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~-FOURTH CONGRESS SECOND SESSION ON PRESENT STATUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PART 32 MAY 26 AND 27, 1976 PHARMACEUTICAL COMPANY PRACTICES IN LABELING AND PROMOTING PRESCRIPTION DRUGS SOLD IN LATIN AMERICA 0 Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 73-9500 WASHINGTON: 1976 For sale by the Superintendent of Documents, U.S. Government Printing Office WashfngtOp, D.C. 20402 Stock Number 052-070-07118-8 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSINESS (94th Congress, 2d Session] GAYLORD NELSON, Wisconsin, Chairman JOHN `SPARKMAN, Alabama JACOB K. JAVITS, New York THOMAS J. MCINTYRE, New Hampshire J. GLENN BEALL, JL, Maryland SAM NUNN, Georgia BILL BROCK, .Tennessee J. BENNET~r JOHNSTON, Louisiana LOWELL P. WEICKER, Ja., Connecticut WILLIAM D. HATHAWAY, Maine DEWBY F. BARTLETT, Oklahoma JAMES ABOUREZK, South Dakota PAUL LAXALT, Nevada FLOYD K. HASKELL, Colorado BOB PACKWOOD, Oregon WALTER F, MONDALE, Minnesota* JOHN C. CULVER, Iowa WILLIAM B. CHERKASKY, Executive Director BENJAMIN GORDON, Staff EcononiiRt JUDAH C. SOMMER, Minority Counsel KAREN YOUNG, Research A8sistant SUBCOMMITTRE ON MoNoPoLY GAYLORD NELSON, Wisconsin, Chairman THOMAS J. McINTYRE, New Hampshire DEWEY F. BARTLETT, Oklahoma WILLIAM D. ~EIATHAWAY, Maine J. GLENN BEALL, Ja., Maryland JAMES ABOUREZK, South Dakota BOB PACKWOOD, Oregon FLOYD K. HASKELL, Colorado JACOB K. JAVITS,~ ~ew York 5Ex officio member. (xi) PAGENO="0003" CONTENTS Testimony of- Ledogar, Robert J., Department of Economic and Social Affairs, Page TJnited Nations New York, N.Y 1~394 Lee, Philip R., 1VLD., professor of social medicine; director, health policy program, school of medicine, University of California, San Francisco, Calif 15377 Silverman, Milton, Ph. D., lecturer in pharmacology, schools of pharmacy and medicine, and senior faculty member, health policy program, TJniversity of California, San Francisco, Calif 15360 Squibb, George S., consultant to the pharmaceutical industry 15404 Wegman, Dr. Myron E., John G. Searle professor of public health at the University of Michigan and dean emeritus of the school of public health 15383 APPENDIX Prepared statements: Ledogar, Robert J., Department of Economic and Social Affairs, United Nations, New York, N.Y 15415 Lee, Philip R., M.D., professor of social medicine; director, health policy program1 school of medicine, University of California, San Francisco, Calif 1~425 Silverman, Milton, Ph. D., lecturer in pharmacology, schools of pharmacy and medicine, and senior faculty member, health policy program, University of California, San Francisco, Calif 15444 Squibb, George S., consultant to the pharmaceutical industry 1~465 Wegman, Dr. Myron E., John G. Searle professor of public health at the University of Michigan and dean emeritus of the school of public health 15476 Letter dated May 31, 1976, to Senator Gaylord Nelson, chair- man, Select Committee on Small Business, U.S. Senate, from Mrs. Alvin F. Zander, Ann Arbor, Mich., with accompanying enclosures 15485 Article, "Rx for Tourists: Beware the Foreign Prescription Drug," by Milton Silverman, from the Washington Post Travel Section, March 13, 1977 15568 Article, "Drug Firms Soften Sales Pitches to Central Americans," by Morton Mints, from the Washington Post, March 20 1977 15574 Letter dated February 28, 1977, to Senator Gaylord ~elson, Chairman, Select Committee on Small Business, U.S. Senate, from Milton Silverman, Ph. D., University of California, San Francisco, Calif 15577 HEARING DATES May 26, 1976: Morning session 15359 May 27, 1976: Morning session 15393 (III) PAGENO="0004" PAGENO="0005" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in. the Pharmaceutical Industry) WEDNESDAY, MAY .26, 1976 U.S. SF,NATE, SUBCOMMITTEE ON MONOrOLY OF THE SELECT CoMMITTEE ON SMALL BusINEss, Wa8kington, D.C. The subcommittee met, pursuant to notice, at 10 a.rn., in room 318, the Russell Senate Office Building, Senator J. Glenn Beall, Jr. presiding. Present: Senator Beall. Also present: Benjamin Gordon, staff economist; Judah C. SOm- mer, minority counsel; and Karen Young, research assistant. Senator BEALL. The subcommittee will come to order. At the outset let inc apologize for keeping everybody waiting. When Senator Nelson graciously asked me to preside on his behalf, we had to readjust our schedule. As you can note, there is one light on above us which indicates there is a vote on the Senate floor. I will make a brief opening statem~nt. We will start the testimony. I will disappear briefly while you are giving your testimony and I will be right back after I vote, however. The Monopoly Subcommittee . of the Senate Small Business Com- mittee is holding hearings today and tomorrow on drug company practices in the promotion and labeling of drugs in the United States and Latin America. The subcommittee has accumulated considerable evidence over the years that the drug companies are not telling the same story about their drugs in all countries. Claims for their effectiveness and ~he extent of disclosure of hazards vary from country to country. A par- ticularly blatant example is the well-known antibiotic chlorampheni- col. While the labeling in this country mentions serious side effects, including aplastic anemia, grey syndrome (which causes death) and says that this drug should be used only when less dangerous drugs ~re not effective, the labeling in Italy stated that: It is a very significant fact that Chioromycetin therapy Is conspicuously devoid of side effects. The medication enjoys a high degree of tolerance with both adults and children. In the few cases where reactions have occurred, these are generally limited to mild nausea or diarrhea and only rarely does their gravity impose suspension of treatment. It is interesting to note that at the annual meeting of the stock- holders of the Warner-Lambert Company in 1972, 97 percent of (15359) PAGENO="0006" 15360 COMPETITIVE PROBLEMS IN THE DRtrG INDUSTRY the stockholders voted "no" to a resolution that the corporation change its policy by divulging to foreign doctors what U.S. law now demands that it tell U.S. doctors about the toxicity of its Chloromycetin, a product of its Parke-Davis division. Many drugs have been removed from the market in the United States-about, 6,000 of them in the last few years-because of lack of efficacy or unreasonable risks to the public. Yet these same drugs are still being sold in foreign countries. The effect of these practices on the people of these countries, especially Latin America, as well as on the U.S. public, will be discussed by our panel of distinguished wit- nesses today and tomorrow. The first witness is Dr. Milton Silverman, who is a lecturer in pharmacology, the schools of pharmacy and medicine, and the senior faculty member of the health policy program at the University of California in San Francisco. Dr. Silverman, it is a pleasure. to have you with us this morning and we look forward to receiving your testimony. You may proceed. And, as I said, during the course of your testimony I will slip out to go vote but I will be right back. But do not let my departure deter your testimony in any way. You may proceed as you wish. STATEMENT OP MILTON SILVERMAN, PH. D., LECTURER IN PHAR- MACOLOGy, SCHOOLS OP PHARMACY AND MEDICINE, AND SENIOR PACULT~ MEMBER, HEALTH POLICY PROGRAM, UNIVERSITY OP CALIFORNIA, SAN FRANCISCO, CALIF. Dr. SILVERMAN. Thank you, Mr. Chairman. I am pleased to be able to respond to your invitation and to meet with you today to report on how the multinational drug companies promote their prescription drug products to physicians in this country and to physicians and other health professionals in a number of Latin American countries. I must note at the outset that I am not a physician myself or a pharmacist. I am a pharmacologist. And I must further note that any views I may express here today are entirely my own, and do not neces- sarily represent those of my university. And, as a final prefactory statement, let me acknowledge that with- out the dedicated and courageous pioneering investigations conducted by this committe~ and especially by Senator Nelson and Benjamin Gordon, much of the work that my colleagues and I have been able to accomplish over the past few years in our own investigations would have been far more difficult if not totally impossible. The research on which I am prepared to report today will be official- ly published tomorrow by the University of California Press under the title "The Drugging of the Americas." It involves an indepth study of the promotion to the medical profession of 26 different drugs- active ingredients_rnar~eted in the form of some 40 products by 28 global drug companies. Most of these companies are based in the United States, but it is important to note that some of them are based in Europe, notably iii Switzerland, France, and West Germany. The drugs that we selected for investigation are, beyond doubt, valu- able and in some cases lifesaving. There can be no question that they PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15361 have saved many lives, not only in this country but in the Latin Amer- ican countries. But their effective use depends on their appropriate use. Although each is demonstrably effective in one or more eonditi~ns, each has equally demonstrable hazards. Some of the side effects may be only annoying, like a stuffy nose or a rash, others may be serious or fatal. And it is only with the knowledge of both, the good and the bad, the advantages and the potential hazards, can a physician in any country select the right drug to prescribe for each patient to get the maximum benefit with the least possible risk. In the United States physicians are given such information-4he good and the bad-in the package insert or in what is known as "Physicians' Desk Reference," or PDR, with which I know some of you are quite familiar. The drug company is not obliged to publish in PDR; he may elect to do so in the form of paid advertising. This book, sometimes called the "bible for prescribers," is distributed an- nually at no cost to every practicing physician of this country. Although the statements in both the package insert and PDR are prepared and paid for by the drug industry, no firm can niake any statement it wants. The claims for efficacy or usefulness are re- stricted to those for which the company has submitted what is known as convincing scientific evidence to the Food and Drug Administra- tion; and all potential hazards must be fully and openly disclosed. In some cases, the company is required to include a special warning which may read something to the general effect of: "Do not use for trivial conditions." It is important to emphasize that this information, recjuirecl by law, is intended only to inform the physician. The physician, if he wants, may use the drug for any indication, approved or not. He may ignore the warnings partially or entirely. For many years, as you pointed out, it has been known that the situation in other countries is somewhat different. As this committee disclosed at its hearings almost a decade ago, the Parke-Davis brand of chioramphenicol-known as Chloromycetin-carried warnings that were very strict in the United States but far more relaxed in Great Britain. And some of us, I am sure, will recall that when this dis- crepancy was called to the attention of a company official, he offered the del!ense that full disclosure of hazards was not required by British law, and, in fact, he went on to say that in his mind, British physicians would be insulted if full disclosure of hazards were included in advertising. That revelation before this committee was a brief but tremendously important prelude to what we can report today. In our own studies, we investigated these 26 drugs as they were promoted in the United States, and also in Mexico, the six Central American countries-Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama, along with the Dominican Republic-and in Colombia, Ecuador, Brazil, and Argentina. Mr. GORDON. Dr. Silverman, why did you not also include other countries like Venezuela, Bolivia, Peru, or Chile ~ Dr. SILVERMAN. Because, Mr. Gordon, in these other countries. there is no such comparable volume. The drug information is included almost entirely in the form of catalogs, which gives dosage forms, PAGENO="0008" 15362 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY concentrations, and price. The countries that we selected are those that have books comparable to PDR. Essentially, we conducted a comparison of what each company said about its product to physicians in the United States through PDR, and what it said about its identical product to Latin American phy- sicians in somewhat comparable-but not entirely comparable-Latin American reference volumes. Two points are important here. In the first place, I personally am in no position either to support or to condemn the policies and the decisions of FDA as these are reflected in PDR. But PDR, I think, may be viewed as a rather useful standard for comparison. It has the virtual blessings of an important governmental agency; it is based in large part on the advice of distinguished governmental and nongovernmental experts; it is widely distributed to physicians, and frequently used by them. And the drug industry in this country, although it may continue to dispute certain FDA decisions, has learned to live with them and to live with them without substantial financial trauma. In the second place, it must be understood that PDR and the Latin American books are not exactly the same. In PDR, the, statements presumably have governmental approval.. The promotional statements in the Latin American books, however, do not have approval from any governmental agency; they say what the company wants to say. :Among the books that we have looked at is one known as the "Diccionario de Especialidades Farmaceuticas," which is published in one edition for Mexico-published in Spanishr--another edition for Central America, and still a third edition for Ecuador and Co- lombia. Another, published in Portuguese, is the "Index Terapeutico Moderno," in Brazil, and another which I brought along with me is the Argentine "Therapia Vademecum," which also is somewhat dif- ferent. In the case of the other Latin American books, the company says what it wants, and this is generally published without any formal or informal governmental approval or blessing. For the Argentine book, the material is written not `by the com- panies but by the board of editors and, accordingly, the company has no responsibility for what is published. We have included it in our study if only to indicate to our readers what kinds of informa- tion are presented to physicians in Argentina. A second fact came out very quickly. In the United States, the list of the contraindications, and warn- ings, .and potential adverse reactions is lengthy and detailed. Virtu- ally every unhappy, serious, or possible lethal side effect to which a physician should be alert is included. But in striking contrast, the potential hazards published in the Latin American volumes are usually minimized or glossed over or totally ignored. In some instances, the company may disclose that the drug may perhaps cause stuffiness of the nose, but neglects to mention that the drug can kill you. In some cases, not a single danger is disclosed. Let me cite a few examples. PAGENO="0009" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15363 ANTIBIOTICS Consider first the antibiotic chioramphenicol, which has figured so prominently in the hearings of this committee. It is unquestion- ably a potent and useful drug, but its known dangers are such that it is promoted in the United States for only such serious infections as typhoid fever and a few other life-threatening but relatively infre- quent infections in which the causative organism is shown to be sus- ceptible to the drug. Physicians in this country are advised not to use it in trivial in- f&~tions, or when other effective, but less dangerous drugs are avail- able. In Mexico and Colombia, the Parke-Davis brand marketed as Chloromycetin is promoted for use not only for life-threatening con- ditions but also for tonsillitis, pharyngitis, bronchitis, urinary tract infections, ulcerative colitis, pneumonia, staphylococcus infections, streptococcus infections, eye infections, yaws, and gonorrhea. In Central America, a competitive brand marketed by McKesson is recommended for whooping cough. In the United States, the Parke-Davis product carries a long list of contraindications, warnings, and adverse reactions. Perhaps the most alarming of these include aplastic anemia and other serious or fatal diseases of the blood-forming system. In Mexico, the Parke-Davis product carries only a limited lst of warnings. In Central America, no contraindications or wftrnings are given, and no adverse reactions are disclosed. The McKesson product statement discloses a few hazards in Cen- tral America but none in Colombia and Ecuador. In the case of tetracycline, marketed by Lederle under the name of Acliromycin, numerous adverse reactions are given in the United States, a few in Mexico and Brazil, and none in the Central American countries. For Squibb's amphotericin B, marketed as Fungizone, physicians in this country are told `that this valuable but potentially toxic anti- biotic should be used primarily for the treatment of progressive and potentially fatal forms of fungal infections. No such warning is listed in the Latin American promotion. Schering's Garamycin carries roughly the same indications in the United States and Latin America, but the warnings are minimized in the Latin American promotion. ORAL CONTRACEPTIVES A similar situation was discovered in the case of a number of oral contraceptives-Ovulen marketed by Searle, Norlestrin or Prole$trin marketed by Parke-Davis, Ortho Novum marketed by Otho, Novulon marketed by Johnson, Norinyl marketed by Syntex, and Ovral or Anfertil marketed by Wyeth. In PDR, all of these are described as indicated for only one use- contraception. In the Latin American countries, they are openly rec- ommended for contraception, and also for the control of premenstrual PAGENO="0010" 15364 COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY tension, menstrual pain, problems of the menopause, and a host of other conditions. In the United States, physicians are warned of the possibility of many side-effects, especially thromboembolic. changes that can lead to serious or fatal blood clots. In Latin America, for all the products studied here, the risk of thromboembolic changes is ignored. No adverse reactions of any kind are given for the Searle. product in Ecuador, Colombia, or Brazil, for the Parke-Davis product in Central America, and for the Wyeth product in Ecuador, Colombia, or Brazil. Mr. GORDON. I might remind you that the labeling in the United States says that one out of every 2,000 women who take the oral con- traceptives is hospitalized because of blood clots. That statement is not used in foreign countries? Dr. SILVERMAN. To my knowledge, Mr. Gordon, this is not made known to Latin American physicians. ANTI-ARTHRITICS For Ciba-Geigy's anti-arthritjs drugs Butazolidin and Tandearil, only a few indications for use are approved in the United States' but many in Mexico, Central America, Colombia, and Ecuador. In con- trast, the warnings are numerous in this country but few in Latin America. No adverse reactions of any kind are disclosed for McKesson's com- petitive brands in Central America, Colombia, or Ecuador. United States physicians are cautioned against the use of such drugs for prolonged periods. The result may be serious or fatal adverse reactions. A somewhat similar warning is given in Mexico, but the matter is not mentioned in the other countries. In the United States, Merck's Indocin is approved for use in four serious forms of arthritic disease. In Latin America, many other in- dications are recommended. In the case of this product, it seems noteworthy that the hazards listed in the Latin American countries are approximately the same as those given in this country. CORTICOSTEROIDS Four widely-used corticosteroid hormones were included in our in- vestigation-Schering's Meticorten and Celestone, Lederle's Aristo- cort or Ledercort, and Upjohn's Medrol. All can be of great value in the control of arthritis, asthma, and a variety of other conditions. But all of them, especially if used for excessive periods', may cause un- pleasant or deadly side-effects-a flare-up of latent tuberculosis, bone- softening and fractures of the vertebral bones, peptic ulcer with perforation and hemorrhage, psychic changes, and many others. Few of these hazards are disclosed for Meticorten in Latin America, and none of Cele~stone in Central America, Colombia, Ecuador, and Brazil. For both Aristocort and Medrol, the major hazards are glossed over or given in nonspecific terms. The promotion of another steroid hormone, Winthrop's Winstrol, offers even more striking inconsistencies. It is described to Latin PAGENO="0011" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15365 American physicians as useful to increase weight, appetite, and strength. Such indications are not listed in PDR. What is disclosed in PDR is the risk of such adverse reactions as * stunting the growth of children, jaundice, interference with normal sexual development in children, and undesirable sexual changes in adults. Few of these are disclosed in Mexico and Brazil, still fewer in Central America, and none in Colombia and Ecuador. TRANQUILIZERS Among the so-called major or antipsychotic tranquilizers included in our study were Sandoz's Mellaril and SKF's Stelazine. As with other drug classes, the approved indications for use are few in the United States and numerous in Latin America. Among the indications not approved in this country but listed for the Sandoz product in Central America is use of the drug for the treatment of children with behav- ioral disorders, hostility reactions, inability to adapt in school, in~om- nia, sleep walking, bed-wetting, and nail-biting. Many adverse i~eac- tions for Mellaril are disclosed in the United States, a few in Me~nco, but none in Central America, Colombia, or Ecuador. In the case of Stelazine, physicians in the United States are warned of. the risk of the development of tardive dyskinesia-a disorder marked by involuntary movements of the lips, tongue, hands, fingers, and feet. Speech may be seriously affected, the face distorted, and maintenance of body position impossible. In some patients, the condi- tion may become irreversible. No effective treatment is known. In the promotion of Stelazine, the danger of this developme~it is disclosed to physicians in the United States. It is not listed in the ref- erence works in Mexico, Central America, or Brazil. In fact, no adverse reactions are listed for Stelazine in the Central American countries or Brazil. ANTIDEPRESSANTS With the antidepressants, the story is the same-rigorously limited indications for use in the United States, with full disclosure of hazards. The reverse is obvious in Latin America-many recommendations, but few hazards disclosed. This holds for Ciba-Geigy's Tofranil and Lake- side's Norpramin. In the case of Lilly's Aventyl, however, indications for use are limited in both the United States and Mexico, and th~ dis- closure of~ hazards is similar in the two countries. With Warner-Chilcott's Nardil, a member of the particularly dan- gerous group of MAO-inhibitor antidepressants, a long list of contra- indications, warnings, and adverse reactions is disclosed to physicians in the United States, only relatively minor dangers are noted in Mexico, and none is disclosed in the Central American countries. ANTICONVULSANTS Our last group includes three anticonvulsants widely used for the control of epilepsy. One is diphenylhydantoin, or phenytoin, marketed by Parke-Davis as Dilantin and by McKesson as Kessodantin. The promotion of the Parke-Davis product discloses only a few hazards in Mexico, fewer still in Colombia and Ecuador, and none in Central America. Only one warning is presented for the McKesson product in PAGENO="0012" 15366 COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY Central America, Colombia, and Ecuador, and no adverse reactions are disclosed. A similar situation was found for Sandoz's Mesantoin, with only one warning presented to physicians in the Central American coun- tries, and no adverse reactions disclosed. With Ciba-Geigy's Tegretol, numerous adverse reactions are dis- closed to physician in the United States, a few to their colleagues in Mexico, Colombia, and Ecuador, but none to physicians in Central America or Brazil. Mr. Goiu~oN. Dr. Silverman, do you have any idea on what basis a company decides which indications to promote in each country. and which hazards to disclose? Dr. SILVERMAN. Obviously this represents company policy. But we were told by drug promotion experts in some Latin American coun- tries that. generally they work on the basis that if your competitor is claiming five effective uses for his product, you have got to claim at least six for yours. And if he discloses three hazards, you are out of your mind if you disclose four. Mr. GORDON. Well, these global drug companies that you have been discussing were informed of your investigations annd your findings, were they not? Dr. SiLVERMAN. Yes, sir. Mr. GORDON.. You have discussed it with them? Dr. SILVERMAN. We have discussed it in considerable detail with them. One of the problems that we have all faced is the difficulty to esti- mate with any precision the prices that patients are forced to pay for this kind of promotion. They pay not in terms of pesos or quetzals or colones, but in needless injury and needless death. Information on the frequency of adverse drug reactions in Latin America is far from adequate, just as it is far from adequate in the United States and in Europe. Nevertheless, in every country in which we have worked, medical experts-especially hematologists, pathol- ogists, and microbiologists-have expressed to us their dismay, their frustration, and their anger at what one described to us as "this whole sickening business." They have described to us the rise of resistant strains of bacteria, due probably and almost certainly to the excessive and irrational use of antibiotics.. And with our own eyes, we have seen physicians and pharmacists distributing these potent drugs as if they were popcorn. They have described the rate of fatal aplastic anemia in Mexico, now one of the highest reported in the world, related in substantial part to the use of chloramphenicol. In Guatemala, one leading expert told us that when a child is given chloramphenicol for typhoid fever, and it dies from aplastic anemia, this is a tragedy but perhaps an un- avoidable tragedy. But where it happens when the drug is used to treat a case of virus pneumonia, or an undiagnosed respiratory infec- tion, or a sore throat, this is unconscionable. Others have told us of serious reactions to amphotericiñ B when it. is given to treat minor fungus infections without any of the precau- tions made known to U.S. physicians. They have told us of serious or fatal blood disorders, including agranulocytosis and aplastic anemia, following prolonged use of anti- arthritis drugs. PAGENO="0013" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15367 They have told us of the excessive use of steroids resulting in J~er- forated peptic ulcer or explosive flareups of tuberculosis and other diseases. They have told us of cases of permanent brain damage caused by excessive use of antipsychotic tranquilizers, and sometimes by such tranquilizers given to control bed wetting or nailbiting in children, or an inability to get along in school. We do not know how often such tragedies occur. In most cases, it seems, neither the patient nor his family, nor even the physician, is aware that the irrational use of a drug was responsible. One fact that may possibly be related is that generally throughout the Latin American countries there is no such thing as medical mal- practice. Malpractice suits are unknown. Another related factor may be the influence and the numbers of detail men, or the visitadores. In the United States, we calculate that there is one detail man for every 10 physicians. In Ecuador, there is one for every eight physicians. In Columbia, there is one for every five. And in Guatemala, Mexico, and Brazil, there is one for about every three. There are some physicians in Latin America who take advice from none of these visitadores, whom they call visiting professors of therapeutics. In some cases, they will not even let the detail men into their offices or their hospitals. There are other physicians who take advice only from these company representatives. Senator BEALL. Are these educated people? Dr. SILVERMAN. Well, they are educated. In some countries they are required to have a high school diploma. In other countries, the re- quirements are a little more vigorous. And I believe it is Costa Rica that is now implementing a law that they must have a degree either in pharmacy or in medicine. Senator BEALL. But primarily they are salesmen. Is that correct? Dr. SILVERMAN. Yes, sir. Senator BEALL. Thank you. Mr. GoiwoN. May I ask a question at this point, Mr. Chairman? Is there any possibility that any of these drugs, like chlorampheni- col, for instance, might be less dangerous for people in Latin America than for those in the United States? Dr. SILVERMAN. Mr. Gordon, this arose when the first reports came, I believe, from Bogota, Colombia. Somebody wrote a letter to the New England Journal of Medicine saying, Isn't it marvelous that Chioromycetin produces these horrible results in Europe and North America but it does not happen in Colombia. It must be sometl~ing In the genetic system ot Colombians that protects them. And this brought on a torrent of letters from hematologists and pathologists who said that this is a lot of nonsense; that ther~ had been many, many deaths from aplastic anemia. And he said "All you have to do is start looking for them and you will find them." The best information we can get now-and this comes primarily from hematologists in Mexico-is that there is a higher suscept~biiitv to aplastic anemia that may be related in part to the proportion of Indian blood in the nationid blood pool. We are certainly not ~ware of any genetic protection that keeps Latin Americans immune from these unhappy side effects. PAGENO="0014" 15368 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator BEALL. I notice on page 12 you were talking about "physi- cians and pharmacists"-but more importantly, physicians-"physi- cians are distributing these potent drugs as if they were popcorn." Dr. SILVERMAN. Physicians and pharmacists, Mr. Chairman? Senator BEALL. All right. Dr. SILVERMAN. This is another factor that intensifies the problem. Senator BEALL. I read your testimony. But is the implication that physicians are distributing them so freely because they are not aware of their effects or because they just are anxious to distribute them? Dr. SILVERMAN. Mr. Chairman, I do not know the reasons for their actions. All .1 know is what their actions are. They are distributing them with or wit!hout prescriptions. Senator BEALL. With respect to the drugs we are discussing, is the situation such that they require a prescription in the United States for some of them but do not require a prescription elsewhere? Is that right? Dr. SILVERMAN. No, sir. They require a prescription in the United States. And in most of the Latin countries, there are laws saying that they also require a prescription. It has been the feeling of my associates and myself that with the probable exception of the mor- phine alkaloids and a few other drugs, you can obtain any prescrip- tion drug that you want in almost any Latin American country with or without a prescription. Senator BEALL. You can get a prescription drug without a prescrip- tion in a Latin American country? Dr. SILVERMAN. Yes, sir. Senator BEALL. Would improved drug information remedy the situation? Dr. SILVERMAN. We would hope it would, yes, sir. Senator BEALL. `Why would it? Is that the most effective way to remedy the situation in South America? Dr. SILVERMAN. I think it is one of the requirements. The infor- mation that goes to physicians, in our mind, is inadequate. The phar- macists, who also prescribe and dispense, have even less information available. Senator BEALL. As a practical matter, although these drugs are made in the United States, this is a marketing practice of the drug com- panies. Is that correct? Dr. SILVERMAN. These drugs may or may not be made in the United States. Senator BEALL. Well, as a practical matter, to what extent do we have the authority to require manufacturers here or elsewhere to pro- vide information outside the United States? Dr. SILVERMAN. To the best of my knowledp'e, Mr. Chairman. there are no laws in the books which would control what a drug com- pany based in this country must say to physicians in a foreign country. Dr. LEE. Mr. Chairman, following the hearings of this committee in 196~ and 1968 on chioramphenicol. with widespread nublicity to the public, the use of chioramphenicol declined drsmatically in the TTnited States. The laws re~'arding the promotion of chloramphenieol were not changed. The behavior of physicians, however, changed dram~'t~- cally as the information about the adverse effects of the drug was PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15~69 disseminated, not only more widely to physicians and to the general public. The public became aware of the iDroblem just as they have with oral contraceptives thanks to public hearings. It is not a matter )ust of disseminating the information to the profession, but the gen- eral public must also be made more aware of the possible hazard. The way the drugs are promoted in Latin America, the physicians and the pharmacists are not adequately informed of the possible adverse ef- fects of the drugs which Dr. Silverman has described. Dr. SILVERMAN. In some countries, Mr. Chairman, we found that no one is allowed to practice as a pharmacist unless he has consider- able advanced training. In some cases, this could be comparable to training in pharmacy in the United States. In other countries, th.e requirements are so loose that an individual can become a lice~ised pharmacist providing he has served 5 years as an assistant to a pharmacist and can show that he is of good moral character. He i~ not required to take any examination of any kind. I can cite one instance which always will be memorable to us. We were in San Jose, the capital of Costa Rica, and for some reason- we needed some over-the-counter drug-we went into what is the largest pharmacy in the country. There was a long counter with a great many people in white jackets waiting on the customers. I stood in line behind one nice little old lady. If I had to make a curb- stone diagnosis, I would probably say that she was suffering from a severe thyroid disease. She was nervous, tense, and jittery, and very thin. When she came up to the man to wait on her, she reached into her dress and brought out a scrap of paper-it was not, a prescrip- tion; it was a piece of butcher paper, I think, on which she had ~vrit- ten something recommer~ded by somebody or other-and she asked for a drug called Largactil, which is one of the trade names ~or a very effective, very potent tranquilizer used in the control of psychosis. The pharmacist's assistant said, if my translation was right, that he had something much better. I watched him carefully. He did, not look at any book, he did not consult with any of his colleagues. He. went to a shelf behind him, and he brought down a bottle of one of the more potent antit~hyroid drugs. It is widely used, very ef- fective, but it has known hazards. Ordinarily, physicians i~i the United States would not prescribe a drug like this unless they had subjected the patient to thoroug~h diagnostic studies. Some physicians will even hospitalize their patients before they start them ofl this drug. But in this case, the clerk just counted out the prereq~iis~te number of tablets, collected the proper number of colones from the lady, who walked out. And we watched this in amaz~ment. After we got out of the store, my colleague and I still cannot agree whether this assistant was aged 14 or 13 or 12. I know he had. not begun to shave yet. Senator BEALL. Well the question I have is. whose fault is that? Dr. SILVERMAN. I think this fault has to be shared. Senator BEALL. By whom? Dr. SILVERMAN. Partly by the drug industry, partly for not making available more accurate information to physicians and pharrni~cistS. Senator BEALL. Well, wait a minute. I can understana a sitoation of a physician giving a drug to an individual, and he might not have accurate information. But here you have a case of a minor w~rking PAGENO="0016" 15370 COMPETITIVE PROBLEMS IN TH~ DRUG INDUSTRY behind a drug counter selling a drug. And I have no difficulty blam- ing that on the licensing authorities in the country where the sale was made. I have a little difficulty in shifting that blame back to stme- body here in the United States, however. I think that it is reprehensi- ble that people in those countries do not have better standards for the people who are going to dispense these drugs. But you said that in this instance the danger of the drug was fairly common knowledge to physicians, but a 14-year-old kid was dispensing it. Dr. SILVERMAN.' Right. It would be very easy to point the finger to examples of this sort- and there are many like this-in which a law has clearly been viola~te.d. But as a citizen of the United States, I do not feel that I can point a finger at any other country for failures to enforce its laws. Senator BEALL. Well, I can understand bad marketing practices and over-aggressive marketing factors, but the example you `gave m~ I think is one where the fault clearly rests with the individual who was dispensing the drug, who was not equipped to handle the job that he is performing. And I have a hard time putting that responsibility back on somebody some place else other than the people that are run- ning the pharmacy and perhaps those charged with the licensing of the pharmacy. Dr. SILVERMAN. Well, let us match that with the use of this drug Largactil, also called chlorpromazine, which is prescribed by physi- cians down there who are unaware of the'known hazards of the thug. This is legal. The physician is not violating any national laws. But he has not `been presented with adequate information by the manufac- turer. Senator BEALL. That is a reprehensible marketing practice. Dr. SILVERMAN. I think it might'be considered so. Senator B'EALL. All right. But I think we have to disassociate those two. You have to talk about the marketing practices, on the one hand, which We may or may not be able to do something about, and licensing standards in foreign countries, on the other hand, whichI do not think we can do anything about, as bad as they are, except perhaps create the kind of interna- tional discussion that would cause people to come up with better standards. Excuse me, doctor, please go ahead. Dr. SILVERMAN. All right. When these inconsistencies__inconsistent between what the com- pany is saying about its product in this country and what it is saying in Latin America-became apparent to us, we showed them to the heads of some of the American and European countries involved, and we asked how these could be explained. I think it is important to em- phasize that in no instance did the company spokesman deny the dif- ferences. Their responses usually included a number of ciifterent de- fenses. For example, they would tell us that Latin American physicians do not need any' warnings; they are already aware of any hazards. Such a claim, we learned, totally infuriates Latin American medical specialists, particularly those teaching in medical schools, and clinical pharmacologists, and by pathologists and hemotologists, who by the nature of their specialties, are most aware of the damage done and where the bodies are buried. PAGENO="0017" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 15371 Another defense is that they make more full disclosure in their package inserts, but we found there are also discrepancies in these inserts, which are not always full or complete. Furthermore, many physicians do not see these package inserts, and usually they are quickly thrown into the wastepaper basket. And at least in some areas, the use of package inserts themselves, even for physicians, is pro- hibited by law. We have been told it is their detail men who gives each physician full information on hazards. This, as Mr. Gordon will recall, is a defense we have long heard in this country, but in Latin America, as in the United States, it is generally held that you do not knock your own product, particularly if you are working on commission. I should point out here that the Latin American situation is somewhat different in that many, if not most, of the Latin American physicians are em- ployed by the government. We have been told that, in most o~f these countries, a physician cannot possibly expect to earn an income of more than $6 or $7 thousand a year. The average detail man makes far more. We have also been told that physicians know that if they write to the company, it will be glad to send them more complete information. This is one defense that I do not think deserves even the dignity of a comment. We have been told that no drug manufacturer would engage in such shoddy practices, that would tamper with the truth or cover np dan- gers, because in the long run this would cost him the confidenc~ o.f the medical profession. I do not know the answer to this one so far as Latin American physicians are concerned. I do not know that much about the Latin American medical profession. But I do know that where the profession in this country is concerned, such a defense is nonsense. Over the years, we have witnessed the record of the so-called "Dear Doctor letters," through which many major drug companies were re-j quired by FDA to notify every physician in the country that they had, in fact, tampered with the truth, or made claims that could not be supported, or they failed to disclose hazards. We have seen the re- markable cases of Chioromycetin and MER/29, both of which were investigated by this committee, and all the resultant civil suits for damages. And we have also found out what happened to the good name of the companies, to their reputation with the medical profes- sion, and to their annual sales and their annual profits. And what happened? The answer is distressingly clear; by and large, nothing happened. There are two additional defenses that perhaps are more nol*worthy. The companies tell us that the differences in promotion represent honest differences in opinion. That is to say, "We are honestly con- vinced from the scientific data we have that we are right and FDA is wrong." A drug, for example, might be proposed for use in the con- dition such as acne and FDA may turn it down. But the ôompany says, "Well, we are convinced it is good and safe for acne, and we pro- pose to so market it and promote it in Latin America." We have also found out that the idea of such differences of honest opinion would be more palatable if we could find that a company said one thing in the United States, where FDA is constantly looking over 18-950 0 -11 * 2 PAGENO="0018" 15372 COMPETITIVE PROBLEMS IN THE DRUG INDUS~Pfiy its shoulder, and something else throughout Latin America. But we find it a little more difficult to accept when it is obvious that what a company says about its product in Mexico City is not the same as what it says in Guatemala City or in San Jose de Costa Rica, which in turn is different from what it says in Colombia or Ecuador or Rio de Janeiro. And, finally, there is the statement: "Each of our foreign subsicliar- ies is managed by a citizen of the country. He knows the laws and reg- ulations, and he abides by them. We are not breaking any laws." This defense has apparently been impenetrable. The hearings of this committee, Mr. Chairman, were effectively blocked from further in- vestigation on Chloromycetin. One of the reasons is now clear. It is iiot easy to obtain copies of Latin American drug laws in this country. Fortunately, it became possible for us to work on the spot in a number of Latin American countries to acquire up-to-date copies of the laws, and to analyze them with the aid of Latin American attorneys and drug specialists, both governmental and private. The legal situation may be summarized as follows: In a number of countries, when the companies say they are not breaking any laws, they are telling the truth. They are not breaking any laws because there are no laws requiring disclosure of hazards. Each company can follow its own conscience and its own ethical stand~ ards, and that is the end of it. In a few countries, there is a kind of a grey zone; the picture is not so clear. Governmental officials believe they probably have the legal authority to require full disclosure, but the authority has never been spelled out in adequate detail, and the laws have not been enforced. But in some countries-notably Colombia__there is no lack of clar- ity. The laws are on the books. They require full disclosure of all haz- ards to all physicians. And these laws are now being flaunted. If the companies say they are not breaking the laws in Colombia, they are lying. Let me, if I may, Mr. Chairman, recite a portion of the Colombian laws. In one section, the National Health Code says, "In the labels of the products there must be included the name of the product, the num- ber of the license, the dosage, the manner of use, the contraindications, the name of the producing laboratory and the sales price to the pub- lie." And even more potent and completely clear is this regulation passed in 1963: In the text of propaganda, whatever the medium used, in the literature to the medical profession, in the labels, in the package, and In the literature or package inserts accompanying the drugs, there should always appear the contraindica- tions, secondary effects, and precautions for use. Senator BEALL. Doctor? Dr. SILVERMAN. Yes, sir. Senator BEALL. Now, you are saying in the case of Colombia, the law is on the books and you are saying that the people are breaking the law. Why does not Colombia enforce the law? Dr. SILVERMAN. That is a matter for the Colombian Government to determine. Senator BEALL. I know; but what bothers me about our discussion here is what can we do about that? If a country has a law that says that it is illegal to do something, and a U.S. company is making some- PAGENO="0019" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15373 thing and selling it in that country in violation of its laws, what can we in the United States do about that, other than publicize it? Dr. SILVERMAN. It is my understanding that there is nothing that the Food and Drug Administration or the U.S. Congress can do. Senator BEALL. Why is not the United Nations' World Health Or- ganization more active in this field? Dr. SILVERMAN. I think this is a matter that Dr. Wegman can ad- dress with much more competence than I, Mr. Chairman. Senator BEALL. All right; we will wait for his testimony. Dr. SILVERMAN. Incidentally, one internationally famed healtli edu- cator, Dr. ,Jose Felix Patino, the former Minister of Health ~n Co- lombia, put it this way to us. He said, "U.S. manufacturers would be put to shame if the U.S. public knew how they are promoting their products in Latin America." Colombia is only one of the countries that has perfectly clear laws on the books. The other three are El Salvador, Honduras, and Panama. Even within some of the multinational companies, top medical scien- tists are beginning to discover the situation for themselves, ai~d they have told us that they are appalled to find what their own firnis have been doing. I believe that when this record is disclosed to company boards of directors and to company stoákholders, at least some of them, too. will be appalled. Senator BEALL. In order to make sure we actually have the record clear, what percent of these drugs that we are talking about this morning are produced in the United States and what percent are pro- duced in wholly owned and partially owned subsidiaries in South America? Dr. SILVERMAN. So far as I am aware, Mr. Chairman, none ~f them is produced in final dosage form in the IJnited States. Senator BEALL. They are all produced elsewhere? Dr. SILVERMAN. I understand that they are put in final dosage form and bottled elsewhere. Senator BEALL. Would that mean that the FDA would have no au~ thority over them at all since they are not produced here jn final dosage form? Dr. SILVERMAN. That is my understanding, Mr. Chairman. Senator BEALL. So there is no way anybody in the United States can reach these drugs, legally. Dr. LEE. The only way I think that anything can be done by the FDA, Mr. Chairman, would be if the Agency for International De- velopment provided a loan or a grant for the purchase of drugs in the United States, which then would be shipped to a Latin American country. Senator BEALL. And put in final form. Dr. LEE. The drugs would be put in final form in the United States and shipped abroad. Senator BEALL. I see. Dr. LEE. We would have to find out from AID how much of that is done, but I would question whether much of it is done. Senator BEALL. Would the FDA have authority over any drug put in final form regardless of where it goes in the United States? Dr. SILVERMAN. In the United States? Yes, sir, I believe it does. Dr. LEE. Yes, sir. PAGENO="0020" 15374 COMPETITIVE PROBL.EM$ IN THE DRUG INDUSTRY If it is manufactured in the United States, it would, Senator BEALL, If manufactured. Dr. SILVERMAN. And bottled and labeled here. Senator BEALL. And if put, in final form here, the FDA has authority. Dr. LER. Yes. Senator BEALL. And you are distinguishing between drugs bought with and without AID funds? Dr. LEE. The FDA could do something about that. Senator BEALL. You can do that whether AID buys it or not? Dr. LEE. Yes, I believe so. Senator BEALL. It has been pointed out by the staff here that the law says that "So long as it is not in conflict with the laws of the country to which it is intended for export it is legal." So if it does not violate the laws of that country it is all right for them to produce it and ship it out. Excuse me. Go ahead. Dr. SILVERMAN. One other aspect that I think deserves a little more attention, Mr. Chairman, is that the medical care system in Latin America is not the same as that in the United States. There are many Latin American patients who, for whatever reason, do not have ready access to a physician. If they or their children are stricken by an ill- ness,. they can get care at low or no cost in many instances bygoing to a social security hospital. Unfortunately, the supply of physicians in most of these countries is not adequate to meet the needs. Accord- mgly, if you need medical care for yourself or one of your children, you may have to go to a hospital and stand in line for many hours, starting maybe at 5 or 6 o'clock in the morning, and waiting for many hours and sometimes many days before you can get in to see a physican. Under such conditions, if you have a serious acute illness, or if your child is seriously ill and possibly dying, you have two alternatives. You can ~o to a private physician-and there are some excellent pri- vate physicians in Latin America-but for this you have to pay cash. You might have to pay a large doctor bill amounting to perhaps as much as $2 a visit. This does not sound like much, but if you are living on a per capita income of $200 a year, it is a lot of money. The only other alternative the patient has is to go directly to a pharmacist. And even though, as We mentioned before, this may be against the national laws, the pharmacist not merely dispenses the drug, he prescribes it and lie diagnoses. In some instances, particularly in the smaller villages, there is no physician. The only health profes- sional available is the pharmacist, and he has no recourse except to do the best he can. And in some instances, the pharmacist practices every- thing up to and including surgery. Still further out, in the more remote parts of the country, there are not even pharmacists, and the medical care is given by the village witch doctor, who may prescribe herbs or incantations or whatever. In some instances-and we are nOt sure how this comes to pass-he may dis- pense potent antibiotics. The crux of the problem, as we see it, is not whether a physician or a pharmacist will be influenced in his prescribing decisions by such factors as poverty or cultural attitudes, the incidence of disease, and so on. It is whether or not he is given ready access to the scientific facts PAGENO="0021" COMPETITIVE PROBLEMS IN PEE DR1JG INDTJSPR~ 15375 on which he can base the appropriate precribing decision. It is whether or not the drug companies tell the truth and all the truth. Again, the problem is not simply a matter of violating laws in the developing nations, as important as that may be. It is that what should be the ob)ective presentation of knowledge is being twisted by the morals of the marketplace. That is, if it is possible and you can get by with it, it is ethical. The problem is that medical science is being prostituted. There are, Mr. Chairman, many related aspects on which others far more competent than I may wish to comment. There are matters of drug prices and the handsome profits that some of these global drug companies have been extracting by means of their promotional practices in Latin America. This may be blood money, indeed. There are the matters of ethics and morality, and how drug com- panies view their social responsibilities and to whom they feel responsi- ble, whether it is to their corporate officers, their stockholders, or pa- tients here and abroad. And there is the mafter of telling the truth, `all the truth, and of deciding whether the `truth depends on international borders, whether what is truth in one country may be untruth in another. For example, I find great difficulty in comprehending how a company can describe one of its products as dangerous in San Diego but safe a few miles across the border in Tiajuana, or how it can promote the product as effective in only 4 conditions in Washington, D.C., in 10 in Mexico, and in 17 in Central America. There is another aspect that I am sure has not escaped the attention of this committee. Over the years, we have all heard American drug companies individually complain bitterly in public that the present FDA laws are excessively harsh and, in fact, are totally unnecessary. The companies insist they would live up to their moral and sodal re- sponsibilities, laws or no laws. The record of their performance in Latin America, where the laws have been safely bent, or broken, or ignored, or where there are no legal restrictions on drug promotion, might, to coin an expression, make a person wonder. Remaining for consideration is what can be done about this un- pleasant affair. As I noted earlier, so far as I c~n determi~ie, there is nothing that FDA can do under existing law, especially if the product is' put into final dosage form and bottled outside of the United States. And even though the Congress is empowered under the Constitution to* regulate foreign and domestic commerce, it is my understanding that the Congress :cannot enact any laws to regulate this kind of foreign commerce. Instead, it is my belief that there are a number of thiñgs that, must not be done. There are some that could be done and s~me that must be done. Among the steps that must not be taken is to attempt in anyway, to act as Big Brother, to try and export the policies and practices `of FDA to Latin America, to export our clinical or social standards, or to tell Latin American physicians and pharmacists how they should praótice their professions. We must never tell Latin American legislators what drug laws they should enact. Any such efforts on the part of this or any PAGENO="0022" 15376 COMPETITIVE PROBLEMS Th.t T13E. DRUG INDU&I'RY other country would be impracticable, morally indefensible, and impertinent. Then there are certain steps that might be taken. Most important, I believe, would be to alert, mobilize, and support the world medical- scientific community, the health scientists, and the health professionals of every nation. I believe very strongly that the international medical- scientific community has the unavoidable responsibility, not merely to recommend, but to assure that full and objective information on drug products is made available to all nations in which they are marketed, and to all physicians and all pharmacists who may prescribe or dis- pense. It should be the responsibility of this world medical-scientific community to resolve the differences of opinion that will inevitably arise and to set at least minimum guidelines. Now this international medical-scientific community has no formal structure-it has no officers, no bylaws, no official delegates-but it is far from impotent. Even without any legal powers, it has already played a key role in having controls placed on the use of human sub- jects in medical research, assuring more humane treatment of pris- oners, reducing enviromental pollution, slowing, the world population explosion, and placing at least some safeguards on so-called genetic engineering. Although it should not-and probably cannot-dictate to aphysician how he prescribes, it should see to it that each physican has available to him full and honest information. And, finally, there is one thing that must be done. The existence and the nature of the problem must be made fully known to all countries, their physicians, their pharmacists, and their patients. It should be made fully known to all drug companies-their officers, their boards of directors, and their stockholders. In your committee hearings today and tomorrow, Mr. Chairman, in the publishing of our findings, I believe we have taken the first step to achieve this goal. Thank you, sir. Senator BEALL. Thank you, Doctor. I think we should be concerned about problems of this sort. It seems to me that it, as a matter of public interest or for public health, we establish policies in this country relating to the admonitions or the warnings that are placed on the drug containers as a matter of policy, then I think it isreasonable to assume that the producers of the drugs should also produce those same warnings for people wherever they live, even outside the United States. And I would hope tl1~ the drug companies would fe~el compelled to do that. At the same time, I think that we have to be careful that we do not tar American producers with the inadequacies of local government regulations or local laws. Dr. SILVERMAN. I agree. Senator BEALL. And I think there is too much of that around the world. And I would hope that as a result of using world health or- ganizations and other international organizations we could get some influence brought to bear on that problem and improve licensing and training that is available for people in these governments who are dis~ensin~drags~ ~. .. ~.. . Dr. Le~i xt,T'l~lie~re. ~ t~)rJ( PAGENO="0023" COMPETITIVE PROBLEMS ]N THE DRUG INDUSTRY 15377 STATEMENT OP PHILIP B. LEE, `M.D., PROFESSOR OF SOCIAL MEDI- `CINE, DIRECTOR, HEALTH POLICY PROGRAM, SCHOOL OF MEDI- CINE, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, CALIF. Dr. LEE. Mr. Chairman, I am pleased to have this opportunity to appear before the Subcommittee on Monopoly, Small Business Com- mittee, to respond to the committee's request to discuss the results of Dr. Silverman's studies on drug product promotion in Latin Amer- ica. Like Dr. Silverman, the views I express are my own and do not necessarily represent those of my colleagues at the University of California. Although I have had the opportunity of reviewing the results of Dr. Silverman's studies in detail, I focus on the statement which I would like to submit for the record, and the remarks that will sum- marize that statement, on one problem, specifically, the development of drug-resistant pathogenic bacteria and the relationship of this prob- lem to drug promotion, physician and pharmacist prescribing and d~s- pensing in Latin America. Specifically, in