PAGENO="0001" COMPETITIVE PROBLEMS IN TF~E DRUG INDUSTRY ~1O&3?I,~ HEARINGS BEFORE THE SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITThE ON SMALL BUSINESS UNITED STATES SENATE NINETY-FOURTH CONGRESS FIRST SESSION ON PRESENT STAPUS OF COMPETITION IN THE PHARMACEUTICAL INDUSTRY PAET 28 JANtIARY ~1% JL~L~Y~ 9 AND iO~ 1975 ORAL HYPOGLYCEMIC DRUGS [CONTINUEDJ Printed for the use of the Select Committee on Small Business U.S. GOVERNMENT PRINTING OFFICE 56-592 WASHINGTON: 197.5 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 - Price $4.00 PAGENO="0002" SELECT COMMITTEE ON SMALL BUSthE~S [Created pursuant toS.'Res. 58, 81st Cong.] GAYLORD NELSON, Wisconsin, Chairman JOHN SPARKMAN, Alàbáma JACO~ K. ~AV~1~S, New York THOMAS J. McINTYRE, New Hampshire ~T. GLENN BEALL, Jil., Maryland SAM NUNN, Georg1a~ BILL I3BQCK,, Tefipessee', J. BENNETT JOHNSTON, Louisiana LOWJ~LL P~WEI~KER, JiL, Connecticut WILLIAM D. HATHAWAY, Maine DEWEY F. BARTLETT, Oklahoma JAMES ABOUREZK, South Dakota PALL ~4XAZT Nevada FLOYD K. HASKELL, Colorado BOB PACKWOOD, Oregon DICK CLARK, Iowa WALTER F. MONDALE, Minnesota WILLIAM B. CHEaItA~KY, Staff Director BENJAMIN Goapon, Staff Eçoito'niist JTJDAII C~ SoMMan, Minority Co~assel ~ KLATTfr Rei~earc1v Assis'tant SuucoMl\4ITTgli ON MONOPOLY GAYLORD NELSON, Wisconsin, Chairman THOMAS J. McINTYRE, New Hampshire DEWEY F. BARTLETT, Oklahoma WILLIAM D. HATHAWAY, Maine ,. ~. ~LEI~ BE~LL, Ja., Maryland .TAMES ABOTJREZK, SO~th Dakotk ` ~OB I~ACKWOOD, Oregon FLOYD K. HASKELL, Colorado JACOB K. JAVITS,* New York *Ex officio member. ` (II) PAGENO="0003" CONTENTS Testimony of- Chayet, Neil L., Counsel, accompanied by Robert F. Bradley, M.D., Chairman, Committee for the Care of the Diabetic, JOslin Clinic, Page Boston, Mass 13277 Chester, Edward M, M.D., Professor of MedLciI~e,, Case Western ReservC University, and Director, Athbulatory Medicine Teaching Clinic, Cleveland Metropolitan General Hospital 13309 Felig, Philip, M.D., Professor and Vice Chairman, Department of Internal Medicine Yale University School of Medicine -. - - 13318 Lamer, Joseph, M.J3., Ph. D., Professor and Chairman, Department of Pharmacology, and Director of the Diabetes and E~idocrinoJogy Center, University of, Virginia SChool of Medicine_ - - 13324 Meier, Paul, Ph. D., Professor of Statistics, University of Chicago, Chicago, Ill 13267 Falumbo, ~ ~ M.D., Assistant Professor of Medicine, Mayo Medical School :~:_, 13273 Ricketts, [~Ienry T., M.D., Professor of Medicine Emeritus, University of Chicago Medical School 13264 Schmidt, Alexander M., M.D., Commissioner, Food a~nd Drug Ad- ministration, accompanied by~ Rich~ird Merrill, Chief Counsel, Food and Drug Administration; J Richard Crout, M.D., Director, bureau of Drugs, Food and Drug Administration; James M. Biletad, M.D.~ Group Leader, Division of Metabolism and EndOcrine Drug Prod- ucts, Bureau of Drugs, Food and Drug Administration; and Robert Wetherell, Director, Office of Legislative Services, Food and Drug Administration 13200 Sims, Ethan A. I-I., M.D., Professor of Medicine, College of Medicine, University of Vermont, Burlington, Vt 13329 White, Colin~ M.D.~ Professor of Public Health, Department of Epidemiology and Public Health, Yale University School of Medi- cine, New Haven, Conn 13258 Zele~, Marvin, Ph. D,, Professor of Statistical Science and Director, Statistical Laboratory, State University of New York at Buifalo__ 13271 APPENDIX Exhibits provided ~or the hearing record by the Subcommittee on Monopoly: "Report of the Committee for the Assessment of Biometric Aspects of Controlled Trials of Hypoglycemic Agents," article from the Journal of the American Medical Asaociation j~337 "The Effects of Long Term Therapy With Oral Hypoglycemic Agents on the Oral Glucose Tolerance Teat Dynamics ift Chemical Di- abetes," presentation at the 33d Annual Meeting of the Americab Diabetes Association on June 23, 1973 in Chicago, Ill' 1337k "Assessing Survival in a Diabetic Population," by Paula Helene Kanarek, a thesis submitted to the Faculty of the Harvard School of Public Health, Boston, Mass.; January 1973, excerpts 13393 (~III) PAGENO="0004" Iv "A.M.A. Aide Let Upjohn Use Letter To Sell Drug," by David ~`age Burnham, article from The New York Times, July 8, 1975 13413 "Oral* Hypoglycemic Agents," excerpt from the Pharmacological Basis of ~Therapeutics, fifth edition, Goodman and Gilman pages 1519-1524 - 13414 Letter dated August 21, 1975, to hearing clerk, Food and Drug Administration, from Max Miller, M.D~, professor, Case Western Reserve University 13421 Presentation of Sidney M. Wolfe, M.D., and Anita Johnson, Public Citizen's Health Research Group, ttr the FDA hearings on proposed labeling for diabetes drugs, August 20, 1975 13423 "Oral Hypoglycer~iic Agents Are Worthwhile," by Robert F. Btad1~th 1VLD., JOslin Cliriic, ~o~tdn 1~'1a~ - . -- 13427 "AMk (~ffk~1aI Let cofir~3an~ LT~e ~nte" b~ ~tuM~t Arié~ba~h, th'tiÔ1~ from thQ Washington Post, July 9~ 1q75 13439 Letter dated ]~ebru~ry I~, 19'lS, t~ ~èh~tot Gaylord ~ Ohai~ nt~th, Select C imfttée ott ~m~ll ~itsinè~, U.S. ~ front Dr. Paul Meier, Pro~e~O~ o~ ~tatiétiO~, ThiIvè±sity of OMOa~o 13440 Letter dateti ~arch 11, 1075, to Sen~tor~GaylOtd Nelsott, Cha1rttia~ Select Cmnnuittec ott Sttiall B~niness, [1.~. S~n~te, frorri ~ei9b~i~t IL Mc1)a~de, ~fr., PresidOnt arid Chief Operating Officer, IJSV hai~n~-~ cetitic~1 Carp 13448 Letter dated April 1, 1q75, td ~1ott. Alé~iañder M. SCliñ~tidt aD., Coinffilssidtief, Food and Drug Adxttinisttatiott, from SOnath~ Gaylord Nelson, Chairman, Select Committee on Small is', tLs. Senate 13452 t~ettet dated April 10, 1975, to Senator Gaylord Nelson, Chai~, Select Committee ott ~tr1all Bushië~ T.Y.~. Sefiate, frdi~ Robert C. Wetherell, Jr., Director, Office of Legisititi* Servic~, F~dd anti t~iig Admi5istrtttiOn~- 13453 Lettei~ dated Febrttary 14, 197&, to Sen~tor Ga~r1ord NelsOn, Chaif-~ man, Select Committee on Small ~usiries~, U.S. Senate, frOnt Neil L, Chayet, Attorney at LaW, Cha~et and Somrenreicb, P. C., with ae~oippatiy1tt~ enciOsttre 13454 Letter dated May 21, 1~75, to Neil L. Cht~yet, Attot4e~ at Law dha3tet and Sontteru~e1cb, ?. C., front Benjathin Gord~tt, ~ta~ Economist, Select Committee on Small Business, U.S. senate 13457 Lettêi~ dated ~ul~r 10, 1975, to Be~j~tnirt ~4ordon, Sta~ff EConOntist, select Committee on Small Bushies~, U.s. Senate, from Nell L. Cha~*et, Attorney at Law, Ohayet ati~ Sotttten~cicb, P. C., ~th acéontpanyh~g enclosure 13457 Not1c~ of Public Hearing arid Proposed Labelift~ by the Fci~d a~d Iiru~ Adntittisti~tiOfl, Depnrtment o( Health, Education, afid Weif~tre, 21 CPIt Part 31(1, I~ockét 140. 75N-0062~ July 1 I$7&~.... 13462 Letter dated June 10, 1975, to Alexander M. Schmidt, M.b., Com- missioner, Food and Drug Administration, from Sidney M. Wolfe, M.D, Health Research Groui 13530 ~`The PI3A and Hypoglycemic IDrugs," by John K. DavidsOtt, M.D., Ph.D.~ article from the Journal of the American Medical Ass~cia~- t~on, Vol. 232 No. 8,, May ~6, 1q75, pages 853-~55 13535 ~`~ovérnthent f~r!s-l~tYA Proposes Important ReVisiOn," artiCle from Drug Therapy, Janue~y 1915 .~ 13538 "Oral Antidiabetfo Agents Have a Tmite4 Place itt Manttgeinetit and May Be Harwfi4," b~ Albert I. ~inegrad~ Ee~ S. c~eriient~ ~r., and Anthony D. Morri~Oi~ ijtiiversity Of P~tttxs~lva~ttia ~ehOoi of Medicine - 13541 "Ii~1if~o Efl~ects of' Tolbtttamidè on tl~O Sympat.ho-Adrølild ~y~teth," by Chung-Yi ~EIsu, Gary Brooker, Mtchaçl ~. Peac~i, Thotnas 0. Westf all, and Joseph Lai~ner, artiCle frOm Diabetes, Vol. 24, Stipple- merit 2, June 15, 1975 13556 "A Study of the Chronic Effects of Tolbutamide in the Rhesus Monkey," by J. Borensztajn, G. S. Getz,S. Glagov, A. Rubenstein, C. H. Ts'ao, and R. W. Wissler, FDA No. 72-114, February 15, 1975 13560 :Letter dated May 30, 1975, to Senator Gaylord Nelson, Chairman, Select Committee on Small Business, U.S. Senate, from Robert C. Wetherell, Jr., Director, Office of Legislative Services, Food and Drug Administration, with accompanying enclosures 13568 PAGENO="0005" V Prepared statements~ ~ Chayet, Neil L., Counsel, accompanied by Robert F. Bradley, M.D., Chairman, Committee for the Care of the Diabetic, Joslin Clinic, Page Boston, Ma~s 13620 "Role of Diabetes in Congestive Heart Failure: The Framingham Study," by W. B. Eannel, M.D., M. Ujortland, Ph.D., and W. P. Castelli, M.D., article from The American Journal of Cardiology, Vol. 34, pages 29-34, July 1974 ~. 13637 Chester, Edward M., M.D., Professor of Medicine, Case Western Reserve University, and Director, Ambulatory Medicine Teaching Clinic, Cleveland Metropolitan General Hospital 13643 Table 1.-Comparative usage of oral hypoglycemic agents, Cleveland Metropolitan General Hospital, 1968-1975 13653 Table 11.-Yearly use of insulin stocked in pharmacy, Cleveland Metropolitan General Hospital, based on accessible records, 1968-1975 13654 Fel~g, Philip M.D., Professor and Vice Chairman, Department of Internal Medicine, Yale University School of Medicine 1~655 Lamer, Joseph, M.D., Ph.D., Professor and Chairman, Department of Pharmacology, and Director of the Diabetes and Endocrinology Center, University of Virginia School of Medicine 13659 Meier, Paul, Ph.D., Professor of Statistics, University of Chicago, Chicago, Ill 1~665 Palumbo, P. J., M.D., Assistant Professor of Medicine, Mayo Medical School 13667 Ricketts, Henry T., M.D., Professor of Medicine Emeritus, University of Chicago Medical School 1~3670 Sims, Ethan A. H., M.D., Professor of Medicine, College of Medicine, University of Vermont, Burlington, Vt 13676 White, Cohn, M.D., Professor of Public Health, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Conn 13689 Zelen, Marvin, Ph.D., Professor of Statistical Science and Director, Statistical Laboratory, State University of New York at Buff alo - 13694 Exhibits provided by the Food and Drug Administration: Prepared statement of Alexander M. Schmidt, M.D., Commissioner, Food and Drug Administration 13697 Proposed labeling indications, contraindications and warning sections for oral hypoglycemic drugs of the sulfonyJi~ire~ c~tegory~ 1371i~ HEARING DATES January 31, 1975: Morning session ~. 13~7' July 9, 1975: Morning session 13289 July 10, 1975: Morning session 13309 PAGENO="0006" PAGENO="0007" COMPETITIVE PROBLEMS IN THE DRUG `INDUSTRY (Present Status of Competition in the Pharniac~utica1 Industry) FRIDAY, JANUARY 81, 1975 U.S. SENATE, SUBCOMMITTEE `ON MONOPQLY OF THE SELECT COMMITTEE ON SMALL BUSINEss, Washington, D.O. The subcommittee met, pui~suant to recess, at 10:07 a.m., in room 1114, Dirksen Senate Office Building, Senator Gaylord Nelson (chair- man of t'he full committee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist, and Kay Klatt, research assistant. The CHAIRMAN. Today the Monopoly Subcommittee of the Senate Small Business Committee is resuming its hearings on the oral hypo- glycermic drugs initiated on September 18, 19, and 30 of last year~ Our witnesses today will discuss recent studies dealing with the safety, efficacy and usefulness of this class of drugs. The list of witnesses includes four members of the committee selected by the internationally, renowned Biometric Society as well as a member of the Mayo Clinic. Additional witnesses to appear are Mr. Neil Chayet and Dr. Robert Bradley, counsel and chairman respectively of the Committee on the Care of the Diabetic. Our first witness this morning is Dr. Cohn White, professor of public health, `Yale University School of Medicine, New Haven, Oonn. Dr. White, your statement will be printed in full in the record, ai~d you may present it however you desire, and extemporize as much as you wish. Would you identify the organization you represent `for the record, or first, for the reporter. Perhaps each of you, starting on my far right, would identify yourself for the reporter, so if yon address yourself to some question we shall be able to identify you. Dr. MElEE. I am Paul Meier, professor of statistics at the Unive~.~ s~ty of Chicago. ` , ` .` `Dr. RIçKETTS. Dr. Ricketts, Un.i~rsity of Chicago. ` Dr. WHITE. Cohn `White, professor of public health, Yale `University. , ` , " , Dr. ZELEN. Marvin Zelen, professor' of statistical science, State University of New York, Buffalo. " " , 13257 PAGENO="0008" 13258 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Dr. PALUMBO. Pat Palumbo, Mayo Clinic. [The statements and ob~ servations made in this testimony are my own and do not necessarily represent official policy of the Mayo Institution.] The CHAIRMAN. Thank you, gentlemen, for taking the time from your busy work to come here and testify today. Now, if each of you, when you speak, would pull ~he mi~ro~hone up closely and speak directly into it, we si'~all be able to hear you. Go ahead, Dr. White. STATEMENT 01? COLIN WHITE, M,~., PROFESSOR OP PUBLIC HEALTH, DEPARTMENT `OP EPIDEMIOLOGY AND PUBLIC HEALTH, YALE UNIVERSITY SCHOOL OP MEDICINE, NEW HAVEN, CONNI Dr. Wnrn~. Senator Nelson, I am the chairman of a committee which w~s appointed by the Biometric Society and, funded by the National Institute of Health to carry Out the following mission: One, to make an in-depth assessment of the scientific quality of the UGDP study and in particular of the biometric aspects of the design, conduct, and analysis of the trial; two, to make a similar assessment of other `controlled trials of oral hypoglycemic agents. Tl'~e CHAIRMAN. Would you identify the Biometric Society in at least a brief description so that th~ record will be clear on that.1 Dr. W~II~E. The Biometric Society is an international society o~ people who are interested in the application of statistical data to biological problems. The CIIAtRMAN. Who are' the rnemb~rs? That is, what is' the eligibility of your membership.? Dr. Wnrri~. Membership is attained by application and the' corn~ mittee decides the qualifications of those who wish to join. In general, membership is governed by interest in the work of the society. The CHAIRMAN. Are there any special required scientific qualifica~ tions? Dr. WrnPR. I think an expression of interest is all that is neôessary. The CHAIRMAN. Is this an international soQiety? Dr. WHrv~. It is. The CI~Ani1~EA~. And are yQU president of this society? Dr. WliITE. No, I am not. I am chairman of the committee that was appoh~ted by the society for this particular purpose. The CHAIRM4N. And the society selected the members of the com~~ mittee of which you are chairman for the purpose of. evaluating the UGDP study? Dr.'WrnTE. Yes. The CHArEtMAN. k~'o ahead, doctor. Di~. WmTE. The ~oinmittee eo~isisted of six members: J~ohn Gilbert, Harvard 1J~iversity; Paul Meler, University of Chicago; Chris L. Rumke, Free Uni~rer~1ty, Amsterdam; :ROdO1fQ Sara~ci, PIsa, Italy; Marvin Zelen, S~tate t~iiversity `of Ne* York at Buffalo; Cohn White, Yale University. 1 See Biometric Society study, page 13337. PAGENO="0009" ~0~PiTIV~ PBQ~L~5 IN r~I~ ~RUG INDU~ 1a259 Th~ full thmmittee nie~ o~ si~ oeeasions over a 2-year period and. ha~ completed a report which will be publisJie~ on :February 10 i~ the Journal of the American Medical Association. Th~ `work of the IJGDP i~ ~tillin progreiss' and 1 tbhik it: 1~ fair to say that diabetologists in general await with interest the finding~ on the treatmei~t by insulin. There has ne~rer been ~` study of corn- parable scope and thoroughness on the long-term effects of this agent in suMects with maturity~onset diabetes. In the meanwhile, however, controversy ha~ arisen about the data concerr~iug tolbutamide. The committee saw as its maii~ task the investigation of the reported excess cardiovascular mortality in the stibjects recelv* ing this drug. It is interesting to note that the UGi~P pre- sented results on phenformin which are quite comp~rabie to `those on tolbutamide: the death rate from gardiova~cul~r catlse~ was apprô~i- mately the same in the two cases. rflle 1~idings on phenfo~mix~, if one can ~udge from the absence of criticism, appear to hav~e been accepted by medical scientists, even if they have not so far been tr~isl~ted effectively into medical praèti'ce. Yet these fi~d~ugs~ also were made by the UGDP using the methQds that have come under he~vy criticism when applied to tolbutamide, Because of the many factors which iufluence survivorship in a chronic disease such as maturity-onset diabetes, oaref~l method~ of investigation are needed, and, in particular, eontrol groups `~re:~ssen~ ti~1. Consequently we reviewed oaly such trials as we~ cont~oJ4ed. It then became' clear that the major st~&dy to cou~ider, other than tha TJGDP, was the study in Bedford EngIand~ organized by X~'r~ H. .Abby Keen and Dr. R. 3. Jarrett. It should be said at once, h~w- ,that the Bedford study, based on 125 patients in e~eh &f th~ two' treatment groups was not comparable in Size or in detail t~ the UGDP in which approximately 200 patients were followed `on ench of five treatments. The work of the committee appointed by `the Biometric Soci~t~ fell into four sections: One: Visits were made to ~he t~GDP coordinating center and' t~ two of the' cooperating `ciin1~al centers to study methods used in th~ triaL Two' T}t~ methods and findings `of the UGDP stud~.t `were discussed with several authors who had written' about them, and' the `BecU~ord study was discussed with I~r. Keen au~ Dr. Jarr~tt. Three: The publish~d criticisms `of the' UGDP were reviewed in t~iI. Comparable criticisms of the Bedford stud~r do not e~tst~ though several of the major criticisms made about the UG~P woui~ apply a f~'rtiori to the Bedf~rd ~tudy~ Four :Ne~ analyseS w~re made o~ the data from the UGDP and Bedfo~rd studies, the. data being kindly made available by the UireMtors e~ne4. Critics have poin~ted out t~at ii~ the I~GDP study the total mpr- tsiaty w~ not si~ificanUy higher in the tolh~e4ami4e groi~ than ~in the placebo gi~oup, even though there ~wa~ a signifi~cant `dige~~*w~i ii~ the cse~ of~ deaths frem ca iovaseula~r causes. We consii~er that this criti~isw has some weightbut is not eonirincing. Criticisms that have been commonly made but which, in our view, are not Co1~eCt~ are' PAGENO="0010" 13260 OOMPETITIVE PROBLEMS IN THE DRUG `INDTJSTW~ One: The `finding of excess mortality in the tolbutamide group was due to the data obtained from just a few clinics.' These are objections we do not find valid. . Two: The studies of Keen et al. and of Paasikivi contradict the IJGDP. Three: The baseline differences among the treatment groups ac~ count for the finding of the adverse effects from tolbutamide. On this point I might remark that none of the criticis, to my knowledge, has given serious consideration to the multiple logisticS method that wa~ used by the UGDP to take the effect of `baseline risk factors' intQ account. Until they do this they have not carried out an adequate review of the TJGDP analysis. The CHAIRMAN. And your group did do that? Dr. WHITE. Yes, we did. Four: The findings on the effect of tolbutamide are flawed by the failure to adapt dosage to individual need. Five: The evidence wa~ not adequate to justify the' discontinuation~ of the oral drugs. In our analysis of the TJGDP data we have used the same multiple logistic model as was employed' by th~ `UGDP investigators, but have taken additional variables into account to allow for the time each subject was under study and for differences `between `clinics. We confirm the principal finding from the `simpler `study of failure rates; namely, that the cardiovascular death rate was higher in patients receiving tolbutamide than' in those receiving placebo. This differ-~ ence remains after adjustment for the effect of baseline ~ariablës and cardiovascular risk factors. We have also made an analysis in which the extent of adherene~ to assigned treatment was taken into account. The highest death rate was found' in the tolbutamide group who adhered 100 percent to their treatment and who did not modify the dose. In an analysis of the data from the Bedford trial we found no difference in death rate between the placebo and the tolbutamide group. As indicated above, we do not interpret this failure to find a difference as a contradiction of the more thorough UGDI? study. `The conclusion of the committee is that it, remains with the pro- ponents of the oral agents to conduct scientificall~ adequate studies to justify the continued `use of such agents. The CHAIRMAN. Well, ~put in different words, are you saying that it is the judgment of the Biometric Society that it was a statistically valid sample, and a scientifically conducted study, and that the result~ of `the' study-are the conclusions valid? Is that what yon are saying? Dr. WIUTE. Yes. We support the principal findings of the UGDP study. We `do make some mii~ior critiei~ms in the report, bu~ we do, im general, support the main finding~ ` ` ` ` ` ` The CHAIRMAN. `And the `main finding is~hat? `Dr. Wnim. That there is an excess mortality in the group receiv-~ ing tolbutamide as compared with the group `on the pl~eebo. ` ` The OI~ATRMA~. Well, did' you find any evidence at all' that th~ oral ~hypoglycemic drugs retarded or pr~evented ` vascular cornplica~ tions of' diabetes? ` ` ` ` ` ` ` ` Dr. WmTE. That aspect of the study is one that we did not under- take. We considered that our main responsibility was to look intG PAGENO="0011" COMPETITIVE PROBLEMS I~ TI~E DRUG INDUSTRY 13261 the question of mortality effects. There is evidence still to come in on the long-term effects of the various treatments that were used. Mr. GoRDoN. One question. You say it remains with the proponents of the oral agents to conduct scientifically adequate studies to justify the continued~ use of such agents. Now, when we had the UGDP people here before us, they stated that they discontinued the use of these agents because they founçl it was ethically untenable to keep on giving these drugs to people~ be- cause they were satisfied that it was causing a lot of harm. How do you feel about that? Dr. WHITE. I think that if the group decided that it was ethically untenable, that would settle the question then and there as far as public policy were concerned. If they could persuade a responsible group otherwise, then the only kind of evidence that would be accept- able to us is evidence obtained from a controlled trial. The CHAIRMAN. Any of you gentlemen may comment on this. Is my memory correct that the UGDP study then concluded that diet was a better way of managing the problem than `by tolbutam~de and other oral hypoglycemics? Was that their general conclusion? Dr. WHITE. Yes. I think that is a question on which Dr. Ricketts would have a more valuable opinion than I have. Dr. RIOKETTS. Well, I suppose it was done because tolbutamidev apparently was no better than diet. The CHAIRMAN. Than diet? Dr. RICKETTS. Yes. And since it was a little dangerous' they would say naturally after a certain number of deaths that they had better stop. The CHAIRMAN. The general conclusion of the study was that diet was better than tolbutamide or oral hypoglycemics of any kind. Is that correct? Dr. ~IOKETTS. Well, I am not quite sure that is the .way to put jt. I think I just said, and I guess I will hive to repeat it, that tolbuta~ mide was no better than~ diet, and if that is true, and if it looked as if the tolbutamide was rather dangerous, then anybody *ould say, let us stop tolbutamide and do what we can with the diet. Does that answer your question? The CHAIRMAN. Yes. Dr. MEIER. There is one point I would like to `emphasize, and that is that neither our committee, the supporters of the IJGDP, nor those who think it was `an invalid study, believe that this is a simple ques- tion. It is complex, and I do not think it is capable of ,a simple answer of `the form that was' suggested, namely: "Here is' a `drug that is `of no value. It is toxic. We ought to abandon it." ` ` " There are special subgroups of patients who a~'e not successful' with diet, are unable to take insulin', and I think most `of the com- ments before this committee and elsewhere have pointed to su~h. subgroups. For these, tolbutamide may `haveS `definite value. But the question of whether it should be' used more widely, as it now is, re- mains difficult also. It is the case that the IJGDP investigators' themselves were not unanimous about the desirability of dropping tolbutamide from the UGDP study. The discussion that `went on there was very well described in a paper by one of the participants~ PAGENO="0012" 1~262 ~oMr~a'rrIv~ ~crn~s IN ~ ~ INPT,I~RY Dr. Theodôr~ Schwa~tz,1 The teii~ion~ the pulling and ha~ili~ig, the malor differences of opinio~i that led ~o t~iat final decision, mu~ all be taken into account in trying to interpret the mearnn~ of that cieci~ sion. it wa~ jnadged likely that toibutamide was toxic; but the evi~ deuce wa~ not considered conclusive. So I do not think we can say that there is a clear, flat conclusion tlmt comes out of thi~, and I think reasonable people may ~ome to son~ewh~t di~erent conclusions, rrhe C~AIRMAN. Clear conclusions about what? Dr. MEI]~. About *rhether tolbutamide should be aband~oned by all physicians in the treatment of diabetes. The CuAIu~rA~. That; really is not the issue, is it? Dr. MuIER. I think the issue is what we ought to do, not whether we have reached a firm conclusion. I do not think we have reached a completely firm conclusion as my statement will show, I deplore the fact that we are not in a position to reach a firmer conclusion than we now have, but I would support the final statement of the Bio- metric Society comitdtte&s r~iort~ which suggests that; a new study might be eonducted~ I think it would be ethically legitimate to con~; duct a new study. I myself think it i~ not ethically legitimate to con- titiue to use the drug without a new study. The CHAIRMAN. The issue is not whether you should prohibit it~ use under any circumstance on any patient in any situation., The question is, as a general proposition, should you use it in those cases where the patient situation can be managed by diet? For example, Dr. John Davidson said that at the Grady Memorial Bospital it was finally concluded after the study-~I think they had some 6~5OO patients, which I believe was the largest group in th~ ~o~nt~y-~-that they would take them of~ the drug and if my recollec- tion is correct their patients were better managed on diet. He sa~id it was tough medicine to swallow because they had lived with oral hypoglycemics, thought they did well, studied the iYGDP~ study, which, they concluded, was right. rrhen, in a mOre precise ansi*er-'-I believe I am correct, and if I am not~ I will correct the record~-~-he thought that maybe in a. very, very small percentage of cases, I think he said it might be I percent or less, an oral hypoglycemic would be indicated to be used, He did ~ot state, what that case was, so I do not know whether that waS an ~nsurance policy statement or not, But in any event, is that not the question: `Not whether 7~u should abolish these drugs, but whether ~n those cases where diet can inan~ ~ge the problem, it should be used? And is it not the con~iu5ion of the TJGDP study, as well as Dr. Davidson at Grady ~[emoHai IIos~ pital-and the doctor from Mayo will address hithself to this 4u1es~ tloti also~'-that there is a very,; very small percentage of cases in which it i~ indicated, but that it iS widely used ~n cases where it is yiOt indicated4 Is that a fair genetalization? Dr. MEmn~ I think the question reall3r is whether the evidence is of such over~helmM~ clarity `that the conclusion `reached by these gentlemen Should be' a regulation imposed by law up~m the ntedioal 1The~prntd~o~troversy ~ .& Pei,sonal Pet~speet1~e (A.fluaia of Intei~na1 Med1cI*~. PAGENO="0013" COMPE4~1~t11~ `r o~i~s m~ ~ inu~ ~ I32~$ co~iuniby generaLly. If we `were solidly convinced that ~tolbutami~e were poison, there would be no doubt about it, and if the hcueüt~H~k ratio wa~ çlefini~ly proved to be unfavorable, then I think we wouLd seek' regulation to prevent its general use. What I am saying is that I do not think the eiriden~co is thait~ Qlear. I think that sqine inv~sti~ators have come to the kind of con~ elusion that yçu cribed, an~ not being a phys~ciau, I have no jndep~R1d~nt op1n~lo~ about whether their e*perieuce is one that could be generalized to all physicians. I think there is enough room for doubt th~,t I ~puld be hesitant to seek r~guiation to determine absolutely that the drug may not be used except in that 1 percent of cases. I çlo think that there is enou~ evidence against it that even though we might allow the community to use its judgment with relatively little restriction, that it would only be appropriate to do that as long as we are setting about immediately to settle the remaining doubts. I am sorry that the state of affairs does not lead me to a feeling that we know all the answers. I think there are important answers we do not yet know, and therefore I would be reluctant to go so ~ar as to say that the use of tolbutamide should by law be restricted to the 1 percent subgroup. The CHAIRMAN. I do not think anyone is dealing in absolutes here, and of course there are all kinds of medicines in the mark~t- place which are widely used for `nonindicated cases. This, it seems to me, from what I have heard from the experts is what we are talking about here. The conclusions reached at Grady Memorial Hospital was that there was a very, very small number of cases ~n which the or~I hypoglycemics were indicated, that the large percentage was better managed by diet, and that their results' after mor~ than 3 yCars showed that the patients were better than they ~vere before, and this is what the TJGDP study indicates, I assume you agreed that the study was statistically valid ~al- though being a scientist I am sure you want to say that nobody caji be absolutely sure, which is of course true. Nobody is ab~oIuteIy sure about anythii~g, but you' do endorse the position of the Biometric Society in their evaluation of the UGDP study, is that correct? Dr. MRIRR. Let me' say that I wholeheartedly endorse the report that the Biometric Society Committee put out,' and I will disc~i~ that further in my statement. The CHAIRMAN. Dr.: Palumbo, did you want to comment?' ~Jr. PA~tTMBO~ May `I? ` ` ` As a physician and clinician who is involved in the treatment o~ diabetic patients, I think that we have to make a reasonable ~id'g- merit on the basis of a randomized clinical trial such as the tTGDP as to what we are going to do for the pati~nt who sits in front of us; find the decision here is based upon. the first principle that each physician is committed to; and that is-4f I may, use the Latii2 phi~ase, "primum non nocere," which "translated means, ~`d~o ii~ narm. And therefore, it has tO be el~ar that our treatment i~ n~t ing harm to the patient. Now, we may, under unusual cireuth~tsA4ces, elect for a risk-benefit ratio, but I think for the majority of our PAGENO="0014" 13264 ~oM?ETTTIVE PROBLEMS IN ~THE DRVG INDUSTRY practice and the practice in this country that it should be that these agents should be curtailed. The UGDP study's conclusions should be accepted. Mr. GORDON. Dr. Palumbo, did you people at the Mayo Clinic stop using these drugs? Dr. PALUMBO. We have stopped using them routinely. We were never very "gung-ho" about them in the first place, but we had used them prior to 1970. When the results of the University Group Dia- betes Program came out, we accepted the conclusions and, adjusted our practice accordingly. Subsequent to that~ a couple of our members of the department of statistics and epidemiology looked into the matter with a whole group of people with Dr. Cornfield in the group, and they came up with the conclusion in 1971 or 1972 that the studies were valid and that the conclusions were justified despite all of the possible, you know, flaws or criticisms you can point out with any prospective study. We had accepted these conclusions as valid in 1970 when the re- sults were promulgated. We do not use the agents routinely, only under the unusual circumstance if a patient says, I absolutely refuse to take insulin, then we usually assign them to an oral hypoglycemic agent. I still have this reservation that we are using these agents solely to control blood sugar; and we are not absolutely convinced that the control of blood sugar makes any difference anyway. In fact, that is one of the findings from `the UGDP study that perhaps blood glucose did not have any relationship to complica- tions, and so you are introducing' an agent to control blood sugar which of itself may be harmful to `the patient., I think there is no question that this agent has to be curtailed. The CHAIRMAN. Curtailed, did you say? Dr. PALtrMBO. Curtailed, c-u-r-t-a-i-l-e-d. The CHAIRMAN. Thank you very much, Doctor. We will proceed to the next witness, and as I stated a few moments ago, feel free to comment on any question asked or any statement made by other witnesses. Our next witness is Dr. Henry Ricketts, University of Chicago Medical School, Department of Medicine. Dr. Ricketts, we are very pleased to have you here this morning. You may present your statement however you desire. STATEMENT 0]? HENRY T. RICKETTS, M.D., PROPESSOR OP MEDI. CINE EMERITUS, UNIVERSITY OP CHICAGO MEDICAL SCHOOL Dr. RICKETTS. Thank you very much. I feel a little embarrassed to read the first paragraph, but I sup- pose I ought to declare myself as to what I am. I studied-well, first of all, I am emeritus professor at the Univer- sity of Chicago Medical School. I have studied diabetes and cared for patients with diabetes and conducted researches in this specialty for 34 years. I have been president of the American Diabetes Asso- ciation and' cofounder and president of the Chicago Diabetes Association. PAGENO="0015" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13265 I have served on the study section of endocrinology and metabol- ism, Grants Division, National Institute of Arthritis and Metabolic Diseases, and have served as a contributor and an associate editor of the journal "Diabetes." I think that is probably enough. My connection with the Committee of the Biometric Society was that of a consultant diabetologist, and I attended most of the meet- ings. I was struck by the thoroughness with which the members of the committee made their investigation. I detected no bias for or against the UGDP study. The committee listened to more who criticized the study than. to those who were less opposed or favor- able. The committee did not hesitate to ask the coordinating center in Baltimore for raw data when a point was in doubt, and members made trips to the center and to several participating clinics to check methods, procedures, and results. No uncertainty `was too small to leave unresolved. I should remind you that the TJGDP was set up to determine whether various treatments for diabetes would minimize the mainly vascular complications that notoriously accompany that disease. It is ironic that a full report dealing with complications has not yet been published because, in the third and fourth years of the study, an alarming preponderance of deaths had accumulated in the tolbuta- mide group. The investi.gators, then, per force, had to turn their attention to mortality and survival. I was not a participant of the TJGDP study, but I followed it closely. Despite some imperfections, I think that the results' aIld conclusions of the TJGIDP have shown tolbutamide and phenformiti, and probably their cousins, to be dangerous drugs, especially when taken for extended periods of time. I stand by my opinion of 4 years ago, expressed with the help of a committee of the America~i Diabetes Association in the editorial statement accompanying the first report of the TJGDP. I quote: "The TJGDP mortality study shows that death rates were essentially the same in the IYA:E~ group"-I suppose I have to explain that. Mr. GORDON. Is that the insulin variable group? Dr. RICKETTS. Yes. I will explain that later. The TJGDP mortality study shows that the death rates were essentiafly the same in the people who had various dosages of insulin and which maintained more nearly normal fasting blood glucose levels than in the more poorly controlled groups of the placebo and the other groups. This would appear to mean that efforts to establish good control of hypogly- cemia in the kind of population studied had no effect on mortality. The real lesson of the data is that if diet plus insulin does not reduce inor- tality below that experienced with diet alone, it Is highly improbable that oral hypoglycemic agents will do so. There is indeed no doubt about the reality of the greater number of cardio- vascular deaths observed in the TOLB group as compared with all other treat- ment groups. Inquiry into the reasons for this has been both intensive and extensive. Aside from the most proximate explanation, that tolbutamide may have been directly and solely responsible, the possibility that the tolbutamicle population, by chance and despite randomization, entered the study with more or greater risk factors than the other populations bad to be scrupulously in- vestigated. Although this possibility has, in the opinion of the ADA Ad Hoc Editorial and Advisor~ Committee, not been excluded, the weight of statistical analysis PAGENO="0016" 132(~ Co TIY~ p~j~ ~ makes It prc~bai~te that the ~ces~ ro~a~cuku~ mortality Fa TO~B is at- tft~Yl~ either to 1i~e dr*g ~t~elf o~ to t~n idere4 and unknown ~aetors~ Iii U~e absence of evidence for the Fatter, suspicion would naturally attach to tol- butamide. The WQrthilty study is at least s~~ge~tlve enough to put a damper on What appears to be thC indiscriminate use Of all oral bypoglyceni&c age~ets in the treatment oi~ mild or moderate, adult-~mset dia1~etes. Mtboi~h tolbutamide, for practical reasons; has been the only sultouylurea drug investigated by UGDE. This is 4 years ago. The chance that other compounds of this fami1~ may be shxitlarl~ lnvol~ed ca~inot be dismissed despite differences in molecular structnre, Jt wou~4 not be justifiable at this point, bowe~er, to proiiU$t the mamiJfaetlire and use of su1fony1w~ea drugs, for they will i~robably continue to fill a need in special circUmstances. If these drugs are dangerous, what course should we take? `You have just heard that their manufacture of the drug should not be forbidden, and for reason. For exampJe, how do we treat a diabetic patient who ought to be taking insulin but is living alone with a broken, or amputated, or paralyzed arm that prevents him from using a syringe and needle? One who is blind and cannot measure his dose of insulin? One who is old and tremulous? One who is mentally disturbed? And finally, one who refuses to take insulin, In another vein, there are diabetics who are engaged in hazardous occupations and ought not to take insulin for fear of reactions. We ought to make allowance for these j~atients, even though the oral agents are not very effective and, I believe in the long run, may be harmful. The CHAIRMAN. Does this list of exceptions include most or all of the exceptions that you could think of? Dr. RIcK~'rTs. Well, I think so, yes. I might think further, but that is quite a number. The CHAIRMAN. All right, please go ahead. Dr. RIOEETTS. But if we continue to make these agents available, as I think we must, how do we protect other diabetics who would like to use them but should not? Insulin comes to the patient with a package insert that carries a great deal of information, incli~ding certain warnings. The oral agents come to the patient in silence because they have been re- garded as innocuous, needing no instructions except the doctor's directions for dosage and timing. This must change. But it is the physician who should lead the way, and I hope that; the report of the Biometric Society will in time convert the many ~urremt unbciiever~. Meanwhil -~$d this might seem t~ be prepos-. terous-it zthgl~t not be too radical to ask the FDA, under proper authority, to transfer the oral. hypogiycemi~ agents to the circum- scribed schedule II of dangerous drugs along with barbiturates, amphetamines, ~nd certain narcotics. Phy~iciaus might learn that the oral agents are not exactly safe,, and the requirements of BNDD prescriptions, if for dubious need,. might become a salutary nuisance. This arrangement, of course, would have holes in it-and I can see some-but It might have the effect of helping to reduce the use of a product that too many pa..~. tients c~uid well do without. ` . . . PAGENO="0017" CoMr~IVE PR~E~f~ i~( ~E~i~' mtTia; ~D~STBY I~32~7 Th~ ~CIA~R~A~. Than~k yo~ very much, Doctor. Our next w~itaëss is D~. Paul MciM~, ~Dcpartment ~f Statistics, Tjniversity o~ `Chiçngo. Dr. 2~feier. STATE1YIERT OP PAUL HEIER, PH. D., PROPESSO1~ O~I? STATISTICS,. UNIVERSITY 01' CHICAGO, CHIcAGO, ILL. Dr. MI~ER. Mr. Ohairman, I speak as a member of the Biom~tri~ Society Committee on biometric aspects o~f controlled cliaiical t'±ials of hypoglycemic agents, which report is under discus~ion ~todny. Professor White has outlined our problem and our findi~gs. Professor Zelen will speak about some of the particular criticisms~ made of the UGDP report. I shall speak a little more generally about the role that I see for clinical trials in guiding our decisions about tnod~s of therapy. It happens that in March of 1970 I testified before this cOmmittee on the subject of risks of thromboembolism due to the use of ~ai contraceptives. I spoke then of the deplorable lack of prospective controlled clinical studies on the effects of oral contraceptives. I discussed possible reasons for that lack. Let me quote a few lines from that earlier testimony. I said: Frankly, the required research, although important, is not especially appeal- ing to scientists. It is not fundamental and it is not exciting. It is diffidult,. it is expensive, and It is fraught with the risk of attack from all sides. Who would willingly prepare himself for such a study, make an application to be weighed competitively with others on scientific merit, and risk the loss of support halfway through the study when a review committee with diffei~ent views or priorities comes to consider renewal of support, all this when he stabds to gain so little in scientific recognition or otherwise? Evidently, for whatever reasons, there is no sound' body of scientific stu4les concerning these possible effects available today, a situation wbic~i I regard e s scandalous. If we proceed in the future as we have In the ~last, we will contlime to stumble from one t~ntative and inadequately supported conclusion to anotl~er, always relying on data which come to band, and which were not designed ~or the purpose. The planning of better studies is difficult, and the recruitment of investigators willing to commit their efforts to these purposes may be mOre difflcttlt still, I believe both are possible and essential to the public welfare. At the time those words were written, I had no knowledge of the UGDP, but they could scarcely have been more apt.' Let me interpolate in my prepared statement my warm commenda~- tion for the group of, pi~ysicians and statisticians who undertook the `UGDP study. With whatever limitations, this i~ far ai~d, away tlae best evidence we have to date on tolbutamide toxicity. it `is an ~xcel- lent study. No o~ie study can answer all ~f ~the relevant questiol3s, but that is scarcely the fault' of these investigators, and 1 am led to modify my statement about the lack of excitement a~d, interest that such studies could generate. I think this group has shown us that there is new ground to `be. broken through some of the work that they have done in the theo~y of the conduct of controlled clinical trial~ and they `have also con- tributed substantial new knowledge. to1 an importa~it medical probleni. ~T return to my statement. - , -~ 56-592--75----2 PAGENO="0018" 13268 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY The CHAIRMAN. May I ask a question? You state that although the UGDP study has its defects; it is an excellent study proving the case against tolbutamide. Is there a comparable study that proves the case for tolbutamide, really? Dr. METER. No, there is not. The CHAIRMAN. What did you mean by that, then? Is there no case? You were so equivocable in what you were saying awhile back and now I do not quite follow you. You endorse the IJGDP study, but then you say the case against the drug has not been proved. Do you mean absolutely proved 1,000 percent, or is it 99, or what? I cannot follow your testimony at all. Dr. METER. I understand your question, Senator. A major point that I hope to leave with you is that in this area of clinical research we will often feel obliged to stop a study before we achieve a high degree of certainty. We wish it were otherwise. It would be very nice if we could say for certain. "These are the facts. Now everyone must fall into line and follow the facts." IJnder the circumstances we find that we must make decisions in the face of substantial uncertainty. Whereas I believe that the TJ&DP is the best evidence that we have, I believe that the study was indeed ended. before we could be certain. Take note that I am not trying to make an especially cautious statement about a virtually proven fact. The evidence of toxicity is substantial, but in itself by no means conclusive. The CHAIRMAN. Before you could be certain what? Dr. MEIER. That the drug is toxic. Before we could be dead certain of that they pulled it off the study~ The CHAIRMAN. Before you could be certain that the drug was toxic. Dr. MEIER. Yes, before we could be certain that it causes heart attacks. The evidence pointed that way but before it was certain, in my opinion, they quite properly withdrew tolbutamide on ethical (grounds. Senator, I wish I could say that a good study necessarily gives a solid answer to a reasonable question. A good study, ethically done, may leave us with considerable residual uncertainty. I am sorry if that is confusing but I feel that that is the circumstance. The CHAIRMAN. It is confusing. I suppose you are familiar with the Kefauver amendments of 1962. In 1938, the Congress, because of the sulfanilamide disaster, passed legislation that there should be adequately controlled studies to prove the safety of a drug before it is marketed. Then in the midst of the dispute over the Kefauver proposals the thalidomide case arose and the Congress passed legis- lation that there has to be adequately controlled studies to prove the efficacy of the drug. I think most scientists agree that this is sound. You should not put drugs on the market that are not safe, safe by a scientific meas- urement in a cost-benefit ratio. Any active compound, as everybody knows, has side effects and may be serious. So we are dealing with a situation here where the question is do you put into the marketplace for broad usage or even a narrow usage a drug for which the efficacy has not been proved by carefully controlled scientific studies? There are no adequately controlled PAGENO="0019" COMPETITIVE PROBLEMS IN THE DBtTQ INDUSTRT 13269 studi~s that prove it. Yet there is a comprehensive 10-year study that raises a very serious cloud over both. the safety and efficaQy of this class of drugs. That is what we ai~e dealing with, is it not? Dr. M1~izR. indeed, it does raise a very serious clOud but you seem to be urging me to conclude that it is proved, and there is qmte a diffei~eiice between a very serious cloud and proof.. The CHAIRMAN. I am nOt trying to do that at all. What~ I am try- ing to urge you to appreciate~ at least is what the. law is, and th~t is that you do not int~oduce active compounds. for use in ñiedical~ prac. tice and use them broadly unless there is proof they do some good, ~ind particrdarly when there seems to be some serious indications that they do harm. That is the issue here, is it not? We used to put drugs into the marketplace prior tO 1938, and there was no proof of ~afety and no proof of efficacy. And in the whole history of the development of drugs down through the history of mankind there is hardly half a dozen of them that survived as being safe or efficacious. Most of the drugs people have taken for hundreds of years had no efficacy at all. They might have been safe because they did nothing. . . But we are dealing with a question here of a study that indicates there are serious side effects and a study that indicates that there does not appear to be any possible usefulness except in limited ca~es. That is the issue we are dealing with. Dr. METER. I agree, and I think the difference we are arguing about is the difference in how solid the evidence is. I would further agree that we need to define policy in the face of uncertainty, that we cannot wait for final proof. The CHAIRMAN. Let me ask you this question. If you had the UGDP study before the drug was marketed, do you think it would be marketed under the law? Dr. METER. I doubt it. Shall I continue? The~ CHAIRMAN. Yes. Go ahead. Dr. METER. It is true that the UGDP had defects. It is true, alsO, that it falls short of proving the case against tolbutamide. Noneth~.. less, as Professor Cornfield remarked in testimony here last Sep~ tember, the UGDP today provides the best available information on the possible toxicity of tolbutamide. As to defects, there are no studies which are entirely free of them, and it was the judgment of our committee that this study was well conceived ai~d executed, and that those defeats we could identify did not give reason to doubt the findings. As to it being inconclusive, that was inevitable in the nature of the case. Once the investigators became convinced that there was substantial evidence of toxicity, and not of corresponding benefits th~y had no choice but to withdraw the drug. I hus we are left with an ominous yet inconclusive result, and I believe that this is a typical outcome which we may~ expect to see repeated in many other instances. It may be, in such a case, that the commun~ity of physicians will decide that, although not conclusive, that the evidence is sufficient to abandbn the drug. Or, on the con- trary, as in the UGDP case, they may conclude that the evidence does not require them to give it up. PAGENO="0020" 1327(~ COM~iTIV~E I~EtOELEM?S IN `rBE ~E~RtY~G i~m~nsm~ in The ~la4~ter ~oase, ho~w~ver, I ean ~ee ~no a1tei~nativ~ to The ~nitia~. tion of ~a ~new cl~ieal t~rial, oxiadu~ted ~y ~ s~cian~ iancommiced by the first one. I ~houk1 extpect, ~fl any ~event, that i~boi~ p~hysicians rntd pa~tient~s ~h!oqild be made as ~nHy in~formed abaiwt fhe e~d~enee i~s is feasible. I go so far as to* hope that fbhe experience to date ~ith ~orai hypo. glycemic drugs may convince ins That &inicai trials should he a ooiit~uin~ oom~pone~t of d\rug .eurveilance for any dr~g, from the first 1da~ of its release, and so long ~s substanitial doubt abo~t the baia~ace of risks and bene~ts remains. ~)he Cu~AIR~Aw. I think everybody would a~iree that your last sentence would state an ideal situation which we would ~ii hope someday would be a~hi~ed. `I~r. M~n. Seiaatqr, I would hope that day would be ea~y rather than late. I sp*e sentiments like this 5 years ago before `this committee. I de~eri~hed in some detail ways in which authority might be given to the FDA, and methods by which the funds could be allocated to such studies. I was pleased to see that in testimony in September Dr. Prout argued along quite similar ~ines. I do not think I see anything in the line ot legislation that would tend to move u~ in that direction, and I would hope there may be some. The IO~UIRMA'N, I do not ~think we need the legislation, but prob~ ably do need the money. But I think There is no doubt that it would b~ ~very sound to start good clinical trials once `a drug is marketed, because if there is not, we `would have to rely upon the reports of physicians' observations around the country. It may take a long time for individual physicians to accumulate enough data to associate with some adverse e~ect because individual observations would have to be reported thirou~h medical journals or to each other, and that would take quite a while. Your recommendation is very sound and I do not believe anyone would disagree with you on that. Dr. METER. I would just like to point out that in this case it depended upon an interested academic group, physicians and statisrn ticia~n~, to decide that it ought to be done and to con'vince an NIH study section' that it ought to be funded, `at ~quite a high price, in N~IH terths. That seems to me `to `be an unacceptable way `to operate. If such `a drng is to be marketed, the sales of that drug not simply the taxpayers' money, should contribute to carrying out a study. I think there are proper ways in which that obligation could be laid upon the. manufacturers who are selling the product t~ see that the funds are supplied, not `because they feel like it, but because they must do so. And that is the kind of le~i~lation I would hope to see. The O~IA~R~1AN. As you might recall if you read the testimony in additi~n `to "the testimony you gave yourself 5 years ago, ~when I r~sed the ~iues'tion ~ibout `studies `to detet~mine how many thierograms of estrogen could be put into' an ora~l ~ontraoeptive and still ~be e~1FeQtJive, the answe~ was, well, it would be very hard to gst vOlun~ teers `to ru~i that risk. I `do not `think that is the case. I think there' would be plenty of v~lunteers ~ho are seriously concerned about whether or not' they got pregnant now or 6 months later, who `would be put j~to a, `test ~ see whether you could dramatically reduce the ipiqr~grarns of ~estrogen in the~' oral contraceptive, and it seems quite' PAGENO="0021" COMREW[~IV~ J?I~O~LBMS IN THE ]~EUG W~UST~Y 1a2Th n~tt~ that s~ fa~ M I 1rnow,~ i~~ ex.periment~ of th~t~ kind ~ ye1~ been made, ai~d ~e h~d~ 15Q microgi~u pills in ther mark~tp1&ee, wi~ile~ Ein~tuid ~ve~ ~head~ wit1~ ~O, We tpok testimoi~y~ front au English scientist. But you are absolutely rights we have not done the kind of eon~ trolled studies we ought tOr do. Thank youi very much for your testimony. Our next witness is Dr. Marvin Zelen, Statistical Laboratory~ ~UNYAB, Amherst,. N.Y. STATEME~IT OP l~ARVIN ZE~EN, PH. D~ PROPES$O~ OP STAT*U~ CAL SCIE1~OB A1~D DIREC~OB.,~ STATISTICAL LAB ATOB~Y~ ~4~& UNIVERSITY OP NEW YORK AT BUFFALO `Dr. ZELEN. Senator Nelson, thank you for tkis oppàrt~unMy to appear before this committee. My general eomment~ w~li be divided into two parts. The first topic I wish to comment on is how is it that able ~nd respected clinicians can disagree with the interpr~tation of the UGDP data ~ The tolibutamide cardiovascular death rate us more than dottble compared to ather treatments~ Yet many clinicians ~ho treat adult onset diabetes find it difticuit to accept ~nth a fig~re. For many of them, this elevated cardiovascui~r death rate, does z~ot ~ppear to have been perceived in the clinic. I would like to examine other factors which may lead to ele~tatea cardiovascular mortality. According to the UGDP data,. the eardi~o~ vascular death rate for individuals above the age of ~3 is appro~i~ mately five times that of individuals. ~3 or younger; pe~ipie with nrteriai calcification at time of diagnosis have fou±~ times the cardip.. vascular death rate compared to those' without arterial caiciflc~atio~i; the initial glucose tolerance test, called GTT, as used by the UGDP investigators, shows that those with a GTT above ~&, the median value, have double the rate of cardiovascular deaths conipau'ed ~o those who have a GTT below the median; men have a donbl~d cardiov~ular death rate compared to women. Although the nun~. bers quoted are rounded for simplicity, it is clear that in the c1in~ there are many factors simultaneously influencing cardiovascular deaths~ Several of these have greater or eqnal effect on th~ cardiO~ vascular death r~t~ compared to the effect of tolbutamide~ As a resuit~ it would be difficult for a clinician to' perceive an elevated cardió. vascular death rate associated with tolbutamicle. Such an effect wmi4 be almost completely obscured by these other important factors. Onl:y if there i~ careful and st~uctttred recordkee~ping on a Iarg~ numI~r of patients would a changed cardiovascular death rate o~ two to three be detected. The analysis of such multifaceted chtta re~ quires more sophisticated data analytic methods than those in com~ mon usage by clinicians. Next, I wish to comment on some features of the Biometrics Society report. A criticism of the original. UGDP ~nalysis is that i1~ failed to explore the effects of several factors acting simultaneously on the cardiovascular mortality. Our committee did in fact consider this matter very carefully. We found that when one examines the PAGENO="0022" 13272 COMPETITI\~E PR0BL~MS IN TH~ DRUG INDUSPR~ group of older women, age greater than 53, the tolbutamide cardio- vascular death rate is almost five times that of the placebo group~ It is in this group of older women where the tolbutamide excess cardiovascular mortality is most dramatically shown. Finally, I wish to comment on the problem of planning and analyz- ing clinical investigations in which patients are expected to be on chronic medications for a period of many years. It is important in planning these long-term studies to allow the clinician to change the medication if it is in the best interests of the patient. This can result in ai~ altered dose or even a change in the medication. The UGDP protocol did allow the clinician this freedom. A protocol which does not `allow this flexibility may not be in the best interests of the patients under study. The, CHAIRMAN. In evaluating this study, did you or did you not conclude that the authority of the clinician to alter protocol, which I assume some did, had any adverse effect, or did it prejudice the study' in any way? Dr. ZELRN. No~!' In addition to modified or changed medications, patients may, on occasion, not take their medication at all. In' the Biometrics Report, these problems were examined in considerable detail. It is our con- elusion that the greatest statistically significant difference between tothutamide and placebo occurs in the group who have taken their prescribed medication in exactly the manner specified in the protocol' for the entirO period `of followup. * To conclude, I wish to state that the interpretation of the data is difficult due to the small number of deaths relative to the total num- ber of patients. In our endeavors we have analyzed the data in many other ways which have not been put in our final report. Our conclu-~ sion is' that the weight of eviden~e points to tolbutamide as being responsible for the excess cardiovascular mortality. If I may, Senator Nelson, I would like to comment on some general aspects of clinical trials that have, surfaced during' our di~cussion. Obtaining scientific evidence using the clinical trial method is the most difficult way of obtaining scientific evidence and should be' used only as a last resort. I speak from long experience. My `research group, the statistical laboratory at the State University of New York at Buffalo, is involved in over 60 clinical trials at the present time in all areas of cancer treatment. It is very difficult, `time cOnsuming, there is a great~'deal of aggravation arising from the vagaries of the funding agencies~ ` . ` ` ` ` I think to' mount long-term studies, either of oral hypoglycemic agents .or anything else, shOuld only be taken after much carelul thought and after all other' ways of attempting to obtain such evi- dence have been `thoroughly examined. Mounting these trials should~ not be done very casually. ` ` ` ` ` The CHAIRMAN. Thank you very much. ` Our next witné~ss is Dr. Palumbo, the' assistant professor of medi- cine, Mayo Medic~'al School, Rochester, Minn. . * * You may present your statement however you desir~ and e~ttem- porize on it if `yo~i `desire. ` , ` ` ` ~` PAGENO="0023" COMPETITIVE PROBLEMS IN THE DEtG INDUSTRY 13273~ STATEMENT OP P. i PALUMBO, M.D., ASSISTANT PROFESSOR OP MEDICINE, MAYO MEDICAL SCHOOL Dr. PALUMBO. The comparison of treatment for a disorder can't only be `evaluated through controlled, randomized, clinical trials.. Hints and leads from retrospective `studies can be extremely valu- able in leading to a new hypothesis and may be the basis of justiflàa- tion of a randomized trial. However, standing alone they car~not form the basis of any firm conclusions concerning treatment, effects. The preliminary analysis of our data of the incidence, prevalence~ and mortality of diabetes mellitus in Rochester, Mimi~, between 1945 and 1970 contains some hints that survivorship may be `lower in diabetics on oral antidiabetic agents, and we grouped them all to- gether: These are sulfonylureas and phenformin. Mr. GORDON. About how many people were you following? Dr. PALtTMBO. We were following over 1,000 [1,090 to be exac'ti patients with diabetes over that 25-year period. There were only 138~ on oral agents out of that group. Mr. GORDON. How did ,they fare? Dr. PALUMI~O. Their survivorship was less, but however there are group differences that have `to be taken into account, and therefore' we cannot make any firm, conclusions, Our statisticians are very loath. to leave themselves open to the, criticism that a retrospective study can lead to firm conclusions [regarding treatment]. All we can say is it suggests or hints that the oral agents pltis other factors may affect survivorship of the diabetic. As a clinician-k- and I am deviating from my statement-as a clinician, I would e~-~ pect that the oral agent group would be similar to the diet group~ the same group, the sanie isehemic heart disease, the sathe hyper~- tension, et cetera, and I would have expected them [patients on ora' agents] to have the same survival curve as the patients on diet alone.;~ that is, the oral agent group should have been similar' to those on diet' alone. However, the' survivorship of those patients on oral agents whei~ compared with a group of the general population, similar in age anc~ sex ~or our midwestern area, the death rate or rather relative sur- vivorship for the group of diabetic patients showed that the ora~ agent group was much lower. The CHAIRMAN. Now, wait a minute. Ton. said the `death rate and~ survival. You cannot have it both ways. Dr. PALUMBO. Their survivorship was lower. The CHAIRMAN. The higher `incidence of death. Dr. PALUMBO. That is right,' and in the fir~t 3 years there was a difference in the death rate for cardiovascular mortality in the oral agent group, or there was a higher death rate from cardiovascular deaths. ` , The CHAIRMA~T. This was retrospective? . Dr. PALtTMBO. This' was retrospective. The groups `are not corn- parable. The, insulin `group `is yot~nger, has a higher blood sugar and in our study has a higher p~rcent'age of stroke actually, whic,h, should f~ror a poor survivorship. The oral agent ~nd diet group- PAGENO="0024" ~3274 `cOMPETiTIV~ P~O~LEM~ LW T~E D~RU$ INDUSTRY and remember w~ do riot 1ia~ a~ placebo to compare this with, so that for the di~t-~orai agent groi~p,~ they are pretty comparable with regard to ischemic heart disease. There is Tess strOke in the oral agent group than the diet group at th~ time of diagnosis of diabetes, but retinopathy was higher in the oral agent group, and blood p~s~ sure was 6 percent higher in the oral agent group. These are group differences that have to be taken into account. A~U we c~an say from our study is that it suggests that the oral~gen~s may be one of the factors that may adversely affect survivorship in the diabetic. Such an observation-I am returning to my statement now-such an observation would point to the need for controlled, rando~mzed ~chiniaal trials to study the possible adverse effect of variou& treat- ments on survivorship in the diabetic. The University Group Diabetes Program was a ra13dom~ze~ trial study. to evaluate the influence of treatment on diabetic eoznplaca- tions. A statistically significant, adverse effect on survivorsliip was noted after patients had been on tolbutamide and phenformin for 5 or more years. These data have been reviewed by others~ and the review was published in the journal, I believe, "Diabetes~" by Dr. Cornfield [the journal was .JAMA, 1971] and also~bad been reviewed by our own statisticians, and the conclusions have been fonnd to be sound. I have to rely on their conclusions because I am a clinician and not an epidemologist or stati~tieian. Was there a question, Senator ~ The CItAIRMAN. You concluded that the UGDP stucI~y was sound? Dr. PAWMB0. The conclusions are sound; that is correct. In my ~opinion as a diabetologist, another randomized trial study of trcat~ ment in diabetes is not ethically justified, as the data from the University Group Diabetes Program clearly indicate, from my stand~ point, an adverse effect of the oral antidiahetic agents on survivor- ship in the diabetic. The use of these oral agents, therefore~ should b~ curtailed. The CHAIRMAN. How long after the UGDP study was published did the Mayo Clinic conclude that they would not use the oral hypo~ glycemic agents except in special circumstances? Dr. PALuMBO. There was a meeting of the American Diaheto~ Association, I believe-and maybe Dr. Ricketta can correct me-ia .June 1969, was it, that published those results, or maybe it was the following year. Dr. RICKETTS. 1970, actually. Dr. PALUMBO. It was 1970, and subsequent to that time we began to inform all patients about the risk involved with the use of the oral agents~ We took patients o~ the oral agents and tried them on diet alone afte~ir iAfonning them of the possible risks imvo~ved~ We have not followed those patients to see how they have done, except thal~ our own clinical impression is, as ~r, 4d~n hiaa ah~ea4y rp~b~d~from his committee, that they do iust as weil, and I did not feel that a lot of these patients needed to be on oral antidiabetic agents. When. the plasma glucose. or their response to tr~atxueut to diet ~has not been satisfactory, we have advised insulin therapy, because we feel insulin at least does no harm. Even if it has been shown not to do any good, at least it does not do harm. It does protect the pa- PAGENO="0025" co~1~mVE ~OBLEMS i~ ~ p~c~ ~ 13275 tient from the acute complication, of ketoaci~sis if they are prone to that. We would never have used these oral agents bt the ketoacidosis' prone patients anyway, but in any event if I were to err now, I would err on letting tho blood sugar drift a little bit upward aM not worry so much at keeping it at a certain partienlar level. And tl~erefore, our observed policy has been t~ curtail the u~e of these `agents. I do not use them routinely. I tai~e patients o~ when they are referred to us. We warn them about the possible hazards, and we transfer them to insulin therapy. We are wore ~ tertiary center than a primary center. We are describing here in the study patients alluded to, our own patients from Rochester, Minn., from a popula~ tion of about 50~0O0, so we do provide primary care for that popular tion, but the majority of our patients that we see in th~ diabetes clinics, which number about 8,000 to 10,000 patients a year would be told exactly the same thing, that the oral agents may be deleterious to their health and that we would recommem&d, if t alone does not control their diabetes, that they are placed on insulin therapy. Most of our patients have been willing to accept this when we have shown them how to adinjimister the insulin~ There has been no particular problem. It certainly would be nice to administer an agent orally and take care of the blood sugar, but unfortunately if the agent has b~en shown to cause an increased mortality from cardiovascular death, we would be reluctant to use this agent. As I stated previously, I feel a physician should do no harm. The CH~th~AN. Do I understand you are saying t~iat `this posi~ tion is a policy of the clinic? Dr. PALTJMBO. Well, as a member of the diabetes committee of the institution, it is our recommended policy. Obviously, I cannot speak for the 400 or ~O0 physician.~ we have on stalL There way be sothe who migl~t be, but I think we have disseminated the information widely in conferences and through memoranda, I believe the position is pretty clear that we have accepted the findings of the University Group Diabetes Program, that patients all must be informed `about the hazards of these drugs and that only under nisusual circumstances would they be prescribed. There would be very few patients that woul4 not see us in the diabetes `clinic, so that it is impossible that a smafl group of pa- tients. might be treated with oral agents. I rather doubt that, since we maintain close contact with all of our colleagues and dis~minate mtermation through conferences audi memoranda. The Ci ~ Does'anyone on the panel wish to mahe an obser- ~at~on on any of the points that have been raised thus far in the testimony or on any questions that have been asited. Dr. Bieice~'rs~ Yes, Senator Nelson, just a rather small point. It ~s well J~n~wn that a great many people, and this is particularly women, are overweight. I mean to say diabetic people. W~ struggle and p'~ach and do all we can to~get them to lose weight, and fi~~ll~r, some of them do. It does not last awfully long but nevertheless the~r do, And of co~øse if the ~1~~ity is controlled, the blood sugar goes elow,n~, and `this is what we want, And thus it went fo~r a lo~tg, long time until tolbutamide came in, and then what happened? ,Doctm~s began to give tolbutamide and tell them it is good for them, and PAGENO="0026" 13276 ö0MPETITIVE PI~BL~MS IN THE DBTJG INDIJSTRT they began to take them. But what did they do? They took their toitbutamide but now they did not think that they needed to diet. And this is very sad. It is a poor outcome of this business we are talking about. The CHAIRMAN. Thank you. Dr. Zelen, did you have a comment? Dr. ZELEN. Yes. There have been some who suggest that another UGDP-like trial be mounted. The CHAIRMAN. I am sorry. I did' not get the first part. Dr. ZELEN. There have been some individuals who suggest that an- other UGDP-type trial be mounted. Judging from the experience with this one, it is likely to take 6 to 10 years before any conclusions will be reached. Furthermore, with the recent change in patient consent, people face the following situation. If an individual comes to a clinician who is participating in such a trial, the physician, by law, has to in- form the patient of the risks involved. The scenario would go some~ thing like this. The physician would state: There are a large group of people in the cuuntry who believe that tolbuta- mide may be dangerous. A study has been completed purporting to show this. However, there is conflicting evidence to believe that the Interpretation may be in doubt. Consequently we are going to try again. Well; I think most people would not like to be part of such a scheme, and it might be very difficult to enlist patient volunteers.. The CHAIRMAN. Well, was there anything in evaluating the TJGDP study that would indicate some necessity for repeating the same study? Dr. ZELEN. In my opinion, no! Mr. GORDON. May I ask a question at this point? `Dr. MEJER. I would just like to clarify my own position. I have not taken a position on whether there should be restrictions on tolbutamide. What I have said is that if it is to continue to be widely used, then 1 think it imperative that another study be mounted. I hope I make `that clear. It is now being widely' used long after the UGDP report was `published and discussed. If that situation is to continue, then I would see no ethical choice for those who use it but to mount another study. Mr. GORDON. But `what are they going to do in the meantime? Are they going to keep on using it widely while the 6- or 8- or 10-year study goes on? Dr. MEIER. That is a matter that `I presume the FDA is actively studying right now. The report of the TJGDP appeared, received commendation from the ADA and the AMA, but as a matter of fact; the community continued to use the drug. Barring administrativ~ action, I presume they: would still continue to use the drug~ and I ~m saying that if there is no action to prevent that, then I think there should be action to further study the matter. Mr. GORtON. How about the newer drugs that have not been re- leased yet? Dr. MEIER. I would hope that they would be `studied. If they are to be released, I would hope that proper studies would be initiated immediately. ` ` ` ` PAGENO="0027" COMPETITIVE PROBLEMS IN TUE DRUG INDUSTRY 18277 Mr. GolmoN. In the Keen study, in the placebo group 30 percent were over 70 years old, and in the tolbutamide group there was 18 percent who were over 70. According to the Biometric Society report, the difference is sta- tistically significant at the 5-percent level. Do you know the com- parable differencç~ in the UGDP? It was much smaller, was it not? Dr. MEIER. Yes, the IJGDP was conducted with, very careful ran- domization, as described in our report. The Keen study used a much more informal kind of allocation scheme, and indeed, in respect to age, the Keen study had a much wider discrepancy between the groups than did the UGDP. Mr. GORDON. So the baseline characteristics were more similar in the TJGDP than they were in the Keen study. Dr. MEIER. Yes. Mr. GORDON. I just wanted to clear that up. The CHAIRMAN. Is there any other observation any of you gentle- men have on any aspect of this? Well, the committee wants to thank you very much for taking the time to come here and present the results of your study for the record of this committee. We appreciate it very much. Thank you. If you have anything supplementary that occurs to you that y~u think will be useful for the record, the record will be opened for another 2 weeks and you may submit it for printing in the record, Our next witnesses will be Dr. Robert Bradley, chairman of the Committee on the Care of the Diabetic, Joslin Clinic, Boston, Mass., and Mr. Neil Chayet, counsel. The committee appreciates you gentlemen taking the time to ap- pear before the committee. You may present your statement however you desire. It will be printed in full in the record.1 * STATEMENT OP NEIL L. CIIAYET, COUNSEL, ACCOMPANIED BY ROBERT F. BRADLEY, M.D., CHAIRMAN, COMMITTEE FOR THE CARE OP THE DIABETIC, JOSLIN CLINIC, BOSTON, `MASS. Mr. CHAYET. `Thank you very much, Senator. My name is Neil L. Chayet. I am a member Of th~ law firm of Chayet & Sonnenrei~h, and I appear as counsel for the Committee on the Care of the Diabetic. The CHAIRMAN. Counsel for whom? Mr. CHAYET. The Committee on the Care of the Diabetic. The CHAIRMAN. Are you also counsel for the Medical Tribune? Mr. CHAYET. I would be glad, Senator, to submit it, a list of all my clients,' if you care to subpena it. I still believe, however, in the con- cept of attorney-client privilege and the confidentiality of that' rela- tionship, which I kno* does not mean that much around here anymore, but I still value it very highly. If you care to sub'pena a list of my clienth, I would be glad to provide it. We have many clients and represent many groups, indi- viduals, publications; and others. The CHAIRMAN. You are the first witness we have had who is embarrassed `about .wh'om he represented. , " 1 prepared statement, page 13620. PAGENO="0028" 13278 ~Q~TI'~IVE ~RO~4EMS ~N ~ PEUG ZNPU~TRY Mr. Ci~~r. I am not embarrassed at all. As I said to y?~i, I am willj~g to prpyide it nuder ~ proper subpei~. I believe in confi~ dentiaTity and that is my response to that question. May I oontimie, sir? The CH~ni~Aw, Go ahead. Mr. CiI~Y~T. Thank you.. With me is Dr. Robert BraclJey, wh~ is director o Joshu Clime and who is a1~o the eh~irman o~ the ~ommitt~e on the Car~ of the Diabetic, I have a written statement which I would like to submit and ask that it be printed in full in the record. The CII4nP~EAN, It will be printed in full in the record as though read and you may present extemporaneously whatever you desire. Mr. CHAYET. Thank you very much, sir. This matter has continued~n~w for nearly 5 years and the Com- mittee for the Care of the Diabetic as well as physicians and s~ieiitists~ throughout the country have been engaged fully in this controversy. When my involvement began, ~t was solely as a lawyer for a client. I now have another interest in this matter which I would like tc disclose to the committee at this time. Since I began handling this matter in 1971 my mother has been. diagnosed as a diabetic, and she has become very severely ill and~ crippled by this disease; and so while I still function as an attorney heçe, I also have a personal interest in this matter because of this situation. The Committee for the Care of the Diabetic is a group of leading diabetologists from all over the United States which was formed in November of 1970. rt initially sought to deal with the Govern- ment administratively before seelciug legal counsel. The CEAIRMAN. Are you saying this was the year that the Com- mittee for the Care of the Diabetic was created? Mr. CHAYET. Yes, sir. It was created shortly after the results of the UGDP were first brought forth; I did not become counsel until about a year later, It is clear from the record that there was exten- sive correspondence between Dr. Bradley and the Committee and the FDA in an attempt t~ settle this matter administrati~ely. These are not litigious individuals. They chose the courts only as a last resort beca1use there was simplir no place else to turn. When I first reviewed this matter from a legal point of view it concerned me that if a doctor continued to prescribe this medication in the face of a package insert which indicated there was an in- creased risk of cardiovascular disease, it appeared to the, having looked at same recent cases, that such physician could well be sued for malpractice. I have found several cases where the package insert was introduced as expert testimony into evidence. That was my initial concern from the legal point of view; there is, however, a far greater concern, and that is the impact that this entire matter has had on millions of patients throughout the country; it is the fear and the panic that has be~en caused: by a combination of governmental action and the press, and by the great confusion that has swirled around this issue that has really done the damage. And while the issue of potential malpractice actions is still pres- ent, it is now much more a question of how patients react when they PAGENO="0029" dOM~T1flV~E ~Oi~t]~iM~ I~ ~It~ t~*UG ~ i*%7g read press reports of deaths ~Ueged1y ~at~s~d by o~l hy~gl~th~iic agents. how can they r~ta{ii itny conficl~n~e m thei± p~y~lan in light of such reports ~ We are cOlt med with not only the pt'oteetiOn of the physician from a niaipt'a~tice action, but of equal iutipôrtaiiee, the protection of his patient from the actions that have ocei~rMd again this very week; actiOn~ siffitiar to What oect~l±ed in 19~O~ ~h~II ~ln.a~ ture press re1~ase~ again he~aIded this a bia~d view of oontmv~y~ It is most unfôrttt~a1~O Senat;or. The O1IAIRMA~. We1~l, I gtues~ ~~on have made it clear. Y~u a~re re~ ferring to what yoti belieire to be C~nftt~iolt and doubt~ *hlch have resulted from stories respepting the TIGDP ~tttdy. Is that What you are sayIng? Mr~ CHAYET. Is there a~ny question about that Senator? For ~ ample, I will qttOte a TIPI report in the BOst~~ Globe, tuesday, January 2, 1975. The report is pathetically ipa~ctirate "Ai1 intei~~ tional soientifie jury has supported the much debated ~ thai~ th~ oral diabetes drug used by 1.5 million Americans are probithly kiflifio~ 10,000 to 15,000 ôl them pearly." And the inaccttraey iS not the fault of the pres~ It is the fau~t ~ those who are giving the releases and the fault of those *h~ ~ written and released the editorial statement *hi~h acoomp~n1ed the Biometric Report which reviewed the TJGDP sthdy~ The Biometric Study~ ilt many wayS is a vet7 ~cholat'iy e~udy, b~t what was dane with It is most unfortunate. And that is Wher~ the problem lies. Tt is a repeating pattern by thOse who seek to Stifle and muzzle the couitroYei'Sy whiëli nobody can any longei4 deny. The CtxAIRMA~. I have not seen all of those ~tOt1~s~ bitt the st~ries I have seen were l?ased upon an editorial that is appearing, ap~aI~ ently, in support of the troi~~ study, ift the Journal of ~he Anierlèai~ Medical Society. Then the ~toties WetO written ~rOm that. N~*, I have n~t seen what the joaftal said, but i~ the journal story wa~ exaggerated, that would be a matter of whoever te~ported th~ story~ I guess. Mr. CHAYET. Well, that is the problem, Senator. Tt is ~ne aggera~ tioti on top of another. Yon have the l3iotn~tric Study, then, sOffi~One wHte~ an editorial and refers to "possibly some 10,000 to 1~,000 deaths"-no statement of which appeared ii~ the Biometric Studjr~~~ and then the press reportS that an ititS national hhi~4ibboit j~iry found 10,000 to i~,Oo0 deaths a year. And I think we are well aware of the political proeesS to kfio* that this IS the way it goes; and we in the legal and SOiehtiflO eommunities have to take steps to prevent this frOnt ocdurthi~. Aftd thd~e StepS WetS nevet1~aken in this sittta~. ti~h, aftd I regret that. The O~AIu~A~. I uxidOrStthid What you ate Saying. I have been in politics :Mr many, many years, and have been "dQnS in" maii~, hiany times. Bitt I have not suggested that we abolish the freedom of the press. Mr. CnA~EI~. I guess when we get done In Senator, we at have the riSk Of that because of Out pitblie ~QsIt1oii. But the millions of people out there do iiOt take that risk, and that is why I am COn~ cerned about it. That is the poiitt. It is not the prOSS *h~ch sh~ttTd be téstriCted bitt thoSe Who provide the erroneous Iiiforn~atithi tO the preSS. PAGENO="0030" 1.3280 cOMPETmVE PROBLEMS IN. THE DRUG INDUSTRY As f Or the tIGDP study itself, I am, not at this point going to discuss its scientific flaws in. detail. Although I am a lawyer, not a scientist, I would `ethphasize, however, something which strikes me as' very important; and it is. the final `paragraph of the U.GDP study, which reads: "It should be noted that `any conclusion reached in `this study pertains only `to the type of `patients studied"-~nd a very particular .group of people were studi.ed'-"and only to the specific hypoglycemic agents used. Extrapolation of findings obtained in the IJGDP to other~ dosage schedules ~f the same drug"-and dosage sche~14leS other than those used iii clinical practice were used in that study-~---"or to othejr chemically related hypoglycemic agents not in- cluded in this study, mu~t be made on a judgmental and nonstatistical basis." No~, those are `the words' of the study Itself. And yet,. in spite of these words, w~ see an unfortunat~ extrapolation, contrary to the very words of the UGDP study; and `I would only say, Senator, that ques- tio~s of- , , ~, . , , . The CHAIRMAN. May I say, just a~i~oment? I wa~ looking at the final paragraph, and the final paragraph,. ~s it reads to i~ie, is: "In cpnciusion,"-t'his is the- Mr~. CrrA1'n~r. Excuse me, Senator; i~ is .th~ next-to-last paragraph at page 814 of the stucly~ I am sorry. Tl~e~ CHAI~AN. Well, `let me say this, so they juxtapose. "In con- clusion, we consider, in the light of, the UGDP findings, it remain~. with the proponents Qf.the oral hypoglycemic to ponduct scientifically adequate ~tudies to justify the continued use of thich agents." Mr. CIUYET. Unfortunately, yOu are reading from the wrong study, Senator.: ` . , ` ` , The CHQI4RMAN. This i's the Biometric Soeie~y Study. Mr. C~IAYET. I know. I am not talking about th~t, sir. What I ~a~d very clearly is that `I am talking about the TJGDP study. You see, thia is how,it goes.. The CHAIRMAN. I misunderstood. Mr. CiLj~ET~ This is how the con'fusion, esca'lat'es. The, CHAIRMAN. I am sorry I misunderstood you. We will put ,the two tog~ther, \sO that everybody can x~ead them. Go ahead with your testimony. . . , ` ` ` ` Mr.~CEAYET. That will be fine,. Senator, As~t said,, I am not. going to concentrate on the IJGDP study itself, or even the specifics of the Biometric "study. I oniy want to `make one point, and I *ould like to make it as clearly as I can. There is great controversy in this. situation, and it is not going to go away. It does not matter how many people are lined up on either ,side-and I am perfccthy cognizant of the fact that `the `press releases describe the bluç~ibbon jury of experts who are for ,the UGOP, and when any- b'ody on th'e . other side is mentioned, they a±e re~orred ,to as a group of practicing physicians. I realize these are subtleties, but they aic subtleties, that have resulted from the fact that~the Government has made a fundamental error in this situation; that is,' it has tried to muzzle a controversy, which has `been put forth in good faith by very eminent, very learned, and qualified people. ` Now, I know `that $8 million and 10 years is a long time, and `a lot of money, a'nd criticism is difficult. `It is not to be given or taken PAGENO="0031" COMPETITIVE PROBLEMS. IN TIlE DIWG INDUSTRY 18281 lightly: But ~h~t `is the way it is; nothiflg is gOilig to make t~l's study free frOm controversy. Nothing thus far has settled this con- troversy, and Dr. Chalmers can write editorials entitled "Settling the UGDP ~tudy" as long as he wants, and it is not going to resolve the issue. I ~ould like to now move on and state exactly what the Committee on the Care of the Diabetic is seeking to accomplish, First of all, thay I state that, when I began this matter L sought to restrict the TJGDP findings on the label. I thought the study was so flawed, based on what I had learned from the physicians I represent that it should not appear on the labeling. However, I later 1~led an amended coinp'laiht in the/ Federtid court, because there is the possi- bility that the, study `had some. merit Cv.en though it is flawed. We are not' haying that the~e drugs' absQl'utely do not cause certain problems because we do not know. But the UGDP study did not' give `us the answer, and pretending it did does not help us at all. `What we are `seeking' is a. label which reflects fair balauee~ which reflects tl~ fact that there may be a problem with the drugs, which indieates the stitdy' results and the controversy surrounding them. There have, `been many "eminent people supporting both sides. The evidence which has been ,presented clearly points up the existei~ce of conflict and controversy which now must `be admitted by all. To~ fail' to~indicate such çontrpyersy on the label is most inappropriate.~ At this point, I would like to discuss the lawsuit, Senator, I belie~re that the action is unprecedented. It is the first time, `to my knowledge, that a group of physicians and patients-and I emphasize that the plaintiffs include patients-in a class action representing' all physi- cians and patients similarly situated-~-have sued the Government and the mailufacturers to'prevent the Government from forcing the label change along the biased lines `that it~ sought and the manufacturers from' buckling nuder to `FDA~ pressures, `for a variety of reasons, . and voluntarily changing th~ label. It is on the basis of that lawsuit that we secured, in November of 1973, a preliminary'' injunction halting the Government from ordering the label change and halting the com- paiiies frQr~ vWuntarily altering it~ We' have not~ sought to h~ld up labeling, and ~Ido not understand why it has taken `so' long for tl~e FDA to move f0rs~y~rd,'with labeling. This case was. before the `court of appeals on July 31, 1973. Why is it that 18 months later, we still have no' revised, labeling? `One reason ma,y1be the' unrealistic expecta- tion that the Biometric Study would settle the matter once and for, all and then the. ~abe~ing could proc~td. ` ` Well, that has not happened. And. `the Committee for `the Care' o~ the Diabetic. will go back toc'c~urt~ and will, take evety `step it has to `take, `to prevent a one~ided, bia~ed label' from emei~ging; and the Biometric .Soci~ty Study does not a~lthr"our re~olve. I might add' that we have had less than 2' days `to review the Biometric. Report. `Why did we only have 2 days? `Why Was it not: `made available t'&rnen'l'ike Dr. Bradley, and the other members of the Committee `on `the' Care of the Diabetic? I asked the AMA why it was not; `and they' `~áid they could not allow' this because the' Bioinetric Society `said `not to release it to anyone; anyone except I)r. `Chalmers, `that ~is~ Why was the biometric Society so 5e~retivè abbut "this docnmeiit'?' T would very much like you t~ find oflt~' Senator; the answer probably is that NIH insisted pn secrecy. The result is that a document is going PAGENO="0032" 1328~ ~dMrx~E1v~ ~LL\~tS i~ TH~ irnua INDTJeTRY to be printed in ~ journal in 2 weeks, a document which is not given to oth~r~ for re~'iew despite the known eontrover~y which exists. Then the AMA ~a1l~ a preptiblication press conference~ and ftnnounees an article that i~ to be printed in 2 ek~, and the restilt is a headlme which appears in papers throughout the country which spea1~s of 15,000 people dying each year, which has nothing whatsoever to do with any of the material to be pubUshed~ I think it is irre~ponsable, and I ara e~treme1y disappointed that the AMA has seen fit to take this n~iea~ure; I can only asôribe it to some naivete, they never should have functioned in this manher. The O~IA~RMAN. I hare not, by the way, see~1 either the editorial, nor have I yet seen the report of the Biometric Society. Mr. OiiA~'. You ought to read 1t~ It IS most interesting, particiF. larly the editorial. The CHAIIt~A~. Well, I have not seen it. Mr. O~AY~t'. SenatorS I am sorry to go on for so long, but you said something previously about the l~gal aspects involved in this matter, and you ~efe'rred `to the Food, Drn~ and Oosmetio Act. I would like to address myself to this aspect of thl~ very important ~4uestion. W~ have depended on a regniatioti' of the FDA Itself, which reads as follows: The existence of a difference of opinion among e~perth ~nalffied b~ tr~i~thg arid etpetietwe; as to the trrith of ri representation tha(Th or sug~este'd in the labeling Is a i~Oct the falinre to re~a1 which ma~ reri~ler me labeling ml slead~ 1ng~ if there is a material weight Of o~iniori contrary to such representations. What thIs means is, if a manufacturer seek~ an NDA `and he knows that there is controversy o~rer his product, he has a duty to come forward, if there is a material weight of opinion' ~a~nst his drug, and inforth the Ft~A. Wh~ `dOes not the aovcrnrnent h~e a similar obli~çation' to inform physi~cians that there is a mate~ial weigltt of opinioti contrary to its findings? Why has the Government sought to repeal thi~ regulation When the ~a5e was returited ~to the agenc.y by the ~Ourt of appeals? Does this principle e~i5t only for the manu~ facttirers? If there is material weight of opinion against a position why is it stifled and not reftected-~u~t because it Is the Government position? That i~ my question. I have not yet received an appropriate answer. The C~tAt~w~. Well, just let me ~ay~-if `we are addressing Onr~ Selves to the same thing-~4hat J carry no brief for everything the FDA does, but, as a matter ol fact, they have in `a very massive way done eñ~tly what y~u 5~y they have not done.' In ~ceordahce with the 1~62 amendments to the ~efauve1t Act, ~the FDA contira~ted with the National Academy of Sciences-National' Research cotiu~il wh'i~h Set up panels on all kinds of drugs. These panels evaluated thotis~~ ands of `drugs and then made recommendations. And the FDA took very positive action on a large number of drugs, perhaps `as many as ~,000 of theth~ Mr. C~i~t. That is' true. The cin~~. Informing the public abotit their `deficiencies. Mr. CHATET. I `do not want to imply that the FDA dbés not do any~ thing pr~per ~t all. The FDA has done a great ~deal' of fine, very valuab1~, very important work, and I never want to deprecate that PAGENO="0033" COMPETITIVE ,PROBLEMS I±~ ~HE DRUG INDUSTRY 13283 for a moment. But in t~his case,-an~I I do not know why, but-in this case, the process ha~ broken d~w~ frretrievably. The. FDA is not liv- ing up to its mandate in this case; it has not, and it' is not at' the present time. And what its mandate is, it seems to me; is to pre~ent information, but to do so fairly and impartially; and `it. is' not doing so, Let me explain what I mean by this. When one applies for. an NDA, the substantial evidence test is ap~hed. The thrust of im~le- mentation of the Food,, Drug and Cosmetic' Act has been to do `away with clinical'opinion insomuch as possible, and reduce it to controlled, statistical studies. That may be a very laudable goal in some cases, but in other caseS, it can lead' to great difficulty, ~s in this case. There is substantial evidence of efficacy of these drugs-as they do lower the blood' sü~ar~nnd that is the efficacy which is claimed. The q~iest~on is, what is the result of lowering blood sugar, and how dangerous are these drugs. This is where one gets into difficulty. There is `a question as to whether the TJGDP study can be con- sidered substantial evidence, as it appears to be so flawed. I' think that the `study is reflective of a great deal of effort and, in many~ ~v~ys, it was a very complicated and very sophisticated study. It is indeed unfbrtunate' that improper extrapolation has caused it to reach this result. Let us assume, then, that the IJGDP constitnte~ substantial eiri- dence. It is important to realize that wq are de~tling with a warning which is to appear on the label. If a drug is approved for efficacy and is being m~rketèd and a problem d~elops. with the `drug,: I thi~ik that problem ought to be reflected on the labeling, and in this ca~e, it should be sq indicated as to the oral hypoglycemic `drugs. So, what does one do? Let us say substantial evidence is not ~n issue but, rather, someone comes up with a clinical opinion that there is a problem here. That controversy should be adeq~uateiy refleet~d on the labeL Where there is great controversy about findings such' as TJ'GDP, we want to have the FDA indicate such controversy on tl~e label, even if they are not exactly sure that it is a final or totally correct' warning. The fact that there is controversy about a particular finding, and there is no final answer does not mean that you ignore the con- troversy. Where you do a substantial evidence study that costs $8 million, and lasts 9 years, and it is wrong, you are confronted with a major problem. You are in serious trouble. You cannot replicate it, because it is going to take another 10 years, if you can find `the $8 million to do it. So you have a problem-and I hope the Go~ern~ ment is not going to say that, just because we have a study that. cost $8 million and lasted 9 years, therefore, that is substantial .evidence and it cannot be wrong; because, as I say in my statement, there have been mistakes made-very costly mistakes made-~iñ research, as in all human endeavor,, and there will be again in the futur~e. For this reason, I feel' that the FDA regulation itself `should be applied in this particular `situation. We have already filed oqmments against the suggestion by FDA that this regulation be repealed. And we will go back to court, if we have to, to prevent this' regulation from being repealed iii this particular case. W~ believe the UGDP study has 56-592-75---3 PAGENO="0034" 13284 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY such severe inherent problems that, unless the controversy is indi- cated, it will be misleading to the public and to the physicians who are responsible for treating this problem. I mentioned this article in the Globe. Dr. Bradley will tell you how many people have called the Josl'in Clinic in the last few days, and have been so upset. I have heard similar statements from other physicians, telling the how many of their patients become upset by the press releases which have occurred. I do not blame the Bio- metric Society. They said things such asthe following-I am reading now from the Biometric Society: "There remains the question whether tolbutarnide, although ineffective in a fixed-dose regimen, might be an effective therapy as ordinarily used." That is right in the Biometric Report, Senator. `In other words, if they used the drug properly,, maybe it would' be~ effective therapy. Very interesting- that is why I say, it is not these reports per se that are causing the problem for the public. It is what' people are doing with these reports. The CHAIRMA~. I think it should be known you are reading ex- cerpts. The fact of the matter is that the members who did the study agreed with the TJGDP study results. The fact is that one of the greatest clinics in the world, the Mayo Clinic, has accepted the re- port. It is accepted at Grady Memorial Hospital in Atlanta. Those `were two of the witnesses. *So sure, there are' scientific disputes, but this society which was independently chosen of very distinguished people, have concluded that it was a valid statistical study, but the record is clear on that, anyway. Mr. CHAYET. The record is not that clear, I would like in closing to summarize my position for the record if I may, Senator. The CHAIRMAN. Sure. Mr. CHAYET. I think we need new labeling right away. I would like to dispel any doubts at all that we are standing in the way of new labeling. We need it, and I am sorry we do not have it up' `to this `particular point, `and I hope we will `have it soon. I also- The ChAIRMAN. Excuse me for interrupting. The committee coun- sel tells me that the FDA is going to testify very soon on the ques- tion of labeling. I did not realize it was already scheduled. Mr. CHAYET. Fine. But I think we need this labeling very badly, by that I mean labeling that will be fairly balanced and indicate the scientific con- troversy. This raises the question of what do we do about the con- troversy. Although I heard what the doctors said before about the difficulty of launching another study lIke this, I really do not see any way of avoiding it, unfortunately, at the present time, because what we have at the moment does not answer the critical and crucial questions raised. Regardless of an additional study, I think there ought to be balanced labeling so that doctors will use this drug properly and be aware of `the controversy while, as quickly as pos- sible, we ought to have additional studies. I would `say, Senator, there ought to be at least one study that is as lengthy and as fully PAGENO="0035" COMPE~1TIV~ PROBLEMS IN THE DRUG INDUSTRY 13~85 funded a~ this, and we ought to stop putting money into trying to justify a flawed study. Instead we ought to try to correct it, cøme up with a better study, and come up with the answer which retdly is of such ithportance to millions of people throughout the countjy. I thank you very much, Senator. Dr. Bradley? The CHAIRMAN. You are an articulate advocate, and I appreciate. yOur testimony. Mr. CHAThT. Thank you, sir. The CHAIRMAN. Doctor, we are glad to have you back again. Is there anything you would like to add? Dr. BRADLEY. Yes. I 4would like to make a few comments, Senator Nelson. I would like to start, if I may, with a slight anecodote, and this just to change the pace a little bit. Yesterday one of my associ- ates came up. to me proudly and said I want you to meet Mr. X. He now is down to his ideal weight of 150 pounds. A little ovei~ a year ago he weighed 275 pounds, and at that time was taking 80 units of insulin. Now he weighs down to his ideal weight, and his glucose tolerance test is normal, so that this is an illusti~ation, I think, of the benefits of weight loss and of diet. One of the first things I want to affirm is that the idea of diet as treatment for diabetics did not originate with Dr. Davidson, or with the UGDP or with Dr. Ricketts. As a matter of fact, one of the reasons the Joslin Clinic has been criticized over the years is that they have so rigidly insisted upon diet as primary treatment, whether people are On just diet alone, or whether they are taking insulin or pills. This continues to be the case and has been so all along. So if you will pardon my digression, I would like to come back to the other issue if I may. I think Mr. Chayet quite rightly has emphasized that the controversy remains, but I would like to ap- proach it along three or four hues with you briefly, if I may. First of all, the Biometric Study, I think most of us realized, would, to a certain degree, be moderately supportive, . and I think those words appear in the study of the TJGDP experiment. We did not expect anything different. I would not have been here just because I knew the BiometHe Study Report was going to appear, because it does not answer the fundamental questions in this whole issue. They did not address themselves specifically to two questions whicl1 I have raised all along, and now I realize I must send you a publica~ tion that has appeared within' the last year or so which I prepared for "Controversies in Medicine," and I would be happy to send you copies of that if you wish for the record. The CHAIRMAN. Thank you. Dr. BRADLEY. And without going into much detail, these relate to unknowns, if you will, and they are what clinicians, those people taking care of people with diabetes, are more aware of, perhaps a little more humble about than others looking at it from a purely scientific standpoint. There could be unknowns that we have no wa~ of knowing about, but there can be two specific unknowns that come to mind, and these are critical, really, and they are as follows: First, the level of coronary heart disease, the condition of the heart in the diabetics at baseline was not known. I emphasized this in my PAGENO="0036" 13286 cOMP~TIV~ PROffl~EMS IN. .TB~ DRV.~' ~I~T~Y Ipr~vious testimony. The tools for evaluating the~e were crude. ~bere * WaS some kTffiwledge about it, but not enough was known so that one could really say these treatment grOups were the same. Second, and. this is crucial to the whole thing, they did not' really know how long diabetes had been present. NOW, diabetes is a risk factor in all of the patients in all of the groups of the study, Most clinicians know quite well nowaldays, and there is good statistical evidence to back it up, that the major effect of diabetes ~n' vascular disease relates to how long one has it-~-its duration. And unfortu- nately, in ad~lts it is very difficult to know how long diabetes has been present. We have a little clue from the study. I think Dr.. Ze'len or one of the other witnesses referred~ to the glucose tolerkm3e tests. The clue is a very iiiterestin'g one in that when one looks at the glucose toler- ance test in the group on. tolbutamide, there were more people in the tolbutamide' groups who had higher fasting blood sugars, and I think, more at every interval of the glucose tolerance tests, than in any other of the treatment groups, certainly more than was the case of .placebo~ . . . This~ means, then, two . things. Subgroup `(~.)`: Their diabetes was some*hat~ more severe as a group at baseline; and (2) they may have had diabetes Thuger. N~ow, we have no way of proving or disproving it~ We can present evidence on both sides, but it raises the same.. kind of uncertainty about the hardness of the TJGDP, and I think I gained~ this from Dr. Meier~s testimony, a lack of hardness. Tile was not quite willing ~to say that this was a very hard kind of decision. I think this is where we have to be very careful in accepting these results hook, line, and sinker. Now, we~ have a further hint that there may have been more risk in that when you add up the numerators of the various risk factors in the patients on tolbutamide, they were somewhat more. The key issue here is, again, that this d~oes not prove that tolbuta- mide and phenformin are not hazardous. They may still be. And our problem is how do we resolve this. Sir, if I may, I would like to make a few more suggestions that might help us all come to a solution of the problem. First: I' think the role of Government has unfortunately gotten to be a. little bit too strong here. Mr. Chayet' has referred to this, and it is alluded' to. in our statement. But I will focus specifically on the FDA. We have `been concerned~ all~ along that the Ffl~A~ has' not gone ahead with labeling which was reasonabl~' balanced. That was all we' `wanted, `somethii~g that acknowledged the fact that true con- ~troversy existed; that would not lay undue concern upon the mihds of physicians and their patients, yet'enough so that they would be caretul, but also allow us to get' about *our business' of educating physicians and patients. This is what has fallen terribly behind and is the reason these drugs are being used altogether too much today in diabetic patients of this type throughout the couhtry. * I will come back to that in a moment. NOw, you asked a very important question, and that is about the benefits. In my original statement in September I indicated that PAGENO="0037" COMPWI'ITIV~ ~RO~LEMS IN THE DRUG INDUSTRY 13287 these drugs are not oral hypoglycemic drugs. This is a semau~tic er~or on the part of Dr. Palumbo, who may he here `to defend himself. They really ai'e oral blood sugar lowering drugs~ They may pro- duce hypoglycemia, but that i~ not their blood sugar lowermg agei~ts, and they do this very clearly. No scientist in his right mmd wOuld argue with this, that they do it very clearly in selected patiei~ts, not all of the patients of the type that were studied in the TIGDP, but in a majority of them. The problem is they do not continue to do it. And second: There may be a hazard from a cardiovascular stand- point, so they are suspect in two areas. Now, in terms of other kinds of benefits which the TJGDP study was set up to evaluate, I do not believe they were set up to evaluate cardiovascular mortality. They wanted to see, did these patients have more diabetic neuropathy after a period of time? Did tl~ey have retinopathy, involvement of the eyes? Did they have more kidney involvement? Did they have more cataracts? Did they have more infectious disease? I think the end point was listed as vascular complications in gen- eral, as a mixed bag, but they really were looking for those complica- tions which are more specifically related to~diabetes. At the moment we do not have data relative to such end points ~n terms of effectiveness, long term effectiveness. The only data we have is relative to the blood sugar. If these drugs do not lower the blood sugar, no thoughtful diabetologist would continue to use them. Now, certainly if he does not believe that lowering the blood sugar might protect from these complications, he would not use these drugs. So at the moment we must deal in terms of blood sugar lowerii~g and maintaining it. Now, what I would like to see happen, I would hope from these hearings, is that we would get away from this controversy. Frankly, I think it is ridiculous. I think the people who suffer from this p~- tentially are patients. The controversy has held up our getting to- gether and trying to approach the problem not by governmental fiat, not by Dr. National Institutes of Health or by Dr. FDA, but by the appropriate cooperative statements of objectives in terms of treat- ment of patients. And if we cannot agree on objectives, maybe we will have more controversy. But I think we should agree on objec- tives that relate to using these drugs, if they are going to be used at all, in such a way that the one effect we know about, namely, lower- ing of blood sugar, is indeed guaranteed in patients. If we do not do that, I think patients either will be stopped because of govern~ mental fiat, and a law forbidding them, or a policy, or else physician~ will go on using it in patients. And if there is a hazard, then Obr viously they are being exposed to it. I think we must realize there may be a hazard. There is no ques~ tion about it. And our committee has never tried to say that this wa~ not a possibility. All we wanted to do was to be sure that the situa- tion was put in balance. That is all. Thank you. The CHAIRMAN. Well, thank you very much, Dr. Bradley. I ap- preciate your taking the time from your busy schedule to come here and testify today. PAGENO="0038" 13288 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Well, thank you very much, gentlemen. Mr. CHAYET. Thank you. The CHAIRMAN. Did any of the members of the biometrics panel wish to comment for the record on any of the statements made by Dr. Bradley? All right. Thank you very much. [Whereupon, at 12:08 p.m., the subcommittee adjourned, subject to the call of the Chair.] PAGENO="0039" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) WEDNESDAY, JULY 9, 1975 U.S. SENATE, SUBCOMMITTEE ON MONOPOLY OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C. The subcommittee met, pursuant to notice, at 10:15 a.m. in room 318, Russell Senate Office Building, Senator Gaylot~d Nelson (cha~ir- man of the full committee) presiding. Present: Senator Nelson. Also present: Benjamin Gordon, staff economist, and Kay Klatt, research assistant. The CHAIRMAN. Today the Monopoly Subcommittee of the Sen~tte Small Business Committee resumes its hearings on the safety, efficacy, and use of oral blood-sugar-lowering drugs, which are taken by diabetics. Well-controlled studies showed that users of these drugs are 2½ to 3 times more apt to die from heart problems than thosc w~o depend solely on diet or diet and insulin. According to expert testi- mony, these drugs also have limited uses, and Dr. John Davidson, the director of the largest university-based diabetes clinic in this country, estimated that more than 99 percent of the people usii~g these drugs should not be using them. In early 1974 the FDA moved to change the labeling of the blo~d sugar lowering drugs to reflect the latest scientific evidence about their dangers and lack of efficacy, but the agency's efforts were blocked by a court order. Nevertheless, recent additional studies confirming the dangers of these drugs have made a change in tl~ie labeling imperative, and the Commissioner of the Food and Drt~g Administration is here today to discuss the new labeling of the or~d blood~sugar-lowering agents as well as the recent human and animal studies that confirm the need for prescribing physicians to be in- formed in the clearest terms possible of the latest knowledge in tl~e field. The new labeling-as well as other aspects of these drugs-will be discussed tomorrow by a number of medical experts. Dr. Schmidt, you may present your testimony however you desire. The statement will be printed in full in the record.' See prepared statement, page 13697. 13289 PAGENO="0040" 13290 COMrETITIVE PROBLEMS IN THE DRtTG INDUSTRY STATEMENT OF ALEXANDER M. SCHMIDT, M.D., COMMISSIONER, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY RICH- ARD MERRILL, CHIEF COUNSEL, FOOD AND DRUG ADMINISTRA- TION; L RICHARD CROUT, 1VLD., DIRECTOR, BU~U OF DRUGS, FOOD AND DRUG ADMINISTflATION; JAMES M. ~BiLSTAD, M.D., GROUT LEADER, DIVISION OP METABOLISM A~TD ENDOCRINE DRUG PRODUCTS, BUREAU OF, DRUGS, FOOD ANi~ DRUG ADMIN- ISTRATION; AND ROBERT WETHERELL, DIRECTOR, OFFICE OF LEGISLATIVE SERVICES, FOOD AND DRUG ADMINISTRATION Dr. SCHMIDT. Thank you, Mr. Chairman. Because the statement I have is relatively brief, I thought I wOuld go through it. I am accompanied this morning by Dr. Richard Crout, Director of the Bureau, of Drugs, on my right and your left, and Mr. Richard Merrill, Chief Counsel of the Food and Drug Adminis- tration, behind me. To my left is Mr. Robert Wetherell, Director of our `Office of Legislative Services, and to my right, Dr. Bilstad, our Group Leader of the Division of Metabolism and Endocrine Drug Products. We are pleased to be here this morning to discuss our current actions regarding the oral hypoglycemic drugs. As you are well aware, labeling for this class of' drugs has been the subject of extended public controversy and legal challenge for a num- ber o~ years. The' Agency `has now published a proposed regulation providing new labeling for this class of drugs. The ~proposa1 appeared in the Federal Register on July 7, 1~97~ and asked for comment on the labeling. It also announced a public hearing to be held ou August 20, of this year to `afford interested persons a further oppor- tunity to comment. ` ` Last September, I summarized before this subcommittee the, actions of the FDA that followed the `report in 1970 of the results of the utliversity group diabetes program study. TodayS 1 will review the events `that have taken place since Fny previous testimony and will discuss, in some detail, of course, aspects of the proposed labeling. Mr. GORDON. May I interrupt you for just ~ second, Dr. Schmidt? As I understand it, new labeling was originally proposed by the FDA `in 1972. Is that correct? Dr. SCHMtDT. That .is correct. Mr. GoRDoN. So~ you have already had comments on that labeling. You stated in your statement which appeared in the Federal Register, that you did not expect any major new information. In fact, it is on page 15 of the Federal Register insertion. You have the results of Other studies including animal studies which support the UGDP study. Why do you, then, have to go through the same long procedures again, that is, proposing changes, having 60 days for comments, hav- ing administrative hearings, and so on? `Is that for legal purposes? Dr. SCHMIDT. Well, we spent a considerable amount of time dis- cussing and deciding on the best procedure to use in going ahead with the labeling change and quite deliberately chose the form&. rule- making procedure which in effect this is. And I think the reason the rulemaking procedure is clearly the best way to go is that the goals PAGENO="0041" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13~9i that we have in this whole process include not only the revisior~ of the labeling but `the dissefriinatioh' of information, the education of the great number of people, physicians and others, who are inter- ested in this subject. ` We are interested in educating everyone as to our firm' behef~ in this area and the rulemaking procedure allows public discussion, public debate, public comment, a process through which many peo~ ple can become informed and become edudat~d, and we thrnk~ the benefits of this in' this area are obvious and all to the good. Second, we would' wis1~ to avoid further litigation, if that is pos-: sible, and One can perhaps avoid litigation by achieving' consensus and one of the, best ways of achieving consensus is through public debate and discussion. We further think that the rulemaking procedure done formally could strengthen any court case that might evolve. And' I could t~sk Mr. Merrill to comment on that. Mr. MEmaLL. `Senator Nelson, Mr. Gordon, there is a second reason behind the way we are proceeding `now. Nothing would ple~se us more th'an to avoid reinstitution of that lawsuit in the Court of Appeals in the first circuit. But it is our belief that we should follQw the regular rulemaking route prescribed by our procedures in the Ad- ministrative Procedures Act. We strengthen ourselves in any subsequent court challenge of this labeling. It fortes the court to, in effect, conclude that we' were demonstrably wrong. It puts the burden `on any challenge or to esti~b~. lish that we were arbitrary and capricious~ on the basis of the evidence and information that we assembled in this administnttive proceeding. The CHAIRMAN. Go ahead. ` , ` ` Dr. SCHMIDT. Because' o~ the controversy' among ph~ysicians con- cerning the TJGDP study on the oral hypoglycemia bibeling pze- viously' proposed by us based on the use of the TiTGDP study, we decided the publication of the propOse~ labeling in the Federal Begis- ter should await c~ntpl~tion" ~fi' the ~etailed study of the 1JGDP study by the Biontetriid Soci~y. The report of the ~oóiety was published in the February 10, 1975, issue of the Journal' of the~American' ` MediCal `Assoei~tiOr~, }n testi~ mony before the subcommittee last J'aiu~aty b~ the members of tl~e society who conducted~ the re~iew,: a review of their conclusiofis was provided for you. The Biometric Society committee asses~ed the scientific quality of the TJGDP study, particularly the design, coi~- duct, and' analysis of `the trial. And, as well, the committee evaluated other controlled trials in- volving oral' hypoglycemic agents.~ The committee discussed in detail criticisms of the UGDP study and concluded that they found, "most of the criticisms unpersua'sive~" ` , Specifically, the Biometric Society committee con'clud'ed that first, the criticism'that patient selection was' inappropriate, was "largely irrelevant" to the validity of the evidence for the toxicity of `the oral agents~ ` Second, the critieism that total' thortality ifl the tolbutamide was not significantly different from that in the placebo group had some weight and "the `toxic' effeCt of th~ oral" hypoglycemics cannot be affirmed with the certainty that would be present if total mortality were significantly different." PAGENO="0042" 13292 COMPETITIVE PROBLEMS IN THE I~RUG INDUSTRY Third, excess mortality in tolbutamide-treated patients was not confined to a few clinics, as critics have claimed. Fourth, although there was a "puzzling anomaly" concerning the distribution of sexes to the treatment groups within clinics, they could find an assignable cause for this distribution and have no reason to think that this study had been compromised by a breakdown in the randomization of patients to the treatment groups. The committee particularly analyzed the criticism that there were important differences in baseline cardiovascular variables among the groups and concluded that there was no evidence that the baseline differences arising from the randomization contributed in any im- portant way to the finding of adverse effect from tolbutamide. Another conclusion was that the criticism that oral hypoglycemic drugs were given in fixed dosage was not relevant to the question~ of whether the drugs were toxic. The committee also noted that the fixed dose given was about equal to average recommended dose. They further concluded that although it would have been easier to interpret findings were there more data on mortality, that is if the study had been carried out longer, they did not criticize the UGDP investigators for having made the de- cision when they did. The committee said: Nevertheless, the result of that decision is to leave us with some residual uncertainty about the meaning of the findings, a point that is well `understood by the UGDP investigators themselves. And last, the committee said that' other studies said to contradict the findings of `the UGDP study do not in fact do so. The CHAIRMAN. Dr. Schmidt, yesterday and today-yesterday in the New York Times, today in the Washington Post-there is a story referring to `a letter that was written early this year by Dr. James Sammons, executive Vice president of the AMA to the Upjohn Co. in which, as I read the story, he is critical of the UGDP study and the evaluation by the Biometric Society of that study. Among other things his letter states:' "A considerable body of expert scientific opinion contradicts these published findings." Then the letter was sent to the State medical societies and county medical societies, and 1,100 of detail men of Upjohn were furnished copies of the letter. Obviously, it attacks the findings of the UGDP and as well the evaluation of the Biometric Society of those findings, which appeared in the Journal of the American Medical Association. My question is, the UGDA study extended over 10 years; is that correct? Dr. SCHMIDT.' The study began in 1961, ~nd the evaluation of it is still going on now. The CHAIRMAN. It started in 1961. On page 4 of your prepared statement you quote from the Biometric Society report that other studies said to contradict the findings of the UGDP study do not in fact do so. Are you aware of any carefully designed scientific studies that have been conducted that refute the findings of the UGDP? Dr. SCHMIDT. No, sir, we are not. The CHAIRMAN. So, as far as the Food and Drug Administration is concerned, you are not aware of any scientific studies that contra- dict the UGDP findings? PAGENO="0043" COMPl~TITIV~ PR0BLEM~ IN THE DRUG. INDUSTRY 13293 Dr. Sc~rn~xmT. N9 well-designed studies; no, sir. The CH*IEMAN. Well, I will not ask you what you think the m~ti~ vation of Dr. Sammons i~ because I think everybody knows. Go ahead, I will print in the record this article from the New York Times as well as the Washington Post on this subject at the appropriate place in the record.1 Dr. SCHMIDT. In addition to evaluating criticisms of the IJGDP study, the Biometric Society conducted extensive new analyses of the UGDP data, taking into account the effect of various baseline variables and cardiovascular risk factors. These analyses coi~firmed that cardiovascular, mortality was increased in the tolbutamide gro~lp. This increase was statistically significant for the patient p~pi~la- tion taken as a whole and in the subgroup of females, especially in women over the age of 53, but not in the male subgroup. This dQes not mean that the studies show that the drug carries less risk in males. On this point, the committee concluded: The data do not support the same conclusions for men, but one possible ~ea~ son is that the smaller number of patients in, the male group results~ in a lack of sensitivity to detect differences of mo~erate magnitude. An important finding was that the highest death rate, occurred in the ~oup of patients who adhered most closely to the tolbutamide regimen and did r~ot hai~e their dose modified. A1SQ,, when the analy~is was cOnducted according to an approach called the survival modeIi~g method, which takes into account the proportion of time each patient received the assigned medication, women in the tQlbutamide group had a statistically significant increase in both cardiovascular alid total mortality. The Biometric Society committee summarized its conclusions in the final sections of its report as follows-and I need to point out that all of page 5 on my copy is, in effect, taken from the conciusio~s of the cOmmittee. And they said: On the question of cardiovascular mortality due to tolbutamide and phen. forthin, we consider that the UGDP trial has raised suspicions that cannot be dismissed on the basis of other evidejice presently available. It further went on: We find most of the criticisms levelled against the UGDP findings on this point unpersuasive. The possibility that deaths ma~V ha~ve been allocated to cardiovascular causes preferentially In the groups receiving oral therapy exists, and, in view of the "~ionsignlflcance" of differences in total mortality, some reservations about the conclusion that the oral bypoglycemics are toxic mttst remain. Nonetheless, we consider the evidence of harmfulness moderately strong. The risk is clearly seen in the group of older women. Whether it affects all subgrOups of patients cannot be decided on `the basis of the available data, owing to the small number of deaths involved in these subgroups., In conclusion- They Wbnt on: We consider that' In the light of the IJGDP ~ndlngs, It remains with the proponents of the or~il hypoglycemics to conduct scientifically adequate studies to justify the continued use of such agents. Mr. GORDON. You stated before to the chairman that they have nOt come up with these scientific stt~dies. 1 See pages 13413 and~ 13439 PAGENO="0044" 13294' cOMPETITIVE PROBLEMS IN T1~E " ~DRIJG INDUSTRY Dr. SC~IMIDT. That is coi~rect. The cornmitte~ c'oneluded~ that there were no data that refuted the principal éonciusions of the UGDP study, and we* agree with that. Mr. GORDON. But setting aside, ~oi~ the thoment, the oa~rdiovascu- lar deaths, have* the opponents of your proposed labeling supplied si~bstaatial evidence-as required by law~*L~that the oral hypogly~emic agents `have a beneficial effevt on the' long-term v~scul~r complica- tions of, diabetes?. In other words, .1 am' talking ab&t~t efficacy in treatincr diabetes. Dr. ~`CflMIDT. Yes, I see; I have a little problem with your ques'- tion because it implies that wI'iat is required by lai~r would be that these~ drugs would have a beneficial e~ect on the bug-term vascular complications of diabetes. And in fact, we have no' substantial evi- dence on that point. `Mr. GORDON. But, that is required. by law, is it not? Dr. ScHMIDT. Well, no, because it depends upon the' cinims made and if the claim fo~ these drugs was that `they infiuenae\ the long- term mortality, the~ they would indeed need' substantial evidence. But, if the claim is that they lower blOod sugar or relieve symptoms- in other words, if they hai~e that effect and' b~e~e is su~stai~tini evi- dence for that, then that is what is required by law for that W~iing.' And we do have substantial evid~nce that these Qb~ugs~ h~wer blood sugar and that they' relieve sympto~s~ Mr.' GouioN. Well, does it 5tate~ that the purpose is merely' to re- lie've' symptom's aild ~hat is' all?' `Dr. SCHMID~r~ Well, no,' but you se~, `what you are doing is two things: oxie is you are pointing out the need for revised h~beling, and' we firmly agreed with this. In times past, as `1 believe I said list time I w~s here, it was believed b~r most physicians that lower- ing the blood sugar in the dinbetic' ~oubd have a beneficial effect upon the long-term mortality figure~ of diabetic patients. We analo- gized this t~ the i~lea that lowering blood pressure w~uld~ prolong the life of individuals with hypertension. And what' we are deter- mining by some substantial `evidence is that `lowering blood pres- sure in hypertensives does prolong lives in those `individuals that have high blood pressure. , We are learning things aboi~t the lowering of the blood sugar in, diabetics that surprise us. And so' we are in a different position now than we were in the past when the labels may have been silent on the issue of w]~ether or iiot lowering glucose prolongs the life of a diabetic. We' may have' applied this cause and effect relationship. What we need to do now i.s to separate out now clearly the treatment of peo- pie in order to relieve symptoms, which is very important. I have taken care of many diabetics. And you can be sick if you are a diabetic. You can feel terrible when you are' a d'iabetic~ And in symptomatic diabetics, the normaiiza~ti~n of blood sugar, which relieves symptoms as it does in some, is a very important thing. But we have to separate that and substantial evidence for that and that claim from the effect that that might or might not have on longevity of individuals with diabetes. Mr. GORDON. Now, even if the results of the' TTGDP study were not conclusive-let's assume they are not conclusive-but ai e hkely, PAGENO="0045" COMPETITIVE PROBLEMS I~ THE DRUG INDUSTRY 13295 or even suggestive, would ~iot the absence of the beneficial effect on the long-term complications of diabetes mean that the benefit-to-risk ratio for these drugs is unfavorable. Dr. SCHMmT. Well this comes back again to that same point of separating out treatment of the symptomatic diabetic who cannot take insulin, or who is not normalized by diet, that small grou~ of people. Clearly, the benefit-risk ratio for that small group o,f mdi- v~duals is such that we believe the drugs are safe and effective for them and should be available for their treatment. Mr. GORDON. Only for lowering blood sugar-is that right? Dr. SCH1~IIDT, That's right. Mr. GORDON. And for a limited period of time? Dr. SCHMIDT. And for symptomatic patients. Now if you are talk-~ ing about asymptomatic patients, then my belief is that the drugs simply should not be used. Dr. GROUT. I would agree with Dr. Schmidt as a physician. On the other hand, the asymptomatic patient is what the argument, the true argument, is all about. So, I think when you see estimates, or hear estimates of whether the oral drugs should be used in 1 percent, or 10 percent or 20 percntor 50 percent of the people now taking them, what you are hearing arc differences of medical opinion on whether or not the lowering of the blood sugar in asymptomatic patients may stave off long-term cardiovascular disease. And I think an important point to realize is that we do not view the IJGDP study as ~onclnsive on thut point. Nor did, the biometric study review the study on that point. The point we feel cOhsiderably more secure about is the evidence that the drugs may increase ca~dio- vascular mortality. Whether the lowering of blood sugar staves, off such mortality and is a compensating benefit for these drugs is an unanswered question, and the labeling reflects that point. The CHAIRMAN. Is it not also correct that the study concludes that the purpose can be accomplished by diet better than the use of the drug-except for. that rare small number you are making refereii~ce to? Dr. GROUT. I think a number of physicians, including ourseh~es, would draw that interpretation from the study. Your `question was, did the study. per se show that? And the answer is, not precisely. But that would be the cOnclusion, pe~~le would draw from the study and it is an importanb point., T3ecat~se the question has been asked," if usage. of tl3ese drugs goes down, does that mean that,, u~age of ~nsuhn will automatica1~1y go up? . And ~n our opinion, `and I think, in the opinion of a number of physicians, the answer to that is flC). The best alternative therapy for the great majority of patients n~w on these drugs is diet. We be'ieve that the changes in the practice of medicme that ought to occur at this point in time will focu~ more on the value of `diet than on replacement of oral' hypoglycemic' drugs with insulin. The CHAIRMAN. Dr. Davidson at Grady Memorial Hospital sajcl in his testimony 1 that he thought perhaps the oral hypoglyoemics 1 See testimony of ~Tohn K. Davidson, M.D., Ph. D., director, Diabetes Unit, Emory School of Medicine atid Grady Memorial Hospital, In bearings "Competitive Problems in the Drug Industry," part 25, pages 10838-10854. PAGENO="0046" 13296 CoMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY were indicated in about 1 percent of the cases. I have a note here that Dr. Bradley thought 20 percent and Dr. Weingrad 10 percent. I believe Dr. Davidson testified that they had the largest university based diabetes clinic in the country. Is that your memory? Dr. CROUT. As far as I know, yes. The CHAIRMAN. I think that was his testimony. You may recall he testified that since they used the oral hypoglycemics for many, many years, it was hard for them to conclude that they have been wrong, but they concluded they were. And he testified that they had taken everybody off the drugs. As I recall, he said they got better results by managing his patients with diet alone than when they were using the oral hypoglycemics. Do you remember that testimony?' Dr. CRouT. Yes. The CiiAIRMAN. Are you aware of whether or not that is the ex- perience in other clinics? Dr. CROUT. I think that is a common opinion among many good diabetologists. And I think that actually Dr. Bradley would harbor the same opinion, I believe, and `you could confirm this with him, that his figure of 20 percent represents his opinion of the number of dia- betics who might need drugs if greater emphasis were given to diet. So we do not contest those figures at all. I would point out that nobody to my knowledge, including Dr. Davidson, has ever published in the medical literature sharp studies on this issue. Dr. Davidson's views are largely `in testimony before this committee, not in the medical literature. Sq. real studies to define 1, percent, 10 percent, 20 percent are not available either. Mr. GoRDoN. I t11~ink Dr. Davidsoir also publishd an article in the journal of the American Medical Association recently, did he not? Here it is: May 26, this year.' Dr. CROUT. I think it was a comment. But to really present the data that were presented before this committee in a full published form has ,not occurred to my knowledge. The CHAIRMAN. Go ahead Qoctor. Dr. SCHMIDT. In addition to the Biometric Society report, other information has recently become available. First, the IJGDP has published recently their detailed report of, the results' of the phen- formin study. In additiOn to reporting that cardiovascular mortality and total mortality were greater in the phenformin-treated grotip than in the other treatmeht groups, the report presented evidence that pheuformin `therapy resulted in increased blood pressure and heart rate, thus suggesting possible. mechanisms by which this drug might influence cardiovascular mortality. Mr. GoRDoN. Dr. Schmidt, are you saying here that the benefit-to- risk ratio o1~ phenformin is even more unfavorable than for `the other oral hypoglycemics? Dr. SCHi'~çIDT. Yes, .that would be the, conclusion one would 4raw from this study, yes. Mr. GoRDoN. In a study published in a book called "Controversy in Internal Medicine" by Winegraçl, Clements and Morrison, TJni- versity of `Pennsylvania School of Medicine, Dr. Allan Winegrad, PAGENO="0047" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13297 with whom, I am sure, you are acquainted as being an eminent scientist and clinician, and others stated that phenformin has no role in the treatment of diabetes mellitus. Do you agree with Dr. Wine- grad? Dr. SCHMIDT. Well, Dr. Crout and I have been discussing this for some time. And with your permission, I will let him describe our feelings on this. Dr. CROUT. Let me wear two hats. The first hat is as a physician. And I agree with him. The second hat, Director of the Burei~u of Drugs, where we have to deal with the issue of action on that point. Let me state the reason why the benefit to risk for phenformin is less than for the other drugs. This drug may cause lactic acido~is, a potentially fatal complication in patients who take it. So, there is a clear added hazard, in addition to ~vhat it does to cardiovas~ular mortality. Now, the incidence of that lactic acidosis has. in the past been thought to be quite low. As more and more information comes along, it looks like it is higher than we had anticipated. And that issue of lactic acidosis was brought before our Metabolic and Endocrine Advisory Committee more than a year ago. At that time they recommended that a warning be placed on the drug, but that it stay on the market. We are gçing to take the issue back to that committee and take up that issue again. But, it is a separate issue, it is a separate issue from the labeling on cardio- vascular mortality. On that, as far as we know, phenformin is the same as the sulfonylureas. We are dealing here with two adverse effects. And it is the sum of those two that I think is the import~nt issue. Mr. GORDON. As a medical scientist, could you tell us what the medical justification is for having this drug on the market? Dr. C~OUT. What my personal opinion is? Mr. GoiwoN. Yes. Dr. CROUT. I would support Dr. Winegrad. I personally would not use the drug. Mr. GORDON. Then you see no reason for this drug to be on the market. Is that correct? Dr. CROUT. You are asking me as a medical scientist? Mr. GORDON. As a medical scientist. Dr. GROUT. As a medical scientist, yes, I don't see any such reason. Mr. GORDON. Well, then, why is it not being taken off the mar1~et? Why aren't steps going to be taken to take it off if there is no n~edi- cal, justification? After all, is that not the purpose? Dr. CROUT. As I point out, we will take that back' to our advi~ory committee. It is hardly a universal opinion. And neither I nor any- body else in the Federal Government that I am awa~re of has the power to simply exercise hi~ ,personal opinion in .the drug reg~ila- tion business. , . If I may wear that hat of the Director of the Bureau of Drttgs, we will take that back to our advisory committee. We will atte~npt to see what support there is for a po~ition that phenformin should not be marketed. We will take appropriate action after that. That is a separate issi~e from this labeling. PAGENO="0048" 13298 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. MERRILL, Mr. Gordon, Dr. Grout makes a point that is too important uiot to reemphasize. And we have been spending a lot of time in the Food and Drug Administration trying to insist that drug manufacturers back up their claims with adequate and well-controlled clinical studies-scientific evidence and not on opinion. And for the very same reason we are reluctant to rely upon our own instinctive judgments. We would like the backing of the scientific community, and strong scientific evidence. We think it is obtainable. But we want to be sure. The CHAIRMAN.' Go ahead Doctor. Dr. SpHMIDT. At hearings before this subcommittee this past Janu- ary, Di~. P. J. Palumbo reported that a retrospective study of dia- betic patients treated at the Mayo Clinic suggests that survival was lower in those patients treated with hypoglycemic agents compared to those patients treated with either insulin or diet. Dr. Palumbo's full study has not yet been published.1 Another study, a retrospective study of patients treated at the Joslin Clinic reported in a doctoral thesis by P. Kanarek, can `be interpreted as providing results that are consistent with those of the TJGDP. Although we have seen this study, it has not yet been subjected to a full review by statistical and epidemioio'gical experts.2 At this point we can say that certain subgrotips of insulin- treated patients appear to have better survival rates than tolbuta- mide-treated patients with comparable glucose abnormalities. Studies of this type, however, always present problems in interpretation because of doubts regarding comparability of treatment groups and because treatments are not randomly allocated. Thus, although the retrospective stu4ies of Palumbo and Kanarek may or may not, when fully analyzed, `add sup~o'rt to the TJGDP findings, the prospective UGDP study must be accorded far greater weight and is alone a sufficient basis for our proposed actions. DoctOrs Tan, Bradley, GIea~on and Soeldner have teported on the long-term effects-4 years-of hypoglycemic agents' on the oral glucose tolerance test ~nd blood lipids in chemical diabetics `at the annual meeting of the American Diabetes Association, in 1978- abstract in "Diabetes" 22 (~uppl. 1) 290, 1973. `The in~restigators' abstract reported there was no significant difference in the improve- ment in glucose tolerance between patients receiving oral hypo- glycemi~ agents and patients receiving a placebo. `The full report of this study has not yet been published, but it appears that the hires- tigators studied glucose tolerance on the day following discontinua- tion of the drugs. Their findings thus would indicate only that the oral agents do not lead to improved glucose tolerance in the absence of continued use of the drug. - In another study, Dr. K W. Wissler, in an FDA-supported inves- tigation, examined the chronic effects of tolbutamide in the rhesus monkey. He found that coronary artery lesions were almost two times more ferquen't and three times more severe in the tolbutamide- treated animals than in the control animals. FDA recently received 1 HearIngs before the SubcQmlflittee on Monotoly~ Se~eet Committee on Small Business, U.S. Senate, 94th Congress, 1st Session, on Safety, Efficacy, and tise of Antibiotjcs- Clirulamycin and Lincomycln, January 28, 29, and July 8, 1975, Part 27. 