I say, our ultimate, if they refuse to do it, our ultimate step would have to be to withdraw approval. Senator NELsoN. I understand. I would like to ask another question in the research field. This concerns the report based on the workshop sponsored by NIH on "Metabolic Effects of Gonadal Hormone and Contraceptive Ster- oids." In the preface on page 9, I quote: PAGENO="0357" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6797 Until recently, the metabolic effects of the contraceptive steroids have been inadequately investigated or ignored. These accumulated data and other sug- gest that no tissue or organ system is * * * a biological function and/or more ~ * effect of contraceptive steroids. Many of these changes appear to be reversible after short periods of treatment. But it is impossible to form judg- ments on the reversibility of some of the changes resulting from prolonged administration. This question becomes more important daily for the many patients who already had long-term contraceptive steroid treatment. It seems to me this raises a very serious question, since we really do not know what the consequences of these metabolic changes are over a long period of time. My question is: Are you satisfied that we are doing enough research on this aspect of the problem, and if not, do you have some view about what we ought to be doing? Dr. EDWARDS. By "this aspect of the problem," you are referring to the time period over which the oral contraceptive is given a par~ ticular patient; right? Senator NELSON. And the metabolic effects of it. Dr. EDWARDS. And the permanent effects this might have on the patient's metabolic system, et cetera. I share with you concern about this, and certainly I think this is an area that we have to look at very seriously, along with groups at the National Institute. I have personal reservations about allowing the oral contraceptive t~o be given over indefinite periods of time. I have no knowledge of scientific evidence at the moment that would substantiate this view, but I think that some of the retrospective and prospective studies we are proposing or actually have in progress at the moment. will help answer some of these questions. But it is a very serious subject of concern and I think it is one I hope our advisory group will address themselves to this next week. Senator NELSON. That is the question of extended administration without interruption? Dr. EDWARDS. Right, and what kind of studies would best allow us to make some scientific judgment on the advisability of this, or what is the ideal length of time over which one of the oral contraceptives can be given. Senator NELSON. As you know, we have had a number of wit- iiesses who have expressed their opinion, again without having the proof, as you said, WhO had reservations such as you have indicated you have. One of the witnesses said that he would not want to have it used more than 2 or 3 years contimiously without interruption. Others expressed a similar viewpoint about long-term usage, simply because we do not have the studies that would indicate whether or not the metabolic changes that are effectuated on account of the administration of the pill have any long-term damaging effects. Do I understand you to say that the new committee being consti- tuted now on obstetrics and gynecology will address itself to the question of length of time the drug should be administered? Dr. EDWARDS. I think there are a number of areas that we would like to have them address their attention to, but this certainly is one of the areas that should receive a high priority on the agenda of the committee. PAGENO="0358" 6798 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY To complete the review of our studies in which we are indirectly involved, I will mention that we have participated in the monitoring of the prospective study of oral contraceptive users being conducted under support from the National Institute of Child Health and Development, at the Kaiser Permanente Foundation in Walnut Creek, Calif. In addition, we have participated in the review of two planned retrospective studies relating to the possible effects of oral contra- ceptives on carcinoma of the breast submitted to and approved by the National Institute of Child Health and Development.. Funding for these studies has not yet been approved. This investment in research, in our judgment, is necessary to better define the hazards of the oral contraceptive. The questions of safety must be answered in so far as is possible for science to find the answers. And we at the Food and Drug Administration must continuously review our previous decisions in light of new scientific knowledge. We have plans underway to develop other studies. These include the effect of oral contraceptive drugs in prediabetjc and diabetic patients; c togenetic studies in spontaneous and induced abortions; development of other teclmiques to assess the effects of oral contra- ceptives on endocrine function during adolescence; and the metabo- lism of the hormonal contraceptives and Possible interaction with other drugs. In order to get these studies under way, it will require an increase in our current research budget from approxnnatelv $700,000 in fiscal year 1970. to over $3 million. I would like to turn to another subject which will require very substantial funding if we are to do an effective job. This is the need for a comprehensive drug surveillance system. Because of the limited nature of premarketing clinical trials, we cannot expect to observe all of the adverse reactions that may occur. WTe are cleaTing with comparatively small numbers of patients who are screened carefully and regularly. The difficulty of detecting adverse reactions is great. Our statisticians tell us that an adverse reaction expected to occur at a rate of 1 in every 1,000 will not be observed at all in 37 percent. of studies using 1,000 subjects. In other words, to be 90 percent certain of observing such a high rate of adverse reaction, a study would need to include 10,000 or more sub- jects. Therefore, it is essential that all approved drugs be kept under close surveillance through an effective adverse reaction reporting system. At present this system in the TTnitecl States depends for the most part on voluntary submission of adverse reactions by physi- cians and hospitals and, of course, the required reports from the drug manufacturers. it is unfortunate, but true, that we receive reports on only a small percentage of the total number of adverse reactions that occur. This limited access to the medical record makes it extremely difficult, to evaluate cause and effect. WTe must move in the direction of significantly improving our surveillance system. I would estimate it would take at least a third of our present budget to establish such a comprehensive reporting system. PAGENO="0359" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6799 Senator NELSON. Would this be compulsory? Dr. EDWARDS. No. At least we are not in any position at this point to make reporting compulsory. But I think with the right kind of a system, a computerized system, where the medical record is far more computerized than it is at the present time would be helpful. I do not think it would have to be a compulsory system to get a reasona- bly good response in terms of drug reportmg. Senator NELSON. We had that, of course, in some of the commun- ic~ible diseases. * Dr. EDWARDS. I think though that for this, Senator Nelson, for this to be effective, really an effective reporting system, we are even- tiially going to have to get the record out of the doctor's office. Obviously this is where some of the minor reactions occur and it is not just the hospital record. I think the time is coming when we will have a medical record that is automated, a centralized medical record, if you will. When this happens, I do not believe it will be a matter of whether report- ing will be compulsory or noncompulsory, it will be on the record. And I think all of this is within the realm of possibility. Senator NELSON. I must say, in looking at one of the reports sub- mitted to the physician by the FDA, the number of questions and the fine lines, that it is a kind of discouraging thing for the physi- cian to fill out. As you know, all Federal forms somehow or another get to be enormously detailed. It might help, I suppose, if there were some way to simplify it. Dr. EDWARDS. I suspect you are correct, and I have not had an opportunity to look at the system that we use, but I am certain that what you say is true. And I think in terms of developing an adverse reporting system, we have to look at what the FDA requires, as well as what the system provides generally. So we will be looking at our capabilities in this regard, too. Senator NELSON. Thank you. Dr. EDWARDS. Under the present system we try to keep the physi- cian abreast of adverse reactions as we become aware of them. This is certainly true with regard to the oral contraceptives. There is no quostion that it is vitally important to communicate this information to the physician, but there is also corresponding need to keep the patient well informed. I believe that the patient should receive as much accurate information as is necessary for her to make certain decisions. Let me examine for just a moment how women are currently being informed as regards the oral contraceptive. They get a good deal of information and misinformation from sources other than the physician-through newspapers, pamphlets, books, television, andl from discussion with others. This additional information is reaching a large number of people in a short period of time. While we can control the prescribing information which goes to the physician and any printed or graphic matter that may ultimately reach the patient through him, we have no such opportu- nity to see that other presentations are accurate, balanced, and prop- erly informative. PAGENO="0360" 6800 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I have come to the conclusion that the information being supplied to the patient in the case of the oral contraceptive is insufficient and that a reevaluation of our present policies is in order. Accordingly, I have asked our Bureau of Drugs to examine this area of consumer information and to give me their recommenda- tions. I have with me today. which I will submit to you, a statement which we are going to publish in the Federal Register so that all interested parties will have an opportunity to comment on it. This statement is the proposed language for a reminder leaflet of uniform content which will be placed by the manufacturer into each package of oral contraceptives produced. This leaflet is designed to reinforce the information provided the patient by her physiciiin. I emphasize the word "reminder" as its purpose is to recall to the patient her discussion with the physician when she made her decision to begin taking an oral contraceptive. I will not read this unless you would like. (The statement follows:) WHAT You SHOULD KNOW ABOUT BIRTH CONTROL PILLS (ORAL CONTRACEPTIVE PRODUCTS) All of the oral contraceptive pills are highly effective for preventing preg- nancy, when taken according to the approved directions. Your doctor has taken your medical history and has given you a careful physical examination. He has discussed with you the risks of oral contraceptives, and has decided that you can take this drug safely. This leaflet is your reminder of what your doctor has told you. Keep it handy and talk to hlin if you think you are experiencing any of the conditions you find described. A WARNING ABOUT `BLOOD CLOTS" There is a definite association between blood-clotting disorders and the use of oral contraceptives. The risk of this complication is six times higher for users than for lion-users. The majority of blood-clotting disorders are not fatal. The estimated death rate from blood-clotting in women not taking the pill is one in 200,000 each year; for users, the death rate is about six in 200,000. Women who have or w-ho have had blood clots in the legs, lung, or brain should not take this drug. You should stop taking it and call your doctor immediately if you develop severe leg or chest pain, if you cough up blood, if you experience sudden and severe headaches, or if you cannot see clearly. WHO SHOULD NOT TAKE BIRTH CONTROL I'ILLS Besides w-omen who have or who have had blood clots, other women who should not use oral contraceptives are those who have serious liver disease, cancer of time breast or certain other cancers, and vaginal bleeding of unknown cause. SPECIAL PROBLEMS If you have heart or kidney disease, asthma, high blood pressure, diabetes, epilepsy, fibroids of the uterus, migraine headaches, or if you have had any problems w-ith mental depression, your doctor has indicated you need special supervision while taking oral contraceptives. Even if you don't have special problems, he will want to see you regularly to check your blood pressure, examine your breasts, and make certain other tests. When you take the pill as directed, you should have your period each month. If you miss a period, and if you are sure you have been taking the pill as directed, continue your schedule. If you have not been taking the pill as directed and if you miss one period, stop taking it and call your doctor. If you miss two periods, see your doctor even though you have been taking the pill as PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6801 directed. When you stop taking the pill, your periods may be irregular for some time. During this time you may have trouble becoming pregnant. If you have had a baby which you are breast feeding, you should know that if you start taking the pill its hormones are in your milk. The pill may also cause a decrease in your milk flow. After you have had a baby, check with your doctor before starting to take oral contraceptives again. WHAT TO EXPECT Oral contraceptives normally produce certain reactions which are more fre- quent the first few weeks after you start taking them. You may notive unex- pected bleeding or spotting and experience changes in your period. Your breasts may feel tender, look larger, and discharge slightly. Some women gain weight while others lose it. You may also have episodes of nausea and vomit- ing. You may notice a darkening of the skin in certain areas. OTHER REACTIONS TO ORAL CONTRACEPTIVES In addition to blood clots, other reactions produced by the pill may be seri- ous. These include mental depression, swelling, skin rash, jaundice or yellow pigment in your eyes, increase in blood pressure, and increase in the sugar content of your blood similar to that seen in diabetes. POSSIBLE REACTIONS Women taking the pill have reported headaches, nervousness, dizziness, fatigue, and backache. Changes in appetite and sex drive, pain when urinating, growth of more body hair, loss of scalp hair, and nervousness and irritability before the period also have been reported. These reactions may or may not be directly related to the pill. NOTE ABOUT CANCER Scientists know the hormones in the pill (estrogen and progestrone) have caused cancer in animals, but they have no proof that the pill causes cancer in humans. Because your doctor knows this, he will want to examine you regu- larly. REMEMBER While you are taking -~, call your doctor promptly if you notice any unusual change in your health. Have regular checkups and your doctor's approval for a new prescription. Senator NEr~soN. I would appreciate it if you would read it. I have not read it yet. I might have a question. Dr. EDwARDs. I might read the first page and then summarize the rest of it and any of the technical matter. The title of this is "What You Sliouki Know About Birth Control Pills." All of the oral contraceptive pills are highly effective for preventing preg- nancy, when taken according to the approved directions. Your doctor has taken your medical history and has given you the risks of oral contraceptives, and has decided that you can take this drug safely. This leaflet is your reminder of what your doctor has told you. Keep it handy and talk to him if you think you are experiencing any of the conditions you find described. Then the next section is a warning about blood clots. 