the statement I discuss in detail the problems that arose in Central America because of an epi- demic of Shiga dysentary due `to Shigella dysenteriae strains resistant to chloramphenicol, tetracycline, streptomycin, and sulfonamides, and the problems that arose in Mexico because of an epidemic of typhoid fever caused by chioramphenicol-resistant Salmonella typhi. Uiitil the epidemic of typhoid `fever in Mexico in 1972, chloramphenicol was the drug of choice for this disease throughout the world. In Mexico, it proved ineffective because of drug resistance. The development of pathogenic bacterial resistance to antimicrobial drugs has been a serious problem in the United States since the de- velopment of penicillin-resistant staphylococci in the 1950's. In the 1960's resistant strains of meningocoocci appeared causing mei~iingitis in members of the Armed Forces, Patients with bacillary dysentery in Various parts of the world were found to harbor strains of Shigella resistant to several antimicrobial drugs. In the late 1960's the epidemic of Sluga dysentery in Central America was caused by Shigella resist- ant to chioramphenicol and other antimicrobial drugs. In the 1970's a typhoid fever epidemic in Mexico was found to be due to' Salmonella typlii strains resistant to chloramphenicol. Re- cently, in the United States and in Egypt, cases of meningitis due to Hemophilus influenza strains resistant to ampicillin and penicillin have been reported. In 1975, physicians at the U.S. Naval Medical Research Unit No. 3, in Cairo, Egypt, reported for the first time isolation of chloramphenicol-resistant Salmonella paratyplii A in a patient admitted with chronic enteric fever. The problem is not limited to the United States, it is a worldwide problem. `The increasing prevalence of drug-resistant strains of bacteria is apparently related to the widespread use of antibiotics and' other anti- microbial agents. This is due, to a considerable extent, to irrational prescribing by physicians, irrational dispensing by pharmacists where they are permitted to dispense antibiotics `~vithout a physician's con- sent, and to the promotional practices by, the drug companies that en- courage irrational prescribing and dispensing. I should note here-and I think Dr. Wegman will also emphasize- that the promotion is not oniy by U.S. multinational corporations but PAGENO="0024" 15378 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY by corporations based in Switzerland, Germany, France, and England. So that it is not exclusively a U.S. problem. Senator BEALL. Are the promotional practices generally the cause of the irrational dispensing and prescribing of drugs? Dr. LEE. I think they are, in part, related to that. In Latin Amer- ica, I think that the educational programs for physicians and phar- macists are inadequate, as they are in the United States. The promo- tional practices by the pharmaceutical companies also foster irrational prescribing and dispensing. The continuing education of physicians in the United States is larg~dy dependent on the drug companies. That is also true in Latin American countries. After physicians com- plete their basic training they continue to get information which is not fully accurate. They are not provided the information that they need to prescribe rationally and for the pharmacists to dispense rationally. Dr. Silverman in his testimony dealt at some length with the pro- motion of chioramphenicol in Latin America, and in my statement I discussed this in detail. What are the consequences of the type of promotion that we see for antibiotics, specifically chioramphenicol, in Latin America? First, physicians and pharmacists will be more likely to prescribe and dispense chioramphenicol either when it is not needed, when it is contraindicated, or when other drugs would be more appropriate. Patients will be more likely to take chioramphenicol without par- ticular concern for the possible hazards or they may be totally unaware of the hazards, and some will undoubtedly suffer serious, indeed fatal, side effects. The regulation of the manufacture, promotion and marketing of drugs is the responsibility of the government in each country where the drugs are made, sold and promoted. Drug companies may, and indeed do, adopt standards that exceed the requirements in many countries. The regulations of the drug industry in Mexico, Guate- mala or any other country should, however, be a matter of concern for the United States. because inadequate regulations poses a hazard both ~for the citizens of the countries involved and for. the visitors to those countries, and potentially for those who never traveled to the countries. In short, inadequate regulation poses a potential threat to world health and this is narticularly. true because of the emergence of drug resistant strains of bacteria. In my statement I detailed same of the history, the pharmacology and the microbiology that is involved in this problem. In Latin America there are, of course, millions~ of residents of those countries who are exposed to these hazards. It is also important to note that 21/2 million residents of the United States travel to Mexico annually. Millions more travel to Central America and to other Latin American countries, as do travelers from Europe, Asia and Africa. At least one-third of the travelers to Mexico and many other Latin American countries are likely to suffer an episode of gastroenteritis during or following their trip. If they develop that they are very likely to be prescribed a potentially dangerous drug, chioramphenicol, as an example. They then may develop a serious side effect either during or subsequent to that treatment. PAGENO="0025" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15379 In addition to the hazards to the visitor, we have noticed in the United States the development of an increasing number of cases o.f Shiga dysentery due to drug resistant organisms. In Guatemala, the epidemic of Shiga dysentery killed 12,500 people; in El Salvador, 2,000 additional deaths occurred. Many of those who died were young children or old people. We have not seen that kind of high mortality rate in the United States but we have seen an increase in the number of cases. In 1965 there was one case of Shiga dysentery in the United States. In 1968-this was before the epidemic in Central America- there were five cases. In 1972, there were 70 cases, and 58 of those were in the border States of California, Arizona, Texas and New Mexico. I am sorry I do not have more recent information, but it may well be that those cases have continued to increase. Perhaps even more important than the Shiga dysentery epidemic was the epidemic of typhoid fever in Mexico which illustrates the problems that arise when the organisms causing the disease are re- sistant to the drug of choice, in this case, chloramphenicol. In May 1972, Mexican authorities announced the existenc~ of a widespread outbreak of typhoid fever. A total of 6,342 cases were re- ported in 1972, a 100 percent increase over the 1971 total. The epidemic subsided in mid-1973. Many of the early cases were treated with chloramphenicol and many of them died because it was not known initially that the drug was resistant to chioramphenicol, a drug that had been used for more than 20 years to treat the disease and treat it very effectively. In addition to the thousands of cases of chioramphenicol resistant typhoid fever reported in Mexico during the epidemic, cases due to the Mexican epidemic strain of San~&oneila typhi were also later reported in the United States and Great Britain. There have been isolated cases of chioramphenicol resistance to &thnonella typhi-that is the cause of typhoid fever-since 1950. But prior to the Mexican epidemic in 1972, no epidemic was caused by a resistant strain. There have been cases reported in England, India, West Africa, Greece, Israel, Chile, Kuwait and Spain. And in the cases from Kuwait, for example, they arose in at least three different places: one in Aden, one in Cairo, and one in Pakistan. The resistance to ehioramphenicol is due to a resistance factor that can be transmitted to other bacterial strains so that it can spread to other enteric organisms and produce other cases of drug resistant in- fection with interric bacteria. Senator BEALL. What, if anything, did you find about chiorampheni- col in China? Dr. LEE. Well it is interesting. Dr. Wegman and I went to China together on a mission in 1973, and I was really appalled at the way they use chioramphenicol. It was used frequently in out-patient clinics and hospitals. It was used even by barefoot doctors to treat febrile illness, much as it is used in many other developing countries. There was little evidence that the prescribers were sufficiently aware of the possible adverse effects. It is interesting that some of the articles that have appeared in Chinese medical journals have decried the misuse of antibiotics in out-patient clinics, specifically the overuse and misuse of ehioramphenicol. So that some of the people there are aware of the PAGENO="0026" 15380 COMPEflTIvE PROBL~EMS IN THE DRUG INDUSTRY problems. But it appeared to be misused there as it is misused in many other parts of the world. Myron, would you agree with that observation? Dr. WEGMAN. I would agree entirely, Mr. Chairman. I too was struck by the overuse. It seems that the knowledge of the danger simply has not penetrated into that vast country. `One of the problems is that China, we found to our surprise, had no single, monolithic health sys- tern; there are a whole series of health systems, making communication more difficult. Senator BEALL. They cannot communicate. They have great problems. Mr. GORDON. Do they not have access to the PDR and the material that we have in this country? Dr. LEE. Not out in the rural areas, Mr. Gordon. Certainly, the aCa- demic physicians and the people in the major hospital centers that we talked to were well aware of the hazards. Senator BEALL. `The medical elite, so to speak. Dr. LEE. Right. But that~ information was not disseminated widely, as it should have been. Dr. SILVERMAN. Mr. Chairman, if I might, I think it is important to recognize that the rationality of the use of chloramphenicol may depend on other circumstances. For example, I think Dr. Lee and Dr. Wegman would be horrified at the way chioramphenicol is used in some of the larger metropolitan areas in Latin America. There, we hope the use is beginning to drop off. But out in the jungles, this is a different situ- ation. The physicians or the pharmacists or even the witch doctors practicing there do not have access to a whole arsenal of different antibiotics. They have miserable sys't~ms of preserving materials. They have very limited transportation facilities. They have essentially no laboratory facilities to culture which type of organism is involved. And there, I think, the health practitioners take what is clearly a cal- culated risk. They recognize that if they use chloramphenicol they possibly cause a few hundred cases of serious or fatal aplastic anemia. But on the other hand, they may save the lives of thousands or tens of thousands of patients from dying from an infectious disease. Senator BEALL. Am I correct? You are talking about chiorampheni- col, about a drug where everybody seems to know, or everybody who is trained seems to know the consequences of the. use of this drug. Are you suggesting that in the case of this drug the drug companies are not adequately warning people as to its effects? You indicate that although in the medical centers the people do know, they have not told the people for whom they are prescribing the drug what the side effects are. Dr. LEE. In Latin America that certainly is the case. Even' in~the United States part of the problem is the continued irrational pres~rib- ing of chioramphenicol by physicians who do get the warnings and do have the information available. There is still some misuse `of it here, but it does not compare to the extent of the misuse that we have now seen in Latin America. When we see the development of epidemics of typhoid fever or Shiga dysentery caused by chloramphenicol' resist- ant organisms, that is evidence of a' possible consequence of the misuse in a developing country where the sanitation is not as adequate and PAGENO="0027" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15381 where these diseases are more endemic than they are in the United States. Senator BEALL. Well my question is, is it the fault of the pro4ucer of the drug or is it the fault of the medical fraternity in those coun- tries that this is taking place? Dr. LEE. It is all three. It is the fault of the pharmacy profession, the medical profession, and the drug industry. Senator BEALL. But in no particular order. Dr. LEE. I would say in no particular order. Dr. SILVERMAN. A. partial answer to that question, Mr. Chairmá~n, is that in the offices of some of the finest practitioners in Latin America, particularly in the medical schools and their great hospitals, they have on their shelves not merely the Latin American books, but they also have PDR, which they brought in themselves from the United States, and that is where they got their information. Senator BEALL. In very limited numbers. Dr. SILVERMAN. I said only the very best practitioners. Dr. LEE. Let me just turn to my recommendations, Mr. Chairman, which begin on page 16. In my statement I address myself to the prob- lems of the regulatory policies particularly related to the promotion and dispensing of drugs because I think that is a basic problem. We can do less about medical education and less about pharmacy education. First, I think that all major U.S. pharmaceutical firms that market drugs in Latin America should be asked to review their presei~t pro- motional practices or those of their affiliates and adopt a standard of promotion and marketing throughout the world that is fully con- sistent with, if not identical to, the practices required in the United States. Second, the American public should be made aware of the hazards posed by the misuse of antibiotics, particularly the problems posed for travelers, where antibiotics may be dispensed without a prescription and the individual receiving the drug need not be informed about the potential hazards. Perhaps the U.S. Public Health Service could de- velop an informational document for international travelers on the problems posed by the misuse of antimicrobial agents. You can get information about immunization, but I have not seen comparable in- formation about the hazards posed by the misuse of antimicrobial drugs. Third, the Center for Disease Control (CDC) should be given the resources nscessary or needed to carry out the.clinical, epidemiological and laboratory studies necessary to determine the nature and extent of the health hazards posed by the emergence of drug resistant patho- genic organisms. The CDC should have the staff, facilities and equip- ment to monitor the emergence of resistant strains, to work with local health departments and. hospitals and others to study the problems as they arise. The Director of CDC should be asked to report amwally on the problem. of drug resistant pathogenic organisms, the hazards posed and what actions are appropriate to reduce or eliminate the hazards. Fourth, the Department of State and the Department of Health, Education, and Welfare should be fully appraised of Dr. Silverman's findings and requested to propose policies to deal with the problem to PAGENO="0028" 15382 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the World Health Organization, particularly to the office for the Western Hemisphere Region, the Pan American Health Organization. Fifth, the FDA should be asked to review its authorities and report to the Congress what measures, including new legislative authority, might be taken to restrict the use of critically important antibiotics, such as chloramphenicol, to those patients where its use is essential. Finally, Mr. Chairman, let me join with Dr. Silverman and com- mend you, Senator Nelson, and other members of this committee, and the committee staff, particularly Mr. Ben Gordon, for again bringing to the attention of the Congress and the American people a serious problem related to the promotion, marketing, prescribing, dispensing and use of drugs that poses a very real hazard to our health. Thank you. Senator BEALL. Thank you, Dr. Lee. I appreciate. your suggestions because it seems to me that your suggestions are very reasonable. and very practical. This is more than just a local problem as far as we in the United States are concerned. This does appear to be something that will have to be handled through international organizations and certainly something that deserves high priority and consideration in those international organizations. Dr. LEE. We have an expert on that on my right. Mr. GORDON. Dr. Lee, Dr. Silverman found that the oral contracep- tives were not promoted properly in Latin America and no notice was given about blood clotting and so forth. Do you have any comments to make on that? Dr. LEE. Yes; it poses a very great problem for the women who receive those drugs. It poses a problem for the physicians who pre- scribe the drug who may really be unaware of the hazard. As we have learned in the United States, as physicians became aware of the haz- ard here, and as the general public became aware of it, thanks to, among others, this committee and Morton Mintz of the Washington Post, the use of oral contraceptives dropped dramatically, and people were able to make choices. I think the same choices ought to be available to physicians and to patients in Latin America who receive oral con- traceptives, because otherwise they are exposed to undue risks. Mr. GORDON. Well, my understanding from your testimony is that it really is not a Latin American problem, but it is a world problem because it does affect us here, too. Dr. LEE. Absolutely. Mr. GORDON. So the U.S. Government is concerned to some extent. is that not right? Dr. LEE. Yes; the Government should be concerned because any American traveler to Mexico may develop diarrhea and may go to a physician or a pharmacist and get a prescription for chloramphenicol without being aware that it is chioramphenicol. The same thing can happen in Spain, the same thing can happen in Egypt where chlor- amphenicol is the drug of choice for fevers of unknown origin. It can happen a]most anywhere in the world. Senator BEALL. I think you have provided an answer for this com- mittee in that respect, Doctor. I think this committee should write a letter to the Public Health Service suggesting they publish a docu- ment-we can do that today-that warns American foreign travelers of the kind of situations they might run into if they get into a foreign PAGENO="0029" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15383 country and a certain drug is given to them for their use. That is one of your suggestions at the top of page 17, and I think we ought to fol- low through on that suggestion. Thank you very much, Dr. Lee. I appreciate your testimony. Dr. l~egman? STATEMENT OP DR. MYRON E. WEO1VIAN, JOHN G. SEARLE PItO- PESSOR OP PUBLIC HEALTH AT THE UNIVERSITY OP MICH~GAN AND DEAN EMERITUS OP THE SCHOOL OP PUBLIC HEALTH Dr. WEGMAN. Mr. Chairman, I am Myron E. Wegman, John G. Searle professor of public health at the University of Michigan and dean emeritus of the school of public health. I have a prepared statement, Mr. Chairman, which I have submitted for the record. I should like to elaborate on it orally. Let me explain, first, that my presence here has two bases. In the first place, I have spent a great many years in the international health field. Before coming to Michigan I was for almost 9 years a full-time staff member of the Pan American Sanitary Bureau, which serves as the regional office for the Americas of the World Health Organization. During the last 4 years I was Secretary-General and have traveled throughout Latin America. The other base is that I am chairman of an ad hoc seminar group in Ann Arbor, which is attempting to bring together a group of peo- ple from a number of fields-medicine, dentistry, nursing, law, phar- macy, psychology, and ethics-to work on ways of achieving rational use of medicine. The stimulus for bringing of our group together was a tragedy that was suffered by Professor and Mrs. Zander of our faculty, whose daughter, while traveling in Spain, was given a dru for a completely irrational use. She came back to Ann Arbor, an despite many, many blood transfusions, died of aplastic anemia. The Zanders have devoted themselves to preventing recurrences of this tragedy and a good deal of my own knowledge comes from the efforts of Mrs. Zander and Professor Zander in providing information. Our committee has gone into many of the problems involved-one having to do with the ethical values. We have also tried to look at com- mercial aspects, educational aspects, professional education, and edu- cation of the public. I ought to point out, however, Mr. Chairman, that my presence here is as an individual because our seminar has not reached conclusions or formulated its recommendations yet. I want first to call attention to something perhaps already known to most people in this room. Latin America is an area of the world that is particularly sensitive in regard to drugs. There are a nwnber of reasons for this. The pharmaceutical industry is very poorly deVeloped, so most of Latin America is particularly susceptible to imported drugs. There is, however, some promise for change. Recently, as ~ou may know, the Andean Pact countries-the six countries along the range of the Andes-have come together in a variety of ways; among them Peru is trying to take the lead in providing a center for manufacturing generic drugs and drugs that will be more readily available. There is one other important fact. In most of the countries of Latin America, as has been brought out in previous testimony, the analog PAGENO="0030" 15384 COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY of the Food and Drug Administration, usually in the Ministry' of Health, is far less powerful and far more susceptible to outside pres- sure. Furthermore, in any developing economy there is a general tend- ency to put marketplace considerations ahead of welfare aspects. As you made clear in your own remarks, Mr. Chairman, a very im- portant way t~ get at this problem is through professional education of physicians. 1~rofessional education is sharply limited in Latin America through lack of resources. One phase in which I am intimately con- cerned now has to do with providing textbooks. In many Latin Ameri- can countries up to recently, most of th~students in medical school used, instead of textbooks, mimeographed notes or notes that they took themselves. I am a trustee of the Pan American Health and Educa- tion Foundation, which, with a loan from the InterAmerican Devel- opment Bank, is providing textbooks to students at half price. I believe this can be an exceedingly important measure for achieving better use of drugs, among other aspects of medical education. Mr. Chairman, you asked earlier in this hearing about why the WHO and PAHO are not doing more in this field. Actually they have done quite a lot. Last year, our seminar had the privilege of a long session with Dr. Marcolino Gomes Candau, the Director-General Emer- itus of the World Health Organization. A Brazilian, he was Director- General for 20 years. He is a member of our faculty and in residence with us in Ann Arbor roughly 5 weeks a year. He summarized for us the various actions and resolutions of the World Health Organization that have been taken in regard to use of medicinal drugs. Let me cite just a few of those. Perhaps one of the most important was in 1963 when World Health Assembly resolution 16.36 asked the member states to inform the organization immediately of problems with dr~;gs and asked the Director-General to transmit this informa- tion to all governments. As one instance our Food and Drug Admin- istration notified WHO in 1971 of a tightening of regulations regard- ing chioramphenicol and on June 25, 1971, the Director-General sent a circular to every country of the world giving full details of this warning. Sad to say, little action resulted. In May of 1968, 8 years ago, the 21st World Health Assembly adopted a resolution on ethical and scientific criteria for the advertis- ing of drugs. I have included in my formal statement a reprint of that resolution as adopted. More recently, WHO has set up a unit in Geneva for monitoring adverse reactions reported by the governments of the world. I am quoting from the Annual Report by the Director- General for 1975, presented to the World Health Assembly this very month. There was a total of roughly 100,000 reports received on about 12~00O drugs, but from only 21 of the 150 member countries of WHO. Of even greater significance for the future was a discussion at the World Health Assembly in 1973 ending with a request to the Director- General to study (1) the feasibility of an international reporting sys- tem which would provide data on the scientific basis and conditions for registration and withdrawal of individual drugs and (2) whether practical minimum requirements could be established internationally. These might be problems in any international agreement `because it nrobably would require ratification by the various parliaments of the different countries. But it is hoped that in the end the World Health Organization would be able to introduce such a reporting system. PAGENO="0031" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15885 It is of interest, Mr. Chairman, that in the debate on this resolution every single one of the countries that took part in the debate supported the idea more or less vigorously. But there was an interesting kind of division: The small countries all supported it wholeheartedly; the big countries gave slightly less enthusiastic support, warning of the dan- gers and problems of interfering with confidentiality involved in reporting. More recently, just a year ago the 1975 Assembly adopted a resolu- tion on standards for quality control of drugs, another area in which WHO has worked intensively. You may know that it was only some 5 years after establishment of the World Health Organization that, in 1952, the first International Pharmacopeia was adopted. All of these efforts, unfortunately, Mr. Chairman, have accomplished very little and emphasizes your earlier question: Why don't they do more? I think it goes back, in essence, to the fact that the World Health Organization and the Pan American Health Organization are jnter- governmental units. They can pass resolutions which may be noble and high sounding. They can distribute information. They can give advice. They can outline better procedures. But in the end it falls upon the Ministry of Health of each country and these Ministries simply do not have the clout to compete with other parts of their own goverflment when commerical interests are involved. Fundamentally, Mr. Chairman, as Dr. Silverman and Dr. Lee and you yourself have pointed out, what goes on in any country is the re- sponsibility of that country. When a manufacturer says it is not illegal to make exaggerated claims in a country that has no laws against doing so, he is absolutely correct, legally. But, Mr. Chairman, here is where the problem of et!hical and moral values comes in. It just seems to me, as a professional person, absolutely indefensible for a company to say that because there is a high incidence of typhoid fever in a giver~ coun- try one ought to treat every case of diarrhea with chloramphenicol. Mr. Chairman, I have lived in the era when we did not have `anti- biotics or chemo-therapeutics. When I was a medical student and an intern I had the experience of seeing case after case of influenza bacil- lus meningitis die. When I was Pediatrician-in-Chief at Charity Hos- pital in New Orleans, the first time I used chioramphenicol in ~ child with influenza bacillus meningitis was one of the most dramat~c inci- dents in my medical career. This was an 18 month old baby with the highest fever that I have seen anywhere. The child had a temperature of 109.2 on admission to the hospital, and this was confirmed with any number of thermometers. The child was treated with chioramphenicol, and within 36 hours the baby was standing up in bed yelling for food. This kind of experience is a very powerful influence on a physician who has seen children get well from a disease he always considered fatal. But it is still dangerous nonsense to use chloramphenièol rou- tinely for every ease of meningitis. You must know what you are deal- ing with. Diarrheal disease is a prime example. In 19Th, the year after the tragic death of their daughter, Professor and Mrs. Zander traveled in. Spain and brought home this poster which was on the drugstore coun- ters, Chlorostrep, a product of Parke-Davis of Spain. The poster says, in effect, "Don't allow diarrhea to interfere with your vacation. Take Chlorostrep at the first problem." This drug is a combination of chior- PAGENO="0032" 15386 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY amphenicol and dihydroestreptomicine. As you may know, streptomy- cm, although not commonly in small doses, carries the risk of causing deafness. Thus, if you take this fine combination, you run the risk of becoming deaf before you die. And its usefulness for most causes of diarrhea commonly seen is negligible. Senator BEALL. Is that drug available in the United States? Dr. WEGMAN. I do not know, but as far as I know it is not. Senator BEALL. It would not be permitted to be made available in the United States? Dr. WEGMAN. I believe so because the FDA is opposed to fixed com- binations of antibiotics. But the chioramphenicol is far the more dangerous drug. Mr. Chairman, Mrs. Zander has prepared a listing of their own in- vestigation and copies of some of the material, copies of this ad, copies of the letters written by the drug companies to doctors and to phar- macists urging the use of this combination and other formulations of chioramphenicol. Senator BEALL. We will receive that for the record and we will also print it in the record of these hearings. Dr. WEGMAN. Thank you, sir.' In our seminar at Ann Arbor we recognized that, in any free-market society, it is the ethical duty of management of a company to make profit for its stockholders, but it seems to us there is equal ethical re- sponsibility to present to all physicians and pharmacists objective and complete information not just on the utility hut on the dangers of its products. Every physician knows that every single drug he uses, even the salt that he uses, has risks that go with benefits. The problem is getting the balance between these two. It seems to us that in the adver- tising and the promoting of these drugs human considerations must come before profit considerations. It may be, Mr. Chairman, that this conflict is irreconcilable. It may he that the profit motive is never going to let the companies give out every bit of information, some of which is going to interfere with their profits. If that is so, then it seems to me that the kind of pres- sures that can be built-up through public hearings such as this, through the measures that Dr. Lee suggested in his testimony, can keep the subject constantly before the public and keep constant pressure on the pharmaceutical houses. What can the U.S. Government do? I am told by my colleagues in the Pan American Health Organization and in the World Health Organization that our Food and Drug Administration has cooperated well with international health organizations in supplying informa- tion. I think FDA ought to be encouraged in those efforts and asked to help even more. It would be. very useful if other parts of Govern- ment-the Department of Commerce, Department of the Interior, T)epartment of Agriculture, and other parts of Government involved iii international export-would also recognize that health considera- tions for human beings everywhere have great significance for us right here. Now I am aware-I think you brought this out yourself-there is little that can be done through our laws to control a foreign subsidiary 1 See letter dated May 81, 1976, to Senator Gaylord Nelson, from Mrs. Alvin F. Zander, page i5485. PAGENO="0033" COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 15387 of one of our countries that is working entirely abroad. It is equally true that Swiss, German, French and other manufacturers are prob- ably as guilt~ as the TJ.S.-based companies in terms of inadequate information. It seems to me, Mr. Chairman, however, that for us to use the argu- ment that because our competitors do something we are absolvec~ of criticism is absolutely shameful. I think a country that prides itself on leadership cannot be justified in saying because our competitors engage in reprehensible practice we have to follow suit, or even show the way. I have often wondered whether there is a feasible approach through the tax laws. I am told that there are investigations b~mg made of using our tax laws, in making allowances for taxes paid abroad, to achieve some control of TJ.S.-based national companies. But this is a matter on which I am a complete novice and there are many experts in Government who might be motivated to look into the matter. But let me talk a little about what can be done through PAHO and WHO. Mr. Chairman, the major motion for bringing the interna- tional health organizations into being was foreign quarantine, the at- tempt, going back to the Middle Ages, to keep preventable disease out of a country by stopping it at the border. Modern experience has taught us that this approach is essentially futile for most diseases. There are now only four diseases, fortunately, over which are included in the international quarantine regulations of the World Health Or- ganization. We have recognized that the much more important way to prevent disease from entering a country is through controlling it at its source and increasing use has been made of the advisory work of the World Health Organization. It `seems to me that this approach has great promise in the area we are discussing and there are a number of things there that can be done to strengthen the work of PAHO and WHO for this purpose. For example, it seems to me not unreasonable for your committee to ask `the U.S. Delegation `to the World ]Elealth Assembly to sponsor a resolution which would call on all manufac- turers, everywhere in the world, at least to make their advertising in any one country basically the same as the advertising in oth~rs. As Dr. Silverman has pointed out, how can a company justify advertising one thing in San Diego and another thing in Tiju'ana? If we could at least make this kind of moral pressure, for what it is worth, on the companies of the world, it might be helpful. 1 might point out that there are a number of international associa- tions that are in what the World Health Organization calls "Official Relations." They are known as Non-Government Organizations (NGO). Among them are the International Union of Pharmacology, the International Pharmaceutical Federation, and even more interest- ing, the International Federation of Pharmaceutical Manufacturers Associations. They would have the privilege of participating in the discussion on the resolution I suggest and~ would I hope, exert some sort of moral pressure on their own members for more humanitarian behavior. rurther attention might be given to education of the health pro- fessions. I would hope that this committee might make pre~sure for additional support to the Pan American Health Organization and to the Pan American Health and Education Foundation for the textbook 73-950 0 - 77 - 3 PAGENO="0034" 15388 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY program and for improving the training of all people in the health professions. Pharmacists may be as important as physicians. Pharma- cists are prescribing drugs, legally or illegally, but they are funda- mentally human beings with an interest in saving lives, and with better education they will do a better job. Finally, one very important aspect has to do with international in- formation system. The World Health Assembly is going on right now in Geneva. I am not sure whether the Director-General's report on the feasibility study will have come before this Assembly or not, but it is sure to be discussed at the next Assembly a year from now. This gives ample time for th~United States to prepare a position of strong sup- port. My own feeling is that, although the legal aspects need to be pursued, information, education, and moral pressure, are exceedingly important. Mr. Chairman, I want again to echo the words of my predecessors in congratulating you and the committee on bringing this matter be- fore the public. Thank you. Senator BEALL. Thank you, Dr. Wegman, for your testimony. It seems to me that you make a very important point about commu- nications. I think obviously it is necessary for us to do everything we can to impress upon the conscience of the producers the necessity of making the same information available all over the world wherever they are marketing the drug. And I also think that by our example, hopefully, we can get other producers in other countries to follow us and come up to our standards as we do in so many things rather than have us be dragged down to theirs. But it seems to me that for the im- mediate future we also have to spend a great deal of our effort in im- proving communications through the international organizations so that the word gets out to people who are dispensing drugs poorly be- cause of lack of training. You are suggesting, I believe, that we devote some time to strengthen the organizations so that they can develop better means of communicating with professionals and semiprofes-. sionals and unskilled dispensers, particularly in South America. And I think that is a very worthwhile suggestion. Dr. WEGMAN. We also see, I think, Mr. Chairman, the value of strengthening our own abilities in the United States. The example of smallpox eradication will have very great benefits throughout the world. The leader in the World Health Organization for that program happens to be from the CDC in the United States, Dr. P. A. Hender- son. The major impetus to that program was given by the U.S. Gov- ernment with a regional program in Africa. And because of the research capability of that U.S.-backed group, they were able to find out how best to proceed to achieve effective eradication. The development of drug-resistant diseases and drug-resistant bacteria are a new kind of problem. Enhancing the ability of our own CDC to study this problem, and disseminate the information, would add another dimension. There was one other thing-I just made a note of this as we were going along-which may be appropriate. In the United States major foundations and major universities, both private and public, have very large investments in the drug industry. Ought not those foundations exert influence on the policies of those companies through the stocks PAGENO="0035" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15389 that they own to improve their promotional practices? These institu- tions are given special tax privilege by the U.S. Government-the tax privileges and might respond, if they learned of the results of Dr. Silverman's study, to undertake appropriate action on the companies. Many of the foundations have policies in the area of social respon- sibility and do try to influence the policies of the companies that they invest in. I am sure that is not common for all universities. I am sure it is not common for all foundations. But this may be another avenue worth pursuing. Dr. SILVERMAN. Mr. Chairman, there is another avenue that de- serves particular emphasis. When my associates, Dr. Aida LeRoy and Mia Lydecker, and I finished our compilation, we took all our data, some of which I showed to the committee today, and sent it to every one of the drug companies involved, asking them to check for the accuracy of the translations and the fairness of our presentation. Very few changes were requested, and in every instance, we acceded tO the company's request. We thought that they were the better )udges of accuracy than we were. During our study, it turned out that not all companies were using the same approaches. In my discussion today, I cited only those cases in which there were glaring differences between the promotional cam- paign in the United States and the campaign by the same company elsewhere. But there were two companies that were a little different. We found out that they were saying precisely or essentially the same thing in all countries for the products we studied. We went to the heads of these companies, or their representatives, and said "How come?" One of them said, "We figure that this ap- proach of full disclosure is probably going to cost us sales for the short run, but in the long run we will profit." And officials of the other company explained their attitude by saying, "Well, we sleep better at night that way." Senator BEALL. Well, I think it would be worthwhile to identify those companies, doctor. We do not want to characterize this as an industry-wide problem. There are companies that recognize their re- sponsibility and I think that since we identify those people whom we criticize, I think we should identify those people whom we applaud, also. Dr. SILVERMAN. I would be glad to identify them. One of them is Merck and the other is Syntex. Senator BEALL. Thank you, doctor. Mr. SOMMER. Dr. Wegman, is PDR translated into Spanish? Is it available in Spanish? Dr. WEGMAN. I do not know. I do not belieye I have seen it in Spanish. Dr. SILVERMAN. I do not believe so. As a partial answer to your question, much of the material that is disseminated to physicians in the United States through what is called "The Medical Letter"-this is the publication of a nonprofit organiza- tion, which is based here, and sends copies on subscription to tens of thousand physicians of the United States-is now being regularly translated into Spanish and sent to several thousand Latin American physicians in some countries. PAGENO="0036" 15390 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. WEGMAN. I might add to that, Milton. You may not know, but ~he foundation that I am on, the Pan American Health and Education Foundation, is underwriting the reprinting of the Spanish version of The Medical Letter, "Carta MMica," and is distributing it to every country in Latin America which wants it, at no cost to the govern- ment. Several countries are distributing "Carta Médica" widely, al- though, for cost reasons some of the advantage of The Medical Letter is lost. A great beauty of The Medical Letter is that it is a 4-page lea$et that comes every 2 weeks and can be read with speed. For rea- sons of economy in the Spanish reproduction, most governments dis- tribute six issues at once, every quarter, which makes it less likely to be read and assimilated. Mr. SOMMER. But is there any discussion in the foundation that you were referring to that are doing the PDR in Spanish? It seem~ to me that that ought to be a step in the right direction in getting the data distributed throughout Latin America. Dr. LEE. PDR, you know, is a book of drug advertisements, it is paid advertising. Mr. SOMMER. But Dr. Silverman, I think, referred to it as meeting the FDA standards. Dr. LEE. Yes. It contains a limited number of drugs, and only the drugs that the drug companies want are included in the PDR. Dr. WEGMAN. Let me point out another problem with translation; it would have to be an adaptation because drug names are different in Latin America. A drug identified by one name here goes under a com- pletely different name in Latin America. For example, in one of the communications that was sent to the countries by WtTo some years ago, the list of sy~ionyms for chioramphenicol would knock your eye out. I have it right handy here, I think. There are at least 50 or 60 different synonyms for chloramphenicol sold in different countries. Dr. LEE. We have been trying for 10 years to get a drug compendium in the United States that would replace the PDR. I think if we could do that or if a similar document could be produced for the Latin. American countries, a p~aotical, useful compendium that could essen- tially replace the PDR in the physician's office, which is where it is found in the United States and where it is used every day by physi- cians as they write prescriptions, would be an excellent idea. Senator BEALL. Senator Nelson has a bill in to provide for a compendium. Dr. LEE. Yes, he does. And if a comparable action could be taken through, let us say the Pan American Health Organization, with some stimulus from the United States to do that, I think that might be very helpful. Mr. GORDON. The problem of multiplicity of names, of course, was dramatized by the thalidomide case, if you will recall. We had testi- mony by Dr. Helen Taussig that even after the alarm went out about thalidomide throughout the world, children were still being born in Brazil and other countries with defective limbs because when they were told about thalidomide they went to their medicine cabinets and saw Kevadon, Contergan, Profamil, `Slip~ Sedahs, and perhaps more than 80 other names. It was just impossible to take them oft the market. I have one question for Dr. Wegman. I understand that you went to Cuba not too long ago. PAGENO="0037" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 153~1 Dr. WEGMAN. You have anticipated me. I wanted to bring that in. I had a fascinating visit to Cuba last summer and I was able to .~ontrast it a little bit with China, the other Socialist society that I had visited. My situation in Cuba was quite different from China, as Phil remembers. When we were there, we were deaf, dumb and blind be- cause we could not read or understand Chinese. In Cuba, I am com- pletely fluent with the language and I have been there many times before so that I was able to make comparisons. One thing was very striking. I passed a number of drug stores as I was driving around-I was visiting the Ministry of Health on Pan American Health and Education Foundation and PAHO business-and the drug stores all had almost empty shelves. So I asked what was going on here, and they said well, up to January 1959 our drug stores on a worldwide basis stocked some 40,000 pharmaceutical items. Today, the list is down to 1,400. I might point out-and I do not necessarily wish to say that there is any causal relation-that health indices in Cuba have improved dramatically since 1959. The infant mortality has dropped to where it is by far the lowest in Latin America. I am ashamed of the fact that for so many years the Cubans were unable to get antibiotics that they needed during the blockade. Now they are getting them in other ways. But I think there is a distinct advantage to the fact that the amount of drugs they have been able to import has been cut down. Senator BEALL. Thank you, doctors. We appreciate your coming this morning. And we will recess the subcommittee until tomorrow morning at 9:30. * [Whereupon, at 11 :58 a.m., the subcommittee was recessed, to re- convene at 9:30 a.m., Thursday, May 27, 1976.] PAGENO="0038" PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) THURSDAY, MAY 27, 1976 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS, Wa8hington, D.C. The subcommittee convened, pursuant to recess, at 9:35 a.m., in room 318, Russell Senate Office Building, Senator Jacob Javits presiding. Present: Senator Javits. Also present: Benjamin Gordon, staff economist; Judah C. Sommer, minority counsel; and Karen Young, research assistant. Senator JAVITS. The subcommittee will come to order. This morning we will hear as witnesses Mr. Robert Ledogar, De- partment of Economic and Social Affairs, United Nations, New York, N.Y., and Mr. George Squibb of North Kingston, R.I. The Chair wishes to make a brief opening statement before the hear- ing commences. Today's hearing continues the Senate Monopoly Subcommittee's examination of pharmaceutical company practices in labeling and pro- moting prescription drugs sold in Latin America. I share the concern expressed by the witnesses and by Senator Beall, who chaired yesterday's hearing, respecting the questionable practices of some drug companies in promoting the use, of their drugs without adequate or appropriate prescribing information. However, Senator Beall through his questioning of the witn~sses, it must be clearly understood that: a. Misleading and incomplete information to promote the sale of drugs by some American drug companies or their foreign subsidiaries in Latin America is beyond the jurisdiction of the Food and Drug Ad- ministration which regulates drug advertisements and promotion in this country. b. Improper marketing practices should be subject to the legislative control of the foreign country in which they take place, for what goes on within any country is the responsibility of `that country. Grave questions have been raised that certain drug promotion prac- tices abroad may be legally correct, but are they ethically and morally less than honest? Now, it is my judgment that the United States may well have means to call domestic pharmaceutical concerns to account in the marketing of pharmaceuticals in foreign countries in order to require them to (15393) PAGENO="0040" 15394 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY follow more ethical procedures in their advertising and labeling re- cjuirements and the course which is in accord with and does not violate the laws of the country where the drug is marketed. The question to be decided is whether the means, which I believe the United States does have, should be invoked or not. Such enlighten- ment as the witnesses can give us on that subject would be very welcome. Mr. Ledogar, would you proceed? We hope that you will confine your direct statement to 10 minutes and the total statement will be included in the record, even though you omit some part of it. Proceed in any way you wish. STATEMENT OP ROBERT ~. LEDOGAR, DEPARTMENT OP ECONOMIC AND SOCIAL APPAIRS, UNITED NATIONS, NEW YORK, N.Y. Mr. LEDOGAR. My name is Robert Ledogar, Senator, and I am pre- senting my statement as a private citizen. Senator JAVITS. That is, you are not appearing here in any repre- sentative capacity for the United Nations? Mr. LEDOGAR. That is right. Senator JAVITS. This is just a way of identifying what you do for a living? Mr. LED0GAR. That is right. I joined the United Nations after I completed the work in question, and my testimony in no way repre- sents a position of the United Nations. Senator JAVITS. Proceed. Mr. LEDOGAR, My statement consists of four parts: First, a brief summary of what I consider to be the main problems with the devel- opment, marketing and use of prescription drugs in Latin America; second, the relation of transnational pharmaceutical corporations to these problems; third, the impact of U.S. foreign policy on the situa- tion; and fourth, some recommendations. As a preface, however, I am obliged to make it clear that I speak only as a private citizen. Although I am currently serving with the staff of the United Nations, my remarks here today are the outcome of investigations carried on before I joined the U.N. in preparation for a book entitled "Hungry for Profits: U.S. Food & Drug Multi- nationals in Latin America." This book was published by IDOC/ North America, but the work was completed prior to my current U.N. affiliation. Consequently, what I have to say does not rest on any information obtained as a U.N. staff member, nor does it reflect the official views of the United Nations. There are two sets of problems besetting Latin America with respect to pharmaceutical products. The first afl~ects the urban middle and upper classes for the most part, and it is a problem of excessive con- sumption of pharmaceutical products under unnecessarily hazardous conditions. Those who can afford it may buy almost any non-narcotic drug without prescription (despite a statement on the label which says that the drug is for sale by prescription only), and the labeling and advertising of such products, generally speaking, carry fewer warnings and claim more extensive healing powers than is permitted for the same product in the United States or Western Europe. Exam- PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15895 pies of such labeling and advertising are given in my book called "Hungry for Profits, as well as the works of Drs. Silverman and Lee. The second and more serious problem is that of the low-income majority of Latin Americans who, for the most part, do not consume pharmaceuticals in great quantity because those products which are available are too expensive and/or unsuited to their needs. Seventy- two percent of Brazilians, for example, die before the age of 50; 10 percent of them die before their first birthday. Communicable and endemic diseases aggravated by malnutrition are the main causes of such deaths. What Brazil, like most other countries of Latin America, needs from the pharmaceutical industry is the development of very inex- pensive drugs to combat diseases like tuberculosis, measles, diphtheria, whooping cough, schistosomiasis, Chagas disease, and the myriad of intestinal infections which ravage. the low-income populations. This means that research and development must be carried out with these local and low-income concerns primarily in mind. This is, unfortu- nately, not the kind of R. & D. which receives highest priority in the multinational pharmaceutical business. Nearly all of the pharmaceutical products on sale throughoi~t the world today are discovered and developed in the United States or Europe. Since multinational firms make their money by selling to the higher income populations of North America, Europe, and Japan, along with the urban middle and upper classes of Asia, Africa, and Latin America, they have very little economic incentive to produce cheap drugs to combat diseases from which their main customers do not suffer. Now, my purpose is not to make the transnational pharmaceutical industry the scapegoat for all of Latin America's ills. The industry has discovered and developed drugs and vaccines which have saved millions of lives among rich and poor. Even if one believes that such discoveries and more might have taken place if the industry were structured differently than it is, credit should be given where it is due. Latin American governments certainly bear a very large share of the responsibility for the problems I have just described. They invited multinational industry to their shores and, even though this was done frequently with the active encouragement of the U.S. Government, they could have refused; and they remain free to expel, nationalize, or otherwise discipline these firms. But, I think one can fairly blame the multinational industry for at least two things: For the. maintenance of high prices on drugs cur- rently available and for its tendency to favor the political, economic and therapeutic status quo. Multinational industry's role in the main- tenance of high prices on the international market has already been investigated by this subcommittee and will perhaps be discussed fur- ther by other witnesses at these hearings. I am more concerued with the industry's failure to produce what the people really need and its ability to resist efforts by concerned local interests to develop a low- cost chemotherapy more suited to such needs. When~ for example, 45 percent of a sample of foreign-held pat- ents registered in Argentina from 1957-67 were for products which were neither being manufactured nor imported into Argentina, the effect could only have been to discourage Argentine research and PAGENO="0042" 15396 COMPETITIVE PROBLEMS IN `PUB DRUG INDUSTRY development. Transnational industry frequently enters Latin America or expands there by buying out already existing local firms. In indi- vidual cases, such mergers may have beneficial effects, but the overall ]mpact is again to reduce the incentive and scope for local research and development. This is especially the case when transnational firms dominate the en- tire industry, as they do in many Latin American countries where they may be responsible for three-quarters or more of total sales volume. Most of the raw materials for drugs sold in Latin America come from outside Latin America. Central America, for example, imports 90 percent of its raw mate- rials for drugs. This is hardly the road to self-sufficiency. And the multinationals openly resist efforts by Latin American govern- ments to foster an independent national research and development capability. An ambitious and well-financed plan mounted in Brazil in 1971 to utilize government, university and other local laboratories to pro- duce 400 basic medicines cheaply and efficiently for. nationwide dis- tribution was openly resisted by foreign-owned firms, in the end, the plan was emasculated, resulting in only a very small transfer of sec- ondary R. & P. facilities by a few companies to Brazil. Mr. GORDON. How did they resist? What did they do to show their resistance? Mr. LEDOGAR. Well, we. have, reported several public statements on the part of Executives of the trausnational. firms in opposition to the. Government's plan in this respect. No one knows exactly the internal workings of Brazilian politics, except those deeply involved in it, but the public statements, I think, bear witness to their opposition. Mr. GORDON. Thank you. Senator JAvrrs. Proceed. Mr. LEDOGAR. Just as they complain about excessive controls by the FDA in this country, the multinational firms are hardly likely to favor an improvement in the. ge.nerall~ inadequate government con- trol systems in Latin America for drug labeling and marketing. Since the investigative work for my book was completed, several trans- national drug firms from the United States have admitted to giving bribes to officials of foreign governments. None of the countries have been identified. I was able to obtain evidence on bribery in Latin America only in the case of one firm-a Swiss company which had a list of 135 Brazilian regulatory officials to whom it gave small "donations"-but everyone knows that bribery is a frequent occurrence. The transnationals say they..have to engage in it in order to survive. As individual companies, they probably do. The point is that they are able to unite and flex their muscles when their common interests are seriously threatened. Despite the fact that they dominate the drug industry in many countries, the multinationals have done little to change the regulatory status quo. One can only conclude that it suits their purposes inst as it is. Where does U.S. foreign policy come into all of this? First of all, despite some recent changes in legislation, our `Government offers substantial encouragement to foreign investment by transnationai firms PAGENO="0043" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15397 headquartered in this country through tax incentives, guarantees, loans and the services of our commercial representatives abroad. Di'ug compailies have taken special advantage of these incentives as sev- eral examples in my book illustrate. In a broader way, however, U.S. foreign policy supports the activi- ties of transnational firms overseas by openly encouraging the mainte- nance of a "favorable business climate" in those countries we consider to be our friends. We support regimes which encourage investment by U.S. firms. Relations are cooler with countries which place heavy re- strictions on such investment. Our special relationship with Brazil, for example, is due in part to that nation's heavy reliance on, and strong encouragement of, U.S. private investment as opposed to the more restrictive attitude of the Andean Pact countries. The crux of the problem is here. For most business a "favorable investment climate" means a minimum of Government interference. Simplified rules and regulations, tax incentives, freedom to compete with (and/or buy out) local industries, a limit to price controls, plenty of cheap labor and little labor militancy-this in itself be- speaks a conservative, if not repressive, type of regime. But with the pharmaceutical industry there are added requirements. In their case, a "favorable business climate" also means: Weakness of safety controls on labeling and advertising; no efforts to cOntrol the proliferation of brand names; freedom to locate research and de- velopment facilities wherever these are most profitable for the com- pany; absence of adverse publicity; and freedom to produce and sell not necessarily what is most needed in the country but what i~ more economically efficient from the standpoint of profits. This puts the U.S. Government in the position of supporting activi- ties which are contrary to the best interests of the majority of people in Latin America. It makes us the ally of transnational business in its tendency to support the status quo and oppose change. What can be done to change this situation? A general review of our Government's whole supportive attit~ide to- ward U.S. foreign investments, together with the specific incentives, is certainly in order, but that is a very large issue which transcends this committee's present specific concern with the pharmaceutical industry. Short of such a broad policy review, there is very little that the U.S. Government can do unilaterally to alter the conduct of U.S. firms act- ing through local subsidiaries overseas. We cannot interfere in the in- ternal affairs of other nations to impose standards of our own. There are serious difficulties, moreover, with the imposition of unilateral con- trols by the U.S. Government on U.S.