2 study by P. Kanarek, page 13393. PAGENO="0049" COMPETITIVE PROBLEMS IN THE DRUG INWYSTRY 13299 the final report on this study, which has not yet been published in the literature. FDA, at br. Wissler's request, is supporting further study of the pathologic findings by seve~ai independent pathologists. Dr. D. F. Wu, et aL, reported on the effects of tolbutamide on heart function in dogs, with chemically induced thabetes, at the methng of the American Federation for Clinical Research this past May. The investigators reported that after 1 year of treatment With tolbutamide the left ventricular function was reduced alid cardiac morphology altered compared to control groups. The animal studies do not necessarily bear directly on the ex~ess cardiovascular mortality seen in tolbutamide-treated humans in the TJGDP study, but they do suggest overall mechanisms by Which this might have occurred. Now, as you know, Mr. Chairman, it has been the vieW of the FDA since 1970, that the findings of the TJGDP study should be reflected in a warning in the labeling for oral hypoglycemic drugs and in turn, in the use by physicians of these drugs. Let me e~n- phasize that this view does not require that we conclude the study provides absolute proof of hazard, The UGDP study is an adequate and well-controlled study-by far the most exten~iite and best exa~n- ination of the long-term effects of oral hypoglycemic agents yet ei7er undertal~en. The finding of an increased cardiovascular mortality in tolbuta- mide and in phenformin-treated patients cannot be attributed to atiy shortcomings of study design or execution. This finding, despite any residual uncertainty that may remain, requires a clear warning to physicians. Prudence dictates that a warning be issued whene~er there is sufficient evidence to believe that a drug m~y be hazardq~is d~ carry a risk, and that such a warning is necessary for the sa~fe and effective use of the drug by physicians and patients. :Enough, time h~s now pnssed for interested persons to. have studiet the ~i~nn~t~ic Society report and the recent detailed UGDP report on ph~nformin. The Agency has, therefore, published for, co~rnnerit a gu1,ati~n proposing new labeling for the oral hypoglycemic labelh~g. ~ter- ested' p~rsons may comment on the proposal by Septehibor ~, 1975, and a public hearii~g will be held on August ~0, 1975. Final `iaheli~g regulations will not be published until after all comments ar~d materials have been considered. Our proposed labeling has two sections of particular importance; a boxed warning stating that there may be an increased risk of cardi~- vascular death associated with the use of oral hypoglycemic drugs and a new indications section that limits use of these drugs to p~- tients whose symptoms or blood glucose abnorm~alities can~iot be controlled by diet alone and who cannot take insulin for one of a number of specified reasons. N?w, I would like to discuss both of these sections in greater detail. And they are both reproduced in full in an attachment to the statement. The warning describes the UGDP study and its f1nding~. It has been contended that certain studies said not to support th~ findings of the UG1T~P study should be mentioned in the warnin section to provide the "fair balance." We have concluded, however, an made clear in revised regualtions that if scientific data exist to sup- port a warning, the warning must be presented in unambiguou~ 56-592-75------4 PAGENO="0050" 13300 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY terms without disclaimers or qualifications that would undermine or destroy its usefulness. There is, therefore, no mention in the proposed warning of other studies involving the oral hypoglycemic drugs. The mention of studies in which increased cardiovascular mortality was not found would serve only to encumber the warning. Mr. GORDON. Dr. Schmidt, you say that the warning must be stated in vigorous terms without disclaimers. Why, then, does the warning include-you do not have It in your statement, b~it it is in- cluded in the Federal Register statement-"that, despite the con- ~troversy regarding the interpretation of these results, the findings of the TJGDP study provide adequate scientific basis for this warning"? Is it not true that the presence of controversy about the need for the wording is irrelevant and is distracting? Is that not an encumbrance, in a way? Dr. SCHMIDT. No. We definitely do not feel it is an encumbrance, and I ~personally feel that it is absolutely necessary to the creditibility of warning that we state that the TJGDP study, despite this contro- versy, provides sufficient evidence for the w~rning. I think that were we to remain silent, or to ignore the fact that many physicians and many experts have said, in efrect, forget the UGDP study-if we w~re to remain silent on that, it would be so o~yious, cause so many ques- tions, make people wonder why we were in a sense trying to finesse the issue, that it is to me absolutely necessary in order to have a credible statement that we say that very clearly. The IJGDP study is sufficient to provide a sound basis ,for this warniflg, and the con- troversy does not controvert the fact that the, study provides that avenue. Mr. GORDON. Well, I thought that it is not just the IJGDP shidy that you are basing the label on. It is the TJGDP study, the B~p- metric Society study; you referred to the Wissler stud~r, the Wu studies, the Tan' studies. Dr. SCHMIDT. No, I did just. now in the statement. The warning is based on the UGDP study. Mr. GORDON. Solely.? Dr. SCHMIDT. Yes, sir. I can make a couple of other points. The first is that the encumbrance of other studies is not present, `and I think that the warning statement is `much better for another reason; it relates to credibility. It makes the statement believable, and it renders it, I think, much less. subject to attack and discredit. As I said early on, one of our goals here is to achieve a professional con- census about the use of these drugs. So I just strongly believe that the warning, stated as it is, makes .a much better statement., Mr. MERRILL. May I inject one comment? Your question, Mr. Gordon, is one that will be asked of us again. I have no doubt, that the charge will be made that we are speaking out of both sides of our mputh in these very two documents. In one it will be argued we say there can be no encumbrance of the warning, and in the other we seek to encumber i~t. That is not true. In the context of this warning, the s~t~ternent that the administration of oral hypoglycemic drugs pi~y be a~soqiated with inCre~sed cau~d~iovásc~ilar mortalities as corn- pared to treatr~ient with' diet alone aád diet with insulin is tw~ full paragraphs a*ay from the line you just quoted. In addition, the PAGENO="0051" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13301 reference is to the controversy about the interpretation of the U~DP study, and says nothing about the significance. of the warning. So I do not have any difficulty at all reconciling the two statements. Mr. GORDON. One other thing. You also proposed a boxed warn- ing at the beginning of the warning section of the labeling. Is ~hat not correct? Dr. ScH~IIDT. Yes, in the proposal. That is where it i.s put. Mr. GORDON. Why not put the boxed warning at the beginningS of the labeling, as with chlorarnphenicol and lincomycin and 4hn- damycin? Dr. SCHMIDT. Speaking only for myself, when I went through it, its location was logical. It was at the beginning of the warning sec- tion, where many are, and the thought did not cross my mind that it could be or should be or might be removed from the warning th~ng, a~d stuck at the beginning. I think that it is an interesting sugge~- tion, a valuable comment, and is one that we wilt evaluate, reevah~ate. There is certainly no-it need not stay where it is. The CHAIRMAN. With respect to the UGDP study, if my memory serves me correctly, it was reviewed at the .re~juest of Dr. Marstan, the then Director at NIH, by Dr. Chalmers, who at that time. was .at NIH. It was reviewed by somebody else prior to calling upon the Biometric Society to evaluate it, wa~ it not? Dr. CROUT. It was reviewed by a number of people, and it was reviewed by ~our own staff. It was rev~ewed by people, at the NIH. It was reviewed also by critics. So, rather simultaneously, there were several reviews that appeared in early- to mid~187I. It was re,vie~ed by Dr. Seltzer. Dr. Schor and Professor Cornfield also had detailed reviews of it. The CHAIRMAN. Well, what were the conclusions of the other groups that reviewed it? Dr. CROTJT. The major conclusions of Dr. Seltzer and Dr. Sc]~tor were that the study had flaws in its fundamental design and execu- tion to the extent that it was worthless, and that was the begim~ing of the controversy. Dr. Cornfield then felt that those criticisths, while correct in certain respects, were insufficient to negate ~he study. I must also say ~Dr. Alvin Feinstein also had a very critipal review. So, the major critical reviews were those of Schor, Feinstein, and Seltzer. The major supporting review has been the Biomet~ic Society, and the review by Cornfield, In our opinion, the review by the Biometric Society was in 1~ar greater detail, far greater depth, than any of the others, and is again the overriding review of the study. The CHAIRMAN. The Biometric Society was a review for the per- pose of evaluating the validity of the studies. Is that correct? Dr. CROUT. That is correct~ and it is the only review conducted, in a sense, by a third party. You see, the controversy. was begun by Dr. Feinstein, Dr. Seltzer, and Dr. .Schor; and, in a sense, they wëi~e parties to one~side of the controversy. Dr. Corn~1~ld was a con- sultant to the study, . ~nd in defending it was, in a sense, on ~t~e T.JGDP side. So the Biometric, Society review was, in ou~ opinion, not only the most detailed and thorough, but it also wa~ by a thb~d party. All the people were previously involved in the `controversy. PAGENO="0052" 13302 CoMP~TITXVE PROBLEMS IN Tfl~ DRUG INDUSTRY That is really why we waited so long for that report, and believe it is so important, The CnAntMAN. Go ahead. Dr. ScrnumT. Our warning also points out that, although only one sulfonylurea and one biguanidé were included in the TJGDP study, it is prudent from a safety standpoint, in view of the similarities in chemical structure and mode of action of drugs within each of these two categories, to consider that the UGDP findings may apply to the other drugs in each category. The warniug has thus been applied to all sulfonylurea drugs, and the one biguanide drug marketed in this country. Finally, the warning sectiOn states that the clear implication of the finding that tolbutamide and phenformin may carry a risk not asso- ciated with insulin; the drug, the label will state: "Should be used in preference to insulin only in patients with maturity onset diabetes * whose symptoms or blood-glucose level cannot be controlled by diet alone and only when the advantages in the individual patient justify the potential risk (see Indications). The patient should be informed of the advantages and potential risks of the (drug) and of alterna- tive modes of therapy and should participate in the decision to use this drug." We have concluded that a patient population exists for which these drugs, properly labeled, can be considered safe and effective. We have also concluded, however, that this patient population is a limited one. The OI~[AIRMAN. This is part of the warning, is it? Dr. ScIIMnxr. Yes, sir. The CHAIRMAN. The label states that the patient should be in- formed of the advantages and so on, and should participate in the decision to use the drug. I am wondering what you are getting at there. If in fact you have a patient, who cannot manage it for what- ever reason,, psychologically, mentally, physically, or what have you; could nOt use insulin or could, not b~ kept on a diet, and the doctor ~onclud~s you should reduo~ the blood sugar level, that is a case for which, I would assume, there is general a~greement that an oral hypo- glycemic would be indicated. Is that correct? Dr. SCHMIWr. Yes, sir. `The CHAIRMAN. Well, now, then, when you say they should par- ticipate in the decision to use one of the drugs, are you then talking about that very large number of people whose problem can be han- d'l~d effectively by diet? Are you sayiiig to the physician that be~fore you put them on an oral hypoglycemic. they must be notified it is the behel of the physician that their problem can be handled by diet; that it would be better to use the diet, and that the doctor should attempt to persuade him to do ~o, and understand that the use of th~ drug may have adverse effects, and that the patieiit would be better off on a diet. Is that what you are talking about? Dr. SCHMIDT. No. I think that this is really quite explicit. The warning says that the drug should be used in preference to insulin only in patients with maturity-onset diabetes, who cannot be con- trolled by diet alone, and oniy ~vhen the advantages in the individual patient justify the potential risk. Now, this narrows it down to that PAGENO="0053" COMP~Pfl~IVB PROBLEMS IN TI~E~ DRUG IN~IJSTRT 13&03 very small group of patie1~ts~ we h~ye talked~ about before? who for whatever reason cannot be controlled by diet or cannot take insulin. So first of all, we are talking about jUSt `this small g~oup~ and t~ien second, we are say'ing that the patient i~iust be knowledge~b1e. Gpod medical practice' dictates that the patient is knowledgeable about the options of control by diet, control by insulin, and if the, choice by the physician is to be the oral hypoglycemic agput, w~ are saym~ that the patient should be knowledgeable. about the risks of this drug' to `which he may be subjected. Now, I could use another analogy that may, help a little. bit. If one has hypertension, he really ought to avoid salt. Now, I do not know if you have ever tried a salt-fiee diet, but a salt-free diet or low- salt diet is an extremely difficult, and in many respects uncomfort- able sort of trial. When drugs came along that increased the renal excretion of sodium, there was a very strong tendency on the part of the patients to say, this solves my problem. I can now eat salt again~ and have tasty food, and take the drug, and everything is fine. I will be just as well off as I was when I was on a salt-free d~et. Physicians. found it much easier to prescribe, a pill than it was to fight-~and believe me, it is a constant struggle with patients ~o keep them on a salt-free diet, or to control a diabetic by' diet. So,.. taking the pill was really kind of a step toward the brave new world. Now, when I used to. inform my patients. that, yes, they could io~er their sodium. with this drug, and not be as ,strict about their di~t; but when they took a drug, they were running these risks. Sometimes for the first time, I got compliance on the part of my patients with this sodium-free diet, the lo~ sodium diet. Now~, what I am talking about is~ simply good medical practice tl~at would, be accepted as good medical practice by, anyone. And we are say~ig, in this ~abelix~g, that `patients, for the reasons I just illustrated with my analogy, m*st be informed of this possibility of,increased risks;. a~u4 as pai~t o~ their management, they mast know the options ,of insulin and qf th~ir using. dietary coi$rol. *, ` ` ` The CHAIR~N~' Well,. then., if I iip4erstaud the whole paragraph. quoted there, it is~ addressed to' a ~e~y narrow speotrun~, of patients. Dr. Sc~xD~r. Quito ~o,, yes. . ` The CimAn~Aw. And, if I iñterp~t it, right, you are saying that if, as a practical matter, the patient's blood sugar can be controlled 1y diet, the doctor should not give him the drug. Dr. Soim~mT. That is our opinion,' yes. flut, as~ I indicated,~ we do believe that there is a small patient population for which these drugs, properly labeled, can be considered safe and e~ëctive, ax~d we have also concluded though that this patient population is quite limited. The CHAIrnXAN. I have forgotten the figure of the estimate of the number of patients per year that were, receiving prescriptions fpr oral hypoglycei~'ics? Was it 1.5 milli9n?. Dr. SOUMIDT. About 11/2 million patients is a rou~h estimate. The CHATRI~tAN. iou. testified a. few months ago that there has not been any care±ui stuthes to show what. percentage of those receiving oral hypoglycemics are receiving them for properly indicated. reasox~s. PAGENO="0054" 13304 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY If the figure is 1 million and a half and if you take, even Dr. Brad- ley's estimate of only 20 percent, Dr. Bradley is saying that 80 per- cent of a million and a half people-about i,200,000-should not be using them. In the view of Dr. Davidson, only 1 percent should he taking them which~ means that `almost the whole million and a half are exposed to needless risks; Only 150,000 diabetics are taking them for proper indications. Is that correct? Dr. SCHMIDT. It would be hard for me to believe that anymore than, say, one out of five or two out of five, at the absolute outside, of people who are now getting these drugs by these indications should get them. The CHAIRMAN. Well, if you go above one out of five you are above Dr. Bradley, who has been one of the most vocal critics of the UGDP study. Dr. SC1Th~IDT. I have really no sound basis on which to pick a number. Dr. CROtIT. I seem to think you are emphasizing' the importance of this relabeling and what it means to the practice of medicine. I would also emphasize that' we are talking about the United States and point out that these drugs are used worldwide. No country has yet, to thy knowledge, put a warning of this type on the labeling, and, yet, we do know that when the Food and Drug Administration of the United States does something it tends to cascade worldwide. These drugs are' used enormonsly in Europe. I am told, for exr ample, that the number one selling prescription drug in `Germany is not a tranquilizer as it is in the United States, but an oral hypo~ glycemic drug. So' this partièular action `will, I think, have world impact., and we are sensitive to that. it is also whyit `is so terribly important to the drug' industry because it is multinational. Mr. GORDON. In an article in the Journal of the American Medical Association, Dr. John Davidson stated': There has been a striking increase in death rate and decrease in life expect- ancy in maturity onset diabetics in America, Europe, Asia, Africa, and Aus- tralia during th~ last 20 years. These changes have paralleled the increasingly widespread neglected diet therapy and the almost unbridled enthusiasm among many physicians and patients for the use of ~ulfonylureas and treatments of choice. `They seem to parallel the rise, and the uses and increaCe in these drttgs and increase in the death rate and the decrease in life~ expectancy among diabetics. Do you have any comments to make on that? Dr. CROUT. We have not reviewed that situation, and I would not want to engage in the sensationalization of putting thos~' two things together. That statement may be true or not true. I do not know. The CHAIRMAN. Go ahead. Dr. SCHMIDT. The limitation of the treatment population to pa- tients on whom insulin cannot be used has been opposed' in the past on the ground that it has interfered with the practice of medicine.' We recognize that drug labeling has an impact upon the p1 actice of medicine, and I think' it should' for this reason. The FoQd and Drug Administration has an obligation to ensure that drug labeling is as correct and accurate as possible. It must, moreover, meet the statutory standard of describing the conditions and use under which PAGENO="0055" C0MPETITIVI~ PROBLEMS ~IN THE DRUG INDUSTRY 13305 the drug may be considered safe and effective. If a known hazard and potential risk leads to the conclusion that a drug may be used safely only' on certain patients, this limitation on use must be expressed in labeling. The indications section, in addition to describing the populatibu in whom these drugs is indicated, points out that "in considering t~ie use of (drug) in asymptomatic patients, it should be reco~niz~d that whether or not controlling the blood glucose is effective in pre- venting the long-term cardiovascular or neural complications of d~a- betes is an unanswered scientific question." This emphasizes the different benefit-risk considerations that obtain in the symptomatic patient who, needs alternative treatment if insulin cannot be used, and the asymptornatic patient, whose n'eed for alternative treatment is debatable. I think we have discussed this point at some length previously.. You asked that I comment bn `the promotion of these drugs. We cannot conclude that advertising for these productsha~s been generally violative. It has, however7 been based upon labeling that is in need of modification. It is clear that promotional materials must change radically to reflect the new warning and restricted indications. YQu can be assured that we will be monitoring the advertising of the~e products closely after the ne~ labeling becomes final to see that they do, indeed, do so. The CHAIRMAN. i~o you permit reminder `advertising, and how do you handle them? Dr. SCHMIDT. Well, we permit reminder ads, yes. The CHAIRMAN. With no claim? Mr. MERRILL. This drug, Senator,' carried a boxed warnin~. We have in preparation a final order that is responsive to a notice~ of proposed rulemaki~ig published last year that would prohibit ~the u~e' of reminder ads for any drug that carries a boxed warning. The CHAIRMAN. I see, so any advertising would include the `box. Mr. MERRILL. It would include a brief summary-the full range `of information. ` The CHAIRMAN. I see, go ahead. Dr. SCHMIDT. It is important to realize that the use of these oral hypoglycemics remains widespread despite the, UGDP study and despite the rather limited ability of the drugs after a few years of use, even to lower the blood sugar. Total prescriptions for this class, according to the National Prescription Audit, have been stable b~- tween 19 million and 21 million since 1967 (except for an apparent dip in 1969.) The CHAIRMAN. That is per year? Dr. SCHMIDT. Yes. The CHAIRMAN. What does that prescription mean in this context? Dr. SCHMIDT. Well, any `one individual would during the year r~- ceive more than one prescription. The CHAIRMAN. Well, if 1½ million people `were getting it,' o~ course, it would not always necessarily be the same' person. Dr. SCHMIDT. Well, if these figures are' accurate what that means is the average person would receive over 15 prescriptions or one prescription a month. I will not put my career on the line toward the' PAGENO="0056" 13306 COMP'ETITI~VE~ PROBLEMS I~ T~IE DRUG i~puSmY accuracy of those figures, though. Generally, physicians control when they se~ patients~ by writing presc~iptions~ though, and I used, for example, to he sure that I would see a patient at ~uch ~nd such a' time by being sure that he ran out of medicine and had to cOme in, so that it is not unusual for indications of this kind to have more prescriptions than some others. But the point of these relatively high figures is that there is a great deal of common practice to overcome before use of the oral. agents will proceed to what we would consider to be proper levels. It is anticipated that publicity attendant upon publication of pro- posed labeling by FDA and the announcement of the upcoming public hearing, as well as publicity relating to today's. hearing, will bring the new labeling to the attention of physician~s, as we begin the long process of persuading them that the UGDP findings should change the way they treat diabetics. in addition we plan to issue a drug bulletin when the labeling for these drugs is made final. We will monitor the use of these drugs and will take additional measures as necessary to publicize the labeling. This concludes my formal statement. I will be happy to respond to additional questions. The CHAIRMAN, Thank you, Doctor., I note your comment that there is a great deal of ,coirimon practice to overcome before the use of oral agents would recede to its proper levels. I think yOu face a formidable task, considering that you have. Dr. SamrhOns of' The AMA writing to all the State medical and county medical societies in the country and then Upjohn Co., using his letter. We received a~ letter from 13r. Max Miller, who, as you know,, is director of the UG'DP study. He sent along a copy of the letter that was sent to him by a doctor r~porting on what the. Upjohn sale~man said to this doctor about the study. Dr. Miller did not wish that the doctor's name who wrote to him be disclosed, but he did not object to his own name being used. , , This doctor wrote to Dr. Miller and said, "Deai~ Max,~, Here , i~ a summary of what the Upjohn salesman said to me in, his visit yester- day: (1) there is no' cause-and-effect relationship revealed in the study between the use of Orin'ase and the incidents of coronary dis- ease; (2). the statistics are so comp~1icated that only a student of sta- tistics ban evaluate' them; (3) 2½ less coronaries in the study would, not change the results; (4) 35 diabetologists do not accept the results. of the, study; (5.) the director of the study in Cincinnati dOes not accept the results; (6) two other men in the study do not accept the results; (7) Dr. Kent of Cleveland does not accept the results of the study; (8) Cincinnati added patients from it~ cardiac, unit to fill its quota of diabetic patients; (9) most' of the coronaries came from two centers; (10) there wasno follow-up on~ five patients in the study; (.lj) the dose of .Oriila'se was fixed so, therefore, it was not a correct dose for many patients; (12) the Joslin Clinic and other diabetes clinics have reviewed their cases i~1 their clinics, and the result cannot support the results of the university study; and (13) the FDA will probably modify the ruling on Orinase. During the interyiew he. had a copy"-that is the Upjohn representative-"of the Medical Tribune in his hand which he referred to from time to time." PAGENO="0057" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13~3O7 So, considering that Upjohn has 1,100 detail men and other efforts by the industry, you have a long battle ahead of you to achieve a standard of rational prescribing of oral hypoglycemics despite the fact that there are no scientific studies refuting the careful studies done by the UGDP or the Biometric Society's evaluation. As is cl~ar from here, the Biometric Society refuted charges that are made by the detail men. I would have this printed in full in the record. Dr. SCHMIDT. I would sincerely hope that the medical profession, itself, and particularly the diabetologists would respond to what to me is a clear challenge in all of this and would be able to separate out the principal issue and that is the following: For whom, for wijat group of individuals, are these drugs suitable, given the IJGDP study? And as I have indicated earlier in many, many conversations I have had with the most vigorous opponents of the UGDP study, there is an agreement that these drugs are grossly overus~d. Once there is agreement to that, that identifies a very serious problem, which is, in essence then, apart from the controversy of the UGDP study. And if 80 percent of these drugs are misused, that identifies a problem to which the medical profession itself must ~e- spond, and I will be bitterly disappointed if it does not. Mr. GORDON. Doctor, suppose you are disappointed and use does not go down? That is a possibility. What do you think of the idea±- I brought this up yesterday with respect to lincomycin and clinda- mycin-about having corrective advertising with surveys by the FD~A. and continuation of the corrective advertising, as in the FTC's Hawaiian Punch case, until the use actually drops? Dr. SCHMIDT. We will, as I indicated, monitor the use of these drugs. We will certainly monitor the advertising, and we will see if, indeed, these drugs do become in effect unsafe and this can be showb, then I would probably have a long talk with Mr. Merrill, but I do not know. It is hard for me to hypothesize. Mr. GORDON. May we get periodic reports on the use of the~e drugs as you get them? Dr. SCHMIDT. Certainly. I would be happy to. The CHAIRMAN. You get reports monthly? Dr. SCHMIDT. Well, we follow certain surveys that are done, such as the prescription audit survey that I mentioned and others, Thei~e are some commercial sources of data and others that we follow t4t can give at least an estimation of the use of the drugs. We can also undertake surveys of our own. Mr. MERRILL. Our information is not as good about drugs in this class as it would about antibiotics, which are certified, of course, and thus, we know how much is being produced. But we have access to pretty good numbers. The CHAIRMAN. Thank you very much, Dr. Schmidt, for your very valuable testimony today. The hearings will open tomorrow mornin at 10 o'clock in the same room. Senator Abourezk will preside as have hearings starting on the energy legislation in the Finance Committee that has come over from the House. Thank you. {Whereupon, at 11 :35 a.m., the subcommittee recessed to reconvene at 10 a.m., the next day.] PAGENO="0058" PAGENO="0059" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Present Status of Competition in the Pharmaceutical Industry) TEURSDAY, ~~ULY 10, 1975 U.S. SENATE, SUBCOMMITTEE ON MoNOPoLY OF THE SELECT COMMITTEE ON SMALL BUSINESS, Washington, D.C~ The subcommittee met, pursuant to notice, at 10:05 a.m., in room 318, Russell Senate Office Building, Senator James Abourezk pi'e- siding. Present: Senator Abourezk. Also present: Benjamin Gordon, staff economist, and Kay Klatt, research assistant. Senator ABOUREZK. The hearings will come to order. Part of the panel is here this morning, Dr. Sims and Dr. Chester. Is that right? Dr. Felig and Dr. Lamer will be here soon. Unfortunately, I have to run over to the Senate Democratic Caucus for a few minutes. I am going to open the hearings now, and Y?U can begin your testimony. I shall ask Benjamin Gordon, our staff economist to receive your testimony until I come back, so that we do not interrupt the hearings. I shall he back as soon as I can. So, if you are ready to begin your testimony, we are ready ~o receive it.1 STATEMENT OP EDWARD M. CHESTER, M.D., PRGFESSOR OP MED~[- CINE, CASE WESTERN RESERVE UNIVERSITY, AND DIRECT0~, AMBULATORY MEDICINE TEACHING CLINIC,' CLEVELAND METROPOLITAN GENERAL HOSPITAL Dr. CHESTER. Mr. Chairman, I am pleased to respond to ~he inv~- tation to testify concerning the use of oral hypoglycemic agents i~i the treatment of diabetes mellitus. I am a professor of medicine at~ Case Western Reserve University and director of the ambulatory medicine teaching clinic at Cleve- land Metropolitan General Hospital. A large segment of my time is devoted to teaching 3- and 4-year medical students during their clinical clerkships. My research efforts have been directed toward an understanding of the eye changes which are associated with diabetes meUitus. Eoi~ 1 See prepared statement, page 13643. 13309 PAGENO="0060" 13310 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the past 16 years I have been active in the direction of the diabetes clinic at Cleveland Metropolitan General Hospital. Prior to 1959, when I joined the full-time faculty of Case Western Reserve Urn- versity at Cleveland Metropolitan General Hospital I had been engaged in the practice of internal medicine for 18 years in a subur- ban area of Cleveland. My practice dealt chiefly with patients who suffered from cardiovascular disease and/or diabetes mellitus. Dur- ing the years of* practice I served as `a part-time teacher at Case Western Reserve University at Cleveland Metropolitan General Hos- pital. The diabetes clinic at Cleveland Metropolitan General Hospital provides care to approximately 500 patients with diabetes mellitus per year. This totals approximately 2,000 patient visits per year. Approximately 80 percent of the patients have the maturity onset form of the disease. Prior to 1973, the majority of this group of patients were treated with oral hypoglycemic agents with a limited degree of success. Although dietary instruction was provided for the patients, there was little compliance. When the results of the UGDP study were issued in 1970, we be- came concerned with our use of the oral hypoglycemic agents. We urged the physicians who cared for patients with diabetes in the clinic and hospital to pay heed to the results of the above study and to reevaluate their treatment of the maturity onset group of patients. In an attempt to learn the extent of the use of oral hypoglycemic agents and their cost; the amounts of these medications di~pensed by our staff were recorded from 1968 to early 1972, and I would refer you to table I. Review of these data diselosed an alarming in- crease in the use of these agents from 1968 through 1970. Response to the recommendations of the UGDP study was reflected by~a modest decrease mthe use of the oral agents during 1971 and 1972. Because we behevecF that the use of these agents was still excessive, the fol- lowing letter was dispatched to the chairman, pharmacy committee of the hospital on May 24, 1973. The results of the University Group Diabetes Program, UGDP, Diabetes, 19, Supplement 2, 747-830, 1970, allows one to develop the following conclusions concerning the safety and effectiveness of the oral hypoglycemic drugs, specific- ally the sulonylurea group, Tolbuta~ide and Chiorpropamide. (1') In the group treated with Tolbutamide there was a significant increase In deaths from cardiovascular disease, as compared with those treated with either insulin or strict adherence to a calculated diet. (2) ribat Tolbtttamide was not as effec- tive as either insulin or strict adherence to an isocaloric diet in the control of levels of, blood, sugar. The UGDP study subsequently reported comparable results with the use of Phenformin, JA.M.A., 217 No. 777-784, 1971. It is only fair to point out that there are skeptics who do not accept the results of the above study. I accept the results of the study and believe that the use of Sulfonylureas, Tolbutamide and ChlorprOpamide, and the Biguanides, Phenoformin, should be restricted because they appear to be hazardous to health and are far less effec- tive and more expensive than Insulin. I suggest that we implement a form of control which would restrict the use of $ulfonylnrea drugs, Tolbutamide and Chlorpropamide, and Phenformin with the following exceptions: One, patients who cannot administer Insulin to themselves because of severe visual impairment or other physical handicaps such as neurologic disorders which impair use of arms and hands. Two, patients who refuse to use insulin. PAGENO="0061" ~O1~tPETITIVE PROBLE~ IN. ~ DRUG I~pus~ir 13311 In order to acc~mpIish. ~ contrQl, the department. of medicine Would PFO- vide a list of phystciaz~s who could authorize the use o~ the drugs unaer dis- cussion. Other se~vtces may wish to provide a ~ithilar mechanism. `In 1972, $30,000 were expended' for T~lbutamid~, Pheirforniln, and Oblor- jropamide. Substitution of insulin would be less costly. The results of this educational reminder and form of contrdl~ro- ditced the results noted in table I. Table II indirectly indicates that many of the patients prev1o~isly receiving oral agents were started on insulin therapy. I would like to add that i,f we totaled the cost of the oral agents in 1970, it i~eaohed $56,000. By 1974, this was reduäed 55 percent (sic) to $9,676. That in- formation is not recorded on the table. Continuous review of the use of the oral agents is' in progi~ess'with the intent of f~irther decreasing their u'ae except un~et' th& circinn- stances noted' in the letter of Ma~ 24, 1973. It is a~pp'arelIt `that re- striction of the use of these `medications in a hospital can b~ a~cco~np- lished by education of patients and physicians `atn4' `by proy4dih~g a method for control.' The problem is unfOrtunately not A~ simple' for a variety of reasons when one attempts to achidve similar `results with patients who are under the care of privatu physicians. Among these reasons are: One, that the conclusions of the `UGDP study are not accepted by some diabetologists. " , Mr. GOlwoN. May I interrupt for just a momthiti E'~en the critics of the UGDP study admit that `i~ `i~ tlie~b~st~ st~idy conducted in this field. Other studies, including animal stadies, have confirmed the validity of its'conclu~ions. Why, then, have some physicians-even some with, prestigious `names in the diabetes field-continued to attack these studies, even though they acknowledge lack of effectiveness of these drngs? Dr. CnEsn~R. M~. Gordon, this is extremely difficult to'understand. I can envision that some of them believe that lowering the blood sugar may prevent the vascular disease. However, there is no evi- dence to support that contention. Mr. GOItDON. Would any'other witnesses care to comment? Dr. SIMS. Would you be willing, Dr. Chester, to add as a qualifying phrase in thIs group of noninsulin dependent, predominantly over- weight diabetics? ]~n other words, I am asking you, would you make the same statement for the juvenile diabetics? Dr. CHESTER. Would I make a different statement for the juver~ile diabetics? No. I think that there are no data to support the concept that the con- trol of diabetes, as we measure it, namely levels of blood sugar and quantities Of sugar in the urine, will' prevent the development of ~he vascular diseases that we see in the' coronary arteries, the peripheral vessels, and in ~the eye. ` M~. GoiwoN. Dr. Felig, would you care to cowmet~t? Dr. Fi~pi,G. I' agree with Dr. Chester's `remarks. I think' that the kinds of treatments available t~' us, be it insulin, oral agenth, or diet, ar~ such that we do not fully restore the patie4t,'s metabolism to normal, and I think that we can at least explain, why we `might not see the improvement in' prevention' of ~va~seular diseas~. I might comment on the point that you raised. as to wh~ people in the fi~ce of evidence of lack of effectiveness still criticize the UGI~P. PAGENO="0062" 13312 COMPETITIVE PROB~JEMS IN THE DRUG INDUSTRY It should be recognized that some of the most vocal critics of the UGDP have raised issues regarding experimental design, statistical methodology, and some basic aspects of the approach to clinical trials without necessarily tending to promote the use of the oral agents, as such. But, this has then been misinterpreted as a validation of the oral agents. Specifically, one of my own colleagues at Yale, Dr. Albert Feinstein, has been a notable critic of the UGDP study. Dr. Feinstein is an outstanding biostatician, clinical epidemiologist, as well as internist. The basis of his criticism is not directed at trying to promote the use of the oral agents; but he has looked upon this particular study and has raised some statistical questions. Others have unfortunately used his objections as evidence for the perpetua- tion of a treatment which they themselves say is hardly effective. Mr. GORDON. Dr. Feinstein, as I understand it, has never made that clear, that he is not really pushing the drugs. Dr. FELIG. Well, while this may not be clear from his public state- ments, knowing him well and havi~ng worked closely with him, and since we both have appeared on papels on this issue in New Haven, it is quite clear that he does not particularly favor the utilization of these agents but, he is merely raising questions of experimental design.. Dr. SIMS. If I could just add a word. I do agree with Dr. Felig that,as ordinarily carried out, the partial regulation of blood glucose has not had demonstrable effect in pre- venting gross cardiovascular lesions in the group of largely oyer- weight people in the UGDP, most of whom did not actually need insulin, I do believe, however, and Dr. Crout made this point yesterday, that we do not have the evidence from the UGDP to justify extend- ing a spirit of therapeutic nihilism with respect to blood sugar regu- lation to. all types of lesions and in all types of diabetes. I do feel that with Dr. Felig, that has ordinarily accomplished the regulation of blood glucose, it is not altering the cardiovascular effects from all the measurements we have up to now in the group of over- weight people who do not actually need insulin anyway. I do feel, and I think Dr. Crout made the point yesterday, that we do not have the evidence on that study to extend the therapeutic nihilism in applying it to all parts of the body. Would you agree with that? Dr. FELIG. I would agree. Mr. GORDON. Dr. Chester, please proceed. Dr. CI-TEST~R. Two, that education of physicians lags well behind the knowledge developed through research. Unfortunately, drug com- pany literature provides the major source of information for many physicians. Three, the lack of adequate patient education in their understand- in~ of diabetes and the hazards of oral, hypoglycemic agents. Four, the failure adequately to impress the patients with sufficient understanding of the importance of a calculated isocaloric diet and their failure to comply in this respect. Five, the case of using oral medication compared with the in- jection of insulin. The UGDP study clearly demonstrated that standard doses of oral hypoglycemic agents `did not effectively reduce levels of blood PAGENO="0063" COMPETITIVE PROBLEMS IN THE DRVG INDUSThY 13~13 sugar over a 5-year period~ These data confirmed j?revious ~stiic~ies which disclosed that the succesS rate in managing diabetes with tol- butamide at the end of 5 years was only 13 percent. Mr. GoBr~oN. Dr. Chester, what precisely does the 13 perceiit rejire- sent? Does it mean that in only 13 percent of the ca~es w~s the ~ol- butamide successful in lowering blood sugar at the end of 5 yeai~s? Dr. CHESTER. At the end of 5 `years. There may be early ~uccess if one measures levels of blood sugar. This is called primary faili~re. That is, there is no response `*~thin 1 month. In ~fiect blood su~ar levels are not at the range that one desires withifi that period. Tl~en there are secondary failures in patients who initially appear to re- spond. Again, this is determined by levels of blood sugar. Sub~e- quently, over each year there are more and more called secondary failures, so that by the time the 5-year period arrives, at least in this study, only 13 percent were still responding. Therefore, we have a drug with limited effectiveness that pro- gressively loses its effectiveness. Mr. GQRDON. Well, there is no evidence that lowering blood sugar prevents tha vascular complications resulting from diabetes. Is that not correct? Dr. CHESTER. Yes. Mr. GoiwoN. Then, what are we actually accomplishing when ~ve lower blood sugar? Dr. `CHESTER.' Well, we do accomplish a variety of' things. If the blood sugar level becorqes exces~~ve, then the amount of urine, ~ et cetera, are passed out into the urine, and the patient not only lobes tremendous amounts of water and becomes dehydrated, but may suffer from some of the loss of the electrolytes. Second, continuation of poorly controlled diabetes, again measured by levels of blood sugar, may be followed by a variety of very serious manifestations. One is diabetic ketoacidosis, where presumably, l~e- cause of lack of insulin and other factors, large amounts of the fat are broken down, mobilized, converted to a number of substances known as ketone bodies. As these substances accumulate, the patie4it may become unconscious and death may follow. There is a comparable state in which the blood sugar reaches e~- tremely high levels, perhaps in the range of 1,000 or above, where `extreme loss of water becomes critical. These patients may becon~e unconscious and die within a relatively short period of time if nçt treated adequately. There is also t~ie question of whether or not keeping bl6od sug~r at given levels will prevent infection. This is difficult to document. What we do know, however, is that the individual with diabetes whp develops infection, unless we treat the diabetes vigorously aud simul.! taneously treat the infection,' the patient i~ likely to suffer and ma~y die. S~, there are reasons to try to reach given le~eis of blood sugar. The difficulty is that in general no one of us knows what the optimu4'i level may be. It is extremely difficult tO restore the blood' ~ugár levels to those that supposedly normal people wOuld carry throughout the day witho~t the risk of develop~ng extremely low blood sugar or hypoglycemia, which in turn may damage the brain and cause other problems. PAGENO="0064" 13314 C0MP~TITIVE PR0BI~1EMS IN TI DRUG INDUSTRY Mr. GoiwoN. Would any of the other witnesses care to comment? Dr.. SIMs. .1 thin1~ that it is fair 1?o sa~ that jn~Uh~ as~ we now' a~d~ minister it to a'p~tient, particularl~r one with a high~de~rBe of iflsulin resistance, falls fa~ shOrt of re~ro~dt~eifl~ i~h~ elegance of corilroi that the nQrmal body accomplishes. }So', we have to kee4~ ~ reser~atiou in our minds as to whether, when arid if the day cOnne~ ~vhen we can more precisely regulate iusuli~n administration tht~u~h an artificial paucreas, multiple injections, Or some such, the results with respect to vascular disea~e might not. be quite differeflt. I am just arguing against a general attitude and nihilism that might lead to some of the complications that Dr. Chester mentioned. Mr. GORDON. Any other comments? Dr. Chester, please proceed. Dr. ChESTER. These data confirm previous studies `tha~t `disclose that the success rate. in mauag~ng diabe1~es with tolbutamides at the end of 5 years was Only 13 perdent~ Eelap~e or secondary failure is recorded as 22 percent within 5 years. After 6 to ~T years of thc~rapy with oral hypoglycemic agents, only 6 to 12 perceilt remain well cOn- trolled. Yet, despite the ineffectiveness of these hypoglycemic agents and their demonstrated relationship to increased rñortality from cardiovascular disease, these drugs are still widely use4 in the treat- ment of matllrity-onset diabetes. I have noted previotisly the reasons for the failure on the part of physicians and patiefits to heed, the warmng of the hazards and ineffectiveness c~f. tliis~group,,of drugs. There appear to be three apprOaohes tO this ~robleifl. `I~hese include an immediate restriction of their use through firm warning arid label- ing via the FDA, a long-term educational process, and the develop- ment of more rigid' drug testing requirements. Mr. GORDON. May 1 interrupt at this point? Is it your opinion that warnings and strong labeling by the FDA will have an effect on the use of these drugs? Dr. CHESTER. I would say yes,. provided the labeling is done on the patient's drug box or bottle. Although I think it is fair to say that the insert in the drug package should have these warnings, by and large physicians and certainly patient's do not see them. Mr. GORDON. hr the light of previous experience, do you not think that something stronger and more dramatic might be more effective? Dr. CHESTER.. Yes. I would put a label right on the box or bottle that the patient has, indicating that this is a hazardous drug. Mr. GORDON. Maybe a skull and crossbones? Dr. CHESTER'. Yes. I would put on a skull and crossbones. Mr. GORDON~ I am kidding, by the way. Are you serious about that? Dr. `CHESTER. Well, something close to It. Mr. GORDON. In the light of what you know about these drugs, and if the drug firms were ~only now seeking approval to market them, would you approve' them as being safe and effective for the' purposes claimed? Dr~ OH~sm~. No. If they' are related to the sulfonyl~~irea group or to thebiguanides, I can not see that any modificatipns~iu the drug or prolonging their half-life, or `making them more potent, will resolve this problem.' ` ` Mr. GOEDON, So, those drugs that are now in the NDA process, which are now being considered by the Food and Drug Admini~tr~- PAGENO="0065" ~OMPI~i1ir]~ P~ Si,IN~i~ffl D ~7S~y 4~3815 tion, ~he~g1yb~ide~, ~the npprov~t~kte~on~s th áa~n th~ mavk~t~owy~ôu tain1y~if1~ttrn~er~ stand it, wou1duiotappxo~ the~othe~ ~nes. Isthat a~ ~o~e~tassiin~ption? Dr. ~Oi IRJ~That is tw~eet. Mr, xo~ If, as you~tate~ tho~o~al hyp~g1~c~inics ~re a~pot~ntiai hazard~tó health, ~nd if *e are~no1isurethatthey~re eff~etiwe;~what is these~se~f nsingthern? D*r~ U sa'ER.~WeU~ there are people~who,~ cfor~ ~reasonsanentiohed, retuse to ~take~ins~1in, or, a~e teohandicapp~dnto ixs& it. But ~p~tren- th~tic~J4y,:we~ ha~e `been faced with the hanclieappedcp~tie~for many years b~fore wech~d the oralagents. There ~re ways to ~d- minister bn~iiuindn the .handica,pped ~if its ruse is inthcathd. For example, there acre ~ywinge~ for the &ithlni~tratiom of insulin that ~~icb~ ~ssed by p~ople w~th extreme'y ~i~itedi~i~ion, ~They ~ome ~under a vasr~ety,of trade names, Essential~y th~y ~eønsist~of am in~ulin syringe inwhich you canriock the Tplunger~so that~itcannot5go b~rond a, given.~dos~ ; so that if as j~atient were to ~eceiire~O units~ of :ins~lin, for example, you could set the plunger at that ievelz E~enwith~lin~ted visionrthepati~nt~c~n ~titMraw the in~ulin from the vialand can ject ~it ~nto thessthigh~ith little difticuity. I think the other thing that we ~imist consi~er~ ~nd `this isrpar4i~u.. larly tmeinrla,~ge i~iics~ such ~s ~ou~s, that ~e frequ~n4Jy do not have, good., o~nta~t with re~ati~ves who might ber'wi~c1ring `to ~i~arn~this r~techi~iqme. fot~1y,~~ enois~gh f1~ortsis rn~td~ t~ ~clo this. `The p~actioing~ physi~iawhas anc adiva~utwge. He~ofben knows the sfa~1s~ly w~ll~ a~id .1 m~gh~c ~te p~r~thet~ca1~iy, that ~hiie~i~a,pta~ice, ~i1is wasnos,prQb~rn.rL w~sable tQ ~get~am.i~Iy ~1~mb~rsrto ~ th~w~to ~adm~iister insulin. `4sgeneies ~no~u communities cam ~ftens pro~id~ ~ ~ we~bave as~Visict4~g ~N~isirse tAs~ociatjojr~in Ci~vel~,nd )t~hat~v-ifl perfuche~ice. M~. O~RDeN. What pu~zies n~e is ~f these du~igs are harmful' to ~ they ~ to ~p'le who are ~ Dr.~ Gs~i~. Y~, tb~yare~a~d I woulcics~y't~at~nyt ~ime~~ase them, there is a calculated risk. The patient and thefa~aily ~sheuldfr this ~i*. Mr. (~-OawOw. ~In other woths,~being handie~ipped ~or being blind doeS not iaaclte you Wimnneto. the msks. Dr. Uu~ ~n.~t~hat is ~c~rreot. Mr. GORDON. Doctor, go àh~ad. Dr. G~I~s~En,R~con ew1atic~is: Quo :Jmmed~ate warnh3g to all phy$ieiansof~'th~ ~u~ds by, a:huUGthi ~fr~m the~fl~L stfttimg1~he .foflo~wb~,g: ,~a) ~~rsu~'t~tbiy ek1~ci4a,ted iso~akric~ s~l4~t ~ser~s ~as the cQrne~o~c ~ re ~ a~le~t~a1 ~l~i~~ry `~a ge~nt,~pr~ ~ tutcdd~L ;(~)~jJ~ quater,~e~ls ~of blood ~g~r~a,uuot jtaj~a(~d ~ith tl~ ~ ~ in es~b~ence of r~yn~pt,oZn~ ~~ss~i~atec1. ~i~h S ~ ii~sti~ute4; ~d) ~ ~mie~nt~re, aip~t t~a1c l~~a~J toc h~~dr~ho.uid (bet ws~d, ~after cthe ,~p~i~tt1~s ~ of ~tl!4s f~ct, ~ 5~-~-_7~__5 PAGENO="0066" 13316 COMPETITIVE PROBLEMS IN THE DRUG I~DVSTRY under the following circumstances: One; If the patient is handi- capped by serious visual loss or other physically incapacitating dis- orders; and two, if the patient refuses to use insulin. The drug companies should be required to include the above facts on the package inserts of medication, despite the fact that physicians infrequently read them. Some method of identifying these medica- tions as hazardous must be developed for patient protection. Two: Long-term educational effort. Medical school educators, dm1- clans who care for patients in university and community hospitals must emphasize the facts known about these drugs to medical stu- *dents, house officers, and physicians in practice. Efforts should be made to reach the last mentioned through post-graduate courses and through the development of self-educational units in an attempt to providQ more reliable and scientifically based information to counter- act th~ biased and often inaccurate statements issued by pharmaceu- tica~ cOinpanies and the throw away pseudomedical periodicals. ~,vital step in the educational process is the need to encourage and support the young investigator. Greater availability of research and training grants through the National Institutes of Health or other Government agencies should be encouraged. For, it is through the development of such investigators and teachers that the many prob- lems related to diabetes may be resolved. Three: Adequate long-term trials before drugs are released for use. Most dimgs, and this applies to the oral hypoglycemic agents, were initially tested for their ability to lower levels of blood sugar in animals. Search for toxicity was made as well. These studies were short in duration. After short-term trials in man were made by able investigators and clinicians, the drugs were released. Subsequent long-term studies of these drugs were retrospective and dealt only with their ability to alter levels of blood sugar and lipids. The TJGDP study was the first well-controlled prospective study and was designed to determine the role of thes~ drugs in the development of vascular disease. Thus, many years elapsed before medications, which were commonly used1 were found to be hazardous to health and to possess very limited effectiveness. Standards for long-term studies must be developed by the FDA to insure adequate clinical trials of drugs be- fore their release. The steps inçlicated above am~e likely to be met with severe outcry and resistance by pharmaceutical companies and scientists and clini- cians who do not accept the conclusions of the TJGDP study. Con- tinued support of the medical socIeties, particularly the American Diabetes Association, would be essential. Restriction in the use of theoral hypoglycemic ag~nts would ~ig- nificantly alter modes of care for the patient with diabetes. To begin, it would needfully provide ,a great emphasis on the impOrtance of dietary management. In many instanc~s with adherence to diet, ade- quate reduction of blood ~uga~ and removal of, symptoms would fol- low. Physicians or their assistants would have to instruct patIents in the use of insulin when dIet, ai~ne did n~t suffice.: Thus, mo~re teach- ing wQuld b~ n~eded, for each patient. Perhaps more teaching re- lated t~ mecb~nisn-~s inv~lyed in the producti~n'. of the dis~ase, the need for preventing infections manifestations of hypoglycemia, and PAGENO="0067" COMPETITIVE PROBL]~MS IN TW~ DRUG INDUSTRY 13317 other measures would be taught as well. Since the cost of insulin is considerably less per patient than oral hypQglycemio agents, t1~ere would be a decrease in total cost. The issue of the clinical use of research information is exemplified by the mixed reception of the results and recommendations of the TJGDP study. Why, one may ask, are there delays in the trans- mission of research data to it~ clinical applications? There are several reasons: One: Early research data may be pre- sented initially to select groups in research societies ~nd published in journals which are read by only highly trained speeiahsts. In ackli.. tion, most articles are not published for at least 6 months after tl~ey have been submitted. Two: Further delay occurs because of the need for clinical testing. Three: When the information is finally released, there are varying degrees of receptivity and understanding. Here we deal with a number of variables which include initial training and continuing education of physicians. Medical educators, both basic scientists and clinicians, and medical societies must play an important role in narrowing the gap between delivery of research information and its clinical application. Corrective measures in this regard are most likely to be effective if medical students, fellows, and house officers in training are a4e- quately prepared to receive audi evaluate research data. This requires improvement in the teaching of basic science, biostatistics, and clini- cal pharmacology during medical school and postgraduate training programs. As a teacher of students and physicians in training dur- ing their formative years, one is aware of the need to stimulate them to share in the joy of learning. Such an effect develops and fosters intellectual curiosity, critical thinking, and the self-discipline re- quired for continued intellectual development throughout their c~- reerS. During their period of formal training, they will recognize the need to continue their education once they embark upon their careers as practitioners. Reading current literature, attending medical meet- ings, utilization of self-educational material, and attending specific postgraduate courses are effective approaches. Physicians should be urged, `if practicing in groups, to exchange information and ideas with peers. Journal clubs and conferences could be developed. As a former pi~actitioner, I found that becoming a part-time teacher at a university affiliated hospital was an excellent learning ~xp~rience an~1 a considerable stimulus to encourage my own intellectual develop- ment. Medical schools should encourage suitably trained physicians to participate In clinical teaching. The task of communicating with the well-established pi~actitioner is more difficult. Those who are well trained in various major specialitie~ generally keep abreast of new developments in their area of interest and expertis~ through many of the educational methods previously mentiOned. TJhfortunately, there is another group of physicians who, because they are either overwotked or inadequately trained, find o~ take little time to i~ead or attend educational meetings, and rely upor~ ill-informed pharmaceutical ~corbpany ~ep~'esentathes and thedical thro~áwayS for their sources. of information. Malr3r of them. observe that because of theiv lack of~ scientific backgro.und and ti~e~ tren~e~id~ot~ PAGENO="0068" 13318 co~P~Ti~rIvE PftGB~EM IN ~L~I~2E ~EU~G I~AUST~Y burst ~f new h~for*mation tha~t they cam~ot under~taud and pro~b from eu~rea~t n~e~1icai ~i~beratu~re. They are thus oe~ri~y pmq~e~d to accept new research data which are dinically .ap~1icabie. ~s a re~ sn~t, they s~re~t eqi~ppex~ to be~critie~ü od~ someof the. dai~ms ~y&rug eompan~ies o~E.,the eff&~theness~ o~;v~rio~lits forms of thera4~y. It is di~ult ~for m~ to envisien n~a~or correetive asures ~or this group. Obviously they ehould be uiged to M~tend postgraduate courses in wtrióh efforts woul~t be m~de to hring them abreast of cur- rent understanding of disease and thera~py. The Academy of ~euera1 Practice has made ~effo~ts to promote asich courses. Medictd ~chools, medIcal societies at local and national levels must share in this edu- ~ational process. Thank you. Mr. Go~mo~r. Thank you ~rery ¶m~h, Dr. Chester. There is one more ~caastion I woukl like to ask you, buct I thiiik I shall save it for later because .1 think That the four of you may wish to discuss it. The next question is: ~Iavayou read the p~roposed label- ing and what am your comments on it? But I shall wait, and maybe we can talk ~bout it as a group. Dr. Felig, would you please give your statement? ~TA1~FII~E~tT OF P~BI1IP FELIG, ED., Th~)F~SSO~R UD ViCE OKAIB~ IVIAN, DEP T~/IE~T ~O!F mTE~NAL ~V ~CiNE, TALE ~R1V~- 1SXTh' SO~!OOL OP U~CINE Dr. F~o~ I am p~1ease& to have this opportunity to participate in these heariicigs on the o'r~al i~iypog1ycemic drugs. Over 5 years have ~ow elapsed scinee~the ithtis~l presentation of the findings of the University G-toup Diabetes I~rogram indicating an increased risk of do~h from cardiovascular disease in patients treated with tolbutamide or phen- formin. ~Sinee that time, there has beeti considerable debate and con- troversy in ttlie medical profession as to the validityof these findings and their ho~p1ications with respect to the treafment of diabetic patients. My &iscussion will ~focus on the ~foliowing areas: One, those aspects of the pharmacdlo~y tand ~linical app~lic~tions of the oral hyp&g'iy- comic agents in ~hich there is fairly uniform agreement amo~g pro- ponents as ~w~ll ~as opponei~tts of the'IYODP study; two, the impact which the fi'xtd4i~gs ~f the IYGDP study have had on medical practice; and three, the `mechanisms by which the prescribing `hthits of physi- cians maybe faltered. Virtually all e~perts in the field of diabetes agree that `the oral hypoglycemic agents are drugs of convenience. They are convenient because they may be `taken oraliy as opposed to the injections of insniin. Moi~e iinprtantly, `they are coneenient because `they do not requfre the ~elf~discipliue and m~iianoe ~iuhei~ent in `a reduci~ug dietary regimen. `In contrast `to the effiects of ins~liu in'the patient ~vith dUabetic coma, the cmi h~pogly~erPic ~gei~s are not lifesaving kkrflgS~ Fm~therrnore, ~ic convincing e~ridenoe ~ available which indicates i~hat megniotion ~f blood sugar 1y oral 4gents rataPds or preveilts ctbe iox~g~~term tlegenera~tive e plicat3m~s of diabetes ~hi1i mal ecttbe~eyes, kidney, or `nerwu~ s~stezn. .: .. PAGENO="0069" COE~ETIYE~ PEOBT~EM~T i~ TR~ Wti~E~r iN~USti?RY i3~31~ M~. ~ Yoiis~ty ti~iuV the~re~ i~ no e vi~ci~g evid~ae that ~ tm4Iing~ blood ~ig~r prev~nt~ or~ r~ta~s~ the vaseular co~~lieation~ resulting from diabetes. b titat e~se,~ehen,i~ there. aaiy sense. i~ u~'ng druga that ai~e harm- ful t~ acco~npli~~i soni~th~iiig that s~e &on't kno~w is hei~fui~ ]Dr~ FtLIth Patie~ts may dei~& some benefit from oral agen~t~ by virtue of~ their ets on the acute o~i short-term consequences of. the high blood siig~r. When the blood sugar rises to the point of causing excessi~ve urination, as~ Dr. hester has indicated, the depletion. of certain, essential body m.ine~rais~ electrolytes,. is harmfuL Tn that ~ir~ cmasta~nce,. there are patients who, because of their total unwiiihg- ness to use insulin, could benefit from t~Iae ora' drugs, in the sense that thely couJ4 have symptomatic reiief~ So, in that short-term or limited sense, one could. ascribe a~ therapeutic benefit from these. d~gs~ Whether or not that outweighs the consequence or the potential risk is something that is the essence of ~iinical judgment. Mr.. GOnioN~ We have asked Dr. ~khn Davidson, who. is director of the diabetics clinic in Atlanta., Ga., what percentage ~f the peo'~l~ using these drugs should actually be using them. He stated that maybe 1 percent of the people who are using them should be using them; or, 99 percent should not be' using them~ We asked Dr. Brad~ey who is one; of the proponents of the use of this. drug-or at least so he seems to be-the same question. He said that about 80 perc~nt of the people who were using them should not be using them. Tl~en I asked T)r.. Winegrad the same. question on the telephone,. and he estimated about ~0 percent of the. people... ~ yo.u see,. you have fr~in 80 percent to 99 percent of those who a~e using them that.. should not be using them. Would you gen.tlëmen care to. make any estimates,. given your experience, given, the fact that maybe 11/2 million people are using these drugs? Dr. Fi~o. I am firmly convinced that there is overutilization,. and we think that the' fignre of 80 percent represents a very conserva- tive estimate of overutilization, We estimate that probably somewhere in the n.eigbborhood of 9) percent should be treated. with means other than the oral agents. Mr. GoRDoN. Would the other.s. agree with you? Dr.. CHESTER. I WOuld. Dr. t~tNnn I would think 90 percent or more.. Dr.. SIMS.. I think it is a game of selecting a figure. But it is worth en~phasizing that,. if there is a. minute percent in' which the dri~g is indicated and th'e arugs are allowed to., remain on t,l~ .rn~rket fQ.r that reason', the realities are that it will c~ntiuue. to' be used on many more patients. I believe it is for that reason that the FDA and. others have to play an active role in education, as. was emphasized at the' lmarin.~ yeste.rday. S Mr. &ORDON. Dr. Felig, please proceed. Dr. Fi~i~. It is thus clear,. I think, from what the other experts hç~re have said., as well as from what is generally recognized, that these drugs arei useful in a very limited number of patients with aduJt~-onset diabetes namei~y, those with symptoms due .~ `an elë-. vated' blood sugar in whom dietary measures have failed and in whom insulin is impractical or refused by the patient. While some PAGENO="0070" 13320 GOMPETITIV~ PROBL~MS ~ `T~E DRUG I~ThU~TRY experts would inchde patientS ~i~h' an elev~ted blood sugar who a~'e asymptomatiC, ~therë is tmiversal `agrement that these drugs are overprescribed in the United States. All of the abOve w~s iii faCt well recognized before the UGDP study i~aJ~ ~eported.. The effect `Of the UGDP has been to add evi- denie of a telationship between oral agents and increased cardio- vascular niortality. This relationship has been considered conclusive by some, persuasive by others, and at the least possible by all, in- eluding the most severe critics of the UGDP. Given the fact that: One, these agents are drugs of convenience; two, they are overpre~ scribed ; `three, they may' increase cardiovascular mortality; and four, tha1~ the practice of medicine is usually governed by the axiom "Primum non nocere"-"above all, do no harm"-one may question whether the ~flndings of the UGDP study have resulted in a change in the clinical treatment of diabetes. Unfortunately, the answer is very definitely no. The most recently available data reveal that the total prescriptions for oral hypoglycemic agents increased 5.5 per- cent between 1972 and 1973. This represents a total of over 19 mil- lion prescriptions costing over $100 million and involving over 11/2 million patients. Mr. GORDON. Can you explain why the use of these drugs has in- creased in the face of the known results of recent studies-human and animal-that show that these drugs are harmful? Dr. FELIG. I think it is difficult for me to assign a specific factor or factors. I think that what we are dealing with has been an over- ridding tendency to use a convenient method which both the physi- cian and the patient are likely to be more willing to tolerate or to follow. In addition, we have the influence of a `very vocal group which has been so severely critical of the UGDP that the effect has been to totally mute any of their own concerns regarding the overprescription of these dri~gs. So, I think what we have is the practicing physician faced with a choice between different methods, one of which is more convenient than others; a~id, lie is being bombarded with informa- tion that could be reassuring regarding his convenient method be- cause the data suggesting that this may be hazardous is constantly being attacked. Mr. GORDON. How about advertising? Dr. FELiG. I think when we talk about the data being attacked, it becomes difficult to separate the constant criticism of the UGDP by those who attack it from a seemingly scientific viewpoint and fail to point out that it is overprescribed'on the one hand, from those who are actually advertising the drugs. Given the profusion of literature to which the physician is subjected, much of which is not really scien- tific but a pseudoscience, one can' appreciate the quandary of the prac- ticing physician. He may not have `the opportunity or perhaps does not avail himself of a more dispassionate form of instruction, so as to make adequate or appropriate decisions. Since all agree that these agents are overprescribed and, at the least, possibly toxic, it is apparent that the experts in the field of diabetes have failed to appropriately influence the clinical manage- ment of this disorder. To rectify this situation, I would propose the following: PAGENO="0071" COMPETITWE PROBL~M~ IN. TII~ DRUG INDUSTI~Y i3~21 One: Leading proponents as well as critics of the TJGDP study should meet f~r the purpos~ of issUing a joint statement in wh~ch the primaoy o~ diet ana the ~bvious need fo~ ~rest~iction in the ~ise of oral hypoglycemic ag~its is clearly ~pelled out. Mr. GoRDoN. What kind of a 1oint statement? To w~hoin woulcLit b~ directed? Dr. FELIG. I think we have witnessed, now, for th~ last 5 sears, since, the report of the UGDP study, that physici~hs W~io had b~en very critical of this have tende~l to band together ahd Deiease st~te- ments as ~the Comwittee for the Care of the Diabetic Patie~t, et cetera. ~This gr9up, I tith~k, would be one wJ~ieh is so clearly iden~ tified as pritical of the TJGDP, that I would hp~è they would be~p~rt of a joint statement together with other individuals who have been proponents of the TJGDP, or who have not attacked it, so as to come to some joint statement regarding the overall situations in which these agents should be prescribed. It is interesting that in the criticism of the IJGDP, the severe critics do not generally raise an argument as to the situations in which the drug is indicated, but restrict their argument to the ques~ tion of whether there is absolutely incontrovertible data that ,th~se agents will be harmful. They should in fact be addressing themselves to the facts before us; namely, that we have a situation in this coun1~ry in which a potentially toxic drug is being widely overprescribed. If one assumes to be, or in any way is willing to be called an expert in the field, he has a responsibility which goes with that designation; namely, to influence the prescribing habits and over-all practice of medicfrie by his colleagues. I think this is where the field of diabetes has been remiss, and in particular those who have been critical of the UGDP. They have failed, as I think all medicine has failed, to rectify a sit~a tion which all agree is not optimal from the standpoint of the patient. Mr. GORDON. When Dr. Bradley testified here, he acknowledged that these drugs are vastly overused. I do not know whether he used the word vastly, but I am putting that in. Nevertheless, it appears that in his attacks on the UGDP study, he is essentially promoting the use of these drugs. Is that a correct conclusion from what you have stated? Dr. FELIG. I would think that any group or statement that tends to accentuate the criticism of the TJGDP and is not accompanied at the same time at least by an equally forcible statement indicating that these drugs are overprescribed, will have the effect of perpetuating the use of the agents; or, probably more likely, they would promote their utilization. So, it becomes very difficult to divorce comments from such critibs of the TJGDP from an effect which is very similar to that which would occur with a drug promotional type of statement. Mr. GORDON. I conclude from what you state-and I ask you ~f this is. a valid conclusion-that it is really the responsibility of the critics of the UGDP to insure that there is some rectification in prescribing habits of physicians today. Dr. FELIG. I think it is the responsibility of all experts in the field. That responsibility becomes that much more manifest and incumben~t PAGENO="0072" 1 çQ1~I~2V~ L~ p~ ind~i~t~ th~t ~thb ~qi1~t4on'. bbfié. If is a1tha~g~iu& ha~ b~en ~aM ~ ~ ~a~ièht to dO ah~ythin~ I~ th~ skin~ ~t ev~F~y ~p~iertt 1 s~&~ii1d~ r~e'~to tak~ ii th~ w~ in ~c~ich I pi~e~h~ th~ a~tOt~ii~tlv~s.. If I s~ ~6u1~I~yóii 1i1k~ th~~ n~è~ thbi~th o~t this n~d~iáin& th~t has to he rnjected with a needle I think we ea~t all p~edi~t what pro ort On ~oti~lli r~fh~é a pathxftil iiij~cti~ e$ery day. So, I L t1~i~thé~ c1 i~ptibm. of .1 t1~~ p~±thft~iht~ i~ext of th~ dhi~ Of! th~ T~ st ~ieftt r~i~1~th~at r~i~ents'~ a th~è ~tti~ftt~p'art w~hkh is ~A~ffi~+ f6i~ ~ th&ad-~ ~tc~iis~ tI~L~ e~ti~l~ frbtWYP~StiI1d!Y.~ ~ e~rit ~oMh~) U~PP~t1id~3r~ an~d ratity ~ )Hb*é~er~sd 1ot4~ `~iich' a ~t~thffiM~ attadki~1~ ~`or ~ñ~I resWt~s~a ~ of tlies~ agthits whi~h chataetetizes `curreilt ~medi- shOu1d~ be p1ac~e& on dietary marr~gbn1~nt ~rather ~ tl~& ii~t~r d~ioti `~of n~d~a1~ ~t~idM~~ ai~!d~1n ~poSt~ course~ o~i th~ti ~thi~fit"o~ di~thMt~ shO1i1~tl `be th~d~i~k~ on' de~eiOØ~g~ in~!~ro'~ed~ iti~ènt cdti~liaii{èé anç1'~succes~' in' ad~eitht~ `to~ t1~ie' la~bèlin'g of oraF ~ a' w~rning tha~t é~id~i~ has beei~ catdib~va~iil'~t mort~Iity; restrictM ~tÔ ad~iltLo1~set hate fa~le~d ari&"ins1ili~ is re~ the propDsed 1ab~ll~i~' t~ti~ the ~honid ii~f~r~i' the pat~it shotdd p~ir-. vai~t~ges, if any, that he is a~ dr~ W1~ d~y6i~ ~ ~ PAGENO="0073" w r~ ~ ~ bo~h ~°r the p~tie~t si~ st~ement f~Ea~ he ~othe~ ~t~Q ~%1~O ~i~itt~ IQte ~ 4Ljc1~4 ~s~e ~ Mr. GoitroN. Wotdd not this also be another way of ~u~tt~pg ~wn on the use of these drugs ~ Dr. FELT ~ ~ ~ J~ ,ti~i~ that one ~~ou1d run the ri~sk- if we were to have such a situation of written informed consent ~ts a roq~i~ei~nt ~or ~ p~r~t~ct4~r ~ ~[ ~t~k we 14 i~i a ~ev~v~ ~is1~ ~ i~ ~t~ii~ ~yj~~h tre~t~nt ~i other cIrcumstajices `tQt~ily ~l~e4 to the orai agents; where, ~or exarnp~Ie a potenM~lly toxi& antibiotic could ~be a4~inièfered or is consid~rèd ~pp~priate treatment for a particula~r i~J~o~i. ~ i~g~t ~I~çl ~ ~iti~tion wjie~e treat~er~t j~ interferred with because of the need to obtain ~formed consent. ~[r. ~O~1~DON. Any other comments? Dr. L~RNER. I feel the sa~the way. It ~think iih~t it wonid ~be ~e~y good from ~he point of view of mini~ni!zing ~the use of the drug, `hut it ~pu'ld be ye~y ~1i~fficii~t from `the point o~ view of the ~ne~à1ity o1~ ~he~ituati~on~if it were applied a~ro~s the board. how would you de~j~ which di~gs to app~r this to, an~t whidh ones not? Mr. GOIWON. *Tell, it~ ëoiild be used in ~ertain drsigs ~which ~re known to be to~i~. ~Fo~ ~a~ple, ~cb d~p~gs ~ ~ç~ip~pl~ico1, wh~i~b ~is alsç .ya~tly o~vEsmsed? oç clindi~myc~in, or ~l~corn~zeip, ~w1Mch ~ic y~tly pycli~c~1 Pl~~e f~t th~t ~oi~ a~pply theip to a ~éw drug~or ~ ç1r~g~ 4q~s p~t ~ ~i~e~~iy ~ ~s ~p to every drug. ~r. ~i'~ç~G. `~; situatiau o~pin~ ~9, a mec4nis~ip of tq ~ ~ ~tr~g, 1Ô~t ~ ~1i~AT~ a ~et 1~fprn~ed c~~se~at IOVi~e PAGENO="0074" 13324 cOMPi~nTIvE `PROBI4EMS IN THE DRUG INDTJSThY Dr. LARNER. This would, I think, present a difficult choice situa- tion. I mean, what would you do with-all dtugs are potentially toxic, and what would you do in the case of digitalis where- Mr. GoRDoN. But the benef~ts may outwe~h the risks. It may be toxic, but the numerator representing the benefits is such that for the purposes claimed, digitalis ha~a favorable r~ti'd. Now; for the~ drugs, I do not know. Clindamycin, as you know, ison the line. These drugs are vastly overused. Some drugs may not be vastly overused. I do not know. Dr. Sims? Dr. SIMs. `I think it would be more consist~nt with the whole idea of peer review, which is prominent today, to have a physician simply justify in the record use of the particular agent under the circuim stances. I am reminded of an informed consent form that appeared in Science, years ago, by Greenberg, I think it, was, for a hernia op- eration. He listed all of the possible, hOrrible things that could happen, and indicated it would have to be sigued by the patient's lawyer and another-in-law as well. I believe that if informed con- sent was required for everything, we would end up in a difficult situation. Mr. GoRDoN. Dr. Felig, would you proceed? Dr. FELIC. There has been much discussion in the: lay press and medical journals of the need to maintain the physician's freedom of choice in the treatment of his or her, patients. I believe that our overriding concern as physicians is to do no harm. As experts in the field of diabetes, our primary obligation should be to improve the lot of our patients by influencing current treatment practices rather than perpetuating a situation which is at the least wasteful and at worst causing an unnecessary shortening of lifespan in adult- onset diabetics. Mr. GORDON. Thank you very much. Dr. Lamer, would you proceed with your statement? STATEMENT OP JOSEPH LARNER, M.D., PH. D,, PROFESSOR AND CHAIRMAN, DEPARTMENT OP PHARMACOLOGY, AND DIRECTOR OF THE DIABETES AND ENDOCRINOLOGY CENTER, UNIVERSITY OP VIRGINIA SCHOOL OF MEDICINE Dr. LARNER. I am responding to five points which Senator Nelson wrote in his letter of June 19, as follows: Point number one, the proper labeling of the oral hypogTycemic drugs in the light of the studies recently conducted with these drugs. Having reviewed the literature, I have come to the following conclusion which is quoted from chapter 71, written by myself and R. C. Haynes, Jr., of a standard textbook in pharmacology, Goodman and Gilman's textbook, fifth edition, to appear in September 1975. The sulfonylureas should be used only in subjects with diabetes of the mattirity-onset type' who cannot be treated with diet alone or who are un- willing or unable to take insulin if weight reduction and dietary control fail. The physician must realize that he is using these agents only to control symptoms associated with hyperglycemia and that dietary control with or with- out insulin is more effective for this purpose. PAGENO="0075" COMPE~ITIV~ PEOBL~MS IN `~IIE DRUG INDUSTR1~ 13325 The major complications and life-threatening 4isord~rs~ associ~ted with diabetes are heart disease, kidney disease, blindness, and limb gangrene, There is no evidence that sulfonylureas ameliorate or pre~ vent these d1~orders. While in marry instances in medicine the physi- cian must prescribe for ivert symptoms, we all prefer to correct the ~und~rlying problem if possible. Unfortunately, this is not presently possible with diabetes without additional basic and clinical investilga~ tion. There is no evidence that sulfonylureas will assist in the un4er-' lying problem. Since these agents would appear to relieve primarily the symptoms of hypoglycemia, one should restrict their use until ~e~s costly and perhaps safer measures have been used-diet with or without insulin. For this reason, I feel that there should be stronger labeling of the oral hypoglycemic drugs in the package insert. With regard to the nature of the labeling, I feel that the stronger 1972 FDA draft is preferable to the weaker 1974 draft for the reasons just 4is- cussed. Mr. GORDON. Dr. Lamer, this is a question actually for the pa~iel rather than for you alone, but I would like you to take the lead in this. Yesterday the Commissioner of the Food and Drug Administra- tion acknowledged that phenformin has even a more unfavorable benefit to risk ratio than the other oral hypoglycemics. In an article that appeared in Controversy in Internal Medicine Dr. Albert Winegrad and two others wrote that the biguanides have no role in the treatment of diabetes mellitus. In addition, the Director of the Bureau of Drugs, Dr. Crout, yesterday could see no justification ~or this drug to be on the market. That's phenformin. How do you feel about this? Do you find any medical justification for that particular drug to be on the market? Dr. LARNER. Well, I would generally agree that probably there is no-at the present time-medical indication for phenformin that I c~n think of. That would be my feeling. I do not see any justification for phenformin being prescribed at all. Mr. GORDON. Dr. Chester? Dr. CHESTER. I would agree. It is not only hazardous; but it is al- most totally ineffective. Mr. GORDON. Dr. Sims? Dr. SIMs. I thinl~ that first of all we ought to speak specifically about phenformin and not the biguanides as a group. Mr. GORDON. I am talking about phenformin, which is the only biguanide on the market now. Dr. Sm~s. There is a tendency~ to condemn the whole group. Phei~-. formin does some very interesting things and some of them resemble the effects of exercise lowering insulin, and whatnot. Further re- search may develop new drugs of this class which will do what or~e wants without the side reactions. So, I would not say that it should be a blanket condemnation of. all of that type of drug. But, on tl~e other hand, my own feeling about phenformin is that the labeling should be shortened to four words: Not for internal use. PAGENO="0076" 13326 ~or1~rIv~ r4~S Mr. (~rnoN. In other words, take it off the a~aarket. Dr. Smrs. Big~ht. Mr. OQED0N. Br. Felig~? Dr. Fc~. I agree with the other speakers. Th~ usef~iness o~ phenformhi is extremely limit~ed~ if it exists at all. I ticnk th~re ~s no question t1i~t the risks e~oeed those that we ha~e with any ~other i~orm oi~ ~ntM~abetic treatment. I do not think it w~d be any loss ~f this were remoi~ed frmn the r1e(. Mr. ~ Ana yon ~gree with Dr. Grout that the drug ~shouliI be rexncr~red from the market-~-is that correct~ Dr. ~ I agree with its extremely limited usefulness. Mr. GORDON. Would the record show that four witnesses agree with Dr. Grout. Dr. iiarner~ pien~se proceed with your statement. Dr. LARNER. Two, the effect of these studies on medical practice. To my knowiedge these sthdies have had a variety of effeet~s on medical practice. The total utilization of this group of agents, how~ ever, has not seemed to durnge mi~veh. For example, when the results ~of the atudies were initially unnoanced, some ~physicians ?changed their patients to other sulfonylurea analogs not realizing that the fundamental pharmacology should be quite similar to the drugs ~studied. This obviously demonstrates the need for additional post- graduate tr~ining and education of some of the medical community. some physicians a'ocepted the results of the study and some ques- ~tioned the design and control nature of the experiment. This con- troversy has undoubtedly been apparent to this committee. On the whole, these studies indica* that the use of oral hypoglycemic agents should be limited to the small percentage of patients with diabetes for whom other therapies have pr~wen impossible to carry out. Three, the availab~iity of scientific evidence, if any, which demon- ~trates the benefits of oral hypoglycemics. I know of no evidence that directly demonstrates that the oral hypoglycemics are life-saving or life.proionging: in the therapy of diabetic patients. The major therapeutic problem in diabetes is no longer the acute ketoacidosis which used to be the cause of death before the intro- duction of insulin. Rather, it is the long term or chronic vascular complications of the disease. In other words, the major problem now is the well recognized thickening and other damage to the blood vessels throughout the body leading to kidney disease, heart disease, blindness, and gangrene in the limbs. We still do not know the answer to the following fundamental question, "If the blood glucose level in the diabetic patient o~nld be controlled as precisely as that of a nondiabetic through the use of an insulin delivery system yet to be developed, would there still be vascular complications ~" In other words, we are dealing with a situation here, where there is a fluctuation as a result of three meals per day of the amount of insulin delivered from-in a very regulated man- tier, and, to date, we have not been able to duplicate this situation in the diabetic patient, such as it exists in the normal. And the PAGENO="0077" C~1~IVE ~ IN THE DRUG INDVSTR)~ 13Z27 question is if ~e ~xuJd duplicate it theoretically, could we prevent the vascular complications. rri~ second part to this is; alternatively, is there some factor or factors involved oth~r than proper insulin delivery which leads to these harmful ~ffects on the blood ysssels? Basic and clinical invcsti~ g~tors are working on this question with respect to msulin at prescnt. Mr. Goiwo~ Can you give us some more information about the kinds of research being conducted in this area Dr. L~nN~i~ Yea, very simply, ~or example, the question that is n~w being investigated in diabetic humans is whether to return to the early methods of therapy, using several injections of rapidiy acting insulin, for example three injections of the rapidly acting insulin, coordinated With meals, leads to a better situation with regard to the prevention of thickening of the blood vessels and the vascular complications. In other Words, biopsy studies are being done to investigate whether an insulin delivery system of three injections or multiple injections of rapidly acting insulin, rather than a single injection or several injtectlona, or slower acting insulin are more effective im prertnting the vascular complications than the therapy with long- acting insulins. Now~ this type of questioning is being done in humans and analogous and even more sophisticated experiments are being done in animal systems. So, my point is, we don't yet have the answer to that question with insulin. And, insulin is itself a direct hormone replacement therapy. And for this reason, if we don't have the answer with insulin yet, we certainly don't have the answer with the sulfonylurea drugs. What we need is accelerated research in this area to answer this question. Fortunately, we have enough information now to be able to phrase the question in a sound way as an either/or type of ques- tion. Either it is the insulin delivery system, or It is not. And we should be able to get a yes/no answer on this situation. Until we do, we can't go forth, in terms of other applications, until we under- stand the theGry. For this reason, I feel there is no direct evidence that these or~al a~gcnts tt~re beneficial, that is, in the sense of life saving or life prescr~v~ng. Mr. GoRDoN. You seem to emphasize "directly." Is there any in4i- rect evidence, whate~ver that means Dr. LARN~R. Neither direct or mdirect. I didn't mean to distinguish between them. Numbei~ four, the problems of tran~lating the results of basic re.! search deve~o~ed b~ medical scientists to the practice of medicine. This is a very broad question, and we could spend a great deal of time discussing it~. Briefly, I ana of the opinion that scientists today a~re more bware than ever before of the importance of a~piying their fundamental stut~ies to the, practice of medicine. For `~xan~ple, in my own field, pharmacology, there has been a st~ong dev~elepment in the area of c~nical .pharmacolqgy which a~k- dress~s itself t~ this problem: gamely, the application of iundamental PAGENO="0078" 13328 COMPETITIVE PROBLEMS I~ TEE DRuG INDUSTRY laboratory findings to the patient in order to understand and treat the disease process. For example, the sulfonylureas have been used clinically for about 20 years, yet a great deal of information regarding these compounds is still lacking. The metabolism of these compounds in patients and their precise mechanism of action are still very poorly known. These have been complicated problems and require additional studies in both animal systems as well as patients. Scientists are very interested in coordinating such diverse efforts and studies. I feel that clinical research work in this area should be further nurtured, but that it must be balanced by a broad base in fundamental animal research as well. And other aspects of the subject which you think might be helpful to the subcommittee. I feel strongly that the time has come in terms of the oral hypo. glycemic agents to restudy their efforts in animals and patients. It is my feeling that since recent animal studies are proving of con- siderable interest in terms of the actions of these drugs on organs such as the heart, adrenal glands, and liver, it would be wise to re- study these compounds in animal systems during the time their clinical use is reevaluated in order to see whether we can gain an understanding of the mechanism of the c~rdiovas~ular deaths or even reproduce them in animals. Here I note with particular interest two recent pieces of data in animals: One, the summary statement of the work of Wissler et al. which states that in rhesus monkey fed an average American diet for 74 weeks containing 20 milligrams per kilogram tolbutamide, there were present in the coronary arteries two times more frequent and three times more severe atheromatous changes than in the coronary arteries of control monkeys; two, the work of Hsu et al. from our Department of Pharmacology at Virginia which demonstrates that in heart, adrenal medulla, and other organs, sulfonylureas inhibited cate- cholamine release from the nerve endings of the antonomic nerves. Thus the function of the autonomic nervous system, which provides the involuntary control for many of the organs of the body, is sig- niflc~ntly influenced by these drugs. Therefore, I feel that it is time to caution physicians about the use of these drugs, and to restudy them in the clinical and basic laboratory much more extensively. Mr. GORDON. Dr. Lamer, thank you very much. With respect to the Wissler study in rhesus monkeys, what con- clusions can be drawn from this for humans? Dr. LARNER. Well, I think, the obvious warning can be put on that these may be potentially harmful drugs., that they may affect selectively, the coronary arteries, that these changes in the artery, may lead to malfunction and difficulty in the heart. I think the warning is obvious. I think that more studies need to be done, both of anatomical nature, and of a functi6nal nature. These studies reported here were of an anatomical nature, in ~which the structural changes were pointed out. And I think they must also be accompanied by studies in which the function of the heart i~ also studied, so that we will have some more information. PAGENO="0079" COMPETITIVE PROBLEMS IN TI~E DRUG INDUSTRY 13329. But I definitely think that, since these were done in primate~,, a species which is closer to human species than the rodents and so forth, they definitely should be taken seriously and consid~red seriously. Mr. GORDON. Thank you very much. Dr. Sims, would you proceed with your statement? 1 STATEMENT OP ETHAN A. H. SIMS, l~D., PROFESSOR OP MEDICINE, COLLEGE OF MEDICINE, UNIVERSITY OP VERMONT, BURLING- * TON, VT.2 Dr. SIMs. Mr. Gordon and members of the committee a ritual of hornblowing seems to be in order at the beginning of these state- inents, so I will mention that I have had experience with a number of diabetic patients over a consi4erable period at Yale New HaVen Hospital and in Vermont, though not as many as has Dr. Chester. I am a member of the workshop on obesity of the National Dia- betes Commission and of the advisory and editorial group for the Fogarty International Center conferences on obesity. The backgroi~nd of a lot that I have to say is contained in the volume from the cen- ters based on the last conference, which is to be released this sumther by the Government Printing Office. I do not claim to be an exp~rt in anything except in our research work persuading volunteers to gain weight. I would like to acknowledge a major contribution to my written statement of my wife Dorothea, who is a Fellow in Health Care of the Radcliffe Institute, and is working on diabetes education, and also of my son Nat, who has been writing a history of the UG~~ as his undergraduate thesis at Harvard. They have both been ddIng their best to educate me. I have included a brief summary at the beginning of my *rit~i statement, but instead of that I will read a restatement of SQR~e of the points which I believe should be emphasized. To my ki~ów1e~dge they have not been emphasized at these hearings before. I would like just to list the main points, which I want to be' sure to get over. To my knowledge, they have not been emphasized in these hearings previously. One: Obesity is now recognized as a factor predisposing to n~n- insulin dependent diabetes in those who are genetically susceptible. Untreated obesity represents a long-term risk in relation to cardio- vascular and also other diseases. Two: Insulin, in addition to its well-known action of lowerbig blood sugar, is a hormone which promotes the deposition of fat. Three: The intense preoccupation with one aspect of the UGDP, the cardiovascular mortality, and the accompanying sometimes ac~i- monious debate has blurred Our perc~ption of the fact that at least 50 percent of the maturity onset diabetes in the study were over~ weight and underexerciseci. and that both th~ sulfOnylureas and insu- Tin work to make them fatter. This is a threat to their well-beir~g, `See prepared. statensint, page 13676 2 Dr. Sims on sabbatical leave at the EndocrIne Division Tufts-N. B. Medical Center Boston, Mass. * * *.. PAGENO="0080" c6i~i~i~v~ ~ ~ an,~cT ft ireA~~ ~ ~v~d1 t~bii~1ié~d ~k f~t~r ~1~àk~ ~a~d ~r~td~tr th~d otj~ diseases. Mr. GORDON. t~r. ~iiuis~ &th `S,TthI e~f5l~1ii hd~v iIÔ~th iii~li~ àkid th~ oral hypoglycemics promote obesity? You have just said th~t they do, is that right? Dr. SIMS. Eveh in thn~lI ~IñOUiIt~ i~~thih tu~ ~ the i~M~se ~f f~tty acids from ~the fat deposits in both .experime~tal and spon- taneous obesity ~y p1 ovidnig ex~~ 1h~lrn, ~ith~ b~ ~n~rtlM or by ~i~rbig ~u1~ `~Ms ~ii?~'h~ ~ in~t444~ ~sè~ ~w~i~t gain is enhanced. I will go into this in a few minutes in a bit frio~Ye ~ With alJ due, rpspect to Dr. Max Miller, who is here today in the ai~c~~ I *~L1~t like to sa~ thkt the 1*e~ttheftt oft~ons s~lectèd for the Ut~t)'i~, ~*hi~ re~e~entèd the pr~tiling o~5tMxis o~ i~&)~ ~re öift o~f da~tè iió~v. Th~ d6 i~dt i~ciiide ekcrcisc or ii~teñ~it7e e~lu~c~ttioi~, or s~v~f~i~ óther iiê~ver in~Tho~ds O~ hth~ethe~tt, s~th~ of *hich can 1~lly ié~r~é 1~lie övèft diabetic ~1tato. W~ rAu~t cO~c1t1de th~tt neith~r ~l~on~yl ~, si~id~ thé~r iñci1~i~e t1~ê ~ ~et~i~th!i of thkhlitt,, hth~ in~ii1h~ it~èlf ar~ ii i~at~d f~r the ~ti~e~t- of the o~rci~~eigfrt ~h~d T emphà~si~e o$~&~~Wcight, th~tiittty- oi~ét di~~tic. f~ht: Muèh of the db~Iei~i of ~tathtit~r-ôh~t di iê~be~ Is ~ ~iice dt oi~tr A iè~rld~n affli~eht po~t-WOi~d Wa~ ~[i iIfêst~I~~ A1tef~- ir~g thi~ i±th~r ~r~4~fitII3t revt~rs~ the di~b~ti~ ~tat~, ~ p~'oIohged use ~f th~ sulfonylureas will not. It~'ik~: 1~±crcis~ or ifiet~ed liwei ~of physical acti~it~ is ~ ~ans of eV~iitiOñ ~thd t~e~t~nè1~t which has bé~n s~td1~ ighor~d at these thã~ ~hei~evth~ diet is m~enMan~d, as i~ the pro- for thC dr~l a~ciit~, It ~hott1d b~ as diet ~nd ~sed i~Mi~i tMt~. Tt~i~ is bee~i~st~ Offi~ is with both the e~e~gy out~ht ~hefi ~tith!it. bfl~f c tO eThIior~te ~ bit. hi ~ i~ thO ifi~uiii~i the ~ècOnd of the 1'/2 usii~ll~ o~tet- of those in the TJGD~P ~*&è O~rer 2~ pe~cei1t ii *Cight. Arid ~ think, Dr. Chester, did ~ou of ~O ~efceiit o~te~rweight in ~tOth d1ei~e1kn4 ther~ i~ ~t i~tiiCë to ~ihO a~Wlon itt~t1 thO fà~L The th~u1in In. the blOod is it is ifi1h4w~te hi the f~tb~ Of the rCsisttthce df fOod. This bdiI h stress oh the ul~lth~t~l~7 bC fOllo*Od b~ f~i1ti~e ~thd Eleiit dWbétes. ~ 1ra~rO tO khb~ wheFe h~ is *ith r~pect the disCFd~r. AM ~e ~l~o hhve to k~dw ~ h~e i~ ~i Wci'glit. WO i~i1Ow h OitF *~Fi~ iii Verththit with normal volunteers, who have no fámi~Iy history p~ di~b~ Oi~ obe~ity~ ttntl whti h~ve atgtreed to d~hb4~ã~tOI~ ~a~hI ~th~ht, that this insulin resistance may develop secondarily to the obesity ~td d~t~F- eating. It is also completely reversible. PAGENO="0081" thM~t%~v~ ~ i~ ~ ~ 1~L ~ We â~~i it~t~ôi~ f~ô~i th~ ~ ~ i~w~igM p~1~ts~ ai~ ~dWè~t1, th~ii~ h~s~thti ~k~i~~fiM ~tThtiis ~ Th ~ thiI~ ¼~h~1 to ~ ~ ih~tek~ th~ bbé,~4%~7 ~i~i&~ ~tir~ t~ a14 ~ the insulin resistance of our patient. The T1(Th~ ~Wd~e~ ~iMv~çI ~eati~ th&b~h~t ~tct~iiy4~ Wh&b ifi the grtht~ gi~reh thlbut~thiM~è ~idt hi the tW~ gi~tei~ his~t1i~ tLIt ~f the fii~e ~i~Ot~~s th~rC W~ ~ 1o~ &f ~bd~ñ 8 ~ of 1~ 1YOd~t ~i~ht Mitiafly, ~ ~ F~suit ~f the ~oth~rat~ dMtM~r r~stieth~Ei *hi~h they iv~ ~fl gIw~i. The ~i&~bo gthi~p M~d t4~ ~h~bt~1$Yi group, maintained this loss throughout thiS study, ~ in th1~ th~ j~hMifot~ñih gi~oiip ~t~s ae~afly ~e betthr thah the ~ee~rô~ ~ other h~h~1, ~tients in ~Oth the tblbutkthikI~ ~iid the tM lh~411$n g~b~nj~, n&~t ô~i1y i~egaihE~4 the *eigM iMitially iost~ but ~IhM i*~iI a~hó\re their ~*igiiiaI Mseline. So, the~e i~ a ~OnMd ~Me tfiff~enee in the ~ttdy betwe~ñ the Wei~ht o~ tlthse recei~tiñg hi lih o!i~ ~u~fbrI3~1- i1~S ~s O~DdSE~d to the piaeebO g~up. What *te the other opti~ons ávsii~b1e to tis iti tcY7& Ati~I I s~e the~ a~ ~fo11ôWs: hi the S tCitih~r 1~ he~iMg beTh~'~ thi~ eo~nrti44itee 1a~t f aft, Thy. J~oMi I)a~ik1eb~i g~akte his ek~e~iei~~Ce ~n thM*iM~ o~l ~ge~th~ f~tô~i ~Oap~ttietits ~t the G~a&y s~pit~d h~ Athtutk. As y~u ~ he ha~ 6rt~d ~rthe~ on hiS expe14~Ce in The M~y ~ issue of the Journal of American MediCSi ASs~~~hiti~ii, ~d I eug~e~t thta't this ~rtic~~ be part of the record ~f thie heaI4iig. ~y a eom~re- hOnslve and ri~'Oroi~ks FegiMCi~ Which ifréhided ~5 hourS `of edu ion ~ ~atiefft, he ~ beeti able to achieve substantta~ *eight redttcti~n hi ?ti~ to ~9O percent oT the ~tiêhts and has eSsefitiaIi~r 4~é~Pe~5d their OVe~t d~ab~tic sthte. This i~ ~ôMCChifrg q~tè ~h~ei~t f~Oin ~the t6k~ p~c~ibthth Of ~ tiiabetic diet of Which nio&t of tie l~ 4~een ~ He inà1nt~4W~ that ~iM d~abetié patients Who ~rC ~5~~ht ~*~h t~hè~ ~esent thethS~i~r~5 ean be éôfrttO'l~et1 *ith~ift tt~ Of his~uihi, ~f they a~f~e ~vefi SuCh ~ regimen, ai~d, renieniber %h~tt thifl `cdtiti4t~s peFcent of the g!t~oiI~ bi niattit~it~-onset di~e~ee that ~ tk1kiii~ nbok~t. Yes~ei~d~y sOffithod~ `asked ~S, `well, if inSui~hi ~ Sb cbtit~ahid~ cated in this group, of patients, shouldn't we have a package `wai~h1n~ ~oi' iM~sulin as weil, alk~st it'S tiSe hi the e~~t diabetic ~ yoti th~nk %b~tit ~it~ th~±e ~aily `ShoWd be SuCh a *aFfthi~, So, ~t. ~*heI1 Co~miS'SionSr Set~M~4dt ~e%S dO*e `with the b~al ~geht~, he can rewrite the pk'cka,ge 1i&bei for ltisttli~. Se'~hd, there k~e MO~ë rlW$±~ue friè~nS of ~Chiès~in~ WM~ht hs~. Dr~ ~a~1~Soft M~d `orher~ have ~O~tiM~eS hi~i~tMted tfferap~ of seriously obese d~~b~Vi~ ~vit1!i ,brWf ~1!aSth~ig. T1ker~ ti~e !i~oW iie* t~i~iqueS ~ ifro'd~f~e4, so-c~l1~ed protein sparhig i~vatio~tt tha't can eiMfip~lieh *thg'ht iose ~4~tthont a da~nagii~ l'OsS Of h6~y prdt~it~. riltiese regimens so~netimes very dramatically reverse the WCrt di~- )~e't1e stkt'~ a'S ~wCi~l. thOy ht~ve been prb~en in e~f~iy pi'ot work to be a fttl adjnt~et ~kr iMithil w~ight loss. I woiu!ld i~a~i~e that be ~t~nO frtid~r s14 ~risiOn ~atid We hive ffitI~1I ffi6~e to a~Milit theM. th~e i~ ti ~$vhele ~ie* 1~eld Of ha~1~1r~l ~ tt~ kp~lied i~O b~OTh thhig' ~nd ~i~sic~i ~ `~h~h ~a~t bob p~t4~etit ~it~od~ry b~S~c lif~et~de. r On~h~i~l~ 1~l~e bhtth~ ~ PAGENO="0082" 13332 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY many of the problems ought not to go to the physician working with the limited resources he may have available or to the pharmaceutical house. ,A. lot of our current problem is a reflection simply of our American lifestyle. Mt. G oic. May I interrupt for just a second? Do I understand what you are saying is that an additional danger of these oral hypoglycemic'agents-I mean their very presence has been a danger-~- because it has taken the attention of the doctor and the patient away from the essentials of diet and exercise to a much less rigorous~ regimen of just taking pilis? Dr. SIMS. Thank you for stating it so well, That is precisely what I mean. The presence of this option over the 20 years that it has been a~railable h~s been undesirable just for that reason. In the preinsulin days, when Dr. Allan did not have that particular op- tion, he did very well with diet in this type of patient. I am pleased also to see that you mentioned exerciSe. That is about the fourth time' the word has been mentioned in any of these hearings. Mr. GORDON. And one other point: Am I also correct in that you are also saying-I am trying to summarize this in my own words- that insulin and the oral hypoglycemic agents are really treating or at least being used to treat symptoms and not the basic problem which would require a change in lifestyle, which would include diet and considerable exercise? Dr. SIMS. Precisely. Consider the problem, say, of a relatively young housewife who has had a couple of babies and gained a lot of weight. Unfortunately she has selected the wrong parents, who are both diabetic, and her grandmother was obese. If she develops giucosuria, the odds are that the average dietary effort in the busy physician's office will not correct it. She is already running an ele- vated blood insulin and has an increased insulin response. If then we give her a shot of insulin every day, we are instituting a regimen that will just progressively make her gain more and more. And ultimately the increased weight is going to interfere with her well- being and probably will have a greater negative impact on her sur- vival than might the toxicity of the oral agents itself had she been given them. Now, the fourth option is exercise. I emphasize it as a potent means of treating a patient, although I am well aware that the pa- tient applying to a large hospital' clinic, elderly or far advanced in his disease, is not going to join the squash team. Mr. GORDON. Dr. Sims, I might point out to you that there are certain hazards in exercise, too. One being the broken' bone that `I have in my foot. That is the result of playing tennis. Dr. SIMS. Perhaps, Mr. Gordon, if you should have been exercis- ing more, maybe your metatarsal bone would have stood up under the strain. `To resume, support for the use of exercise is given by some work by ~a Dr. Bjorntorp in Sweden, who measured the insulin response in obese, middle-aged men before and after a course of physical training, even though he urged them not to lose weight. The insulin response to glucose was markedly reduced. In' other words, exercise alone did much to decrease the insulin resistance which is a major problem, in~ the maturity onset diabetic. The r effect, of exercise~ is PAGENO="0083" COM~TITIVE PRQBLE~S I~ TEE' DRUG INDTJSTR~ 13~33 something that every insulin-depend~nt diabetic know~ well. A lo1~ of formerly overweight patients have learned to rely on physical ac~ tivity to maintain their weight loss. I believe that these options should be emphasized in `the package labeling for the sulfonylureas. And `on page 9 of my Aill statement I have written out a suggestion for altered labeling. Mr. GORDON. That will be included in the record, All your state~ ments will be put into the record. Dr. SIMS. I would like,, finally, to say that what we have b~en talking about is changing people's lifestyle, which is a very d~ffi- cult thing. Some may say it simply cannot be accomplishe& Btit I suggest that our lifestyles have been reversed once, largely as a suit of advertising, and they might be reversed again, by education. And I was very pleased yesterday to see the degree to which ]~r. Schmidt and the staff of the FDA. are concerned ~vith this aspect~ of their responsibility. Thank you very much for the opportunity to emphasize these points. Mr. GORDON. Thank you very much, Dr. Sims. I must say that exercise was one aspect that was really not empl~a~. sized in our previous hearings. I brought up the subject of exerc~se when Dr. Schmidt was testifying some time in September, but I do not think that we spent very much time talking about it. Dr. SIMS. I remember that you mentioned Dr. Jesse Roth's silg- gestion that exercise actually did have some long-term effects, a~id that Dr. Schmidt demolished the idea. I think that one of the `problems with evaluating exercise as a modality of treatment, is that it is hard to measure, and also it can~ not just be prescribed like a dose of an oral agent. But I think t1'~at we ha~re the techniques now to run a prospective study, perhaps an- other UGDP study, which will include the variables of exercise arid of vigorous weight reduction like that produced in `the Grady H~s- pital program. I think that we would see results which would make the meager benefits achieved for the p~tients in the various groups of the `[JGDP seem insignificant. Mr. GORDON. Is this being emphasized at the University of Ver- mont?' Dr. SIMS. We say and do a lot about it, yes. Mr. GORDON. I have just one more question. This is' a question about the labeling. It is addressed to the four of you. And that' is: Have you read the proposed labeling and, what are your comments on'it? We can start with Dr.' Felig and go from left to right. Dr. FELIG. I am pleased to see, in terms of labeling, that the FDA. is apparently making a `stand to change the labeling, and I ~o believe there has been some change, as regards to, previOus ~ugges- tions with regard `to the iabe]ing; namely, that this would' apply to the entire group Of oral `hypoglycemic ag~nts rather than "be re- stricted to phenformin and tolbutamide, but also the ot1~ier sulfonyl- urèaic agents. I am concerned about the question of the `indication in cl~abet~c `patients without qualifying the fact that it should be re~t~ioted, mainly of symptomatic diabetic patients. I recognize that there are PAGENO="0084" 1~4 ~ ?~&~ i~ tho~ thai ~biiM b~ll~v~e t~h~tt ~ ~ Ii~th~it t~f$~sod ~ng~u', kL th~ ~ ~Yf ~ ~iki~'ht b~ ~ai~ i~Mi~b Thit ~L ~W~1~d pr~f~r to see, based on the available evidenoB, ~ ~4ffiifl~t th 1~e ~kthehng that this be ~4itfki~ly i~or th~ rn$~~tic dieb~ti~ patient, b~caiise it is o~iy h~ tha~ th~t~isthnc~ that Ic ioall~ hai~e ~d~ncc tif th~ benefits. There is a lot of idonce of tl~ risk, bet wo ~re conøerne& with nsk~ b~ofit i~tio~ and ~e ~itght to ei~phas~ze the utilization, of these drugs only in situations where one can provide e1~i&cncc of benefits. Sympto- ffi~t~c ~ii~f `Wo~ktd be sidi~re~ a benefit, witho~tt any question, ~nd tM~ i~ .WIYy I i~ot~d f~vo~r ~ iabeiling whioh emphasizes the iitiportalice of 4~Stri~thd utili~tiotn t~ the sy~ 1~matic diabetic pntient~-~-cleatly, ~c~tl~iet'e ~iiot hi~s 1~ai~cd end wiiore insulin is reftsed by the putient. ~. Go~oow. frcidenthdly, we ~rill send a ~opy of yo~ir comments to the ~bod ~nd Drug Administi~ation to be included in their record bef~re they issue the final order. Dr. Lamer? * Dir. ~ Well, in general, I am very pleased that the move- ment to insert the labeling is now going on, and it presumably will `be consummated, and I, in general, agree with the labeling as it is ~r!t~a up. I wouM feel ~ little bit more comfortable if perhaps something spe~ifie toald be ssid in the labeling about warning physicians ad~ ministering these agents to patients who have demonstrated cardiac preblein~, ~or `etamp1e~ with abnormal eiectrocs~rdiagra~ms ~nd so forth, I would like to see a little bit more of that type of warning. Mr. GORDON. Dr. Chester. Dr. Ciiws~i~. I agree in general, but there are two things that disturb me, and one, on page ~9, the very first sentence: "The Oom~ rniseioner also ~ontludes that, a patient population exists for which these `drugs, properly labeled, can be considered as safe and `e~fec~ I ~woUld take issue with, "safe" and would indicate that the e~ec~ tiveness is limited. And the other thing that bothers me----and I `cannot find in this document-is how the patient will ever See the label. Will it be on the bOttle with a skull end crossbones? Mr. GORDON. Maybe that should be made more explicit in the pro. posal. Dr. CH~ss~tR~ I would think so. Mr. GO~RDtN. We shall send that on to the. FDA. Dr. Sims? Dr. SIMS. I have already described some ways in which the label~ ing could be modi~fied to include kiention of `other pre~erable options for treatment. The question has been raised as tie whether the FDA has `the right to dictate to the physician how he wiU manage his par- ticular patient. Another question is whether, if specific priorities and options are outlined, the physician would then become m~di'co legally liable to suit if he does not follow them. I believe that tIie~~ fears are a distortion, The FDA, in seCtion ~O5 of the Food and Drug and Cosmetic Legislation, is given the responsibility to deter- ~biue~ to jhsar~~ rather, the `eftlcacy of a drug. Now, e1~cacy is a rela- tive thing," and if there are other options which are better, the ~riig PAGENO="0085" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13$35 no longer can be considered efficacious. So, I thinl~ it is appropr~ate for the FDA. to list the options. Also, regardless of any warnin~ that is issued, the physician is in the ultimate position to say, `I am ~tware of your warning; it does not apply to my particular patient, because of such-and-such condition." He can write that on the record ~and will not be vulnerable for legal suit, if his reasoning is valid. So that I think that the two fears are not grounded, and I think that furthermore, we all have the problem of educating patients ~nd getting them to go along with this. I think we could regard~ an ap- propriate warning as a useful adjunct in our own education àf the patient. I think that the package labeling should be written i±~ a form. and language that the patient is able to understand. We are ~entering an era where patients with chronic diseases are no longer satisfied to be passive sheep waiting on the word of the doctor. Rather, they are assuming more the role of a client of the physician working together with him toward the management of their lifelQng problem. Mr. GoRDoN. On behalf of the chairman, Senator Nelson, Senator Abourezk, and myself, I want to thank you very much for coming here and for your very informative contribution to our record. Thank you very much, gentlemen. The hearing is recessed, subject to the call of the Chair. [Whereupon, at 11:50 a,m., the hearing was recessed, to reconvene ~subject to the call of the Chair.] PAGENO="0086" PAGENO="0087" APPENDIX EXHIBITS PROVIDED FOR ~hrE HEARING RECORD BY THE SUBCOMMITTEE ON MONOPOLY [From the Journal of the American Medical Association] REPORT OF THE COMMITTEE FOR THE ASSESSMENT OF BIOMETRIC ASPECTS O~' CONTROLLED TRXALS OF HYPOGT~YCEMIC AGENTS Sec. 1. Introduction. 2. Clinical trials In general. 3. UGDP trial, 3.1 Methods. 3.1.1 The selection of patients. 3.1.2 Randomization and allocation of treatments. 3.1.3 Data collection. 3.1.4 Methods of data analysis. 3.2 Findings. 4. Other studies of hypoglycemic agents. 4.1 Keen et al (The Bedford study). 4.2 Paasjkivi. 4.3 Feldman etal 4.4 Tzargournis and Reynerston. 4.5 Summary 5. CritIcisms of the trials of oral hypoglycemic aget~ts. 5.1 Main issue in criticisms of the UGDP trial. 5.2 Selection of patients. 5.8 The TJGDP mortality findings. 5.4 Failure to adapt dosage of drugs to Individual need. 5.5 Discontinuation of tolbutamide and phenformin In tTG-DP study. 6. Data from the UGDP and Bedford trials. 6.1 TJGDP data. 6.1.1 Randomization by ser within clinics. 6.1.2 Cardiovascular failure Fates. 6.1.3 Multiple logistic model. 6.1.4 Analysis with respect to adherence to as~igned treatment. 6.1.4.1 The extent of the problem. 6.1.4.2 Statistical analysis. 6.2 The Bedford trial. 6.2.1 Cardiovascular events. 6.2.2 Mortality data, 6.2.2.1 Failure rates and death rates, 62.2.2 Multiple logistic model. 7. Conclusions. 7.1 Protocol. 7.2 Conduct of the study. 7.3 Methods of analysis. 7.4 Findings. References. Appendix A Use of the logistic model. Appendix B Relative allocation method. Appendix C Survival modeling method. Tables. 13837 PAGENO="0088" 13338 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY COMMITTEE FOB THE ASSESSMENT OF BIOMETRIC ASPECTS OF CONTROLLED TRIALS OF HYPOGLYCEMIC AGENTS ~JOHN P~ GILBERT, PHD RODOLFO SARACCI, MD Office of Information Technology Sezione di Biostatistica e Harvard University Epidemiologia Clinica Cambridge, Mass ~J~oy~tqrio di Fisiologia Clinica 4e1 p~ Pisa, Italy PAUL MEIER, PHD ~J~VIN ZELEN, PHD Departp~ient of Statistics Statistical Science Division~ Univ~sit~ ~ ~J~iç~gq State Un1yer~it~ of New Yç~k Chicago at B~~aIo CHRISTIAN L. RIJMKE, Mt~ Cox~ ~ ~ BS (Chairman) Afdeling Mediscbe Statistlek Department of ~lpidemlology and Vrije Universiteit L~ublic Health Amsterdam Yale University ~lb njiyz~ ~ ~E J~TE~ $~c~~r PETER ARMITAGE, PuD BERTHOLD SCHNEIDEn, DPIIIL Department of Medical Statistics Department fur Biometric und and Epiden~jolog3r Medizinisp~ I~9~p~tik London School of Hygiene and ~ eej~~~ Tropical Medicine Hannover, W~t Ø~i~y London TResearch Associate 1THEODORE HOLFORD, P~ ~ ~. ~ MP Department of Epidemiology and Departm~ ()~ ;~4w~ Public Health Q~ Yale University chicago New Haven, Conn 1. I~F~?B~DIWT~ON In a report that was published as a supplement l~p ~ ~v~pber 1970 i~,ie of Diabete.s~, The University Group ~ ~ ~J$P~?) concluded ~t~t in patients with adult-onset diabetes, "talbutamide and ~ ~a~y be less e~tc~ tive [in pro1~~~ i~ ~ ~4~t ~ * ~t 441~1~ i~ ~ cardiovascui~tr mortality is concerned.~ ~, 2~) ~ tJj~ s~b~p jl~re~t~ wi~4i ~c~itamide, 12~7~~ died from cardiovascular causes, as compáre~ ~ ~4% ~ ~r~er in the o~lWr treatment groups. As a result of t~es~ ~ jJ~e j5~o~ ~4 Drug Adn~i~i- stration (FDi4) ~ec1 t~1 ~Ø4~ ~ ~e u~4 ~nly in pat1~s w~ ~ia~l ln~, ~1~%bJ~ ~ 4~ çp~l~ n~4 ~ coi~t~o~W by diet a1~e, and who, for some good ~ ~ ~ t~t~çl ~ i~L. The findings of the UGDP and the action of the FD4 1~a4 ~t 4~amatic imRaet. Tolbutamide had been in gei~p~ ~ ~ ~ie trq4 ~ ~ ~etes since jiI~q~it 1956 and was thought to be a safe and, ~ff~ct~y~ ~ug, ~ T~TGp~ iieport was t~ully scrutinized by many, and, though 4e~e~4e4 by ~ ~ya~s severely ~d ~xhaus~~ ~m~1~iq~4 ~y ~isr~ 4 ~ç~p ~f ~ cpi~ti~s s~ç~4 legal action ~o enjoin the FDA from issuing a labelin~ p Icy ~b~t ~vpu)4 d~s~Q1~rage the ~ pf tolbutamide. In 1971 the UGDP reported that treatment ~i~h iex~fi~r~1im hydrochlori4e also resulted in an excess cardiovascular 4p~4i ~r~i~e aji~4 i~4eed, an qx~e~s overall death rate. (3) These findings have not bee~i ~~4e~y ~~141ssed, and ~$ir impact on the treatment of diabetes ~ The UGDP study is the largest controli~l i~n~i,ç~,l 4~a~ af ~ hypo4y~c~z$c agents to date. Other studies of these agents are in ~ ~th prelithmn~ry results, however, that appear to differ from those of th~ ~ The Natipi~al Institutes of Health (NIH), which has ~ ~ ~ ~e~l~t the need Qf a reviewofevidence~ available in all the trials, ~o~i~g1y, çn J~tne 9, 1972, b~ie director of the NIH at that' time, Robert Q. Marston,~1~~X~, ~rQte as follow~ .~to the chairman of the group presenting this report: References at end of article. PAGENO="0089" i'~ ~kj~ ~Mr~I~ ~ At my request, on SepteM1~ 14, 1~i', ~ ~óz~xñrs~ Cirnimers, Associate Di- rector of N~H. fQr. Clinical pare,. i~uv~ted the PresMent q~ t~ ~metj~i~ Soc&~r~ P~~S~5J! ~ ~ t~ á~o1~t~a d~d~ñ1i~t~e to çth~sider t~ie bi~m~trnc a~pe~ts o1~ ~ ~ri~ti~o~ dr~t1 hi~k!~Mi~ ag~ii~s. T ~ii~ ~ifdrüi~t~ ~J~iht~ t~ co~- mittee has now bqen 4~pointe~ and that you Jaav4 á~5e~d to ~et a~i~ ~h&irñi1~1L. f~t~±~i~ of ~EH ~ I~iIiS~ th~C~e~ a~f~ f~t4i1n t~IA~. fact t1kiI~. ~ fdit~ n11ffft~i~ Ath~iç~th~ ~ 4~ déth~IØ ~ ~ ab~i~i~t 1~e~giyeernt& a~ t~h~ ~ tMrt~&~i~e o~1~ th~ ~t1~ o~ ~ ct~u~~ d~èr ii.~ ni~ffl:1~ d~äl~fi&ai~ ieiyJi~iftgeat~d~ ~Xth ortif 14y~~o~iycethic ~geiith. it is~ n~is~tboüt tWoa1fnt~e~ t1~Lè f~~ft~ ~Ôt~P ~i~iiet~es PrOgrän~ ifrst réporf~ci~ tJ~t ~tfi~ or~t~i d~1i±~1~ ~ I~i1~1~ i~ë~e~s~ tile death rat~e from cai~d~o~ . ~ ~aii~e~ . E~t~tu~ df t1~ê Wk~è djf~i»=áI i~. d~C tli~ d~n~gs in t~e tre~1~ m~h~O~ dib~t~ it i~1D~1$61~tth1t t~h~t~ tl~e ~ ási~êct~ o~ I~1i~ evidence eo~i- cE~nli1~g thea~geñ4~ ~ todátcef~j1 ~ ~Ibe& th~ ~tht ls!üli of tb~ tY~4~i~ ~hk1~ d~ehd~ in ~r~at ii~ea~ure oii~ the. bi~ mt~1~d~ át~o~ th~ ~ ~ 1. to make an in-depth assessmetit O~ t~1ie s~it~e I~lf~ o~ t~ tJ(~D~ st~ad~ that lii ~ri~tiTh~ Of th~ ~loñ~tth ~S~ofs of t1~e ~ési~±t,, cOnid~uet,~ anc1~ axt~1~ of. the~ ifl1~; 2~ i~o iMk~i a~ ~thiiiar a th1E#nt~ of otii~ ~oñi~rOI1e~d tI~IaIS ~f or~d ~ypuglyct~m~c ag~êftt~. ~ ctt~e~ i~ iirg~1 ItO ntittzè all tile sour~~ it ñOed~ ~O ar$~te at a sa~ctö1~~ a~s~e~; aiid~ to p~pare a r~p~t foi~ p flcát~on.~ flte Cbmmift~e~ sfro~ild~ f~t f±ee Ito obIt~iil eipe~t help lii ~rOi~ai~fn~ t~hi~ i~ë1~Ort aiUt Ito call c~n. repre~entatives of ~rthi~iit d i~l1tr~ a~ ~O t~aiTh~: A1thQU~h nO i~riOr a~- pi~ovhl 1~ Ith~ ~ i~ r~4il1r~ed~ *~ sh~all extiect to be ke~tt informed of the cdil~1li~tOn~ a~ WeSt de~e1to~. ~Phe c~oththit~tee- w~ apj~~'Oliffed b~y the 1~rO~1deil1~ of the 1~iil~t1~ic S~Oelety ai~d~ fl~'Wrë1~t~ it~~fkn~s. The' ~hU ththiñ~ttth~ fr~It on ~ o~t~io~i~ d~llthig~ thO pe~1dd~ f~Ofn A~1~tst X9~ tc~ Ci&~thtiet' 1~4'. h1 dtIti~nt, tIle ~1tii~dj~ean iri~hlbe~j?It n~t OflC~ ~ ~ gt~U~, and tlt& t!~ ~ëtr~' dI& ilkèWl~e. lS~ th~t dont'~e ot th~~ ne~tIl~g~ ~l ttt~tlO~fS ~*ere hdid *iIth J~A~ ~W]~d ate t~It1~itár *IItIi Itb~ clthldal Itti~tl~ of ~E~i' ~l~e~X& a~,tit~ ~*f~i~ to fhu1thtf~h's of'tithe, tItré' ~OththiIt1teé w~ abl~ to lilIttu~ o1tl~t a o~! t1~e' tSeO~l~ *1~o ~trEt io~l~ëa1t~l~O' lIt tfti~ iie~i~i~. It ~t1~h~e's th t~rd ~iec1at tha~±~ fbi' h~li~ gF~eir Ity ~o~Ile~rf ~, d4~; 1~ttI~ ~et!oiI14~ It~ô t!eftf; ~l'~ra~ ln~ieth~, h4t~'; i~. 3. 3~th¼Itt, 1ttA~ ~ti~; ftI~t~ ~ ~ItU. ~ J~O1ln ~. O~lW~ali, lfP; ~t~tnle~ ~ 1~h~; tht~ 1~o1~e~ ~ltzE~t','fttD. - The full committee visited the Coordinating~ Qenter of the 1~GD~' at ~alIt~-- m~e' a'th~ à~ snhcOthlthltte'e' ñia~d~- ~ ft~i~th~t~ i~i~lt ltd t1O~' We ~r~ltse~ t~Sdd i~i rtttklOmtzltlg ttth~ a11~odOthSii of ti'ea~tilitht~ dfrti~tia~d f~. 1~i1rnf, ~ j3~t~, th~ ditt~Ie~tOi' Of the dilnafh~ (~ntOr ilmi iii~ st~tt p4~M~ e~t~hs1'$~d tt~ta- tidlis thid~ off~in'~tl~ d~thL of ~-tV~f it~~i~it ~arr~ it~niii; ~11~ P~It~~ ~ltfs~- kfra11~' m~d~ê dl~ta ~t~dI~t~%le t~bth- tl~ ~t1ttf~ tfi~t' i~e dItd~ ñis~ ~Q1i~gtI~ cdiItt. Sth~t~tthtfttd~ ~*ItsttW wth~e ~ThSd ltb It1~ ce~athrs at i~?o~Itdn at1tft~f1~eihi1aft thnt~ par&i~*tItet 1~n th~ T?(!i1~ tti'IaIt. - SIlidè~ ~ of tIle r(i1~P Is sItItl'14 iii pi'ogi'e~s~ ft is ndf pO~s$~hI~ to' a~ss~s~ the ~n*~ out&lne of the trial. hr perltletrhlr, mittcft of the o~ta .011 nOflfataIe'veni~ still r'èi11kI11~ ~ñ~\ibhisIl~& `~he~ C n11ittd~ saw' as ith th11M tO~k It~e4 lCstl~thio~ of the excess cardiovascular mortality In the subjects who had.-recei~of ltoThnt~ - ann~e'. ft rc~1e*C~ in d~teii repor1~s of th'e U~i~ on tli~ ~ nfl~~, 1Mse~- lifle dalta,, thict ndrthlLtl results (1, 2); the ortgiiial c~nt~ oil *Ili~ these se~ pdrtu wete b~l~IecT ; ailci the cOmthe1i,ta1~~ that' hiS ap~OarC'd' in ltIl~ lite$ittti~e i~ to' tile' en~I of i~rhi'eli M,4~ ~The ni'ottaftty' dkta e~rCrc~d~ a ~ei'i~id 0 8.5 ~`C&ts efld111~ In' ~ctebet~ i~; tIle' ~o111111j~tltC'e hitS se~i1 la1~i o'~ethf]t ~g~in~es~. bnt si4Ce tbe~ *e~ i~ot fttaalt the dçltiuled dat~I o1~, ~h1cb Itht~ ~k~éist itit~d ~`e±~- no't ~ft~tIf~d~ hjñ~a~l~~' rd.