1-lere we indicate there is a definite association between hloodclotting disor- ders and the use of oral contraceptives. The risk of this complication is six times higher for users than for nonusers. And although the majority of blood-clotting disorders are not fatal, the estimated death rate from blood clotting in women not taking the pill is 1 in 200,000 each year. For the user, the death rate is about 6 in 200,000. PAGENO="0362" 6802 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Women who have blood clots in the legs, lungs, or brain, should not take this drug. You should stop taking it and call your doctor immediately if you develop severe leg or chest pain, if you cough up blood, if you experience sudden or severe headaches, or if you cannot see clearly. Senator NELSON. The figures that have been used frequently before the committee indicate that hospitalization from blood clot- ting occurs in 1 of every 2,000 users. Is there any reason for not using that figure in here? Dr. JENNINGS. I think, Senator, there are any number of ways we could express this. All the data we have on this Particular Phenome- non, both morbidity and mortality, are somewhat inexact. I think what we attempted to do here was zero in on the most serious aspect of this, and to give the woman some idea of the magnitude of the problem. In other words, it would not be enough for her to know that the rate was increased for users by a certain number, four to nine times, unless she had some idea of the magnitude; one in a thousand multi- plied by four to nine times would be a large number. One in 200,000 multiplied by approximately six or four to nine would be a much smaller number. And I think that is what we are trying to get across here, that there is an increased risk among users compared to nonusers and that for the most serious result of this complication, the fatality, occurs in this order of frequency. Senator NELSON. I notice that in the Dear Doctor letter of June 28, 1968, which included the package insert, the hospitalization rates of morbidity age 20 to 24, it is 4 per 100,000. If I interpret this correctly, you have the hospitalization rate of almost one in 2,000. Am I interpreting it. correctly? Dr. *JENNINGs. Yes, I think that w-oulcl be one way of putting it. That was a hospitalization rate, which is one indication of morbid- ity. I think what we attempted to do here was not a literal transla- tion of the information given to the physician, who is, after all, much more sophisticated andi capable of handling these numbers, but to try in a simple fashion to alert the woman to the fact that there was an increased risk andi then to give her some idea of the magni- tude of this, especially in relation to the most important, that is, the fatality. Senator NELSON. WTe1I, all I say, as just a layman reading it, is that when you talk about the dleath rate being one in 200,000 for women not taking the pill audI for users six in 200,000, those are very large figures. But when you get down to the more practical aspect in a higher incidence and talk about almost one in 2,000 being hosnitalized, which is a very high incidence, it is a figure that is much easier to understand, audI dloes not just talk about. deaths, it talks about hospitalization rates. I just raise the question because it seems to me, a very significant statistic to include. If I were a patient, I would want to know that one in 200,000 die who were not. taking the pill and six in 200,000 do who are taking it, audi I might say to myself, well, that six out of 200,000 is very low. On the other hand, if you wouldl sa one out. of 2.000 is Q~oing to be hospitalized by blood clots alone, that is a pretty dramatic figure, PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6803 and I would think it is one that is quite understandable and ought to be used. Dr. EDWARDS. I think your point is well taken, and I would emphasize that this is not the final package. This is for discussion purposes primarily, and we certainly anticipate making changes, as requested by groups such as your committee and others. I think your particular point is a good one. Senator I)0LE. Dr. Edwards, this insert has been in the making for sometime; is that correct? Dr. EDWARDS. Right. Senator DOLE. I am not certain whether the average person real- izes there is any great risk if it is one out of 200,000 or six out of 200,000. We have had witnesses indicate we should not include a laundry list with medication, because to do so would confuse the patient. I am not certain where you draw the line, whether you should indicate any numbers, whether you should indicate there is some risk. The question is how to best comn'mnicate with patients, but we do not want to frighten th~ few people left who are not frightened as a result of these hearings. I would hope that we do not try to rewrite the memorandum in committee hearing. Senator NELSON. I hope the Commissioner did not think I was trying to rewrite the memorandum; I was just asking the question for inforn'iation purposes because I thought it was a good question. I would not think of trying to write the memorandum, but I would think it is within the province of a member of the committee or any citizen in America, and there are 200 million of them, to ask a ques- tion. Senator DOLE. We have asked several questions. Dr. EDWARDS. Certainly our intent is not to frighten anyone away from the pill, but it is our intent to prepare a document, and as I say, I will not stand on this particular document, but prepare a doc- ument that gives the facts in an unemotional way so that the many, many patients in this country who are receiving the oral contracep- tive by renewal of prescriptions, et cetera, will at least have some access to appropriate information. Senator DOLE. Will this be an additional piece of information, in addition to what the drugmaker himself may include? Are we going to have two pieces of literature to read, or does this supersede any- thing else? Dr. EDWARDS. I believe I am correct-Dr. Jennings can correct me- that at the present time there are no inserts in these packages per se, are there? Dr. JENNINGS. No, there are not. Dr. EDWARDS. Except for the physician. I)r. JENNINGS. That is right. But I think the Senator is referring to the booklets that are frequently prepared. Senator DOLE. Right. Dr. JENNINGS. For patient use. Senator DOLE. You have one entitled "So Close to Nature" which we had last week. PAGENO="0364" 6804 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. JENNINGS. That is right. No, sir, those are devised and dis- tributed by the companies on a voluntary basis. And they are subject to regulation in the sense that they cannot exceed the approved package insert. The dispensed package to the patient contains, as a rule, a simple set of directions for use, which we have approved for these products. This does not in any way refer to the safety or efficacy of the prod- ucts, but simply tells the patient how to take the dose, and gives her a few cautions. We feel that this has not served the purpose for which the leaflet under discussion today was designed. Senator DOLE. WTe still rely, I assume, on the doctor-patient rela- tionship. we are not trying to preempt. the doctor's role in dealing with patients. Dr. EDWARDS. Absolutely not. As a matter of fact, we certainly do not want to do anything in our action that is going to interfere with this doctor-patient. relationship. Being a physician, I am extremely aware of it and feel it is an absolute essential to get patient care. You certainly know, as well as I, that we are talking about some- thing a little bit different in the case of the oral contraceptive-and I will show you an example of what we are talking about, the patient information on the oral contraceptive package written here on the front of the package. the package insert which has all of this information which goes to the physician. This is a difficult. question. though, as to what kind of information you provide the patient- Senator DOLE. We have had well-qualified witnesses who have dis- cussed the pros and cons of information. Some indicate they rely solely on the physician; others indicate that. we should have the insert. Perhaps this is sort of the middle ground and does not inter- fere with the doctor-patient relationship. It is a relative thing to say two out of 200,000 or six out of 200.000. compared to all of the other risks that we cont.end with daily. I am not certain what the benefits of numbers are. It may have some effect. on a person to read she may be one of the six. Per- Imps not.. Dr. EluvAnDs. Unless you would like. I could just indicate the sec- tions we have here. The next section is who should not take the birth control pills. rfhen the next section of the document is special problems. And here we talk about if you have heart disease, kidney, and so forth your doctor has indicated-maybe I had better read this. If you have heart or kidney disease, asthma, high blood pressure, diabetes, epilepsy, fibroids of the uterus, migraine headaches, or if you have had any problems with mental depression, your doctor has indicated you need special supervision while taking oral contraceptives. Even if you do not have special problems, he will want to see you regularly to check your blood pressure. The next paragraph, we indicate some of the pregnancy warnings. And in the last paragraph, if one has a ba.by, the dangers of taking the pill at that particular point in time while nursing the baby. Next, we go into a sect.ion what to expect. The next section is other reactions to the oral contraceptive. PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDTJSTRY 6805 The next section is possible reactions. Then we have a special note about cancer: Scientists know the hormones in the pill, estrogen and progesterone, have caused cancer in animals, but they have no proof that the pill causes cancer in humans. Because your d&ctor knows this, he will want to examine you regularly. Senator NELSON. May I ask a question at this point? On the phrasing, "because your doctor knows this he wants t~ examine you regularly"., I guess the one thing that there was univer- sal agreement about by all witnesses who testified was on the point of physical examinations. They were all agreed that, without any question whatsoever, there should be a regular physical. A specialist in cardiovascular disease recommended an examination once in three months for blood pressure. Another said once a year, all other wit- nesses saying six months, or one witness saying six to eight months. Most recommended every six months. T am wondering-and it appears some significant percentage are not examined at all-I am wondering if it would be worthwhile to haveS a statement that all doctors agree that there should be a regu- lar physical examination without trying to designate a time. Dr. EDWARDS. I think that would be very appropriate. I think we certainly would agree with you, that anyone taking the oral contra- ceptive should have a regular physical examination. Senator NELSON. Let me say, Doctor, I think this is a tremen- dously significant step that you have taken and that it requires con- siderable courage to do so, since it has never been done before. And I have some understanding of the kinds of problems that are raised by requiring a packaging insert for the user. So I do commend you for your courage and far-sightedness in doing it. This is the specific issue that we raised last year. We called the hearing for the purpose of informing the public, and I expressed my opinion at that time that I thought it was very important for the user to have some information about it, because of the nature and the widespread use of these drugs and the difference between them and drugs prescribed for disease situations. So I think this is a sig- nificant step forward. I commend you for it. Senator MCINTYRE. Mr. Commissioner, a question has risen in my mind that I think you can help me with. Now, this proposed official draft of information that you feel should be known to the potential user, it is my understanding that many of the pharmaceutical houses put out pamphlets which explain problems, and which discuss the product that they have, and give general information on its characteristics. I have been wondering if under the Food and Drug Administra- tion regulations, would it be required that these pamphlets that are put out by individual business concerns contain a summary of this, I will call it, official enclosure in the package. Would it be required under your regulations that a summary of this information be con- tained in all of the pharmaceutical houses' promotional material? Dr. EDWARDS. I would like to have Mr. Goodrich answer that. PAGENO="0366" 6806 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. G-00DRIcI-I. LTnder the existing situation, Senator, if the com- pany chooses to put out a consumer book on a voluntary basis, as of now it is required to have a full disclosure in terms understandable to the ladies, which is a summary of the package insert material we now propose to make mandatory in all of the packets. Senator MCINTYRE. The answer is generally yes, a summary of this information would be included in future Pamphlets that are put out by various pharmaceutical houses concerning tile pill? Mr. 000DRICI-I. This document itself is the summary of the neces- sary information. Senator NELSON. Did I understand you correctly, that in tile liter- ature put out by the companies. they will be required to put a sum- mary of this? Mr. Goonnicii. Yes. If they have a separate little booklet, like the One you were examining the other day on "So Close to Nature", that kind of booklet would have to have tile essence of what is in this consumer message we are preparing now. Senator NELSON. I want to commend you again. I did not realize it extended to tile literature put out by the company, and I think it is a very sound step. Senator DOLE. You say in the first paragraph that the patient has discussed this with his doctor, and I quote: He has discussed with you the risk of all contraceptives and has decided that you can take this drug safely. Then on the same page, in bold type: Who Should Not Take Birth Control Pills. Are we saying in effect that no doctor would prescribe birth con- trol pills to anyone who has had any history of blood clots or liver disease. and the other things you mention in that paragraph? Are we gettlng into a contest here with the physician? Dr. EDWARDS. Absolutely not. I think tile point being here that in our judgment, although we certainly do not have tile actual figures, there are an awful lot of ladies in this country who are taking the oral contraceptive, and are not under the supervision of a doctor. And here we are trying to accomplish two tilings: are trying to remind tile lady who is luldler tile observation of a physician that she silOuldl see her physician regularly without just calling and getting a renewal of iler prescription. are also tryung to direct it to that particular lady who gets her prescription through another friend, or someone that sile never bothers to see. WTe certainly do not want to get ourselves in a position wilere we are trying to be the doctor. because we in no way are attempting to do such. Senator DOLE. In other words, if the doctor prescribes under any conditions, if he were qualified, and said it was safe, you are not taking issue witil what he says. Dr. EDWARDS. Yes. Our problem, as you well know, is not that we are particuilarly concerned Wltll tile Patiellt who is under the good care of a physician. We are not worried about that patient. PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6807 But we are worried about the patient who visits the physician once every 2 or 3 years or not at all. This is the patient we are trying to direct our attention to. Senator DOLE. I know it is difficult to cover all situations in a memo, I can understand it is directed primarily to those who do not have a regular checkup and maybe have not seen the doctor in the first instance, may have some other way acquired the pill, but it will be published in the Federal Register and there will be comments, unquestionably. Dr. EDWARDS. rfhis is a long way from being the final document., but at least it is a start, in our judgment, in the right direction. In conclusion, Mr. Chairman, there is no question about the effec- tiveness of oral contraceptives. Some questions of safety have arisen during this first decade of widespread use. We have examined the evidence of risk and we have resolved the safety issue for the pres- ent, as I have testified. I have indicated our need to continue and expand research projects for the discovery of vital safety informa- tion, and I have emphasized our lack of a comprehensive surveil- lance system. These are, to be sure, future needs. The action we must take now, immediately, in my opinion, is to help inform the 8.5 million American women now taking oral con- traceptives of the risk involved. This action is commensurate with our mandate for assuring the public of safe and effective new drugs. In this and all matters, we will continue to exercise scientifically sound, legally correct, and administratively mature judgment on behalf of the public health. Thank you. Senator MCINTYRE. Referring to page 2 of your statement, you noted that the first oral contraceptive was approved for sale in this country on June 23, 1960. Would you please comment on the quan- tity and quality of the data submitted in support of this New Drug Application? Dr. EDWARDS. If I may, I would like to have Dr. Jennings answer that question. Dr. JENNINGS. I cannot at this moment, Mr. Senator, give you the exact number of cases that were included. The data probably by today?s standard would seem somewhat scanty. There were field trials conducted in large numbers of women, and in relatively smaller amounts for fairly long periods of time, so that at the time the drug was approved for marketing in this country, the people concerned with the approval felt that they could approve it for a period of time of 2 years. The first products were limited in duration of use for 2 years. Senator MCINTYRE. I take it from your answer and from previous testimony, that the data that was available at that time, prior to the approval of these drugs would not be adequate in terms of the rules that we have today? Dr. JENNINGS. I am not sure of that, Senator. I say that by today's standard, I am sure it would be considered somewhat skimpy. Senator MCINTYRE. Somewhat what? PAGENO="0368" 6808 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. JENNINGS. Scanty. That is, the numbers were not large, but there were, I believe, some 300 women who had completed the 2 years for which the product was originally approved. Now, the quality of the data, I am not prepared to comment on at this time, but I think that is something that also enters into the pic- ture. Since approval, of course, there have been considerable data required and submitted to the Food and Drug Administration, regarding both the safety and efficacy of these products. Senator MCINTYRE. In your answer, you have indicated as far as quantity was concerned it was rather skimpy. l)r. JENNINGS. That is right, sir. Senator MCINTYRE. And you have also asked for an opportunity, and I will request it. that. you comment on the quality of that infor- mation at that time. Would you provide that for the record? Dr. JENNINGS. Yes. sir.' Senator MCINTYRE. How soon after the approval of the original New Drug Application did the first report of t.hromboembolic side effects come to the agency's attent.ion? Dr. JENNINGS. I cannot answer that with any degree of exacti- tude, but I believe that it was within a matter of months. Senator MCINTYRE. Pardon me? Dr. JENNINGS. A matter of months. Senator MCINTYRE. Somewhere between one and 12 months? Dr. JENNINGS. Probably within our first-well. I am not sure, I would rather not give you an exact answer until I have had a chance to check it.. Senator MCINTYRE. Will you furnish the exact answer for the record, please.1 You quoted the September 12, 1963, report. of the Wrhzht Commit- tee to the effect that "No significant increases in the risk of throm- hoembolic disease had been demonstrated." Did FDA not., in fact. issue two different versions of the Wright Committee report.? Dr. JENNINGS. I am unaware of that, sir. Mr. Goodrich may be able to answer. Mr. GOODRICH. There was a first report which was found by Dr. WTright to have some statistical errors in it and those errors were corrected. Senat.or MCINTYRE. How did the finding of the August 4. 