-based firms in the absence of similar controls on European and Japanese firms by their Govern- ments. What our Government can do is to support multilateral efforts toward the greater regulation of transnational investment in less de- veloped countries as well as independent multilateral efforts to assist less developed countries in solving their most serious health problems. I would like to offer the following specific recommendations: (1) That the U.S. Government take an active role in seeking an international convention on the conditions of trade, sale, mar- ketitig, advertising, and labeling of pharmaceutical products. I have in mind a role similar to that taken most recently by our PAGENO="0044" 15398 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Government in urging international action on the question of bribery in international business dealings. (2) That the U.S. Government support the recommendation of the United Nations Group of Eminent Persons (of which you, yourself, Senator, were a member) that the affiliates of trans- national corporations should be required to reveal to host govern- ments any sales prohibitions and restrictions in manufacturing imposed by home or other host countries with respect to the health and safety of consumers. (3) That the U.S. Government, through its representatives to the World Health Organization, support current efforts of that organization to improve its international system of information on drugs and look for ways to restructure the Geneva Research Center for monitoring adverse reactions to drugs so that it may be more suited to the needs of less developed countries. (4) That the U.S. Government offer, preferably through multi- lateral channels, financial and technical assistance, independent of any influence from private U.S. firms, for improving the capacity of regulatory agencies in less developed countries to exercise con- trol over the pharmaceutical industry. (5) Finally, but most important, that the United States re- double the research efforts of its own Government agencies and offer, through multilateral channels, more technical and financial aid to independent, noncommercial research facilities in less de- veloped countries to discover and develop cheaper and better drugs to combat the diseases which afflict and shorten the lives of many millions of our fellow human beings. Mr. Chairman, these recommendations do not constitute the total solution to the problems I have described earlier, but if they were to be carried out we would have made a good start. Senator JAVITS. Thank you, Mr. Ledogar. It is very interesting. Now, it would be simple for me to ask you to identify the Swiss firm to which you refer. Is there any reason why it should not be identified? Mr. LEDOGAR. It is identified in my book, Senator. Senator JAVITS. As what? It is published. Mr. LEDOGAR. Let me check to be perfectly accurate. Senator JAVITS. And refer us to the page in your book where it is identified. Mr. LEDOGAR. It is Ciba-Geigy, on page 1~t. Senator JAVITS. Ciba-Geigy? Mr. LEDOGAR. Yes. Senator JAvITS. And is there any part of the book you want to put' into the record to tell us the story? Mr. LEDOGAR. I can quote it. It is a single paragraph if you wish. jt reads: Sources within the Brazilian parliament recently called for an investigation into the compromising relationship between multinational pharmaceutical firms and the nation's drug control agencies. A parliamentary investigating committee was given an initial documeut of the Swiss firm Ciba-Geigy containing a list of over 135 public officials in the SNFMF [which is the Brazilian regulatory agency) and other licensing agencies who receive small gifts and donatibns from the company. PAGENO="0045" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15399 I can give the source for that, which is a newspaper report from Brazil. Senator JAVITS. What is the newspaper? Mr. LEDOGAR. I will give you that in a second. It is Diario do Com~r- cio, Belo Horizonte, May 3, 1975. Senator JAvITs. A local paper? Mr. LEDOGAR. Yes. Senator JAVITs. And that was an accusation, of course. You have no other proof than that, have you? In other words~ the newspaper said so and that does not prove it. Mr. LEDOGAR. The newspaper reported the statement made in Parliament. Senator JAVITS. A parliamentary flap over it? Mr. LEDOGAR. That is right. Senator JAvIT5. But that is the total proof, is that right, that you have? Mr. LED0GAR. Yes what I have is the newspaper report about the parliamentary inquiry in Brazil. Senator JAvrrs. Related to the parliamentary inquiry and that is the total evidence that you have that backs up your statement? Mr. LEDOGAR. That is the evidence I have. Senator JAVITS. Well, I think it is only fair to make clear what the evidence is so that we do not accept a statement of fact as being a fact because it is, as far as I can see, a newspaper report on the charges. Mr. LEDOGAR. I know of no evidence that the charges were ever denied. Senator JAVITS. They never denied them, is that right? Mr. LEDOGAR. Not to my knowledge. Senator JAvITs. That does not prove it. I happen to be a lawyer, and I just want to be fair in anything you say. I am not in any way challenging you, but I do think it is important to have the basis set forth on the record, that is the basis for your statement. The other thing that interests me about this is your own statement that any one of these countries could deal with the situation, sould it not? For example, you say in Brazil there is a very promising effort to produce 400 basic medicines and so on which was emasculated, et cetera, and the fact it was openly resisted by foreign-owned firms, again it is nothing wrong with openly resisting if they think it is wrong. You say in this case they prevailed,, but is that not the fault of Brazil? What do you want the United States to do about that? Mr. LEDOGAR. Senator, there is a general U.S. foreign policy favor- ing the interest of the multinational firms. I cannot prove that the United States exerted pressure in this case, but there is the general climate. Everyone in the Brazilian Govern- ment knows that policies restricting business practices and unfavorable to the interest of multinationals are not generally looked upon by the U.S. Government as in the good interest of the mutual relations be- tween our countries. PAGENO="0046" 15400 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator JAVITS. So it is a climate that you complain of. Mr. LEDOGAR. Yes. Senator JAvIT5. Does that climate differ in different countries, have you found? Mr. LEDOGAR. Yes, it does, Senator. For example, the group of so-called Andean Pact countries have developed a series of fairly strong restrictions on foreign investment. They do not refuse foreign investment by any means, but they have very special rules under which foreign investment is allowed, restric- tions on profit, packaging and soon. Senator JAvrrs. So that the climate which you complain of created by the U.S. Government does not extend to the Andean Pact countries. In other words, it is not a universal climate created by the United States. What you say is, it is true in some countries and not in others. You have just given us an example of Brazil as contrasted with the Andean Pact countries, Peru and the others. Mr. LEDOOAR. That is correct, but I believe our policy generally favors the Brazilian approach rather than that of the Andean Pact countries. Senator JAVITS. Nonetheless, if the country wants to do it, there is nothing in our policy that stops them. Mr. LEDOOAR. That is correct. Senator JAVPrS. Colombia is an Andean Pact country. We enjoy ex- cellent relations with Colombia. Mr. LEDOGAR. Yes. Senator JAVITS. So it is not necessarily built into the American dip- lomatic system either. Mr. LEDOGAR. The reason I raise the issue here, Senator, is I do not believe it is necessarily involved in every aspect of our foreign rela- tions, but I think this climate is generally favored and I think that the United States policy should be more judicious, particularly with regard to these issues which affect the consumers, such as safety regulation and the improvement of the safety regulating mechanisms in these countries. Senator JAVITS. Well, what you are really arguing, as I see it, is that lax regulations and controls should not be what the pharmaceutical companies themselves seek; that they ought to be more public spirited than that. Is that not what you are really arguing? It is a fact that notwithstanding the U.S. climate that you charge, I am not necessarily in agreement, but it is true there are countries which do what they think they ought to do. Mr. LEDOGAR. Senator, I do not believe a great deal in urging public spiritedness to companies. I do not believe it achieves a great deal. I recommend multinational action to improve the climate. Senator JAVITS. The OECD this morning announced a new set of ethical rules for what they call transnational corporations. Mr. LEDOGAR. Yes. Senator JAvITS. Have you looked at those? Mr. LEDOGAR. Yes, I have. Senator JAVITS. Do you know anything about those? Mr. LEDOGAR. I know what I have read in the New York Times this morning. PAGENO="0047" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15401 Senator JAVITS. Do you have any opinion on whether that is the kind of thing you want to see happen ~ Mr. LI~DOGAR. WelL again, going on the newspaper report, it appears the United States adopt.ed a generally conservative position, as op. posed to Sweden, with regard to the revealing of information. For example-apparently because the United States prevailed-~--the convention, or the agreements calls for public revealing of the op~rat- ing results and sales by geo~raphical area rather than by country, and I suspect the case was similar with regard to No. ~ which calls for revealing research and development expenditures for the enterprise as a whole, rather than research and development expenditures by country. Now, in the case of the O~CD countries, this may not be as im- portant as in the case of less developed countries. What I've urged is that in such negotiations the United States adont au attitude which is not so defensive of the interest of business and not consistently take the stance that seems to be represented here. Senator JAvrrs. Well, I was with Secretary Kissinger and I beljeve that .a most enlightened and forward-looking setup of proposals was made to the developing countries. I was also his adviser at the session of the United Nations General Assembly in early September last year where again we observed the advanced proposals. I did not consider those particularly reactionary or conservative. Now, all I am raising, Mr. Ledogar, is that these may be your views, but you are not God either, neither am I or anybody else. They are your views and you have opinions, but that does not mean that the United States is wrong. That is all I raise with you. This happens to be in the business I know something about which is the international practices of transnational corporations. I am interested in your view about the substance, and I think that is a much stronger argument, if you will allow me to suggest it to you, the ultimate fact is because there is a lot to economics and a lot to business, more than the evidence on which you base it. For example, I would not indict a company as guilty of giving bribes on a parliamentary speech or the report of a newspaper. You are saying you are reporting a fact that the paper said so and so and t~ member of Parliament said the same thing, but that does not necessarily convict an enterprise. It would take a lot more proof than that as illustrated in the investi- gation by the subcommittee headed by Frank Church. I am impressed with the fact that the kinds of medicines, at the kind of price that should be helping the many millions of people, with all kinds of intestinal illnesses in countries like Brazil, are simply not made available because, you say, it is not profitable to do ~o. Now, do you recommend that the United States offer aid of that kind? The United States can give direct aid in tons of aspirin or anything else it wants to, is that not so? Mr. L1~DOGAR. I do recommend U.S. aid of a certain kind. Very often, in the past, U.S. aid has been tied in with the develop- ment of the subsidiaries of the U.S. corporations. PAGENO="0048" 15402 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator JAvips. How do they do that? Mr. LEDOGAR. Well, we had the Cooley loans up until the end of the 1960's where foreign exchange funds were loaned to American com- panies to develop their enterprises in the aid-receiving countries. U.S. foreign aid is very frequently tied in with the purchase of Amen- materials, and so on. This committee has, itself, investigated the purchasing by U.S. AID of pharmaceuticals from American companies and others for delivery to less developed countries. What I would urge is aid to independent and multilateral research and development, which is not necessarily tied in with the interest of American business abroad. Senator JAvIT5. Well, now, suppose the U.S. Government purchased from pharmaceutical companies vast quantities of some simple remedy for diarrhea. What objection is there to that as long as it got to the ultimate consumer at low prices? Why not buy it from U.S. firms? They are probably the cheapest arid the best. I am talking about doing what you want to do. Why exclude purchase from U.S. firms? Mr. LEDOGAR. I do not necessarily exclude purchase from U.S. firms, but the key issue is local research and development under conditions of priority for the needs of the people in that country. Senator JAVITS. But local research and development may not be very good, whereas the international research and development is. Mr. LEDOGAR. That is the problem. It needs to be improved. Senator JAVITS. Why scale glass mountains when you have excellent research facilities in Switzerland and the United States, Canada, France, and Germany? Why not use those? What is the magic of local research facilities? Mr. LEDOGAR. As you said, it is not good business to do research and development for diseases of the pepole who cannot pay for drugs. Senator JAvrrs. But we are talking now about the locus of research and development, not the substantive part of it. Mr. LEDOGAR. That is right. Senator JAvITS. The United States and the Soviets are now cooper- ating and trying to do something about many forms of cancer. That will benefit the whole world. What is wrong with that? If you tried to locate that activity in some country which has no facilities, no technicians, no experts, maybe not even the climate for it, what is the purpose? Research is international. Why does it particularly have to be local? As long as it is done with an eye to the broadest human use, that is all I am saying. Would you Concur with that statement? Mr. LEDOGAR. I concur in that. Senator JAvrrs. As long as it is done? Mr. LEDOGAR. That is right. Senator JAVITS. What about the World Health Organization? Haye you looked into what it is doing in these areas? PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15403 Mr. LE000AR. Yes, I have, Senator. There have been a number of efforts over the years by the World Health Organization to improve the situation with regard to information and regulation of the drug industry, and of course, to improve research and development. Unfortunately, many of those efforts in the World Health Orga- nization have not succeeded, again due to differences of opinion nad piorities between developed and less developed countries re~re- sentatives within the World Health Organization. Senator JAvrrs. Well, Mr. Ledogar, thank you very much. I app're- ciate everything you have said, and mind you, my examination may sound contentious to you but I think you do have a valid thesis, and I was trying to refine it and really get it down to what we can wisely do. Mr. LEDOGAR. I appreciate that. Senator JAVITS. Mr. Gordon, any questions? Mr. GORDON. Mr. Ledogar, do you know the percentage of profits to net worth or to investment derived by multinational drug com$nies from their foreign operations as compared to those from their domes- tic operations? Mr. LEDOGAR. Mr. Gordon, that kind of information is reported in round figures in annual reports by drug companies but the figures themselves are contested. Mr. GoRDoN. Actually, they are not reported in annual reports ac- curately because of the practice of overpricing imports and under- pricing exports. Mr. LEDOGAR. Well, my point is the annual reports state a global figure for foreign income from foreign operation as opposed to income from domestic-type operations in many cases. However, it is highly questionable whether or not those figures rep- resent actual profit because they do not report the results of under- pricing of exports or overpricing of imports in the receiving cou~itries. We're talking about the general practice of transfer pricing. No one has effectively been able to determine the real figures. There have been reports on individual cases showing that real profits ar~ much hb»=~her than.actually reported. For example, Global Reach, the book by B'arnett and Muller, re- ported on a study in Colombia which calculated overnricing of im- ports and overpricing of exports by a group of multinational firms and then divided the total into the declared net worth of thOir sub- sicliaries in Colombia. It was found that effective `annual rates of return ranged from 92.1 percent to 9&~.1 percent and the average was `T9.1 percent. The average of declared profits submitted to the Colombia Tax Authorities by these same firms was 6.~' percent. There are other studies of this same kind, but in general the re- porting is simply not there. This is one of the major concerns of peo- ple in this field: To improve the international reporting of real rates of return. Mr. GORDON. Are you aware of the hearings that we had on this particular subject, that is, the overpricing of imports and under- prr~inP' of exports? Mr. LEDOGAR. Yes, I am. I refer to it briefly in my book. There were cases of overpricing reported in Colombia, and when the authori- 13-950 0 - 77 - 4 PAGENO="0050" 15404 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ties compared import drug prices with other countries in Latin Amer- ica, they found very great discrepancies from one country to another. The United States found similar discrepancies of prices when it in- vestigated, in this subcommittee, the prices charged to the U.S. AID in the period from 1968 to 1969. For example, for tetracyclines, the cost in Pakistan was $370 per kilogram. Ir~ Colombia, the same company charged $100 per kilogram. Bristol Myers in Colombia charged $250 per kilogram and $190 per kilogram in Pakistan, and so on down the line. There were these series of differential prices with no apparent reason. Mr. GORDON. Thank you. Senator JAvITS. Thank you, Mr. Ledogar. It is very kind of you to come. We appreciate your testimony. Mr. Ledogar, you do not have to stand by unless you wish to. Mr. Squibb, you may proceed. STATEMENT OP GEORGE S. SQUIBB, CONSULTANT TO THE PHARMACEUTICAL INDUSTRY Mr. SQUIBB. My name is George S. Squibb. I live at 1545 Boston Neck Road in Saunderstown, R.I., and I am here at the request of the committee. I am a consultant to the pharmaceutical industry, with which I have been associated for 40 years in various capacities-30 years with E. R. Squibb & Sons, finally as vice president for market- ing, and the last 9 or 10 years with various small manufacturing pharmaceutical companies one of which, Barr Laboratories of North- vale, N.J., I now serve as director. During my career I have served on board of directors, executive management committees, patent and research committees, and in all kinds of professional and trade groups in nearly every State in the country. I have been active in committee work for the PMA and NPC, the two major industry trade groups, and was elected to two terms as chairman of the National Pharmaceutical Council. I am a lawyer, member of the New York Bar, with special graduate study at the Food and Drug Law Institute. I know the pharmaceuti- cal business backward and forward, and am vitally concerned with its future both personally and from the conviction that all matters affect- ing public health must be of vital importance to all of us in the years ahead. Over 10 years ago I was given an assignment by my company to study the relationships between the pharmaceutical industry and vari- ous Government offices and legislatures, Federal and State, because at that time there was a particularly sharp concern on the part of some of the industry's managers that things were changing in the. pattern of public awareness of the procedures of medical care and that a little attention to this developing situation might be helpful. That assignment resulted in the production of two papers on the problems and practices of the pharmaceutical industry, both of which are part of the record of these hearings. Into these papers I injected a little gentle advice to the industry which caused all sorts of uproar at the time, but which I now have the satisfaction to note was all good and PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15405 has been picked up as their own gospel by many of those who were most horrified at the original expression. As a matter of fact as I review those words of 8 or 9 years ago in the light of current events I am amazed at how close to the mark they were in foretelling what was going to happen in the pharmaceutical field given the attitudes which were then, and still are prevelant. All of which only goes to prove that developments are predictable on the one hand, and on the other that the legend of the unheeded prophet, Cassandra, is still rele- vant today. Not having learned any restrictive lesson from this earlier experi- ence, I am here again to discuss some recent controversies involving the pharmaceutical industry, and to express from my experience what might be a way to avoid such unpleasant situations in the future. I am here today to express from my experience what might be a way to avoid the situation which we are discussing now, the promo- tional excesses in countries outside the United States by U.S. firms. Certainly none of us, in the industry or outside it, can take any pride or satisfaction in listening to the recital of the promotional ex- cesses that the committee has heard in the last few days. Essentially. however, this is just the newest example of the fact that pharmaceuti- cal managers live and work in a goldfish bowl which makes all of their actions reviewable by a large and varied audience of critics, mQst 0± whom are not inclined to be overly sympathetic. The root of most of th~ problems that t~he industry has with its critics over promotional matters is the feeling that somehow sales pressures, advertising, commercial exploitation and selling in its strict dollar and cents aspects are all foreign to, and incompatible with, the practice by the physician of his profession. Choice of treatment, drug selection, and indeed, the whole physician-patient relationship seem not properly affected by any forces outside the physician's training, abilities and understanding of the patient and his malady. The idea that anything coming out of such fields as advertising, sampling, sa.les pressures, price advantage, or third party recommenda- tion of any kind could intrude on this relationship is somehow ~epug- nant to the public who still regard the medical profession as a sort of prefabricated-all-knowing-group of specialists of superior and per- haps even secret powers who need no help or direction from those inspired by motives other than the specific cure of the patient at hand. Commercialism of all kinds, and medicine2 have always been uneasy associates. It is difficult to keep this relationship in proper balance, and it is the struggle to do so that leads to hearings of this type, and eventually is the cause of much of the governmental regulation im- posed on the industry. We now have before us examples of how promotional activities vary from country to country on the same drug by the same company. Indeed, it appears that promotional claims for certain drugs which are forbidden in this country are emphatically stated in other coun- tries, and that a fair case can be made for what looks like the exploi- tation of ignorance of peoples who lack the medical scientific ex- perience which has evolved in the United States in the last 30 years or so. It is difficult to imagine any justification at all for the pro- motion or sale of `a drug for an indication for which is not a specific, or any promotion or sale of a drug without adequate information as PAGENO="0052" 15406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to the side effects, toxic or otherwise, of the dosage recommended. No- where is there any voice of industry who would argue for such courses of action, and yet here are examples of just such things happening. How can this be? In the record of hearings of this committee are two significant ex- planations offered as to just how these promotional differences between countries are explained or rationalized. One approach is the one set forth by the president of a major pharmaceutical house that whatever standards, indications, or claims for a drug are approved by the in- house scientific staff of his organization as to the "medical posi- tioning" of a product, that is their standard of guidance, everywhere in the world. He stated further and specifically that they would not use the standard of what is approved by FDA for that drug in this coun- try if there should be any difference. The more you think about this approach the more puzzling the ethical implications become. It takes quite a bit of self-confidence, and perhaps even arrogance, to be able to ignore completely any findings by the FDA contrary to your own. While the track record of the FDA includes some questionable judg- ments in the past that have not held up to the test of time, certainly the vast body of its findings and its regulations are sound, and prob- ably are the production of the most advanced system of drug review operating in the world today. However, if such a policy were actually used, there would be no variation in promotion among different coun- tries except where regulation required some limitation. It would ap- pear from testimony given here that is practically never the case, and variation exists in the promotional claims for the same product among countries which have virtually no regulations at all. Therefore, it is doubtful even a pharmaceutical house with an internal business- research relationship of extraordinary balance and understanding can or does follow any such policy to the letter today. The second approach is described by a former medical director of a larg~e pharmaceutical house which maintained two different medical staffs, one apparently with a less rigid approach to promotional. pro- cedures which could be used Overseas. Somehow, I feel this latter ap- proach, or variations of it is the more common, and probably the more easily rationalized of the two. It must be recognized that there is such a thing as honest difference of informed medical opinion on the evaluation of individual drugs. It seems that there is always available some medical specialist or some source of information to contradict opinions expressed by others. It has been said time and time a~ain that medicine is not an exact sci- ence, and certainly drug utilization appears to be one of its more inexact areas. But for the purposes of public health today, a judgment has to be made and a line drawn somewhere. It is suggested that a lit- tle line drawing is now indicated. There are at least two complicating factors which get in the way of a quick and easy solution to this problem. First, is the obviously different opinions that scientists of good reputations and sincerity have about not only the physical qualities of drugs, but a1so about the whole philosophy of risk versus anticipated therapeutic benefit. Government regulatory bodies tend toward policies which take abso- lute safety as the dominant note, while independent scientists tend to evaluate a drug more on a risk-versus-results basis with the individual PAGENO="0053" COMPETITIVE PROBLE~tS IN TIlE DRUG INDUSTRY 15407 physician determining the applicability of the particular drug tQ a particular case. Second, there is the basic doubt as to a universal and. automatic com- petence of the FDA or any other governmental agency in all matters it touches. Rigid acceptance of FDA controls, with appeal or review difficult and very expensive, makes for an unsatisfactory system. Polit- ical pressures are significant in drug control regulation when they should not be, and there is sometimes too much shortsighted action taken just to get rid of an immediate problem. This results in an ever- increasing body of industry rules which tend to develop into a rigid formula for establishing black and white, without any regard for the vast grey area which exists in medical procedures. It would seem that one of the best ways that is now available to evaluate a new product, or a new use of an old one, is to try it in a mar- ket where there is some latitude permitted in promotion efforts. This is not to justify in any way exploitation of a product for indications known to be wrong, or without warning of possible side effects that have been established by previous use elsewhere. Full disclosure is always essential. Absence of conscious deception is always essential. Acknowledgment of different opinion is always essential. After that, if there is still room for use of the product with advantage to the pa- tient, it is clear there should be opportunity to do so. Mr. GORDON. In your prepared statement you said:" * * * that one of the best ways that is now available to evaluate a new product, or a new use of an old one, is to try i,t in a market with some latitude per- mitted in the promotional efforts." You are not implying this takes place, are you? Mr. SQUIBB. Certainly not. Mr. GORDON. You agree that opinions are not sufficient, but we need "adequate and well-controlled studies." Mr. SQUIBB. I mean sound medical opinions. Mr. GORDON. Resulting from adequate and well-controlled studies. Mr. SQUIBB. Resulting from medical studies. It could be all types of studies, or course, made in different geographic situations and for different conditions of living in different parts of the world. For honest men of good will, the problem is exquisitely difficult. Such scientists do not accept the automatic infallibility of Govern- ment regulators, nor do they accept the limitations placed by arbitrary controls on their own conclusions. Dishonest men who deliberately exploit ignorance to their own ad- vantage by offering hope of cure without concern for anything except the monetary return to themselves are the object of our effol'ts here today. Just where and how to separate the two groups should ~e easy. but in fact gets more and more difficult as medicine increases in its potency and complexity. As far as the established companies of the American pharmaceutical industry are concerned, and it seems that all too often they are the ones that are concerned with the problem under discussion here, the solution ought to be found right in their own internal operations. The industry constantly claims for itself high standards of ethics and close attention to its admitted unique high degree of social respon- sibility, yet all too often it seems to fail in this regard in promotional matters. It would seem that as a matter of policy, if the question PAGENO="0054" 15408 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY were effectively put, no board of directors of a responsible American pharmaceutical house in this day and age of sensitivity to con- sumer criticism would ever knowingly permit its companies' products to be marketed under double or deceptive staildards, or in any way whatsoever that would result in extraordinary risk to the public in any part of the world. Mr. GORDoN. You recall the opening statement of Senator Beall yesterday. He referred to the annual meeting of the stockholders of the Warner-Lambert Pharmaceutical Co. in 1972 where 97 percent of the stockholders voted "No" on a resolution that the company change its policy by divulging to foreign doctors what U.S. law now demands, that it tells U.S. doctors about the toxicity of its Chloromy- cetin, a product of its Parke-Davis division. Mr. SQUIBB. I cannot imagine such a thing could happen if the di- rectors were really aware of what they were saying. I do not think they were in that case, in my opinion. To me, it is impossible to conceive that anyone would vote that way if they knew what they were doing. Mr. GORDON. But they did, 97 percent of them. Mr. SQUIBB. Sure, the management voted as by proxy. The shareholders sent in their proxies and they voted for that statement, but I do not think they realized what they were saying. Mr. GORDON. Yes, they did, because Dr. David Lewis and Dr. Rich- ard Burack explained at the meeting the cotisequences of the present policy. Nevertheleas, they still voted 97 percent. Mr. SQUIBB. That, of course, is the point I'll make later. If industry continues to ignore, either willfully or through ignor- ance, the results are the same and we are going to get for the industry a whole series of regulatory developments which are going to be un- favorable to them. There is no question about that. I would certainly hope that no board of directors would ever again, or at least after these hearings and perhaps after the publicity given the matter, would come out with anything like a position such as that. The fact is that such questions are rarely, if ever, put to the Boards. It is customary for the directors to leave all day-to-day operating procedures to its field management, and then simply to inspect the financial results of such procedure. In the pharmaceutical industry, something a lot more responsible than that is called for on the part of directors. They must question precisely the way their organization is carrying out its social responsi- bility and to set specific standards and guidelines for the pron~tion of its products. / If they feel that their own research staff is of such caliber and in- tegrity as to set standards and to control and limit all promotion activ- ities of the company, then this should be their policy and it should be applied everywhere uniformly where regulation permits. If they should wish to~föllow such a policy without regard for `outside opinion except where such opinion is imposed upon them by law, it would be their right to do so. Without making the individual judgments them- selves, they would still have to understand exactly how such judgments were arrived at between the sales and scientific departments of their organizations and would accept the infallibility of those decisions with the clear understanding that theirs was the final responsibility. It is PAGENO="0055" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15409 doubtful that any board today, in spite of the Warner-Lambert deci- sion, would take such an extreme position, and we heard yesterday some others who testified recently in this matter, in contradiction to outside opinion, but by following such a procedure of observation and review, a board would establish an ethically consistent approach to all promotional programs for its company~s products no matter where the promotion was directed. The current trend toward the personal responsibility of corporate officers and directors for all actions of their companies, and particu- larly those which affect the health and welfare of their customers, is one which has to be taken very seriously, indeed, in the pharmaceutical industry and here is a good place to start. It seems clear that n~ost boards would prefer to rely on some combination of their own internal research standard and that of the FDA, or other appropriate regula- tory body. But any such combination would have to define and estab- lish, in advance, guidelines for aggressive promotion men for whom sales volume is the overriding issue. If the pharmaceutical industry cannot find within its own opera- tions the solution to the obvious problem it creates for itself by prOmo- tional practices which set different standards for different peoples, then a solution will be forced on it in one way or another from outside. Several possibilities are immediately apparent, the most obvious being expanded governmental regulatory control made possible by enaI~ling legislation. Certainly, `the conduct of American industry overseas is receiving all kinds of attention these days, most of it sharply critical, and there will be plenty of precedents for the imposition by the PDA of some kind of sanctions against those who stray from U.S. stand- ards in their conduct of their foreign business ventures. Even if the only practical `method to do so is to demand industry to protect its stockholders from the liability claims inevitably arising from damages related to improper drug use by observing defensible standards of product, a way can and will be found to do it. Control through the World Health Organization is another possible way to insure that only balanced, accurate, and scientifically docu- mented claims are made for medicinal preparations anywhere in the world. This body could certainly assume an advisory position in this area which would be of great value especially to those countries with- out their own body of scientific knowledge and expertise. Nine years ago Dr. Helen Taussig has described to the committee in earlier hearings some of the possibilities that could be developed along World Health lines, but clearly a lot more study is neces~ar~ to make sure that objective medical standards can be so achieved staying clear of all the varying social and political pressures that all too often seem to become dominant in a global approach to any problem. Nine years ago before this committee I stated that a pharmaceutical manager must accept the fact that his industry indeed carries a high degree of social responsibility or he can see that social responsibility spelled' out for him slowly but surely by legislation prescribing more and more of his operations, and taking over more and more of the functions he now guards so fiercely. The thrust of those hearings concerned prices in the pharmaceutical industry, but my comment is just ~ applicable today to promotional practices which seem to the public to ignore any feeling of responsi- PAGENO="0056" 15410 COMPETrTIVE PROBLEMS IN THE DRUG INDUSTRY bility toward the patient, and clearly go against the most basic princi- ples of medical ethics. By continuing such practices the industry~ is making serious long-range trouble for itself, if not here today, then down the line as foreign governments become more alive to public health problems. It is very stupid, indeed, for a well-established, profitable and pro- gressive industry to endorse or to permit practices in its sales promo- tion areas which can produce only the short term dollar return, and then will lead to restrictive controls which will overreach the abuses with which we are now concerned and go on to other pharmaceutical affairs now left unregulated. Such is the inevitable result of the abuse of corporate power, and it's about time that corporate management realized it. I would like to see the pharmaceutical industry take the lead in that realization. Thank you. Senator JAVITS. Mr. Squibb, I find your presentation very, very in- teresting, but as a practical matter, do you really think the acceptance by American pharmaceutical concerns of their social responsibility is likely soon enough to be responsive to the goals which have been testi- fied to in the context of these hearings? Mr. SQUIBB. Sir, it could start tomorrow. I am always optimistic. It has been my family's philosophy for 125 or 130 years that these things are all possible. We have seen an increasing development of a social responsibility over a long time, but I would rather see it worked out that way than through Government regulations. It is hearings like this and the publicity that we saw in the papers this morning that I think force the industry into these improved social responsibilities. I think there is no question about it that the climate today, changing just in the last 2 years, in the degree of the responsibility of the boards of directors is going to have an effect on some of these things that go on in the pharmaceutical business, particularly because it involves health. Senator JAvITS. Your family has an enviable reputation and position in this field. Of course, you yourself by testifying here evidence your own social resnonsibility. I understand your own feeling in the matter and it is very laudable. I must say I, too, wish business would shake itself up, but often Government cannot wait for that but must induce it. What I am interested in-and your whole testimony supports this- is that many of the charges of excess promotion and lack of disclosure ar~ assumed by your testimony. You assume that a good deal of what has been charged here is true. Mr. SQUIBB. I know it is true. I do not assume it. I know it. Senator JAVITS. Well, your testimony is very important because it describes a most deplorable situation. I have really two questions for you and then I must leave. Perhaps counsel would wish to ask some further questions. One is this: Do von believe from your experience that it would be practical to apply FDA standards to overseas sales and promotion or PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSPRY 15411 is there a reason why some different set of standards should apply where local law does not call for standards like those of the FDA? Mr. SQUIBB. I do not believe I follow your question. Senator JAvrrs. In other words, if we assume local law permits standards other than those set by the FDA for domestic sales and pro- motion, do you think that there should be different standards abroad by pharmaceutical companies from those which the FDA requires them to apply here, or should they be the same everywhere? Mr. SQUIBB. Ido not necessarily accept the fact that the FDA stand- ards for all products are the correct ones, but you do not have to ac- cept that for it is not so much a question of legality as a question of the ethical, the proper, true, fair and complete explanation of the use and nature of the product that is under question. Whether it is law or not, in my opinion, makes no difference; the law will require you to do cer- tain things, but your ethical approach should be the same everywhere. Senator JAVITS. Well, I think that to meis the key. If there is no reason why uniform standards cannot be applied everywhere, then I see no reason why you should not strive to*ard that as an objective. If means are not available, let us say there are no doctors in an area-and that is true in much of the world-then you may have to omit some element of the standards; but as far as they can be applied, let us put it that way, you feel that whatever is done here ought to be done everywhere as far as it can be done? Mr. SQUIBB. If it is the correct and proper way from what w~ hear then, it is the correct and proper approach to the individual problem. Senator JAVITS. Well, Mr. Squibb, thank you very much, It ~eems to me that is the key point that I wish to bring out under questioning. Mr. Ledogar, did you have a comment you wish to make on this? Mr. LEDOGAR. If I may, very briefly. I do not think the issue is really universal standards. The Business and Industry Advisory Committee which represents U.S. multinational firms raised that issue when commenting on the report of the United Nations group of eminent persons of which you were a member. The issue is disclosure. Apparently, there is a resistance within in- dustry to even disclose to host governments the FDA requirements with regard to health and safety on drugs. I do not believe that there can be universal standards because the needs vary greatly from one country to another, but we can at least let everyone know around the world what the FDA requires and that will go a long way toward enabling governments to judge for them- selves what the specific dangers of a drug are and to apply that infor- mation to the conditions in their country. Senator JAVITS. Well, Mr. Ledogar, I see nothing inconsistent be- tween what you have said and what Mr. Squibb and I have been say- ing because the FDA r&iuires the very publicity and information which you have just mentioned. It is an element. I see no difference. What is the difference? Mr. LE000AR. But the FDA cannot require it overseas. Senator JAVITS. I understand that but what we are trying to find out is if there is any way we can. That is what we are here for. Mr. LEDOGAR. Yes, and I believe it should be done. PAGENO="0058" 15412 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Senator JAvITs. In other words, are you against our applying of FDA standards to the extent possible overseas as well as domestically? Mr. LEDOGAR. Yes, I think in some cases it can be an interference in the internal affairs of another government. Senator JAVITS. And that is your reason for being against? Mr. LEDOGAR. Also because standards cannot be the same all around the world. Senator JAVITS. No one said they are to be the same. All we said is insofar as it is possible, but you do not accept that? You say we would be interfering in the internal affairs of another government? Mr. LEDOGAR. I do not believe we can unilaterally impose them. Senator JAvrrs. No one is trying to impose them sir. All we are saying is if we can find a way to do it that we should make FDA standards universal insofar as they can be applied in each given country. Mr. LEDOGAR. I am simply saying a first step is disclosure. Senator JAvIT5. All right, Mr. Ledogar, thank you. Do you have questions, Mr. Gordon? Mr. GORDON. Mr. Squibb, on the top of page 6, you stated that: "Government regulatory bodies tend toward policies which take ab- solute safety and so on and so forth, and then you say while the inde- pendent scientists tend to evaluate a drug on a risk-benefit basis." Is that not what the FDA uses as a basis for approving or rejecting a drug? Mr. SQUIBB. I would think, for example, of the Delaney amendment. Mr. GORDON. That does not deal with drugs. That deals with food additives. Mr. SQUIBB. But I say Government regulatory bodies tend to look toward absolute safety, and they have to because of the publicity at- tenclant to any accident or any fatal or harmful results of the drug. I think that is a well-established fact and it is inevitable that they do so. We heard some testimony yesterday from Dr. Lee that the indi- vidual physician can determine whether the illness or the condition for which he is using the drug is such as to warrant risking the chance of serious side effects from the drug. There is no question about that possibility, whereas the regulation may say specifically it cannot be used for that indication for the reason there are a lot of serious side effects. The risk factor that an individual physician can determine is often a major consideration as to whether that drug is properly used. Mr. GORDON. In your prepared statement you also say: Z~There is the basic doubt as to a universal and automatic competence of FDA or any other governmental agency in all matters it touches." I merely want to emphasize that at least the FDA does not have a financial interest in getting a drug on the market, whereas a company generally does. Mr. SQUIBB. That is right. This is `again the problem I point out, the difficulty and conflict between commercialism and medicine. It is a very difficult problem, and of course, all these companies that make these remarkable drugs are commercial operations which re- quire a profit for their stockholders on the one hand, then on the other PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15413 there are these principles of social responsibility and medical ethics which are difficult often to correlate. This is why we are struggling here today. Senator JAVITS. Thank you very much, Mr. Squibb and Mr. Ledogar. The subcommittee will stand in recess, subject to the call of the Chair. [Whereupon, at 10:45 a~m., the subcommittee recessed to reconvene at the call of the Chair.] PAGENO="0060" PAGENO="0061" APPENDIX STATEMENT BY * ROBERT J. LEDOGAR AUTHOR AND PRIVATE CITIZEN BEFORE SUBCOMMITTEE ON MONOPOLY SENATE SMALL BUSINESS COMMITTEE May 27, 1976 My statement, Mr. Chairman, will consist of four parts: first, a brief summary of what I consider to be the main problems with the development, marketing and use of prescription drugs in Latin America; second, the relation of. transnational pharmaceutical corporations to these problems; third, the impact of United States for- eign policy on the situation; and fourth, some recommen- dations. As a preface, however, I am obliged to make it clear that I speak only as a private citizen. Although I am currently serving with the staff of the United Nat~Lons, my remarks here today are the outcome of investigatiOtiS carried on before I joined the U.N. in preparation for a book entitled Hungry For Profits: U.S. Food g Drug Mi4ti- nationals in Latin America. This book was published by IDOC/North America, but the work was completed prior to my current U.N. affiliation. Consequently, what I have (15415) PAGENO="0062" 15416 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Statement, Robert J. Ledogar, 5/27/76 - 2 to say does not rest on any information obtained as a U.N. staff member, nor does it reflect the official views of the United Nations. There are two sets of problems besetting Latin Airier- ica with respect to pharmaceutical products. The first affects the urban middle and upper classes for the most part, and it is a problem of excessive consumption of pharmaceutical products under unnecessarily hazardous con- ditions. Those who can afford it may buy almost any non- narcotic drug without prescription (despite a statement on the label which says that the drug is for sale by pre- scription only), and the labelling and advertising of such products, generally speaking, carry fewer warnings and claim more extensive healing powers than is permitted for the same product in the United States or Western Europe. Examples of such labelling and advertising are given in my book, as well as in the works of Drs. Silverman and Lee. The second and more serious problem is that of the low-income majority of Latin Americans who, for the most part, do not consume pharmaceuticals in great quantity be- cause those products which are available are too expensive and/or unsuited to their needs. 72% of Brazilians, for example, die before the age of 50; 10% of them die before their first birthday. Communicable and endemic diseases aggravated by malnutrition are the main causes of such deaths. What Brazil,~ like most other countries of Latin PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15417 Statement, Robert J. Ledogar, 5/27/76 - 3 America, needs from the pharmaceutical industry is the development of very inexpensive drugs to combat diseases like tuberculosis, measles, diptheria, whooping cough, schistosoniasis, Chagas disease, and the myriad of in- testinal infections which ravage the low-income popula- tions. This means that research and development must be carried out with these local and low-income concerns primarily in mind. This is not the kind of RCD which receives highest priority in the multinational pharma- ceutical business. Nearly all of the pharmaceutical products on sale throughout the world today are discov-~ ered and developed in the United States or Europe. Since multinational firms make their money by selling to the higher income populations of North America, Europe, and Japan, along with the urban middle and upper classes of Asia, Africa and Latin America, they have very little economic incentive to produce cheap drugs to combat diseases from which their main customers do not suffer. My purpose is not to make the transnational phar- maceutical industry the scapegoat for all of Latin America's ills. The industry has discovered and devel- oped drugs and vaccines which have saved millions of lives among rich and poor. Even if one believes that such discoveries and more might have taken place if the industry were structured differently than it is, credit should be given where it is due. Latin American govern- PAGENO="0064" 15418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Statement, Robert J. Ledogar, 5/27/76 - 4 ments certainly bear a very large share of the responsi- bility for the problems I have just described. They invited multinational industry to their shores and, even though this was done frequently with the active encour- agement of the U.S. government, they could have refused; and they remain free to expel, nationalize, or otherwise discipline these firms. But one can fairly blame the multinational industry for at least two things: for the maintenance of high prices on drugs currently available and for its tendency to favor the political, economic and therapeutic status quo. Multinational industry's role in the maintenance of high prices on the international market has already been investigated by this subcommittee and will perhaps be discussed further by other witnesses at these hearings. I am more concerned with the industry's failure to produce what the people really need and its ability to resist ef- forts by concerned local interests to develop a low cost chemotherapy more suited to such needs. When, for exam- ple, 45% of a sample of foreign-held patents registered in Argentina from 1957-67 were for products which were neither being manufactured nor imported into Argentina, the effect could only have been to discourage Argentine research and development. Transnational industry fre- quently enters Latin America or expands there by ~uying out already existing local firms. In individual cases PAGENO="0065" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15419 Statement, Robert J. Ledogar, 5/27/76 5 such mergers may have beneficial effects, but the overall impact is again to reduce the incentive and scope for local research and.development. This is especially the case when transnational firms dominate the entire indus- try, as they do in many Latin American countries where they may be responsible for three-quarters or more of total sales volume. Most of' the raw materials for drugs sold in Latin America come from outside Latin America. Central America imports 90% of its raw materials for drugs. This is hardly the road to self-sufficiency. And the multinationals openly resist efforts by Latin Ameri- can governments to foster an independent national research and development capability. An ambitious and well-financed plan mounted in Brazil in 1971 to utilize government, university and other local laboratories to produce ~00 basic medicines cheaply and efficiently for nation-wide distribution was openly resisted by the for- eign-owned firms. In the end the plan was emasculated, resulting in only a very small transfer of secondary R~D facilities by a fe~i companies to Brazil. Just as they complain about excessive controls by the FDA in this country, the multinational firms are hardly likely to favor an improvement in the generally inadequate government control systems in Latin America for drug labelling and marketing. Since the investiga- tive work for my book was completed, several transnation- 73-950 0 - 77 - 5 PAGENO="0066" 15420 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Statement, Robert J. Ledogar, 5/27/76 - 6 al drug firms from the United States have admitted to giving bribes to officials of foreign governments. None of the countries have been identified. I was able to obtain evidence on bribery in Latin America only in the case of one firm-a Swiss company which had a list of 135 Brazilian regulatory officials to whom it gave small "donations"-but everyone knows that bribery is a fre- quent occurrence. The transnatjonals say they have to engage in it in order to survive. As individual compan- ies they probably do. The point is that they are able to unite and flex their muscles when their common interests are seriously threatened. Despite the fact that they dominate the drug industry in many countries, the multi- nationals have dorFe little to change the regulatory status quo. One can only conclude that it suits their purposes just as it is. Where does United States foreign policy come into all of this? First of all, despite some recent changes in legislation, our government offers substantial encour- agement to foreign investment by transnationaj. firms headquartered in this country through tax incentives, guarantees, loans and the services of our commercial representatives abroad. Drug companies have taken spe- cial advantage of these incentives as several examples in my book illustrate. In a broader way, however, U.S. foreign policy sup- PAGENO="0067" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15421 Statement, Robert J. Ledogar, 5/27/76 - 7 ports the activities of transnational firms overseas by openly encouraging the maintenance of a `favorable busi- ness climate" in those countries we consider to be our friends. We support regimes which encourage investment by U.S. firms. Relations are cooler with countries which place heavy restrictions on such investment. Our special relationship with Brazil, for example, is due in part to that nation's heavy reliance on, and strong encouragement of, U.S. private investment as opposed to the more re- strictive attitude of the Andean Pact countries. The crux of the problem is here. For most business a "favorable investment climate" means a minimum of gov- ernment interference. Simplified rules and regulations, tax incentives, freedom to compete with (and/or buy out) local industries, a limit to price controls, plenty of cheap labor and little labor mi1itancy-~--this in itself bespeaks a conservative, if not repressive, type of regime. But with the pharmaceutical industry there are added re- quirements. In their case, a "favorable business climate" also means: weakness of safety controls on labelling and advertising; no efforts to control the proliferation of brand names; freedom to locate research and development facilities wherever these are most profitable for the company; absence of adverse publicity; and freedom to produce and sell not necessarily what is most needed in the country but what is more economically efficient from PAGENO="0068" 15422 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Statement, Robert J. Ledogar, 5/27/76 - 8 the standpoint of profits. This puts the United States government in the posi- tion of supporting activities which are contrary to the best interests of the majority of people in Latin America. It makes us the ally of transnational business in its tendency to support the status quo and oppose change. What can be done to change this situation? A gen- eral review of our government's whole supportive attitude toward U.S. foreign investments, together with the spe- cific incentives, is certainly in order, but that is a very large issue which transcends this committee's pre- sent specific concern with the pharmaceutical industry. Short of such a broad policy review, there is very little that the U.S. government can do unilaterally to alter the conduct of U.S. firms acting through local subsidiaries overseas. We cannot interfere in the internal affairs of other nations to impose standards of our own. There are serious difficulties, moreover, with the imposition of unilateral controls by the U.S. government on U.S.