~OtIt thi. gehfdrlullI' (3~)--w'a~ e effli in teitt~t ~$1tt I~i ~tieW of'-tilef~t. ithl~t~til~ i~h~ttl IMI~I~ on' thit1~ ~01~jtetlt. ~n'~ still il i~i~Itsile~l, tilO cOñuMtthe' CUd 11ot r~iloth' til~ 1~it~tc d~tt~t oh tild ~et~ of~ thI# tf~atn~ènt: 1~o~ a ~lfnffikr rettstin it 1Th~s ~fren c011~ lli11Itt~i'1 ~~tt~ntioi± to tile' iI~Ow ñol thtl'é ts in the thllftCt*ulthTh ~thd~4~ - ~he ~Othth*I~ hit's ~ th~ itIl~il'ett tlcIli~c~é avM-thht~ ~f t1It~ einlt o I~ oil o1~frCr cblitrdflèd trMTh of Orth hfl~o~i~eiMd a)~f1f~ ~ ~`e~rdil'c'e I mitd~ tO' MI of these, `Iknlf the' thatih eta~s o~ tilts' i~CtiO*t Its `On' tll~ stu'df' b~ the U47~DP and the Bedfe~4 ~tpdy çrganized by Keen. (57 6) - References n~ Qt ~t~c1~ PAGENO="0090" 13340 cOMPETiTIVE PROBLEMS. ~ THE DRUG INDUSTRY 2. CLXWIC~L TRIALS IN GENERAL The evidenëe considered by the committee *aS almost wholl~ derived from randomized clinical trials, and it"is appropriate to be~ib *ith, ,`sothe general remarks about this type of study; The effects of drugs, whether bOneflcial or adverse, can be asse~sëd in various ways. A traditional approach is to present a small number of case reports that ai~e judged against other dlinieal experieifce. This kind of cOmparison between a few observations on a new treatment and a larger experience on standard treatments, may be convincing when the new drug has a clear-cut effect. More otten, though, a new trOatment produces a small improvemezit as compared with the standard treatment, or there is a relatively large number of variables that affect the outcome of therapy. `In such situatiOiis; c~së, stttUles~ l~owever carefully carried out, do not provide clear evidence of the imp~bvefzient What is needed is a controlled study using groups of explicitly defined patients who are comparable in all relevant respects, or whose potential lack of comparability c~n be allowed for in the analysis of the data. Serious attempts to conduct large-scale controlled trials can be traced back to the 19th century or earlieu~. (7). The essential ingredients of present-day trials, however, are found notably in those planned during and after World War II, particularly those for the treatment of tuberculosis a~nd cancer, and for prophylaxis against infectious diseases. (8--12) We may identify for special com- ment three aspects of a clinical trial to which much thought has been given; the assignment of treatments to patients, the assessment of the outcome for each patient, and the analysis and interpretation of the results, It is very desirable that assignment of treatments to. patients be done by a random mechanism, the most convenleint form of which is a table of random numbers. Randomization ensures that groups are unlikely to differ materially in any prognostic factOr, known or unknOWn. `More specifically, it enables the investigator to determine the probability that observed differences in outcome between groups are due to sampling fluctuations rather than to real differences in treatment effects. Only when this probability is small can we feel confident that the treatment effects are really different. Without randomization there is no guarantee that differences in outcome are not due to the investigator's tendency to assign certain treatments predominantly to patients who have a poorer than average prognosis-a tendency of which be might be quite unaware. A further advantage of randomization is that it facilitates the use of methods for maintaining "blind" assessment, although it does not necessarily' ensure their success. If the response to treatment is thought to be influenced by one or more quali- tative variables-such as sex, clinic, or stage of disease-a stratified system of allocation may be used to ensure that the treatment groups are balanced for these variables. Alternatively, simple random allocation may be. relied on to produce near-equality of the groups for these particular variables, with a post h'oc adjustment of the treatment comparisons in the subsequent analysis. Experience has shown that the assessment of the response of a patient to a specific treatment may sometimes be influenced when either the patient or the investigator knows which treatment is being given. Even if such influence did not apply in a particular instance, it might be very difficult to be confident of this; hence * * * The analysis of the results of a clinical trial centers on estimating the mag- nitude of treatment effects and assessing the precision of these .estimates. The analysis will need to take account of concomitant variables and to adjust for ai~iy large discrepancies in base line characteristics arising despite the randomi- zation. Furthermore, there might be interactions between treatments and various characteristics of patients, i.e.. a tendeilcy for the differenc~s between the e1~fects of particular treatments to vary with difference categories of patients. In evaluating the results of trials, one must bear in mind the important role played by sample size in the ability of a trial to detect a difference of a given size. In trials of chronic diseases, where special importance lies in the rate of mortality or in the incidence of particular episodes of morbidity, the accuracy of the results will Increase both with the number of patients entered into the treatment groups and also with the length of the follow-up period. When a trial with. a relatively small number of patients ~r a short follow-up, References at end of article. PAGENO="0091" ~OMPETITIV~ ?RO~LEMS IN TH~ l~EUG INDUSTRY 13341 or both; fails to confirm a diff~renceapparently révealéd bya larger trial; ~he discrepancy may well be e~~lained by the relativel~r large rándom~errOrs Inher- ~nt in a small study. Any clinical trial imposes an administrative burddn on the iiavestigator in addition to the effort that he would in any case have to give to the eare of ~iis patients. Much of the additional burden ii accounted for b~ the need to pro- duce careful and unambiguous records of all the relevant clinical obsetvations. The random allocation of treatments does not in itself cause much extra work during the trial, although a good deal of effort may go Into the pre~arat~on of a detailed plan for randomization and blind assessment. Many large-sétde trials can only be mounted as collaborative studies, since any one medical center Would provide an inadequate number of patients. Multicenter trials give rise to special problems of coordination, and there must be a clear prOtoéol for the Study. It is necessary to ensure that principal Investigators from different centers meet regularly and to establish a co-ordinating center that monit9rs the standards of the study, that receives the records as they become available, and that analyzes the data at regular intervals. One of the moSt difficult prob- lems in multi-institution trials is to have an adequate quality control system for the data. The processing of data from a clinical trial, particularly a multi- center trial, is also a substantial task that must be properly handled to ensure the efficiency, and indeed the success, of the trial.. Randomized clinical trials pose ethical problems. Some of these are commOn to all medical research involving human subjects, but others are specific to t~ils particular form of study. Three important questions are (1) Is it ethical to assign the proposed treatments to patients according to a study design dra*n up by the investigator, even if the patients have given informed consent? (2) What are the criteria that should allow an investigator to depart from an assigned treatment? 0 When and how should a trial be stopped, or its desi~n be modified, if one of the treatments seems to differ markedly from the othE~rs in either adverse or beneficial. response? These and similar questions have received much attention (13, 14) and *e cannot discuss them fully here. A few points, however, are particularly relevi~nt to the studies under consideration. The investigator's belief is well-found~d. Investigators will differ both in their readiness to undertake a randomized trial and in their reluctance to continue in the face of accumulating data st~g- gesting that a difference may exist in the response to the treatments, In vegard to this latter decision, statistical evidence about the possible size of the dift~r- ence is relevant, as is also a consideration of the sequential nature of the an~tl- ysis, which may well place exaggerated importance on transitory random fiuctu~ ations. Different people will make different assessments of the evidence that may be available from other studies, many of them perhaps nonrandomized, a~d of, the risks and benefits of continuing or stopping the trial. No criteria wfll satisfy everyone. No matter bow long a trial of this sequential type continues, some will criticize it for going on too long and others for stppping before su~fl- ciently conclusive evidence has been obtained. In any attempt to review t$ propriety of particular decision to stop using all or some treatments in a trial, one must bear in mind the range of decisions that might reasonably and prop- erly, be reached. 3. THE U~OP TRIAL 3.1 Methods Patients began to be recruited for the TJGDP trial in 19E1, and curre~it plans are to continue follow-up through August 1975. The objectives and mCt~.. ods of the trial are described in the published reports (1, 2) and the followir~g account is confined to a review of a few salient features. 8.1.1 Selection of patients The method of recruitment of patients varied somewhat among the 12 ce~i- t~rs involved. Some patients were obtained from diabetes clinics or through referral by physicians, and others through special screening procedures. Pit- tients were considered as suitable candidates for th~ trial if diabetes bad Jeen recognized within the preceding year. From these candidates, all. those wl~o met one of the following conditions were excluded: (1') those who did not shoW a pos~tive diagnosis by a standardized glucose tolerance test; (2) patients with a history of ketoacidosis; (3) those who did not remain free of kOtosis durir~g References at end of article. PAGENO="0092" 1~3842 COMP~Y1~ITiV~ ` ?ROBLEMS IN TINE DIjIJG . I~WU~TRY a one~n~unth pE~riQd ~f treatment b~ diet ~ a1~e oir who, dmiu~g tht~ o~e-inciith~t period o1~ o~vatio~i,~ were j~$g~d ua~*i~b1e q~r unwU~Ung to ~o1Lo~w the study proto~oI ; and (4) thos~ whO had any serious conctition th~b1~ in ~ jUdgrnent~ of~ t1i~ ~lin~ie~ p~ys$~oia~n~ implied a~ 14~ e~p~tanay o~ Lees than five years.. A~ a i~su1t,.. th~ t~P si~bje~t& may be though o1~ as a gr~p o1~ patients with~ aduit-oiis~t~ nouketotii~ diOetes~ Thete~ wa~ a ,prepoaderan~e~ o1~ w~rneu, wbo~ made .ui~ 7~% oJ~, the tota1~ t~iabete~ ranged~ in severL1~y trom asymptomatic,.. with nç g.lyeosu.ria, to symptornatc4 with prma~ent glycoauvia. and markec~ byperglycem~t~ A description of the patients ia g4veu by the UGDP (4~. pp~ 777- 7~3) in the form of several tables that present dlstributiou~sof base4ine charac-. teristicS of those in the study. Tn the ~ many of the critexia~ for oxeluding subjects were, well defined. There wnr~ also sjtua.tlons, however, in ~bich the clinic physician had to use his .iudigment-~-fbr exantp1e~ in screening to obtain patients with a. mi~hnum life~ expectan~y. of ~ve yearn1 [n view of this a~d of thc faet that patients were~ drawn from , various sources, it, would ba expected that clinics might differ s~stematieally in the charactcr~sties of,the subjects selected. 3:1.2 ~t~ot d3UZ ltt~id~in `~f t4~ni~nt~ Tild T1~J~ ttM~' ~v~i ~tt ngt~c1 at( a baiatn~d ~eslgh, ~tr~tifi~d by bIock~ of 1~O th~ i4 ~ tient~ witlith ~lthies but without other res~r1etious oa. the pattern of assignment of tthat~h~±1t to thts, Tiilt1aIi~ d~ring 19d1 In ~ ol~ se~et1 ~flttf~s, the fbilrtreamttettts-rarlaiile-dose'itisiilhr (IvAn), standard- ddne lnsnthi (`Th~Pti), tolBnthinlcle', ~lid p'laeebo-were afiochted randomly to ~Lttit~tLt~ itt lil6cks of 1~-f~Mn' subJects In each of the four n~eatments Ill ran- dotti otder. t~i i~2~-i~i6~ phettf~rlttin WaS added to the ti~atttiettts at five new cthttc~ ~is~ Well a~ at Otte of the original ess~eii and, in ordOr to achieve overa1i~ ~atit~ itt tIlo tdta~ number of patients assigned' to each treatment, the block s1~e' Was fL~é'd' at f4, with each i~Tocit containing si~ subjects receivIng ~hen- to~iilitt, dilti IWO `redei~ittg' each of the four oIlier ti~eanneuit~n For purposes. of administrative .efficiertcy~, ihdivithml patients receiving toT- htttattMe `dr' pionel3tj were' ttot assigned inilqiiel~ idCtttiftOd me'dleation, but Were siippl~ed' as folloWs: For the folbnttmlde assignments, numbers 1' to 24 were s~l1t at raiidbni IntO tWo gtoil~~ Of T~ dflO grOU~ oi~ numbers heing assigned to' iith~e'bO and the reniaftider to bottle'S' that Would be' used for toThutamide~ 1~acb of th~ th'st 24 51Thjt~c't5 receivIng ~lacclbO Or t~tbtitanil'dt~ itt a giuren clinic Was~ aliOtt*d a te~ltrtttte' bottlO Muhber, the se~tience' then' being re~~ettted. Bottles 2~l th~ougb 4S Were used for patientS assigned to toibtitamide' itt the clinics that' also tl~ed phenfornitti. As g eotisecjttecee of this orrangP~xient for the distributloli of medication, sotnetiftics two and Ss most three subjects it~ fi gIven ~Tii1i~ Were. Sttppiied with~ i~e'fitl~5l hoti'ie" niftObCr~. The administrariva ath'snta'ge of Slits, sehe'me is that e'flclI ~linfe' coiUti be' giten a~ ittltthi' sttpply of 4S w1ique1~ labeled fnedications a~nd cOttid~ order ttdthtioitai supplies, aS rie'ed arOse, WithOut burdening the' ccnttal pharmae~ With rè5pe'ri~ihilft~' fOr' moie' than ~kio separately lab~Ied~ ic~tlOriS. The ,orafl~ gfren nthd~lcttfIoits in the tolbitiamide' Stticly Were' In tablet form. ~1~'II~ ~ntt~tititi~tibff of phenfarrnin itt The ~~eOlid pttrt of the study required' a change in the method of administration, since phenformin is supplIi~d as' gvaatr1e~* filled capsules. In this part of the sftd3~ all control medication for new patients. was given as capsules. Tolbutamide was still supplied as tablets but, unitnown t~ tl1t~ ~au~t1C1pa~thig ël1nI~~, pl~eeho iii the' f6rsi of t~bletS WS's ttet ~i~ett in the Iif0r~thhk e'thties. t~eW bottle n*thbth~S ~49 tn 72) We~e' uSe'd for the capstti'e's,. bitl thW sttnte' the'tbod of resupply was In executing this plan, liStS Of ord~u~ed ti'Oaftnent~ S igatiterits we..1jre~s11~ed1 in advance for `each clinic by the Coordinating "Cente'r, Randont permutationa of 16 from' tl~ tables given by Cochran and Cox (15) Were used for the treat- thettt alloCS'ti0ttS Iii the' ftrtit sh~ ~thiiCn; and' tile ~SILd tthres' (1w)' Were em- pTh~e't1 for' th clinIcs itt Wili~il ~hettf~WeitS waS admtnisrered. The assignments' *e're, enteted th a mg book, and spncs was left on each liSt for entry of the thtnie Slid Identifying nuthbet of the ~ttthint and the datit of `a i~rirnent Pc f~e'tiit~tc tnfthttton of. tte~tittenC, asSignment re'~ttesis' could be macto by the clittit tO ste' ~dotdinhti~ig Ce'nt~t att~ f4i~d ~y telephotte', itt which eSSe a himifo~ nuniber of ittdi~rh1ua'ls had authority, to revorti the pame of the patie'nt mt the References at end of article. PAGENO="0093" ~OMP~PI~VE ~ ~ ~ I~Rt1G 1~D~t~V~ ~ :approp~i~tte line ~f ~ ~ ~ ~ aiadl r~o~rt ba~k ~ ~n~s&~eeteU tb~r~p3~ . as sh~wii km the 1~st, that 4s,~1t~r Ls~r ~!r I~v!tR o~r~a ~øt~I~ flk~rnb~. C~a~ft~r~ 1et~s wer~ i~angk~d tbs~i~e~t~. ~ the a~M~M~a&~t ~e~i~lis might ~rne by rn~a41, &~d th~ ~ ~Ye ~i~j~Ottt~d ~ in ~t1~ ~an~n~r~ All 4i~it- ~rnent ~assignm~fflis ware inad~e in ~t1a~ sa~nence mid ~ttt in ifre mt~a~ioti iist.~ Once treat4nen13sw~e ~ssign~d, the~a~ was thitiiMad by t~e clinic. titbi th~rapies net being "ttlind," rei~piired `n~ ~nr%her ~en~ld~ration~ Th ~1T~ cas~ o~ orally given medication, however, l~he traatinent was i~ntified ~only by ~ botUe ~nurnber. ~.1.3 Data coZlction Ollineal wnd laboratery &aba were ebtained ini~i~fly and nt ~nhsequeat i,navt- erly follow-up visits. Provision wee niade for ~gat4th~g death re~orts from the clinic. phy~ieigzi wko prepar~fl1 a auiaa~ry 4f the ~na4iqa1 record a~cI ef the ~t- tendiiig pliy$icinn's description of the ~circtunstances ~nrrouud4~g the death. 4 copy of the death eeztiticate and also a ~eopy of the ant sy rejart, if ~ne exthted, were funitsbed to a central pa Leonsisting of ~ap internist and. a j*th- ologiat. This panel ~nade the final decision as to the eanse of death and ~I~y dad so without knowledge of iibe treatment group to wlfleh the patient bed been assigned. 3.1.4 Mctkofs of data anni~~sis As the UUDP rnudy progressed, it, appeared, nne~pectediy, that the ,~a:tL~nts treated witb~tolbutamide ~bad.an excess i~ortality fro~,ear4ioxaseular canses. ~This called for statistical technigues tO provide ways of eval~ating the~ao~gni- tutle of treatment. differeneeshi.wortality. g2 T~st.-The first naethod was to perform a X2 test to eom~are the prier- tion who died In the placebo-treated,groi~p with that in each of th~Ather.grO~ps. Life table aeml~jsis.-,In a study such *~s the tJ~ThP trial, sii~bjec~s are en- rolled over a period of time, so that when the stu4y ends, the ie~~tb %of ~o~1p~- up has varied from individual toindividnaL Xu o~d~r to Mjnat. f~r these cli~tor- ~enees, the i~v~sUgat~rs used a life table method. This involv~s, e~timatim~g, fi~r each treatment group. the survival curve, that is, the ~pr~por~iQ~n, pf surviving a given number of years. Multiple logistic rmo4o~.-Since tlie~4eath rates were affected by many factors, the distribution of which differed somewhat from one treatment group to an- ~otber, it wasr desirable ~to lInd a metbsi of a&}usting fer these tti~erenee5 in base4ine variables. A. multiple Ipgistic model waS apteynd fer this ~purjm~ese. `The ruse of. such a uwdel can be ~i~ded as an a*n~at to take into noe4 `simultaneously the covaviables that affeet the auteoa~e. The projsability of death is ~presseU as a fmsction of the base-hue rl?iefliables, and the dMa are ij~ed to estimate the parameters that appear in this function. The statistical umtL~ed~s that were applied were those appropriate ,for large pamples. Monte Carlo monitoring procedure.-~i'o rpro~Me a ttatistiCal b~si~ ~er com- paring drug~pIactho dl'fferenees In mortalit~ asihe study js~ceeeded~ bounda~ies ~Cor thiS dffferenee `weSe censtruoted b~ siatc,lation. The to simmth~tbe ` rtd1i't~ dtfhrences that wo*ld ObSe~ivedh~i4)tbe ~n~taigty rates from the 4~5~t~1961 VS `life table `been in effect for igroups ~vcritli the same age, race, `~thd sex as `the `indttidutts iii the study gisiups. ~Uppcr and lo~wer bounds were set to the ~differenee in ileath rates over 1~imc in ~u~h a way i~hsrt there was a ~rebaI~iIlty of only .05 that a greater diffarence wonld~be obse~red if the 5~-~14~61 death ratashadprevailsd. Liloelihrood ~ further method used d,y the ~UG~),P 40 ffionitor the umber of deaths was the calculation of relative betting odds (flBO~ This I~ a i~ayes1an stati5t1~àI~pr~ce~tLrerby ~l4dhaat dttempt `was linatte to rin~~~o- rate a prior belief iii a hypothesis ~b~ut the difference ~botsme~n ~the ekrutu1w~i'vc mortality, as ealeiflated from the life table, Of the titug-t~roated groap ~ the corresponding rate for `plaeebo~treated group. 3~2 Fiadin4is , , . . , ` , . By October 7, 196~, a total of 8~ deaths had occprred in the,Aur4zditiinl 4r~at~ went oupai~ ,f~C these~J~ ~erQ~due ~o ~ 4tó~sc*larennses. ifl~e, uns$~er cf `ps~iients i~tlt5*y assigned to ~ rnsut~gpoups:au4 jhe i~ardent c~4ea*bs airesbown he:~topipottion of~Th14e I. . lU~ferences at end of article. . PAGENO="0094" 1.3344 COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY A 12 analysis of these data indicated that there were differences, not statis- tically significant, in the proportion dead from all causes, but the tolbutamide- treated group bad a significantly greater proportion of deaths from cardio- vascular causes than did the placebo-treated group. Analysis by the life table method confirmed these results. Since there were differences in the base-line' characteristics of the patients in the various treatment groups, however, the question arose as to whether the differences in cardiovascular mortality rates might be adequately explained by differences in the incidence of risk factors~ The conclusions from the use of the logistic model (17) indicated that the ex- pected number of deaths due to cardiovascular causes in the tolbutamide group if it indeed had the same cardiovascular mortality as the placebo group, was only 10.7, whereas 26 cardiovascular deaths had been observed. Further con- firmation of these analyses was obtained from the Monte Carlo monitoring pro- cedure and the likelihOod calculations. ence, the investigators concluded ~-that there was an excess of cardiovascular deaths in the tolbutamide group-an cx.- cess group that could not be explained by differences in the base-line variables. A closing date of Jan. 6, 1971, was used for the analysis of mortality data in the group receiving phenformin and those receiving other treatments at th~ phenformin clinics. A total of 47 deaths occurred, of which 37 were due to cardiovascular causes. The treatment groups in this case are the groups in the' clinics where phenformin was used. The number of patients and the percent dead in the various treatment groups (3) are given iii the bottom portion, of' Table 1. The investigators concluded that there was an excess of cardiovascular deaths In the phenformin group, and further analysis showed that the, excess could not be explained by baseline differences in the groups at risk. ~he, relatively few pubiished finding on nonfatal untoward events in the `IJGDP trial show only minor `dIfferences among the treatment groups, (3) and `these data will not be considered further in this report. In 1969, a decision was made to discontinue treatment with tolbutamide. In contrast to the controversy that this action of the UGDP investigators provoked, there has been relatively little discussion of the decision, taken in 1971, to dis- continue treatment with phenformin, and this latter step is not considered in detail in the' present report.' 4. OTHER STUDIES or HYPOGLYCEMIC AGENTS In this section, fotir other controlled studies of hypoglycemic agents will' be reviewed. Uncontrolled studies will not be discussed because it is extremely difficult to tell which of the effects observed in such cases are due to the treat- ment and which are due to the selection of patients and their assignment to the treatment groups. The studies under discussion are identified by their authors. ` 4.1 Keen et r1 (5, 6) (The Bedford Study) The ~ubje'cts for this trial were `people in whom the capillary blood glucose level, measured two hours after a 50~gm~glucose load, was between 120 and .200 .mg/100 nil. Of the 248 persons ~dentifled in this way, 228 were recruited through a screening program and 20 from a glaucoma study. The subjects are described as being borderline between norman and diabetic, and presumably had milder disease, on the average, than those included in the UGDP study. The latter had an average two-hour blood glucose level of 229 mg/lOU ml, but this was not necessarily strictly comparable to that obtained In the Bedford study since the glucose load and conditions of the test were not identical in the two studies. ` ` , , The subjects studied by Dr. Keen and his colleagues included 129 males and .119 femalea, so that the percentage of females was 48, considerably lower than the 71% in the .TJUDP study. The average age of the males was 55.4 and of the females 58.9 years. These ages, were higher by 1.3' and 6.8 years, respectively than those of the corresponding groups in the UGDP. All subjects entered the trial, effectively,, on one of two dates~ June 1, 1962 or Jan. 1, 1964, and all were studied at one center. ` ` ` , Half of the subjectS were treated' with~ tQi1n.~tamide, 0.5 gm twiee `daily, and the othev half with placebo tablets. Ii~'additi0~i, dne half of each of `these'groiI~s was recommended to limit carbohydrate intake to 120 gm daily and the other References at end of article. , , "~` " ~` , ~` , , PAGENO="0095" COMPETITIVE PROBLEMS IN THE DRUG INDUSTIfr 13345 half simply to reduce their intake ~f table sugar. The dose of tolbut~m1de W~s two thirds of that used by the UGDI~. The sfibjeets were allocated to the trea~t- metit groups by a method of randomization that was based on the use of ~ürn- bers read from a telephone book. here was no stratification according to risk factors prior to the randomization. At the time of entry to the trial, information was obtained on age, sex, wei~bt~ clinical history of arterial disease, blood pressure, and blood glucose level. ~ol- low-up examinations were conducted at Intervals of every six months except on three occasions when the interval was `one year. The cardiovascular coxt~po- nent of the follow-up examination included the administration of the I~ose questionnaire and the taking of an electrocardiogram. TwO types of outcome have been considered in the an~yses: (1) death, eit~ier from cardiivascular causes, as identified on the death certificate, or from all causes; or (2) cardiovascular events, which, in addition to death from car~Iio- vascular causes, include cardiac infarction, angina, worsening of the BOG, on- set of claudicatlon, and stroke. ~he trial was planned as a double-blind study, A list `of treatment assignments was a~cailabIe to the principal investigator dud was occ~siinally consulted by him when it was thought that the welfare of the patient required it. rrhe principal investigator is confident that the decoded in- formation was promptly forgotten by him and did not influence his assessment of the patient's outcome. The findings reported by Keen and Jarrett (6) on cardiovascular events at the end of the seven years of study are given in Table 2. The authors noted that in each treatment group, the frequency of ~ardio~as~ cular events was, as expected, higher in the subjects who were thought a priori to be at higher risk. They found no evidence of a treatment difference in the h~gh;ri~s1t, group but "In the low risk indlviduals~ the rate oi~ events in the tolbut- aniide-treated group is about half that in the placebo group, a difference sigr~ifl~ cant at the 2% level." (6) They further conclude, "a significant degree of jiri- mary protection against cardiovascular events can be conferred by tolbutam~de in mildly and moderately hyperglycemic people." Mortality data from the same study are presented in a report by Keen. (5) At the end of'eight. years from the beginning of the trial,' 25 deaths had been. observed in the placebo group and 24 in the tolbutamide grofip, 14 of the forther and 12 of the latter, being due to cardiovascular causes. Both total death rate and that from cardiovascular causes were at approximately the same level in the two treatment groups. The total death rate of 19.8% was approximately double that observed in the UGDP study. One important factor in this differetice is the relatively high ~rdportion of subjects over 70 yearC ofagO in the BedfOr~ study, as shown in Table 3 Another might be that in the Bedford study thOre was no selection based on the likelihood of a five-year survival, as was employed by the UGDP. The data of Table 3 show the higher mean age of the Bedford subjects as compared with those in the UGDP. The percent over 70 years of age is as high as 238 in the former and only 5.9 in the latter. Table 3 also provides an instance of a differefice in the distribution of ba~~- `line variables betweOn `the two treatment groups of the Bedford study. Of the placebo group, 29.8% are over 70 years of age as compared with 17.9% of the tolbutarnide group. The difference is statistically significant at the 5% level.. In section 6 of this report, an analysis will be given to take such differences in base-line variables into account. 4.2 Paasikivi (18) ` This Is a study of hypoglycemic treatment in 178 survivors from a first ~ cardial infarction. A further 92 patients who had been treated for an infarction during the same period were excluded fOr various reasons. The antthypoglycemic agent was tolbutamide, which was tested against a placebo.' Even or odd birth date determined whether the patient received placebo or tolbutamide. The maximal' dose of tolbutamide given ~vas I gm; this was alse the usual dose since it was given to nil' but 28% of the patients, who mos~Iy received 0.75 gm/day. The period of follow-up ranged froth 1 `to 5.5 ~ears, the average being 2.9 years foi~ the tolbni~amide groupand 3.0' years for the plaee~x~ grOup. ` ` ` ` ` ` Sixteen patients of 83 (19%) died in the control group, and t8nf 95' (14'~) died in the tolbutamide group. All deaths were considered to have-been due te H ` !`` ~ `~ References at end of article. PAGENO="0096" i8~46 QQ~ET~TI~ ~ ~ `1~ p1~3~ J~1~~Y ~r~t~e ~ ~ ~1~? th~~t ~2 ~o~a4~s, ~5 ~ço$~s ~ ~ t~j~J~e- trE~:tt~U ~ ~o t1a~t..ft~ ~e Iy~t~g~ 4i~i~e~t~ ~ i~ ,o~ l:oibth;~~i~4e ~ ~ 4xeap~~r~cj~1o ~e ~a ~Uo~1 ~e~t ~of to1bpt4~uj~e trç~~t ,o~ ~ ~r~v~1 ~ter 4J~ ~31m~ ~ ~j~ç~4e of a `first invocardiai infarction. Aftei~ five ye~u~, ~ ~~i'e ~ ~ ~i~nc~ ii~ ~s ~ ~ T~4s ~S~3dy i~i~er cqi4rp~s nor ~or~trac1i~1~t1ie ~Y~J? ~ ~Jae ut~j~oii ~up~er d~ç~i ~ .~t ofle cf ~a ~1ty~pn~et4ia~et ,~4 t~ ~p~t~pt~ J~i~ tq ~e~h~ç1 ~ ~çpo~ed tø a ~ti~ely e~m~U c~o~e fQr ~ Øioj~ter t~n~ ~]~i ~~l~ei in t~e TJGDP st~4y. 4.3 Feldman et al. (19) Ree~areh ~dbj~ts in this study were ~5O ~aiabul~tory pa~jent~ with flewly ~diseo~rered a~yrnptoi~ati'c diabetes, Who were between tl~e .~ges çf X5 ~d `years, :~ree of other' diseases, ~nd not taking dri~gs kp~Qwn to i~~uence carho- Jiydra~e niet~Olism adversely. `They were ~ariç1onily as~g~ied t~ tolb~tnmi4e (1 ~gm daily), phei~forpiin (100 mg "d~ily), or p1~tç~bo treatinei~t to test w~et1&er the orally glvun thiigs'were ~ffect1ve'1n pi-evé~t~ng or po~t~~il4g overt 4iai~etes Inthese s~s~eçts. ~hu study began in Deçern~er 1064, ~ the ~p~b~Juh~d ~tta eover the `fi~t ~ of ob~er~ation. ~ average a~e ~t ~ was `44~4 years and therei~avebeen only `t~o `deaths. Conse~uent~y, `t~e~ ~ ~e insi~- cient as yet to throw light o~i ~e re]atiye ~ort~i~y rates ~assoct*te4 with the 4iffei~~nt treatments. ~ (MO) A~prospee~e~st1~y Of b37 p ientswith~prernature c~roiiary'~a~'tery: disOase was `begnu in1~65to~e~alua*e~theiuduence ~f~henforrnin `(~50 to 10O~g daily) on mortality 4rom eardlovaseular disease. In a snbgroup of 104 patiei~ts, ran- d~inized with ~spe~t to' ~henform1n `treatment, or to diet alone, nine deaths ~ecnrre~ 8g~50~ e~tvobpat4eirts `and~slx deat7hs~ * *4* to~kave~di~betes were excluded In this study, as were obese individuals, so that the ~eneralizatton eftheseresnlts to~maturlty-onset diabetics is~ du t~us.'(Itdst~Is~ hiiipattant~to ia~te that there were only ~b9ut~50papien~ts in eaoh~ group4n ~th1s4 study. ~be sinalldi4!t~erenees in the si~or1*lity rates for dttfereflt ` eat1n~1~t~ ~b rgdd~iJ~y ~the UGDP ~heu~there were about ~00 mdi- vklualslu iea~ih Atrer~tmeat4~graup could ~not be `deteeted *lthLthi~h probabilthy wben~grou~ dfL~0dduals4areAstn~dldd. ~.5 ~n~irp~y ~ ~v4~v~g ~as ,a ~b~~1e he~e~pe ç~f jibe. cont~$led eU~b~al trials of. orAl ~ thatc the unly' ~eiortality de4a that are. ~xieu- ~sivef~l~i17fpr onripnppo~r 4arethese ~om the UUDP ~stndy:~and those from the Eedford trial. Th~e ~ .1~n e~t~~4t the~t~IDP trial. ~The~ii~~al ~ ~4~t~in, ~44Z) b~çr~ ~) S~~- er, (~3)~~ud ~ 1~i ç~4iç~i, ~ rials and ç~i entgri~,~j~qut ~. U(~J~? ~4riAi4 ~id~ t~ey tue 4~e~le4 ~p4~4y~ çui these ~eponts ~or~sQu 1. ,~ ~ave~p $~d ~ie~ ~i1p&i~t~ç~n of two rejOIn~ders. The fir~t was by Cornfield, (~) ~my~io ~~Ø.~se4 ii~n~alf to refuting the criticisms of Schor and also some crIticisms that ,had t~ppeared in the report by Feinstein. The scond rejoinder article by Proi~it ct al (~95) was spe~i~ea~1ly ~*e~to~ ee~i4er ~ Selt~er~s communica- tion. ` ~a~iy ci the 4ci~ms~t~a~e ~made 4jn ~these ~artic1es would ~apply, ~some- times even more stroi~gly, 4~o~ be ed4~emmd~ stUdy~but~itiw~s the~ ~ trial~that ~ t~C~ie~d~iCS4 efl~iI~gs1Qb4~4s) la~tor~triaJ rso oonj~ter to ~ kbe~ efnlAess sa~etyf$amni~1e, iu1tis~wp- pie te~4b~4~th ~c1a~si~nau ~c1u ~i~e ~nethod~ ~at ~e&t0~th~lt, ~1mau4&be eef~*i~, si14~ii~ed, ` ~ p~S~d~ft~mns; a re~v1ew of both trials by members of the committee will be included in~tmL*~e- 4uent s~t1~ps.; ` ` ` ` ` ` ` References at end of article. PAGENO="0097" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY~ 13347 5.1 Main issue in criticisms of the UODF trial The primary issue' of cont~ern In the published criticism of the UGDI~ is whether or not the evidence pointing to toxicity of the oral agents is v~1id. Thus, in Seltzer's discussiom of the design. of the trial, (23) all of the nine points he raised bear on this question to an important degree. In the fol1o~ing account, most attention is therefore given to the UGDP mortality findings, but in addition, reference Is made to the selection of patbmts, the dosage ~che4ule adopted, and the decisiOn to discontinue the use of tolbutamide and phenfor~nin in the UGDP study. 5.2 selection of patients The first point raised by Seltzer, and also discussed by others, concerns the selection of patients. Crjftclsm of the criteria used embraces the recruitment of subjects known to have concurrent disease (including cardiac disease), the inclusion of some who did not have diabetes, the exclusion of those judged (on somewhat vague criteria) to have a life expectancy of less than five years, and the inevitable arbitrary exclusion of those who proved uncooperative. The determination of criteria for admission to the study depended on ethical as well as many practical cotisiderations, and was inevitably, to some extent, arbitrary. It is almost never practicable, and rarely desirable, to make trE~at- nient comparisons in a strictly random sample from some defined populatio~l of subjects. To be useful for clinical purposes, however, the' study patients sbo1~lld be so well described as to be identifiable by the cllntcian and should also. be among those for whom the competing tJ~erapies are used or considered. The choice of specific selection criteria adopted by the UGDI? was a respor~si- bility that was shared with zaedical experts and is not a topic on which this. comniittee as a whole claims primary competence. It is important to recognize,. however, that criticism of the choices made is largely irrelevant, to the prim~ry issue raised by the critics. ~or example, the concern about possible tolbutamide toxicity would not really be lessened If it could be shown that the study g~oiip, contained some nondiabetics. A drug found toxic in such subjects would r~ot likely be counted safe for persons with well-documented mild .diabetes either. The criteria for inclusion or exclusion do influence the efficiency ~f the study, and the extent to which its findings can be generalized, but have littlä beari42g on the issue of toxicity. We turn to criticisms that are more important in tl~s regard. , 5.3 The T]GDP mortality findings The implication of the UGDP mortallt~ ±esults is that the oral hypoglycemi~s are responsible for an increase in cardiovascular mortality, but that they ~o not affect mortality from other causes; Several kinds of criticiSms have been raised about this interpretation, of which we conSider' the following to be t1~te niost important. a. Although the total death rate' was higher in the tolbutamide group than ~n those receiving placebo, the difference was not significant. Correspondingly, the death rate from noncardiovaseular causes was higher in the placebo group than in the tolbutamide group. As O'Sullivan et al (24) have commented, "Interpret~- tion of a study showing no increased risk of * * * If there were subtle cues that could lead to somewhat different recording of signs and symptoms for different groups, it is conceivable that deaths of u4- certain cause might be more likely to be assigned to a cardiovascular cause in tl~e tolbutamide and phenformin groups than In the others. It will be appr~- elated that the review panel nsed in the UGDP study had no independent aCcess to primary "objective" data, but depended on data already Structured `and tç~ some extent interpreted by the clinic physician. Under these circumstances it is not too surprising that in only 2 of 89 cases was there a major disagreement between the panel and the clinic physician. The use of a review panel was an indispensable choice, especially for monitoring possible differences in procedure among clinics. However, its independent contribution to the actual assignment of cause of death should not be, thought of as large. The Uç~P took unusuall~# strong measures to minimize the possibility of bia~d evaluatlop and took care to use well-defined end point~. in arrl~ing at ,a diagnosis of cause of death. Nonetheless, the possibility of this sort of biased recording cannot be ~~ule4 out completely. ` References at end of article. 50-592-75--------7 PAGENO="0098" 13348 COMPETITIVE PhOBLEMS IN ~I'HE DEUG INDUSTRY Our view of this criticism of the UGDP findings is that it has some weight (although we do not interpret it as a criticism of the action of the UGDP) and that the to~dc effect of the oral h~çrpog1ycenilc's cannot be affirmed with the ceF~ tainty that would' be present if total mortality were significantly' different. b. The excess mortality appears clearly In only a few of the clinics. This might suggest a peculiarity or defect connected with the study methods em- ployed there, and this~ would have to be understood before any reasonable inter- pretation of drug effects could be made, We have considered the question of whether the differences in results between clinics are such as to cast doubt on the meaning of the IJGDP findings. We recognize that a clinic in a middle class suburban area is likely to have patients different in many ways from those of an Inner city environment, so the fact that clinics diffet is in itself not at all surprising. It would at least call for an exp]i~nation, nonetheless, if a toxic effect were clearly dis~ernible in one set of clinics and a contrary effect in others. We present data in sectIon 6 (Table A.3) that beàrC on this point. Looking at the failure rates for females and comparing placebo with tôlbutainide groups, we note that there were seven clinics In' which there was at least one cardiovascular least in one group or the other. The patients receiving tOlbutaniide bad the higher rate in six of these. In the `case of males, the tolbutamide rate wa~ the higher in five of seven inst&nce~. We conclude that the excess mortality is not in fact confined to a few clinics and that this * * * As mentioned previously, the study of Paasiklvi gave findings that cannot be appropriately transferred to the UGDP population ifi view of the differences in dosage of tolbutamide, duration of study, and population at risk. The study of Keen and his colleagues, however, `deals with a j~opulation of borderline diabetics somewhat comparable to the UGDP group except that they were mostly ascertained by screening. Since the investigation is still under way, we can consider only the findings currently' available. Keen (5) ,found that the death rates for all causes and, for cardiovascular causes were essentially the same in the tolbutamide' and placebo groups, but that the* various pathologic~il outcomes that he designated collectively as cardiovascular events were signifi- cantly less common among low risk subjects receiving tolbutamide than among comparable subjects receiving placebo. The resources available In the Bedford study did not permit as thorough an investigation as was possible in the TJGDP. The randomization of patients was carried out without the detailed attention to documentation that a major trial demands. There was restricted coverage of background variables, and all the usual safeguards for the maintenance of "blindness" could not be ensured. Finally, as the work is unfinished, a definitive analysis has still to be produced. The provisional data that Dr. Keen has kindly sent us are reviewed in section 6 and do not throw doubt on the UGDP findings, in regard to deaths from cardio- vascular causes. We have regarded the data on deaths as more relevant for comparison with the UGDP and also more clearly defined than the data on cardiovascular events. d. A fourth criticism that has figured prominently in the literature is that the randomization did not succeed in allocating to the treatment groups patients who were comparable with respect to base-line risk factors. Since we have had access to the original data, we have been able to carry out an anlysis that was designed to test whether in fact the differences in mortality in the tolbutamide and placebo groups could be explained by the base-line differences. Our findings. which are given in section 6, take into account the differences between centers and the differences in length of treatment, as well as the base-line variables. They support the view of Cornfield (17) that there is no evidence that the base- line differences arising from the randomization contributed in any importanj~ way to the finding of adverse effects from tolbutamide. 5.4 FaiZure to adapt dosage of dr~gé to i~uUDkZnal t'teed Feinstein (21) has noted that the oral drugs "were given in unsatisfactory dosage to many people who did not need them," and others have made a similar criticism. It Is true that the use of a fixed dose of drug, which was also the ap- proach adopted by Feldman et al (19) mId I~een et al,(C) limits the generaliza- tion that can be made about therapeutic effects, but since the dose of tolbutanilde is about equal to the aIrerage recommended for therapeutic use, an evaluation References at end of article. PAGENO="0099" COMPETITIVE PROBLEMS IN TI~E DRUG INDUSTRY 13349 of its possible toxic effect is highly relevant. Moreover, the prOblem of whe~ber a $u~ject with mild diabetes who would not normally take any hy~oglycE~inic drugs can avoiA some vascular compUcattons. pf the disea~e by doir~gso is one that the trial was deslgueçj tQ iflum1~ate o~r sQive. We do not already. have the answer, to this; what is understood well is that certain patients. re~ujre h~po- gly~emic drugs for current needs. ~t is another question as to ~hetber these patients, and those, with milder disease, can produce a . prophylactic e1~ect against vascular abnormalities by taking .hypoglycemjcs In an attempt to m4iu- tam strict control of thejr disease. ThIs is a matter for research and not for the simple implementation of current therapeutic practice.. 5.5 Disoontinncftion of tolbi~ttamid~ a4id phenformi,n in the TIGDP StlAdy The action of the UGDP in `discontinuing the use of tolbutamide and p'hen~or- mlii has been criticized by those who beUeve that the trial of these treatm~its should have been continued in order to obtain more definitive results. It wo~i1d have been easier to interpret the findings if there were more data on mortality. We recognize that the pr~cise point at which suspicion of to~ictty outweighs the need for scientific Information is uncertain and that the choice might have been made differently by another equally qualified group of observers. Altbot~gh we are not in a position to défen4 the timing of the UGDP decision in this matter, it is clear that ethics would dictate that a decision abOut witbdra~ra'l had to be made before all important questions concerning the effect of the drug were resolved. We do not criticize the UGDP investigators for having made the decision when they did. Nevertheless, the result of that decision is to leave us with some residual uncertainty about the meaning of the findings, a point that is well understood by the UGOP investigators themselves. 6. DATA rno~ TITE UGDP AND nEDFORD ThIALs The directors of the tTGDP and Bedford trials have klndl3t' made available certain data that we requested from them In order to review evidence concer~- big the death rate of subjects taking part in contrOlled trials of oral bypogl~- cemic agents. In the case of the IJGDP, the data of interest extehded to the time at which the drug was discontinued. Events subsequent to that would cast light on the effects, If any, of previous use of the drugs~-a question to whb~h we do not propose to address ourselves. tn the case of the Bedford trial, data are still being accumulated, and we have examined those available `up to June 1972. These must, of course, be regarded as provisional. In both trials the data bear on many questions of great interest that we did not consider since they had limited relevance, if any, to our charge. A simple method of studying data from a long-term clinical trial is to estimaI~e failure rates for various population groups. Failure may be taken to be an~~ adverse event; commonly, as in the present context, it is interpreted as deat]~. The failure rate for a group after a certain length of follow-up is .the rate at which the survivors are then dying. If the failure rate for a group is constant throughout follow-up (so-called exponential survival), its value, Y, may be estimated by Y=lc/t, where k Is the number of deaths in the group and t, tb~ number of persons-periods at risk, each subject contributing a survival perioc~ or, if death has not occurred, a period of observation. Approximately, log Y may be regarded as normally distributed with a mear~ of mY and a variance of 1/k. S The failure rate takes into account the length of time for which each subject has been exposed to risk and can be made specific both for demographic char~ acteristics of the subjects and for risk factors of interest. In the present context we have chosen a three-month period as an appropriate unit of time in ~alculat- ing exposure to risk. Simple and informative as the faIlure rates are in many cases, they become unwieldy and increasi~giy variable as subjects are cross-classified j~ more and more ways. We have therefore made use of the logistic model in order to carry out a more detailed analysis of the UGDP and the Bedford data.. 6.1 tTGDP data S S In thIs section, we consider a problem relating to randomization and we pre- sent our analyses based on failure rates and on the multiple logistk~ model, We also report analyses designed to take into account the extent of adherence to treatment. . S PAGENO="0100" 13350 COMPETITIVE PROBLEMS IN ~HE ~D:RtjG INDTJSTRY 6.1.1 11ando.mi7.~ationby ser ij.,ithin clinics In con~parIng i~iortality in the treatment groups' In relation to background variabie~s, the ~J.~GD1? investigators presented data that showed `that the excess ot cardiovascular deaths `in the tolbutamide group was. particutarly marked among the females. The' mortality was 1O.6% in `the tolbutamide group as against 2.1% In the placebo group; the corresponding `rates for ma1e~ were 17.5% and 11.1% respectively. In `the course of reviewii'ig this finding in the individual clitiics we discovered a puzzling' anomaly concerning the distribution of the two sexes to the fQur treatment grofips within clinics~ Table A.1 shows the numbers of patients of each sex allocated to each treat- ment gronp within each clinic. The proportion of males all cated to placebo was surprisingly high in Boston and in, Seattle. The discrep~'~ncy in Seattle alone wOuld ~~resent an unusual event in random allocation X2~=1i.31 on `1 df; P -.001) "and the results taken as a whole are also anomalous (X~=33.33 on 12 df; P-.001). These unexpected findings do not in themselves explain the cardiovascular mortality diffd~ences. In an analysis discussed later in this section, adjustments are made for sex and clinic as welt as other covariables, and there is no sub- stantial change in the apparent effect of toIbutamide treatment on cardiovascular mortality. A more important point is whether thOse findings provide evidence of a breakdown of the randomization procedure-a contingency that might have grave implicatiolls for the credibility of the whole study. The randomisation procedure used by the UGOP has already been described briefly in sectIon 3.1.2. In an. attempt to find an explanation for the peculiar allocation by sex within clinics, the committee reviewed the randomization in detail. We were given access to the log books in which th~ `Coordinating Center maintained records of the allocation of each patient to a treatment group and were impressed by the quality of the documentation that the investigators provided. We were not able to find an assignable cause for the surprising allo- cation of the sexes to treatments but have no reason to think that the stud~r has been compromised by a b]eakdown ih the randomization of patients to the treatment groups. Because of the imbalance of sexes in the * * * however, allow- ance for tbi~ has been made in our analysis. In institutions such as Seattle, in which no cardiovascular deaths occurred in either the placebo or tolbutamide groups, there would, of course, be no effect due to the imbalance. In general, however, aU analyses of the data should be adjusted simultaneously for sex and clinic. 6.1.2 Cardiovascular failure rates Cardiovascular, failure rates in the TJGDP study are presented in T~hles A.2 through A.4. The rate for the tolbutamide group is 5.471,000,' quarter-yearS (Table A.2, top) and this is significantly higher than the rate for the placebo group. In the next two parts of Table A.2 the rates for the' treatment groups are presented separately for the two sexes, and the differential bCtween the placebo and tolbutamide groups is substantial and significant for females (4.4 vs 0.8) hut less marked and nonsignificant for males (7.5 vs 5.0). The number of subjects at risk is smaller for the males than fOr the females, and the chance of detecting treatment differences is therefore greater for the latter group. The results are consistent with the view that the tolbutamide rate is higher for both sexes, but if the males were considered in isolation, the evidence in their case would not be strong. ~urther, it is the older women who in ,patticular show substai%t~ally different rates ~or the two treatment groups. Athong women ov~er 53 years of `age receiving . tolbutamide, the rate is 8.6~% and for those re- ceiviiig placOJo, 1.4%' For younger women the' corresponding `rates are 0.6% and 0.5%. In Table, A.3 the failure rates are presented by sex ~thd treatment group at each clinic. these are the data that have already been referred to in section 5.3 `to make the, point that excess mortality in the tolbutanhide group was `not conflende to a feW `clinics. In the case of the females it was observed at the clinics in Boston, Minneapolis, Williamson, Cincinnati, Cleveland, and Birming- ham. Of the remaining six dines, four bad leSs than 200 quarter-years of pa- tent eyposnre and showed. no deaths from' ,ca~d1ovascUlar causes in either treat- ment gron~ ~ñ the part of th~ table showing data, for both. sexe~ combined ft .i~ sqe~a ~that in seven clini~ the failure rate in the tplbutamide group. was huigher `and in t*o It was lowei~ than `in the placebo group and that in three there was no information. PAGENO="0101" .OOMPE~ITIVE~ ~RO~L1~MS IN ~ ~H1~ PRIJG INDV~T~1T l3aM 0.1.3 1kf~Ztipie Zbg~$tic moZeZ ` . We have ü~ed the sair~e model as was employed by the UGDP Investigators, in which th~ probability of death Was expressed as ~t function of the treatn~ent' and of the. base-line variable$. We have, however, added additional variab1~s, 1 to take account of the time between enrollment of the subject and completion of the study, and 11 to account for the inflaence of the clifltes. The' lengthy list of variables that was assembled in this way is shown in Table A.5.A b~ief account of the method of analysis based on the multiple logistic model is given in appendix A. (26). The analysis leads to the findings reported in Table A,6.1. As shown in the upper portion of Table A.6.1, the potential length of follow- up, that is, the length of time from admission to the study to the time of a~ial- ysis, proved, as one would expect, to b~ a highly significant predictor ol! cardio- vascular death, the valt~e' of X2 on 1 df being 23.56. This variable was not in- cluded in the analyses done by UGt~P. Many of the demographic i~arlables and risk factors studied by the UGDP were also highly significant predictors of par- diovaseular death. After adjusting for the UGDP variables, treatments, ~nd potential length' of follow-up in the analysis, no additional significant improve- ment was made by adding the clinic effects; ho~ver, the UGDP base-line variables as a group still remained highly significant. It is worthy of note that the clinic effects remained significant after adjustment `had been' made for demographic variables and treatment. It was the `additional a~jUstiflent by means of the variable length of follow-up' that reduced the clinic effects t~p a nonsignificant level. Although the finding of clinic differences would not be ~ur- prising, since they might be due' to differences in the patient' populations or clinical practice, this indicates that most of the dif~erei~ees are ~expTained by adjuattig for the different length of follow-up~ The most Important point in this analysis is whether or not the adjustments for cOvariables could be responsible for the treatment differences observed. Qur analysis indicates that the treatment effects ba~re been changed very little by this adjustment. Tolbutamide treatment vs an `average' of other treatme~its, ~dju~ted for a subset of the demographic variables and time of potentie" foll&w- up, showed a X2 of 12.14 on 1 df. In comparing the tolbutamide treatment with the other treatments, it is apparent that this contrast accounts for almost `the entire treatment Offect, and thus there is no significant `difference bet~ceen `the insulin treatments and placebo. When the data are presented separately for males and' female In the next two parts of Table A.6.1, the comparison' of tolbutamide with the remaining' treatments results in a 12 of 2.56 on I df ifi the case of males and 9.06 itt 1 df in the ease of females. The effect of tolbutamide may further b~ c~mpared' with the placebo treat'thOnt alotte in such a way `that the ,ixmnlin grcmps u'lso supply information on the demographic variables.' Under these circwm~tanees, the 12 that tests for `thO adjusted effect of the tolbutamide treatment te `O~5 for fliales and 11.70 for females. These result'S indicate that the effect of'tolbiif,amide treat- ment is signifieayit in fethales but not in. mflles. ` Table A.6.3 shows that the coefficient `foi~ the tolbutainide 1~reafment' eft~et is 2.1158 in females and 0.35~8 in males, and that the standard errors are 0.7094 and 0.4983; respectively. This implies, as noted before, `that the effect is significant' only in females. The effeCt in females, however, is `hot significantly different from that in males. `The analysis by meafis of the multiple logistic modOl `confirms the princijal finding' from the simpler study of failure' rates, namely, that the cardiovascular death' rate `Was higher in certain patienth receiving tOlbutamide thafi in~ `th~se receiving placebo. This result was definite in the case of femai~s; it "they wOll be true also of males, but the" evidence iii that group is not st~tistically algntfi cant. The multiple logistic analysis indicates that the difference `in death `rates' remains after adjustment has been made for the effect of vario'i~ base-li~ie variables and cardiovascular risk factors. ` 6.1.4 AnaZysfs'with respect to adherence to essiyned frcatrnent ,` ,` The UGDP' pi~otocol sp~ëified fl±ad doses for the pacebi, `tôlbutafni'de and `in- sulin standard treatthents. AltOrntions' were permltted'only if `the patiebt Oeoi~ld itot be safely niainl~aifled On the assigned"medicatiOn ~chedule,"~ ~1odification of the dosage on th~'basis of elevated lbood glucose 1evel~ alone' was not permitt~d. Adjustments of `the `dose `for the `patients taking variable-dOse ittsulin,~bowev~r, fleferences at end of article. PAGENO="0102" J.3352 COMPEITITIVE PI~OflLEMS IN THE DRUG INDUSTET ~eould be made on the basis of the observed blood glucose ievel~ from the short~ times `of the glucose tolerance test. Since some patients did not adhere corn- :pletely to the assigned treatment, they may have gone for periods of time without any medication or with a modified. dose, or they may have switched to `another therapy. It is clear that the interpretation of the UGDP data could be Influenced by such variation in the assigned treatment. The UGDP analysis and the analysis discussed In the preceding part of this report are based on the assigned treat- ments. In this section * * * Caution must be taken, however, in the interpretation of these results. It Is quite possible that adherence is related to bnportnt base-line or other unknown variables for some treatment groups and not for others. If such were the case~ subgroups having a. particular pattern of adherence rnigbt not yield fair compari- sons of treatment. The analyses presented In this section are designed to ac- count for. the known base-line influences. owever, without the use of random- ization to form treatment groups, there is no assurance that an unknown prog~ nostic variable is present that affects adherence patterns selectively for differ- ent treatment groups and thus invalidatOs the treatment comparisons. 6.14.1 The ea~tent of the problem Table 4 summarizes the number of patients who continued taking their assigned treatment for the entire follow-up period, and the number who, for at least one quarter, changed to other treatments or none. rlhus, for the 205 pa- tients initially assigned to the placebo group, 76 (37%) continued receivi~g placebo for the entire period of follow-up, and the remainder, had at least one quarter of nonassigned treatment as follows: 1 (0.5%) received tolbutamide; 7 (3%), insulin at a variable dose; 92 (45%), no treatment; 4 (2%), tolbut- amide and no treatment; and 24 (12%), insulin and no treatment. (One pa- tient did not fit any of these categories.) An int.eresting point is that 168 (82%) of the patients initially assigned placebo were receiving either the pla- cebo or no medication for the entire study. Since the initial treatment . groups were assigned to their treatment by chance, these patients could be regarded as representative of the UGDP patient population. Tbu~, over the average fol- low-np time of 6.15 years, a very large proportion of the patients could be maintained without medication. Another consideration in evaluating the extent of the problem of adherence is the proportion of follow~up time Individuals continued receivii~g their initial therapy exactly as prescribed in the protocol, Table 5 classifies the patients by the proportion of their total follow-up time spent receiving treatment initially assigned. In `order to compare the extent of adherence of receiving standard- dose insulin with the adherence of other patients treated with, insulin, a dose modification of variable-dose insulin after the initial titratiop dose was regard- ed as a "modification." Note that 26% (218/828) of the entire population were 100% adherers for the total follow-up period and some 23% of the patients were receiving the initial treatment less than 50% Qf the total follow-up time. Table 6 summarizes the total follow-up time (patient-years) with treatment exactly as assigned. with the assigned treatment at a mo4ifled dose, and with other treatments. Note that for each of the treatmetn groups, 14% to 16% of the follow-up time was spent receiving no medication at alL Fprther, the proportion `of foliow~~up time that patients spent receiving the fixed `dose of tel- butainide was 58% and receiving the fixed dose of insulIn, 55%, It is interesting that for 25% of the follow~.up period, the tolbutamide patients were taking a dose other than that specified by the protocol; similarly, for 30% of the follow-up period, the standard-dose insulin group was taking an altered dose of insulin. 6.1.4.2 ~tatistieat analysia The `statistical analysis of the TJGDP data in relation to adherence to treat- ment is divided into two portions. The first pari uses a lionstandard method that was developed for the ptoblem at hand and will be called the rek~tive allocation method. It takes lute cOnsideration (1) time spent receiving no medlcati~n, (2) time spent receiving ~nodlfled doses of the initially assigned therapy, and (3) time receiving other than the initialb~ assigned' medication. The second. method of analyss is called the Rnrljival `ntode7~in~j method and is based on techniques recently developed by Cox (27) for modeling survival data when base-line References at end of article. PAGENO="0103" COMPEPITIVE PROBLEMS IN THE DRUG INDUSTRY ~133~3 (concomitant) variables that affect the outcome ar~ present. Both ana~yses led to the conclusion that women receiving tolbutamide ilaire higher total inor- tality and higher cardiovascular mortallty than women receiving placebo. This holds especially for the older women (over ~3 years of age). Relative allocation method-The basic idea of this method is explained in appendix B. The problem is to allocate the number of patients, and the de~tbs, to the treatments when individuals have not been receiving the initially assign- ed treatment for the full follow-up time. The method of relative alloc4tion a ssigns numbers of both patients and deaths to the treatments in such a way that they are proportional to the length of time the patients have been taking each treatment. Suppose a subject has been in the study for ten years, ba~f of them with the initially assigned treatment and half with no treatment. This subject would contribute half an observation to each of these categories. If the subject had died, half a des th would be allocated to each of the two categories. The sum of these allocations defines an effective sample size, n', and an effe~tive number of deaths, d'. We then define as follows: death rate =0' =d'/n' If time of follow-up is allocated in a similar way to the various treatm~nts, and T is the total follow-up time for a subgroup, then failure rate Y' = d'/T Appendix Table A7d presents data on total deaths (d'), cardiovascUlar deaths (d") and effective sample size (n') by initially assigned treatment ~nd by treatment received; and in Table £7.2, the calculation of 0' and of ~` is illustrated. Table A.7.2 summarizes the death rates and failure rates corresponding to assigned treatment without modification, treatment modified by change of dose, and no treatment. The cardiovascular mortality associated with tolbutau~ide is highest among the four assigned treatments, regardlcss of whether the tr~at- meuts are pursued with modification ~r without. A comparison of the ca$io- vascular mortality in the tolbutamide vs the placebo groups results in ~tatist~cal significance at P~~015 (no treatment modification), P = .00 (doses chang~d), and P=~.50 (no drug) ; using the Fisher test for combining tests of significatice, one finds that the overall result is significant at the P=.007 level. Since there appeared to be a randomization anomaly with regard to the allo- cation of treatments with respect to sex, it is of interest to examine the eff~cts of dose modification for each sex. Table A.7.3 summarizes the cardiovasci~lar mortality by sex and dose modification. It is clear that the largest difference in cardiovascular mortality between the placebo and the tolbutamide groups occurs in the female group not having any dose modification (P=.004). A simi~le, overall statistical analysis can be carried out on the mortality rates given In Table £7.3 by ranking then for each of the six dose-modification groups (ro~Vs) and assigning to treatments within a group the ranks 1 through 4. Since those receiving tolbutamlde have the higb~st mortality in five groups and the next highest in one group, this group has a rank sum of 5(4)±3=23; the rank sums for the other treatments are as follows: placebo, l~; standarçl-dose insulin, ~2; and variable-dose insulin, 13. The probability of obtaining a rank sum eqpal to or higher than ~3 if there were no difference between the treatments is P~.O07. (This probability is the ratio ~f the number pf ways of obtai~ipg a rank sum equal to or greater than 2~ to the total number of posslbhhitie~, ie, 28(6(6) )/ (24) (6)). If one were to make a tWo~tailed statistical test, the P value woUld be multiplied by 2; je, P~.O14. Another way to analyze the effect of adherence is to partition the data 4c- cording to both (a) dose modification and (b) whether the patients adhered to the initially assigned drug for the complete follow-up period. Table A.7.4 sum- marizes the cardiovascular death rates according to these twO variables. The highest death rate is found In tb~ tolbutamide group who were 100% adherers, and had no dose modification. The comparison of placebo vs tolbutamide for this subgroup is significant at the P=.O03 level. The comparison of placebo vs t~l- butamide in the ease of the other three subgroups is not significant. The cardio- vascular death rate for the three tobbutamMe s~bgr~ups ~ho either did not adhere completely to the medication or bad a dose modification is 7.6/9$.9=,08. A comparison of this proportion with that for the subgroup that adhered CoUl- pletely and had no dose modification (21) gave signjficance at the P=.04~2 References at end of article. PAGENO="0104" 13354 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY level. This is in line with the view that if tolbutamide do~s indeed Increase the risk of Cardiovascular death, taking less of it should lower the death rate. It thus appears that a significant number of the cardiovascular deaths In the tolbutamide group are associated with patients who took the drug for every quarter of the follow-up period without any dose alteration. An attempt has been made to examine this further by subdividing the groups involved. Table A.7.5 presents data separately for males and females. Note that the relative allo- cation of cardiovascular deaths to the female placebo group totals 2.5, (The total number of cardiovascular deaths among females was 3, of which the rela- tive allocation method assigned 1.2 to no drug treatment and 0.4 to insulin.) A comparison of placebo vs tolbutamide in the group of females who had 100% adherence and no modification of dose results in significance at the P-.01 level. None of the other comparisons of placebo vs tolbutamide are significant at P-.05. The data cannot be meaningfully partitioned if all four treatment groups are kept separate. One way to make a finer subdivision of the covariables is to compare tolbutamide with a composite of the other three treatments. Table A.7.6 summarizes the cardiovascular deat~i rates with respect to both sex and age at entry, using the cut-off age of 53 years (53 years represents the median age at entry). From this table, it is clear that there are too few cardiovascular deaths in the younger women to justify any comparison of tolbutamide with the control treatments. However, this comparison in the older women who adhered 100% and did not modify the dose is significant at the P=.03 level. There are too few patients in the male subgroups to be able to detect real differences by making simple comparisons, although in five of the six instances the talbut- amide group has the higher rate. SurvivaZ modeling method-The analysis in the preceding section was car- ried out by simple partitions and comparisons of the treatment groups. To take account of the effect of institutions, demographic variables, and base-line van- a1~les, however, more sophisticated statistical methods are required. In this Section the UGDP data are analysed by means of a statistical technique recently developed by Cox (21) and modified. (28) The method relates failure rates to both the treatments under study and concomitant variables (institutions, base- line variables, and demographic variables). The method, as used in this analysis, took into account the proportion of time each patient was receiving the assigned medication, the time of treatment with other protocol medications, and the time during which no medication was used. (See appendix C for details.) A preliminary analysis was carried out for both total and cardiovascular deaths by means of the following con- comitant variables to determine which were important: 4 treatments, 1 variable representing no treatment, the 14 UGDP base-line variables, sum of the initial glucose tolerance tests, 4 variables aSsociated with interaction between treat- merits (including no treatment), and 12 institutions. The results of the analysis shoived that a mbdel could be used that included, in addition to the treatments, 7 base-line variables (sex, race, age, digitalis history, electrocardiographic ab- normality, presence of irrterial calcification, sum of the glucose tolerance tests), arid the :F2 Institutions. A final analysis was then done with the usc~ of a model incorporating these variables. It was done Independently for males and females to allow for dIfferential treatment responses, and was carried out separately for total deaths and cardiorascular deaths. The final results of the analysIs can be expressed as a ratio ut adjusted failure rates of different treatments. The term adjusted refers to the failure rates after allowing for the effects of the concomitant variables. The data can be summarized by presenting the natural logarithm of the ratio of failure rates and its associated standard deviation. Table A.7,7 exhibitS these quantities, comparing each treatment ~vith the placebo. Also given is a compjirison of placebo vs no medication. The conclusion is that for women lii the. tolbutamide group, as compared with placebo, there is an e~eessive mortality, both cardiovascular and total deaths. The difference is more dramatic (P~.008 for the cardiovascular deaths, although it is also significant for total deaths among women (P~.04). Thus. this analysis supports the conclusions reached in the previous section that tolbutanuide, as used in this study; produces an excess mortality of cardiovascu- lar causes in women, when compared against placebo. The data do not support the same conclusions for men, but one possible reason is that the smaller number of patients in the male group results in lack of sensitivity to detect differences of moderate magnitude. References at end of article. . . PAGENO="0105" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13355~ 6.2 The Bedford trial The data supplied information on both cardiovascular events and mortality. 6.2.1 Oardiovascular events In the analysis of the data from th~ Bedford study the authors devote ma~ór attention to "cardiovascular eventa." These have been described by Keen ~nd Jarrett (6) as "a mixed bag" and Indeed do raise problems of classification~ in that the events are not mutually e~i1~t~Ive and are ascertained partly by q~es- tionnaire, partly by electrocardiographic evidence, and partly from mortality data. They include reported episodes of angina and intermittent claudication, and this could cause ambiguity, since reports of pain may be greatly infiuen~ed by variations In the mood of the subject and in the style of inquiry. In view of the lack of a formal procedure to ensure blind evaluation, the results of si~ich analyses do not lead to firm conclusions. 6.2.2 Mortality data These will be examined by two methods: the estimation of failure rates a~id death rates, and the use of the multiple logistic model. 6.2.2.1 Failure rates and death rates These two rates differ only in their denominator, which is person-periods in the first case and persons in the second. The numerator in each instance is t~ie number of deaths. The two rates are highly correlated for this set of data, since there was little variation in the length of exposure to risk. In Table A.8.1 the influence of. binary background variables on the death r~te is shown. The rate is increased by hypertension, hyperglycemia, and arter~al disease. It is higher for females than fQr males and higher for those over 45 years of age than for younger patients. In Table A.8.2, placebo and tolbutamide treatments are compared, taking into account the background variables one or two at a time. In no case is the~e adequate evidence of a difference between the two treatments. In Table A.8.3, the death rates (by treatment group and sex) are given fpr more finely divided age groups. The reason for this is that as shown in Table 3, the proportion of older subjects is higher in the placebo groups, and age is~ therefore a potentially confounding variable in the comparison of treatmeht effects. Owing to the relativ.~1y small numbers of subjects in the individual age groups, the rates are somewhat irregular. The effect of age is marked, but the~e is no evidence of a difference between the treatment groups. 6.2.2.2 Multiple logistic model In this trial, all the patients were entered Into the study at essentially two different points in time and not over a period of time, as in the UGDP. rllhis feature enables some simplification of the analysis of the data. To adjust for the differences in the length of follow-up~ and possibly for other differences as well, between those who entered at the two different times, an indicator variable was included in the logistic analysis to distinguish the two groups of subjects. The variables included in the logistic analysis of these data are given in Table A.9.1. The results of the analyss Of the fledford study deaths due to cardiovascular causes and deaths due to all causes are shown in Table A.9.2. The variances introduced in this analysis were significant in predicting death either from all causes (X2'=81.02 on 5 df) or from cardiovascular causes (X2 = 55,16 on 5 df). Adjusting for these variables, however, did not change the basic conclusio~i reached from the unadjusted analysis that the death rates did not differ sig- nificantly according to treatment. 7. CONCLUsIONS In this section we summarize our overall findings of the TJGDP study with respect to the protocol, ~he conduct of the study, the methods of analysis, an~I the findings. 7.1 Protocol Question. Was the target population lor this study an appropriate one? Answer. Critics have pointed out that certain patients were required to ac- cept treatment that would not normally conform to clinical practice, and their References at end of article. PAGENO="0106" 13356 COMPETITIVE PROBLEMS I]~ THE DRUG INDUSTRY argue, therefore, that the target population was unsuitable. Such a claim, how- ever, overlooks the important but ili-understo~d prophylactic aspect of the trial, in which certain treatments were given to patients who, initially at least, could safely go without drugs, in order to test whether the common vascular complications of diabetes could be prevented. The issue was the testing, of Cer- thin possibly preventive treatments rather than the implementation of certain. standard therapeutic regimens. Question. Was the decision to in~lude phenformin in the study justified? Answer. In the e\rent it proved to be, since valuable information was obtained about the limitations of that drng. Its use, however, greatly complicated an already difficult study. It is clear tl~at one of the problems of a long-term clinical trial iS that potentially interesting therapies may develop while the trial Is In progress, and the natural desire to include them may divert resources. The omission of a history of smoking was a blunder. 7.2 Uond'uet of the study This was necessarily a lengthy and complex trial, and a substantia1~ pioneer-~ lug effort was needed to mount it succe~fully. We have raised a question of whether the randomization was properly carried out. The only evidence that it might not bi~ve been is the data on the allocation of treatments according te the sex of the patient. Against this possibility are two * * * 7.3 Methods of anaZysis The UGDP investigators sought to examine their data from a number of different points of view, and in so doing tbe~ made use of some relatively un- familiar and exploratory statistical techniques. In some cases these methods would not necessarily have been chosen by Other grottps of statisticians faced with the same situation, but since the results of all the analyses tended to point in the same direction, there would be little advantage in discussing at length the weight to be attached to the different analyses. The likelihood calculations seem to us to ttdd very little to the other analyses. The results are rather difficult to grasp and require rather arbitrary weighting to be given to the likelihood of different hypotheses. The method does not take concomitant variables into account. The Monte Carlo monitoring procedure was a major attempt to overcome the selective effect of a secjuential analysis of the mortality data. The investiga- tors were concerned lest they had paid undue attention to contrasts between treatments at a particular moment when extreme fiu~tuatlons might have oc- curred. Their method was ingenious, and although minor points of criticism may be raised, we do not think that these materially affect the issue. (Some of these points might be (1) the use of national mortality data, with death rates higher than those in the study population; (2) the use of an `~average1' survival curve for all patients in the sImulation; (3) the adding of life table death rates at different ages to obtain the death rates during intervals; and (4) the arbitrari- ness of the linear boundaries. 1~or an alternative approach to the sequential analysis of survival data, using internal comparisons only, see Breslow and Haug. (29)) The detailed outcome of such a monitoring procedure is of no great importance. The decision to stop the use of tolbutamide must have depend- ed on considerations of various sorts, among which the monitoring procedure provided a contribution-no more than that. The UGDP did not try to determine whether interactions were present in their data. This criticism was raised by Feinstein and is valid. 7.4 Findings Although we have concerned ourselves almost entirely with Issues related to the possible toxicity of tolbutamide, we wish to point out that one of the valuable aspects of the completed TJGDP trial will be the provision of data on the long-term treatment of adult-onset diabetes with insulin, It is already clear that the benefits from this treatment are not dramatic, and the only worthwhile information about them will have to come from the relatively precise methOds of a controlled clinical trial. In this sphere, the TJGDP trial has no competitor. Indeed, we would generalize from this and point out the * * * On the question of cardiovascular mortality due to tolbutamide and phen- formin, we consider that the UGDP trial has raised suspicions that cannot be dismissed on the basis of other evidence presently available. We find most of the criticisms levelled against the UGDP findings on this point unpersuasive. The possibility that deaths may have been allocated to car- References at end of article. PAGENO="0107" `cOMP~EnTIV~ PRO1~LRMS IN TEE DRUG IND~lSTRY 13~57 ~liovaseular causea preferentially in the groups receiving `oral therapy e~dsts, and, in view of the "nonsignificance" of differences in total mortality, some reservation about the conclusion that the oral bypergiycenaics are toxic *flust remain. Nonetheless, we consider the evidence of harntftlness moder~Lte1y strong. The risk Is clearly seen in the group of older women `a~ shown in ~able A.2. Whether it acects all subgroups'. ~f patients cannot ber decided on the basis of the available data. owing to the small number of deaths involved in these subgroups. There remains the question of generalization of these findings. A's has been frequently pointed out, the conditions of drug use in this study were, to some extent, abnormal. Tolbutamide dosage is varied in practice, aiid the pa1~ient unable to maintain adequate `control with lolbutamide could be shifted to in- sulin. A good deal rests, then, on the matter of whether tolbutamide is act~ally toxic~ If this should~ be admitted, it `is hard to see. how it could be regai~ded as a reasonable therapy, even when given in variable rather than axed dosage. If, however, this finding is rejected, there remains the question of whether tolbutamide, although ineffective in this fixed-dose regimen, might be an effective therapy as ordinarily used. The UGDP gives up direct answer to this question, but the dose of tolbutamide ordinarily employed varies only moderately.' There is also the question of the extent to which the UGDP subjects rea~on- ably represent the population of maturity-onset diabetics who. are candidates for oral therapy. Little of the . commentary available to us raises questions on this point, and we assume that the UGDP population is representativeS o~ a large fraction of the maturity-onset, non-Insulin-dependent, diabetic populat~on. In conclusion, we consider that in the light of the UGDP findings, it remains with the proponents of the oral , hyperglycemJ~cs to conduct scientifically ade- quate studies to justify the continued use ~f such agents. REFERENOnS (1) A study of `the effect's of hypoglycemic agents' on i~ascular compllcation~ in patients with adult-onset diabetes: I. resign, methods and baseline results, Uni- versity Group Dia'betes Program. Diabete$ 19(suppl 2) :747-783, 1970. (2) A stu'dy of the effects of hypoglycenile `agents on vascular complications in patients with adult-onset diabetes: II. Mortality Results, Universlty Group Diabetes Program, Diabetes 19(suppl 2) :7~7-830 ;l970~ (3) Effects of hypoglycemic agents `on vascular complicationa in patients with adult-onset diabetes: IV. A preliminary r~~ni~rt on nhenformln results, Univers~ty Group Diabetes Program. JAMA 217:7.77-784, 1971. (Jr) A ;~tudy of the effeets of hypoglycemic agents on v'ascular complications In patients with adult-onset diabetes III. Clhiical implications if UGDP results, University Group Diabetes Program. JAMA 218:1400-1410, 1971. (5) Keen H: Factors influencing the progress of atherosclerosis in the diabet~c. Aeta Diabetol Lat 8(suppl 1) :444r-4E6. 1971. (6) Keen H, Jarrett RJ: The effect of carbohydrate tolerance on plasma lipids and atherosclerosis in man, in Jones' 113' (ed) : Atherosclerosis. Berlin, Spr~ngér- Verlag, 1970, p 435. (7) Bull JP The historical development of chinièal therapeutic tri~'l's. J Chron Dis 10:218-248, 1959. (8) Burdette WJ, Geh'an BA: The Planning and Anal~ijsis of Clinical Studi~s Springfield, Ill, Charles C Thomas, Ppblisher, 1970. (9) Hill AB: Statistical ilfethods in Clinical and Preventive Mediç~ine. Londo Oxford University Press, 1962. (10) Lasagna L: The controlled clinical trial: Theory' and practice. J Citron Dis 1 :S58-367, 1955. (11) Witts U: Medical Surveys and Clinical Trials, ed 2. London, Oa~fo~d University Press, 1964. (12) Zubi~od C'G: Multiclinic `trials in cancer chemotherapy. Can Med Assoc ~T ~7 :101-103, 1967. (13) Beecher HE: Research and the Individual. Bost'o~, Little, Brown & CQ~ 1970. (14) The Institutional Guide to DREW policy on protection of human subject~~. National Institutes of Health, US Dept of Health, Education, and Welfare. PAGENO="0108" 13358 00 ErnTIv~ PROBLEMS IN TI~E DRUG INDUSTRY (15) Cochran WG, Cox G: Ecoperimental Designs, ed 2. New York, John~ Wiley & Sons, 1957. (16) A Million Random I~iyLts With 100,000 Normal Deviates, Rand Corpora- lion. Glencoe, Ill, The Free Press, 1955. (17) Cornfield J: The University Group Diabetes Program: A further statis- tical analysis of the mortality findings. ,TAMA 217:1676-1687, 1971. (18) Paasikivi J: Long-term tolbutamide `treatment after myocardial infarc- tion. Acta Med Scand, suppl 507, 1970, pp 1-82. (19) Feldman 11, Crawford D, Ela'shoff R, et al: Progress report on the prophy- lactic use of oral hypoglycemic drugs in asymptomatie diabetes: Neurovascular studies. AdvMetab Disord 2(suppl 2) :557-567, 1973. (20) T'aagournis M, Re3~nertson R: Mortality from coronary heart disease dur- ing phenformin therapy. Ann Intern Med 76:587-592, 1972. (21) Feinstein AR: Olinical biøstatistics: VIII. An analytic appraisal of the University Group Diabetes Program (UGDP) study. Olin Pharmacol 12 :167-191, 1971. (22) Schor S: The University Group l)iabetes Program: A statistician looks at the mortality results. JAMA 217:1671-1675, 1971. (23) Seltzer 118: A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes 21:076-979, 1972. (24) O'Sullivan JB, Mahan CM, D'Agostino RB: Critique of the UGDP mor- tality analyses. New York, Academic Press, to be published. (25) Prou't TE, I~natterud GL, Meinert CL, et `al: The TJDGP controversy: Clinical trials versus clinical Impressions. Diabetes 21 :1035-1040, 1972. (26) Cox DR: Analysis of Binary Data. London, Methuen & Co, Ltd, 1970. (27) Cox DR: Regression models and life tables (with discussion). J B Statis- tical Soc Br 34:187-220, 1972. (28) Kal'b~eisch JD, Prentice RL: Marginal likelihoods based on C~nx's re- gression and life model. Biometrika 60:267-277, 1973. (29) Breslow N, Hang C: Sequential comparison of exponential survival curves. J Am Statistical Assoc 339 :691-697, 1972. APPENDIX A Use of the logistic model ~,. The logistic model has bten recognized as being very useful for studies in which there are only two outc~ries,. for example, death or survival (-6) In this use of the modelit is assumed that the probability of death, P, depends on m independ- ent variables, Xi, X2, * * ~`, Xp, according to the relation ~ 1 where Ab0+ b1X1+ b2X2... +bmXm On each subject in the UGDP trial, the data available were the m independent variables and an outcome variable that was given the value 0 or 1 according to whether the patient survived or died The multiple regression equation was fitted to relate the probability of death to the independent variables A maximum likelihood procedure was used to find estimates of the regression coefficients b0,b1,. . . bp Groups of people such as those receiving a treatment or those from a particular clinic were incorporated into the model by the inclusion of an indicator variable that, for a given individual, took the value 1 if the indivudual was in that group, and 0 otherwise In order to avoid redundancy, there must be one fewer variable for clinics than there were clinics, and so for other sets of categories To allow for the varying lengths of follow-up, potential length of follow~up (ie, the length of time between entry into the study and the end of the study) was entered as a covariable in the regression. As a test of the various covariables in the logit regression, the likelihood ratio x2 was computed. The likelihood ratio x2 can be computed for a set of parameters, 1~, by comparison with a set of parameters j3'~' to which, under the null hypothesis, PAGENO="0109" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 133E~ p constraints have been applied If the maximum likelihood e~tin1atos of th~ set of parameters are j3 and 13* respectively, then -2 in [L(13*)/L(13)1 is asym~toti- cally distributed as x2 on p degrees of freedom, where L(.) denoted the likeli~iood function When investigating the regression coefficients them~e1ves, one can use the fact that they asymptotically have a' multivariate normal distribution with a variance-covariance [1(13)1_i where `(13) mXm This en~I~les one to, obtain estimates of the `standard deviation of the estin~ate~ of the regression par~~eters~ Table £5 gives a lint of the yariables tl~at were considered in the analy~s of the TJGDP data and Table AA~1 summarizes the fmndings,on them. `The es~ates of the regression coefficients when ~d1 of these, variables have been includec~ are. given in Table £6.2. As often happens when one does multiple regression Mth' many parameters, there are redundaucie~, ~o that a relatively small subset o~ the variables gives nearly as good a prediction a's the' entire set. In looking fo~' an appropriate subset of variables, one still Includes the variables that are of g~eat- est interest, in this case, the treatment effects. Sex was also included becau~e of an interest in the treatment effects for dach sex. It has already been noted that after adjusting for treatment variables,, demographic variables, and t1m~ of follow-up, the clinic differences were not significant, and so the variables for~ clinics were dropped. Other demographic variables ~were added to the regression until the maximum of the likelihood did nut differ significantly from the maxi- mum of the likelihQoe when all the' ~ariablès were 1nclud&~. `The Ord~r in w~iich the var!âbies tvere entered' into the regression depended `on `th~ absO1ut~ value Of' T (see Table A.6.2), the large values being entered first. The subset `of v~rla~blev thus identified (age, sex, systolic biood,pressure, electrocardiographic abnor~nal- ity, cholesterol level, and arterial calcification) is indicated in Table AS and these were used in the further analysls~ A regression analysis with tbIs'subs~t ~f, variables other than sex was also done separately for each sex. ~1'he results o~ the analysis using the subset of variables are sumtharized in Table 9.6.1, as we~I as in Table A.6.3,. ~his analysis indicated that the treatment effects may be different from the two sexes' The harmful dfeet of tothutamide treatmeilt ~`5 ihost appafent for women, although the effect for men, is not significantly different from tlia~io~ women. It is not clear whether thC'~eskT1th fth~ tolbutamide apply only to women or whether the effect on won~en is were obvious because of the larger num1~ers. involved. , ` ` Table A.6.4 g1s~es the number of deaths observed in each' treatment gr~mp, broken down by age and se~ `along with th~e,number e~pected OR: ~ ~J! tl~ model using the subset of yariable~ just mentioned. It appears that the m?d'el does reasonably well in' predict'ihg tbe~niimber of death~',iil each group. The variables used in the analysis of the Bedford study data are showr~ in Table A.9.1. The a~aly~is was done for all cáüses"and `cardio~ascular' cause~ of death;' Ond~the rO~ulf a are ~umlnarized in Table £9.2. The regression eoeffici4nts ol)fained when all the variables are included are shown in' Table £9.3. APPENIMX B Relative allocation method , ` In this section we outline th~ rudimnEthts of"the `re'ative allocation (RA) method of analysis. Define ~S~"= Total fol1ç~w-up time f~r the at~~ incUvi dua~ (a= 1,2,..., u); `.~ 1S~= Total follpw up time for the ç~th indIvidual ç~t~ the ~ lrea~ment (m= 0,1,2,3,4); ` ` ` ` ` " " wj~=Sja/&~B~Oldtivetime On i~h ~tteatment~fo .~iiy'qa~; öa f1 if ath individual is dead (or if cardiovascular death) ` ~ 0 otherwise. `` ` ` `a", We shall denote the treatments placebo, tolbutamide, standard-dose insthin, and variable-dose insulin by the sub~cr~pts i~ 1,2,3,4, and i=0 will refer to no treatment. Therefore, the 0th patient ih the study supplies the vector ~f in~o~m-~ tion (2a,Wia,öa)j~ 0,1,2,3,4. "1)he~relative allocation `number of deaths for the i~ trOntmen.t is deflne4 ~y d,' ~ PAGENO="0110" i3360 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Similarly the effective number of observations for the ~t1~ treatment is The proportion of deaths for the jtI~ treatment is theh estimated by' The ~} can be defined to take on the value unity depending `on i~hethër one is calculating mortality for total deaths or cardiovascular deaths. The estimate of the proportion of deaths associated with a treatment is usually ddne for a subset of patients according to whether the patients belong to the sub- set or not. If' C defines such a class, then the 1~A deaths and sample sizes are d~"(C)=~ ~ flj'(C)=~Wja ` d~'(C) /n~' (C)~ If there isno difference between the treatments for patients b~iOhgh~ to a particular class, the `probability of dying while hi the study does not depend on the treatment, ,ie, P{~a(C)1}O(C), . *here aEC. Consequently (conditional on the' ~w~} ~being fixed), we have and *~sar tO~'(C) -o~'(C) ~`2 {A~~~(C)'± A~1.(C) -2A~,(C) }., where ` O ,~,2~e(C)(,j_O(C)) =~ wjawja/[nj'(C)nj"(C)'l. a~C Approximate tests of ~ignificance can be made by taking ``[O~' (C) -oj' (C) ]Nvar'~O~' (C)'~-O~' (C)1 ` tie have a standard normal distribution. *. . . . " ;" `~ In an~analegous ~ay the failuro rate For `the ~ treatment and p~tie,ntsbe~onging to class Cis defixicdby . . x~'(C) =~o~'(C)/t~(C), where t~(C)'E ~,/n~'(C) a C is the .~ssociated average follow-ii~p time. Thus~ conditional on' ~he average ~olIow-u~ tiinn, the variance of a differen~e between two failure rateC is var tX~'(C) ~-X~'(C') =e~?'{B~~(C) ±B11(C) -~-2B~1(C) }, ~where . 0 0 B~1(C) = A~1(C)/[t~(C)t1(C)1. 41~PuNDIx c *` 0 0 M~1üz~ ikW~tIvod `. The thodei used Thr the survival .n~oduling method expresses the lo,garitba~ of ~the failure rate for the a patient as log ~~=log x(t)+~1 Xsaa'~l, 2, .. . fl, PAGENO="0111" COMPETITIVE PROBLEMS J~ TI~ DR~JG INDUSTRY 1,3$61 where X (t) and {~3~} are unknown parameters to be estimated and {x,als== l,~,..., p and p covariables associated with the ath patient. The x-variables for the four protocol treatments were taken to be equal to the proportion of time the a~~' individual was on the particular proto~o1 treatment. That is, if the first fo~ir ~3 coefficients refer to the treatments in t1~e stt~ndard order, then X~=WSa for s=l,2,3,4. If a patient receiving standnrd-~do~e insulin had an altered dose of insulin, this was regarded as contributing jnformation to the variable-dose insulin group. The estimates of ~ (s~ l,2,a,4) corre~pon4 to the logarithm of the ratip of the failure rate of the 5th treatment to that of the period for which no medication is taken. The differences ~ estimate. the logarithm of the ratio of the 5t~i treatment to placebo. These ratios are "adjusted" ratios that have been adjusted for base-line and demographic variables as well as institutions. The mo d~l is based on the work of Oox, (p7) utilizing a modification suggested by Kalbf1e~sch and Prentice. (p8) REFERENCER TABLE 1.-UGDP STUDY: TREATMENT GROUPS AND CAUSES OF DEATH Percent dead Number All Cardiova~cuIar Treatment group of subjects causes c~uses ~ Clinics using tolbutamide: Placebo 205 10.2 4. 9 Tolbutamide 204 14. 7 12. 7 9. 5 6. 2 Standard dose insulin 210 Variable dose insulin 204 8. 8 5. 9 Clinics using phenformin: Placebo 64 9. 4 3. 1 Phenformin 204 15. 2 12.7 8.8 Standard dose insulin 68 4. 6 Variable dose insulin 65 6. TABLE 2.-BEDFORD STUDY (6): CARDIOVASCULAR EVENTS AND TOLBUTAMIDE Placebo . Tolbutamide - With event With event N~mberof~-- . -- Numberof - -1--~ subjects Number Percent Subjects Number Pertent ~ Both risk groups: Both sexes 123 . 46 37. 4 125 34 7.2 62 19 0.6 Male 69 ~5 36.2 Female 54 21 38.9 63 15 3.8 High risk group:' Both sexes 34 39 55.9 41 21 51.2 Male 14 10 71.4 14 11 78.6 Female 20 9 45. 0 . 27 10 ~7. 0 Low risk group: Both sexes 89 27 30.3 84 13 15.5 Male 55 15 27.3 48 8 16.7 Female ~4 12 35.3 36 5 13.9 ~ 1 The high risk group consisted of those who, on coming iritothe trial, had cIearolink~al evidence of cardiovascular dis~ase or clinically signiticant hypertension. TABLE 3.-BEDFORD (5) AND UODP $TUDI~S: AGE DISTRiBUTIONS Bedfor d study UGDP study Placebo Tolbutamide --- Placebo - Tolbutamide -~-, -~- Age Nun~ber Percent Number Percent Number Percent Number Percent 20 to 29 7 5,6 6 4.9 7 3.4 3 1.5 30 to 39 7 5.6 12 9.8 25 12.2 23 10. 3 40 to 49 22 17.6 22 17.9 51 24. 9 45 2Z. 1 50 to 59 25 20. Q 34 27.6 60 29.3 74 36.3 60 to 69 27 21.6 27 22.0 46 22.4 51 25.0 70 to 79 30 ~4, 0 20 16. 3 16 7. 8 8 3. 9 80 and over I ~.6 2 1.6 0 0 0 0 All ages 125 100.0 123 100.0 205 100.0 204 100.0 Mean age 58.6 55.4 52.2 53.0 PAGENO="0112" 8 -3 TABLE 4.-NUMBER OF PATIENTS BY ASSIGNED TREATMENT AND BY TREATMENT SUBSEQUENTLY USED FOR AT LEAST ONE QUARTER 0 - Standard dose Variable dose Tolbutamids and Variable dose insulin - Placebo Tolbutamide insulin insulin None none and none Number -Percent Number Percent Number -- Percent ~Number Percent Number Percent Number - Percent Ptumber Percent Subsequent treatment - Assigned treatment Placebo Tolbutamjde Standarddoselnsulin - VariaLs1~doseinsulin ~ Total ; - - 76 37 0 0 0 - 1 0.5 106 52.0 -~1 0.5 0 0 0 - 50 24. 0 7 8 51 82 3 4 24 40 92 75 104 119 . 45 37 50 58 - 4- 2 20 -. 12 G...~ 15 7 4 .2 - 3 1204 204 210 204 !~ ~ .3 ~ ~ ~ ~ 76 9 - 108 13 50 6 - 148 18 390 47 - 11 3 - 35 5 - - 822 --- - I One patient omitted. Did not fit any of these categories. - . - - 0 C12 PAGENO="0113" -4 Go TABLE 5.-NUMBER OF PATIENTS BY INITIAL TREATMENT I AND PROPORTION OF FOLLOWUP TIME Ot~ THAT TREATMENT 0 L~J Proportion of total fol lowup time on initial treatment . - ~. ~ 0 001 to 0.25 026 to 0.50 0.51 to 075 0.76 to O~99 1. 11 Initial Treatment Number Percent Number Percent- Number Percent Number Percent -- Number Percent Number Percent Total 02 Placebo Tolbutanilde Standard dose insulin 3 3 6 1.5 1. 5 3.0 19 18 21 9 9 10 19 9 17 8 23 11 21 10 79 39 15 7 74 36 - 41 20 &~ - 33 64 77 50 31 38 24 205 204 210 .~+ Z Variable dose insulin2 3 1.5 23 11 35 17 47 23 69 34 27 13 204 Total 15 1.8 81 10 94 11 124 15 ~291 35 218 : 26 823 1 Without dose modification. 2 Figures reflect proportion of time on initial-titration i nsulin dose. - - - - Q z 02 PAGENO="0114" 13364 COt~L'I~IVE PROBI~M~ I~ T~ DRTJ~ INDUS~RT TABLE 6.-PATIENT FOLLOWLJP TIME (PATIENT-YEARS) BY ASSIGNED TREATMENT AND TREATMENT RECEIVED Assigned treatment Standard dose Variable dose Placebo Tolbutamide insulin insulin Totals Per- Per- Per- Per- Per- Treatment Received Number cent Number cent Number cent Number cent Number cent As assigned 693.8 65.0 712.6 58 709.3 55.0 5 304.0 24.0 2, 419.7 48 Other treatment: 2 Placebo 319.3 25.0 319.3 6 Tolbutamide 3.3 ..3 3044 25 4.6 .4 3.3 .3 315.3 6 Variable dose insulim - - 43.3 3.0 32.9 3 389.0 3Q.O 3 789.8 62.0 1, 255. 1 25 None 198.6 16.0 180.9 15 198.0 15.0 177.4 14.0 754.8 15 Total 1, 258. 3 1, 230. 5 ~, 300. 9 1, 274. 5 5,064.2 I This figure represents total patient years on initially selected dose of insu'in. This includes assigned treatment but with modification of dose. * This figure represents total patient years on with insulin at a dose different from the initial dose. PAGENO="0115" COMP~TI9rIVE PROBLEMS IN T~D~ DRUG I~DTJ~TRY 1~336~ )- ~ 0)+~ >< ~ ~ ~ II 2 0) 00 0~ 2 ~ 00Q~ 00 2 ~ ~ 1:~0~! ~ ~ C,) ~ 2 t)~0r~ooo, p C,) ~ =)00_~~ C~ ~ I)) C')~I*~ `~)c~J LU 2 G) ~ - L)~C0C~J P~ U.) 2 ~co ~ U.) CC) 2 )~0) 00~~C~ >< >- 00 2 Q~C~JI)CC)o0 .~! 00 C) H''''' CO a) 00 ,,,, ``` > PAGENO="0116" 13366 COMPI~TITIVE PROBLEMS IN THE DRUG INDTJBTRY TABLE A.2.-UGDP DATA: CARDIOVASCULAR FAILURE RATES FOR EACH TREATMENT GROUP Treatment group Number of N patients Total time umber of at risk taUures quarter-years Fai~ure rate (in thousandt) Both ~exe~ Placebo Tolbutamide Standard dose insulin Variable dose insulin Males: 205 204 210 204 10 26 13 12 5, 033. 6 4, 922. 2 5, 203. 9 5, 098. 1 2. 0 5. 3 2. 5 2. 4 Placebo Tolbutamide Standard doseinsulin Variable dose insulin Women: 63 63 57 46 7 11 5 2 ~ 1, 389. 2 1, 491. 5 1,340.0 1,137.5 5. 2 7. 4 3.7 1.8 Placebo Tolbutamide standard insulin dose Variable dose insulin 142 141 153 158 3 15 8 10 3,644. 4 3, 430. 7 3, 863. 8 3, 960. 6 . 8 4. 4 2. 1 2. 5 TABLE A.4.-UGDP DATA: CARDIOVAS~ULAR FAILURE RATES FOR EACH TREATMENT GROUP BY AGE, AND SEX Treatment Group Number of patients N umber of tai~ures Total time at risk, quarter- years Failure rate (in thousands) Males: «=53~rold; Placebo Tolbufamide Standard dose insulin 28 26 28 1 5 0 664. 6 656. 6 722.5 1. 5 7. 6 0 Variable dose insulin 2~ «=S3yrold: Placebo 35 Tolbutamide *31 Standard dose insulin 29 Variable dose insulin 25 ~53yrold: Placebo 85 Tolbutamide 71 Standard dose insulin 7~ Variable dose insulin 82 «=S3yrold: Placebo - 58 T~lbutamide 70 Standard dose insulin ~ ~74. Variable dose insulin_ .~_ 76 . ~ ~ , ~ ~ 1 ~ 6 6 5 1 1 1 1 1 2 14 7 9 521. 7 ~ 724. 5 834. 9 611.6 615. 8 ~ 2, 187. 8 1,793,8 2,048.6 2, 118.9 ~ 1, 456. 6 1, 636.9 1, 815. 2 1, 841.7 1. 9 8. 3 7. 2 8.1 1, 6 . 5 .6 .5 . 5 1.4 8.6 3. 9 4. 9 PAGENO="0117" COMPETITIVE ~ROBI~EMS `IN TUE DRUG INDUSTE~ 133~7 TABLE AS-VARIABLES USED IN THE LOGISTIC ANALYSIS OF THE UGOP DATA Time: Length of thee from admission to study to time of analysis Treatments:'(Coded 1 if the patient was assigned to the treatment and 0 otherwIse). Tolbutamide~ Insulin (standard-dose). Insulin (variable-dose). Demographic variables and risk factors: ("demographic variableg"). Age.2 Sex (1=male, 2=female). Race (1 white, 2=nonwhite). Relative body weight. Systolic blood pressure.2 Diastolic blood pressure. History of use of digitalis (1=yes, 2=no.). History of angina pectoris (1=yes, 2= no). Significant electrocardiographic abnormality 21 (1=yes, 2=no). Serum cholesteroLa X-ray evidgnce of arterial calcification 24 (0=no, 2=yes). Fasting value from baseline glucose tolerance test. Serum çreatinine value, mg 100 ml. Visual acuityforboth eyes(0= >20/200 for both eyes; 1 = «=20/200foreither eye). Clinics:' (Coded 1 if the patient was in the clinic and 0 otherWise). Boston. Minneapolis. New York. Williamson. Cincinnati. Cleveland. Baltimore. Birmingham. Chicago. St. Louis. San Juan. 1 There is 1 fewer treatment variable than there are treatments, and 1 fewer clinic variable than clinics. This avoids redundancy; in effect, the treatments are compared to the missing treatment (placebo) and the clinics to the mis~ing clinic (Seattle). 2 These variables constitute the subset referred to in tables A. 6.1 and 6.3. Sex was not included as a variable ifl the analyses done separately for each sex. a Major or minor Q-waves, S-I depression, T-wave inversion, complete heart block, teft bUndle-branch bIdcK,~or yen- tricular tachycardia. 4 Evidence of arterial calcification noted in both Of 2 independent readings of the same set of soft tissue X-rays of the right lower limb. PAGENO="0118" 13868 cO~fl'ETITIVE P~ftOBLEMS I~ TH~ flRUG ~NDUSTEY TABLE A.6.-ANALYSIS OF CARDI~VASCULAR DEATHS IN1 IH6 IJGDP TRIALS USiNG THE LOGISTIC MODEL Likelihood df ratioXa p 1 a 3 14 3 11 3 3 11 11 14 1. 2 6 19 3 1 2 1 2 706.03 .001 23.56 .00]. 10.46 .02 10.68 .02 95.87 .001 11.55 .01 12.30 0]. 27.68 .01 10.91 .02 11.98 .02 14.33 30.53 .01 82.56 .001 11.66 .001 0,32 - 83.05 .001 27.19 12.31 .01 8.49 .01 0.17 12.14 3.82 159. 53 .001 35.45 .001 5.07 0.35 Both sexes: Constant Time Treatments Treatments adjusted for time Demographic variables and risk factors Treatments adjusted for demographic variables Treatments adjusted for demographic variables and time Clinics adjusted for treatments and time Treatments adjusted for clinics and time Treatments adjusted br demographic variables, clinics, and tin~e Clinics adjusted for demographic variables, time, and treatments Clinics adjusted for demographic variahies and treatments Demographic variables adjusted for clinics, time, and treatments Tolbutamide treatments adjusted for demographic variables, clinics, and time Other treatments adjusted for demographit variables, clinic, time, and tolbutamide treatment Subset of demographic variables adjusted for treatment and time 1 Other demographic variables and clinics Treatments adjusted for subset of demographic variables and time Tolbutamide treatment adjusted for subset of demographic variables, time, and insulin treatments (tolbutamide vs. placebo) Insulin treatments adjusted for subset of demographic variables, time, and tolbutamide treatment (insulin vs. placebo) Tolbutamide treatment adjusted for subset of demographic variables and time (tolbuta- micle vs. other treatments) Insulin treatments adjusted for subset of demographic variables and time (insulin vs. other treatments) Men: Constant_. Demogr4phid variabtes and time Treatments adjusted for variables and time Tolbutan,ide treatmtnt adjusted for insulin treatments, demographic variables, and time (tolbutamide vs. placebo~. Insulin treatments adjusted for demographic varibles time and tolbutamide treatment (ihsullh Vs. placebo) Tolbutamide treatment adjusted for demographic variables and time (tolbutamide vs. othdr treatments) Insulin treatments adjusted for demographic variables and time (insulin vs. other treatments) Women: Constant Demographic variables and time Treatments adjusted for variables and time Tolbutemide treatment adjusted for insulin treatments, demographic variables, and time (tolbutamide vs. placebo) Insulin treatments adjusted for demographic variables, time, and tolubuamide treat- ment (insulin vs. placebo) Tolbutamide treatment adjusted for demographic variables and time (tolbutamide vs. other treatments) Insulin treatments adjusted for variables and time (insulin vs. other treatments) 6 3 2 2 6 3 2 2 2.52 2.56 4.72 551.79 .001 67.66 12.23 - 11.70 .01 252 9.06 .01 0.53 1See table A.5. PAGENO="0119" -4 m -4 -4 Cr) - -4~ - Ci~ C) C) (~ C~ -4 ~ C,) Cr)-4 C ~ ci -4 -4 0 -4 0 C) ~ ~ ~ ~a ~-°~ ~. :~ ::~:F~-~: C C) N) OO(~) ~N) PAGENO="0120" ~9MPETITIVE PROBLEMS IN THE DBUG INDTJSTRY ~ C' CJ c'J co~ c c~oo Lt)(~ C'C~ C%~~ ~C~4C~ ~C~C)U)C) ~C%4~C~J ~ C~) -- - ~ -~°` ~ -~ co u~ ~, ~ ~, ~ ~ r-~ c~c~Ø ~c~3 ~ ~ (~, ~ ~ ~ ~,, - c~c~o~ ~ ~ ~2°'~ 0) ~ C') >- C,, ~o c~ ~ ~ CC ~ ~ ~(C) ~ coc ~`o~ c~c~ c~ ~4~'4 C?)C~CC~~~ id~©~ C) C,, C 0 ~ 00 ~ r-~ ~ 0 ~ - - - ~ - - r E 0, C) PAGENO="0121" COMPETITIVE PROBLEMS IN TEE DRUG INDUSTRY 13371 C) (CC) (0 -~C) C)C)~ QC)C)C) C)C)CC) C)C)~C) (Cc~4C)cC r-C0)'- 0)~-~C) 0J~.(Cc~) 0)C)0) C)C~4C)C) C)C)~'-4 C)C)C)C) C)~C)C) QC)C) C~J (C) ~(C C)'-~ C) C) (0 C) C) (01~ (C C) (0(000 ~)Ø) C) C) C) C)(CC)C) C) C)C) ~ C'4 (C 00 c~ C) 0000)(C C) C)C) C) - C) C) C) C) C) -C) C)C) C) C) C~JN~ ~C)C'1C~ C%J(C(~4 O0~0(0 00(000(0 0C~J04C)J (C C) LO) C) ~ F~ C) C) C0~-~CO(0 C)~C)C) ~C)C'~ C)C)C)~C) C)C)C)~C) C)C)L~)C) C) ~ C~ C'4 o0~o0O 04 (C) 040- (0 C)~ CO L000 C) (000(0 C) (0(0 (C) (0(0 C) ~ _C)__ C)C)_C) C)C)_C) C)C)_C) ~ 04 (004 `-04 04 C) 04 04~ 0)00 0404(4 ~-~-) PAGENO="0122" 13372 COMPETITIVE PROBI43~MS IN TUR DRUG INDUSTRY TABLE A.6.2.-UGDP DATA: ESTIMATES OF THE COEFFICIENTS, THEIR STANDARD DEVIATIONS AND TI FOR THE LOGISTIC REGRESSIONS USING ALL VARIABLES Variable Coefficient Standard deviation T Age Sex 00692 -.3956 0.0213 .3919 3.25 -1.01 Race Relative weight Blood pressure Systolic Diastolic Digitalis use by history Angina by history Abnormal ECG Cholesterol Arterial calcification Glucose tolerance test -.6432 -1. 1122 0143 -.0125 -.6748 -.6519 1. 3907 . 0041 27~0 0011 .4560 .7768 . 0076 .0154 .5117 .5171 .5693 . 0026 . 1877 .0031 -1.41 -1. 43 1. 89 -.81 -1.32 -1.26 2.44 1. 58 1. 47 .36 Serum creatinine - Visual acuity - Boston . 6990 -. 1592 1.3005 . 8727 . 6095 1. 2477 . 80 -. 26 1.04 Minneapolis New York 1.5444 .8680 11989 1,3323 1.29 .65 Williamson Cincinnati - Cleveland 1.0567 2, 3536 .8507 1.2473 1. 3089 1. 4507 .85 1. 80 .59 Baltimore Birmingham Chicago - - St. Louis San Juan Time Tolbutamide insulin: -.1780 .6587 1. 1578 4500 .3470 .4362 1. 2412 1. 6263 1.3571 1.3484 1. 5386 1.5304 1. 1805 . 4470 -.11 .49 .86 .29 .23 2.42 2. 78 Standard dose .2424 .4939 .49 Variable dose -. 0005 . 5257 -. 001 Constant -8. 8522 2. 9440 -3, 01 1 Estimate divided by standard deviation. TABLE A.6.4.-UGDP DATA: NUMBER OF CARDIOVASCULAR DEATHS OBSERVED AND PREDICTED FROM THE LOGISTIC MODEL Treatment Placebo Tolbutamide Standard dose insulin Variable dose insulin IViales: «=53: Observed Expected >53: Observed Expected Total: Observed Expected Females: «=53: Observe& Expected >53: Observed Expected Total: Observed Expected 1 0.521 6 3.640 5 2.600 6 9.310 0 0.952 5 4.398 1 0.447 1 3.130 7 4.162 1 0.898 2 4. 940 11 11.910 1 3.260 14 10. 829 5 5.350 1 1.107 7 6. 543 2 3.577 1 1.057 9 7. 365 3 5. 838 15 14. 088 8 7. 649 10 8.422 PAGENO="0123" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13373 TABLE A.7.1.--UGDP DATA: RELATIVE ALlOCATION OF TOTAL AND CARDIOVASCULAR DEATHS AND EFFEC1hVE SAMPLE SIZE Assigned treatment Standard Variable Treatment received Placebo Tolbutamide dose insulin dose insulin Totals Treatment as assigned: 1 d' d" Dose modification or other treatment: 12.9 19.9 6.9 26.9 6.4 17.9 3.9 5.6 115.6 119.5 65,7 53,9 46.6 33.8 354.7 Placebo: ci' 2.8 2.8 d" n' 1.0 48.6 - 1.0 48.6 Tolbutamidd: . d' 0 7.7 0 0 7.7 d" n' 0 5,7 0 0 .5 51.4 .8 .6 5.7 53.3 Variable dose insulin: d' None: 1.2 .4 12.5 38.5 1.2 .4 8.6 54.6 6. 9 10. 7 111. 1 3 121. 9 ~2.6 14.8 250. 6 d' 4,1 2.0 .6 2.6 9.3 d" n' Totals: 1.4 2.0 .5 1.8 33.4 22.4 32.4 27.6 5.7 115.8 d' ci" ~1.0 30.0 20.0 18,0 10. 0 26. 0 `13. 0 12. 0 89,0 61.0 205,0 204.0 210.0 204.0 823.0 I d' indicates total deaths; d", deaths from cardiovascular causes; and n', effectiva sample size. 2 These figures are associated with the initially selected doqeof idsulin. 3 These figures are associated with the subsequently selected dose of insulin. TABLE A.7.2-UGDP DATA: DEATH R ATES A ND FAILURE RATES BY ASSIGNED TREATMENT AN D DOSE GIV~N 1 Dose given ` Assigned Treatment Placebo Standard dose Tolbutamide insulin Variable dose insulin 2 CàrdiQvascUlar deaths: As assigned: 0' Dose modified: 0' No drug: 0' Total deaths: As assigned: 0' Dose modified: 0' No drug: 0' ` 0.06 .9 .02 .3 .04 .7 .1~1 1.9 .06 .9 .12 2,1 ` 0.15 0.06 2.5 1.0 .11 .08 1.9 1.2 .09 .02 1.1 .3 .17 .11 2.8 1.8 .15 .11 2.5 1.8 .09 ` .02 Li .25 0.10 1.8 ~04 .6 .07 1.0 .13 ~.3 .07 ~.1 .09 ~.5 I Death rate (8')is effective number of deaths/effective sample size; failure rate (A') is deaths per hpndred patie~it- years of follow-up. 2 Combining both modification groups results in 0'=10.2/175.9=0. 0., X'=0.9 for cardiovascular deaths; 0'=15.4/ 175.9=0.09, X'=1.4 for total deaths. PAGENO="0124" 13374 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE A.7.3.-UGDP DATA: CARDIOVASCULAR DtATH RATES BY ASSIGNED TREATMENT SEX, AND DOSE GIVEN 1 Assigned treatment Standard dose Variable dose Dose given Placebo Tolbutamide insulin Insulin Females: As assigned 1. 4/79. 8=0.02 10. 8/780=0. 14 3. 9/52. 8=0.07 4.6142. 4=0. 11 Dose modified 0/33. 6=0 3/39.7=0. 08 3. 7/76. 4=0. 05 3,6/94. 3=0. 04 No drug 1. 2/23. 6=0. 05 1.2/19.6=0.06 0.4/23.5=0.02 1. 8/20. 9=~Q. 09 Males: As assigned 5/35. 9=0. 14 7. 0/41.5=0. 17 1/14. 0=0.07 1/11. 5=0. 09 Dose modified 1/15. 0=0.07 2. 7/11. 7=0. 23 3. 9/33. 7=0. 12 1/27. 6=0. 4 No drug .2/9.8=0.02 0. 8/8.6=0.09 0. 1/9.0=0.01 0/6.7=0 I Tables give ratio of cardiovascular-deaths (relative allocation) to number of patients (relative allocation). 2 Combining both dose modification groupsfor IVAR results in the following: females 0 =8.2/136.7 =06; males 0 =2/39.1=.05. TABLE A.7.4.-UGDP DATA: CARDIOVASCULAR DEATH RATES BY ADHERENCE AND DOSE MODIElC~TION Treatment Dose Standard Variable Modification Placebo Tolbutamide dp~e insulin dose insulin Totals . 100 percent ad- herence :1 No 4/64=0.06 16/77=0.21 4/51=0.08 4/27=0.15 28/219=0.13 Yes 1/12= . 08 4/29= . 14 3/50= .06 2/55= .04 10/146=0. 07 <100 percent adherence: .06 No 2.4/51.6= .05 1.9/42.5= .04 4.6/60.1= .08 1.6/26.9= .06 10.5/181.1= Yes 1.8/36.6= .05 1.7/22.4= .08 0.9/15.7= .06 2.6/66.9= .04 7/141.6=05 Totals 912/164.2= .06 23.6/170.9= . 14. 12. 5/176.8= .07 10.2/175.8= .06 55. 5/687.7= .08 1 100% adherence is defined as taking the initially assigned drug for every quarter of follow-up. TABLE A.7.5.-UGDP DATA: CARDIOVASCULAR DEATH RATES BY ASSIGNED TREATMENT, SEX AND COMPLIANCE - Compliance1 . Treatment Placebo Tolbutamide Standard dose insulin Variable dose insulin Females: - 100 percent adherence-no dose modification 0/41=0 9/51=0.18 1/28=0.04 3/21=0.14 <100 percent adherence or dose modification 1.3/72.3= . 02 4. 8/66. 6= . 07 6. 6/101. 2= - 07 5. 2/115. 8= . 04 No drug ).. 2/23.6= .05 1.2/19.6= .06 0.4/22. 5= .02 1.8/20.9= .09 Males: 100 percent adherence-no dose modification 4/23= . 17 7/26= .27 2/22= .09 1/6= . 17 <100 percent adherence or dose modification 2/27. 8= .07 2.7/27. 2= . 10 2. 9/25.7 = . it 1/32. 9= . 03 No drug 0.2/9.8= .02 0.8/8.6= .09 0.1/9= .01 0/6.7= 0 ICompliance Is based on both adherence to the assigned treatment group and use of the prescribed dose. PAGENO="0125" COMPETITIVE PEO~I4EMS IN `ri~ ~uo ~irs~n~ 13375 TABLE A.7.6.~-UGDP DATA: CARDIOVASCULAR MORTALITY RATES BY SEX, COMPLIANCE, AND MEDIAN AGE AT ENTRY Compliance Control' Tolbutaàdde F Females: «=53 yr old: 100 percent-no [3M 2 <100 percent or DM No drug >53yrold: 100 percent-no DM <100 percent or DM Nocirug Males: 0/45=0 2.6/155.9=. 02 O.4/39=.0t ~ 4/45=. 09 1O.5/133.4=.08 3/28=11 0/22=0 1/33. 41.03 0/11.79 0 9/29=~. 31 3. 8/33.2=r. 11 1.2/6.9=~.17 «=53 yr old: 100 percent-no DM <100 percent or DM No drug >53 yr old: 100 percent-no DM <100 percent or DM No drug 1/23=. 04 1/35.6=. 03 0/16.7= 0 6/28=.21 4.9/51=. 10 0.3/8.8=.03 3/10=~. 30 1.8/10.5=. 17 02/4.99.04 4/16=4.25 0.9/16. 7=~. 05 0.6/3.7=s.16 ` Control is made of of placebo and standard- and variable-dose insulin treatment groups. 2 DM indicates dose modification. TABLE A.77.-UGDP DATA: TREATMENT' VS PLACEBO ADJUSTED LOGARITHMS OF RATIOS OF FAILURE RATES BY SEX FOR CARDIOVASCULAR AND TOTAL DEATHS ToIb/Plbo ISTD/Plbo IVAR/PIbo None/~'lbo , Cardiovascular deaths: Female: Log ratio 2. 64 1.79 1.75 3. 69 SD2 99 i.o5 1.03 3.21 P3 .008 .09 .09 .16 Male: -.29 -4.48 Log ratio - . 094 -. SD .59 .69 .86 2.08 .73 .03 P .87 Total deaths: Female: Log ratio 1. 12 - 23 . 64 -h-. 51 SD .55 .63 .56 .78 .26 .52 p .04 .72 Male: Log ratio -.30 .037 -1.49 -Los st .5 0 .86 1.18 .08 .16 p .56 .94 *____*__ -,_-,--_ ,---,-,__ ~ ~_~_ ~,___ ,,___ ~ *____*_ ~,,--,_:.--.- .~_ ~______~___~ ~ *.___~. *~___ ~ 1 ToIb indicates tolbutamide; Pibo, placebo; ISTD, standard-dOse insulin; and IVAR. variable-dose insulin. 2 Refers to estimate of standard deviation of log of ratio of failure rates. Refers to test of significance (two-tail) using normal theory. TABLE A8.1.-BEDFORD DATA: INFLUENCE OF BACKGROUND VARIABLES ON DEATH RATES ~ Factor Hypertension: No 27/193=0 14 1- 54 Yes 15/53=0. 28 3. 41 Blood glucose level: «=139 mg/100 ml 17/124=0. 14 L 55 >139 mg/lb ml 25/123=0. 20 3.28 Arterial disease: 14 1. 54 No Yes 12/30=0. 40 5. 02 Sex: Male 20/1290.15 376 Female 22/119=0 18 2. 08 `Age: «=45 yr 0/54=0 >45 yr 42/194=0. 22 2. 52 , j is the number of deaths/total. j)i is the number of deaths/totOl time followed up (6-mo periods). PAGENO="0126" 13376 cO~?ETITIV~. PRO~LEM~: IN THE DRUG INDUSTRY TABLE A.82.-BEDFORD DATA: DEATH RATES FOR PLACEBO AND TOLBUTAMIDE GROUPS, BY BACKGROUND VARIABLES Variable Placebo Tothutamide p* - Hypertension: No -- Yes. Blood glucose level: <139 mg/100 ml >139 mg/tOO ml Sex: 24/125=0.19 17/102= .17 7/23= . 30 10/64= 16 14/61= 23 ~ 18/123=0.14 ~ 10/93= 11 8/30= 27 7/60= 12 11/63= . 17 Males (>45 yr old).... Females (>45 yr old) Arterial disease: 11/52= . 21 13/46= 28 9/46= . 20 9/50= . 18 Yes: Females Males - - ~ No: 2/7= 29 6/8= . 1/6= .17 3/9= .33 Females Males - Hypertension: Yes: 11/50= .2 5/60= . 08 8/56= . 14 6/52= . 12 ~ Females Males -- -..-= No: 5/15= .33 2/8= .25 4/23= . 17 4/7= 57 Females Males Blood glucose level: <139 mg/tOO ml: Females Males >139 mg/100 ml: Females Males 8/42= .19 9/60= . 15 3/28= .11 7/36= .19 10/29= . 34 4/32= . 12 5/39= .13 5/54= . 09 4/32= . 12 3/28= .11 5/30= . 17 6/33= . 18 is the number of deaths/total. TABLEA.8.3.-BEDFORD DATA: NUMBER AT RISK, NUMBER OF DEATHS, AND DEATH RATE BY AGE, SEX, AND TREATMENT Age, years Males Females Placebo Tolbutamide Placebo Tolbutamide 20 to 29 30 to 39 40 to 49 50 to 59 60 to 69 70 to 79 80 and over All ages 0/4=0 0/6=0 0/10=0 1/19= .05 6/14= .43 6/12= .50 3/3=L0O 0/4=0 0/4=0 1/14= . 07 3/18= . 17 3/12= .25 5/8= .62 1/1=1.00 0/3=0 0/1=0 1/12= .08 3/6= .50 1/13= .08 11/18= .61 3/4= ,75 0/2=0 0/8=0 0/8=0 3/16= . 19 5/15= .33 7/12= .58 0/1=-.0O 16/68= .24 13/61= .21 19/57= .33 15/6~= .24 PAGENO="0127" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY i33~7 TABLE A.9.1.-VARIABLES USED IN THE LOGISTIC ANALYSIS OF THE BEDFORD STUDY DATA Group: A variable indicating whether the individual entered the study in 1962 or 1964. Tolbutamide: A variable indicating that the patient was receiving tolbutamide. Diet: A variable indicating that the patient was receiving dietary advice Tolbutamide-diet interaction: A variable indicating that the patient was receiving both dietary advice and tolbutaniide. Variables: Sex. Age. Arterial disease history(O=no, 1=yes) Significant hypertension (0= no, 1 =yes) Blood glucose. TABLE A.9.2.-ANALYSIS OF CAUSES OF DEATH IN THE BEDFORD TRIAL USING THE LOGISTIC MODEL Source df Likelihood ratiokt Deaths from all causes: Constant - 1 62. 68 (p-<.OOl) Group 1 0.00 Tolbutamide adjusted for group and diet 1 0. 90 Diet adjusted for group and tolbutamide 1 0. 02 Tolbutamide-diet interaction adjusted for group, diet and tolbutamide 1 0. 57 Variables adjusted for group, diet, tolbutamide, and tolbutamide-diet interaction 5 81. 02 (p<00~) Tolbutamide adjusted for group, diet, and variables 1 0. 02 Diet adjusted for group, tolbutamide, and variables 1 0. 19 Tolbutamide-diet interaction adjusted for group, tolbutatnide, diet, and va~iabIes 1 0. 01 Deaths from cardiovascular causes: Constant 1 118. 17 (p<.O0~) Group 1 0.14 Tolbutamide adjusted for group and diet 1 1. 02 Diet adjusted for group and tolbutamide 1 0. 73 Tolbutamide-diet interaction adjusted for group, diet, and tolbutamide 1 0. 66 Variables adjusted fo~ group, diet, tolbutamide, and tolbutamide-diet interaction. 5 55. 16 (p<.tI0~) Tolbutamide adjusted for group, diet, ahd variables 1 0. 06 I Diet adjusted for group, tolbutamide, and variables 1 0. 22 Tolbutamide-diet interaction adjusted for group, tolbutamide, diet~ and variables 1 0. 03 TABLE A.9.3-I3EDFORD DATA: ESTIMATES OF THE COEFFICIENTS, THEIR STANDARD DEVIATION, AND Ti FOR T~E LOGISTIC REGRESSION ON CARDIOVASCULAR AND ALL DEATHS Cardiovascular deaths Standard All deaths - Standard Coefficient deviation T Coefficient deviation T Sex - -0. 19~0 0. 4231 -0. 46 -0. 0856 0. 3776 -0. 23 Age Arterial disease history Significant hypertension Blood glucose Group Diet Tolbutamide._ Constant .1069 .0207 1. 1197 . 4908 .7126 .4386 -.0009 .0091 .8525 .7124 .1842 .3922 -.0967 .4039 -8.4326 1.8741 5.16 2.28 1.62 -.10 1.20 .47 -.24 -4.50 .1259 . 7148 ,4399 -.0109 .7279 -.1557 .0448 -7.4192 .0194 4798 .4119 .0084 .6668 .3541 ,3634 1.6450 6.4 1. 4 .1.07 -1.3 1.0 -.44 .1 -4.5 1 T is the estimate divided by the standard deviation PAGENO="0128" THE EFFECTS OF LONG TERM THERAPY WITH ORAL HYPOGLYCEMIC AGENTS ON THE ORAL GLucosE TOLERANCE TEsT DYNAMICS IN CHEMICAL DIABETICS (M.H. Tan,* M.D., CA. Graham, M.D., R.F. Bradley, M.D., R.E. Gleason, Ph.D., and J.S. Soeldner, M.D.) From the Joslin Clinic and the E. P. Joslin Research Laboratory, in the De- partment of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, and the New England Deaconess Hospital, Boston, Massachusetts Supported by U.S.P.H.S. grants AM-09748, AM-04146, AM-05077, the Joslin Diabetes Foundation, Inc., Boston, Mass., the Upjohn Company, Kalamazoo, Michigan, the Eli Lilly Company, Indianapolis, Indiana, and Pfizer, Inc., New York City, New York Presented at the 33rd Annual meetng of the American Diabetes Association on June 23, 1973 in Chicago, Illinois A13STRACT The effect of fixed doses of oral hypoglycemic agents and placebo upon the blood glucose, serum insulin, triglyceride and cholesterol responses during oral glucose tolerance tests done annually for up to 4 years follow-up was studied, in a double blind manner, in 5 groups of mild chemical diabetics. The drugs used were chlorpropamide (100 mg O.D.), tolbutamide (500 mg b.i.d.), phen- formin (50 mg C.D.), acetohexamide (250 mg O.D.) and placebo. Each subject wag given an individualized diet aimed at attaining and maintaining ideal weight, Comparison by Clii square analysis between the placebo group and each of the drug groups showed: (a) no significant differences with regards to the number of subjects with normal glucose tolerance test in each of the tests and (b) no change in the insulin secretion dynamics. Comparison between the initial test and each of the subsequent tests within each group showed: (a) a greater number of subjects had normal glucose toelance in test 2 in the placebo group, test 2 and 3 in the tolbutainide group and tests 2-4 in the chiorpropa- mide `group; (b) no change in the insulin secretion dynamics except in the chlorpropamide group where there was an increase insulin/glucose ratio in test 2 and (c) no change in the fasting serum triglyceride and cholesterol levels. INTRODUCTION A goal in the detection of the early stages of diabetes mellitus is the hope that prompt therapeutic intervention may retard the clincal manifestations of the later stages of the disease. Both remisson of the disease (1,2) and improve- ment of the carbohydrate tolerance (3-16) following the use of oral bypoglyce- agents have been reported. Some groups reported the improvement of the car- bohydrate tolerance to be associated with incrased insulin secretion (4~-7) whilst others indicated otherwise (8-16). A lowering of fasting serum lipid levels in diabetics treated with oral hypoglycemic agents has also been reported (5, 10, 17-20). Most of the above studies were performed after relatively short term (weeks to months) therapy with the oral hypoglycemic agents, The pr~s- ent study reports on the effects of long term (up to four years) therapy with fixed doses of oral hypoglycemic agents and diet upon (a) the glucose toler- ance, (b) the insulin secretion dynamics, and (c) the lipid dynamics during oral glucose tolerance tests of chemical diabetics. METHODS AND SUBJECTS Over a six year period, 365 mild chemical diabetics participated, with in- formed consent, in a double blind prospective study to evaluate the influence *Fellow, Medical Research Council of Canada. 13378 PAGENO="0129" COMPETITIVE PRO~LEl\~S IN THE DRTJG IN1~USTR~ 13379 of fixed doses of oral hypoglycemic agents and proper diet on the nati~ra1 history of the disease. Each of them was asymptomatic, had normal fas1~ing blood glucose levels, but had two abnormal oral glucose tolerance tests prior to entering the study. They were randomly assigned to four groups, each group taking a different drug. In each group one out of every four subjects was placed on a placebo (fig 1). The drugs used were: Chiorpropamide 100 mg daily, Tolbutamide 500 mg twice daily, Plienformin 50 mg daly and Acetohexa- mide 250 mg daily, Drug adherence was assessed by history during the follow up visits every three months. Each subject was given an individualized diet aimed at attaining and maintaining ideal weight as defined by the Metropolitan Life Insurance Company-1959. In this prelminary report, oniy male subjects who had at least two tests ~ind complete data (namely, glucose, insulin, cholesterole and triglyceride values) in the initial (test 1) and subsequent tests (test 2-5) were included. As shown in table. 1, there were 37 in the placebo group, 18 in the chiorpropamide, 28 in the tolbutamide group, 23 in the phenformin group and 14 in the acetohe~ca- mide group. As the follow up years increased, the number of subjects in each group decreased. Each subject had an oral glucose tolerance test (100 ing dextrose) at the beginning of the study (test 1) and then annually during the follow up ye~trs. Each subject followed his usual diet which contained 100-200 grams carbo- hydrate and took no medication on the day of the test. Each test was done after an overnight fast and begun between 0800 and 0900 hours. Blood samples were obtained by venipuncture prior to and at 30, 60, 120 and 180 minutes after ingesting the glucose. Blood glucose was measured by Hoffman's method as modified for the AutoAnalyzer (21). Serum insulin was assayed by the double atitbody method of Soeldner and Slone (22). Serum cholesterole and triglycer- ides were measured by the Technicon AutoAnalyzer method (23). The criteria for an abnormal oral glucose tolerance test are those used in ~he Joslin Clinic. A test was judged abnormal if any one blood glucose value at a given time interval exceeded that listed below: Fasting = 100 mg/dl, 30 mm. = 160 mg/dl, 60 mm = 160 mg/dl, 120 mm = 120 mg/dl and 180 mm-hO mg/dL The criteria for normal fasting serum cholesterol and triglycerides are thOse of Goldstein et al (24). Statistical analyses were done by Chi Square, paired and unpaired Students' t-tests as indicated. COMPARISON OF THE GROUPS AT THE BEGINNING or THE STUDY The placebo group did not differ significantly from each of the treated groups in mean age and percent ideal weight at the beginning of the study and in subsequent years (table 2). The percentage of obese subjects n each group was also comparable. A comparison of the percent ideal weight of the subjects in each between the initial test and each of the subsequent tests was made by paired `t' analysis. No significant difference was noted except in the phenf9r- mm group. In this group there was a significant decrease in percent ideal weight in test 2 (100.2±2.9 p<0.01) and test 5 (98.2±3.7 p- -J C') LU > I- -I LU LU ~1 C', .~ ~ ~ a).- ~ ~- > LU C,, COMPETITIVE E PROBLEMS LU C,, ~ ~ ~*~V)> LU C') a) *~ ~ ~ LU C', .E ~ -S -a;.-=> ~- .~ LU C,, ~ z IN THE DRUG 00 ~ r.~c~O~,-a OOIg,u,C') r~oo O~ r-~a)o,CO d' ~c~c do ~ ~~C',C~4 u~OO0~4 ~ ~C%~ 0 0 - 0 ~ 0 PAGENO="0156" 13406 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY LU e.JOO C~) O~© C,, ~ c*.J ©- c `~ ~ ~U) ~ g~jr-.c~ LU ~ oooO~c~ C/) Ø©~© ~ U)'~ U~oO E ~ ~ ~ L&. I ~ ~ ~ I ~ -J ~ E ~ ~ > C ~ U):~U)._ . ~ U) ~ a) .C C'~C. ~ LU 00 U, 00 > (0 OC)) - oD C) C~) - -J LU ~ ~ ~ z PAGENO="0157" COMPETITIVE PROBLEMS IN THE~ DRUG INDUSTRY 13407 E I' LU C,, ~ Co.; 0~~ 00 0000 C~J 00 - 0~ (0 ~ 00 CC) CC) 0000 00000000 00 00 (0(0 00~-~ CC) 00 CC)CCJ 00 0)0) ~ 0000000 0 r~ o~ r~ (0(00000 0 00 0 ~ CC) CC) CC) 00 00 0) ~0) CC) CC) 0) ~ 00 ~~~~(DCC) 1~- (0 0 o 0~ - C~J ~ F~ 0)l~ 00 ~00) ~ 00 ~(ooor~ 00 CC~ C'J (0 ~ 00CC. 0) ~Ø0) CC)0) I-. LU 00 U- 0 C,) Cl) C~) -J C,, 0 C-) -J C, 00 0 0 -J 00 00 01: >~ C,) >- 00 -J > > 00 (`-I LU > 01: -J LU 00 LU -J 00 I- .0 00 LU C,) 00 CC: 0(0 ~5 0 PAGENO="0158" PROBLEMS IN THE LU QOO~-~ `-° ~ ~ ~ ~ c~''> ~ C~J `0,- c))00~r.~ = ~ ~ I~ N. 0000 ~ c'J 0) - ~ ~ .~ ~ ~ ~ ~ ~ 0)> c,J > > E 0 U. 0 E 13408 COMPETITIVE Cl) = I- LU C.) C'., > 0 0 C.) C,, 0 C.) -J CD 0 0 0 -J 00 0 LU Cl) >. 00 -J > > C') LU > -J LU LU -J 00 DRUG INDUSTRY 00 *00 0 C..) ~ 0) ~ PAGENO="0159" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13409 LU 00 C~JC~) C,, ©O ~ a) ~ .~ ~ 8~ E ~ ~ ~ ~ ~ 0 - z ~ ~ 0 Q >~ ~ ~ ~ I ~ 0 _J~ a) ~ ~ .&~th*~ ~ I- ~ 0 r~. ~ r% ~ C~J~C~) `~J~OC~-~ PAGENO="0160" 13410 COMPETITIVE PROBLEMS LU C,, IN THE DRUG INDUSTRY (00)0) (00)0)) 0)0)_ 00-0) 0)0) 0) z LU C,, 00~~'; LU C,, LU C,, ~ 00 LU C,, ~ ~ z E Li. 4) 5 00000)0 0 - (0(0000) 0)00- 0) 00 r~ 0) 000000 00000)) 0)J 00 0)) 0000 C)) (0(0~ 00 (0(i) ~ 00 ~,j ~J C') C~) 0)00 H 0) 00*** 0) 0) 0)) C') 0) - C') 0) CO = I- LU 0) 00 -J C.) CO > 0 0) 00 C.) o CO 0) C.) 4) -J CO 0) 0 00) 0 = CO 00< LU CO >.~ 00 _J 0) >~; 00 0. C') LU > I- -J LU 00 LU -J 00 C') 00(00)) 0)0)0)- (000(0(0 000)0)00 (00) 00 00 0) 0000 C') 0) H LU C,) ~- `O.~ 0000 ~()0)0)0) >(0)0)0)0) 00 PAGENO="0161" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13411 00 00 ~ ~`. o~ N) 00 N. 00 ~ CC) - CC)COCC CL) *~ C)) 0000 C) 00 C) 0)000)00 0)0 N. - E ~ ~. .2 ~ 00 00 00 2 00 c~ o C., ~ E ~ ~.. a.'. >. 2 00 00 00 0) 00 - C)) U) N) CC) CC ~ CC) CC) ~j ~ 000NJ NJ *~ 00 C) 000)00 r~ 0)000)0 0)0N. 00 ~ o~ C,, I ~C 2 -J ~ E d ~**~ ~ = U) C)COC 2 00~OO00 0L~. >. . 00 00 00 co ~ I. 2 00 ~ 00 - LU -J 00 CC CCCC) U) U) ~ 00 0)000000 N. 0000 CC CC 8 E o~*~ ~ 00~~* 22 0 00 C') ~ CC) CC N. (ON. ON) (CC) NJ 00 0 NJ C) 000000 C) COON. 00 N. 00CC - - 0 00 00 .CC: ~:~: ~:~: ~: ~:~: co LJJLU *- `.~ 0CC)u5(I) ~0 ~ OCC)U)C#) 2 PAGENO="0162" 13412 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY C~) ~ (0 (000 u~ 00 C~ 00000 e.i 000 ~ 0 r~ r~c~J 0 2 ~ E o°~ o~ ~ 0 0 0) - 00 ~ ~*** a... C) I ~ 0 00 ~; ::::,: ::i:,:; ::::: 2 0 0 ~ ~ 00 ~ -J 00 0 0 ~ ~ 0 0 0 HE~~ ~ ~ 0 00 .