1963, version differ from the one you quoted, from the September 12, 1963, version? Mr. GooDRICh. The first. report. of the Wright Committee indicated that on the basis of the statistical figures, the statistical calculations made, that there was an increased risk of thromboembolic disorder in ladies, as I remember, age 35 or older. I would have to go back to the record, but the problem t.here was that statisticians that looked at time information concluded that the incidence of thromboembolic disorders in nonusers. the data on which the comparison had been made, were inadequate and therefore there was no basis on which 1 See p. 6821. PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6809 they could find a statistically significant difference in the appearance of thromboembolic disorders in these age groups. Dr. Wright wrote to the Commissioner almost immediately to say that the statistical error had been discovered. The first report had been sent to the Journal of the American Medical Association, and the error was corrected. But the problem was identified as a statistical error by the calcu- lation of the normal risk based on the nonuser experience. Senator MCINTYRE. Well, the reason for the change was based on the lack of what was considered to be sufficiently definite statistical information on the occurrence of thromboembolic disease in nonusers? Mr. G00DRTCII. Yes. Of course, Senator, the reporting of the expe- rience with the users, as we have indicated here today, is probably underreported. That figure was not a perfect figure, either. But the company had had reported to it a number of these episodes, we had received some through our own reporting system, so we had one figure there. Then we had to learn what the incidence of these thromboembolic episodes would be in a normal population within these age groups before you could determine that what was being observed among the users was an increase in thromboembolic disorders. When the figures were turned over to a statistician, his conclusion was that there was no basis oii which to draw a statistical significant result. Dr. Wright communicated that to the Commissioner in an urgent fashion, and the report was corrected in September. Senator MCINTYRE. Well, I think I ought to move along. I just ask that excerpts from these two reports showing the deletion that took place on page 14 of the September 1~ version as compared with the August 4 version, be included in the record at this point, with- out objection. Did both the August and September versions of the report not conclude that on the basis of the available information, the deficien- cies of which have already been pointed out, a relationship between use of the pill and thromboembolic disorders, should be regarded as "neither established nor excluded?" Mr. GOODRICH. Right. (The information follows:) EXCERPT FROM AUGUST 4, 1963, REPORT ON EN0vID 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 from 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. EXCERPT FROM SEPTEMBER 12, 1963, REPORT ON EN0vID 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 from the use of Enovid in this population group has been demonstrated. 40-471-70-pt. 10-vol. 2-24 PAGENO="0370" 6810 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator MCINTYRE. Because of these deficiencies in the available information, the Wright~ Committee recommended: That a carefully planned and controlled prospective study be initiated with the objective of obtaining more conclusive data regarding the incidence of thromboemboljsm and death from such conditions in both untreated females and those under treatment of this type among the pertinent age groups. What actions were taken by FDA to implement this recommenda- tion in the 3-year period between the issuance of the Wright Com- mittee report and the first report of the Advisory Committee on Obstetrics and Gynecology in August of 1966? Mr. GOODRICH. Dr. Wright. did make that recommendation in the report. He also sent a letter to the Commissioner with it, in which he recognized that the preparation and execution of a prospective study would be difficult, if not impossible. We would be glad to supply that letter to the Senator, if he would like to have it. Nonetheless, the problem there was that in order to do a meaning- fill prospective study involved thousands of ladies, under carefully controlled circumstances, by that I mean having number of patients in the order of 10,000 examined at intervals of about 6 months, which was simply beyond our capal)ihtv of financing, and the con- clusion was reached about the time of the first Heilman report that the quickest. and most effective way of obtaining information-relia- ble information about thromboembolic episodes-was to do a con- trolled retrospective study. That retrospective study was financed and completed. We, in the meantime, got the retrospective experience from Eng- land. Even today, it is not Possible for us within the resources Dr. Edwards has explained here, to mount a prospective study with the numbers of patients that would be necessary. We think a prosjective study is no longer necessary with respect. to thromboembolic epi- sodes, but a Prospective study may very well he meaningful in some other parameters. Senator MCINTYRE. On pages 3 and 4 of the Commissioner's state- ment, you list eight recommendations contained in the 1966 report of the Hellman Committee, and describe efforts made by FDA to implement six of them. However, you make no niention of efforts to implement. the other two. One of these was the restatement of the Wright Committee recommendation to support prospective studies utilizing groups of subjects especially amenable to long-term fol- low-ups. Now, your answer, I suppose. covers it, but I want to ask it for the record: has FDA as vet undertaken or caused to be undertaken studies such as these, and if so. when? ~Ir. Gooonic~u. Again, the prospective study recommended by the I-Iellman Committee in 1966 was not undertaken. Instead, the retrospectjve study was l)laimed and executed. We have recently, as outlined on Dr. Edwards' statement., beginning on pages 8 through 9, summarized the research that is underway and given.the dates. No. 6, on page 9, describes a prospective study at the University of Miami. I believe there is also one underway at Temple Univer- sity, and the Walnut Hill Study. Senator MCINTYRE. That is a carbohydrate metabolism.studv.? PAGENO="0371" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 6811 Mr. GOODRICH. These are parameters, I thought I made it clear we had enough data from the retrospective studies to say that a cause and effect had been established for thromboembolic disorders. WTe have now tied the proof to that effect. These other issues are the issues that have been identified to us, which do need a prospective study, and we are trying to fund those within the limits of our resources. Senator MCINTYRE. Some of that information you got from the retrospective study made in England; right? Mr. G00DRICI-I. Yes, we did. We received that and we put out a notice in 1968 of the British experience. In addition, the Sartwell study was underway at our financing at that moment, and when we received the results, we thought it was highly pertinent to advise physicians in the United States what this experience had been, that the same experience had been encounterd in conditions in this coun- try. That was the purpose of the January letter to the profession. Senator MCINTYRE. The other recommendation in the 1966 report of the Hellman Committee, for which you described no efforts at implen'ientation, was the one calling for support of laboratory inves- tigation on carbohydrate metabolism, lipid metabolism, renal func- tion, blood coagulation mechanisms, and potential carcinogenic effects in animals and man. On the basis of our earlier hearings, we know that studies have been done in virtually all of these categories by scientists at various institutions. What role, if any, did FDA play in causing these stud- ies to be undertaken or in supporting them? Mr. Goomncii. We will have to yield to Dr. Schrogie on the exact details of the financing. Dr. SCHROGIE. Each of the subject areas includes studies under support from the Food and Drug Administration. In other words, we were directly responsible for developing and funding studies on these specific subjects and if you refer to the list of projects, some- what later in the testimony, I think ~OU will see the correlation between the projects that we are presently supporting and recom- mendation No. 5 on pa.ge 3. Senator MCINTYRE. You are telling us what FDA is doing now. My question was directed at what were you doing in 1965 and 1966 to support these programs and studies that we now have knowledge of by virtue of witnesses that have been here? Dr. SCI-IROGIE. These studies were started at different points in time since 1966. It was in 1966 that as a result of the Advisory Com- mittee report that additional funding was given to FDA to initiate such studies. The Sart~well study was initiated at that time, the study on car- bohydrate metabolism was initiated during 1967, and a feasibility study relating to a prospective study on carcinogenesis was also undertaken at that time. The other studies were phased in during 1968 and 1969, as they could be developed and as funds became available to support them. So tile pi~ogram developed in an orderly fashion over the space of 3 or 4 years. Senator MCINTYRE. Assuming you are familiar with- the witnesses who have appeared before this committee and described their var- PAGENO="0372" 6812 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ions studies, can you name any one or two of these studies that. FDA has supported? Dr. Sd-modE. Among the witnesses? Senator MCINTYRE. From the witnesses who have been here. Dr. SCHR0GIE. Dr. Speflacy has been under support from the Food and Drug Administration since 1967. Senator MCINTYRE. Any others? Senator I)0LE. I-low about Dr. Wynn ? Dr. SCI-IROGIE. Dr. Wynn is funded by the National Institut.e of Child Health and Human Development. I would add in terms of timing, both Dr. Wynn's study of carbohydrate metabolism and 111)id metabolism, and also the prospective multiphasic study of oral contraceptive users being conducted at the Kaiser Permanente Foun- dation at Walnut Creek, Calif., were initiated by NIH a.roi.md 1966. Senator MCINTYRE. You have now described to me all of the stud- ies that FDA has supported among the witnesses who have appeared here and described their studies for this commit-tee. Dr. SCHR0GIE. To the best of my present recollection, yes. Senator MCINTYRE. Well, to me anyway-I may be wrong, in 1960, the drug went on the market.. And FDA seems to be getting into the act by 1966, in a. concerted way by starting some of these studies. Anyway, on page 5, you quote the conclusions of the Hell- man committee's second report, 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 designation safe within the intent of the legislation. Now, I appreciate that you nrobably touched on that before I got here. Now, t.his last- phase, "safe within the intent of the legislation," has given us in this committee considerable concern, because we could not know exactly what it. means. The law itself does not define the word "safe". Although Dr. Heliman confirmed that he wrote the statement, he says he obtained this phrase from Mr. Goodrich. So perhaps Mr. Goodrich will tell us what it means and cite for us the appropriate reference in which the legislative intent was stated. Now. I do not know whether you got int-o this before I got here. Mr. GOODTITCII. We did, but I do not mind repeating it-, Senator. Senator MCINTYRE. In deference to the members of the committee, von can make a succinct reply. I\lr. GOODIIICTT. I will do t.hat. The issue balancing benefit to risk ill reaching a safety decision caine to the Food and Drug Adminis- tration very shortly after the enactment of the first new drug provi- sion in 1938. \\Te could never have approved a number of classes of drugs, such as the corticost-eroids, without balancing benefit to risk. When Dr. Hellman called me, he asked if there was in the legisla- tive development anywhere that I knew of a discussion of this point. It happened that there had been a- very comprehensive discussion of this before the Intergovernmental Relations Subcommittee of the I-louse and before the Commit.tee on Interstate and Foreign Corn- inerce and before the Antitrust Subcommnittee at the t.ime of the enactment of the 1962 Drug Amendments. PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6813 If we review the history of those, you will find that it was pointed out that the Food and Drug Administration from the very first had been reaching safety decisions on balancing benefit to risk. Else there could not have been the drugs on the market we have today. Senator MCINTYRE. It is my understanding that in your answer you are not talking about the legislative history of the enactment of the 1938 law, but about the hearings and discussions before the Intergovernmental Relations Subcommittee of the 1-louse. Mr. GOODRICH. Intergovernmental Relations Subcommittee of the 1-louse Committee on Government Operations was one group. Sena- tor Humphrey had a drug investigation here in the Senate, so did Senator Kefauver. This issue has been a recurring one at every dis- cussion of the activities of the Food and Drug Administration in this area. I am simply trying to summarize it briefly, to say that any drug that has any benefit at all is very likely to have side effects and contraindications. A medical judgment has to be made on that basis. We. did eluci- date our thinking in this in more detail before the Fountain Sub- committee than any other place I know of. Senator MCINTYRE. Well, actually, as I understand it, what you have given us here is a summary of what FDA's interpretation has been as explained to various committees in the Congress. Mr. GOODRICH. Yes. Senator MCINTYRE. Wouldn't it have been better to have said that, instead of talking about the intent of the legislation? Wouldn't this be more accurate? Mr. GOODRICH. Probably so, I did not write the sentence, and I might not have chosen those words. But I do accept full responsibil- ity -for having talked with Dr. Hellman about this and having directed him to that discussion of the benefit-to-risk issue that was elucidated before the Fountain Subcommittee. That was the place that I knew that it had been explained in most detail. I sent him a photocopy or Xeroxed copy of that discussion. Senator MCINTYRE. I understand what this is now. Actually, in 1938, the law was just absent of any legislative history explaining the intent with respect to the statutory meaning of the word "safe". Mr. GOODRICH. And the reason was that the revision of the Fed- eral Food and Drug Cosmetic Act started in 1933. It was practically at the end point in 1937. The bill, indeed, had passed both I-louses of Congress, when the elixir sulfanilamide episode occurred. This focused on the need for new drug provisions. These provlslon were proposed as separate legislation and were added on to that legislation at the very end, and there was no real discussion of the legislative intent there, other than to be sure that we protected the public from episodes of acute poisoning, which was what had been involved in the elixir sulfanilamide case. Senator MCINTYRE. Thank you. On page 6, Mr. Commissioner, you state that FDA met with industry representatives on November 14, 1969, to discuss labeling changes pursuant to the second part of the 1-Iellman Committee report. PAGENO="0374" 6814 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Since the report was issued on August 1, 1969, would you please tell the committee why it took 31/2 months just to get together with the industry to discuss labeling changes? Dr. EDWARDS. Again, Senator, if I could turn this over to Dr. Jen- thugs. I did not happen to be on board at that time. Dr. JEXXIXG5. Senator Mcintyre, I was aboard at that time, but not in any capacity where I could have expedited that review. It does take a certain amount of time, first of all, to decide exactly what the report meant to us in the way of labeling. Tile committee, after all, did not address themselves directly to tile matter of label- ing. And then we had discussions mcliviclualiy with various repre- sentatives of industry about the labeling. I can only blame what seems to be an inordinate delay at this time on our rather occasionally cumbersome administrative procedures. Remember, that we were making rather significant changes in the labeling, we were in a position of persuading and sometimes with considerable resistance, some