-based firms in the absence of similar controls on European and Japanese firms by their governments. What our government can do is to support multilat- eral efforts toward the greater regulation of transna- tional investment in less developed countries as well as independent multilateral efforts to assist less developed countries in solving their most serious health problems. I would like to offer the following specific recommendations: PAGENO="0069" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15423 Statement, Robert J. Ledogar, 5/27/76 - 9 1) That the United States government take an active role in seeking an international convention on the condi- tions of trade, sale, marketing, advertising and la- belling of pharmaceutical products. I have in mind a role similar to that taken most recently by our gov- ernment in urging international action on the question of bribery in international business dealings. 2) That the United States government support the recom- mendation of the United Nations Group of Emrninent Persons that the affiliates of transnational corpora- tions should be required to reveal to host govern- ments any sales prohibitions and restrictions in man- ufacturing imposed by home or other host countries with respect to the health and safety of consumers. 3) That the United States government, through its repre- sentatives to the World Health Organization, support current efforts of that organization to improve its International System of Information on Drugs and look for ways to restructure the Geneva Research Center for Monitoring Adverse Reactions to Drugs so that it may be more suited to the needs of less developed countries. 4) That the United States government offer, preferably through multilateral channels, financial and techni- cal assistance, independent of any influence from private U.S. firms, for improving the capacity of PAGENO="0070" 15424 COMPETITIVE PROBLEMS IN THE DRUG INDTJS~y Statement, Robert J. Ledogar, 5/27/76 - 10 of regulatory agencies in less developed countries to exercise control over the pharmaceutical industry. 5) Finally, but most important, that the United States redouble the research efforts of its own government agencies and offer, through multilateral channels, more technical and financial aid to independent, non- commercial research facilities in less developed countries to discover and develop cheaper and better drugs to combat the diseases which afflict and short- en the lives of many millions of our fellow human beings. Mr. chairman, these recommendations do not consti- tute the total solution to the problems I have described earlier, but if they were to be carried out we would have made a good start. PAGENO="0071" COMPETITIVE PROBLEMS IN THE 1)~UG INDUSTRY 15425 STATEMENT BY Philip R. Lee, M. D. * BEFORE THE SUBCOMMITTEE ON MONOPOLY SMALL BUSINESS COMMITTEE UNITED STATES SENATE May 26, 1976 Mr. Chairman and members of the Subcommittee: I am pleased to have this opportunity to appear before the Subcommittee on Monopoly, Small Business Committee to respond to your request to discuss the results of Dr. Silverman's studies on drug product promotion in Latin America. Like Dr. Silverman, the views I express are my own and do not necessarily represent those of my colleagues at the University of California. Although I have had the opportunity of reviewing the results of Dr. Silverman's studies in detail, I want to focus my remarks today on the problem of drug resistant pathogenic bacteria and the relationship of this problem to drug promotion, physician and pharmacist prescribing, and pharmacist dispensing * in Latin America. * Professor of Social Medicine; Director, Health Policy Program, School of Medicine, University of California, San Francisco. PAGENO="0072" 15426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Specifically, I will discuss in some detail the problems that arose in Central America because of an epidemic of Shiga dysentary due to Shigella dysenterlae strains resistant to chloramphenicol, tetracycline, streptomycin and sulfonamides, and the problems that arose in Mexico because of an epidemic of typhoid fever caused by chloramphenicol resistant Salmonella typhi. Until the epidemic of typhoid fever in Mexico in 1972, chloramphenicol was the drug of choice for this disease throughout the world. In Mexico it proved ineffective because of drug resistance. The epidemic of Shiga dysentery was due to chloramphenlcol resistant organisms, but because the treatment of choice is ampicillin this was not a matter of prime importance. That epidemic was important because It spread rapidly among susceptible populations and it had a high fatality rate. The patient with Shiga dysentery suffers from explosive diarrhea, with up to 40 bowel xrovements per day, blood and mucus in the stools, severe cramps and dehydration. The preferred treatment of choice is ampicillin when the organisms are susceptible, which is usually the case. In other forms of Shigellosis the frequency of resistance of the pathogens to ampicillin and other antimicrobial agents has restricted drug therapy to only those patients with serious illness. Why do I choose to focus my remarks on the problem of drug resistant enteric pathogens in Mexico and Central America, when Dr. Silverman's study included a wide range of drugs from antibiotics to tranquilizers? I do so because I believe the problem is related to the promotional practices of the drug companies, it is serious and it can affect not only the residents of the countries involved and all those who visit there as well, but people who have never traveled to Latin America. 2. PAGENO="0073" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15427 The development of pathogenic bacterial resistance to antimicrobial drugs has been a serious problem in the United States since the development of penicillin resistant staphylococci in the 1950's. In the 1960's resistant ~trai.ns of menin- gocoocci appeared, causing meningitis in members of the Armed Forces. Patients with bacillary dysentery in various parts of the world were found to harbor strains of Shigella resistant to several antimicrobial drugs. In the late 1960's the epidemic of Shiga dysentery in Central America was caused by Shigella resistant to chioramphenicol and other antimicrobial drugs. In the 1970's a typhoid fever epidemic in Mexico was found to be due to Salmonella typhi strains resistant to chloramphenicol. Recently, in the United States and Egypt cases of meningitis due to Hemophilus Influenza strains resistant to ampicillin and penicillin have been reported. In 1975, physicians at the U. S. Naval Medical Research Unit No. 3 in Cairo, Egypt, reported for the first time Isolating chlorarnphenicol resistant Salmonella paratyphi-A from a patient admitted with chronic entenic fever. The increasing prevalence of drug resistant strains of bacteria is, .in part, apparently related to the widespread use of antibiotics and other antimicrobial agents. This use is due to a considerable extent to irrational prescribing by physicians, irrational dispensing by pharmacists where they are permitted to dispense antibiotics without a physician's consent and to the underlying promotional practices by the drug companies that encourage irrational prescribing and dispensing. It is within the context of the worldwide problem of increasing drug resistance that I want to discuss the recent Shiga dysentery epidemic in Central America and the typhoid fever epidemic in Mexico. In both cases the causative organisms were resistant to chioramphenicol, a fact of great importance, particularly in the Mexican epidemic. 3. PAGENO="0074" 15428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Chloramph~ikol is an antibiotic which is well known to this Committee because of the Committee hearings on the subject in 1967 and 1968, and the subsequent hearings on antibiotics, particularly in 1972. Chioramphenicol marketed in the United States since 1949, is unquestionably a potent antibiotic. But b~cause its use may result in serious adverse effects, including fatal blood dyscrasias (aplastic anemia, thrombocytopenia and granulo- cytopenia) it must not be used when less dangerous drugs will be effective. In the United States the Food and Drug Administration (~`DA) limits approval of the conditions for which it may be promoted by manufacturers to infections caused bySalrnox~flatyphi sensitive to chloramphenjcol, and the following serious infections caused by susceptible strains: --Salrmnella species; - - lien-iophilus Influenza~ specifically rneningococcal infections; Rlckettsia strains; - - Lymphgranuloma..psjttaco~ group; - - Various gram negative bacteria causing bacteremia, meningitis or other Serious gram negative infections; and - - Other susceptible organisms that have been demonstrated to be resistant to all other appropriate antimicrobial agents. In spite of these clear indications and the fact that chloramphenicol can be dispensed in the United States only ona physician's prescription, there is still significant misuse and overuse. In a recent study in Tennessee, for example, It was found that half the chloramphenicol prescriptions for Medicaid patients were 4. PAGENO="0075" COMPETITIVE PROBLEMS IN TEE DRUG INT)tTSTRY 15429 for upper respiratory infection. Fortunately only 204 of the 3,409 physicians participating in that program prescribed chioramphenicol. The problem was primarily with the 20 physIcians who wrote 55 percent of the chioramphenicol prescriptions. For most of the patients who received a chlorarnphenicol prescription It was prescribed unwisely. It is unfortuante that the prescribing patterns of some physicians, such as those found in the Tennessee study, still persist. The trend with respect to chioramphenicol in the United States has improved significantly in the past decade. lit the late 1960's, prior to important hearings by this Committee which brought the hazards of chloramphenicol use to the publics attention, the FI~A certified more than 40 million grams of chloranphenicol annually. After the hearings, in the early 1970's, the figures were between 6-8 million grams annually. This is still far mo re than is needed for the patients for when chloraxnphenicol is indicated, but it does show that change is possible. Part of the improvement was due, in my opinion, to improved public understanding stemming from your Committee's hearings. The situation that Dr. Silverman found in his study of drug promotion in Latin America is far different and far more serious and one that poses a greater hazard for the public. In his testimony today he noted: In Mexico and Colombia, the Parke-Davis brand marketed as Chloromycetin is promoted for use not only for life-threatening conditions but also for tonsillitis, pharynsitis, bronchitis, urinary tract infections, ulcerative colitis, pneumonia, staphy- lococcus infections, streptococcus infections, eye infectIons, yaws, and gonorrhea. 5. PAGENO="0076" 15430 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In Central America, a competitive brand marketed by McKesson is recommended for whooping cough. In the United States, the Parke-Davis product carries a long list of contraindications, warnings, and adverse reactions. Perhaps the most alarming of these include aplastic anemia and other serious or fatal diseases of the ~od-forming system. In Mexico, the Parke-Davis product carries only a limited list of warnings. In Central America, no contraindications or warnings are given, and no adverse reactions are disclosed. The McKesson product statement discloses a few hazards in Central America but none in Colombia and Ecuador. What are the consequences of this type of promotion? What are the possible hazards? First, physicians and pharmacists will be more likely to prescribe and dispense chioramphenicol either when it is not needed, when it is contraindicatedI,or when other drugs would be more appropriate. Patients will be fnore likely to take chloramphenicol without particular concern for the possible hazards,or they may be totally unaware of the hazards and some will undoubtedly suffer serious, indeed fatal, side effects. Dr. Silverman has already noted that Mexico has an unusually high rate of fatal aplastic anemia, related, at least in part, to the widespread, irrational use of'chloramphenicol. This is reason enough to markedly restrict the promotion, prescribing and dispensing of chloramphenicol in thc~ e countries in which It is used. 6. PAGENO="0077" COMPETITIVE PROBLEMS IN TIIE~ DIUJG INDUSTRY 151~31 The regulation of the manufacture, promotion and marketing of drugs is the responsibility of the government In each country where drugs are made, sold and promoted. Drug companies may, and indeed do, adopt standards that exceed the requirements in many countries. The regulation of the drug industry in Mexico, Guatemala or any other country should, however, be a matter of concern for the United States because inadequate regulation poses a hazard both for the citizens of the countries involved, for visitors to those countries and potentially for those who may never travel. In short, inadequate regulation poses a potential threat to world health. The emergence and widespread prevalence of drug resistant enteric pathogens in two recent Latin American epidemics illustrate these problems. T~hese epidemics were a menace not only to the people of Central Arx~erlca and Mexico, but they were also a potential hazard to all those who visited there. In order to explain why I believe the development of drug resistant enteric pathogens respresents a serious problem, I must review a little history, a little pharmacology and some n~icroblology. In the early l960s, it was found that patients with baciflary dysentery harbored strains of Shi~ella that were resistant to several antimicrobial drugs. When these resistant strains were cultured 10 vitro with sensitive strains of Shigella or even other gram negative bacteria, the genes for multiple drug resistance were transferred to the drug senstive strains without simultaneous transfer of any other genetic marker from the donor strain. The resistance (R) factors have been identified, and resistant strains have been found not only IA hospital populations but also in domestic livestock, especially when antibiotics 7. PAGENO="0078" 15432 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY were routinely present in the animal feed. They have also been found in the enteric (intestinal) bacteria of a human population never exposed to antibiotics (2). for therapeutic purposes. In discussing this phenomena, Gddstein, Aronson and Kalman observed: Thus, the transfer factors evidently occur widely; the extensive use of antibiotics merely favoring their proliferation by a selection mechanism. They constitute a significant problem in hospital patients, as evidenced by a study in which stool cultures from 100 apparently normal hospitalized infants (3) revealed multiple drug re3istant bacteria in 81 of them. Why is drug resistance.important? Why is it important that the resistance (R) factor can be transferred to other enteric organisms? What does all this have to do with the promotion of drugs in Latin America? The problem is important to the millions of people who live in Latin America, it is important for the 2. 5 million residents of the United States who travel to Mexico annually, it is important to the millions of residents of the United States, Europe, Asia and Africa who travel to Mexico and the other Latin American countries every year. At least one-third of the travelers to Mexic.' and many other Latin American countries are likely to suffer an episode of (4) gastroenterit~s during or following their trip. Although many of these are minor, many are serious and some have proved lethal. There are three enteric infections that pose significant potential risks to Americans or others traveling in Mexico and other Latin American countries: 8. PAGENO="0079" COMPEPITIVE 1~ROBJJ~MS IN TEE DRUG INDUSTRY 15433 typhoid fever (~lmonella typhi), Shiga dysentery (~jella dysenteriae type one) and amebiaeis (Centamoeba histolytica). In 1969, Shiga dystentery appeared in Central America in epidemic forms after an absence of several decades. The epidemic began in Guatemala in late 1968 or early 1969. The epidemic spread through Guatemala, British Honduras, El Salvador, Honduras and Nicaragua; the following year it appeared in Costa Rica and Mexico, In Guatemala alone there were an estimated 12, 500 deaths and in El Salvador an additional 2,000 deaths occura~ed. The death rate from Shiga dysentery in Guatemala in 1969 was five times that of 1968 and sevenfold greater than in 1967. In a report on this epidemic from the United States Center for Disease Control in Atlanta, Georgia, it was noted: The Central American strain displayed urtusual virulence, with a case-fatality ratio for untreated patients of 8.4 percent; the ratio was 10-15 percent for those whose illnesses were severe enough to require hospitalization, although appropriate therapy reduced fatalities to one percent. The epidemic strain was resistant to tetracycline, streptornycin, chioramphenicol and (5) sulfonamides. Fortunately the organisms were not resistant to ampicillin, which is the treatment of choice in cases of Shiga dysentery. The cases were not limited to Central America and Mexico. Shortly after Shiga dysentery appeared in Mexico, increasing numbers of cases were noted in the United States. In 20 cases reported in California, 18 of the 20 9. PAGENO="0080" 15434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY patients had visited Mexico or Central America. In addltiøn, cases have been reported in the United States among individuals who had not traveled to Mexico or Central America, indicating that there had been transmission within the United States. - Since the 1969 epidemic of Shiga dysentery in Guatemala, there has been a steady increase in the cases of Shiga bacillus dysentery reported in the United States. The cases reported by the Center for Disease Control between 1965 and 1972 were as fo1lows:~6~ Border Other Year States* States Total 1965 0 1 1 1966 2 .0 2 1967 0 3. 3 1968 4 1 5 1969 3 11 14 1970 13 15 28 1971 38 4 42 1972 58 12 70 * California, Arizona, Texas, New Mexico. The greatest increase in cases has been in the border states of California, Arizona, Texas and New Mexico where the total rose from three in 1969 to 58 in 1972. Nationwide the total number of cases of Shiga dysentery rose from 14 in 1969 to 70 in 1972. 10. PAGENO="0081" C0MPEPITIVE I~ROBLEMS IN TI~E DRUG INDUSTRY 15435 The Shiga dysentery epidemic subsided almost as quicidy as it developed. The hazard of a possible future epidemic is not only the severity of the disease, but the fac~t that strains may develop which are.xesistant not only to chioramphenicol and the sulfonamides, but also to ampicillin, which is the drug of choice in patients with Shiga dysentery. The epidemic of typhoid fever In Mexico in 1972 illustrates the problems that arise when the organisms causing the disease are resistant to the drug of choice, in this case chloramphenicol. In May 1972, Mexican authorities announced the existence of a widespread outbreak of typhoid fever. A total of 6,342 cases was reported in 1972, a 100 percent increase over the 1971 total. The epidemic in Mexico subsided in mId- 1973. Isolates of S~k~Qne~ii3~ typhi from the epidemic demonstrated R,factor.mediated resistance to cblorampbenicOl, streptomycin, tetracycline and sulfonamides; a phenomena similar to that previously found in other Latin American enteric (intestinal) pathogens. In a report from the United States Center for Disease Control It was noted: At the outset of the epidemic the case-fatality rate was greatly elevated, averaging 13. 5 percent for March and April of 1972. Ninety-six percent of all al'cnalla typhi strains isolated at the tinle were later determined to be resistant to chloramphe~Ol. The `fact that this drug was then still considered the treatment of choice for typhoid fever probably accounted for the initially high fatality rate. However, where 11. 73-950 0 - 77 - 6 PAGENO="0082" 15436 COMPETiTIvE PROBLEMS IN THE DRUG INDU&]YRY antibiotic resistance to the epidemic strain (phage type degraded Vi approaching A) was recognized, the change to ampicilliri as (7) standard therapy resulted in a rapid decline in mortality. The experience of the LaRaza Infectious Disease Hospital in Mexico City, the source of most of the bacteriologically confirmed cases, illustrated the magnitude and seriousness of the epidemic. In 1970, the hospital reported 179 cases of typhoid fever. In 1971, the number of cases in the hospital rose to 197. In 1972, 1,676 cases of typhoid fever were treated with 60 deaths. This is a case fatality rate of 3. 6 percent. In 1973, the number of cases dropped to 681 with 13 deaths (a case fatality rate of 1. 9 percent). By 1974, the number of cases had dropped to the pre-e~ic~mic level, with 191 cases and (8) no deaths. Although the use of ampicillin was effective ii many of the cases treated in the Mexican epidemic, this fact can hardly be a cause for optimism, as noted by Anderson and Smith: The poor response to chloramphenicol is hardly surprising, but ampicillin, to which the Mexican strain is sensitive in vitro, has proved a disappointment in general for the treatment of * typhoid fever, and it would be an error to regard it as anything (9) better than a second-line drug in this respect. In addition to the linusands of cases of chloramphenicol resistant * typhoid fever reported in Mexico during the epidemic, cases due to the Mexican epic~mLc strain of ~~onel1atyphl (~ typhi) ware also reported in the United States and Great Britain. 12. PAGENO="0083" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15437 Chloramphenicol resistance has been reported in individual strains of ~ typhi since 1950, but prior to the Mexican epidemic in 1972 no epklemtc cauesdby a resistant strain bad been reported. According to Anderson (12) and Smith chioramphenicol resistance in ~5~,lrnatella. typhi was apparently first reported in England in 1950. It was subsequently reported in India, West Africa, Greece, Israel, Chile, Kuwait and Spain. In the cases from Kuwait, each case was suspected of being infected in a different place- - one in Aden, one in Carlo, and one in Pakistan. The resistance in the Greek and Israeli strains was caused by a transferable extrachromosomal element known as a resistance (R) factor. In the strains isolated for the three cases In Kuwait the organisms were resistant to arnpicillin, chloranphenicol and tetracyclines. This resistance factàr (ACT) was also transferable en bloc at high frequency to eschericbia coli. It was Anderson's* and Smith's view that the S. typbl acquIred the ACT resistance (R) factor in Kuwait, although it is possible that it is widespread throughout the Middle East. The ~xu~ie typhi isolated from a case in London that apparently originated in Spain was resistant to chlo.ramphénicOl, strq~omycin and sulfonamides. The resistance was transferred en Moc at low freqiency' to escherithia coli. The problems are not limited to Europe, the Middle East and the Americas. In April 1975, drug resistant bacterial pathogens were found .in stool cultures of Vietnamese children evacuated to the United States. The following bacterial pathogens we.re isolated from 49 percent of 367 stool specimens: 13. PAGENO="0084" 15438 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Shigelia 16 (4.3%) - -~ Salmonella 15 (4. 1%) Enteropathic E. coil 161 (44%) - Edwardslella 7 (1.9%) -~ Yersini~pseudotubercu1osis 2 (0.5%) -- Arizerra 1 (0.3%) Among the Shisella isolates, the most common antibiotic sensitivity pattern was resistance to ampicillin, tetracycline and chloramph*nicol with susceptibility retained b colistin, gentamicin and sulfamethoxazole-trimethoprim. Antibiotic sensitivity among the ~h~one11a and enteropatheric E coil was more variable. None of the bacterial pathogens Isolated among the Vietnamese children were ,~ioi~l1a. typhi, but they were nonetheless the cause of serious (11) disease in a number of children. Although the isolation of antibiotic resistant...S~ella and Salmonella appear to have been isolated incidents, the Mexican epidemic of typhoid fever demonstrated that the threat of epidemics due to cbloramphenicol resistant ~almonelIa exists. The risk is greatest i~'.countrles with:high levels of. poverty, poor sanitation, crowded living condltions,~the presenceof &Imonelia typhi and the widespread use of antibiotics. Cases of typhoid fever due to the chioramphenicol resistant strain of ~a~r~on~e1la. typhi that caused the Mexican epidemic have been reported in the United States and Great Britain. Eighty cases, in 17 states, have been reported in the United States since the Mexican epidemic. Although this does not pose 14. PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15439 an immediate threat in the United Statesor Great Britain the problem is potentially serious on a worldwide basis. In discussing the problem, Anderson and Smith observed: The ultimate appearance of epidemic strains of S. typhi carrying K factors coding for chlorarnphenlcol resistance is most likely in countries where two conditions are satisfied. The first Is that typhoid fever must be common, so that the organism Is frequently present in the human intestine. The second condition is that cliloramphenicol should be used indiscriminately, so that its widespread selective pressure will promote the emergence of stable R factors coding for the respective resistance. Both these conditions are satisfied in Mexico: it is a country with a relatively high incidence of typhoid fever; and not only is chlorampheflicOl used on a large scale by doctors but It can be (12) bought by the general public. Why do I dwell on this problem at such length and ignore the other problems that may arise In Latin America because of the promotion of prescrip- tion drugs by multinational corporations tia t Dr. Silverman has described? I do so, Mr. Chairman, because I. believe the indiscriminate use of chioramphenicol in Latin America, specifically in Mexico, is related to the way this drug is promoted and it is also related to the prevalence of cbloram- phenicol resistant enteric pathogens, such as ~on~Ua typhi. 15. PAGENO="0086" 15440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In my opinion the regulatory policies related to the promotion and dispensing of chioramphenicol in Mexico and other Latin American countries are seriously inadequate and pose a threat to world health. Not only must the regulations relating to the drug industry be changed, but those relating to prescribing and dispensing must also be changed. In discussing the occurrence of chloramphenlcol resistant strainsof 1~~- ~na t~bI ki England, Anderson and Smith of the Enteric Reference Laboratory, Public Health Laboratory Service, pointed the way to what must be done: The British cases of typhoid Infected in Mexico, and the epidemic which caused them, are a warning of this, and are a reminder that if antibiotics such as cblorampbenlcol are to retain their efficacy for important diseases, their use should be largely' If not entirely restricted to those diseases throughout (13) the world. In concluding, Mr. Chairman, I would like to propose a five step course of action to begin to deal with the promotional practices of multinational drug companies in Latin America. First, all major United States pharmaceutical firms that market drugs in Latin America should be asked to review their present promotional practices and adopt a standard of promotion and marketing throughout the,world that Is fully consistent with, if not identical to, the practices required in the United States. Second, the American public should be made aware of the hazards posed by the misuse of antibiotics, particularly the problems posed for travelers to 16. PAGENO="0087" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15441 countries where antibiotics may be dispensed-without a prescription and the individual receiving the drug need not be informed about its potential hazards. Perhaps the United States Public Health Service could develop an informational document for international travelers on the problems posed by the misuse of antimicrobial agents. Third, the Center for Disease Control (CDC) sho~ld be given the resources needed to carry out the clinical, epidemiologic and laboratory studies necessary to determine the nature and extent of the health hazard posed by the emergence of drug resistant pathogenic organisms. The CDC should have the staff, facilities and equipment to monitor the emergence of resistant strains, to work with local health departments and others to study problems as they arise. The director of CDC should be asked to report annually on the problems of drug resistant pathogenic organisms, the hazards posed and what acticns are appropriate to reduce or eliminate the hazards. Fourth, the Department of State and the Department of Health, Education and Welfare should be fully apprised of Dr. Silverman's findings and requested to propose policies to deal with the problem to the World Health Organization, particularly the office for the Western Hemisphere Region, the Pan Americar~ Sanitary Bureau. Fifth, the FDA should be asked to review its authorities and report to Congress what measures, including new legislative authority, might be taken to restrict the use of critically important antibiotics, such as chioramphenicol, to those patients where its use is essential. 17. PAGENO="0088" 15442 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Finally, Mr. Chairman, let me commend you, the members of this Committee and the Committee staff, particularly Mr. Ben Gordon, for again bringing to the attention of Congress and the American people a serious problem related to the promotion, marketing, prescribing, dispensing and use of drugs that poses a very real hazard to our health. 18. PAGENO="0089" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15443 REFERENCES 1. Ray, W.A., Federspiel, C.F. and Schaffner, W.; "Prescribing Chloram- phenicol in Ambulatory Practice: An Epiderniological Study Among Tennessee Medicaid Recipients," Annals of Internal Medicine~84: 269, 1976. 2. Goldstein, A., Aronson, L. and Kalman, S. M.; Principles of Drug Ac~f~: The Basis of Pharmaco~9gy, New York, John Wiley and Sons, 1974, p. 521. 3. ibld;p. 521. 4. Weissman. J.B., Rice, P.A., Krogstad, D.J., Baine, W.B. and Gangaros~, E. J.; "Risk of Severe intestinal Infection to the Traveler in Mexico," Journal of infectious Diseases, 128: 574-577, October 1973. 5. ~j4jp. 574. 6. Weissman, J. B., Marton, K. I., Lewis, J. N., Friedmann, C. T. H. and Gangarosa, E. J.; "Impact in the United States of the Shiga Dysentery Pandemic of Central America and Mexico: A Review of Surveillance Data Through 1972," Journal of Infectious DiseaseQ, 129: 218-223, February 1974. 7.. Gonzalez-Cortez, A., Bahena, J.G., delaBarca, C.C. and Bressudo,M.; "Typhi Fever Follow-Up in Mexico, 1974, "Morbidity and Mortali~y~ 24: 155, April 26, 1975. 8. Ibid;p. 155. 9. Anderson, E. S. and Smith, H. R. ;"ChloramphenicOl Resistance in the Typhoid Bacillus," British Medical Journal, August 5, 1972, p. 650. 10. Ibid;p. 649. 11. Goldsmith, R., Stark, F., Smith, C., Healy, C., Donegan, E., Jucllav, V. and Stalcup, A.; "Orphan Airlift: Enteric Pathogens Isolated from Vietnamese Children Immigrating to the United States, ` 235: 2174-2116, May 10, 1976. 12. Anderson and Smith;~p. Cit., p. 650. 13. Anderson and Smith;~p.~1~~ p. 6S0. 19. PAGENO="0090" 15444 COMPETITIVE PROBLEMS IN THE DRUG INDtJS1~RY Statement by Milton Silverman, Ph.D. Lecturer in Pharmacology, Schools of Pharmacy and Medicine, and Senior Faculty Member, Health Policy Program, University of California, San Francisco before Subcommittee on Monopoly, U.S. Senate Small Business Committee May 26, 1976 PAGENO="0091" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY' 15445 Mr. Chairman: I am pleased to respond to your invitation and meet with you and. your fellow committee members to report on how the multi- national drug companies promote their prescription drug products in X~he United States, and how they or their affiliates or sub- sidiaries promote the identical products in Latin America. I must note at the outset that I am not a physician or a pharmacist. I am a pharmacologist. I must further note that any views Imay express here today are my own, and do not neces- s&ril.y; represent those of my university. And,. as.a final prefatory. statement, let me acknowledge that without the dedicated and courageous pioneering investigations conducted by you and your committee1 and especially by Mr. Benjamin Gordon, much of the work that my colleagues and I have been able to accomplish over the past years in our own investi- gations would have been far more difficult if not impossible. The research on which I am prepared to report today will be published tomorrow by the Univa~rsity of California Press under the title of The Drugging of the Americas. It involves an in- depth study of the promotion to the medical profession of 26 drugs marketed in the form of 40 products by 23 global drug com- panies. Most of these firms are American. Others are based in Switzerland, France, and West Germany. The drugs we selected for investigation are, beyond doubt, valuable and in some cases life-saving--but only when they are PAGENO="0092" 15446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY used appropriately. Although each is demonstrably effective in one or more. conditions, each has equally demonstrable hazards. Some of the side-effects may be only annoying. Others may be Serious or fatal. Only-with a knowledge of both the advantages and the poten- tial-hazards can a physician select the right drug to prescribe for each.patient--to get the maximum benefit with the least pos- ~Sit~le risk. ~n the United States, physicians are given such information-- the-good and the bad--in what is known as the package insert. In many instances, the essential elements of the package insert are *~ublished--jf the manufacturer so elects--in PDR, ~y~icians' iYesk Reference. This book, sometimes called the "bible for pre- scribers," :is distributed annually at no cast to every practicing physician.. Although the statements are prepared- -and paid for- -by the drug -industry, no firm is free to make any statements it may de- sire. Claims for efficacy or t~sefulness are restricted to those for which the company has submitted convincing scientific evi- dence to the Food and Drug Administration. -All potential hazards must be fully and openly discl~osed, In some cases, the company is required to include a special warning, such as "Do not use for trivial conditions," It is important to emphasize. that such information, required by law, is intended only to inform the physician. If he wants, -the physician may use the drug for an unapproved indication. He 2. PAGENO="0093" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15447 may ignore the warnings partially or totally. For many years, it has been known that the situati9n in some other countries is somewhat different. As you yourself disclosed a decade ago in your hearings on Chioronycetin- - the Parke-Davis brand of chloramphefliCol- -the warnings published for the product in the United States were far more strict than those included in promotion in Great Britain. You will recall, Mr. Chairman, that when you called this discrepancy to the attention of a company official, he offered the defense that full disclosure of hazards was not required by British law. That revelation before your committee was a brief but impor- tant prelude to what we can report today. In our own studies, we investigated the 26 drugs as they were promoted in the United States, Mexico, the six Central American countries--Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama--and in Colombia, Ecuador, Brazil, and Argentina. Essentially, we conducted a comparison of what each company said about its product to physicians in the United States through PDR, and what it said about the identical product to Latin Ameri- can physicians in somewhat comparable Latin American' reference volumes. Here, two points are important. First, I am in no position either to support or to condemn the policies and decisions of FDA as reflected in PDR~ But ~ 3. PAGENO="0094" 15448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY may be viewed as auseful standard for comparison, since it has the virtual blessingsof an important government agency, it is based in large part on the advice of distinguished nongovern- mental experts, it is widely distributed to physicians and fre- quently used by them, and the drug industry- -although it may .4ispute certain FDA decisions- -has learned to live with them, and ~to Live with them without substantial financial trauma. Second, it must be clearly understood that PDR and the Latin American reference books are not the same. In PDR, the statements -presumably have governmentaL approval The promotional state- mentsin the Latin American books, however, do not have official. ~approval from any governmen~al agency; they say what the company wants to say. There is still one other exception. In Argentina, the state- ments are written not by the companies but by the editors. Ac- cordingly, the companies bear no responsibility for this pro- motional material. Comparison of the drug promotion shows two facts beyond dis- ~pute: 1. In. the United States,, the promotional claims for ef- Licacy- -the indications for use--are generally brief. In most -cases, they conform to the views expressed in standard textbooks of pharmacology and in such authoritative and internationally-recog- nized works as Goodman and Gilman's The Pharmacological Basis of !rherapeutics and the AMA's ArIA Drug Evaluations. In contrast, in the .4. PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15449 Latin American books, the claims for efficacy are long, numerous, and often--at least in my mind--grossly exaggerated. 2. In the United States, the list of the contraindications, warnings, and potential adverse reactions is lengthy and de- tailed. Virtually every unhappy, serious, or possibly lethal side- effect to which a physician should be alert is included. But in striking contrast, th~ potential hazards published in the Latin American volumes are usually minimized, glossed over, or totally ignored. In some cases, not a single danger is dis- cløsed. Let me cite some examples-- Antibiotics Consider first the antibiotic chloramphenicOl, which.has fl~ured so prominently in the hearings of this committee. It is unquestionably a potent and useful drug, but its knowm dangers aresuch that it is promoted in the United States for only such serious infections as typhoid .f ever and a few other life- threatening but relatively infrequent infections in which the causative organism is shown to be susceptible to. the drug. Physicians in this country are advised not to use it in trivial infections, or when other effective but less dangerous drugs are available. . In Mexico and Colombia, the .Parke-Davis brand marketed as Chloromycetim is promoted for use not only for life_threatening ôonditions but also for tonsillitis, pharyngitis, bronchitis, 5. PAGENO="0096" 15450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY urinary tract infections, ulcerative colitis, pneumonia, staphy- lococcus infections, streptococcus infections, eye infections, yaws, and gonorrhea. In Central America, a competitive brand marketed by McKesson is recommended for whooping cough. In the United States, the Parke-Davis product carries a long list of contraindications,warnjngs, and adverse reactions. Per- haps the most alarming of these include aplastic anemia and other serious or fatal diseases of the blood-forming system. In Mexico, the Parke-Davis product carries only a limited list of warnings. In Central America, no contraindications or warnings are given, and no adverse reactions are disclosed. The McKesson product statement discloses a few hazards in Central America but none in Colombia and Ecuador. In the case of tetracycline,, marketed by Lederle under the name of Achromycin, numerous adverse reactions are given in the United States, a few in Mexico and Brazil, and none in the Central American countries. For Squibb's amphotericin B, marketed as Fungizone, physicians in this country are told that' this valuable but potentially toxic ~antibiotic should be used primarily for the' treatment of progres- 8ive and potentially fatal forms of fungal infections. No such warning is listed in the Latin American promotion. Schering's Caramycin carries roughly the same indications in the United States and Latin America, but the warnings are minimized 6. PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15451 in the Latin American promotion, Oral Contraceptives A similar situation was discovered in the case of a number of oral contraceptives--Ovulen marketed by Searle, Norlestrin or Prolestrin marketed by Parke-Davis, Ortho Novum marketed by Otho, Novulon marketed by Johnson, Norinyl marketed by Syntex, and Ovral or Anfertil marketed by Wyeth, In PDR, all of these are described as indicated for only one use--contraception. In the Latin American countries, they are openly recommended for contraception, and also for the control of premenstrual tension, menstrual pain, problems of the menopause, and a host of other conditions, In the. United States, physicians are warned of the possibi- lity of many side-effects, especially thromboembolic changes that can lead to serious or fatal blood clots. In Latin America, for all the products studied here, the risk of thromboembolic changes is ignored, No adverse reactions of any kind are given for the Searle product in Ecuador, Colombia, or Brazil, for the Parke-Davis product in Central America, and for the Wyeth product in Ecuador, Colombia, or Brazil, Anti-Arthritics For Ciba-Geigy's anti-arthritis drugs Butazolidin and Tandearil, only a few indications for use are approved in the United States but many in Mexico, Central America, Colombia, and Ecuador. In contrast, the warnings are numerous in this country but few in Latin America. * 7. 73-950 0 - 77 - 7. PAGENO="0098" 15452 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY No adverse reactions of any kind are disclosed for McKes- son's competitive brands in Central America, Colombia, or Ecuador. U.S. physicians are cautioned against the use of such drugs for prolonged periods. The result may be serious or fatal adverse reactions. A somewhat similar warning is given in Mexico, but the matter is not mentioned in the other countries, In the United States, Merck's Indocin is approved for use in four serious forms of arthritiè disease, In Latin America, many other indications are recommended. In the case of this product, it seems' noteworthy that the hazards listed in the Latin Ameriëan countries are approximately the same as those given in this country, Corticosteroids Four widely-used corticosteroid hormones were included in our investigation__Schering5 Meticorten and Celestone, Lederle's Aristocort or Ledercort, and Upjohn's Medrol. All can be of great value in the control of arthritis, asthma, and a variety of other conditions. But all of them, especially if used for excessive periods, may cause unpleasant or'deadly side-effects--a flare-up of latent tuberculosis, bone-softening and fractures of the ver- tebral bones, peptic ulcer with perforation and hemorrhage, psy- chic changes, and many others. Few of these hazards are disclosed for Meticorteri in Latin America, and none for Celestone in Central America Colombia, Ecuador, and Brazil. For both Aristocort and Medrol, the major hazards are glossed over or given in nonspecific terms, 8, PAGENO="0099" COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY 15453 The promotion of another steroid hormone, Winthrop's Winstrol, offers even more striking inconsistencies. It is de- scribed to Latin American physicians as useful to increase weight, appetite, and strength. *Such indications are not listed in PDR. What is disclosed in PDR is the risk of such adverse re- actions as stunting the growth of children, jaundice, interfe- rence with normal sexual development in children, and undesi- rable sexual changes in adults. Few of these are disclosed in Mexico and Brazil, still fewer in Central America, and none in Colombia and Ecuador. Tranciullizers Among the so-called major or antipsychotic tranquilizers in- cluded in our study were Sandoz's Mellaril and SKF's Stelazine. As with other drug classes, the approved indications for use are few~in the United States and numerous in Latin America. Among the :indications not approved in this country but listed for the Sandoz product in Central America is use of the drug for the treatment of óhildr~en with behavioral disorders, hostility re- actions, inability to adapt in .school, insomnia, sleep walking, b~dwetting, and nail biting. Many adverse reactions for Mellaril are disclosed in the United States, a few in Mexico, but none in Central America, Colombia, or Ecuador. In the case of Stelazine, physicians in the United States are warned of the risk of the development of tardive dyskinesia--a disorder marked by involuntary movements of the lips, tongue, 9. PAGENO="0100" 15454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY hands, fingers, and feet. Speech may be seriously affected, the face distorted, and maintenance of body position impossible. In some patients, the condition may become irreversible. No effec- tive treatment is known. In the promotion of Stelazine, the danger of this develop- ment is disclosed to physicians in the United States, It is not listed in the reference works in Mexico, Central America, or Bra- 2i1. In fact, no adverse reactio~s are listed for Stelazine in the Central American countries or Brazil. Antidepres sants With the antidepressants, the story is the same--rigorously limited indications for use in the United States, with full dis- closure of hazards. The reverse is obvious in Latin America-- many recommendations, but few hazards disclosed. This holds for Ciba-Geigy's Tofranil and Lakeside's Norpramin. In the case of Lilly's Aventyl, however, indications for use are limited in both the United States and Mexico, and the disclosure of hazards is similar in the two countries. With Warner-Chilcott's Nardil, a member of the particularly dangerous group of MAO-inhibitor antidepressants, a long list of contraindications, warnings, and adverse reactions is disclosed to physicians in the United States, only relatively minor dangers are noted in Mexico, and none is disclosed in the Central American countries. 10. PAGENO="0101" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15455 Anticonvulsants Our last group includes three anticonvulsants widely used for the control of epilepsy. One is diphenylhydantoin, or pheny- tom, marketed by Parke-Davis as Dilantin and by McKesson as Kessodantin. The promotion of the Parke-Davis productdiscloses only a few hazards in Mexico, fewer still in Colombia and Ecuador, and none in Central America. Only one warning is presented for the McKesson product in Central America, Colombia, and Ecuador, and no adverse reactions are disclosed. A similar sit~iat1oñ was found for Sandoz's Mesantoin, with only one ~arning presented to physicians in the Central American countries, and no adverse reactions disclosed, With Ciba-Geigy's Tegretol, numerous adverse reactions are disclosed to physicians in theUnited States, a few to their colleagues in Mexico, Colombia and Ecuador, but none to physi- cians in Central America or Brazil. It is difficult to estimate with any precision the prices that patients are forced to pair for this kind of promotion- -pay not in terms of pesos or quetzals orcolones, but in needless injury and needless death. Information on the frequency of adverse drug reactions in Latin America is far from adequate, just as it is far from ade- quate in the United States and Europe, Nevertheless, in every country in which we have worked, medical experts--especially hematologists, pathologists, and microbiologists --have expressed 11. PAGENO="0102" 15456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to us their dismay, their frustration, their anger at what one ~1escribed as "this whole sickening business," - -~They have described to us the rise of resistant strains of bacteria, due almost certainly to the excessive and irrational use, of antibiotics. Physicians and pharmacists are distributing these potent.drugs as if they were popcorn. --They have described the rate of fatal aplastic anemia in Mexico, now one of the highest in the world, related in substan- tial part to the use of chloramphenicol. One leading tnicrobio- logist in Guatemala told us, "When a child is given chlorarnphe- nicol for typhoid fever, and it dies from aplastic anemia, this is a tragedy but perhaps an unavoidable tragedy. But where it happens when the drug is used to treat a case of virus pneumonia, or an undiagnosed respiratory infection, dr a sore throat, this is unconscionable," - -Others have told us of serious reactions to amphotericin B, given to treat minor fungus infections without any of the pre- cautions made kmown to U.S. physicians. - - -They have told us of serious or fatal blood disorders- -in- cluding agranulocytosis and aplastic anemia- -following prolonged use of anti-arthritis drugs. - -They have told us of the excessive use of steroids result- ing in perforated peptic ulcer or explosive flare-ups of tuber- culosis or candidiasis. - - -They have told us of the cases of permanent brain damage caused by excessive use of antipsychotic tranquilizers--and some- 12, PAGENO="0103" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15457 times by tranquilizers given to control bed wetting or nail- biting in children, or an inability to get along in school. We do not know how often such tragedies occur. In most cases, it seems, neither the patient nor his family, nor even the physician, is aware that the irrational use of a drug was respon- sible. One fact that may possibly be related is that, generally throughout the Latin American countries, there is no such thing as medical malpractice. Malpractice suits are unknown. Another related factor may be the influence and the numbers of detail men, or visitadQr~s. In the United States, there is one detail men for about 10 physicians. In Ecuador, there is one for every 8 physicians. In Colombia, there is one for every 5. Amd in Guatemala, Mexico, and Brazil, there is one for every 3. There are. some physicians in Latin America who take advice from none of these visitadores, whom they call "visiting professors :of therapeutics." There are other physicians who take advice only from these company representatives. In many of these countries, the average detail man makes a bigger income, part salary and part commission, than does the average physician. The inconsistencies we have-found are glaring. I suspect that similar differences could be found in the case of many other products marketed by many other global drug firms. 13. PAGENO="0104" 15458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY When these inconsistencies became apparent to us, we showed them to heads of some of the American and ~European companies in- volved, and asked how these could be explained. In no instance did the company spokesman deny the differences. Their responses usually included these defenses: 1. "Latin American physicians don't need any warnings. They're already aware of any hazards." (Such a claim, we learned, totally infuriates Latin American medical specialists-- medical school professors, clinical pharmacologists, and parti- cularly hematologists and pathologists who, by the nature of their specialties, are most aware of the damage done and where the bodies are buried.) 2. "We make more full disclosure in our package inserts." But, we have found, there are also discrepancies in these in- serts, which are not always full or complete. Further, many phy- sicians do not see the package inserts, and usually they are quickly discarded.) 3. "It is our detail men who give each physician full infor- mation on hazards," (This is a defense we have long heard in this country. But in Latin America, as in the United States, it is generally held that "you don't knock your own product"--certainly not if you're working on commission. 4. "Physicians know that, .if they write to us, we will be glad to send them more complete information," (This defense does not deserve the dignity of a comment,) 14. PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG i~usm~ 15459 5. It is said that "no drug manufacturer would engage in such shoddy practices--would tamper with the truth, or cover up dangers--because in the long run, this would cost him the eonf i- dence of the medical profession." (I don't know the answer to this one so far as Latin American physicians are concerned. I don't know that much about the Latin American medical profession. I do know, however, that where the profession in the United States in concerned, such a defense is nonsense. Over the years, we have witnessed the record of the so-called "Dear Doctor let- ters," through which many major drug companies were required by FDA to notify every physician in the country that they had, in fact, tampered with the truth, or made claims that could not be supported, or failed to disclose hazards. We have seen the re- markable cases of Chioromycetin and MER/29; and all the civil suits for damages. And what happened to the good name of the companies--to their reputation with the medical profession--to their annual sales and their annual profits? The answer is di- stressingly clear--by and large, essentially nothing happened.) There are two additional defenses that are more noteworthy- - 6. "The differences in promotion represent honest differen- ces in opinion. That is, we're honestly convinced that we're right and FDA is wrong." (Such an attitude might be more palata- ble if a company said one thing to physicians ir~ the United States, where FDA is constantly looking over its shoulder, and another thing to all physicians everywhere in Latin America. It is more difficult to accept, however, when it is obvious that 15. PAGENO="0106" 15460 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY what a company says about its product in Mexico City is not the same as what it says in Guatemala City or San Jose de Costa Rica, which is different from what it says in 8ogota, Colombia, or Quito, Ecuador, or Rio de Janeiro. 7. And finally, there's the statement; "Each of our foreign subsidiaries is managed by a citizen of the country. He knows the laws and regulations, and abides by them. We're not breaking any laws." This defense has apparently been impenetrable. In your own hearings, Mr. Chairman, it was effective in blocking further in- vestigations. The reason is clear; copies of up-to-date Latin American drug laws are not easily available in this country. For- tunately, it became possible for us to work on the spot in Latin America, to acquire copies of the laws, and to analyze them with the aid of Latin American attorneys and drug specialists, both governmental and private. The legal situation may b~ summarized as follows: --In a number of countries, the companies are telling the truth. They are not breaking any drug laws because there are no laws requiring disclosure of hazards. Each company cart follow its own conscience and its own ethical standards --In a few countries, the picture is not clear. Governmental officials believe they have the legal authority to require full disclosure, but the authority has not been spelled out 16. PAGENO="0107" COM1~EPITIVE PROBLEMS IN TID~ DRUG INDUSTRY 15461 in adequate detail. - -But in some countries--notably Colombia- - there is no lack of clarity. The laws are on the books. They require full disclosure of all hazards to all physicians. And these laws are being flaunted. If companies say they are not breaking the laws in Colombia, they are lying. One internationally-famed health educator, Dr. Jose' Felix Patino, the former Minister of Health in Colombia, put it this way to us: "U.S. manufacturers would be put to shame if the U.S. public knew how they are promoting their products in Latin Ameri- ca." Even within some of the multinational companies, top medical scientists are beginning to discover the sitiation for themselves. They are appalled to find what their own firms have been doing. I believe that when this record is disclosed to company boards of directors and to company stockholders, they, too, will be appalled. In any consideration of this whole unappetizing business, ful~. recognition must naturally be given to the fact that what consti- tutes good medical practice- - or rational drug use- -may often be influenced by many factors: the extent of poverty, literacy, pur- chasing power, standards of living, access to health care, the prevalence of particular diseases; the particular population groups at risk, social and cultural standards, and religious attitudes. 17, PAGENO="0108" 15462 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Thus. what may be unacceptable medical care in the cities may be acceptable in the jungle. What may be unacceptable to a wealthy patient, who can afford to obtain first-class medical. care, may be tolerated by a peasant or an inhabitant of the barrios, who exists on an average per capita income of $200 a year. It must also be recognized that many Latin American patients- - for whatever the reason--do not have ready access to a physician. If they or their children are stricken, they seek help from the pharmacist. In many communities, there is no physician, and the pharmacist is the only health professional available. According- ly, even though this may be in violation of the law, the phar- macist has no other recourse: he must diagnose, he must pre- scribe, and he must dispense. Tragically, the drug information available to the pharmacist is usually no better than that sup- plied to physicians, and he may be dangerously uninformed or mis- informed. Here, then, is the crux of the problem: it is not whether a physician or a pharmacist will be influenced in his prescribing decisions by such factors as poverty, cultural attitudes, and the like. It is whether or not he is given ready access to the scientific facts on which he can base the appropriate prescribing decision. It is whether or not the drug companies tell the truth--and all the truth, The problem is not simply a matter of violating laws in the developing nations, as important as that may be, It is that what should be the objective presentation of knowledge is being 18. PAGENO="0109" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15463 twisted by the morals of the marketplace. It is that medical science is being prostituted. There are, Mr. Chairman, many related aspects on which others fa~ more competent than I may wish to comment. There are the matters of drug price's and the handsome pro- fits that global drug companies have been extracting by means of their promotional practices in Latin America, This may be blood money, indeed. There are the matters of ethics and morality, and how drug companies view their social responsibilities- -to their corporate officers, their stockholders, and to patients here and abroad. There is the matter of telling the truth- -all the truth- - and of deciding whether the truth depends on international borders, whether what is truth in one country may be untruth in another, Thus, I find great difficulty in comprehending how a company can describe one of its products a~ dangerous in San Diego but safe a few miles across the border in Tijuana. Or how it can promote the product as effective in only four conditions in Washington, D.C., in ten in Mexico, and in seventeen in Central America, Finally, Mr. Chairman, there is one additional aspect that I am sure has not escaped your attention. Over the years, you 19. PAGENO="0110" 15464 COMPETITIV~E PROBLEMS IN THE DRUG INDUSTRY and I have heard American drug companies bitterly complain in public that the present FDA laws are excessively harsh and, in fact, are actually unnecessary. The companies insist they would live up to their moral and social responsibilities, laws or no laws. The record of their performance in Latin America, where the laws have been safely bent, broken, or ignored, or where there are no legal restrictions on drug promotion, might-~to coin an expression--make a person wonder. 