~* o,0 0:0: ~ 00 LULU ~ LULLJ ~UJ~'LU z 0 CI) ~ CI) - Z 0 ~ c~ Z 0 c'~ -i 2 PAGENO="0163" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13413 [From The New York Times, luly 8, 1976] A.M.A. AIDE LET UPJOHN USE LETTER To SElL DRUG (By David Burnham) WASHINGTON, July 7-The chief executive officer of the American Medical As- sociation wrote a letter early this year to state and county officials of the ~tsso- elation minimizing questions that had been raised in the association's own maga- zine about the safety of a widely used diabetes drug. The official, according to confidential A.M.A. documents, then permitted the 1,100 salesmen of the largest manufacturer of the controversial drug to use his letter in their sales talks despite a warning that such use violated A.M.A. pQllcy and might prove embarrassing. Details about the distribution of the letter, written by Dr. James H. Samn~ons, executive vice president of the A.M.A., became known as the Food and Drug Ad- ministration published today a proposed rule requiring a new label for the drug stating that it may lead to death from heart disease. The drugs are often called oral hypoglycemic drugs. They are taken by mouth by an estimated 1'/2 million adult diabetics to lower blood sugar level. The pills are believed to represent a $100-million market for the pharmaceutical industry. Dr. Sammons sent his letter concerning oral hypoglycemics to the executives of state, county and medical speciality societies on Jan. 28. The letter said that the Feb. 10 issue of The Journal of the American Medical Association would contain both an article and an editorial raising questions about the drugs. I Dr. Sammons said that the article, by a committee of the Biometric Sodiety, supported an earlier critical study of oral hypoglycemics that had been challenged by some other scientists. He reported that the editorial, written by Dr. Thomas Chalmers, formerly with the National Institutes of Health, alleged that the drug might be associated with as many as 10,000 to 15,000 unnecessary deaths a year in the United States alone. "A considerable body of expert scientific opinion contradicts these published findings," Dr. Sammons wrote. "Diabetic patients should not be influenced by press reports, and should continue on whatever diabetic management program their own physician had prescribed." Shortly after Dr. Sammons wrote his letter, the Upjohn Company requested permission to reprint it for use by Upjohn salesmen. The company manufactures two oral hypoglycemic drug products under the brand names Orinase and Toll- nase. The Upjohn product Orinase has been for years the most widely used o~ the oral hypoglycemic drugs. An A.M.A. staff lawyer said in a memorandum dated March 18 that the "policy of the A.M.A. is that the association's name may not be used for trade purpo~es." "Permission to reprint A.M.A. materials has not been granted if there is any indication that the name of the association or its materials will be used in any manner that might directly or indirectly be construed as an endorsement b~ the A.M.A. of a particular product or manufacturer," the memo said. The staff lawyer, Betty Jane Anderson, said that if this policy was waived, "Dr. Sammons should be cautioned that the use made of the letter by Upjohn salesmen may cause embarrassment to him personally or to the A.M.A. COMMENT BY COMPANY The lawyer added that "Upjohn's purpose could be better accomplished by having an article presenting the other side of the controversy published in The Journal of the American Medical Association." A notation at the bottom o~ the memorandum indicated that a copy of it had been sent to Dr. Sammons. A spokesman for Upjohn, reached at the company's headquarters in Michigan, said that the A.M.A. had granted the request for use of the letter, and that copies of Dr. Sammon's letter had been given to each of the company's 1,100 salesMen. The spokesman was unable to say how frequently the letter had been used. The warning that the Food and Drug Administration proposed requiring on the PAGENO="0164" 13414 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY label of the drugs would be set in boldface type and would say: "Oral hypogly- cemic drugs may be associated with increased cardiovascular mortality as corn- pared to treatment with diet alone or diet plus insulin." Cardiovascular mortality means death from disorders of the heart and cir- culatory system. ADVANTAGE AND RISK The warning would indicate that the drugs should be used only for adult pa- tients not totally dependent on insulin, whose blood sugar cannot be controlled by diet alone and who can not or will not take Insulin. The warning would also say that the doctor should inform the patient of the advantages and potential risks of the drugs, and that the patient should partici- pate in the decision whether to use them. The F.D.A.'s warning would apply to a number of oral drug products in addi- tion to the two manufactured by Upjohn. These include: Diabinese, Pfizer, Inc.; Dynelor, Eli Lilly & Co.; two forms of a drug called DBI, Geigy Pharmaceuticals; two forms of the drug Meltrol, USV Pharmaceutical Laboratories, Inc., and the drug Tolbutamide from Premo Pharmaceutics Laboratorities, Inc. [Excerpt from The Pharmocological Basis of Therapeutics, Pifth Edition, Goodman and Oilman] ORAL HYPOGLYCEMIC AGENTS History. An important event in the history of the treatment of diabetes mel- litus was the introduction of orally effective hypoglycemic agents. Janbon and coworkers (1942), in the course of clinical studies on the treatment of typhoid fever, discovered that a sulfonamide (p-amino-benzene-sulfonamido-isopropyl- thiadiazole) induced hypoglycemia. Janbon's colleague Loubatiêres (1957), made the fundamental discovery that the compound exerted no hypoglycemic effect in the completely pancreatec,tomized animal and suggested that the action was the result of stimulation of the pancreas to secrete insulin. There was no practical application of these findings until Franke and Fuchs capitalized on the discovery that the antibacterial agent carbutanvkie lowered the blood sugar In patients treated for infectious diseases. These workers demonstrated the apparent usefulness of carbutamide in the treatment of diabetes mellitus. Soon thereafter, the compound tolbutanUde was introduced. This substance is not antibacterial, is less toxic than carbutamide, and soon became popular for the management of certain diabetic patients. Tolbutamide is a member of the class of oral hypoglycemic agents designated as sulfonylureas. Another group of compounds, the biguanides, was developed independently of the sulfonylureas. Historically, the development began with the discovery In 1918 by Watanabe that guanidine is hypoglycemic in rats. Guanidine and its substituted derivatives were found to be too toxic to be therapeutically useful. Diguanides, two guanidine molecules joined by a chain of methylene groups, were more effective and less toxic than the substituted guanidines. SYNTHALIN A, a potent diguanide, was given clinical trial in diabetes, but it also was found to be too toxic for therapeutic use. Finally, phenformin (Ungar et al., 1957), a member of the biguanide series (derived from two molecules of guanidine with elimination of ammonia), was found to have an apparently acceptable toxicity, and this compound has since had widespread use. STILFONYLUREAS Chemistry. A number of sulfonylurea compounds exert hypoglycemic activity. The commercially available preparations are tolbutarnule, acetohewamuie, toZa,~iamide, and civiorpropamide, which have the following structural formulas: PAGENO="0165" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13415 ,CH2~-CH2-CH2 H3C_~))-SO2~NH-C-NH~N\ CH2-CH2----CH2 Tokizamide CI_ SO NH-~-C--NH -(CH2)2CH3 Chiorpropornide All of the effective compounds are arylsulfonylureas with substitutions on the benzene and the urea groups. In the case of tolbutamide, the aryl group is tolyl and the urea substitution is butyl. Tolbutamide differs from the antibacterial compound carbutamide in having methyl instead of amino on the benzene ring. This substitution accounts for the loss of antibacterial properties and for the reduction of toxicity. Mechanism of Action. The sulfonylureas stimulate the islet tissue to secrete insulin. The evidence, coming as it does from a variety of experimental and clinical studies, unequivocally supports such a conclusion. Administration of sulfonylureas increases the concentration of insulin in the pancreatic vein in cross-circulation experiments. Recipient animals, diabetic or nondiabetic, ex- hibit hypoglycemia in response to. the infusion of pancreatic vein blood from donor animals treated with sulfonylureas but not to the infusion of mesenteric or femoral vein blood from the same animals. Sulfonylureas cause degranulatlon of the p cells, a phenomenon associated with increased rate of secretion of ii~su- lin. Clinical studies demonstrate that the sulfonylureas are ineffective in com- pletely pancreatectomized patients and in juvenile-onset diabetic subjects. On the other hand, they are effective in maturity-onset diabetic patients in whom the pancreas retains the capacity to secrete insulin. Tolbutamide Acetohexamide PAGENO="0166" 13416 CO~ETITIVE PROBLEMS IN THE DRUG INDUSTRY Although the molecular mechanism of action of these agents is not understood, several pertinent observations have been made, Hellman and associates (1971) concluded that labeled tolbutamide is restricted in its action to the extracellular space and does not need to enter the p cell. The invoked release of insulin is immediate and is intimately related to the action of glucose; the drug may sensitize the cell to the normal secretagogue (Widstrorn and Cerasi, 1973). Sulfonylureas do not increase the secretion of glucagon. Extrapancreatic effects of the sulfonylureas have been noted in various organs, and certain of these may potentiate the effects of insulin. A reduction in the hepatic uptake of endogenous insulin has been described (Marshall et of., 1970). Tolbutamide enhances the antilipolytic action of insulin in adipose tissue. This appears to be related to an altered effectiveness of cyclic AMP rather than to any change in metabolism of the cyclic nucleotide (Brown et of., 1972; Fain et al., 1972), and an inhibitory effect of the drug on cyclic AMP-dependent protein kinase has been observed (Wray and Harris, 1973). Other reports indicate a variety of influences on cyclic AMP metabolism in different tissues (Brooker and Fichman, 1971; Kuo et al., 1972; Lasseter et of., 1972); their significance is diffi- cult to assess. Duration of action, fate, and excretion. The sulfonylureas are absorbed from the gastrointestinal tract and hence are effective when given by mouth. The most important difference among the sulfonylureas, for clinical purposes, is in their duration of action; in increasing order they are tolbutamide, acetohexamide, tolazamide, and chiorpropamide. Tolbutamide can be detected in the blood within 30 minutes after oral adminis- tration; peak concentrations are reached within 3 to 5 hours. The drug is bound to plasma proteins. Tolbutamide is oxidized in the body to butyl-p-carboxyphenyl- sulfonylurea, which is a major excretory product. The half-life of tolbutamide is about 5 hours. Two or occasionally three doses are required daily. Acetohea~amide is rapidly absorbed, and maximal hypoglycemic activity is observed about 3 hours after ingestion. The total duration of action is 12 to 24 hours. Much of the activity is ascribable to a metabolite, hydrocyhecamide, which has a plasma half-life of about 6 hours; the parent compound, acetohexamide, has a plasma half-life of 11/3 hours. In persons with normal renal and hepatic function, more than 80% is excreted, largely as metabolites, in 24 hours. Two doses are usually required daily. Tofaza~mide is slowly absorbed; the onset of hypoglycemic action occurs at 4 to 6 hours and persists at a significant level up to 15 hours after a single dose. Tolazamide is metabolized to a number of hypoglycemic substances that are largely excreted by the kidney. For most patients controlled by tolazamide, a single daily dose is sufficient; a few patients require administration of the drug twice daily. Chlorpropanvtde is also rapidly absorbed from the gastrointestinal tract and is bound to plasma proteins. In contrast to tolbutamide, chiorpropamide is not metabolically altered to any significant degree and is excreted very slowly in unchanged form. The half-life of a single dose is about 36 hours, or seven times as long as that of tolbutamide. With daily doses of 250 to 500 mg, blood concen- trations may not be expected to reach a plateau before 3 or more days. Chlorprop- amide is administered in a single daily dose. Toxicity. O'Donovan (1959) analyzed the incidence of side effects to tolbut- amide in 9168 cases. The total incidence of side effects was 3.2%; the drug was withdrawn in 1.5% of the patients. The reactions have been classified as hemato- logical (0.24%), cutaneous (1.1%), and gastrointestinal (1.4%). Of the 22 subjects exhibiting hematological abnormalities, 19 had a transient leukopenla; in 9 instances, the leukocyte count returned to normal despite continuation of the drug. Paresthesia, tinnitus, and headache may also occur. The total incidence of untoward reactions is about 6% for ch~orpropamide (hematological, 0.6; cutaneous, 3; gastrointestinal, 2; and jaundice, 0.4%). The jaundice is of the cholestatic type and is usually transient. Hyponatremia has been reported in a small number of patients treated with tolbutamide and chlorpropamide. Experience with acetoheo~amide and toks~zamide suggests that the frequency and the kinds of toxic reactions are similar to those encountered with tolbut- amide and chiorpropamide. Hematological (leukopenia, agranulocytosis, throm- bocytopenia, pancytopenia, and hemolytic anemia), cutaneous (rashes, photo- sensitivity), gastrointestinal (nausea, vomiting, rarely hemorrhage), and hepatic PAGENO="0167" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13417 (increased serum alkaline phosphatase, cholestatic jaundice) reactions have been reported. Hypoglycemic reactions, including coma, may occur (Seltzer, 1972a). While they are usually not severe, several fatalities have been reported. Hypoglycemic episodes may last for several days so that prolonged or repeated glucose ad- ministration is required. Reactions have occurred after one dose, after several days of treatment, or after months of drug administration. Most reactions are observed in patients over 50 years of age, and they are more likely to occur in patients with impaired hepatic or renal function. Overdosage or inadequat~ or irregular food intake may initiate hypoglycemia. Drugs that may increase the risk of hypoglycemia from sulfonylureas include other hypoglycemic agents, sul- fonamides, propranolol, salicylates, phenylbutazone, probenecide, dicum~rol, chioramphenicol, monoamine oxidase inhibitors, and alcohol. Sulfonylureas should not be used in a patient with hepatic or renal in- sufficiency because of the important role of the liver in their metabolism an4 of the kidney in the excretion of the drugs and their metabolites. Intolerance to alcohol reminiscent of the disulfiram reaction has occurred occasionally in pa- tients taking sulfonylureas. These `agents are also not recommended for use in pregnancy, but only s$rse data have been reported on this point. Teratogenesis in animals has been ob- served to follow the administration `of large doses. A cooperative clinical trial in 12 university-based clinics (University Group Diabetes Program; UGDP) was established in 1961 to determine if the cor~trol of blood glucose concentration helps to prevent or delay vascular disease in non- insulin-requiring diabetic patients. About 200 subjects in each of five thbra- peutic regimens were treated with diet and either placebo, a standard dose of tolbutamide, a standard dose `of insulin, a variable dose of insulin, or a standard dose of phenformin. During a period of over 8 years of observation, there were 120 deaths, in- cluding 87 from cardiovascular causes; while 10 to 12 cardiovascular deaths occur- red in each of the placebo or insulin groups, 26 such deaths (a significantly bi~ber number) were recorded among the patients in each group taking oral hypoglyce- mic agents. The overall mortality rate was correspondingly higher in these two groups of diabetic patients. The conclusions of thjs study were that the comb~na- tion of diet and either tolbutamide or phenformin was no more effective in pro- longing life than diet alone; furthermore, it was felt that diet and either tol- butamide or phenformin may. be less effective than diet aYone or diet together with insulin in preventing cardiovascular mortality. (See University Group Dia- betes Program, 1970; Knatterud et al, 1971.) Since the UGDP report, a flood of comments and reports have appeared, J~oth critical (see Seltzer, 1972b) and supportive of this massive study. However, no warning has yet been included in the package inserts for these drugs, and there have now appeared a "second generation" of even more potent sulfonylureas (gli- midine and glibeiu,lamide), which are in clinical use in Europe and elsewi~ere. Additional studies have continued to indicate an increased incidence of seri- ous difficulties in patients taking oral hypoglycemic drugs. More episodes of ventricular tachycardia and ventricular fibrillation were noted in such diabetic subjects, usually during the early stages of acute myocardial infarction, al- though there was no difference in the number of deaths (Clayman, 1974; Soler et a!., 1974). Patients taking oral hypoglycemic agents in England have I~een reported to have twice the incidence of myocardial infarctions observed in ~ub- jects being treated with diet alone (Boyle et al. 1972; Hadden et a!., 1972). Furthermore, at the instigation of the Director of the National Institutes of Health, the Biometric Society appointed a committee to review the UGDP re- port. The committee concluded that the shortcomings of the study do not in- validate the observations and conclusions, the most pertinent of which are described above, and that other studies do not contradict that of the UGDP. (See Chalmers, 1975; Report of the Committee, 1975.) Preparations and Dosage. Tolbutamide, U.S.P. (0RINA5E), is marketed in the form of 500-mg tablets. The sodium salt (1 g) is also available for administra- tion intravenously for diagnostic use. Aoetohe~rarnide, U.S.P. (DYMELOR), is atail- able in 250- and 500-mg tablets. Tolazarnide, U.S.P. (T0LINAsE), is supplied in 100-, 250-, and 500-mg tablets. Uhlorpropamide, U.S.P. (DIABINE5E), is marketed as 100- and 250-mg tablets. PAGENO="0168" 13418 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The usual daily dose of tolbutamide is 1000 mg, while 2000 mg is the maxi- mally effective total dose; corresponding dosages are 500 and 1500 mg for acetohexamide. Tolazamide and chiorpropamide are usually administered in a daily dosage of 250 ing, while 750 to 1000 mg is maximal. Therapeutic Uses. The sulfonylureas should be used only in subjects with diabetes of the maturity-onset type who cannot be treated with diet alone or who are unwilling or unable to take insulin if weight reduction and dietary control fail. The physician must realize that he is using these agents only to control symptoms associated with hypoglycemia, and that dietary control with or without insulin is more effective for this purpose. There is no evidence that the oral hypoglycemic agents prevent cardiovascular complications from diabetes, and the best data available suggest that the incidence of such complications Is increased in patients taking these drugs. This is obviously too high a price for the convenience of an oral agent, unless all other measures have been exhausted. In general, the likelihood of adequate control with an oral hypoglycemic agent is inversely proportional to the dose of insulin required to maintain the patient. When the insulin requirement is in excess of 40 units per day, the chances of success are relatively low. The sulfonylureas are of no value in the juvenile- onset type of diabetes, in which the pancreas has lost all or nearly all of its capac- ity to secrete insulin. However, whatever the age of onset, in unstable, ketoacidotic diabetes, sulfonylureas will not provide adequate control. such patients require insulin, and attempts to control them with oral therapy are dangerous and doomed to failure. Deaths from acidosis and dehydration have occurred in patients with unstable ketotic diabetes in whom regulation was attempted with sulfonylureas. There is no fixed dosage of sulfonylurea to be used in diabetes mellitus. Treat- ment is guided by the individual patient's response, which must be frequently monitored with chemical determinations, because the requirements change from time to time. The mildly diabetic patient, whose insulin requirement is fewer than 20 units daily, can be started on the usual dose of the agent chosen, and at the same time all insulin is discontinued. The dose is then adjusted up or down, depending on the patient's response. In the instance of chiorpropamide, about 3 days is required to attain steady-state concentrations in blood. Consequently, upward adjustments of dose should be made at 3-day intervals. Patients of advanced age should begin with about half the usual daily dose, for some are very responsive to sulfonylureas and may develop severe hypoglycemia after usual doses. During the period of initiating treatment, all patients should test their urine four times daily and communicate the results to the physician daily. The patient who requires more than 20 and fewer than 40 units of insulin daily should be started on the usual dose of the chosen agent and his insulin dosage should simultaneously be reduced by 50%. Phereafter, guided by the patient's response, insulin dosage is progressively reduced and eventually dis- continued. Sulfonylurea dosage may need adjustment. The patient requiring more than 40 units of insulin daily should be given the usual dose of the agent chosen and his insulin dosage should be reduced by 25%. Insulin is then cautiously withdrawn and eventually discontinued, and sulfonyl- urea is adjusted according to the observed response. It is to be emphasized that the chance of success is relatively poor. In the patient who requires more than 40 units of insulin daily, it may be desirable to carry out the attempted transfer to the sulfonylurea therapy in the hospital to provide assurance against develop- ment of dehydration and acidosis. Stimulation of the pancreas of the maturity-onset diabetic can often maintain these subjects under ordinary circumstances. However, when insulin require- ments are increased, as fever, surgical interventions, or trauma, the sulfonylureas are inadequate and the patient must be given Insulin to carry him through such critical situations. Weight reduction is of the greatest importance in the treatment of diabetes. A vigorous effort must be made by the patient and the physician to reduce the patient's weight as an integral part of diabetic treatment, irrespective of the drug chosen. Patients whose diabetes is not controlled by sulfonylureas from the initiation of treatment are said to experience "primary failure." Patients whose diabetes is regulated for a month or more after beginning sulfonylurea treatment, fol- PAGENO="0169" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13419 lowing which inability to maintain control developes, are said to experience "sec- ondary failure." The incidence of this type of failure may be very high, regard- less of the agent chosen. In patients with pancreatic islet-cell tumors, the blood glucose concentration drops rapidly after intravenous injection of tolbutamide and remains low for about 3 hours. A similar effect is not observed in other hypoglycemic states, and tolbutamide administration can thus be used as a diagnostic test. Serum in~- munoreactive insulin determinations should also be performed. Care is necessary, since fatal hypoglycemia has occurred. In addition, reports have appeared of the successful treatment of reactive hypoglycemias due to a variety of causes with sulfonylureas (Anderson and Herman, 1971). BIGUANIDE5: PHENFOEMIN Chemistry and Preparations. The only commercially available preparation in the biguanide series of hypoglycemic agents is phenformin. Its structural formula is as follows: ~ Phenformin Phenformin Hydrochloride, U.S.P. (DBI, MELTR0L), is marketed as 25-mg tablet$ and as a 50- and 100-mg time-disintegration capsules. Mechanism of Action. The biguanides differ significantly from the sulfony- lureas in the mechanism of their hypoglycemic effect. Thus, phenformin does not act by stimulating secretion of insulin by the pancreas, hypoglycemia is not readily induced in normal human subjects, the concentration of insulin in the plasma is not increased, and the morphology of the fi cell is uninfluenced. Basically, three actions have been described. In vitro, phenformin, in relativelV large doses, increases glucose utilization by enhancing anaerobic glycolysis (see Williams and Porte, 1974). This is thought to occur as a result of, or coincident with, an inhibition of cellular respiration. As a result, adenosine triphosphate (ATP) concentrations fall and those of lactate increase. A second action of the drug is to decrease gluconeogenesis (see Gordon and de Hartog, 1973; Haecke~, 1973). The third and most recently recognized is inhibition of intestinal absorp- tion of glucose ard probably certain other substances as well; for example, decreased absorption of vitamin B1, has been observed (Berger et al., 1972). Phenformin does not act in the normal subject (at least as readily as it does in the diabetic), presumably because the increase in peripheral glucose utiliza- tion Is compensated for by an increase in hepatic glucose output. Phenformin has been used experimentally to correct the hypoglycemia that may follow abnormally rapid intestinal absorption of glucose (Permutt et al, 1973). Absorption and Duration of Action. Phenformin is adequately absorbed frota the gastrointestinal tract. The drug has a short half-life (3 hours) and a corr~- spondingly brief duration of action. The hypoglycemic effect may be prolonged to between 6 and 14 hours with the use of timed-disintegration capsules. Toxicity. Phenformin may cause a metallic taste, nausea, anorexia, vomiting, diarrhea, or cramps in some patients, particularly if the dose is greater than 200 mg per day. Reduction of the dose or withdrawal of the drug results in prompt disappearance of the untoward reactions. Weight loss and weakness may som~- times occur. The cause of ketonuria during phenformin therapy has been the subject Of debate. It is most common in patients with unstable juvenile-onset diabetes treated with a combination of insulin and phenformin. While it may at times re- flect an insufficient insulin dosage, at other times it is associated wfth normal plasma glucose concentrations. Therefore, in patients taking both insulin ai~d phenformin in whom ketosis develops, plasma glucose concentration should l~e measured before the insulin dosage is increased, to avoid hypoglycemic reactions. 56-592 0 - 75 - pt. 28 - 12 PAGENO="0170" 13420 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The recommended treatment for ketosis with normal plasma glucose concentra- tions is a reduction of phenformin dosage or an increase of dietary carbohydrate intake. Increased concentration of lactic acid in the blood without ketosis has been reported to occur in patients with severe renal or cardiovascular impairment under phenformin treatment. However, the drug may not contribute to the lactacidemia, since such severely ill diabetic patients may exhibit lactacidemia even when treated with insulin. Results obtained with phenformin in the UGDP study are discussed above. Diabetic subjects with severe hepatic or renal insufficiency or congestive heart failure are not suitable candidates for oral hypoglycemic therapy. Almost no data are available concerning the effects of phenformin in pregnancy, and its administration during pregnancy is currently not recommended. Therapeutic Uses. Phenformin is used in the treatment of maturity-onset dia- betes according to the principles presented above for the sulfonylureas. The patient is started on two tablets, 25 mg each, one before breakfast and the other before supper. The dose is increased until control of the diabetic state is attained or until digestive disturbances limit further increase in dosage. The total daily dose is usually somewhere between 100 and 150 mg. However, doses as high as 400 mg per day are tolerated by some patients. A single 50-mg, timed-disintegra- tion capsule may be substituted as the equivalent of two 25-mg tablets in divided doses. It is claimed that about 70% of maturity-onset diabetic patients who are im- perfectly controlled by either a sulfonylurea or phenformin alone respond favor- ably to the concurrent use of these agents (Beaser, 1960; Unger et al., 1960). The fact that the sulfonylureas and the biguaniles act by different mechanisms to reduce hyperglycemia lends support to this contention (see Breidahl et al., 1972). However, since the indications for the use of either phenformin or a sulfonylurea are now severely constricted, such combination therapy should represent the choice of the physician who has exhausted every other alternatitive. PAGENO="0171" COMPETITfl~E PROBLEMS IN THE DRUG INDUSTRY 13421 SE WESTERN RESERVE UNIVERSITY `CLEVELAND, OHIO 44106 August 21,1975 Hearing Clerk Food and Drug Administration Room 4-65 5600 Fishers Lane Rockville, Maryland 20852 Dear Sir: I regard it as a privilege to have this opportunity to discuss the proposed FDA labeling on the use of oral hypoglycemic agents. It is indeed appropriate that such direct action has finally being taken if the scientific basis for medical practice is to have any real significance. The heated discussions that followed the publication of the findings of the longest and largest prospective controlled clinical trial in the history of therapeuti~s serve only to point up the critical issues involved in the practice of medicine today. These issues involve the crucial question as to the basis for the judgement of the physician for choosing the optimum treatment for the patients entrusted to his care. Is the decision to be based on ttclinical impression", anecdotal stories and wishful opinions, or will it be based on substantial evidence from adequate, well-controlled clinical investigations? If modern medicine is to have a firm foundation in basic and clinical science the wisdom of the Drug Amendments of 1962 resulting from the thalidomide disaster becomes crystal clear. The scientific design, merit or validity of the UGDP study has been amply confirmed by the most intensive and extensive reviews in the history of medicine. When the evidence of excessive cardio- vascular mortality first surfaced after several years of the trial~ outside consultants were brought in to review the data independent~y. After the report was made public at the A.D.A. meeting in St. Loui~ in June of 1970, separate peer review committees appointed by the American Diabetes Association, the A.M.A. Committee on Drugs and the Medical Letter accepted the basic conclusions of the study. Because of the alleged contradictory findings from other studies, none of which approached in any way the magnitude or relevance of the UGDP study an elite committee of the internationally based Biometrics Society over a period of two years reviewed all these controlled trials and in their report published on February 10, 1975 the J.A.M.A. caine up with essentially the same conclusions and recommendations. This report like the UGDP reports will stand as nonumental and classical papers in the history of clinical medicine. 3partrnent (if ~i4edicine kesith' Hospital PAGENO="0172" 13422 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY August 21, 1975 Page 2. Whatever other fragmentary data that has appeared since 1970 have only served to support the general conclusions. It is interesting to me that the total efforts of the Committee on Ca~'e of the Diabetic has been directed to the criticism and denigration of the UGDP study and that no sound scientific evidence has been brought forth since the introduction of the oral hypoglycemic agents in 1955 to show any long-tern benefit whatsoever. It is a sad commentary that despite the expenditure of some 10-15 billion dollars by the diabetic public throughout the world over these twenty years, the drug companies and their adherents have failed to come up with any studies that adequately prove that any reduction in morbidity and mortality has resulted from the long-term use of their drugs. If the logical concept of scientific proven benefit over risk as defined by the laws established by Congress in 1962 is to have any meaning for the twenty million to 30 million diabetic patients 111 the world the strongest possible warnings clearly stated should be implemented as soon as possible. The UGDP studies were published in 1970 and yet by August 1975 no clear labeling warning has as yet been issued by the government agency responsible by law to protect the American public. I would appreciate having a transcipt of the hearings of August 20th, 1975 when they are available. Very truly yours Max Miller, M. D. Professor PAGENO="0173" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 13423 PRESEN1~ATION OF SIDNEY H. WOLFE, M.D. AND ANITA JOHNSON, PUBLIC CITIZEN' S HEALTH RESEARCH GROU~', to the FDA HEARINGS ON PROPOSED LABELLING FOR DIABETES DRUGS August 20, 1975 It is now more than 5 years since the findings of the University Group Diabetes Program (UGDP) were presented at the American Diabetes Association annual meeting. Despite the findings of increased cardiovascular mortality in patients taking oral diabetes drugs and their lack of efficacy, their use has continued. Over the last 5 years, however, several of the largest diabetes treatment centers have swung strongly away from using these agents. The question is, why are 1 1/2 million American adult onset diabetics being given drugs costing more than 100 million dollars per year, killing an estimated 10-15,000 patients per year and not having any demonstrable benefits in treating diabetes? There are three reasons which appear to explain this irrational state of affairs: 1. The pride of physicians 2. The inadequacy of most diet programs for diabetics 3. The profits of the drug industry 33 Pride As candidly stated this year by Dr. Frank Davidoff -- Professor of Medicine a~ diabetes specialist for the University of Connecticut Medical School -- and probably unspoken but thought by thousands of other physicians, pride plays a major role in the continued prescribing of these drugs by doctors in the face of evidence to the contrary. (Testimony - Sept. 19, 1974, Senate S~nall Business Subcommittee). "It is one thing to challenge the safety of a drug . . . . But to be told that the drugs we had been giving to diabetics for 12 years were unnecessary, beside the point, in a word ineffective, was, as I see it, a more serious blow to our professional pride.' We submit that the pride of doctors is standin9 in the way of giving the best treatment to their patients and that this is irresponsible medicine if not malpractice. ~.L ~ According to Dr. Ethan Sims, diabetes specialist and Professor of Medicine at the University of Vermont Medical School, "If we grant that there are 1 1/2 million patients reportedly taking oral agents and that 50% are grossly overweight, we have 750,000 patients with diabetes and obesity who are probably also less physically active than they should be. If we assume that 90% of them are not exposed to any vigorous and comprehensive regimen such as that at the Grady Hospital, 675,000 are left with their obesity essentially untreated and 4 Out O~ 5 are taking an agent which increases their obesity. The taking of oral medication lulls both physician and patient into believing that something worthwhile is being accomplished, while the options which could PAGENO="0174" 13424 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY -~- make a fundamental difference in a patients life and survival are being neglected." (ibid, Senate Hearings) Dr. John Davidson, Director of the Grady Hospital (Atlanta) Diabetes Unit which has been very successful in getting diabetics off of the oral drugs, has said, "Why do so many physicians have little success in treating it? (the problem of obese diabetics]. * . . In my experience, at least 80% of diet therapy failures are due to physician failure, not patient failure." (ibid, Senate Hearings) 3) Profits In a letter to the FDA, requesting to speak at this hearing. B .R. Allen of Upjohn commented that: "The proposed class labelling of oral diabetes drugs. is, in our view, inappropriate, uninformative, and hence mis- leading. Translated into English, Upjohn -- which has about 40% of the $100 million American market for oral diabetes drugs -- doesn't want its leading money-makers -- tolbutamide (Orinase) and tolazamide (Tolinase) -- to suffer in sales andprof its just because scientific studies show the drugs are ineffective and extremely dangerous. That the extraordinary profits of Upjohn, Pfizer, Ciba-Geigy and Lilly -- who have cornered this several hundred million dollars per year worldwide market for these drugs -- has had a major effect on the irresponsible delay in ending the massive misuse of these drugs is not arguable. In addition to sponsoring hundreds of "educational" symposia around the country -- with academic facades -- intended to assure doctors that these drugs are 0.R., the drug industry has kept the AMA alive with infusions of advertising revenue and political contributions and, in return, the AMA has written reassuring letters (Dr. Sammons) to physicians about these drugs. To demonstrate how much of a curtailment of profits would occur if the abuse of these drugs were ended, cxnsider the experience at Cleveland Metropolitan General Hospital. At the peak of use of the oral diabetes drugs (1970) at that hospital, expenditures per year were as follows: Tolbutamide Phenformin Q~naseJ~ _________ $32,376 $7,857 After use was restricted, the 1975 figures were: $6,966 $138.00 a savings of $38,000 or 78% of the $48,527 these drugs. In the face of pride, profits, and inadequate dietary manage- ment, aided and abetted by court delays, the FDA has somehow found it possible to delay for almost 5 years finalized labelling changes for these drugs. Anita Johnson will discuss our specific criticisms of the present version of proposed labelling (the third in 3 years) but I would make the following addition. Chiorpropamide jpiabinase~ $8, 294 (projected by the hospital) $3,371 1970 expenditures for PAGENO="0175" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13425 It is not enough to have labelling -- albeit strengthened -- on a product which the patients doctor has already decided to prescribe. Pat lenta oust be given information in the doctors off ice which will allow them to participate in the serious decision to use these drugs. Specifically, future use of oral diabetes agents should be preceded by a written informed consent form including, but not limited to the following information: INFORMED CONSEWF FOR USE OF ORAL DIABETES DRUGS 1. 1 have participated in a program of dietary control and physical exercise including at least 25 hours of instruction. 2. This program did not succeed iD weight reduction or control of blood sugar and Dr .___ __ told me that insulin was the preferred drug if one had to be used, 3. I refuse (or am physically unable) to ta)~ insulin. 4. I am aware of the increased risk of cardiovascular death from taking oral diabetes drugs and of the animal study showing that one of them (Tolbutanide) causes a significant increase in coronary artery disease and that therapeutic efficacy has not been proven. In light of the above I agree to take (oral diabetes drug). Date Patient's Signature Recommendations for the Label 1. The antidlabetic drugs should he indicated only for patients with symptoms from high blood sugar, whose symptoms cannot be controlled by diet or insulin. They should be used by patients who cannot be controlled by diet ~nl~' if such patients also cannot inject insulin. The label as proposed by FDA approves use in a broader group of patients those whose "symptoms cannot be controlled by diet alone and in whom insulin cannot be used because of patient on- willingness, erratic adherence to the injection regimen, poor vision, physical or mental handicap, insulin allergy, employment requirements or other factors." The FDA label essentially condones use in symptomatic patients when insulin is merely ~cgf~_njfflt to use. Mere inconvenience is not a legitimate reason, in our view, to sustain the known risks of th~se drugs. The FDA label also indicates use in patients without cymptoms. 2. The label as proposed by FDA grants an indication to patients with high blood sugar who do not have symptoms The Food, Drug and Cosmetic Act requires that all indication~ be supported by "substantial evidence," evidence from "adequate and well -controlled investigations, including ci inical investigations ` Obviously, since these patients l~ye~ no short-term symptoms of diabetefr~, such PAGENO="0176" 13426 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY -4- as dizziness, polyuria, etc. the drugs are not effective in treating short-term symptoms. Some diabetes doctors believe that they prevent long term symptoms of diabetes such as vascular deterioration. However, there is no scientific substantiation of this belief. 3. The label should state that there is substantial evidence that these drugs are ~ effective for the prevention of the long- term symptoms of diabetes. FDA has proposed new regulations for all prescription drug labels which contains the following re- quirement: If there is a cormeon belief that the drug may be effective for a certain use or if there is a coimson use of the drug for that condition, but the pre- ponderance of evidence related to such use indicates that the drug is ineffective, the package insert shall state that there is a lack of evidence that the drug is effective for that use, a. 1.112 (3)(d), 40 ~. ~ 67, 15392ff. The UGDP study demonstrated that these drugs are ineffective in preventing the long-term effects of diabetes. 4. The Warning section should state that these drugs ~ associated with increased cardiovascular mortality, without referring to the TJGDP study. The proposed warning states that the drugs !fl~ be associated with increased cardiovascular mortality and that "This warning is based on the study conducted by the U.G.D.P." together with details of that study. If the UGDP reference is retained, the other studies which confirm the tTOD? findings must also be cited. Otherwise, the warning will give the false impression that the UGDP findings are isolated and unique, which they are not. Since the UGDP study, laboratory studies have pinpointed the mode of adverse action on the heart. This mode of action has been confirmed in humans by catheterization studies. Another study has described a significant rise in ventricular fibrillation in patients on these drugs. Two epidemiological studies have shown an abruptly increased mortality among diabetics since these drugs were introduced. Three retrospective clinical trials confirm the UGDP results, as do two cohort studies, the Kanarek study, based on patients at the Joslin Clinic, and the Palumbo study based on patients at the Mayo Clinic. 5. The Warning section should not include a statement that there is controversy as to the need for the warning. The FDA proposed warning says: "Despite controversy regarding the interpretation of these results, the findings of the UGD? study provide adequate scientific basis for this warning, thereby including a statement of controversy. The 1972 lawsuit, Bradley v. Weinberger, raised this issue. Bradley, who had the habit of prescribing these drugs, sued to prevent FDA from putting a warning on the label, or, if that failed, to get a statement in the warning that there was a difference of opinion among experts concerning the need for a warning. The case was never decided on the merits. However, FDA contested Bradley stating that warnings ahould not contain disclaimers which would encumber and dilute the warning. Now FDA is reversing its position and including a "controversy" statement. We agree with FDA's earlier view that this statement is unwarranted and from a health point of view, counterproductive. Without these changes in labelling, the addition of informed consent and immediate finaliz~,~ of these improved regulations, the FDA, to the delight of the drug companies, will be condemning American diabetics to a continuation of the needless death end waste of precious h~al~h do,Liars, PAGENO="0177" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1342~7 Oral Hypoglycemic Agents * Are Worthwhile ROBERT F. BRADLEY Joslin Clinic, Boston, Massachusetts The controversy evoked by the University Croup Diabetes Program (UCI)l' results reported in December, 1970,1 and a few months later,2 has quite prnptrly rekindled the interest of clinicians in the need for intensive dietary thvra~)y *`~ the adult maturity-onset diabetic and has provided another example of po.ssth!i insidious effects of foreign compounds administered to humans. It has al..n exhumed the more basic controversy, namely, that relating to the benefits, if any. which can be gained from the rigid metabolic control of diabetes niellitns. a~ reviewed previously in the first edition of this text.3 The UCDP study by all odds had the best designed and the most lauclalk objectives of any yet undertaken. Unfortunately as they "cyeballcd" the dali week by week and month l)y month and saw first a cluster of deaths in patiiut~ treated with variable doses of insulin and then a somewhat larger cluster in thme treated with tolbutainicic, the biostatisticians held sway. Clinicians, shaken by their lack of expertise in biostatisties and forgetting that the study was nit intended to evaluate mortality results,' bo~vecl graciously to the intonationS Of those who extrapolated the data to the maturity-onset diabetic populatn)n at large. The tragedy of this issue rests both in the possibility that the implicatu)ie~ of the UCI)P study are entirely correct, arki the equal pOSsil)ility (bitt they ii~ completely invalid, i.e., that the observed cardiovascular events resulted front a ICj)OS itomy Of individi tals treated ~vith tolbutait tide or phenforinin Win) Were greater cardiovascular risks at baseline.' Regam(lk'ss of the many arguments that have l)een presented pro niitl Coil. one must keep in mind the preliminary nature of the results, namely, that th~ total cardiovascular deaths Oceinritog in the UCI)P stu(ly represented only `~ pCJ~ cent of those diabetic pal it'nts Comprising the entire study pOptllittU)fl. The sulfonylureas (carbutaniidc', tolbntaniide, chloipropanndc, acettth°'x.t midle, tohoziunkle, glybenzeyclaznide) and biguanido's (phenforinin, inotfriin!l. and bti fominin ) lower 1)100(1 glucose levels 1))' (Ii 1rmiitg flI('ClOtniSiflS. Soidi 80 effect of these oral hypoglycemic agents used singly or in combination itas boon 404 PAGENO="0178" 13428 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY J1OJWRT F. IU1ADIEY 405 well documented in appropriately sekctcd hyperglyccmic individuals and accounts for their ~vidcspread usage in the United States and other countries during the past 17 years. In many of the more responsive patic'nts with maturity- ~insct diabetes, normal 1)100(1 glucose levels are more readily attainable than with (1U~t or insulin. Despite numerous reports during the early years of their clinical use that these compounds would effectively lower 1)100(1 glucose leVelS in 50 to 75 per cent of matUrity-(~nset diabetics who ~~`crç not insulin dependent or kctoacidosis-prone and whose diabetes began at age 40 or older, physicians familiar ~vitli insidious long-term problems of the diabetic have from the beginning been concerned. that patients SO treated might be less well controlled and more prone to premature (le~'e1opmcnt of these complications than individuals treated with insulin. Experi- ence has provided ample evidence that for one reason or another oral hypo- glycemic agents lose their effectiveness at varying but relatively short intervals of time after initiation of treatment. The rate of such "secondary failure" depends upon many factors, including patient selection and dietary cooperation, thera- peutic objectives, and the manner in which the oral hypoglycemic agents are used. A lucid presentation of "primary" vs. "secondary failure" ~nd the effect their definition has upon long-term "failure" has recently been published.8 The element of convenience for middle-aged and elderly people is obvious, but always has had to be balanced agains.t the increased cost for those who took more than minimal doses and the possibility that physicians and patients alike would rely too heavily upon their effectiveness, so that diet would be either ignored or less carefully* lulloweci.. If benefit is to be anticipated from lowering blood glucose levels as ~vell as reversing lipid, protein, and other metabolic abnormalities associated with insulin (l('fkit, what should be the 1)100(1 glucose levels attained? From the early days of their use, many sets of criteria have been utilized by those involved in the study' of (lial)etie patients. In general, these have fallen into two categories: (1) those who consider the oral hypoglycemic agents effective despite blood glucose levels in excess of normal, provided the symptoms of diabetes have been relieved and remain so, and (2) others, such as Marble and his associates, including this auth ior, whose objective has been normoglyeemia and aglycosuria, in accordance with the criteria originally published by Camerini-i)avalos et al in 1957S (Table 1). In defense of the former is the fact that in many maturity-onset diabetic ))at icuts whose 1)100(1 glucose levels remain elevated despite dietary adherence, the addition of oral hypoglycemic agents lowers 1)100(1 glucose levels to a degree comparable to that readily obtained with insulin and relieves syniptoiiis, so that little would be gained by. insisting upon a more rigid standard of metabolic control. Recognizing that evidence for time lx'nefits of tight metabolic control renm:nns controversial, the adoption of such standards would seem to be reason- able. On the other hand, if it is true that protection from long-term complications is attainable only tlnough the more rigid control of 1)100(1 glucose levels, tIme latter criteria slmoulci be applie(l, ~ind if tIme standards are not aLt mined, more rmlenth&'ss application of diet and insulin if necessary is required. At l)meseiit (lie fimmulanmemital eommtrovers~' continues to be that related to the possible benefits of such control Considerable new t'vidcnce is availal)le today', unfortunately no PAGENO="0179" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13429 OIIAI. I IYI'OCI.YCEM IC ACE~TS AIU WOItTI ~ !"~`~ Table 1. Josli:a Clinic Standard for Bk~d Cb:co.~' Control in Diabetic Patients `i:rc:tcd wit/a Oral Ilypoglyecm ic Coin pounds: Standards of Control 0:1(1 Dcgrcc of (:o,zirolf ft ELATION TO FOOl) GOOD FAIlS Tilood Urine l3loocl Urine . Sugars ~`nig./iOO an?.) Sugar (per cent) Sugarf (mg./lOO niL) Sugar (per cent) Fasting 110 Trace 130 0.1 All 1 hr. p.c. 2 hr. p.c. 150 130 0.3 0.1 * 180 150 0.5 0.3 oIhe~ ca~cs 3 hr. pc. 110 Trace 130 0.1 - °For purpose of classification as to degree of control 70 per cent or more of vahws mant conform with standards listed in the table. ~ These standard values are the highest acceptable. lChtcosc as determined by the Soniogyi-Nclson procedure. mqre COnClUSIVe than the data of 20 years ago. Meanwhile the practicing phvsi. clan is busily and assuredly attempting to lower blood cholesterol levels, l,ut i~ not certain how assiduously to work toward lowering blood glucose levels, and if so, how much. A major concern has been the possil)ility that these oral agents might pro. duco or allow the earlier development of the following: (1) islet cell failure with consequent decompensation of endogenous insulin function and greater activity of the diabetes; (2) infections; (3) neuropathy; (4) cataracts; (5) onset or annie rapid progression of niicroangiopatlay; and (6) greater morbidity and/or nmr~ tality from accelerated macroangiopathy, particularly that involving the coronar>~, cerebral, and peripheral vaseulature. Because no good evidence had ever be~a presented to suggest that oral hypoglycemic agents were "antidiabetic,' which would mean that, they were inherently capable o delaying or pres'c~tit~g tluse more serious problems, the only reasonable benefit to be expected would _lw consequent to a net increase in the effectiveness of endogenous insulin, as inclI cated by lowering of the 1)100(1 glucose level over and above that obtainable svit~s diet. Thus, if siga~ifieant lowering of 1)100(1 glucose levels could not be attained and then maintained, there would be no basis for using any of the currently available oral hypoglycemic agents. The extent to wllicll oral hypoglycemic agents have succeeded or failed with regard to these potential problems will be briefly reviewed. ISLET Ceu. FUNCTION That snlfonylureas lower blood glucose levels primarily by increasing insuli~1 secretion from the paIlcreils la:is beeis dcfin~tely provcd.G I Iowcver, it )I~IS IUI1 been contended by some investigators that extrapancreatie tffects of st~lf0i Yl reas, particularly those related to hepatic glucose release, contribute to (lac dEecl~ upon glncosc.G Recently considerable data have conrirnscd extrispancreatic 8cftC)lI~. which are demonstrable in the absence of insulin at cellular sites and with cOl~ PAGENO="0180" 13430 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY JIOBEIIT P. IThADLEY. 407 centrationof drug cornpatil)Ic with the clinical setting.° In addition, a portioii of the cifects of sulfonylurcas may relate to inhibition of cyclic AMP pliospiso- dicsterase, with a consequent net increase in cyclic AMP.'° One must also keep in mind the significant, and sometimes serious, hypo- glycemia induced by sulfonylurea drugs. None of those currently available is an exception. Some of these enhanced hypoglycemic effects of the sulfonylureas have been related to the coincident use of other drugs such as salicylates, mona- mine oxidasc inhibitors, phenylbutazonc, sulfonamides, sulfisoxazole, sulfapi (`na- zole, coumarin anticoagulants, and phenyramidol. Occasional patients on sulfonylurca drugs are suspected of having a rapid loss of endogenous insulin function because it appeared necessary after a short period of treatment to give insulin to control the diabetes. Such observations Ol)VIOUSIy have suggested that the sulfonylurca might have accelerated the deple- tion of pancreatic insulin. However, studies in animals chronically treated with sulfonylureas have not supported ti us concept. Rather, there has been consistent histologic evidence of an increase in the number of beta cell mitoscs, hypertrophy of the islets, and an increase in mass of islet tissue.6' 9 No data have been presented to suggest that biguanidcs "wear out" the insulin mechanism. The means by which l)iguanidles lower blood glucose levels in (liabetics, but not in normal humans, remains unccrtain~ By whatever means they net, these substances lower blood glucose levels in clial)C~iC il)diVidUalS having some available endogenous or exogenous insulin, albeit more gradually than is noted in responsive diabetic individuals following sulfonylurcas. Available endogenous or administered insulin simply appears to be niore effective when phmeuiformin or other biguanides are administered. Tn the absence of any demon- strable effect of these compounds upon the pancreatic islet cc'll, it is not surpris- ing there is no evidence thus far that (lial)etes is worsened ITiCtal)oli('ally by their iulnuinistratiOn. A number of studies have suggested that sulfonvlureas or biguanides may ameliorate "chemical" or "latent" dialx'tcs6 (as dc'fined by the American ))iabctes A~sociat ion''). A ill tough inconclusive, observationS of no adverse (`fk'cts have now accumulated for a sufficient number of years to allow one to assume that at h'ast no worsening of the diabetes is likely to be Produced. lxrEc-rJoN At one time the incrc~scd susceptibility of the diabetic to invasive local and systemic infection accounted for an important portion of the niorhidity and mom'- talitv among (lialmetics, \\`jthi ifflplovc(l control of diabetes following the avail- ability of insulin and the proper tms~ of ~nitilaotic treatment, infections ifl the (hal mt't ie 110w 1)OSC 01 mcli less of a prol koi Recent studies have helped to clarify the iSstl(' as to whether the diabetic is indeed muon' suseeptibk' to infection Defects in host dc'ft'nsc' (`all be r('hiit('d to 11 ic d `grt'es of hivpt'rglvc'inia and/or ketoacidosis. `" `~ Ui ~`Oi it r( ihled dial n'tes (if short (lflratiOil may not 1w associated with, a great likelihood of infection, bitt when present over a period of weeks and mouths tin' patient becomes more sums- (`(`1ltibi~'. `I'lnms fur no studies have (`heady (lefimicd the critical degree or duration PAGENO="0181" COMPETITIVE PROBLEMS IN THE DRuG INDuSTRY 13431 408 OHAL IYPOCI.Yc;EM IC A(;Et~Ts Mm ~ORTI Iwl nu.: of uncontrolled diabetes, but inctabohc COntrol IS well accepted as a (und.uuental Palt of the preventive prograiii in avoiding fungal infection and acLive (uherctt- losis, as well as l)acterlal infection. Perhaps the most common and easily clen)onsLral)k example clinically is the persistence of Candida ii ifections 1)r0(1OC- ing vulvovaginitis in the female 011(1 balonitis in the male, responding poorly to specific therapy such as nystatin or gentian violet hut (Iramnatically improving with the cessat )fl of or marked improvement in excessive glycosuria anti hyp~r-' glycemia. Such improvement is readily shown to occur in the diabetic patient responsive to oral hypoglycemic therapy, with rapidity of improvement com- parable to that obtained with insulin. Similar responses can be obtained in certain p~ttiettts with nearly normal endogenous insulin reserve upon application of diet and, of course, with the adnunistration of insulin. To date there has been no indication in patients responsive to oral hypo- giycernic agents, when pioperly combined with reasonable dietary adhcren~e, that flC\V infection or aggra~'ation of existing infection has occurred as a result of the use of oral rather than insulin therapy. NEUROPATUY No controlled studies have proved that metabolic control prevents the devël- opment of ncuropathy. Flowever, neuropathy, particularly the more severe types such as amyotrophy, anesthetic feet, Charcot joints, and so forth, classically develops in the adult who seems to have had a short duration of diabetes, l)Ut who was unknowingly hyperglycemic for a period of time, or in the ~atient with known diabetes of longer duration in whom therapy was inappropriate or inade- quate. Although diabetic patients may at times have an exacerbation of sympto~ns due to neuropathy following treatment of any kind, and although on oCcasion hypoglycemia may itself induce neuropatimy, the usual clinical observation is that following improved metabolic control by whatever means, many manifestations of neuropathy improve sooner or later. - Recent biocIieniieal data demonstrating the presence of the poiyoi patli~vity in nerve suggest a mechanism by which increased ambient glucose concentratiOns in the Schwann cell activate the formation of sorbitoi,'4 so that nerve function may be compromised. To date the critical circulating blood glucose levels for activation of this pathway have not been clearly demonstrated, hut its possible major mctal)olic role in the production of neuropathy provides further evidence for tile desirability of keeping blood glucose levels as close to norma! as is readily obtainable. CATARAcTS At least two morphologic types of cataract OCCUL in diabetes. These are: (1) the snowflake, flocculent, or mnetai)nlic cataract, occurring mainly in juveniles with grossly uncontrolled (liIll)(tCs; and (2) the senile cataract due to sclerosis of tile lens nucleus, indistinguishable from that ~eeu in the nonchabctic and the COUullOflest type Ol)Served in adult (hal)etie 1)atidllts. The inure rapid maturation of senile cataract in the diabetic than in the nondiabetie has recently been ic- PAGENO="0182" 13432 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY flOJ3EIIT F. DflADLEY 409 emphasized by studies showing grossly poorer dial)etic control in patients having cataract extraction than among tho average patients attending a diOl)etie clinie.~' These obseivatioiis, and demonstrations of the appropriate enzymc~ in the lens of man for activation of the polyol pathway' by existing byp(1glyCemiiL,1~' `~ lend considerable support to the long-held Opinion that poorly controlled diabetes is a factor in the rate of maturation in ~emlc cataract as well as in the developt~icnt of metabolic or snowflake cataract.35' ~ Although of lesser importance, the ~vcll known relation of refractive changes in the eye of the diabetic to changing blood glucose levels would be still another basis for adequate blood glucose control, at least in terms of the quality of daily living. M1CI1OAr~GIOPATKY The microangiopathy of diabetes involves small blood v~ssels, particularly capillaries supplying many tissues. The possible value of careful metal)Ol ic control in protecting the inclivi~lual from clinically important retinal and/or renal vascular disease has been the subject of major controversy `fo~;25 years. The UCDP study was directed in major part towitrd seeking an flnswcr to this question. Thus far, neither the prospective UCDP study nor otbe~ studies, all wholly or in part retrospective in nature, have proved conclusively that significant benefit is to be gained from any tighter control of the metabolic components of dial)ctes than is necessary' to avoid the symptoms of diabetes, ketoaciclosis, and so forth. Detailed reviews of this subject have either supported no relationship between careful metabolic control and the pre~'e~tion of inicroangiopathy,'9 or indicated that such. control improves the chances of preventing severer grades of clinical micro- angiopathy, such as retinitis prohifcrans and/or nephropathy with renal failure.20 Despite the. lack of unanimity concerning this controversy, recent biochemi- cal data tend to shift the weight of evidence in the direction of favoring tight lnetal)olic control. In particular, the observations of Spiro regarding the role of hyperglycemia as a stimulus to the biosynthesis of basement membrane material of the renal glomerulus,~' and observations of l)aselncnt membrane thickening shto~ving an apparent correlation with tlur~itiOii of insulin deficit,2 appear to bolster tie practice of ti ose 1)1 ~vsicians who strive for normoglycci nia. Meanwhile, although not specifically related to eflects upon microangio- patliy, sufficient data have accumulated to support the ,`ole of striving for normoglycemia as assiduously as possible in assuring survival of the fetus of the diabetic mother.2" MACl~oANC1orATIlv Although neuropatl~y. increased susc'ept il3ihity to infect ion, and inicroangio- path alt' the most s1)(Ciflc manifestations of diabct(s ,,~(`lhit~is at;~l ame of pam'- ticular concern bc'eiumse of their ~ulvc'rse efi&'cts up()im mmnnv )`01113g('1 i)at i('flts, t he overall greatest problem in terms of I1lOll'idit\' and ,mimmt'tahitv is that iclated to involvement of inc'dii,mu ammd larger vessels, espreiallr' the cOronary, der(i)ral all(l lower m'xtrt'nmity arteries. TIme prtvaknee of suelt vascular lesions is high in the PAGENO="0183" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1433 410 ORAL ILY1'OCL\CLMIC ACENTS AI1E \VOIlTIt\VII1LE Table 2. Causes of Dcatli in 912 Diabetics (Per Cciii of 701(1! Dcal1is,~ 1966_1969* Va~cu1ar disease, total 74.3 Cardiac ~4.6 Renal 8.0 Cercbrovascular 10.0 Cangrenc, "circulatory" 1.7 Cancer 12.8 Infectious, Non-TOC All others . 0.0 °Expericnce of the Joslin Clinic. gcne~al popuhrtion, but cardiovascular disease as a cause of death is nearly doubled in the diabetic. Table 2 shows that cardiovascular causes account for ~tt least two thirds of the mortality in the diabetic population as a whole. With such a high frequency and with so -many factors other than diabetes playing a potential role, any attempts to a.~sess the possible benefits of diabetes treatment a~c extremely difficult to evaluate. An additional problem in trying to judge t~ie effects ~of therapy directed toward improved diabetes control is that in the adult maturity-Onset dial)etic the duration of hyperglycemia is extremely difficult to ascertain, except in those individuals who have been subjected to blood glucose measurements from early in life either because of a family history or as part of ioutine examinations. Many observations relate vascular disease of medium-sized arteries to tl~e presence of hyperglycemia.2' Perhaps the earliest, and certainly, one of the most striking, has bccii derived from the huge autopsy series of Bell at the University of Minnesota27 (Table 3), . which points out the extraordinary prevalence of peripheral vascular disease and gangrene in the hyperglycemic individual. Such associations appear to ju~tify efforts of physicians within, reason to provide "metabolic control" of diabetes. In the clinical use of oral hypoglycemic agents, the assumption has been that lowering blood glucose would reverse the metabolic abnormalities related to insulin deficits, such as those in protein and lipid metabolism, much as such defects are reversible with comparable degrees of blood glucose lowering follow- ing insulin. As has been summarized else~vhere,28 various types of circulating li1~id abnormalities are reversible with sulfonyluicas in those patients who have suffi- cient endogenous insulin, such that blood glucose levels fall to normal following the administration of one of these oral agents. On the other hand, a number of Table 3. Results of /tulopsies Following Ailicrosclcrotic Gangrene° NONDl\1~ETiC (50,733) m~nEric (2130) n.vrio or (PER CENT) (eRa CENT) ritia~uExcr ----- ~ ,1 F M F l)iabetic/No,,dialwtk Age 20-40 0 0 .3.4 0 All Ages > 40 40-CO 0.1 0.03 14.7 . 14.0 M 53:1 00-80 0.45 0.4(3 24.3 24.0 . F 71:1 °lroin Bell, E. T.: Amer. J. Cla~. Path, 28:27, 1957. PAGENO="0184" 13434 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY flO8Ei~F F. BRADLEY * 411 reports have demonstrated persisting abnormalities in cholesterol, free fatty acids, .ind triglycerides in individuals who were reccMn~ a sulforiylurc'a, lmt on close inspection of the (btta, "control" was dcterinrncd only by measurements of fasting blocnl glucose levels, and even these were persistently elevated. However, ,sbnorsnahtms in circulating lipids associated with imperfect management of ~li..btvs using oral hypoglycemic agents have been shown to be reversible by the a'l(l)tiO') of sufficient iiisulm to improve blrmi,d ~1ucose lcvels.2~ This Ol)5('rVatiOfl has l)eCn one of the factoms which have supportei.l the use of more rigid 1)100(1 glucose criteria OS an Ol)jCCtiVc in treatment with oral hypoglycemic agents, be tIny sulfonyhircas or biguanicles. Thus far there is no clear_cut: evidence that ),loocl lipid abnormalities clue to relative insulin deficit arc more or less likely to Ime preventable or reversible at comparable blood glucose levels w'hcther insulin or oral hypoglye~mic agents are uscJ. A real problem has been the tendency for physicians to use oral hypogly~ c'cmnic agents not in an ideal manner, but rather f~r the sake of convenience, with too little emphasis upon diet, adequate choice or dosage of the agent used, or p~~p~'r selection of the patient. In such situations. obviously, the performance of oral hypoglycemic agents should be less effective than that of insulin, assuming ilmat control of blood glucose and lipid abn~irmalities arc' indeed important in slowing clown progression of macroangiopathy. `l'be above observations arc critical in evaluating studies such as the Univer- ~ity Group Diabetes Program (UCDP'~. which recorded more cardiovascular th'atlms in patients receiving tolbutamicit' or phenformin than in those treated with diet and placebo, diet and standard dose of insulin, or diet and a variable dose of insulin. The res~ilts ma~' be interpreted as follows: (1) If it is true that tilhuitamide, as a rosult of an inotropie effect up~m the myocardium2~ or via some other .flI('Ch:lnisifl. and an unrelated compound such as plienformnin, tluough some ummith'ntifk'd mechanism, actually contribute to ~`ardio~'aseular death, the serious- mn'~s of this particular end point would w~'li~h ~) heavily that the use of these i~iai hypoglycemic agents should be sumuni:uily discontinued. (2) On the other imumuil, if these oral agents were secmninglv less dFective because of their improper umw. time question is \Vhether the results wouhi be iniproveci by correct usag(' and what time criteria should be for such ~ ,,3-~ Time third pOsSil)ility is that imm.ulvertent signilicant differences in basdine cardiovascular risk factors mieomnmted for the less favorable CardiO\a5e~l3m' °~°~Y ~ ~n treated with tollMmtamidc or phenforimmi ai~I that the sttmcly doc's not prove or uikpmuve lack of effectiveness for tolhut;itiitdt' imp to the tutU' it ~~`as discontinued (P1)1mm tin' st nd (October, 1969) or for pluemmternmimm ( dliSCOittimltm('d January, 1971 ). I In' hitter is more than a mere possibility. for time imiterpretat omis of UC1)P results I y the investigators, the Anmc'rican Diabet ~`s .~ss,idat ion," the Con ncil on Drugs `1 liii' Aim u'mica n Mccl ic'al Assoc'iatiomi_~ and the U.S. Food and Drum g Ad ni nist ma- tiummi'- ~ based upon statistical grounds tlm.ut do not take into acdOmlimt tin' clinical I'.utkguommn(1 (if kl)(>wledg('. cOmicermming coromi.mry ln'am't disease in the (lid (`te. Time $ll,ul)\ fI,usvs iii the UCI)P study mmk~' ammv t'~tuapul:ut ion of time results to time (Im,mi)ttic popumlutiom at large o'xtrm'miit'lv ima.'.irdous. amid a ntmumll)er of Ol)jeC'ti(mmmS r('uuma,mi Ippareimt to the clinician: I. lit idact'lm trcat('(l p;mticnts not ii single mimyocordial immfarctiomi ~~`as ru'corckcl ammmommmg time c'amolio~'ascomlim' (baths. PAGENO="0185" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 13435 412 OT1AT. Il\L~OCE.YCL~%ttC Ac~:NrS A1IL~ W01~TIIWJU1.O 2. A characteristic feature of cardiovaseuhtr mortality in the diabetic is the female predisposition to dying, o'qualiiig or exceeding that Ol)served among Inales.2h UC flP findings of fewer than one half as many cardiovascular deaths in females as c upared to mniiks in plitceb() treated diabetics indicated a hick of full eXPI,CSSiOO of tlIC efrCcts of oIi~ibetcs upon cardiovascular mortality in this group; i.e., the diabetes was milder and/or of shorter duration, or the numberS were too smiill. 3. Cardiovascular risk factoms at baseline were present ~~ti1i greater frequc'm~cy in patients on toihutanude than in those treated with placebo or with small fixed doses of insulin ("insulin standard"). Although univ one factor, blood cholesterol levels equal to or greator than 300 nig./ 100 ml., reached statistical significance in its greater frequency in toll)utanhidc treated patients, out of a total of 10 baseline risk factors, nine occurred more often in the tolbutamide treated than in the placebo group. On comparison with "insulin standard" treated patients, seven cardiovascular risk factors were present at baseline with greater frequency in tolbutarmde treated patients as compared to three affecting mnoic patients in the "insulin standard' group. 4. The prevalence of coronary heart disease as evidenced by `~signifkant ECC abnormality" at baseline was extremely low in all treatment groups (Table 4's. especially in view of time higher frequencies of digitalis usage, qf angina pectoris, and of ECG abnormalities in diabetics of comparable a~c reported in the litcrature.~ ~ When. the original baseline findings were reported by the UCDP investigators in 1967, different criteria for ECC abnormality were used, so that on the basis of the electrocardiogram, a distinctly greater prevalence of coronary heart disease was reported in time tolbutanmide as compared to placebo, insulin standard, or insulin variable groups of patients.34 5. The duration of diabetes among patients entering the UGDP study were indeterminate. I-Iowcver, elevated fasting blood glucose and greater increments of post glucose l)lOOd levels were found in more tolbutanmide treated patiemmts at baseline than in any other treatment group. Therefore, more tolbutan mide treated patients had severer and/or longer durations of dial)ctcs meihitus. 6. For an end P01rmt~ (cardiovascular mortality) having an extremely high prevalence in the diabetic population in which a number of risk factors, both Table 4. UCDP Stud y~W6P vs. 1970f Selected Baseline Cardirnxiscular Risk Factors INSUlIN' INSULIN rLAcFtmo T0LIWTAMn)md STAND. VAISIATITE TOTAL No. Per Ccut No. J't'r Gnu No. Per Cent No. Per Ccnt No. Per Cent Significant ECC'. abnormality 1967 30 (15.2) 48 (210) 40 (19.3) 39 (19.3) 157 (~94) Significant EGG abnormality 1970 llntory of digitali' inc histOry of anasna pectoris -~ 6 ( 3.0) 9 ( 4.5) 10 ( 5.0) 8 15 14 ~ ( 4.0) ( 7.6) ( 7.0) ~ 11 12 .16 ( 5.3) ( 5.8) ( 7.7) 8 ( 4.0) 10 ( 5.0) 7 ( 3.5) ~ 33 46 47 ( 4.1) ( 5.7) ( 5.8) °1tnfcrence 34. I Reference 1. 56-592 0 - 75 - pt. 28 - 13 PAGENO="0186" 13436 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY flOBEflT F. BflADLF.Y 4j3 known and unknown, were present, the number of individuals reaching that end point was too small to permit a definitive conclusion. Sutnnia;y The benefits of oral liypo~lycemic agents arc limited to those diabetic patients who arc responsive, in that symptoms of diabetes are al)scnt and blood glucose levels are significantly and consistently lowered (20 per cent or more) below pretreatmc'nt values. Under these conditions, benefits may be summarized as definite or qualified. DEFINiTE 1. Convenience. 2. In those with diminished vision, arthritis, or other problems, who find injection of insulin difficult or impossible. 3. For individuals whose diabetes is not controllable by diet a~id whose employment and/or economic status might be jeopardized by the taking of insulin. 4. In certain patients with allergy to insulin, in whom desensitization is dirncult or cannot readily be maintained. 5. In truly responsive diabetics in whom iiormoglycemia is more readily attained than with insulin. QUALW1E1) If lowering of lipid and other metabolic abnormalities related to iflSUlifl deficit are important in protecting the diabetic from earlier progression of vrtseu- Jar lesions and neuropathy, as well as from infection, the use of oral hy~)oglyceInie agents is of benefit in patients who attain "sjgnifk;uitjv" lower blood glucose values than arc attainal)le 1)V USC of diet alone. Mv criteria for such 1)100(1 glucose values are that on two out of three occasions the blood glucose, ~v1iencver drawn, is normal. Data from the UGDP study have thus far COntTil)Ut(d nothing to the contro- \Tc'I5)' rcgar(ling the Cth'(hvclleSS of 1)100(1 glucose (OI)tlOl afl(1 are ~uf1\cic'nt1y in (loul)t as to t1i~.' apparent lesser benefits of tolbutamide audi ph(nformm OS COOL- pared [0 dicE alone or diet and insulin, so that the results c~ituiot at l)1eSeIlt 1)C (Xtrap(~latc(1 to the diabetic population at large. They (10 not ~varr~mt discontmua- (ion of the appropriate routine clinical use of oral hypoglycemic agents. References L Ti,' UnivcrsLv (rtu,~ i')alit,s Pograni: A stmlv of (1( (.1f('Ct~ Of i,Vj)O~t\(('1)ic aernts 011 ~`asut,iar (impi i:t iu~ ~, pt ii it ~vitI, adult ~ot (1 iahtcs. ii. ~ it lOy results: i)ialn.is 19( Sppl. 2) :7S~. 1970. PAGENO="0187" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 13437 414 OflAt~ 1 IYPC C1 .YC1~~t IC AC1~ rs Ant: \VORTI IWI 11L1~ 2. Knattcrnd, C. L, Meinert, C. L, Klimt, C. IL, 0.borne. 11. K., and Martin, 1). 1k: Fifeets of hypoglycemic agezits on vascular complkati'ms i~ patitnt' with adiilt-oi*set (Ha- bitt's. 1\'. A L)r('ltlIIlry re))Ort no pht'ntonoio ti'~'iIt~. j.A.M.:~. 217:777, 1971. 3. Marble, A. Contr~1 of dial ides lt',.,~eiis or postponis vaseisl:ir compiieatinhls. In l'lflog~r, F. J., lteioian. A. S., and I"iiiland, M. (eds. ) Coulrorerxij in I,itrr'uzI .~t('dkihC. Philadelphia, W. B. Saiiiiders Company, 1966, p. 191.. 4. Feiiitein, A. 11..: An an:tlytie appraiiai of the tJnivc'rsity Croiip ))iabetes Program (UCI)P) Study. Cliii. Phannaeul. `Iiivr. 12:1 67, 1971. 5. keen, IL, and Janet t, It. j.: F1ItCIS of oral hy~)'.iycemic agents on cardiovascular (IISeZ1SC. In Fajans, S. S., and Snssmsu, K. E. (ecls. ) : I)iabcft'x ,\It'!Ii!us: l)iagno~i.~' and Treat- 711(111. Vol. 111. Nev,' York, American I)iabttcs ,\ssociatiou, Inc., 1971., p. 167. 6. Krali, L. P.: The oral lmypogiyecmic agents. In Marble, A., ~VIiiIe, 1'.. Itradley, II. F., and Kraii, L. 1'. (eds.): Jo.'din's Diabetes Mdllitus. 11th ed. Philadelphia, Lea & Febiger, 3971, p. 302. 7. Baloditisos, M. C., Cleason, 11. E., Bradley, R. F., and Marble, A.: Long-term tolbutamnide therapy in diabetes. A co~~tioli~'d study of tin' frcjumemicy of cardiovascular disease mmml other findings. In lInt t~r(~cid, \V. j. 11.. amid Van W'esteriog. \V. (eds.) : ToIbi~ta- wide . . . after `len Years. l'roc,'ediogs of the Brook Lodge Symposium, Augusta, Michigan, March 0-7, 1907. Amsterdam, Excerpts Medica Foundation. 1967, p. 270. 8. Camcriui-Davaios, 11., Itoot, H. F., and Marl)1e, A.: Clinical cxpenenccs with carbutarm~ide (BZ-55). 1)iabetes 6:74, 1957. 9. Lebovitz, 11. E., and Feldman, J. M.: Oral hypoglycemic agents: Mechanisms of action. In Fajans, S. S., and Sossman, K. E., (eds.): Diabetes MelIitmi.r: Diagnosis and Treat- ment. \`oi. III. New Yoik, American Diabetes Association, Inc., 1971, p. i'll. 10. Roth, J., Prout, `F. E., Coldfinc, I. I)., Wolfe, S. M., \Iuenzer, J., Crauer, L. E., and Mar- cus, M. L.: Sulfonyiurcas: Efiects in vivo and iii vitro. (NuT Conferences.) Ann. Intern. Med. 75:607, 1971. 11. Fajans, S. S.: Classification and natural history of genetic diabetes mellitus. in Fajans, S. S., and Smmssunan. K. E. (eds.): Diabetes ,\Iellitu.c: Diagnosis and Treatment. Vol. III. New Ynuk, American Diabetes Association, lime., 1971, p. 89. 12. Bagdade, J. I).: Infections. In Fajans, S. S.. and Sussmnan, K. E. (eds.): 1)iabetcs Mcli jt us: Diagnosis and Treatment. Vol. III. New York, American Diabetes Association, Inc., 1971, p. 211. 13. Younger, 1)., and Iladley, W. 13.: Infection and dtal)etes. In Marble, A., White, P., Brad- ley, It. F. and .Krall, L. P. (eds.): Jo.slin'.s Diabetes ,`mlell4tus. 11th cd. Fhiladelpbia, Lea & Fcbigcr, 1971, P. 621. 14. Prockop, L. I).: Diabetic neuropathy. In Fajans, S. S.. and Snssman, K. E. (eds.): Dia- betes ~`m!elIitizs: i)iagnovis and Treatment. Vol. 111. New York', American Diabetes Association, Inc., 1971, p. 347. -. 15. Clinical aspects of cataract in diabetes. in Caird, F. I., Pine, A., and Barnscll, `1'. C. (eds.): 1)iabctcs an(i time Eije. Oxford, lllacksvell Scientific Publications. 1969, p. 127. 16. \Vinegrad. A. I., Cknients, It. S., and Morrison, A. I).: Jim Fajaus, S. S., and Sussnian, K. E. (cds.): Diabetes Mellitims: i)iagimosis and `I'rcatinent. \`ol. LIE, New Yomk, American l)inbctes Assoeiatiøn, lime., 1971, ~. 209. 17. The nn'tabolism of the l(.nS ill rm'latoii to (`us opacities in diabetes. In Caird, F. I., ~irie, A., and ltamn.ccll, `F. C. (cds.): Diabetes and tIme Eye. Oxford, Biackwell Scientific Publications, 1969, P. 140. 18. Bradlcs', U. F'., nod Itanmos, E.: `tin' eves and diabetes. In Marble, A., White, P., Bradley, U, F., and K'rail, I,. P. ( eds. ) : Jo.sIin's Diabetes Mellilims. I ith d. Philadelphia, Lea & Felmiger, 1971, p. 478. 19. Knoxs'les, II. C., Jr., Guest, C. NI., 1.amnpe, 1. Km.'ssler, Nt., and Skiilniaim. 1'. C.: The course of juvenile diabel is treated wit ii m:mllmlt'aSml r('(l d mt. 1)iabeti's 11:239, 1905. 20. Ntarl)le, A.: Augiopmthy iii diabetes: Aim uu~nlved prnlmleimi. ( `[`lie lkm:ting Ntcm(mrial Lee- tore.) Diabetes 10:825. 1967. 21. Spiro, 11. C,: Pnthoph:y~iolocy. Ii. lIin~i mimmical 1)asis of tin. diahet k' mmmkroaimginpathy. In Fajamms, S. S., and Smmssmaim, I. F. ( isis. ) : J)iolwtr.s ,~hllUmm.s: I)iattmmo.sis (mud `treat- wemit. Vol. Ill, New York, Amneric:mn I)iai,'tes :\ssm)ci:mti(m:m, Inc., 1971, p. 275. 22. Spiro, It. C., aim:1 Spiro, NI. 1. : Eli mit of (li:mlutes oii liii: hiim.yiitlmesis of time renal ghmmnn:rnlar basi'mn,'imt mnimmmlmr:mimm. I)inbmti'. 20:6 II. 1971. 23. Kilo, C., Voglm'r, N. J. mmmd \Vilhi:mmimsuii, J. U.: Bcmu'iimmuit umeiuliramu' tl,iekm'i:iimg in diabetes. Jim J"ajans, S. S.. amid Su'.soma:m. K. F. ( eds. ) : Diabetes ,IImlIitm:v: I)iagmmnsi~ arid l'tC(Itl?ietlt. Vol. Ill. New \`mmrk, Amnimican 1)imhctcs Assochmtimmn, lime., 1971, p. 289. PAGENO="0188" 13438 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ROBERT F. RUAI)I.EY 415 21. ~,Vhife, P.: Pregnancy anti diabetes. In Marble, A., White, P., Bra(lhy, 11. F., and 1(rail, L. P. (edit.): Jo'Jin's J)kthctcit A~JdIa1u.s. 11th ((1. 1'Iilaclclphia, J~ ~ Febiger, 1971, p. 581. 2.3. J'ctlersen, J.: Management of the pregnant diabetic. In Fajans, S. S., and Snssman, K. E. (edit.): Diabcf~s 4~1cI1iti,s: Diognoitiv and Treatunut. \`ol. 111, Ncw York, American Diabetes Msoeiatiun, Inc., 1971, p.235. 20. Bra(iley, 11. F.: Cardiova~cu1ar disease. In Marble, A., White, P., Bradley, U. F., and KralI, I.,. P. (edit.): )u.slin's 1)iabek.s ?~!ellitus. 11th ccl. Philadelphia, Lea & Febiger, 1971, p. 417. 27. Bell, E. T: Atherosclerotic gangrene of the lower extremities in (iiabctic and flOn-(iiai)etiC persons~ Amer. J. Clin. Path. 28:27, 1957. * 28. Bradley1 11. F.: Cardiovascular disease. In Marble, A., \Vhitc, P., Bradley, 11. F., and Krail, L. i': (edit.): Joslin's Diabetes .\fdllhtu.s. 1 itiL ccl. Philadelphia, Lea & Febiger, 1971, p. 429-430. 29. Lev~y, C. S., Palmer, 11. C.. Lasseter, K. C., and McCarthy, 3.: Effect of toibutamide on adenyl cyclase in rabbit and human heart and contractility of isolated rabbit atria. 3. Clin. Enclocr'. 33:371, 1971. 30. flieketts, 11. T.: Editorial Statement. October 7, 1970. Diabetes 19(Supt4. 2):iii-v, 1970. 31. A.M.A. Council on 1)rugs: Statement regarding the University (;roup Diabetes Program (UGDP) Study. Xovember 2, 1970. Diabetes 19( Snppl. 2) :vi-"ii, 1970. 32. Food and Drug Adminisliation Current Drug Inforntat ion Bulletin, October 30, 1970. 33. Bryfogle, 3. W., and Bradley, 11. F. The vascular complications of diabetes mc~Jlitus. A clinical study. Diabetes ~:150, 1057. 34. }~limt, C. R., Meinert, C. I.., Miller, M., arid Knowles, H. C.: University Croup Diabetes Program (UCDP): A study of the relationships of therapy, to vascular and other complications of diabetes. in Butterfield, \V. 3. II., and Van Westerliig, %V. (edit.): Tolbutamidc . . . After Ten )`cars. Amsterdam, Excerpta Medica Foundation, 1967, p. 261. PAGENO="0189" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 134~39 [From the Washington Post, July 9, 1975] AMA OFFICIAL LET COMPANY USE NAME (By Stuart Auerbach) A top official of the American Medical Association allowed drug compa~iy salesmen to use a letter from him as part of their effort to persuade doctOrs to continue prescribing a controversial drug that has been blamed for as many as 15,000 unnecessary deaths a year. Dr. James H. Sammons, AMA executive vice president, gave his permission to Upjohn Co. salesmen in March despite an opinion from an AMA lawyer tl~at it is against the association's policy to use its name for business purposes. The letter from Sammons downplayed questions about the safety of widely prescribed anti-diabetic drugs that had been raised in the AMA's magazi~ie, the Journal of the American Medical Association. His letter and the opinion of AMA lawyer Betty Jane Anderson were made available to newspapers by a man who was identified himself as a former A1~tA employee dismissed in a staff cutback. The documents were verified by AMA officials. In a Jan. 28 letter, Sammons warned about 400 medical society executiVes around the country that the Feb. 10 issue of JAMA would contain a confiri~ia- tion by the Biometric Society of a 10-year study that showed that some anti- diabetic drugs, known as hypoglycemics, cause more people to die of heart dis- ease than they save from dying of diabetes. The society is an impartial group of statisticians dealing with medical issues. The original study, done by the University Group Diabetes Program (UGDI?), was hotly contested by many diabetes specialists when it was released four years ago. But a large number agreed with the UGDP findings, and the U.S. Food and Drug Administration last week ordered that advertising for the drugs n~ust contain the warning that they may cause death from heart disease. The drugs are used by an estimated 1.5 million Americans to lower tbeir blood sugar, and represent an estimated $100 million-a-year business for the pharmaceutical industry. Upjohn sells two leading brands of the drugs- Orinase, for years the most widely prescribed oral hypoglycemic pill, and Toli- nase. Upjohn said it wanted to use Sammons' letter "as a result of the confusion from the Feb. 10 JAMA story." It would be used by Upjohn salesmen in dis- cussions with doctors "should the subject arise." Sammons' letter reported that an editorial in JAMA wo"l'1 ~y th~ `-`~r~ `~-r~ probably associated with "10,000 to 15,000 unnecessary deaths" a year in the United States. The editorial was written by Dr. Thomas C. Chalmers, dean and president of the Mt. Sinai Medical College in New York and former director of the Natiönal Institutes of Health's Clinic Center in Bethesda. Nevertheless, Sammons wrote: "A considerable body of expert scientific opinion contradicts these publiehed findings. Diabetic patients should not be influenced by press reports, and shOuld continue on whatever diabetic management program their own physician has prescribed." When Upjohn asked to distribute the letter to its salesmen, AMA attorney Anderson wrote Sammons, "The policy of the AMA is that the association's name may not be used for trade purposes. "Permission to reprint AMA materials has not been granted if there is any indication that the name of the association or its materials will be used in any manner that might directly be construed as an endorsement by the AMA of a particular product or manufacturer." Later in the niemo, she warned Sammons that the use of the letter of Upjohn salesmen "may cause embarrassment to him personally or to the AMA." "Upjohn's purpose could be better accomplished by having an article present- ing the other side of the controversy published in JAMA," she said. On March 17, JAMA published a letter by Dr. M. Hubbard Jr., Upjohn's president opposing the AMA editorial and the Biometrics study, and on May 26 it published a series of letters and articles from other doctors who believe in the drugs. PAGENO="0190" 13440 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY THE UNIVERSITY OF CHICAGO DEPARTMENT OF STATISTICS 1118 EAST 58TH STREET CHICAGO * ILLINOIS 60637 17 February 1975 Senator Gaylord Nelson Chairman, Monopoly Subcommittee Senate Small Business Committee 424 Russell Senate Office Bldg. Washington, D.C. 20510 Dear Senator Nelson: I have revts~ed the transcript of my testimony before your Com- mittee on 31 January and I think it may be useful to restate the position I was supporting in our exchange. First, it was entirely proper for the UGDP investigators to withdraw Tolbutamide from the study as soon as they had substantial doubts about its safety. However, as a consequence, they could not reach a firm conclusion about it. Their own conclusion was stated as follows: "... the findings of this study indicate that the combi- nation of diet and tolbutamide therapy is no more effective than diet alone in prolonging life. Moreover, the findings suggest that tolbutamide and diet may be less effective than diet alone or than diet and insulin at least insofar as cardiovascular mortality is concerned." I think that statement should be taken at face value, and not as a polite substitute for a more forceful condemnation of Tolbutamide. Second, in the light of all available evidence, a decision must be made about the appropriate legal or regulatory steps to be taken about the distribution of Tolbutamide. The suggestion made by Dr. Ricketts seems to me appropriate. Enough doubt about its effective- ness in ordinary use and concern about toxicity exists to warrant im- posing some additional reporting burden on the physician who prescribes it. Finally, of far more importance than the decisions to be made about Tolbutamide is the continuing lack of procedures for accumulating reliable information about the effects of drugs for which the balance of risk and benefit is uncertain. The answer cannot be entirely a matter of adding more and more requirements before a drug is released for marketing. I am not convinced that present regulations have sub- stantially impeded the adoption of valuable drugs, but pushed too far, PAGENO="0191" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 13441 they certainly could. I should prefer to see drugs made available Øn the basis of reasonable evidence of safety and efficacy, and to require that appropriate studies should be carried out until the matter of i~isk vs. benefit is settled beyond reasonable doubt. Sincerely yours, Paul Meier P.S. I enclose a recent curriculum vitae, in accordance with your request. PM/tk PAGENO="0192" 13442 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY February 1975 PAUL MEIER Personal: Born 24 July 1924, New York City. Education: B.S. Oberlin College Physics, Mathematics 1941-45 Brown University Intersession Program in Applied Mathematics 1945 M.A. Princeton University Mathematics 1945-47 (Mathematical Logic) Study and Research in Statistics 1947-48 Ph.D. Princeton University Mathematics 1951 (Statistics) Professional Career: 1948-49 Assistant Professor of Mathematics, Lehigh University. 1949-51 Research Secretary, Philadelphia Tuberculosis and Health Associa- tion (part-time). 1951-52 Research Associate, Analytical Research Group, Forrestal Research Center, Princeton University. 1952-57 Department of Biostatistics, School of Hygiene and Public Health, The Johns Hopkins University (1952-53, Research Associate; 1953-55, Assistant Professor; 1955-57, Associate Professor). 1957- Department of Statistics and Division of Biological Sciences, University of Chicago (1957-62, Associate Professor; 1962- Professor of Statistics; 1960-66, Chairman, Department of Statistics; 1962-69, Director, Biological Sciences Computation Facilities; 1968-74, Professor of Theoretical Biology; 1970-71, Acting Chairman, Department of Statistics; 1973-74, Chairman, Department of Statistics; 1975- Ralph and Mary Otis Isham Professor of Statistics and of the Pharmacological and Physiological Sciences). 1966-67 National Institutes of Health Special Fellow at the University of London (School of Hygiene and Tropical Medicine, and Imperial College), on leave from the University of Chicago. PAGENO="0193" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13443 Professional Memberships: American Statistical Association, Fellow; Board of Directors; Vice-President, 1965-67; Chairman, Committee on Computers in Statistics, 1967; Chairman, Section on Training, 1974. Biometric Society, Executive Committee, ENAR, President, ENAR, 1967. Institute of Mathematical Statistics, Chairman of Editorial Board, IMS-University of Chicago Press Monographs in Statistics, 1961-64 and 1968- Royal Statistical Society, Fellow. American Association for the Advancement of Science, Fellow. American Mathematical Society. Mathematical Association of America. Association for Symbolic Logic. Society for Industrial and Applied Mathematics. Association for Computing Machinery. American Public Health Association, Fellow. American Thoracic Society, Fellow. American Heart Association, Fellow, Council on Epidemiology. Consultant Activities and Special Appointments: 1955 Consultant on Statistical Problems in the Pharma- ceutical Industry. 1959 Consultant on Sampling and other Statistical Problems in Transportation. 1959-62 Member, Committee on Lung Cancer, American Cancer Society. 1960-66 Consultant, The RAND Corporation. 1965-70 Member, Special Study Section, Biomathematics and Statistics, National Institute of General Medica'. Sciences (NIH) PAGENO="0194" 13444 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1967-71 Member, Therapeutic Evaluation Committee, National Heart Institute (NIH). 1968 Member, Diet-Heart Feasibility Study Review Committee, National Heart Institute (NIH). 1970- Member, National Academy of Sciences Committee on Biological Effects of Atmospheric Pollution. 1971- Member, Advisory Board, Environmental Health Resource Center. 1972- Member, Task Force on Health Considerations of a National Energy Policy, American Public Health Association. 1973- Member, Advisory Board of Veterans Administration Cooperative Study of the Pathogenic Effects of the Sickle Cell Trait. 1973- Member, ASA Advisory Committee to Statistical Policy Division - Office of Management and Budget, Executive Office of the President. 1973- Member, Committee for the Assessment of Biometric Aspects of Controlled Trials of Hypoglycemic Agents. 1974- Member, Panel on Airborne Particles and Panel on SOS, Assembly of Life Sciences, National Research Council. 1974-75 Sigma Xi Lecturer. 1974- Member, Advisory Council for the Department of Statistics at Princeton University. 1974- Member, Computer and Biomathematical Sciences Study Section, National Institutes of Health. Honorary Societies: Phi Beta Kappa Sigma Xi Publications: (1) "Timing of the distribution of events between observa- tions. A contribution to the theory of follow-up studies" (with T. E. Harris and J. W. Tukey), Human Biology, 22 (1950), 249-270. PAGENO="0195" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13445 (2) "Tuberculosis among diabetics" (with others), Am. Rev. of Tuberculosis, 65 (1952), 1-50. (3) "Effects of simultaneous skin tests on size of tubercu~in reactions" (with others), Am. Rev, of Tuberculosis, 65 (1952), 201-205. (4) "Variance of a weighted mean," Biometrics, 9 (1953), 59-73. (5) "On the theory of the indicator-dilution method for measurement of blood flow and volume" (with Kenneth L. Zierler), J.of Applied Physiology, 6 (1954), 731-744. (6) "Analysis of sinple lattice designs with unequal sets of replications," J. Am. Stat. Assoc., 49 (1954), 786- 813. (7) "Note on estimation in a Markov process with constant transition rates," Human Biology, 27 (1955), 121-124. (8) "Vitamin B12 Serum concentration in 528 apparently healthy human subjects of ages 12-94" (with others), 3. of Geron- tolo~g~y, 12 (1957), 32-38. (9) "Analysis of a bubble method for estimation of and in whole blood" (with R. H. Shepard), 3. Appl. Phy~s., 11 (1957), 250-259. (10) "Safety testing of poliomyelitis vaccine," Science, 125 (1957), 106 7-1071. (11) "Absorption of vitamin B12 enhanced by D-sorbitol" (with others), Am. 3. Clinical Nutrition, 6 (1958), 30-33. (12) "Reconsideration of methodology in studies of pain relief" (with others), Biometrics, 14 (1958), 330-342. (13) "Nonparametric estimation from incomplete observations" (with E. L. Kaplan), .J.Am. Stat. Assoc., 53 (1958), 457-481. (14) "Variability of critical flicker fusion thresholds in brain-injured children" (with others), A.M.A. Archiy~ of Neurology and Psychiatry, 80 (1958) , 6 82-688. (15) Appendix A of Secret Detention by the Chicago Police (with William H. Kruskal), Clencoe: The Free Press, (1959) , 35-31. (16) "Further consideration of methodo1o~y in studies of pain relief" (with S. N. Free), BiometrIcs, 17 (1961), 576~-583. PAGENO="0196" 13446 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (17) "Fluorospectrophotometric analysis on cervical epithelial cells' (with George L. Wied, Anita M. Messina and Richard R. J3lough), ActaCytologica, 8 (1964), 61-67. (18) "An electronic data processing program for cytologic screening projects for uterine carcinoma" (with George L. Wied and Linda M. Clark), Acts Cytologica, 8 (1964), 385-397. (19) "Fluorospectrophotometric analyses of endometrial and endocervical epithelial cells" (with George L. Wied, Anita M. Messina, Jose I, Manglano and Richard R. Blough), Acta Cytologica, 8 (1964), 408-415. (20) "DNA-assessments on fuelgen stained endometrial cells and comparison with fluorometric values" (with George L. Wied, Anita N, Messina and Ethel Rosenthal), J.Lab. Investiga tion, 14 (1965), 1494-1499. (21) "Statistical evaluation of the effect of hormonal contra- ceptives on the cytological smear pattern" (with George L. Wied, M. Edward Davis, Richard Frank, Peter B. Segal, and Ethel Rosenthal), Obstet. and Gyne., 27 (1966), 327-334. (22) "Analysis of morbidity and mortality of children irradiated in fetal life" (with M. L. Griem and Glen D. Dobben), Radiology, 88 (1967), 347-349. (23) "Analysis of morbidity and mortality of children irradiated in fetal life" (with M. L. Griem, Glen D. Dobben, and D. J. Mewissen), Radiation Biology of the Fetal and Juvenile Mammal, AEC Symposium Series, 17 (1969), 651-660. (24) "Mass field trials of the diet-heart question" (with members of the Diet-Heart Review Panel of the National Heart Institute), American Heart Association Monograph, 28 (1969), 1-51. (25) Statement of evaluation of risks in use of oral contra- ceptives, before the Subcommittee on Monopoly (Nelson Committee), Senate Select Committee on Small Business, 24 February 1970. (26) "Hazards in oral contraception: The case for further tests," Midway, (1970), 87-95. (27) "The biggest public health experiment ever: The 1954 field trial of the Salk poliomyelit4s vaccine," in Statistics: A Guide to the Unknown, Frederick Mosteller, et al, eds., Holden-Day, Inc., (1972), 2-13. (28) "Air Pollution and Pulmonary Cancer" (with Bertram Carnow), Arch. Environ. Health, 27 (1973), 207-218. PAGENO="0197" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13447 (29) "Effects of low-dose prenatal irradiation in humans: Analysis of Chicago Lying-In data and comparison with other studies" (with B. E. Oppenheim and M. L. Griem), Radiation Research, 57 (1974), 508-544. In Press and In Preparation (30) "The effects of diagnostic X-ray exposure on the human fetus: An examination of the evidence" (with B. E. Oppenheim and M. L. Griem). Accepted for publication in Radiology. (31) "Statistics and medical experimentation," Presidential Invited Address, Meeting of the Biometric Society (ENAR~, March 1974, Tallahassee, Florida. To appear in BiometrLcs. (32) ~`Estimation of a distribution funttion from incomplete observatiotis." To appear in Studies in Probability and Statistics: The M. S. Bartlett Festsehrift, 1975. (33) "Ascorbic acid and the common cold: An evaluation of its efficacy and toxicity" (with H. H. H. Dykes). Accepted for publication in the Journal of the American Medical Association. (34) "Man as th~ experimental animal," Sigma Xi Lecture, (1974). To be submitted to the American Scientist. PAGENO="0198" 13448 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY USV PHARMACEUTICAL CORPORATION 1 SCARSDALE ROAD TU( KAHOL, NI W YORK 0707 HERBERT H. Mc DADE, JR. PRESIDENT CHIEF OPLRA1INC OFFICER March 11, 1975 The Honorable Senator Gaylord Nelson Chairman - Monopoly Subcommittee on the Senate Small Business Committee The United States Senate Washington, D. C. 20510 Dear Senator Nelson: As the discoverer and developer of phenformin, USV Pharmaceutical Corporation has been following the con- troversy regarding the UGDP study; and, at your invitation, on October 21, 1974 we submitted to your Subcommittee the Company's general policy concerning the appropriate use of hypoglycemic agents, various criticisms of the UGDP study and comments concerning the reports of other groups which have studied these agents. Our comments, as expressed in that letter, remain the same; however, in reading the transcript of the testimony before your Subcommittee on January 31, 1975, we feel compelled to amplify our previous letter. The testimony of The Chairman of The Committee for the Assessment of Biometric Aspects of Controlled Trials of Hypoglycemic Agents reflected the following statement: "The findings on phenformin, if one can judge from the absence of criticism, appear to have been accepted by medical scientists, even if they have not so far been translated effectively into medical practice. Yet these findings also PAGENO="0199" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13449 were made by the UGDP using the methods that have come. under heavy criticism when applied to tolbutamide." A similar implication of absence of criticism of the UGDP with respect to phenformin appears at the end of section 3.1 (Findings) of the Biometric Committee's Report published in the February 1975 issue of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION. We believe it is necessary to dispute any implication that the criticisms leveled against the UGDP study are concerned with the drug, tolbutamide, alone. To the contrary, the substantive criticisms made, although perhaps naming tolbutamide specifically, apply equally with respect to phenformin inasmuch as the structuring of the two trials under the UGDP was nearly identical. Further, it should be pointed out that because of the nature of phenfonnin, the rather late introduction of its trials, and a variety of other material factors, the phenformin portion of the UGDP necessarily becomes the subject of additional criticisms. There are several reasons why criticism of the UGDP study most generally is publicized in terms of tolbutamide. Tolbutamide was the first of the two drugs to be studied by the UGDP in fact, tolbutamide preceded phenformin in the study by 18 months. Likewise, the first data generated by the studies were those on tolbutamide. Second, and just as importantly, the final Report of the UGDP on phenformin had yet not been published as of the date of the Biometric Committee's review. Since it is not generally recognized as scientifically proper to comment upon, or criticize, work presented only in pre~ liminary form, it is natural that there had been less formal criticism on the phenformin aspect of the UGDP PAGENO="0200" 13450 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY study. Under these circumstances, it was to be expected that criticism of the UGDP study was more likely to be framed in terms of tolbutamide; however, this should not, in our opinion, be interpreted to mean that as to phem- formin, the results of the UGDP study "have been accepted by medical scientists." The Biometric Committee obviously considered important the fact that the final UGDP Report on phenformin had not yet been published and, in fact, the Committee did not consider the basic data on the effects of phenformin treatment. This is clearly reflected in the following quotation from Section 1 (Introduction) of the Biometric Committee's Report: "The preliminary report on phenformin was considered in September of 1973, but in view of the fact that the final report on that subject was still unpublished, the Committee did not request the basic data on the effects of this treatment." In addition, the Biometric Committee recognized in its Report that the introduction of phenformin to the UGDP ."greatly complicated an already difficult study." [See Section 7. 1 (Conclusion, Protocol)]. Based upon these and other factors, it is our conclusion that the Report of the Biometric Committee does not resolve the controversy surrounding the UGDP study. It does not resolve the general criticisms of the UGDP study set forth in our letter of October 21, 1974, nor does it resolve the specific issues relative to phenformin. We greatly appreciate this opportunity to present these PAGENO="0201" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13451 views to you, and respectfully request that they be made a part of the record in this matter. Very truly yours, USV PHARNAçEUTICAL CORPORATION ~ \ Herbert H. NcDade, Jr. President Chief Operating Officer HHNcD,Jr. /mem 56-592 0 - 75 - pt. 28 - 14 PAGENO="0202" 13452 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY FD~HASKELL,COL~ ~Cn~te~ ~~a1e2 ~~ena~e WALTER F. MONDALE. MINN. SELECT COMMITTEE ON SMALL BUSINESS DIRECTOR (CREATED PURSUANT TOE. RES. 58,8ISTcONORE8S) WASHINGTON, D.C. 20510 April 1. 1975 The Bonorable Alexander M. Schmidt Commissioner Food and Drug Administration Washington, D. C. Dear Mr. Commissioner, During your testimony befor. our Monopoly Subcommittee on January 29, 1975 Mr. Butt stated that the Department of Justice declined to file at least seven criminal cases that the FDA forwarded to them for prosecution on false advertising issues. In this connection, I should be extremely grateful if you would supply the Subcommittee with the names of the firms, dates, products involved, FDA's letters of transmittal and the response of the Department of .7ustice to FDA in each of these cases as well as for other cases which Mr. Butt may not have been aware of Kindest personal regards. Sincerely, Gaylord Nelson Chairman Monopoly Subcommittee PAGENO="0203" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13453 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION ROCKVILLE, MARYLAND 20852 APR 101975 Honorable ~aylord Nelson Chairman, Monopoly Subcommittee Select Committee on Small Business United States Senate Washington, D.C. 20510 Dear Senator Nelson: Thank you for your April 1 letter to Commissioner Schmidt requesting information concerning certain criminal cases involving false advertising charges forwarded to the Department of Justice by the Food and Drug Administration which that Department has decided not to file. We have begun a review of our files to assemble the information you requested and will supply you with an answer in the near future. If we can be of any assistance in any other way, please let us know. Sincerely yours, >i4~-V( (~4~L//,~. Robert C. Wetherell, Jr., DirectoV Office of Legislative Services PAGENO="0204" Senator Gaylord Nelson Senate Office Building Washington, D.C. Dear Senator Nelson: I am enclosing for your information a letter which I sent to Dootor Schmidt shortly after my testi- cony before you. It is my hope that in accordance with this letter some reasonable conclusion to this dispute will be forthcoming. I understand that hearings will be held again before your Subcommittee at which the FDA will be present. I am requesting at this time an opportunity to testify at that session so that the proper balance can once again be provided to the Subcommittee deliberations. Thank you for your continued attention to this matter. ry 1 yours, N il Ch~\ NLC CF Enc. 13454 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY CHAYET AND SONNENREICH, P. C. ATTORNEYS AT LAW 6 FAYETTE STREET BOSTON, MASSACHUSETTS 02116 February 1W, 1975 wAsHINOToN,D. C. 20037' PAGENO="0205" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13455 CHAYET AND SONNENREICH, P. C. ATIORNEYS AT LAW 6 FAYETTE STREET BOSTON, MASSACHUSETTS 02116 MICHAEL ~N~~NRE~CH (ei~) 357-0202 WATERGATE R00,$UITE 720 ~ February 11, 1975 WASHINGTON, 0. C.20037 Dr. Alexander Schmidt, Commissioner Food and Drug Administration Department of Health, Education and Welfare 5600 Fishers Lane Rockville, Maryland 20852 Dear Dr. Schmidt: It is my understanding that additional hearings are to be held later this month on the subject of oral hypoglycemic drugs before the Subcommittee on Monopoly, chaired by Senator Gaylord Nelson. It is my further understanding that the Food and Drug Administration will be asked to provide testimony at this hearing. I would suggest a meeting between my client and FDA officials to discuss in detail proposed label- ing changes by FDA and to determine whether there now exists labeling acceptable to both sides. It is my belief that more can be accomplished at an informal meeting than in testimony before congressional committees and protracted legal proceedings. Your testimony on September 20, lg7t~, indicated that there exists substantial controversy with regard to oral hypoglycemic drugs. You stated: " I have personally talked with many diabetologists around the country, and I am sure you know of the degree of controversy that yet remains about the UGDP Study. If that has not been brought up before the Committee, I think it really should be because many `experts' do publicly attack the UGDP study." I would also like to note the following portion of Mr. Mutt's testimony that same day: "We must then stand upon the scientific basis for our decision.. . .That is why in part we are waiting for the Biometric Society report as well as amending our regulation Section 1.3, to which the Commissioner has already averted, to settle the legal issue that was also involved in the case." The hope was expressed by both you and Mr. Mutt that the Biometric Society study would settle this matter. Although we have had only a brief period of time to review this study, I am authorized by my clients to inform you that, despite Dr. Chalmers' editorial entitled "Settling the UGDP Controversy," the controversy is in fact not settled. It is doubtful whether any single review of the UGDP study could settle the fundamenta]~ questions which have resulted in the controversy concerning PAGENO="0206" 13456 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY this study. What is needed is a new prospective study or studies to resolve the issues raised regarding oral hypoglycemics, coupled with immediate, balanced labeling reflecting the controversy. The Committee on the Care of the Diabetic intends to pursue, through the National Institutes of Health, access to the raw data of the UGDP Study and further to continu~ its opposition to the proposed amend- ment of Regulation 1,3, as expressed in comments which we filed relative to this regulation. I would like to call your' attention to the fact that one of the most fruitful aspects of this matter which has continued these many years was the meeting held with FDA officials in October 1973. At that meeting I felt that real progress was made in achieving labeling acceptable to all parties engaged in this controversy. I am enclosing a draft of this labeling prepared by the Committee on the Care of the Diabetic and request that all parties meet once again at the FDA to further discuss this matter, We offer our full cooperation in continuing the dialogue between the FDA and the Committee on the Care of the Diabetic which will result in new fairly balanced labeling which reflects the current scientific status which we feel, and have felt, is urgently needed. Very truly yours, Neil L. Chayet NLC:GF PAGENO="0207" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRT 13457 U.S. SENATE, SELECT COMMITTEE ON SM&u~ BuSINESS, Washington, D.C., May 27, 1975. NEIL L. CHAYET, Esq., Ohayet and Sonnenreich, P.C. Boston, Mass. DEAR MR. CHAYET: This is in response to your letter of February 14, 1975 accompanied by your correspondence with Commissioner Schmidt of the Food and Drug Administration, as well as your prior phone request to me. It is true that our Monopoly Subcommittee plans to hold another bearing on the oral hypoglycemic drugs, at which time the FDA will testify on labeling changes. Although your request to appear once again before the Subcommittee Is appreciated, this will not be necessary since your position is already part oi~ the hearing transcript. However, should you desire to place additional materia~ Into the record following the final testimony of the FDA, you may do so. In the meantime, I should be extremely grateful if you would send us ~ complete list of members (and their addresses) of the Committee on the Care of the Diabetic, the organization you represent. Your contittued interest in the work of our Subcommittee is appreciated. Sincerely, BENJAMIN GORDON, Staff Economist. CHAYET AND SONNENREICH, P. C., ATTORNEYS AT LAW, Boston, Mass., July 10, 1975. MR. BENJAMIN GORDON, Staff Economist, U.S. Senate, Select Committee on Small Business, Washington, D.C. DEAR MR. GORDON: I am in receipt of your recent letter referring the reque~t of the Committee on the Care of the Diabetic (COD) to testify before the Monopoly Subcommittee in the hearings held this week relative to labeling of oral hypoglycemic drugs. As you know, COD has been involved in the labeling controversy for several years, appearing before administrative, legislative, and judicial bodies. Froi~i the list of witnesses who appeared before the subcommittee, it would appear that the testimony offered this week represented only one side of the controversy. Particularly in view of very recent developments in the controversy, i.e. tl~e FDA's proposed relabeling of the drugs (Federal Register, Vol. 40, No. 18Q, pp 28582-28595), COD regrets not having been permitted to testify, as its testi- mony could have availed the Subcommittee of a more balanced view of tl~e issues. I am enclosing, per your request, a list of COD members, Kindly include this letter on the record of the proceedings. Very truly yours, NEIL L. CHAYET. Enclosure. Frank N. Allan, Chairman Emeritus, Medical Department, Lahey Clinic, 44 Barnstable Road, West Newton, Massachusetts 02165. Seymour Alterman, M.D., 1688 Meridan Avenue, Miami Beach, Florida 38139. Shepard G. Aronson, M.D., 150 East 56th Street, New York, N. Y. 10022. James B. Ashmore, M.D., Professor of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana. Donald M. Barnard, M.D., Fargo Clinic, Fargo, N.D. Donald Barnett, M.D., Joslin Clinic, 15 Joslln Road, Boston, Massachusetts 02215. Samuel B. Beaser, M.D., 31 Bay State Road, Boston, Massachusetts. Lewis H. Biben, M.D., 618 MedIcal Science Building, 916 NIneteenth StreØt, N.W., Washington, D. 0. 20006. Keith Borden, M.D., Chief, Diabetes Products, The Upjohn Company, Kalamazoo, Michigan 49001. Angela Bowen, M.D., 1015 West 4th Street, Olympia, Washington 98501. Robert F. Bradley, M.D., Medical Director, Joslin Clinic, 15 Joslin Road, Bosto~, Massachusetts 02215. PAGENO="0208" 13458 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY George Brown, M.D., 2021 Grand Concourse, Bronx, New York 10453. R. A. Camerini-Davalos, MD., Associate Professor in Medicine, New York Medi- cal College, Flower and Fifth Avenue Hospitals, 1249 Fifth Avenue, New York, New York 10029. John J. Canary, M.D., Director, Division of Endocrinology and Metabolic Disease, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, D. C. 20007. William Castelli, M.D., Department of Preventive Medicine, Harvard Medical School, Longwood Avenue, Boston, Massachusetts 02115. David R. Challoner, M.D., Associate Professor, Assistant Chairman, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Mr. Neil Chayet, 461 East 57th Street, New York, N.Y. John W. Chriss, M.D., Medical Center, 2436 Morgan Street, Corpus Christi, Texas. A. Richard Christlieb, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachu- setts 02215. Burton D. Cohen, M.D., Chief, Section of Metabolism, The Bronx Hospital, 1276 Fulton Avenue, Bronx, New York 10456. Daniel T. Coughlin, Director Government Affairs, The Upjohn Company, Suite 904, 1101 Seventeenth Street, N.W., Washington, D.C., 20036. DeWitt E. DeLawter, M.D., 500 Prospect Place, Chevy Chase, Maryland. Harold L. Dobson, M.D., Herman Hospital, Texas Medical Center, 1203 Ross Sterling Avenue, Houston, Texas 77025. Henry Dolger, M.D., 11 East 86th Street, New York, New York 10028. Arthur H. Dube, M.D., Associate Professor of Clinical Medicine, Upstate Medical Center, Syracuse, New York. Sigmund Falk, M.D., Chief, Diabetes Clinic, 15 West 11th Street, New York, New York 10014. Alvan R. Feinstein, M.D., Professor of Medicine & Epidemiology, Yale Univer- sity Medical School, New Haven, Connecticut. Leonard Felder, M.D., 26 Fifth Avenue, New York, New York 10011. Robert Feldman, M.D., Director of Metabolic Research, Kaiser Permanente Medical Foundation, 280 West McArthur Boulevard, Oakland, California 94611. Philip W. Felts, M.D., Assistant Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. B. Dan Ferguson, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. Peter H. Forsham, M.D., Chief of Endocrinology, Professor, Department of Medicine, University of California Medical Center, San Francisco, Cali- fornia 94122. Daniel Foster, M.D., Associate Professor of Internal Medicine, University of Texas, Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, Texas 75235. Adolph Friedman, M.D~. 1712 Eye Street, N.W., Washington, D. C. 20006. Gerald J. Friedman, M.D., 850 Park Avenue, New York, New York. Richard L. Fulton, M.D., 1211 Dublin Road, Columbus, Ohio. Edward J. Gallagher, M.D., 10090 Main Street, Fairfax, Virginia. Edwin W. Gates, M.D., 625 Sixth Street, Niagara Falls, New York 14301. H. Howard Goldstein, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. George Goodkin, M.D., Senior Associate Medical Director, The Equitable Life Assurance Society of the United States, 1285 Avenue of the Americas, New York, New York 10019. Irving Graef, M.D., 791 Park Avenue, New York, New York. Charles A. Graham, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. Robert C. Green, Jr., M.D., 230 W. Boscawen Street, Winchester, Virginia 22601. Barnett Greenhouse, M.D., 129 Whitney Ave., New Haven, Conn. Richard D. Grimaldi, M.D., Director of Diabetes, Bellevue Maternity Hospital, P. 0. Box 1030, Stop 11 Troy Road, Schenectady, New York 12301. William B. Hadley, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. Robert R. Hare, M.D., 2250 N. W. Flanders, Portland, Oregon 97207. Edgar A. Haunz, M.D., Professor and Chairman, Department of Medicine, Uni- versity of North Dakota, Grand Forks, North Dakota 58201. PAGENO="0209" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13459 Richard D. Hohi, M.D., Associate Physician, Division of Metabolic Diseases, Henry Ford Hospital, 2799 Grand Boulevard W., Detroit, Michigan 48202. H. Morris Horn, M.D. FACP, Texas Diabetis Assoc., 3434 Swiss Ave., Suite 305, Dallas, Texas 75204. Jesse D. Ibarra, Jr., M.D., Scott & White Clinic, Temple, Texas 76501. W. P. U. Jackson, M.D., Dept. of Medicine, University of Medicine, University of Cape Town Observatory, Cape Towns SOUTH AFRICA. Wyman E. Jacobson, M.D., Section on Endocrinology and Diabetes, St. Lou$s Park Medical Center, 4959 Excelsior Boulevard, Minneapolis, Minnesota 55416. George M. Jones, M.D., Past President, Texas Diabetes Assoc., Clinical Profes- sor of Internal Medicine, Southwestern Medical College of the University of Texas, Dallas, Texas. William R. Jordan, M.D., 1631 Monument Avenue, Richmond, Virginia 23220. Allen P. Joslin, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. Miles Kahan, M.D., 2405 Avenue P, Brooklyn, New York 11299. Dorothy Kahkonen, M.D., Associate Physician, Division of Metabolic Diseases, Henry Ford Hospital, 2799 Grand Boulevard W., Detroit, Michigan 48202. W. B. Kannel, M.D., Framingham Heart Study, 123 Lincoln Street, Framingbai~i, Massachusetts 01701. Norman M. Kaplan, M.D., Associate Professor of Internal Medicine, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, Texas 73235. George A. Kaufman, M.D., 888 Grand Concourse, Bronx, New York. Mr. Terry G. Kelley, Public Relations Associate, The Upjohn Company, Kala- mazoo, Michigan 49001. Mavis P. Kelsey, M.D., Kelsey-SeybQld Clinic, 6624 Fannin, Houston, Texas 77025. M. H. Kolodny, M.D., 1020 Park Avenue, New York, New York. George P. Kozak, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 02215. Leo P. Krall, M.D., Director of Education, Joslin Diabetes Foundation, 15 Joslin Road, Boston, Massachusetts 02215. Bernard T. Kravitz, M.D., Montefiore Hospital Medical Group, 3444 Kossuth Avenue, Bronx, New York 10467. Arthur Krosnick, M.D., Coordinator Diabetes, Endocrine and Metabolic Disease Program, Division of Chronic Illness Control, Department of Health, P.O. Box 1540, John Fitch Plaza, Trenton, New Jersey 08625. William Kurstin, M.D., 618 Medical Science Building, 916 Nineteenth Street, N.W., Washington, D. C. 20006. Thomas H. Lanibert, M.D., Scripps Clinic and Research FoundatIon, 476 PrOs- pect Street, La Jolla, California 92037. Richard L. Landau, M.D., Professor of Medicine, Head of Endocrinology S~c- tion, University of Chicago, Chicago, Illinois 60637. Ira J. Laufer, M.D., 45 Gramercy Park North, New York, New York 10010. Louis Lasagna, M.D., Department of Medicine, Strong Memorial Hospital, Crit- tenden Boulevard, Rochester, New York. Ann M. Lawrence, M.D., Associate Professor of Medicine, Section on Endoc- rinology, University of Chicago School of Medicine, Chicago, Illinois 60637. Sydney S. Lazarus, M.D., Chief of Pathology, Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center, Rutland Road and East 49th Street, Brooklyn, New York 11203. Paul Leifer, M.D., 1860 Grand Concourse, Bronx, New York 10457. Rachmiel Levine, M.D., Chief, Endocrinoligy Service, City of Hope Medical Center, Duarte, California 91010. Leon M. Levitt, M.D., 95 Buckingham Road, Brooklyn, New York 11226. Samuel D. Loube, M.D., Washington Internal Medicine Group, 2400 H Street, N.W., Suite 7, Washington, D.C. 20037. Glen W. McDonald, M.D., 426 Merkle Drive, Norman, Oklahoma. Leonard L. Madison, M.D., Professor of Internal Medicine, University of TeZas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas. Alexander Marble, M.D., President, Joslin Diabetes Foundation, 15 Joslin Road, Boston, Massachusetts 02215. Leona Miller, M.D., Associate Professor of Medicine, University of Southern California School of Medicine, Los Angeles, California. Merton M. Minter, M.D., Minter Clinic, Nix Professiinal Building, San Antonio, Texas 78205. PAGENO="0210" 13460 COMPETITIVE PROBLEMS IN THE I~RUG INDUSTRY James M. Moses, M.D., Fairlington Professional Building, 1707 Osage Street. Alexandria, Virginia 22302. Henry J. Oppenheimer, M.D., 141 North Meramec, Clayton, Missouri 63105. Mr. Harold Rlvkin, 510 Plymouth Avenue, Minneapolis, Minnesota. Morris H. Rosenberg, M.D., Suite 702, University Medical BuildIng, 2141 K Street, N.W., Washington, D.C. 20037. A. H. Rubenstein, M.D., Associate Professor, Department of Medicine, Section of Endocrinology, University of Chicago, Chicago, Illinois 60637. John W. Runyan, Jr., M.D., 951 Court Avenue, Memphis, Tennessee 38103. Elliot L. Sagall, M.D., 454 Brookline Avenue, Boston, Massachusetts 02215. Aaron G. Saidman, M.D., 5530 Wisconsin Ave., Chevy Chase, Md. 20015. Dominick J. Savino, M.D., 27 Prospect Park West, Brooklyn, New York 11215. George F. Schmitt, M.D., 30 Southeast 8th Street, Miami, Florida 33131. A. Schonfeld, M.D., 50 Central Park South, New York, New York. Stanley Schor, Ph.D., Temple University Health Services Center, Broad and Ontario, Philadelphia, Pennsylvania 19140. 0. Peter Schumacher, M.D., Cleveland Clinic, 2020 East 93rd Street, Cleveland, Ohio. Seymour Schutzer, M.D., 67 Cedar Drive, Great Neck, New York 11021. Zdenko Skrabalo, M.D., University of Zagreb Diabetes Center, Zagreb, Yugo- slavia. J. Stuart Soeldner, M.D., Assistant Professor of Medicine, Harvard University School of MedicIne, 170 Pilgrim Street, Boston, Massachusetts 02115. Maxwell Spring, M.D., Clinical Assistant Professor of Medicine, New York Medical College, 5th Avenue at 106th Street, New York, New York. John W. Stephens, M.D., 2250 N.W. Flanders, Portland, Oregon 97207. Daniel B. Stone, M.D., 530 Doctors Bldg., Omaha, Nebraska 68131. Samuel J. N. Sugar, M.D., 4637 Eastern Avenue, Washington, D. C. 20018. Karl E. Sussman, M.D., Associate Professor of Medicine, Acting Head, Division of Endocrinology, University of Colorado Medical School, 4200 East Ninth Avenue, Denver, Colorado 80220. Lawrence J. Thomas, M.D., 11801 Rockville Pike, Rockville, Maryland 20852. James Tullis, M.D., Chief of Medicine, New England Deaconess Hospital, Boston, Massachusetts. John B. O'Sullivan, M.D., Chief, Diabetes and Arthritis, Field Research Unit, U. S. Public Health Service, 408 Atlantic Avenue, Boston, Massachusetts 02118. Kar' R. Paley, M.D., Chief, Metabolic Clinic, Lenox Hill Hospital, 77th Street & Park Avenue, New York, New York. Arthur M. Parker, M.D., 380 East 18th Street, Brooklyn, New York 11226. Jean 0. Partamian, M.D., Associate Physician, Division of Metabolic Diseases, Henry Ford Hospital, 2799 Grand Boulvard W., Detroit, Michigan 48202. John W. Partridge, M.D., Editor, Diabetes Bulletin, 2222 N.W. Lovejoy Street, Portland, Oregon. Marjorie Peebles-Meyers, M.D., 3790 Woodward Avenue, Detroit, Michigan 48201. L. Lewis Pennock, M.D., Forbes-Oakland Medical Building, 3347 Forbes Avenue, Pittsburgh, Pennsylvania 15218. W. E. Redfern, M.D., Associate Physician, Division of Metabolic Diseases, Henry Ford Hospital, 2799 Grand Boulevard W., Detroit, Michigan 48202. Robert L. Reeves, M.D., F.A.C.P., 1015 West 4th Street, Olympia, Washington 98501. Harold Rifkin, M.D., Montefiore Hospital and Medical Center, 1111 East 210th Street, Bronx, New York 10467. Howard S. Schwartz, M.D., 3201 Grand Concourse, Bronx, New York 10468. Laurence F. Segar, M.D., 8700 Dean Dr. #1908, Ventura, Calif. 98003. Donald W. Seldin, M.D., Professor and Chairman Department of Medicine, University of Texas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Hoibrooke S. Seltzer, M.D.. Chief of Endocrinology, Veterans Administration Hospital, 4500 South Lancaster, Dallas, Texas 75216. Thomas Sharkey, M.D., 60 Wyoming Street, Dayton, Ohio 45409. L. Benjamin Sheppard, M.D., 301 Medical Arts Building, Richmond, Virginia. Charles Shuman. M.D., Temple University Health Services Center, Broad and Ontario, Philadelphia, Pennsylvania 19140. Abraham A. Silver, M.D., 6210 Park Heights Avenue, Baltimore, Maryland. PAGENO="0211" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13461 Marvin D. Siperstein, M.D., Professor of Internal Medicine, University of Texas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Janet D. Sherman, M.D., 18181 W. 12 Mile Rd., Lathrup Village, Michigan. Roger H. Unger, M.D., Veterans Administration Hospital, 4500 S. Lancaster Road, Dallas, Texas 75216. Alexander G. Vongries, M.D., Asst. Director, Clinical Development, Ciba-Gel~y Corp., Summit, NJ. 07901. Robert C. Warner, M.D., Asst. Prof. of Medicine, University of N. Dakota, Fargo, N. Dakota. Harry F. Wechsler, M.D., 737 Park Avenue, New York, New York. Irving Weckell, M.D., 7 Pont Street, Great Neck, New York. Charles Weller, M.D., 17 North Chatsworth Avenue, Larchmont, New York 10538. George Welsh, M.D., III, Director of Continuing Education for Health Sciences, University of Vermont Medical School, Burlington, Vermont. Priscilla White, M.D., Joslin Clinic, 15 Joslin Road, Boston, Massachusetts 022~5. Fred W. Whitehouse, M.D., Chief, Division of Metabolic Diseases, Henry Ford Hospital, 2799 Grand Boulevard W., Dejroit, Michigan 48202. David S. Wilcox, M.D., President, Connecticut Diabetes Association, 85 Jeff~r* son Street, Hartford, Connecticut 06109. T. Franklin Williams, Monroe County Hospital, East Henrietta Road, Rochester, New York. Charles W. Wilson, M.D., Harbor and Olean Blvd., Port Charlotte, Florida 339~0. Jean D. Wilson, M.D., Professor of Internal Medicine, University of Texas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Albert I. Winegrad, M.D., Director of Cox Institute, Hospital of the Universlt~V of Pennsylvania, Philadelphia, Pennsylvania 19104. Donna Younger, M.D., Joslin ClInic, 15 Joslin Road, Boston, Massachusetts 02215. Leonard Zimmerman, Group Service Agency, 342 Madison Avenue, New Yo~k, New York 10017. Akira Ilorinchi, M.D., 3-33-15 Minimimagome, Otliku, Tokyo, JAPAN. Bernard Leibel, M.D., 200 St. Clare Street W., Toronto, Ontario, CANADA. John A. Moorhouse, M.D., Director, Endocrine and Metabolic Laboratory, Winnipeg General Hospital, Winnipeg, CANADA. PAGENO="0212" 13462 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FOOD AND DRUG ADMINISTRATION [21 CFR PART 310] [DOCKET NO. 75N-OO62]. ORAL HYPOGLYCEMIC DRUGS NOTICE OF PUBLIC HEARING AND PROPOSED LABELING The Commissioner of Food and Drugs is proposing labeling for all oral hypoglycemic drugs and announcing a legislative-type public hearing on the issues involved. Labeling for this class of drugs has been the subject of extended public controversy and legal challenge for several years. The Commissioner believes that it is now essential to resolve the outstanding issues in this matter and that it is in the interest of the public health to consider the views of all parties in achieving such resolution. Accordingly, this notice proposes class labeling for oral hypoglycemic drugs that, on the basis of all information available to the Food and Drug Administration, the Commissioner believes is con- sistent with the requirements of the Federal Food, Drug, and Cosmetic Act and reflects current scientific knowledge on the safety and effect- iveness of these drugs. The Commissioner invites all interested persons to submit written comments on the proposed labeling. In addition, the Commissioner's designee, the Director of the Bureau of Drugs, will conduct an oral 75-415 PAGENO="0213" COMPETITIVE PROBLEMS IN TH~ DRTJG INDUSTRY 1346~ public hearing to afford interested persons a further opportunity for the presentation of data, information, and views. In the Com- missioner's judgment, the subject matter of this notice is of sufficient importance to justify the use of this additional procedure, as provided in Part 2, Subpart E, of the regulations governing the administrative practice and procedures of the Food and Drug Administration, published in the FEDERAL REGISTER of Nay 27, 1975 (40 FR 23025). Interested persons may submit comments on the labeling proposed in this notice by (insert date 60 daSrs after date of pub1icationi~ the FEDERAL REGISTER). In addition, any interested person may submit data, information, or views in writing any time within 15 days after the conclusion of the public hearing. It is the intention of the Food and Drug Administration to conduct the public hearing prior to the expiration of the time for submitting comments, and the Commissioner therefore encourages interested persons to submit their comments as soon as possible, to allow review prior to the hearing. After consideration of all written and oral comments and all data, information, and views presented at the public hearing, the Commissioner will promulgate in the FEDERAL REGISTER a final regula- tion prescribing labeling for oral hypoglycemic drugs, applicable PAGENO="0214" 13464 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY to all drug products in this class It is anticipated that the final labeling will conform with the guidelines for labeling of prescription drugs proposed by the Commissioner on April 7 1975 (40 FR 15392) I. GENERAL BACKGROUND The following new drug applications have been approved for oral hypoglycenic drugs: 1 NDA 10 670 Orinase tablets containing tolbutamide The Upjohn Co., 7000 Portage Rd., Kalamazoo, MI 49001. 