of the members of industry to go along with us. And it just took that period of time. Senator MCINTyRE. Thank you for your frankness. Now, on page eight, you list a number of studies presently under- way whicil are supported by FDA. Item No. 2 is all investigation of the carcinogenic potential and other effects of two experimental oral contraceptives. Would you please identify these compounds for us and tell us why they are being investigated. Dr. SCHROGTE. These compounds are MX 665 and WY 4355. Senator MCINTyRE. Just a minute. You sound like tile Pentagon now. Dr. SCITROGIE. Because they are experimental compounds, brand or generic names are not commonly used. These compounds had been in clinical investi~ation some years ago. Limited studies in dogs being performed at tile same time, showed that they were associated with tile production of breast tumors. For this reason, the clinical investi- gations were terminated. It was felt. as a result of these findings, which at that time were quite preliminary and limitedi to dogs, that much more dletailed aild extensive studlies in both dlogs andl another species, the monkey, Shouldi be undlertaken, not only to further evaluate what might happen undler chronic dlosing with these particular dirugs, but also as an early warning to identify similar effects with either other mvesti- gational compoundls or compoundls that are presently Oil the market. The FDA for its part is supporting the studies of these two par- ticular drugs. Industry is supporting a mucll more extensive array of studies on investigational and some of the marketedl cOmpoundis, following the same protocol which was dlevisedl by the Foodl and Drug Adlminist.ration. Senator MCINTYRE. Doctor, would you please tell us whether amId how closely tllese two prodlucts may be related to products now Oil the market. Dr. SCIIROGIE. In terms of chemical structure, of course, there are some similarities, since they all belong to the same general series of PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6815 compounds. They are different, though, in the fact they do have unique structural arrangements. Senator MCINTYRE. In describing the prospective studies now unclerwa at the TJniversity of Miami, you say many important find- ings have been revealed already. Would you please describe some of them for us. Dr. Scm~oGIE. Findings to date, first of all, indicated the extent to which there are disturbances in carbohydrate metabolism as meas- ured by a variety of standard procedures, such as glucose tolerance and plasma insulin levels. When the studies first started there was no real idea as to what degree these changes would occur or how sig- nificant they would be. Over the years, experience has indicated that the changes, while they are consistent, are generally not of severe magnitude. I think this is one of the most important findings. Our goal in this project has been directed toward getting at the mechanism of the effect, and to date the work that has been done, particularly in animals, has not verified some of the questions that have been raised concerning mechanism. More recently, studies being conducted there have indicated that certain compounds have a greater propensity for changes in glucose tolerance or carbohydrate metabolism. This finding, which indicates differences between com- pounds, is very important. Senator MCINTYRE. On page 10, Commissioner, you say that in order to get certain proposed studies underway, FDA must increase its research support from $700,000, its budget in fiscal 1970, to over $3 million. Does your budget request for fiscal 1971 include any increase for this purpose and, if so, how much? Dr. EDWARDS. It does include, Senator, an increase. I cannot give you the specific answer to this in terms of our total research effort. As you well know, the research at Food and Drug Administration, permits a minimal amount of basic research, far more immediate research, and the budgeting system that has been in use is a difficult one to evaluate. I do not have this information today. I can provide it to you, however. Senator MCINTYRE. I think we could take that for the record.' WTe want a new baligarne in this field and a great deal more emphasis than we have in the past. This question is directed to Dr. Jennings. It relates to one of the answers that you were giving about low estrogen. Dr. JENNINGS. Yes, sir. Senator MCINTYRE. Of the two estrogenic substances in the pills now on the market, is ethinyl estradiol not more potent, on a milli- gram-to-milligram basis, than mestranol? Dr. JENNINGS. I will have to preface my answer, Senator, by saying that I am not an expert in this area, but, yes, we have reason to believe that is so. Senator MCINTYRE. What is the difference in potency of these two substances? Dr. JENNINGS. I do not think that has been established with abso- 1 See p. 6819. PAGENO="0376" 6816 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lute certainty, but generally speaking, it is accepted that the ratio of potency is roughly comparable to the ratio in which they appear in these marketed products. That is, that the .05 milligrams of ethinyl estradiol is apnroximatelv equal to the .08 milligrams of mestranol. Senator MCINTYRE. If this is so, if you decide to establish upper limits on the amount of estrogen in the pills, you will actually have to set different limits on each of the substances in order to assure comparability, will you not? l)r. JENNINGS. Earlier in the testimony, Senator, we did discuss this to some extent, when we thought that the British data had not taken sufficient cognizance of this possibility to be directly applica- ble to our situation here. Yes, I think that if we attempt to establish an upper limit, we will have to take into account. not only the estrogenisity of the two estrogens, ethinvi estradiol and mestranol, but also when the prod- ucts are used in combination, the estrogenisity of the progesterones, as well. So, it may turn out to be a fairly complicated process. Senator MCINTYRE. Thank you very much, Doctor. Senator DOLE. .Tu~t one or two questions. Dr. Edwards. first of all, I appreciate your testimony and the tes- timony of Dr. Jennings and Mr. Gocclrich. It has been very helpful to the committee. Do von feel there be any implication of excessive risks because this reminder is inserted in every package? Dr. Euwxnns. Well, as I said at the beginning, Senator, I feel that with any potent drug, like the drugs that are used in the oral con- tra ceptive, there are significant risks. Senator DOLE. Are you saying that the risks are accepted as a medical fact by the FI)A? Dr. EDWARDS. I beg your pardon? Senator Dovr. Are we saving necessary risks set forth in the mem- orandum are acceflted by FDA as a matter of fact? Dr. Enw.~nns. Yes. And under the right supervision, these are acce~table risks to take; right. This is an informative process, as far as we are concerned, hut within the conditions of labeling we feel these are acceptable risks to take. Senator MCINTYRE. Mr. Chairman, at what now appears to be the conchision of these hearings, I would like to say I am both surprised and disaupointeci to find that the Food and Drug Administration, which has leeal responsibility for assuring the safety of all drugs on the market, after allowing the birth control pill to come on the market on the has~s of onestionable evidence, has also failed to take the lead ill seeing that adequate studies are being done to answ-er the onestions which have been raised about the safety of these drugs since they came on the market. instead, FDA's Posture has consistently been one of reacting to studies done elsewhere, and in many instances, in other countries. I think these hearings have made it quite clear that there are a number of still unresolved questions about the safety of the birth control pill. I hope that in the future FDA will he more aggressive PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6817 and will take the lead in seeing that adequate research is undertaken to answer these questions. In the meantime, Mr. Chairman, I am happy to learn that FDA will take action to see that the known and potential side effects and complications of these products are brought directly to the attention of potential users so that a woman will be able to make a rational decision as to whether she wants to use this or some other method of contraception. I believe this action is a direct result of these hearings, and for this, if for no other reason, I believe the hearings have served a very worthwhile purpose. Thank you, ~ir. Chairman. Senator NELSON. Let me say that I do not think there is any ques- tion from the testimony that there has been a failure to have the kind of broad-scale studies starting back in 1960 that we should have had. Where the responsibility lies for that, I am not sure, but I do want to say Commissioner Edwards, who has only been in office for a few months, has moved vigorously in this area and has taken an historic action that no previous Commissioner before has ever taken, that it certainly required courage to do so, because I am familiar with the medical politics involved. I think it was a sound decision and I want to commend the Com- missioner for his actions on this issue, and I am satisfied from what I know of him that he understands and will lend his strong support to necessary research that I think every expert recognizes ought to be done and should have been commenced earlier. So I commend the Commissioner and thank you for appearing here today. Dr. EDWARDS. Thank you. Senator DOLE. Mr. Chairman, I have a brief statement. First of all, I share the view expressed by the chairman; we certainly appre- ciate the aggressive interest demonstrated by Dr. Edwards. Mr. Chairman, I assume this will be the final day of the pill hear- i iigs, is that correct? Senator TNELSON. tJnless there is some vacuun'i in the record that ought to be filled in order to have a balanced and complete record. Senator DoLE. That would be helpful, but we can assume that per- haps this is the final day. Perhaps some reflection is in order. There is some difficulty in my mind in trying to place the hear- ings within the subcommittee's jurisdiction. The chairman has expressed his idea of the hearings' purpose. The desire to know whether the American public has been properly informed is admira- ble, but it lacks germaneness to the subcommittee's mandate. Regardless of the authority under whicli we are ~)ur5ning this investigation, we must recognize that the impact has been substan- tial. We have at least belatedly seen some elements of balance estab- lished for the record, if not in the publicity surrounding the hear- ings. 1-Teadhines such as "Pill Takers Held More Cancer Prone" were the hallmarks of January's hearings. Testimony raising questions casting doubt dominated the hearings and the headlines. Risks pre- dominated over benefits. Fears were emphasized over effectiveness. PAGENO="0378" 6818 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The interval between the January and February hearings began to show the dimensions of the reaction. It is accurate to say that these hearmgs may not have originated the fear evidenced the past few months. Nonetheless, these hearings have amplified the doubts and uncertainties the American woman has had about oral contracep- tives. Another unfortunate aspect of these hearings is that no new knowledge has been disclosed. Several witnesses have related that all of the "disclosures" made are well known by the medical profession. The witnesses appearing at the February hearings have been less prone toward total emphasis on the dangers of oral contraceptives. The headlines have reflected this trend and perhaps some assurance has been provided to America's 8.5 million pilltaking women. Dr. Edwards' testimony has been especially valuable in establish- ing a broad and balanced record. And certainly, the overview he provided brings a sense of perspective to bear on the issues and the questions we are dealing with as we conclude these hearings. Hopefulh-. some of the unanswered questions may be answered quickly. I believe the American woman is entitled to know. She is perhaps frightened and confused as a result of these hearings, and hopefully, this committee will now carry on quickly through some written findings or written report as suggested by Senator Javits, and hopefully this will be of some assistance, not only to the Ameri- can public, but to Dr. Edwards and the FDA. Senator NELSON. I will not take the time to respond, except to say that although very little of the information presented here or per- Imps none of it was new to the experts in the field, quite obviously a lot of it was not known to the practicing physician who prescribes the pill and the public which consumes it. And the fact that the Commissioner himself recognizedi the necessity for producing a package insert which I announced as one of the purposes of the hearings last year, I think amply justifies the hearings. The people of the country are entitled to imow the facts about the pill, and since two-thirdls of the doctors were not informing the user, this package insert will perform that function. I happen to be one of those who believes that the public is intelli- gent enough to receive and evaluate and make decisions on informa- tion that the Government has. And this was all Government infor- mation, nip )ubl icized previously. It is a little bit like Laos. A lot of people in the Pentagon do not want us to know what is going on in Laos because it would frighten us, but I think the iiublic ought to know-. That concludes the hearings. Senator I)0LE. Mr. Chairman. I certainly do not have any quarrel with the public's right to know, but they could have known without sensational publicity had we held executive hearings. We would not have frightened 3 or 4 million women. There would not be a group described yesterday as "unwanted Nelson babies" down the pike about 7 or 8 months from now. Senator NELSON. Thank you. (The subsequent information submittedi by the Food andl Drug Administration follows:) PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6819 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, FOOD AND DRUG ADMINISTRATION, Rockville, McI., 20852 June 3 1970. I-IoN. GAYLORD A. NELSON, Chairman, Subcommittee on Monopoly, Select Committee on Small Business, U.S. Senate, TVashington, D.C. DEAR MR. CHAIRMAN: During the hearings on the Pharmaceutical Industry conducted on March 4, 1070 by the Subcommittee on Monopoly of the Select Committee on Small Business, several requests were made for additional infor- ination. During the testimony, Senator McIntyre asked if the budget request for Fiscal Year 1071 included any increase for additional research involving oral contraceptives. The Food and Drug Administration's budget for Fiscal Year 1071 does not include an increase over that budgeted for Fiscal Year 1970 ($700,000) for research projects concerning oral contraceptives. In addition the following are enclosed: 1. Copy of "Report on ENOVID" (August 4, 1963) 2. Copy of "Final Report on ENOVID" (September 12, 1963) 3. Copies of correspondence regarding the change from the first version (8/4/63) of the Wright Committee report to the final version (9/12/63) of the report. The remaining information requested for the record will follow as soon as it is available. Sincerely yours, ROBERT C. WETHERELL For M. J. Ryan, Acting Director, Office of Legislative Services. 3 Enclosures ["Report on Enovid," August 4, 1963, and "Final Report on Enovid," September 12, 1963, appears in Oral Contraceptives-Volume Three- Appendixes. I CONFIDENTIAL New York, N.Y., August 30, 1963. DR. LEONARD SCHUMAN, School of Public Health, University of Minnesota, MinneapolIs 14, Minnesota DEAR DR. SCHUMAN: A careful rechecking of the statistical data prepared for the Ad Hoc Committee on Enovid of the Federal Drug Administration by Drs. Leonard Schuman and Peter James has resulted in the discovery of an arithmetical error in the computation. This has been explained to me in some detail by Dr. Schuman. The result of correction of this error is that the appar- ent risk associated with the use of Enovid in women from 35 years to 45 years has been found to be non-existent. In other words, the conclusion of the statis- tical study is that no increased risk of deaths from thromboembolism in Enovid users has been established. This correction was verified by the Federal Drug Administration and it was decided to try to have the corrected version published in the JAMA. The original version was in the course of going to press. I had a lengthy telephone conversation with John Talbot and I w-as con- fronted with the immediate choice of either allowing the original version to be printed or to make an editorial deletion over the phone which resulted in the removal of reference to increased risk in the older age groups. The latter choice seemed obviously best since publishing the erroneous report in the JAMA would have established a situation whereby we would be correcting it for years to come. It is unfortunate that any reports were released prior to this but the 1osition can be taken that these were preliminary and that the final summary report is the one which will appear in the September 7th issue of the JAMA. I hope that you understand the position in which I found myself and will approve of the action which I took. Dr. Schuman will forward the details of PAGENO="0380" 6820 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the corrected data to each of you shortly. The JAMA article will not contain data tal)les so this did not present a problem. With very best regards I remain, Sincerely yours, IRVING S. WRIGHT, M.D. (Cc: Dr. L. Schuman, Colonel W. Crosby, Dr. J. Spittell, Jr., Dr. G. D. Penick, Dr. B. Alexander, Dr. W. M. Allen, Dr. C. L. Spurling, Dr. Roy Hertz, Commissioner G. P. Larrick, Dr. M. S. Calderone, Dr. G. Douglas.) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SiuwIcE. TVashington 25, D.C. August 29, 1963. Dn. IRVING S. WRIGHT, Cornell University Medical College, New York, N.Y. DEAR TRy: I have had occasion to repeat tests of significance on the rate dif- ferences contained in Table VI of our report on Enovid. This was prompted by a question from an outside source as to how a rate of 46.0 per million among Enovid users at the age group 40-44 could be statistically significantly differ- ent from the general population rate of 12.3 per million (even though large) when it w-as based on but 2 deaths. Retesting of significance leads me to the embarrassing discovery that an error in entering the Poisson table was made. I was under the impression that this had been rechecked but apparently it was not. The correction now reveals that neither the differences for the 35-39 year age-group nor for the 40-44 year age-group are statistically significant. T would suggest that you circulate this fact among the other members of the Committee. I am including my suggested revision of the pertinent sections in the text of the report for circulation to the Committee. Following their com- ment and approval of a new final version, I would suggest you notify the Food and Drug Administration for whatever action they may need to take. May I also suggest that the new version be circulated widely, possibly in the A.M.A. Journal. Sincerely yours, LEONARD M. SCHUMAN, M.D., Professor of Epidemiology. (Enclosure.) MEMORANDUM OF TELEPHONE CoNvERsATION BETWEEN DR. SCHUMAN, AD Hoc COMMITTEE (ENovID) AND MATTTTEW J. ELLEXHORN. M.D.. ACTING CITIEF. TN- VESTIGATIONAL DRUG BRANCH. AUGUST 27. 1903 (4 :30 p.m.) Dr. Schuman called me and stated that he had spoken to Dr. Irving Wright. Chairman of the AD HOC Committee on Enovid. I had previously spoken to Dr. Wright this afternoon at approximately 3 :00 p.m. and told him that Dr. ~ehuman. Dr. Chien of Searle and our own Mr. Peter James of our Statistical Denartment had conferred yesterday and discovered errors in the statistical evaluation of the Enovid report. The statistical errors in the Enovid report were brourht to Dr. Chien's attention by another individual and Dr. Cliien immediately sought conference w-ith Dr. Schuman and Mr. James. I stated to Dr. Wright that he should confer with Dr. Schuman for the particulars in this matter. Dr. Schuman called and said that Dr. Wright thought we had sent this report to the AMA and if so to hold it up until we have the necessary chanres incorporated. I asked Dr. Schuman about the bibliography which was absent from the final printed report. He stated that he had it and would send it to Dr. Wright who would in turn send it to us to incorporate as part of the report. Dr. Schuman will write a revision of the report to incorporate the recent statistical changes. He will then submit it to the members of the com- mittee and to Dr. Wriaht. After the committee has had time to study this revi- sion they will meet with Dr. Wright and Dr. Wright will then write a letter to the FDA incorporating these changes. Dr. Schuman said that he and Dr. Wriahit were holding up their drafts to the Humphrey Committee. He also PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6821 stated that Dr. Wright wants some copies of the final report. I stated that I would supply those to him. I relayed this information to Mr. Rankin who stated that he wanted to discuss this with Mr. Larrick this afternoon. MATTHEW J. ELLENHORN, M.D. (Cc: WBRankin, OC, RGSinith, BM, ARuskin, DND.) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, FOOD AND DRUG ADMINISTRATION, ftockviile, Md., June 3 1970. HON. GAYLORD A. NELSON, Chairman, Subcommittee on Monopoly, Select Committee on Small Business, U.S. Senate, Washington, D.C. DEAR MR. CHAIRMAN: The information requested for the record during Com- missioner Charles C. Edwards' testimony on March 4, 1970, before the Senate Select Committee on Small Business, Subcommittee on Monopoly is herewith subnntted: Your request and that of Senator McIntyre for thromboembolic data are essentially the same. The following tabulation provides the requested informa- tion. ORAL CONTRACEPTIVES-NUMBER OF CASES OF THROMBOEMBOLIC PHENOMENA REPORTED TO FDA FROM ALL SOURCES BY YEAR OF REPORTING, MAY 1, 1970 Year Fatal Nonfatal Total 1966-67 1968 58 29 310 152 368 181 1969 29 167 196 Total 116 629 745 NOTE: Data prior to 1966 is not available in any meaningful form to make a comparative determination; as the standards at that time were quite different from those during the period of 1966 through 1969. The Committee on Obstetrics and Gynecology came to the conclusion that the pre-1966 data would not be very useful and recommended use of more comprehensive data starting with the year 1966. Senator McIntyre requested that we comment on the quality of the data sub- mitted in support of the first oral contraceptive approved for sale in this coun- try on June 23, 1960. Much of the data submitted in support of this oral contraceptive seems to be rather superficial in content in the light of our present state of knowledge regarding oral contraceptives. Some of the data is little more than testimonial or opinionative in character. Many areas of investigation that would now be required were either not carried out or were not evaluated to an acceptable extent. The studies conducted were certainly not of as high a quality as we now demand, based in part on our hindsight. The material submitted appears to have been deficient with regards to data relative to 1) carbohydrate and lipid metabolism, 2) ophthalmological evalua- tion, 3) follow-up on newborns (resulting either subsequent to method discon- tinuance or as a result of method or patient failure) for anomalies or genetic defects, 4) cervical cytological studies, conducted before, during, and after medication, 5) renal function studies, 6) cardiovascular evaluation, 7) thor- ough physical examinations including breast examinations, prior to, during, and after termination of drug use, 8) adequate liver function studies, 9) long term efficacy studies, 10) animal studies, 11) coagulation and other clinical pathology studies. Senator McIntyre asked how soon after the approval of the original new drug application for an oral contraceptive did the first report of thromboem- bolism side effects come to tile Agency's attention. A report in our files indicates that a number of reports of thromboenlbolic episodes associated with tile use of oral contraceptives appeared in the litera- ture in 1961. One report was in The Lancet on November 18, 1961. While we PAGENO="0382" 6822 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY do not believe that it is possible to determine from our files when the first report of this effect first came to the attention of the FDA, we were certainly aware of them when they appeared in the literature. Under separate cover, we have submitted additional information concerning the Wright Committee Reports. If we can supply additional information or be of further assistance, please call us. Sincerely yours, XE. J. RYAN, Act h~g Director, Office of Legislative Services. (Whereupon, at 12 :05 p.m., the committee adjourned.) (Upon the direction of the Chairman, ii~formation pertaining to the subject of the hearings is included:) [From the Evening Star, January 22, 1970] WASHINGTON CLosE-UP-AssEssING BLAME IN `PILL' CONFUSION (By Judith Randal) To this observer, the sheer, unadulterated confusion that now prevails about the safety of `the pill" is less the fault of either the pharmaceutical manufac- turers or the Food and Drug Administration than the failure of government on a somewhat different score. This is not to say that-in their eagerness for profits-the makers of oral contraceptives have been entirely candid about the risks. It has come to light during the course of current Senate hearings, for example, that as early as the first clinical trials in Puerto Rico in the l9.50s. there were some sudden and uii- explained deaths which were never officially reported in the medical literature and w-ere likely traceable to the pill. Nor can the FDA be entirely exonerated. The same Senate hearings are inak- ing it clear that the agency has not always done all it could have to inform the medical profession of the nature of the risks involved in the long-terni use of chemical contraception. The importance of the first British study linking the pill to thromboeinbolisms or blood clots, for instance, was deemphasized by the FDA on the grounds that British and American racial stocks are somewhat dissimilar genetically and that therefore the experience of the one country might not be applicable to the other. This strange line of reasoning with regard to foreign data of this caliber has no other precedent. Had the evidence that thalidomide caused deformities in Eu- ropean children been ignored, there would have been many more such children born here. 1-lowever. the real problem with the pill goes back to the clays when Richard XE. Nixon w-as vice president, and his chief, President Eisenhower, was averse to assuming leadership of the family planning movement in a world already threat- ened by the population explosion. (Eisenhower was to change his views after leaving office. but that is another story.) In lhGO, when oral contraceptives were licensed, government officials felt that because the subject might be politically embarrassing, birth control measures, in- sofar as possible. should be none of its concern. The then struggling fanmily plan- 1nng movement, therefore, had little choice but to make common cause with the profit-oriented drug companies, and the lions share of the funding for research and development then passed by default to them. Progestin and, particularly, estrogen, the hormones of which the many formu- lations of the "pill" are made. influence not only the reproductive tract, but also many other organs and tissues. including the pituitary gland. the master switch of the nervous system. By the time of the pill's introduction, many of these influences were known. With what one of last week's w-itnesses called "the retropecttoscope," it is easy to see that testing should have taken them into account-particularly because oral contraceptives were designed to deal with overpopulation, a social rather than a physical ill. A concurrent approach to this same problem u-as, of course, the intra-uterine device (IUD), which, whatever its other drawbacks, didn't affect the body as a whole and has since proved to be almost as effective and about twice as safe as the pill, PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6823 This reporter remembers that in the middle 1960s, when she worked on a maga- zine for doctors supported entirely by drug advertising (as most publications for physicians are), orders were to give more coverage to oral contraceptives than to the IUD. The reason? The IUD costs only pennies and has to be brought only once, and if it is lost can be cheaply replaced. The pill, on the other hand, re- quires dollars of investment month-in and month-out, giving the drug companies the opportunity to sell the same protection over and over again. Economic considerations dictated that the pill become the darling of pharma- ceutical-manufacturer marketing efforts to physicians and the public, and thus the birth control method of choice for the middle class. This, in turn, made it the preference in public family planning projects, w-here women of lower economic strata who were given a choice of methods quite naturally opted for what they had heard to be the best. Word gets around abroad as at home, so that when w-omen in underdeveloped countries are urged to accept the aoop," many of them want to know- why they can't have "the pill," suspecting on the basis of sound precedent that they are being made the targets of a colonialist plot. The pill, for all its established and alleged hazards-cancer, stroke, blood- vessel and rheumatic diseases, to mention but a few-has revolutionized public attitudes toward birth control and is thus a powerful force for population stabil- ity in the world today. The danger is that the whole concept of family planning w-iil be discredited by the drawbacks of the present generation of the pill. This would be-~to use a not- altogether-inept simile-like throwing the baby out with the bath water. [From The Washington Post, March 24, 1070] BIRTH PILL WARNING Is DILUTED (By Stuart Auerbach) The Food and Drug Administration is w-atering dow-n its detailed listing of potential dangers from birth control pills after organized medicine, drug manu- facturers and population control groups put pressure on government officials. "The more we got to thinking about it, the more we thought that we had put too much clinical material in it," said FDA Commissioner Charles C. Edwards, who released the w-arning with a flourish at a recent Senate hearing. We decided it wasn't our role to play doctor or to scare people away from the pill," he said. The decision to rew-rite the warning, which will go directly to the 81/~ million American women w-ho use the pill-something not done with any other prescrip- tion drug-was made after talks with doctors, manufacturers and Planned Par- enthood, Dr. Edw-ards said. But he insisted that the final version will be an effective warning. He said his tw-o aims are to tell women that the pill is "a safe but potent drug" and to remind doctors that they have to keep close checks on patients for whom they p~escribe oral contraceptives. One draft, printed yesterday in the McGraw-Hill Washington Drug Letter, is 96 words long compared to the 600-word original. The new version mentions only one complication-blood clotting-without say- ing as the original did, that the risk of this to women taking the pill is six times greater than for non-users. Omitted from this draft, but in the original, are warnings that women with liver disease, cancers and unexplained vaginal bleeding should not take the pill. Also omitted are cautionary statements concerning the use of the pill by women with a history of heart or kidney diseases, high blood pressure, diabetes, epilepsy, fiberous tissue in the uterus, migraine headaches or emotional problems. "That is not a final draft," said Frank Acosta, FDA's press spokesman, "We are still working on it. They (the Washington Drug Letter reporters) got a draft along the way." But neither Acosta nor Edwards would reveal how detailed the final version would be. Dr. Roger 0. Egeberg, the assistant secretary of health, education and wel- fare for health and and Edwards' boss, reportedly persuaded the FDA commis- sioner to rewrite the pill warning. PAGENO="0384" 6824 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY `Dr. Egeberg thought it was too long," Acosta said. The American Medical Association's role in influencing the changes was re- vealed by AMA President Gerald D. Dorman in a recent issue of the AMA News. "What appeared in the press (after the Senate hearing) was an early draft that was being considered within FDA," Dr. Dorman said. "We have reason to assume significant changes will be made before the final proposal will be published." Dorman's statement is at variance with what Edwards told the Senate sub- committee when he released the original version, which he said would be pub- lished within 10 days in the Federal Register `so all interested parties will have an opportunity to comment on it." The AMA, reportedly, is opposed to the warning because it might weaken the traditional doctor-patient relationship and lead to malpractice suits. Drug companies thought the w-arning gave too much emphasis to the dangers of the pill and not enough to its benefits. Agencies such as Planned Parenthood, concerned about the w-orld population explosion, feared that the pill warning would lead to unwanted pregnancies. [From The New York Times, March 24, 1970] F.D.A. RESTRICTING WARNING ON PILL-A DRAFT REvIsIoN INDICATES ORIGINAL Is TONED DOWN WASHINGTON, March 2~3 (AP)-~The Food and Drug Administration is toning dow-n its announced package w-arning for 8.5 million users of oral contraceptive~ after pressure from physicians, drug manufacturers and high Government officials. An F.D.A. spokesman and sources in the Department of Health, Education and Welfare confirmed today that the 600-word leaflet announced earlier this month was being extensively reworded. The original leaflet referred to such serious possible reactions to the pill as blood clots, mental depression, swelling, skin rash, jaundice. high blood pressure, and elevation of blood sugar levels similar * One draft revision runs less than 100 words, mentions only a single specific danger from oral contraceptive use, and deletes detailed suggestions on w-hen women using the pill should see a physician. "Any similarity between this draft and what the F.D.A. proposed is purely coincidental," said one knowledgeable Senate source. Dr. Charles C. Edwards, F.D.A. commissioner, to read to a Senate monopoly subcommittee on March 4 the leaflet's specific w-ording, which he said, "We are going to publish in The Federal Register so that all interested parties will have an opportunity to comment on it." WARNING ON PACKAGES The warning would be contained in all packages of oral contraceptives for the education of users. It is not unusual for an agency to revise a proposed regulation after publica- tion and after receipt of comments. But it is unusual, informed sources said, for the regulation to be drastically rew-orded before publication and before formal comment is received. When asked about the revision, Dr. Edwards said today that the drafting process still was under way and the agency would require some kind of a warn- ing leaflet-a first for prescription drugs. He did not disavow the authenticity of one draft revision obtained by a re- porter. Other F.D.A. officials said the draft had been ordered lengthened. SouRces in the office of the Assistant Secretary of Health, Education and Wel- fare said revision of the leaflet was necessary for "legal and professional acceptance." Dr. Edwards ruffled bureaucratic feathers when he told the Senate subcorn- mittee about the leaflet and its specific warning without first informing his superior, Dr. Roger 0. Egeberg, Assistant Secretary of Health, Education, and Welfare. COMPLAINT BY A.M.A. The American Medical Association complained to Dr. Egeberg and the HEW. Secretary Robert H. Finch, that the leaflet would interfere with the doctor- patient relationship and possibly could lead to malpractice suits. PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY `6825 The drug industry objected, contending that the leaflet overemphasized dan- gers and minimized benefits from oral contraceptives. The revised draft leaflet has this to say about the pill's dangers: "As with all effective drugs, they may cause side effects in sonic cases and should not be taken at all by some. Rare instances of blood clotting are the most important known complications of the oral contraceptives." The original wording was much sharper on clots. It said: "There is a definite association between blood clotting disorders and the use of contraceptives. The risk of this complication is six times higher for users than for nonusers." The original warning offered signpost symptoms requiring immediate medical attention. It also said: "Your doctor has taken your niedical history and has given you a careful physical examination." The revised draft said the contraceptives "should be taken only under the supervision of a physician," and users should have "periodic examinations at intervals set by your doctors." [Press Release, March 23, 1970] (From the Office of U.S. Senator Thomas J. Mcintyre) WASHINGTON, D.C.