20. PAGENO="0111" COMPETITIVE PROBLEMS IN THE DRtTO INDUSTRY 15465 STATEMENT BY GEORGE S. SQUIBB, CONSULTANT TO PHARMACEUTICAL INDUSTRY BEFORE SUBCOMMITTEE ON MONOPOLY SENATE SMALL BUSINESS COMMITTEE MAY 27, 1976 Over ten years ago I was given an assignment by my company to study the relationships between the pharmaceutical industry and various government offices and legislatures, federal and state, because at that time there was a particularly sharp concern on the part of some of the industry's managers that things were changing in the pattern of public awareness of the procedures of medical care and that a little attention to this developing sit-. ustion might be helpful. That assignment resulted in the production of two papers on the problems and practices of the pharmaceutical industry, both of which are part of the record of these hearings. Into these papers I injected a little gentle advice to the industry which caused all sorts of uproar at the time, but which I now have the satisfaction to note was all good and has been picked up as their own gospel by many of those who were most horrified at the original expression. As a matter of fact as I review those words of eight or nine years ago in the light of current events I am amazed at how close to the mark they were in foretelling what was going to happen in the pharmaceuticalfield given the attitudes which were then, and still are prevelant. All of which only goes to prove that developments are predictable on the one hand, and on the other that the legend of the unheeded prophet, Cassandra, is still relevant today. PAGENO="0112" 1ö466 COMPETITIVE PROBLEMS IN TIlE. DRUG INDUSTRY Not having learned any restrictive lesson from this earlier experience, I am here again to discuss some recent controversies involving the pharmaceutical industry, and to express from my experience what might be a way to avoid such unpleasant situa-' tions in the future. Certainly none of us, in the industry or outside it, can take any pride or satisfaction in listening to the recital of the promotional excesses that the Comm~ttee has heard in the last few days. Essentially however, this is just the newest example of the fact that pharmaceutical managers live and work in a gold.. fish bowl which makes all of their actions reviewable by a large and varied audience of critics, most of whom are not inclined to be overly sympathetic. The root of most of the problems that the industry has with its critics over promotional matters is the feeling that somehow sales pressures, advertising, commercial exploitation, and selling in its strict dollar and cents aspects are all foreign to, and incompatible with, the practice by the physician of his profession. Choice of treatment, drug selection, and indeed, the whole physician-patient relationship seem not properly affected by any forces outside the physician's training, abilities and understanding of the oatient and his malady. The idea that anything coming out of such fields as advertising, sampling, sales pressures, price advantage, or third party recommendation of any kind could intrude on this relationship is somehow repugnant to the public 2 PAGENO="0113" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 15467 who still regard the medical profession as a sort of pre~fabricated- all~-knowing..group of specialists of superior and perhaps even secret powers who need no help or direction from those inspired by motives other than the specific cure of the patient at hand. Commercialism of all kinds, and medicine, have always been uneasy associates. It is difficult to keep this relationship in proper balance, and it is the struggle to do so that leads to hearings of this type, artd eventually is the cause of much of the govern~ mental regulation imposed on the industry. We now have before us examples of how promotional activities vary from country to country on the same drug by the same company. Indeed it appears that promotional claims for certain drugs which are forbidden in this country are emphatically stated in other countries, and that a fair case can be made for what looks like the expld~tation of ignorance of peoples who lack the medical scientific experience which has evolved in the United States in the last thirty years or so. It is difficult to imagine any justification at all for the promotion or sale of a drug for an indication for which is not a specific, or any promotion or sale of a drug wIthout adequate information as to the siae effects, toxic or otherwise, of the dosage recommended. Nowhere is there any voice of industry who would argue for such courses of action, and yet here are examples of just such things happening. Flow can this be? 3 73.950 0 - 77 - 8 PAGENO="0114" 15468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In the record of hearings of this Committee are two signif.. icant exDlanatjons offered as to just how these promotional differences between countries are explained or rationalized. One approach is the one set forth by the president of a major pharmaceutical house that whatever standards, indications, or claims for a drug are approved by the in.house scientific staff of his organization as to the "medical positioning" of a product, that is their standard of guidance, everywhere in the world. He stated further and specifically that they would not use the standard of what is approved by FDA for that drag in this country if there should be any difference. The more you think about this approach the more puzzling the ethical implications become. It takes Quite a bit of self~confidence, and perhaps even arrogance, to be able to ignore completely any findings by the FDA contrary to your own. While the track record of the FDA includes some questionable judgments in the past that have not held up to the test of time, certainly the vast body of its findings and its regulation are sound, and probably are the production of the most advanced system of drug review operating in the world today. However, if such a policy were actually used there would be no variation in promotion among different countries except where regulation required some limitation. It would appear from tes timony given here that is never the case, and variation exists in the promotional claims for the same product among countries which have no virtually regulations at all. Therefore it is 4 PAGENO="0115" COMPETITIVE PROBLEMS IN THE. DRUG INDUSTRY 15469 doubtful. even a pharmaceutical house with an internal bueinese~. research relationships of extraordinary balance and understanding can or does follow any such policy to the letter today. The second approach is described by a former medical director of a large pharmaceutical house which maintained two 9iferent medical staffs, one apparently with a less rigid approa~ch to promotional procedures which could be used overseas. Somehow I feel. this latter approach, or variations of it is the more common, and Drobably the more easily rationalized of the two. It must be recognized that there is such a thing as honest difference of informed medical. opinion on the evaluation of individual drugs. It seems that there is always available some medical soecialist or some source of information to contra~ diet opinions expressed by others. It has been said time and time again that medicine isnot an exact science, and certainly drug utilization appears to be one of its more inexact areas. But for the purposes of public health today, a judgment has to be made and a line drawn somewhere. It is suggested that a little line drawing is now indicated. There are at least two complicating factors which get in the way of a quick and easy solution to this problem. First, is the obviously different opinions that scientists of good reputa.~ tions and sincerity have about not only the physical. qualities ot drugs, but also about the whole philosophy of risk versus anticipated 5 PAGENO="0116" 15470 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRy therapeutic benefit. Government regulatory bodies terd towards policies which take absolute safety as the dominant note, while independent scientists tend to evaluate a drug more on a risk.. versus..results basis with the individual physician determining the applicability of the particular drug to a particular case. Second, there is the basic doubt as to a universal and automatic competence of the FDA or any other governmental agency in all matters it touches. Rigid acceptance of FDA controls, with appeal or review difficult and very ex~ensive, makes for a unsatisfactory system. Political pressures are significant in drug control regulation when they should not be, and there is sometimes too much short-.sighted action taken just to get rid of an immediate problem. This results in an ever increasing body of industry rules which tend to develop into a rigid formula for establish.. ing black and white, without any regard for the vast gray area which exists in medical procedures. It would seem that one of the best ways that is now available to evaluate a new product, or a new use, of an old one, is to try it in a market where there is some latitude permitted in promo- tion efforts. This is not to justify in any way exploitation of a product for indications known to be wrong, or without warn- ing of possible side effects that have been established by previous use elsewhere. Full disclosure is ~ essential. Absence of conscious deception is ~ essential. Acknowledgement of 6 PAGENO="0117" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15471 different opinion is always essential. After that, if there is still room for use of the product with advantage to the patient, it is clear there should be opportunity to do so. For honest men of good will the problem is exquisitely difficult. Such scientists do not accept the automatic infal. libility of government regulators, nor do they accept the limitations placed by arbitrary controls on their own conclusions. Dishonest men who deliberately exploit ignorance to their own advantage by offering hope of cure without concern for any~ thing except the monetary return to themselves are the object of our efforts here today. Just where and how to separate the two groups should be easy, but in fact gets more and more difTi.' cult as medicine increases in its potency and complexity. As far as the established companies of the American Fharm~ aceutical industry are concerned, and it seems that all too often they are the ones that are concerned with the problem under dis cussion here, the solution ought to be found right in their own internal operations. The industry constantly claims for itself high standards of ethics and close attention to its admitted unicue high degree of social responsibi.lity, yet all too often it seems to fail in this regard in promotional matters. It would seem that as a matter of policy, if the question were effectively put, no Board of Directors of a responsible American Pharmaceutical house in this day and age of sensitivity to 7 PAGENO="0118" 15472 COMPETITIVE PROBLEMS IN THE DRUG INDtrsThy to consumer criticism would ever knowingly permit, its companies' products to be marketed under double or deceptive standards, or in any way whatsoever that would result in extraordinary risk to the public an any part of the world. The fact is that such auestion is rarely, if ever, put to the Boards. It is customary for the Directors to leave all day-to.day operating procedures to its field management, and then simply to inspect the financial results of such procedure. In the pharmaceutical industry some~ thing a lot more responsible than that is called for on the part of Directors. They must question precisely the way their organ~ ization is carrying out its social responsibility and to set specific standards and guidelines for the promotion of its products. If they feel that their own research staff is of such caliber and integrity as to set standards and to control and limit all pr\omotion activities of the company, then this should be their policy and it should be applied everywhere uniformly where regu~ lation permits. If they should wish to follow such a policy without regard for outside opinion except where such opinion is imposed upon them by law, it would be their right to do so. Without making the individual judgments themselves, they would still have to understand exactly how such judgments were arrived at between the sales and scientific departments of their organi.~ zations and would accept the infallibility of those decisions with the clear understanding that theirs was the final responsi.. bility. It is doubtful that any Board today would take such an 8 0 PAGENO="0119" COMPETITIVE PROBLEMS IN THE.. DRUG INDUSTRY 15473 extreme position in contradiction to outside opinion, but by following such a procedure of observation and review a Board would establish an ethically consistent approach to all oromo- tional programs for its company's products no matter where the promotion was directed. The current trend towards the personal responsibility of corporate officers and directors for all actions of their companies, and particularly those which affect the health and welfare of their customers, is one which has to be taken very seriously in the pharmaceutical industry and here is a good place to start. It seems clear that most Boards would prefer to rely on some combination of their own internal research stanc~rd and that of the FDA, or other appropriate regulatory. body. But any such combination would define and establish, in advance, guidelines for aggressive promotion men for whom sales volume is the over- riding issue. If the pharmaceutical industry can not find within its own operations the solution to the obvious problem it creates for itself by promotional practices which set different standards for different peoples, then a solution will be forced on it in one way or another from outside. Several possibilities are immediately apparent, the most obvious being expanded governmental regulatory control made possible by enabling legislation. Certainly the conduct of American industry overseas is receiving all kinds of attention these days, most of it sharply critical, and there will be plenty of precedents for the imposition by the FDA of 9 PAGENO="0120" 15474 COMPETrnVE PROBLEMS IN THE DRUG INDUSTRY some kind of sanctions against those iho stray from U.S. standards in their conduct of their foreign business ventures. Even if the only practical method to do so is to demani industry protect its stockholders from the liability claims arising from damages re~ lated to improper drug use by observing defensible standards of product, a way can and will be found to do it. Control through the World Heath Organization is another possible way to ensure that only balanced, accurate, and scienti- ficaUy documented claims are made for medicinal preparations anywhere in the world. This body could certainly assume an advisory position in this area which would be of great value especially to those countries without their own body of scientific knowledge and expertise. Dr. Helen Taussig has described to the Committee in earlier hearings some of the possibilities that could be developed along World Health lines, but clearly a lot more study is necessary to make sure that objective medical standards can be so achieved staying clear of all the varying social and political pressures that all too often seem to become dominant in a global approach to any problem. Nine years ago before this Committee I stated that a pharm~. aceutical manager must accept the fact that his industry indeed carries a high degree of social responsibility or he can see that social responsibility spelled out for him slowly but surely by legislation prescribing more and more of his operations, and 10 PAGENO="0121" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 154~5 taking over more and more of the functions be now guards so fiercely. The thrust of those hearings concerned prices in the pharmaceutical industry, but my comment is just as applicable today to promotional practices which seem to the public to ignore any feeling of responsibility towards~the patient, and clearly go against, the most basic principles of medical ethics. By continuing such practices the industry is making serious long range trouble for itself, if not here today, then down the line as foreign governments become more alive to public health problems. It is very stupid, indeed, for a well established, profitable, and progressive industry to endorse or to permit practices in its sales promotion areas which can produce only the short.term dollar return, and then will lead to restrictive controls which will overreach the abuses with which we are now concerned and go on to other pharmaceutical affairs now left unregulated. Such is the inevitable result of the abuse of corporate power, and it's about time that corporate management realized it. I would like to see the pharmaceutical industry take the lead in that realization. 11 PAGENO="0122" 15476 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY Testimony, May 26, 1976, before Subcommittee on Monopoly, U.S. Senate Committee on Small Business. I am Myron E. Wegman, John G. Searle Professor of Public Health at the University of Michigan*and Dean Emeritus of the School of Public Health. My presence here today has two bases: my long concern with health in Latin America and my present position as chairman of an ad hoc seminar on achieving rational use of medicines. My contacts with Latin America date back twenty-five years, from early consultation work and then almost nineyearsof full-time employment with the Pan American Sanitary Bureau, Secretariat of the Pan American Health Organization and Regional Office of the World Health Organization, the last four years as Secretary-General. I have traveled extensively in the Americas and still serve as consultant to the Bureau in a variety of ways. I am also a member of the WHO Expert Advisory Panel on Health Manpower. Our seminar in Ann Arbor was stimulated by Professor and Mrs. Alvin Zander, who brought together a group of us, including professors from a variety of fields, including medicine, dentistry, law, nursing, pharmacy, psychology, and ethics, to examine various aspects of the problem of achieving rational use of medicines. The Zanders have faced personal tragedy in the loss of a daughter under circumstances overwhelmingly suggestive of the fact that medicine she had received while on foreign travel was not rationally prescribed for the illness she was suffering. She died of the type of blood dyscrasia described over and over again before this committee. As we got into the problem we could hardly believe the frightfully misleading and incomplete promotion of drugs in many countries of the world, including Spain and Latin America. We learned early that many drug companies *majling address Ann Arbor, Michigan 48109. PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRVG INDUSTRY 15477 Testimony, May 26, 1976, before Subcommittee on Monopoly, U.S. Senate Committee on Small Business. had no compunction about saying one thing at home and another abroad. I should note, to be sure, that U.S. centered companies are no different in this respect from companies with headquarters in other parts of the world. Our seminar early decided to broaden its interests to consider the ethical values involved, utilizing a small grant from a program called University Values Year, to bring in guest speakers. We have tried to look at commercial aspects, professional educational aspects, private practice aspects, legislative aspects, and patient behavior and health education aspects. I should note that in my presence here I am speaking as an individual since our seminar group has not yet formulated its conclusions or reached consensus on recommendations; these we expect to have ready this fall. Latin America is a particularly sensitive area of the world in regard t? drug promotion and utilization. The people of Latin America have the same kind of fascination with drugs and specific medication that is found in every part of the world. They are, however, more vulnerable to imported drugs since the national pharmaceutical industry in the various countries is much less developed than in the U.S.A. or Western Europe. This situation is changing and the government of Peru, for instance, has recently taken the lead, on behalf of the Andean Pact countries, in developing national resources for producing generic drugs. In another respect, that of local quality control, a national equivalent of our Food and Drug Administration is either essentially absent in many Latin American countries or has seriously limited powers and resources. The problem is further complicated because in any developing economy there is a general tendency to give market-place considerations precedence over regulatory or consumer protective activities. PAGENO="0124" 15478 COMPETITIVE PROBLEMS IN THE DRUG INDTJSThY Testimony, May 26, 1976, before Subcommittee on -3- Monopoly, U.S. Senate Committee on Small Business. Finally, one important way to get at irrational use of drugs is through better education of the physicians who prescribe the drugs and the pharma- cists who dispense them without prescription, legally or illegally. Yet most Latin American countries have major problems with education of professional health personnel. The oldest medical school in the hemisphere is that of the University of San Marcos, in Lima, Peru, but it, along with the great majority of the medical schools in the various countries, suffers from shortage of equipment and teaching resources. Improving health professions education has been a long-standing concern of PAHO and WHO. The Pan American Health and Education Foundation, of which I am a Trustee, is engaged in an important program to help get textbooks to medical and nursing students in every country of Latin America at reduced rates. The problem of limited educational resources makes it more difficult to compete with the educational efforts of the pharmaceutical companies, each of which, naturally, is intent upon promoting its own product and has easy access to sophisticated advertising and informational techniques. Thus the question of partisan promotion of drugs is significant at all levels of medical education. Mr. Chairman, to my knowledge, your own interest in the problem of drug distribution in this area goes back many years. I am aware of the hearings you held some years ago at which testimony was received on the efforts of the Pan American Health Organization and the World Health Organization to provide help and guidance to the member countries and to foster a spirit of international cooperation in this field. Nevertheless, I thought it might be useful to mention some of the PAHO/WHO activities in this field. During my own period as a full-time staff member of the PAGENO="0125" COMPEPITWE PROBLEMS IN THE DRUG INDUSTRY 15479 Testimony, May 26, 1976, before Subcommittee on - Monopoly, U.S. Senate Committee on Small Business. Pan American Health OrganizatiOn I recall a number of Latin American countries asking for help in controlling the quality and advertising of drugs distributed in those countries. Among the most significant of~the many World Health Assembly resolutions in this field was WHA 16.36, adopted in May 1963, asking member states to inform the Organization immediately of problems with drugs and asking the Director-General to transmit information received in this way to member states. One specific example of action under this resolution came from a report to WHO by our Food and Drug Administration that, because of th~ incidence of reactions, FDA was requiring even stricter labeling of chloramphenicOl. The Director-General sent a circular to all countries on 25 June 1971, giving full details, but, sad to say, little action resulted. Incidentally, this was not the first time WHO had warned governments about blood dyscrasia with chioramphenicol. In May, 1968, the Twenty-first World Health Assembly adopted a statement of fundamental principles for the advertising of pharmaceutical products, specifying ethical and scientific criteria, and called these to the attention of every member government. The text of WHA 21.41 follows; PAGENO="0126" 15480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Testimony, May 26, 1976, before Subcommittee on Monopoly, U.S. Senate Committee on Small Business ~~`IIA2I.4t The Twenty-first World Health Assembly Having considered the Director-General's report on phar- maceutical advertising; Having noted resolution EB4I.R24 of the Executive Board on the matter; Considering that, if it is sot objective, pharmaceutical adver- tising in whatever form is detriissetstat to ttte heatth of the public; and Holding that the adherence to certain fundameistal principles for site advertising of pharisstsccuticat products is essential, UROCS Member Staten to enforce tise application of the ethical and scientific criteria for pharmaceutical advertising as annexed to thin resolution. ANNEX ETHICAL AND sCIENTIFIC CRITERIA FOR PlIARMACEIITICAL ADVERTISING Alt advertising on a drug should be truthful and reliable, It must ttot contain incorrect statements, half-truths or us- verifiable assertions about the contents, effects (therapeutic as well as toxic) or indications of the drug or pharmaceutical apeciality concerned. 4thertising to the Medical and Related Profesaions In describing ttte properties of a drug and its use, stress should be laid on rendering ftscts and data, wtsercas general statements should be avoided, Statements ulsould be supported by adequate and acceptable scientific evidence. Ambiguity nsusl be avoided. Promotional material should not be exaggerated or misleading. A full description, based on current scientific knowledge, should include information on the producer and sponsor of the product advertised; full designation (using generic or non- proprietary nausea) of the nature and content of active itsgre. dient(s) per dose; actiots and uses; dosage, form of administra- tion, and mode of application; side-effects and adverse reactions; precautions and cotttra-indicatiosn; treatment in case of poison- ing; and references to the scientific or professional literature, A fair balance should be maintained is presenting itiformation on effectiveness on the otse hand and adverse reactions and contra-indications on the other, Advertising to the Pith/ic Advertisetsients to tlse public should not be permitted for prescription drugs, for the trealtnse,tt of certain diseases and conditiotts whieln can be treated only by a doctor and of which certain countries have established hats, or in a form wlsich brings about fear or distress, or whicts declares specific remedies to be infallible, or suggests that they are recommended by members of the medical prpfession, May 1968 168,20 PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15481 Testimony, May 26, 1976, 6 before Subcommittee on Monopoly, U.S. Senate Committee on Small Business Even more recently the Organization strengthened its long-time activity in monitoring adverse reactions by setting up a central unit in Geneva. As of November 1, 1975, only a small fraction of WHO's 150 member countries were reporting systematically, yet 101 ,000 reports were received about 12,000 drugs. In another attempt to help regulate production of drugs resolution WHA 28.65 was adopted in May of 1975 on revised requirements for `good practices in the manufacture and quality control of drugs," calling on the member countries to adopt measures for quality control not only in manufacture but also in imported drugs. All of these efforts, sadly, have accomplished precious little. There are a number of reasons for this paucity of action~ WHO can pass noble and high sounding resolutions, distribute information, give advice, outline better procedures, but in the end, unfortunately, most ministries of health, even when the authority exists, simply do not have the clout to compete with other parts of government or with the commercial interests involved. Another difficulty is that most of the countries of the world simply do not have the resources either for control of drugs manufactured internally or for those imported. The WHO Expert Committees have done yeoman service in setting up standards that can be followed by all countries but until conditions change most of the people of the world are not going to have the benefit of these standards. Fundamentally, responsibility for what goes on within any country is the responsibility of that country. In the strictest sense the manufacturer who says "It is not illegal for me to make exaggerated claims in a country PAGENO="0128" 15482 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Testimony, May 26, 1976, before Subcommittee on - Monopoly, U.S. Senate Committee on Small Business. that has no laws against exaggerated claims.' is legally correct. This is where the problem of ethical and moral values come in. It appears to me, as a professional person, absolutely unconscionable for a manufacturer to hide behind such a defense when human lives are involved. It is simply not true that, because a particular antibiotic may need to be prescribed more often in a developing country, where the diseases for which it is useful are more prevalent, it is therefore justifiable to exaggerate the indications and minimize the contraindications. This is arrant and dangerous nonsense, as is the argument that reactions are less frequent in these countries, where, in fact, there is inadequate reporting. It is one thing to say that in a country with a high incidence of typhoid fever one may be justified in treating a typical clinical picture without awaiting laboratory confirmation. It is another to imply that because typhoid is prevalent the drug should be promoted for every case of diarrhea. In 1947 I wrote a short paper on what I called Noxicity of Antibiotics. At that time most people were concerned with toxic reactions but I argued that there were at least three other "noxa" involved--encouragement of the development of resistant strains, interference with bacterial balance, which leads to overgrowth of other organisms, and a "masking" phenomenon, where overdependence on the antibiotic closes the physician's eyes to the need for other diagnostic and therapeutic efforts. These difficulties have not disappeared and are perhaps even more important in developing countries with insufficient health manpower. In our seminar in Ann Arbor we have discussed the ethical and moral values involved. There is no doubt but that in a free-market society it is the ethical responsibility of a company management to earn profits PAGENO="0129" COMPETITIVE PROBLEMS IN THE DRUG INDUSIFRY I548~ Testimony, May 26, 1976, before Subconinittee on - Monopoly, U.S. Senate Committee on Small Business. for its stockholders. But, equally, it has ethical responsibility to present to all physicians and pharmacists objective and complete information on the utility and the dangers of its products. Every physician knows that, on occasion, a dangerous drug must be used because the potential benefits outweigh the risks, but that is no excuse at all for downplaying those risks or exaggerating the benefits. Human considerations must come before profit considerations, yet the record developed at your own earlier hearings, Mr. Chairman, carries overwhelming evidence of the callous way such distortions have been carried out, and the situation has not changed. What can the U.S. Government do? I am told by my colleagues in the Pan American Health Organization and World Health Organization that our Food and Drug Administration has cooperated with the international health organizations in supplying information and providing technical advice and consultation. FDA should be supported in these efforts and we should look for means to obtain more cooperation in relation to health considerations from other branches of government, including those branches dealing with commerce and industry. - I understand that there is no way to compel U.S. companies to change procedures of subsidiaries in other countries, that carry out all of their operations within other countries. Furthermore, the situation that we are discussing here is by no means unique to U.S. companies. Swiss, German, French, and other manufacturers are no different in their operations. It is a shameful posture, however, for a nation that prides itself on leadership, to say that, because one's competitors engage in reprehensible practices, one is justified in following suit (or in showing the way!). Is there not some way to approach U.S.-based, multi-national corporations, 13-950 0 - 77 - 9 PAGENO="0130" 15484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Testimony, May 26, 1976, before Subcommittee on - Monopoly, U.S. Senate Committee on Small Business. which depend so much on maneuvering tax liabilities among their operations, through controlling write-offs of taxes in other countries? Other steps, small as they are, might also be taken. The U.S. delegation could sponsor a resolution at the next World Health Assembly calling on all manufacturers everywhere to make their promotional materials similar among all countries or else to inform the various ministries of health how promotional materials differ, and ~ The International Federation of Pharmaceutical Manufacturers Associations and the International Pharmaceutical Federation are non-governmental organizations in official relations with WHO and thus have the privilege of taking part in the discussion of such a resolution. In turn it is to be hoped that these federations would exercise more pressure on their own members for higher standards. Further attention might be given to education of the health professions in more rational use of drugs through greater support by the U.S. Government for International assistance, both our own AID program and that of PAHO/WHO. Mr. Chairman, may I commend you again for studying this important problem. The very fact that you are bringing the actual situation to light is of benefit in itself. What you, report and what you recommend can, I believe, benefit the health of all people. PAGENO="0131" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15485 ANN ARBOR, MIciL, May 81, 1976. Senator GAYLORD NELSON, Chairman, Senate Subcommittee on Monopoly, Select Committee on Small BuBi- ne88, U.S. Senate, Washington, D.C. DEAR SENATOR Nnr~soN: In the May 26.-27 hearing on Promotion and Labeli*g of Drugs in Latin America, the Warner-Lambert Company's Annual Meeting of May 1972 was frequently mentioned. Among ether references to the meeting, Mr. George Squibb testified that "It would seem that as a matter of policy, if the question were effectively put, no Board of Directors of a responsible American pharmaceutical house in this day and age of sensitivity to consumer criticism would ever knowingly permit its companies' products to be marketed under do~ible or deceptive standards or in anyway whatsoever that would involve extraordi- nary risk to the public in any part of the world." He was then asked how he would explain the Warner-Lambert Company's 97 percent "No"~ vote in the annual meeting even after Dr. Lewis and Dr. Burach had informed them of the medical ~ealltles of the issue, particularly the case of the Parke Davis Company's Chioromycetin labeling in many countries abroad which contrasted so striki~igly with the United States label. As I recall, Mr. Squibb replied that he could not Imagine that such a thing could happen, that it could only have happened i~ the Directors were not really aware of the issue and thus did not understand the problem. Since I had attended the Annual Meeting of Warner-Lambert, spoken with Mr. Weiringa and Dr. Hodges, President and Vice President for Research for Parke Davis which Is part of the Warner-Lambert Company, after the meeting, and had knowledge of the aftermath of the meeting In relation to Chioro- mycetin labeling abroad, I thought I could clarify the issue of what went on from the viewpoint of my own experience at least and that my account would serve as an example of United States drug company labeling and promotion abroad and of efforts to change labeling of one drug as well as shed light on some of the testimony given in this hearing.' Mr. Judah Sommer, minority counsel of the Subcommittee, suggested that I write a letter to the Subcommittee to be entered into the record of the testimony of the 27th. Dr. Myron Wegman, who testified on the 26th, had already entered into the record our-my husband's and mine-documentation of Parke~Davis Cbloromycettn labeling in Spain. Attached is the list of that documentation that Dr Wegman entered into the testimony on May 26th and that also documents this account. It would be more meaningful if the documentation could immediately follow this account at the end of the May 27th testimony. Mr. Benjamin `Gordon originally asked my husband or me to testify but we decided that Dr. Wegman's testimony would be more valuable. Sincerely yours, Mrs. ALVIN F. ZANDER. c. to Mr. Ben Gordon. Address until June 19: % Mr. Ed Bordin, Rte. 3 Idlewood Beach, Xlolland, MIch. 1-616-335-9812. STATEMENT or MRS. ALVIN F. ZANDER Our daughter died, of aplastic anemia in January 1972 after having been given a medicine by a physician in Spain for a minor ailment, which medicine we believe, was the most likely cause of her death. Shortly after her death it was called to our attention that Parke Davi$ Chloro- mycetin labels in Spain and other countries did not carry warnings that possibly fatal aplastic anemia might follow its use and listed many more Indications for use, some trivial than the United States label. A letter we wrote to the Parke Davis Company Inaniring if this were a fact and, if so, what were the reasons justifying it, elicited no reply. When we learned that Warner-Lambert's Annual Meeting had on the agenda a proposal by the Project on Corporate Responsibility and forced onto the agenda by the Federal Trade Commission, that labels abroad should be the same as the FDA-approved labels In the United States, we decided that I should attend the meeting. Dr. Lewis and Dr. Burach and others did speak at the meeting attended by the Board of Directors about what inadequate labeling abroad actually meant in terms of death and suffering. I recall one of these doctors stating that a recent study on incidence of fatal aplastic anemia after taking chioramphenicol PAGENO="0132" 15486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (generic name for Parke Davis's brand ~Jhloromycetin) was similar to that of the thalidomide victims, the only difference being that the victims of aplastic anemia were dead and their plight could not speak for them. The vote was a little more than 97 percent against the proposal. It was a vote of the stock- holders and the proposal was specifically that the labeling should be the same abroad as In the United States which brought In other issues than the funda- mental one of pharmaceutical companies providing objective, scientific, and complete information on proper use of their products In whatever country they are sold so that, as Mr. Squibb speculated, perhaps the question was not well put. Nevertheless, Information on the fundamental issue of what inadequate misleading labeling can mean at least of one drug, Chloromycetin, in terms of human life has been brought to the attention of the company. As a consumer whose daughter had recently died of aplastic anemia and whose letters to the Parke Davis Company were unanswered, I spoke after the end of the business meeting during the question and answer period and was only allowed to read from a one-page statement but was not allowed to read the Spanish label for Chioromycetin that I had brought with me which contra- dicted the chairman's, Warner-Laml~rt's chief executive officer's, statement that warnings of possible fatal aplastic anemia were indeed included. After the meeting Mr. Weiringa, then President of Parke Davis and now, I believe, president of Warner-Lambert, said that he had not seen the letter ad- dressed to him and that he would arrange an Interview for me with him or preferably the medical director, Dr. Robert Hodges, Vice President for Research, as being more knowledgeable of medical aspects. At my request, he also said I could bring a physician with me and that he would give me the Chloromy~etin labels for the countries abroad In which Parke Davis sold its products which, It seemed to me, were just elementary basic information needed to consider the issue intelligently by anyone-me, the President, the Board, the stockholders. Shortly thereafter, however, Mr. Weiringa rescinded his offer, saying supplying such Information was "against the policy of the company". This meant that we had to go through the time-consuming process of trying to collect Chloromycetin labels from abroad on our own travels and those of our friends for in many countries, since Chloromycetjn Is sold over-the-counter, to anyone and without a prescription, the labels are readily available. These labels varied greatly from those more similar to ours in the United States, such as in England, to many with no warnings at all and as many as 45 listed indications for use, many of them trivial. The Parke Davis Chloromycetjn United States label has very strong, repeated, and explained warnings of possible fatal aplastic anemia and other warnings and states that It must not be used for minor illnesses, only for very serious Illnesses susceptible to Its action that cannot be treated with any less hazardous medicine. Dr. Ronald Bishop and I met with Dr. Hodges for a long and cordial interview. Dr. Hodges described his own personal views of the product and explained the company's position regarding why labels were different abroad. (I have a file of notes of all my conversations and copies of letters and other statements of Parke Davis officials giving their views and will send them to include In the testimony If the Subcommittee so desires.) l)r. Hodges asked to see the Spanish label and when I Inquired who was responsible for the labeling of Parke Davis products abroad, he replied that he was not but did not say who was responsible. It seemed strange to me that someone in his position would have to ask me to see the label when the Chioromycetin foreign labels were almost sure to be brought up at the annual meeting. We then sent the Spanish label first, then later Chioromycetin labels from other countries to Mr. Weiringa, the President. Within a few months Mr. Weir- Inga called to say that the company had revised its Chloromycetin Monograph which is the company's basic Information on the drug, is sent to all their inter- national locations, and is used as the basis-along with each country's regula- tory system's input-for labels in that country. Mr. Weiringa said that the new Monograph was essentially the same as the United States label but would not give us a copy since it was again "against company policy". Nor could an Amer- ican physician obtain a copy, only a practicing physician in a foreign country In which Chloromycetin was sold. Upon inquiry, Dr. Hodges said the Monograph was basically the same as the United States label except that indications would vary in different countries and he was very definite that the company would not give us a copy or any information of this type. So again many months-- about eight, I think-were spent In our finally successful efforts to obtain the Monograph from abroad. PAGENO="0133" COMPETITIVE PROBLEMS IN THE DRUG I~DUSTEY 15487 The Monograph was a great improvement over the information in the labels we had pre~riously collected, warning of the possibility of fatal aplastic anemia and stressing that Chioromycetin must ~ot be used for trivial illnesses. The prescription against use for trivial illnesses came many years after-I tbi~k about twenty-it had been required by the FDA on the United States label! However, the new Monograph omitted some Important points such as that the recommended blood studies which could detect blood dycrasias, such as aplas1~ic anemia related to dosage and prolonged use, so that the drug could be stopped and the blood-manufacturing bone marrow could reverse Itself back to normal, these blood studies could not be relied upon to detect the fatal Irreversible type of aplastic anemia which did not appear for weeks or months after use of choramphenicol. This means that a physician prescribing chloramphenicol has no way of knowing whether the next patient to whom lie gives chloramphenicol may be the rare individual who will die of aplastic anemia, a disease affecting the blood-manufacturing ability of the bone marrow so that the victim has insuf- ficient red cells to fight off anemia, Insufficient white cells to fight off Infection, and not enough platelets to stop the flow of blood anywhere, so he must live off the blood of others as long as possible, perhaps a few months, while under- going steroid therapy with Its many devastating effects. Letters from physicians In medical journals are blaming lack of this Information abroad for overuse of chloramphenicol because the conscientious physician believes he can catch and reverse aplastic anemia if he takes blood studies, Also the new Monograph still encourages much unnecessary use. We obtained the opinions of seven physi- cians all of whom were critical of the new Monograph. We have included In our documentation a copy of the opinions of Dr. Harry Dowling, former head of the AMA Council of Drugs, on the inadequacies of even this new Improved Chloromycetin Monograph for other countries. (We will ask permission to pro- vide the opinions of the other physicians if it would be useful to include them.) Again it took some time before we were able to obtain abroad any new labels based on the new Monograph. These new labels were a real improvement `but bad faults similar to the new Monograph. Such faults and omissions may seem slight but they can cause unnecessary death to someone so In fact they are very important. We have a few samples of Parke-Davis Chloromycetin 1972 advertising in Spain sent to us by some Spanish doctors which carry no warnings, only that one could write to the company for information. Also the Parke-Davis entries for Chloromycetin in the Vademecum Dalmon, Spain's PDR (Physician's Desk Reference in U.S.) are also Inadequate. A Spanish physician has painstakingly analyzed the devastating inadequacies of this publication of the pharmaceutical companies giving information on use of their products and his findings have appeared in medical journals here as well as abroad. Enclosed, is a letter-to-the- editor in the British medh~al journal Lancet, June 22, 1974, p. 1281 clearly showing the extent of Improper over~the-counter use of chloramphei~icol In Spain. We also received an example of promotion to the public In Spain of Chloro- strep, a Parke-Davis product which is a combination of chloramphenieol and streptomycin, promoted to use for common summer diarrheas, again with no warnings and also a letter sent to physicians in Spain by the Parke-Davis Company reminding them In the coming summer travel season with increased "common and infectious entercholitis" to use this product of "well proven effi- cacy and therapeutic safety" which will "produce a fast remission of the symp- toms in your patients, avoiding at the same time any complication." (My emphasis.) To make this gross distortion of Information on possible effects of Chioromycetin even more reprehensible, these letters were sent after the new Monograph was written which stated clearly the risk of fatal aplastic anemia and that Chioromyctin was not to be used for trivial illnesses. We did write to Parke-Davis about this particular Item since our only grandchild ~ras unex~ pectedly traveling in Spain and this Parke-Davis promotion was directed at a common complaint of travelers there-but we received no reply. In the fall of 1973 we went to Spain and had conversations with two Spanish physicians who vividly described the Inadequacies of Information on use of medi- cines by pharmaceutical companies and with the Chief of the Antibiotics Divi- sion and the Director of the Division of Chemical Analysis of the Centro Naclonal `de farmacoblologla (Control of Medicines) who described the present, perhaps more hopeful situation, (Notes of these conversations are included in PAGENO="0134" 15488 Coi~nETITIvE PROBLEMS IN THE DRUG INDUSTRY the documents submitted.) with improved chioramphenicol labels and the begin- ning of an adverse reaction reporting system. Our experience, beginning with the Warner-Lambert Annual Meeting, sug- gests that perhaps basic information on just exactly what kind of labeling abroad, at least for Chloromycetin, the Parke Davis Company was producing was not known to top officers, stockholders, and most likely Board Members. When this was brought rather forcibly to their attention, even though the vote against the proposal was 97%, steps were taken in the case of Chloromycetin to rectify the inadequate label. I do not know what other response was made by the company. Mr. Squibb's conjecture that the vote could only have happened if the Directors were not really aware of the issue, that they did not realize fully the preblem, in essence may be right in terms of the deeper issue involved, that of a pharma- ceutical company providing objective, scientific, and complete information on its products whether at home in the United States or abroad. We heartily endorse Mr. Squibb's recommendations that Boards of Directors must act more responsibly, "must question precisely the way their organization is carrying out its social responsibility and set specific standards and guidelines for the promotion of its products" and that "corporate officers and directors should be held personally responsible for all the actions of their companies and particularly those which affect the health and welfare of their customers" and that such responsibility should be strictly enforced. The information given or not given by a pharmaceutical company about its product can and does always very directly mean life or death, health or sickness to its consumers and whether it is one or the other depends basically on the in- tegrity and vigilance of the Board of Directors, the officers, and the personnel of the company. Otherwise, as Mr. Squibb said, "If the pharmaceutical industry cannot find within its own operations the solution to the obvious problem it creates for itself by promotional practices which. set different standards for different peoples, then a solution will be forced on it in one way or another from outside." Also the failure, from our point of view, of the Parke Davis Company to produce a Chloromycetin Monograph for its international locations comparable to the one worked out with the FDA for United States makes one seriously cpiestion whether even with the best of intentions a pharmaceutical company can give objectives, scientific, and complete information on its products when it must also serve its other commercial responsibility to its stockholders. Will there continue to be unnecessary deaths such as the one of a young woman, a Mrs. Anderson, who followed almost exactly in our Judy's footsteps the following summer and died the same way-slowly, painfully, and unneces- sarily-but in her case the coroner has the bottle containing chioramphenicol which she bought over the counter in Spain for a minor "smokers" cough? Or will these hearings Spur action to bring about necessary change? PAGENO="0135" COMPETITIVE PROBLEMS IN TBE DRUG INDUSTRY 15489 ~p Hxample of United States Drug Company Labeling & profliotion Abroad Samples of information on Chloronqrcetifl (chioramphenicol) provided by the Parke Davis Company in Spain 1969-197)4 acquired by Mr. and Mrs. Alvin Zander. Labeling 1. Parke Davis Chloroinycetin label in U.S. 2. Parke Davis Cbloroinycetin labels in Spain acquired in 1969-1973. 3. Parke Davis new Chloros~'cetin Monograph sent to all international locations as basis for new labeling. ~. Dr. Harry Dowling~s "opinions, not proven facts" on the new Monograph. 5. Zanders' comparison of new Monograph with U.S. label. 6. New Parke-Davis Chloroinycetin Spanish label based on new Monograph, July 1913. 7. Zanders' comparison of new $~anish label with U.S. label. 6. Parke Davis Chloromycetin entries in Vademecum Daimon, Nov. 1972. Spanish physicians' desk reference published by pharmaceutical companies. 9. Parke Davis Chlorornyoetin advertising samples, Nov. 1972. 10. Parke Davis Oblorostrep advertisements directed to public, mid 1973. U. Letter to physicians in Spain promoting Chiorostrep by Parke Davis, April 25, 1973. 12. Parke-Davis Chlorostrep label, older one acquired September 1973. 13. Parke Davis Chiorostrep label, new one based on 1973 Chloromycetin Monograph. Control of Medioine6 in S~4~ 1)4. Control of medicines in Spain asperceived by Mr. and Mrs. Zander after personal interviews in Spain with two physicians and two officials. 3.5. Notes on conversations with two Spanish physicians, September 1973. 16. Notes on interview with Chief of Antibiotic Division and Director of Division of Chemical Analysis of the Centro Nacional de Farmacobiologia (Control of Medicines), Madrid, September 1973. 17. Centra Nacional de Farmacobiologia (cNDF( `a new statements on obloramphenicol used as a basis for new labeling of chloramphenicol products of Parke-Davis and other companies in Spain. PAGENO="0136" 15490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Ln~ 1. Parke Davis Chioroctycetin label in U.S. i~o:o bottle nil box htve `the iollov;ing in~onnation which ifnnot on the $panish box~:bottl, O/iiTTIOII - ~ederal la~: wrohibits diopons~.n~ without wrescription. - Blood dyscrabian nay bo e.orociated with the ue~s of claloreanmhonicol. It is esixontitil that wiequato blood studies be made. Bee enclosed v:ornjn/Ts ~nd precautions, V/I~BING - ICoop out of the roach of children (aloe TJNTJAI JiDIY/T DO/IN is ~ivon.) (~ae~ ~hy itiwn~ oe~~hAn~p~eutipa1Spocja1tjoo"Bjo3onjon1s gives the eerie (C £rt LOB A T~ NB N Co 5) DBscr'~pTtoN Chlortmphxlxol leon liblotly bet Ic oil ally cafyl for, erdohold bt rayed tey~ Ilnotinnooxcoed ,y stat itoexpytiblt to 11/ aisebiol of rots ohyn lees pntxnlixffy codaS thotatitic egontsxro Iroffeyl eorconttolndlootcd. Scout lontyg iee.to'nticl to d'teeunino itt lodioctod ice, bet roy be crotorred oonoeurrontly mO dice caStS tone "todlootiare" Cation) ACT1OI:$ AND PANI'e\COtOCY do ylt000hlotomphaxiool exerts rnoirfyo botonloetatia efftotot e oNe aerge or ammo at cxx g potitlos bootoxux and iccotioc in `iffy ogrinot Ookxttclan, the lymphoorcoufomt.pecltaooic group end V/brie Cbalyooo.ltio pmeioafotlyeotixtogoinot$nlunonnllo typhiend Heotophilae Iof.'yeoloe, The toodo ot oct/on Ic hooch ln)ertctauoo or inhibition of protein cyntheele in lntcct aciteond in oolf.tnoo oyatouoe. Chloromphonicot odenlnietonod orolly Ic cboorbod rapidly fran the trtyetlnol tract to controlled atudios in edalt oolueteore as/etc the recommended doeoge ot to mo/kg/day, e dotage ott ctn. catty Scott t000 dotes moe glare. Uclog the rniotoblclcgloel aesop method, the aoeraoo coat carom coot oce 1.2 meg/mi. One ttoareltor the f/rot dcte.Acuniietioaefttctgoat opocknlee to tO.4mcg./rl.etterthetitth dOSe ott cm. taco eoeete bode ron~ed from 5-14 meg/mt. coer tIme dli Sonioce end txtnt blood dyextce, fne!oot~e Startle, hypnyloetio hoot booS retort, ctoyfastio eflououxotuibk/nci to ohlotxmytteiool ohioh laterteym/notod iotnuhesmlx. Cloox dynoteicn hoc accarrod otter both oloft ton end prnixo~d thcrci'y ~ifh hit doe. Chloe. ogerte oil be o5~tion, to dxeOrlbod tn thn "lnt/eoticrs" ecotlor. panic, cc Oronul000tol,tnfo, bolore hay boaonea lrroaorelbc, each etyd!oe outlet he solid ox to dotcot bore mnrrxo deprccolyn Crier to docteymeot of ep!xytle onomtlo. To oxutelo oxyroyxlato PAGENO="0137" *7!~ 0 a H 4 a; jj~r> r~: ~ ii a ft PAGENO="0138" 15492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~\`~j ~ ~ ~ ~ ~ Lw~c~' ~~-h ~ \4 7~. The `to encid box 1O~!UG the P'tllolviniVirc:rorsatbon which is not o~ tho cpenish box. `. CiiUSION - Poderal mv, prohib~te dispen3in~e without prescription. - Itlood dys~r~siEcc rim.y be wosocia~ed with the uce o~ ohloroxnphoniool. It is essential that adetjuate blood studies be made. See enclosed warnings and regulations. - Seep out of the rooch o~ children. (nico USUAL ADULt DOSS is given.) (Tue Ph~rstctionit Dusk P.oferoncs to Pharcotacoutical Ztieci~ltios Biolo,~icalo dive the same intoxmation.) Ct~L~SYC~T1N b. ft.Icff,e.vza. ccccifl.-oiiy messIc~sct icciocticco vcuc,~ c~e;~tia b~tcd,cecoth~ bcetfremt,, ms&ngt5e or Outs occettihic vs which hcce boofdoronetret,d to be 3. Cystic fibrotic rrfrnrss COtcTCAOJOIATIOSS vice! t tovtivtvdsrtsd Is ivdhidcc!c with e history ci vr,tvc i.yurc~:l,vt d/vrtc.k contest vii. 1 `sit ct ho ,ssd ruoCJwTlouls tiny .i:dttcshtstd Lntttcsyd by pssicdic bhcd chide. di .svtsvd cci ,ypcnnlc ci srtitclccytscscto, lthsbtpcsic. thscv. it siwsId is stOlid tist citch ctsidies dc set tv: t.vnthi i~tt yit:r,vcwtt tic ssvccrcibts type of bcse 2. Pcycthid cct.st'sscf ho dca etiovld be ~oidcd dcccliv .tblo, Odd tchc Id vvt iccecti ed lcvefrclcc cy~uIrod tepfvitctoo i Ecccoctcc b!td otto vtysccclttrcri cdsslclslsttict of ho cccvi. tic dcc hi iv.'i~t.,s,t vdt,tcfic PiOtc5Ovc if the lctc:if, the dttccje bce ~ict vtcnd.cy es eccttttbiy, the bleed ecceeciccticsc dv:sivy clips brecce: et ecictiel tceic ptluto cc ye eli: Icocy 5. Pceccs,tieis etsc:id be cecil if thoeccy of p~civctiico cod fctltcrm cc csc.id tic': sysdiocce teoletty. (Sec Adcccoc ceeeelece.i Scitc disc iwctcthctsld be cesct,liy folleecod d:cisc therepy et tlcc 8. Pc:c.dies chevtd be coed tic thecepy dccc. lectetiec b~cwcso of the ececibility of cole offect. osthe eccoifo ictect. 5. `the ccc ci chic oct~btctic c~ wills ether .ctibictic., moy result in cc ccrc5rccth c! cesusiuccoeticlc OrgAn lets,, tietuudirg fcc~i. it if toctiecto cc:ord byc000uuce.ptibiecroodiom,ycpoordeftcgth,spy..pprcpri,tc `vcc,crcoohcctdbec,tucn .3 NJ PAGENO="0139" COMPETITIVE PROBLEMS IN ~HE DRUG INDUSTRY 15493 CHL~O~YC1~TIN ADVE72SB GfACT2O2OS 1. Blood Dysorosios The soot sorious 5400150 shoot or ohleremphsricsl is boos msrroo depsos$sn, Ssoious sod hotel blood dyr session foploshic srsm)s, hy. pos)oshiOenolO)f, throrobsuy)000n)o, sod O1~OuI0OytOpo1'k) knosso to sosur 0)101 ho 0001iOhtfy,300 0) o~00enohonoo). As irroustoibth A ryors bIb 1)51 oh hose rooouo 0nob~os on, y:hioh is doss reloAd. ho PbThA)i0r hi risk, tithe 00)01 ouoebsr 01 dry~.uooooAtod dysororios, su4 3) ho this) Oyn:bo~ oh obr.0177 oooot00od dyosroolos is oooyu0lo the CoiIio,n)o bests Asso'ob3 bytho Coh)oro)o V.odios) Aooyo3h'yn on.) lbs SteIn Oopyeisn'rbof Publo Hon)lh if Ju'ruoey 1007, the 30 01 b,') o,nhot,o 050013 yes osteeshod at 1:24,270 to 1:40,070 Thoro hs':o boo ey r'epbets oh op)ssht orrm)a sttr)bulsd to oh)orem. phortoo) ohiob 0)01 toro')ootod In )oukoo3o, Ponosysror) oooburou) homo3ob)nyris hoe siso boos sported. 2. Gostrohrhoohinei Roestione fksyssr, usnr)l)oO, 3oso)h)s sod etomst)t)s, disrr hoe sod eotsosss))t)s 3, ldourotox)o Rnoohions )`h057yoht, Slid 000roes)or, moololosofuslorisod delirium hose been dsroribsd lit shoots rsoc)oA~ sh)oromphsoiosi. Oph)o sod psn)phsrsh oour74 hsoo boorroponiod, usurily 1t))ouo)oO isootorm th~rspy. it this 000010, the dryo should be prooeyh)y o)thdrson. 4. t'hyporsnrhsih)uity Rooot)ore boos, mossier rrd ose)oulseoeshss, srrthssdeme, urt)osrts sod sos pholoole may 000sr. Hershsimernesst)sns hose ooourrod during thoropy for typhoid tsar. 5. "Grey Sytrdromo" Tools r500t)ons ios)uOio~ totolitlos hose ossurroot ri lbs pnsmsture slid rsyborn: the s3ro sod symptoms rososkyisot oy)th thossrssst)Oos hess buss rb)orrod to cc Ohs `3rsy syndrome". 