2. NDA 15,500, Tolinase tablets containing tolazamide; The Upjohn Co 3 NDA 11 641 Diabinese containing chlorpropamide Pfizer Inc 235 E 42d St New York NY 10017 4 NDA 13 378 Dymelor containing acetohexamide Eli Lilly & Co Indianapolis IN 46206 5 NDA 11 624 DEl tablets containing phenformin hydrochloride Geigy Pharmaceuticals Ardsley NY 10502 6 NDA 12 752 DBI-TD capsules containing phenformin hydrochloride Geigy Pharmaceuticals 7 NDA 17 126 Meltrol-50-100 capsules containing phenformin hydrochloride USV Pharmaceutical Corp 1 Scarsdale Rd Tuckahoe NY 10707 8 NDA 17 127 Meltrol-25 tablets containing phenformin hydrochloride * USV Pharmaceutical Corp. * 9 NDA 12 678 Tolbutamide tablets conraining tolbutamide Premo Pharmaceuticals Laboratories Inc 111 Leuning St South Hackensack NJ 07606 PAGENO="0215" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 134~5 The class of oral hypoglycemic drugs can be grouped into two categories on the basis of chemical structure: the sulfonylurea category (represented by acetohexamide, chiorpropamide, tolazamide, and tolbutamide) and the biguanide category (represented by phenfortnin hydrochloride). The mode of action and adverse effects are different for these two categories of oral hypoglycemic drugs. Accordingly, separate labeling is proposed for each category of drug. Under section 505 of the Federal Food, Drug, and Cosmetic Act, the Commissioner is responsible for. assuring that all new drugs have been shown to be safe and effective for their intended uses and that their labeling is not false or misleading. Exercise of this responsibility often requires reexamination of the safety, effective- ness, or labeling of drugs previously approved. The statutory scheme contemplates that new information may require the Commissioner to prescribe changes in the labeling of a drug, to reveal newly discovere4 limitations on use or warn of previously unanticipated hazards. And if labeling can no longer be written to assure that the benefits of use of a drug outweigh the risks of possible harm, the Commissioner is empowered, and obligated, to withdraw marketing approval. The Commissioner believes that information about potential risks of oral hypoglycemic drugs obtained subsequent to their initial approval for marketing requires revision of their labeling. PAGENO="0216" 13466 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Specifically, he believes the study of modes of treatment for adult- onset diabetes conducted by the University Group Diabetes Program requiree the addition of a warning about possible cardiovascular compli- cations associated with the use of such drugs. Because of the importance of this matter and the concerns it has generated among physicians and their patients, the Commissioner has concluded that it is appropriate to invite exploration of the issues in a public forum before reaching a final determination on the wording of the labeling, including the warning. The scientific and legal issues relating to the labeling of oral hypoglycemic drugs have been the subject of protracted public debate. To resolve the many complex questions that have been raised, it is essential that the important issues be identified and that public comment be directed to these issues. The following discussion is presented to summarize the history of the oral hypoglycemic labeling controversy, to identify the issues that have arisen during the con- troversy, and to explain the position of the Food and Drug Administration on these issues. II. ORIGIN OF THE LABELING CONTROVERSY Although insulin and the oral hypoglycemic drugs are both effective in lowering the blood glucose level in patients with maturity-onset diabetes, it is not clear that this reduction of blood glucose has a beneficial effect on the long term vascular complications of diabetes. ~ ~ ~ .__. .*___ .__.___~,__~ In an attempt to answer this question, the National Institute of Arthritis, PAGENO="0217" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13467 Metabolism, and Digestive Diseases of the National Institutes of Health sponsored a long term, prospective clinical trial. The study, begun in 1961, was conducted by the University Group Diabetes Program (UGDP) in 12 university medical centers. Patients selected for the study were maturity-onset diabetics who had been diagnosed no more than 1 year prior to entry into the study and did not require insulin to remain symptom-free. - All patients were given an appropriate diabetic diet and were randomly assigned to one of four different treatment groups: (1) Fixed dose of tolbutamide (1.5 grams/day), (2) Fixed dose of insulin (10 to 16 units based on body surface area), (3) Variable dose of insulin adjust~d to control the blood glucose, or (4) Placebo. Eighteen months after the study began, a fifth group was added in which the treatment was a fixed dose of phenformin hydrochloride (100 milligrams/day). Patient recruitment was completed in 1966 with a total of 1,027 patients in the entire study and approximately 200 patients per treatment group. By 1969 the unexpected finding of a significantly higher mortality due to cardiovascular causes was present in the tolbutamide group (12.7 percent or 26 out of 204) compared to the placebo group (4.9 percent or 10 out of 205), the fixed-dose insulin group (6.2 percent or 13. out of 210), and the variable insulin group (5.9 percent or 12 out of 204). After evaluating the available data, the investigators decided to discon- tinue use of tolbutamide in the study because they concluded that no ~-.-, benefit had been shown for these patients and there was evidence that .--,- _. ..__.. ,.___.. .__ ..___ .._.__ _.*___~~__*.* ~.- *~. -, _._ ~..~_*__*__._*__*, ___._.__ ,- ~ the long term use of this drug was associated with a serious side effect. -. -... ..-.-... -. .- ..........-,- .--..~--. .......,.... ,..-,...--. .-- .. .,. ..-. .. .. ,,-.-.. ,-.-,. ~______________..____ 56-592 0 - 75 - pt. 28 - 15 PAGENO="0218" 13468 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A report on the findings of the UGDP was submitted to the Food and Drug Administration in March 1970. The i~eport concluded that "the findings of this study provide no evidence that the combination _~**__.* **.__*. ~.___*__._.. -- __.** _. .*__ --- -- *__*.___ -- ._~_ _.__ *_*___*__.__ _*___*._* ._. ~ ~ of diet and tolbutamide therapy as described and used for mild non- insulin dependent diabetics is more effective than diet alone. Moreover, the findings suggest that tolbutamide and diet nay be less effective, at least insofar as cardiovascular mortality is concerned, than diet :- .,~. -*--. -. alone or than diet plus insulin." The Food and Drug Administration reviewed the report and convened an ad hoc meeting of experts on May 21, 1970, to evaluate the findings. The report was scheduled for pre- sentation at the annual meeting of the American Diabetes Association on June 14, 1970. The program and abstracts for the meeting of the American Diabetes Association were disseminated in May, however, and the general findings of the IJGDP study became widely publicized in the press. In view of this publicity, FDA released a statement to the press on May 22, 1970, indicating that the agency agreed with the UCDP's stated conclusions and would require labeling changes for the oral hypoglycemic drugs to reflect results of the study. PAGENO="0219" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13469 In October 1970, FDA distributed a Current Drug Information Bulletin to physicians and other health professionals confirming its agreenent with the stated conclusions of the UGDP study. The agency recommended that use of sulfonylurea agents be limited to those patients with symptomatic onset, nonketotic diabetes who cannot be ad ately controlled by diet or weight loss alone and in whom the addition of insulin is imprac- tical or unacceptable. I The first report of the UGDP study was published in November 1970 as a supplement to Diab~j~, the journal ~of the American Diabetes Association (ref. 1). An accompanying editorial statement representing the view o~ the American Diabetes Association (ref. 2) made the following therapeutic recommendations: The clearest indication for oral agents is diabetes of mild or moderate severity in a patient who proves to be poorly controlled with diet and who is unable or unwilling to take insulin. In adult- onset diabetes with hyperglycemia and glycosuria, symptomatic or not, and in the absence of ketosis, a trial with an appropriate diet should come first. If this does not establish satisfactory control, insulin iè to be preferred to other therapeutic ~ controlling hyperglycemia and the UGDP study - indicates that it may be safer. ~ _.~~__* ~`_,---- _~_.._ ._ ~ ~ ._____* ~_..* PAGENO="0220" 13470 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY A statement published at the same time by The American Medical Association Council on Drugs (ref. 3) included the following recommendations: Although some flaws exist in the UGDP study, it clearly demonstrates that every effort should be made by the physician to control the symptomatic, maturity-onset diabetic with diet alone. Should this fail, treatment with insulin or oral hypoglycemic agents should be undertaken. If oral hypoglycemic agents are selected for therapy the results of the UGDP study should be kept in mind. Therefore, the consideration of treatment with oral hypoglycemic agents should be secondary to the use of insulin. In May 1971 the use of phenformin in the UGDP study also was discon- tinued because there was a significantly higher cardiovascular mortality in the phenformin group (12.7 percent or 26 out of 204) compared to the other treatment groups. The preliminary results with phenformin were published in August 1971 (ref. 4). An additional report by the UGDP published in November 1971 discussed the clinical implications of the UGDP study (ref. 5). In June 1971 the Food and Drug Administration issued a Drug Bulletim outlining changes in the labeling for all sulfonylurea drugs. The Drug Bulletin stated that diet and reduction of excess weight are the foundation of therapy of diabetes mellitus, and that when the disease is adequately controlled by these measures, no other therapy is indicated. PAGENO="0221" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13471 The Bullef in also stated that the sulfonylurea agents are indicated in the treatment of adult-onset, nonketotic diabetes mellitus which cannot be adequately controlled by diet and reduction of excess weight alone and when, in the judgment of the physician, insulin treatment is not feasi1~le. From the time the results of the UGDP study were first reported, the study was subjected to intense criticism by both clinicians and statisti- cians (ref. 6 through 12). The basic scientific criticisms of the study were as follows: 1. Patient selection was inappropriate in that many patients had such mild diabetes that neither oral drugs nor insulin was indicated. 2. Total mortality in the tolbutamide group was not significantly different from that in the placebo group. 3. Excess cardiovascular mortality occurred in only a few clinics. 4. Randomization was not successful; therefore, the tolbutanide group was not comparable to the other groups at the outset of the study with respect to baseline cardiovascular risk factors. 5. With the exception of the variable insulin group, patients were maintained on a fixed drug dosage, contrary to the principles of good medical practice. 6. The use of tolbutamide and phenformin in the study was termir~ated~ prematurely, i.e., before definitive results were obtained. 7. The results of the study are contradicted by the studies of Keen (ref. 13 through 15) and of Paasikivi (ref. 16). These criticisms were in turn analyzed by representatives of the IJGDP (ref. 17) and by a statistician who had served as a consultant tp the IJGDP (ref. 18) and were rejected as a basis for invalidating the conclusions of the UGDP study. By this time, however, a widespread PAGENO="0222" 13472 COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY belief had developed among many physicians that the UGDP study was somehow flawed in terms of its design and execution and therefore could not serve as a proper basis for a warning to the medical profession Uncertainty about the scientific quality of the UGDP study has been a prominent feature of all critical commentary since 1970 and has clearly inhibited acceptance by the medical profession of the study's most troubling finding namely that the administration of either tolbutamide or phenfornin to patients with maturity-onset diabetes was associated with an increase in cardiovascular moxtality Undoubtedly one reason many practicing physicians were surprised ~ tlie findings of the UGDP study is that the reported increase in cardio- - ~ .._*_._~_ ~ ~_~.___~_____ .*. _~~____.._ ~~-~-- *_.~_~.*_. ___. ~ ___*_*_*._~__.. - vascular-mortality--though statistically significant--is not of the magnitude which can be readily detected.by the individual physician in the course of practice The Commissioner recognizes that a large number of physicians still do not accept the position of the Food and Drug Administration as expressed in the FDA Drug Bulletin, or the position of the American Diabetes Association and the American Medical Association Council on * Drugs as expressed *in the -references cited. An outcome of this dis- agreement was a prolonged legal confrontation that precluded the inclusion of warnings in the labeling for oral hypoglycemic drugs similar to those appearing in the Drug Bulletin III LEGAL CHALLENGE TO THE LABELING OF ORAL HYPOGLYCEMIC DRUGS In November 1970 a group of physicians known as the Committee * on the Care of the Diabetic was formed to oppose the proposed warning PAGENO="0223" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 134~3 labeling for oral hypoglycemic drugs. The group included some of the country's leading diabetologists. In October 1971 the Committee on the Care of the Diabetic petitioned the Commissioner to rescind his position that labeling for oral hypogly~- cemic drugs must contain a warning of associated cardiovascular hazards. The committee maintained that the UGDP study cons~ituted an improper basis for the agency's decision, because it had been criticized on scientific, clinical, statistical, aç~d other grounds. The Committee on the Care of Diabetes cited "conç sing data," particularly the studies of Keen et al. (ref. 13 through 15) and Paasikivi (ref. 16), which, it contended, demonstrated the safety of oral hypoglycemic therapy. The committee also insisted that labe~4~g for .these drugs must reflect a "fairbalanc&'ofscientific~n~n~d cite the alleged deficiencies of the UGDP study and the controversial nature of its conclusions as well as the data in controversy. After thorough evaluation of all the materials submitted to the agency,' the Commissioner formally replied to counsel for the Committee on the Care of the Diabetic on June 5, 1972. The Commissioner's letter responded to each of the criticisms raised by the committee concerning the UGDP study and the agency's position. The Commissioner reaffirmed the position of the Food and Drug Administration that an undiluted and unencumbered warning in the labeling of the oral hypoglycemic drugs regarding cardiovascular hazards was fully warranted by the available ~ evidence. PAGENO="0224" 13474 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The agency's position on labeling for these drugs was again stated in an FDA Drug Bulletin issued in May 1972. Based on the results for phenformin reported by the UGDP in 1971, the following labeling changes were to apply to the biguanide drugs as well as the sulfonylurea drugs: Because of the apparent increased cardiovascular hazard associated with oral hypoglycemic agents, they are indicated in adult-onset, nonketotic diabetes mellitus only when the condition cannot be adequately controlled by diet and red~iction of excess weight alone, and when, in the judgment of the physician, insulin cannot be employed because of patient unwilling- ness, poor adherence to injection regimen, physical disabilities such as poor vision and unsteady hands, insulin allergy, employment requirements, and other similar factors. On July 13, 1972, counsel for the Committee on the Care of the Diabetic requested a formal evidentiary hearing before the agency. The Commissioner advised the petitioners that they were not entitled to a hearing since their submission did not meet the statutory standard of "substantial evidence" and stated that the Commissioner's letters constituted final agency action. Soon thereafter suit was filed in the United States District Court for the District of Massachusetts by a group of 178 physicians, many of them members of the Committee on the Care of the Diabetic, asking that the Food and Drug Administration be enjoined from requiring manu- facturers to include a warning of associated cardiovascular hazards PAGENO="0225" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13475 in their labeling for oral hypoglycemic drugs (Bradley v. Richardson, Civil No. 72-2517 M (D. Mass. 1972)). A temporary restraining order was entered by the court on the sane day. A hearing on the notion for a preliminary injunction was held before Judge Campbell on August 17, 1972, and,, on August 30, 1972, he denied an injunction. Judge Campbell concluded that the plaintiffs had not demonstrated a reasonable probability of prevailing on the merits since the admini- strative action of the Food and Drug Administration, requiring an unencumbered warning, was a reasonable exercise of its statutory duty and the potential harm to users of the drugs was greater than any harm to the manufacturers or prescribers. Judge Campbell further observed that the Food and Drug Administration labeling requirements would not preclude physicians from exercising their best clinical judgment. The plaintiffs filed another motion for a temporary restraining order and preliminary injuction on October 17, 1972, specifically reqtlest- ing that the agency be enjoined unless the drug warning was redrafted to incorporate their views concerning the interpretation of the TJGDP study. The plaintiffs argued that, without such a discussion, the labeling required by the Food and Drug Administration was misleading because it failed to reveal the existence of divergent opinion among experts, contrary to the agency's own regulation, § 1.3 (21 CFR 1.3). On November 3, 1972, the District Court issued a temporary restraining order, which became a preliminary injunction on November 7, 1972, restraining the agency from implementing the labeling. PAGENO="0226" 13476 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY On July 31, 1973, the United States Court of Appeals for the First Circuit vacated the District Court's injunction and remanded the case to the Food and Drug Administration for its further deter- mination. In its opinion the Court ruled that the plaintiffs failed to exhaust their administrative remedies regarding the issues presented. The Court expressed its awareness of negotiations between the parties to arrive at a mutually acceptable solution even during litigation, and also expressed its belief that the remand could well produce the most informed and responsible solution possible (483 F.2d 410 (1st. Cir. 1973)). In its opinion the Court of Appeals also noted apparent incon- sistency between the agency's regulation on the disclosure of differences of medical opinion in § 1.3 and the substantial evidence requirements added to the Federal Food, Drug, and Cosmetic Act by the Drug Amendments of 1962. The Court directed the Commissioner to consider § 1.3 as it relates not only to the substantial evidence standard but also to the misbranding requirements of the act. The agency is revising § 1.3, by order published elsewhere in this issue of the FEDERAL REGISTER, to bring the regulation into conformity with these related provisions of the law. As revised § 1.3 does not permit a statement of differences of opinion in required warnings in the -:-.- -- labeling of drugs. PAGENO="0227" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13477 It should be noted that no manufacturer of oral hypoglycemic drugs has initiated proceedings challenging the Commissioner's authority to require changes in the labeling of its products, or ~ that the agency proposed to require. After the Court of Appeals vacated the preliminary injunction in July 1973, the Food and Drug Administration undertook additional discussions concerning the labeling of the oral hypoglycemic agents with interested individuals and gr~ups. In October 1973, the Director, Bureau of Drugs, and other members of the Food and Drug *Administration met with representatives of the Committee on the Care of the Diabetic, the American Medical Association, the Americat~ Diabetes Association, the National Institutes of Health, and manu- facturers of hypoglycemic drugs to discuss procedures that would facilitate the. issuance of appropriate labeling. Based upon the discussion and input from the agency's staff, proposed labeling revisions were circulated for comments in February 1974 to those who attended the meeting and to other interested persons. Addressees were also invited to meet with agency officials, if desired, to discuss the labeling. Four such meetings were held between March 21 and April 24, 1974. The minutes of these meetings have been placed on public display in the office of the Hearing Clerk. PAGENO="0228" 13478 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The responses to the proposed labeling, including comnents received at these meetings, revealed continuing major differences of opinion over the scientific validity of the UGDP study and over the asserted need for "fair balance" and the acknowledgment of "controversy" in the proposed warning. In addition, the Food and Drug Administration was advised that a major outside Teview, described below, of the UGDP study by a committee of the Biometrics Society was near completion. The agency therefore decided to postpone implementation of the warning until this review was published. Since the UGDP study was the basis for the proposed warning, the Commissioner believed that this independent review of the statistical validity of the study should be available to all interested persons before taking definitive action. The review by the committee of the Biometrics Society required extensive reanalysis of the data in the UGDP study and was mat published until February 10, 1975 (ref. 19). A more detailed report of the UGDP on phenformin was also published recently (ref. 20). The Commissioner believes that sufficient time has passed to~h~y~ permitted all interested persons to study these reports. Since no maj or new inf ormation in regard to the UGDP study a an Commissioner believes it is now essential to effect all labeling changes that are appropriate and necessary on the basis of the UGDP study. On June 11, 1975, and June 18, 1975, representatives of the Food and Drug Administration met with representatives of the Committee on the Care of the Diabetic to discuss late drafts of the Indications and PAGENO="0229" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13479 Warnings sections of the labeling proposed in this notice. The representatives of the Committee on the Care of the Diabetic included one of the plaintiffs in Bradlei v. Weinberger and the plaintiffs' attorney. The purpose of these meetings was to engage in good faith negotiation in an attempt to resolve outstanding issues in conformity with the intent of the Court of Appeals. Memoranda of these meetings and of subsequent phone calls and drafts of labeling discussed at the _______*._* _*~.__.*~_ ._ _. *.* --- _._. ._ _._ ._ ._ -- ---- ._ ---- meetings are on file in the office of the Hearing Clerk. IV. REVIEW OF BIOSTATISTICAL ISSUES BY THE COMMITTEE OF THE BIOMETRICS SOCIETY The UGDP study was subjected to intense adverse criticism (ref. 6 through 12) largely on the basis of its design and the statistical analysis of the results. For this reason, the National Institute of Arthritis, Metabolism, and Digestive Diseases, which financed the UGDP study, sought an independent review of the study. In 1972 a contract was awarded to the Biometrics Society, an inter- national organization of biostatisticians, to make an in-depth assess- ment of the scientific quality of the UGDP study, particularly the biometric aspects of the design, conduct, and analysis of the trial, and a similar assessment of other controlled trials involving oral hypoglycemic agents. A committee of six members was selected to undertake this task. The committee visited the UGDP coordinating center and two of the clinical centers to study methods used in the trial, reviewed PAGENO="0230" 13480 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY published criticisms of the UGDP study in detail, interviewed both critics and supporters of the study, and made new analyses from the original data On the basis of this in-depth review the Biometrics Societ) committee commented as follows on the major criticisms of the IJGDP study 1. The criticism that patient selection was inappropriate was considered to be `largely irrelevant to the primary issue raised by the critics viz the validity of the evidence pointing to excess mortality in the tolbutamide~ and phenformin-treated groups The committee argued that even if it could be shown that the study group contained some non_diabetics* * * (a] drug found toxic in such subjects would not likely be counted safe for persons with we1p~ume~t~e&m~.1d. diabetes either." 2. Wih respect to the criticism that total mortality in the tolbutamide group was not significantly different from that in the placebo group the committee concluded that this criticism `has some weight (although we do not interpret it as a criticism of the action of the UGDP) and that the toxic effect of the oral hypoglycemics cannot be affirmed with the certainty that would be present if total mortality were significantly different 3 In response to the criticism that excess mortality occurred in only a few clinics the committee presented calculations of the data to take account of the number of patients treated in each clinic and the duration of their treatment and concluded that the excess mortality PAGENO="0231" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13481 is not in fact confined to a few clinics and, that this particular criticisn should not be taken to detract from the interpretation of the UGDP findings." 4. The contention that randomization was not successful was studied in detail by the committee which identified "a puzzling anomaly concerning the distribution of the two sexes to the four treatment groups within clinics." The committee reviewed the randomization procedure in detail and examined the log books contain- ing records of the allocation of each patient. The committee's report reads: "We were not able to find an assignable cause for the surprising allocation of the sexes to treatments but have no reason to think that the study has been compromised by a breakdown in the randomization of patients to the treatment groups. Because of the imbalance of sexes in the treatment groups in some clinics, however, allowance for this has been made in our analysis." The committee went on to analyze the data by several different statistical approaches, including those used originally by the UGDP investigation. The com- mittee concluded: "Our findings* * * take into account the differences between centers and the differences in length of treatment, as well as the baseline variables. They support the view of Cornfield [ref. 18] that there is no evidence that the baseline differences arising from ~he randomization contributed in any important way to the finding of adverse effect from tolbutamide." PAGENO="0232" 13482 COMPETITIVE PROBLEMS IN THE' DRUG INDUSTRY 5. The criticism that the oral hypoglycemic drugs were given in fixed dosage was rejected by the committee, with respect to conclusions regarding toxicity, as follows: "It is true that the use of a fixed dose of drug, which was also the approach adopted by Feldnan et al. [ref. 211 and Keen and Jarrett [ref. 14], limits the generalization about therapeutic effects, but since the dose of tolbutamide is about equal to the average recommended for therapeutic use, an evalu- ation of its possible toxic effect is~highly relevant." 6. Concerning the criticism that the use of tolbutamide and phenformin was terminated prematurely, the committee acknowledged that "It would have been easier to interpret the findings if there were more data on mortality." The committee also recognized, however, the ethical issues raised by continuing these drugs in the study and concluded: "We do not criticize the UGDP investigators for having made the decision when they did. Nevertheless, the result of that decision is to leave us with some residual uncertainty about the meaning of the findings, a point that is well understood by the UGDP investigators themselves." 7. , In considering the criticism that the results of the UGDP study are contradicted by the studies of Keen (ref. 13 through 15) and of Paasikivi (ref. 16), the committee analyzed these studies in detail. With respect to the data of Keen and his colleagues, they concluded that, in their ongoing prospective study, neither cardiovascular mortality nor total mortality in the tolbutamide group is significantly different from PAGENO="0233" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 1348~3 that in the placebo group. Because of imperfections in the randomization process and in the maintenance of blinding, and because of the pre- liminary nature of the data obtained to date, the committee concluded that "the provisional data that Dr. Keen has kindly sent us~' * * do not throw doubt on the UCDP findings in regard to deaths from cardiovascular causes." In regard to the Paasikivi study, which appeared to show a beneficial effect of tolbutamide on mortality in the first year in patients who survived a first nyocardial infarction, the committee concluded: "This study' neither confirms nor contradicts the IJGDP findings, as the population under consideration was not one of maturity- onset diabetics, and the patients taking tolbutamide had been exposed to a relatively small dose for a shorter time than that applied in the UGDP study." The studies of Feldman et al. (ref. 21) and of Tzagournis and Reynertson (ref. 22) were also briefly reviewed by the committee. Their conclusion was that in neither study has a sufficient number of deaths yet occurred to permit meaningful interpretation of results. In addition to evaluating these criticisms of the tIGDP study, the Biometrics Society committee conducted extensive new analyses of the UGDP data, taking into account the effect of various baseline variables and cardiovascular risk factors. These analyses confirmed that cardio vascular mortality was increased in the tolbutamide group. ~ was ~ agp of 53, but not in males. An important finding was that the highest death rate occurred in the group of patients who adhered most closely to the tolbutamide regimen and did not have their dose modified. Also when 56-592 0 - 75 - pt. 28 - 16 PAGENO="0234" 13484 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the analysis was conducted according to an approach called the survival modeling method, which takes into account the proportion of time each patient received the assigned medication, women in the tolbutamide group had a statistièally significant increase in both cardiovascular and total mortality. This does not mean that the study necessarily showed the drug to carry less risk in males. On this point the committee concluded: "The data do Cot support the same conclusions for men, but one possible reason is that the smalLer number of patients in the male group results in lack of sensitivity to detect differences of moderate magnitude." In the final section of its report, the Biometrics Society committee summarized its conclusions: Although we have concerned ourselves almost entirely with issues related to the possible toxicity of tolbutamide, we wish to point out that one of the valuable aspects of the completed TJGDP trial will be the provision of data on the long term treatment of adult- `onset diabetes with insulin. It is already * clear that the benefits from this treatment are not dramatic, and the only worthwhile information about them will have to come from the relatively precise methods of a controlled clinical trial'. In this sphere, the UGt~P trial has no competitor* * * PAGENO="0235" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1348~ On the question of cardiovascular nortality _.___ ~ ___..__ .~.__ - -~- ~ __~__.. _.__ ~ _*~---.;-_.-__-.-__--_ due to tolbutamide and phenformin we consider that the UGDP trial has raised suspicions that cannot be dismissed on the basis of other evidence presently available. .-.- .~.., ..-- ~ -.-..- .~.-...-.-. ..- .. -~. ..... We find most of the criticism levelled against the UGDP findings on this point unper- suasive The possibility that deaths may have been allocated to cardiovascular causes prefer- entially in the groups receiving oral therapy exists, and, in view of the `nonsignificance' of differences in total mortality, some reservations about the conclusion that the oral hyperglycemics [sic} are toxic must remain Nonetheless we consider the evidence of harmfulness moderately strong The risk is clearly seen in the group of older women* * * Whether it affects all subgroups of patients cannot be decided on - the basis of the available data owing to the small number of deaths involved in these subgroups* * * PAGENO="0236" 13486 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In conclusion, we consider that in the light of the UGDP findings, it remains with the proponents of the oral hyperglycemics [sic} to conduct scientifically adequate studies to justify the continued use of such agents. V. RECENT ADDITIONAL INFORMATION ON SAFETY OF ORAL HYPOGLYCEMIC DRUGS The more detailed report. on the results of the phenformin study was published recently by the UGDP (ref. 20). In addition to the higher mortality from all causes and from cardiovascular causes observed in the phenformin-treated group compared to the other treatment groups,_evidence was presented that phenformin therapy resulted in increased blood pressure levels and heart rate, thus suggesting possible mechanisms by which this drug might influence cardiovascular mortality. Recently, additional reports relating to the safety of oral hypo- glycemic drugs have appeared: 1. At hearings before the Subcommittee on Monopoly of the Select Committee on Small Business, U.S. Senate, on January 31, 1975, Dr. P. J. Palumbo reported that a retrospective study of diabetic patients treated at the Mayo Clinic suggests that survival was lower in those patients treated with oral hypoglycemic agents, compared to those patients treated with insulin. The full study has not yet been published. 2. A retrospective study of diabetic patients treated at the Joslin Clinic, reported in a doctoral thesis (ref. 23), can be interpreted as providing results that are consistent with those of the UGDP. This study has not yet appeared in the medical literature. PAGENO="0237" COMPETITIVE PROBLEMS IN THE DRuG INDTJSTRY 13487 3. A positive inotropic effect, i.e., increased force of muscular contraction, of sulfonylurea agents on the heart muscle has been demon- strated (ref. 24 and 25). The increased oxygen requirement resulting from such an effect could have a deleterious effect in patients with coronary artery disease. Limited animal studies also suggest that the sulfonylurea agents may affect the excitability of heart muscle (ref. 25), which could predispose the heart to develop abnormal rhythms, particularly in the presence of a decreased oxygen supply. 4. Results from a study on the, chronic effects of tolbutamide in the rhesus monkey by R. W. Wissler et al. (FDA contract 72-114) indicate there is an increased frequency and severity of atherosclerotic lesions in the coronary arteries of the tolbutanide-fed monkeys compared to the control monkeys (ref. 26). The final report of this study is under review. While neither of the two epidemiological studies is a prospective clinical trial such as the UGDP study, the preliminary reports indicate that further information casting doubt on the safety of the oral hypogl~- cemic drugs may be forthcoming. And, although the animal findings cannot be considered necessarily relevant to the issue of excess cardio- vascular mortality in diabetic patients, they indicate that sulfonylureas may have potentially adverse effects on the cardiovascular system of certain animals which can be detected by appropriate pharmacological and ~~icaltest~ In addition to these reports, two critiques of the Biometrics Society committee report have recently been published (ref. 27 and 28). PAGENO="0238" 13488 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY VI. DISCUSSION OF PROPOSED LABELING FOR ORAL HYPOGLYCEMIC DRUGS The judgment of the Commissioner that changes must be made in the labeling of the oral hypoglycemic drugs to reflect the findings of the UGDP study is well known from previously published statements. The Commissioner is therefore proposing labeling in this notice for public comment and scheduling a public hearing to receive additional data information and views After consideration of all materials submitted, the COmmissioner will publish final labeling for oral hypoglycemic drugs in the FEDERAL REGISTER. The warning proposed in this labeling for oral hypoglycemic drugs is based primarily on a thorough review and evaluation of the UGDP study In proposing the overall labeling the Commissioner has also carefully considered 1. Published reviews, criticisms, and rejoinders to criticisms of the UGDP study. 2. Other scientific and clinical investigations of the oral hypoglycemic agents.. . . 3 The advice of experts 4 Comments submitted to the agency by interested persons The Commissioner reaffirms his conclusion that the UGDP study is an adequate and well-controlled clinical trial which is the most extensive and detailed examination of long term administration of hypoglycemic agents yet undertaken Although the study has shortcomings which might be expected in any clinical trial of this complexity PAGENO="0239" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 134~9 the shortcomings do not invalidate the central finding that there appears to be an increased risk of cardiovascular mortality associated with the administration of tolbutamide and of phen- forniin to maturity-onset diabetic patients, compared to treatment with diet alone or diet plus insulin. This conclusion has in the past been reached independently by the IJGDP investigators, the FDA, and the Biometrics Society committee, and is again affirmed by the Commissioner. Other clinical trials of these oral hypoglycemic drugs are not comparable to the UGDP study and provide insufficient evidence to negate the findings of the UGDP study. Accordingly, although comments concerning the validity of the UGDP study and its conclusion will be accepted, comments on this issue that contribute no new information and only reiterate published criticisms, which have already been extensively reviewed by the Food and Drug Administration, are not considered useful at this time. -The Commissioner proposes that a boxed warning concerning the possible increased risk of cardiovascular mortality be included in the. labeling for these drugs. This warning is based on the findings of the UGDP study. The Commissioner emphasizes that the requirement for such a warning does not depend upon an absolute certainty that the findings of the UGDP study are correct. Prudence dictates that PAGENO="0240" 13490 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a warning be issued whenever there is sufficient evidence from controlled or uncontrolled studies to believe that a drug may be hazardous or carry a risk and that such warning is necessary for safe and effective use of the drug by physicians and paUents. The Federal Food, Drm~g, and Cosmetic Act provides no standard for the amount or character of scientific evidence required for the issuance of a warning. The decision to require a warning is a matter of judgment ~ must be made in light ~of both the availables e evidence and the opinion of experts who interpret that evidence. The Commissioner believes that the UGDP study is a validly conducted trial and accepts the opinion of the Biometric Society committee and other experts that the increased cardiovascular mortality found in this trial* to be associated with these drugs cannot reasonably be attributed to scientific shortcomings in the study. Under those circumstances, a clear warning is necessary even though a residual uncertainty over thd correctness of the study may be present. Warnings may properly be required on the basis of evidence that falls short of conclusive proof. In conformity with Food and Drug Administration policy that warnings must be presented in unambiguous, terms without disclaimers or qualifications that would undermine or destroy their usefulness, there is no mention in the proposed warning of other studies involving the oral hypoglycemic drugs. The mention of studies~ in which increased cardiovascular mortality was not found would serve only to encumber the warning and would therefore not be con- `sistent with revised ~ 1.3. Comments concerning the principle of PAGENO="0241" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13491 an unencumbered warning, which have been received and considered in conjunction with the proposed revision of ~ 1.3 published in the FEDERAL REGISTER of September 16, 1974 (39 FR 33229), are addressed in the final regulation published elsewhere in this issue of the FEDERAL REGISTER. The proposed warning does, however, contain a statement acknowledg- ing the controversy that exists over the interpretation of the TJGDP study and states that, in spite of this, the IJGDP findings provide adequate scientific basis for a warning. The purpose of this statement is to emphasize clearly the basis for the warning. Comments on specific wording in the proposed warning are invited by this notice. The Commis- sioner advises, however, that he does not intend to reopen consideration of the principle of an unencumbered warning which is embodied in the final regulation relating to § 1.3. The Commissioner concludes that, from the standpoint of patient safety, it is prudent to apply the possible increased risk of cardio- vascular mortality for tolbutamide and phenformin to other sulfonylurea and biguanide drugs in view of the similarities in chemical structure and mode of action for members within each of these two categories. This position was endorsed by the Endocrinology and Metabolism Advisory Committee of the FDA at its meeting on June 28, 1971, but additional comment at thià time would also be appropriate. PAGENO="0242" 13492 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The Commissioner also concludes that a patient population exists for which these drugs, properly labeled, can be consid~4 sfe and effective. Marketing therefore may continue. The Commissioner is proposing, however, that this patient population be limited to patients with maturity-onset diabetes whose symptoms or blood glucose level cannot be controlled by diet alone and who cannot take insulin for one or more of the reasons identified in the labeling. This restriction in labeling has been opposed in the past on the ground that it interfered with the practice of medicine. The Commissioner recognizes that drug labeling impacts on the practice of medicine. For this reason the Food and Drug Administration has an obligation to ensure that drug labeling is as correct and accurate as possible and meets the statutory standard of describing the conditions of use under which the drug may be considered safe and effective. Those limitations on use that properly derive from a known hazard or potential risk must, in the interest of safety, be included in drug labeling. This principle is stated in the proposed regulations on prescription drug labeling (published in the FEDERAL REGISTER of April 7, 1975 (40 FR 15392)), time for comment on which has been extended to August 6, 1975, by notice published in the FEDERAL REGISTER of June 11, 1975 (40 FR 24909). The Commissioner proposes the appended labeling for oral hypoglycemic agents of the sulfonylurea and biguanide categories as labeling providing the essential information .for the safe and effective use of these drugs. Comments addressed to any portion of the labeling will be considered. PAGENO="0243" COMPETITIVE PROBLEMS IN THE DRuG INDTJSTRY 13493 REFERENCES Copies of all references cited below are on public display in the office of the Hearing Clerk, Food and Drug Administration, Room 4-65, 5600 Fishers Lane, Rockville, MD 20852: 1. The University Group Diabetes Program, "A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients with Adult-p Onset Diabetes. I. Design, Methods and Baseline Results. II. Mortailty Results," Diabetes, 19 (supp. 2):747-830, 1970. 2. Ricketts, H. T., "Editorial Statement," Diabetes, 19 (supp. 2): iii-v, 1970. 3. AMA Council on Drugs, "Statement Regarding the University Grou~ Diabetes Program (UGDP) Study," Diabetes, 19 (supp. 2):vi-vii, 1970. 4. The University Group Diabetes Program, "Effects of Hypoglycemic Agents on Vascular Complications in Patients with Adult-Onset Diabetes. IV. A Preliminary Report on Phenformin Results," Journal of the American Medical Association, 217:777-784, l~7l. 5. The University Group Diabetes Program, "Effects of Hypoglycemic Agents on Vascular Complications in Patients with Adult-Onset Diabetes. III. Clinical Implications of UGDP Results," Journal of the American Medical Association, 218:1400-1410, 1971. 6. Reeves, R. L'., "Erroneous Interpretation of Data" (corresponde~ice), Northwest Medicine, 69:470, 1970. PAGENO="0244" 13494 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 7. Hare, R. L., "Therapeutics--by Headline and Edict," Northwest Medicine, 70:118-119, 1971. 8. ,Feinstein, A. R., "Clinical Biostatistics. VIII. An Analytic Appraisal of the University Group Diabetes Program (UGDP) Study," Clinical Pharmacology and Therapeutics, 12:167-191, 1971. 9. Schor, S., "The University Group Diabetes Program. A Statistician Looks at the Mortality Results," Journal of the American Medical Association, 217:1671-1675, 1971. 10. Seltzer, H. D., "Tolbutamide Mortality in the Six Phenformin Clin~ics," (letter to the editor), Journal of_the American Medical Association, 218:594, 1971. 11. Bramdman, 0., "University Group Diabetes Program and the Practicing Physician," Journal of the Medical Society of New Jersey~, 68:909-911, 1971. 12. Seltzer, H. S., "A Summary of Criticisms of the Findings and Conclusions of the tiniversity Group Diabetes Program (UGDP)," Diabetes, 21:976-979, 1972. 13. Keen, H., R. 3. Jarrett, C. Chlouverakis, and D. R. Boyns, "The Effect of Treatment of Moderate Hyperglycemia on the Incidence of Arterial Disease," Postgraduate Medical Journal, 44:960-965, 1968. 14. Keen, H., and R. 3. Jarrett, "The Effect of Carbohydrate Tolerance on Plasma Lipids and Atherosclerosis In Man," in Atherosclerosis, R. 3. Jones, editor,. Berlin, Springer-Verlag, 1970, pp. 435-444. 15. Keen, H., "Factors Influencing the Progress of Atherosclerosis in the Diabetic," Acts Diabetolo~ca Latina, 8 (supp. l):444-456, 1971. PAGENO="0245" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13495 16. Paasikivi, J., "Long-Term Tolbutamide Treatment after Myocardial Infarction. A Clinical Biochemical Study of 178 Patients Without Overt Diabetes," Acta Medica Scandinavica, Supplernent, 507:3-82, 1970. 17. Prout, T. E., G. L. Knatterud, C. L. Meinert and C. R. Klint, "The UGDP Controversy. Clinical Trials Versus Clinical Impressions," Diabetes, 21:1035-1040, 1972. 18. Cornfield, J., "The University Group Diabetes Program. A Further Statistical Analysis of the MortalityFindings," Journal of the American Medical Association, 217:1676-1687, 1971. 19. "Report of the Committee for the Assessment of Biometric Aspects of Controlled Trials of Hypoglycemic Agents," Journal of the American Medical Association, 231:583-608, 1975. 20. The University Group Diabetes Program, "A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients with Adult- Onset Diabetes. V. Evaluation of Phenformin Therapy," Diabetes, 24 (supp. 1) :65-184, 1975. 21. Feldman, R., D. Crawford, R. Elashoff, and A. Glass, "Progress Report on the Prophylactic Use of Oral Hypoglycemic Drugs in Asymptomatic Diabetes: Neurovascular Studies," Advances in Metabolic Disorders, 2 (supp. 2):557-567, 1973. 22. Tzagournis, N., and R. Reynertson, "Mortality from Coronary Heart Disease During Phenformin Therapy," Annals of Internal Medicine, 76:587-592, 1972. 23. Kanarek, P. H., "Assessing Survival in a Diabetic Population,'~ thesis, Harvard School of Public Health, Boston, January 1973. PAGENO="0246" 13496 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 24 Lasseter K C C S Levey R F Palmer and J S McCarthy `The Effect of Sulfonylurea Drugs on Rabbit Myocardial Contractibility, Canine Purkinje Fiber Automaticity and Adenyl Cyclose Activity from Rabbit and Human Hearts The Journal of Clinical Investigation 51 2429- 2434, 1972 25 Levey G S K C Lasseter and R F Palmer Sulfonylureas and the Heart Annual Review of Medicine 25 69-74 1974 26 Wissler R W J Borensztajn G S Godfrey G Seymour A Rubenstein C H Ts'ao A Study of the Chronic Effects of Tolbutamide in the Rhesus Monkey FDA contract 72-114 February 15 1975 27. Bradley, R. F., H. Dolger, P. H. Forsham, and H. Seltzer, Settling the IJGDP Controversy?' Journal of the American Medical Association 232 813-817 1975 28 O'Sullivan J B and R B D'Agostino Decisive Factors in the Tolbutamide Controversy Journal of the American Medical Association, 232:825-829, 1975. PAGENO="0247" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13497 VII. NOTICE OF PUBLIC HEARING The Commissioner concludes that, to permit maximum public participation in the development of labeling requii~enents for oral hypoglycemic drug products, a public hearing shall be held to pro- vide an opportunity for interested persons to present data, information, and views on the proposed labeling. This public hearing is ordered pursuant to § 2.400(a) (21 CFR 2.400(a)) and shall be conducted in accordance with the procedures established in Subpart E of Part 2 of the regulations. The Commissioner has designated J. Richard Grout, M.D., Director, Bureau of Drugs, to be the presiding officer at such hearing, to be held August 20, 1975, beginning at 9 a.m. in Conference Rm. E, Parklawn Bldg., 5600 Fishers Lane, Rockville, MD 20852. Interested persons who wish to make an oral presentation at the hearing shall file a written notice of appearance with the Hearing Clerk, Food and Drug Administration, Bin. 4-65, 5600 Fishers Lane, Rockville, MD 20852 by close of business August 6, 1975. The PAGENO="0248" 13498 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY notice of appearance shall state the approximate amount of time requested by the person for presentation. It shall also give the telephone number of the person to be contacted regarding the schedule for presentation. Individuals and organizations with common interests are strongly urged to consolidate or coordinate their presentations because of the limitations of time. By August 11, 1975, the Food and Drug Administration will communicate by telephone with each person who requested an opportunity to be heard, regarding the time his or her oral presentation is scheduled to begin aiid the amount of time allocated for his or her presentation. The Food and Drug Administration may require joint presentations by persons sharing common views. The Food and Drug Administration will prepare a hearing schedule, listing the participants and the time allotted to each, which shall be filed with the Hearing Clerk and a copy mailed to each participant. The hearing will be transcribed. Any interested person may, consis- tent with the orderly conduct of the meeting, also record or otherwise make his or her own transcript of the meeting. Each participant may use the allotted time however he or she desires, consistent with decorum and order, and may present written data, information or views for inclusion in the record of the hearing. Any person who desires to submit an advance written statement may do so in qu~ntuplicate to the Hearing Clerk. All written comments and statements submitted before PAGENO="0249" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13499 August 15, 1975, will be reviewed by the presiding officer prior to the hearing, so that full repetition at the hearing will be unnecessary. A participant nay be accompanied by any number of additional persons. If a participant is not present when his or her presentation is scheduled to begin, the participants following will be taken in ordet. An attempt will be made to hear any scheduled participant who misses his assigned time at the conclusion of the hearing. Other interested persons attending the hearing who did not request an opportunity to speak will be given an opportunity to make oral presentations at the conclusion of the hearing to the extent that time permits. The presiding officer, as well as any other Food and Drug Admin~ istration employee serving with him as a panel, may question any participant during or at the conclusion of his presentation. No other persons attending the hearing may question a participant. The presiding officer may allot additional time to any participant if he concludes that it is in the public interest, but may not reduce the time allotted to anyone. The record of the hearing will remain open until September 5, l~i75, for the submission of any additional written statements or comments regarding oral presentations made at the hearing. No written submission, or any portion thereof, made in response to this notice shall be received or held in confidence. The administrative record of this rule making proceeding shall consist of all relevant FEDERAL REGISTER notices and the documents to which they refer, all 56-592 0 - 75 - pt. 28 - 17 PAGENO="0250" 13500 cO~n'ETITIvE PROBLEMS IN ThIE DRUG INDUSTRY written submissions made in response to this notice, and the transcript of the oral hearing made by the Food and Drug Administration. The administrative record of the proceeding shall be made available for public examination. VIII. PROPOSED REGULATION FOR THE LABELING * OF ORAL HYPOGLYCEMIC DRUGS Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (secs. 502, 505, 701(a), 52 Stat. 1050-1053, as amended, 1055 (21 U.S.C. 352, 355, 371(a))) anc~. under authority delegated to him (21 CFR 2.120), the Commissioner proposes that Part 310 of Subchapter D of Title 21 of the Code of Federal Regulations be amended by adding a new § 310.510 as follows: § 310.510 Labeling for oral hypo~lycemic drugs. (a) An adequate and well-controlled clinical trial (the University Group Diabetes Program study) has indicated that there appears to be an increased risk of cardiovascular mortality associated with the administration of tolbutamide and of phenformin (oral hypoglycemic drugs of the sulfonylurea and biguanide categories, respectively) to maturity-onset diabetic patients as compared to treatment with diet alone or diet plus insulin. The Commissioner concludes that in view of the great similarities in chemical structure an~1 mode of action for drugs within each of these two categories, it is prudent from a safety standpoint to consider that the possible increased PAGENO="0251" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 135O1 risk of cardiovascular mortality for tolbutamide and phenformin also applies to other sulfonylurea and biguanide drugs. Therefore, the labeling for oral hypoglycemic drugs shall describe properly the conditions for their use and include a warning concerning the possible increased risk of cardiovascular mortality associated with such use, as set forth in paragraphs (b) and Cc) of this section. (b) Labeling for oral hypoglycemic drugs of the sulfonylurea category shall be as follows: DESCRIPTION (Trade name, established name) is an oral blood-glucose-lowering drug of the sulfonylurea category. It is a white, crystalline compound, formulated as a tablet for oral administration. (Manufacturer to add structural formula and other appropriate information.) ACTIONS Administration of (drug) appears to lower the blood glucose initially by stimulating the release of insulin from the pancreas; the effect is thus dependent on functioning beta cells in the pancreatic islets. The mechanism by which (drug) lowers blood glucose during long term administration has not been clearly established. Many patients who at first demonstrate an adequate glucose-lowering effect with a sulfonylurea PAGENO="0252" 13502 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY agent subsequently prove to be no longer satis- factorily responsive, i.e., secondary failure may occur. (Manufacturer to supply information about: 1. Absorption. 2. Metabolism and excretion. 3. Plasma half-life and the effect of hepatic or renal Impairment on blood levels, metabolism, and excretion. 4. Peak and duration of glucose-lowering effect, indicating the duration of effect rela- tive to the class of sulfonylurea agents, e.g., shortest acting, longest acting, etc. 5. Mechanism of drug interaction with agents that Impair or potentiate drug effect.) PAGENO="0253" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13503 INDICATIONS (Drug) is indicated to control symptoms ue to hyperglycemia in patients with maturity-onset nonketotic diabetes mellitus whose symptoms cannot be controlled by diet alone and in whom insulin cannot be used because of patient unwillingness, erratic adherence to the injection regimen, poor vision, physical or mental handicap, insulin allergy, employment requirements, or other similar factors. (Drug) may also be used to lower blood glucose in asymptomatic patients whose blood glucose elevation cannot be controlled by diet alone and in whom insulin cannot be used for any of the above reasons. In considering the use of (drug) in asymptomatic patients, it should be recognized that whether or not controllin~ the blood glucose is effective in preventing the long term cardiovascular or neural complications of diabetes is an unanswered scientific question. The use of (drug) may be associated with an increased risk of cardiovascular mortality as compated to diet alone or diet plus insulin; see WARNINGS. For this reason, it should be used only PAGENO="0254" 13504 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY when the advantages in the individual patient justify the potential risk. The patient should be inforned of the advantages and potential risks of (drug) and of alternative nodes of therapy and should participate in the decision ou The foundation of therapy in the obese maturity-onset diabetic is caloric restric~tion and weight loss. Proper zlietary management alone is often effective in controlling the blood glucose and eliminating symptoms of polydipsia and polyuria. Use of (drug) must be considered by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism f or avoiding dietary rastraint . Many patients who are initially responsive to oral hypoglycemic drugs become unresponsive or poorly responsive over a period of time, usually 1 to 5 years. (Drug) should be given only to patients demonstrated to be responsive to it; see DOSAGE AND ADMINISTRATION for dis- PAGENO="0255" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 135O5 administration of (drug) may be sufficient during periods of transient loss of control. Concomitant Therapykith a Biguanide: (Drug) may be used in conjunction with phen- formin to control symptoms due to hyperglycemia in patients with maturity-onset nonketotic dia- betes mellitus whose symptoms cannot be controlled by diet and maximum recommended Boses of either drug alone and in whom insulin cannot be used for any of the reasons cited above. In considering the use of concomitant therapy, it should be noted that both a sulfonylurea drug (tolbutamide) and a biguanide drug (phenformin) have been reported to be associated with increased cardiovascular mortality; see WARNINGS. In addition, phenformin can PAGENO="0256" 13506 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY produce lethal lactic acidosis in some patients. Thus the use of (drug) in association with phenformin carries a greater ~ of (drug) alone. If a judgment is made that (drug) and phenformin are to be used together in a particular patient, it should be established that the patient is responsive to both drugs. This may be accomplished either by a trial of each d~ug separately or by adding the second drug and then tapering the dosage of the first, observing for diminished control of blood glucose. Once the need for both drugs is established, the desired control of blood sugar may be obtained by adjusting the dose of either drug. The possibility of hypoglycemia should be anticipated and appropriate precautions taken. See package insert for phenformin hydrochloride f or CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION. C~TRAINDICATIONS (Drug) is contraindicated in patients with: 1. Known hypersensitivity or allergy to the drug. 2. Diabetic ketoacidosis, with or without coma. Such patients should be treated with insulin. PAGENO="0257" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13507 WARNINGS SPECIAL WARNINGS ON CARDIOVASCULAR MORTALITY (This subsection of labeling to be boxed set in boldface type, andplaced at the beginning of~ ~ectio~flab&~L~ The administration of oral hypoglycemic drug nay be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (TJGDP), a long term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in prevent- ing or delaying vascular complications in patients with maturity-onset nonketotic diabetes. The study involved 1,027 patients who were randomly assigned to one of five treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970; Diabetes, 24 (supp. l):65-184, 1975). PAGENO="0258" 13508 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbut- amide (1.5 grams per day) or diet plus a fixed dose of phenformin (100 milligrams per day) had a rate of cardio- vascular mortality approximately twice that of patients treated with diet alone or diet plus insulin. Total mortality was increased in both the tolbut- amide- and phenformin-treated groups, but this increase was statistically significant only for phenformin. Despite controversy regarding the interpretation of these results, the findings of the,UGDP study provide adequate scientific basis f or this warning. Although only,one drug in the sulfonylurea category (tolbutamide) and, one in the biguanide category (phenformin) were included in this study, it is prudent from a safety standpoint to consider that this result may also apply to other oral hypoglycemic drugs in these categories, in view of the close similarities in mode of action and chemical structure among the drugs in each category. PAGENO="0259" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13509 (Drug) should be used in preference to insulin only in patients with maturity-onset diabetes whose symptoms or blood glucose level cannot be con- trolled by diet alone and only when the advantages in the individual patient justify the potential risk; see INDICATIONS. The patient should be informed of the advantages and potential risks of (drug) and of alternative modes of therapy and should participate in the decision to use this drug. (Drug) is not effective in patients with juvenile diabetes or insulin-dependent diabetes at any age. Such patients should be treated with insulin. The concomitant long term use of insulin and (drug) in an individual patient is, in view of the potential risk of increased cardio- vascular mortality siith (drug), less safe on a benefit- risk basis than the use of insulin alone. PAGENO="0260" 13510 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The effectiveness of any oral hypoglycemic drug, including (drug), in lowering blood glucose to a desired level decreases in a large number of patients as the drug is administered over a period of months or years, in part because the patient's blood glucose tends to rise over time and in part because of diminished, responsiveness to the drug. This phenomenon is known as secondary failure to distinguish it from primary failure in which the drug ~s ineffective in an individual patient at the time of its initial adminis- tration. See DOSAGE AND ADMINISTRATION. Renal or hepatic insufficiency may cause elevated blood levels of (drug) and increase the risk of serious hypoglycemic reactions. Pre,~~,n~: (Data and interpretation related to reproduction and teratology studies to be supplied by manufacturer). Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. Neonatal hypoglycemia has been reported more frequently following use of the longer-acting agents. If (drug) PAGENO="0261" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13511 is used during pregnancy, it should be discontinued (tine period to be supplied by manufacturer) before the expected delivery date. PRECAUTIONS ~~ypog1ycernia: All sulfonylurea drugs are capable of producing severe hypoglycemia.' Particularly susceptible are elderly patients, patients with impaired hepatic or renal function, patients who are debilitated or malnourished, and patients with adrenal or pituitary insufficiency. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when more than one glucose- lowering drug is used. (To be inserted for chlorpropamide only:) Because of the long half-life of chlorpropamide, patients who become hypoglycemic during therapy recjuire careful supervision of the dose for at least 3 to 5 days, during which time frequent feedings are essential. It nay be necessary to hospitalize such patients and give intravenous glucose. Certain drugs may potentiate the hypoglycemiè action of (drug), including plienylbutazone, oxyphen- butazone, salicylates, sulfonamides, chloramphenicol, probenecid, coumarin~, monoarni n~ oxidase inhibitors, and beta-adrenergic blocking agents. See ACTIONS. PAGENO="0262" 13512 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY When such drugs are administered to a patient receiving (drug), the patient should be observed closely for hypoglycemia. Loss of Control of Blood Sujar When a patient stabili7ed on any diabetic regimen is exposed to stress such as fever trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to d±scontinue (drug) and administer insulin. Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other oral diuretics corticosteriods and (to be supplied by manufacturer) When such drugs are administered to a patient receiving (drug), the patient should be carefully observed for Loss of control Pseudo-albumimuria(tolbutamideoni~y) Urine containing a tolbi~tamide metabolite may give a false positive reaction for albumin if the acidification-after-boiling test is used because this procedure causes the metabolite to precipitate as flocculent particles. Use of the sulfosalicylic acid test circumvents this problem. PAGENO="0263" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13513 ADVERSE REACTIONS Hypoglycemia: See PRECAUTIONS. Gastrointestinal Reactions: Cholestatic jaundice may occur rarely; (drug) should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn are the most common reactions, occurring in (manu- facturer to supply estimate of incidence). They tend to be dose related and may disappear when dosage is reduced. Dermatologic Reactions: Allergic skin reac- tions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occur (manufacturer to provide estimate of incidence). These may be transient and may disappear despite continued use of (drug); if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensi- tivity reactions have been reported. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported. PAGENO="0264" 13514 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Metabolic Reactions~ Hepatic porphyria, disulf iran-like reactions (manufacturer to supply further details). (To be inserted for chlorpropamide only:) Endocrine Reactions: On rare occasions (drug) has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome result from excessive water retention and include hyponatremia, low serum osinolality, and high urine osmolality. D9SACE AND &DMINI~~RATIpN There is no fixed dosage regimen for the management of diabetes nellitus with (drug) or any other agent. In addition to the usual monitor- ing of urinary glucose, the patient's blood glucose must also be monitored periodically: a, To determine the minimum drug dosage that will lower the blood glucose adequately. b. To detect primary failure, i.e., inadequate lowering of blood glucose when the drug is first used, even though dose has been raised to the maximum level recommended; and PAGENO="0265" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13515 c. To detect secondary failure, i.e., loss of adequate blood-glucose-lowering response after an initial period of effectiveness. (Drug) should be discontinued, with careful monitoring of blood glucose at least annually to be certain that (drug) is continuing to lower the blood glucose. Short term administration of (drug) may be sufficient during periods of transient loss of control. (Manufacturer to supply the following details of dosage for each sulfonylurea: 1. Usual starting dose. 2. Maximum dose. 3. Dose beyond which a response is usually not seen if patient has not already had some response. 4. Usual maintenance dose. 5. Dosage interval, with reasons, e.g., avoid GI tolerance, short half-life of drug, etc. 6. Caution regarding dosage in elderly.) HOW SUPPLIED (To be supplied by manufacturer.) 56-592 0 - 75 - pt. 28 - 18 PAGENO="0266" 13516 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (c) Labeling for oral hypoglycemic drugs of the biguanide category shall be as follows: DESCRIPTION (Trade name, established name) is an oral blood-glucose-lowering drug of the biguanide category. It is a white, crystalline, water- soluble compound, formulated as (to be supplied by firm) for oral administration. (Manufacturer to add structural formula and other appropriate information). ACTIONS The mechanism of action of phenfornin is not established but its ability to cause increased peripheral glucose uptake in vitro appears to be related to its inhibition of cellular oxidative processes. It does not stimulate insulin production. Many patients who at first demonstrate an adequate glucose-lowering effect with (drug) subsequently prove to be no longer satisfactorily responsive, I.e., secondary failure may occur. PAGENO="0267" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13517 (Manufacturer to supply information about: 1. Absorption. 2. Metabolism and excretion. 3. Plasma half-life and the effect of hepatic or renal impairment on blood levels, metabolism, and excretion. 4. Peak and duration of glucose-lowering effect. 5. Mechanism of drug interaction with agents that impair or potentiate drug effect.) INDICATIONS Identical to sulfonylurea label, except for substitution of the following section relating to concomitant therapy: Concomitant Therapy: Phenformin may be used in conjunction with a sulfonylurea to control symptoms due to hyperglycemia in patients with maturity-onset nonketotic diabetes mellitus whose symptoms cannot be controlled by diet and maximum recommended doses of either drug alOne and in whom insulin cannot be used for any of the reasons cited above. PAGENO="0268" 13518 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In considering the use of concomitant therapy, it should be noted that both phen- formin and a sulfonylurea drug (tolbutamide) have been reported to be associated with increased cardiovascular mortality; see WARNLNCS. Thus the use of phenformin in association with a sulfonylurea may carry a greater risk than the use of phenformin alone. If a judgment is made that phenformin and a sulfonylurea are to be used together in a particular patient, it should be established that the patient is responsive to both drugs. This may be accomplished either by a trial of each drug separately or by adding the second drug and then tapering the dosage of the first, observing for diminished control of blood glucose. Once the need for both drugs is established, the desired control of blood sugar may be obtained by adjusting the dose of either drug. The possibility of hypoglycemia should be anticipated, and appropriate precautions taken. See package insert for the appropriate sulfonylurea for CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION. PAGENO="0269" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 13519 CONTRAINDICATIONS (Drug) is contraindicated in patients with: 1. Known hypersensitivity or allergy to the drug. 2. A history of lactic acidosis. 3. Disease states associated with hypoxetnia including cardiovascular collapse and acute inyocardial infarction. 4. Severe renal disease. 5. Alcoholism, 6. Diabetic ketoacidosis with or without coma. Such patients should be treated with insulin. PAGENO="0270" 13520 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY WARNINGS SPECIAL WARNING ON CARDIOVASCULAR MORTALITY (Identical to boxed, boldface sulfonylurea labeling.) (Drug) is not adequate therapy in patients with juvenile diabetes or insulin-dependent dia- betes at any age. Such patients should be treated with diet and insulin. The concomitant long term use of insulin and (drug) in an individual patient is, in view of the risk of increased cardiovascular mortality with (drug), less safe on a benefit-risk basis than the use of insulin alone. The effectiveness of any oral hypoglycemic drug, including (drug), in lowering blood glucose to a desired level decreases in a large number of patients as the drug is administered over a period of months or years, in part because the patient's PAGENO="0271" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 13521 blood glucose tends to rise over time and in part because of diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient at the time of its initial administration. See DOSAGE AND ADMINISTRATION. Lactic Acidosis: There have been numerous reports of lactic acidosis in patients receiving phenformin. Lactic acidosis is an often fatal metabolic acidosis characterized by elevated blood lactate le~els, an increased lactate-to- pyruvate ratio, and decreased blood pH. Azotemia ranging from mild to severe is present in most of the reported cases of lactic acidosis. Azotemia can result from dehydration, and some patients developing lactic acidosis associated with azotenia have had normal serum creatinine levels when properly hydrated. The following specific pre- cautions should be observed when administering phenformin: PAGENO="0272" 13522 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a. Impairment of renal function increases the risk of lactic acidosis. Renal function tests, such as serum creatinine, should be performed prior to phenformin therapy and at least annually thereafter. Phenformin should not be used in patients with impaired renal function, e.g., serum creatinine over 1.5 milli- grams/lOO milliliters, except in extraordinary circumstances. b. Cardiovascular collapse (shock), con- gestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and also may cause prerenal azotemia. Use of phenformin in patients particularly prone to develop such conditions must be carefully considered and the risks weighed against possible benefits. When such events occur in patients on phenformin therapy, the drug should be discontinued promptly. c. Gastrointestinal disturbances are the most common adverse reactions to phenformin therapy. These symptoms must be distinguished from the symptoms of developing lactic acidosis. Anorexia PAGENO="0273" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13523 and mild nausea are common side effects of phen- formin, particularly upon initiation of therapy. Nausea, vomiting, malaise, or abdominal pain may herald the onset of lactic acidosis. The patient should be instructed to notify the physician immediately at the onset of any of these gastrointestinal symptoms or of hyperven- tilation. Phenformim should be withdrawn until the situation is clarified by determination of serum electrolytes and ketones, blood glucose, and, if indicated, blood pH, lactate, and pyruvate levels. d. Lactic acidosis has a significant mortality and, when suspected, must be treated promptly by discontinuing phenformim and giving bicarbonate infusions and other appropriate therapy even before the results of lactate determinations are available. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis in the absence of ketonuria and ketonemia, uremia, and methanol or salicylate poisoning. PAGENO="0274" 13524 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY e, The physician should use special caution after initiating phenformin therapy, after in~ creasing the drug dosage, and in circumstances that nay cause dehydration leading to impaired renal function. f. Alcohol is known to potentiate the effect of phenformin in elevating blood lactate levels, and patients should be warned against excessive alcoholic intake while receiving phenformin. g. Impaired hepatic function has been associated with some cases of lactic acidosis. Particular caution must be observed when admin- istering (drug) to patients with hepatic disease. ~re~nancy: (Data and interpretation related to reproduction and teratology studies to be supplied by manufacturer). PRECAUTIONS ~p~~ycemia: Hypoglycemia is unusual in patients receiving (drug) alone, but may occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when more than one hypogly- cemic drug is used. PAGENO="0275" COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY 13525 (Manufacturer to supply paragraph on potentiating drugs.) Loss of Control of Blood Sugar: Identical to sulfonylurea labeling. ~nClinica1 Status of Previous~ Controlled D~~~jc: A diabetic patient previously well-controlled on phenformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose, and, if indicated, blood pH, lactate, and pyruvate levels. Acidosis of either form necessitates withdrawing phenformin and initiating other appropriate corrective measures. Starvatio~jet~Q~~s This must be differentiated from insulin-deficient ketosis and is characterized by ketonuria with, little or no glucosuria and relatively normal blood glucose levels. This may result from excessive dosage of phenfornin or insufficient carbohydrate intake. PAGENO="0276" 13526 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ADVERSE REACTIONS ~yp~og1ycernia: See PRECAUTIONS. Gastrointestinal Reactions: Gastrointestinal distur1~ances such as anorexia, nausea, vomiting, and diarrhea are the most common adverse reactions (manufacturer to supply frequency) and are dose related. These symptoms must be distinguished from the prodromata of lactic acidosis. See WARNINGS section for discussion of lactic acidosis. They may also cause dehydration and prerenal azotemia, which require discontinuation of the drug until renal function is again normal. Phenformin should be discontinued if vomiting occurs, An unpleasant metallic taste is a warning signal of impending gastrointestinal disturbances. Dermato1o~ic Reactions: (Manufacturer to supply data, including estimate of incidence.) Miscellaneous Reactions: Fatigue and weakness. Anorexia, nausea, and vomiting may occur in association with the intake of alcohol. PAGENO="0277" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13527 DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the managementof diabetic mellitus with (drug) or any other agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically: a. To determine the minimum drug dosage that will lower the blood glucose adequately. b. To detect primary failure, i.e., inadequate lowering of the blood glucose when the drug is first used, even though dose has been raised to the maximum level recommended. c. To detect secondary failure, i.e., loss of adequate blood-glucose-lowering response after an initial period of effectiveness. Drug should be discontinued with careful monitoring of blood glucose at least annually to be certain that (drug) is continuing to lower the blood glucose. Short term administration of (drug) nay be sufficient during periods of transient loss of control. PAGENO="0278" 13528 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY (Manufacturer to 5U~~iY the following details of dosage: 1. Usual starting dose. 2. Maximum dose. 3. Dose beyond which a response is usually not seen if patient has not already had some response. 4. Usual maintenance dose. 5. Dosage interval, with reasons, e.g., avoid CI intolerance, short half-life of drug, etc. 6. Caution regarding docage in elderly.) HOW SUPPLIED (To be supplied by manufacturer.) (d) Each holder of an approved new drug application for an oral hypoglycemic agent shall submit a supplement to his application under the provisions of § 314.8(d) of this chapter to provide for labeling as described in paragraphs (b) and (c) of this section. The labeling in such supplement shall be identical in wording to the labeling in paragraphs (b) or (c) of this section where precise wording is specified, shall provide information on each of the points where wording is delegated to the manufacturer, and shall contain no additional or extraneous information. Such supplement shall be submitted within 10 days after (effective date of the final regulation). Any oral hypoglycemic drug with labeling not in compliance with this section and shipped into interstate commerce after (60 days after effective date of the final regulation) shall be subject to reguThtory action. PAGENO="0279" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 13529 Interested persons may, on or before (insert date 60 days after d~teof publication in the FEDERAL REGISTER), submit to the Hearing Clerk, Food and Drug Administration, Rn. 4-65, 5600 Fishers Lane, Rockville, MD 20852, written comments regarding this proposal. Comments shall be filed in quintuplicate and shall be identified with the Hearii~g Clerk docket number found in the document heading. Received comments may be seen in the above office during working hours, Monday through Friday. \ll / Dated:____________________ PAGENO="0280" 13530 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY jJubc Cmzen June 10,1975 Alexander M. Schmidt, M.D. Commissioner, Food and Drug Administration Federal Building 8 200 "C" St. S.W. Washington, D.C. 20204 Dear Dr. Schmidt: This letter is to urge immediate publication of a warning to patients and doctors about all oral drugs used to treat diabetes. New evidence from four previously unreported studies combined with previous evidence demands this action to prevent the unnecessary death of thousands of diabetics and waste of more than 100 million - dollars a year on these drugs. It is now five years since the University Group Diabetes Program (UGDP) reported that there was a significant excess cardio- vascular mortality in patients taking an oral diabetes drug (tolbutamide-ORINASE). Although ~romu1gation of an FDA-proposed warning label for ~ such drugs was enjoined in 1972 by a Federal District Court, this was reversed in July, 1973 by the U.S. Court of Appeals. Thus, the FDA has delayed for almost two years the 1. "Although the specific sulfonylurea drug studied by UGDP was tolbutamide, the conclusions apply equally to all sulfonylureas-- Diabinase, Orinase, and Tolinase--because of their close chemical relationship." "...the conclusions apply to DBI and Meltrol as well" (FDA Drug Bulletin, May 1972). LEADING ORAL "ANTIDIABETES" DRUGS TOTAL PRESCRIPTIONS PER YEAR FOR U.S.1 197Q ___ Diabinase (Pfizer) 5.845,000 6,201,000 +7.8% Orinase (Upjohn) 5,290,000 4,998,000 -5.5% DRI (Geigy) 4,035,000 4,282,000 +6.1% Dyrnelor (Lilly) 1,553,000 1,462,000 -5.8% Tolinase (Upjohn~~ ________ 1,975,000 j~4.6% Total Prescriptions 18,369,000 19,381,000 +5.5% (including all oral drugs) (National Disease & Therapeutic Index, l972& 1973, LEA Inc., Ambler,PA.) PAGENO="0281" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13531 publication of a warning label which would, `if properly worded, cause most adult diabetics to be taken off these dangerous, ineffective, and expensive drugs. During this interval of irresponsible delay by the FDA1 approci- mately 250 million dollars worth of these drugs have been consumed in this country alone and, according to experts, 20,000-30,000 unnecessary deaths due to these drugs have probably oc~curred.2 Of the 1.5 million people currently using these drugs, it is estimated that 80% to 90%, at least, could be controlled as well or better-~ and certainly mare safely--by diet or, in a very small number of cases, insulin. Although the published medical literature contains ample evidence of the increased risk of death and lack of efficacy of these drugs, the FDA is aware of four additional studies the results of which have not yet been made known to the public. A brief review of these studies follows: 1. p~pub1ished Study on Mortai~t~L~ii) Josl in ~ Although many doctors who have been wedded tO the idea that these pills benefit diabetics have attacked the findings of the UGDP study, none have been as vocal as the doctors of the Joslin Clinic in Boston. Aside from organizing the law suit against the FDA to block promulgation of the warning label three years ago, Dr. Robert Bradley (Joslin Director) and his cohort have devoted considerable time to presentations at drug_company-financed meetings around the country aimed at maintaining doctors "faith" in these drugs. It is thus all the more striking to find that a study of the Joslin Clinic's own patients yields results similar to those found by the UGDP. A Harvard Ph.D. thesis by Paula Kanarek entitled "Assessing Survival in a Diabetic Population" and dated January 1973 was a retrospective study of 6300 patients at the Joslin Clinic. Begun after the UGDP study, its stated purpose was to study the effect of various types of therapy on the survival of diabetic patients, particularly to see "if individuals treated with tolbutamide (ORINASE) are more likely to die from cardiovascular causes. * ." The results of the study showed that: a)~'For individuals who survive at least 5 years, however, the relative survival experience for persons receiving tolbutarnide is worse in all cases than that of those on diet. * ." (p. 111-16) .certainly in all risk categories, the probability of dying from cardiovascular causes in 5-10 years was consistently higher in the tolbutamide c~roup than in the diet group (iII-l7) 2. Senate Hearings on Oral Hypoglycemic Drugs, Sept. 1974, p.10803. 3. ~ ~j, 854, May 26, 1975. 56-592 0 - 75 - pt. 28 - 19 PAGENO="0282" 13532 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY c)". ..the results of this observational study suggest that the findings of the UGDP may be generalized to other diabetic populations." (111-23) 2. FDA-Sponsored Study of the E ffect o~Lo uami~e on Developme~pJ~ ~f çoron~ry ~rtQry Disease In Monkeys - This study, FDA contract *72-l14,was done by researchers headed by Dr. Robert Wissler, Professor of Pathology at the University of Chicago. Begun in 1972, the final report was submitted to FDA in February, 1975. Monkeys were placed on an "Average American Diet" and one-half were given tolbutamide at a dosage comparable to that taken by diabetics. The study was continued for two years with the following findings: a) Coronary artery disease was found ~W~imes more often in animals taking tolbutamide than in animals on diet alone. b) The coronary artery disease caused by the drug was ~ii~ ~~yer~ than that developing Spontaneously from the diet alone. Although the UGDP and Joslin studies showing increased death in humans from cardiovascular `disease due to these drugs are clear enough, the Wissler study is the first experimental confirmation of the mechanism whereby the human deaths ahve occured. Since it has been known for more than 30 years that most diabetics die from cardiovascular complications, such animal studies should have ~ marketing. 3. A Study by Dr. C.R. Wu,, et al.,of New Jersey Medical School, presented May 3, 1975 in Atlantic City at the American Federation for Clinical Research meeting also looked at the effect of tolbut- amide on the heart of diabetic dogs. At therapeutic doses (equivalent to those taken by diabetic patients) the function and structure of the heart was worsened by 1 year of treatment with tolbutamide. 4. IThpublished Study of Joslin Clinic Patients Showing Lack of ~~icacy of 4 Oral Diabetes Druq~. In addition, we have just obtained a copy of a study by researchers at the Joslin Clinic which clearly demonstrates that the oral antidiabetic drugs fail to achieve their intended beneficial" purpose, namely lowering of blood sugar. 365 adult-onset diabetics were placed on an individualized diet and given either a placebo, tolbutamide (ORINASE), chlorpropamide 4. The Effects of Long Term Therapy with Oral Hypoglycemic Agents on the Oral Glucose Tolerance Test Dynamics in Chemical Diabetics (Tan, Graham, Bradley et.al.) PAGENO="0283" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13533 (DIABINASE), phenformin (DBI) or acetohexarnide (DYMELOR). At the end of four ynars on diet and either placebo or one of the four drugs, ~ no evic~ence that any of the four drug ~ tol~ar~c~~an diet and a plaç~. This study, although completed more than 2 1/2 years ago and presented in summary form at a meeting of the American Diabetes Association June 23, 1973, has never been published. It is likely that one or both of the following factors are responsible for its non-publication: 1. The Joslin Clinic is the center of advocacy (aside from the drug companies) for the use of these diabetes drugs. 2. The study was supported by Upjohn (makers of Orinase arid Tolinase), Lilly (Dymelor) and Pfizer (Diabinase). TheY degree to which the Joslin Clinic adheres to their "faith" in these drugs despite all the evidence--including data from their own patients--to the contrary can be seen in the testimony of Joslir~ Director Dr. Robert Bradley before the Senate hearings last fall: "Data from the UGDP Study have thus far contributed nothing to the controversy regarding the effectiveness of blood sugar control and.. .the results cannot at present be extrapolated to the diabetic population at large." Select Committee on Small Business (p. 10986). If the UGIDP study didn't convince Dr. Bradley, surely the combination of increased mortality and lack of efficacy of these drugs in his ow~n Clinic should. WARNING LABEL AND MALPRACTICE At the heart of opposition by both drug industry and doctor opposition to the proposed warning label is the question of medical malpractice. A strong label, warning against using the drugs unless am adequate trial on diet therapy has been attempted and making doctors (and patients) aware of the increased risk of cardiovascular death,would likely become grounds for malpractice if these caveats were not heeded. ~ on April 15, 197& we commented on the way FDA had already weakened the warning label proposed for comment onJan.28, 1974 from the earliest draft published in the FDA Drug Bulletin, May 1972. (See enclosed~. In testimony before Senator Nelson last fall, Dr. Thomas Chalmers, Dean of Mount Sinai Medical School discussed labelling: "The new FDA labelling should be strong enough to warn all physicians that they are distinctly putting their patient at risk by using oral agents when diet or insulin will suffice. The wording PAGENO="0284" 13534 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY should be such that doctors will be compelled to protect themselves from a later malpractice suit by obtaining truly informed consent from their patients, and by demonstrating in the patient's record that the patient's symptoms could not be controlled by diet and/or insulin." (Nelson Hearings, - p. 10999). Faced with such a warning label, most doctors, in the interests of their patients (and themselves) would make a much greater effort to avoid use of these dangerous drugs. In summary, it is long past the time for FDA to have issued a strong warning label for these drugs. Any further delay should result in sanctions against all FDA officials who have been responsible. Sincerely, Sidney M. Wolfe, M.D. Anita Joh `on, esg. PAGENO="0285" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 13535 1When Friends or Patients Ask About. William H. Crosby, MD, Coordinator John K. Davidson, MD, PhD THE NELSON Committee hearings in the US Senate (Sept 18 to 20, 1974) explored the safety, effectiveness, and use of hypoglycemic drugs. A dozen witnesses, including the Food and Drug Administration (FDA) Commis- sioner ,~,L.Aj5xynder Schmidt, gave testimony concerning the implica- tions of the University Group Diabe- tes Program (UGDP) articles for medical practice. Concern was ex- pressed because the FDA Bureau of Drugs had not required appropriately written package inserts warning phy- sicians and the drug-consuming pub- lic of the dangers inherent in the in- discriminate use of sulfonylureas and phenformin hydrochloride. There was agreement that caloric restriction with weight reduction is the pre- len-ed method of treatment for the maturity-onset diabetic who is above deal body weight, and that such ther- y is always safe and with intensive ~ducation and follow-up is usually ef- fective. The UGDP investigators ended the tolbutamide (sulfonylurea) study in 1969 and the pheseformin study in lii7l, when careful statistical analysis showed a death rate more than twice that expected for each drug when compared to the death rates in the three other groups in the study (pla- cebo, a standard dose of insulin that resulted in a moderately elevated mean fasting blood glucose level, and a variable dose of insulin that re- suited in a near-normal mean fasting blood glucose level). Death rates in the placebo and insulin groups were sim- ilar. There were no significant differ- ences in the rate of development or progression of chronic complications (retinopathy, nephropathy, neuropa- thy, arteriopathy) in the survivors of any of the five treatment groups. Are Oral Hypoglycemic Drugs Safe and Effective? In addition to the increased cardio- vascular mortality with tolbutamide therapy or with phenformin therapy of approximately 1% per year, there are many other adverse effects of oral hypoglycemic drugs. These include prolonged sulfonylurea-induced hy- poglycemia and phenformin-induced lactic acidosis, both of which have ter- minated fatally in a number of pa- tients. Extrapancreatic effects of the sul- fonylureas include hypothyroidism, skin rashes and photosensitivity, corneal opacities, blood dyscrasias, in- creased fibrinolytic activity, hype- natremia, water retention, jaundice, liver-enzyme inhibition, heart ef- fects (including inotropism, increased oxygen need, and microgranulomas), elevated blood pressure, altered elec- troencephalogram in epilepsy, and in- creased stomach-acid secretioti. The sulfonylurea drugs compete for carrier-protein binding sites with many other drugs, including sqlfona- mides, salicylates, phenylbutazone, monoamine oxidase inhibitors, thia- zides, and barbiturates. The pharma- cological effect of all of these drugs, including the sulfonylureas, may be increased when they are displaced from their combining sites; thus1 com- bination drug therapy may have tiuany unanticipated toxic consequences. The difficulties in maintaining stable anticoagulation therapy in the pres- The FDA and Hypoglycemic Drugs The Author: John K. Davidson received his B5 degree In 1943 and MD degree in 1945 at Emory University. Atlanta. He was a research fellow of the American Diabetes Association from 1961 to i965 at the University of Toronto, where he won the Starr medal in 1963 for his work on nonsuppressible insolin-like activity and studies of beta cell fonction. He ret ceived the PhD degree in Physiology in 1965 at the University of Toronto, and joined the laculty with appointments in physiology and medicine. He retorned to Emory University in 1968, where he is now director of the Diabetes Unit at Grady Memorial Hospital and professor of medicine Ha has been on the Buard of Directors of the American Diabetes Association since 1970, and directed its sixth Allied Health Poslgraduate Course in Atlanta in 1974. His research interests ate in insulin immunity, immunologic in- sulin resistance and its treatment with sulfated insulin, and investigations of various techniques of implementing ef- fective diet therapy and weight reduction in obese maturity-onset diubetics. It you isish to suggest a topic or write an an- seer for this texture, write to William H. Crosby, ltD Scripps Ciinic and Research Fouvdaliort, La Jolla, CA 92037 Reprint requesrs to Department of Medicine, Emory University Ochool of Medicine, 69 Butler Sr SE, Atlanta, GA 30303 lDr. Davidson). JAMA. May 26. 1975 . Vol 232, No 6 FDA and Hypoglycemic Drugs-Davidson 853 PAGENO="0286" 13536 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY ence of sulfonylureas and the poten- tiation of alcohol by sulfonylureas with an occasional disulfiram-like re- action are well substantiated. Phenformin increases anaerobic glycolysis and lactate production and may produce lactic acidosis; it in- creases blood pressure, heart rate, and need for digitalis; and it de- creases gluconeogenesis and glucose absorption. There has been a striking increase in death rate and a decrease in life expectancy in maturity-onset diabet- cs in America, Europe, Asia, Africa, and Australia during the last 20 years. These changes have paralleled the inceas~~lyi~Fsnege1f ~e~hera ~ bridled enthusiasm amon man - sician patients for the use of ~ treatments of choi~. ~ safe, it should not shorten life expectancy nor be associated with fatal side ef- fects or with severe drug reactions. The . increased number of cardio- vascular deaths in the UGDP study, the not uncommon occurrences of ir- feversible hj~micjaind9~- a~~and death with sulfonylureas and fatal lactic acidosis with phenformin, and the previously noted decreased life expectancy of the maturity-onset diabetic population throughout the world are the dramatic cbnsequences of unrestricted use of oral hypoglyce- mic drugs. Thus, one is forced to the conclusion that both sulfonylureas and phenformin are unsafe. It has been known for a long time that ri and seconda drug treatment failures are common wit ti~ifon~li:ea1 and phenformin; these failures have usually necessi- tated insulin therapy. As early as 1957, it was noted that blood glucose levels were frequently as low on pla- cebo as on tolbutamide therapy. In a 1974 report, blood sugar levelsdid not rise in 30 of 50 patients when single- blind placebo was substituted for chlorpropamide. In 20 patients, the level rose modestly on a placebo reg- men; however, in only four of the 20 patients did chiorpropamide help at- tain fasting normoglycemia (blood glucose level, <140 mg/100 ml). If a drug is to be considered effec tive, it should rave t or dela the ap- those above ideal body weight), (2) pea ance of complications or pro ong the hyperglycemic maturity-onset di- life, as well as lower the blood glucose abe~j~g~or below ideal bodywgjght, l~~T'mn a ~ (3) the hyperglycemic pregnant din sulfonylureas and phenformin appar- )~gtj.c., and (4) the hypogglycemiçjuve ~ The prime them- prevent or delay complic~y)ons~~,~,,. peutic objective when insulin is used d6~'~not 1owe~Eh~hlood lucose level is to attain normoglycemia as fre- in an o tima as ion in the majority quently as possible, with hypogly- o~patien s, neit er sulfo~y~,~2r cemia being as infrequent as possible. ~~~i~can be considered effec- The slight discomfort of insulin injec- tiveJliiFipy despite the claim~"~? tions is a minor price to pay for several rug companies and some the generally acknowledged physi- iciansoTh7ontry~ ologic actions and life-sustaining Safe and Effective Alternatives properties of the hormone. I~~L therapy, optimally us~d, is safe, sac Appropriate ~ (in- is almost universally eflectity in lo'~ - cludingperiod~. of fasting ,for up to ering the blood glucose level. one week) usually lowers the blood - - - Responsibility for glucose level dramatically in the indlscnmlnate Use obese diabetic. With ij~(pg~vei s~~jan..follow-~p, a diet ad- At the present time, about 1,500,000 herence rate of 96% has been reported erans are beine treatecjm'it.j~ recently. Siieces&ratas in reducing oral hypoglycemic drug~s. At the Nel- the weight of obese diabetic patients son Committee hearings, different at Grady Memorial Hospital and witnesses estimated that from less Emory University School of Medicine than 1% to 20% of the patients in Atlanta have varied in different being ~`i~wiiTi these agents were groups of patients from ~Q7e~to 90%.~ ~lhei~iJ by such therapy. Do- with the most intensively instructed pending on which opinion one accepts and monitored patients having the as valid, this means that from greatest degree of success (unpub- 1,200,000 to 1,485,000 Americans are lished data). To modify successfully a being inappropriately treated and patient's long-established habits of should have their oral agent therapy food intake, it is mandatory that the discontinued. The drugs are probably physician be competent in calculating being used excessively because the ideal body weight and in writing the physician wants to do something correct dietary prescription. The pa- when he makes a diagnosis of diabe- tient's adherence to diet is facilitated tea, and the patient wants something by use of an easily understood diet done. The easiest thing to do is to manual anTJhtënsive instruction write a prescription for a pill, because over a long period of time by physi- 0it takes only a little time and it neces- cian, nurse, and dietitian. Patientsat f~sitates no signifi~nt change in, Grady Hospital are now given about I!~sient's life-style. Thus, the physi- 25 hours of individual and gro~pJ~ (~ cian writes a prescription for a medi-~ struction over a one-year period. Diet ~cation that he has been led to believe therapy is universally saf~, and when is safe and effective, when it is almost pursued aggressively it is effective in certainly unsafe and is frequently a large majority of matiirity-oñiet di- ineffective. abetics. The FDA has not required properly In the diabetic above ideal body written package inserts for the sul- weight who is not acutely decompen- fonylureas and phenformin because sated (plasma glucose level, 500 of a legal barrier erected by litigation mg/dl or higher, or moderate to large instituted by the Committee on the acetonuria), only a one-week fast and Care of the Diabetic. For this reason, intensive follow-up caloric restriction physicians and the dru -consuming is needed. In addition to appropriate pj~j,ç have not been honestly an diet and exercise ~ optimal j,~- fully informed of the dangers inher- sulin therapy is neede~1 in (1) the ant in the continued widespread use ~i3Tdëiompensated diabetic (even of these drugs. ~ 854 JAMA. May 26, 1975 * Vol 232. No 8 FDA and Hypoglycemic Drugs-Davidson PAGENO="0287" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13537 has now been removed. Commissioner Schmidt has indicated that when the audit of the UGDP study by the Bio- metrics Society is published [Feb 10 issue of J~4MA.-ED], the FDA will move swiftly and forcefully to order labeling of the sulfonylureas and phenformin to reflect the results of the UGDP study. He anticipates that this action will discourage future in- discriminate use of the drugs. If the drugs are used in the future, it would be prudent for the physician to have the patient sign an informed g~py,~ht ag~reement indicating that he has been informed of the possible hazards associated with such drugs and that he accepts the full responsi- bility for the effects of such therapy. For physicians who are concerned about the consequences of discon- tinuing the use of oral hypoglycemic agents by their patients, there is a reassuring precedent for such action. Four years ago, in the wake of the UGDP report, oral agent therapy was abandoned at Grady Hospital, involv- ing 1~00 patients. Eighteen months later, the blood glucose levels~,~Q_% of these patients were satisfkctorily controlled on di~Fthera alone. Since 1972, t e emphasis on digt ther- apy and weight reduction has been intensified, and during the ladt year insulin ~ in all patients who are above ideal body weight. Additional Readings A study of the effects of hypoglycemic agents on vascular complications in patients with adult- onset diabetes, University Group Diabetes Pro- gram. Diabetes l9lssppl 2):747-830, 1970. Effects of hypoglycemic agents on vascular complications in patients with adolt-onset diobe- tow IV, A preliminary report on phenformin re coIls, University Grnop Diabetes Program. JAMA 217:777-784, 1971. Proat TE: Adverse effects of the oral hypo- glycemicdrugs. in Pro-eedsng.m,ffhc E'ighlh C'oo. geese of the Jsternuli,,val Diabetes Federalioei. Amsterdam, Excerpts Medics, 1974, pp 612-623. Hurwitz D, McCuistion AC: Tolbutamide: A double-blind study of its effect in diabetes. N Engl J Med 257:931-933, 1957. Len-Ran A: Trial of placebo in long-term chlorpropaniide-treated diabetics. Diobetotogia 10:197-200, 1974. Weinsier RL. Seeman A, Herrera MG, et al: Diet therapy of diabetes: Description of a suc- cessful methodologic approach to gaining diet adherance. Diabetes 23.669-673, 1974. Davidson 3K, Goldsmith MP: Diabetes (7oide- hook: Diet Section. Colamhua, Ga, Litho-Krome Co, 1971. JAMA 75 YEARS AGO May26, 1900 Carcinoma in Early Life [Walter L. Bierring, MD, pp 1295-1298] Carcinoma is usually regarded as the malignant tumor of later life, having its le- gitimate age limit at 35, though it is most frequently met with after 40 years of age. Wt'h increasing study of the malignant neoplasms, age is gradually losing its hold as a criterion of difference betseeen sar- coma and carcinoma, the former being found at almost any age, while carcinoma :s beginning to he noticed more frequently `bring tb: ":srlier de'-sdes of life. i':iri'insma in early life often has a slow "or-, mu 1km' th:mt si later sears may he .:tt,.st or a consi,leral:ls: length of time. ThaI `:ancvr in earle life is hei'oming more iriolasn: :s very evident: whether it keeps Pace siGh tb, general increase in carci- noma will be difficult to determine. Cer- tainly a collective study of the statistics re- veals the unfortunate fact that the mortality rate of carcinoma is on the in- crease. Roowell Park calls attention to the statistics of New York State, showing 2,363 deaths in 1887 against 4,456 in 1898. In England and Wales, where careful records are kept, the rate of occurrence of cancer has increased from 1 in 5,046 Popu- lation in 1840 to tin 1,306 in the year 1896, an increaue of five times in fifty years. This increase can hardly be ascribed as due to improvements in methods of diagnosis, for rather the reverse is the case, since many cases that were formerly diagnosed as cancer are now properly classified where they belong in other lists. While the etiology of cancer remains ob- scure, there is but little hope that the fu- ture a-ill offer any abatement is this pro- gressive increase. As careful observation continues to note the occurrence of carci- noma in the earlier slecades of life, there is removed from the list of predisposing causes, the influence of age. It has been an attrsm'tivm' explanation to :setrliistm Is the lesseni':l physiologic resist- ance in connective tissue the rOle of per- mitting atyl)ical prisliferation of epithe- hum beyond its normal limits. With advancing age the submucous, subcutane- ous and interstitial connective tissues Sn- dergo atrophic changes, while the covering or lining epithelial elements seem to retain their usual vitality. When glands reach the limit of their functional rOle in the orga- nism, the danger from carcinoma is mOst marked, while it diminishes again when complete atrophy has taken place. When cancer occurs thus in the developing dec- ades of life, the above influences can hardly be considered. . -. In the entire field of pathology, no sub- ject has proved more alluring to physician and investigator than the etiology of carci- noma. It was no wonder that the develop- ment of bacteriologic methods gave a mighty impetus to the search for an etio- logic agent, the result of which is well known. Numerous forms of cell inclu- sions-cancer bodies-have been observed and variously interpreted. As yet it is evident that the real cause of carcinoma has not been demonstrated. Perhaps it will lie necessary to completely modify our culture methods. Perhaps our optical :sids are inaili'quate in magnifying liss'er, hut unless tb, light conies soon, the 19th century svill close with the genesis sf cancer as much a mystery as when the cen- tory hogan. JAMA, May 26, 1975 * Vol 232, No 8 FDA and Hypoglycemic Drugs-Davidson 855 PAGENO="0288" 13538 C.OMPETITIVE PROBLEMS IN THE DRUG INDUSTRY GOVERNMENT Rx's FDA proposes important revision According to a recent FDA-proposed regula- ti()n on Ial)elmg (package insert), a food, drug, device, or cosmetic is "misbranded' if the labeling does not reveal: 1. facts that appear in other statements (et al) about the product; 2. consequences which may result from using the product (either as prescribed or as it is usually used). However, the regulation's prohibitions are more important than its requirements. Material facts (10 not, according to the FDA, permit or require a statement of differences of opinion with respect to warnings (including contraindications, precautions, adverse reac- tions, and other information relating to possi- ble product hazards) required in labeling for food, drugs, devices or cosmetics under the act." (Italics ours.) Furthermore, the proposed regulation does not "permit or require a state- ment of differences of opinion with respect to the effectiveness of a drug unless each of the Opinions expressed is supported i~y sul)stantial evidence of effectiveness In the regulation's preamble, the FDA gives us significant insight into why they have made the above proposal. The current regula- hon states that ``the existence of a difference of opinion aniong experts qualified by scien- tific training and experience, as to the truth of a representation made or suggested in the labeling is a fact (among other facts) the failure to reveal which may render the label- ing misleading if there is a material weight of opinion contrary to such representation. (In other words, according to the regulation they want to revise, differences of opinion are re (Itlired.) In 1971, the FDA published a notice that the labeling for oral hypoglycemic drugs used in the treatment of adult onset diabetes must contain a warning against cardiovascular con- sequences reportedly associated with the use of these drugs. Later that year a group of physicians petitioned the FDA to withdraw or modify this requirement, because they l)elieved that the warning was unjustifIed, aid that if it were required, it should be acconi - panied by a statement of the differences of opinion among experts about the neci'ssit ~ IT the warning. The FDA Commissioner denied the petition, and manufacturers of oral hy- poglycemic drugs had to include the warning in their labeling. The FDA felt that an un- diluted statement was justified, since there was significant clinical evidence to su~)port the warning, and that the physicians who pre- sented the petition did not have enough cvi- dence to dispute the need for the warning: The physicians then brought suit to enjoin the labeling change on the grounds that, i~y not in- cluding the difference of opinion, the drug would l)e misbranded according to the al)ove regulation. The,.EDA contended thatsince statements ~of drug effectiveness and tj:uthful labeling, were supj,~osed to l)e ~)i~sed,,on `~substantial,~ eyjdeI)ce' rather. ~tb~piinedica~opiniqn,, the labeling suggested by these physicians would l)e misleading. Flowever, the district court en- tered a preliminary injunction prohibiting the Fl)A from requiring the warning because, the court concluded, there was a r('asonable likelihood that the labeling proposed by the FDA did not com~)ly with current regulations. \Vhen the F1)A appealed, the Unitel ~StatesCpur~ of' Appeal~icited th~ inconsisten~ cy l~veen the way~,the. curi:ei~t ~l)A~ggula;~ tion reads and the "substantial evidence~. re~_ (luireilleists that bad 1)een added to the Food Drug Therapy / January 1975 PAGENO="0289" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13539 Prescribing Information for TUSSEND®~ and TUSSEND®EXPECTOR~NT~j CONTRAIN DICATIONS: Hypersensitivity to any of the formula ingredients. INDICATIONS: Tussend and Tussend Expectorant anti- tussive-decongestants are indicated when exhausting cough spasm accompanies upper respiratory tract con- gestion. They are useful in the symptomatic relief of upper respiratory congestion due to allergic conditions, the com- mon cold, sinusitis and acute bronchitis. PRECAUTIONS: Tussend and Tussend Expectorant should' be used cautiously in individ- uals with severe hypertension, diabetes mellitus, hyper- thyroidism or urinary reten- tion. Continuous use over an extended period is generally contraindicated since hydro- codone may cause addiction. ADVERSE REACTIONS: As with any narcotic analgesic, hydrocodone may cause gastrointestinal upset in children and nausea in adults. These reactions have been reported, although rarely, following the administration of Tussend or Tussend Expectorant. DOSAGE AND ADMINISTRA- TION: Adults, and children over 90 lb., one tablet or one teaspoonful; children 50 to 90 lb., 1/2 teaspoonful; children 25 to 50 lb., 1/4 teaspoonful. May be given 3 or 4 times a day as needed. CAUTION: Federal law prohibits dispensing without prescription. DOW PHARMACEUTICALS The Dow chemical company Indianapolis, nd. 46268 ~i~d Drug Act by, Congress in .1962. The court then voided the injunction and gave the case back to the FDA for "further determination." Now the FDA had to either allow inclusion of conflicting opinions about the oral hy- poglycemics drug warning or revise the regulation. They decided to revise the regula- tion. According to the 1962 Food and Drug Act: And: "If an article is alleged to l)e ms~randed l)ecause the labeling is misleading, then in de- termining whether the labeling is mi~leading there shall l)e taken into account (among other things) not only representatior~s ma(le or suggested by statement, word, design, de- vice, or any combination thereof, but also the extent to which the labeling fails to reveal facts material in the light of such representa- tions or material with respect to conse- quences which may result from the use of the article to which the labeling relates under the conditions of use prescribed in the labeling thereof or under such conditions of. use as are customary or usual." "Unless its labeling bears (1) adequate direc- tions for use; and (2) such adequate warnings against use in those pathological conditiOns or l)y children where its use ~y be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users: Provided, That where any requirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the pUl)lic health, the Secretary shall promulgate regulations exempting such drug or device from such requirement." The law also (as everyone probably knøws by now) states that a new drug may not be ap- proved for marketing if it is unsafe or ineffec- tive for the conditions for which it is supposed to be used. The FDA finds the use of the word "may" (underlined in the quotation above) particu- larly significant, since it implies lack of univer- sal agreement among experts. The word "may" thus is supposed to make it unnecessary to include the specific medical controversy surrounding the warning. The FDA comments that warnings have been required on drug (continued on p. 82) Drug Therapy / January 1975 PAGENO="0290" 13540 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY lal)elS by the Food and Drug Administration when there is significant medical evidence of a poSSiI)Ie health hazard without waiting for a causal relationship to be established by defini- tive stu(lies, which in some instances may not be feasible or would take many years. It states that in this way, physicians are fully informed of known potential dangers and the public is better protected. These warnings must be stated in clear and~iini~~~[èrms without disc~or ~jii~iThici1Wons that the FDA says would under ñiTh~or des~ [heir i anii~ij apd use mess,' ~ihat~ii1T~ii~h warnings are by their ver nature, a )out ~OSSi) e anger on y. T ese ~ l~,utte~asne~mie~ labeling to reflect su~didebate, and, the sa is e )a e an isa reemen s oul sr in pro essiona journa s and S m osia 1)ut not in rug a e ing. e prescription drug label ~ the guidance of a physi- cian-it does not constitute a legal require- ment and, the FDA adds, a physician does not violate federal law when he prescribes a drug contrary to a warning in its approved labeling. In 1938, when the Federal Food and Drug Cosmetic Act was passed, personal expert judgment was the standard for determining drug effectiveness. The only way to satisfy that standard when the experts' opinions differed was to state 1)0th sides of the issue in the labeling for the drug. In the regulation preamble, however, F1)A states that by 1960, the scientific principles of modern drug test- ing using statistically valid controlled studies had become fully developed and accepted, and claims of drug effectiveness (and thus the truthfulness of' drug labeling) should be deter- mined! by adequate and well-controlled in- vestigations, including clinical investigations by qualified experts. The stated purpose of requiring scientific studies was to eliminate individual clinical ob- servation and opinion as the measure of a drug's effectiveness, since the opinions of indi- vidual physicians reflecting their personal ex- perience, empirical observation, and tradi- tional practice do not satisfy the requirements of sound scientific investigation and thus do not conform to the standards established by the Drug Amendments of 1962. FDA notes that the Drug Amendments of 1962 are clearly intended to supersede tl~e earlier reliance on medical opinion, and that therefore regulations should reflect th~~ new standard. In commenting on the concept of "fair bal- ance" argued by the physicians in attacking the labeling for oral hypoglycemic drugs, FDA states that a draft of proposed new regulations will soon be published in the Federal Register. These regulations will implement "fair bal- ance" for prescription drug labeling in the same way that present regulations do for prescription drug advertising. In both adver- tising and labeling, the required "balance" refers to how information on drug safety and effectiveness is presented and not to differences of judgment al)out that informa- tion. The FDA concludes that the present regulation is inconsistent with current legal requirements and with contemporary medical and scientific principles. Since Congress has determined that t'he effectiveness of new drugs must be established by substantial evi- dence, the FDA thinks that a difference of medical opinion about labeling claims of effec- tiveness is not legally sufficient and is not a material fact unless the opinion is supported by evidence which meets the legal standard. The FDA goes on to say that some controversy exists in the medical profession about most statements in prescription drug labeling, and that permitting or requiring statements of these opinions on all such matters would de- str()y the present usefulness of prescription drug Ial)eling. The Commissioner thus concludes that there is no justification for presenting differences of' medical opinion in any warning statements relating to possil)le product hazards. The Fl)A feels that the law 1)resul)- poses a difference of medical opinion, since warnings of' drug dangers will be requiredl even though the danger itself may not be es- tablished l)ut merely potential. Furthermore, they think there is O() reason to allow these warnings to be discounted by including an opinion that the warning is really not neces- sary at all. For these reasons the FDA proposes that the standing regulations be revised!. (39 Federal Register 33229, Sept. 16, 1974) 1 Drug Therapy / January 1975 PAGENO="0291" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13541 Controversy in Internal Medicine II Ed. by Ingelfinger, Ebert, Finland, and Relman. W.B. Saunders Co. Phila. 1974 Oral Antidiabetic Agents Have a Limited Place in Management and May Be Harmful* ALBERT I. WINEGRAD, REX S. CIEMENTS, JR., and ANTHONY D. MORRISON University of Pennsylvania School of Medicine The manner in which most physicians now manage their patients with adult- onset diabetes might best be termed "benign neglect." In part, this is a conse- * quence of the continuing controversy over the aims and the efficacy of presently available therapy. Just how benign current practice really is remains to be deter- mined; however, it includes certain aspects that are difficult to justify, such as the common misuse of the sulfonylurea compounds and the biguanide derivatives. The indications for continued medical intervention are not so obvious in adult-onset diabetics as in juvenile diabetics since, irrespective of their age at diagnosis, patients with the adult-onset form of the disease exhibit little tendency to ketoacidosis. There is general agreement that ~fforts to lower the blood glucose are indicated in patients who are symptomatic as the result of hyperglycemia, and that delay in the effective treatment of symptomatic hyperglycemia in adult- onset diabetics may be a major factor in the development of hyperglycemic non- ketotic coma. At the time of diagnosis, patients with adult-onset diabetes are a heterogeneous group not only with regard to symptoms, but also with regard to the presence of the complications of diabetes and the coexistence of other condi- tions (e.g., hypertension and arteriosclerotic cardiovascular disease) that might be expected to alter their prognosis. There is littlç~eement as to benefit of that designed ~ symptoms directly related to ° This review was supported in part by Grant AM04722, National Institutes of Health, U.S.P.H.S., and a grant from the John A. Hartford Foundation. Dr. \Vinegrs~l is the recipient of Research Career Development Award GM06405 from the National Institute of General Medical Sciences. PAGENO="0292" 13542 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY What Is the Value of "Control"? Physicians are divided on the value of attcmpts to achieve an approximation of normal glucose metabolism in the hope that this will influence the develop ment or progression of the late complications. (It is symptomatic of the state the field that measures to modify other demonstrable abnormalities, such as hyperlipoproteinernias, have received minimal consideration.) Much of the present controversy over the value of "control" is nonsense. The players in this philosophical sport are trapped by the definitions and unstated assumptions that constitute the rules of this game. In the treatment of adult-onset diabetics, coo- venience is the overriding consideration in the minds of most physicians. which may be understandable since the value of treatment in asymptomatic patients is disputed. The effort and expense required to achieve as~d to document an appro\i- mation of normal blood glucose concentrations throughout the day preclude tLi~ type of treatment for most patients. None of the reported clinical trials desigm d to evaluate the value of "control" has made a serious attempt to achieve normali- zation of blood glucose fluctuations. The frequency with which this goal can achieved in a large population of adult-onset diabetics by presently available means has never been evaluated. In essence we have been subjected to a heat 1 dispute over the value of a form of therapy that is only rarely attempted and even more rarely achieved. Recent studies suggest that fluctuations in the blood glucose concentrati in nondiabetic subjects on a normal diet are restricted to a relatively narr°\' range. However, when evaluating blood glucose concentrations in adult-onset diabetics, physicians almost invariably apply arbitrary standards that bear litti relationship to the levels observed in nondiabetics. In addition, it is commoni~ assumed that if there were a relationship between the blood glucose level aod the pathological processes responsible for complications, it should be appai from comparisons of groups of patients who have had persistently diffei degrees of abnormal blood glucose levels. Although the basis of this belief difficult to perceive, it is rarely questioned. A blood glucose concentration tilL fluctuates between 110 mg. per cent and 180 mg. per cent in a 39 year 01(1 100 throughout the day cannot be considered normal, even though most physicia~~ would consider this. good or excellent "control." One of the undisputed aspects of the recent reports of the University Grout Diabetes Program (UGDP)1' 2 is the record of the quality of "control" achie' in adult-onset diabetics treated in university medical centers by a variet therapeutic regimens, most of which are similar to those now cornnionly eu ployed. None of the treatment groups in the UDPG study had a nomial fastin - blood glucose at any time during the initial four plus years of the study. Diiiri fluctuations in blood glucose on the patients' usual diet and with their tiLl' physical activity were not assessed. However, at regular intervals the path it were given a 50-gin, oral glucose load one half hour after their morning incdu tion, and the blood glucose was determined one hour later. Although the 1071 mean blood glucose level at one hour was observed in the patients treate(l ~~it' adjusted insulin dosages, even in this group the mean one-hour value excess of 200 mg. per cent in more than half the tests during the initial four pilL- PAGENO="0293" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13543 years. It is difficult to assemble totally appropriate age and sex matched control data, but in a recent study of normal males with no family history of diabetes (ages 22 to 28), the mean blood glucose one hour after a 50 gm. glucose load was 90.6±5.7 iiig. per cent,3 and in the studies of Ned et al.~ the mean blood glucose one hour after a 100 gm. glucose load in patients with no family history of diabetes (ages 30 to 39) was 104.3±7.1 mg per cent in males and 93.7±6.~ mg. per cent in females.° The data available would suggest that most of the patients in the UDPG study had persistently abnormal fluctuations in blood glucose concentration irrespective of the treatment prescribed. Although the UDPG study was a pioneer effort to improve the quality of clinical trials, it shares one of the common deficiencies of such studies in that it included no group of patients who had an essentially normal range of blood glucose fluctuation throughout the day. Another frivolous aspect of the current controversy is the simplistic fashion in which the pathogenesis of the late complications of diabetes is viewed by most physicians. Each of the diverse clinical syndromes lumped into this unfor- tunate term has a very complex pathological basis, and in some instances a dis- tinction must be made between processes responsible for acute symptoms and those which operate in the production of predisposing pathological lesions. There is little to support the widespread belief that each of the late complications is primarily a reflection of diabetic microangiopathy. There is no convincing evi- dence that alterations in capillary structure play a determining role in the pathogenesis of the common symmetrical peripheral neuropathic syndromes associated with diabetes mellitus,~ nor is there convincing evidence that this process contributes to the increased frequency with which arterial occlusions occur in specific portions of the vascular system. In patients dying of diabetic nephropathy the pathological findings almost invariably include alterations other than those unique to diabetes mellitus; thus, arteriolosclerosis and intimal fibrosis of the renal arteries are often present.6 Therefore, in any organ system, the pathological changes that are associated with diabetes mellitus may very well be subject to modification by independently determined genetic and environmental factors. However, this is rarely considered in efforts to evaluate the factors responsible for the clinical course in diabetics. As an example, although the recent studies of Hazzard et al.