-Senator Thomas J. McIntyre (D-N.H.) today made the following statement concerning news stories that the Food and Drug Adminis- tration has watered down its proposed consumer label warning on known and potential dangers of birth control pills: `I am deeply disturbed by press stories indicating that the Food and Drug Administration has watered down the consumer labeling for birth control pills which the agency proposed before the Monopoly Subcommittee on Small Business earlier this month. "As a member of the subcommittee I had been concerned that women who might be considering use of the Pill were not being provided the necessary infor- mation concerning its known and pOtential dangers to enable them to make an in- formed and rational decision as tO whether they wanted to use the Pill or some other method of contraception. I thought that the labeling proposed by Commis- sioner Edwards at the hearings went a long way toward answering this need. I anticipated that it would be published in essentially the same form in the Federal Register so that all interested parties would have opportunity to comment before the order was finalized. "Needless to say, I was amazed to hear that the agency had shortened the label statement from 000 words to 00 words, and if the text carried in press accounts is accurate, deleted much of the essential information, even before the order was published. "It is my understanding that since the story broke in the press, FDA is again re-writing the label statement to put some of the original information back in. I hope that this is true and I shall look forward to reviewing the final version when it is printed~" [From The Washington Post, April 6, 1970] PILL ADVICE STILL UNCLEAR AS FDA SPURNS NEW WORDING-AGENCY PREFERS SI-TORT WARNING, DESPITE PROTESTS (By Morton Mintz) An entirely new warning to users of the Pill has been recommended to the Food and Drug Administration by its outside advisers on birth control. At least temporarily, however, the FDA is rejecting the recommendation in favor of a proposal of its own. Thus it was still unclear yesterday what advice an estimated S.~S million women eventually will get with each package of oral contraceptive pills. The recommended new warning resulted from a hitherto undisclosed develop- ment last Wednesday-the invasion by two members of the Women's Liberation Movement of a closed meeting of the Advisory Committee on Obstetrics and Gynecology at FDA headquarters in Rockville. 40-471-70-pt. 16-vol. 2-25 PAGENO="0386" 6826 COMPETITIVE PROBLEMS IN THE DRUG LNDUSTRY After hearing the Women's Liberation protests, Dr. Roy Hertz, a committee member, wrote this draft for a sticker to be affixed to every package of I)ilIS "Do not take these pills without your doctor's continued supervision. Contact him if you experience any unusual symptoms, particularly the following : 1. Severe headache. 2. Blurred vision. 3. Pain in the legs. 4. Pain in the chest or cough. ~. Irregular or missed periods." All but `5" can he symptoms of blood-clotting diseases. The committee suggested that the FDA publish the draft in the Federal Regis- ter and drop a 06-w-ord agency proposal that would tell women about the Pill in general terms. with none of the committee's emphasis on symptoms and what to do about them. A Women's Liberation member denounced the 06-word statement as "w-orse than no w-arning at all." However. Commissioner Charles C. Edwards told a reporter last week that if the Secretary of Health, Education, and Welfare approves, the FDA soon will pub- lish the 96-w-ord statement "without any change." At the end of a 30-day period for filing of comments, he said, the agency will consider modifications, giving "very top priority" to the advisory committee draft. Dr. Edwards emphasized that he was not foreclosing the possibility that the statement ultimately adopted will be stronger than the 96-word version. His primary goal is to start the legal process by w-hich a w-arning of some kind will go directly to users, he said. The Women's Liberation members-Alice Wolfson (who w-as accompanied by her husband) and Judy Spelman-used a ruse to get into the advisory committee meeting. After an uproar. an agreement was reached under which they w-ould be present for discussion of the package insert problem but absent for discussion of data- which is to be published soon-indicating lower clotting rates with pills that are of the low-estrogen variety. The I)rOteSts were directed mainly at the FDA's abandonment of "What You Should Know About Birth Control Pills," a 600-word package insert that Dr. Edwards unveiled on March 4 at a heai'ing held by Sen. Gaylord Nelson (D-Wis.). "What You Should Know . . ."-w-hich Edwards. at that time. said w-ould be published in the Federal Register-says clotting diseases in users of the Pill occur six times as frequently as in non-users. points out that these diseases annually kill six users in 200.000.and specifies numerous other known and possible hazards. Nelson told the commissioner that he saw no reason why "What You Should Know . . ." should not be revised to state the clotting rates more understandably -one user in 2.000 hospitalized every year for example. He termed both the fa- tality and hospitalization rates "very high." The FDA did not dispute this at the hearing. But Dr. Edwards later abandoned "What You Should Know- . . ." for the 96-w-ord version, w-hicli mentions only one complication, clotting, and says instances of it are "rare." Dr. Edwards has said he abandoned "What You Should Know . . ." because it contains "too much clinical material," and because "it wasn't our job to play doctor or to scare people away from the Pill." He denied he was pressured by top HEW officials. The medical profession and population-control forces are known to have been deeply upset by "What You Should Know- . . ." There w-as major unhappiness, too. in the FDA Advisory Committee, which is composed of physicians. AMERICAN PATIENTS ASSOCIATION, Washington, D.C., March 27, 1970. COMMISSIONER CHARLES C. EDWARDS, Food and Drug Administration, Washington, D.C. DEAR CoMMIsSIONER EDWARDS: Reports in the press concerning revisions of your proposed labeling for oral contraceptives are quite disturbing. While the text you released March 3 may have had some rough spots, we are alarmed to learn that the proposed patient information is to be drastically revised in order to protect physi- cians, rather than patients. We hope the press reports are incomplete; but w'e are led to believe they are accurate in all respects. PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6827 If you are heeding the advice of non-governmental interest groups in the draft- ing of a final OC label, then we ask fOr an opportunity to participate also. In any case, we would remind you that thefinal printed labeling of any approved drug is a public document. If the FDA-which, in your appearance before Senator Nelson, seemed to take an important step forward in the public interest-cannot handle patient information equitably and responsibly, our Association and its sister Foundation will have to consider what actions they may pursue to fill a vacuum of responsibility in the handling of these public, albeit arcane, documents. We look forward to an early reply. Cordially, THEODORE 0. CRON, President. cc: Senator Gaylord Nelson Representative L. H. Fountain [From the Washington Post, April 8, 1970] HEW PUBLISHES WARNING ON PILL The Department of Health, Education, and Welfare settled yesterday on a fourth version of a warning to be enclosed in every package of birth control pills. The language is not necessarily final. After publication today in the Federal Register comments can be filed for 30 days. Then this language or a modification w-ill be ordered into effect, provided there is not a court challenge. The fourth version, announced by HEW Secretary Robert H. Fflich at the end of a press conference on civil rights, follows: "The oral contraceptives are powerful, effective drugs. Do not take these drugs w-ithout your doctor's continued supervision. As with all effective drugs they may cause side effects in some cases and should not be taken at all by some. Rare in- stances of abnormal blood clotting are the most important known complications of the oral contraceptives. These points were discussed with you when you chose this method of contraception. "While you are taking this drug, you should have periodic examinations at inter- vals set by your doctor. Tell your doctor if you notice any of the following: 1. Severe headache: 2. Blurred vision; 3. Pain in the legs; 4. Pain in the chest or unexplained cough; 5. Irregular or missed periods. The portion of the warning dealing generally w-ith the pill was taken from a 06-word proposal that Dr. Charles C. Edwards had wanted to publish and which, in turn, was a watered-down version `of an 800 word warning he had endorsed on March 4 at a hearing before Sen. Gaylord Nelson (D-Wis.). The second portion of the warning-advising women to be alert to possible symptoms of blood-clotting and gynecological disorders-had been recommended by the FDA's outside advisers on the pill. HEW overrode Dr. Edwards, who had tentatively rejected the advice of the con- sultants. Secretary Finch acknowledged that he now has endorsed a compromise, which he called "a delicate balance." He said he believed the shorter statement is more likely to be read. [From the Evening Star, April 7, 1970] FDA MOVES TO EN~'OR0E REVISED WARNING ON "PILL" (By Judith Randal) In the Federal Register tomorrow the Food and Drug Administration will publish a statement on the birth control pill which, unless there are further changes, will be included in every package of oral contraceptives that reaches a consumer's hands. The 120-word statement, released today at a press conference by Secretary of Health, Education and Welfare Robert H. Finch and Dr. Jessie Steinfeld, the surgeon general, is considerably shorter than the 600~word preliminary version which was read to a Senate committee on March 4 by FDA Commissioner Charles C. Edwards. PAGENO="0388" 6828 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It tells women that "oral contraceptives are powerful, effective drugs" which should not be taken without a "doctor's constant supervision" and,that "they may cause side effects in some cases and should not be taken at all l)y some." This is the full statement: *"The oral contraceptives are powerful, effective drugs. Do not take these drugs without your doctor's continued supervision. As with all effective drugs they may cause side effects in some cases and should not be taken at all by some. Rare instances of abnormal blood clotting are the most important known complication of the oral contraceptives. These points were discussed with you when you chose this method of contraception. "While you are taking this drug, you should have a periodic examination at intervals set by your doctor. Tell your doctor should you notice any of the following: "1. Severe headache "2. Blurred vision "3. Pain in the legs "4. Pain in the chest or unexplained cough "5. Irregular or missed periods." After tomorrow's publication physicians, drug manufacturers and other inter- ested parties will have 30 days to register comments and complaints with the FDA. Unless these are deemed sufficiently significant to warrant changes, the message will be included in every package of contraceptives in a few months' time. [From the Federal Register, Vol. 35, No. 70. April 10, 1970, pp. 5962-5963] DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE-FOOD AND DRUG ADMINISTRATION [21 CFR Part 130] NEW DRUGS Proposed ~S'tatement of Policy Concerning Oral Contraceptive Labeling Directed to Laymen. Pursuant to the provisions of the Federal Food, Drug, and Cosmetic Act (secs. 502 (a), (f), 505, 701(a), 52 Stat. 1050-53, as amended, 1055; 21 U.S.C. 352 (a), (f), 355, 371(a)) and under the authority delegated to the Commissioner o Food and Drugs (21 CFR 2.120), it is proposed that he following new section be added to Subpart A of Part 130: § 130. Oral contraceptive preparations; labeling directed to the patient. (a) The Food and Drug Administration is charged with assuring both physi- cians and patients that drugs are safe and effective for their intended uses. The full disclosure of information to physicians concerning such things as the effec- tiveness, contraindications, Warnings, precautions and adverse reactions is an important element in the discharge of this responsibility. In view- of this, the Administration has reviewed the oral contraceptive products, taking into account the following factors: the products contain potent steriod horomones which affect many organ systems; they are used for long periods of time by large numbers of women who, for the most part, are healthy and take them as a matter of choice for prophylaxis against pregnancy, in full know-ledge of other means of contracep- tion; and because of their indications they are sometimes used without adequate medical supervision. They represent, therefore, the prototype of drugs for which well-founded patient information is desirable. (b) In view of the foregoing, it is deemed to be in the public interest to present to users of oral contraceptives factual information as to the risks and possible side effects associated with their use by requiring, as part of their labeling, appropriate information in lay language. The information would emphasize to the patient the need for continuing surveillance and supervision by a physician. The Commissioner of Food and Drugs is aware that this represents a departure from the traditional approach to the dissemination of information regarding prescription drugs via the doctor/patient relationship, and stresses that it is not intended to weaken or replace that channel, but rather because of the unusual pattern of use by these drugs, to reinforce the efforts of the physician to inform the patient in a balanced fashion of the risks attendant upon the use of oral contraceptives. PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6829 (c) (1) The oral contraceptives are restricted to prescription sale, and their labeling is required to bear information under which practitioners licensed to administer the drugs can use them safely and for the purpose for which they are intended. In addition, in the case of, oral contraceptive drugs, the Oommissioner concludes that it is necessary in the best interests of users that the following printed information for patients be included in the package dispensed to the patient: `ORAL CONTRACEPTIVES (BIRTH CONTROL PILLS) "The oral contraceptives are powerful, effective drugs. Do not take these drugs without your doctor's continued supervision. As with all effective drugs, they may cause side effects in some cases and should not be taken at all by some. Rare instances of abnormal blood clotting are the most important known complica- tion of the oral contraceptives. These points were discussed with you when you chose this method of contraception. "While you are taking this drug, you should have peridoic examinations at intervals set by your doctor. Notify your doctor if you notice any of the following: "1. Severe headache. "2. Blurred vision. "3. Pain in the legs. "4. Pain in the chest or unexplained cough. "5. Irregular or missed periods." (2) Providing this information to users may be accomplished by including it in each package of the type intended for the user as follows: (i) If such package includes other printed materials for the patient (e.g., dosage schedules), the text of the information in subparagraph (1) of this para- graph shall be an integral part of the printed material and be in boldface type set out in a box, preceding all other printed text. (ii) If such package does not include printed material for the patient, the text of the information in subparagraph (1) `Of this paragraph shall be provided as a printed