005 0500 of "prey Cyltdooms" trap beet reported in on rAnt born to a mothor hooirp nssoiyod chhorsophto)ooi durirg iobor.Coo toss hoe boss retorted ho s3 month flinCh, The taiiooietp summonisas Ohs clinical And laboratory stud)estthatttsuo boor msdesnthsee paRents: 4 00 PAGENO="0140" 15494 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CHV)tSor~yc!TIN (1) (a soot eeoeo thoaopy soith 0500aeafphoy(oo( hod boos (astito$od ho (hoOds hotorsof(fs. (2) Sysaotoms (last opyosoad oftea (to 4 days of ceatlaoood t'ootanonf 3) The syof~tooas etoodsed to the fhtooola~oodoy: (b) p100(005 poflid (((solo: to) 00000(o)yy 0000yoo, ((00 (10(040 (pooled Sy 1'f(u(411~°~f~~ff td) dyoth oifhh otto, to~oeo Of 01000) of (5400 oyeapfosys 4) Thy (((00 ohs of $yeootoeoo hoof oases) to 001(40 0103 0005oeo)od (0) t'eotiooi~0( 10000(100(1)0 000tohldoo 10001(0 ofoosooo((y 5(511050500 Stole of yhiteyso~y.jyy( (0,0(0) (o0(t./fofl. ofiof yyoo(od dysas). tot Too~,l~o1,oo of Do yopoo oDly oCdofte of (ho fooooi~)ad stoat c.~ ADD ~.~t1)STTATSOt4 DOSAGE RECOOI/.400Afl0145 FOR ORAL CI4LORAMPhtf5/OCOL PREPAtIAT(Oy(S The (110)01/f of (1011001001001150d0000tb;( to Oh001ooffyh010oo( toll) (Of 00(00 llfe(0(s bo(ooofs 0 ood 20 co./l/. TOo doolod fo.1000(4)to- salad. 00oe~~ 0(50 ffo,/oC./o.oy dold(d OhIo 4 doooo at ((001(0(5 of COo Eoaey( (a obeto/o oieo,oesefooyo (a.)., y1en~t~o ~ad 010)400 (afoot, eohieootsooo yoo1000stJoos. CDofo0(p10ool001, (0 o:~ 04)1f)4io~o So Ob50100f010(tyfpf)105(0500,(dbO ff041f.100(odold hobo s000otoaoyso)os 1000(IOthd050100504fdb005ddoydol)hododsd:000.:100dI*0hf,f500 Adul to Adutto Should eoyoioo (Oof5./k5./dey(toyf0o(ofO'lfyyfo250of~ 00)04(0 cooS (0 (ho. body uoi~hI) is otloidod 4feb30 (.ho,e 1015004(0. (0 l.ayaoyood Oyosjo 40(0100 lotg,/°.g.fd.ty loeç0(eou blood 0000(ol111101f the pothoooa b4tfhoef hl~h 40100 050o)d bo doy~ofo4 oo foss us 0(s0l~ sOOty to 500toboloo ood 00010)0 (he dao~, Is Ouloyyo of ioapofod soloS peooooeee doto~oe shootd be sdjootod eooo~dD~;~. )Soe diooot~u)~~ bytoboss tyloota.) 1100050 00100) o( O00001oIaofioy of tOo 81(o) 0 (by bh Chfldroo 0oso~oot5o 00./k(./dey dioldod 1(04 dooso 500.hoor o~Oo1oo(y pOlio b) 1400(00(0014(20 otfootioo e5e(oot 1(005 S~o~fp(ibto oegooieoa~, Saooas to (loss (o.~, boutotemis 10050oo51010( 005001011y ohen s00(oslo 0014)1055 t(uld ooy0sl(t14fttfl~ 5(0 4001(44, mop 1004010 doso~o op to 104 05/04/0 be~ooøe,(t(s 0000mmoedod OhsO dooo~e be eedocsd to 50m~./it~/4syoss PAGENO="0141" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15495 cYC~tTm pn01lble. Ctddron er/Ut repaIred loot kidney tanctlan say retaIn races icy 00100(110 p7 the dero. t7owbyrn Infort7s ~Sce opctlnn FlOod "Gory Syndrome" under "AdveroO Reactions.0) Atntol o725 no./ko.ldsy ln4orqaol dneea010.hoar/ntOt0015 usually produces end ,eroi.t.,:'c rtero017'atcns In blood sod t7ssooo odn~uete to control ernst Iot~ctnr,nhiubthOfral2ISlnNt0tdd.i7000tt1d d000t7olnth000lndloldUols. drrea'.t.d nyu//art inlon007e, 500/lId On oboe only to necintein the blood l's, taNt'rn, Intoner nndlnor/p 010/ 7000/00 0~ too mIni ottO rn7,/k5.100y 000.01! 1/lu/rd itt4don005tthOOr lertonnnlo,Iherce do.it';r ronor'ne,r/,lt.I7:0~dlt:rS. I/ole 1/lItlyle ore lnnn'otaro (or err/natty lrnpulrod In odoltot, riot, rI NO d,a&000lA//d ohith land tO locr0500 erOS ;unoesdlflg bIonIc and Chil1/ron wIth tmmatute Mrtobollc Processes dunn /120 r/.Jkn.( day ,oill as,olly produce thotQpoat/o eon. nI/hr h/Il i her bland shtht Inn uu:nl//y tohoonOd by n/orclOohnisoes. esp~A00 UtFOrtitATtON 1/etorole rn. 371, Chlonnrrau000 (oII'oonphcn/uoltspsulatl, each contaIn 200 r~. chll'010liitlictl, a/Or/hO I' ieab~ius ottO sod too, and RolI.Psk' Cypsal'ao Nt. eu, C7luborlyor.tin lthluru'tOl/OrluIll ospealost. east, contaIneD rn~. hhInrOIChlnuol. o,y7/sd in panki~t0 otOSand 000. ~apcaIne No. atO, Chlolonycotin bnIlornirlOleNCol capsules), sack oontoil ItO nra. chlnnclnylllionl, cypllod In puuka~eo 1)05 cod 100. CiIl,000MOCETIN, booed otchlorolnphenlcol, Rep. U.S. Pat. Ott. PARKI3, DAVIS ~IThJ~ & COMPANY 121002000 5 0 1 u DSTROII/ MICHIGAN, U, S. A. Hi Si ~ `?T)f~~:0I~-u `aclAMe.( 73-950 0- 77 - .10 PAGENO="0142" 15496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Parke Davis Chloromycetin labels in Spain acquired in 1969-1p73. c&~t~ /~ Purchased in Madridg Spain ~ ~ L'~ ~ s On October 29, 1969 ~ inserts May~~'g~ust & Noves~ber ]972),(..&t~-" ~~73)~ To the EecicaL Profession: ~ ~ ~ i~ ) ~ ~ CHLOROMYCETIN (*) ~ (*) Registered trademark. Cblorosqrcetin (chloramphènicol, P. D. and Co.) is a crystallized antibiotic with specific therapeutic activity against a great variety of pathogenic micro-organisms. Chioromycetin is absorbed very well when administered orally and quickly gives effective concentrations in the fluids and tissues of the organism. Dosage and Administration In general, clinical experience with Chloromycetin in acute and chronic infections of adults indicates that the majority respond tapidly to an oral ~agage~of 50 mg per kilo weight per day, administered fractionally over several days or until the signs and symptoms of the infection have been brought under control. When the temperature becomes normal, a 25 ag per kilo weight per day, administered fractionally, is generally sufficient, On the basis of an analysis of the dosage used in adults, it has been established that a total dose of Chioroncycetin ranging between 10 and 15 g is sufficient in the sak majority of acute infections. It may be necessary to give 15 g or more in chronic infections. The interval between doses should never be greater than 6 heurs, in order that the concentration of Chioromycetin in the blood may never drop below the minimal effective concentration. In the majority of infections, the dosage of Chloromycetin for infants an children at the beginning of thera~sy is calculated at between 50 and 100 per kilo weight per day, administered fractionally at ~n-to-6-hour intervals. In a severe infection, 75 to 100 mg per kilo weight per day may be given at the beginning of the therapy. A dosage of 30 to 50 mg per kilo weight is PAGENO="0143" COMPETITIVE PROBLEMS IN THE I~RUG I~DUSTRY 15497 generally adequate afterward. Wsrn~.r~. Apparently because of physiological immaturity, premature infants and infents~born at term who are less than 1 aonth of age require ~ ~pecial dosage. These children often have diffimulties with doses that A~~Z are tolerated well byolder children. A ~ more than 25 rag per kilogram weight per day, administered fractionally at intervals of 6 to 8 hours, is suggested for prematures. For infants born at term but less than 1 month old, a1~e o~ not more than 50 rag per kilogram weight per day is suggested, given at intervals of 6 to 8 hours. The dosage should be adjusted according to the of. prolonged administration blood levels of the antibiotic in case~Jimxwktskxt~ia or the use of doses greater than those recommended. Clinical Indications Chloromycetin is effective in many clinical conditions, including typhoid fever and other salmonelloses; bacillary dysentery (shigellosis) and other enteric infections; pertussis, infections of the urinary tract; and viral respiratory infections (bacteria~jpneumonie),gsr~ peritonitis, brucellosis; ocular and otic infections, meningitis, riokettsial diseases (Rocky Mount spotted fever, typhus, scrub typhus), and venereal infections. Tolerance Chlorosycetin is generally well tolerated, and changes in the blood to3low~ its use~1It is desirable, nevertheless, to make periodic examinatic of the blood in oases of prolonged or intermittent administration. The use of elevated doses of Chloromycetin in prematures and infant born at term but less than 1 month old has been associated with abdominal distension with or without eaesis, progressi\e pallid cyanosis, or vasomol 5'Uasomn# collapse, in some cases with fatal results. These adverse effects have not been reported in children with ~ggg~of,50 rag per kilogren weight per day or less. Interruption of the therapy has corrected the adverse effects in many cases, and the patient's recovery has been complete. PAGENO="0144" 15498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY SI ch:ccc~ccc:c c!cc fccicA!, P. 0. p dc.) cc cc cccsib)AOcc ccictslicc. sio,~:c~5ccpccc~ccc ~cccc.csicdsic El dIc!c c;ccsiccco cbccclcc ccc,' 5cc ccc ccci p sic cpccccccc cc llqc:dcc p ccjisicc dcl ocgccicccc. 000IPICACION V ACM9IISTRAC)0N 0cc çccccc', Ic ccpcc c:icicc ccc ci Ch!cccycccic cc cc icfcccic. .ccc.;cccys:ccciccc!c;ccc.cchcyccs.ccdcccccc.Cccccs cisc sic 25 cc;. pc. k::c dc pccc p pc. dc, c!~c ccc! sic Ch.cccccjcc:.c qcc ccc.!c cci.c 0 y 15 ;. Sc cc cc!cc,'cccccccsic.cccpPccccccccccccccc 5 g. c cclc. t~cc dccic ccccc ccbcc ccc cccycccc sic ccc hcccc, 9ic~ sic ccIcc ccccc ciccci.cAcAP sic c cccccccccccsic dc Cic.ccccycc:!cc cc Lc sic i.:cc!0. sic! Ch!cccccyccc.c pccc cc!ccccc p cPcc dc Sc cccc?cct.cc, cc Sc cccpcc!c cc cc 50 p l~ cc;. pc. ki!c sic pccc p pc. sis, cdcccicscc,'cc cc Ic:ccc,lcc sic c,sccc* s ccic hcccc. A! ccccccc~c cc ccccpsicc.cc cc ccc ccicccic cccccc cc pccdcc sciccc!ccccc cc 75 150 cc;. pc. c~c cc pccc p pcc ~ c:pccsic, ccc cicc,hcccicc sic 30 AOvcccccaA..-'-Lcccciccc pcccccccc $ p icc ccccidcc c cAccccicc sic sic cc ccc Ic cc!cd, c!cccclcs.ccc;c dc!ccic c icccccdccccc lc!c!c~.cc. cc. tcdcc ccc siccis 55cc c!cccdcc pcc c:Icc sic ccdc sdcd. Sc cA;ccc pccc cc cPcc pccccccccccc ccc siccflcAcisic sic ccc ccic dc 25 cc. ccc k!c;cccccsic pccc pcc cc, fccccicccdccccc,c, c :cccccc!cc sic ccc s ccccc hccc,. Pccc cc ccciciccisi,cc!cc sic ccccc sic cc ccc sic ,sicd ca cAgcccccc~ dcc;liccc,cc sic có cclc dc 52 cci. p;. 5'c'cc sic pccc pcc dc, )cccc,cccsisccccc cssccc:cc sic ccc c cc! l'.cccc Sc cc ccccs sic csicc.ccccc.c., pccc.,cc,'; 0 c.csic~~c~ cc ccc cci.b4~,cc dcbcc cccc,c ccccc 5Aic pccc 5c;!J,cc Sc dAc)ccc~c IND)CAC)ONcS CLINICAl Pu Cc'cccccpcct~ cc dccc cc ccchcc ccccsics C)csiac p ccccc cc!ccc'c!cc,c. si.ccc~cc5c Iccc:!c )c,.c;cc5c) p cc, ,ciccccccccc.si,,_;c ccc fcc.cc, `ciccc!cccc cic cc ccc cc-cc )ccc.cccs dcl cpccclc cccccccccc;c (ccccccp;5, bcccccccccc p pc cccc paciccc;: c, bc'ccclcc;c; .cfcccccccc ccc!cc,c p 51ccc, ccccicc:,j;, sic (Cclccc sic cc Ajccccccc Acccscc dilcc, sicccc Lcccicl jcpccccc) icfccclccc, cccdcc;c. Pc. is cccccc), .1 Ciclcccccpccc;c cc bcc tc!cccdc, p Ac cc,:i.ccc *clcccc,c pcccsisiccc sic ccc;cs *c cc ccccc sic cdccj',cccc, cc,ccp*cc,cccccc p!ccccc:dccccccccjccsi cc c!;ccccc ccccc ccc cccA;ccccc )ccc!cc Ac cc 5cc cc~c: lcciccciccccc.cccsiccc.) `Eac;pc cc,cc.cc cc ccccc~;c5c cc cfccCc cccccccc cc cccchccccicccccc. ENVASE cciccc,,pc,ccc cc ccccc.c'p cc cdpcclc, sic 250 ccc~. (95' 279), Ic scsi, (2724, cccc~,-~~ ~ ARKEc DAViS ~1D? ~ COMpA~1 Lcbccccccjcc Pccdlpc!cc Dccccl,, IcScIc;5,c, S. U. A Lcbcccccclcs Pcckc Cc/ic, S. A. S. Mcdcld 79 7 PAGENO="0145" Monografia cle Cloranfenicol La experiencia cilnica ha demostrado que el ctoranfenicoi (ChioromyCetin, Parke-Davis) es un antibiótico eficaz en una gran variedad de procesos infecciosos bacterianos y ricket- tsiaies. Eu actividad antimicrobiana es marcada atraviesa fácilmente as barreras orgánicas y se difunde rápidamente en casi todos los tejidos y liquidos del organismo. ACTIVIDAD V FARMACOLOGIA El cloranfenicol ejerce principalmente una acción bacte- riostática sobre un amptio espectrO de bacterias gramnega- tivas y grampositivaS y as también activo contra as ncket- tsias y los microorganismOs del grupo linfogranulorna-Psita- cosis. Es particularmente activo contra Ia Salmonella typhi y ci HaemolilUS infiuenzae. Su mecanismo de acción consiste en at entorpecimientO o Ia inhibiciOn de Ia sintesis proteica. que se verifica tanto en células intactas como en sistemas enzimáticOS aceluiares. En contraste con to qua ocurre con otros antibióticos, at desarrolto de resistencia al cioranfe- nicol, tanto experimentaimente como en et humano, parece ser reducido. Administrado par via oral, ci cloranfenicol as rápidamen- te absorbido en ci tuba digestivo y alcanza concentraciones determinabtes en sangre media hora después de su adminis- tración. La concentraciôfl méxima de cloranfenicol libre después de is administraciófl de Ia primera dosis ocurre generaimente en ci transcurso de una hora. El cloranfenicot as excretado principaimente por ci riiión, eiiminãndose en Ia orina entre ci 68 % y más dci 90 % de Is dosis; en Ia bills y en las heces se encuentran pequenas cantidades de cioranfenicot activo. El cloranlenicot se di- funde rápidameflte en casi todos los tejidos y liquidos del organisrno; pasa al liquido cefalorraquideo. sun en ausencta de inftamaciôn nienhngea. También aicanza concentraciOfles determinabtes en los tiquidos pleuritico y ascitico. y en a saliva y Ia secreción iáctea. Sc difunde rápidamentc en los medios dci 00. En Ia sangre dci cordon umbilical dcl tecién nacido atcanza concentraciOflea alga más bajas qua en a sangre materna. 3. Parke Davis new Cbloro.~cetifl Monograph sent to all international locations as basis for new labeling. kLO~L~ ~ 5 is~- P ~t ~ 3 MADRID - ESPAF~A ci 0 I PAGENO="0146" El palmitato de cloranfenicol es hidrolizado en ci intes- tino y libera cloranfenicol, y siempre que contenga ci poll- morfo eficaz da concentraciones sanguineas del anlibiOtico similares a las obtenidas con otras formas de cloranfenicol para administraciOn oral. El succinalo sOdico de cloranfenicof, administrado por via inlravenosa o inlramuscular, lambién es hidrolizado en ci organisrno y da cloranfenicol libre. Como el cuccinalo sOdico de cloranfenicol adminislrado parentéricamente es en parte excrelado como lal por ci riñón antes de que se ye- rifique su hidrOlisis, da concenlraciones séricas de cloran- fenicol libre más bajas que las que se obtienen con dosis equivalenles de cloranfenicol por via oral, pero clinicamenle eficaces. INDICACIONES El cloranfenicol, un agente terapéutico muy activo, no debe ser empleado en procesos infecciosos leves y debe ser adminislrado segün indicación e instrucciones médicas. El cloranfenicol está indicado en: Meningitis bacteriana. Fiebre lifoidea. Ricketlsiosis. Infecciones intraoculares. Infecciones causadas por microorganismos del género bacleroides, septicemias causadas por bacterias gramnega- livas. Otras infecciones graves en las que los estudios baclcrio- ldgicos o el crilerio clinico indican que el cloranfenicol es un antibiOtico adecuado. También es clinicamenle eficaz en: Disenteria bacilar. lnfecciones causadas por el bacilo de Friedlãnder. Infecciones eslafilococicas. Neumonias bacterianas. Gastroenlerilis infantil. Laringotraqucobronquitis. Brucelosis (fiebre de Malta). Psitacosjs. Tracoma. COlera. La experiencia clinics ha demostrado Ia eficacia del do- ranfentcol en Is terapéutica de procesos infecciosos en of- talmologia, otorrinolaringotogia y dermatologia. CONTRAINDICACIONES El cloradfenicol está. contraindicado en caso de ar'~: dentes de hipersensibilidad al mismo yb de rescc~c.;. xicas provocadas por él. ADVERTENCIAS Y PRECAUCIONES La administraciOn dcl cloranfenicol puede acompaCarse del desarrollo de discrasias sanguineas, inclusive anemia aplásica. Siempre que sea posible, es convenienle efectuar hemogramas antes de inslituir Ia terapéulica con ci cloran- fenicol y repelirlos a inlervalos adecuados duranle Is misma, especialmente en caso de terapéutica prolongada o intermi- lenle. Se debe considerar Ia posibilidad de inlerrumpir Ia ad- ministraciOn de clorantenicol si hay disminución de cual- quiera de los elementos figurados de Is sangrc imputable al mismo, contrapesando esle efecto con Ia gravedad y Is evo- Iuciôn del proceso infeccioso. Se deben evitar tralamienlos repetidos con ci cloranfenicol, ssi como su administración concurrente con otros fármscos que se sabe causan depre- sión de Is médula ósea y sun anemia aplásica. Se debe administrar ci clorantenicol segCin indicacion e instrucciones médicas, y no se debe emplear en procesos in- fecciosos leves. Como otros antibiólicos, ci cloranfenicol puede alcanzar concentraciones sanguineas excesivas a:. - ~`: dosis con- vencionales cuando se Ic admisistra . , -. ~r. issufi- cicada hepdtica 0 renal, inclusive Ia debida nrnadurez lislo- lógica en ci prematuro y ci recién nacido a lérmino. No se debe administrar ci cloranfenicol durante ci parto. El medico debe recordar tsmbién quc, durante Ia lac- tancia, el cloranfenicol Cs cxcretado en Is secreciOn Iáctea. Como Is de otros antibiólicos, Is sdministraciôn de do- ranfenicol puede acompanarse de superinfecciOn por micro- organismos no susceplibles, inclusive hongos. El cloranfenicol no es usa excepción con respecto a Is intcracciOn de fármacos; en consecucncia, en los casos en que se Ic administra concurrentemente con anticoagulantcs 0 anticonvulsivos, puede ser necesario ajustar Is dos.ificacidn dc cstos agcnles Icrspéuticos en conformidad. I' C C I LT.i 0 ITJ TJ2 ii 2 PAGENO="0147" REACCIONES ADVERSAS REACCIONES HEMATOLOGICAS: Se ha atribuido el desarrollo de -discrasias sanguineas. inclusive anemia aplásica, a Ia administraciOa de cloranfe- nicol. Se han observado dos tipos de depresiôn de la.nrédula ósea. lino de los tipos ocurre durante Ia terapéuttca. es re- versible con Ia interrupciôn de Ia misma y estd relacionado con Ia dosificacidn. El otro tipo, irreversible en más de Ia milad de los casos. ocurre rararnente, puede presentarse semanas o meses des- pués de terminada Ia terspéutica no estã relacionado con Ia dosificaciôn pero posiblemente con una predisposiciOn here- ditaria y puede evolucionar hacia una anemia aplásica que puede ser letal. La incidencia comunicada de anemia apId- sica varia en todo el mundo. También se ha comunicado Ia observación en casos de anemia hipoplásica, dv trombocitopeniia y de granulocito- penia consecuentemente a Ia administración del cloranfe- niC& REACCIONES GASTROINTESTINALES Pueden presentarse náuseas, vémitos, glositis y esloma- this, diarrea y enterocolitis; Ia incidencia en baja. REACCIONES NEUROLOGICAS Se ha informado acerca de casos de neuritis optics y de neuritis perildrics coincidentes, por 10 general, con un trata- miento prolongado. REACCIONES DE HIPERSENSIEILIDAD: A veces ocurren reacciones de hipersensibilidad. SINDROME GRIS: En prematuros y reciOn nacidos a lérmino han ocurrido reacciones tOxicas y hasty letales; los signos y sintomss que acompaCan a estas reacciones constituyefl lo que se conoce como "sindrome gris". Se ha comunicado un solo caso de sindrome gris en us niño de Ices meses. y otro caso Onico en - un i-ecién nacido a cuya madre se Ic habia administrado do- ranfenicol por via intravenosa durante ci parto. Los puntos siguientes resumen las caracteristicas del `sindrome grin: 1. En Ia mayoria de los casos en habia institurdo Ia Inca- péutica dentro de las primeras 48 horas de vida. 2. Las manilestaciones clinicas aparecierOn despuds de tres o cuatro dias de trstamiento continuo con cloran- fenicol, administrado segUn Ia dosilicaci5n conven- cional para adultos. impropia pars niños de esa edad y no tolerada por nIbs. 3. El orden de aparicidn de los sintomas tue ci siguiente: a) Distension abdominal con o sin vOmitos. b) Cianosis pOlida progresiva. c) Colapso vssomotor, frecuentemenle acompañado de respiraciôn irregular. d) Muerte pocas horas después de Ia apariciOn de las manilestaciones clinicas. 4. La evolucidn del proceso desde Ia aparictOn de las manilestaciofles clinicas hasta el exitus letalls fue lanto mad rapids cuanto mãs elevada Ia dosilicaciOft de cloranlenicol. - 5. Con frecuencia, en los casos en que en nterrumpiO Ia terapéutica inmedistamente después de Ia aparictOn de las manilestaciofles clinicas, el proceso ye invirtid, con restablecimiento completo del criOo. DOSIFICACION Y ADMINISTRACION Por to general en recomienda una dosilicacidn de 50 mg/kg/dia, fraccionsda en cuatro dosis administradas a inlervalos de seis horns. En casos excepcionales, comb los de infeccidn causada por microorgaflisfiuOs mnoderadamente resislenles o de intecciôn grave, como septicemia o menin- gitis, se puede aumenlar Ia dosificaciófl a 100 mg/kg/dia. Sin embargo. esta dosilicaciOn man elevada debe reducirse, tan pronto como sea posible. a criterio del medico. En casos muy graves o en los que Ia administracidn oral de cboranfenicol no es faclible, se puede admin~strar mnicral- menle el cborantenicol por via inlravenona o intramuscular en forma de succinalO. En tales canon se recomienda pasar a administrar el cboranfenicol por via oral tan pronto como sea posibte, a crilerio del medico. En casos de insuliciencia hepâtica o renal, Ia capacidad de metabolizar o excretar el cboranfenicol puede estar reds- cida. por to que el medico deberC ajustar Ia dosilicadmOfl en conformidad. - C) I-I 5 PAGENO="0148" PREMATUAOS. RECIEN NACIDOS A TERMINO V OTROS NIROS CON NMADUREZ F1SiOLO,3ICA. (Véase "Sindrome Gris~' bajo REACCIONES ADVERSAS.) Por io general, una dosificaciOn de 25 mg/kg/dia, frac- cionada en cuatro dosE administradas a intervaios de scm horas, produce y mantiene concentraciones sanguineas a histicas de ctoranfenicoi adecuadas para dominar is mayoria de as ntecc,ones en prematuros, reciEn nacidos a término otros niños con inmadurez fisioiOgica. Generalmente, des- pues de as dos primeras semanas de vida, los nacidos a tér- mino pueden toicrar una dosificaciór, maxima de 50 mg/kg! dia, fraccionada en cuatro dosis administradas a intervalos de seis horas. En caso de duda se puede verificar a concen- traciôn sérica de cloranfenicot mediante métodos analiticos. COMENTARIO CLINICO INFECCIONES MENINGEAS: Muchos microorganismos capaces de causar meningitis, especialmenta ci Haemophitus influenzae, ci neumococo, ci maningococo, ci astraptococo y ci estafilococo son suscep- tibies ai ctoranfenicoi, ci cuai pass at iiquido cefaiorraquideo aun en ausencia de inftamación meningea. No se puede de- morar ia instituciEn de ia tarapéutica hasta conocer los resul- tados de las pruebas de iaboratorio. Muchos clinicos consi- deran at cioranfenicol como ci medicamento de eiacción en casos de meningitis causada por H. inftuenzae, puesto qua casi todas las cepas de este microorganismo son suscepti. bies a dicho antibiótico. Sc racomienda is administracida parentérica da cioranfenicoi hasta que ci paciente sea capaz de tomar las formas orates dci antibiótico. RICKETTSiO5IS: La raspuasta at ciaronfenicol de los pacientes con una rickettsiosis, inclusive ci tifus exantemático, ci tifus murino, a enfermedad de Briti-Ziasser, ia fiabre fiuviai japonesa (en. fermadad de Tsutsugamushi), ia fiebrs de las Montaflss Ro- cosas, is fiebre 0 y is virueta rickcttsiai, ha sido espectacixiar, con ciiminación virtual de a mortatidad y scortamiento mar- cado de a evotución de Ia entermedad. Ei promedio de dura- ciôn dci periodo febrit dcspues de Ia inslitución de Ia terapeu- tica con cioranfenicot as da dos dies en ios pacientes con tifus exentemAtico. y de tres a cuatro dies en los pacientes con otras rickettsiosis. Se debe prolonger ci tratamiento du- rante cuatro dias despues de ia normatizsción de Ia tampa- ratura y durante no macos de seis dias en total. Los pacientes que racaen responden tan bien ai tr~tamiento como los pa- denIes con una infeccion primaria. o En os pacientas con fiebre de ias MontaCas Rocosas, Ia tamperatura se normaiiza airededor dat cuarto dia despues de inst~tuida ta terapéutica. Se dabe continuer at tratamiento durante 24 horas daspues de ia normaiizacjôn de ia tern- peratura. FiEBRE TiFOtDEA: Muchas autoridadas consideran ci cioranfenicci como ci medicamento da aiecciôn de is tcrapéutics de ia fiabra ti- foidaa. For io general, ia temparatura se normatiza tres o cuatro dies después de instituida Ia terapeutica, indepan- diantamenic de ia.edad dci paciente y da Ia gravadad o del periodo de avoiuciôn dci procako infeccioso. A fin da dismi- nuir Ia posibiiidad de racaida, as importante continuer Ia terapeut,ca durante ocho o diaz dias después de Ia normail- zscaOn de Ia temperature. No sa recomiartda ci ciorsnfanjcoi para ci tratam,ento de los portadoras da baciios da ia Ii. loidaa. OTRAS iNFECCiONE5 GRAVES: Cuando ci medico cuenta con los medios da iaboratorjo ~ rtccesar,os pare Ia ejacución corrects de pruebas de suscep- ~ tib,i,dad in vitro dci microorganismo infectante a los antibac. tarianos da qua dusponc, pueda decidir basar su uso dci do- rsnfanicoi sobra ios rasuitados de tales pruebas. Sin em- bargo, debe lacer prasanta qua se deben considerar ios ra- suitados de dichas pruebas sotamente como una guia pare is saiacciôn dci antibacteriano spropiado, ys qua an ciartas dtrcunstanciss puaden no scr fidedignos. como ocurre an ci ~ caso de is S. typhi OTRAS SALMONELOSiS En ianto qua ci ciorsnfenicoi ha dcmostrsclo ser un agante tcrapéutico Utit pars mcjorsr y scortar is cvoiuciôn clinics de las saimonciosis distinias de is fiebre tifoidee, toe rasuitados no son tan uniformes como en ésts. La duración recomen. dads dat irstsmiento as is misma qua pare is fiebre tifoidea. DISENTERiA BACILAR (SHiGELOSIS) V OTRAS 1NFECCiO- ~ NES ENTERiCAS: - 13 Si b,en las medides de sostén, como ia reposicion de ~ eiactrôlitos y Is hidreteclOn, son muy imporlentes, ci cioren- 14 fenicot puade contribuir e a erredicectén de toe microorga- nismos y at dominjo de a infecciôn. 7 PAGENO="0149" ENFERMEDADES VENEREAS: Ei ciorantenicoi es eiicaz en aigunaa e~termedades ye- néreaa, como ci granuloma icguinai, ci iinfogranuioma ye- nerco y Ia bienorragia reaiaienic a oiroa anIibiOticos. 0 SEPTICEMIAS: El cioranfcrricoi ha dcmoatrado aer Uiii en caaoa tie sep- ticcmia cauaada por microorganiamoa auacepiiblca at mismo. Ea particularmente vaiioao en caana tie aepticemia debida a bacteriaa gram negativaa. INFECCIONES DE LAS ViAS RESPIRATOR1AS: Debido a su ampiio capeciro bacieriano y a au capacidad - dc difuslAn en ci foco infeccioao, ci cioranfenicoi puede aer vaiioso en ci iraiamiento dc caaoa de iniccciôn grave tic las vias rcspiraioriaa cauaadaa por microorganiamoa suaccpii- bica at miamo. INFECC1ONES QUiRL1RG1CAS: 0 Las infeccionca quirtirgicas, como infccciOn de a herida operatoria, pcriioniiia o absccaos iniraabdominaics secun- t"t darios a perforaciOn intestinal, ciivcriicuiar o apendicuiar, ge- L~ ncraimcntc son causadas por microorganismos ausccptibics al cioranfcnicoi. Debido a us ampiio capectro bacteriano, qua cbarca pariicuiarmcnic todas las ccpas dc microorganismos dc los géncros Closiridium y Eacicroidcs, y a as capacidad de difusion en ci foco infeccioso, ci cioranienicol pucdc scr vaiioso en dichaa compiicaciones. En icics circunsiancias ac dcbc adminisirario, an a dositicaciOp recomendada, sOlo coma coadyuvanic tic Ia cirugis. OTRAS 1NFECCIONES: Sc ha observado asimismo qua ci cioranfenicoi as cficaz an a tcrapéutica tic varias oiras infccciones, coma La bru- cctosis, barionciosia, ficbrc recurranic, pcaIc bubOnica, paiia- cosis, tracoma c infcccionca causadcs por microorganiamos ci tic Los géncros Bactcroidcs y Ciostrictium. ci TAI.1,5555 cRaflcns is- us an inc -nnsunn.-ysg.n di I. Fmc5n, 23.-Mndfld -27 a . I-n Ot C;' Co PAGENO="0150" C)1 ~ \~ 73 ~ZS ~ ~s~'t ~ J 0 Clinical use has established chloramphenicol (Chlororny- cetin*, Parke-Davis) as an effective antibiotic in a wide variety of bacterial and rickettsial infections. It possesses high anti- ~ microbial activity, crosses tissue barriers readily, and diffuses l~ widely and rapidly through nearly all body tissues and fluids. Chloramphenicol exerts mainly a bacteriostatic effect on a ~ ~ 7(~R~V~ ~ ~ bacteria and ~d ~ ~"~" ` ~"~* ~ ~ ~ ~ lmo If ~yph ~ y Th rno~e of chlornmphenico), Parke-Davis) action is through interference with or inhibition of protein ~4 synthesis in intact cells and in cell-free systems. Development ~J of resistance to chloramphenicol, both experimentally and in man, appears to be tow in contrast to other antibiotics. Chloramphenicol administered orally is absorbed rapidly from the gastrointestinal tract, producing detectable concen- 1-4 trations in the blood within one-half hour after administration. !~ Average peak serum levels of free chloramphenicol after the first dose generally occur within one hour. The principal route of excretion of chloramphenico) is through the urine, total urinary excretion ranging from 68 to over 90 percent. Smalt amounts of active drug are found in the ble and feces. Chloramphenicot diffuses rapidly through- ~ out tissues and body fluids. Chloransphenicol enters cerebro- spinal fluid even in the absence of meningeat inflammat)on. Measurable levels ace also detectable in pleural and ascitic fluids, saliva, and in milk. It diffuses readity into the aqueous and vitreous humors of the eye. Transport across the placental barrier occurs with somewhat lower concentration in cord blood than in maternal blood. Chloramphenicol Palmitate which contains the effective polymorph is hydrotized no free chloramphenicol before r absorption..Resu)ting blood concentrations are similar to those produced by the administration of other oral forms of chlor- amphenicol. PARKEDAVIS Chloramphenicol sodium succinate when administered intravenously or intramuscularly is also hydrolyzed to free chloramphenicol within the body. Part of the parenterally PAGENO="0151" administered chloransphenicol sodium succinate is excreted by the kidneys prior to hydrolysis and, although serum levels of free chloramphenicol are tower than when a comparable dose of chloramphenicol is given orally, they are clinically effective. lNDCATlONS Chloramphenicol is a potent therapeutic agent and should not be used for trivial infections. It should be administered according to the instructions of a medical practitioner. Chlor- amphenicot is specifically indicated for: bacterial meningitis typhoid fever rickettsial infections / intraocular infections bacteroides infections septicemias due to gram.negative organisms other serious infections where bacteriological evidence `kn~ ~ or clinical judgment indicates that chioramphenicot is an appropriate antibiotic. .5 It is also clinically effective in: bacillary dysentery - infections due to FriedlSnder's bacillus j.,. staphylococcal infections -, - .- bacterial pneurnonias infantile gastroenteritis laryngotracheal bronchitis undulant fever IBrucellosisl .. psittacosis " trachorria cholera Clinical eperience has demonstrated the value of chloram- phenicol in the treatment of infective conditions in ophthal- mology, ototogy, and dermatology. Chloramphenicol is contraindicated in individuals with a history of previous hypersensitivity and/or toxic reaction to the drug. .4~\I .~ Blood dyscrasias including aplastic anemia may be associat- ed with the administration of chtoramphenicol. If facil:ties are available, it is well to determine the routine blood profile ~ before therapy, and blood studies should be repeated at appropriate intervals especially during prolonged or intermit- tent therapy. Consideration should be given to discontinuing the drug if evidence of depression of any of she blood ete- ments appears attributable to chloramphenicOl, weighing these effects against the seriousness and course of the disease under treatment. Repeated cosrses of chioramphenicol and ~` concurrent therapy with other drugs known to cause bone marrow depression or even aplastic anemia should be avo:ded. CfilorampheniCOt should be administered according to the direction of a medical practitioner, and it should not be used for the treatment of trivial infect!ons. ~ ~ -`V Encessive blood levels, as with other antibiotics, may result from administration of the recommended dose .to patients with impaired liver or kidney fanction, including those due to immature metabolic processes in the premature and full-term infant. Chloramphenicol should not be administered during labor. The medical practitioner should also remember that chlor- amphenicol is excreted in the milk of the lactating mother. As with other antibiotics, the use of chloramphenicol may result in an overgrowth of non-susceptible organisms including fungi. Chloramphenicol is not atone in the phenomenon of drug interaction and when patients are concurrently receiving anti- coagulants or anticonvulsants, dosage adjustment of these agents may be necessary. HEMATOLOGICAL REACTIONS: Blood dyscrasias including aplastic anemia have been attri- buted to the administration of chloramphenicol. Two types of bone marrow depression have been observed. One type may occur during therapy, is reversible on cessation of treat- ment, and is dose related. The second type which may occur weeks to months after therapy is rare; it may be genetically related, and is not dose I. 3 0 PAGENO="0152" related. In more than half of the cases, it is irreversible, It may lead to aptastic anemia which may be fatal. The reported incidence of aplastic anemia varies throughout the wortd. Hypoplastic anemia, thrombocytopenia, and granulocyto- penia have also been described following administration of chloramphenicol. GASTROINTESTINAL REACTIONS, Nausea, vomiting, glossitis and stomatitis, diarrhea and enlerocolitis may occur; incidence is low, NEUROLOGICAL REACTIONS: Optic and peripheral neuritis have been reported usually following long-term dosage. HYPERSENSITIVITY REACTIONS: Sensitivity reactions are sometimes encountered, GRAY SYNDROME, Toxic reactions including fatalities have occurred in the premature and newborn infant; the signs and symptoms asso- ciated with these reactions are known as the "gray syndrome". Single repoits have appeared in an infant as old as three months, and in an infant born of a mother receiving chlor- amphenicot intravenously during labor. The following points summarize the studies of the "gray syndrome". 1, In most instances therapy has been instituted within the first 48 hours of life. 2. Symptoms first appeared after 3 to 4 days of continued treatment with conventional adult dosage of chloram- phen:col not tolerated by and incorrect for this age group. 3, The symptoms appeared in the following order: a. Abdominal distention with or without vomiting. b. Progressive pallid cyanosis. c. Vasomotor collapse, frequently accompanied by irregular respiration. d. Death within a few hours of onset of symptoms. 4. Progression of symptoms from onset to exitus was accel- erated with higher dosage schedules. 5. In some cases upon early recognition of the ansocfated symptomatology, termination of therapy frequently re- versed the process with complete recovery. Dosage of 50 mg/kg/day in divided doses at sin-hour intervals is recommended for the average patient. in excep- tional cases, such as with patients having infections due to moderately resistant organisms or suffering from infections such as septicemia or meningitis, dosage schedules up to 100 mg./kgJday may be prescribed. However, these high doses should be decreased as soon as clinically indicated. Chioramphenicol in the form of chioramphenicol succinate may be administered intravenously or intramuscularly in seri- ously ill patients or under conditions in which the patient is not able to take the drug by mouth. In such instances, it is highly desirable that the physician change over to orally administered cloramphenicol as soon as is practicable. In instances of impaired hepatic or renal function, the ability to metabolize or excrete chloramphenicol may be reduced and the medical practitioner should adjust the dose accord- ingly. PREMATURE AND NEWBORN INFANTS AND CHILDREN WITH IMMATURE METABOLIC PROCESSES see grny syndrome under ADVERSE REACTIONS) A total of 25 mg/kg/day divided into four doses at six-hour intervals usually produces and maintains a concenlration of chioramphenicol in blood and tissues adequate to control most infections in premature and newborn infants and children with immature metabolic processes. After the first two weeks of life, full-term infants ordinarily may receive up to a total of 50 mg/kg/day equally divided into four doses at six-hour intervals. Precise control of serum blood levels, when in doubt, may be achieved through analytical methods. - `S~N ~ MENINGEAL INFECTIONS, Many microorganisms causing meningitis, especially Memo- philus inffuenzae, pneumococc, and meningococci as well as streptococci and staphylococci, are susceptible to chiorarn- phenicol. The drug enters the cerebrospinal fluid even in the absence of meningeal inflammation(jnstitution of therapy cannot be d~layed until results of laboratory tests are known) ;`~ `~ Many clinicians consider chioramphenicol the drug of choice ~. for meningitis caused by Hemophilus influenzae...gy virtualjy- all strains are sensitive to this antibiotic. Parenteral ~0mg6'is recommended until the patient is able to take oral medication. ,. -.~ 5 I' C,' 0 w t~rJ l~l2 PAGENO="0153" RICKETTSIAL DISEASES: The response of patients with rickettsial infecttons, including epidemic and marine typhus, Brilf-Zinsser'S disease, scrub typhus, Rocky Mountain Spotted Fever [spotted fever, tick fever, tick typhus (England), Fiebre Petequ:al (Colombia), Febere Maculosa (Brazil)), Q fever, and rickettsial pox has been dramatic with virtual eliminalion of mortality and marked shortening of the course of illness. Average length of febrile period after administration of chloramphenicol is 2 days in patients with epidemic typhus fever and 3 to 4 days in those with other rickettsial fevers. Treatment should be carried out for a minimum of 6 days or 4 days after the temperature returns to normal Patients in relapse respond as readily to treatment as do those with primary infection. In patients with Rocky Mountain Spotted Fever, deferves- cence of fever occurs about the fourth day after therapy is started. Treatment should be continued for 24 hours after normal temperature is attained. TYPHOID FEVER: ChloramphenicOl is considered by many authorities as the drug of choice for this disease. After therapy is started, fever generally subsides in 3 or 4 days regardless of age, severity of illness or stage of disease. To lessen possibility of relapse, ills important that therapy be continued for from B to 10 days after reaching the afebrile period. Chloramphenicol is not recommended for routine treatment of the typhoid "carrier state". OTHER SERIOUS INFECTIONS, When facilities are available for the accurate performance of in vitro bacterial sensitivity tests against the infecting organism, the medical practitioner may wish to be guided in his use of chloramphenicol by the results of such testing. He should remember, however, that the disc and other sensitivity methods are to be regarded only as a guide to appropriate therapy since in vitro tests may, under certain circumstances, be unreliable such as with S. typhi. OTHER SALMONELLOSES, While chloramphenicol has proved to be a useful thera- peutic agent in ameliorating and shortening the clinical course of salmonella infections other than typhoid, results are not as uniform. Recommended duration of treatment is the same as for typhoid fever. DYSENTERY DUE TO SNIGELLA OR OTHER ENTERIC PATNOGENS: While supportive measures such as electrolyte and fluid replacement are most important, chloramphen:col has served to eradicate the infectious agent and to control the infection. VENEREAL INFECTIONS: ChloramphenicOl is effective in some venereal infections such as granuloma inguinale, lymphogranaloma venereum, and cases of gonorrhea resistant to other ~ SEPTICEMIAS: ~ Chloramphenicol has proved"lIseful in septicemias due to microorganisms susceptible to its action. It is particularly valuable in gram-negative bacterial septicemias. RESPIRATORY TRACT INFECTIONS, Because of its wide antibacterial spectrum and its ability to-, diffuse into infective foci, chloramphenicol may be of value / ,3Jr)f in the treatment of severe respiratory tract infections due to ~ susceptible microorganisms. SURGICAL INFECTIONS: Surgical infections such as severe post-operative wound infections, peritonitis, or intraabdominal abscess from ruptured intestine, diverticula, or appendix, usually are due to micro- organisms sensitive to chloramphenicol Again, because of its wide antibacterial spectrum, including particularly all stra:ns\ of clostridia and bacteroides, and ability to diffuse into infec-t~'. tive foci, chloramphenicol may be of value in such complij r Administration in the recommended dosage should be adjunctive to surgical intervention. MISCELLANEOUS INFECTIONS: ChloramphenicOl has also been found effective in the treat- ment of brucellosis, bartonellosis, relapsing fever, plague, ~~tacsi trachoma, bacteroides, and clostridiat infections. ci 6 PAGENO="0154" 15508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 14. Dr, Harry Dowling's "opinions, not proven facts" on the new Monograph. ~ :~D~c~ti~ HARRY F, DOWLING. M. 0. GREAT FALLS VIRGINIA 22O6~ T~~EPH~~R7593I2Q November 25, 1973 Prof. and Mrs. Alvin Sander 3 Harvard Place Ann Arbor, Michigan ~8lOk Dear Mr. and Mrs. Sander: I apologize for taking so long to answer your letter, but I have been on an extended vacation since it case andhave just gotten to it. In general, pharmaceutical firms are not likely to restrict their claims in labels and advertisements unless they are specifically required to do so. Pressure from the medical profession and the public has some effect, but usually not as much as that which r'sults from the require- ments of a regulating agency. As I have shown on page 252 of my book, "Medicines for Man" (Knopf, 1970) advertisements in the leading journals in England were not as completely informative and balanced as advertise- ments for the ease drugs in this country. Although professional ethics and social consciousness are at as high a level in England, their regu- latory agencies do not have control of advertising. In the southern European countries, such as Spain, one has the impression that almost anything goes with respect to advertising of drugs. Public opinion and professional attitudes lag well behind those of Great Britain, Hol- land, the Scandinavian countries, Canada and the United States. This is reflected, as you have indicated, in the advertisement for chlormm- phenicol which you sent me. The open,ing statement that chloromycetin has therapeutic activity against a grest variety of pathogenic micro-organimms would probably not be allowed in an advertieement by the FDA because, leading off as it does, it immediately gives the impression that the antibiotic should be used in many infections. The information about the gray syndrome (paragraphs 5, page 1,and 6, page 2) is not adequately explmined. It results from the fact that the kidneys of infants do not have the capacity to metabolize chloramphenicol, thus allowing it to build up in the blood to dangerous concentrations. Full disclosure requires that doctors be warned not to use it in thie age group unless absolutely necessary and then only if the concentration in the blood can be monitored. (In this respect, the American version is probably deficient). The symptoms of the condition should be given in detail. The rarity of the blood dyscrasias is stressed in the Spanish label- ling, without a parallel explanation of the fact that aplastic anemia fol- loving the use of chlorasphenicol is almost always fatal, and, as you indi- cate, usually continues even if administration of the antibiotic is stopped. PAGENO="0155" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15509 The aplastic anemias and other fatal blood dyscrasims should be sepa- rated out from the depression in the number of lucocytes which can be detected by blood counts and which disappears when the chlorsmphiCol is discontinued. Many people believe that these are separate entities. At any rate, it is questionable whether frequent blood counts will ever alert the physician to the appearance of aplastic anemia in time to pre- vent death from occurring. If the drug is to be allowed on the market at all, there should be a conspicuous warning about these serious blood cyscrasias as in the American labelling. In my opinion, no ~ diagnosis (including typhoid fever) should lead the physician to select chloramphenicol as the drug of choice today (since some other safer drug is available for for every condition in which it could be used, and the other drug is just as good or better than chlorasphenicol. This includes ampicillin for typhoid fever and tetracycline for H. influenzae meningitis). Ac- cordingly, chloramphefliCOl should be a secondary drug, to be used only when bacteriologic evidence shows that chloramphenicOl is effective against the pathogenic micro-organism causing the disease while other safer antibiotics are not effective, or in cases where the patient is hyperseneitiVe to the other antibiotic. The American labelling takes this into consideration. In summary, I believe that the Spanish labelling is not comprehen- sive enough with respect to indications and adverse reactions, that it should contain a specific warning regarding severe blood dyscrasias in a conspicuous place, and that, as it stands, it suggests that the drug should be used for sany infections for which I do not believe it is indicated, and that the present labelling will encourage overuse of the antibiotic. I sympathize with you in the deep sorrow which follows the tragic death of your daughter and admire the way you are respondiag so cod- structively instead of giving way to despair. I hope that your efforts will bring much-needed reforms. - Sinc.rel7,~/ ,~ ~ / ~~arr~ F.~Dowling PAGENO="0156" 15510 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY HARRY F. DOWLING. N. D. 208 BLISS LANE GREAT FALLS, VIRGINIA 22066 TELEPHoNE 758-3120 December 19, 1973 Prof. and Mrs. Alvin Zander 3 Harvard Place Ann Arbor, Michigan 48l0L* Dear Mr. and Mrs. Zander: I have no objection to your quoting what I wrote, so long as you make it clear that it isrnL.~ojnjon and not what I consider to be oroved fact in eve For instance, mosU~eai~ri~j eieV~ that c1i1~i~- a~henicol is the drug of choice for H. inluenzae meningitis, because many articles have been written about its use and they consider tetracycline more toxic for infants than chloramphenicol. Also, everyone does not agree that blood counts may not predict the onset of aplastic anemia in tine to keep the full-blown disease of aplastic anemia from developing. In answer to your question, I do not believe that working for a stricter U. S. label would be very valuable in controlling labelling abroad. Rather, since the U. S. label now contains statements that should be on labels abroad, the best thing to do is to push for them. With regard to the longer monograph, I have the following criticisms: (1) The second paragraph on page 1 does not distinguish between in vitro susceptibility and clinical effectiveness. it starts off talking about bacteriontatic effect and ends with a clinical judgment, that it is particularly effective against Salmonella typhi and Hemophilus influonzae. This gives the impression that the drug should be used for any of the con- ditions in the total list. (2) On page 2, under indications, the statement is made that "chlor- amphenicol is specifically indicated for" and this is followed by some spe- cific indications, such as typhoid and rickettsial infections and some very general categories, such as bacterial meningitis, It is of course not spe- cifically indicated in all types of bacterial meningitis. The same criti- cism applies to ifltraocular infections and septicemias due to gram negative organisms. The next list of infections should be headed, "lt is sometir'.es clinically cffective in: The last paragraph about infective con- ditions in ophthalmology, otology and dermatology is so loose as to be al- most ludicrous. in other words, I do not think this monograph as it stands is the prop- er basis for good labelling. Sincerely, PAGENO="0157" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15511 5. Zanders' comparison of new Monograph with U.S. label. * Oonpnxisoon ot the Parke-4),wia Nowly..Beviaed Ohioromycotin Monograph l~1.~.nt to All International Tjocattonr, end the Parke..Davie U.S. lorooayce~.n label ~ (end Physioians'Conaentm). k A great laprovemeet war*iag of fatal aplastic anemia and against trivial use. Sow- ever. The United Statee label boginc with a very strong, boxed, and at timee underlined WA1~NING that cartons cad fatal blood dysorotnias, including aplastio anemia are known to occur after adninietration of ohlorampheniool, that it ao~t not be used in trivial illnesses or when not indicated or an a prophylactic to prevent bacterial infection, and that blood etudtee during treatoant are eseential. In contrast, the Parke..Daviu Monograph begins with a very poeltive descriptive stetenent on ties drug: "Clinical one baa ~atablinhed chloranpbenicol (Clelorowycetin, Perke-Davie) as en effective antibiotic in a mido variety of bacterial and richett. sial infeciione~ ~L'rio U.S. denoriptire etatement which followe the WDSIINP box, on the contrary, in in eceentially restrictive torus, stating that it is an antibiotic that " should ha renorved for ncriouo infections caused br ol(vnioms cunceutible to its ateeJoicrobial citoets shea lone potentially haordoue thnrnpcutio agents are ineffective or contraindionted. Sensitivity tenting in eceentini to deternine ito indicated use, but way be perforued concurrently with Therapy initiated on clinical impression thatbne of the indicated conCtitione exinto (son "indication" e~ctjo~).~ Parke-Davis Coon diecuss adores bcaatologicel reactions from use of ~loraayeettn including ap~antie encrein but in general the Ifonograph downplsye both the ioticicnoo and rtortality rate of irreversible aplentic nnooin cad ~voo lees detailed infoawotlon Than the U.S. label so t1,nt the ireportonee of thin adverse reaction is diwinishod. She one good irepartent principle of use that Pate-Davis ctaten clearly, but without the U.S. e~aaplee end crnphaeio, ire that Chlororoyoetin ohotild not ho used for trivial ilinennee. However, thin in not onnuØl. Ae we underetared it, the baoio concept of the U.S. label is tiart because of the ponnible udverne reactions, enpecinily the cartoon and fatal hcuntologiorrl reactions, use of ~hlororeyeetln nienuld be restricted ovon in trereteront of serious dinonsos to those which cannot be treated by any loon potcntially irazordoun drug road that t'rle need for Chlorowyoettn caret be dotarained by prior eenreitivity tasting of The rrr~cro- organism involved (except for a Low very aerioue conditions whore initial twectoent with Chlornreyoetin way ho lnr~itntod concurrently with sensitivity tooting in crier to change to another loon hasardores therapeutic agent as soon us pocerible) and its use must be eooorrpzuiied by blood etudico, preferably uhilo the patient in in a hoe- pita). In contrast, the Parke-Dale 1~enogrwph, instead of coarsely vsnt'detlug one (except for trivial illoorrese) in rio crooner in vwhieh it is now reotrietoci in the U.i3~, otill ocean to us to eaccvavrree uronceosrarsy urn. The najor oint of the U.S. label is to restrict urncecsar~y use are rsreoh as possible in orrJos to Unit the reasebor os: w'neeeoanry aplartic eac.sin aceDia. tno Pnrkv-v)avin 1 w;:rw:~h papa irecavice to the U.. basic principle b~ listing the adverse ranctirsia (ertreout Thu oatreoo)g * c have re yes:' thtre1le'l cuarrosrutive orurlycie ic bsr: urn Ui vUowsy `Lairarur ~. PAGENO="0158" 15512 COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY strong U.S. warnings) but rejecting the U.S. method end princinle of restricting v.nneoessary woo and, in fact, in many subtle end some not.so..subfle ways encourag- ing such use in the Indications and Clinical Diooueeion sections, their initial description of the doug, and throughout the Monograph. The Monograph beik. implies many more Indications for use 1) in listing and discuesin~ diceasea in which Chlorr.. mycetin is "effective", " of value", and "useful", 2) by using much broader disease terms such as "intraocular infections", "infective condittons in ppthslmology, oto- logy,. and dermatology", "respiratory tract ~ and "surgical infeotionc", and 3) sometimes by more epeoifioal~y naming a disease that wcsl].d not be included in theU.S. Indications such as "lwryngetrachosl bronchitis", Another way in which the Monograph encourages greater use in by omitting other important negative facts in the U.S. label which would restrict usc, such an $ 1) that blood studies do not ~)Prec1ude the later appearance of Irreversible tin onemia~ 2) that blood dys. crasiae have occurred after both short-term and prolonged therapy, and 3) that there are reporta of aplastio anenia attributable to ch]orncphenicol which later terminated in leukemia, and by omitting U.S. instructions: 1) that repeated courses of the drug should be avoided whenever possible, 2) taut chlorcmphenicol must not be used as a prophylactic agent to prevent bacteria], infection, and s) that troatcent should not be continued longer than required to produce a cure with little or no rink of reiapme, We have also solicitod idic vices~ of wonbere of the uodica) profession to oonfim or correct our )udpycent. Tho -iwo doctors that have nlrondy responded have the sane bacio reaction to the Monograph as ours. A benatologint friend strongly criticised the Monograph moatly for its otyle, saying it is written more to sell Chlorozyoettn than to edueato the phyeioian in ito proper use. So said if the com- pany bad wanted to educate thepbyeioisn, they `would have started the Monograph with a strong ~Terming and given wore prominence to statements that it should not be weed for tri'yinl i],ineeseo, The section on Indications is of ton only indicating where Chloronycetin is effective; for awry of the conditions it should indicate use other drugs if they had taken iota aeoouat the rick/benefit ratio, in his opinion. Me fools Parho.~avis misused the word indications, often indicating condittono where it "nay be uceful" circa other ncidjejries should be urod first. He calls attention to the fact that the U.S. label begins the Indicatioru section with a ospitolired statement of the very restrictive principles governing use of Obloro- nycetin, which is titally lacking in the Parke-]krvia Monograph. A physiologist Ct~end nice thinks the Monograph and the U.S. label arc very different, saying `that they rot only differ factually on acne inportant Points but in particular and moot important, they differ in tone; the !!onogrsph essentially osying that there are lots of places to wee Ohiorcerycotin, ~ a groat dreg and the U.S. label snyin~~ to be very coo'ful, only use it under very special circur. stances. ~e elco says that many of the Indications ( or implications for ladicer. PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15513 ostione under both ~ndiont~oo0 mmd Clinical ttte~ scion) core either not iuo~nded in toe UstofU.S. IndiccottOnO or could only possibly be in~ludoti under the Ld. general indication of sestoun infcctiofl8 which, Itoocerer, the U.S. quoclidies with the phrase ` for which leon potentially deongerouc drugs are irceffootive or oontr.' jrcdicatod", a very icoportnnt r tmtcttve ctencrczl qwciificotion Paske~Dnvi5 doec not wonton, Another doctor friend ~I o~ib~d the Hanograph en `l~ou~ly written~t ~. the ~wOPh'0 IcoditocottonO end, Z nosemo, topliontionlo for use pith a epeolaliot in infectious cliseacea. Until we obtwtn thin cerport opinions our comments cocod conpnricon should be aonsid~red the personal rocotton of lepn'c? not vnll~infozeted on classification of dioooxeee, for iesotwoow. Another hematologist comsentin'~ on the bematol.ogical warnings in the !¼lonogrectth said that what the Monograwli states is true but it is so soft wcd~lled it will be relatively incffective in restricting uae compared to the U.S. label. Again the comment was made that it is not what is said but how it is said. so that there is not enough emphasis on adverse effects. ( is jsteetous diseases) ~ ~tiU another dootor,wilo did not consent on the whole L!onopraph, seemed to agree ocith~tectiono in ties Clinical ~.scuseion dealing with the very serious diseases specifically listed in the U.S. lmbelçwhich warranted initial use of ohloraapheflicol with concurre~et té~ting~ even thourh ~or some he stated that there were equally effec- tive drugs. He criticised the Septicemia section as warranting more information end concluded that in some instances the information ice general and disappointinply brief and would like to see the Company a~ephaeizo more strongly that chlorcnphenisol is not an agent that should be used for the treathont of obids or for fsvers. Asether doctor in eoamanioable diseases felt that the waraisga and descriptions ef adverse affects ate clearly presented is the Monograph but agreed that a stats- test àf'~warai*g en the eontsinera sold overseas "would be huaane". Another differonof. between the Porke~Sasto 1eonoprwph for other couhtrico and thoPnrke-~lsViC U.S. label is in the cmonncr of adsintatmtion of Obloromycotin Sue- otnats. ~scc Liocoogruph doscriboec intromuculor use of Chiorosqieotiel Secciiceato no "clinically effective althowik ts~m Levels cf free eblorempheesoicol are lower then when a cosparoblo dome of oh~Les~phoflioO1. is given orally." Xn oontxsoot, the U.S. banned inlwsenuscoclor ndntnintrfstioel as iadffoctivo, apprcoving only intravenous parenter'4 aclthnictrntion, PAGENO="0160" 15514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A gantroenterolopint who beltovee that Chlorroycetin ohoul d he ured for the treat t!nt of tootediately life tbrnaterth'- infeotione ouch no t~hoif fever rod for no ~ then' infectiouse candittoen unleen the reenoneible orgenion in clearly identified, han been danonetrote. at tetno oonoitiva only to ohiorno honicol, nd tf the clinical eituntion in ranch that the rdnk of eitholdlnq treatment in enter than the rink of Ste edmiaielration yet onlires that there eve arditi:no notably in boutheat Ae~ there there a a rave ehortne of rhyniciana and there difforont criteria may nnply (taioua he hesitater it content on t eee without local inrwledpe) but to teen not see why rentrictionn on the use of ohloranohenicol in lit. low nhonld be loonened `hen it coate t- countrien etch en (}errcny, En;ftand or 5pain adore the rroblem of physician deneity end nhyeinion coveratro in not ntrt1kin~-ly different tan it in in this country, aekee the folloelno oonaentt on the na l-crke..Devie anterialas l)to far ar the new 1bno~mraph is concerned, it Ii ~udrnent it it' not ruffioient to confine theindicotione to oonditione which eve htnot trirtol ", Pot trivial ie one thin-a and life threatening ie another, Moreover, i ny judnont the ?tonocçrnph itt deftciont in that it fatlo to make clear that it roar tnntnnoen al tentative eodrl itier of treotnont nay he available which ore equally effective and eaton. Since this it an area in hioh he in' not to ex~ pert, he eo'aate ott morn) tint `n expert to neeti-na itearn, Es to particularly conceroed obaut haclonioiooa and rn'auaoeoncnl Lnfeotione. 2) to for at t a ret itpenieh label heeed i-n the no Sono-raoh in enneerned, he rays it contains a rnrning but it ie nai titer loud zion' clear. It' a ohrenl pa' i neat on ortttna'rr' `-a that of it a 2,2, ova-Bunt and he aeee no renoon hr it obou'O nt he. Me also orittoirno the clonint: etatenent 4Jor oonalete iontnaoti,o on voneribin oonntil t the t duct or -v rh, available at the raqueet of a ohycicion. ~, nay op that he ft-ala that it to not the reponoihitity of the physician to have to write to the mnpany nt any Bathe oonn-arning adverse reaotionw. einoe thin plocen the ranprcrtbtliira on the rhoodoron- tin thy4otaa which in clearly that c$ the nnnufnctto-cr, 3) Ho ga-ar on ta oat-rent n tin nra-a t5raal rnat-nrte.t-, In perticular that of thloroatrep, rhich appenro to ho a onnt:'nied -ronotionti. campaign in which Chioronmycetia in in foot o.ntined `i th another nmtthiotic, A furthar oonoern of hi, in toot tue o:-znottncl materIal `toes not arnttnn ofreree tOtOti an, Ha feele that if theae advert-c ranctions a-n-' anythtnr other than trivial It rhoul t, both in thin and other inotaran. Bin nntntef out tint it n-tnt- uneful to st-he a door `immttno- tics bet-eta oroeotiooal literature sneirana-that nit end werninio inoerted in tie pathetic homier-or ctrnt tFean a-arein:r say to, In othor words an coat-restive proxeotional ceoont~u cannot he otatnet by ron nontly outplayed -entrain c onee tao package in port. charmed, The -otnotionol. r.ntrtal in teen b: anny~ the tnrrntn:e aro oeen b few. He fount it difficult t- uator~ cart "by tiepron ntiuanl natori at should he allotted to to continue in the non r La »=ioh ii to doot with Uhloruntrep, zr inatnnee, in tapais. laokaaao ioevrto not,- cv - :oy not itoet the let Ion' of the low, Thea- roroly neat the enirit of tie low, tIc crporieoce `fIb odtcarotte ndvertioing may be ut-ed to illuntrate the point, Us o nnidorcd Barn `hrnniih `hi oron mop pu--tar partfoolnrlv `-tfaz-aive and would waznl:. out-pat t lint aft tu.hLc4ian aver to name Ot Xnrke.zetnic So brough to the attv.ntion oP npuropri e legi dotty. authur-iiica. PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15515 6. New Parke-Dab~s Chloromycetin S~sanisb label based o~i new Monograph, July 1973. ~ ~ (jVrnL5~O' A In Porooldn Medico: El Chlornmycello Iclorantenlcol Parko.Davls) es urn antibldtlco crlstsllzado con actlvldad terapCullca contra una gran nanladad do microorganlarnos patdgenoo. El Chlproonycctlo so absorbs muy blon per vIa oral p da r)pldamenta con. ceotraci0005 ollcaces on los llquidos y telldos dcl orgaolamo. 