~ would suggest that inherited abnormalities in lipopro- tein metabolism are commonly associated with myocardial infarction, the distri- bution of patients with such abnormalities has not yet been assessed in clinical trials of diabetic therapy. Another reason why caution must be exercised in the evaluation of clinical trials is the problem of asymptomatic but irreversible pathology in the patients studied. It is notoriously difficult to (late the onset of an abnormality in glucose tolerance in adult-onset diabetics, and this problem is magnified by the recent realization that asymptomatie adult-onset diabetes may occur in children and young adults and does not appear to progress to the ketosis-prone type of the ~ The effects of sex and increasing age on fasting blood glucose levels, and on the response toa 100-gm. oral glucose tolerance test in patients with no family history of diabetes have been well documented in patients up to age 39. PAGENO="0294" 13544 cO~nETITIVE PROBLEMS IN THE DRUG INDUSTRY disease.8 Thus, the presence of asymptomatic pathology in newly diagnosed adult-onset diabetics cannot be used as a telling argument against a relationship to the metabolic abnormalities associated with diabetes mellitus. The failure to consistently observe improvement in specific diabetic compli- cations following the institution of "stricter control" is frequently used as evidence that the pathogcnesis of these conditions. is unrelated to the consequences of an impaired insulin secretory mechanism. To cite hut one example of the limitations of this reasoning, recent studies have demonstrated that the majority of a group of newly diagnosed adult-onset diabetics w'ith normal standard neurologic examinations and without symptoms of neuropathy could be shown to have widespread fuiictional abnormalities in their peripheral nervous system when suitably sensitive techniques were employed.9 Biopsies of peripheral nerves from asymptomatic adult-onset diabetics without clinical evidence of neuropathy have also revealed pathological changes similar to those found in the nerves of patients with clinical neuropathy (although of a lesser degree) 10 Thus, the development of the clinical manifestations of diabetic neuropathy may represent a late stage in the pathological process and have irreversible elements. Whether or not patients with clinically apparent peripheral neuropathy respond to efforts to improve "control" can provide little information concerning its pathogenesis or its prevention. The host of invasive techniques which would he required to assemble suitably characteri~.ed subjects for study (e.g., coronary angiography. renal and peripheral nerve biopsies, fluoroscein retinography, and so forth almost precludes meaningful large scale clinical trials. Many physicians also believe that the controversy over the relationship between the metabolic derangements that result from an altered insulin secretory mechanism and alterations in the capillary basement membrane in diabetics has been resolved and that the two are clearly unrelated. This stems from the provoc- ative studies of Siperstein and associates, who were the first to apply quantitative techniques to the assessment of capillary basement membrane thickness (CBMT) .~ They recognized the inherent technical problems in attempting to measure CBMT in many organs and demonstrated that skeletal muscle biopsies provide a means of obtaining suitable material for study from large numbers of patients. Their data indicated that muscle CBMT was significantly greater in diabetics and that the degree of thickening appeared to be unrelated to the duration of known disease or to its "severity." ~\foreover, their studies suggested that in patients genetically at high risk for the development of diabetes mellifus, increased muscle CBMT was present prior to the development of a detectable abnormality in glucose tolerance. Siperstein's work has been a major contribution and stimulus. However, some of his observations and interpretations have been seriously challenged by Kilo et al., who have concluded that muscle CBMT is usually within normal limits at the outset of clinical diabetes mellitus and increases with duration of disease.12 There are differences in methodology and in patient selection in these studies, and the resulting controversy has not been resolved. The studies of ~stcrby suggest that in the kidney the alterations in glomerular capillary structure are not present at the outset of clinical diabetes in young adults but progress with increased duration of the disease.13 Thus, it would be premature to conclude that the demonstrable metabolic abnormalities PAGENO="0295" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13545 in diabetes mellitus are totally unrelated to the development or progression of alterations in capillary structure. A similar conclusion would have to be drawn with regard to data available from studies of experimental diabetes in animals~ particularly in view of recent preliminary reports of the production of retina~ capillary microaneurysms in rats with chronic streptozotocin diabetes.14 From this cursory review it would appear that at the present time the physi- cian treating adult-onset diabetics has a clear responsibility to prevent symp- tomatic hyperglycemia; the advantages of maintaining a normal or nearly normal range of blood glucose fluctuations remain to be evaluated hut cannot be excluded. The choice of therapeutic aims must be a conscious decision by the physician, and one in which an informed patient participates. The patient's age, the presence of other serious medical problems, the presence or absence of specific clinical complications, and the patient's motivation are practical considerations.. The importance of Weight Control Whether the physician believes that the prevention of symptomatic hyper- glycemia is an adequate goal in a given patient, or whether a strenuous effort is undertaken to achieve a normalization of glucose metabolism, the relationship between increased body weight and hyperglycemia that so frequently exists in adult-onset diabetics must be considered. In the UGDP study the adult-onset diabetics averaged + 33 per cent of ideal body weight at the outset.'5 It has b~ observed repeatedly that many adult-onset diabetics will exhibit improvement in ~i~g~o~h T~emia if a significant reduction in bod~y ~ight c~ achieve . (Whether this is due to~~t reduction per seorto a decrease in ~iEoh~d~te~e r~ñ~ins to be deterrnined2°' ") The UGDP studies pi~~e an in ication of the effectiveness o present efforts to achieve weight reduction and the resultant improvement in diabetic "control." All the patient groups in the UGDP study exhibited a fall in mean body weight at the time of the first follow-up visit. However, the maximum decrease for any group was 4.2 lbs (less than 3 per cent of initial mean weight), which was observed in the patients treated with diet plus a placebo. In this group the early weight loss was not. sustained, and the mean body weight remained close to 98 per cent of the initial weight throughout the subsequent four plus years. The initial weight loss was associated with a fall in both the mean fasting blood glucose level and in the glucose level observed one hour after the ingestion of 50 gm. of glucose. Subse- quently both of these parameters of "control" rose progressively throughout the remainder of the study. Although the patients receiving tolbutamide or insulin (in fixed or varying dosages) also received dietary instruction, their initial weight loss was less than that observed in the placebo group, and no further reduction in mean body weight was observed during the subsequent four years. These data suggest that current efforts to achieve weight reduction in adult-onset diabetics are ineffective, at least as currently practiced in medical outpatient clinics. The difficulties encountered in achieving weight reduction in chronically PAGENO="0296" 13546 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY obese nondiabetic subjects have been well documented, and the psychiatric implications of food to some patients are recognized; however, it is not certain that the experience with these chronically obese patients provides a meaningful index of the results that could be obtained in patients with adult-onset diabetes Veight reduction r the safest ~ sufficient to prevent hyperglycemic s rn toms in the majority of adult-onset diabetics. Moreover, in t e absence of si nificant wei~ t re uction, t e e cac Qf 6fber ai'~ts emp oye to lower blood glucose appears to be considerably ~ ~ large percentage of patients. Diet instruction is confusing and reflects the pseudoscience that presently surrounds the question of an appropriate diet for adult-onset diabetics. Dietary instructions should be as simple as possible. The justification for modifications in dietary composition remains to be established: however, in the face of evidence of persistent abnormalities in plasma lipoproteins, we suggest modifications similar to those recently outlined by Fredrickson and his co- workers.18 One of the factors that may contribute to the failure of diet therapy is the long period between follow-up visits-three-month intervals being not uncommon. The commercial weight reduction groups have demonstrated the value of reinforcement provided by frequent weight checks, and brief visits in which weight is checked by an office nurse can be helpful in many patients. Increased physical activity is often dismissed as of little benefit; however, for most 40 year old Americans a 15-minute daily walk would represent a significant increase in physical activity. A conscientious effort to increase physical activit' is in our hands a si"nificarii factor in those patients in w' om a, reduction in ~ight and improved glucose evels are achie~vd. It isO interest that a recent ~ insulin secretion observediuii~iaikedTy ~ by oug t ere are many a u t-onset diabetics in whom lifelong patterns of overeating and limited physical activity are practically immutable, the fact remains that o encourage reduced caloric intake and ~rease p ~ysical activity have been abandone man ysicians. There is little iitifi ca iOn or t ~e use of any pharmacolo ie agent in asym tomatic adult-onset ~ possi ilty o attain~~i `e'cotrol"byweight_reduction has been given an adequate trial. It is now eommon ~ begin ~ asymptomatic adult- ~ oreover, t e patient is instructed that the oral hypoglycemic agents may provoke hypoglycemic symptoms w'hich can be relieved by the ingestion of free carbohydrate. For many patients, who are understandably anxious about their newly diagnosed disease, this becomes a sanctioned invitation to unrestricted calorie intake. It is not surprising that sig- nificant weight reduction and maintenance of normal body weight aie rarely achieved under these conditions, fo~ bgth phvsiçi~n~p4. p~ept~ b~~c:pme to~ view the nature and amount of the drug iqgçs~cd ~ "controlling" adult onse diabetes PAGENO="0297" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13547 Limited Effectiveness of Oral Hypoglycemic Agents If the physician resorts to pharmacologic agents to prevent symptomatic hyperglycemia in adult-onset diabetics before demonstrating the necessity for their use, then one might hope that he would at least document the effectiveness of the agent employed. Since a fixed dosage of 1.5 gm. per day of tolbutamide was employed, the data derived from the UCDP study are not completely applicable. ~ dos~g.~~nge,.a.nd the experience of this study is probably not too unrepresenta- tive of the long-term efficacy of sulfonylureas in adult-onset diabetics in whom significant weight reduction is not achieved. In the UDGP study there was an initial improvement in fasting blood sugar and also in the blood glucose level observed one hour after a glucose load. This improved "control" paralleled the initial and transient weight loss which had occurred in these patients. Subse- quently there was a progressive rise in mean fasting blood glucose and over the remaining four plus years it rarely differed from that of the group receiving a placebo by more than 15 mg. per cent (the mean values in 1)0th groups being persistently abnormal). The blood glucose level after a glucose load also tended to increase progressively in the patients treated with tolbutamide, and the mean value was rarely more than 20 mg. per cent different from that of the placebo group. At the end of four plus years the mean value in the group treated with tolbutamide was 244 mg. per cent, whereas the value for the placebo group was 251 mg. per cent. Thus, one may question whether the use of tolbutamide under these conditions ~ ~ ~ `T'ff~i~i~i~rcsponsible for the development of refractoriness to sul- fonylurea therapy in patients in whom an initial response is observed are still uncertain, and the data on its incidence are difficult to interpret.20 Values ranging from 0.3 to 30 per cent have been reported, and there is a suggestion that the incidence increases with known duration of diabetes. The uncertainty results, in part, from differences in patient selection, in criteria for failure, and in the extent to which other factors such as weight gain and dosage were considered. Unfor tunately physicians exercise little selectivit in administerin sulfonylureaor Jg~~i es ton u-onset ia ~ imposed by obesity2 arid are slow to raise the question of efficac . One can only ness at the number of patients present receivinl these drugs in w iom t eir withdrawal would not signi cant v alter the dail' fluctuations in 00 lucose evels. Our own ence wou ~ fraction of the patients who Hive received the drug for a prolonged period iidln whom obesity persists. - In gener~17~oth p~i~ians and patie are reuctant to stop ~i1Thypo- glycemic therapy once it has been instituted. In many instances random blood glucose values of 200 to 300 mg. per cent are observed over a period of months to years before the physician reluctantly concludes that the drug has become ineffective. The usual course under these circumstances is to resort to another sulfonylurca in the hope of finding One that is "effective," and often to combine this with a biguanide. ~ ~~rrent misuse of the sulfo- 56-592 0 - 75 - pt. 29 - 20 PAGENO="0298" 13548 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY nylureas and the bi uanides is that man atients are subjected to the expencc an p0 entia hazard of long-term treatment to attain a relative imite coal- free om rom ~ypergycemic symptoms-w i c tie agents are use&undercondi~ tions in which their efficacy is restricted and is only rarely adequately assessed, ~ of adult-onset diabetics in whom the use of the sulfonylureas can produce furth~r improvement in the range of fluctuations of blood glucose over that resulting from the correction of obesity. These agents may also be effective in some non. obese adult-onset diabetics. We do not eschew the use of sulfon `lureas i to prevent sym tomatic Ii' er cemi to achieve an a roximation of normal uctuations in blood glucose. In both instances, however, the consequence f ~ n rited if obesit * esent. I t ic a i on a p iarniacologic agent is ~ / j ~ We do not believe that the / iguani es ave an established lace in the treatment of diabetics. Many physicians are reluctant to accept t ic act t at t e su onylureas and the biguanides are not appropriate agents in circumstances in which rapid cor- rection of the metabolic abnormalities is required. An obvious instance is when ketonemia develops either in association with an acute infection or following the institution of therapy for an unrelated disease that requires the use of agents that can impair endogenous insulin secretion and/or decrease its apparent effective- ness. In these circumstances insulin is indicated, since neither the sulfonylureas nor the biguanides provide significant protection against the development of ketoacidosis. Even in the more common situation in which the previously untreated patient presents with marked polydipsia, polyuria, and weight loss without ketonemia, one cannot predict with any certainty whether the patient will respond to sulfonylurea or biguanide therapy. Under these circumstances, and particularly if there is an associated illness that predisposes to dehydration, it is wiser to use insulin for the acute correction of hyperglycemia and the relief of symptoms. Nonetheless, many physicians attempt trials at treatment with thq sulfonylureas or the biguanides with a resulting delay in effective therapy that in some instances may contribute to the development of hyperglycemic nonketotic coma. The use of insulin to achieve acute improvement does not imply that the patients will necessarily require exogenous insulin once they have been stabilized for a significant period. When there is a demonstrated requirement for the addition of a pharmacologic agent to correct symptomatic hyperglycemia, there is a curious reluctance to employ insulin in the management of adult-onset diabetics. This stemi, in part, from the misconception that these patients are invariably insulin hypersecretors and that insulin resistance is a major factor in the pathogenesis of this syndrome. The bulk of the present evidence (which Kipnis has admirably reviewed21) clearly indicates that most adult-onset diabetics exhibit an impaired insulin secretory mechanism when compared with appropriately matched age, sex, and weight groups. Moreover, although obesity in both the normal and diabetic individual is associated with an apparent decrease in the biologic effectiveness of insulin, the diabetic state per se does not appear to be associated with any signifi- cant degree of insulin' antagonism (if one excludes specific. circumstances such as I PAGENO="0299" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13549 ketoacidosis). In nremains the preferred pharmacologic agentbeçauseofit~ assured and continued efficacy and its protective value in circumstances in which ~ Since 1972 there have been improvements in ~ preparations available, as the result of the application of methods developed to separate insulin, pro-insulin, and related peptides. Preliminary data suggest that these newer preparations may significantly reduce the immunologic responses to the administration of porcine and bovine insulin and the associated clinical problems.22 23 However, the present methods for the administration of insulin to adult-onset diabetics are far from ideal. We have no practical method of repro- ducing the timed relationship between food ingestion and insulin secretion that Occurs in normals nor of selectively exposing the liver to the pulses of insulir~ that normally occur in portal venous blood after eating. Therefore, there is little reason to believe that present forms of insulin treatment reproduce normal physiology. The primary advantage of the sulfonylureas is that they can be administered orally. The resulting convenience is a real but not necessarily compelling con- sideration when there is a manifest requirement for a pharmacologic hypo- glycemic agent. The specific circumstances in a given patient should determine the choice, and while our own preference is to employ insulin, there is no good reason why a carefully controlled trial-preferably with one of the shorter acting sulfonylureas-should not be undertaken. The physician should, however, con- sider the possibility that eontraindications to the use of sulfonylureas may exist (e.g., renal impairment or liver disease) and that sulfonylurea therapy may influence the metabolism of other pharmacologic agents (e.g., bishydroxycumarin and sulfonamides). The limitations of our knowledge concerning the role of insulin deficiency in certain situations lead us to prefer the use of insulin in patients with manifest symmetrical peripheral neuropathy with or without asso- ciated chronic foot ulcers, and in individuals in whom repeated skin infections or poorly healing surgical wounds are present. However, it must be admitted that this is clearly a prejudice on our part. Hazards of Treatment with Sulfonylureas Insulin or sulfonylurea therapies are not without hazard. With insulin the major concerns are hypoglycemia and problems resulting from the administration of foreign protein( s). The safety of treatment with the sulfonylureas is, however, the point most fiercely disputed at the moment. It should be apparent from thç initial section of this discussion that we have serious reservations about the conclusions that can be drawn from any of the published clinical studies, irre- spective of the elegance of the statistical methods employed to deal with their inherent deficiencies. A causal relationship between the treatment prescribed in the UDPG study and the subsequent clinical course of these patients would be difficult to establish on the basis of the information available. The excess cardiq vascular moitaIity~obscrved in the groups treated with tolbutamide~~en- formin cannot be dismissed, since the manner in which these agents were PAGENO="0300" 13550 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY the misuse of ~hç~ç ag~pt~ jrj ~çç~nipipn practice. If subsequent data provided by the UDPG group provide evidence of an unusual form 1 coronary artery disease in the patients treated with tolbutamide and phenformin. or of an unusual propensity to cardiac arrliythmias, to pulmonary emboli, or ~ shock in the patients who died of cardiovascular disease, the case may be strengthened. However, although we feel that the sulfonylureas have a limited role in the treatment of adult-onset diabetes, we would not abandon their use en the basis of the findings of the UDPG study. Nevertheless, this study has served the useful purpose of reminding physicians that the use of sulfonylureas and biguanides is not without hazard, and that as with any pharmacologic agent. the possibility of unanticipated effects must be considered. Hypoglycemia and hypersensitivity reactions have been the major problems encountered in the use of the sulfonylureas. Hypoglycemia resulting froq~~3e drugs can be prolonged and n~y ~ ~ö~pob~di~ch aiThiorpropamide. Many of the reported instances havej~ltcd ~ im ait~ rena unc ion.-4 n a ition, it as ecn recognized that chlorpropamide can induce a syndrome characterized by hyponatremia, impaired mental function, and evidence of inappropriate antidiuretic hormone activity.25 The pernicious aspect of this syndrome is that in elderly patients (in whom it has been most frequently observed) the impaired mental function could easily be attributed to other causes. There is little reason to believe that the effects of the sulfonylureas are restricted to the pancreatic p-cells. Specific compounds have been shown to alter thyroid function,24 to modify adenyl cyclase activity in cardiac muscle,27 to augment antidiuresis,25 and to alter lipolytic activity in isolated adipose tissuc.~ However, with the exception of the UGDP study, the reported incidence of serious problems resulting from the use of the shorter acting sulfonylureas has been remarkably low. Nonetheless, the prolonged administration of sulfon lureas to adult-onset ~ s with any pharmacologic ~ the indications for its use, and is not acceptable unless Th ëfis~d~oiRtib~ted to b~e effe~tivë~~~ - - Why Do We Use the Biguanides? As we have previousl mentioned we find it difficult to *ustif ~ J biguanides in~trea~ei~ of diab ndwoul4discouraet~LJt is doubtful that these agents would be employed at all if it were not for the fact that they can be administered orally. While there are gaps in our knowledge of the manner in which insulin and the sulfonylureas lower blood glucose levels in diabetics, there is some reassurance that these effects arc mediated, in part, by the correction of metabolic abnormalities resulting from an altered insuRn secretory mechanism. Whether the long-term effects of the sulfonylureas result primarily from an action on the pancreatic p-cells is a point that is difficult to document, but the ability Of these agents to stimulate insulin secretion in adult- PAGENO="0301" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13551 onset diabetics in whom they are effective is undisputed. In contrast, the manner in which phenformin lo\vers blood glucose in human diabetics, or in animals with alloxan diabetes, remains an enigma, ~ tar data a able are not reassui~pg.An effect on insulin secretion has been excluded, although some residual endogenous insulin secretion is necessary for phcnforrnin to be effective in lowering blood glucosc.~~g~r et a!. have reported that phenformniinp~~~ ~ peripheral glucose utilization albeit with an increased rate of lactate production.3° The applicability of data derived from other species must be questioned because of the marked species variation in susceptibility to the hypoglycemic effects of phenformin. Thus, Kreisberg and associates dispute any effect of phenformin on decreasing hepatic glucose production or release in man.3° However, at high concentrations phenformin does inhibit gluconeogenesis in isolated perfused rat liver.30 In none of the isolated tissues in which the effects of phenformin have been examined is there clear evidence that phenformin restores a pattern of metabolism resembling that observed in the animal with a normal insulin secretory mechanism. More to the point, biguanides are ineffective in the prevention of keto- acidosis, and there is no evidence that they have the assured efficacy of insulin in the ~ suitable agent to use in those patients in whom a serious effort to achieve a normal range of blood glucose fluctuation is undertaken with the aim of correct- ing the underlying derangements in tissue metabolism that may contribute to the pathogenesis of the late complications.,jii patients in whom efforts at weight reduction have failed to remove the threat of symptomatic by er 1 cemia, biguanides have no o vious advantage over insu in or tesulfonylureas (unless one wish~ lewitseecs on gi~6~a sorptim~as an advan~g~). There is ~ of adult-onset iabctes, un ess one will accept its use nj~flt to ~~~p~ent with sulfonylureas. Sinesuitablealternativesaiiab1~th~ii&aiinnlQL titio~lrisei~ailed in this practice esca es us. The UDPG study reported a significant excess car sovascu ar mortality in the groups treated with phen- formin, but again the causal nature of this relationship is difficult to establish. However, there remains the distinct possibility that phenformin may represent a pharmacologic hazard in a group of patients who tend to develop general or local circulatory insufficiency. We believe this. may contribute to the association between phenformin administration and the development of clinical lactic acidosis.3' Lactic Aciclosis The pathogenesis of lactic acidosis in those instances in which there is no obvious evidence of local tissue hypoxia is poorly understood. However, it is clear that in many tissues the rate of lactate production under normal conditions is in PAGENO="0302" 13552 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY a range that represents only a small fraction of the tissues' total capacity. In many tissues thc ratcs of conversion of glucose to pyruvate and l'ictate ase kept it small fraction of total capacity by chemical signals generated as a consequence of the operation of the Krebs cycle and the electron transport system in which oxygen is the final acceptor. The effect of anoxia on the rate of lactate production in a tissue such as muscle results from a decrease in the signals which are usually generated as a consequence of respiration and an increase in glycolysis. Under these conditions the end product of gl~ colysis sppcsrs purnarily `is lactate sinci a secondaiy consequence of imp'iiied iespn'stion is `in mci ease in the eytoplasrna free NADH/NAD iatio which is one of the f'ictois determining the satso of lactate/pyruvate in the cytoplasm There is no doubt that in lactic acidosis `is us diabetic ketoacidosis the rate of pioduction of a norm'sl product can be incieasd to le~ els th'it thi eaten the oi ganism s e'astence Lactate released into the cii eul'i tion b) othei tissus is iemo~ ed in laige part by the liver where it is utill7ed to i considerible degree foi the sesynthesis of glucose The oni) ~alue of this urn phstic outline is to stiess the point that f'ictois that peirnit the e'tpiession of the tiemendous htent cap'scitv for lact'ite production in many tissues or which impair the capacity of the liver to dispose of lactate, may eventuate in lactic acidosis It is well estiblished in idult onset diabetics thit chionic phenfoimin administration i esults in sigmflcant elevation of blood lactate concenti `itions While in most patients the levels obseii ed gii e little ciuse for concern the effect does appear to be dose related 32 There is theiefore the possibility that at sufficiently high concentiations phenfoirnin might induce lactic acidosis in humans eithei by inereasmg peripher'il lactate pioduction or b) decieasin. hepatic utilization oi both This would appeai to be the cisc since these arc well documented instances in which phenformin was taken foi suicid il puiposes w ith the subsequent development of lactic icidosis The biguanides are unlikely to be the sole ciuse of the increased ficquencv of lactic acidosis in diabetics since this syndrome has been observed in pitients who are not receiving these diugs Adult onset dribetics are as a group mdi viduals at inciessed sisk to the development of a number of acute conditions which may produce local cireulitory changes conducive to the development of either incieased lictate production or impaired disposition It seems difficult to exclude the possibility that under these circumstsnces the pi esence of biquanides may potentiate the dci eiopment of lactic icidosis The effoits to exclude this possibility are not totally convincing thus the failure of bigusmdes to potentiate markedly the rise in blood lactate in rats exposed to low oxygen tensions ignores the relative insensitivity of this animal to the effects of these compounds. We find ourselves in agreement with Oliva, who concluded: "It remains possible that the association of phenformin and lactic acidosis is coincidental since lactic acidosis may occur in diabetic subjects not taking phenfoi mm as is eli as in non di ibetic subjects The v eight of the indirect evidence however strongly suggests thit phenformin plays a causil or contubutoiy iole in the pioduction of lactic acidosis 31 It is inteiestmg that the only death specifically ascribed to lactic acidosis in the UDPG study occuried in a patient in the group receiving phenfoirnin In sum since phenfoimin fills no unique iequirement in the trest ment of adult~onset diabetes, since its mode of action is uncertain but unlikely PAGENO="0303" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13553 to be corrective of derangements resulting from an impaired ilisulin secretory mechanism, and since its relationship to lactic acidosis is unsettled, there is no valid reason to employ it in these patients. Summary The present state of treatment for adult-onset diabetes is admittedly inade- quate, except for the prevention of symptomatic hyperglycemia. The data derived from clinical studies and from experimental work provide no basis for excluding the possibility that normalization of blood glucose fluctuations may significantly modify the development and progression of diabetic complications. However, the value of this form of therapy has never been adequately tested, and its immediate aims are difficult to achieve with present methods. It is an approach that should be considered primarily in younger diabetics without evidence of irreversible pathology who are capable of making an informed commitment to this form of treatment. In the majority of adult-onset diabetics the aim of therapy is of necessity restricted to the prevention of symptomatic hyperglycemia, and irrespective of the arbitrary assessments of "control" employed, most of these patients will have blood glucose levels which persistently fluctuate in the abnormal range. The use of any pharmacologic agent in this group of patients should be justified by excluding the possibility that reduced caloric intake and increased exercise will not remove the threat of symptomatic hyperglycemia. In present practice the sulfonylureas and the biguanides are often used without adequate indication and under circumstances in which they are unlikely to be of any benefit. In addition, patients are exposed to the expense and potential hazard of prolonged treatment with these agents without adequate concern for their ef~cacy. Insulin is the drug of choice when ketoacidosis threatens, or when an acute improvement in symptomatic hyperglycemia is required. In asymptomatic pa- tients with a demonstrated requirement for a pharmacologic hypoglycemic agent, we believe insulin to be preferred, but a `veil controlled trial of a sulfonylurea is not necessarily contraindicated. Bi~uanides have ~p ~ ~L diabetes mellitus. References 1. The University Group Diabetes Program: A study of the effects of hypoglycemic agents or' vascular complications in patients with adult-onset diabetes. I: Design, methods and baseline results. II: Mortality results. Diabetes 79 (Suppl. 2) :747-830, 1970. 2. Knatterud, C. L., Meinert, C. L., Klimt, C. R., et al: The University Group Diabetes Pro- gram: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. IV. A preliminary report on phenformin results. J.A.M.A. 217:777-784, 1971. 3. Förster, H., Hasibeck, M., and Mehnert, H.: Metabolic studies following the oral ingestion of different doses of glucose. Diabetes 21:1102-1108, 1972. PAGENO="0304" 13554 COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 4. United States Department of Health, Education, and \Velfare, Public Health Service, Divi- sion of Chronic Diseases: Genetics ansi the Epidemiology of Chronic Diseases. Wash- ington, D.C., Government Printing Office, PHS Publication No. 1163, 1965, p. 113. 5. Winegrad, A. I.: Diabetic sseuropathy. (Editorial.) New Eng. J. Mcd. 286:1261-1262, 1972. 6. Warren, S., Le Compte, P. M., and Legg, H. A.: The Pathology of Diabetes Melhitu.s. Philadelphia, Lea & Fcbiger, 1966, pp. 200-201. 7. Hazzard, W. R., Goldstein, j. L., Schrott, H. G., et al.: Ilyperlipidemia in coronary heart disease: Lipoprotein characteristics of a classification based on genetic analysis. J. Clin. Invest. 51:43a-44a, 1972. 8. Fajans, S. S.: What is diabetes? Definition, diagnosis, and course. Med. Clin. N. Amer. 55:793-805, 1971. 9. Chochinov, R. H., Ullyot, C. L. E., and Moorhouse, J. A.: Sensory perception thresholds in patients with juvenile diabetes and their close relatives. New Eng. J. Med. 286: 1233-1237, 1972. 10. Chopra, J. S., Hurwitz, L. J., and Montgomery, D. A. D.: The pathogenesis of sural nerve changes in diabetes mellitus. Brain 92:391-418, 1969. 11. Siperstein, M. D., Unger, R. H., and Madison, L. L.: Studies of muscle capillary basement membranes in normal subjects, diabetic and prediahetic subjects. J. Clin. Invest. 47:1973-1999, 1968. 12. Kilo, C., Vogler, N., and Williamson, J. R.: Muscle capillary basement membrane changes related to aging and to diabetes snellitus. Diabetes 21:881-905, 1972. 13. Østerby, II.: Diabetic glonserulopathy. A quantitative electron microscopic study of the initial phases, Diabetes: Proceedings of the Seventh Congress of the International Diabetes Federation, Buenos Aires, August 23-28, 1970 (International Congress Series No. 231). Edited by R. R. Rodriguez and J. Valiance-Owen. Amsterdam, Excerpta Medica, 1971, pp. 793-803. 14. Leuenberger, L., Cameron, D., Stauffacher, W., et al.: Ocular lesions in rats rendered chronically diabetic with streptozotocin. Ophthal. Res. 2:189-204, 1971. 15. Coldner, M. C., Knatterud, C. L., assd Prout, T. E.: The University Group Diabetes Pro- gram: Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. III. Clinical implications of the UGDP results. J.A.M.A. 218: 1400-1410, 1971. 16. Grey, N., and Kipnis, D. M.: Effect of diet composition on the hyperinsulinemia of obesity. New Eng. J. Med. 285:827-831, 1971. 17. Bruozell, J. D., Lerner, R. L., Hazzard, W. R., et al.: Improved glucose tolerance with high carbohydrate feeding in mild diabetes. New Eng. J. Med. 284:521-524, 1971. 18. Levy, R. I., Fredrickson, 1). S., Shsilman, B., et al.: Dietary and drug treatment of primary hyperlipoproteinemia. Ann. Intern, Med. 77:267-294, 1972. 19. Björntorp, P., Fahlén, M., Grimby, G., et al.: The effects of physical training and acute physical work on plasma insulin in obesity. Europ. J. Clin. Invest. 2:274, 1972. 20. Krall, L. P.: The oral hypoglycemic agents. in Marble, A., White, P., Bradley, B. F., and Krall, L. F. (eds.): Josbn's Diabetes Mellitus. Philadelphia, Lea & Febiger, 1971, p. 315. 21. Kipnis, D. M.: Insulin secretion in normal and diabetic individuals. Advances Intern. Mcd. 16:103-134, 1970. 22. Schlichtkruli, J., Brange, J., Christianson, A. H., et al.: Clinical aspects of insulin- antigenicity. Diabetes 21 ( Suppl. 2) :649-656, 1972. 23. Root, H. A., Chance, R. E., and Galloway, J. A.: Immunogenicity of insulin. Diabetes 21 (Suppl. 2):657-660, 1972. 24. Seltzer, H. S.: Drug-induced hypoglycemia: A review based on 473 cases. Diabetes 21:955- 968, 1972. 25. Weissman, P. N., Shenkman, L., and Gregerman, B. I.: Chlorpropamide hyponsstremia: Drug-induced inappropriate antidiuretic-hormone activity. New Eng. J. Med. 284: 65-71, 1971. 26. Brown, J., and Solomon, D. H.: Effects of tolbutamide and carbutamide on thyroid func- tion. Metabolism 5:813-819, 1956. 27. Lasseter, K. C., Levey, G. S., Palmer, R. F., et al: The effect of sulfonylurea drugs on rabbit myocardial contractility, canine purkinjc fiber automaticity, and arlenyl cyclase activity from rabbit and human hearts. J. Chin. Invest. 51 :2429-2434, 1972. 28. Stone, D. B., Brown, J. D., and Cox, C. P.: Effect of tolbutamide and phenformin on hipolysis in adipose tissue in vitro. Amer. J. Physiol. 210:26-30, 1966. PAGENO="0305" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13555 29. Kruger, F. A., Altschtild, B. A., Halloboiigh; S. L., et al.: Studies on the site and niecha- nism of action on phenforniin. II. Phenformin inhibition of glucose transport by the rat intestine. Diabetes 19:50-52, 1970. 30. Kreisberg, B. A., Owen, W. C., and Siegal, A. M.: Ilyperlacticacidemia in man: Ethanol- phenformin synergism. j. Clin. Endocrinol. 34:29-35, 1972. 31. Oliva, P. B.: Lactic acidosis. Amer. J. Med. 48:209-225, 1970. 32. Craig, J. W,, Miller, M., Woodward, IL, et ii.: Influence of phenethylbiguanide on lactic, pyruvic, and citric acids in diabetic patients. Diabetes 9:186-193, 1960. 33. Davidson, M. B., Bogarth, W. R., Challoner, D. R., et a!.: Phenformin hypoglycemia and lactic acidosis. New Eng. J. Med. 275:886-888, 1966. PAGENO="0306" 13556 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY IN VITRO EFFECTS OF TOLBUTAMIDE ON THE SYMPATHO-ADRENAL SYSTEM. Chung-Yi Hsu, Gary Brooker, Michael J. Peach, and Thomas C. Westfall, Charlottesville, Va. (Introduced by Joseph Larner,* Charlottesville, Va.) High concentrations of tolbutamide (6.6 mM and 10 mM) provoked massive discharge of catecholamines from the perfused cat adrenal gland. Differential estimation of secreted catecho- lamines revealed preferential release of epinephrine by these concentrations of tolbutamide. At concentrations within the therapeutically effective range (0.1 to 1.0 mM), tolbutamide depressed basal, nicotine-, KC1-, and glucagon-induced cate- cholamine release from the cat adrenal glands and nicotine- and KC1-,induced 3ti-nore~4inephrine release from perfused guinea pig hearts in a dose dependent manner. This inhibitory action of tolbutamide was quickly reversed following removal of the drug from the perfusion solution. Prolonged perfusion for 20 mm or longer with tolbutamide resulted in a sustained depression of catecholamine secretion from the cat adrenal. Withdrawal of the drug caused catecholamine secretion to reach a steady state level which was higher than the level observed just before tolbutamide perfusion was begun. This rebound phenomenon was occasionally manifested by an outburst of catecholamine release. Carboxytolbutamide, the major metabolite of tolbutamide, showed no effect on basal as well as stimulated catecholamine secretion. If tolbutamide acts similarly in vivo on the sjmpathoadrenal system, then the detailed concentration versus time relationships of tolbutamide could be of considerable importance in its pharma- cological action and possible toxicological effects. The Journal of the American Diabetes Association,DIABETES. Volume 24 Supplement 2 , 35th Annual Meeting. June 15-17, 1975. pp 414, #88 PAGENO="0307" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 13557 Reprinted from 21 March 1975, Volume 187, pp. 1086-1087 Inhibition of Catecholamine Release by Tolbutamide and Other Sulfonylureas Chung-Yi Hsu, Gary Brooker, Michael J. Peach and Thomas C. Westfall Copyright@ 1975 by the American Association for the Advancement of Science PAGENO="0308" 13558 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Sulfonylureas are oral hypoglycemic agents which have been utilized exten- sively in the treatment of adult-onset diabetes mellitus. The primary action of this group of agents has been at- tributed to the direct stimulation of pancreatic beta cells to release insulin (1). However, the poor correlation be- tween their insulin-releasing effect and diabetic control has led to speculation of extrapancreatic actions of sulfonyl- ureas (2). Herein we report an effect of tolbutamide and other sulfonylureas on the spontaneous and nicotine- induced release of catecholamines from isolated cat adrenal glands (3) and on amide amkte tolbutamide ((0.2 mM) (1mM) (1 mM) Fig. 1. The effects of four sulfonylureas on the release of [`HINE induced by nico- tine in isolated guinea pig hearts, measured in disintegrations per minute. Release of [`H] was stimulated by a single injec- tion of nicotine. Five minutes before and after injection, one of the sulfonylureas or the vehicle used to dissolve sulfosylureas (control) was present. Asterigk denotes difference from control is significant at P < .001. NS., not significant. nicotine-induced release of (3H]norepi- nephrine ([3H]NE) from isolated guinea pig hearts (4). These observations sug- gest that sulfonylureas have a direct inhibitory acfion on the sympatho- adrenal system. Isolated cat adrenal glands were retro- gradely perfused with phosphate-buf- fered Locke's solution, and the adrenal catecholaminc secretion was monitored by a modification of the procedure of Robinson and Watts (5). This experi- mental procedure has been reported in detail previously (6). The effect of tolbutamide on the spontaneous secre- tion of catecholamines was observed by perfusing the glands with Locke's solu- tion containing tolbutamide (0.1, 0.3, or 1 mM) for 5 minutes. To study the effect of sulfonylureas on the nicotine- induced release of catecholamines, each gland was stimulated twice by per- fusion with nicotine (10°M) for 1 minute. Five minutes before and 5 minutes after the first stimulation by nicotine, the adrenal was perfused with either tolbutamide (0.3 or 1 mM) or tolazamide (0.2 mM). The adminis- tration of nicotine was repeated 30 minutes after termination of the per- fusion with sulfonylureas and served as a control response. Endogenous norepinephrine stores in isolated guinea pig hearts were pre- labeled with {3H]NE. Hearts were stim- uated to release (3H]NE by single in- jections of nicotine (4 x 10-i mole) 20 minutes after [°H]NE labeling. The perfusate effluents from the hearts were continuously collected and analyzed for ~H]NE by liquid scintillation spec- trometry (7). To study the effect of sulfonylureas on nicotine-induced re- lease of myocardial (~H1NE, sulfonyl- ureas (tolbutamide, 1 mM; carboxytol- butamide, 1 mM; tolazamide, 0.2 mM; glybenclamide, 0.025 mM) were indi- vidually added to the perfusion fluid from 5 minutes before to 5 minutes after the injection of nicotine. The spontaneous output of catechola- mines from the cat adrenal gland usu- ally became stable 1 hour after the initiation of perfusion with Locke's solution. Tolbutamide (0.3 or 1 mM) caused a decline in spontaneous cate- cholamine output (see Table 1). This inhibitory effect of tolbutamide was re- versible. Nicotine-induced release of adrenal catecholamines was also sup- pressed by tolbutamide. When adrenal glands were stimulated consecutively at 30-minute intervals by the samedose of nicotine (10-°M for 1 minute), the response to the second stimulation was Table I. Effect of tolbutamide and tolazasnide on spontaneous and nicotine-induced release of total catecholsmines from isolated cst adrenal glands. Each gland served as its own control. The data sre expressed as percent of control. The number of glands studied is indicated in parentheses after the mean ± S.E.M. Catecholamines released Drugs (% of control) (mM) Nicotine- Spontaneous* inducedt Tolbutamide 0.1 95±2(3) 0.3 72±6(5)0 77± 5(4)0 1.0 62±8(5)0 56±10(7)0 Tolazamide 0.2 51 ± 7(3)0 IRate of spontaneous output is the presence of aulfonylurea (na/mis) divided by the rate of spontaneous output is the sbsence of sulfonylurea (ag/mis)] X 100. Control spontaneous ostpot was 230 ± 30 ng/min. 0 INicotine-isduced release is the presence of sulfonylurea (og) divided by nicotine-induced release in the absence of sulfonyl urea (sg) x 100. Control nicotine-Induced release was 12,210 ± 1,330 ng. I siguiflant at P < .01 Inhibition of Catecholainine Release by Tolbutamide and Other Sulfonylureas Abstract. Tolbutamide and other suifonylureas inhibited spontaneous and nicotine-induced release of catecholamines from the perfused cat adrenal gland and nicotine-induced release of [°H]norepinephrine from isolated guinea pig hearts. Of the sulfonylureas tested, the order of potency of this inhibitory effect paralleled the hypoglycemic action. These results raise the possibility that the inhibition of the sympathoadrenal system may contribute in part to the hypo- glycemic action of sulfonylureas. PAGENO="0309" COMPETITIVE PROBLEMS IN THE DRIJG INDTJSTRY 13559 only 60 to 70 percent of the initial response (data not shown). When tolbutamide (0.3 or 1 mM) was pres- ent only during the initial exposure to nicotine, the second response to nico- tine was then greater than the first. Tolazanside (0.2 mM) exerted a simi- lar inhibitory action (see Table 1). Nicotine-induced release of [°H]NE from the isolated guinea pig hearts was also inhibited by several sulfonylureas (tolbutamide, tolazamide, and glyben- clamide). The order of potency in in- hibiting catecholamine release by these sulfonylureas was glybenclamide> to!- azamide > tolbutamide (Fig. 1). Car- boxytolbutamide, a major metabolite of tolbutamide without hypoglycemic action (8), showed no inhibitory effect on induced 13H]NE release. In vivo studies have led to the postu- late that sulfonyluress may possess a direct stimulatory action on the adrenal medulla (9). Since epinephrine release is increased by insulin-induced hypo- glycemia (10. 11), the previous in vivo observations with sulfonylureas may be an indirect result of the hypo- glycemia following insulin release. The present in vitro studies demonstrate that sulfonylureas act directly to inhibit the release of catecholamine from the fe- line adrenal medulla and from the adre- nergic nerve terminals in guinea pig hearts. This effect of sulfonyluress was observed when catecholsmine secre- tion was stimulated by nicotine or other secretagogues such as glucsgon or KCI (3, 4). Pittman snd Hszelwood selected doses of insulin and tolbutamide which caused similar degrees of hypoglycemia in chickens and found elevated plasma epinephrine levels only in those snimals in which the hypoglycemia was induced by insulin (11). This absence of epi- nephrine release in response to tolbu- tsmide-induced hypoglycemia suggests that this drug probably inhibits adrenal catecholamine release in intact animsis. In general the metabolic effects of cstecholsmines oppose the sctions of in- sulin (12). Physiological concentra- tions of catecholamines are known to inhibit insulin release (13). It was in- teresting to note that for the two sul- fonyluress tested in cat adrenal glands and for the four tested in guinea pig hearts, the order of potency in in- hibiting catecholamine release paral- leled their hypoglycemic potency (1, 9). Results from the present experiments raise the possibility that this extra- pancreatic action on the sympatho- adrenal system may contribute in part to the hypoglycemic effect of sulfonyl- ureas. CHSJNG-YI Hsu, GARY BROOKER MICHAEL J. PEACH THOMAS C. WESTFALL Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville 22903 Reforenees sad Notes 1, 5, F. Pfeiffer, K. Sclsoffllng, H. Ditschuneit, IL Zeigler, is Oral Hylsoglyceeeic Agents, G, D. Campbell, Ed. (Academic Press, New York, 1969), p. 39. 2. J. M. Feldman aed H. 5. Lebovilz, Arch. lssern. Med. 123, 314 (1969). 3. C.-Y. Hsu, Fed. Proc. 33, 524 (1974). 4. , T. C. Westtall, M. 3. Peach, Phor- musologlst 16, 191 (1974). 5. R. L. Robinson and D. T. Walls, Cue. Chew,. 51, 986 (1965); R. L. Robinson, J. Pharmdcot. Exp. The,. 156, 252 (1967). 6. M. J. Peach, F. 1,1. `Sumpus, P. A. Khairallah, I. Pharmacol. Lop, The,. 116, 366 (1971). 7. T. C, Westfall and M. Brasled, Ibid. 182, 409 (1972). 5. 3. M. Feldman and H. 5. Lebovitz, Diabetes 18, 529 (1969). 9. A. BOnder, Aust. N.Z. I. Med. 5 (Suppl. 2), 22 (1971); W. E. Doling, E. H. Morley, 1, E. Nezamis, Proc. Soc. Lop. Blot. Med. 93, 132 (1956), 10. U. S. von Euler and R. Lutl, Metabolism 1, 528 (1952); A. Goldfien, M. S. Zilch, R. H. Despointes, 3. 5. Brthsne, Endocrinology 62, 749 (1958). II. R. P. Pitlman and R. L. Hazelwood, Comp. Blochem. Physlol. 45A, 141 (1973). 12. 3. W. Enslsck and R. H. Williams in Handbook nj Physiology, sect. 7, vol. 1, Endocrine Pancreas, D. E. Steiner sod N. Freinkel, Eds. (Williams & Wilkins, Balti- mote, 1974), p. 665. 13. 0. Forte, Jr., and R. P. Robertson, Fed. Proc. 32. 1792 (1973). 14. We thank Drs. W. 5. Doling and K. Gun. deesen ot the Upjohn Company toe supply- ing the sultonylareas used in these studies. Supported by NIH.NS 10260, PHS NHLI HL 12706, NIH P17 AM17042.Ol, und Hoff. mann-LaRoche, Inc. 27 September 1974 PAGENO="0310" 13560 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY A STUDY OF THE CHRONIC EFFECTS OF TOLBUTAMIDE IN THE RHESUS MONKEY FDA # 72-114 By: Jayme Borensztajn, M.D., Ph.D. Arthur Rubenstein, M.D. Assistant Professor Professor Department of Pathology Department of Medicine University of Chicago University of Chicago Godfrey S. Getz, M.D., Ph.D. Chung Hsin Ts'ao, Ph.D. Professor Assistant Professor Departments of Pathology Department of Pathology and Biochemistry Northwestern University University of Chicago Seymour Glagov, M.D. Robert W. Wissler, Ph.D., M.D. professor Donald N. Pritzker Professor Department of Pathology Department of Pathology University of Chicago University of Chicago February 15, 1975 PAGENO="0311" COMPETITIVE PROBLEMS IN THE DRuG INDIJSTRY 13561 A. INTRODUCTION The aim of this project was to study the effects of chronic adminis- tration of tolbutamide to normal Rhesus monkeys maintained on an atherogenic diet. The rationale for carrying out such a project was derived from the observations of the University Group Diabetes Project which suggested that diabetic patients treated with t~lbutaznide had an increased incidence of fatal events related to myocardial infarction when compared.to patients managed on placebo or insulin (1). These studies raised the possibility that tolbutamide administration might accelerate the development of atherogenic processes. To test this possibility the Rhesus monkey model was chosen because of ample evidence showing that atherosclerosis can be produced in this species by simple dietary manipulations, and that the qualitative aspects of the resulting lesions closely resemble atherosclerosis in man. The "Average American Table Prepared Diet" was used for this study because it was considered to be better to use a relatively mild (and slow) atherogenic dietary regimen if one wanted maximum opportunity for a drug to show either a positive or negative effect. Furthermore, it was thought beat to work with dietary ingredients similar to those that people in `the U.S.A commonly consume. Three chronic (2 year) experiments `conducted in this laboratory over a ten year period have indicated that this ration `was well accepted by the Rhesus monkey and consistently. resulted in mild to moderate atheromatous change with blood lipid levels not too far above levels commonly found in people consuming this type of diet. PAGENO="0312" 13562 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Study of coronary artery lesions The coronary artery sections were taken at nine predetermined sites in the main coronary artery (Figure G.6.) and were sectioned on the freezing ~CO2) microtome and stained wjth Oil Red 0 for fat. The other nine adjoining sections that were obtained from the sane sites were embedded in paraffin and stained by hematoxylin and eosin and Gomori trichrome aldehyde fuchsin. They revealed a very unexpected and disturbing trend; coronary artery lesions in the treee main coronary arteries were almost two times more frequent end al- most exactly three times more severe in the tolbutamide-treated animals than in the control animals in relation to the amount of lipid deposited in the intima and media (Table G.6.) ~* The intimal proliferation noted in the coronary arteries of the tolbutaxside tested animals was also somewhat more severe than in the controls but this difference was not statintically signi- ficant. Figure G. 7. presents photcasicrographs of average types of coronary lesions stained for lipids in paired animals. Lower and higher magnification in the same lesioOs shows the intimal proliferation and lipid deposition in sections of the two types of monkeys. Moderate intimal proliferation and lipid deposition in the intimas and innermost media can be Seen in animals treated with tolbutamide. Pancreatic islet evaluation The pancreatic islets of those animals were carefully examined by means of two stains, the Gomori trichrcsne-aldehyde-fuchsin stain and the ~ciuori chrome alum hematoxylin stain. These histological preparations were made from three Bouin's fixed complete cross sections of the pancreas, taken from its tail, body and head. *The detailed microscopic evaluations for these coronary lesions as done independently by each pathologist are presented pair-by-pair in Appendix IV. PAGENO="0313" TABLE 81. PLAN OF THE ~PERIMEffl~ IN RHESUS MONKEYS FEB AVERAGE ANERICAN DIET WITH OR WITHOUT TOLBUTNIIDE G1~OuP ~ NUMEER OF ANIMALS DIET FED FOR A PERIOD OF 18 frONT-IS . j 9 (7)A AVERAGE AMERICAN flIEr - 250 G/DAY . II 9(7) AVERAGE AMERICAN Din- AND TOLBUTAMIDEB ~ 20 MG/KG/DAY - PAIR FED 0 0 w ~J2 A. THE EXPERIMENT WAS STARTED WIT-i 9. ANIMALS PER GROUP1 BUT 2 ANIMALS DIED AT 1~4 MGNTHS AND THEIR CONTROLS WERE AUTOPSIED AT ThE SAME TIME B TOLBUTAMIDE - UPJOHN COMPANY PAGENO="0314" Ti\RLE G.6. CD 0 0 02 L~i 02 MICROSCOPIC. FINDINGS IN CORONARY ARTERIES OF RHESUS MONKEYS FED. AVERAGE kiERICAN DIET WITh OR WITHOUT TOLBUTANIDE GROUP No~ OF PNIW~LS . DIET . . . .FREQUENCY~ . . SEVERI~~ . . . II .., 9(7) . 9(7) . A\~ERAGEARERICA DIET AVERAGE P~1ER!CAN DIET ... : .~ AND. TOLBIJTMIDE . . 31±6~3 . : 65+~~5 . .. . . . O~18±O~O3 . O~56÷O~O6 . p. i. "Rarely, it may be necessary' to stop thl~Sidè therkpy before ~hyptdtalemla' can be alleviated." S S ` j. "In states of pre-coma of hepatic origin, thiázide dltitètics' ma~~ trecitltate coma~" The promotional text of the advertisement contSin5s 1!~tulty "and `xhisleadii~g representations as follows: ` `. `/ ~, `~ ` ~` 5' a. The claims that the use of Salutensin will "get blo~ preoSu~e~dow5n so~u- er" and that `use of Salutensin will yield "iliore ~ ilyper- tension," than "just thia~Mde-rOserpine" have not been' approved foi~ labeling, nor is there evidence in the New Drug Application to support theth. ` b. Referring to the combination of thiazide, resei~pine and protoveratriné~'A the ad states: "Clinically, the advantages of such ,a combination have~ been summed up as follows: `The concomitant use of résérpine and the' thia~idOs and veratrum' has greatly Widened the therapeutic `and to~ic rahge, niaking veratrum more effective and simple to administer *` * * `~tt is unfortunate that more physicians `do not take advantage of veratrum,' thlazlde, tind reser~iné to' lower the arterial, pressure simply, ~effectively and without ~ide effects," Tj~te ad uses referenCe #2 (~`innerty) foi' the two-senténCe,statemhnt `quoted above. Such statement Is objectiOnable for the following, reasOps / " (1) The reader is led to believe that Finnerty iise5d ~ iti 13i5 study In fact, he prescribed Veriloid (alkavervir) `and' Unitensin (`eryptena~ mine)'. (l~rotoveratrine A iS a, purified single alkaloid `Isolated from' ~er~trnm album. Alkavervir is a partially tiuriflOd extract epntainiug a thixture of alka- loids, obtained from Vertitrum viride. Cryptetianhine is an alkalOid `derived from an extract of Veratrum viride.) , ` `~ ` " (2) The ad misleads by quoting Finherty out pf co~itext. The' i~e~der i~'led to believe that the author waS advising th'e'reader `th~t t~ comblhia'tloti `of vera~ tr,um, reserpine and thiaziçle lOwers blOod ~ressiire~'ef~etiveiy aftd tt~ilhont~sitle effect when a "simple" dosage' sch'edtile, `supposedly like tb~ öné `Bri~tOl `reconh- mends, is followed. A review of Finnerty's artlcI~t' SlibW'ed thIs ~i~t "to be'~tbe case, for in the `Several setitences lOCated betwehtC tIle two neiitØnces S tjuoted, the autjiOr gives these detailed instrtictlons: the patffiuit `~h~thd ~kt ~t~the 5s~the time every day the patient shotild hOt ett1~ fOi' tWO 1IOth~S attoS taking veM ttuin'; a gool beginning `dosage of `vth t±unl ls~'2 mg~ t e~t1hiés, a day, é.g~,' aftéy breakfast, mid~afternoon and at bed'Vihie~ and t~n `gi~aduaily~,tnci'ease~ over a~eriod ef `two to three' weeks-up tç~btit not e~ceediifg 4 mg. thteë times a day.' ` / ` ` ` ` .//~ ~ , `, `: ~ :` ` /5 ,~`:` / Also related to the problem of effectiveness and safet~r' ure the author S. ments elsewhere in his article that the tLt~Zh4è~' (eblortlalhd&ne~-~whiCh Incidenta'ly is not a thiazide) component of Ms eomttinntloti therapy was given in a sIngle 50 mg daily dose (note thi[t the reeOmzuehde~l dosage range fGr the hydrOllume~hiaStde in SalutetiSht"ih higher átid the' Scheduiè'perniit's"the' tloSb 56-592---Th------~22 PAGENO="0330" 13580 COMPETITIVE PROBLEMS ~N THE DIWG INDUSTRY of the diuretic to be given up to four times a day) ; that it was necessary to administer supplemental pott~ssium to those digitalized patients who had been given ~ trial oi~ other thiazjc~es-ot1~r thai~ chiorthalidone-to avoid ai~rbyth~ mias , that a marked increase in toxic reactions occurs when more than ~ O~25 rug. of reserpiiie per day is~ administe~'ed (note that the dosage rai~ge recoin~ mended in the package insert for the reserpine component in Saluteusm may be much higher than that recommended by Finnerty); that because mental depression from reserpine has resulted in suicides, monthly checkup Is man- datory; that the combinatlop of veratrum, thiazide and reserpine Is indicated in moderately severe hypertension,. and that be does not advocate the combina- tion in mild or severe hypertension. 21 UJ~.U. 352(f) (1) [Ileg. 1.106(b) (4)]: Salutensin ~s a prescription drug within the meaning of 21 U.S.C. 353(b) (1) (0) in that it is limited to prescrip- tion use by its approved new drug application. Accordingly, since adequate di- rections for lay use cannot be written for a prescription drug, it is clear that the labeling for Salutensin berç involved did not bear adequate directions for lay use as required by 21 U S C 352(f) (1) Furthermore, the Saluteusin in volved here was not Oxempt from 21 U.S.C, 352(f) (1) as provided for by regu- latiOns 21 CFR 1.106(b) since it failed to comply with the condition for cx- einption set forth in subparagraph 4(1) of such regulations. This condition requires that any labeling of a prescriptiOn drug shall contain adequate Informa- tion for use including lUdicatlons, effects, dosages, routes, methods and fre- quency and duration of administration and any relevant hazards, contraindi- cations, side etfect~ and precautions under which practitioners licensed by law to administer the drug can use the drug safely and for the purpose for which it is ipteuded and, if the drug is subject to 21 U.S.C. 355, the labeling providing such information shall be substantially the same as the labeling authorized by the approved new drug application for such drug. In the case of Salutens~n, examination of the Mailing Piece designated as "SH 3852 RV", which is labeling for the drug as described iii regulations ~1 CFR 1.105(1), has disclosed that such labeling Is not substantially the same as that which is set forth in the approved new, drug application for the drug. 1. ThIs mailing piece deviates substantially from the approved package insert labeling by failing to disclose the following side effects, warnings and precau- tions: a. Reduction of serum electrolyte concentrations may occur with Salutensin "resulting in hypochloremia, hypochloremis alkalosis, hyponatemia . . ." The warning in the mailing piece that "alterations In electrolyte balance . . . may occur~' does not clearly inform the reader that the electrolytes, sodium and chloride, can be depressed below normal levels to cause these potentially serious cljnical states. b If indicated potassium loss often may be easily replaced by including potassium-rich foods in the diet (tomato juice or orange juice or other citric juice, banana, etc.). Patients unable or unwilling to take fruIt juice may be given potassium chloride 1 Ow 2 to 4 tImes daily by mouth. Rarely, it may be necessary to stop thiazide therapy before hypokalepua can be alleviated c. Some patients may have "insomnia" and "nightmares." 2. The promotional text of this mailing pi~ce contains these faults:. a. The claims that the use of Salutensin will "get blood pressure down sooner", and that the use of Salutensin will result In "more successful management of hypertension , than lust thiazide reserpine lrrve not been approved for label lug, nor Is there evidence In the NDA to support them. b. This mailing piece also refers t~ the work by ~innerty (reference #2) In such manner as to mislead the reader. c The company's descri~tlon of the work by Smith (reference #3) exagger ates a claim for etflc&cy ~et~ fails to mention s1d~ effects reported by the author. (1) The reader is not told that the subjects in this study were hospitalized and had an average age of T7. years. Without this Information he' Is prevented from correetly ciraluating the. results ,Qf the author~ and from posing the ques~ t on of whether or pot these patleIits copid be expected to show similar blood pressure reductions on just one of the Ingredients of Salutensin, i.e. the reserpine. or the hydroflumethlazide. ` ` " (2) Further, the mailing `piece falls to reveal' that the physicians attending these patients were allowed to adjust the dosage of the drug within a range of 1 t~ 4 tablets, daily. Tbi~ ~tnformat1on Is clearly set out in the approved package hlsert. The failure. to reveal this in the' mailing piece Is misleading because the PAGENO="0331" COMPETITIVE I~ROBLEMS IN THE DRUG INDUSTRY 13581, headline implies that the results were obtained with "only one or two tablets t~ (lay." ~ . ~ ,~ ~ ~ ~ ~ ~ (3) The mailing piece does not show fair balance. It attempts to exaggerate safety with a quotation from one paper (Finnerty), but, in an attep~pt to exag~ gerate efficacy claims, presents the report by Smith without revealing that twelve of the author's 45 patients bad side effects such as nausea, vertigo, Weakness and dizziness while on Sajutensin, and that dosage in these cases had to be reduced in order to reduce the side effects. Further, the original Smith report~ In the NDA points out that several patients had side effects which were not "minimized" by reduction in dose and that two additional patients had side effects while on Salutensin; one with nausea, and another with abdominal pain. The Smith report shows that some patients on Salutensin experienced side effects on dosages (2 tablets daily) within the range recommended by the com- pany. Examination of the Salutensin Mailing Piece designated as "511 3919 RV-2" disclosed the following: 1. The information in this. mailing piece is lacking in its treatment of the drug's side effects, etc., as described above In the analysis of ma1~ing piece N~, 511 3852 RV. 2. The promotional section of this mailing piece contains the same faults as described above in relation to mailing piece No SIT 3852 RV plus additional errors concerned with the use of two additional research papers. a. The mailing piece misrepresents the work of Spiotta (reference #6, a~ report to Bristol Laboratories) and a graph "adapted from Splotta," * (1) The company seriously misleads by failing to tell the reader that the study represented by the graph was on only one patient. As evidence, see use of same graph in the enclosed October 1961 mailing piece which specified that this is the result of a study of a single case. What is more, there were only two patients In the Spiotta study who received serial additions of the ingredi' ents of Salutensin In the order shown in the graph, namely Saluron, protovera- trine A, and then reserpine. (2) The company fails to inform the reader that when all the Ingredients were added each of the 7 patients in this phase of this study was finally receiv- big 200 mg. of ~iydrofiumetblazide, 0.5 mg. o~ reserpine and 0.8 mg. of protovera- trine A per day (equivalent to 4 Salutensin tablets) and that not all of the patients were receiving the three components in the same order shown in the graph. The failure to disclose this is misleading because the headline in the promotional section of the. mailing piece implies that the graphed results were obtained with "only one or two tablets a day." (3) The company also fails to tell the reader that Spiotta studied additional patients who received only 2 of the 3 ingredients of Salutensin; that be found, for Instance, results with hydrofiumethiazide plus reserpine which were similar to those with Salutensin in some cases. Such information does not support the idea in the promotion that Salutensin is better than a combination of only two of its three components, and that protoveratrine A is needed for more successful antihypertensive therapy. It is apparent that the Splotta study (and it Is the only study in the NDA on the serial addition of each Salutensin component). involved an insufficient number of patients to warrant making any ~.sound judgment regarding the comparative efficacy claim which thu headline states "instead of just thiazide-reserpine, use Salutensin." b. The mailing piece presents the work of Thomas (reference #8, a report to Bristol Laboratories) and `a graph purporting to show the effectiveness of~ S~lutensin'in longstanding hypertension of moderate severity. The reader is led to believe that all 40 patIents received only Salutensin, and that the dose, as claimed In the headline of the promotion, was "one or two tablets per day" for all patients. On the contrary the approved package insert itself merely states the following about results with Salutensin in the Thomas study: * (1) "Thomas noted that In many patients It was possible to. eliminate' bydral- azine which patients had been taking peevionsly." (Emphasis added) (2)' "StatIstical analysis of the data indicated `that the supplementary dose of reserpine could be considerably reduced `while they were on Salutensln lii order to maintain satisfactory control of their hypertension." At least ten. of the patients were taking supplementary doses of reserpine (3) "A few of the patients required the addition of other antihypertensive (reserpine, bydralazine, inversine, Singoserp, c~bk~rothlazide) agents' with Salu-' tensin in `order to maintain satisfactory control ~of their hypertension." The "few" patients referred to above numbered at least ten. PAGENO="0332" 13582 COMPETITIVE PROBLEMS IN ~THE~ DRUG INDUSTRY U) "Sonte received as Iittl~ ~as 1 tablet daily others as much as 4 tablets~ daily, the dose being adjusted according to individual patient response as the study progressed." The headline in the mailing piece, however, ifivites the reader to believe that Thomas also found that the daily dose required to keep blood pressure down was"one or two tablets". Examination of~ the Salutensin monograph appearing In the 1965 edition of the PDIt reveal.s a third instance where. labeling is not substantially the same as that which is set forth in the approved new drug application. In the same way as described above at page 8, paragraph 1 in relation to Mailing Piece "811 8852 RV" this monograph fails to provide full disclosure Concerning the drug's side effects warnings and precautions. II-~Prostaphlin: 21 U.S.C. 352(f) (1) (Reg. 1.106(5) (4) )-Prostaphlin i.s a prescription drug and, as such, adequate directions for lay use cannot be written for it. It is quite obvious then that the labeling of the `Prostaphlin here involved di~ not bear adequate directions for lay use as required by 21 U.S~O. g5~(f) (1'). Fur- thermore, the Prostaphlin was not exempt from 21 U.s.C. 352(f) (1) as provided by regulations 21 CFR 1.106(b) ~ince it failed to comply with the conditions for exemption set forth in subparagraph 4(i) of such regulations. This condi- thai requires that any labaling. of a prescription drug shall contain adequate information, for use including indications, `effects, dosages, routes, methods and frequency and duration of athninistrati'ón and any relevant hazards, contrain- dications, side effects `and precautloils under which `practitioners licen~ed by law to administer the drug can use the drug safely and for the p1~frposes for which it'ls Intended. Further if the drug `is subject `to 21 U.S.C. 857, the labeling providing such info~mation `must be' substantially the ~ame as the labeling required as a Condition fOr the certification Of alich drug (Sea regulatIons' 21 CFR 146.2(b) and 146.4(a) ~1)). In the ease Of Prostaphiin, examination of the monograph for such' drug in the 1965 edition of the Physicians~ Desk Refer- ence, which is labeling for the drug as deScribed in regulations 21 CFR 1.105(1)', has disclosed that such labeling is not substantially the same as the labeling (package insert) which was submitted for purposes of obtaining certification. Examples of the omission of important items of informatiQn in the Prostaphlin mohograph In the PDR which are Contained in the package `insert labeling sub- mitted for purposes of certification are ~et forth below: `1. That `safet~r for use of the `drug In pregnancy has not been established. 2. That periodic assessment of organ system functions, including renal, hepatic nnd hemato~eVetic, should be made during leng-terni therapy with the drug. 8. A warning that anaphylactoid reactions to the drug' have been encountered. 4. A warning tkat hazards of anaphylaxis to patients with.' a history of peni- d111h allergy xr4ust be `balanced against' the prognosis if the drug is withheld.' The Prostaphlin monograph in the 1965 editIon of Physicians' Desk Refer- ence also differs from the package Insert labeling submitted for purposes of certification In that the monograph is `false and misleading because of the following: i The monograph implies that the drug Prostaphlin is safe and effective when used in accordance with the information' contained' in the monograph, when `jI~ fact thiS `monograph does not provide' all the information required i~or sa~C aild effectt~e use of the' drug because it fails to include the warnings referred to under the four points discussed in the' preceding paragraph.' `2. `The mono~ráph includes `the statement "No anaphylactie reactions have been encountered" `which statethCnt iscontrary tofact. , `3. The monograph tnclndeC th~' statement "Reactibns to' this penicillin ha~ve 1~een `infrequent ahd mild in' natiu~e". which l's misleading because of the `phrase 4'mIid in' nature." ` ` ` 21 `U.S.C. 852(1)'.-It Is ftrther alleged that Prostaphlin when introduced' lr~tO. interstate commerce wa~ `xnisbi~and~d within the' `meaning Of 21. U.S.C. ~52(1) in that it' was, represented as ~ drug composed ef a ~ertifiable antibiotic, namely sodium oxadilhin, and it was ~not' from a; batch with reSpect id which a' certificate or"release issued pursuant to Sectioi~ 857 wa~ in"e~ect *ith reSpect to sñ~b drug since the cettiuIcatd WhiCh was issued on Február~' 4~ 1965~ for' such `batch `had' bèeh obtained' throu~gh mfsrepreseiltation and Concealment of a ma- terial fact. The application for' `c~rtiff~atloh constituted a mlsrepreSeñtatioñ niid' was a concealment df a indterial' faci `in that it' purported' to be preCeded or ac~~ónipani'ed by- sj~ecimeiis of all labeling te be `used for suCh drug when' `hi fact PAGENO="0333" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1358* it failed to include the ~thonograph of said drug which appeared in the 196~ Edition of the Physiciaus' Desk I~ofei~ence. (See~21 CFE 146.2(b) and 21 CF~ 146.4(a) (1)). EVIt~EN~E OF VIOLATIVE SHIPMENTS On June 16, 1965, Food and Drug Inspector Joseph S. Slayton collected a sample of Salutensin from a lot of 72 60-tablet bottles which were held at McKesson and Robbins, Inc., Pittsb~irgh, Penilsylvania. A copy of an invoice and shipping records in the. forii~ of a motor express bill of Lading and/or freight bill showed that the lot had been received from the defendant's South Hackensack, New Jersey warehouse on or about 5/13/65. Inspector Slayton also obtained from Dr. James K. Spence of Pittsburgh, P~nnsylvania a state- ment that he is a regular subscriber of the publication entitled "The Antietican Journal of Cardiology." The doctor further identified pages 41 and 42 of the Salutensin advertisement in this publication bearitig a Noveffiber 1964 issue date. On January 17, 1966, Food and Drug Inspector Alfred M Levy obtained a statement from Donald J. Tie~rney, Production Manager of Fisher-Stevens, Inc. (Mailing Service for Bristol Laboratories) atte~ing to the fact that a total of 9,693 four page mailing pieces identified as SH 3852 RY and Sli 3919 RV-~2 and relating to Salutensin were mailed to ph~~rsicians in Pennsylvania; on May 26, 1964, and July 15, 1964. Actual samples ~of these mailing pieces were also iden- tified and furnished to the inspector. On October 29, 1965 Food and Drug Inspector Joseph P. Brochetti collected a sathple of Protaphliri from a lot of 10 48-capsule vials which Were held at McKesson & Robbins Drug Division, 445 Fort Pitt Boulevard, Pittsburg, Penn- sylvania. A copy of an irifoice, the bill ~f lading, receiving record and dealer's statement showed that the lot had been received from the defendant's Sotith Jiackensack, New Jersey warehouse on~or about September 12, 1965. * HEkEING Pt4ISUAET TO 21 TY.S~C. 355 Pursuant to the Notice of hearing regarding Salutensin dated August 9, 1965, Dr. Harold Frediani of Bristol Laboratories called the Food and Drug Administration's Buffalo District dfflc~ on August 11, 1965 `aid w~s prot1ded with d~tails concerning the ~peciflc charges involving representations in the medical journal advertisement of Novethbe~ 1964 and in the labeling referred to as mailing pieces S~I 8852 RV and SH 3919 RV-2. S S The Hearing Was orlgffiaI1~r scheduled for August 24, 1965 but wa~ subse- quently rescheduled at the request of the citee for September 7, 1965. The firhi's answer was in the f~r'n1 of a 16~age letter dated: September 3, I96~. The letter bore the ~ignatuie Of Hubert O~ Peltier, M.D., Medi(~al Direetdr Of IflristOl Lab- oratorlea This Wi'ltten ahswer denied all dllegatidrIs. It ~il1aintained that the advertisement' complained of complied With all pertinent requirements of the law. Likewise, the answer maintains that the mailing pieces invOlvOd contfiitied adequate directions and information for the practitiotier. The lirni contended that the Salutensin aèWertisem'ent in the November 1964 issue of the American Journal Of CardiolOg~T doti'stituted an "alerting device" when read by the physi- cian, and further referred the physician to the official package circular. The interence was that the advertisemefit "in its entirety" included package insert information not present in said advertisement. The firm likewise denied that the mailing pieces SH 3852 RV and Sil 3919 RV-2 failed to contain full dis- closure relative to side effects and warnings, etc. They contended the pertinent information given was all that a physician needed in order to use the drug; and that Only unnecessary elaboration coiltained in the official'package circular had been omitted. Throughout the written response, the firm contends and infers that many of the cautionary and warning statemetits, (although present in ap- proved labeling), are superfluous and would not be needed by a physician, who would be aware of these omitted statements. The answer further indicated that the respondents would appreciate meeting with appropriate persons in the Washington headquarters o~ the Food and Drug Athflinistratlon to discuss the matter with a view toward preventing such futuredifferences. S Representatives of the firm met with Food and Drug Administration officials in Washington on October 11, 1965. The majority of the violations were dis- cussed and the firm promised corrections in `both future Salutensin advertise- ments and mailing pieces. PAGENO="0334" 13584 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Pursuant to the Notice of Hearing regarding Prostaphlin dated November 4, 1965, and setting the Hearing date for November 17, 1965, the firm submitted an answer in the form of a four page letter dated November 16, 1965, signed by Hubert C. Peltier, M.D., Medical Director of Bristol Laboratories. The firm's answer, in essence, denied the charges made by the Government. However, it also included a somewhat corrected galley proposed for the 1966 Physicians' Desk Reference relative to the Prostaphlin monograph. CONCLUSIONS We believe that the factors which have 1~een set forth in some detail above show that the labeling and advertisements used by this firm have not met the standards required by law. The omissions and deceptive statements involved were numerous and serious. Moreover~ the required warnings were already well known to the company. As to Salutensin they were set down in the New Drug Application labeling and as to Prostaphlin they were included in the labeling submitted prior to antibiotic certification (package insert). In drug advertising the law does not provide for product ~outing, or "puffing" when it entails a com- promise in the requirement of full disclosure. The advertisement and mailing pieces involved in the Salutensin charge are replete with half-truths designed more to boost sales than to provide a physician with the information essential to the proper and safe prescription of that drug. As to Prostapblin not only did the company fail to submit the Physicians' Desk Reference labeling as part of its request for batch certification as specifically required by regulations (21 CFR 146.2(b)) but the monograph which it did place in the Physicians' Desk Reference was at serious variance with the existing approved package insert. More oversight or carelessness cannot excuse the violations complained of here. The manufacturers of potent drugs, better than others, know the potential haz- ards of their products. Busy physicians should. and must be able to rely on statements concerning a product without referring back to the original source to look for inconsistencies and contraindications. We believe the prosecution is fully warranted. WITNuSSES The principal witnesses in this case will include the government inspectors who collected samples of the two drugs involved; witnesses to establish the interstate shipment of the drugs, the Issuance of the PDIt,' mailing pieces. and advertisement; medical officers from the Food and Drug Administration's Bureau of Medicine who will testify concerning the approved New Drug Appli- cation for Salutensin, the certification for this batch of Prostaphlin, the* ap- proved labeling and the seriou~ nature of the alleged misbranding. It Is requested that if the form of Information l~ amended, that the United States Attorney furnish us with a copy thereof, and that we be kept advised of the progress and disposition of the case. Upon request, we shall render every further assistance. Very truly yours, WILLIAM W. GooDRICH, A8si8tant Genei~al Counsel, Food and Drug Division. MARcH 26, 1969. Re Bristol-Myers Co.-Alleged Violation of the Federal l~ood, Drug, and Cos- metic Act, F.D.C. No. 52397 Mr. WILLIAM W. GooDRICH, Assistant General Counsel, Food, Drug, and Environmental Health Division, Department of HeaZth~ Education, and Welfare, Washington, D.C. DEAR Mn. Goomucn: We have carefully considered the request for prosecu- tion of the above-mentioned company for alleged violations of the Federal Food, Drug, and Cosmetic Act stemming from its promotional activity in the field of advertising and labeling for the drugs Salutensin and Prostaphhin in 1965. Since this mattel- was first referred to us the triul of the Abbott case, while unsuccessful, estabflshed a judicial precedent for the Government's contention that the monographs appearIng in the Physicians Desk fleference are labeling. We understand that the Bristol~M3rers Co. and the industry in general have accepted this determination and have been more careful to make c~rtain that PAGENO="0335" COMPETITIV1i~ PRO13L]~M~ IN TIlE DR~YG INIILYSTEY 135~ the monographs closely correspond to the approved labeling. In addition, as a result of the Court's interpretation of the phrase "~ubstan'tially the same" a~ used in the former regulation ~21 C.F.R. 1.105) the agency has c1iange~1 the regulations under which the labeling violatiOn would be l~rought. This, o~ course, is also applicable in the case of the mailing piece, the use of which was claimed to violate the labeling regul~tions~ Thus, the institution of the criminal action requested would not serve any useful purpose in obtaining a judicial interpretation of the present labeling regulations or as to what constitutes labeling, Any prosecutions based upon the advertisement of Salutensin in the medical publication for November, 1965, must be predicated upon the regulation which was in force, at that time. This prosecution would necessarily involve certain contentions relative to the meaning of the statute and regulations with refer- ence to practices which are not distinctly set out therein. Inasmuch as the agency Is in the process of issuing new regulations which will clearly and in detail inform those subject thereto concerning what information is expected to be included and what conduct is prohibited, it is our opinion that the agencys interpretation of the statute can be best advanced by defending any judicial challenge to the issuance of the regulation, or if none is forthcoming, by bring- ing either a civil seizure or a criminal prosecution based on acts occurring after the regulations have become effective. The institution of previous criminal proceedings has made known to the In- dustry that this Department intends to make use of criminal sanctions for enforcement of the labeling and advertising provisions of the statute whenever it is necessary to do so to prevent the use use of Improper promotional materi- als. Industry publications contain accounts of instances In which dru~ manu- facturers have, after consultation with agency rep~esentatlves, circularized the medical profession calling attention to improper advertisements or mailing pieces and correcting any misstatements therein. Representatives of the subject company have stated that It has ma~de an effort to comply ~vtth the'regulations and intends to do so in the future. They have protested that a misunderstanding as to what practices constituted a violation was possible under the regulations then In force and that Bristol- Myers' violation was occasioned by such a mistake. Accordingly, we do not' believe that the suggested criminal prosecution Is required to obtain judicial detei~minatlon as to legal contentions of the agency or as a necessary aid to enforcement of the Act and regulations. Therefore, prosecution is declined. While we stand ready to use any of the enforcement procedures prescribed by the statute to Insure `that prescrl~tIQn ad~ertlsing flt~ the requirements, of the statute and the regulatlOn~, candor requires us to observe that `In those in~1ances where we have secured criminal convictions for thI~ type of violation, the penalties imposed by the Courts have not been such a~ to provide effective deterrents. On the other hand,' the technique reCently employed by the~ Com- missioner of Food and Drugs, about which we have read in the trade media, appears to, provide, more ass~irance of future compliance on the part of, those Companies `subject `to the regulations. It seems obvious that an ethical pharma- ceutical company will regard the so-called ,Dear Doctor iette~ as a more oppro- brious experience than any other available enforcement measure, particularly since it has not been the Commissioner's practice to recommend for prosecu- tion the responsible individuals Of tile offending corporations. We urge that the Commissioner of Food and Drugs continue to utilize this technique which he has~ stated has proved very effective? while resorting to civil or criminal l1ti~ation only in respect to those, recalcitrant offenders, if any there be, as to whom other measures have proved ineffCc,tIve~, If the Government can shOw that prosecution is resorted to only in such circumstances, the Courts may well adopt a different attitude in lmposingsentence. We are closing our file on this matter. Sincerely, WILL WILsoN, AssiBtGnt Attorney Ge~eraZ, UriminaZ Division. By ILu~oLn P. SHAPm0, CMej' Adntin,istrative Reguk~tions Election. PAGENO="0336" 13586 COMPEI'ITIyE PROBLEMS IN T~IE DRUG INDUSTRY S JaNUARY 17, 1967. ~n re~y re~r t~, F.~.C. ~ ` ~ ~T~Q~1~Y `~N~RAL, : Dep~ti~nen~ `qf~ Jn$ti~e,~,L. S S `Wi~~~on, D,U. , , S S S DE~R MR. ATTORNEY GENERAL: We request the inStitution of criminal `pro- ceedings in~der th~ `Federal Food, Drug,' aiid Cosmetk~ Act, against Rexar Phar- ~naca1 Corporation, `B~rookLyn, New york, Mr.' Armin Rosner and Mr. Martin Benjamin. ` S S The offenses complained of `occurred during the' period from about April 18, i964, to about October 1, `1965, an~d invoTve the int~odiiction into' interstate corn- meI~ce at Brook'yn, New YoI'k, for .deThrery' to Teaneck, Fort Lee and Paramus, New jersey, of Oby-Rex tablets and'~ttme disintegration capsules and Obetrol tàblet~. "~ ` There kre transmitted'heirewith a suggested form of criminal informatioi and `the folltwing exhibits ` ` S , (1) Copies' of Notice `of Hearing. ` ` ` ` ` ` (2) Copies of bottle labeLs~fo~r Oby~-fl,ex and Obetrol tablets. (3) Copies of package,' hisert labeling (the approved New Drug Application hi'belixtg) for Obetrol5 tablets. ` ` ` S (4) Copy of the advertisement for Obetrol tablets Which appeared in Modern Medicine for September 13,?1965. S ` S `SECTIONS ON THE ACT INVOLVED `~he ~p~çrth ion thai~ges:, fpur violations of 21 U.S~C. 331(d) in that the f~4ntt~ .eaused4~e iutrod*ction into interstate commerce of new' drugs, the "Ob~~ ça~sules and t~b1ets,, wb4cb was in violation o~"2i U.S.C. ~55(a), `since `ho apptoval' of an, application filed, pu-r~ant to 21' U.5C~ `3~5(b) was effective with resp~ct tq the 4rugs.. ,~ , S , ` S S 5 5 * ~he `Information al~q~al1eges,jn one ~ount that t~efQ~etro~ tablets were mis- branded within t~e'mehnipg of 21 IJ~S~Q., 352(n) in that the' defendants failed to include in tl3e advertisement caused to be issued by tben~ with respect to',the drug in ~Uie September 13, 1965,' issue of `the Mpdern Medicine~ a true statement of information `in brief swnma~y relating' to shje effects and contraindications and effectiveness of such drug~ as `require4 by regulations 21 SC~R 1~1O~(e.). and (f)(2).' ` S ` ` ` S ` ` S REASONS FOR INVESTIGATIONS S S On July 24 1959 tb~ ft~m i~ec~ed an appiove~ New Drug Application for `~ prodijic~ ~coown ,a~ O~etr~I ~aMets in .10 ai~id, 20'z~ffligra~, s1~rezigths. Obeti~ol cous~sted of a combmat~on.pf sour 4ifferen1~ apipheta~ine s~lts in equ~l ~tr~ng~s as'fd~bws ~etliampI~et~u~ije ~acc1lamte ~ethaIr1pb~ts~pine Hydrochloride 4fltpbelamine Sulfate DE~rQ ~mpbeta~nme Sulfate Qbetrol, `was the trade name u~ed wher~ the drug was 5°id to whol~alers while Oby Rex was the trade name used when the same drug was ~olcl to doctors. The drug i~ill be referred to á~ "Obêts'ol" in the letter in the inte~'est of clarit~'. ` `, ` 5 ,, 5 Ii~ 1962, the F9od and D,~ug Administration learned that tb~ firm was dis- trib"u'ting a'. 30 milligram tab,lOt, and' caj~sule under the ,nam,ë of "Obetrol" `with- out a, supp'ementaL New Drug Application. lowever, there was no eVidence that `the firm was sbipp1~g this drug in interstate commerce at that time. On February 6, 1963~ Food and Drug Administration Inspector Ernest ,Schn*lz inspeèt~ed this firm and learned that it was still manufacturing the 30 milligram ,Obétrol cáp~ules and tablets, but apparently not shipping the drug in inter~tate `commerce. Mr. Armin Uosner, tile President of the ~lrm, was asked by the in- ~pector about the 30 milligram dosage form and his i~easOns for not filing a New Drug Application or a supplemental New Drug Application fo~ these prod- ucts. Mr. Rosner replied that he was of the opinion that the New Drug Applica- tion for Obetrol allowed dosage~ up to 60 milligrams per day. He pointed out that the directions for use for fhe 30 milligram tablets provided that the daily dosage fell within this range. He, therefore, questioned the need for submitting a supplemental New Drug Application or a second New Drug Application for the 30 milligram dosage form. He was advised by Inspector Schmalz to discuss this matter with the Food and Drug Administration's New Drug Branch in Washington, D.C. PAGENO="0337" CO~4PETITIVE PROBLEMS.. IN TH~ DRUG INDUSThY 13581 On Augusl~, 4 and 5, 1964, Fpq~an4 Drug Administration In~pectors ~Jarl ~, Lorentzson and Cbar1e~ Thorne ii~speete'd the firmand learned that~ it' wa~ stl~1 znarn~facturing the 30 milligram Qbebroi ~tablet and capsuleand shIpping it'. i~ interstate commerce without an~apprO\red New Drug Apf1b~ation., ~ ,~a up to this inspection, the Food and Drtig Adniinistration ~o1lected ~ 30 milligram Obetrol time disintegration capsules and tablet~ In interState commerce. (Counts I and U) `. S Ln the spring of 1964, the firm submitted a Supp1e~en1i~'l New Drug A~pli~a# tion. At that time, it came to the attention of the Bureau `of Medicine ~tthØ Food and Drug Administration that the firm was advertising lt~ 10 and 20 milligram Obetrol tablets with the use of ~false and~ misleading claim ~Sbmé of the objections raised by the Bureau of Medicine to the fiI'In"s adv~rtl~1ug were as follows: . S S S (1) It failed to list Obertol's side effects" `` ` `: S (2) It implied that Obetrol was unique in that it was safer and more e,ffec-5 tive than other amphetamines. Thia `claim `was unsupportable âñd illogièal. (3) It claimed that Obetrol was effective in "difficult cases," where~, `the two papers referred to in the advertisement did not demon~trate~ this fact.' In addition, these two papers contained identical cases, were writtei~ by' the same authors, but were published in two separate journals. S (4) It invited the misuse of the drug without proper r~gnrd' fOr patient- safety by quoting, out of context, in such a way as to conceal the fact that some patients could not tolerate the drug at all, and others found it necessary to reduce the dosage, to avoid dangerous side effects. ` (5) It tampered with a direct quote thr~ugb the insertion of a phrase,, a wrongful act aggravated (a) by' the fact `that `there was' no ififbrmation in the author's article justifying the idea suggested' in the `inserted phrase; and (b) by the fact that the tampering invited a dangerous over-çonfi~ience' In the use of Obetrol in cardiovascular patients in whom the drug was contraindleated. The quote from the author's article reads as follows, wilh. the Words the defendants inserted being in brackets: "In the cOoperati~0 ~atithat (Obetro]] was markedly befleficial in producing the desirable Weight lOss ~vjth mi4tmal side effect5,'~ven In [the cdsO of a high j~rçentage of $tlebthj With cardthvas- cular and other chronic ailments `which [r1orthally'1 make use of other a~phetá~ amines lmdesitable because of t1de,eftOcts.'~ `, S * ~, , , ` ~` On August 4, `1l~64, Mt."Armin Rosner am,~ his átt~rne~ n~et With ye~tesenta~ tives of the 1~ood and Drug Administration and' were advised to discontinue their' current advertising campaign with respect to Obëtrol tablets., The firm then advised the representatives o~ the Food and Drug Administratiok that It manufactured and sold a 30 milligram Obetrol tablet and capsule without an approved New Drug Application, since it was of the opinion tb~tt the subx4ission of a New Drug Application was not necessary, as it was selling this' drhg di- rectly to physicians. S ` In a letter dated August 12, .1964, from Rexar Pharmacal Corporation'to the ~ood,and Drug Administration, the firm promised to discontinue all `advertis- ing of the Obetrol 10 and 20 mg. tablets and to discontinue the manufa~turè. of' Obetrol tabletS and capsules `in excess of 20~ milligrams. The firm then pro- posed a revised labeling as part of, its supplemental New' Drug Application for Obetrol tablets, The final l~beling for the drug was approve4 by the Food and Drug Administration on `July 13, 1965. Shortly after the labeling was approved, the Food and Drug Administration learned that the firm had once more reinstituted an advertising and prthtto- tional campaign for Obetrol. The firm placed an advertisement ja the Septem- ber 13, 1965, issue of Modern Medicine, which did not state in brief summary, oi at all, those precautions as set forth in the approved New Qrug'A,ppli&Ltion labeling for the drug, which were, pertinent with respect to the use recommended or suggested in the advertisement as required by. the regulations 21 CFR 1.105(e) and (f) (2) in that, the, brief s~mm~ry failed to state that the d~ug should be uSed' with caution in indh'iduals `With anoxeria, insomnia, vasomotor instability, asthenia, psychopathic perspnality, a ~i~tory of homicidal or nuicidal tendencies, and Individuals *ho are ktiowii to be hypera~tive to' `sywpàtbom,i~ nieti~ agents or emotionajlyunstalle indivldual$ who are known to be suscept- ible tO drug abuse,;"and that certalumOhoamilie oxMasq lnh~bitors may ~o~en- tiate the action of Obetrol. Consequently, the~ rood and Drug Administration collected a sample of Obetrol (Count V). The defendants may claim that since the advertisement in Modern Medicine contained a brief summary of side effects and contrainclications, as set forth PAGENO="0338" 13588 COMPETITIVE PROBLEMS IN THE D1~UG INDUSThY in the approved New Drug Application labeling, they have not violated Section 502(n) o~ th~ Act,~ no.r ~egu1ations 21 OFE 1.105(e) and (f) , as these sections and regulations only require a brief summary of side effects and contraindica- tions as set forth h~ the approved New Drug Application labeling, no mentloii being made of precautions. We. believe that "side effects" and "contraindications" certainly include "pre- cautions". as this word Is used In the approved New Drug. Application labeling. Congress clearly' intended that . prescription drtig manufacturers should provide physicians with adequate warnings in prescription drug advertisements of those conditions In which use of the drug entailed a high degree of risk. It is pure sophistry to contend that Congress wanted physicians' to be warned of side effeet~ gn'd ecintrajudications as `se~ forth in the approved New Drug Applica- tion labeling, but not to be warned of the "precautions" ~s set forth in the approved New Drug Application labeling. On September 29, 1965, Food and Drug Administration Inspector Paul T. Wiener inspected this firm and learned that It was still manufacturing and shipping In interstate commerce 30 mg. Obetrol tablets without an effective New Drug Application. As a follow-up to this inspection, the Food and Drug Administration collected two samples of Obetrol 80 mg. tablets in interstate commerce because the article was a new drug without an approved New Drug Application (Counts III iind IV). iiisiosr or FIRM ~ND INnIVIDUAL5 This firm flr~t came to th~ attention of the Food and Dr~ig Admiflistration in early 1953 when the Connecticut State Division of Drugs, Devices, and Cos- metics referred a sample of dextro amphetamine sulfate to the Food and Drug Administration's Office because the label declared a fictitious name and address of a manufacturer. The manufacturer and ~hipper were believed to have actually been Rexa.r Pbarma~al Corp. As .a result of this complaint, an initial inspection of the firm was made on March 11, 1953, which disclosed `that the firm was operating with poor manufacturing contrái conditions. The original sample which bore the fictitiOus name and address of the manufacturer was assayed and, found to contain only 72% of labeled amount `of dextro-amphetamine sul- fate. However, the sample was placed in perpianent abeyance because it could not be dofjnjtely"ascertained that the sub$ct firm was the manufacturer. and distributor of these amphetamine tablets. The firm u as again inspected on December 15 1953 at which time according to Mr Armin Rosner the firm ~ as doing a minimal business The firm was not then shipping its drugsin interstate commerce. The firm was inspected once more on February 15, 195~, at which time it was learned that the firm was manufacturing Obetrol. a new drug, without an eff cclii e New Drug Application and shipping the drug while using false and misleading claims. As a follow-up to this inspection, a sample was collected which resulted in a Hearing on September 28, 1956W The sample was placed in permanent abeyance, however, because the firm agreed: (1) to revise its label- ing in an eftort to bring the drug in compliance with the law, and (2) to submit N~w Drug Application for the 10 and 20 mg. Obetrol tablets. The fli~m was inspected on .~Tuly 25. 1955, at whjch time it was learned that tia firm was shipping another new drpg namely Obertina tablets a combine tion of amphetamine and rauwolfia serpentine without an effective New Drug l~pplication Nowever the Food and Drug Administration could not obtain a s~trnple of the product in interstate eon~mpr.ce and. no aetlon was bi~ought. A follow-up Inspection, made qn July 8, 1958, showed that the firm was mark- ing time while its New Drug. Application, for Obetrol was under study by the Food and ~rug. Adminictration. ` The firm was again issued a Notice of He~r1ng in early 1963 because it had shipped a new drug' consisting of thyroid and 30 mg.. of amphetamine salts withou1~ an effective New Drug `Application, At the time of the' Hearing, the respondent stated that a New Drug Application was unnecessary as the drug was shipped under, what the firm termed. a physician-pharmacist relationship.. The firm had made this. drug to. order, for one, physician. The number was placed rn permapent abeyance It was Its position that Rexar Pharmacal Corp was simply asked to fill a prescriptI~n for the physici~~i~ No further action was taken because' th.e firm agreed to discbhtlnue the interst~te distribution of this product.. . ` ` *. . .. . ` . PAGENO="0339" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13589 On February 6, 1963, the firm was again inspected and the Food and Drug Administration learned that the firm was distributing Obetrol tablets iii viola- tion of Its New Drug Application. A seizure was made of this drug in Los Angeles, California. EVIDENCE OF VIOLATIVE SHIPMENT Counts I and II This sample was collected on August 8, 1964, from J. Raymond McSplrit D.O., 703 Cedar Lane, Teaneck, New Jersey, by Inspector Frederick T. Merola. The sample was identified by Dr. MeSpirit, who furnished the Inspector with an invoice showing that thO drugs were shipped by Rexar Pharmacal Corp. from Brooklyn, New York on or about April 18, 1964. Counts III and IV This sample was collecled on October 5, 1965, from Dafliel Reider, D.O~, 2361 Lemoine Avenue, Fort Lee, New Jersey, by Inspector Paul T. Wiener. The samph~ was identified by Dr. Reider, who furnished the Inspector with an invoice showing that the drugs were shipped by Rexar Pharmacal Corp. from Brooklyn, New York, on or about March 1, 1965. Count V rlhis sample was collected on December 15, 1965, from D. Katzm'an & Co., 670 Winters Avenue, Paramus, New Jersey, by Inspector Alfred M. Levy. The sample was identified by Mr. Stanley Szewczyck, a buyer for the firm, who furnished the Inspector with an invoice showing that the drug had been shipped by Rexar Pharmacal Corp. from Brooklyn, New York, on or about October 1, 1965. On December `29, 1965, Inspector Levy obtained from Richard P. Keating, M.D., 130 Prospect Street, Ridgewood, New Jersey, the September 13, 1965, issue of Modern Medicine, together with an appropriate affidavit signed by Dr. I~eating. RESPONSIBILITY OF INDIVIDUALS Both Mr. Armin Rosner,' President, and Mr. Martin Benjamin, Vice President, share equally the responsibility for the conduct of the firm. During the Inspection of February 6, 1963, the Inspector observed that both men were familiar with the manufacturing and control procedures. They told the inspector they shared equally In the responsibility for making major decisions in the firm's opera- tions. During the inspection of August 3, 4 and 5, 1964, the Inspectors obtained information and specimens of the advertisements of Obetrol tablets from Mr. Martin Benjamin. At that time, Mr. Arinin Rosner told the inspectors that he considered the responsibility for operations of the fitm, Including labeling, ship- ping and sanitation, to be a joint onQ between himself and Mr. Benjamin. Both men, the Inspector noted, knew exactly what was going on in the operatlob of this business. During the Inspection of September 29, 1965, Mr. Benjamin told the Inspector that Mr. Rosner was in charge of plant sanitation, shipping and manufacturing operations and that Mr. Benjamin was active In sales and promotion. In the last three to four years, botl~ Mr. Rosner and Mr. Benjamin have dealt with the Inspectors either singly or together during each of the inspections made by the Food and Drug Administration. The firm Is small enough so that each of the two men was aware of what was going' on in the firm. In addition, they jointly set co~ipany policy and were equally responsible for the labeling and the advertising for the drugs which were, shipped in interstate commerce. HEARING HELD PURSUANT TO 21 U.S.C~ 335 A Notice `of Hearing was issued to Rexar Pharmacal Corp., Mr. Arwin Rosner and Mr Martin Ben)amln on January 10 1966 charging the shipment in inter state commerce of a New Drug, the 30 mg. dosage form of `Obetrol, without an approved New Drug Application. It was also alleged that the firm had mis.~ branded its Obetrol `10 mg~ tablets because of medical journal advertising which did not state Ill brief summary, or at all, certain side effects and con- traindicatlons as set forth in its approved New Drug Application labeling for the drug. Mr. Rosner and Mr. Benjamin, together with their attorney and con- sultants, appeared at the Hearing. The respondents first addressed themselves to the charge concerning the omis- sion of a precautionary statement In the advertising for the drug, Obetrol. They claimed that they `were guided by a press release issued by the Food and Drug PAGENO="0340" i!3590 COMPETmvE ?ROEL~M~ IN ~ DEUG INDUSTRY -Administratiop on No'~ember 23, 19~4, pertaining' to ~he info~matiót~ required in a brief stimmary. They also stated that the~ wei~e guided by other firms' advertising for similar drug prodhcta In additio~, they f~lt that the' context of the advertisements was geared for physicians, and since the doctors them- selves received other material, such~ as brOchures, the doctors undoubtedly v ould have some realization of the precautionary guides to be observed. How- ever, they admitted that they were ~vrong in. omitting the. premutionary state- `aents, and. they, assured' the Food a'nd Drug Admiinstratlon that this error bad been corrected in the current advertising for the drug. The firm knew full well that the gravamen of the regulations was pertaining to prescription drug advertising. it had been warned In 1964 tha1~ its drug ad- vertising for this `product was false and misleading. It had di~cu~sed Vith the Food and Drug Administration the advertising drug regulations and bow to correct its advertising. Despite this information, the `firm blatently advertised this drug in the summer of 1965 without giving full inforinatioti as required by the regulations. The precau'tionar~ statements, which the firm omitted,. con- tained the moSt important information about the cautions to be observed in patients with anorexia, insomnia, vasomotor instability, asthenla, psychopathic personality, a history of homicidal or suicidal tendencies, and individuals who are known to be hyperactive to sympathomimetic agents or emotionally un- stable individuals who are known to be si~sceptible tp drug abuse; and that certain monOamine oxidasé inhthlto,~s rn~y potentiate ~`the action of Obetrol. With respect to the interstate shiptheñts of the Obetrol 30 mg. ,tab1et~. and capsules, the firm stated that, this drug was sold by the firm siuc.e 19~. Hence, the firm was `under the impression that the drug fell, within, the scope of the `grandfather ~lause" and a New l5rug Application was `pot nece~sary., UnfortwiatelV for the de±endants, the "grandfather clause" (Pub. L. 87-781, Section 107) requires `that the drug be generally recognised, as of October 9, 1962, as safe when used for the purposes intended. This drug was not so recog- nized on that date. The second point the firm made at this Hearing was that the' drugs were sold directly .to p~ysici~ns and,not through regular commercial channels. This, it said, was an ordinary `,`~hysi~ian-~har~naej5t" relationship, whereby the firm was simply filling a, pr~,scription for the physicianS The defense' fails to explain how .an ord?r i,nv~lvi~g some 3,QOQ tablets sold' to one physician and a 1,000 tablet order to a second physician is' the same as prescribing for an individual patient as j~ u,~ually done In the. pbysicjan's~ daily. practice of medicine. Another objection to the defendant's defense is that~ when~ there is a violatl~n of 21 U.S.C. 355(a), there is no exemption for any so-called "Physician-Pharmacist" relationship, As you recall, the ~1rst four counts charge a violation of 21 U.S.C. 855(a)~ The firm had been previously advised that this conception of theirs was wrong during the Hearing held in early 1963 The third point the firm made was that the 30 itig. tablets came within the limits of the, 60 mg. daily dosage requirements under their New Drug Applica- tion for the firm's 10 and 20 mg. Obetrol tablets. This argument had no merit since the ,New Drug Application provided for the marketing of a `specific formu- lation of the drug with specific labeling. The formulation and labeling for these 30 mg. preparations differed from that provided for by the New Drug Appli- cation, hence, these preparations were not covered by the New Drug Applica. tio~L. ` ` Lastly, the respondents stated that they were currently preparing to submit ~t New Drug Application for th'eir 80 mg. Obetrol tablets and capsules. This Application is still pending. The firm was well aware of our position with re- spect to the status of this drug. It was advised In August, 1964, that the Food and Drug Adminfstratlon considered these preparations to be New Drugs with- out an effective N~w Drug Application and was tOld that the Food and Drug Administration could not condone the marketing of this drug in interstate commerce without an approved New Drug Application. Yet, the firm chose to continue the sale of this drug without an approved New t'rug Application. It is noteworthy that, at the time of the Hearing, the firm indi~ated, thai it bad ceased distributing this drug in Interstate commerce, but that it was ~till sell- ing this drug in intrastate commOi~ce. CONCLUSIONS Warnings at Adrnini~trative Hearings and at meetings with the Bureau of ~tedicine of the Food and Drug Administration have gone unheeded by this PAGENO="0341" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 135ki firm. It had been advise~ as far back as 1958 that its 80 xr*g. Obetrol tablet and capsules were NeW Drugs. t~espite this warning, the firm still faile~d to flu a NeW t~rug Application for thes~ cI~ugs and continued td ship them in inter~ state commerce Without an apprb~ed NCw ~~rug Application. Sjmila~ly, the firn~ was advised in early i~64 that its advertising for its Obet~,ol 10 and 20 mg. tab- lets was false aild misleading and that it could only advertise the drugs through the use of claims set forth in the labelitig approve~1 in the firm's New Drug Application. While It is true the firm discontinued advertising its 10 and 20 mg. Obetrol tablets until the new labeling for these drugs was approved in the summer of `1965, the firm started to' il1~gal1y advertise again as soon as the final printed labeling had been approved. T~h1s time the firm omitted the pre- cautionary~ statements wl~ich relate to the side effects, contraiiidications, and effectiveness required to be 1~air1y ~resente~l iii the advertising by the regulations under the drug advertising sectioh of the law. It is onr opinion that prosecution ~f the firm and the two responsible individuals i~ fully warranted. WITNESSES rp~~ principal withesses in this case will be the Government inspectors who collected the samp1e~; cooperating physicians who subscribe to Modern Mcdi- cine and' medical officers of the Food and Drug Administration's Bureau of Medicine who can testify as to the approved New-Drug appiicatious, approved labeling, and the serious hature of the alleged medical journal advertising misbranding. It is requested that, if the InfOrmation is amended, the United States Attorney Lurnish us with a copy thereof; also, that the United States Attorney keep us advised of the progress of the case and its disposition. The New York Djstrict of the Food and Drug `Administration will arrange for the presence of the necessary' witnesses and assist in the presentation of the case. Upon request, we shall render such further assistance a~, may be possible. Very truly yours, WILLIAM W. Goormicu, Assistant General Counsel, Food and Drug Division. `U'N~TED STATES DEPARTMaNT~ OF JuSTICE, Washington, D.C., April 24, 1967. lIe Rexar Pharmacal Corp., Arthin Rosner, and Martin Benjamin, FDC No. 58053, Federal Food, Drug, and Cosmetic Act. , DEAR Mu. G00DRICII This Is in reply to your letter to the Attorney General of January 17, 1967, in which you request the institution of criminal proceedings against `the `above~captioned subjeets for viOlations of the 1~ederal FOod, Drug, and Cosmetic Act committed' between Api~l1, 1964, and October, 1965. We have carefully reviewed the staten~ients set out in your letter Concerning the subjOcts' activities telative `to' the sale `of certain chug' products. As to the fifth count, we are not disposed toward the `conclusion expressed in `your letter that the words of the statute; also used in your regulations, r~quirjng a statement `of ôontra4ndicatl'ons, side eiT~cts, and effectiveness `in prescription drug advertisements are~ so dearly Inclusive of "precautions" a~ to~ `ive the `sub- jects "fair warning" flint su~h items must be included. We have observed that in the advertisement in Modern Medicine in September, 1965, the $~bjects included,' nuder the statutory headings,' the' full and exact language f~ind under those headings in the labelin~ approved `by the ~oód and' fl'rt~g Admial- stratton. There Is nothing in the Act' or `the regulations to indicate that the words `therein have a larger meaning than that of the approved labeling. Accordingly, we' are of the opinion that the advertisement to wl~icb reference was made in `your letter is not violative of the Act. MoreOver, we do not `believe that the factual `situation here `Is' such' that the Government would be * able to prevail in the event the theory suggested In your letter were `to be tried out in a criminal prosecution of ~Re~ar and its officers. Therefore, prosecution is declined as to the charges set out In Count V of your suggested informatJpi~i. Inasmuch as the violations o~ April 18, 1964, and, March 1, 1965, were not reported to u~ for criminal proseentien until `after the appearance of the adver- tisement in Moder~.i Medicine in September, 1965, we `are uncertain as to whether you are of the opinion that prosecution Is merited on the basis of those acts PAGENO="0342" 13592 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY alone. Since your letter leaves the impression (p. 9) tl~at the subjects have flied a supplemental new drug application covering the 30 mg dosage form for "Obetrol" and you do not indicate whether or not the application has been rejected, it would appear that In this respect compliance with the Act may be deemed to have been achieved. Therefore, we are withholding further action with regard to the violations of April 18, 1964, and March 1, 1965, in order that you may inform us as to whether you believe prosecution for these violations should be instituted. In view of the factual situations outlined in your letter we are particularly inter- ested in being informed as to the status of any supplemental application for the 30 mg dosage form. You will undoubtedly appreciate the force of an argu. merit to a jury that physicians could have prescribed two 80 nig doses per day which would have been within the allowable lifitatlon of the approved labeling and which wotild have been available to patients by `taking one 20 mg and one 10 mg tablet. If there is any sound medical reason why such dosage should not be prescribed and thus why 30 mg tablets should not be available to physicians, we would be able to counteract any such defense with some force. Whether or not such reason exists is therefore a factor to which we would attach considerable Importance in the event prosecution is' requested as to the foregoing violations. We also believe that it would be helpful to know `whether the subjects In any way solicited the sale of the 30 mg tablets on April 18, 1964, and March 1, 1965, to Doctors McSpirit and Reider respectively, or whether such sales were solely as a result of unsolicited orders by the purchasers. Sincerely, FRED M. VINS0N, Jr., As8l8tant Attorney General, Criminal Divi~lon. By ITAROLD P. SHAPIRO, Chief, Admini8trative Regulatione Section. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, September 26, 1967. Attention Harold P. Shapiro, Chief. Administrative Regulations Section. Re Rexar Pharmacal Corp., Armin Rosner, and Martin Benjamin. Your ref: FMV :JWK :mlh, 21-52-246. F.D.C. No. 58053. Hon. F~no M. VIN5ON, Jr., Assistant Attorney General, CrinUnal Diiiision, Department of Justice, Wash- ington, D.C. DEAR Mn. VIN5ON: We have considered with the Food and t~rug Administra.. tion the questions `that you raised concerning this case. The four counts which allege violations of 21 U.S.C. 331(d) are strbng counts involving the distribution of iinapproved new drugs, and would by them- selves, support criminal action. The firm did submit a supplemental new drug application for Oby.Rex 80 mg., but it was iCcomplete and the firm has been advised of this. Therefore, compliance has not been achieved. Moreover, the firm was advised In 1964 both to discontinue their violative advertising and that a 80 mg. tablet would require a new drug application. It Is irrelevant that a physician could have prescribed a 20 mg~ and a' 10, mg. tablet, thereby: giving his ,patient a total of 30 mg. at each dose. This does not make It jeg~lfor the firm to market a 30 mg. dose without complying with the new drug requirements. Had' a doctor ~o prescribed, be wOuld have ezceeded th~ ,~Ihn1ts of the `sa~ety approval in the new drug application. While he may, In `h:ls, discretion, prescribe an excessive dose for~ his oivn patient, he does so at the rjsk of civil liability for exceeding the dosage that has been proved safe as required by law The fact is that the consensus of medical opinion holds that the dosage of ~0 mg. per tablet is riot generally recognized an safe. To say that a person can take 20 5-grain aspirins at one time Is not to say that it is per- missible to n~ak~ a 1.00-grain aspirin tablet,' * .~ The Administration's file does not reflect tliat the ~rm has detail men or uses other means for, the direct solicitation of orders:from physicians. PAGENO="0343" COMPETITIVE PROBLEMS IN THE DRTYO INDUSTRY 13~8 In regard to the count based on the advertisement in Modern Medicine, Sep- tember, 1965, we would ask you to reconsider yOur decision not to prosecute with the following considerations, We have previously written, yo~ our views as to the legal necessity f~r including in the brief summary, information from the package insert titlØd there "warnings" and "precautions". [United States v. Wyeth Laboratories, F.D.C. 52673 Your ref: FMV :JNK :mfs. 21-62-326 22A-48-201 The law ré- quires that every ad for a prescription drug shall present in brief sununar~' form "such other information * * * relating t~ side effects, contraindications, and effectiveness as shall be prescribed in regulations." The regulations require that this summary shall fairly show the e~ect1ve- ness of the drug in the conditions for which it is recommended, * * * togethe~ ss ith those side effects and contramdications that are pertinent with respect to the uses suggested in the. advertisement and any other. use or uses for whicl~ the dosage form advertised is commonly prescribed. When the drug is an ap~ proved new drug this information shall be the information from the approve~I new drug applicatIon. Here, the information omitted, though headed precautions in the approved labeling, was information relating to side effects and contraindications. It warned against use of the drug by persons with anorexia~ insomnia, vasomotor instability and other conditions. This was to tell the physician that such per- sons might experience serious side effects-so serious that the drug should be avoided. While the drug may not be compl~tely contraindicated for all persons with these symptoms, it is contraindicated in some,, and in others, side effects are to be expected. So literally this information was related and pertinent to side effects and con- traindications in the medical sense. Far more important, however, is the fact that Congress used "side effects" and "contraindications" in 502(n) to cover the relevant hazards-whether so denominated in the labeling so-called precautions or warnings. The legislative history on this point clearly shows that Congress intended the physician to be fully informed by those ads, since they recognized that the majority of doctors learn about drl~gs from such promotions. This has been discussed in greater detail ~n our previous letter. For example, the provision, that ads could be exempted from all of the requirements of informing the physician, if they included a statement that full information could be. obtained on request, was rejected on the fiqor of the House. Cong. Rec. House 87th. Cong., 2d Sess., September 27, 1962, pp. 19928-9. The information to be supplied would he the full disclosure inserts which were required even then to include "precan- t~ons". The sponsor of this amendment, Representative Blatnik, specifically stated that~ "There Is ample evidence to demonstrate that because of time limi- tations physicians rely on drug advertisements a great deal in deciding which they should prescribe for their patients. It is incumbent upon us t~ assure that no false or misleading information is inadvertently relied upon.", . p. 19922, and then, "I want to . see this bill so drawn as to make sure that doctors get all available information * * *" [in the advertisement itself], p~ 19923. To leave a doctor with the impression that no special consideration or care need be given to a patient with anorexia, etc. is certainly misleading. President Kennedy's proposed amendment on advertising to the $enate Bill was offered on the ground that "Such advertisements should be required to make fair disclosure to physicians of the information (good oI~ bad) needed to permit them to do a better ~ob of selecting drugs for use in tbe~r practice Letter from President I~ennedy to Senator Eastiand, August 4, 1992,. reported Cong. Rec. Senate, August 6, 1962, p. 14682. This would, in our opinion, include precautions. . We think that a reading of `the Legislative History on this matter leaves no doubt that the information lacking in this ad was of the sort that Congress intended be'pmsented to the physician. If we may be of any further assistance, please do not hesitate to call upon us. Sincerely yours, WILLIAM W. Goonnxou, 48sistant Genera' Coun8eZ, Food and Drug D~vlslon. PAGENO="0344" 13594 `COMPET1TIV~ ~ROBLEMS I~ TIlE ;DRtG t~ThUSThY OcroPE~ 25, 1967. Re Re~arPharma~aj Corp., FDO!No.~580~3. Mr. WII~rAM W. GOODRICH, Aesi$tant Genera~ Counsel, DepartmetU of Heait1~, `Education, anI Welfare, ~Wa~1vinØon, D.C. DRAR 1~ln, GOODRICH: This iS in response to your letter of September 28, 1967, `in which you answered certain questions which we ,raised in our letter to you dated `Apr~1 24, 1967. The views ~Ou express concerning the subject's advertise- ment of the drug Oby-Rex in' Modern Medicine for September, 1965, have been carefully Considered. However, s~e have observed that, although the statute ~nd the regulations ~pertaihing to advertising refer only to "side effects" and ~ontraindications", other re~i1ations pertainitig to the labeling of ~prescrip- tion `drugs. refer to "i~eIevant `baz~ttds,' cOhtralndicatlôhs, side effects, and pre- cai~tlOns'~ (foi' examiile, see; `21 C.F.R. ~ectiOn 1.106(b) (~) (i); 1.10~6(b) (4) (i); 130.4(c) ;~i30~9(d) (`I); 130.11(á) (1) and (3)),: Thus, ,`whCre the' agency `has `desired. tc1~req~iire inclusion of informatiOn hi the labeling of a prescription drug of "hazards" or "precautions", it has done so by using thoSe specific wOrds even though in' the same sentenCe it has required the inclusion of "side effects" and "contraindicatlOns." Accordingly, It appears that the agency has recognized that ~acIi ~of these `words has a separate definite meaning ahd we could not ,s~s~iit a eo~tentiOn that "j~lrecautions" are inCibded by implication in the statutory language, particularly In an instance in which the labeling of the drug as approved by `the `agency distinguished between what constitutes "side effects and contraindlcations" and "p~eeautions." Therefore, prosecution on the jasi~ of th'e failure of the subjects to include in the advertisement a statement of the "precautions" is declined. Insofar g~ the counts pertaining to the shipment; on April 18, 1964, and March 1, 1965, to Doctors ~tcSpjrit and Reider, according to their request, of ~o mg strength' tablets of' Oby-Rev and Oby-Rev M tablatC a~e coffcerned, we are not persu~~ded `that such `drastic action as ctiminal prosecution is required, ~r that'if it were instituted a successful rOsttlt could be obtained. `The offenses took place between two and one half and three and ` one half ye~ra~agt~bi~'t were not reported until January of this year. Despite your state- ment that compliance has not been achieved, no additional violations have been repQrted and the stthjects ha~e filed a supplemental new `drug application requestli~g approval for the 30 nig dosage form. Although this application has bcCh cbatacte~ized us "incomplete" it has not been with'drawn nor has the ag4~ne~'táken á~iy steps lOoking toward a refusal to' approve it. App~rently the subjeè,ts `âa~e attempting ,to com~1et'é the ap~lication. `Thus, `despite your sthte~ p~ebt aS to~h'e' cOfisensus of ni~!iieai' Opinion, the reCord befOre the agency is ~n~b `a~te:leave op~n `the question `as to, whether suCh dosage' form is proper: I~i addition, the faCts that under the' approv~d'.labelir~g a, dosage totaling 60 mg pcr~ day~may ev~rItuaily `b~ ~eached in lhe n~mlnistràtton o~ this drñg and that `the dosage form of `the `shipment was ~~~ciilcafly Oi~dered by' licensed phyatcialis wilo are legally entitled and ethically required to prescribe for their p~ttOi~t~ `the dosa*e dictated b~ their `own judgment, based fipOn `a knowledge of `thCfr patients' requirethei~ `Will' te~id to weaken any ctiminal prosecution. Accordingly, it is ~çur view that `the time' which ha~ eiap~ed `since the COm- mission' of the ~1olati'on and' the factual' Situation `make thi~ an unattractive c~i~ for i~xdt~al action. Moreover, shice the subjects have not sold `this dosage India hiulua1~éiy~in `fñte±state cOmmeree'and `have filed 4 `snp~lemental applica- tioii ~ovcr~g~it~use,' It would ~ee~ prosecution fs net tueeessaz.~r to `enforce corn- ~lignee wtth~tbe re~nlrepaetit ef t1~e, law; ` `, ` thus, prosecution is de~l1ned~ " Sincerely, , , " ~` `` , P~ED ~f. VzNso~, Jr.,' 4ssistánt~AttOr~iey' General, - , Crim*iai Dioi8ion. By IIA1iOLD P. SItAPIRO, Chief, Administrative Regulatjons Section. PAGENO="0345" COMPETITIVE PROBLEMS IN T~E I)RUG INDUSTRY 13~9~5 DEPARTMr~T O1~ HRALVI, EDtCATION, ~ND WELrARu, 4prU 18,1968. Attention JIarold P~ Shapiro, Chief, Administrative Regulations Section. Re Rexar Pbarmacal~ ,Corp~, Your Ref. ~MV':JWK :adj 2J--52-~246, J?DC ~ó. 53053. lIon. FRED M. VIN50N, Jr., Assistant Attorney General, Criminal Division, TJ.