leaflet in boldface type. (iii) Include in each bulk package intended for multiple dispensing, a suffi- cient number of the information leaflets, with instructions to the pharmacist to include one with each prescription dispensed. (d) Written, printed, or graphic materials on the use of a drug that are dis- seminated by or on behalf of the manufacturer, packager, or distributor to the patient, are regarded as labeling. The Commissioner also concludes that it is necessary that full information in lay language, concerning effectiveness, contra- indications, warnings, precautions, and adverse reactions be incorporated promi- nently in the beginning of any such materials. (e) The marketing of oral contraceptives may be continued if all the follow- ing conditions are met within 30 days of the date of publication of this section in the FEDERAL REGIsTER. (1) The labeling of such preparations shipped within the jurisdiction of the Act is in accord with paragraphs (c) (1) and (2), and (d) of this section. (2) The holder of an approved new-drug `application for such preparation submits a supplement to his new-drug application under the provisions of § 130.9(d) of this chapter to provide for labeling as described in paragraphs (c) and (d) of this section. Such labeling may be put into use without advance approval of the Food and Drug Administration. All interested persons are invited to submit their views in writing, prefer- ably in quintuplicate, regarding this proposal. Such views and comments should be addressed to the Hearing Clerk, Department of Health, Education, and Welfare Room 6-62, 5600 Fishers Lane, Rockville, Md. 20852, within 30 days fol- lowing the date of publication of this notice in the FEDERAL REGISTER. Com- ments may be accompanied by a memorandum or brief in support thereof. (Sees. 502 (a), (f) 505, 701(a), 52 Stat. 1050-53, as amended, 1055; 21 U.S.C. 352 (a), (f),3'55,371(a)) Dated: March 26, 1970. CHARLES C'. EDWARDS, (Jomrn~issIoner of' Food and Dm'ug~. [FR. Doe. 70-4463; Filed, Apr. 9, 1970; 8 :48 n.m.] PAGENO="0390" 6830 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY U.S. SENATE, SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C., May 7, 1970. THE HEARING CLERK, Department of Health, Education, and Welfare, 1?ockville, Md. DEAR SIR: I am writing to comment on the proposed package insert that will be a part of each package of oral contraceptives received by the user. Dr. Charles Edwards. Commissioner of the Food and Drug Administration, is to be commended for his positive recognition of the importance of the concept of informed consent in the use of oral contraceptives. This prescription drug (lifters from all others in that it is very widely prescribed for healthy users and in that for a substantial percentage of users, at least, there sire effective alternative methods of birth control. The issue is whether the user is entitled to be informed about the benefits. risks, and side effects of oral contraceptives and alternative methods. This is the essence of the matter. It is my view that users are entitled to know what the government and the experts know. Obviously this poses difficult practical problems. The fundamental responsi- bility rests with the prescribing physician. Nevertheless, a simple, direct re- minder notice should be available to the user at all times since it cannot be expected that millions of people are going to remember their physician's ad- vice for long periods of time. Furthermore, it is clear that a substantial per- centage of users w-ere not given any advice on risks and side effects at all. It seems to me that contra-indications ought to be listed since the scientific community is agreed that those with certain histories should not use the oral contraceptive. This w-ill help assure that they do not. One sentence in the proposed reminder notice raises, I think, a serious ques- tion. That sentence is. "Rare instances of abnormal blood clotting are the most important known complication of the oral contraceptives." The word rare is a subjective term that means something different to each reader. In my ow-n sub- jective judgment, the word rare is inaccurate as used here, since the hospitaliza- tion rates due to thrombo-embolic disease in users is one in two thousand. Serious questions are also being raised concerning the metabolic effects of long-term use. In the comprehensive volume edited by Drs. H. A. Salhanick. D. M. Kipni's, and R. L. Vande Wiele, the editors state in the preface, "Until recently, the metabolic effects of the sex steroids have been inadequately in- vestigated or iguored. These accumulated data and others suggest that no tissue or organ system is free from a biological, functional, and/or morphological effect of a contraceptive steroids. Many of these changes appear to be reversible after short periods of treatment, but it is impossible to form judgments on the re- versibility of some of the changes resulting from prolonged administration. This question becomes more important daily for the many patient's who have already had long-term contraceptive steroid treatment." All of these matters pose serious, difficult medical and public policy questions. It is doubtful whether any individual has at his fingertips the final `best answer. I would suggest, therefore, that public hearings be conducted on this iss~ie so that the collective wisdom of the scientific community and the public may be focused on the issue. It would, I think, be a valuable source of information and opinion for developing the most useful and practicable reminder insert. Sincerely yours, GAYLORD NELSON, U.S. Senator. [From Science News, March 14. 1970] FDA GOES TO THE CONSUMER According to the Food and Drug Administration's last pronouncement on the subject, oral contraceptives are safe-at least by legal definition. But in its Sep- tember report (SN: 0/13, p. 198), the outgrowth of three years of evaluation by the FDA'S Advisory Committee on Obstetrics and Gynecology, the agency raised as many questions as it answered about the side effects of birth control pills, and by no means gave them a clean slate. In time decade since oral contraceptives were first marketed, reports of know-n PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6831 and suspected hazards have circulated through the medical literature and thie press with steadily increasing frequency. Recent Senate hearimigs held by Gay- lord Nelson (D-Wis.), provided a public forum at which experts recited accumu- lated data linking the pills to everything from weight gain to blood clots and cancer. Moved by mounting evidence of danger and by public and political pressure, FDA Commissioner Charles C. Edwards first circulated a warning to doctors in a special letter (SN: 1/24, p. 93), then took the final day of the Nelson hearings as the occasion for announcing a virtually unprecedented action. The FDA, Dr. Edwards said, will require drug houses to include in every pack- age of oral contraceptives a pamlJhlet cataloguing in lay language the risks linked to their use. While it is standard procedure to have manufacturers supply physicians and pharmacists with details of side effects of prescription drugs, the information ordinarily goes to the patient only at the discretion of his physician. At present, there is only one exception. Persons with bronchial asthma who inhale a drug called Isoproteronaireceive a leaflet cautioning them against over- dosing themselves and instructing them in the drug's proper use with every pre- scription. "However," says FDA'S chief counsel William Goodrich, "the informa- tion is nowhere near as detailed as that proposed for birth control pills." Further, Goodrich says, FDA has no intention of extending its requirement that information on risks go directly to the patient on other types of drugs. Though oral contraceptives are no different than other prescription drugs from a legal view, FDA considers them unique in that they are taken by overwhelming imm- hers of healthy individuals. An estimated eight and a half million women in the United States are or have been on the pill. In spite of FDA'S avowed intention to control pills, spokesmen for the Pharma- ceutical Manufacturers Association and for individual drug companies fear it could set a dangerous precedent. A representative of G. D. Searle & Co., makers of Enovids, finds, for example, -that it is not inconceivable that similar cautionary imiformation might 1)0 proposed for individuals taking amphetamines or smallpox vaccinations from their physicians. On a risk versus benefit basis, amphetamines have long been and vaccinations (SN: 1/31, p. 129) are now under fire. For the present, however, neither the drug makers nor the American Medical. Association is raising a hue and cry against Dr. Edwards' plan. Generally, they say, they have no objection to informing patients directly about the side effects of the pill. And an official statement from the AMA goes as far as to say, "The medical profession regards the pill, in most cases, as a convenience rather than a traditional medication and hence the patient must bear her share of the legal and moral responsibility for taking it." Nevertheless, it is naive to suppose that the proposed warning pamphlet will be included in packages within the next two months. Delays are expected to occur when the process of establishing the precise way. Spokesmen * * * drug manufacturers indicate that they have objections to por- tions of the wording of the proposed statement, which spells out a definite asso- ciation between oral contraceptives and blood clots-the risk is six times higher for users"-cites connections with mental depression, jaundice, high blood pres- sure and diabetes, and declares that while there is no evidence that the pill causes cancer in women, doctors w-ill want `to examine patients regularly on this score. Goodrich and lawyers for the PMA affirm that at present the drug manufac- turers have no plans to try to block FDA'S move on legal groiuicls. However, if the final w'ording turns out to be too strong for their liking, the lawyers speculate that the issue could be taken to court on grounds that, because physicians inform their patients about birth control pills, the pamphlet is unnecessary or that it interferes with the physician-patient relationships. While protesting any intention of interfering with that relationship, Dr. Ed- wards says, "I have come to the conclusion that the information being supplied to the patient in the case of oral contraceptives is insufficient." And that, says Nelson, is why be held the hearings. [From the Washington Post, May 11, 1970] AMA Opposus "PILL" WARNING (By Morton Mintz) - The American Medical Association has attacked a proposed warning to users of birth-control pills as "a dangerous departure from present practice" and has urged the Food and Drug Administration to renounce the whole idea. PAGENO="0392" 6832 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Indications are that most doctors generally agree. But Sen. Gaylord Nelson (D-Wis.), persuaded by his recent hearings that women have been inadequately jnformed about demonstrated and possible risks. told the FDA that "users are entitled to know what the goverinnent and the ex- perts know." He urged the FDA to hold public hearings on the issue. His position is supported by consumer advocates, some scientists and the Women's Liberation Movement, among others. The AMA and Nelson statements are among about 500 formal comments filed with the Department of Health. Education and Welfare since April 10. when HEW published the warning statement proposed for inclusion in every package of oral contraceptives. Yesterday was the deadline for submission of mailed comments. William W. Goodrich. FDA's counsel, said that all of the statements filed by organized medical groups take positions similar to the AMA's. w-hidh is that "the best way to inform patients effectively is through the physician." During the Nelson hearings. New-sw-eek for Feb. 0 reported that tw-o out of every three w-omen on the Pills told poll-takers that their doctors had not ad- vised them of the risks. The I)rOPosed warning leaflet, which is subject to modification, blends the views of HEW Secretars- Robert H. Finch and FDA Commissioner Charles C. Edwards. It is a dilution of a long, strong statement that Dr. Edwards originally had proposed. The statement says the pills are "pow-erful. effective drugs," should not be taken "w-ithout your doctor's continued supervision." "may cause side effects in some cases" and cause "rare instances of abnormal blood clotting." Five symp- toms are listed which if experienced should cause a user to notify her doctor. In a speech last Tuesday in Philadelphia, Dr. Edw-ards said the FDA is "giving careful consideration to all view-s. but it is our intention to carry through w-ith a final order" requiring a leaflet in every package of pills. He said he saw no other answer to the fact that "a very `substantial number" of pill users "are not under medical supervision." His hope is that a leaflet in the package "would lead them to seek medical advice before continuing to take the pill." For the AMA. Dr. Ernest B. How-ard. executive vice president, said there should be no statement to the user at all. `in the best interests of the patient and the practice of quality medicine . . . It intrudes upon the patient-physician rela- tionship" and "w-ould lead to confusion and alarm among many patients and could result in harm to some," Because the pills are prescription dm'ugs. it is "the resj)onsibility of the phsysi- elan to inform his patients of the potential hazards," Dr. Howard continued. "In counseling on family planning . . . he should provide information that will enable the patient to make an intelligent decision," Dr. Howard added. "When medical supervision is lacking, how-ever, it is unlikely that the proposed leaflet w-ill correct the situation." Nelson, in his formal comment to FDA. conimended Comniissioner Edw-ards for giving "positive recognition" to "the importance of the concept of informed (on- sent in the use of oral contraceptives." The senator agreed that "the fundamental responsibility rests w-ith the pre- scribing physicians." But, he said. "a simple. direct reminder notice should be available to the user at all times since it cannot be expected that millions of peo- pie are going to remember their physician's advice for long periods of time." [From the Washington Poit. June 24. 1970] AMA PLEDGES ALL-OUT FIGHT AGAINST BIRTH-PILL WARNING (By Victor Cohn) CHICAGO. June 23-The American Medical Association today promised a "legal and legislative battle" against a printed w-arning due soon in every package of birth control pills. ]3ut Dr. Charles C. Edwards, commissioner of the Food and Drug adminis- tration. defended the warning as a kind of "insurance policy" in the patient's interest. PAGENO="0393" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6833 The warning-ordered by the FDA this month despite AMA and other medical opposition-would tell women of possible side effects such as increased risk of blood clotting and advise "careful discussion with your doctor." "We must remember that we are long past the medicine man times when no patient knew anything about medicine except where it hurt," Edwards told a meeting here of the Pharmaceutical Advertising Club. At almost the same hour, the AMA house of delegates voted to oppose "any requirement that interjects a federal agency between a physician and his patient." The resolution listed these objections: "The proposal to supply information on side effects . . . intrudes on the patient-physician relationship and compromises individual medical evaluation The proposed statement would confuse and alarm many patients. The pack- age insert is an inappropriate means of providing a patient with information regarding any prescription drug; the most effective way to inform the patient is through the physician." The resolution also stressed "the importance of making certain this FDA re- quirement not be extended to other prescription drugs." The AMA also attacked the FDA for withdrawing drugs from the market on the basis of recommendations made by review panels "without consulting clin- ical practitioners." It criticized release of drug information to the public before informing doctors. This last was specifically triggered by an FDA statement that pills for dia- betes control may be ineffective and even harmful. That statement was based on a new University of Maryland study, one which is being questioned now by a number of diabetes specialists. The AMA delegates-this time in agreement with federal health officials- strongly opposed Justice Department rather than health agency jurisdiction over dangerous and potentially dangerous drugs. Justice officials want the au- thority both to declare drugs dangerous and to decide who may use them in research. AMA delegates then turned to an even broader health issue the health of the public, especially `those who are poor and lack care. `Sunday an AMA committee heard a series of consumer delegations complain for three hours over medical and hospital failures. The meeting was sometimes unruly, and the chairmanship was *seized by a consumer spokesman. One AMA delegate today said such sessions should be held again only if there are "no takeovers" and there is "protection of AMA members and guests from obscenities." His view did not prevail. The delegates voted to consider holding such a forum at every AMA meeting, as well as establishing a "multi-ethnic advisory commit- tee" on the special health care problems of minority groups. [From The Progressive, May 1970, pp. 25-27] THE PILL AND THE PUBLIc's RIGHT TO KNow (By Morton Mintz) MORTON MINTZ, a seasoned student of the drug industry, is the author of "The Pill: An Alarming Report," just published by Beacon Press in