000u°ICACION V ACIMINI$T55ACION Por lv 000sral an recornlerda urn doolflcarldo do 50 mg/kgfdla, fracclonada ao cualro decis adoninislrodan a lnlrreo'ulos do solo horos. En Cases eoCcpclo' rules, cvlue Inn ole lnlcccidn caunadu poe uclcronrgani$moo nooderadanrenta reclelenloc a do Irlecclolu sraus. coons seplicemla 0 nooningitis. so puedo aumennar Ia doslflcaolSn a 500 mo/ko/dla. SIn embargo, cola deslticaoiOn mds elcouda debo roduclnso tan prunlo cemo sea poelbie, a cnllerla dal moldico. Encacos do losuficiercia hepdtlca o canal, Ia capacldad do metaluolloar sucrelarel cloranfonlcol puede color rcduclda, Poe lo quo ol coddles dcbsrd aluslar In dosificaciOn en confnrnnidod. lie coos do duda p Si as disport do los modius laboraterlu. so pucdo ucrilicar a concenteaclde serlca do cloranfa elcol nnedlanls moltodosanallnicos. Pnernaturos, rodeo naclolos a ndrmluo p cOres ohms con lnrnadurez OlslolO glca. lVdase ~Sindromo Gnls~ bale retool ones adoortoc.l Poe Is gonenal, une clotlflcacldn do 25 nms/kg/dis, nrocciorada en Cuatro do. sis admlululuudoo a irtorvo los de eels horns produco p marllons cnncontra clones oanuu locus e Irieticas As cloouulenicol odosuodas puns domirar Is ma yorla do lao irbeccionns en prematurns, recOIn cucidus a térmioe y otnos piPes con lnnladaeez flololAgica. Goneralmonte, dospuds do has dos pnirneres aomanas do olda lou nacldue a ndrminu puedon tolorur urn dcsiflcacipn rn) dons do 50 mg/krj/dla, fracciovada en cuatro desls admlnistradas a irtervalns do solo horas. En caso do duds, so ponds nodS loan concentraclde series do cloraufonlcol modlanto mdtodos analltlcos. Por rezenos menclonadas pestsnlonrnenta (vor sindroma sets) aaosa dads no debsedn see ndrmalmeule oscodidas, INDICACI0500 CLINICAS El aso clinlco ho ectablecidu 01 cloranfenlcol IChlerernycotle Parka.Dauisl cairo an avniblOlico de gray clicasia pars unaa00005a uarlsdad do ~rupas do lufscclores bactorlanso, per nickellsias p per llnlegranulumapaltaceais. Peeve ma oran aollvldad antirnicreblana, atraniosa las barrcrao do los toll. duo, so difuude ampliumorto y con rapidea pot coal todos Iso tuildos y llquldes dal noerpo Ivclueo per el liquIclo celalorraquldee. El cloranfonlcel so an aqonno OsrapOsllco roy pulontu, no dcbn sorsti:~oudo pars Infaccienos trlnlalos, 0000 soracluninlolrade bole las Instrucclonos dol mOdlso. El dlnranleulcel debvrd sen censldorado poe el nrddlce pura oh nratarnhorno do gnupos do Inlocclunco bucteroldee, lnlccclonea por olckottolas y per lie. 5o~nauulvnmspsitacuols. La decIsiOn cool tunrada basdndoso en ci copoctrs antibiotics, on Ia c000lcldlv general clinica y oh psalbis clangs quo onsuelva. El Chloronycetln cord espechfhceme000 Indlcade pars Ia rnsnlngitis bactenisna, thebrcs tlfulalaas, sophisnuna poe orsunioucos oearn'nevathveo y otrao oneouro' coo so ties duodo a coidendla bosreniolOgica o el lulcla cllnlce lrdlquen qua Chlcremycolin as oh anliblOthce apeoplodo. La ouperlenola ha demostesde ol ualor do oh cloranfenicol en oh tratamlsnoa do cendlchonco infacclosason eflalnoslosha, elologla p doernatalogla. ADVERIENCIAS Cl clnranlenicol lobe course hub Ia diroccidoc ale on noddice. No dobo ncr 01/lords cv infocclonco Iriulales. Olscruniusan5I~iunucln~'loss anomla apldstica ponder notue aosciedas a Is admiuleltacldr ala cloronlnnlcvl. ArdlisIn do songrcalnloroalcs oprcpludsa dober nor ecolIzados, dnndo oca poolbbo, Co ol coon do quo so plonos pralon. gar c ropotie Ia aslrululslraoidn. El cloeonlcnicnl on nshd ahinoado on ci fanolmeno do lntenaccldn do dogs p cuando los posbcntos eatOn esclblondo concorrcrtrmrnrto ortlcoaguhantso :ntlconsul:ives, aea zdapnaciOe Os Ia doslOlcaclde do sates odhtirnos podnia PAGENO="0162" 15516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY REACCIONES ADVERSAS Discrasla sanguinea e Incluso aplãstica con exitus Ictalls ban sido, en roras Ocasiones, asociadas a a administraclOn do cloranfonicol. Sequedad do boca y con menos frecuencia n~tuseas, ocasionalmente tarnbidn so presenta diarrea o vômitos pero estos sintomas son rams veces tan severos corno para jus. tlficar Ia suspension del antibiOtico. A veces so encuentran casos de reac- clones do sensibilidad, Durante una admlnistraciOn oral proiongada se ha reglstredo neuritis Optlca y periférica. Los nines prernaturos y los rccidn nacidos, dehido a su Inmadu. rez fisiolOgica roquieren una dosificaciOn reducida. En este grupo do edai so han dado casos do reacciones tOxicas e incluso exitus letalis. Las muestras y sintomas quo deben servir do aviso son distension abdomi- nal, letargo, trastomnos respiratorios quo conduco~ a una cianosis grls. Desig. nado el ~sindrome gris. es sabido que está asopiado a unos planes de dosi- ficaciOn excesiva, no apropiada para este grupo, Su progresiOn puede ser in. torrumpida y revertida a condiciOn si so suspende a terapia rápidamente at conocer a tiempo Ia sintomatologia asoclada. ENVASE Ei Chloroinycetin se suminlstra en c~psulas de 250 mg. N.° (379), frascos do 12 y 24. PARA INSTRUCCIONES COMPLETAS SOBRE LA PRESCRIPCION, PUEDEN CONSULTAR LA MONOGRAFIA DEL PRODUCTO A LA DISPOSICION DE LOS MEDICOS OUE LA SOLICITEN. Laboratorlos Parke Davis. S. A. E. Madrid PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15517 Acquired in Nalaga, Spain in July 1973 - CHIORC~(YCETXN Ciiioromycetin (obloramphenicol Parke~Davis) is a crystalized antibiotic with itherapewti~i activity against a great variety of pathogenic micro-organisms. Cbloromycetin is absorbed very well when administered orally and quickly gives effective concentrations in~ the fluids and tissues of the organism. DOSAGE AND A]E~INISTBM~XON Generally a dose of 50 xag/kg,/day is recommended, divided in four doses administered at intervals of 6 hours. In exceptional cases, such as infections caused by moderately resistent micro-organisms, or in serious infections like septicemia andmeningitis, the dose can be increased to 100/mg/kg/day. However, this higher dose should be reduced as soon as it is possible and by the physician's criterion. - . . . In cases of hepatic or renal insufficiency, when the capacity to metabolize or to excrete the chlorampheflicOl can be reduced, the physician should adjust th~ dose accordingly. In cane of doubt and if laboratories are available for tests, the serum concentration of chloramphenicol can be verified by analytic methods. Premature infants, newborn infants and other children with physiological immaturity. (See "Gray Syndrome" under Adverse Reactions).. In general, a dose of 25 mg/kg/day divided in four doses administered at inter- vals of 6 hours produces and maintains chloramphenicol concentrations in blood and tissues adequate to control the majority of infections in premature infants, new- born infants and others with physiological immaturity. Generally after the first two weeks of life full-tens infants can tolerate a manimum dose of 5O~t1g/kg/day, divided in 4 doses administered at intervals of 6 hours. In case of doubt, serum cblorsinphenio6l concentrations should be verified by analytical methods. Because of reasons mentioned hereinafter ( see "Gray syndrome~~) these doses should not be normally exceeded. ClINICAl INDICATIONS Clinical use has established that chlorsmphenicol ( Chloromycetin Parke-Davis) is an antibiotic of great efficacy against an extensive variety of bacterial infec- tions by rickettsial and lymphogrsnuloma-psitacOsis micro-organisms. It has a great anti-microbial activity and diffuses rapidly throughout tissues and body fluids, including the oephalo-sp~inal fluid. Chlorastpheniool is a potent therapuetic agent which should not be used for trivial infections. ft should be administered according to the instructions of a physician. Chlorsmohenicol should be considered by the physician for the treatment of bacteroides infections, infections by riokettsias and lymphogranulOlsa-PsitacoSis. His decision should be based on the antibiotic spectrum, on the geneixtl clinical condition and the possible risk which is involved. Chloromycetin is indicated specifically for bacterial meningitis, typhoid fever, septicemia due to grsm-negative organisms and other serious infections where the bacteriological evidence or the clinical judgment indica~e that Cl4oro- mycetin is the appropriate antibiotic. Experience has demonstrated the value of chloramphenicol in the treatment of infectious conditions in ovhthalmology, otology and dermatology. PAGENO="0164" 15518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WARNING Chioremphenicol should be administered under the direction of a physician. It should not be used for trivial infections. Blood dyscrasias including aplastic anemia may be associated with the adminis- tratLon of oblorsmphenicol~ Blood studies should be repeated at appropriate inter- vals when possible, especially during prolonged or intermittent therapy. Chlorsmphenicol is not alone in the phenom~non of drug Interaction and when patients are concurrently receiving anticoagulants or anticonvulssnts, dosage ad-. justeents of these agents may be necessary. ADVERSE REACTIONS Blood dyscrasias including aplastic anemia with fatalities have been, on rare occasions, associated with the administration of chloramphenicol. Dryness of the mouth and less frequently nausea are occasionally present, as well as diahr- rca and vomiting but these symptoms are rarely severe enough to warrant discontinuing the drug. Sensitivity reactions are sometimew encountered. During prolonged oral administration some optical and peripheral neuritis have been reported. Premature infants and recently new-born infants, due to their physiological immaturity, require a lower dosage. In this age group there have been oases of toxic reactions, including fatalities. The symptoms that should serve as warning are abdominal distention, lethargy respiratory nroblems conducive to cyanosis. Designated as the "Gray Syndrome", it is known to be associated with excessive dosage, not appropriate for this age. Its progression can be interrupted or reversed by discontinuation of the therapy as soon as the syznptomology is observed. PRESENTATION It is administered In capsules of 250 mg. No. (379), In containers of 12 end 24 units. FOR CC~PLETE INSTRUCTIONS ON PRESCRIBING CONSULT THE PRODUCT MONOGRAPH AVAILABLE AT THE BEQUEST OF A PHYSICIAN. PARKE-DAVIS Laboratories Parke Davis, S.A.E. Madrid PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15519 7. Zanders' comparison of new S~anish label with U.S. label. The new Spanish label is a considerah].. improvement over the old Spanish label bot h in its indications for use and in its warnings of adverse effects. The new label states clearly twice- that Chloromycetin should not be used for trivial infections and should be used under the instructions qf a physician, the most important new statement.which, coupled with the warning - twice- of blood dyscrasias including fatal aplastic anemia instead of the bland "changes in the blood following its use are rare" of the old label, should have a salutory effect in cutting down unnecessary use. The new label also states that the decision to use 0hloromycetin should be based on the antibiotic spectrem, the general clinical condition,and the possible risk involved. This is much better than no general guidelines at all as in the old label but it is still wesic compared to the U.S. label. The new labelts indications for use are usually based on the micro-organisms or groups of micro~orgsnisms involved instead of on sites of infeotiouns such as urinary tract infections sad respiratory infections of the old label although tt still includes infections in otology, opthalnology, and dermatology. !~ore importantly the specific t~dications for use are more similar to the more restricted U.S. label list. However, the Spanish label gives the physician the choice of basing his decision to use chlorsmphenicol on bacteriological evidence .~ clinical judgment while the U.S. label says sensitivity testing is e*sential. The new label~after repeating that Chloromycetin should not be used for trivial infections and under 1~re direction of a physician, warns that blood dyscrasias including apl~astic anemia may be associated with administration of chlorsmphenicol and that blood * studies should be repeated at appropriat~intervals when possible especially during pro- longed or intermittent treatuent. ~he o]d la~el had only t~Tay Hyndrome under Warning and under Tolerance just th~"Ohloromycetin is well tolerated and changes in the blood are ware" plum a similar blood cindy statement. The new label repeats both statements under Mverse Reactions, including there, however "aplsticsnemiS with fatalities". Again a distinct improvement over the old but lacking the strength and fullness of the U.S. warning and explanation. The new label also includes other adverse effects: dryness of mouth, nausea, vomiting, sensitivity reactions, optical andper4pheral neuritis, and warns to use lower dosage when given conourrently with antiooagulants and anticonvuleante and in cases of hepatic or renal insufficiency which the old label does not mention. Both labe' a treat the cossibly fatal "Gray Syndrom" for premature and recently new born infaais quite fully, far more so than the blood dysoraeias>.iU contrast to the U.S, label. Por more oDmeents comparing the new Spanish label with the U.S. ~abel, see40Omparisofl hf the new German label with the old German label and the U.S. label. The new Spanish label and the new German label are very music alike being based on the same Wonograph. Howeved., th~new Soanish label is perhaps a little better than the new Semen label in that it stat~i feat Shlotoniycetin should not be used for trivial infections and ehould be used under the direction of a physician in Indic~tious as well as under Warming. The Spanish label also divides the diseases in which'0should be used into those in which its. use should be consideyed mm~ by the physician and those in wh~Oh it is specifically indicated~ The old 0erman label was even worse than the Spanish old label in the tremendous number ,~f iadieai4ons for use; andtht :.0omP5ti5P~ is stronger and. ILmore. de but much of it applies to the Spanish labels. 73.950 0 - 77 11 PAGENO="0166" 15520 CO1\~tPETITIVE PROBLEMS IN THE DRUG INDUSTRY 5. Parke Davis Chioromycetin entries in Vademecusi Daimon, Nov. 1972. Spanish physicians' desk reference published by pharmaceutical companies. ~ -si~U~ Ov~~c~i~ ~ ~-m ~`~o~co -~`.`~ ~ J~LL~/ç~ ~ u~L~J2~ CHLOROMV CETIN Composition: Chioramphenicol Parke Davis. ACTiON: Antibiotic of ample spectrum, which covers a large number of bacteria--gram zegative and gram-positive-- all the microorganisms of the rickettsia, liajtiogranuloma and inguinal as well as psitacosis grariu 10mm. Indications: 1)~phóid fever and othar salmonellas, bacil.lar c~'.sint~ry rickettsiosis, infections of the urinary tract caused by a variety of gram negative and gram positive bacteria, serious surgical infections, including peritonitis, some respiratory infections, meningitis, veneral diseases such as phlenor:agia resistant to othe antibotics, inguinal granuloma and vener'~el lighogranuloma. Sepricemias, bruccelosis, psitacosis, etc. Administration: 50 mg/kg/day, in 4 fraccionated doses every 6 hours. For premature and newly born babies and others with ph~'siological immaturity, 25/mg/kg/day. CAUTION: if it is possible, it is convenient to have hemograms before establishing the Chioromicetin therapy and they should be repeated if a prolonged or intermittent acYainiatration is necessary, or in cases when the dose given is higher than usual, in order to prevent a possible depression of the bone marrow. Although rarely, some irreversible discracias have been observed. The "gray syndrome" has been described in premature and newly born babies. As it concerns to hypersensitive r~actions, soi:a febril reactions, cutaneous eruptions and allergic reactions can be observed. For more information on adverse reactions and indications please write write to the laboratory for a monograph of Chioromicetin. *Presentatjon: CLOROSTREP (capsuls and liquid) Composition: Each capsule or tea spoon contains 125 mg Of Chloromycetin and 125 mg of dihydrostr~ptomycin. Indications: Salmonella and shigella infections, ulcerous colitis, gastroenteritis, pre and post oparatory intestinal tract, etc. Dose; Children: 1 or 2 tea spoons every 6 hr, adults 2-4 capsules sivery 6 hours. Presentation: 8 Capsules in a container. Liquid in a 60 cc bottle. *1.iresentatjon: Capsules of 250 mg,12 in a container; 122,60 pta with 26; 228.90 pta. Cre',m at 1%, tube with 30 g, 79.20 pta. Topical at 10%, 5 cc container, 9~..40 pts. Intramuscular:viala with 1 g, 96.40 pts; with 2 g. 166 pta. Succidate: vial 1 g, 86.30 pta. PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15521 ChloromyCetin Dos~: In g~neral a dos~ of 50 mg/kg/day is r~comm~nded, in 4 doses gtv-n with intarvals of 6 hours. In serious cases like septicemia and meningitis the dose could be incr#ased to 100 mg/kg/day. For premature babies and babies up to a month old it is recommended not to give over 25 mg/kg/day due to th.~ir physiological immaturity. Chloromycetin flask with 12 capsules P.V.P. 122.60 (pesetas 24 " 228.90 Palmitato of Chioromycetin: flask with 60 cc 129.90 Topical chloromycetifl Flask with 5 cc 76.10 p~setas For Siore information about prescribing the product, requ~~5t the monograph which will he awiilable to you and which dese cribes indications and adverse reactions of the product. ~ ~Yi~ L~P~Q-Qc~Lct~ L~~LS(DLQ~~) \ ~ 7 `~ - ~w-~i ~ J~'~ C~-~~'--t c~X ~ Parkelasa with ChloromiCatin &ytic Composition: Combination of two f~nzymes, fibrinolisin and desoxirrribO- nucleosa with chloramphanicol, in ointmant. Action: EflzymatiC and antibiotic debridement. Indications: The same as f or Parkelase whan an infection -a complicatioi~~ is suspected or etists. Burns, wounds, cetvicita, vagihitis, u1cei~s etc. Dose: 1 to 3 daily applications. Pre~enT~e~on: Ointment -tubes with 10 and 30 grams. l~Dosification - "See attached prospect (literature)" 2."Algunas" some respiratory infections 3, a ComoblennOragia" PAGENO="0168" 15522 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY usually have dificulties with doses well tolerated by older children. For prematures it is' suggested no more than 25 mg of ct~1. per kilogram of weight per day, divided and at 6 to 8 hours interval. Por babies less than a month old it is suggested no more than 60 mg per kilogram of weight anc~ daily, divided in doses at 6 or 8 hours interval. When a prolonged adminiaration or larger doses are required, the concentrations of antibiotic in the blood sbould be the guide to graduate the dose. Tolerance: Generally Ch. is well tolerated and blood alterations cons~- cutive to its use are rare. However, it is convenientTb~ have periodical blood tests when its administration is prolonged or interrnitent. In prematures and babies less than a month old the high doses of CL. has been associated with abdominal distension, with or without emesis, cyanosis,pale or progressive, or vasomotor collapse, in some cases with fatal results. These effects have not been reported on children treated with 50 mg of Ch. per kg. per day, or less. The interruption of the therapy has corrected in many cases the adverse effects, with complete recovery. Packing: In containers with 8 capsules and flasks with 60 cc. PARKE DAVIS, MADRID. PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15528 U -~ a U PAGENO="0170" 15524 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a a ~ ~ _ - -- -E-~' - - e Z - - - ~ -~ Q - - $ -` C) - -_ A ~ _~ C - t --- ~- - - -_, - 3 - ~- b I -~ - - - )t c-~ - :~ - ~ -- -~ -~ - - L ~- r> c - - -;~L t:-~ c--- `t ~ zLc~~ PAGENO="0171" Parke Davis - Cont, de los ~ntcriores microurgan no~., cxcepto d~ lOS (10) 0(LUOOS. ,((`( `(ON: ProI~lads de as CL> )1)I)CL~'IOflC) SC' cu,~l:,, as dcl catarro cor.wn. /~).s,'.l.OGA: (lu/k>>, 1 * c'ot.>n~t, 2 gra5. cita 0>: svflLnas ctt>c van, 2 gr>tg. 2 sr~". >t se' ~`.`".`: 1LP1)$, i>>0>,>I dos;'>. lul:~l:N'I'. (C'I('),V V P.1>.!'.: (3ragcac, ei;vac>~ ~LO> :`o, 100 pts. ZARONT$I'.t, IL;u>do CO5/l'O.'J(.'IÜN: l'or 5 cc: 230 rag de l0hosu- xi> .0> (1f>.n,c>/1.tCa.ctiJs>s'c/tan/d.>). IAI'lCA(!()NAS: Antiepilfplico paiA tra(a~ 0/e>tO cspec)Iico dcl pcquctio ntal. I'OSOU7GIA: I/as>>> 6 anna, I cstchta. (250 ag) al .1/a; inaycces tIe 6 a//or. 2 cucI~as. at dOn. ~>I(ts adcl:;ntc, ajustar dais a Ia repuesla clinica. PR/~SLNTAC'1ON: Liquido, frasco con 120 cc. >1*> S~r,>no, 8, dupi. Mudr~( (20) TOCOFEROL.CAROTFfI eoat/'(l,c/C(oN: l'or cc: N>. tIe ~i'flW) dC ti iso, (.00 nsg; C:ro1cn~, 50 (5>>) (utamas. / \`flI('A( `l(>A'l.S: I'stctilid,sd, I >1>0t('t>5~2. as. trOlL)'>, ,>bn Los, `icarreas. I et: seOn, anemias. At'cO"n no,uoIi,anrc tk'I ciclo ucnct,t,aI. /`osoI.or;1.4: I snsp. >1 di:> inttuuusc. Gone,, I S.,!>) tI ll/l'Sl'..\'T.lC'!ON I' 1'.V/'.: lnvcciabk,s do 2 cc, t.a>a cots 8 atop., 43,85 pts. (otas, fr;,sc~ Con 22 cc, 30,75 pts'. vsTAcrrtosr:r41/ A -I' D MASSVO OLE080 (0.1! l'OS/('ION: Jr cc: V>t. A, 400000 ~(.L; Vi>. 1) (c:s',fcrol), `600 000 UI. I'O.SoJ.Om!,(: I an>p. poe v)a bacal poe las flv,!LaLa~s, (litCila (It .çItI,IO, SO>>.) 0 leche. L.a t'a~Oid.o1 tI> 151>>., a cOtcru> mfdico. J'Rl~SJ~'Ni'4 (`II `N Y f'.V./'.: ,lv,polla dc 2 cc, ~ COO 1. 22.55 >>m VITACAROT(ft)E COMPLEJO GOTAS COIl 105/C/ON: Pot cc: l'rovshmtna A Ca- TO/CU), 01/C) U.8.; Vit. fl 500'.) UI.: Ace/to tIC gei,~wt, tIc lOgo VIt. 1.'., II) n>g. /,`>`i)lC',4 ClONL..S~ Las dcl \`1 T.SCAROTL1NS 1.550. J'>')SOf,OG!,t: i>',ual. IRISENT.1 LION V l'.V.P.: Gotar, frasco con 22 cc, 30.45 p1>. VITACAROT'N3 CCMP>FJ0 >050>51MG 01.050 (`O.S!l'().S!('lt'.'o': for aitip.: Vii. 1). 5(0) (bC) UI.: Iros (tan/at A caro(eno, 300 000 (5.1.; Ace/bc Or cc, mc'n do sr/go \`it. 11, 100 mg 1s'I>IC.'I (`IO.VLS: (as dcl Vs ~`sscmtas> ;`sso. J'0.S01.(~;/.1: )>`ual. i'iu~50N'i'4 (`I( `A' V P.1'.!'.: Ampolla do 3 cc, caja c,in 1, 31.80 I)>). V0tCAR0080E PtJRO FORT>S)M0 OLC010 (,`OOIPOSI(''ION: Poe e>sntp.: 500 (/00 U.l. do 1>, os ita>,titia A (`arOtcr>o. /t'.'n!r,'tc/'),vAc: J I.'otcralopias y afece'ka,es ocUl:lecs. r:;qutsstslo. ost>.opatias, oscoporttas, >t>>t't'>it~L'ci.*, calci~lcs'>;pia, cIcstt>o'rzslit;':'n jutes/s a, ascot/as, g'andcs in0ccioiua, sinus>- i/s. oil/s. /`osoF.oc;IA: 1° sematta> 1 ausi'. (s'la hut'aI);, 2.' (CiflatOt, otra ant>>. etc Vcrscs;uocNe COM- `its> >tssts'O duraute ci (tempo (5150 ci nsfdico crc:> op>'rOttso. 1'/?PSLN3ACION V P.1'.!'.: Amj'ol!a do 3 cc, CU:; CoO :~, 35,60 pts. VSTACAR000NE P050 COlA> 0180>0 (`0,5f/'0.Sll"!ON: 10 000 Ui. do Provilan,hs:, A (states'> poe cc. /ND/CA C/OAfS: Vcr VtIACsRol'eNE Pt>so. /`OSOJ,(IG/,'t: !.artant,'.c, 1.5 golan di>;; itiOol do 1.5 nuts, 5.10 got.'>'> at tI/a: tIc 6-15 altos, )52~ gola' dOn. AduI/o.c 25.50 goias tIm. J'Isf.SiN!.ICIO.\ ~ j',i'.I'. (;.u>, )r;scO 22 ~-c, 30,45 p55. COMPETITIVE PROBLEMS IN T~IE DRUG X~DVSTRY 15525 DESCRIPCLONdEI ESPECIAUDADES Pelfetier, S. R. C., Laboratories NOTAS Sto b;>., ,t, 4> tfk'>oses 5)atrnan pars a eta>> n(dka: ci Mt.>", tt. 1'> a,.'(UrUCs, 4~,o ,cswac I> m.sk;r..O st' bat.'>>> Jo us amp)>> u>u;p. Os pr~aasotc; s,fz,;a dirttc/As dl Dr W. Hudoru. PAGENO="0172" C) C) 0 9. Parke Davis Chioromycetin advertising samples, Nov. 1972. `I. ,` ~ `~:` I', N un problema de ajedrez PROBLEMA:juegan blancas ydan mate en tres jugaclas S.....ON;lapag.interior PAGENO="0173" Más de 20 años de experiencia clinica con ;EFIC*CL& TERARELITICA ~ Af~4RL1O EEPEcTRO bacterias gram-positivaS. gram-flegatiVaS. rickettaiaS. y rnicrOorganiSmoS del linfogranuloma venéreo. psitacoSiS. etc. * EFICA-~IA OONSTAF4TE desarrollo minirnO de cepas resistenteS y frecuentefl~~nte eficaz contra cepas resistenteS a otroS antibiôticOS. La investigaclon del CLO ROMICETIN es una tarea permanente en SQLUCION I A3C ~ W~ARKE-DA~iiST * IRiguroso control de calidad * RAPIDA ABSO~CION INTES11NAL La concentraciôn maxima de CIOROMICETIN en sangre. despuêa tie La primera toma se obtiene generairnente en ci tranacurso tie una f-to a AP#IPL~IA DI~IJSION ORGANICA: rapidamente penetra en Los tejidos (incluyendo ci LC.R) y se obtienen concentraciones efectivas en et lugar de La infección. - Más de 20 año$ de experiencia en Ia fabrtcacion del PAGENO="0174" ~Por qué elegir el Porque con el PALMITATO DE CLOROMICETIN Lid. tiene Ia seguridad de que su paciente recibe un producto de eficacla reconocida, ya que de su morfologia crlstaiina controiada (més del 9O/~ de potimorfos no-A) resuita una absorclón optima y unos niveles sangulneos eficaces. Losestudios de Aguiar demues- tran que se obtuvieron niveles sanguineos nlas altos con el polimorfo no-A de cloranfenicot I Comparacion de los niveles en sangre obtenidos con a suspen- siOn de palmitato de cloranfenicol. conteniendo varies proporciones de potmorfos A y no-A. siguiendo a dosis oral simple. equivalente a 1.5 gr. de Cloranfen:col (~/~ de polirnorfo no-A en Ia suspensiOn M: 0 por 100: N: 25 por 100; 0 50 por 100; P; 75 por 100; L lOOpor 100). 0 I, C,' PAGENO="0175" DDSIFICACLOP4: 0 Por Ia general. se recomienda una dosiflcaciôfl de 50 mgfkgjdia, fracciortacla t~i en cuatro dosis adrninistradaS a intervalos de seis horas. En casos graves. -3 como septicemia y meningitis, se puede aumentar a 100 mg/kg/dia `-4 En niños prematuros y nacidos a término de rnenos de un mes de ~ edad. se recornienda no pasar de 25 mg/kg/dia, debido a Is inmadurez fisio- lOgica de los mismos. CLOROI'dIIOETIN. Frasco 12 cSpsulas. P. V.P. 12Z60 pta CLOROfVUCETIN. Frasco 24 cápsutaa P.V. P. 228.90 pta. t4 PALJ%4ITATO DE CLO~IOIVlICETlN. Frasco 60 cc. P.V.P. 129.90 pta. SUCCINATO CE OL.OROI'AICETIN. Vial de 1 gr. P. V.P. 86~0 pta. `-4 CLO~Of~.4ICETIN TC~lCO. Frasco de 5 ~ c. P. V.P. 76.10 pta PARS MAS ~AC0N DE PRESCAIPCIOH DEL PRODUCTO. SOUC4TE MONOGRARA QUE TENEMOS A Eu DISPOSICION 44 DESCRIBIENOO IND4CAC1ONES V REACCIONES ADVERSAS DEL PRODUCTO. PARKE-DAVIS 0! 0! PAGENO="0176" 15530 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ~`&~LI ~~(A"~)ç~ ~ ~ \~t I'2~ ~ ~. ~ * A CHESS PROBLEM: Whites play and ~iv~' `ch'~cb~ fltzit~ in ~ moves. More than 20 years of clinical experience with Chioromycetin: Therapeutic efficacy: Ample spectrum: gfan positiva and gram negative bacteria. Microorganisms of venereal linphogranulona, psitucosis, etc. Constant efficacy: Minimal development of rmsistnnt bodies and frequentlyeff~tive egainst bodies resistant to other antibiotics. Fast intestinal absorption: The maxim concentration of Ch. in the blood after its first ingestion, Is obtained generally in an hour. Ample organic diffusion: Penetrates the tissues (including the L.C.R.) ? and effective con- centrations are obtained in the place of infection. More than 20 years of experience in the fabrication of Ch. guarantee the product. Investigation of Ch. is a permanent tank of Parke Davis - Rigorous control of quality. Why to choose the Palmitato of Chloromyceti~? Because you have the security that your patient receives a product of recognized effectivity, because Its morphology controlled (more than 90 of polimoprhs no-A) results in optimal absorption and effective blood levels. The studies by Aguilar show that higher sanguine levels were obtained with the pollnorph no-A of Ch. (Graph) Sho~ a comparison of the blood levels obtained with the suspension of palmltatd of Ch. containing different amounts of pollmorphs A and no-A. Simple dose equivalent to 1.6 g. (S of polinorph no-A in the suspension: M: 0 for 100; N: 25 for 100,0 60 for 100; P: 75 for 100, L: 100 for 100) / PAGENO="0177" 4c~ 1~P)c~PYt.q~Q ~ ~ (~4~ccQ9~ (c~( ~ ~ ~tc9~ ~ ~4k ~5~t( ~LOROMIUETIN "Dentro del Screening Program de PARKE-DAViS' que comprendió unas 6.000 pruebas con tierra y eon nr~is ste 20.000 ciases de bongos, Burkbolder, en 947, eneotttró sna cepa de bongos, ci Streptomyees Ven~zueiac. sn un~i tierra procedente de Caracas que producIa el CLOROMICETIN activo tanto frente a ion gérmenes gram positivs conlo tegaiivost" Posteriormente, tambidn en PARKE-DAVIS se iogró a sintesis del CLOROMICETIN. Secretos de su mayor eficacia: I. Menor nItmero de resisiencias. 2. Mds ampiio espectro 3. Rtipidas ahsorciôn y difusihitidad. 4. Nivetes sanguineos cievados y proporeionaies con as dosis adntinisiradas. S. Dosificario eorreetansentc. Aduflns: 50mg. pm kiln de pisn y dia. Ni5os: 50 a 00 mg. poe kin dc peso y die. tin ni0ns prematuros se reenmienda so paqar de 25 org. por kiln de peso y din, COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15531 PAGENO="0178" 15532 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY La investigación del CLOROMICETIN sigue sien~ do una tarea permanente en PARKEDAVIS. La eficacia del CLOROMICETfIN responde al más preciso y riguroso control de calidad. PARKEDAVIS, cuyo rigor cientIfico está bien probado, seguirá en su lInea de no combinar el CLOROMICETIN con otrOs antibióticos. PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15533 INTERVENCIONES QUIRURGICAS Infecciones pidgenas estatilocócicas. Peritonitis pör perforaciones ligestivas, cuya flora mixta me dentro del espectro del CLOROMICETIN. tnfecciones biliares Icolecistitis, abscesos labpdticos, etc.). Isfecciones aparato genisoueinario (pielonefritis, cistitit, prostatitis, metritis y flemones perirrenales). puede utilizarse en: Via intramuscular. I ORAMO Localtaaetate, pues no irrita los tejidos. Aerosoles. APARATO RESPIRATORJO Infecciones beotacopulmonares bacterianas y vIrican, especialtacate indicado en a neamonia primarla * asIpica y en Ia los feritsa. "boy Poe boy, de acuerdo con Ia mayorIa de autores,Ia cloromicetina en el antilaidtico que menos resistencia ofrece a losgdensenes tttais habituales de las `(as respiratorian...' EL CLOROMICETIN SUCCINATO Vetsoclisis: Eta ci posl-operatorio y post-partum inmediaton, asi cotno pars los que requieren medidas de relsidratacion y antibioterapia conjutsta. "bsp'riaentaca)O clisica dcl cIronklios ci, mcm's broa'Alsdnnoaees croon's", 1968. l'r',f~o~m A. t)aniaoo. PAGENO="0180" 15534 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRy EL PALMITATO DE CLOROMICETIN PARKE-DAVIS CONTIENE MAS DEL 90 POR 100 DEL POLIMORFO NO-A, FORMA CRISTALINA QUE ASEGURA UNA ABSORCION OPTIMA Y UNOS NIVELES SANGUINEOS MAS EFICACES AL HIDROLIZARSE MEJOR QUE LAS OTRAS FORMAS CRISTALINAS DE PALMITATO DE CLORANFENICOL. Los estudios de Aguilar demuestran que se obtuvieron niveles sanguIneos inás altos con el polimorfo no-A de cloranfenicol. Coniparación de los niveles en sangre obtenidos con a suspension de palmitato de cloranfenicol, conteniendo varies proporciones de poliistorfos A y no-A, siguiendo Is dosis oral simple, equivalents a I ,5 gr. de cloranfenicol (% de polimorfo no-A en a suspensiOn: M: 0 por 100; N: 25 por 100;O: SOpor 100; P: 75 por 100; L: 100 por 100). Este gráfIco muestra que a medida que aumenta el porcentaje de polirnorfo no-A en Ia suspensiOn, el nivel en sangre también se incrernenta. Esto es, prácticarneAle, una (sea recta de. afinidsd. 19 EL PALMITATO DE CLOROM1CETIN presenta un sabor niuy agradable. Especialnaente indicado en infecciones, lutes como: Neumonfas. Tos ferina. Infecciones entéricas. lnfecciones vies urinsrias. ~sleningit I-.. Sulinonelosis. POLIMORFO NO-A MicrofotografIa con microseopio polarizante. NO CC. ~PALMITAtO~DE~J~ S$JSPtNSION DE PALMITATO OE CLORANFtNICO( ORAL 128 mg DE CNL000MVCETIN® ICL0000PINICOL, P. 5. & CIA.) PEDIATRIA At, AFTER DOSING PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15535 *4 cAPSULAS No. 379 ~i: ~ ~ CLORANPENICOL. U. S. P. (PRrIIR-DRVI*) 250 mg El CLOROMICE TIN, por a pèque~ez de su mol~cula, su gran estabilidad y el hecho de que se pr~sCnte en cápsulas garanti7-a una absorción optima y rápida en Ia parte proximal dcl tubo digestiVo. Dada su excelente absorCiOn, a vfa parenteral debe de reservarse sOlo para casos excepciOtlalcs. Frente a las telracicli'saS, el CLOROMICETLN tiene Ia ventaja de que altera escasaflscfltc Ia flora normal dcl intestino gruesO. 5~~ : ~ APARATO RESPIRATOR'O APARATO DIGESTIVO APARATO URINARTO 73~95O 0 77 12 PAGENO="0182" El Cloroinicetin Tópico es una solución de cloranfenicol al 10 pot ciento en propilenglicol, para su uso en infecciones del oIdo (otorrea crónica, otitis media supurativa, infecciones quirOrgicas, etc.) y en el tratanliento tópico de infecciones locales, tales coino quernaduras infectadas, Olceras varicosas, abscesos, etc. 15536 COMPETITIvE PROBLEMS IN TEE~ DRUG INDUSTRy ~ INFECCIONES LOCALES PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY i~537 ~ ~ A ~ ~ -~ V -~ EN ESPA~A, PARKE-DAVIS UTILIZA I'ARA LA SINTESIS DEL CLOROMICETIN LAS MAS MODERNAS TECNICAS DE FABRICACION vk~c~!'\V~-), ~ ~ VISTA GENERAL DE LA FABRICA DE CLOROMICETIN, DE PARKE-DAVIS, EN ALCALA DE HENARES ~o~ay~tC~ L~7C~ PAGENO="0184" 15538 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Cj. ~cLr~QVs,e-L4.A Parke Davis LADORATORY, MADRID,..-Barcelona, Spain c1iL0ROM'~'CETIN ~~The PARKE DAVIS "Screening Program" covered 6,000 tests with earth and more than 20,000 kinds of mushrooms~ Burkholder in 1947 found the Streptonyr~es Venezuelae, a layer of mushrooms, in earth from Caracas, Venezuela, which produced ChioromYcatin active against the gram positive and gram-negative germs.w I. Afterwards, also Parke Davis accomplished the syntesis of Chloromycetin. Its greatest efficacy is:, I. Minor number of resistert bodi~s 2. More ample spectrum 3. Rapid absorption and diffusibility 4. Higher sanguineous levels and proportionate to the administered dose. 5. Correct do as. r~.~j2 cLs ~ ~ ~`~h~1Ae~ CL-, ~ The investigation of Chloroaycetin continues to be a per.- aanent task at Parke Davis. The efficacy of Chloromkcetjn responds to the most precise and tigorous control of its quality. Parke Davis, whose scientific responsibility is well proven, will continue in its pd-icy of not combining the Chloromy.cetin with other antibiotics. SUCCINATO OF CH'LOR0i4Y~5TIn Sodic Succinate of Chloramphenicol Equiv. 1 Gram - Parke Davis -For intramuscular or intravenous use: Prepare the solutions aseptically with distilled water, physiologic serum or dextrose. Registered in the Dept. of Health No. 31367. Parke Davis Laboratories, z'tadrid SURGERY: Pyogenus staphiloccocus infections, neritonitis (perfo- ration in the digestive tiact), its mixed bacterial flora which falls within the spectrum of chiororsycetin. Infections like colecistitis, hepatitis, etc. Infections of the genito-u~inary eposr~tus: oielorw-dritis, ciatitis, prostatis, metritis and pen-renal phle~aon. Respiratory apparatus: Broncopulmonary infections caused by bacteria and virus. Specially indicated in the atypical priaary pneumonia and whopping cough. "As of today arid according to the majority of authors, chioroaycetin is the antibiotic that offers less resistance to the most habitual germs of the respiratory tract. * *Cliniral expertmenration of chioromycetin in chronic bronchial- pulmonary process" 1968, Prof. A.Damiano. PAGENO="0185" COMPETIflVE PROBLEMS IN THE DRtTG INDVSTRY 15~39 Succinato of Ch. (cont.) VenoclisiS: In the post-operative and post-partutfl as wel.l as for the cases requiring re-hydration and anti-biotherapY. Intramuscular. Locally, because it does riot irritate the tissues. Aerosols. PALMITATO OF CMLOROMYCETIN - Suspension of Palmitato of Ch.Oral Each teaspoonful (4 cc) represents 125 mg of Ch. Parke Davis (Shake well before using) IN PEDIATR1CS: Palmitato of Ch. contains more than 90% of the polimorph to-A in crystalline form, which insures optimal absorp- tion and the most efficient sanguine levels because it hydrolizes better than the other crystalline forms of Palmitato of Ch. It has a p3.easant flavor. It is especially indicated in infectionS such as: pneumonias, whooping cough, enteric and urinary infections, meningitis, salmonellosis. (Graphs) Legend: Studies made by Aguilar show tint higher sanguine levels were obtained with the ChI. polinorph no-A. A comparison of the levels obtained by the suspension of Palm. of Ch. ~ontaining several amounts of polimorph A and No..A -following the oral simple dose- of 1.5 gr. of Ch. (% of polimorph no-A in the suspension: M: 0 per 100; N: 25 per 100; 0: 50 per 100; ?:75 per 100, L:lOO per 100). Second graph: shows that along with the increase of percenta~e of polimorph no-A in the suspension, the blood level is also in- creased. This represents practically a straight line of affinity. cHLOP,OMYCETIN: ChloramphCntcO 1 U * S. P. (Parke Davis) 250 zag. Because of its small molecule, its great stability and the fact that it is offered in capsules, guarantees optimal and fast absorption in the proximal part of the digestive tube. Because of its excellent absorption the parenteral way should be used only in exceptional cases. Ch. has advantage over the tetracyclinies that it scarcely alters the inteStinal flora. FOR L0C~L IhCT1S: Topical Chloromycetifl is a solution of ~h. at 10% in propilenglYcol, for use in ear tafectione (chronic othorrea, otitys, post op~rrztive infections, etc.) ar~d for the treatment of local infections as infected wound's (turns), varicose ulcers, abscesses, etc. PAGENO="0186" 2~. tr~ ~ ~ fëLORANFENICQL V SULFATO DE DHIDROESTREPTOMICINA C So ~mosoisoodo mopioso eiCisiooosioep bojo diooooiôo osédios soisooosso. iso sO5Osdsompiosflo~oiasoospeoojosd5p,Oossjofmojo~iom& - Pus iofoooaosoo p~oscsiptioa ooospiooa osfoossu .5 ciosaofeoicol, iooiosioo sdoosoososss. ps005soiooso yssacoiôoes adoossos - sotso silos dopsosido -- deio osddsis Osos,- sisosso oss is ss005rofis do ciosasfesiosi disposossis podido. I 10. Parke Davis Cblorog6.ep advertisements directed to public, mid 1973. V V L r I .1 r C,' Ca Via 0 C) 0 ii ~! La garantla 4 MADRiD - BARCELONA I CHLSTV74 (DiLl) PAGENO="0187" S1i~[P (Cloranfenicol y Sulfate de Dihidroestreptomicina) ATACA POR DOS FRENTES J-~OC&L th~e~R~,M'4 l~t?M tC~L_ Cua~ido sc administra el cloranfenicol ;icr via oral, Ia mayor parte de Ia dosis as ~bsorbida an el intestino, se distribuye en t~jidcs y liquidos dcl organis~no y ajar- - cc *ma acción antibiótica general; Ia can- tidad no absorbida, sin embargo, es sufV clente pars dar uca cancentración de do- anfcaieol tarapóuticamente eficaz en cl intestino. Cuando se administra Ia estrep- tomicina por via oral. prácticamente no es absorbida en el intestino y alcanza en éI ~ma coecaniradión-eleVadL I. C) 0 0 w (j2 I DOSIS - Niños: 1 6 2 cucha,ad,tas cada 6 horas. Aduttos: 2 cdpsttlas cada 4 - 6 horas. PRESENTACION: Frascos de 8 cápswas P.~P~119~8O Fraucusda6Dcc. P.V.P.160.40 PAGENO="0188" 15542 COMPETIflVE PROBLEMS IN. THE DRUG INDUSTRY ~ ~ and 5U1fSt. of flydroeetreptoaiejne I? ATTAcKS bY 1T0 ~Cg% ~1orampberjjoo3~ T4ivydroestreptcai,ine sad Ohlorsmpheniacl when ch1orevspiieni0o~ is adninietered by the oral route, the major pert js abeorbe.~ in the intes~*e, it dieteibutes itself among the tissues and liquids in the orgav4am and erercieses an antibiotic aetiob in general; the sount not absorbed, however, i. enough to give a oon~ oentration therapeutiealiy acceptab'e in the intestine. When strepto.. vapuine is adainietereg by the oral route, prctioal~y it is not absorbed in the intestine and reaches it in a very high concentration. DOSE Children, 1 to 2 ianbpbofl~~15 every 6 hours Adults; 2 capsules every 4 6 hours Bottle of 8 capsules P 7. P. 119.80 Bottie of 60 ~, P.Y.D, 160/40 (Bank page) SELOROS~'p~j~ Cb1ozaaphenj~o~ and Sulfate of Dhyeroeetrept~,,~cine WABNING It is reeoisvneflgeg to use Oblorostrep only under the direction of a physician. It in not recoamended to use it in therapy of trivial (minor) infectious processes. Boy complete prescribing inforsatio~ regarding chloraapbeuicol, including warnings, precautions end adverse reactione amongst them depresmion of the bone marrow please see the monograph on ohlorejnphenicol available on request. WIth iW~ GIJRANTEE OP PABIcE..DayIg MAIMID. BABCMLONA ~i8D.Y.74 (D.Ma) Grafibe*ioa Marques de Cadi.~ 25 Peres Dsp Legal 27- 1974 PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1 ~Lt~ IA~ ~CftC~E~ ~S C~I~LE~S ~ ATACA POR DOS FRENTES PAGENO="0190" 15544 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COL CLORANFENICOL V SULFATO DE DIHIDROESTREPTOMICINA ATACA POR DOS ~RENTES Quando se ~dmini de in dosis es t~a el c~orarifenieoi por v-ia oral, in nayor parte ~ida enel intestino, se distribuye en be tejicos y no y ejerve una acci~n antibiotica general; la can- ~, sin embargo, en suficiente para dar una concentra- enicul terapeuticamenta eficaz en el inte~tine. Quando ptoiaicina por vioa oral, pr~ticnmente no es ab- ~ alcanza en ~l una concentracion elevada. MADRID - BARCELONA PAGENO="0191" COMPETITIVE PROBLEMS IN TEE DREG INDUSTRY 15545 * ~ OJ' ~5'-~' ~-~- "~ <1s~a~ ~`t-l `5* ~OC~tQ~Q 15&o ) QILOROSTREP - Chiorampheflicol and SuJJatC o~ DlhydroestrtOmiCine. Capsules P.V.P. 119,80 LOCAL DIHYDROESThPTOMYCINE Liquid P.V.P. ~S9,60 GENERAL Chioromycatin it Broadens the Bacteria Spectrum for a Greater Clinic Efficacy The association of chlcromphenicOl and streptomycine has a broader bacteria spectrum than any other antibacterian agent clinically used alone. This spectrum extremely broad, attacks the microorganisms that commonly cause the infectious diarrhea, entericand mix infections that can occur in the postoperatorY surgery it attacks by two fronts: When chiorempheflicOl is administered by the oral route, the majority is absorbed in the intestine, it distributes itself among the tissues and liquids in the organism and exercises am antibiotic action in general; the amouht not absorbed, however, is enough to give a concentration therapeutically accepted in the intestine. When(strept is administered by the oral route, practically is not abosrbed in the intestine and reaches in it a vesyhigh concentration. ~~mji~te information on' prescriptions including indications and adverse reactions, write fee the monograph. MADRID, BARCELONA Advertisirgpage Summer and Infectious Diarrheas: Your vacation can be note comp late with CIILOROSTREP It atacks by two fronts. PARICE DAVIS PAGENO="0192" 15546 coi~w.i~vrrPIvE PROBLEMS IN PIlE DRUG INDUSTRY U. Letter to physicians in Spain promoting Chiorostrep by Parke Davis, April 2S, 1973, ~ ~Qei~ ~. ~ (IQ~&-~ ~ JPARkE-DAVISj LABORATORIOS PARKC~DAVIS, S. A. E. MADRID Magrid, 25 de abril de 1973 Distinguido Oo].ega: Con is ilegada del periodo primavera-verano y los cambios higi~nioo-dietetioos, viajes, eto. qua suds impiioar, se prothioe tm visible aumento de inoidenoia de enterooolitis banales e infeociosas. Solamente queremos reoordarie una yes ads, is compro- bada efioaoia y seguridad terapdutioa espeoIfioamente en estos prooesoe del CELOROSTREP, odpstllas y liquido, que aotuando sisultdneamente en dos frentes, looal-iuteatinal y general, `produoird una rApita remisidn de los eintomas en Bus paoientes, evitando las complioaoiones. La reoordamoa especialmente la ~ muy ~Itil espleo en los anoianos. Esperando quete satisfeobo ooh los resultados de nuestro preparado y poni~ndome a su enters disposioidn para ouaiquier asuntorelaoionado con nuestros produotos, Atentamente le saluda, i. ~ Dr. Rioardo Picatoste Merino PARKE-DAVIS, DEPARTAMENTO MEDICO PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15~47 ~>Qc~c (~4J ~ ~ ~O('~ ¼ ,`~ P4ARKE DAVIS LABORATORIES, S.A.E. Madrid Madrid, April 25 1973 Dear Colleague The arrival of the spring-summer season and the dietetic-hYgieniC changes, travelliflg,etc. associated with it, there is a significant riae in the incidence of enterocholiti5,c~~~mon and infectious. Once more we would like to remind you that CHLOROSTRI~P offers a well proven efficacy and therapeutic safety to attack these proces~es. It[s manufactured in capsules and liquid, which attacking by two fr~nts ~local-intestiflal and general, will produce a fast remission of the symptoms in your patients, avoidin at the same time. an com 1 We especially remind you that t e liqul orm is v~y e u or admi~üstra- tion to children and old people. We hope you will be very pleased with the results of our product. We are at your disposal for any matter related with our products. Sincerely yours, Dr. Ricarclo Picatoate Merino PARKE DAVIS, Medical Department. PAGENO="0194" 15548 Coi~tPEnTIvE PROBLEMS IN THE DRUG INDUSTRY 12. Parke~Davis Chiorostrep label, older one acquired September 1973. ~ ?Ylt~ ~A~2LL ,~i~XlLi~ A ~ P~~6n Medics: V S L ~ es w-.~a combiriacido de Ch:o'~e~ln ~ P. k Cia. y d~ epzomscina. en v~sLss irO~O. ~ cap. aula z 2~Ctarad~ta cGt~ieoe 123 cog. cle Ca4a cr.n dc esoos Cuar~ ~os dos agenes ao:zbUlticos esti-c t~oaz:s. e~eocco ~ ar4rii~om çae parece anpiiar el espectro tacter~ano S~L~ Eat.. o~oathdn es de silo; en el traearnJen~o da ctoz~ de t~c ~twoe~o y dc t.cci~as infeccicocs mfr.ao ç~e cc 15 o-~zia dci cation. Se 1~a ectcpieadc ci Ciccc:.-ci, cci ~ Scat ...aoro de a tu o-.ccis atoroeccal y eta :~ ~isros s.-~: oper~c~u~ente, c0rsecc~ivaroente a is exL~pac±ort de ç~sre oi:~a3 *lnZecorne~ ~ prcpsrato~roe~te en cirugia rectal y dci ~ DOEiEiCACIO~ Y ADMINISTRACIOX Se ;uec2e s±nioistrar ci Cl~orostrep en us-a doiScacidcx de 2 sulas = cvci-.arath:a.s cacta sets ions era oscos do dsa.rr-ea ~ en Is enter'zaz drss~.oa La dos~s to~erada se Onicula .~oe ci eo:d~ C11O~.osdO, p~res is d!iidnoestreptomici~a no ~rdcir~ e1eoi~s ~enora~es debid~ a c~ sin cc obsorce en el lrnestjno. En ci pos:~aratorio. c~ eca docilicacicta d:ariamerne dunaroc tres 0 c~tt.ro cilia ao~ de Ia cule su~ca. Es~a combinacidra cc particuiarroeroc situ cut ci conjs.=~sousenue co-u Is adoirn ruactiri cia Uz~uidoa por cia coal. Ira Ins pacacocce io1e-ucicoes causacias por patsigeracs couusu.cs, cs~e tua:us~raco debe *~-~s-~ durauste c~.r~uça o ads tHis. Cunrido cc tO~IiO1 en Eacados conan ~uorua anal tubercuioaa ci Cialorosirep debe sec adurtloistrado en w~ dosiftcsn:n 50a700, a erusruclo is deals silas-ia o ssgcalecdo Un esu~ups-~ de ad==uornaciauu nsás prolongado. PRltCAt~iONES: Las precausuaones ordir.aflas retsti;is a los aniibi~ de anu;..o i~ecu:s como el Cluirrornyceto clatters sec c.ttserrada~ cotta se indica ~a anelsutte. Adeirsis so debe terser ;rcaer.ta cue scsi cuar~~ ~ )iayan ci.tn.siado os nuicrcorgartusrtaos lntestrua:es corn-cues del ciradro tsar. terlar.c os cuu000:cgansrilos no susoeptibies tales ccrruo ronnilha gr~r~~ reeor~.acuu l.a tcca paulge~a 0 normal. Es esutucual ~osier Ursa Cl;: c-cia constance us ~acuerue. SI aparecen rc-zeeas rrufeoclor.es dcr.das a rniccocr~. nlsnscs cc ensce;rittles deben tornarse las rneci:las apcupad.as. La ad ocauradids oral de anrthistarnlnlcos genenairazote ilivianci las reac- clones aAr5cas qiue OC*aiOnataceyie puedera segair ci atrupico tie cusiquje; PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15549 preparacidn antibiotics. Debe interrwnpirse Is terap6utiCa at no so pueden 4omlnar las reacciones de sensibilidad. ADVERTENC1A.~L05 nlños prematuros y los nacidos a término de me. sos do us mes do edad, aparentemente debido a inmadurez iislolOgica, requteren una dosiftcacidfl especial. Estos nifios a menudo tienen dificultades con dosis bien toleradas pot niños de mds ectad. So suglere para los niños prernaturos una dosificaciOn caiculada a base do no rnás de 25 rug. de Chioromycetin pot kilogramO de peso pot dia, fraccionadarnente, a intervalos de sets a ocho horas. Para los nacidOs a tdrmino do menos do un rues do ed~ci so sugiere uris dosificaciOn do no más do 50 rug. de ChiorOmycetin pot kilogramO dd peso pot cUa, frac~ cionadainente, a intervalos do seis a ocho horas. En los casos do adxninis- traciOn prolongada 0 cuando se utilicen dosis mayores que las recomendadas, las concentraciofles sanguineas del antibiOtico deben servir como guia pars graduar la dosificaclOn. TOLERANCIA P0*' 10 general, ci Chiorostrep es bien tolerado, y las alteraclones dO Ia sangre consecutivas a su empleo son raras. Sin embargo. conviene efec. tuar exárnenes, periddicos de sangre. en los casos do administraciOfl proior1~ gada 0 intermitente. En los prematuroS y los naCidos a tdrrnino do inenos de tin rues, ci uSo do dosis elevadas de Chloromycetin ha sido asociadO ccii disteiisidn abdO~ ruins), con 0 sin emesis, cianosis pálida progresiva, o colapso vasomotor, en algunos casos con resultados tatales. No se han comunicado estos efectos adversos en niflos con una dositicaciOn de 50 rug. de Chioromycetin por kilogramo de peso pot dia, o menos. La unterrupcion de Ia tera~ pOutica ha corregido los efectos adversos en nniachos casos, con restablect~ miento completo' do los pacientes. EN VASE El Chlorostrep so suministra en fnasco~ do 8 cspsulas y en forms de l4quldo en trascoS de 60 cc. (N.° 391). Laboratorios Principales, Detroit, Michigan, E. U. A Laboratories Parke Davis, S. A. E. MadrId PAGENO="0196" 15550 COMPET~VE PROBLEMS IN TH~ DRUG INDUSTRY ~ sit::; Sept, 22, JP/3 CHLOROSTRS P Chioroatrep is a comb:Luation of ch.lo:coaiyc ?tln and cithyciro- estrepLomyc~. n in capsuLes and liquid. Each capsule or u~oon.iL. coal nina 125 mg of each antibioiP.c When they are cociblied they axes cisc a syn.erqic action wLich 500515 to broaden Lii~ sucoptible bactcrian spectrum. It. is vary va]uabla in the treatment of entanic in.Cocti.oue of tic type dinrrheic and of the many mixed infactionu found in the surc1ury of the intas Lines . It has hero used aucccraufu .Ly in the tree Leant of anorect-al tuburculocis cad she annul. fistarla aura in port operal-ory cases, aftor ths extirpation of sri infected cydi, and Prc~opera tory cases of rectal aurgery and ini:esiainal surcjcry. DoceLfica Lion a l,~ ~ p It can he administered in doses of 2 or 4 copsu~es or in spoonfuls each every 6 hours in cases of dyarrhcs or dysinteric entaritis. The tolerance is calculated on tha chloromycetin coat ant ~ecauaa the dihydros troj'tomyci no will not produce gOciscra 1 effects; due to the fact that it net absorbed by the intestine. In p:rcoperatory cases this dose can be used 3 or 4 days before the operation. This combination is particularly useful in the puat-apcrstory patients togethcc with the administration of liquidu. orally. In the patients with infections caused by pathojcsns thu treatment should be continued during 5 or 6 days. When used for fistala annal and tuberculosis the CL. should be given in larger dance, increasing the daily dose or following a scheme of longer per] ad of administration. Precautions: The Ord:insry precautions used for antibio~sics of ample spactrum shouLo be observed. ilasidas, it should be noted that wh~a the coseson intca Lina 1 cci croargscni sms are eliminated, the non suceptible micro- orqssniams such as monilie can replaca tie pathocjca or normal tiara. It is i niporLan t to koap coirtant vigil enca of Lho patient. I .1. Iscci infecLione appoer due to microorganisms non susceptible, dun measures shoals] bu applied. C)rsTl ci deJ.ni st-tn Lion of: ant rh:c st-ass] in. cs shcu.I.d a 1 leT] cii-: Ilu' b.[e :iC. :~ t circuit set Iii rurrur tOe S sr iss Li. sr ty sac La 0.0 CIS11IIC( be casi I::,] led Proisata: so if b:i and ss~.s Lu one an :L:r old, sparc:,; tn fr .lVia.i el.o:;~ t-s i sirs tsr] Ly, to nil s.c qs a] il dccc, tin ott Id cc PAGENO="0197" COMPETITIVE PROBLEMS IN Tilt DRUG INDUSTRY 15551 ur;u'i I ly have di f (all iii. Cl luitil ti;~ a a I. 1 Lu I c at ad. ly oletar chi I dunn FOr rareliastras ~t re rc~i~ a "CI a era. a then 29 eq od c~r. ia'r I~:i logrun of voice ar dry cdvi dad aced L G to S hours :tritere -~ eec; beile cc los cc than a ito; [ old 1: 1: a cqr; a La 1 no core tb; GO rag per kiloyrera cf c-;~~I cc (I ;`, di. vt God n Goacs at 6 cc: B lr;uuc; derval. titan a eeL a- 6 cc- .tc-" aL alien or' ierc;r di; -a nrc acre;;; red, the cocicCcc La la-'; at iL.COJ OLi .10 thu blood ;doali be Li 0 j a Go to gnacte' a LO L) fec a. Tole'uo;co: Generally Oh. i a weJi. tol a. iLod a cr6 blood.. a Itceetioc ce~~e-' cuti ee~-t~ its user err rare. IIo.;','vcr i 9 is convenient of have pa rat odi eel blood teats whet :t iai sled ci cLue Lion is prolonij-d or o Larurni tent. In pnernatrcrss earl bela ce I a;. C tlcccn a eo~th oid the 1~igh dooca of (9. has been e-ssoc:i ate1 ~;lth ebdomi i-cl distension, with or witnout ernc'si S. cyanosa a, pal a 0: p:r'occJ; essi ye, or veecrcmO Len ccl 1icpcco, in sauce -ease;; with Cia Lu]. recul Ls . These ef;Lr,acts Ices not been reported on ChXlLGd trot ccl with 50 rag of Ch. par kg. par Gay, or less . Tie Late c:ru l;C on of the therapy has corrected in many cases the aelvece 0 c'[:[ra a, with coinple La recovery. Pncking: In containers eel Lb U cepaolcs and flasks with 60 cc. PIIlKE DAViS, MdDliID. 78.950 0 * 77 * 15 PAGENO="0198" 15552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13. Parke Davis Chiorostrep label, new one based on 1973 Chlorontycetin Monograph, W~G~42 9~ ~ct.. ~I~.d~LWto&. ~ b~4( c~ ~ 13 ~sj~a~ t~) Jt4~eLq A 1 Pcofeaidn Médica: S ~L 7 35 C~1LO~OST~2EP® 1 El ace cihoico ha estabiecido el clorenfeelcol SChionomycetinnt ParkoDavis) canto an antlbldtico ofoctivo do an ampilo espoctro bactonianoonelgoupo de infoccionea poe nickettelas y en ci llnfogrevulotna psltacosie. Pence une gnan ectividad antlmlcnobiana, atraviesa las barreree de ion tej)doe y cc difunde empliamonto con rapiden poe cccl todos ion tejidoc llqaidoa del cuenpo incluso poe ci iiquido cerebroesploci. La aetroptomicina as un antibidtico clinicamento Indicedo en Infeccionos cau. cadas Poe oroanismoo suocnptlbtoo. Adminioteoda pot via oral suebsorcidn cc minima auvque hayan pasado cantldades retail varoonto gnevdes a treads del enema intestinal en cites conceotracivoos. ~htoeestnep cdpsuiao as one combinscidn de clioranfenicot y estreptomiclne: cede capsule contieno 125 tog. do Chloromycetin (cioranfenlcoi Panke.Devla) 125 ma. ale eetroptonnicioa como Sutfato. INDICACIONES El cteranfenlcoi en on potn010 agent, torapdutico. Debe tomerse halo a dl. eccido do un medico y no dobo con utilizado no infecciovos telvialee. El cteaenfenicoi està espoclilvemeoto ivdlcado en Ia meningitis bacteniana, f token tifeidea. Infoccionos pen nickettoles. infecclones bectenosdos, Infocclones In. lreoculaees, neptlcemia debido a oritooistnoo gretonogativos y otnas lntecclo. nec brian doodo Ia ovldencla baotnnloldgioo 0 clinica dictaroloan ci clonsn. feslcol canto el avtibivttico aproplado. La eetneptomlcioa poe via oral no cc eboonblda aistemltlcavcente p pane a trends dcl intestlno en altec concnveractones. muchas bacterlas paidoenae In. teeOinales, incluyeodo ehioelles y el geupo coil. son auscoptibles ecu acciOn becteelcida. El Chiorootrep so usa coo éxito en ci peniodo pra.operatonlo en oponeclonos de colon o recta, infocclones mictas encontredoo en Ia clrugla del IntentIon, eoberculoeie enorectal, fistula oval. evcleloves do quletos y senos plignl. detee lnfectadoa y on infecclonesovtdrlcee a do tlpo dlernelco. PRECAUCIONES El Ctcranfenlcet debe temerse bale Ic direccidn da us mddice. No debe onenne en infecciones tnivtalee. Dleccasiassanc~ulnnaaeiocIpso anemIa apidotics he eido en earns ocesia. nea esociedos a là ednvinlstracldn do cloranfeolcol. En los cases de admi nintrecide peolongada a nepeliciAn do dosln debon hacerse availsin do cavgre * etenoelos eceularas. El clenanfenicoi no està ailnoedo en ci fendvoeno de intvnecoidn do drooc o encode ion pecientes rocibev uovcunnontemevte enticoegulantos a antlcon ontainon, podela ace neceaenie ace adaptacldo de Ia dosiltcacldn de dates. PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRtTG INDVSTRY 1555~ REACCIONES ADVERSAS DiscrasaS sanguineas e incluso anemia aplástica con exitus letatis han sido, en raras ocasiones, asociadas a ía admlnistraciófl de cloranfenicol. Se~ quedad de boca y con menos frecuencia náuseas, ocasionalmente también so presenta diarrea o vOmito pero estos sintomas son raras veces tan ~c'.~ros come para justificar a suspension del antIbiOtico. A veces se encuentrafl casos do roacciones de sonsibilidad. DOSIFICAC1ON La dosis para adultos y niños está calculada ampliamente ~obre ía base do 50 mg de cloranfeniCol por cada kg. de peso/dIa, dividida en dosis con in- tervalos de 6 horas, equivatente a 2 o 4 cápsuias o cucharaditas de suspensiOn. La dosis para niños prematuros y reclén nacidos, tie menos de dos semanas de vida debe ser reducida a 25 mg. de cloranfenicol pot cads Kg. de peso Wa. La causa de esta reducciOn es a inmadurez f~siolOgica presente en oct05 niñoS. Más lnformaciOn acerca de este asunto es proporcionada en ía monograf ía de~ producto bajo el titulo do sindrome gris. En ci periodo pre.oporatoriO puede darse a dosis indicada durante 3 0 4 Was antes do a operaciOn intestrnal. El Chiorostrep Cs particularmente zitii en ci periodo post-oporatorlo, conjuntarnenté con a administractOn de iquidos por via oral. En los pacientes con infecciones causadas por gérmenes patO- genos comunes este tratamiento debe continuarse durante 5 0 6 dias, cuando cc emplea en casos como fistula anal tube~culosa, ci Chiorostrep debe ser administrado en una dosiflcación mayor, aurnentando ía doSis diana 0 Si- gulendo un esquema de administraciOn más prolonçjado. En casos de in~uf i- ciencia hepética o renal Ia capacid3d do metabolizar o excretar ei ~toranfe- nicol puede estar reducida por to que ci medico debo ajustar ía dosis consiguientemeflte. ENVASE El Chiorostrep cc suministra en frascos do 8 capsutas y en formS do tiquldo en frascos do 60 cc. PARA INSTRUCCIONES COMPLETAS SOBRE LA PRESCRIPCION, COt~1SULTAR LA MONOGRAFIA DEL PRODUCTO A LA DISPOSICION DE LOS MEDICOS OUE LA SOUCITEN. Laboratorlos Parke Davis S. A, E. Madrid PAGENO="0200" 15554 coi~n'wrrTIvE PROBLEMS IN THE DRUG INDUSTRY aQ~Q~ CcV~L1á ~ ~ W~riw&~ CHLOROSTREP The~dli~iüc~al~ use has established Cholrarnphenicol as an effective antibiotic of ample bacterial spectrum in the group of infections caused by ric1~etsia and psitacosis limphogranuloma. Its large antimicrobial activity penetrates the tissue barrier5 and expands thru them very quic3ty, as well as in the body fluids., and the spinal fluid. Streptomycirie is clinically indicated in infectioi~s caused by s5usceptible organisms. Orally administrated its absorption is minimal even though large amounts go through the intestinal tract in high concentrations. ~ capsules is a combination of chloramphenicol arid streptomycin; each capsule contains 125 mg. of Ch. and 125 mg. of streptornycine as sulfate. Ch..is a potent therapeut±o agent. It should be used under a ~hysiciàn's directions and should not be used for trivial infections, ~It is specially indicated for bacterial meningitis, typhoid fever, *ri~ketsia, bacteroid infections and intraocular infections; septicêtja due to grthn negative organisms and other serious infections t~he~e bactericlogic or clinic evidence determine the ch. as the approprinte antibiotic. S * The streptomycine used orally is not systematically absorbed and passes thru the intestine in high concentrations, many pathoaen bacteria including shigellas and the coli group, are susceptible to its bactericide action. * .- dh. is used successfully in the pre-operatory stage Of rectal o~ colon surgery, mixed infections found in ifltC5t~. surgery, anal-rectal tuberculosis, anal fistulas, cysts *pilonidal infections as well as enteric or dyarrhea ifli~ Precautions:. Ch. should be used under physician's instrt~Ctr*. not be used for trivial infections. S , ~ * ~. r U * *` * ~ dyscr~ia~ ~ aplastic aflaefl~13 ` ~n rare ocassions'~'~e use of ch. When 3 ~ 5* treatment is necessary,. blood tests should be done at re~~ * PAGENO="0201" COMPETITIVE PEOBLEMB IN TH~ DRUG INDVSPTEY 15555 ChlorampheniCOl is not aligned with drug interaction, therefore, when given to patients together with axiticoagulants or anti-congestion drugs, an adaptation to these might be necessary. Adverse reacti~q~~j dyscracias and even ~plestic anem~a with ~ rare oc~s~ions have been ~ use of chl. Dry mouth, nauseas (less frequent) and o~as~ionallY diarrhea or vomit are present but they rarely are as severe as to justify the suspension of the antibiotic. Sometimes cases of sensitivity reactions are found. Doses: For adults and children is calculated on the basis o~ 50 mg per kg. of weight per day, at 6 hours intervals, equiv. to 2 or 4 capsules or spponfuls of suspePsion. For prematures and newly born babies, less than 2 weeks old the dose should be reduced to 25 mg ch. per kg. of weight daily. Physiological immaturity of these children is the cause of this reduction. More information about this matter is given in the monograph~ of the product, under the title gray syndrome. In the pre-operatory stage this dose can be used during 3 or 4 days before the intestinal surgery. Chlorostrep is particula3~ly useful in the post operatory stage, together with liquids via oral. In cases of pathogen infection the treatment should be continue during 5 or 6 days.Whefl used for annal fistula tuber~Ul0SiS larger doses should be given increasing it or following a scheme more prolonged. In cases of renal insufficiency the ability to metabolize or excrete chl. can be reduced, and the physician should adjust the dose consequently. Packing: IM ôontainers with $ capsules and in flasks of 60 cc. liquid. FOR COMPLETE INSTRUCTIONS ON FEE PRESCRIPTION, cONSULT THE MONOGRAPIW AVAILAb]EP~T REQU~ST FROM THE PH~tSICIANS. w~c~wG DAV1!