$. Department 01 Justice, Washington, D.C. DEAR Sin: You will recall that Mr. Barrett and I met with Mr. Shapiro an~ Mr. Murphy last November to discuss your reasons for declining prosecution~ set forth in your letter of October 25, 1967. We went over the file together and we pointed out that the new drug charge was a serious One because (1) the product was labeled with no warning Infor- mation at all (no package insert was included) and with dose recommendation of "one table once to twice daily", (2) the strength o~ this tablet (30 mg.) which contains methamphetamine (speed) along with amphetamine makes It' a dangerous product, (3) our medical advisors supplied a memorandum describ- ing adverse reactions to 30 mg. dose~ of ai~iphetamine, and (~l) the tw~ sales involved were not isolated transactions. We asked our New York Office for further information. They have sent us an Inspection repOrt covering an inspection in September 1967 and a list of inter- state shipments of this product made iii June 1965 (the month the violation occurred). There were four additional shipments made that month, two ~to con- signees in Ohio, one to a purchaser in Mas~achusetts and One to Long Beach, California. Each shipment involved a bottle or bottles of 100 tablets or capsules. Our letter of September 28, 1967, said that the firm does not have detailmen. The file shows that Mr. Benjamin personally delivered one shipment as a sales- man, You asked whether the fii~m had in fact discontinued the 30 mg. dosage. The 1967 report shows that the firm claims to have discontinued interstate ship. meats but continues to do about $20,000 per year in intrastate business in prod- ucts without approved new drug applications, including Oby Rex iti a 3O mg., Timed Disintegration Capsule and Tablet' fOrm. The firm was also using a "Dear Doctor" promotional letter with physician samples to elevate `mood and and help relieve despondency, claims not approved in the new drug'labeling, for those products and not included in the prescribing Information. It seems, therefore, that the firm despite several warnings has not yet decided to comply with th~ new drug requirements of the law. The pro~osed defendants seem to have little concern' for p~itient safety or little appreciation of the hazL ards in the use,of'high doses of amphetamines. ` "As to the advertising charge; we think there can be no doubt whatever that the information the Company headed "precautions" jn' its labeling Was informa- tion "i'eiated to~ side efeecta and contraindications". Congi'ess uSed differetit language' in Section `502(n~~ than the Agency usOd in its ftill disclosure labeling reg'ulatious promulgate~1' several years befote, but the `intent of' `the Congress was plain, as we have' shown `ib our' discussion of these ádvertisin~ cases' with sour people. ` ` ` ` . ` We simp1~ cannot agree that any ~nateri~tl n~w included in' product brochureS apprOved' o~er the past 28 years in' new drug clearances that is headed "precau- tions" or "warnings", `or indeed' anything other than material `headed' ~`side effects" or "contrai'ndicatiOns",' is not' information related to "side `effects" t~nd "contralndications"~ as `tbos~ terms `were `used in the 1962 Drug Amendments. Not only is this directlrcdntlary to the Congressional `intent and' to' the plain statutory language, it is untrue as a factual matter. In this case, the `precau- tionary information left' out of the ad was the most important information needed for safe `use of the drug. Your dOclination of the new drug charge was based on your appraisal of the l~kellhood of success, the drastic nature of the proposed action, the time lag between the' violations and repOrt~ng them to you, your understanding of the "incomplete status" of the NDA, and on the startling statement that a physician is ethically and legally bound to treat patients with drug dosages beyond the limits of safety proven through the new drug procedures. This action is not drastic when one considers that the' drug ft~volved is a potent amphetamine mixture, with well recognized hazards, which 4espite some years of clinical use in medicine has not beèti shown or recognized' to be safe in the 30 mg: dosage. To place suck an unp~Oved dosage on the market In utter disregard fo1~ the new drug procedure is a substantial violation of law and a distinct disservice to physicians who prescribe and patients who are expected 56-592--75-23 PAGENO="0346" 13596 COMPETITIVE PROBLEMS IN TIlE DRVG INDUSTRY to use prescription drugs. The Incomplete application was rejected by the incom- plete letter.' Our regulations, upheld on this point by the Sixth Circuit `in the Turkel case, call fOr filing over protest if the Cornpan~ wishes to pursue its application. This Gompany `has not done so `and lt& application 15 a closed one. Exceeding approved dosage of drugs Is one of the surest ways to patient injury. Physicians have neither the legal nor the ethical right to experiment with their patients with excessive dosages without the patients informed con~ sent, and when drugs of interstate origin are used, without complianCe with the IWD regulations. Very truly yours, WILLIAM W, GOODRICH, Assistant General Counsel, Food and Drug Division. ~ 29, 1968. Re Rexar Pharmacal Cprp., FDC No. 58058. Mr. WILLIAM W. GOODRICH, Assistant General Counsel, Department of Health, Education, and Welfare, Washington, D.C. DEAR Mn. GOODRICH.: This is to acknowledge receipt of your letter of AprIl 18, 1968, requesting us to reconsider our decision* to dedlln6 prosecution in this matter. Your comments relative to the alleged violation of the advertising provisions o1 the Federal Food, Drug, and Cosmetic Act appear to be the same as those made in at least one other similar matter. (See Syntex Laboratories, Inc., FDC No. 53222.) Our views regarding the narrow issue presented by similar facts were fully set forth in our letters to you pertaining to that matter and in our letter of October 25, 1967, concerning the present submission. We adhere to them and to our decision not to prosecute this matter Insofar as the advertisement is concerned. Neither does the Information contained in your letter warrant any change In our decision not to prosecute on the basis of the" shipments to `Dr. ~1cSpirit In AprIl 1964, and Dr. Reider in March of 1965. Despite the statement that there were four additional shipments in ,June 1965, no evidence has been submitted proving that, the sales were to persons other than duly qualified physicians who ordered the larger dosage `form for the purpose of dispensing them to bona fide patient~ being treated by them. The sales of the drug In New York State do not constitute violations of the Federal law and cannot be construed as exhibiting an intent to violate the. Federal Food, Drug, and Cosmetic Act. Accordingly, we are still of the opinion that the age of the alleged violations and the factual situation present a very poor basis for criminal prosecution. Ti~e facts are such as to raise grave doubts as to whether they constitute a viQlatlon In the legal sense.. Moreover, It Is our belief that the circumstances upon which the Government *ouid be compelled to rely are so unappealing to a judge a~id a jury as to render a cOnviction highly unlikely.' We desire to correct the statement attributed to us In your letter that `a physician is ethically' apd, legally bOund to treat patients, wib drug dosages beyond the limits of safety proven thtongh new drug procedures" That Is not our position. The Correct statement of Our position, to ~Vhich we adhere~ appears In the next to the last paragraph of our letter of October' 25, 1967. For the reasons `Indicated abOve, we ~continue . to `be of the view that prOsecu- tion Qf this ease Is not feasible. We are therefore closing Our file. Sincerely, ` , ` Fnnn, M.. Vixsox, ,Tr., A8sistant Attorney' General, Criminal Division. `By HAROLD P. `SHAPIRO, Chsef AdnHntstratsve RegulatiQna ~ectsOn MAuCE 16, 1967.: ~n reply refer to P\D~C.~No. ~3222; ` `~ ,, ,., The I~ouoràb1e'Arvonxxv GENERAt~,. ` ,~ ,` $ ~epartment of ~1ustice, WasbingtQn, D.C. $ `,., / , , D~AR Mn. ATTORNEY OENERA~: `We `request the IñstltÜtlon of, criminal, pro- ceeth~gs in the District of New Jersey under the Federal Food Drug and PAGENO="0347" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRt 13597 Cosmetic Act, against ~yntex Laboratories, Inc., 1401 Hiliview Drive, t'tilo Altq, `California, and 45 Walnut AV me, Clark; New Jer~ey. The offenses complained of occurred on or about September 29, 1965, November 18, 1965, and February ~8, 1966, and involve the introduction Into interstate commerce at Clark, N~w ,Ter5ey, for delivery to Berkeley, California, of quantities of Norinyl, a prescr~p- tion drug. There are transmitted herewith a suggested form of criminal Information a)id the following exhibits: A. Copy of Notice of Hearing. B. Carton and bottle labels. C. Package insert (approved new drug application labeling). D. Copy of monograph in 1965 Edition of Physicians' Desk Reference. * B. Copy of advertisements in the November 1, 1965, November 15, 1965, ai~d February 1, 1966, Editions of The American Journal of Obstetrics and Gyne- cology; the November, 1965, and February, 1966, Editions of Obstetrics and Gynecology; and the February 14, 1966, Edition of Modern Medicine. SECTIONS OF ACT INVOLVED The Information charges violation of 21 U.S.C. 331(a) in that the defendant caused the Introduction into interstate commerce of quantities of Norinyi which were misbranded as hereinafter described. Count 1.-Time drug was misbranded within the meaning of 21 U.S.C. 352(f)~ (1) in that its labeling failed to bear adequate directions for use and It was not exempt from such requirement since its labeling, a monograph in the 196~ Edition of the Physicians' Desk Reference, failed to comply with the require~ ments of regulations 21 CFR 1.106(b) (4) (i). Counts II an~1 111.-The drug was misbranded Within the meaning of 21 U.S.C. 352(n) in that the defendant failed to include In advertisements caused to be issued by it in the (Count II) November 1 and 15, 1965, Edition of The Amer- ican Journal of Obstetrics and Gynecology and the November, 1965, Edition of Obstetrics and Gynecology, and in the (Count III) February 1, 1966, EditIon of The American Journal of Obstetrics and Gynecology, the February, `1966, Edition of Obstetrics and Gynecology, and in the February 14, 1966, EditIon of Modern Medicine, a true statement of information in brief summary relating to the side effects and contraindicatiOns of the drug as required by regulations 21 CFR 1.105(e) and (f). BACRGEOUND INFORMATION "Norinyl" is a registered trade name used by the defendant fo~ a drug com- posed of 2 mg. of Norethin4rone and 0.1 mg. of Mestranol. At the time of the alleged violations, Norinyl was commonly prescribed as an oral cobtraceptive. Syiltex submitted to the FOod and Drug Administration a new drug applica- tion for Norinyl which was approved on March 5, 1964. At this time, the Com- missioner of the Food and Dr~1g Administration sent a letter to Syntex Labora tories Inc In which be said that the claims made In the labeling were limited by the representations made in the new drug application The Commissioner also said that `the approval of the new drug, application In no' way relieved Syntex Laboratories from complying with all of the provisions of the Federal Food, Drug, and Cosmetic Act. * The 1965 edition of the Physicians Desk Reference published by Medical Economics, Inc., bore a monograph for Norinyl which appeared on pages 962 and 963. The Physicians' Desk fleference is published annually in cooperation wIth the subscribing manufacturers, Th~, purpose of the `Physiciabs' Desk Refer- ence is to make avallabie to physicians Information on ma~or pharmaceutical specialties.. Information appearing In the Physicians' Desk Reference is solely that furnished by the manufacti~rers. This is explained by the, foreward in the 19th EditIon, which contains the following ~tatenient: `~.`The function of the publisher is the compilation o~ga~ization, and distritution ~f the Informm~tion I~acb product description has been prepared by the manufaçturer~ and edited and approved by the manufacturer s Medical Department Medical Dire~tor ot Medical Consultant.", , ` ` * EVIDENCE OF MISBRANDING * ` ` ,, * * Count 1.-The drug, Norinyl, which is a prescription' drug and which is a new drug subject to 21 U.S.C. 355, was not exethpt from the requirements of 21 U.S.C. 852(f) (1)' that adequate directions ~or use appear In its labeling since PAGENO="0348" 1359S COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY it failed to comply with the condition ~or e~em~tf on set forth in the regulatIons 21 C~R 1.106(b) (4).. Such condition requires that, i~ case of a drug subject, to 21 tLS.C. 355, the labelji~g be substaut~aUy the same as the labeling ai4horized by the approved new drug application for such drug. Th1~ w~s not t'~ie with respeót to Norinyl because it~ labeling, the 1965 Edition of the Physiclans' Drug Reference, failed to include the follOwing information which was in the new drug application labeling: (1) A statement concerning the length of experience with the drug, an~1 that although no deleterious effect of the drug on pituitary, ovarian, adrenal or uterine function has been noted, the long-range effect on thesç~ and other organs must await more pro1onge~ ob~ei~vation. (2) The information regardjn~ the, possibility of pregnancy if the treatment schedule is not adhered to; and that, if the regular menses fail to appear and the treatment schedule has. n~dt been adhered to, or, it the patient misses two regular menstrual periods, the possibility of pregnancy should be resolved before resuming Nori~y1. If pre ~tncy is estfibli~shed, Norinyl should be discon- tinued during the period of gestatioli, on the basis that virlllzátion of the female fetus has been reported with oral use of progestational agents or estrogen. (3) The Important information . regarding the possible causal relationship between progestational agents and intravascular clotting. In addition, the Pliysl- clans' Desk Reference labeling contained the statement "it provides maximum protection against unplanned pregnancy and minimizes `undesirable side effects resulting in fewer patient dropouts" which statement was not supported by the approved new drug application labeling. Counts II and IlL-In regard' to the acWertisements upon which the mis- branding charges are based, examination has shown that they omitted certain information which was iti the new drug application labeling and that they Included certain information which was net in such labeling, ~flie nature of such information is alleged in' ` the criminal fliformation. Because of such omission and of such inclusion, the advertisements f~til~d: to include' true statements relating to the side effects and contraindications of Norinyl as required by regulations. S EVIDSNCE OF VIOL4~TIVF SRIPM]ENTS Count 1.-A sample of tw~ 1QO-tablet bottles of ~orinyl was taken at random from a lot of ten such bottles in the shelf stock of the Permanente Services Pharmacy, South San Francisco, California, by Food and Drug Inspector Frank W. Scholl. The lot was identified by Donald B. Mtirray, Manager and Pharma- cisf. in Charge of the Dapite, Division of Perma~ente ~ervices, The, ~erkeley, California, Who said that the lot'l~ad be~n. ~`çceh~eU ,fron~ Sytitex Labor~t~ries, Inc., Clark, New' Jer~ey7 on Octqber ~; , 1965' and subsequently shipped to the above mentioned phai~macy Mr ~1irray ~npplie~ the Ipspec~or with Supporting docuix~ents. , 5 5 5' ` ` Count II -$To ph~slcal sttm~le was dblalr~ed Howeve1' Donald F' Murray of the Dapite Division of ~ermahent~ Serflees S~i'd that his t~rm had' recei'vod 86 twenty-tablet packages and' 48' 100-tabfet bottles of Norl,nyi fr~n Syntex Lab~ Qratories, Inc., clark, New `Jersey, on November 26, 1965. Mr. Murray `supplied Inspector Frank D. Korun with stipporting documents `relating to the shipment. Mr. lflchard IVickel, Assistant Administrator fOr the Samuel Merritt flospital; Oakland, California, provided Inspector Korun with copies Of advertisements' fOr `Norin~l Which appeared in the, l'~ovember 1~ 196~, ariçl Koveniber 15, 1965, Editions' o~ The ,Amèric~n Journal Of Obsteti~ics àiid Gynecology, and the' No- vember, 1965, Edition Of Ohptetrfo~ pxid ~yne~ology. `Count III,-~-A sample of three 100-táb1~t .bqltle~ wa~ taken by T~od aXid. Drug" In~pecto~ ~`ránk I(orun ~t ràndOnl ~rbm a lot of 48 such bdttles at the Dapite Division of'?~frihanen'le~ Ser~tices, ~e,,~erkeie~;, %iiforuia. .`2~b~'1Ot Was ideñti. fled b~ Mr Dçu~ald Mtirra~ who said that thO'flrm receivecj the lot frotu ~ tex Lab'oratoi~ies,' The., Clark, ` New Jersey, on February ~8, ~ COpies ~ docutneil'ts relating tO~'the ship~neñt were provided by ~rs. ~lbrence Thirns; ~ employee of Dapite. Mr, flichard Wlcke'l, Assistant Athii~nistrator for `the Samuel Merritt `Hospital, Oakland,' California, proVided Inspector Koran with copies of advertisements for ,Norinyl which appeared in the' FObruary 14, 1966, Edition of Modern Medicine, the February,' `1966,' Edition of Obstetrics an4I' PAGENO="0349" COMPETITIVE PEOBLEMS IN THE Dl~UG INDUSTRY 135~9 Gynecology, and the February 1, 1966, EdItion of The American Journal of Obstetrics and Gynecol9gy, The headquarters of Syntex ~abora~Qr~qs, Inc., a~e ~esently located In Alto, California, but `nianufaCturiug a1 the time of the allege~ violatiQas was carried out elsewhere. The drug i~i questiQu was manufactured by Synte~ Lab- oratories emplQyees' i~ing eq1i~puiOnt~iôchte~;Qn the premises of Warner-Cbilcott Laboratories, Inc., Morris PIai~s, New J'érsey, This ~a~ufacturlng opêratio~i was under the control of Syntex, J~aboratories, Inc. The shipments of the drug were made by the Syntex Laboratories Er~ñcb In Clark, New Jersey. HEARING HELD PURSUANt TO 21 U.5.C. 335 A Notice of Ilearing issued pursuant to 21 U.S.C. 335 on April 8, 1966, ad1 lressed to Syntex Laboratories, Inc., 1401 Hiliview Drive, Palo Alto, California. A personal response was made by Mr. Vincent Kleinfeld, Attorney for the firm, on April 21, 1966. Mr. Kleinfeld did not question the interstate nature of the shipments and did not deny that the Physicians' Desk Reference was ac- companying labeling as is charged in Count I. Neither did be deny the firm's responsibility for the shipments, for the placing of the monograph in the Physi- cians' Desk Reference, nor for the placement of the advertisements In question in the November issues of the various medical journals. Mr. Kleinfeld said that the firm had no intention of deliberately omitting information from the Physicians' Desk Reference or from medical journal advertising that they believe would have been desired by the Food and Drug Administration. I-Ie said that honest men can differ in opinions as to what is required under the regulations and that Syntex's doctors had believed their medical journal advertising and the monograph in the Physicians' Desk Refer- ciace were in full compliance with the law. Mr. Kleinfeld stated that he himself did not realize the full extent, of the information desired by the Food and Drug Administration to appear i~i these publicatioi~s. Mr. Kleinfeld said be was helping the firm to set up the procedure. for the development of advertising and labeling that will assure full compliance with the requirements of the Food and Drug AdmUnstrat.ion. He had prepared and. submitted to the Food and Drug Admini~tratjon a new propQsed monograph for the Physicians' .Desl~ Reference to be published in the next quarterly supple- ment after it is approved by the l?ood and Drug 4dmjnistration. He had also prepared ~ statement for use in medical jpurnal advertising, as soon as he obtained approval from the Food and Drug Administration. He stated that he was of the opinion that. these proposals would meet all the points raised in the Notice of Hearing but that they Would be changed if they were still not &itisfacto~y to the Food and Drug. Administration, On June 21, 1966, Mr. Kleinfeid, and other representatives of Syntex, Labpra- tories, Inc., met with representatives of the Food and Drug Administration In Washingtofl, D.C. A proposed monograph f~r the I~hysicians' Desk Reference was submitted and discussed as was propo~ed material for journal advertisi~ig. The firm indicated an intention to comply with the~ recommendatioils and re- quirements of the Food and Drug Administration. SEIZURES No seizures were made of the shipments which are the subject of the proposed Information. CONCLUSIONS We have considered the representatioils which wOre made on behalf of the firm at the above hearing. However, we cannot ignore the facts which show that Syiltex Laboratories, Inc., has had ,an ~ttënsive experience In the develop- ment of new drugs and their subsequent distribution in accordance with the flew drug regulations; and that such firm was fully aware of the regulations. which required that the contraindications `and side effects set forth in the ap- proved new drug application labeling be presented in the Physicians' Desk `Reference monograph and in the medical journal advertisements. In these circumstances and in the Interest of protecting the health of the consuhdng public, it is our opinion that criminal prosecution is' necessary to impress upon Syntex Laboratories, Inc., Its responsibility fOr compliance' `with the law, aüd to deter other firms from similar violations of the law. PAGENO="0350" 13600 COMPETITIVE PROBLEMS IN THE, DRUG INDUSTRY WXT~ES$ES The principal witness In this case will,' be the Government Inspectors WhO collected the samples and made the inspections, the Government Analyst who analyzed the tamples, witnesses to establish the inte~state,origin of the samples and the issuance of the advertisements, ~iid medical officers of the Food and Drug Administration's Bureau of Medicine who can testify as to the approred new drug application, the approved labeling, and the serious nature of the alleged medical journal advertising misbranding. It is requested that,' if the form' of Information l~ amended, the United States Attorney furnish us with a copy thereof; also, that be keeps us advised as to the progress of the case and its dieposition. The l'~~ew York District Office of the Food and Drug Administration located at 850 Third Avenue (at 30th Street), Brooklyn, New York 11232, Telephone: 798-1300, will arrange for the presence of the necessary witnesses and assist in the presentation of the case. Upon request, we will render such further assistance as may be possible. Very truly yours, WILLIAM W. GooDRIcH, Assistant General Counsel, Food and Drug Division~ APRIL 22, 1968. R Syntex Laboratories, Inc.,' F.D.O. No. 53222, Federal Food, Drug, and Cos- metic Act Mr. WILLIAM W. Goo~nxcn, AsSistant General Counsel, Department of Health, Education, and Welfare, Washington, D.C. DEAR Mn. GooDRICH: In view of the expressions contained In your letter of March 1, 1968, we have re-examined our previous determination relative to prosecution of this matter. The reasons set out In your letter tend only to rein- force our opinion that this matter does not present a case for prosecution and i'o not a proper settifig In Which to attempt to sustain a judicial Interpretation of the regulations issued' pursuant to Section 352(n) of the Act. We believe that any attempt to secure a judicial interpretation which will enlarge the meaning of the `statutory terms on the `basis of the meaning of the word "relating" as suggested by you would be frustrated by the factual situation. The difficulty inherent in any such attempt is that the labeling which was approved by the Food and Drug Administration contains the same words as are found in the statute and regula~tions,' i.e., "side effects" and "contraindleations." Under each heading, the specific' items or' conditions are listed. Many ~f the conditions which you now contend are side effects or contraiiidlcatlons are not listed under those headings In the labeling but are set out under other headings lii the labeling. In a criminal prosecution, such a factual situation creates an impossible barrier to success. In `all' likelihood, the only result would be to obtain a judicial expression contrary to your desire. In passing, We consider the possibility that the court might find an analogy between the present' situa-' tion and that of Haynes v. United States, -~-~ U.S. -, decided January 29, 1968, wherein the Supreme Court commented that "so' much could not be de- rived from so little.," , , ` ` Moreover, the argument presented relative to the meanings of certain lan- guage used in the advertisement as compared to that of the labeling presents so fine and tenuous a distinction as to render conviction most unlikely. In other instances the suggested violation appears to consist of a failure to furnish information which does not appear In the approved labeling. Specifically, the argument that the statement in the advertisement that the' drug is contraindicated in pregnancy Is not satisfactory because the doctor should have been told to discontinue the drug "at the earliest possible sign of pregn~ney" is untenable. Obviously, the physician is not going to use', the drug' to prevept pregnancy if the patient is pregnant. Neither would' it seem logical to erpect that a `physician would continue its use after the patient became pregnant Moreover under the circumstances, any physician would be aware that contraindicatlons o~ the drug In pregnancy can only mean that it should be discontinued if `the patient becomes pregnant. As to the nec~ssity tot `discontinuance, at the `earliest' possible sign, It will be observed `that the approved labeling under the heading of "Side effects" notes that symptoms "resembling early pregnancy" as well as changes In the `men- PAGENO="0351" COMPETITIVE PROBLEMS IN THE DRUG INDTJSTRY 13601 ~trua1 cycle, including occasional inter~menstrna1 bleeding and spotting arn~ sometimes with the period being missed entirely, may occur. Thus, the ap~ pioved labeling certainly indicates tJ~at some of the e~trliest pOssible ` sign~ of pregnancy may be false one~ which do not justify discontinuancç of the medication Accordingly, a warning to the physician to discontinue the drug at, the "earliest possible" signs of the condition the drug is meant to prevent is not consistent with the approved labeling. , Under these circumstances, we see no justification for any~ attempt to predi- cate a criminal prosecution in the factual situation above described. Your letter states that "contraindication for psychic depression in the ap- proved labeling is directed to patients with a history of psychic depression and not just to those with presently observable psychic depression." However, the language used in the labeling approved by the Food and Drug Administra- tion is not that clear or unatnbiguous. The labeling stated under "contraindi~ ~ations that patients with a history of psychic depression should be carefully observed, and the drug is discontinued if depression recurs to a marked degree.'~ The advertisement stated that the drug was contraindicated in "severe depres- sion.,, Thus, the labeling does not say the drug should not be used in patients with a history of psychic depression or even that it must be discontinued if that condition should appear. Its use is contraindicated only if the condition reap- pears to a marked degree. The advertising statement contraindicating the drug in `the event of severe depression, therefore, does not significantly differ from that of the labeling. Its terseness is not a vice, indeed, a "brief summary" not a verbatim quote of the labeling is all that the Act requires. It will be observed that it is also arguable that the flat contraindication of the advertisement may be considered to be more restrictive than the permissive and rather ambiguous wording of the labeling. While the labeling of the drug might well have included under the heading side effects a warning about the blood clotting possibilities of the drug the fact is that it did not. The Food and. Drug Administration approved labeling which treated it in another fashion, and many courts and juries would con- sider it manifestly unfair for the Government to attempt to impose criminal sanctions for the failure of the subject~to set this condition out as a side effect without having first been advised of the necessity so to do. Additionally, the agency's position is considerably weakened by the fact that in the labeling the coupling of the reference to blood clotting with the favor- able comment of the Ad Hoc Advisory Committee has the effect of minimizing the potential threat to the patient. This circumstance would also tend to dimi- nish the seriousness of the failure to list the condition as a "side effect." Much of the same objection applies to the contention relative to the failure to set forth as a side effect a statement found in the labeling under a `different heading relative to the effect of estrogens on calcium and' phosphorus. In addi- tion to the questionable fairness of a prosecution in these circumstances, the labeling statement does not refer to a definIte knowledge' that the drug has a deleterious effect on calcium and phosphorus metabolism but only to a general medical learning that estrogens are `known to have such an influence. The complaint, therefore, seems to relate to a failure to list as a side effect of th'e drug" a matter of~medical learning which is applicable to, estrogens. Thus, the information does not seem to relate to a side effect of the drug advertised, and for that reason a prosecution based upon this omission is, not sound. Nor do we believe ,that the failure of the advertisement to include the specifl~ details relative to the length of evperience with the drug forms a basis for criminal action. Such Information `wa~ not required as a part of the statement in the tabeling concerning side effects, and the advertisement, did, by inference at least, inform the `physician that "prolonged observation~" bad not taken place. That portion of the advertisement which speaks Of the low Incidence of side effects does not appear to constitute a violation of the statute. In our view, the advertiselnelit does not falsely represent the incidence' of side effects which attends the use of the drug. Although w~ think it is `at least debatable whether the advertisement claims a superiority over other products in connection with the incidence' of side effects, such statements are within the area of `allowable promotion of the drug The statute is in our opinion oriented toward requiring truthfulness in the' area pertaining to safety and effectiveness. We do not read the legislative history as ,indicating that the statute is designe4 to prevent the usual' effort to convince consumers that the advertiser's product is superior to other almost' identical products so long as the' factual statements are true. PAGENO="0352" 13602 COMPETITIVE PROflLEMS I~T' ~TItE DRUG' INDUSTE~ Yoñr letter ieads us to the conclusion that yoiido not contend that `the adver- titement fOr Norin~rl claimed any use not included in the approved Iabelh~g bitt `only that `it did' itot set forth all the side `effecte with `the specificity ~w~tich the agency finds desirable. ~`Our' letter also `states that it `i~ your position that advertisements of newdrngs suh~ect'to prescription use for which applications were approved after October 10, 1962, cannot contain any statement that i~ not in the approved New Drug Application. We' have observed that hadthe advertisement set forth as "side `e~e~ts" some of the statements which' you contend should' have been Were lnchZded such act would be' a direct' violation of the position stated above because the statements of the conditions allegedly `omitted are' not found under that héa~,ling in the approved' labeling. YoUr contentions,' therefore, seem to be diametrically opposed to your argument as' to the necessity that tb~ ad~~ertisëment conform to the labeling. , Although we are declining prosecution based upou the alleged violatioi~s of the `advertising provision of the Act, we do not have the same reservatiOns concerning the violation alleged in Cottnt I of th~ suggested form of informatiOn which relates to the use of improper labeling in the monograph in the Pltysi- clans' Desk If eferenee. We are engagecl in the process of ,redrafting that Count in accordance with the ideas expressed in our rast communication., A copy of our con~mitnication to the United States Attorney will be forwarded to `you `when it is mailed. Sincerely, FRED M~ ~VINSON, Jr., Assistant Attorney General, Criminal Division. By HAROLD P. SHAPIRo, Chief, AdmiflietrGtive Re9uiations $ection. UNXTEI' STATtS DEPARpaENT O~' JuSTIpE, T~T~'~cEi~ SrA~rEs ATTORNEY, FOfl T'HR Dls~ittc~r `ov Nuw JERSEt, Newark, N.J., `May 21, 1968. Attention Ifarold' P. Shapird, ~hie~, Aciministr~tive R~itlations Section. Re Syntex Laboratories, InC., ~t~O No. 53222, Federal `Food, Drug, and Cosmetic Act. Your ~f: FMV :JWK :nic, 21-48-353. DEPARTI~rENT o1~ JitsTIcE, Washington, D.C. DEAR Mn. SHAPIRO: We have, reviewed the file ir~ the above-referenced matter and have concluded that the case lacks prosecutive merit. We recognize that discrepancies between, the mqnograpji; and the' approved labeling do exists However,, the ~~gulati~ns themselves r,equi~e, only' that' the labeling be "substantially" the same, as tliel~~bejing authorized' by the approved new drug ~pplication. The word "~ubstant1aUy", certainly: gave the company some license to synopsize the in~or~uat1on contained in t'he, approved new drug applIcation. A reasonable doubt evists in `Qur minds as to whether the labeling in the monograph is, substantially different fr~m the labeling in the approved new drug application, and we believe that a lay jury would also harbor such a doubt. Moreover, the discrepancies between the monograph and the approved labeling do not appear to have been the result of a purposeful evasion of the regulatory requirements of the Administration but of an honest difference of opinion as to what was required under the regulations. In fact, at the hearing held on April 8, 1966, the firm offered to obviate all future difficulties by submitting sample advertising and' monographs to the Food and Drug Administration before publication. ` In closing, we note that ,the c~ffe~se complained, o~, occu~re4 in Septeinbei~, 1905, almost three years ago. ~o indications of violations of the Food and Drug law subsequent,to ,that date are ~eporied. ,Prosecut'ion at this rather late date would' not be in, the best interests of the Federal Government. Very truly yours, DAVID M. SATE, Jr,~ U.S. Attorney. By MARLENE GRoss, Assistant U.S. Attorney. PAGENO="0353" COMPETITIVE PROBLEMS IN TIlE DRUG INDUSTRY 13603 DEPARTMENT OF HEALTII, EDUCATION, AND WELFARE, May 28, 1968. Attention Fred M. Vinson, Jr~, Assistant Attorney General. Re ~yxLtex. Laboratories, Inc. ,!ou~ ref: FMV :JWK :mch 21-48-353, FDC No. 53222. Hon. RAMSEY CLARK, Attorney Genera'; Department of Justice, Washington, D.C. DJ~AR Sin: This is with reference to your letter of April 22, 1968, and the United States Attorney's leti~ér of May 21, 1968, detlining prosecution on both the advertising and the labeling violations we have reported to you. The United States Attorney declines for the reasons that (1) there Is a reasonable doubt whether the labeling (FDA monograph) is substantially dif~ ferent from the approved labeling, (2) the violations appear tO be the result of honest differences of opinloil as to what is required, and (3) the o~ense is almost three years old and ther care no indications of violations since 1965. (1) There can be no reasonable doubt that the PDR differed from the ap- proved labeling in a substantial way. It was too brief, it was promotionally slanted, and it omitted important information for safe prescribing. (a) .A comparison of the approved labelibg and the PD~I moilograph plainly shows that some of the most vital safety information w~ts omitted from the `monography. A copy of the 1965 omnograph is enclosed. It exaggerates the effectiveness of the drug, and it minimizes the side effects, precatttlohs and contraindicatiOns. We simply cannot understand `how it can b~ said that this ,abbreviated material', and ~particularly the seven lines devoted to side effe~t5, cAn possibly be said to' bO ~i,ibstautial1~ the same as the approved directiOns for safe use of this drug. The substanc~ of the monOgraph, and th'e, ~ub~tanrce of the approved labeling are nbt'the same. S rundamentally, what the Company did was to present a reassuring write-up for the physician's desk which omitted the most important information he needed to' have' to prescribe this drug for his patient~ with safety. As the criminal `information which your office drafted `shows, the physician ~ivas not alerted to the possibility `of effects' on the fetus if a pregnant' woman should take the drug not knowing she was pregnant, he was not alerted to the limited `experi- ence with the dri~ig and Its possible loflg range effects upon a vai~I~ti~ of organ and endocrine systems, includThg~ `pituitary,. ovarlati `adrenal,' uterine, livei~ â~d thyroid be w~ not alerted to the possibility of intravasci~ilar elbtting (a risk nOw' k~own to be `even moi~e' ~iOns tMn In 1965), ~he' *va~ n~t Warned `kbo~it effe~ts un patients ~rith any condition involving calcium Or ~hosphOrus' metabo- `lism, an~ he was not told to, use tlie drug with care in any patient who had a history of psychic depression; ` ` We feel coñfldeitt that we can prove by acceptgblë medical eviden~e that the pr~scribing Information in PDR-1965 was not substantially the'same as the ap- `proved labeling, as the regulations require. And we are equally confident that we can prove the omissions and changes were significant `from the standpoh~t of patient Safety. Our Advisory Comithttèe on Obstetrics and Gynecology," quoted in the Company's lab~lin,g, ~aid that the physiCian must deCide for hi~'patient whether to dccept the risk involved `in the use of oral contracepti~es, small though it may be, but that hA~"~can 4° this WIsely onl~ when there is ptesentad to him dispassionate scientific knowledge of the a'v~ailable data," The' PDR monograph did not serve this purpose, and the violative ads we will discuss later compounded the hazard. ,, `(2) There was no' basis fo~ eor~sid'ering this violation a result of an honest difference of opinion as to "What is required. The `applicable regulations' bad been in effect since 1961, and the Company's performance shows that it did not comply with what was clearly required-it did not pre~ent substantially the same information in PDR a~ in the apprQved 1a~eling. It had the labeling at hand and it chose to omit some of the informatIon from the PDR monograph. (3) Syntex has not been in compliance sincd'1965. The ad Charges you elimi- nated would have shown ftie United State~ AttQruey thiut the same failures to inform continued after that date, Aad ~itbin the `past few, months, on January 22, 1968. we required' the Company to mail a letter t~ all physicians in the United States calling attention to its failure tO iñeludç~' ii~i its then `current ads appropriate w~rnings abo,i~j use of the drug in ~sychic depression and about ,the pqs~ibi1ity p~ t1lro~uiboembolic episodes. A copy of the letter is enclqsed,' , PAGENO="0354" 13604 COMPETITIVE PROBLE&tS IN THE DRUG INDUSTRY Turning to the reasons given in your letter of April 22, 1968, for declining to ~rosecute the advertising violations, we must reiterate what we have fre- quently said to your representatives, that the brief summary is required to disclose true information related to side effects, contraindications, and effec- tiveness as specified in our regulations, not merely the information headed "side effects" and "contraindications" in the approved labeling. We are confident that any qualified expert would regard the information about clotting, calcium and phosphorus metabolism, effect on organ and endo- crine functions, etc., as information related to "side effects" and "contraindi- cation" as those terms were used in the 1962 Drug Amendments. The fact that the information in certain instances was headed "Thyroid Gland", etc., does not make it less information related to side effects than the material in the labeling under the heading "Side Effects~" A mere reading of the package insert estab- lishes this. While criminal prosecutions do sometimes involve strict interpretatIons of regulations, there is "no canon against using common sense" in applying a criminal law. As to the point you make that our understandings of what was said in the advertising are based upon tenuous constructions, we think we should have an opportunity to present these points to a court or `jury with an explanation of their important medical significance. Surely a jury would understand the need to warn a physician, and through him .the patient, that a missed dose or a miscalculation in taking the oral con- traceptive drug may result in pregnancy, and that if that occurs there is danger to the unborn child from continuing to take the drug. Telling the physician that the drug. is contraindicated in pregnancy does not tell him what he really needs to know for his patient's safety in bearing a child. It is the need to alert the user to the hazard to the unborn child which may result from a missed dose or a miscalculation that calls for this early pregnancy warning. On psychic depression, we have noted above that as late as January 1968, Syntex was still not properly presenting the message about this hazard to the profession.: A corrective letter was necessary. What is missing in the ads is the warning that any patient with a history of psychic depression should be care- fully observed (this means the patient should be followed much more closely than the routine patient) if a decision is made by the physician to prescribe the oral contraceptive. A statement that the drug is contraindicated in "severe depression" does not adequately advise the physician of the risk he runs with a patient who has bad depression in the past but now has it under control. Blood clotting has been a problem with these drugs for a long time. When these ads ran, the labeling was required to say that such episodes had, occurred, that a causal relationship had not been established, and that the prob1e~ was under investigation. The ad said nothing about this. Instead, it said the drug was contraindicated in. thrombophlehitls and pulmonary embolism (current or past). This is quite different from telling the physician that the cause and, effect relationship of the oral contraceptive drugs to these serous complications, partic- ularly in the older age groups, was then under scientific ipve~tigation. As you know, this problem has caused a progressive strengthening of the warning as more experience has been gained. Finally, we must express our disagreement with the idea that a drug com- pany can use a literally true statement to convince prescribers that its products aye superior to other identical products. A half-truth is still. sometimes a great * lie. Promotional practices with this class of products have been characterized by the use of such half-truths to gain marketing advantages. We have had to require several companies to discontinpe such ads and to send letters of correc- tion to the profession. For from beIng harmless puffing-which in any event is not tolerated in prescription drug advertr~ements-this kind of promotion affirm atively misrepresents both the `effectiveness and the `safety of the oral contra- ceptives. We have written you at this length because of the serious consequences to the profession and to patients of improper `prescription drug ndvertlsing~ Six million women are considered to be on oral contraceptive drugs at this time in the United States. Their safe use depends upon proper promotion of the drugs to `the profession. Syntex ha~ seriously failed in the instances cited in our recommended prosecution case. Yours very truly, WILtIAM W. Goomnicri. A88istant Genera1 Uoun~?eZ, Food and Drug Divi3ion. PAGENO="0355" COMPETITIVE PROBLEMS I~ THE DRUG I~DUSThY 136~5 MAY 27, 1968. Hon. RAMSEY CLARK, Attorney General, Department of Justice, Washington, D.C. Attention Fred M. Vinson, Jr., Assistant Attorney General. Re Syntex Laboratories, Inc.,Your ref: PNV :JWK,,;meh 21-48-353, ?? No. 5822~. DEAR Sin: This Is with reference to your letter of April 22~ 1968, and the Urdted States Attorney's letter of May 21, 1968, decliningprosecutlOfl on both the adver- tising and the labeling violations we have reported to you. The United States Attorney declines for the reasons that (1) there Is a rea~ sonable doubt whether the lableing (`1?? monograph) Is substantially different from the approved labeling, (2) the violations appear to be the result of honest differences of opinion as to what is required, and (3) the offense is almost three years old and there are no indi~ations of violations since 1965. (1) There can be no reasonable doubt that the ??? differed from the approved labeling in a substantial `way. It was too brief, it was prom~tionaUy slanted, and It omitted important information for safe prescribing, (a) A comparison of the approved `labeling and the PBR monograph plainly shows *th~t some `of `the most vital safety information was~ omitted from the monograph. A copy of the 1965 monograph is enclosed. It exaggerates the effec- tiveness of the drug, and it minimizes the side effects, precautiotis and contra- indications. We simply cannot understand `how it can be said that thjs abbrevi- ated material, and particularly the lines deVoted to side effects, can possi- bly be said to be substantially the same as the approved directions for safe use of this drug. The substance of the monograph and the substance of the approved labeling are not the same. Fundamentally, what the Company did was to present a reassuring write-up for the physician's desk' which omitted the most important information he needed to have to prescribe this drug for his patients' with safety. As the ci~iminal infor- mation which your office drafted sbow~, the physician was not alerted to the possibility of effects on the fetus if a pregnant woman should thke the dru~ not knowing she was pregnant, he was not alerted to the limited experience with the drug and' its possible long range effects upon a variety of organ tind endocrine systems, including pituitary,' ovarian, adrenal, uterine, liver, anil thyroid,' he was not alerted to the possibility of Intravascular ~1ottipg (a risk now known to be even more serious than In 1965); he was not warned about effects on patients with any condition lnvolving'cfllClUm or phosphorus metabolism, and he was `not told to use the drug with care In any patient who bad a history of psychic depression. We feel confident that we can prove by acceptable medical evidence that the prescribing Information in PDR-1965 was not substantially the same as the approved labeling, as the `regulations require. And we are equally confident that we can prove the omissions and changes mor significant front the standpoint of `patient safety. Onr Advisory Cotamittee on ObstetricS and Gynecology, quoted in the Company's labeling, said that `the physician must de~lde for his patient whether to accept the risk involved In the use of oral contraCeptives, ~ma1l though it may be, but that he "can do this wisely only when there is presented to hint dispassionate scientific knowledge of the available data." The PDR mono- graph did not serve this purpose, and the' violative ads we will discuss later compounded the hazard. (2) There was no basis for considering this Violation a result of an honest difference of opinion as to what is reqnired~ The applicable regulations bad been in effect since 1961, `and the Company's performance shows that it did not comply with what was clearly required-it did not present substantially the same Infor- mation in PDR as In the approved labeling. It had the labeling at hand and It chose to omit some of the information from the PDR monograph. (3) Syntex has not been in compliance sl~c~ 19~5. The ad charges you elirrii- nated would have shown the United States Attorney that the same failures ~o inform continued after that date. And within the past few months, oh Janu- ary 22, 1968, we required the Company to mail a letter to all physicians in the United States calling attention to it~ failure to include in Its then current ads appropriate warnings about use of the drug in psychic depression and `about the possibility of thromboenbolic episodes. A copy of the letter is enclosed. PAGENO="0356" 13606 COMPETITIVE I~RQBLEMS IN THE DRUG' INDUSTRY Turning to the reasons given In your letter of April 22, 1968, for declining to prosecute the advertising violations, we must reiterate what we have frequently said to your representatives, that the brief summary is required to disclose true information related to side effec~ts, comtraindjcatj'ons, and effectiveness as sped- fled in our regulations, not merely the information headed "side effects" and "contraindications" in tl~teapp~oved labeling., We are confident, that any qualified expert would regard the information about clotting, calcium and phosphorus metabolism, effect on organ and endocrine func- tions, ete~, as information related to "side effects" and "contrtxlndicatjons" as those terms were used in the ~962 Drug Amep~lments. The fact that the informa- tion in certain instances was headed "Thyrold' Gland", etc,, does not make it less information related to side effeets than. `the material in the labeling under the heading "Side Effects." A mere reading of the package Insert establishes this. While criminal prosecutions do sometimes Involve strict interpretations of regulations, there Is "no canon against using common sense" in applying a criminal law. As to the point you irn~ke that our understandings of what was said in the advertising are based upon tenuous constructions, we think we should have an opportunity to present these p~lnts to a court or jury with an explanation of their important medical signif1ca~ce. Surely a jury would understand the need to wai~n a physician, and through him the patient, that a, missed dose or a miscalculation in takir~g the oral contra- ceptive drug may result in pregnancy, and that. if that occurS there is danger to the unborn child from eoutii~u~ug~to take tliedrug~ Telling the physician that the drug is contrain~flcnted In *pt~egnancy does not tell him what lie really needs to know for his patient's safety in ~bear1ng a child. It is theY need to alert the user to the hazard to the `unhornehild which may result from a missed dose or q~ miscalculation that calls for this early pregnancy warning. On psychic depression, we. have noted above that as late as January 1968, Syntex was still not properly presenting the message about this hazard to the profession. A corrective letter was necessary, What iS missing in the ads Is the warning that any patient with a history of psychic depression should be care- fully ~observed `(this means the patient shoi,ild hie followed much more closely than the~ routine patienty if a decision iS made by the physician `to prescribe the oral con'tra'ceptive~A statement that the drug is contraindicated in. "severe depression" does not adeqnatel'yady}~~~e ~pbysician `of tile risk he man with `a patient whojias bad de~resnion~in the paM bat now h'as it under contrtyl. Blood clotting has'been~aproblem~with these drugs for a long time. When these ads ran, the labeling was required to `nay that Such epiSode~ had eccurred, that a causal relationship had not been astablishe~, and that the problem was under investigation. The ad said nothing about this. Instead, It said the' drug was contraftidjeated in th'r'onibop1il~hjti~, and pulmonary embolism (current or past). This is quite different from telling the `physician tl~at the nause and effect rela- tiapshjp of the oral contraceptive drugs to `these serious complications; particu- larly in the older age groups, was then' under~ scientific investi'g~tion. As you know, this problem has caused a progressive Strengthening of the warning as moreoxperience has been gained. Finally; we must express our disa~reeraent with the idea that a drug company can use a literally true statement to convince pres~ribers' that Its products are superior to other identical products: A balf~truth `IS still sometimes a great lie. Promotional practices with this class ef products have been characterized by the use of such half-truths to gain marketing advantages. We have had `to require several companies to~ discontinue such ads and to send letters of correction to ~he profession. Far from being harmless pufling-which in any event is not tolerated in prescription drug advertisemeflts-_this kind of promotion affirma- tively misrepresents' both the effectiveness and the safety of the oral contra- ceptives. We have writtep you at this length because of the serious consequences to the profession and to patient's `of Improper prescription drug advertising. Six million women are estimated to be on oral contraceptive drugs at this time in the United States. Their safe use dcpends upon proper promotion of PAGENO="0357" COMPETITIVE PROBLEMS IN T~IE DRUG INDUSTRY 13607 the drugs to the profession. Syntex ha~ seriously failed in t~ie instances cite~j ill Oi~r reeOmmertded prosec~ition case. Yours ~rery truly, WILLIAM W. GOoDRIc~iI, Assistant General Counsel, Food and Drug Division. SEPTEMnER 20, 1968. Be Syntex Laboratories, Inc., F.D.C. No. 58222-Federal Food, Drug, an~1 Cosmetic Act. Mr. WILLIAM W. Goon1~IcH, Assistant General Counsel, Department of.Hcalth, Education, and Welfare, Washington, D.C. DEAR Mn. Goonnicu: Enclosed I~ a copy of our letter of eeen date to the United States Attorney at Newark, New Jersey, r~qnesting~that his offi~e rOconsider the above matter in light of your letter of May 21~ 1~~8. YoUr kttention is invited to our suggestion on page two that the tinited States Attorney interview the Food and Drug Administration experts who would be called as witnesses and review the expected testimony of non-Government experts who may also be called. We believe that such aCtion is necessary to ascertain whether or not the differences between the ~ and the approved labeling are substantial. It ts ~luggested that you arrange with the United States Attorney for him to interview the Food and Drug Administration experts and furnish him with a statement of the testimony w~ich may be expected from any other experts who will appear for the Government. Sincerely. FRED M. VINS0N, Jr., Assistant Attorney General, Criminal Division. By HAROLD P. SHAPIRo, Chief, Administrative Regulations Section. SEPTEMEER 20, 1968. Be Seyntex Laboratories, Inc., F.D.C. No. 53222-Federal Food, Drug, and Cosmetic Act. Mr. DAVID M. SATZ, Jr., U.S.. Attorney, Newark, N.J. DEAR Mn. SATZ: After receiving yoUr letter1 Of `May 21, 1D68, recommending that the abo~re-eapti'oned matter be, c'lo~ëd' ~i't1iout `~proseentlon, we received a letter from Mr. Goodrich, `Assistant General Cotti~isè1, Food and Drpg Division,. taking exceptioi~i to your concluslops arid ~questir~g, ~t further conslderatio~. In view of the atrott~ differeflces `of' OpiDi~n held by `Mr. Goodrich, your Office, and ourselves, we suggOsted that ~ ~heeting be árrknged' whereby alil parties could discuss their views. , However, our efforts tq a~range ~uch a fl~eeting l~ave been to' no avail, and sirice the itiatter `is growing~ stale, ~we belIeve `it' is appropriate to f~rward a copy of Mr. Goodrich's 1etter~ We understand that Mr. Good~ich's áss!staiit, Mr. ~otUieb has previoUsly sbowfi `Miss ~i~oss a rough draft Of this letter So that she is familiar with r~s contents You ~vi1l observe that Mr `~kx~4ricb no~ o~nly disagrees with tour concitision that the alleged viotations of the Act which re1,~ite to the monograph on th~ drug Syfl1~~x, which' `appeared inthe P1~y~ici&n~ J3~s~ Ref ere~ice for, 196~, do not justify criminal prosecfltion, bitt aiso With' our decision that tb~aljege~ viola:' `tions of the, ~dvertistng provisions of the Act do not provide a baSis fo~ prose- cution. Insofar as our decision on the latter problem is concerned, the views set forth in Mr. Goodrich's letter have long been known to us and were thoroughly considei~ed at the timC we reached our conclusion. They, therefore, are not, in our view, so persuasive as to result in a change of our views. PAGENO="0358" 13608 COMPETITIVE PROBLEMS IN' THE DRUG INDUSTRY We have noted that Mr. Goodrich strongly disagrees with your analysis of. the discrepancies between the monograph and the approved labeling, In view of (the decision of Judge Lepoid in the Abbott ease, we `think that your point may be well taken but the question Is impossible to evaluate In the absence of ex- pected testimony. Itt would appear that the nature of these differences is a matter that e~ujd heat be decided after discussion witl~ medical experts of the Food and Drug Administration, who would be called at witnesses, as well as a combination of the statements of any outside experts who would be expected to testify on behalf `of the Goyernment. It is, therefore, suggested that you should interview the appropriate Food and Drug Administration experts and examine the statements of expected witnesses before making a final decision. While it appears that the subject has seen the error of its ways and has voluntarily complied with the desires of the Agency both with respect to its P.D.R. labeling and advertising practices, we believe you should balance these factors with the Agency's opinion as to the seriousness of the offense and the necessity for criminal action. We suggest that the Court's attitude toward this kind of an offense may be ascertained at the time it Imposes sentence `in the Ciba matter, which, we undei~stand, is expected to take place shortly and may be considered by you in evaluating this matter, Accordingly, your reconsideration of this matter in the ~ig~t Of Mr. Good- rich's comments will be appreciated. We trust that you will advise us In your final decision. , Sincerely, FRED M. Vixsox, Jr., 4ssistant Attorney General, Criminal Division. By HAROLD P. SHAPIRO, Chief, Administrative Regulations Section. UNFIEO STATES DEPARTMENT OF JUSTICE, UNITED STATES ATTORNEY, rOR THE DISTRICT OF NEW JERSEY, Newark, N.J., October 30, 1968. Attention Harold P. ShapIro, Chief, Administrative Regulations Section. Re Syiltex Laboratories, Inc., F.D.C. No. 53222-Federal Food, Drug and Cos- nietic Act. Your Ref: FMV :JWK :mc, 21-48-35g. DEPARTMENT OF JUSTICE, Washington, D.C. DEAR Mn. SHAPIrO: At your suggestion we have again reconsidered our file in the above-referenced matter and have again concluded that the case lacks prosecutive merit for substantially the reasons set forth In our letter dated May 21, 1968. We do not believe that interviews with medical personnel concerning the discrepancies between the monograph and . approved labeling would affect our opinion regarding the prosecutive merits of this action The regulations them selves give the company sowe license to synopsize the material of the approved labeling in the monograph. Even If medical personnel could convince us that there were substantial differences and that we could in fact carry our burden of proof, we feel that prosecution of this offense that occurred over three years ago would r~ot be in the best interests of the Federal. Government, especially In light of the fact that revised and current monographs do comply with the regulations. *` On October 2~, 1968, the Ciba Pharmaceutical Company was fined $200.00 on each count of a two count Information charging violations similar to those here, In view of the time expended on this c~e by this o~ee. and by the Food dnd Drug AdminIstration we found this resi4t most discouraging In view of the, factors outlined above and in our previous c~rrespondence, we doubt that we could achieve a mOre staisfactory result In this rnatter. Very truly yonrs DAVm M SATE Jr TJS. Attorney. By `M'4Rt.EN$ GROSS, Msistant U.S. Attorney. PAGENO="0359" COMPETITIV1~ PROI3LEMS IN THE DRUG INDUSTRY 136Q9 UNITED STATES DEPARTMENT OF JUSTICE, Washington, D.C., March 25, 1969. Re Syntex Laboratories, Inc., F.D.C. No. 53222-Federal Food, Drug, `and Cos~ metic Act. Your Ref: MG :ch 748447. Mr. WILLIAM W. GOODRICH, Assistant General Counsel, Food, Drug, and Environmental Health DlvlsioiI, Departmen~t of Health, Education, and Welfare, Washington, D.C. DEAR Mn. GOODRICH: We note that you have been furnished with a COPY o± th~ United, States Attorney's letter to us declining prosecution in the above matter. We have carefully considered whether this office should persevere in Its effort to persuade the United States Attorney to agree to prosecution of the above~ captioned matter. Mr. Sats has filed criminal informatlons in two `similar case~ on pi~evious occasions and Is, therefore, familiar with such prosecutions am~ sympathetic to the enforcement efforts of the Food and Drug Administration. It has been noted that in the Abbott case the court seemed to feel that some edi- torializing was permissible under the regulations then In effect, and in the Ciba and Armour cases very small fines were imposed upon the defendants for viola- tions similar to those reported in the instant matter. Also We have observed that new and more comprehensive regulations are about to be adopted in the field of advertising and that the industry seems' to have accepted the' ruling of the Abbott case that the Physician's Desk Reference constitutes labeling. For the above reasons, we do not believe that, any useful purpose will be served by directing the United States Attorney to institute a prosecution which is contrary to his best judgment. Prosecution is, therefore, declined. Sincerely, WILL WILSON, Assistant Attorney General, Criminal Division. By HAROLD P. ShAPIRo, Chief, Administrative Regulations Section. UNITED STATES DEPARTMENT OF JUSTICE, UNITED STATES ATTORNEY, FOR THE DISTRICT OF NEW JERSEY, N&ieark, N.J., March 28, 1969. Attention Alvin L. Gottlieb. Re Syntex Laboratories, Inc.,' Federal Food, Drug, and Cosmetic Act. Your Ref: 58222. U.S. DEPARTMENT OF EEALTH, EDUCATION, AND WELFARE, Office' of the General Counsel, Washington, D.C. Dw~ MR. GOTTLIEB: In view of the fact that prosecution has been declined in the above-captioned matter, we are returning herewith all exhibits furnished to this office. Please be advised that we are closing our file in this matter. Very truly yours, DAVID M. SATZ, Jr., U.S. Attorney. By MARLENE GRoss, Assistant U.S. Attorney. MAY `25, `1967. In Reply Refer to P.D.C,. No.53548. E~on. RAM5nY, CLARN,. ` ` Attorney General, `. ` ` ` Dep~rtment of Justice, . ` ` Washington, D.C. ` DEAR Mn. CLARI~: We request the institution of criminal proceedings under the Federal Food, Drug, and Cosmetic Act, against Warner-Lambert Pharma. ceutical Company, a corporation trading as Warner-Chiieott ~aboratories, at, Morris Plains, New Jersey. The offenses complained of occurred during the period from about February 4, 1966, to about AprIl 22, 1966; and involved the introduction, into interstate PAGENO="0360" 13610 COMPETITIVE PEOI3LEMS IN THE DRUG INDUSTRY commerce at Morris Plains, New Jersey, for delivery to Glendale, New York, and New Ysrk, New York, Quantities of the drug, Peritrate SA (Sustained Ac- tion Pentaerythritol tetranitrate) tablets; wiljcl~ was misbranded, and. a new drug for which no approval of a New Drug Application was effective for all the purposes for which it was offered. TIi~re are transmitted herewith *a suggested form of criminal lnformatiou and the following ~xbibits: 1. CopIes of Notices of Hearing. 2. A copy of the approved New Drug Application labeling. 3. A copy of the mailing piece "490T718 Octol~er 1965" which included a re- print of `Pentaerythritol ~etranitrate As Adjunct Therapy In the Immediate Postinfarction Period" and "The U~e of Coronary Vasodilators In Acute Coro- nary Occlusion." 4. A copy of the adverti~ement from the JQurnal of the American Medical Association ot January 3, 1966, and rebruary 7, 1966, i4entmed PE-GP-527-4C. 5. A copy of the advertisement from the April 15, 1966, and prll 22, 1966, issues of Me4icc~l World News. 6. The package insert for Peritrate S4~. SECTIONS OF THE ACT INVOLVED Count I of the Information charges violation of 21 U.S.C. 331(a) in that tile d~fendánt caused the introduction into interstate commerce of an article of drug which was misbranded within the meaning of the following sections of 21 U.S.C. 352(a) in that its labeli~ig, namely, the reprints contained In the mailing pieces qontained false and misleading statements and representations concern- ing the drug; 352(f) (1) in that ~aid labeling failed to bear adequate directions for use, and the drug was not exempt, since tile labeling was not substantially the same as the labeling in the ~pprbved New Drug Ap~1ication; and 352(n) in that the defendant failed to include in the advertisement caused to be issued by it wth respect to the drug in the January 3, 1966, issue of the Journal of the American Medical Association, ~t true statement of information in brief summary relating to the effectiveness of such drug as required by 21 CFR 1.105(e). Since these charges are set forth at length in the information and wOre also alleged in the seizure of this drug, they will not be repeated here. Count II alleges violation of 21 U.S.C ~31(d) in that the drug may not be introduced into interstate `commerce in `that it was a new drug within the meaning of 21 U.S.C. 321(p) since it was not generally recog~iized as safe, and effective for all of the uses fOr which it was offered in the labeling and approval of a New Drug Application with respect to such uses was not effective. Count III alleges that a s~e~or~d shipment of the drug wasmisbranded within the meaning of 21 ILS.C. 35~(n) in, that the defendant `failed to include in the. adverti~4~nent caused to be issued itt ~the April 15, 1966, and April 22; 1966 issues of Medical World News, a true, statement of information in brie~ summary' relating to the effectiveness of ~uchL drug as required by 21 CPR 1.105(e). BACEGROIJND INFORMATION Peritrate `SA is a tradetnark held by the defendant for the drug, pentaerythri- tol tetranitrate (PETN) in a time release dosage form Warner-Chilcott Labora- tories submitted to the Food and Drug Administration, a New Drug Application for Peritrate SA which was approved on Nq~eniber. 23, 1959. This permitted the thug to be offered for use In angina pectorts' ~iatients. ` , The mailing piece referred to in this case consisted of reprh~ts of ~rtieles' in the medical literature concerning experimental use of PETN.. The mailing piece was actually addressed and mailed by the firm of Clark-O~eill, Itic.; Pah~le~,~ New Jersey. The list of doctors to whom the literature was to be sent `wad suppli'e~ by' Warner-OhllcOtt Labotatories `b~ means Ol' `stiOker labOls which were applied by the flrn~i and it has no record of names. However, Mr. ~obn Owens, Executive Vlce~?reSldent of Clark-O'Neill informed FDA Ii~speetor~ that such a mailing usually includes the New York metro~ol1tan area A total of 91,000 pieces were sent to medical people' throughout the cotintry. The advertisement In the Journal of the American Medical Assoeia4ion (JAMAl issue of January .3, 1966 is a five page color ad. The copy of the ad PAGENO="0361" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13611 enclosed is in black and white, and the graphs do not reproduce clearly because of the contrasting colors used in the magazine. However, the printing can all be read. If this case goes to trial the FDA will obtain back copies of the mag~- zines from the publishers for use. There are no extra copies available at this time. The ad highlights the study made by Alexander Oscharoff, M.D. and re- ported in the article "Pentaerythritol Tetranitrate as adjunct Therapy In tht~ Immediate Post Infarction Period." The same ad was rerun in the February 7, 1966 issue of JAMA. The advertisement for the drug which was run in the April 15, 1966 and April 22, 1966 issues of Medical World News is a two page ad which reports a study conducted by B. L. Brofman, M.D. using Peritrate SA. On February 28, 1966 in the Eastern District of New York, a libel was filed against the shipment represented in Counts I and II and the drug was seized on the same day. The libel alleged that the drug was misbranded in the same manner as Count I does, and also alleged its shipment in violation of the new drug provisions of the Act as now alleged in Count II. Warner-Lambert Pharma- ceutical Company filed a claim of ownership and on May 12, 1966 consented to the entry of a decree of condemnation without admitting the allegations of the libel. The rest was then destroyed. Hearings pursuant to 21 U.s.C. 335 Counts I and 11.-On April 18, 1966, a hearing was held in the Food and Drug Administration's offices in New York, New York, with the following people representing Warner-Lambert: Mr. Robert Clark, President, and Dr. Frank DiTraglia, Medical Director, Warner-Chilcott Laboratories, Mr. James Hoge and Mr. William F. Weigel of the law firm of Rogers, Hoge & Hills. Mr. Weigel stated that the firm recognized the seriousness of the charges, based on the JAMA advertisement but denied any violation of the Food, Drug, and Cosmetic Act. He also submitted a written statement referring to the charges set forth in the Notice of Hearing. Mr. Weigel said that the claims with respect to myocardial blood flow, in- creased oxygen, and collateral circulation were made prior to October 10, 1962 and were therefore in his opinion grandfathered. This would include the claim concerning collateral circulation in the mailing piece allegedly supported by study of Lumb and Hardy. The written statement asserts that the firm never intended to make any claim for the use of the drug in the postinfarction period as found in the mail- ing piece but felt it was necessary to set forth in detail the manner in which the drug had been used in the Oscharoff study. The statement continued that the Oscharoff studies, which claimed that 22 percent more patients treated with Paritrate SA at a time closely following myocardial infarction remained alive after two years than patients treated with a placebo, were used in good faith and the firm had no reason to question the results of the study. In using these results as part of their labeling and advertising, the firm maintained that it was unaware of the fact that technically it might be making a new claim for the drug. Mr. Weigel indicated that since no case law was established as yet on interpretation of the advertising provi- sions of the Act, it was his opinion that it should be established first in civil actions before criminal prosecution should be instituted. Count 111.-On July 22, 1966 a second hearing was held with the following people present, representing Warner Lambert Pharmaceutical Company: Wil- liam F. Weigel, Esq., Attorney with Rogers, Hoge and Hills, Frank J. DiTrag- ha, M.D., Corporated Medical Control Director, Mr. Frank Markoe, Jr., Senior Vice President, Secretary and General Counsel, Warner Lambert Pharmaceut- ical Company. This was held to discuss the deficiencies of the advertisement in Medical World News. Again Mr. Weigel stated that the firm admitted that the shipment had been made and that the firm issued the advertising which was the subject of the hearing, but denied any violation of the law. He emphasized that the ad offered the drug only for use in the treatment of angina pectoris, in accordance with the policy of the Food and Drug Administration that nitrate-containing drugs are considered as useful only in the management of angina pectoris. Warner Lambert denied the charges contending that Dr. Brofman's findings were clin- ically significant and that the manner in which the subjects were chosen, the methodology employed, and the evaluation of the results were in accordance with generally accepted procedures for such studies. Dr. DiTraglia dictated a prepared statement of his interpretation of the study substantially as follows. 56-592 0 - 75 - pt. 28 - 24 PAGENO="0362" 13612 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Study A as done on 20 patients demonstrated equal therapeutic results for Peritrate and the placebo, but this was not statistically significant because the manner in which the study was run left doubt as to whether the effectiveness of the placebo was not a carry over from the drug which had been administered just prior to the placebo period. In Study B the drug was discontinued for a period prior to use of the placebo thus ruling out any carry-over effect from the drug. Dr. DiTraglia stated that the "Company did not believe that it was justified in portraying this * * * finding concerning methodology (the differ- ence between `Study A' and `Study B') and accordingly limited its references to the reports of those patients who received the active medication in the approved manner as demonstrated by `Study B' ". CONCLUSIONS We believe that the evidence indicates that prosecution is warranted in this case. The advertisements in question did not meet the requirements of the Act and would clearly be misleading to physicians who read them. The purpose of these ads is to provide information to the physician who does not have the time to read all of the reports in the medical literature. The law provides that the ad be factual and provide full information on the product, both good and bad, so that the physician can rely on the representations at to the effectiveness and use of drugs without going behind the ad into the studies referred to. Clearly, these ads will not give this service. It is necessary to read beyond what is reported to be fully informed on the studies. In addition, the labeling for Peritrate SA issued by the firm, contained seriously misleading representations with respect to the drug. Mr. Wiegel is in- correct in his interpretation of the grandfather clause. All claims made before passage of the Kefauver-arris Amendments are not automatically protected. Claims made on October 9, 1962 are grandfathered only if the drug was not a new drug at that time. Drug companies have the responsibility to follow the law in all respects. When one company has not met its responsibility, it is open to criminal prose- cution and we believe that it is warranted in this instance. WITNESSES The principal witnesses in this case will be the Government inspectors who collected the samples and other witnesses to prove interstate commerce; and medical officers of the Food and Drug Administration's Bureau of Medicine who can testify as to the approved new drug application, approved labeling, and with other medical experts the serious nature of the alleged labeling and journal advertising misbrandings. It is requested that, if any form of information is filed other than the one enclosed, the United States Attorney furnish us with a copy thereof. The New York District of the Food and Drug Administration will provide assistance to the United States Attorney. Upon request, this office shall render such further assistance as may be possible. Very truly yours, WILLIAM W. GOODRICH, Assistant General Counsel. APRIL 23, 1968. Mr. WILLIAM W. GOODRICH, A ssistant General Counsel, Department of Health, Education, and Welfare, Washint,ton, D.C. Re Warner Lambert Pharmaceutical Co., FDC No. 53548, Federal Food, Drug, and Cosmetic Act. DEAR MR. GOODRICH: This is in response to your letter of February 13, 1968, submitting for our consideration a suggested criminal action against Warner Lambert Pharmaceutical Company arising out of the introduction into inter- state commerce on April 27, 1966, of the drug "Proloid" which was alleged to have been misbranded because of an advertisement which appeared in certain medical journals during February, April, and May of 1966. We have carefully examined the allegations set forth in the suggested form of information, your comments relative to the nature of the violations, and the four exhibits enclosed in your letter. The information set forth in your letter and its enclosures is not sufficient to enable us to ascertain the exact manner PAGENO="0363" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1361,3 in which the advertisement is violative of the statute and regulations. It Is observed that the narrative account in your letter which endeavors to explain the offense does so in almost the same langu~ge as the allegations of the Infor- mation, and provides little or no additional explanation of the reasons why the advertisement violates the law. Inasmuch as the advertisement did not on its face appear to create, at leaSt in the minds of lay persons, the impression and implications seemingly set out in your letter and suggested form of information, we have discussed this matter personally with Dr. Robert S. McCleery, of the Bureau of Medicine, to make certain the position of the FDA and to ascertain the nature of the evidence available to prove the accusation. We have considered the views of Dr. M~- Oleery and have studied the materials submitted by him. It appears that one of the principal reasons prosecution has been suggested is the contention that the first paragraph of the advertisement creates the im- pression, in the mind of the reader, that in his paper Greer was comparing liothyronine with Proloid, when in fact he was comparing it with desiccated thyroid. Our own realing of the advertisement does not create that impression. The wording of the advertisement seems to compare liotbyronine, not with any particular thyroid product, but with more slowly acting thyroids. In addition, we understand from Dr. McOleery that liothyronine has a more abrupt effect in raising the metabolic rate than does Proloid, and that as between Proloid and desiccated thyroid there is practically no difference in the rate at which the metabolism is raised. Accordingly, the fact that Greer may have used desiccated thyroid in his studies is of little Importance since in this area of comparison there is little or no difference between the action of Pro- bid and that of desiccated thyroid. We understand that another of the agency's objections is founded upon the contention that the comparison between liothyronine and Proloid fails to dis- close that there Is a potential danger of precipitating cardiac complications from the use of Proloid. However, Dr. McOleery has advised that the omission refers not to cardiac complications which arise by reason of any abrupt action on the part of Proloid, but such cardiac reactions as might arise generally from the use of all thyroid preparations. Since the advertisement is comparing the dangers arising from an abrupt action of a drug with the effect of a slower acting product, we fail to see how the omitted information could result in any misrepresentation. Another of the agency's contentions relates to the failure of the advertise- ment to state that Proloid is less rapidly metabolized than liothyronine, and, therefore, cannot be withdrawn as rapidly when toxic manifestations appear. Since the gist of the comparison between liothyronine and Proloid is that the latter is slower in raising the metabolism rate, we inquired whether it would not be obvious to a physician that Proloid is less rapidly metabolized and were informed that the rate at which the drug is metabolized is partly dependent upon and partly independent of the general metabolic rate of the body, and, thus, it would be to some extent obvious and to some extent not obvious. In view of this explanation, and the lack of any statement in the approved labeling which indicates that there is a possibility of such toxic manifestations appearing as would require immediate lessening of the metabolic rate, this ground clearly forms no sound basis for criminal action. The agency contends that the advertisement lacked fair balance because it failed to include three statements by Greer in two of which he indicated that other products were not superior to desiccated thyroid; the third deals with the caution to be exercised in treating elderly patients or those with known cardiac complications. But since the quotation from Greer is not such as to create an impression that Greer is of the opinion that Proloid is, in general, better than other thyroid products, there would seem to be no necessity that Greer's views as to the relative over-all superiority of the various products or his caveat concerning treatment of certain types of patients be expressed. Nor is the statement, apparently true, that Proloid is a more precise prepa- ration whose standards exceed USP requirements one which would require the further statement for which the agency contends. The statement in the ad- vertisement is not a quotation and is referenced to a paper by H. S. Kupperman. The language quoted as being omitted is taken from Greer. It seems that the statement in the advertisement is one of fact from which qualified physicians can form their own conclusions. Under these circumstances the opinions of PAGENO="0364" 13614 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY others as to the medical conclusions to be drawn from the facts are not required. The last quotation, the omission of which the agency argues creates a crimi- nal offense, does not appear to be related to the use of the drug advertised but seems to refer to a general medical procedure recommended in the use of all thyroid products by elderly patients. Such an omission again seems to be only a failure to set forth an opinion or conclusion of one medical researcher and is not necessary to complete a factual statement about the drug advertised. There is apparently some basis for questioning the failure of the ad to disclose the chemical identity of some of the components of Proloid with those of the drugs with which the ad undertook to make some comparisons, although we also understand there may be some difference of opinion as to whether there is complete identity, as reflected by the statement of the Company. But assuming the Agency's contention in this regard is supportable, we do not understand you would contend for prosecution on this factor alone. Accordingly, it is our view that the matter is not one which justifies the bringing of a criminal action. Even if the agency contentions are technically correct, a fact as to which there appears to be at least an arguable basis for a different view, they involve technical refinement of the nuances which flow from the statements used as in our judgment to preclude a successful prosecu- tion. We strongly feel that this is not the kind of a matter in which to under- take criminal action. Accordingly, prosecution is declined. Sincerely, FRED M. VIN50N, Jr., Assistant Attorney General, Criminal Division. By HAROLD P. SHAPIRO, Chier, Administrative Regulations section. DECEMBER 5, 1966. The Honorable ATTORNEY GENERAL, Department of Justice, Washington, D.C. Attention Harold P. Shapiro, Chief, Administrative Regulations Section. Re Wyeth Laboratories, Inc., F.D.C. No. 52677, Federal Food, Drug, and Cos- metic Act. Your reference: FMV :JWK :ik, 21-62-326. DEAR MR. ATTORNEY GENERAL: This is in reply to your letter of October 5, 1966. We enclose a revised form of Information which charges the violative shipment of Serax capsules on July 21, 1965 [in lieu of June 17, 1965], as well as on April 25, 1966. At your request, the evidence of the July 21, 1965 shipment has been obtained In order to avoid charging a shipment which occurred before the advertise- ment's publication dates of June 28 and July 5, 1965. The July 21, 1965 shipment charged in Count I of the revised form of Infor- mation involves the introduction into interstate commerce by Wyeth Labora- tories, Inc., at Paoli, Pennsylvania, on July 21, 1965, via the Pennsylvania Rail- road, of 1248 100-capsule bottles of 15 mg. Serax capsules for delivery to Wyeth Laboratories, Division of American Home Products Corporation, Baltimore, Maryland. The April 25, 1966 shipment charged in Count II involves the introduction into interstate commerce by Wyeth Laboratories, Inc., at Paoll, Pennsylvania, on April 25, 1966, via Needham's Motor Service, Inc., of 180 500-capsule bottles of 10 mg. Serax capsules, for delivery to Wyeth Laboratories, Division of Amer- ican Home Products Corporation, Secaucus, New Jersey. ~The violative shipments were made pursuant to Wyeth Finished Stock Trans- fer Orders No. 51481 and 12226, as confirmed by signed statements made by the respective branch managers at the branches where the lots were received after their shipment in interstate commerce. We have noted your request concerning copies of the advertisements which appeared in the April 25, 1966 issue of the Journal of the American Medical Association, the April 18, 1966 issue of Medical Economics, and in the March 1966 issue of the American Journal of Psychiatry. Because those advertise- ments do not photocopy well, one set of the actual advertisements has been ob- tained for your use and is hereby transmitted together with photocopies of the advertisements. PAGENO="0365" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13615 The United States Attorney will be supplied with a set of the actual adver- tisements by the Philadelphia District of the Food and Drug Administration. We should be happy to render any further assistance as may be possible. Sincerely yours, William W. Goodrich, Assistant General Counsel, Food and Drug Division. IN TEE UNITED STATES DISTRICT COUNT FOR THE EASTERN DISTRICT OF PENNSYLVANIA United states of America v. Wyeth Laboratories. Inc., a corporation, No. 21 U.S.C. 331 and 333. Information COUNT I The United States Attorney charges: That Wyeth Laboratories. Inc., a corporation, organized and existing under the laws of the State of New York, and trading and doing business at Philadel- phia and Paoli, Pennsylvania, the defendent herein, did, on or about July 21, 1965, within the Eastern District of Pennsylvania, in violation of the Federal Food, Drug, and Cosmetic Act, [21 U.S.C. 331(a)], unlawfully cause to be intro- duced and delivered for introduction into interstate commerce at Paoli, Penn- sylvania, for delivery to Baltimore, Maryland, a number of bottles containing a drug, namely, Serax; That displayed upon said bottles was certain labeling which consisted, among other things, of the following printed and graphic matter: 100 capsules SERAX (Oxaxepam) 15 mg. Caution: Federal law prohibits dispensing without prescription. Wyeth Laboratories Inc., Philadelphia, Pa. That said drug, when caused to be introduced and delivered for introduction Into interstate commerce as aforesaid, was misbranded within the meaning of 21 U.S.C. 352(a) in that said drug was a prescripition drug which was a new drug subject to 21 U.S.C. 355 and said defendant, the manufacturer of said drug, failed to include in the advertisements caused to be issued by said defend- ant with respect to said drug in the June 28, 1965 and July 5, 1965 issues of the Journal of the American Medical Association, a true statement of information in brief summary relating to the side effects, contraindications and effectiveness of said drug as required by regulations, 21 CFR 1.103(e) and (f), to wit, (1) the aforesaid advertisements did not present a brief summary which fairly showed the effectiveness of said drug in the conditions for which it was recom- mended in the advertisements, together with a showing of all side effects and contraindications of said drug that were pertinent with respect to the uses recommended and suggested in the advertisements, including the information from the approved new drug application labeling for said drug concerning said side effects and contraindications, and (2) the aforesaid advertisements lacked fair balance in presenting with respect to said drug information on effectiveness and information on side effects and contraindications. COIYNT II The United States Attorney further charges: That Wyeth Laboratories, Inc., a corporation organized and existing under the laws of the State of New York and trading and doing business at Philadel- phia and Paoli, Pennsylvania, the defendant, herein, did, on or about April 23, 1966, within the Eastern District of Pennsylvania, in violation of the Federal Food, Drug, and Cosmetic Act, [21 U.S.C. 331(e)], unlawfully cause to be intro- duced and delivered for introduction into interstate commerce at Paoli, Penn- sylvania, for delivery to Secaucus, New Jersey, a number of bottles containing a drug, namely, Serax; That displayed upon said bottles was certain labeling which consisted, among other things, of the following printed and graphic matter: 500 capsules SERAX (Oxaxepam) 10 mg. Caution: Federal law prohibits dispensing without prescription. Wyeth Laboratories Inc., Philadelphia, Pa. PAGENO="0366" 13616 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY That said drug, when caused to be introduced and delivered for introduction into interstate commerce as aforesaid was misbranded within the meaning of 21 U.S.C. 353(n) in that said drug was a prescription drug which was a new drug subject to 21 U.S.C. 355 and said defendant, the manufacturer of said drug, failed to include in the advertisements caused to be issued by said defend- ant with respect to said drug in the April 25, 1966, issue of the Journal of the American Medical Association, in the March 1966 issue of the American Journal of Psychiatry and in the April 18, 1966 issue of Medical Economics a true state- ment of information in brief summary relating to the effectiveness of said drug as required by regulations, 21 CFR 1.105(e) and (f), to wit, (1) the aforesaid advertisements did not present a brief summary which fairly showed the effectiveness of said drug in the conditions for which it was recommended in the advertisements, (2) the aforesaid advertisements lacked fair balance in presenting information on the effectiveness of said drug, and (3) the aforesaid advertisements recommended and suggested said drug for uses which were not set forth in the approved new drug application labeling for said drug. UNITED STATES ATTORNEY FOR THE EASTERN DISTRICT OF PENNSYLVANIA. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, May 15, 1967. The Honorable ATTORNEY GENERAL, Department of Jn8tice, Washington, D.C. Attention Harold P. Shapiro, Chief, Administrative Regulations Section. Re Wyeth Laboratories, Inc., FDC No. 52677, Federal Food, Drug, and Cosmetic Act. Your ref: FMV :JWK :mfs, 21-62-326, 22A-48-20. DEAR MR. ATTORNEY GENERAL: This is in reply to your letter of February 15, 1967, advising of your tentative conclusion that no violation of 21 U.S.C. 352(n) (3) can be proved against the above named company. We believe that a violation of that provision has occurred, since the "message" portion of the advertisements contain false and misleading statements of effec- tiveness of the drug and those misstatements cannot be corrected by a "true statement" of such properties elsewhere in the advertisement under the heading "prescribing information". This conclusion is supported by the language of the section and by the legislative history of 21 U.S.C. 352(n). We think both show that an advertisement cannot meet the "true statement" requirement when it is inconsistent within itself and when it fails to achieve truth in its central theme. The legislative history shows that Congress intended 21 U.S.C. 352(n) to deal completely with the problems of false and misleading advertising. The require- ment that the advertisement include "a true statement of . . . such other in- formation In brief summary relating to side effects, contraindications, and effec- tiveness as shall be required in regulations which shall be issued by the Secre- tary" was meant to give the Secretary authority to promote truthful informa- tion in the entire advertisement. In sponsoring the amendment which restored the section on prescription drug advertising to the Senate bill, Senator Kefauver pointed out that "eminent medical authorities testified that much of drug advertising is misleading and some is false. They further emphasized that when a doctor is misled, his pa- tient's health is endangered." Senate Report No. 1744, 87th Cong., 2nd Sess., p. 39 (1962) [Emphasis added]. Representative Dingell quoted a study by the American Medical Association, during debate on this measure, stating "the most heinous and despicable practice that doctors found was this-'a company knowingly misleading a doctor through bad advertising' ". 103 Cong. Rec. 21086 (September 27, 1962). This provision was intended to provide for "truth in drug advertising", ac- cording to Representative Celler, who likened the desired effect of this amend- ment to the restrictive regulation of information on securities, stating: "Our securities laws provide that stock may not be sold to the public against false or misleading information. I fail to see why we should not be equally stringent in the sale of lifesaving-but potentially dangerous-drugs. PAGENO="0367" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13617 "While I am well aware of the many medical miracles wrought by our modern wonder drugs, and while the drug companies have many splendid accompli~h- ments of which they may justly be proud, I am not convinced that false or mis- leading drug advertising is the price we must pay for pharmaceutical progress." 108 Cong. Rec. p. 21086 (September 27, 1962). Representative Multer referred to the function of the regulations: "The Secretary's regulations necessarily would be limited to a fair summari- zation of side effects, contraindications, as well as effectiveness so that a bal- anced story appropriate to an advertising page could be presented. * * * * * * * "There can be no justification for half truths either in an advertising piece Or in labeling copy. We are dealing with drugs that are lifesaving and which are used in serious, debilitating diseases. Fairness alone requires that the message to physicians be a balanced one giving both the good and the bad of the drug, within the limits of advertising copy, and that the patient's interest not be obscured by a glowing picture of the effectiveness of the drug with no mention at all of its possible side effects and contraindications." 108 Cong. Rec. 21091 (September 27, 1962). These statements illustrate the Congressional concern that the advertisement not mislead the physicians in any way. Certainly, the most obvious way in which advertisements mislead is by omission of side effects and contraindications, and Congress, naturally, focussed a great deal of attention on these facets. HoW- ever, the frequent use of the term "misleading" and the context in which it was used, clearly demonstrate that Congress was concerned with the truth of the whole advertisement. This concern is evident in a number of examples of drug advertisements which were presented on the House floor. Representative Blatnik described for his colleagues "two examples of how ads can mislead". 108 Cong. Rec. 21084 (September 27, 1962). The first was a 3-page advertisement for the drug "Singoserp". He pointed out that the headline for the ad states: "For the first time, the drug that lowered this patient's blood pressure without side effects." Yet elsewhere the ad states that the drug "has infrequent side effects". He criticized, as well, the use of meaningless illustrations: "Obviously they had quite a bit of space because you notice at the bottom one-third of the lefthand page is a picture of a scale. Now that does not provide any fundamental basic knowledge to a doctor because he knows what a weigh- ing scale looks like, but it is in the picture." The ad was printed in several medical journals, although the screening comittee for the Journal of the American Medical Association rejected it be- cause: They felt this advertisement, and I quote, "carries a misleading implica- tion of a broad, too all-inclusive nature." That criticism goes far beyond the mere omission of a "brief summary" of side effects, contraindications, and effectiveness. It is directed to the misleading nature of whole advertisement, and, we submit, reflects the opinion of Repre- sentative Blatnik, the sponsor of the floor amendment that was adopted, as to the abuses which the prescription drug advertising provisions were intended to correct. The second example was fin ad for the drug "Tao". Again, Representative Blatnik criticized the waste of space devoted to a picture of a slide rule: Would you not think they would have used that space to tell what the bad effects, the side effects might be? In short, to tell the whole story. They do not need a slide rule to illustrate what the drug does. He then points out the misleading nature of the ad: Listen to what it says: On the first page it is implied that Tao is a superior antibiotic. And on the other page it says: Tao encompasses even strains of common pathogens (notably straphylo- cocci) [sicj resistent to penicillin and erythromycin. They say it is superior to penicillin. What does the American Medical Associa- tion say about it? They said that this was "altogether too strong and mislead- ing" a statement. This is a quote about this particular advertisement. This particular advertisement claimed that the drug has a greater range of efficacy than penicillin. The American Medical Association committee reported to the advertising agency that this claim "seems completely false since clinically it is quite inferior to penicillin in the treatment of most infections." * * * * * * * PAGENO="0368" 13618 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The American Medical Association rejected this as being completely .false and misleading, yet 6 months later the same ad appeared in four widely used medical journals * * * Here again, the criticism is directed to the false and misleading nature of the advertisement as a whole. The statements in the "message" portion of the ad- vertisement were false and misleading. The addition of a "ture statement" in a "brief summary" of side effects or contraindications or effectiveness might afford the physician other information on which to judge the drug, but could not itself correct the misleading effect of the advertisement. Certainly, the ad- vertisement would be misleading if it asserts that "Tao" is soperior to penicillin in the "message" portion even if the "brief summary" said that it was not. The total effect would be something less that a "true statement" of effectiveness of the drug. Similarly, Representative Dingell described an advertisement for the drug "Medrol", as follows: "I was surprised to find in my study of material involving one medical prac- titioner that an ad appeared in one of the standard publications on the subject showing the photographs of a patient who allegedly suffered from colitis. I was further surprised to find in my additional study that this so-called reputable manufacturer who was advertising had actually gone so far as to use X-ray photos of persons who had not received the drug.These two different photo- graphs of two different patients appeared in the ad with statements in the ad- vertisement purporting to indicate that it was the same patient on a before and after treatment basis, before and after he had received the drug Medrol." "This is the kind of advertisement that the amendment to the drug adver- tisement section tries to correct, to assure that the doctor shall receive to the fullest e~rtent possible the fairest and most complete statement of side effects, contraindications, and efficacy of the drug in simple form." 108 Cong. Rec. 21064 (Sept. 27, 1962). [Emphasis added] The false illustrations in that advertisement occurred in the "message" por- tion, and would not be affected by a true statement of side effects, contraindi- cations, or effectiveness, "in brief summary", or otherwise. From this example, the conclusion is inescapable that Representative Dingell believed that section 502(n) was intended to eliminate false and misleading statements throughout the advertisement. The drug advertising examples given in debate demonstrate that Congress Intended to promote truthful drug advertising in all aspects. The concept of truth in drug advertising would be meaningless if it were interpreted to apply to only a portion of an advertisement. Such an interpretation would illogically limit the meaning of the phrase "true statement" and would do violence to the understanding of the provision by Congress. Rather than preventing half-truths, the provision would enable advertisements to mislead, as has occurred in the instant case, by permitting truth to be mixed with fiction. Certainly, Congress did not want this amendment to promote confusion to physicians. To limit regulation of the advertisement to examination of a portion of It-whether labeled "brief summary" or otherwise-could only have that result. Only if the entire advertisement be subject to the requirement of "a true statement" can 502(n) have the enforcement effect sought by Congress. This very Issue was taken up in the 1963 hearing to establish regulations on prescription drug advertising. The Commissioner stated and the Pharmaceutical Industry agreed that the "true statement" concept applied to the whole ad message. On October 1, 1963, Mr. Larrick wrote to Mr. Gesell, counsel for the Industry, as follows: I. Fair Balance and Prominence. It seems clear to us from the legislative his- tory of section 502(n) that Congress intended this new section to deal com- pletely, and not partially, with the problems of false and misleading advertising which had been called to its attention. The legislative history clearly shows that Congress intended the administering agency to have jurisdiction over the entire advertisement and that the phrase "brief summary" was introduced only to authorize use of a stripped-down statement of the drug's effectiveness, side effects, and contraindications when the sponsor wished to limit the size of his ad. Our regulations are not intended to prohibit use of graphic presentations, headlines, or similar advertising techniques. Our basic purpose is to provide assurance that the advertisement will fairly present the message to the physi- cian of what the drug will do, what its limitations are, and what side effects PAGENO="0369" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13619 and contraindications may attend its use. Somewhat different size type may be used in presenting information with respect to side effects, contraindica- tions, and warnings than that used in the eye-catching headlines. But the regu- lations would not permit the concealment, subordination, or deemphasis of this essential side effect and contraindication information to minimize its disclosure as a part of the total message the advertisement conveys. With this background, we will answer the first four questions. This was placed in the record and was taken to be the understanding of th~ provision and regulations by all parties. Moreover, this interpretation is consistent with other regulation in this field. The terms "false" and "misleading" have been uniformly interpreted to apply to an entire piece of labeling or advertising. Labeling is false and misleading if it contains ambiguities, exaggerations, half-truths, and over-emphasis in an.V respect. United States v. 95 Barrels * * * Vinegar, 265 U.S. 438, 442-443 (1924) V. B. Irons, Inc. v. United States, 224 F.2d 34 (CA. 1, 1957), cert. den. 354 U.S. 923; United States v. 46 Cartons * * * Fairfaj~ Cigarettes, 113 F. Supp. 336 (D.N.J., 1953). Nor do disclaimers in the piece cure false and misleading state- ments. V. B. Irons, Inc. v. United States, supra; Research Laboratories v. United States, 167 F.2d 410 (CA. 9, 1948), cert. den. 334 U.S. 843. The very same considerations apply to advertisements. See Rhodes Pharmacal Co., Inc. v. Federal Trade Commission, 208 F.2d 382, 387 (CA. 7, 1953) and Murray Space Shoe Corporation v. Federal Trade Commission, 304 F.2d 270, 272 (CA. 2, 1962) where the Court cites the Food and Drug case United States v. 95 Barrels of Vinegar, supra, for the proposition that the advertisement as a whole must be examined, and that if the advertisement contains statements capable of both a misleading and a truthful interpretation, the advertisement is misleading. P. Lorillard, Inc. v. Federal Trade Commission, 166 F.2d 44 (C.A. 4, 1950) ; Beckenstette v. Federal Trade Commission, 134 F.2d 369, 371 (CA. 10, 1943). The entire context is examined to determine whether or not the overall impression is misleading and deceptive to the audience. Federal Trade Commis- sion v. Standard Education Society, 303 U.S. 112 (1937); P. Lorillard, Inc. v. Federal Trade Commission, supra. Even though words and sentences of an advertisement may be literally and tecnically true, when they are framed in a setting which may mislead or deceive, the advertisement is violative. Becken- 8tette v. Federal Trade Commission, supra. We enclose a redrafted information for your consideration which charges that the advertisements in their entirety do not include true statements as to effectiveness, side effects, and contraindications. We believe that this informa- tion is sufficient to withstand a motion for a directed verdict. Very truly yours, WILLIAM W. GooDRICH, 4ssistent General Counsel, Food and Drug Division. PAGENO="0370" 13620 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY PREPARED STATEMENTS Statement by Neil L. Chayet, Esquire as Counsel on behalf of the Committee for the Care of the Diabetic before the Subcommittee on Monopoly of the Select Committee on Small Business U.S. Senate January 31, 1975 accompanied by Dr. Robert Bradley Chairman Committee for the Care of the Diabetic PAGENO="0371" COMPETITIVE PROBLEMS IN THE DRTJG INDTJSTRY 13621 Mr. Chairman: On behalf of the Committee for the Care of the Diabetic, Dr. Robert Bradley as Chairman and I as Counsel are pleased to testify today before this Committee on a matter of extreme importance to the medical and scientific community: the continuing controversy relating to the UGDP study. The Committee on the Care of the Diabetic is a group of 180 physicians who represent leading diabetologists and it includes clinicians, researchers and academicians throughout the United States. The group was formed in November 1970 shortly after the UGDP results were released. Its chairman, as I mentioned, is Dr. Robert Bradley, who is here with the today, and its coordinating, committee consists of Drs. Henry Dolger. Peter Forsham, Holbrooke Seltzer, and John B. O'Sullivan. For the last five years. the Committee on the Care of the Diabetic has been engaged in the continuing and often bitter controversy which has surrounded the University Group Diabetes Program (UGDP). This controversy has involved the Congress, the Courts, the National Institutes of Health, the Food and Drug Administration, the manufacturers, and scientists, physicians and patients throughout the United States and, indeed, throughout the world. PAGENO="0372" 13622 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY At the onset, we wish to state, for the record, the position of the Committee on the Care of the Diabetic with regard to the TJGDP study. First it is important to stress what we are not seeking to bring about. We are not asking that the FDA ignore the UGDF findings completely or that these findings not be reflected in the labeling accompanying these drugs. In fact we find it difficult to understand why, some 19 months after this matter was decided by the Court of Appeals for the First Circuit, the FDA has not acted definitively to bring about new labeling. We are seeking new labeling to insure that this study and other relevant studiks will be made known to physicians and their patients. However, such labeling must indicate the fact that there is great controversy surrounding this subject and that a material weight of scientific and medical opinion does not accept the results of the UGDP study. In short, what we are seeking is fair balance in the governmental handling of this matter. I realize that nearly eight million dollars is a great deal of money and t en years is a very long time, and criticism of such an effort is neither to be given nor taken lightly; nevertheless, costly mistakes in research, as in all human endeavors, have been made before, and will be made again, and criticism and controversy will not disappear merely because those who seelc to justify this study pretend that it eit her does not exist or is of no account. We have set out in this testimony some of the fundamental prob- .terns confronting analysis of the UGDP as a study and the Biometric Society's report on that study. PAGENO="0373" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13623 I. The need for science tobe free from governmental in- tervention where there exists validsç nti controverS~y. The power of government is awesome. It must be wielded with discretion as will as tact, with equity as we.l.l as understanding. Partisanship by government throws what can be overwhelming weight into the balances of scientific ex- change. Such partisanship fosters positions which are both dangerous and incomprehensible. After repeatedly seeking the raw UGDP data since 1971, our Committee most recently received a letter from Dr. Whedon of the National Institutes of Health, dated January 27th, stating: `To my knowledge, no one in the Department of Health, Education and Welfare has ever had any of the raw data of the UGDP study." In effect, this data is not available to the experts of our Committee. Despite our inability to obtain TJGDP raw data, we did obtain the Biometric Society report this past Tuesday which states: "Dr. C. Klimt, the Director of the Coo rdinatiCet and his staff provided extensIve tabulations and original data of the UGDP trial." PAGENO="0374" 13624 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The Committee on the Care of the Diabetic has re- peated.ly protested the partisanship of government agencies in this controversy. The release to the press of the UGDP study before its scientific presentation triggered a storm of controversy. Our criticism of multiple flagrant defects in the UGDP study was and still is, apparent.ly, considered ~ challenge to the National Institutes of Health which expended over $7. 7 million for a study which neither tested oral hypo- glycemic therapy as it is practiced nor provided any insights into insulin therapy. * For years patients were carried in a study monitored by NIH personnel- -a study which has become the subject of severe cxiticism by many of the leading diabetologists in the United States. * Otter agencies in HEW, such as the FDA, have enter- ed the scene and, despite the clear existence of valid scientific controversy, the government has to this day sought to impose its will by excluding from ora.l hypoglycemic package inserts the very "fair balance" required by its own regulations. When challenged in the courts, it seeks by regulatory means to ex- empt itself from the preexisting requirement of fairness. PAGENO="0375" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13625 * In a manner not clear to us, a principle investigator of the UGDP was engaged by the FDA an d appears from doc- uments available to us to have participated in the preparation of FDA material relating to the legal aspects of this contro- versy. * When chaflenges to the validity of the study cou.ld not be silenced, the NIH arranged for Dr. Thomas C. Chalmers to have the Biometric Society undertake an ana.lysis primarily of the statistical aspects of the study, despite the fact that many if not most of the central criticism was clinical in na- ture. The same Dr. Chalmers now appears as the author of an editorial in the S. A. M. A. in which he modestly omits his personal role as a government official in arranging for the Biometric Society study as he proceeds to hail its findings, to support it with selections of references relating to experi- mental and human studies, while ~ reports in the literature. I do not know what this is called in science. In politics it has been called a "cover-up". There is need for further in- quiry into the whole area of the treatment of diabetes and also the role of government agencies and individuals in the UGDP affair. PAGENO="0376" 13626 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The government has continually been a party at interest in the UGDP controversy. Government officials should have been sensitive to American judicial and sci- entific processes and should have delegated both the selec- tion of the review body and its mandate to an uninvolved, nonpartisan group. Instead, its actions, in effect, were equivalent to being judge, jury and prosecutor, publicist and apologist. PAGENO="0377" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13627 Ii. The rights of patie nts tp be ull~free1yn properly info rmed Diabetes is strongly affected by emotional factors. Confidence in the physician-patient relationship is essential for optimal management of diabetes. As has happened so often in the past with the UGDP study, patients have been exposed to frightening headlines and unsubstantiated charges before the actual report has either appeared in the scientific press or been presented to a jury of its peers. This week, newspapers, TV and radio were flooded with statements unsupported by data before even the experts and diabetologists of our Committee could obtain any re.levant information. It does not serve the interests of pa- tients nor of the physician-patient relationship, nor of science itself to repeatedly confront such situations in which there is neither time for suitable study and deliberation nor for cor- rective action on the part of the medical profession. This week, the worried diabetic who coflsults his physi- cian can get little comfort from his doctor who has no data on which he can base an informed opinion on the Biometric Report. Both Dr. Chalmers editorial and the Biometric Report will not appear in J. A. M. A. until February. How is the diabetologist 56-592 0 - 75 - pt. 28 - 25 PAGENO="0378" 13628 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY or the practicing physician to know upon what Dr. Chalmers (in editorial and press release) has based his estimate of 10, 000 to 15, 000 deaths; how can they determine, as we have, the fact that some of the very references Dr. Chal- mers puts forth in support of the validity of the UGDP study are in reality in contravention of the UGDP findings? Trial of medical treatment by headline and press release is as bad for science as it is for law, and results, medically, in dis- ruption of patient treatment as it raises unsupported doubts. PAGENO="0379" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13~29 III. Observations on the Biometric Report and the Chalmers Editoria.L At the outset, it should be noted that the authors of the Biometric report do not claim tO be qualified to appraise the clinical aspects of the TJGDP study. The Biometric re- port states: `The choice of specific selections criteria adopted by the UGDP was a responsibility that was shared with medical experts and is not a topic on which this com- mittee as a whole claims primary competence." This dis- avowal of clinical ~ompetence was well taken, as will be seen below. The Biometric report recognizes that "the result ~f [the UGDP] decision to terminate the study [is toj leave us with some residual uncertainty as to the meaning of the findings." The report further states, "We discovered a puzzl- ing anomaly concerning the distribution of the two sexes in the four treatment groups within clinics... The discrepancy in Seattle alone would represent an unusual event in random allocation... A more important point is whether these find- ings provide evidence of a breakdown of the randomization PAGENO="0380" 13630 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY procedure- -a contingency which might have grave impli- cations for the credibility of the whole study... We were not able to find an assignable cause for the surprising a Ilo- cation of the sexes to treatments but have no reason to think the study has been compromised by a breakdown of the ran- domization to the treatment groups." * The Biometric Society could have considered other eviden cc of a possible breakdown of the randomization pro- cedure if they examined the two-fold and even more than three-fold difference in total time at risk as between male and female patients, differences in compliance, autopsy rates, etc. Among the defects in the UGDP study, the Bio- metri~ report states, `The omission of a history of smoking was a blunder. U This is praising with a faint damn as there were other blundering omissions such as the failure to iden- tify patients on thiazides, as well as the failure to identify those patienfs with family histories of heart disease. The Biometric Society mildly observed that the UGDP report "made use of some relevantly unfamiliar and explora- tory techniques'. These very techniques have, for several years, caused critics to raise the question of statistical man- ipulation of data. * It is interesting to note that the calculation of age at death of the data presented by the UGDP shows that alt tolbutamide patients, males and females, had a mean age of 65. 2 and all placebo patients 61. 5 and the difference at death between placebo females and toibutamide females was six years, 59. 8 for placebo and 65. 8 for tolbutamide group. PAGENO="0381" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13631 The Biometric Society report notes that "On the question of cardiovascular mortality due to toibutamide and phenformin we consider that the UGDP trial h~s raised suspicions which cannot be dismissed on the basis of other evidence presently available." However, we believe the Biometric report incorrectly minimizes some of the evi- dence which it analyzes, as in the case of the Paasikivi study which is inconsistent with their thesis of the toxicity of tol- butamide. They omit a recent report of a prospective study which has become a landmark in the field of epidemiology, that of the Framingham group. We have included a copy of this report, published in the American Journal of Cardiology, as an appendix to our testimony. The Biometric group then focuses upon a critical issue:. "There remains the gus stion of generalization of thes~ findin~. As has been frequently point out, t conditions of drug use in this study were, to some extnt abnormaL ud~eiS ~ pentu~- able to obtain inadequate control on tolbutamide could be shifted to insulin." PAGENO="0382" 13632 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY In the conclusions of the UGDP group there is a brief warning against extrapolation of UGDP findings to other dos- ages and other types of patients. One could never judge from the press releases, the news stories, the public actions of government officials that both reports related to a hypothetical test situation and not to the actu!tp~actice of oral hypoglycemic treatment. Under certain circumstances, the Biometric report finds that "There remains the question whether tolbutamide, although ineffective in a fixed dose regimen, might be an effective therapy as ordinarily used." I am sorry that I cannot supply the page citation but wi.ll do so when it is published next month. In their analysis, the Biometric Report apparently ac- cepts the study of Keen et al as statistically valid and atten- tion is drawn to the fact that those authors concluded "a sig- nificant degree of primary protection against cardiovascular events can be conferred by tolbutaniide in moderately and mildly hyperglycemic people." In concluding their analysis of the Paasikivi study they state, "This study neither confirms nor contradicts the UGDP findings as the population under consideration was not PAGENO="0383" COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY 13633 one of maturity onset diabetes, and the patients taking tot- butamide had been exposed to a relatively small dose for a shorter time than applied in the UGDP study." H owever, the report here is internally inconsistent for the Biometric group elsewhere holds that `The concern about possible tol- butamide toxicity would not really be lessened if it could be shown that the study group contained some nondiabetics. A drug found toxic in such subjects would not likely be counted safe for well documented diabetics either." If the authors of the Biometric Report are suggesting that cardiotoxicity ~~se is a central issue, then it becomes difficult to comprehend their failure to accept the Paasikivi report which in any consideration of toxicity qua toxicity is most pertinent. This study was carried out on 178 survivors from a first myocardial infarction. The sensitivity of a dam- aged heart to cardiotoxic substances is reflected in the nar- rowing margin between effective and toxic dose of the cardio- glycosides when used in such situations. It would be remark- able that a cardiotoxic agent given in the period of greatest danger "during the first 12 months [after myocardial infarc- tion] would show a significant difference in favor of tolbuta- mide." Fifteen controls died and only six tolbutamide pa- tients--2-1/2 times more controls than the treated patients. PAGENO="0384" 13634 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY Then 19% of the control group died as compared with 14% of the tolbutamide group with no significant difference in survival after five years. Such a study would weigh heavily against any conclusion that cardiotoxicity was involved in the UGDP tolbutamide patients. It is also disturbing to note that neither the Biometric Report nor the Chalmers editorial saw fit to call attention to the recent report on the Role of Diabetes in Congestive Heart Fai.lure, The Framingham Study" (Am. Jrnl. Cardiology 34: 29-34, July 1974). The findings are pertinent to any consid- eration of cardiotoxic effects of oral hypoglycernics. May we quote from the paper: `Role of Insulin; Further examination of the ~group of patients with dia betes who had congestive_heart failure revealed that more than half were takin~jnsuiin. Treatment of diabetes was therefore su~j~cted to analysis revealing that the on.~y~subgroup of dia betic subjects that sustained a substantial and statistically g~ficant increased risk of co~gq~tive failure was the gr~ treated with insulin. This was demonstrated_~yabivariate regression ana~ysis accounti~gj~r age (Table 9)." PAGENO="0385" COMPETITIVE PROBLEMS IN THE DRIJG INDIJSTRY 13635 The table reveals that insulin increased the risk of congestive failure over oral hypoglycemic agents and other treatments in both men and women aged 45 to 74 years. This finding, from this cias sic non-controversial prospec- tive study of 18 years which reviewed 5, 209 men and wo- men, is in contradiction to the findings of the briefer UGDP study reporting on 823 patients. The Framingharn study is, however, consistent with the findings of Paasikivi study. We find it exceedingly disturbing that the great Framingham study, acknowledged as a true landmark, was neither referred to by Chalmers in the editorial or in the Biometric Report. To the best of our knowledge it a.lso has been conspicuous by its absence from press releases. Our cursory review of the UGDP study and other studies such as the Framingharn study points out that valid scientific controvers~ exists with respect to any conclusions to be drawn in this area at this time. There exists important scientific studies challenging some of the fundamental assump- tions and conclusions drawn from the UGDP study. In the light not only of the UGDP findings but of the controverting studies there is need for new, truly unbiased and well controlled objec- PAGENO="0386" 13636 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY five prospective studies. Action by this Committee can make a significant contribution to the future of American medicine and science by recommending that U. S. govern- mental agencies divorce themselves from partisan partici- pation in the presence of scientific controversy and that government follow a doctrine of equal opportunity for re- search and studies by qualified individuals holding different views. PAGENO="0387" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13637 American Journal of Caraiology 3~i: 29-3l~. (July 197lt). Role of Diabetes in Congesfive Heart Failure: The Framingham Study WILLIAM B. KANNEL, MD, FACC MARTHANA HJORTLAND, PhD' WILLIAM P. CASTELLI, MD Framin,gham, Massachusetts Bethesda, Maryland The Incidence of congestive heart failure was determined in relation to prior diabetic status in 5,209 men and women aged 30 10 62 years fol- lowed up for 18 years in the Framingham study. Men aged 45 to 74 years had more than twice the frequency of congestive failure as their nondiabetic cohorts, and diabetic women had a fivefold increased risk. This excessive risk appears to be caused by factors other than pccel- erated atherogenesis and coronary heart disease. Even when patients with prior coronary or rheumatic heart disease were excluded, the dia- betic subjects had a four- to fivefold Increased risk of congestive heart failure. In women (but not men) with prior coronary disease, diabetes also imposed a threefold increased risk of congestive failure. Fudher- more, the Increased risk of heart failure in the diabetic patients persist- ed after taking into account age, blood pressure, weight and cholester- ol values as well as coronary heart disease. Women with diabetes ap- peared to be especially vulnerable and, irrespective of coronary dis- ease status, had twice the frequency of congestive heart failu~e as men. The excessive risk of heart failure among diabetic subjects was confined to those treated with insulin. The data suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes, as a result of eñher small vessel disease or metabolic disorders. Congestive heart failure is a common end stage of heart disease due to a variety of causes. The incidence is far from trivial. The annual rate is 2.3/1,000 men and 1.4/1,000 women aged 30 years and over.' Despite the availability of potent glycosicles and diuretic agents, Con- gestive heart failure continues to be a lethal process, and half of the patients die within 5 years of onset.1 Previous study' revealed that hypertension and coronary heart disease were the dominant cau~ies, but 14 percent of men and 26 percent of women with congestive flail- ure also had diabetes, an apparent excess. The purpose of this report is to explore the role of diabetes in the development of congestive heart failure and to assess its contribution taking into account the presence of coronary heart disease and atherogenic factors such as hypertension, high serum cholesterol levels, overweight and increased age. Methods From the Framingham Heart Disease Epidemiol- ogy Study, Framingham, Mass., and the Nation- al Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Manuscript accepted February 27, 1974. Address for reprints: William B. Kannel, MD. Framingham Heart Disease Epidemiology Study, 123 Lincoln Sl., Framingham, Mass. 01701. The Framingham study was initiated in 1949 to explore the epidemiology of cardiovascular disease in a general population sample of 5,209 men aud women aged 30 to 62 years. These subjects have been followed up for the de- velopment of cardiovascular disease including congestive heart failure. At every biennial examination each participant has had, in addition to a histocy and physical evaluation, a 13 lead electrocardiogram, a chest X-ray film, tests of vital capacity, urinalysis, measurements of blood sugar, uric acid and cho- lesterol levels and deterr~inations of Framingham relative body weight, Detailed descriptions of the sampling procedure, response rate, methods q( examination and laboratory procedures and the criteria for the outcome of disease have been reported previously.2 July 1974 The American Journal of CARDIOLOGY Volamo 34 29 PAGENO="0388" 13638 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE I Criteria for Congestive Heart Failure Major criteria Paroxysmal nocturnal dyspnea or orthopnea Neck vein distension Rates Cardiomegaly Acute pulmonary edema S, gallop Increased venous pressure »=l6cm H,O Circulation time »=25 second Hepatojugular reflux Minor criteria Ankle edema Night cough Dyspnea on exertion Hepatomegaly Pleural effusion Vital capacity decreased 1/3 frOm maximum Tachycardia (rate »=120/min) Major or minor criterion, Weight loss »=4.5 kg in 5 days in response to treatment Patients were considered to have congestive heart failure if two major or one major and two minor criteria were present concurrently. TABLE II Annual Incidence of Congestive Heart Failure by Age, Sex and Presence of Prior Coronary or Rheumatic Heart Disease: Year Follow-Up Study it Total Pxpulatino 3D xi ROD * Inci- Subjects wi lb Prinr C Persnn New denco Persno New Yearn at CIIF per Years at COP tncidence Age (ye) Risk Events l0OOt Risk Events per 10003 Men 45-54 14.100 28 20 1,074 17 158 55-64 10,414 43 41 1,564 28, 179 65-74 3,700 26 70 762 14 184 Women 45-54 17.598 ii 6 678 5 74 55-64 13,688 45 30 1,202 24 200 65-74 5,232 34 65 766 20 265 CHD = coronary heart disease; CHF = congestive heart failure; RHD = rheumatic heartdisease. Criteria At each biennial examination a diagnosis of c~ngestive heart failure was entertained on clirsical grounds and the opinion of a second examiner obtained. All suspected cases thsis uncovered from biennial clinic examinations or from interim ivfvsrmation olutained from hospital records and physician's office repvsrts were reviesved by a panel of issves- tigalors vising unifusrns criteria. The diagnosis of congestive heart failure was accepted only in persouss with at least tuvo major or one major and tsvo minsr criteria present concur- rently as indicated in Table I. Minor criteria that could be attributed to some other medical conditisan were rejected. Only about half the persons diagnosed as having congestive heart failure at the time of the clinical examination on the basis of the examination or interim hospital or physician's office information were included in this study. Persons who had congestive failure at the time of the ini- tial examination were excluded, leaving a population of 5,192 men and women aged 30 to 62 years at risk. Follow- up study during the ensuing 18 years was reasonably coin- plete, with 80 percent of subjects receiving every possible biennial examination. The remaining 20 percent were seen at less frequent intervals, and admissions to the only gener- al hospital in town were monitored daily, Only 2 percent of the sample were completely lost to follow-up study. Glucose intolerance was assessed from casual blood sugar determinations, urinary sugar values, or a history of clinical "diabetes." Blood sugar levels were determined by the Somogy-Nelson method. A diagnosis of diabetes was made in subjects who (1) had an abnormal glucose tolerance test during hospitalization or their physician's laboratory eval- uation, (2) were taking insulin or oral hypoglycemic agsnts, or (3) had casual blood sugar values> 160 mg/100 ml. Statistical Techniques Incidence rates for congestive failure were ascertained according to diabetic status, age, sex and coronar3i (or rheu- matic) heart disease status. Subjects were reclassified by age at each examination; a case svas defined as a subject free of congestive heart failure at a given examination but having failure at the time of the next biennial examination. The method of Mantel.Hasnzsl3 was used to construct summary chi squares to assess differences in the frequency of congestive heart failure in diabetic and nondiabstic subjects and to estimate the rink of heart failure in the presence of diabetes. To assess the joint and net effect of diabetes taking into ~ccosmnt other related atherogenic vari- ables, musitivariate coefficients were computed and com- pared with bivariate coefficients taking only age into ac- count. Analysis was confined to subjects aged 45 to 74 years since too fesv cases occurred before age 45 for meaningful analysis. The bivariate function to assess the regression of incidence of congestive heart failure on diabetic status and age svas estimated by the nuethod of Walker and Duncan.4 The mnultivariate function wan estimated by the Walker and Duncan maximal likelihood method using, in addition to the variables of age and diabetic status, systolfc blood pressure, serum cholesterol and relative sveight. Results Frequency of congestive heart failure: During the 18 year follow-up period, congestive heart failure, as defined by the specific criteria, developed in 97 men and 86 women aged 45 to 74 years. The inci- dence of heart failure increased sharply with age. As expected, the incidence was considerably greater in the subjects with prior coronary or rheumatic heart disease. There was a male predominance at all ages (Table II), but this predominance appeared to wane with advancing age. Among subjects with prior coro- nary or rheumatic heart disease, there wax a male predominance only under age 55 years. About half of the subjects with a diagnosis of congestive heart fail- ure had coronary disease; more than three-fourths had hypertension. About 16 percent had antecedent diabetes, an apparent excess over the expected rate.' 30 July 1974 The American Journal of CARDIOLOGY Volume 34 PAGENO="0389" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13639 TABLE Ill Annual Incidence of Congestive Heart Failure According to Age Sex and Diabetic Status at Each Biennial Examination: 18 Year Follow-Up Study Diabetic States Age 4 Person Years at Risk 5 to 54 Years New CIII Cases Incidence CHF perJlO,000 Age 55 to 64 Years * Age 65 to 74 Years Person Years at Risk New CIII Cases Incidence CIII per/lO,000 Person Years at Risk. New 6SF Cases ln~idence .CHF per/10,000 Men° . Nondtabetic Diabetic Total 13,696 404 14,100 26 2 28 19 50 20 9,864 550 10,414 40 3 43 41 55 41 3,428 272 3,700 20 6 26 58 221 70 . Women' . Nondiabetic Diabetic Total 17.268 330 17,598 8 3 11 5 91 6 13,156 532 13,688 36 5 41 27 94 30 4,904 328 5,232 25 9 34 57 274 ~5 * Meo: For alt ages combined difference in incidence is statistically sigsificant at(P <0.05). (chi square 6.50); relative risk 2.4. Women: For all ages combined difference in incidence is statistically sigsificant (P <0.01) (chi square 42.54); relative risk 5.3. Method of Mantel- Haeozel. Diabetes and congestive heart failure: During the 18 year study, diabetes was present or developed in 141 men and 151 women, allowing 1,226 person years of follow-up experience for men, 1,190 for women, Almost 40 percent of those labeled "diabet- ic" were treated with insulin. In most of these pa- tients, diabetes was already evident at entry into the etudy. Another 40 percent were treated with oral hy- poglycemic agents and about 20 percent were fol- lowing a diet only or were receiving no treatment. Ex- amination of the incidence of congestive heart failure according to diabetic status at each biennial exami- nation' revealed a distinct excess risk in diabetic subjects of both sexes and at all ages (Table III). The small numbers do not allow accurate age-specific es- timates of risk, but for all ages combined, men had a 2.4-fold increased risk and women a 5-fold increased risk (Table IV). Role of factors leading to atherogenesis and coronary heart disease: Diabetic subjects are gen- erally believed to have higher, than average blood pressures, lipid values and relative weights and to manifest coronary heart disease at an accelerated rate. The excess frequency of congestive heart failure in diabetic subjects could derive from these abnor- malities, particularly the hypertension° and coronary heart disease. However, an examination of the preva- lence of antecedent coronary or rheumatic heart dis- ease in all subjects with congestive heart failure re- vealed the same proportion of subjects with prior heart disease in the diabetic and nondiabetic groups (Table V). This finding suggests that the increased risk of congestive heart failure in the subjects with diabetes has another cause than accelerated athero- genesis and coronary heart disease although age and severity of coronary disease are not taken into ac- Risk of Congestive Heart Failure According to Sex an Status at Each Biennial Examination: 18 Year Follow d Diabetic -Up Study Incidence Credo Age- Perssn Years Annual Adjusted' Diabetic Status At Risk per 10,000 per 10,000 Relative Risk Men Aged 45 to 74 years Nondiabetic 26,988 31,87 32.14 Diabetic 1,226 89.72 75.98 2 36 ` Women Aged 45 to 74 years Nondiabetic 35,322 19.53 19.75 Diabetic 1,190 142.85 101.60 5 14 ` o Indirect method, Significartt at P <0.05 (chi square = 6.50). Significant at P <0.01 (chi square = 12.53). TABLE V Prevalence of Antecedent Coronary (or Rheumatic) Heart Disease (CHD) Among Patients Aged 45 to 74 Years with Congestive Heart Failure (Diabetic vs. Nondiabetic Subjects): 18 Year Fellow-Up Study Diabetic Subjqcts Nendiabelic Subjects With CIII Without CHD With CHD Without CHD Men b 6 54 32 Women 10 7 39 30 Total 15 13 93 62 TABLE IV July 1974 The American Journal of CARDIOLOGY Volume 34 31 PAGENO="0390" 13640 COMPETITIVE PROBLEMS IN TABLE VI Annual Incidence of Congestive Heart Faiture (CHF) According to Sex and Diabetic Status at Each Biennial Examination Excluding Subjects with Coronary (or Rheumatic) Heart Disease Before the Development of Failure: 18 Year Follow-Up Study Annual Incidence Diabetic Status Person New Age~ Years At CHF Crude Adjusted' Risk Cases per 10,000 per 10,000 Relative Risk Men aged 45 to 74 Years Nondiabetic Diabetic Total 23,844 32 13.42 13.53 970 6 61.86 51.41 24,814 38 * Women Aged 45 to 74 Years Nondiabetic Diabetic Total 32,892 30 9.12 9.23. 