hardcover and Fawcett in paper.back. During, the recent hearings on The Pill, spokesmen for population control organizations charged that vast numbers of women were being scared off the drugs, would become pregnant, and would bear children who, being unwanted, would be beaten by their parents. Phyllis Piotrow, former executive director of the Population Crisis Commit- tee, went so far as to suggest that there will be a crop of "Nelson babies," in dubious honor of Senator Gaylord A. Nelson, the Wisconsin Democrat who is chairman of the `Senate Monopoly, Subcommittee. His Republican colleague from Kansas, Senator Robert J. Dole, who can be coun.ted upon by the drug industry for support at climactic moments, came through again. The "Nelson babies" phrase, he said, "is all right with me." If it really is all right, which it really isn't, then it also is all right, presum- ably, to personalize any diseases caused by The Pill-say, "Piotrow strokes" or "Dole .throir.boembolisms." PAGENO="0394" 6834 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY This mean little episode would not be wOrth recounting were it not for a couple of facts. One is that the "Nelson babies' phrase attracted substantial attention in news media. A second fact is that a troubling impression emerges from a reading of the hearing transcript: that the slur on Nelson was 5y1111)tO- matic of the attitudes of certain population control advocates. They were angry not only at Nelson, who happens to be one of the most ardent and articulate supporters of family planning on Capitol Hill. but also at much of the press and even, far-fetched as it may sound, at the application of democratic process to their particular cause, w-orthy and important as it is. Consider Dr. Harold Schulman of Albert Einstein College of Medicine. While denying that he was uring "a type of censorship," he said, If hearings such as this are going to be held. I believe the committee must carefully plan and screen all individuals who are invited to testify as to the content of their testimony." The ABM, Vietnam, Laos-subjects such as these may be the subject of Con- gressional hearings but not, he was suggesting, something as sensitive as The Pill. Dr. Anna L. Southam, of Columbia College of Physicians & Surgeons. told the Subcommittee, "I beg the press to report accurately or not at all." But she cre- ated a strong impression that, deep down, she would prefer no reporting at all to accurate reporting of, say. a statement that The Pill "should l)e monitored and restricted to women who cannot use other methods effectively." That state- ment happens to have been made by Dr. Philip A. Corfman, director of the Celi- ter for Population Research at the National Institute for Child Health and Human Development. Dr. Southam did not say if she w-as troubled by the ac- curate reporting of the uneasiness about w-idespread use of The Pill acknowl- edged by Dr. Louis M. Heliman. former chairman of the Food and Drug Administration's outside consultants on contraception. So far as is known, no one has complained of inaccuracy in the reporting of another authoritative statement: that until recently the effects of The Pill w-ere "inadequately investigated or ignored. . . . No tissue or organ system is free from a biological, functional and/or morphological effect. . . . Many of the changes appear to be reversible after short periods of treatment, but it is impossible to form judgments on the reversibility of some of the changes resulting from pro- longed administration." That statement was made by Dr. Hilton A. Saihanik of Harvard and two other scientists who, in behalf of the National Institutes of Health, ran a workshop on the metabolic effects of The Pill. Dr. Southam also w-as upset by "nonmedical science writers" (possibly includ- ing the generalist writing this article), as was Dr. Schulman. This was a way of saying that they disapprove of those reporters who disclosed, among other things, that the safety of The Pill had not been demonstrated before massive use began. In Dr. Southarn's view, such reporters do "a disservice to the consumer who should depend on her doctor for advice." Which doctor? Southam or Corf- man? Schulman or Salhanik? Perhaps Alan F. Guttmacher, president of Planned Parenthood-World Federation. His ease may be the most interesting of the lot. Physicians have prescribed The Pill for millions of American women-far more than the 8.5 million estimated to be taking it currently. In his preuared state- ment. Dr. Guttmacher cited a Gallup Poll in the February 9 issue of Newsweek. One highly revealing disclosure in the article w-as that two-thirds of the women quitting The Pill said their doctors had failed to apprise them of the risks-some of which, especially blood-clotting diseases. have been demonstrated. When asked about the disclosure by Senator Nelson, Guttmacher said. "No, I do not remember that." Guttmacher did not assert that doctors had educated themselves about The Pill before massively prescribing it; indeed, he conceded-under questioning- that "perhaps the American physician has been remiss in not trying to educate himself about the intricacies of The Pill." For such hope as it may offer, his claim was that the medical profession is "educable." Nelson brought up one of the numerous drug company pamDhlets that made blatantly misleading, and sometimes downright false, euphoric statements about safety. Guttmacher agreed. as he had to do. that such statements were far out of line. But he had not, and other population-control advocates had not, pro- tested the pamphlets when protest might have done some good-during the decade of the 19~Os when doctors were handing them out by the millions. The protests came from the FDA and the "nonmedical science w-riters" disdained by the Southams and the Schulmans. It was with poor grace that the population-control leaders laid down a barram? of attacks on Nelson for holding hearings. the entire purpose of which was to PAGENO="0395" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6835 determine if women were being ad~quateiy informed about known and possible hazards of The Pill. In an exchange with the Senator, Guttmacher did say that the hearings had "served a useful purpose in making the doctor more careful," and General William H. Draper, Jr., honorary chairman of the Population Crisis Committee, predicted that "the long-range effect . . . will be constructive and in the interest of the American people." But on the whole Guttmacher's performance was badly flawed. He went through the tired and meaningless routine of comparing the fatality rates of women on The Pill and women in auto accidents. He kept saying that it hasn't been proved, or that it is "conjecture," that The Pill may cause cancer, heart disease, diabetes, or other diseases. That is true, but he failed to say that the testing which would establish whether The Pill does or does not cause these and other dread maladies has not been done. Last September the FDA's consultants on The Pill produced a report of almost unrelieved grimness. To escape it they came up w-ith a legalistic gimmick. Saying that the law does not define safety, they drew the conclusion that The Pill earns "the designation safe within the intent of the legislation." Dr. Gutrmacher ap- proved of that conclusion. It is "verbiage which is difficult to define," lie testified. "But at least it is verbiage which does create a certain sense of complacency in the user. I)r. Guttmacher himself has produced verbiage which tranquilized women so they could be hormonized. Until studies demonstrated a cause-effect relation be- tween The Pill and clotting, he was saying it hadn't been proved that there was such a connection. "It can be stated flatly that the pills do not interfere with a u-oman's ability to bear children when she stops taking them," he said in a signed article in the February, 1966 issue of Good Ilonsekeeping. It can be stated flatly that this statement, challengeable even before he made it, is in error: Some women do become infertile. In the February 9 Newsweek article, it was noted that eighteen percent of the women polled recently had stopped using The Pill, and that only one-third of them, or six percent, had given as their reason doubts generated by the Nelson hearings. But on February 24, Dr. Elizabeth B. Connell of Columbia, and the next day Dr. Guttmacher, put the blame on Nelson for the entire eighteen percent. With the eighteen percent as a base, they made extrapolations about the ultimate number of resulting pregnancies (with scant regard for those women who switched to methods other than The Pill) and child batterings (without ac- knowledging the lack of an established correlation between children who were unwanted at the time of conception and children who are beaten). It was even suggested that large numbers of w-omen, because of time hearings, already had become pregnant and were seeking abortions. This suggestion was knocked down l)y the calendar. The Nelson hearings began on January 14. Dr. Connell's testimony was figured to have beeii completed and mailed off to the Subcommittee on February 19. That was five or six days short of the time needed for a number of women to be frightened by the hearings, stopp using The Pill, become fertile, conceive, and be reliably tested for pregnancy. Some other points got buried in the rather `fast shuffle in which witnesses such as Dr. Connell engaged. For example, millions of women have given up The Pill over the years because they didn't like the synthetic hormones, or because of other reasons unrelated to criticism of the drugs. Nelson cited a Chicago study showing that within two months of inception of use, forty percent of a group of women `stopped using The Pill. At one point in the hearings Nelson said in exasperation, "I think there has been a rather great con game played on the Aniericnn public." But why would such a thing be done? The answer is in significant part that The Pill drove a wedge between "woman" and "women"-between the individual and social engineering, between safety for one person and efficacy among millions. Once evidence of hazards began to develop and be reported, the population control people were put in a dilemma. How could attention be called to time risks without peril to their cause? How could they call attention to dishonesty in pamphlets published by manufacturers and distributed by doctors without simnul- taneously faulting, say, an assertion such as oiie made by Dr. John Rock, in the January, 1968 issue of Family Circle, that The Pill "is perfectly safe"? How could they help but he nervous about fair reporting? How could they not be privately terrified by the prospects of Senate hearings intended to elicit literally vital facts, rather than "verbiage" which creates "complacency" in the user? PAGENO="0396" 6836 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY During an exchange with Guttmacher. Nelson asked, "Do we have a right not to have public hearings and not to make the information available on the ground that all the press may not carry it the way some people think they ought to carry it? Or that it is too complicated for the public to understand? Is this the kind of decision that we have a right to make, to withhold knowledge developed by the [Government itself], or should these matters be made a matter of public knowledge, counting. as it seems we always have to do, upon the ultimate good judgement of the public to come to a reasonable conclusion? "Very frequently. in a free country. people do not come to reasonable conclu- sions," Nelson went on. "That is no reason for substituting an arbitrary system. * . . This is one of the risks, it seems to me. of having a free society in which there are many risks." It is useful to see The Pill first of all as a piece of technology, much as DDT. say, is a piece of technology, albeit in a vastly different area. We did not know w-hat we were doing when we bought The Pill, just as we did not know what we were doing when we bought DDT. The testing of The Pill having been ludi- crously inadequate, and massive unscientific and sometimes dishonest promotion of The Pill having proceeded apace despite the inadequacy of testing, we are to- day, and will remain for a long time, ignorant of the full range of its potentials for pollution of the bodies of millions of human beings. We have not even under- taken the studies which would tell us of possible effects on the offspring of some of those human beings. The issue is not whether sales of The Pill w-ould be halted (among other things, this w-ould create a bootleg market). Neither is population control the issue (not only because Senator Nelson is for it, but also because the effective- ness of The Pill in controlling world population has been drastically oversold). The issue, rather, is the rational and humane use of technology. It is not easy to forgive a con game in which w-omen who do not need The Pill, because they have acceptable alterimatives. are induced to use it in order to provide reassurance to women who do need it. [From the Evening Star, March 13, 1970] WASHINGTON CLO5E-TJP-'PILL' RAIsEs ISSUE OF RIGHT TO KNOW (By Judith Randal) Two weeks ago today, Sen. Gaylord Nelson, D-Wis., I hen conducting hearings on oral contraceptives, raised one of the most crucial issues confronting society in the 1970s. By that time. Nelson had been charged with inciting the press to sensation- alism. fostering scare headlines, and-by bringing to public attention what the scientific commimity already knew- about possible risks from "the pill"-threaten- ing efforts to contain the population explosion. But what no one else had said in so many w-ords u-as that the real issue raised was the public's right to know-. Nelson saw the opportunity to bring this issue to the fore when Dr. Alan F. Buttmacher. president of Planned Parenthood-World Population, came to the w'itness table. After pointing out that other contraceptive measures, as w-ell as pregnancy, also carry risks, Guttmacher indicated that the dangers of the pill w-ould better have been aired behind closed doors. "I have little faith in detailing the hazards of a drug . . . to a patient," he said, explaining that scientific data is too complicated for laymen to understand. Nelson saw- this as a "right-to-know" issue and decided to attack it head-on. Said he: "We debated on the floor of the Senate at great length the antiballistic missile. which is an incredibly complicated mechanical device w-hich probably nobody in the Congress could explain from a technical standpoint. Should that be dis- cussed because it is complicated and the public really cannot understand it, or should it not? Do we have a right . . . to withhold knowledge developed by time Federal government itself through research and studies and conferences like (those held by) the National Institutes of Health. or should these matters be made a matter of public knowledge. counting. as it seems w-e alw-ays have to do. upon the ulti- mate good judgment of the public to come to a reasonable conclusion?" Nelson. who is on record in favor of family planning and u-ho is an advocate of zemo population growth iu this country and abroad. has touched e sensitive PAGENO="0397" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 6837 nerve. WTe are increasingly finding in our society that too little public advance consideration of possible results from scientific or technological progress may cause a dangerous, even catastrophic, overreaction. The process goes about like this A scientific advance is made, and its manifest promise causes it to be oversold to the public. At the same time, research on what now seems a solved problem slows or grinds to a halt. The public adopts the new advance and uses it en- thusiastically without really understanding its pluses and minuses. In time, drawbacks begin to come to public attention. General revulsion sets in and, lacking possible benefits ofcontinuing research, the public tunes out. At this point, `the very real possibility exists that efforts to solve the problem will be abandoned for good. What is even more serious, perhaps, is that changing attitudes in advanced countries like ours bring themselves to bear in other parts of the world that rely on us for technological inputs. `The pill is one example, and DDT is another. There is no question DDT has `been overused in the United States, w-here it is threatening the environment. Developed countries may well get along nicely without it, but if they decide to abandon it for more expensive forms of pest control, underdeveloped countries `that cannot afford such options are likely to follow suit. If this happens, countless deaths from malaria may occur in Southeast Asia and tropical Africa because of decisions made in the United States and Sweden. This, of course, is written with 20-20 hindsight. Nevertheless, where both the pill and DDT are concerned, something very like what has happened could easily have been predicted--in the case of the pill because its hormonal components exert an influence on many body systems, in the case of DDT' because its poi- sonous properties persist in the environment long after their initial purpose is served. Which brings us back to the public's right to know. Had society at large been informed of the hazards of DDT that were known or suspected 10 years ago, perhaps laws regarding its use would be different from those on the books. Similarly, if women had been told about the hazards in the pill of which the medical profession long has had inklings, two things might have happened. First, many women might have opted for other measures of birth control, which would have been further developed than they now are; and, second, research into safer and equally effective "pills" might have had top-priority attention, which to date it has not. 0 PAGENO="0398"