~ ~ ~ -PM PAGENO="0202" 15556 COMPEPtTIVE PROBLEMS IN !~HE DRUG INDUSTRY Control of Medicines in Spain 114. Control of medicines in Spain asperceived by Mr. and Mrs. Zander after personal interviews in Spain with two physicians and two officials. CONThOL OP MEDICINIES XE SPAIN Our Parke-Ihvis Company in defending Us product information on Ohloromycetin when it is sold abroad always stresses that the company follows the rules of the health regulatory agency of the country in which it is selling its produot,explaifl.- jog, however, that ~~regulations on sales are less strict in some countries end some even limit the labeling", implying that in such countries the health regulatory. agency, not Parke_Davis, is responsible for lack of adequate warnings on their labels. They also advised us to talk to physicians abroad to get their views of Parke-i~vis labels for use of Chlorcmycetin in their own country. At the end of September 1973 we spoke to doot~ and health regulatory officials in Spain on the sub~eot we chose Spain because ?srke..Davis chioramphenicol labeling in Spain in the past has been lacking in warming~ of fatal aplastic anemia and has encou~ed unnecessary use in comparison with the company's U.S. ~h1oromycetin label an~~1nce it now has the new Parki~Davis Chloromycetin Monograph of basic product information and a new label, a substantial improvement but still inadequately stron*iri warnings and use restrict' tions, Also we have the moat documented materials from Spain since it was there that our daughter may have been given oblbrampheniool for tohsilitis that may have been the causek~f hsr death from aplastic anemia. Our belief that theParke~Da,ja Chloromycetin labels most lacking in warnings and encouraging in unnecessary use were precisely in those countries with the weak- eet health regulatory agencies as exemplified in our collection of labels from various countries, was corroborated in the case of Spain by our talks with physi- cians and be~Ath regulatory officials. In the past, at least, if ~arke-Dasis had pushed to include strong warnings of fatal aplastio anemia and to restrict unneces- sary use, especially for relatively trivial i1lnessee~whsn it was required to do so in theU.S., we are convinced that it could have done so in Spain. We first bad lengthy conversations with two physicians in epain who felt so strongly and were so outspoken to us on the past weakness of their country's health regulatory agency arid the power of strong pharmaceutical companies to do as they wished in pushing the sale of their product and also the consequent ignorance of Spanish doctors in general in prescribing ~edicinse that, considering the present political climate in Spain, we do not think it wise to identify them other than to say they are well-trained and experienced in the medical disciplines required to make such judgments. We will identi~~ythem privately but have a real concern for their safety because they are so im$Ssioned in their criticism of their country in this respect. Attached are some notes on these conversations written inmiediately afterwards with identifying items hopefully removed. These physicians had detailed documentation of the inadequacy - and worse - of the information on Use of their products given to the medical profession. by the pharmaceutical companies. Then we had a cordial interview Wit1~ the Directpy of the Division of Antibiotics and the Director o~ the Division of Oheniioal Analysis of the Spanish Centro Nacional de Parmacobiologia ( Control of Medicines). They also said that in the past the problem of control of medicines in Spain bad been severe due to lack of funding and manpower so that powerful pharmaceutical companies did more or less as they wished and acknowledged that chloramphenicol had been too widely used in Spain. However, right now they were very excited andhopeful with the sppointaent of well- qu~ified *irectors of Health and of ONDP which was being thoroughly reorganized, given more funding, and a four or five-fold increase in staff. Indications of the change are seen in their new chlorsmphenicol basic information that is much more restrictive of use, the requirements for all companies producing it to comply tøi~1t these basic ide~in their labela ( not sure they are able to carry this out fully), their beginning to use the world Health Organizations Adverse Reactions yeporting system, the beginning of a drop in use of chloramphsnical. However, they still do not have the manpower and are powerless to control advertining and promotional materials of the pharmaceutical companies including their Spanish publications comparable to our Bb~siciane Desk Reference, and to recall old-labeled medicines when the label is changed ( five years for cblormnphenicol). Attached are notes on the conversation with these official. Both the physicians and health regulatory officials to whom we takked in Spain gave us the distinct impression that in the past at least, there has been very little effeotiv~regu)a~Aing of the pharmaceutical companies and hence we believ&t~J~ ~ Parke-Davis itself that was responsible for t~smany years of inadequate~1aStl~d~!.d ~ PAGENO="0203" CO1~tPEPtTIVE PROBLEMS IN PEE DRUG INDtJSTRY 15557 15. Notes on conversations vith two Spanish physicians, September 1973. Qnveraatione with two Spanish physicians in apaisi Semh~~fl~: Health, in Spain, is considered of a lower level of importance than in the United States as reflected in the fact that the national health agency, Direccion General de Sanidad, is only a section under the Ministryr of the Interio,?snd not a departnent of its own. Also it has in the past been and still largely is ineffective end worse, having been headed by political appointeee, such as Franco's daughter's obstetrician (?) - rather than the best trained and begt..qualified man. Also money interests and downright curruption (bribery) have controlled the health agency and in particular the Centre Nacional de ?armacobiologia (Control of Medicines) which corresponds to our ?D& and which, in Spain, has been "just like the Mafia". The big moneyed oharmaceutical companies can get past laws and prevent laws and rules being passed by thetr power and bribery. Money mice, absolutely. However, a year ago ~?or the first time a good well-qualified man, Dr. Federico Bravo Morate, was appointed as Director of Health and another fine man, Dr. Manuel Reol Tejada, was appointed as head of the Centro Naflonal de ~aneacobiologia. So there may be some changes but the doctors we interviewed bel~re these two with the best will in the world cannot buck the entrenched powerful interests which have held sway so long and which fit into the whole miliue of Pranoo Spain. It was the super capitalists, the very rich)fighting the socialists not Communits in the Civil Wax~ annd they won. Spain has been ruled for their benefit ever since, in a very tight dictatorial system. There has been some easing up or he could not have been taL~king to us in this manner or doing the writing he is. But also there has been clamping down again recently, such as in the selection of the University prebident. In this setting, the sale and use of medicines in Spain is ghastly. Anything to make money, both when some drug oompanies know what they are doing by omitting warnings, directly lying, and denying adverse effects, pushing use of dangerous drugs for all sorts of uses, making 5shotgna" combinatiøfl medicioea of up to eight different drugs in one 4 perfectly incredible things all well documented by one of these physicians.) and also when they don't know what they are doing and through ignorance some companies, such as smaller "kitchen" drug compeniea , putting out potent mddicinee without scarcely any infosmation on use. Advertising in ~reely distributed pharmaceutical companies "journgls" fits the pattern of no warnings, even direct lies, push, push, push sales. ~he whole medicine picture he described is so awful it makes one afraid to put one~self in the hands of a doctor in Spain. And the worst of it is, that from these two physician's point of view~ it is all done because of greed. As one of the doctors said~ only a few people they know in Spain, their close friends, think of money as what it should be "juat a help to living"; to all the rest, nearly everyone, money is everything. The difference in Spain compared to America, in their opinion, is that in the United States we still believe something can be done about it even t~iough money is getting so powerful there ( in 0.54. too, w~J~n make changes. Here in Spain, it is impossible. One of tile doctors says he is not a cynic when be sounds so hopeless; he is a stoic about the Spanish eituation. He said that Spain has no ?ublic Health but it does have a National Health Service for all the people. However, there is m~sch better private health care for those who can ~r~~rd it. Two syetema and that for the poorer people ie definitely inferior. He cited an example of a distant relative of his who in the rational Health Service was diagnosed as heart failure (i) but when he finally went to a private doctor, it was diagnosed as aplastic anemia ~tmom which he died. He said when National Health Service is as unreliable as this, it is oWious one cannot obtain reliable reports of incidence of aplastic anemia in Spain. He mentioned a bare possiblity of a change for the bett~r because he has beard that the big pharmaceutical companies are asking for stricter laws in labeling. He figures this is an effort to drive out the competition of little businesses but it may work to the good in terms of better labeling. He laid Parke~Davis' s new Chloromycetin Monograph and label are good compared to the awful low Spanish standards in labeling but still not good enough for the b): heatth of the people of Spain. When asked if the new label is "appropriate" for Spain, they said "appropriate" ~ov~Spain is not the right word since the Monograph and label PAGENO="0204" 15558 COMPETITIVE PROBL~EMS IN THE DRUG INDUSTRY is "appropriate" to the present situation in Spein and in snother sense it is not. They said the Monograph should be staunger, more like the United States label for the best health for the Spanish people. The health regulatory agency does not require recall of old-labelgd stpck, nor does it require warnings on advertising. He showed us horrible examples of such advertising which the health regulatory ageuc~i is unable to control, One of the doctors also~,ead to us an incredibly long list of all sorts of forms of presentation of a MuSif (?) product as an example of ~very bad product, greatly pushed, and very such used. H~ spoke also of another ~e~y ~oora~td dangerous croduotjfor the right to sell it, he knew that bribery had been involved, having heard certain orders given over the phone. One of these doctors we interviewed has done a very painstaking study with many charts graphically portraying the inadequacies - and worse-of such of the product information supplied b~ the pharmaceitical oompaniesSy going into this kore fully in the?notes, we are afraid that we might identify the author of this study and in the ~ ~olitioal climate of Spain at the present (March, 1974) ~e have some concern for his safety since he is so outspokenly critical. Mven in September when he thought the political situation had greatly improved in Spain, he said he could not testify publicly on these matters when he visited United States as it would not be safe for him in Spain afterwards, H~ in vitally interested in the problem of the low quality of the information given to doctors on use of medicines and has made a serious study of the situation. He has presented Some of his findings to the fine new director of the Centre tmaeional de Psrmaoobiologia who is a friend of his and who welcomed his documented information. He translatad for us a description of chloramphenjcol in a textbook which he had written and 1t had good strong warniflgs and use restrictions but this has not been typical of i r~ormation on ehiorsaphenicol in Spain. He also took down the book most widely used by doctors in Spain arranged by illnesses with recommended medicines for each illness and after "tonsilitis", there was ~ He says it is routinely and very widely used før tonsilitis and in his own mind feels sure that~ Judy must have been given it for tonsilitie When she was in Spain, that it would be the most likely thing she would be given. When we protested that he was suppoaed to be a Umiversity doctor, he said that would not make any difference. The education of doctors in us4of medicines in Spain is very poorly done by the pharmaceutical companies. The education of doctors in medicine in general even in the Universities shows great need for improvement. It is a pig problem. He said, though, the biggest ~roblem is the doctors. ~hey don't know and they don't care~ If every doctor demanded full education in medicine, it would make the difference. Re stresses that the doctor~in Soain are at fault as well as the pharmaceutical companies or more so. He said we could try to see Officials in ~adrid, the Director of Health and the Director of Drugs but that we should ~ot expect anything to happen. But he feels our personal story may add a bit to the possibility of some little change. One of the doctors said it would not be good for him to write an article just singling out ohlorsmphenicol, that the broader problem is more important and a more effecti've way of attacking the problem. Referring to a book by Weinsggsn, a top expert on infectious diseases in U.S.~ he said that in his discussion of aplastio anemia, he ~ividss aplastic anemia into t~wo types: one the hypersensitivity aplastic anemia, the other the toxic type. 1hen he went on to say the hypersensitivity is just a theory but he feels there is something to it since chloraniphenicol induced fatg aplatic anemia is not dose related, appears long after the dZse (long ~time lapse), and has femilial characteritics to a degree, This is what Parke.. avis and othere refer to as the genetic theory. Our ,ftpanish physician tbi~~.rthe gerhio theory explanation can be used as an excuse by thepharmaceutloal c.cmea~jes for not giving aplsjtic anemia possibilities their due. He aayé~t is just a theory but even if it should prove cor~ect, t~rere still should be full w~rnings dto. He said there may be something to the race" `genetic theor~'. Anglo_barons seem more sunoeptible than 5editerraneans thou* conceded the effect on apparent incidence due to more or less adequate reporting and records. He said certainly Spain has cases of aplatic anemia and cited his distant relatj~. Spain has quite a nu*er of cases due to use of benzine In manufacturing. PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRtG i~uSThY 15559 16. Notes on interview with Chief of Antibiotic I)ivision and Director of * Division of Chemical Analysis of the Centro Nacional de Farmacobiologia (Control of Nedi~ines), Madrid, September 1913. laterwiew with Dr. MartineS Arroyo, ~hief of the Antibiotics Division of the Dentro tmaciOnal de P~xmacobiologia and Dr. Gorgia Prr~diz, Director of Division of Chemical Analysis of theContro Mactonal de Fsxmacobiologia on September 28, 1973: The interview withDr. Martinez Arroyo sndDr. Perrandiz was very cordial and conducted in English which may have occasioned some ~tgbt difficulties in under- standing since it was not their mother tongue. The basic impression they left with us was that in the past in Spain the problem of control of medicines has been very severe. The Centro Nacional de Farmacobiologia ( Control of Medicines) has been very weak, headed by political appointees with inadequate backgrounds, under- funded, underetaffed. In this ~ tuatiob the powerful pharmaceutical companies did more or less as they wished and the physicians prescribed more or less as th~ wished. The OND? just did mo~have tbemanpower and funding to control the ~tuation. However, " at this moment" everything is changlng the new Director of Health, Dr. Pederiqp Byavo Eurate and the new Director of the ONDF, Dr. Jose Manuel Meal Tejads ar~ very well., trained people, apparently for the first time. The staff of ~DP has been increased four or five-fold and there has been a totsl reorganization and they are moving to a much larger building. They sound very excited end hopeful of the future, readily a&.aitting that though they have many improvements in the works at present, there nra many things that tpy still cannot do all at once. We were given a copy of the World Halth rgcnisation~ Circular of the United States P5k-required Ohlorce*ycetifl label and two brief statements of the CNDPts mew basic position on use of c~~loswnpherticol Wbioh, we believe, are used as a basis for the new obloramphenicOl labels of all pharmaceutical companies. They are surpri~ngly restricted in the indications for use, much like our label, *surprisjnglyftoonsidering past oblorsmpbeeicol labeling in Spain ,but they do not have strong and full enough warnings of fatal aplastic anemia (pex4iapq,~becauae the Spanish officials th4mseE~~es think that the Spanish people are not~eubject to this reaction, though in the past they bate not kept records. They believe the fatal type is genetic and northern European ~moples, especially Anglo-Saxofla, are more subject to it. (yet they have 32,000,000 tourists each year, mainly from northern Europe). Ho*ever, they have just begun ~with WHO record keeping cf adverse reactions to medicines so ~bat eventually there may be evidence to support or discredit their belief that Spaniards are not as subject to cblorampbefiiOol" related aplastic anemia. They readily agreed that eblorastphenicol has beeti too widely used in Sp*im with much unnecessary use but seid that use is bg.inning to go down, especially with the new medicines coming along, like ampicillin. They estl,mated that 8O~ of chlorampbeflicOl in Spain is prescribed by physicians in the ational Health Service tith the other 2(~% priv*te and sold over.'tbe..counter with no prescription. About our own Pa*e-Davis Company, they said, that it is one of the smaller companies in Spain in aching its own product but said that ~arke.5asis manufactures "tons" of oF,lorampbenicol to sell to other Spanieh pharmaceutiCal companies to market in Spain. They agreed that Parke-5avis 0hloromycetin is a good quality medicine. They asid the new Parke~Davia Monograph and label is , of course, not the some as the U.S. !Mk~requi~ed label and indicated that they personally would like en even stronger label. `hey also said that they would not want United States companies to be required bl the U.S. government to have the same labels in Spain as in the U.S. (the proposal the Project for Corporate Responsibility tried unsuccessfully to have adopted by the five major U.S. exporting pharmaceutical finns) but would want to retuire inCluding fatal w~ningS etc themselves Parke.' 5kvis has stressed that labels should be different in undeveloped and developing countries than in the United States but we had not thought Spain was in this category with countries like Colunbia which Perke-i)avis officials cited as an example. However, these Spanish health regulatory officials said that Spain bealthwiae actuaMly was a developing county and imp~ted it still is to a certain degree today while they are in this process of change. However, they did not go on to say that this justifi*d past labeling of ohleramphenioO~, rather that it explained the poor labeling in the paSt in terms of the weakness of the health regulatory agenc.~. PAGENO="0206" 15560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY They said the CNDP does require the same warnings and use restrictions on all forms of a medicine marketed by a company when the basic lab4 is changed as in the case with the Parkehvis Ohioromycetim label change this past year although we bought Parke..Davis ohlorampheniool products of differe~~ forms of presentation while we were in Spain whose labels varied considerably. They explained this as due to old- labeled products still being available which were still within the five.'year duration of effectiveness. 1n otherwords, they do not require the companies to recall their old~-labeled madicines. They explained even now they still just 4~ not have the manpower to enforce such a regulation. The OlD? is also still unable to control advertising and preao~oflal materials ef ef pharmaceutical companies for the same reason, lack of manpower. They agreed the Parke-Davis promotional materials ~sbowed theawere bad, especially theChloz'ostrep ad and letter to doctors although L believe they were trying to say 0hlorostrep is not meerly as potent as Ohloroayoetin since only 20% is absorbed . (However, the irre.. vessible fatal aplastic anemia is not dose..related and can h triggered by very small doses as well as large dq~aes.) They said the pharmaceutical companies jnst put out such promotional materials without OlD?' e knowledge and they do not have the manpower to monitO'it. The ClIP efficials also Said that the Ya4emec~ Deiaon~ comparable in Spain to our ~hrsio1ans Desk Refere~, widely u~Uby physicians and put out by the pharmaceutical companies~i~n't at all like our ~ nor up to it at all. That they said no other country has anything like the qualtty of the United St~tea ~ end asked so hew could Spain be expected to have something comparable? The gross inadequacy in w~rninge and use tastructions of the product information in the ~~pecug~ino~ has been fully documented by a Spanish dootor, They flatly stated that they do re~sire all other companies to have the sane warnings and use restrictions on all forms of their product as are on the original medicine that was changed, such as Parke.Davis's Chlorcmycetim. In the past,at ~ leatt,wa are not sure this was so as there is quite a ~riation in the chioramphenicol labels of other 8panish companies. At least checking our labels, we are sure it was not and is not required verbatim as in the U.S. labels for chlorampheniool products but apparently they do believe in the principle. Whether it is adhered to and they can enforce it is another question which we did not ask. Dr. Martinez Arroyo and 1*. ?erraztdia were very oordial and friendly, interested in any information we had as well as freely answering our questions even though the manner in which their heel th regulatory agency in the pact handled the labeling of medicines by Øhe pharmaceutical companies could have been embarrassing. They were *0 happy and hopeful of the change in the fortunes of their agency that they looked confidently toward a better futire ira thi~respeot in their country. This optimism, though, wae not shared by the physicians that we talked to earlier who felt ~bat however good the new men are,that they will not be able to buck the powerful *I~*i*d interests in the end. They did say, though, that there ie some hope if a rumor that they had heard is true; that is, that the larger pharmaceut&eal companies in Spaia were beginning to demand stricter labels ( I presume Parke.1¼vis would be one of them) and that they had hopes this may have a good effect even though they felt the reason for the demand was to drive the smaller competitors out of business. PAGENO="0207" COMI'ETITIVE PRO3LEMS IN THE DRUG INI~USTRY 15581 1?. Centra Nacional do Farmacobiologia (CNDF(' s new statements on ch].orampheniCol used as a basis for new labeling of chloramphenicol products of Parke~avis and other companies in Spain. ~ %g~Lt~ CELORAMPHENICOL ~p~fic ~ndica~i~~ 10. Acute infections caused by Sa1floi~ella Typhy (it is not indicated for treatment of the bearers). 20. ~ infections caused by diverse salmonellas, Hinfluenzae (specifically in meningitis infections), Ricketsias of the Limphogranuloma-pSittaCOsis group, Gram negative bacteria causing meningitis pr bacterThmia and, finally, other rganisms sensitive)c~'resistant to all the rest of the an i-microbial agents. p~~ficat~on: To the proper indication of the specialty, the following paragrapb should b~ added: "The daily dose~for adults shbuld not be over two qtams, neither should~be administered for more than ten days'. Secondary Effect~: * After high dose and long treatments, chloramphenicol can give way to leukopenic, granulocitos~ and a~pafm4, there- fore it is very opportune to have *h~1ni~c ~ made during treatment. In some cases it can also provoke neurological reactions * " of intolerance or hyperergias. Cgunteri~dica~zkQn~: Renal insufficiency and women in the first three months of gestation. For newborns and premature babies dos~s over 25 mg/lS mg/kg/day are absolutely counter-indicated (respectively),. The administration should be made via intramuscular and in one single dos4. CAUTION: Its use should be reserved exclusively for the above mentioned indications. ~ ~ PAGENO="0208" 15562 COMPETITIVE PROBLEMS IN THE: DRUG INXflJ5T~Y i~ oQ~w~o~ CC~3w\ ~ Q&~~~\ ~ ~ ~ CLOaANFENICOL nmIcAcIoNEs ESPECIPICAS: 1O.-~ Infecciones agudas por Salrnonela Typ~y (no estandoindica do para tratamiento de portadores). 2Q.- Infeccionos graves por diversas cepas de salmonellas, IL.La f1~nzae (especificamente en infcciones menfngeas), Ricke~ tsias del grupo linfogranuloma-pstttaoosis, bacterias Gram - negativas causantes de meningitis o bacteriomia y, finalmen * to otros organismos sensibles que sean resistentes a todos7 los denu~e agontes antimior~bian~s. POSIPICACION: Se af~adirt~ a la propia de la especialidad ci ci-- * guiente pdrrafo: ItLa dosis diana en aduitos, no debe sobrepasar los doe - gramos, ni prolongarse m~s dé dies dias." EFECTOS SECUNDARIOS~ A dosis olovadas y tratamientos proromgadoe, ci cloranfenA co] puode dar lugar a leucopenia, q,granulocitosis y ane-- ffiia por lo quo es oportuno realizar controles beniI~ticos dM rante ci tratamiento. 4 En algunos casos puede provocar reacciones nounoidgicas, - do intolerancia o hiperbrgicas. CONTRAINDICACTONRS: Insuficiencia renal y mujeros gestantes durante el pnimer/ trime~tre dcl embarazo. En reci~n nacidos y prematuros est~n absolutamente contrai~ dicadas dosis suDeriores a 25 mg.- 15 mg./Kg. dia, respect~ vamente. La administraci6n ser6 por via intramuscular y en una cola dosis. ADVERTENCIA: Debe roservarse su uso exclusivamente para las indicaciones especificas reseiiadas. PAGENO="0209" COMP~IPIVE PROBtEMS IN TITE DI~G INt~tJSThY 15563 CHLORAMPHENICOL The laboratory must justify the use of ChloramphefliCol in this specialty since this is a useful but dangerous antibiotic~~, due to the incidence and seriousness of its secondary effects. ~`~~(4 ~ ~ TherefOre~ it shoudj~e~ ~ infeCt2~Qfl~,f~~r germs sensitive to its action, when other less efficient agents are count~r-indicated. s~pegg~j4~2EQ~ 1. Acute infections caused by salmonella typh~. (it iS not indi~- cated for persons suspected of disease bearing) 2. Serio~ infections by different groups of salmonella, H. influenzae (specifically meningitis), Rickettsia, the group of lixrphogranuloma psittacosis, gram negative bacteria re9ponsible for meningitis and bacte~mia. Finally, against other sensitive organisms which are resistant to all the other antimicrobial agents. ~~is c~ ter-in~d4ca dfor individuals with hyper_SenthtiVity history or toxic reaction to the same and J~nUL2~fl ~ ~ PAGENO="0210" 15564 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CLORANFENICOL El Laboratorio debe justificai~ el empleo de Cloraa fenicol en esta especialidad, ya quo ~ste es un antibi6tico dtil, pez'o peligroso, debido a la incidencia y gravedad de sue efectos secundarios, pox' lo cual de~r~er~arse_i,ara i~ecp~onesa~y~a, por.gérmenes sensibl:es a su acoi6n,cuaa do otrosagentes menos peligrosos son ineficaces o est~n contraindicadoa, Sue indicacignesesi~ecUi~,as son~ Infecciones agudas pox' salmonella typhy (no - estando indicado pai~a tratainiento do portado.- res). 29 I~fecciones a_v~ pox' diversas cepas de sal.~. monella, H. influenzae (espeo~fioamente en fecciones men1~ngeas), Rickettsia, grupo del - linfogranuloma..psittacosis, hacterias gram-ne gativ!as causantes de meningitis y bacteremia y, finalmente, otros organismos sensibles que sean resistentes a todos los demz~s agentes a~ timicrobianos. Est*~ c±ontraindicado en individuos con antecedentes de hipersensibilidad o reacci6n t6xica al mismo y ~jioke~ a~rse,~en inrecckones levies~ resfriados, grjpe~ infecciones de ~arganta Iii çoino profil~ctico para evitar infecciones bacterianas. PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRtG INDUSTRY 15565 CERTAIN WORLD RFAAIL~E A8S~BLY ACTIONS BELATED TO PRODUCTION AND USE OF DRUSS I. Pharmaceutical advertising - Resolution WHA 21.41 (1968). Pg. 144 - Handbook of Resolutions and Decision - a-~ ~ 7~j- ~-i-*e-~ ft~ LI. `Principles of Pharmaceutical QualIty Control and Good Practices in the Manufacture and Quality Control of Drugs (Technical Reports Series No. 418 and WHO Official Record No. l7~ Annex 12, part 1) Resolutions W}IA 22.50 (1969), WHA 23.45 (1970), WHA 24.56 (1971) Handbook of Resolutions and Decisions: pgs. 133 and 134 ~ .)t+A ~8~c(a1S7 r~~-: ~ `~`~?, III. RvaluatiOn of the safety and efficacy o'f drugs - Requests Member States to communicate immediately to WHO: a) any decision to prohibit or limit the availability of a drug already in use, b) any decision tO refuse the approval of a new drug, and c) any approval for general use of a new drug when accompanied by restric- tive provisions; when these decisions a), b) and c) are taken as a result of serious adverse reactions. They are also requested to include in the communication as far as possible the reasons for the action taken and the non-proprietary and other names, and the chemicsl formula or the definition. Resolution WHA 16.36 (1963) - Hsndbook Resolutions and Decision, pg. 139 See also Res. WHA 17.39 (1964) - Handbook Resolutions and Decision, pg. 140 IV. "Monitoring of Adverse Effects of Drugs" Resolutions: WIiA 18.42 (1965), WHA 23.13 (1970). Handbook of Resolutions and Decisions - pgs. 140 and 141. Technical Reports Series No. 498 - Role of national centres in inter- nstionsl drug monitoring. V. Study on: a) the feasibility of an international system providing data on the scientific basis and the conditions of registration and withdrawal of individual drugs; b) practicable minimum requirements and on other efforts to develops comprehensive approach to ensuring the quality, safety and efficacy of drugs, including the feasibility of implementing Article 21 (d) and (a) of the WHO Constitution. Resolutions: WHA 25.61 (1972), Handbook of Resolutions and Decisions pg. 143; and WHA 26.30 and WH.A 26.31. WHO Official Records No. 209 pgs. 14 and 15 and No. 210 pgs. 294 to 307. WHO Constitution Article 21 - The Health Assembly shall have authority to adopt regulations concerning: d) - standards with respect to the ssfety, purity and potency of biological, pharmaceutical and similar products moving in inter- national commerce; d) - advertising and labeling of biological, pharmaceutical and similar products moving in international commerce. PAGENO="0212" 15566 COMPET~FIVE PROBLEMS IN THE DRUG INDUSTRY [From the Lancet, June 22, 1974, page 1281] GHLORAMPHEN1COL SIR,-The indiscriminate use of chicraraphenicol in many countries has been the subject of much concern and attention. Ry~ie et al~varned particularly against the dangers o chioraraphenicol being dispensed without prescription in Spain and reported the case of a woman who died of aplastic an~rnia, some time after treating herself for a minor respiratory infection rith a botth of medicine containing chlorarnphenicol bought from a chemist's shop. This sad story cleatly illustrates the danger of unrestricted dispensing, and even pr~scribing by the chemist's shop attci'idant, of chloramphenicol-con~aining d~'u~s, but does not oIler what could b~ called a quantitative view of the problem. Jrt order to e~aluare t~ds, the following ~a .~as peçforiricd. 30 pharmacies in Barcelona were selected at random but in areas of different socini class. A 32-year-ëld woman walked into each of these pharmacies and told the following story: "My 7-year-old boy has been ill with a fever of 38~C since yesterday. His throat is sore and there are white spots on his tonsls. \Vhat could I give liith ? The attendants at 2 of th~.se shops refused to indicate any treatment and sugge~tod that she should cail a physician. In the remaining 2$ sortie type of remedy was prescribed, and sold, The most commonly dispenst~d remedies were: (1) 11 cases: chioraraphenicol, 100 rag.; plus sulphadiazir,e, 150 rag.; plus sulphamerazine, 150 rag.; plus aminopyrine, 75 rag.; plus camphocarboxylic acid, bismuth salt, 50 rag. These ingredients were present in a brand of suppositories, to be used every twelve bouts. In 6 caaes, two days of treatment were recommended, while in 5 other cases four days of trCat- ment were indicated. In 1 of these cases ampicillin (750 rng. daily for three days) was also given. (2) 6 cases: ehloraniphc;nicol, 250 rag.; plus quinine sulphate, 120 rag.; plus phenylhuta~orte, 120 rag.; plus mcthampyrone, 250 rag. This was also a fixed-dose drug combination presented as suppositories (to be used every twclve hours). Irt 4 cases a four- day course was prescribed and irs the rernsining 2, two diys of treatment were indicated. iii I of the last cases a further 700 rag. * per day of aminopyrine was reeomrneyided; and in ~he other, 800 rag. of tetracycline phosphate complex daily, for two days, was also prescribed. (3) 4 cases: chloraraphenicol, 150 rag,; plus sulphadiazine, * 100 rag.; plus sulphamerazine, 100 rag.; plus su!phamethazine, 100 rag.; plus camphocarhoxylic *~cid, bismuth salt, 125 rag.; plus ansinopyrine, 150 rag.; plus doxarndthasossi,, 02 rag. These were the ingredients ct a brand of suppositories dis- pensed to he taken every twelve hours for two days. In 1 of these cases 750 rag. per day of en oral preparation of phenethicillin was recommended simultaneously. In another, extra tablets of anilnopyrirse were also sold. 1. Latice:, 1972, ii, 1298. 2. Dunne, M., llerhcimcr, A., Newman, M., Ridley, H. ibid., 1973, ii, 781. 3. Verwilghcn, R. la., Verstraete, M. ibid. p. 1217. 4. Ryri~, D. R., fletcher, 3., Langinan, M. J. S., Daniels, H. a ibid. 1973, 1, 150. PAGENO="0213" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15567 (4) SnppOSitOrieS contaituttg diñe~ent xfl~Ktutes of chlor- amphenicol plus suiphonamides, tetracycline, and iuninopyrine, as well as other components, were sold in 4 other cases, the su"t'ested duration of treatment ranging frosts o~e and a half to three days. Iii one of thesC cases oral ampiciLlin, 750 mg. per day, was also prescribed for three and a half d~iys. (5) In 1 of the, ~emainiflg 3 cases oral ampicillin was clis- peris~d (7~t) mg, pet d~iy f~r three and a half days) and in the other 2 tetracyLlisie phosph~tc complex w~s given tc.i t~c ts4e~z orally at ~i dose ot, 375 mg. daily for two days. The results of these experiments hardly need any comment. However, we cannot retraiii from spe~i fic~slJy mentioning the irration~sli1y of the mixtures dispen ccl, arid the pre~eisee in them of potentially dangerous drug~;, such as chiosamphenicOl, aminopyrine, flnd phenylbutazone, to mention only a few. MoreoVer, the insufficiency of tls~ doses. and the short duration of the treatment, as well as the inadequacy of the route of administration, could briisg only little therapeutic benefit, while the dat~g~t ~f ~tinus side-effects remained.. Finally, the fact that al.l these remedies were unrestrictedly sold, while almost two~thirds of them carried a " dispensed by preêcription" sign, deserves consideration. F~cultad de Medicina, s ERILL Universidsd Auton~ssaa de Barcelona, ~ ~ Avda San Antosc~o M~ Claret 167, . U OtJTCH Barcelona 13, Spain. J. A. GARCIA-SEVILLA. 73-950 0 - 77 14 PAGENO="0214" 15568 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From the Washington Post Travel Section, March 13, 1977] Rxfor Tourists: ~ Beware the Foreign. Prçscription Drug* ~ I -, RAVELERS, especially those heading for Latin ~Axnerica, Southern Europe, Asia, and Africa, have long - `*been accustomed to getting admonitions like these: `Don't drink the water. *~` `~bon't eat uncooked vegetables. `Avoid ice cream, whipped cream and ~other products that ñiay have been made from unpasteurized milk.~ * No~r a new and perhaps far more Important warning should be added: `Beware the physician who pre- scribes drugs, and also the pharmacist who may both prescribe and dispense them, who may be unaware of the lim- ited value of these products and of~ their potentially harmful or fatal side- effects. .* Last year, after a long, in-depth study in Mexico, Central America and South America, it was disclosed that. some of these health professionals are~ giving out a potentially deadly anti- biotic to patients suffering from such trivial infections as tonsillitis and lar- yngitis. . Some have treated depression with a combinationof drugs that ~an interact, to cause death...- .;, Some are keeping patients on ster- * old hormones for such prolonged peri- ods. that some have suffered from bone-softening, pressure fractures~ of. `the vertebrae, psychotic changes and; * flare-ups-sometimes fatal-a-of latent ,tuberculosis and other Infections. PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15569 Some have administered excessive dosages of pofent anti-arthritis drugs, `1~e~ii1ti~ ths~rlou~r lethal daniageto th,e blood-formIng tissues,-;.,. ~ - These and similar prescribing blun ders now thoroughly doctupented by Latin American hernatologists, pathol- ogists and other exp'e~ts, do not mean that Latin Alnerican physicians and pharmacists, are poorly,tra1ne~,' poorly `motivated or unable ,~r )rnwlfling to keep up~todate. ,`Some of the health care rendered in the Latin American :`countrles is fully cothpaitsble to the best medicine prniticed in Washing-, ton, Boston, London or Stockholm. On' the,pthe~ hand, some medical care ren- dered in L4tln America is as poor as the worst practiced in `the l~xilted States. ` -: ~nstead, this misuse of drugs in Latin Aninrica- and also in such other countries as Spain, Egypt, India and Taiwan -app~ars to be a reflection of the astounding drug promotion and drug labeling disseminated to physi-, clans and pharmacists by much of the pharmaceutical industry, in this "edu- cational" màteria~ furnished by many drug companies, the efficacy or useful- ness of the drugs is too~ often gràssly exaggerated, and, tbe~ possible `b~zards are minimized, glossed, over or totally, omitted. .. `:.` Or,' ,the promotion may essentlahlj warn the physician,, ~his drug may produce nose stufimess while failing to mention, "This drug may kill your, patient." ` `~ * In our investigation we com~ared' the promotional material furnished to - physicians in the United States and: Latin America~ On 26 weU-known,~ widely used prescription. ~Irug `prod~, ucts ma:rketed under 4O",differe~t brand names by23 global pharmaceut- ical' firms. Some of these companles~ were based In the United States. OthJ' era had thelr.beadquarters in Swltzer-.' land, F'rance or West Germany. In the United States, where, drug promotion and labeling Is under the, strict control of the U.S, FOod antI Drug Administration (FDA), each corn-' pany Is required to limit its claims of usefulness to those that cast be sup- ported by substantial scientific evid- ence. All potential hazards must be clearly disclosed, and occasionally FDA requires. the warnings to be printed in extra large type. In' the Latin American countries, however, a different situation prevails, and the companies generally say what-,, ever they want to say One of the most notable caseshas In- volved the antibiotic chloraxnphenlcol,, marketed in many cQuntries by many different companies. PAGENO="0216" 15570 COMPETITIVE PnOBL~EM8 IN THE DR~7G INDtTBTRy In the United States, It Is described as Indicated only for such lifethreat. ening Infections, as typhoid fever, Rocky Mountain spotted ever, a~rare form of meningitis In children and a few other cOnditions In which Itis con~'~ sidered clearly the drug of choice. Physicians in this country are warned that It iay cause Infrequent but seri~ ous sideeffects, Including a blood dis order known as aplastic' anemia that, 111 some cases, carries a mortality rate of 30 to 60 per cent.~The.drug, the Ia. bels say, should not~e used for trivial infections. ~ .~ But in Latin America, `som~cpI~ipa. nies have recommended cblorarxiphen~~ ~ icol for laryngitis, tracheobron~li1t,is,4 pneumonia, gonorrhea, syphilis, ab. scesses.and other diseases i~ which * other and~safer drugs can' be;Us~, In those countries, thewarñfn~~ and~on~,. * tra1nd1cation~ are minima! or entirely ~omitted4,. 4 *~ Whenthls situation was called toth~ attention of the drug~ companies conS cerned, the responses included such explanations as these: "LaUd American doctors don't need any warnings. They already are aWare of. the:dangers"...~au e~plathat1Qn that Infuriates medical educators andother:, experts. "Thlngiare different In Latin Amer. `1ca"-.~a view that seems to suggest that drugs are far more affectIve and safer south of the Rio Grande. "What's Involved here Is an honest' difference of opinion~~~we feel ~*e:' have enoUgh evidence to show `that.i our drug Is accepts bly safe, but we can't convince the Food and Drug Act.. ministration." . . This last explanation would. proba. bly be more palatable if the company1 said one thing, In . the United States, where Its statements are under the heavy hand of FDA, and something .different in all of Latin America, where the rules are less rigid. PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 15571 ~%ut," said one Colombian health of. fletal, "when we find the company tells one atot~ here in Bogb~â, anoth~ In Quito,.another In Brasilia and itill another In Mexico City, that Is difficult to comprehend.' ~nally, drugeompanles have put up aS~theIr major defense, "We're not breaking any laws." They claim that `tiu~ir foreign subsidiaries or affiliates ave managed by nationals of the coun. * `tty~ tvho knoW the laws and reguta. tion~, and who obey them scrupulous. survey, including an ezamina. tiqu of Latin American di'ug laws, :showed that this defense was valid In `some countries. The companies were *; not violating any drug promotion laws * because no such laws were In e~st* ence. In others, the situation was un. clear, with the laws difficult to ana~ lyze. But in at least four cou.ntr1es-.~ Colombia, Honduras, ElSalvador and Panams.-4aws controlling drug pro. * motion are on the books, and cothpa. nleswere breaking those laws. ` So far as we can determine, none of these practices can be controlled by ~IJ.SI laws. Complicating the situation are ether jfactors: I Most Latin American physicians are ~~frrnpioyedby the government sod p~$ ~jrelatively low salaries. In contt*st, the company, detail inen...the dores" who promote their psedocts ~ pbysicIans-~are employees of prfr**~ ndustry, usually paid at I. psttlrh~' commissions, and not tactmed nock their ewn drugs. M**iyof ~v ~ detail men have hadantya~o~tt .~ education. 4 ** ~* ~ Although many drv4~ h~. quire a prescription wvttt* t~y *$~ ~ sician this requireowi*.ira~e~ ç~r ~inor~phine and its relatives, and for ~,some trai~iquil*iz~rs- ia freqi~ently ig- ~nored. In' most pharmacies, a patient an get a prOscrlpt~on product merely ~,by asking for it. Or the patient can de- scribe his symptoms to the pharmacist, and the pharmacist will then diagnose, ~prescribe and dispense. ;. * If a patient is injured by a prescrip- ~i~on~ drug~* the company, thepliysician T,~nd the pharmacist are, generally safe from retribution There are essentially no effective medical malpractice or :~oduct lia'billty:laws in~most of the countries; *~`. PAGENO="0218" 15572 COMPETITIVE PROBLEMS IN THE DRUG INDUSTET .As an example of what ~àn happen. ~jn this complex situation, we observed -the case of: a woman-thin, ner'vous,~ ~jittery-who went $n~o a large .phar- ~acy in Costa Rica and asked by name ~.f~or a potent tranquilizer.. The clerk *:said he had' something ,~ar better, and Id her a supply of what we recog. ~n!zed as a powerful but dangerous thy~ `roi4 drug. It may havebeen the appro. ~p~iate drug fQr her. But what mad6 ~ event memorable is that we wer~ ~u~nabIe to tel' whether t~ie clerk -who acted `without consulting any ~of his :v~11eagues~-was aged 14,13, or 12.' !:Since these findings were published :~ May.' of 1976,. and 1siznultaneQusly ~resented in testimony before the US. Senate~prnmitteeonMono'~~ !E~i~ have been signs mat me s~u~- tion may b co~re~ed `rnoi'e `swiftly than had been anticipated * ?The findings were widely reported throughout Latin America by ne~rspa- pers, radio and television. *In a number of global drug compa- nies, some officials-es~eciafly those' concerned with research ai~d medical. affairs-are urging their firms to fol- low the same promotional pOlicies they use in the United States in all their for- eign promotion~ ` . ~ *TI~,e United States delegation tothe International Federation of Pharma- ceutical Manufacturers has called for standardized~ drug prothotion, wQrld- wide, with full disclosure of hazards.' *At least .one major drug company `in this country has already changed its promotion in Central Arn'erica,' limft~ ing the:claixns fqr its products and dis- closing their dangers.; . ;`~.~` Until all cornpaniea follow this lead, however, many physicians and phar- macists in many countries may con- tinue to be uninf~rmed Or misin- formed, and' travelers should remain forew~rned. ` *`.~ Milton Silverman, Ph.D., i~.a phar- macolo~istand biochemist, lecturer in *pha~macotogy, SchoOl of Pharmacy, and senior faculty member, Health. Policy Program in the School of Med- icine at the University of California San Francisco. He `is the' author of ~7~'he Drugging of the drnericas." PAGENO="0219" COMPETTTIVE PROBLEMS IN THE DRUG INDUSTRY i55~3 ~&escription Drug Checklist A few ~ L. :t' woj~ld travelerS.. on avoidIngdai~geroua use of prescription drugs:** ,. Remember the4drugs to which `you are-or think you may be-allergie. Before youstart your travels, consult your o.w~ physicIa~i on which drugs- especia11~ th~ose, for.the control of pain and dIarrhea-~~-are4both effective and relatively~ safe1 Note that many. pain. `killers and. antfdiarrhea agents popu- larly prescribed and used in other countries are considered ineffective~r unsafe and accordingly are not permit~ ted on the United States market. Insist that a physician prescribing a drug for you abroad must tell you the~. possible serious side-effects, and which warnlng:symptoths1o keep in mind.' * Use~catition in taldng. a prescription. drug recommended by anyone other than a `physician who prescjibes it spe- cifically for you.~ If' you are on `long.term medlcàtión,. take along an adequate supply. If you may need to replenish `your' supply while you are out of the country, have your own physician or pharmacist give you the generic (or internationally ac- cepted) name of the drug. In many for- eign countries, the product may be marketed under a different brand ~name. If a physician plans to prescribe~ a~ drug for you, tell . him what other drugs-prescription or over.the-count' er-you are also taking. Drug-drug in- teráctions canbe lethaL If anyone-physician, pharmacist or. fellow tourist-tells you that a particu-' lar.drug is perfectly sate, don't believe "him. With few if any exceptions, any drug that is effective canalso be harm- ful and, in some conditions, can be fa- tal .-J'dilton Silverman PAGENO="0220" 15574 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY [From the Washington Post, March 20, 1977] DRUG FIRMS SOFTEN SALES PITCHES TO CENTRAL AMERICANS (B~ MORTON MINTZ) Major niultinatIonarphar~naceuttcaz.~ firms doIn~business In Central A~nièr. lea have begun to tone down promo-'~ tions of poteztdrugs to pb~siclins by limthng claims of benefits while mak lng fuller disclosure'of risks This finding ~`in~d'by~Dr. M*: ton Silverman, ~eof~ali~ forna drug specialist who'~compared. what 15 global eornpaniés-Atherican Swiss and French~-were telling Cen. tral `American doctàrs in: ~ withb what they be anto tell them in 197& Silverman, who revIewed 26 ~videly~ ~sed druãs, gave this sunithary of~his ~I~pdIngs ~` .."~ For nine medicines, the manufac~ tu~ narrowed claims of effective.. flh1$~rtd strengthened the warnings *tø, ~ them comp~rab1e to tliosç they P~lde physicians in the United States, ~ the 1?ood and Drug Ad~~ tZ*th~z~equIres proof of safety and etfectji&~ . ~`°~ t~~~xeductsthe pz~oducers. Were ~ ~reasonab1y f~u11 -55- ~ S~_~ ~ disclosure in 1973 and have continued to do so.". ~ S S *`For 11 `drugs, the com?anies "are coUnuing to ~exaggera~e thé clinical ~ ~v?lues of' the drugs and to minimize, gloss~ver, or totally ignor~e ~the poten./ tiafly' serious or fatal side effects." ~ Fdr fodr drugs, ~the Inânufa'ctur.- era elected to solve the ~ro'b1em by the expedient of* not publ~shing any.. thiifg in 1976 about them." :. ,-~ ~ * Probably the most dramitic'~change: involved Chioromycetin, the Parke.~' Davis brand of an antibicltjc, chlor'~ amphenicol, that causes a fatal bloJ disease in some users. - - In the United States, thf~ FDA has long required the Detroit jirm to say * in the official prescribing iftstructjons ~dvertiseme~t~ that chThraznphen. icoLshoui~i not be used in ~trivia1 in~ feôt.ions," but should be restlicted to a' ,few serious or 1Lfe.threaténing dis.' eases such as typhoid fever. ~ -~ PAGENO="0221" COMPETITIVE PROBI~EMS IN TI~E DETJG INDUSTRY 15~75 Thelabeliug also warns of the. link to the blood d1~easé. `~i ` .~ In Latin Amer'lca in 1973, `Slivesnnan ~sa1d, Park~DavIs~ w,ps * ci~nti~ad1cUng the advice It was giving In the Unlte~ States by rec~omxnending Ch1~oj-omy. cètrn for disorders including' tQnsilli. Its, pharyngitis, eye and ear' lnfec/ ;tlons, abscesses and pneui~ionIa. It di&~ not disclose pote*ntial* advez-s& reac~ thIns including the blood disease, nOr give the medical conditions In w~ilch the drug should not b&~ised. * fly 1976, however; Parke.Da7ls was. ;teuing Central, American physicia'na. virtually the same thing It w~s telling * physicians here, `Silverman said. .,.. He base4 his findings on the 1973 and 1976 entries in the Central Amen. cans Spanish-language'. edltiqn of the' "Dictionary of Phari'naceutical Spe. cialities"~ *, This is a widely,used reference vol. ume that carries entrie~ exactly a~ companies want them and it is distrib- uted annually to every doctor In Costa Rica, El Salvador, Guatemala, Hondu- ras, Nicaragua and Panama, along. * with the Dominican Repu~lic. `The 1976 edition -was `published. Sept. 30, fon~r months after the TJnI- versity of California Press published Silverman's bbok, `The Thrug~t~ th ` " en e' ~iithon- estifled' be~ore the Senate Select SrnaU Business Monop~ly Stlbcommit- and two associates, who compared the.' * labeling of40 drugs provided by 23 in- ternaUonal c~ompanies in the Un1t~d States with the labeling they provided on the same pr6ducts jn 11 Latin American countries. ` Although some ëompanies defended'~ the legality of overstating beflefits and understating risks outside Qf the United States, Silverman testified that they were violating laws in foun countries-Honduras, Panama, El Sal. vador and Colombia-tha1~ required full disclosure of hazards to~ physi. clans. * . * i' News reports on th~ Senate hearing * `were widely published in Latin Ainer ica, Silverman said. .~ *`. ` * At the time, C. Joseph Stetlei~, prest..' dent of the Pharmaceutical Manufac- turers Association in Washington, ac- knowledged "the importance of the questions raised" In `the bearing and said he intended to have' thâm' dis- cussed by The 1nternation~al Federa-' tion of Pharmaceutical Manufactur. ers.'~ ~, ~ ~* PAGENO="0222" 15576 COMPETITIVE PROBLEMS IN PEE DRUG INDUSTRY Three weeks l~tér,~Stetfer went be. fo~'e ~ meeting .of th~e federatiOn `1~ London with an unprec~,dented proposal to adopt a'resôlutio~ calling upon ~he world's drug ébmpanies t'o adhere to `standardized drug labeling ~` and to make full disclosure of haz. ards. * - Stetlar said recently that he raised the issue in part because of the- Sen. ate hearing and, in an apparent refer. ence to the pu-blicity~ "in part' because,, of recurring concetmn expressed in var*" bus other quarters." ~` - -~ The federation rejected Stetler's - * proposal, askthg him Instead to pre~ páreâ policy Ma~Iement~ - As adopted.~ by the federation at a meeting In NO.' vember, the re~olutloii said:~ ~, :That labeling and entries lii pre- scribing guides - for a prescription drug "should be ~consistent with tl~e.: body ç~f scientific and medical evi dence pertaining to that product,~ ~ Ing Into account good medical,~rao. tice and the requirements of each g~v ermnent's regulatory au~horities `~ * That ~`particular ~are shouhi be taken that essential information i~ to methca~l products' safety, contraindIca~. tiolis and s~ide effects is appro~iately commumcat~d~ ~ I * That eàch"of the more lilian 40 `~methb~r associations "encOurágC coth~ pilancé among Its member ~ornpanIes~ with this proposal "~ -` ~ Silverman commented that the fed" eratlon "unhappily~~ dIcj'no~ pro j~ose any ipethod to: implement the move." He said that a body such as the World Health Organization could "set u~p guidelines and maintain sur. veillànce." lie added:- ~ - ~ "Ii remailis' to be seen whether the changes thstitut~d by some. global drug companies' in Central America wllLibe applied ~tO~lI theil products'- throughout t~i~ *Orld; rand whether their lead will be'.fóllowed by other: d~i~ fms, ?~~- ~ PAGENO="0223" COMPETITIVE PROBLEMS IN `T~EI~ DRUG INDUSTRY 15~77 UNIVERSITY OF ( ~, SAN FRANCISCO `4 SCHOOL OF MEDICINE HEALTH POLICY PROGRAM 1326 THIRD AVENUE SAN FRANCISCO, CALIFORNIA 94143 February 28, 1977 Senator Gaylord Nelson Chairman, U.S. Senate Small Business Committee )~2L~ Russell Senate Office Building Washington, D.C. 20510 Dear Senator Nelson: I ant sure you will recall that, with a number of my colleagues, I was pleased to respond to your invitation and to testify before the Subcommittee on Monopoly in May of 1976 on the manner in which global pharmaceutical companies were label.' ing and promoting their products to physicians in Latin America. As based on what many of these companies were stating to Latin American~physicians in 1973 editions of standard reference volumes, this was the situation: 1. In most instances, the Latin American claims fox' the vaInes of these products were grossly exaggerated. 2. In most instances, the warnings, contraindications, and potential serious or lethal adverse reactions were minimined, glossed over, or totally ignored. 3. Regardless of the protestations of the companies that they were fulfilling their ethical and moral responsi~. bilities, and were not violating any laws in the Latin American countries involved, most were actually brea~ ing national laws in at least four of those countries. I am now glad to respond to your request to bring this infornz~' at~iort rip to date. Within the first th~r'ee wee1~s after your hearings, the findings of our study were extensively reported in major newspapers, radio, and television throughout Latin America. Various Lat~n American embassies in Washington, D.C., requested additional information, which we were happy to furnish. On 3une 16, in London, the United States delegation to the International Federation of Pharmaceutical Manufacturers Associations (IFPM1~) urged standardised labeling and promotion of drug products, worldwide, with disclosure of hazards. PAGENO="0224" 15578 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY UNIVERSITY OF RZELEY. DAVIS' 1RV1NL'~ SANTA SAMARA `SANTA GNUS SCHOOL OF MEDICINE HEALTH POLICY PROGRAM 1326 THIRD AVENUE SAN FRANCISCO, CALIFORNIA 94143 During the summer of 1976, we were pleased to reply to requesi~s for additional information from numerous medical, pharmacy, economic, and legal organizations and research centers and in. dividuals in Mexico, Central America, South America, the United Kingdom, France, Belgium, Canada, and the United States. Similar requests were received from individual pharmaceutical firms, and representatives of some of these companies visited us in Sen Francisco to consult on aspects of the problem. On November 11, at its meeting in Bermuda, the council o~ the IFPMA adopted a resolutiQn.~.fopmally intro~h1~e& by the United States delegation....calling upon every drug company to see that labeling "should be consistent with the body of scientific and medical evidence pertaining to that prcxluct," and that "particular care should be taken that essential information as to medical products' safetyf contraindications and side effects is appropriate.. ly communicated.' It is my understanding that this resolution has been in~ormally brought to the attention of the World Health Organization, Perhaps most significant, however, are steps teken even earlier by a number of multinational drug companies, It has rócently been possible for us to study the 1976 issue (publiet~ed in Sep.. tember 1976) of the Central American edition of the fltccionaz'io Especialidades Farmeuticas, and compare the promotI~ni~~ ~U~e- ments made to physicians in 1973 (when we began our research)with those made in 1976. For 26 products, marketed by 15 globa' con- panies....United States, Swiss, and French....these developments were evident: --For 9 products, the companies have elected to tone down their claims and present warnings comparable to those they give to physicians in the United States, - For 2 products, the companies were already making reasonably full disclosure in 1973 and 1~ave continued to do so, - For 11 other products, the companies~..in some cases in violation of Central American laws--are continuing to exaggerate the clinical values of the drugs and to minimize, gloss over, or totally ignore the potentially serious or fatal side effects, (A, SAN FRANCISCO PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDIJSPR'S! 15579 UNIVERSITY OF CALIFORNIA, SAN FRANCISCO BERKELEY' DAVIS IRVINE* LOS SCHOOL OP MEDICINE HEALTH POLICY PROGRAM 1326 THIRD AVENUE SAN FRANCISCO, CALIFORNIA 94143 3 ....Por 14 products, the companies have elected to solve the problem by the expedient of not publishing any promotional naterial about the drugs in the 1976 edition. Perhaps the most striking change involves Parke-.Dsvis' chioramphenicol, an important antibiotic marketed under the name of Chloromycetin. In the United States, the company has told physicians that its ~e should be restricted to a limited number ef serious or life.~threatening diseases, a~ch as typhoid fever, in which practically no other and safer product is as effective. It should not be used in "trivial infections." Physicians are warmed that its demonstrate,d hazards include the possibility of producing a highly lethal aplastic anemia or other blood dyscrasia. In the Central American countries and elsewhere in Latin America, however, the desoription of Chioromycetin in 1973 included recommendations for its use in tonsilitis, pharyngitis,\ eye and ear infections, pneumonia, and abscesses. In the 1973 Central American referenCe volume, not one contraindication, warming, or potential adverse reaction was disclosed. In the 1976 Central American edition, hQwever, Parke-Davis sait Chloromycetin should be used only in serious conditions and never for "trivial infections." There is virtually complete disclosure of contraindications and dangers, including the possible appearance of aplastic anemia. Although much remains to be accomplished, I trust you will s hare iii our gratification that some changes have come about. It is conceivable that some lives will be saved. I trust also that you are aware that my colleagues and I are grateful to you personally and to other manbers of your Sub~ committee for th~ constant and courageous support you have given us over the past years, and to Mr.Benjamifl Gordon for his unfailing assistance. Without such help, much of our work would have been impossible. Cordi 13y yours, Milton Silverman, ?h.D. 0 PAGENO="0226"