980 7 71.43 50.54 33,872 37 5.48t Indirect method. Significant at P <0.51 level (chi square = 0.15 and 17.27 for men and women, respectively). TABLE VII Annual Incidence of Congestive Heart Failure (CHF) According to Sen and Diabetic Status at Each Biennial Enamination in Subjects with Coronary (or Rheumatic) Heart Disease Before the Development of Failure: 18 Year Follow-Up Study Incidence Diabetic Status Persnn New Age- Years CHF Crude per Adjusted' At Risk Cases 10000 per 10,000 Relative Risk Men Aged 45 to 74 Years Nondiabetic Diabetic Total 3,144 54 171.76 172.07 256 5 195.31 190.99 3,390 59 ... ... 1 11 ` Wnmen Aged 45 to 74 Years Nondiabetic Diabetic Total 2,436 39 160.10 147.39 210 10 476.19 465.17 2,646 49 ... ... 16 ~ Indirect method. Significant at p <0.01 level (chi sqnare = 8.51). count in this tabulation. This hypothesis is confirmed by the finding that even when patients with prior coronary or rheumatic heart disease were excluded, patients with diabetes still had a four- to fivefold in- creased rink of congestive heart failure (Table VI). Also, among pernons with prior coronary or rheumat- ic heart disease,.diabetic women had an excess rate of THE DRUG INDUSTRY congestive heart failure. This excess could not b demonstrated for men in the small number of case available (Table VII). Furthermore, a comparison of the regression coef ficients in the bivariate (taking only age into ac count) and multivariate case (taking into accoun blood pressure, cholesterol and relative weight a well) indicates that the effect of diabetes is not me diated through these atherogenic traits (Table VIII). An examination of the regression of the incidence of congestive failure on diabetic status in men with and without coronary heart disease also reveals substan- tial and significant coefficients only for patients without coronary heart disease. The regression coeffi- cients in the multivariate case are only slightly re- duced compared with those in the univariate case (Table VIII). Taking all these facts into consideration it appears unlikely that diabetes promotes congestive failure by accelerating coronary atherogenesis. Nor does it ap- pear that hypertension accounta for the increaned risk. In women, significant regressions are noted in both those with and those without prior coronary heart disease although the coefficients are somewhat larger in the latter group. Also, the coefficients are substantially larger in women than in men. Role of insulin: Further examination of the group of patients with diabetes who had congestive heart failure revealed that more than half were taking insu- lin. Treatment of diabetes was therefore subjected to analysis, revealing that the only subgroup of diabetic subjects that sustained a substantial and statistically significant increased risk of congestive failure was the group treated with insulin. This was demonstrated by a bivariate regression analysis accounting for age (Table IX). Discussion The finding of an increased rink of congestive heart failure in diabetic subjects is not unexpected in view of the frequent association of diabetes with hyperten- sion, hyperlipidemia, obesity and coronary heart dis- ease. The strength of the relation, particularly in women, and the demonstration that the excess risk of myocardial decompensation in the diabetic subject is independent of all these atherogenic traits are unex- pected and indicate some other mechanism. It has been suggested that some form of cardiomyopathy is associated with diabetes.6 The findings reported herein lend some substance to this claim. Metabolic causes of diabetic cardiomyopathy: Such diabetic cardiomyopathy could result from dig. betic microangiopathy or an abnormal myocardial metabolism. The heart normally derives most of its energy for contraction from free fatty acids, although glucose, lactate and pyruvate are also used.7~ Any reduction in oxygen tension immediately produces changes in the electrical and contractile performance of the heart. Efficient metabolism of fatty acid and pyruvate is hampered by hypoxia, leaving only the glycolytic pathway to generate the high energy phos. 32 July 1974 The American Journal of CARDIOLOGY Volume 34 PAGENO="0391" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13641 TABLE VIII Regression of Incidence of Congestive Heart Failure on Diabetes: 18 Year Follow-Up Study Regression Coefficient Men Aged 45 to 74 Years Women Aged 45 to 74 Years Bivariate* Moltioaniatef Bisariate' Moftivaniatet With Prior CHD or RHDt . Coefficient 0.10 006 1.13 ttestl 1.15 0.21 0.12 3.05 2.97 (no. cases/no, at risk) (59/1,700) (58/1,641) (49/1323) Without Prior CHD or RHDJJ (47/1,275) Coefficient 1.33 1.01 1.67 itest 2.94 2.17 (no. cases/no, at risk) 3.88 3.15 (38/12,407) (36/11,899) (37/16,936) (37/16,16ô) 0 The bivariate function was estimated bythe method of Walker and Duncan' using the variables diabetes and age. The multivariafe function was estimated by the method of Walker and Duncan' using the variables diabetes, age, systolic blood pressure, serum cholesterol and Framiogham relative weight. To be included in this group at a given examination (n) the subject most have had coronary or rheumati~ heart disease on or be- fore examination (n + 1). I At test value of 1.96 is significant at the 0.05 level. II To be included in this group at a given examination (n), the subiect must not have had coronary or rheumatic heart disease on or before examination (n + 1). phate bonds to fuel the heart'o work. It thuo appearo TABLE IX that glucose and inoulin fuel the failing hypoxic heart. ~ This hypotheois would explain the difficulty of the diabetic iochemic heart but does not account for myocardial decompensation in the absence of ________________________________________________ hypoxia. However, in the diabetic heart there is come evi- dence to suggest that free fatty acids are also not used efficiently. Hearts of rats with alloxan-induced diabetes have been found to accumulate increased myocarçlial triglyceride in lipid droplets.8 Human di- abetic hearts extract more fatty acid and ketonen than the nondiabetic heart, but in the light of the foregoing this phenomenon could indicate that more free fatty acid is being shunted into structural lipid as less is metabolized for energy. It may be that the diabetic heart, because of faulty utilization of fatty acid must, as in the case of ischemia, fall back on gly- colytic metabolism for energy. Thin places it in jeop- ardy because the utilization of glucose, which is insu- lin-dependent, is also faulty. Thin energy crisis may be further compounded in the diabetic subject by a block between pyruvate and the tricarboxylic acid or Krebs cycle. These major metabolic disturbances could provide a metabolic basin for eventual myocardial failure. The fact that only the insulin-dependent diabetic pa- tient appears peculiarly susceptible to congestive heart failure supports the foregoing in that only these diabetic patients appear to have difficulty with ex- cessive and faulty acid metabolism leading to ketosis as well as impaired glycolysis. The fact that subjects with diabetes of adult onset treated by diet or orally administered drugs have no increased risk of conges- tive heart failure suggests that the central metabolic Regression of the Incidence of Congestive Heart Failure (Without Prior Coronary or Rheumatic Heart Disease') on Treatment of Diabetes: 18 Year Follow.Up Study Bieariate Treatment Cssfficientf t Valse~ Men Aged 45 to 74 Years Insulin 1.76 3.26 Oral hypoglycemic agent 0.68 0.66 Other 0.92 0.90 Women Aged 45 to 74 Years Insulin 2.21 4,47 Oral hypoglycemic agent 0.56 0.54 Other 1.49 1.45 0 To be included in this group at a given examination (n), the subject must not have had coronary or rheumatic heart disease on or before examination (n + 1). The bivariate function was estimated by the method of Walker and Dnncanl using the variables type of diabetic treØt- ment and age. Al value of 1.96 is significant at the 0.05 level. defect promoting failure may be ketosis and insulin deficiency. Once heart failure ensues, the process ap- pears to be self-perpetuating since it has been shown that failure further suppresses insulin release.'° Role of insulin-treated diabetes: The finding that the excess risk of congestive heart failure is con- fined to the insulin-treated diabetic subjects raise~ July 1974 The American Journal of CARDIOLOGY Volume 34 33 PAGENO="0392" 13642 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY three possibilities: (1) Only severe, long-standing dia- betes leads to congestive failure. (2) Only insulin- dependent diabetes promotes cardiomyopathy. (3) The insulin treatment itself is damaging to the myo- cardium. The lack of any discernible increased risk of congestive heart failure in the group treated with tol- butamide or diet tends to exclude severity or dura- tion of diabetes as the sole mechanism since an inter- mediate risk would be expected in this group under this hypothesis. Insulin in itself would not seem to be the culprit since in the patient with keto-resistant di- abetes of adult onset endogenous insulin levels are often high either spontaneously or as a result of stim- ulation. by orally administered hypoglycemic agents Thus, the most tenable hypothesis is the difference in the kind of diabetes, implicating insulin-dependent, ketotic insulinopenic diabetes of early onset as the promoter of cardiac decompensation. It is hard to exclude duration of diabetes or its se- verity from consideration. Congestive heart failure could be primarily a function of either factor and hence exhibit a particular relation to insulin-treated diabetes. Data are too scarce in this cohort to assess the effect of the type of treatment required or used versus the duration or severity of diabetes, and these aspects are difficult to disentangle without conduct- ing a controlled experiment. It would be expected that the insulin-treated group would have more small vessel disease such as nephropathy and retinopathy (and perhaps in the heart as well). We cannot tell from our data. Role of large and small vessel coronary dis- ease: The excess occurrence of heart failure in pa- tients with diabetes could be a result of either large or small vessel disease in the coronary arterial circu- lation. Such diseases particularly of the small vessels, 1. McKee PA, Castet5 WP, McNamara PM, et at: The natural his- tory of congestive heart failure: the Framingham study. N Engt Med 285:1441-1446, 1971 2. Gordon T, Kaneel WB: The Framingham study: an epidemiologi- cat investigation of cardiovascular disease. Sections 1-27, U. S. Govt Printing Office, NHLI, Bethesda, Md. 1968-1972 3. Mantel N, Haenzel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natt Cancer Inst 22: 719-748, 1959 4. Watker SN, Duncan DB: Estimation of the probability of an event as a function of several independent variables. Biometrika 54:167-179, 1967 5. Kannel WB, Castettl WP, McNamara PM, et at: Rote of blood pressure in the development of congestive heart failure: the Framingham study. N Engt J Med 287:781-787. 1972 6. Rubler 5, Dtugash J, Yuceogtu YZ, et at: New type of cardio- myopathy associated with diabetic gtomerulosclerosis. Am Cardiol 30:595-602, 1972 7. Taylor SH: lnsu5n and heart failure. Br Heart J 33:329-333, is more apt to be severe in the insulin-dependent dia- betic patient than in the patient not treated with in- sulin. The ischemic myocardium, which is more de- pendent on glucose and insulin for energy, would be especially vulnerable. All diabetic subjects should have difficulty in coping with an ischemic myocardial episode in view of the dependence of the hypoxic heart for energy on the glycolytic metabolic pathway, which is impaired regardless of the type of diabetes. And, indeed, once coronary disease develops, the dia- betic subject fares worse than the nondiabetic subject - in relation not only to congestive failure, but also to recurrence of infarction, myocardial rupture and sur- vivaL" Accelerated coronary atherosclerosis has been noted in diabetic subjects, and these patients seem to have more myocardial infarctions, especially silent infarctions.'3 The latter observation suggests some difference in pathogenetic mechanism from that of the nondiabetic infarction. Myocardial and small ves- sel abnormalities have been studied less extensively than large vessel disease in the diabetic patient.6 Myocardial hypertrophy and diffuse, patchy fibrosis have been reported more frequently than macroscop- ic myocardial infarction.6 Microangiopathy has been well described in the skin, kidney, retina and skeletal muscle, but has not been well documented in the heart.6 More systematic studies of the diabetic myo- cardium and its small vessels such as those of Blu. menthal and co-workers'3 are urgently needed. These investigators reported more proliferative lesions of arterial branches of all sizes and of venules as welL They also found arteriosclerotic-appearing lesions in the small arteries and arterioles at least twice as fre- quently in diabetic as in notldiabetic patients with coronary disease.'4 1971 8. tJngar I, Gilbert M, Siegel A, et at: Studies on myocardiat me- tabolism in diabetes, Am J Med 18:385-396, 1955 9. Opte LM: Metabolism of the heart in health and disease. Parts 1-3. Am Heart J 76:685-598. 1968; 77:100-122, 383-410, 1969 10. MaJid PA, Sharma B, Meeran MKM, et at: tvsulin and glucose in the treatment of heart failure. Lascet 2:937-931, 1972 11. Editorial: glucose and the heart. Lancet 2:1295-1296, 1972 12. Goldenberg 5, Ales M, Blumenthal HT: Sequelae of arterioscle- rosis of the oorta and coronary arteries: a statistical study in di- abetes mellitus. Diabetes 7:98-108, 1958 13. Kennel WB, McNamara PM, Felnlelb M, et at: The unrecog- nized myocardiat infarction: 14 year follow-up esperience in the Framingharn study. Geriatrics 25:75-87, 1970 14. Blumenthal HT, Alex M, Goldenbert S: A study of lesions of the intramural coronary artery braeches In diabetes meltitus. Arch Pathot 70:27-42, 1960 References 34 July 1974 The AmerIcan Journal of CARDIOLOGY Volume 34 PAGENO="0393" COMPETITIVE PROBLEMS IN THE DR'IJG INDUSTRY 13643 STATEMENT OF EDWARD M. CHESTER, M.D. PROFESSOR OF MEDICINE CASE WESTERN RESERVE UNIVERSITY DIRECTOR OF THE AMBULATORY MEDICINE TEACHING CLINIC CLEVELAND METROPOLITAN GENERAL HOSPITAL 3395 SCRANTON ROAD, CLEVELAND, OHIO 44109 BEFORE THE SUBCOMMITTEE ON MONOPOLY SENA~E SMALL BUSINESS COMMITTEE U.S. SENATE JULY 10, 1975 56-592 0 - 75 - pt. 28 - 26 PAGENO="0394" 13644 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I am pleased to respond to the invitation to testify concerning the use of oral hypoglycemic agents in the treatment of diabetes mellitus. I am a Professor of Medicine at Case Western Reserve University and Director of the Ambulatory Medicine Teaching Clinic at Cleveland Metropolitan General Hospital. A large segment of my time is devoted to teaching 3rd and 4th year medical students during their clinical clerkships. My research efforts have been directed toward an understanding of the eye changes which are associated with diabetes mellitus. For the past 16 years I have been active in the' direction of the Diabetes Clinic at Cleveland Metropolitan General Hospital. Prior to 1959, when I joined the full time faculty of Case Western Reserve University. at Cleveland Metropolitan General Hospital, I had been engaged in the practice of internal medicine for 18 years in a suburban area of Cleveland. My practice dealt chiefly with patients who suffered from cardiovascular disease and/or diabetes mellitus. During the years of practice I served as a part time teacher of Case Western Reserve University at Cleveland Metropolitan General Hospital. The Diabetes Clinic at Cleveland Metropolitan General Hospital provides care for approximately 500 patients with' diabetes mellitus per year. Approximately 80% of the patients have the maturity onset form of the disease. Prior to 1973 the majority of this group of patients were treated with oral hypoglycemic agents with a limited degree of success. Although dietary instruction was provided for the patients, there was little compli4nce. PAGENO="0395" COMPETITIVE PROBLEMS IN THE DRTJG INDUSTRY 13645 When the results of the UGDP study were issued in 1970, we became concerned with our use of the oral hypoglycemic agents. We urged the physicians who cared far patients with diabetes in the clinic and hospital to pay heed to the results of the above study and to re-evaluate their treatment of the maturity onset group of patients. In an attempt to learn the extent of the use of oral hypoglycemic agents and their cost, the amounts of these medications dispensed by our staff were recorded from 1968 to early 1972 (See Table I). Review of these data disclosed an alarming increase in the use of these agents from 1968 through 1970. Response to the recommendations of the UGDP study was reflected by a modest decrease in the use of the oral agents during 1971 and 1972. Because we believed that the use of these agents was still excessive, the following letter was dispatched to the Pharmacy Committee of the hospital early in 1973. May 24, 1973 Emanuel Wolinsky, M.D. Chairman of the Pharmacy Committee Dear Doctor Wolinsky: The results of the University Group Diabetes Program (UGDP) (Diabetes, 19, Supplement 2, 747-830, 1970) allows one to develop the following conclusions concerning the safety and effectiveness of the oral hypoglycemic drugs, specifically the sulonylurea group (Tolbutamide and Chlorpropamide). (1) In the group treated with Tolbutamide there was a significant increase in deaths from cardiovascular disease, as compared with those treated with either insulin or strict adherence to a calculated diet. (2) That Tolbutamide was not as effective as either; jesulin or strict adherence to an isocaloric diet in the control of levels of blood sugar The UGDP study subsequently reported comparable results with the use of Phenformin (J.A.M.A., 217, #6, 777-784, 1971). It is only fair to point out that there are skeptics who do not accept the results of the above study. PAGENO="0396" 13646 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY I accept the results of the study and believe that the use of Sulfonylureas (Tolbutamide and Chlorpr opamide) and the ~iguanides (Phenformin) should be restricted because they appear to be hazardous to health and are far less effective and more expensive than insulin. I suggest that we implement a form of control which would restrict the use of Suifonylurea drugs (Tolbutamide and Chiorpropamide) and Phenformin with the following exceptions: 1. Patients who cannot administer insulin to themselves because of severe visual impairment or other physical handicaps such as neurologic disorders which impair use of arms and hands. 2. Patients who refuse to use insulin. In order to accomplish such control the department of medicine would provide a list of physicians who could authorize the use of the drugs under discussion. Other services may wish to provide a similar mechanism. In 1972, $30, 000 were expended for Tolbutamide, Phenformin, and Chlorpropamide. Substitution of insulin would be less costly. Sincerely yours, Edward M. Chester, M.D. The results of this educational reminder and form of control produced the results noted in Table I. Table II indirectly indicates that many of the patients previously receiving oral agents were started on insulin therapy. Continuous review of the use of the oral agents is in progress with the intent of further decreasing their use except under the circumstances noted in the letter of May 24, 1973. It is apparent that restriction of the use of these medications in a hospital can be accomplished by education of patients and physicians and by providing a method of control. The problem is unfortunately not as simple for a variety of reasons when one attempts to achieve similar results with patients who are under the care of private physicians. Among these reasons are: PAGENO="0397" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13647 1. That the conclusions of the UGDP study are not accepted by some eminent authorities on diabetes mellitus. 2. That education of physicians lags well behind the knowledge developed through research. Unfortunately drug company literature provides the major source of information for many physicians. 3. The lack of adequate patient education in their understanding of diabetes and the hazards of oral hypoglycemic agents. 4. The failure adequately to impress the patients with sufficient understanding of the importance of a calculated isocaloric diet and their failure to comply in this respect. 5. The ease of using oral medication compared with the injection of insulin. The UGDP study clearly demonstrated that standard doses of oral hypoglycemid agents did not effectively reduce levels of blood sugar over a 5 year period. These data confirmed previous studies which disclosed that the success rate in managing diabetes with tolbutamide at the end of 5 years was only 13% (DeLawter and Moss, J.A.M.A., 181, 1962, 156). Relapse or secondary failure is recorded as 22% within 5 years (Camerine -Davalos and Marble, J. A. M. A., 181, 1962, 1). Six to seven years after therapy with oral hypoglycemic agents only 6-12% remain well controlled. (A.M.A. Drug Evaluations, Publishing Sciences Group Inc., 2nd Edition, 1973, p. 130, Alton, Massachusetts). Yet despite the ineffectiveness of these hypoglycemic agents and their demonstrated relationship to increased mortality from cardiovascular disease, these drugs are still widely used in the treatment of maturity onset diabetes. I have noted previously the reasons for the failure-.onJhe:. part of physicians and patients to heed the warning of the hazards and ineffectiveness of this group of drugs. PAGENO="0398" 136~t8 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY There appear to be 3 approaches to this problem. These include an immediate restriction of their use through firm wai ning and labelling via the F D A a long term educational process and the development of more rigid drug testing requirements Recommendations I. Immediate warning to all physicians of the hazards by a bulletin from the F. D. A. stating the following: A A suitably calculated isocaloric diet selves as the cornerstone for the treatment of maturity onset diabetes B A su table tr al of dietary management for seveiai weeks should be instituted first C. If adequate levels of blood sugar cannot be obtained with this regimen, even in the absence of symptoms associated with diabetes insulin therapy should be instituted. D The oral hypoglycemic agents are a potential hazard to health and should be used after the patient has been advised of this fact with caution only under the following circumstances (1) If the patient is handicapped by serious visual loss or other physically incapacitating disorders (2) If the patient refuses to use insulin. The drug companies should be required to include the above facts on the package Inserts of medication despite the fact that physicians infrequently read them Some method of identifying these medications as ha&ardous must be developed for patient protection PAGENO="0399" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13649 Ii. Long term educational effort. Medical school educators, clinicians who care for patients in university and community hospitals must emphasize the facts known about these drugs to medical students, house officers, and physicians in practice. Efforts should be made to reach the last mentioned through post graduate courses and through the development of self educational units in an attempt to provide more reliable and scientifically based information to counteract the biased and often inaccurate statements issued by pharmaceutical companies and the "throw away" psuedomedical periodicals. A vital step in the educational process is the need to encourage and support the young investigator. Greater availability of research and training grants through the National Institutes of Health or other government agencies should be encouraged. For it is through the development of Such investigator~ and teachers that the many problems related to diabetes may be resolved. lit. Adequate long term trials befote drugs are released for use. Most drugs, and this applies to the oral hypoglycemic agents, were initially tested for their ability to lower levels of blood sugar in animals. Search f~r toxicity was made as well. These studies were short in duration. After short term trials in ma~ were made by able investigators and clinicians the drugs were released. Subsequent long term studies of these drugs were retrospective and dealt only with tbeir.ability to alter levels of blood sugar and lipids. The UGDP study was the first well controlled prospective study and was designed to determine the role of these drugs in the development of vascular disease. Thus many years elapsed before medications, which were commonly used, were found to be hazardous to health and to possess very limited effectiveness. Standards for PAGENO="0400" 13650 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY long term studies must be developed by the F.D.A. to insure adequate clinical trials of drugs before their release. The steps indicated above are likely to be met with severe outcry and resistance by pharmaceutical companies and scientists and clinicians who do not accept the conclusions of the UGDP study. Support of the medical societies, particularly the American Diabetes Association would be essential. Restriction in the use of the oral hypoglycemic agents would significantly alter modes of care for the patient with diabetes. To begin, it would needfully provide a great emphasis on the importance of dietary management. In many instances with adherence to diet adequate reduction of blood sugar and removal of symptoms would follow. Physicians or their assistants would have to instruct patients in the use of insulin when diet alone did not suffice. Thus more teaching would be needed for each patient. Perhaps more teaching related to mechanisms involved in the production of the disease, the need for preventing infection, manifestations of hypoglycemia, and other measures would be taught as well. Since the cost of insulin is considerably less per patient than oral hypoglycemic agents there would be a decrease in total cost. The issue of the clinical use of research information is exemplified by the mixed reception of the results and recommendations of the UGDP study. Why, one may ask, are there delays in the transmission of research data to its clinical applications? These are several reasons: 1. Early research data may be presented initially to select groups in research societies and published in journals which are read by only highly trained specia~ist:s. In addition most articles are not published for at least 6 months after they have been submitted. PAGENO="0401" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13651 2. Further delay occurs because of the need for clinical testing. 3. When the information is finally released there are varying degrees of receptivity and understanding. Here we deal with a variety of variables which Include initial training and continuing education of physicians. Medical educators, both basic scientists and clinicians, and medical societies must play an important role in narrowing the gap between delivery of research information and its clinical application. Corrective measures in this regard are mostly likely to be effective if medical students, fellows, and house officers in training are adequately prepared to receive and evaluate research data. This requires improvement in the teaching of basic science, biostatistics, and clinical pharmacology during medical school and post graduate training programs. As a teacher of students and physicians in training during their formative years, one is aware of the need to stimulate them to share in the joy of learning. Such an effect develops and fosters intellectual curiosity, critical thinking, and the self discipline required for continued intellectual development throughout their careers. During their period of formal training they will recognize the need to continue their education once they embark upon their careers as practitioners. Reading current literature, attending medical meetings, utilization of self educational material, and attending specific post graduate coerces ar~ effective approaches. Physicians should be urged, if practicing in groups, to exchange information and ideas with peers. Journal clubs and conferences could be developed. As a former practitioner, I found that becoming a part time teacher at a university affiliated hospital was an excellent learning experience and a considerable stimulus to encourage my own intellectual development. Medical schools should encourage suitably trained physicians to participate in clinical teaching. PAGENO="0402" 13652 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The task of communicating with the well established practitioner is more difficult. Those who are well trained in various major specialities generally keep abreast of new developments in their area of interest and expertise through many of the educational methods previously mentioned. Unfortunately, there is another group of physicians, who because they are either overworked or inadequately trained, find or take little time to read or attend educational meetings, and rely upon ill informed pharmaceutical company representatives and "medical throw aways" for their sources of information. Many of them observe that because of their lack of scientific background and the tremendous burst of new information that they cannot understand and profit from current medical literature. They are thus poorly prepared to accept new research data which are clinically applicable. As a result they are not equipped to be critical of some of the claims by drug comp3nies of the effectiveness of various forms of therapy. * It is difficult for me to envision major corrective measures for this group. Obviously they should be urged to attend post graduate courses in which efforts would be made to bring them abreast of current understanding of disease and therapy. The Academy of General Practice has made efforts to promote such courses. Medical schools, medical societies at local and national levels must share in this educational process. PAGENO="0403" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13653 TABLE I COMPARATIVE USAGE OF ORAL HYPOGLYCEMIC AGENTS CLEVELAND METROPOLITAN GENERAL HOSPITAL The use of Tolbutaniide, Chlorpropamide, and Phenforroin for the years which there are accessible records are as follows: CHLORPROPAMIDE Tablets Used TOLBU TAMIDE Year 1968 1969 1970 1971 * 1972 1973 1974 1975 (To date) 1975 (Projected) PHENFORMIN * Year 1968 1969 1970 1971 1972 1973 1974 1975 (To date) 1975 (Projected) 270,800 525, 300 522, 200 320,600 286,600 .144, 200 83, 500 46, 100 92,200 C~p~ules Used 74, 300 93, 200 97, 000 95,700 61, 300 42, 800 15, 600 1,000 2,000 $62. 00/Thousand $62. 00/Thousand $62. 00/Thousand $62. 00/Thousand $62. 00/Thousand $64. 00/Thousand $69. 62/Thousand $75. 56/Thousand $75. 56/Thousand Cost $73. SO/Thousand $73. 50/Thousand $81. 00/Thousand $80. 00/Thousand $80. 00/Thousand $69. 10/Thousand $69. 00/Thousand $69. 00/Thousand $69. 00/Thousand Total Cost $16, 789k 00 $32, 562. 00 $32,376.00 $19, 877. 00 $17,769.00 $ 9,228.00 $ 5,813.00 $ 6,966.00 Total Cost $ 5,461.00 $ 6,850.00 $ 7,857.00 $ 7,656.00 $ 4,904.00 $ 2,957.00 $ 1,076.00 $ 138.00 Total Cost $ 5,140.00 $ 7,440.00 $ 8,294.00 $ 7,598.00 $ 7,377.00 $ 8,517.00 $ 2,787.00 $ 3,371.00 Tablets Used Coit Year 1968 1969 1970 1971 1972 1973 1974 1975 (To date) 1975 (Projected) 76, 000 110, 000 127,600 116, 900 113, 500 104, 500 34, 200 18, 800 37,600 $67. 64/Thousand $67. 64/Thousand $65. 00/Thousand $65. 00/Thousand $65. 00/Thousand $81. 51/Thousand $81. 51/Thousand $89.66/Thousand $89.66, Thousand June 25, 1975 PAGENO="0404" 13654 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY TABLE U Yearly Use of Insulin Stocked in Pharmacy Cleveland Metropolitan General Rospital Based on Accessible Records Year 10 ml. Vials Total Cost 1968 7,250 $ 6,587.lS~' 1969 6,594 $ 8,119.90 1.970 6,522 $ 7,675.00 1971 7,125 $ 8,405.45 1972 8,065 $ 9,927.00 1973 9,803 $12,130.96 1974 9,814 $15,232.00 1975 (Projected) 9,192 $12,437.00 PAGENO="0405" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13655 Philip Pelig, M.D. Professor and Vice Chairman Department of Internal Medicine Yale University School of Medicine 333 Cedar Street New Haven, Connecticut 06510 Statement Before Subcommittee on Monopoly Senate Small Business Committee July 10, 1975 PAGENO="0406" 13656 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Chairman and Members of the Subcommittee I am pleased to have this opportunity to participate in these hearings on the oral hypoglycenic drugs. Over 5 years have now elapsed since the initial presentatio of the findings of the University Group Diabetes Program indicating an increased risk of death from cardiovascular disease in patients treated with tolbutamide or phenformin. Since that tine there has been considerable debate and controversy in the medical profession as to the validity of these findings and their implications with respect to the treatment of diabetic patients. My discussion will focus on the following areas: (1) Those aspects of the pharmacology and clinical applications of the oral hypoglycemic agents in which there is fairly uniform agreement among proponents as well as opponents of the UGDP study. (2) The impact which the findings of the UGDP study have had on medical practice. (3) The mechanisms by which the prescribing habits of physicians may be altered. Virtually all experts in the field of diabetes agree that the oral hypoglycemic agents are drugs of convenience. They are convenient because they may be taken orally as opposed to the injections of insulin. More importantly, they are convenient because they do not require the self discipline and compliance inherent in a weight- ~ -reducing dietary regimen. In contrast to the effects of insulin in the patient with diabetic coma, the oral hypoglycemic agents are not life saving drugs. Furthermore, no convincing evidence is available which indicates that ~ ~ blood sugar by oral agents retards or pr~y~s~he ~ cations of diabetes which may affect the eyes, kidney or nervous system. It is thus clear that these drugs are useful in a very limited number of patients with adult-onse diabetes: namely, those with symptoms due to an elevated blood sugar in whom dietary measures have failed and in whom insulin is impractical or refused by the patient. While some experts would include patients with an elevated blood sugar who are asymptomatic, there is universal agreement that these drugs are overprescribed in the United States. PAGENO="0407" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13657 All of the above was in fact well recognized before the UGDP study was reported. The effect of the UGDP has been to add evidence of a relationship between oral agents and increased cardiovascular mortality. This relationship has been considered conclusive by some, persuasive by others, and at the least possible by all, including the most severe critics of the UGDP. Given the fact that 1) these agents are drugs of convenience, 2) they are widely overprescribed, 3) they may increase cardiov4scular mortality, and 4) that the practice of medicine is usually governed by the axiom "Primum non nocere" - "above, all do no harm," one may question whether the ftndings of the UGDP study have resulted in a change in the clinical treatment of diabetes. Unfortunately the answer is very definitely no~ The most recently available data reveal that the total prescriptions for oral hypoglycemic agents increased 5.5% between 1972 and 1973. This represents a total of over 19 million prescriptions costing over $100,000,000 and involving over 1½ million patients. Since all agree that these agents are overprescribed and at the least possibly toxic, it is apparent that the experts in the field of diabetes have failed tc~ appropriately influence the clinical management of this disorder. To rectify this situation I would propose the following: 1. Leading proponents as well as criticsNof the UGDP study should meet ~or the purpose of issuing a joint statement in which the primacy of diet and the obvious need for restriction in the use of oral hypoglycemic agents is clearly spelled out. Such a statement can be divorced entirely from the UGUP study. It should be noted in this regard that the critics of the UGDP study often emphasize the limited indications and rarity with which they employ oral agents in their own practices. However)so long as such statements are immediately followed by a statement attacking or discrediting the UCDP, the end result is a perpetuation or exaggeration of the abuCe of these agents which characterizes current medical practice. PAGENO="0408" 13658 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 2. Emphasis should be placed on dietary management rather than oral agents in the instruction of medical students and in postgraduate medical courses on the treatment of diabetes. 3. Research should be undertaken on developing improved methods of assuring patient conpliance and success in adhering to weight-reducing diets. 4. Most importantly, the labeling of oral hypoglycemics should be changed to include: a. A warning that evidence has been reported that these agents may increas cardiovascular mortality; and b. That use of these agents should be restricted to adult-onset diabetics in whom dietary measures have failed and insulin is refused or impractical. Mr. Chairman, there has been much discussion in the lay press and medical journals of the need to maintain the physician's freedom of choice in the treatment of his or her patients. I believe that our overriding concern as physicians is to do no harm. As experts in the field of diabetes our primary obligation should be to improve the lot of our patients by influencing current treatment practices rather than perpetuating a situation which is at the least wasteful and at worst causing an unnecessary shortening of life span in adult-onset diabetics. PAGENO="0409" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 18659 (STATEMENT BY (JOSEPH LARNER M.D., PhD., PROFFESSOR AND CHAIRMAN (DEPARTMENT OF PHARMACOLOGY AN]) DIRECTOR OF THE DIABETES AND (ENDOCRINOLOGY CENTER, UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE, (CHARLOTTESVILLE, VIRGINIA (BEFORE SUBCOMMITTEE ON SMALL BUSINESS (JULY 10, 1975) Honorable Gaylord Nelson and members of the Subcommittee: Senator Nelson: My name is Jbseph Lamer, I am a scientist (pharmacologi~t, biochemist) and physician who has been interested in problems of diabetes for nany years, and who has been working on the mechanism of insulin action for 15 years. I was called and as)çed to testify before this committee, and am pleased to do so. In connection with the five points raised in your letter of June 19, 1975, I respond as follows: 1. The proper labeling of the oral hypoglycemic drugs in the light of the studies recently conducted with these drugs. Having reviewed the literature, I have come to the following conclusion which is quoted from Chapter 71, written by myself ar~d R.C. Haynes, Jr. of a standard textbook in Pharmacology (Goodman and Gilman' s textbook, 5th edition to appear in September, 1975). "The sulfonylureas should be used only in subjects with diabetes of the maturity-onset type who cannot be treated with diet alone or who are unwilling or unable to take insulin if weight reduction and dietary control fail. The physician must realize that he is using these agents only to control symptoms associated with hyperglycemia and that dietary control with or without insulin is more effective for this purpose." 56-592 0 - 75 - pt. 28 - 27 PAGENO="0410" 13660 COMPETITIVE PROBLEMS IN THE DRuG INDUSTRY The major complications and life-threatening disorders associated with diabetes are heart disease, kidney disease, blindness, and limb gangrene. There is no evidence that sulfonylureas ameliorate or prevent these disorders. While in many instances in medicine the physician must prescribe for overt symptoms, we all prefer to correct the underlying problem if possible. Unfortunately, this is not presently possible with diabetes without additional basic and clinical investigation. There is no evidence that sulfonylureas will assist in the underlying problem. Since these agents would appear to relieve primarily the symptoms of hypo- glycemia, one should restrict their use until less costly and perhaps safer measures have been used (diet with or without insulin). For this reason, I feel that there should be stronger labeling of the oral hypoglycemic drugs in the package insert. With regard to the nature of the labeling, I feel that the stronger 1972 FDA draft is preferable to the weaker 1974- draft for the reasons just discussed. 2. The effect of these studies on medical practice. To my knowledge these studies have had a variety of effects on medical practice. The total utilization of this group of agents, however, has not seemed to change much. For example, when the results of the studies were initially announced, some physicians changed their patients to other sulfonylurea analogues not realizing that the fundamental pharmacology should be quite similar to the drugs studied. This obviously demonstrates the PAGENO="0411" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13661 need for additional postgraduate training and education of some of the medical community. Some physicians accepted the results of the study and some questioned the design and control nature of the experiment. This controversy has undoubtedly been apparent to this committee. On the whole, these studies indicate that the use of oral hypoglycemic agents should be limited to the small percentage of patients with diabetes for whom other therapies have proven impossible to carry out. 3. The availability of scientific evidence, if any, which demonstrates the benefits of oral hypoglycemics. I know of no evidence that directly demonstrates that the oral hypoglycenics are life-saving or life-prolonging in the therapy of diabetic patients. The major therapeutic problem in diabetes is no longer the acute ketoacidosis which used to be the cause of death before the introduction of insulin. Rather, it is the long term or chronic vascular complications of the disease. In other words, the major problem, now, is the well recognized thickening and other damage to the blood vessels throughout the body leading to kidney disease, heart disease, blindness, and gangrene in the limbs. We still do not know the answer to the following fundamental question, "If the blood glucose level in the diabetic patient could be controlled as precisely as that of a non-diabetic through the use of an insulin delivery system y~~to be devel9~p~, would there still be vascular complications?" Or, alternatively, is there some factor or factors involved other PAGENO="0412" 13662 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY than proper insulin delivery which leads to these harmful effects on the blood vessels? Basic and clinical investigators are working on this question with respect to insulin at present. Since no answer exists for insulin, which is a direct hormone replacement therapy, obviously no answer exists for the oral hypoglycemic agents. For this reason, I feel there is no direct evidence that these 9ral agents are beneficial, i.e., life-saving or life-preserving. 4. The problems of translating the results of basic research developed by medical scientists to the practice of medicine. This is a very broad question, and we could spend a great deal of time discussing it. Briefly, I am of the opinion that scientists today are more aware than ever before of the importance of applying their fundamental studies to the practice of medicine. For example, in my own field, Pharmacology, there has been a strong development in the area of Clinical Pharmacology which addresses itself to this problem: namely, the application of fundamental laboratory findings to the patient in order to understand and treat the disease process. For example, the sulfonylureas have been used clinically for about 20 years, yet a great deal of information regarding these compounds is still lacking. The metabolism of these compounds in patients and their precise mechanism of action are still unknown. These have been complicated problems and require additional studies in both animal systems as well as patients. Scientists are very interested in coordinating such diverse efforts and studies. I feel that PAGENO="0413" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13663 clinical research work in this area should be further nurtured, but that it must be balanced by a broad base in fundamental ani~nal research as well. 5. Any other aspects of the subject which you think might be helpful to the Subcommittee. I feel strongly~that the time has cone in terms of the oral hypoglycemic agents to restudy their effects in animals and patients. It is my feeling that since recent animal studies are proving of considerable interest in terms of the actions of these drugs on organs such as the heart, adrenal glands, and liver, it would be wise to restudy these compounds in animal systems during the time their clinical use is reevaluated in order to see whether we can gain an understanding of the mechanism of the cardiovascular deaths or even reproduce them in animals. Here I note with particular interest two recent pieces of data in animals: 1) the summary statement of the work of Wissler et al. which states that in rhesus monkeys fed an average American diet for 74 weeks containing 20 mg/kg tolbutamide, there were present in the coronary arteries two times more frequent and three times more severe atheromatous changes than in the coronary arteries of control monkeys. 2) the work of Hsu etal. from our Department of Pharmacology at Virginia which demonstrates that in heart, adrenal medulla and other organs, sulfonylureas inhibited catecholamine release from the nerve endings of the autonomic nerves. Thus the function of the autonomic nervous system, which provides the PAGENO="0414" 13664 COMPETITIVE PROBLEMS IN THE DRIJG INDUSTRY involuntary control for many of the organs of the body, is significantly influenced by these, drugs. Therefore, I feel that it is time to caution physicians about the use of these drugs, and to restudy them in the clinical and basic laboratory much more extensively. PAGENO="0415" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13665 STATEMENT BY PAUL MEIER, PH.D. PROFESSOR OF STATISTICS UNIVERSITY OF CHICAGO CHICAGO, ILLINOIS 60637 BEFORE MONOPOLY SUBCOMMITTEE SENATE SMALL BUSINESS COMMITTEE 31 JANUARY 1975 Mr. Chairman. I speak as a member of the Biometric Society Committee on Biometric Aspects of Controlled Clinical Trials whose report is under discussion today. Professor White has outlined our problem and our findings, and Professor Zelen will speak about some of the particular criticisms made of the U.G.D.P. report. I shall speak a little more generally about the role that I see for clinical trials in guiding our decisions about modes of therapy. It happens that in March of 1970 I testified before this committee o~t the subject of risks of Thronbo-embolism due to the use of oral contraceptives. spoke then of the deplorable lack of prospective controlled clinical stud~Les on the effects of oral contraceptives. I discussed possible reasons for that lack. Let me quote a few lines from that earlier testimony. My explanat~.on for the lack of substantial research on this important problem was as follows: "Frankly, the required research, although important, is not especially appealing to scientists. It is not fundamental and it is not exciting. It is difficult, it is expensive, and it is fraught with the risk of attack from all sides.. Who would willingly prepare himself for such a study, make an application to be weighed competitively with others on scien- tific merit, and risk the loss of support halfway through the study when a review committee with different views or priorities comes to consider renewal of support, when he stands to gain so little in scientific recognition or otherwise? Evidently, for whatever reasons, there is no sound body of scientific studies concerning these possible effects available today, a situation which I regard as scandalous. If we proceed in the future as we have in the past, we will continue to stumble from one tentative and inadequately supported conclusion to another, always relying on data which cone to hand, and which were not designed for the purpose. The planning of better studies is difficult, and the recruitment of investigators willing to commit their efforts to these purposes nay be more difficult still. I believe both are possible and essential to the public welfare." At the time those words were written, I had no knowledge of the U.G.D.P., but they could scarcely have been more apt. PAGENO="0416" 13666 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It is true that the U.G.D.P. had defects. It~is true, also, that it falls short of proving the case against Tolbutainide. Nonetheless, as Professor Cor.tfield remarked in testimony here last September, the U.G.D.P. today provides the best available information on the possible toxicity of Tolbutamide. As to defects, there are no studies which are entirely free of them, and it was the judgment of our committee that this study was weLl conceived and executed and that those defects we could identify did not give reason to doubt the findings. As to it being inconclusive, that was inevitable in the nature of the case. Once the investigators became convinced that there was substantial evidence of toxicity, and not of corresponding benefit, they had no choice but to withdraw the drug. Thus we are left with an ominous yet inconclusive result, and I believe that this is a typical outcome which we nay expect to see repeated in many other instances. It may be, in such a case, that the community of physicians will decide that, although not conclusive, the evidence is sufficient to abandon the drug. Or, on the contrary, as in the U. G.D.P * case, they may conclude that the evidence does not require them to give it up. In the latter case, however, I can see no alternative to the initiation of a new clinical trial, conducted by physicians unconvinced by the first one. I should expect, in any event, that both physicians and patients should be made as fully informed about the evidence as is feasible. I go so far as to hope that the experience to date. with oral hypoglycemic drugs nay convince us that clinical trials should be a continuing component of drug surveillance for any drug, from the first day of its release, and so long as substantial doubt about the balance of risks and benefits remains. PAGENO="0417" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13667 Statement by P. J. Palumbo, M.D. Certified Internist and Endocrinologist Clinician and Clinical Investigator with special interest in diabetes and its complications and hyperlipidemia. Assistant Professor of Medicine Mayo Medical School Rochester, Minnesota 55901 Before Subcommittee on Monopoly Senate Small Business Committee January 31, 1975 PAGENO="0418" 13668 COMPETITIVE PROBLEMS IN THE DRUG INDuSTRY DIABETIC TREATMENT AND SURVIVORSHIP P. J. Palumbo, M.D. The comparison of treatment for a disorder can only be evaluated through controlled randomized, clinical trials. Hints and leads from retrospective studies can be extremely valuable in leading to a new hypothesis and may be the basis of justification of a randomized trial. However standing alone they cannot form the basis of any firm conclusions concerning treatment effects. The preliminary analysis of our data of the incidence, prevalence and mortality of diabetes mellitus in Rochester, Minnesota between 1945 to 1970 contains some hints that survivorship may be lower in diabetics on oral antidiabetic agents, but group differences preclude any firm conclusions regarding this observation. Such an observation would point to the need for controlled randomized clinical trials to study the possible adverse effect of various treatments on survivorship in the diabetic. The University Group Diabetes Program was a randomized trial study to evaluate the influence of treatment on diabetic complications. A statistically significant, adverse effect on survivorship was noted after patients had been on tolbutamide and phenformin for five or more years. These data have been reviewed and the conclusions have been found to be sound. In my opinion, as a diabetologist, another randomized tria\l study of treatment in diabetes is not ethically justified, PAGENO="0419" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13669 as the data from the University Group Diabetes Program clearly indicate an adverse effect of the oral antidiabetic agents on survivorship in the diabetic. The use of these oral agents, therefore, should be curtailed. PAGENO="0420" 13670 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY STATEMENT BY HENRY T. RICKETTS, MD PROFESSOR OF MEDICINE EMERITUS, UNIVERSITY OF CHICAGO, 950 EAST 59TH STREET, CHICAGO, ILLINOIS 60637. BEFORE THE SUBCOMMITTEE OF THE SELECT COMMITTEE, ON SENATE SMALL BUSINESS, JANUARY 31, 1975 I have studied diabetes mellitus, cared for diabetic patients, and conducted researches in this specialty for 34 years. I have been president of the American Diabetes Association and co-founder and president of the Chicago Diabetes Association. I have served on the Study Section of Endocrinology and Metabolism, Grants Division, National Institute of Arthritis and Metabolic Diseases, and have served as a contributor and an assoc~ateeditorof the journal, Diabetes. My connection with the Committee of the Biometric Society was that of a consultant diabetologist, and I attended most of their meetings. I was struck by the thoroughness with which the members of the Committee made their investigation. I detected no bias for or against the UGDP study. The Committee listened to more who criticized the study than to those were were less opposed or favorable. The Committee did not hesitate to ask the Coordinating Center in Baltimore for raw data when a point was in doubt, and members made trips to the Center and to several participating clinics to check methods, procedures, and results. No uncertainty was too small to leave unresolved. PAGENO="0421" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13671 The UGDP was set up to determine whether various treatments for diabetes would minimize the mainly vascular complications that notoriously accompany that disease. It is ironic that a full report dealing with complications has not yet been published because, in the third and fourth years of the study, an alarming preponderance of deaths had accumulated in the tolbutamide group~ The investigators, then, perforce, had to turn their attention to mortality and survival. I was not a participant of the UCDP study, but I followed it closely. Despite some imperfections, I think that the results arid conclusion of the UGDP have shown tolbutamide and phenformin, and probably their cousins, to be dangerous drugs, especially when taken for extended periods of time. I stand by my opinion of four years ago, expressed with the help of a committee of the American Diabetes Association in the editorial statement accompanying the first report of the UGDP (Diabete~, Supplement No. 2, Vol.l9:74783O, 1970). I quote: "...The UGDP mortality study shows that death rates were essentially the same in the IVAR group, which maintained more nearly normal fasting blood glucose levels, as in the more poorly controlled groups of PLBO and ISTD. This would appear to mean that efforts PAGENO="0422" 13672 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY to establish `good'control of hyperglycemia in the kind of population studied (had]no effect on mortality... "The real lesson of the data is that if diet plus insulin does not reduce mortality below that experienced with diet alone, it is highly improbable that oral hypoglycemic agents will do so. There is indeed no doubt about the reality of the greater number of cardiovascular deaths observed in the TOLB group as compared with all other treat- ment groups. Inquiry into the reasons for this has been both intensive and extensive. Aside from the most proximate explanation, that tolbutamide may have been directly and solely responsible, the possibility that the TOLB population, by chance and despite random- ization, entered the study with more or greater risk factors than the other populations had to be scrupulous- ly investigated. Although this possibility has, in the opinion of the ADA Ad lIoc Editorial and Advisory Conrnittee, not been exiuded, the weight of statistical analysis makes it probable that the excess cardiovas- cular mortality in TOLB is attributable either to the PAGENO="0423" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13673 drug itself or to unconsidered and unknown factors. In the absence of evidence for the latter, suspicion would naturally attach to tolbutamide. `The mortality study is at least suggestive enough to put a damper on what appears to be the indiscriminate use of all oral hypoglycemic agents in the treatment of mild or moderate, adult-onset diabetes. Although tolbutamide, for practical reasons, has been the only sulfonylurea drug inves- tigated by UGDP, the chance that other compounds of this family may be similarly involved cannot be dismissed despite differences in molecular structure. It would not be justifiable at this point, however, to prohibit the manufacture and use of sulfonyurea drugs, for they will probably continue to fill a need in special circumstances." If these drugs are dangerous, what course should we take? You have just heard that their manufacture should not be forbidden, and for reason. For example, how do we treat a diabetic patient who ought to be taking insulin but is living alone with a broken, or amputated, or paralyzed arm that prevents him from using a syrir~ge and needle? One who is blind and cannot measure his dose of insulin? PAGENO="0424" 13674 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY One who is old and tremulous? One who is mentally disturbed? And finally, one who refuses to take insulin? In another vein, there are diabetics who are engaged in hazardous occupations and ought not to take insulin for fear of reactions. We ought to make allowance for these patients even though the oral agents are not very effective and, I believe, in the long run, may be harmful. But if we continue to make these agents available, as I think we must, how do we protect other diabetics who would like to use them but should not? Insulin comes to the patient with a package insert that carries a great deal of information, including certain warnings. The oral agents come to the patient in silence because they have been regarded as innocuous, needing no instructions except the doctor's directions for dosage and timing. This must change. But it is the physician who should lead the way, and I hope that the report of the Biometric Society will in time convert the many current unbelievers. Meanwhile, it might not be too radical to ask the FDA, under proper authority, to transfer the oral hypo- glycemic agents to the circumscribed Schedule II of dangerous drugs along with barbiturates, amphetamines, and certain narcotics. Physicians might learn that the oral agents are not exactly safe, and the requirements of BNDD prescriptions, if for dubious need, PAGENO="0425" COMPETITIVE PEOBLE1~~tS IN TEE DRUG ThThUSTEY 13675 might become a salutary nuisance. This arrangement, of course, would have holes in it (and I can see some), but it might~ have the effect of helping to reduce the use of a product that too many patients could well do without. 56-592 0 - 75 - pt. 28 - 28 PAGENO="0426" 13676 COMPETITIVE PROB~JEMS IN T~E DEtG INDtTSTR~ STATEMENT B,Y ETHAN A. H. SIMS, M. D~ PROFESSOR OF MEDICINE, COLL~GE OF MEDICINE, UNIVERSITY OF VERMONT BURLIftGTON, VERMONT 05401 (on sabbatical leave at Endocrine Dlv.., Tufts N. *E. Medical Center Boston, MA 02111 BEFORE MONOPOLY SUBCOMMITTEE SENATE SMALL BUSINESS COMMITTEE JULY 10, 1975 Mr. Chairman, Members of the Committee: I ~am glad to have the Opportunity to testify before this Committee relative to the proper labeling of oral hypoglycemic agents in th~ light of recent studies, and on the problems of translating the results of research to the practice of medicine. I plan to center my remarks on the optimal man- agement of the overweight, non-insulin-dependent diabetic as this relates to' the recommendations included in the proposed labeling. My qualifications include care of diabetic patients at Yale-New Haven Hospital and in Vermont over the past 30 years and former direction of a Metabolic Unit and of an N'IAMD training program in diabetes. 1 have served on special study, sections of the NIH for review of proposals for Diabetes and for Obesity Centers. I am a member of the advisory and editorial group for the Fogarty International Center Conferences on obesity and of the workshop on Obesity of the National Diabetes Commission. SUMMARY I. Obesity is now recognized as a factor predisposimg to non-insulin- dependent diabetes in a genetically susceptible person. Untreated obesity may pose a greater long-term risk in relation to cardio~vascular and other disease than the use of oral agents. II. Insulin, In addition to Its well known function of lowering blood glucose, is a storage hormone. The use of insulin, or of oral agents PAGENO="0427" COMPETITIVE PROBLEMS IN THE DT~tYG INDUSTRY 13677 which stimulate release of insulin promote fatness. III. Intense preoccupation with one aspect of the UGDP study has~ blurred our perceptions of other vitally important data in the study. These data indicate adverse effects of therapy both with sulfonylureaS and with insulin in promoting further development of obesity. This is a recog- nized risk factor for cardiovascular disease. IV. One should not go on Writing package labeling recommendatiGflS based on data comparing the five treatment modes chosen by the invest- igators of the UGDP in the l960s, when these options are now out of date. They do not include preventive and rehabilitative measures available in 1975. V. Lifestyle changes in eating and in physical activity are essent- ial components of the management of non-insulin-dependent diabetes, as well as of cardiovascular disease and are often sufficient in them- selves to restore near normal function. Initiated early they may provide effective prevention. VI. The proposed FDA package labeling for oral agents should reflect these considerations. They should also be written in a form conducive to the education of the patient. VII. The schedule of peer review and publication of the results of randomized prospective clinical trials requires modification, if the results of future studies are to be accepted by interested parties. VIII Efficacy of a drug must be considered in the light of other available options for management. On this basis there is little evidence of acceptable efficacy of the sulfonylureas, except under special circumstances which preclude other therapeutic options. In the case of phenformin the efficiency:efficacY ratio is not acceptable. PAGENO="0428" 1S~7S cO ~TIT O~tbEMS ~ ~RVG ~T~ET I. PROPER LABELING ~F THE ORA YP~GGt~Y~MIC DRUGS tND~E~L'~GHT: OF RECENT STUDIES I believe that the Intense preoccupation with the incr'ease'in córd1ova~cu1ar flt~rta11ty from use of t1~e oral ~agents h'a's drawn attent~ Ion away fr~om matters o~L even greater importance in the nTana~ement of the non insulin &epei~kent diabetic These fnclude the facts that 4 1) ObesIty is now recognized to~ bea predlspas'lng factor for diabetes In a permon ge~ne-tlcal1y su pt44le~. 2) ~~flhS1j~f~, In `addttlon to its well-known futiction of Towering blood glucose, is a storage hor~ori~e and i-ts use and the `use of oral agents which prOmote release of InSulin promote obesIty. 3) Lifestyle changes in eating and in physical activity are essential components of good management of non-insUliri-'depen~Ient dtebet~s and ~of cardfovarcular:disease as well. These changes are often sufficient in Iftieniselves to restore near normal+. function. We should not classify diabetes into juvenile and maturity onset, since the correlation of types with age is poor; Diabetes occurs in two forms, each requiring entirely different management: 1. e. insulin dependent, usually lean and hungry, and non-insulin-deper,dent, usually obese and also insulin resistant, Our studies in Vermont have shown £hat normal volunteers who deliberately gain 20 to 30 per cent above their basal weight develop Insulin resistance i~ similar to that seen In the spontaneously obese. They also had a diminished ability of muscle and fat cells to utilize glucose. Their fat cells enlarged, but did not increase in number, again simfiar to those who spontaneously develop obesity in adult years. These results suggest that in the naturally obese patient at least a part.of the Insulin resistan~e that places astress upon the pencreatlc reserve of Insulin Is secondary to weight gain and is reversible. The UGOP investigators chose their five treatment regimens because PAGENO="0429" COM?~flTI~t ~OB~tJEMS I~ TH~ DRUG I1~iISTRY 1&~79 they rep11cat~e~ th~ cc~mmoniy. a eptedbpt~ofls~of thi ea~1y ~0s~ but they. db not ~`epresent the best optIons available now. Epidenhlol- ogists and cardiologists have defined the risk factors forcardio- vascular disease, which include more than just elevated blood sug~r and fats, I. e. obesity, smoking, and physical inactivity. Of the 1,500,000 patients now taking oral agents, probably 5b per cent are more than 25% over weight (54% of those entering 6 of the 12 clinics of the UGOP study). When these patients are ti4eated with "diet a1on~", It is generally little more than a token gesture in the direction of a low-caloric diet. The success rate for Weight loss is notoriously poor. There is important data in the UGDP study the significance of which is overlooked. With qualified dieticians available) th2re wka~ an initial drop of slightly under 3 %~~rL all groups. Only those taking placebo or phenformin maintained their weight ttiráughout the 16 folloWup periods, and there was no differdnce between placebo and phenformin. On the otherhand, those taking either ~tolbutamide or insulin lost less weight initially and' regained ~weigIrt above their baseline values s that In all there was an 8 per cent difference between the mean rate of the placebo group. This was to be expectE~d since when the patient receives either a sulfonylurea drug or Insulin plasma insulin is increased, thus increasing the tendency to store fat. The Indications listed in the latest FDA recommendation for package labeling calling fOr use of insulin if dtdt~fal'ls t~u,iSiouht'er to our ~ürrent concepts'of the pathopt1y~sio1ogy of ndn-1v~sulin'~dePendén~ diabetes when it is associated with overweight ahdwhen there are other valid options. OTHER OPTIONS FOR TREATMENT. There are other o~tlons in' addition to the five of the UGDP study. These differ from the 000P treatment modes in that they have the potential for reversing, the patient's diabetic state. They Include vigorous andcomj~reheoSive PAGENO="0430" 13680 COMPETITIVE PROBLEMS i~ THE DRUG INDUSTRY regimens which Include education and Increase in physical activity. Now adjuncts Include behavioral self-modlficatløn and proteln.sparlng~ starvation. a) Withdra~l ~ Q~.) Aqe~n~s ~ Intensive We~qht Rcitl9~*. An Important result of the JGDP study was the decision of Dr. John Davidson in Atlanta to discontinue oral agents for 1500 patients at Grady Hospital in Atlanta, as reported on Sept. 18, 1974 to this Committee. I suggest that his recent paper (JAMA 232:853, `75~ on his experience be incorporated In the record of this hearing. 60% of these patients have been control1ed~ without drugs or insulin by an intensive regimen of dietary treatment and exercise, which includes 25 hours of Instruction and the use of special manuals. 50~ 90 % have lost significant amounts of weight, and it has been possible to discontinue insulin therapy in all patients who were Initially above ideal body weigiLt. The short term costs for educ~ atlon of the patient are considerable, but so are the long-term costs to the patient ~of oral agents, which are also susceptible to secondary failure. Dr. Davidson's importa~t e~perimen~, a pilot study which Still requires reporting in full detail, demonstrates not only that patients may do as well with no medication as with oral agents, but also that their overt diabetic state may be at least temporarily reversed. - b). Proteip-Spgrlng~Starvation. We are becoming more experienced In tbe use of.brief-- and occasionally long per-i~ds of semi-starvation to lnltlateweight reduction without consuming essential body protein s well as fat stores. This can be accomplished not by by providing carbohydrate to spare protein, which was the dictum in the past, but by providing optimal protein and minimal carbohydrate to minimIze Insulin stimulation. Sucb~a temporary Spartan aid to acute weight loss is Often surpr~sin~1y ~ve11 tolerated by patients, who may report PAGENO="0431" COMPETIPIVE PROBLEM~S IN THE 1~ETJ~ INDt$TRY i3~81 loss of appetite plus a feeling of well being.. (Genuth JAMA 231: `74). But It obviously cannot represent a panacea and must be cart4led out under clo~e supervision To sustain weight loss other measures are needed. c) Inci~ease j~ Phy~icai Ac~ivity~ I have 1~eft'to the last what may weilbe one of the most important) even if the least tried and the most poorly documented adjuncts for the prevention and treatment of non-insulin-dependent diabetes, namely increase in physical activity. The only reference to exerciSe to date in these hearings was on Sept. 18, 1974 (p 10880). Mr. Gordon quest- ioned Dr. Schmidt regarding the suggestion of Dr. Jesse Roth of the NIAMD that "vigorous exercise lowers blood sugar and that there seems to be a persistent beneficial effect In additiOn to the immediate effect". In answer Dr. Schmidt gave short shrift to exercise asL a major factor in the management of diabetes. I disa~ree with him in this, and have support In the recommendations of the White House Conference on, Food, Nutrition, and Health (Panel 11-3 p 51 Adults in an Affluent Society: The Degenerative Diseases of Middle Age). A relevant study Is that of Dr. Per Bjorntorp in Sweden, who has measured the insulin response of obese middle-aged men before and after a course of physical training. tven though he encouraged them to maLntain their excess weight, their resting insulin and insulin response to glucose was strikingly reduced (Metabolism 19:631 `70). This is not surprising, as any insulin-dependent diabetic learns that exercise lowers the requirement for insulin. Some formerly obes~ persons find that sustelnett increase in physical activ~ty is the only way they can malntain.'weig'ht loss. A lifestyle lncomp~tible with good health often lies be'hind many patients with non-insuj1~n-dependent diabetes. A change' In life' Style with respect to composition of the diet and level of activity PAGENO="0432" 18682 co~n~xi~ o~i~s IN T~E DRUGI U~T~7S~RY is the first and somet+mes the only measure requ1redfor~ many ~uch. diabetics. For those patients who definitely are lnsul1n~depenaent insulin is a necessary and logical adjunQt tO diet therapy. These include 1) the acutely decompensated diabetic (even those above ideal weight) 2) the hyperglycemic maturity onset diabetic at or below ideal weight 3) the hyperglycemic pregnant diabetic and of course 4) the young *insulin~~dependent dlabettc.~ However, for the o~'er~ weight diabetic, use of oral ag~e;nts or Insulin ~s ~both~illogicai and unnecessary, If the measures iridicatec above can restore metàbolic~ balance. Many patients enter thehealth care system toolate in the course of their diabetes or of their lives to modify their lifestyle effect- ively, and the therapeutic options are limited. Our profession should ma~k.e maximum efforts to reach younger members of high~rlsk families with educa'ticrn and programs~ for effective prevention, If `all the above Is true, one might Indulge In an extrapolation regarding the results of usfn,g oral agents in the non-Insulin depend- ent diabetic. Such an. extrapolation is obviously highly conjectural since solid data is not yet available, but I believe that lt.poin'ts In the direction of important truth. If we grant that there are approximately 1,500,000 pat1en~s reptttedly t~aking oral agents and that 501 are gro~s1y ov~erwelght, we~ have 750,000 patIents wlth'::diabetes and obesity who are prob'~bly also less physically act~tve than tJiey~ should be. If we assume that~ 90% of them are not exposed to any vigorous and comprehensive regimen such ~as that at the Grady Hospital, 675,000 are left with their obesity essentially untreated, and 4 out of 5 are taking an agent which increases their obesity. The taking' of oral medication lulls both physician and patient into believing that something worthwhile is~ being accomplished, while the op~tIons which could make a fundamental difference in a patients ,llfe and~, survival PAGENO="0433" ~T~EMS 1* THE P~iYG~ INDV~TRT 13~8'3 are~be~tng ne te~d~. This to i~iyTmir~d, i~~an ifl~por~t~nt con~id~a~t3o'r~ ;. whfcft ~1wa~rs-'~ev~en tire ~e~rl~us ~oi~cev~ about tU~toxl~1ty of th~ a'ftnts Even If t1~e~ b~al aflrits we~ pr~ove~~ ~to~ have j~o ~to~xI~ ~aat$n, their d~tr~imental~ rQ1ea~$ ~a~s~u'bst4tute-'~ `for ~th~r's~a'f~e ~nd potsn~t~V~' rehab~14t~&~ti~s .~lir~es wou1~i remain. `~ To change the way v~e are doiiig ~thlngs~ today is no~t a simple matter, and It Is inappropriate to blame the physician or the. patient for the result of large forces at work In our e~onomy. A considerable reallocation of resources over a period of titne.woul~d be required to bring about a shift from ~a syNptomatic to. a reh~ab~il.~ itative form of therapy.' Dr.. Leon White, Commissioner of Heaith and He~pit&ls in Boston~ recently listed the destructive lifestyle habits in this country and the diseases and disorders they~produce. Social excess of alcohol, overeating, and lack of exercise contribute to obesity and cardiovascular disease. These habits also contribute to diabetes In the genetically predisposed. As reported in the Harvard Medical Newsletter (l;no 39, June `75) Dr. White sta'ted that If the battle to modify lifestyle is to be fought, a major enemy is advertising. But advertising is not the only enemy. Lifestyle modification, if it is to be successful, will adversely affect the pharmaceutical ~industry, the tobacco industry, the alcohol products industry, the food products industry, and the auto Industry. The real challence is to improve health without wrecking the economy. THE RESPONSIBILITY OF TH~ FDA REGARDING LABELING The question remains as to whether the Commissioner of the FDA should indlca'te priorities or treatment or treatment options and whether these represent a constraint on the freedom of the' responsible physician or mak him liable to suit if he doe~s not follow such priorities. Since there is a stated responsibility PAGENO="0434" 13684 00 trzvE ~ ~ under tite Federal Food., trrug, and~Cosmet~c ~ FDA to assure effica y~as~~Ieila~ safety of E%trl*, ~~bai4eve~that~ the~ PD~ haw ~`respoiislbi11ty to maka sucb~ i~ndlcatiOns, since they ~a~fe~t~the ruiat1vee~ffic~cy of a~drug4. ~ might be rated as effective,. but if a ~upeYlór~al~erna~1ve b~e~eines av~aflable,~its .rela~tin,e ~ SiPté tire~'types~ and stages. of diabvtes vav~y, ft teems'to me appro~priat~ 1ó~t~ the FDA to suggest priorities for the use or non~use of' d~rugs at these various stages. The physician retains the ultimate responsibilitY of deciding how his particular `patient relates to the general `guide- lines. Ha shouTd not be nted~colegally'vulnerable for electing any particular' option provided that he can justify his decision an~J a-l~so makes his pati~ent an informed partner in the choice', whenever pOssible. SUGGESTED CHANGE IN PROPOSED LABELING FOR SULFONYLUREA DRUGS In line with the above considerations I suggest that the section on Indicatjon~ for the use of sulfonylurea drugs submitted for the Federal Register (page 40 of the copy available for the hearings) be modified as follows. (Changed wording is underlined). ~j~JetiC patients, with. n i~ul.1nr,depend,ent, diabetes who are ovej~wei.9ht commonly exhlbi,t' insulin, resistance and have elevated fasting Insulin concentrations a,nd ~ncr,eased,,,t'hou,gh,relat1YelY i,nad eqQate Insulin response to~lucose,,. Such patients can, fregueptly ,ehabi,lit,ated,,,and,th.eir overt diabet~ reversed bya vigorous and comprehensive regimen otdietary restrlction.~,in,creased physlca1'ac,~ ivlty. anthweiqh't loss. Th~us neither treatment with~(4rUg) nor i'ns,ulin ,i s 1r~dl,cate4~ unless japplisationof such meuu-res,ist~ptal iz. impractical. (prug).ls Indicated in maturity onset' non-ketotic diabetics `of normal ~or' subnormal weight whose ~)~p~gl,Y~cejpi!*cannot `be controlled by carbohydrate restriction a~,d Increased, actlvj,,,ty and PAGENO="0435" COMPEPIPIVE PROBL1~MS IN TH~ DRtYG INIY~JSTRY 136 5 In whom Insulin cannot be used because of .,,,.slmllar,factorS, When,. e&l~i asy~p~t~rna ~ eJ,~vatI~nfo~o4 glo~e. ,canno~tbe .ç r~ll.e&by~,the~ ahgve measures and in whom 1nSulir~ ..unanswered scientific question." * I have.substituted the word hyperglycemia for asymptomatic here because I do not consider that the UGDPstu~y, with Its limited range of population and limited measurements l~ d~clsiv.e in determin- ing whether hyperglycemia Is related to microangiopathy' Also with a high renal threshold for glucose prolonged hyperglycemia of major, degree may be present without syisptomatic glucosuria. II THE EFFECT OF THE STUDIES OF THE USE OF ORAL AGENTS ON MEDICAL PRACTICE AND PROBLEMS OF TRANSLATING RESULTS OF RESEARCH TO PRACTICE Judging by th,e prescription rates for the various oral agents, the Inipact of the UGDP study on general practice has been negligible. It Is ironic that the sale of phenformin, the agent which has been most clearly shown to produce tachycardia, hypertension, and a sl~nif- icant Increase in both cardiovascular and overall mortality has ncreased In sales (up 5% from `72 to `73). There are suggestions, however, that the use in the vicinity of large medical centers has decreased. The study has provoked a great deal of inquiry into * the use and limitations of prospective randomized clinical trials., The Reasons for the minimal impact have been discussed by others In * detail before this Committee, and I will mention only a:few: 1) Both physicians and patients look for quick solutions in the form of pills or injections. This is understandable because correct- ion of our many health problems today calls for alterations in life style which are not easy to accept and which often call for resOurces which most physicians do not have available. It l's the large problem of PAGENO="0436" 13686 COMPETITIVE PROBLEMS IN THE DRUG INDTJSTEY symptomatic vs. preventive and rehabilitative medicine. 2) The disagreement, wrangling, and finally name calling (scandal, coveru~, drugh~use whore,. etc.) that hat develoced out of the controversy over. one single, though important, aspect of the LJGDP study has tended to weaken public confidence in the medibal~ pr~fession and has obscured ou~ ability to perc~eve the factors of most critical importance to the patient. The Plahning of future randomized, controlled Clinical Trials. To aváid some of the features which have detracted from the impact of th~ sug~est the following; That direct finan~cial support of particular studies by vested interests UGDP I 1) be avoided. 2) That agreement be obtained in advance regarding both the conduct of the study and the release of data. 3) That the final data and that at any critical point in the study be reviewed by a third party unaware of the identity of the experimental groups. 4) The customary piecemeal process for review . and publication of medical work is inappropriate and impractical in the case of a randomized clinical trial which may involve ingrained traditions of clinical practide and academic theory on the one hand and multimillion dollar commercial Interests on the other: It seem to me that the first release should be of a full report which vitally interested parties have had an opportunity to review prior to definitive issue. 5) We are entering a period when patients will take a more active role In deciding their own options for treatment of chronic health problems. In parallel with this I hope that we will see informed, cooperative patients in the early stages of their disease or disorder taking part in clinical studies. tends 6) Medical advertising often A to neutralize the impact of randomized clinical trials, if the results from a particular product are unfavorable. Our profession has a responsibility to see that advertising accepted for our professional publications does not undermine or weaken the Impact of research PAGENO="0437" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13687 and government regulations. As an example, the medical journal which published the full report of the experience of the UGDP with phenformin has continued to print advertisements for phenformin which give no warning regarding hypertension, tachycardia, and cardiovascular death as adverse reactions. 7) Teaching in medical schools and in post-graduate courses should emphasize methods of evaluation of therapeutic agents to a greater extent. At the University of Vermont during several years we have used the UGDP study and its problems as the basis for an interdepartmental teaching exercise. The excellent short book by A. L, Cochrane in England, Effectiveness and Efficiency (Nuffield Provincial Hospitals Trust 1972) should be available in this country as required reading for all health professionals. III. AVAILABILITY OF SCIENTIFIC EVIDENCE DEHONSTRATING BENEFIT OF ORAL AGENTS The UGDP demonstrated no increased effectiveness of tolbutamide as opposed to placebo with respect to mortality or gross evidence of vascular disease in the groups of maturity onset diabetics of the type now receiving oral agents in today's practice. As in other studies there was also evidence of secondary failure. Thus,on the issue of efficacy) were the drug up for initial review today, it doesn't seem likely that it would be approved. The UGDP study also showed that, in this group of largely overweight non-insulin dependent diabetics, lowering the blood glucose concentrations alone gave no objective benefit, altho the techniques for evaluating microangiopathy were insensitive. Therefore, the one justification for continued approval of the sulfonylureas appears to be that there is a very small percent of patients who can't take or will not take insulin, do not respond to other measures, and are severely symptomatic and hyperglycemic. However, to give blanket approval for use of the drug to accomodate this relatively minute fraction of the diabetic population leaves the door wide open for continuation of widespread inappropriate use, with all the disadvantages indicated above. It Is unrealistic to believe that package labeling with suitabl~ warning and suggested priorities will alter the patterns of prescription. 56-592 0 - 75 - pt. 28 - 29 PAGENO="0438" 13688 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY It therefore seems to me to be justifiable and appropriate to classify the sulfonyl- urea compounds, along with other drugs with circumscribed uses and significant adverse effects, to sharply limited cliihical situations by placing them in a restricted category and requiring written justification for their use in a particular situation. This would not curtail their use where there is strong indication, but would limit much uninformed or ill-considered use. The justification that is advanced for continued use of phenformin is that it does not stimulate insulin release while lowering blood gluco~o and therefore is ideal, as the advertisements say, for releasing patients from entrapment in their fat cells. The UGDP study showed that the patients who took phenformin maintained their initial weight loss, and had approximately 8 % lower body weight at the close of the study than those taking tolbutamide or insulin. There was, however, no difference from those taking the placebo and the clearcut evidence of tachycardia, hypertension and increased total and cardiovascular mortality seen in the UGDP study in addition to the potential of producing lactic acidosis indicates a price in toxicity too great to pay for any relative advantage over oral agents with respect to weight loss. Therefore I believe that it is past time that this agent should be disapproved. PAGENO="0439" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13689 Statement of Cohn White Professor of Public Health Yale Universj~y School of Jedicinc New Haven, Connecticut ()(5l~) Before the Sub-committ~ee on lonopolv of the Small Business Committee U. S. Senate January 31, 1975. Mister Chairman and Members of the Sub-committee: I am the chairman of a committee which was appointed by the Biometric Society and funded by the National Institutes of Health to carry out the following mission: i. to make an in-depth assessment of the scientific quality of the UGDP study and in particular of the biometric aspects of the design, conduct, and analysis of the trial; ii. to make a similar assessment of other controlled trials of oral hypoglycemic agents. The committee consisted of six members: John P. Gilbert, Harvard University Paul Meier, University of Chicago Chris L. Rt~nke, Free University, Amsterdam Rodolfo Saracci, Pisa, Italy Marvin Zelen, State University of New York at Buffalo Cohn White, Yale University PAGENO="0440" 13690 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Two officers of the Biometric Society attended several of the meetings as observers: Peter Armitage, London School of Hygiene and Tronical Medicine; and Berthold Schneider, Ilannover, l~est German~. The research associate for the committee was Theodore lolford, and the consultant diabetologist was Henry 1. Ricketts. The full committee met on six occasions over a two ~`ear neriod and has completed a report which will be published on February l() in the Journal of the American ~1edical Association. The work of the U.G.1).P. is still in progress and I think it is fair to say that diabetologists in general await with interest the findings on the treatment by insulin. There has never been a study of comparable scope and thoroughness on the long-term effects of this agent in subjects with maturity-onset diabetes. In the meanwhile, however, controversy has arisen about the data concerning tolbutamide, and the committee saw as its main task the investigation of the reported excess cardiovascular mortality in the subjects receiving this drug. It is interesting to note that the U.G.D.P. presented results on phenformin which are quite com- parable to those on tolbutamide: the death rate from cardiovascular causes was approximately the same in the two cases. The findings on phenformin, if one can judge from the absence of criticism, appear to have been accepted by medical scientists, even if they have not so far been translated effect- ively into medical practice. Yet these findings also were made by the U.G.D using the methods that have come under heavy criticism when applied to tolbutainide. Because of the many factors which influence survivorship in a chronic disease such as maturity-onset diabetes, careful methods of investigation PAGENO="0441" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13691 are needed, and, in particular, control groups are essential. ConsequentlY we reviewed only such trials as were controlled. It then became clear that the major study to consider, other than the U.G.D.P., was the study in Bedford, England, organised by Dr. H. Keen and Dr. 1. .1. *Jarrctt. It should be said at once, however, that the Bedford study, based on 125 patients in each of two treatment groups was not comparable in size or th detail to the U.G.D.P. in which approximately 201) patients were followed on each of five treatments. The work of the committee appointed by the Biometric Society fell ibto four sections: 1. Visits were made to the U.G.D.P. co-ordinating Center and to two of the co-operating clinical centers to study methods used in the trial. 2. The methods and findings of the U.G.D.P. study were discussed with several authors who had written about them, and the Bedford study was discussed with Dr. Keen and Dr. Jarrett. 3. The published criticisms of the (J.G.D.P. were reviewed in detail. Comparable criticisms of the Bedford study do not exist, though several of the major criticisms made about the U.G.D.P. would apply a fortiori to the Bedford study. 4. New analyses were made of the data from the U.G.I).P. and Bedford studies, the data being kindly made available by the directors concerned. Critics have pointed out that in the U.G.D.P. study the total mortality was not significantly higher in the tolbutamide group than in the placebo group, even though there was a significant difference in the case of deaths from cardiovascular causes. We consider that this cirticism has some weight but is not convincing. Criticisms that have been commonly made but which, in our view, are not correct are: PAGENO="0442" 13692 COMPETITIVE PROBLEMS I~ THE DRUG INDUSTRY (1) the excess mortality in the tolbutamide group was due to the data obtained from just a few clinics: (2) the studies of Keen et al and of Paasikivi contradict the J.G.I).P. (3) the baseline differences among the treatment groims account for the finding of the adverse effects from tolbutamide. bn this point I might remark that none of the critics, to my knowledge, has given serious con- sideration to the multiple logistic method that was used by the tl.(.D.P. to take the effect of baseline risk factors into account. Until they do they have not carried out an adequate review of the IJ.G.U.P. analysis. (4) the findings on the effect of tolbutamide are flawed by the failure to adapt dosage to individual need. (5) the evidence was not adequate to justify the discontinuation of the oral drugs. In our analysis of the U.G.D.P. data we have used the same multiple logistic model as was employed by the U.G.L).P. investigators, hut have taken additional variables into account to allow for the time each subject was under study and for differences between clinics. We confirm the principal find- ing from the simpler study of failure rates, namely that the cardiovascular death rate was higher in patients receiving tolbutarnide than in those receiving placebo. This difference remains after adjustment for the effect of baseline variables and cardiovascular risk factors. We have also made an analysis in which the extent of adherence to assigned treatment was taken into account. The highest death rate was found in the tolbutamide group who adhered 100% to their treatment and who did not modify the dose. In an analysis of the data from the Bedford trial we found no difference in death rate between the placebo and the tolbutainide group. As indicated PAGENO="0443" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13693 above, we do not interpret this failure to find a difference as a con- tradiction of the more thorough U.G.D.P. study. The conclusion of the committee is that it remains with the proponents of the oral agents to conduct scientifically adequate studies to justify the continued use of such agents. PAGENO="0444" 13694 COMPETITIVE PROBLEMS IN THE DRtTG INDUSTRY Statement of Dr. Marvin Zelen, Director Statistical Laboratory, State University of New York at Buffalo Mr. Chairman and Members of the Committee. Thank you for this opportunity to appear before this Committee. My comments will be divided into two parts. How is it that able and respected clinicians can disagree with the interpretation of the UGDP data? The tolbutamide cardiovascular death rate is more than double compared to other treatments. Yet many clinicians who treat adult onset diabetes find it difficult to accept such a figure. For many of them, this elevated cardiovascular death rate does not appear to have been perceived in the clinic. Let us examine other factors which may lead to elevated cardiovascular mortality. According to the UGDP data, the cardiovascular death rate for individuals above the age of 53 is approximately five times that of individuals 53 or younger; people with arterial calcification at time of diagnosis have four, times the cardiovascular death rate compared to those without arterial calcification; the initial glucose tolerance test (GTT), as used by the UGDP investigators, shows that. those with a GTT above 723 (the median value) have double tho rate of cardiovascular deaths compared to those who have a GTT below the median; men have a doubled cardiovascular death rate compared PAGENO="0445" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13695 to women. Although the numbers quoted are "rounded" for simplicity, it is clear that in the clinic there are many factors simultaneously influencing cardiovascular deaths. Several of these have greater or equal effect on the cardio- vascular death rate compared to the effect of tolbutamide. As a result, it would be difficult for a clinician to perceive an elevated cardiovascular death rate associated with tolbutamide. Such an effect would be almost completely obscured by these other important factors. Only if there is careful and structured record keeping on a large number of patients would a changed cardiovascular death rate of 2-3 be detected. The analysis of such multi-faceted data requires more sophisticated data analytic methods than those in common usage by clinicians. Next, I wish to discuss some features of the Biometrics Society report. A criticism .of the original UGDP analysis is that it failed to explore the effects of several factors acting simultaneously on the cardiovascular mortality. Our Committee did in fact consider this matter very carefully. We found that when one examines the group of older women (age greater than 53) the tolbutamide cardiovascular death rate is almost five times that of the placebo group. It is in this group of older women where the tolbutamide excess cardiovascular mortality is most dramatically shown. Finally, I wish to comment on the problem of planning and analyzing clinical investigations in which patients are PAGENO="0446" 13696 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY expected to be on chronic medications for a period of many years. It is important in planning these long term studies to allow the clinician to change the medication if it is in the best interests of the patient. This can result in an altered dose or even a change in the medication. The tJGDP protocol did allow the clinician this freedom. .A protocol which does not allow this flexibilIty may not be in the best interests of the patients under study. In addition to modified or changed medications, patients may, on occasion, not take their medication at all. In the Biometrics Report, these problems were examined in considerable detail. It is our conclusion that the greatest statistically significant difference between tolbutamide and placebo occurs in the group who have taken their prescribed medication in exactly the manner specified in the protocol for the entire period of follow-up. To conclude, I wish to state that the interpretation of the data is difficult due to the small number of deaths relative to the total number of patients. In our endeavors we have analyzed the data in many other ways which have not been put into our final report. Our conclusion is that the weight of evidence points to tolbutamide as being responsible for excess cardiovascular mortality. PAGENO="0447" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13697 EXHIBITS PROVIDED BY THE FOOD AND DRUG ADMINISTRATION STATEMENT BY ALEXANDER M. SCHMIDT, M.D. COMMI SSIONER FOOD AND DRUG ADMINISTRATION PUBLIC HEALTH SERVICE DEPARThENT OF HEALTH, EDUCATION, AND WELFARE BEFORE THE SUBCOMMITTEE ON MONOPOLY SELECT COMMITTEE ON SMALL BUSINESS UNITED STATES SENATE JULY 9, 1975 PAGENO="0448" 13698 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY Mr. Chairman: I am pleased to appear today before this subcommittee to discuss current Food and Drug Administration (FDA) actions relating to oral hypoglycemic drugs. As you are well aware, labeling for this class of drugs has been the subject of extended public controversy and legal challenge. The Food and Drug Administration (FDA) has now published a proposed regulation providing new labeling for this class of drugs, which appeared in the Federal Register of July 7, 1975, and has invited comments on this labeling. A public hearing will be held on August 20, 1975 to afford interested persons a further opportunity to comment. On September 20, 1974, I summarized before this subcommittee the actions of the FDA that followed the report of the results of the University Group Diabetes Program (UGDP) study. Today I will review the events that have taken place since my previous testimony and I will discuss in some detail important aspects of our proposed labeling changes. REVIEW OF BIOSTATISTICAL ISSUES BY THE C~MMITTEE Of THE BIOMETRIC ~CIETY Because of the controversy concerning the UGDP study and the oral hypoglycemic labeling previously proposed by FDA based on the findings of that study, we decided that publication of proposed labeling should await completion of a detailed review of the UGDP study by the Biometric Society, a distinguished international organization of biostatisticians. The Society's report was published in the February 10, 1975 issue of the PAGENO="0449" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13699 Journal of the American Medical Associatiofl. Testimony before this subcommittee on January 31, 1975, by the members of the Biometric Society who had conducted the review, had provided a preview of their conclusions. The Biometric Society Committee assessed the scientific quality of the UGDP study, particularly the design, conduct, and analysis of the trial, and evaluated other controlled trials involving oral hypoglycemic agents. The committeediscussed in detail the published criticisms of the UGDP study and found that "most of the criticisms unpersuasive." Specifically, the committee concluded that: 1. The criticism that patient selection had been inappropriate was "largely irrelevant" to the validity of the evidence for the toxicity of the oral agents. 2. The criticism that total mortality in the tolbutamide group was not significantly different from that in the placebo group had some weight and "the toxic effect of the oral hypoglycemics cannot be affirmed with the certainty that would be present if total mortality were significantly different." 3. Excess mortality in tolbutamide-treated patients was not confined to a few clinics, as critics had claimed. PAGENO="0450" 13700 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 4. The committee particularly analyzed the criticism that there were important differences in base-line cardiovascular variables among the groups and concluded that there was "~ * * no evidence that the base-line differences arising from the randomization contributed in any important way to the finding of adverse effect from tolbutamide." 5. The criticism that oral hypoglycemic drugs were given in fixed dosage was not relevant to the question of whether the drugs were toxic. 6. Although the committee acknowledged that, "It would have been easier to interpret the findings if there were more data on mortality." [that is, if the study had been carried on longer], it did "* * * not criticize the UGDP investigators for having made the decision when they did." The committee further said: "Nevertheless., the result of that decision is to leave us with some residual uncertainty about the meaning of the findings, a point that is well understood by the UGDP investigators themselves." 7. Other studies said to contraJict the findings of the UGDP study do not in fact do so. PAGENO="0451" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13701 In addition to evaluating criticisms of the UGDP study, the Biometric Society Committee conducted extensive new analyses of the UGDP data, taking into account the effect of various base-line variables and cardiovascular risk factors. The committee's a~,alyses confirmed that cardiovascular mortality was increased in the tolbutamide group. The increase was statistically significant for the patient population taken as a whole and in the subgroup of females, especially in women over the age of 53, but not in the male subgroup. This does not mean that the study demonstrated that the drug carries less risk in males. On this point the committee concluded: "The data do not support the same conclusions for men, but one possible reason is that the smaller number of patients in the male group results in lack of sensitivity to detect differences of moderate magnitude." An important finding was that the highest death rate occurred in the group of patients who adhered most closely to the tolbutamide regimen and did not have their dose modified. Also, when the analysis was conducted according to the survival modeling method, which takes into account the proportion of time each patient received the assigned medication, women in the tolbutamide group showed statistically significant increase in both cardiovascular and total mortality. The Biometric Society Committee summarized conclusions in the final section of its report as follows: PAGENO="0452" 13702 COMPE:TITIVE PROBLEMS IN THE DRUG INDUSTRY `On the question of cardiovascular mortality due to tolbutamide and phenformin, we consider that the UGDP trial has raised suspicions that cannot be dismissed on the basis of other evidence presently available. "We find most of the criticisms levelled against the UGDP findings on this point unpersuasive. The possibility that deaths may have been allocated to cardiovascular causes preferentially in the groups receiving oral therapy exists, and, in view of the `nonsignificance' of differences in total mortality, some reservations about the conclusion that the oral hypoglycemics are toxic must remain. Nonetheless, we consider the evidence of harmfulness moderately strong.. The risk is clearly seen in the group of older women * * Whether it affects all subgroups of patients cannot be decided on the basis of the available data, owing to the small number of deaths involved in these subgroups. In conclusion, we consider that in the light of the UGDP findings, it remains with the proponents of the oral hypoglycemics to conduct scientifically adequate studies to justify the continued use of such agents. ADDITIONAL INFORMATION PERTAINING TO ORAL HYPOGLYCEMIC DRUGS In addition to the Biometric Society report, other information has become available recently. PAGENO="0453" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13703 1. The UGDP recently published its detailed report of the results of the phenforriin study (Diabetes, 24 (suppl 1): 65.-184, 1975). In addition to reporting that cardiovascular mortality and total mortality were greater in the phenformin-treated group than in the other treatment groups, the report presented evidence that phenformin therapy resulted in increased blood pressure and heart rate, thus suggesting possible mechanisms by which this drug might influence cardiovascular mortality. 2. At hearings before this Subcommittee on January 31, 1975, Dr. P. J. Palumbo reported that a retrospective study of diabetic patients treated at the Mayo Clinic suggests that survival was lower in those patients treated with oral hypoglycemic agents, compared to those patients treated with insulin or diet. Dr. Palumbo's full study has not yet been published. 3. A retrospective study of diabetic patients treated at the Joslin Clinic, reported in a doctoral thesis by P. Kanarek, can be interpreted as providing results that are consistent with those of the UGDP. Although we have seen this study, it has not yet been subjected to full review by statistical and epidemiologic experts. At this point, we can say that certain subgroups of insulin-treated patients appear to have better survival rates than tolbutamide-treated patients with comparable glucose abnormalities. Studies of this type, however, always present difficulties in interpretation because of doubts 56-~92 0 - 75 - pt. 28 - 30 PAGENO="0454" 13704 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY regarding comparability of the treatment groups and because treatments are not rai~domly allocated. Thus, although the retrospective studies of Palumbo and Kanarek may or may not, when fully analyzed, add support to the UGDP findings, the prospective UGDP study must be accorded far greater weight and is alone a sufficient basis for our proposed actions. 4. Drs. Tan, Bradley, Gleason, and Soeldner reported on the long- term (4 years) effects of hypoglycemic agents on the oral glucose tolerance test and blood lipids in chemical diabetics at the annual meeting of the American Diabetes Association in 1973 (abstract in Diabetes 22 (suppl 1): 290, 1973). The investigators' abstract indicated that there was no significant difference in the improvement in glucose tolerance in patients receiving oral hypoglycemic agents compared with patients receiving placebo. The full report of this study has not yet been published, but it appears that the investigators studied glucose tolerance on the day following discontinuation of the drugs. Their findings thus would indicate only that the oral agents do not lead to improved glucose tolerance in the absence of continued use of the drug. 5. Dr. R. W. Wissler, et al., in an FDA-supported study, examined the chronic effects of tolbutamide in the rhesus monkey. He found that coronary artery lesions were almost two times more frequent and three times more severe in the tolbutamide-treated animals than PAGENO="0455" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13705 in the control animals. The FDA recently received the final report on this study, which has not yet been published in the literature. At Dr. Wissler's request, FDA is supporting a further review of the pathologic findings by several independent pathologists. 6. Dr. D. F. Wu, et al., reported on the effects of tolbutamide on heart function in dogs with chemically induced diabetes at the meeting of the American Federation for Clinical Research on May ~, 1975 (abstract in Clinical Research 22:2l5A, 1975). The investi~ators found that, after one year of treatment with tolbutamide, left ventricular function was reduced and cardiac morphology altered compared to the control groups. The animal studies do not necessarily bear directly on the excess cardiovascular mortality seen in tolbutamide-treated patients In the UGDP study, but they do suggest several mechanisms by which this might have occurred. PROPOSED LABELING FOR ORAL HYPOGLYCEMIC DRUGS Mr. Chairman, as you know, it has been the position of the FDA since 1970 that the findings of the UGDP study should be reflected in a warning in the labeling for oral hypoglycemic drugs and, in turn, in the use by PAGENO="0456" 13706 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY physicians of these drugs. Let me emphasize that this view does not require that we conclude the study provides absolute proof of hazard. The UGDP study is an adequate and well-controlled study -- by far the most extensive and bast examination of the long term effects of Oral hypoglycemic agents yet undertaken -- and the finding of an increased cardiovascular mortality in tolbutamide and in phenformin~treated patients cannot be attributed to any shortcomings of study design or execution. This finding, despite any residual uncertainty that may remain, requires a clear warning to physicians. Prudence dictates that a warning be issued whenever there is sufficient evidence to believe that a drug may be hazardous or carry a risk and that such warning is necessary to assure the safe and effective use of the drug by physicians. Enough time has now passed for interested persons to have studied the Biometric Society report and the recent detailed UGDP report on phenformin. The Agency has, therefore, published for comment a regulation proposing new labeling for the oral hypoglycemic labeling. Interested persons may comment on the proposal by September 5, 1975, and a public hearing will be held on August 20, 1975. Final labeling regulations will not be published until after all comments and materials have been considered. The proposed labeling contains two sections of particular importance: a Boxed -Warning stating that there may be an increased risk of cardio- vascular death associated with the use of oral hypoglycemic drugs and a new indications section that limits use of these drug to patients PAGENO="0457" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13707 whose symptoms or blood glucose abnormalities cannot be controlled by diet alone and who cannot take insulin for one of a number of specified reasons. Let me discuss each of these sections in greater detail; they are reproduced in full in an attachment. The Warning describes the UGDP study and its findings. It has been contended that certain studies said not to support the findings Of the UGDP study should be mentioned in the warning section to provide `fair balance." We have concluded, however, and made clear in revised section 1.3 of our regulations (also published July 7, 1975), that if scientific data exist to support a warning, the warning must be presented in unambiguous terms without disclaimers or qualifications that would undermine or destroy its usefulness. There is, therefore, no mention in the proposed warning of other studies involving the oral hypoglycemic drugs. The mention of studies in which increased cardiovascular mortality was not found, would serve only to encumber the warning. The Warning also points out that although only one sulfonylurea and one biguanide were included in the UGDP study, it is prudent from a safety standpoint, in view of the similarities in chemical structure and mode of action of drugs within each of these two categories, to consider that the UGDP findings may apply to all other products in each category. The Warning is thus identical for all the sulfonylurea drugs; only one biguanide drug is marketed in this country. PAGENO="0458" 13708 COMPETITIVE PROBLEMS TN THE DRUG INDUSTRY Finally, the warnings section makes explicit the clear implication of the finding that tolbutamide and phenformin may carry a risk not associated with insulin: `(Drug) should be used in preference to insulin only in patients with maturity onset diabetes whose symptoms or blood-glucose level cannot be controlled by diet alone and only when the advantages in the individual patient justify the potential risk; see Indications. The patient should be informed of the advantages and potential risks of (drug) and of alternative modes of therapy and should participate in the decision to use this drug." `4e have concluded that a patient population exists for which these drugs, properly labeled, can be considered as safe and effective. We have also concluded, however, that this patient population is a limited one. The proposal to limit the treatment population to patients in whom insulin cannot be used has been opposed in the past on the ground that it interfered with the practice of medicine. We recognize that drug labeling has an impact on the practice of medicine. For this reason the Food and Drug Administration has an obligation to ensure that labeling is as correct and accurate as possible. It must, however, meet the statutory standard of describing the conditions of use under which a drug may be considered safe and effective. If a known hazard or potential risk leads to the conclusion that a drug may be used safety only in certain patients, this limitation on use must be expressed in labeling. The indications section, in addition to describing the population in whom these drugs are indicated, points out that "in considering the use of (drug) in asymptomatic patients, it should be recognized that PAGENO="0459" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13709 whether or not controlling the blood glucose is effective in preventina the long-term cardiovascular or neural complications of diabetes i~ an unanswered scientific question.' This emphasizes the different benefit- risk considerations that obtain in the symptomatic patient who needs alternative treatment if insulin cannot be used, and the asymptoma1~ic patient, whose need for alternative treatment is problematical. Mr. Chairman, you asked that I comment on the promotion of these drugs. Advertising for these products has not violated general legal require- nents, but it has been based upon labeling that has been in need of modification. It is clear that promotional materials must change radically to reflect the new warning and the restricted indications. You can be assured that we will be monitoring the promotion of these products closely after the new labeling becomes final, to see that they do so. It is important to recognize that the use of the oral hypoglycemics remains widespread despite the UGDP findings and despite the rather limited capability of the drugs, after a few years of use, even to lower the blood sugar. Total prescriptions for this class, according to the National Prescription Audit (a survey of IMS America) have been stable between 19 million and 21 million since 1967 (except for an apparent dip in 1969). There is thus a great deal of common practice to overcome before use of the oral agents will recede to its proper lebels. It is anticipated that publicity attendant upon our publication of proposed labeling and announcement of the upcoming public hearing PAGENO="0460" 13710 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY as well as public interest in todays hearing will bring the new labeling to the attention of physicians and help begin to persuade them that the UGDP findings should change the way they treat diabetic patients. In addition, the FDA plans to issue a Drug Bulletin when the labeling for these drugs is made final. We will monitor the use of these drugs and will take additional measures as necessary to publicize the final labeling. I will be pleased, Mr. Chairman, to answer any questions. PAGENO="0461" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13711 PROPOSED LABELING INDICATIONSICONTRAINDICATIONS AND WARNINGS SECTIONS FOR ORAL HYPOGLYCEMIC DRUGS OF THE SULFONYLUREA CATEGORY. INDICATIONS * (Drug) is indicated to control symptoms due to hyperglycemia in patients with maturity-onset nonketotic diabetes mellitus whose symptoms cannot be controlled by diet alone and in whom insulin cannot be used because of patient unwillingness, erratic adherence to the injection regimen, poor vision, physical or mental handicap, insulin allergy, employment requirements, or other similar factors. (Drug) may also be used to lower blood glucose in asymptomatic patients whose blood glucose elevation cannot be controlled by diet alone and in whom insulin cannot be used for any of the above reasons. In considering the use of (drug) in asymptomatic patients, it should be recognized that whether or not controlling the blood glucose is effective in preventing the long term cardiovascular or neural complications of diabetes is an unanswered scientific question. The use of (drug) may be associated with an increased risk of cardiovascular mortality as compared to diet alone or diet plus insulin; see WARNINGS. For this reason, it should be used only PAGENO="0462" 13712 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY when the advantages in the individual patient justify the potential risk. The patient should be informed of the advantages and potential risks of (drug) and of alternative modes of therapy and should participate in the decision to use this drug. The foundation of therapy in the obese maturity-onset diabetic is caloric restriction and weight loss. Proper dietary management alone is often effective in controlling the blood glucose and eliminating symptoms of polydipsia and polyuria. Use of (drug) must be considered by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Many patients who are initially responsive to oral hypoglycemic drugs become unresponsive or poorly responsive over a period of time, usually 1 to 5 years. (Drug) should be given only to patients demonstrated to be responsive to it; see DOSAGE AND ADMINISTRATION for dis' cussion of secondary failure. Short term PAGENO="0463" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 13713 administration of (drug) may be sufficient during periods of transient loss of control. Concomitant Thera~p~ withaBiguanide: (Drug) may be ~ised in conjunction with phen' formin to control symptoms due to hyperglycemia in patients with maturity~onset nonketotic dia-' betes mellitus whose symptoms cannot be controlled by diet and maximum recommended doses of either drug alone and in whom insulin cannot be used for any of the reasons cited above. In considering the use of concomitant therapy, it should be noted that both a sulfonylurea drug (tolbutamide) and a biguanide; drug (phenforinin) have been reported to be associated with increased cardiovascular mortality; see WARNINGS. In addition, phenformin can PAGENO="0464" 13714 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY produce lethal lactic acidosis in son~e patients. Thus the use of (drug) in association with phenfortnin carries a greater risk than the use of (drug) alone. If a judgment is made that (drug) and phenformin are to be used together in a particular patient, it should be established that the patient is * responsive to both drugs. This may be accomplished either by a trial of each drug separately or by adding the second drug and then tapering the dosage of the first, observing for diminished * control of blood glucose. Once the need for both drugs is established, the desired contr9l of blood sugar may be obtained by adjusting the dose of either drug. The possibility of hypoglycemia should be anticipated and appropriate precautions taken. See package insert for phenfortnin hy4rochloride for CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION. CONTRAINDICATIONS (Drug) is contraindicated in patients with: 1. Known hypersensitivity or allergy to the drug. 2. Diabetic ketoacidosis, with or without coma. Such patients should be treated with insulin. PAGENO="0465" COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY 1~71 5 WARNINGS SPECIAL WARNINQS ON CMDIOVASCULAR MORTALITY (This subsection of labeling to be boxed, set in boldface type, and placed at the beginning of WARNINGS section of labeling:.) The administration of oral hypoglycemic drugs may be associated with J~ncreased cardiovascular mortality as compared to treatment with diet alone or diet plui. insulin. This warning is based on the study conducted by the University Group Diabetes~Program (UGD?), a long term prospective clinical trialdesigrted to evaluate the effectiveness of glucose-4owering drugs in prevent- lug or delaying vascular complications in patients with maturity-onset nonketotic diabetes. The study involved 1,027 patients who were randomly assigned to one of five treatment groups ~ betes, 19 (supp. 2): 747~-83O, 1970; Diabetes, 24 (supp. l):65-184, 1975), PAGENO="0466" 13716 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The IJGDP reported that patients treated for 5 to 8 years with diet plus a fixed.dose of tolbut- amide (1.5 grams per day) or diet plus a fixed dose of phenforinin (100 milligrams per day) had a rate of cardio-~ vascular mortality approximately twice that of patients treated with diet alone or diet plus insulin. Total mortality was increased in both the to1but~ amide- and phenformin-treated groups, but this increase was statistically significant only for phenfortain. Despite controversy regarding the interpretation of these results, the findings of the UCDP study provide adequate scientific basis for this warning. Although only one drug in the sulfonylurea category (tolbutamide) and. one in th~ biguanide category (phenfortnin) were included in this study, it is prudent from a safety standpoint to consider that this result may also apply to other oral hypoglycemic drugs in these categories, in view of the close similarities in mode of action and chemical structure among the drugs in each category. PAGENO="0467" COMPETITIVE PROBLEMSIN THE DRUG INDUSTRY 13717 (Drug) should be used in preference to insulin only In patients with maturity-onset diabetes * whose symptoms or blood glucose level cannot be con- * trolled by diet alone and only when the advantages in the individual patient justify the potential risk; see INDICATIONS. The patient should be informed of the advantages and potential risks of (drug) and of alternative modes of therapy and should participate in the decision to use this drug. (Drug) is not effective in patients with juvenile diabetes or insulin-dependent diabetes at any age. Sucl~ patients should be treated with insulin. The concomitant long term use of insulin and (drug) in an individual patient is, In vi of the potential risk of increased c~rdio- vascular mortality with (drug), less safe on a benef it- risk basis than the use of Insulin alone. PAGENO="0468" 13718 COMPETITIVE PROBLEMS IN THE DRUG INDUSTRY The effectiveness of any ~rai hypoglycemi'~ drug, including (drug), In lowering blood ~1ucose to c desired level decreases in a large numb2r of patiento as tie drug is administered over a period of months or years, in part because the patient's blood glucose tends to rise over time and in part because of diminished responsiveness to the drug. This phenomenon is known as secondary failure to distinguish it from primary failure in which the drug is ineffective in an individual patient at the time of its initial adminis- tration. See DOSAGE AND AD~flNISTRATION. Itenal or hepatic insufficiency may cause elevated blood level~ of (drug) and increase the risk of serious hypoglycemic reactions. P~~nan~çy: (Data and interpretation related to reproduction and teratology studies to be supplied by manufacturer). Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. Neonatal hypoglycemia has been reported more frequently following use of the 1/9n~'er-acting agents. If (drug) is t~sed during pregnancy, it should be discon~in"ed (time period to be supplied b7 rnanufactu'er, he~ore * the expected delivery date. 0