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IJnited States General Accounting Office Report to Congressional Requesters Octobt?r 1992 WOMEN’S HEALTH FDA Needs to Ensure More Study of Gender Differences~in Prescription Drug Testing, II II 147861 GAO/HRD-93-1’7 . United States General Accounting Office Washington, D.C. 20548 Human Resources Division B-243898 October 29,1992 The Honorable Henry A. Waxman Chairman, Subcommittee on Health and the Environment Committee on Energy and Commerce House of Representatives The Honorable Patricia Schroeder Co-Chair, Congressional Caucus for Women’s Issues House of Representatives The Honorable Olympia J. Snowe Co-Chair, Congressional Caucus for Women’s Issues House of Representatives Drug therapy is the most common and one of the most important forms of medical treatment used for men and women. Because of physiological differences, however, men and women can respond differently to the same prescription drug. %or example, women tend to metabolize some antihypertensive and cardiovascular drugs at a slower rate than men. Also, drug interactions with women’s hormones and women’s use of oral contraceptives during their childbearing years can cause different responses. Despite evidence of important differences in the way gender can affect drug response, drug manufacturers may not be studying drug test data for possible gender-related differences. Given the potential for different responses to drugs based on gender, you expressed concern that women could be at risk if the Food and Drug Administration (FDA) approves drugs on the basis of clinical trials’ in which women were underrepresented. At your request, we examined FDA'S policies and the pharmaceutical industry’s practices regarding research on women in prescription drug testing. We reviewed FDA'S policy guidance for drug manufacturers and interviewed FDA, National Institutes of Health (NIH), and Institute of Medicine officials; pharmaceutical representatives; and experts in pharmacology. We also performed an extensive literature search on topics related to drug testing and clinical trials (see bibliography). We did not ‘Clinical drug rrials involve ksting a new drug in humans to determine whether it has thcrapcutic hcmcfit in fighting disrase. Page 1 GAO/H&D-93-17 Women in Prescription Drug Testing ~B-243898 ..-.-._.._.--.. .-... .“.___._._ - evaluate the appropriateness of FDA'S policy that excludes women of childbearing potential from participating in early clinical drug trials. Further, we did not identify the level of female participation in initial drug testing. In our examination of drug manufacturers’ testing practices in the United States, you asked us to provide information on the prescription drugs FDA approved over a recent 3-l/2-year period. Specifically, we were to determine (1) the representation of women in drug testing, (2) the sufficiency of female participation in drug trials to assess significant gender-related differences, (3) the extent to which trial data were analyzed for differences in response related to gender, and (4) whether studies were conducted to examine drug interaction with the varying hormonal status of women and oral contraceptive use. Because FDA could not readily identify the level of female participation in trials for the drugs in our study, we surveyed all drug manufacturers that obtained FDA approval of drugs containing new chemical properties from January 1988 to June 1991. The questionnaire sought detailed information on the participation of women in clinical drug trials conducted in the United States. We provided our questionnaire results to FDA. A detailed discussion of our objectives, scope, and methodology is in appendix I. A copy of the survey questionnaire, annotated to show total responses to each question, is in appendix II. Results in Brief guidance to drug manufacturers recommends that they test new drugs on representative patient populations. FDA, however, does not define “representative,” and manufacturers are not consistent in their application of FDA'S guidance. A quarter of the drug manufacturers in an industry survey reported that they do not deliberately recruit representative numbers of women as participants in drug trials. Further, more than half said that FDA asked them to include women in drug trials, but the remainder said they had not been asked. FDA Women were included in clinical trials for all the drugs in our survey but were generally underrepresented in those trials. Our standard of representativeness is a comparison of the proportion of women among clinical trial participants with the proportion of women among those persons with the disease for which the drug is intended. Using this approach, we determined that for more than 60 percent of the drugs, the representation of women in the test population was less than the Page 2 GAO/HBD-93-17 Women in Prescription Drug Testing a ._____._-.-“,__^-_-” __---.- -B-243898 .._--._~ __-__- representation of women in the population with the corresponding disease. Although women may not be proportionately represented in trials for some drugs, there were enough to detect gender-related differences in response for most drugs in our survey. The absolute number of women in clinical drug trials is a key determinate of whether manufacturers can detect significant differences in response that may be related to gender, according to FDA. We observed, however, that while the trials supporting most drugs did include at least 250 women, the minimum number suggested by FDA, for about a third of the drugs, fewer than 250 women were included as trial participants. Even when enough women are included in drug testing, often trial data are not analyzed to determine if women’s responses to a drug differed from those of men. Also, many drug manufacturers do not study whether their drugs specifically interact with the hormones present in women, including hormones commonly found in oral contraceptives. This lack of knowledge about gender-related differences in drug response can create a critical gap in information about how best to tailor drug therapies to women. Background An agency within the Department of Health and Human Services, FDA is the nation’s oldest consumer-protection agency. It regulates nearly $1 trillion worth of products made available annually to the public by the food, drug, medical device, and cosmetic industries2 Pharmaceutical sales represent more than $40 billion of this amount. primary regulatory responsibility regarding pharmaceuticals is to approve new drugs before they are marketed to the public. Annually, FDA approves an average of 20 new prescription drugs. The agency fulfills its drug approval responsibilities by (1) providing guidance for drug manufacturers’ use in conducting clinical trials in humans, (2) reviewing manufacturers’ proposals for conducting clinical trials to ensure that they are performed in a safe and ethical manner, and (3) evaluating new drugs for which premarket approval is sought to ensure that they are safe and effective. Also, FDA approves new drug labeling. The label indicates the medical conditions and patient populations for which the drug has been tested and approved as safe and effective. FDA'S 2FI)A’s basic authority is derived from the Federal Food, Drug, and Cosmetic Act, as amended (21 USC. 301 et seq.). FDA also has responsibilities under other laws. Page 3 GAQ/HRD-93-17 Women in Prescription Drug Testing Ir _ _,......._.. ..-- --.____-B-243898 .--. _ _ __.____--___ &~ T’&ting and Approval I’rowss In approving new drugs for marketing, FDA must assure that the public health is protected by carefully assessing the risks and benefits associated with new drugs. Drug manufacturers must demonstrate the safety and efficacy (effectiveness) of new drugs through strict testing before FDA approves them for therapeutic use. After new drugs are tested in the laboratory and on animals and shown to have possible therapeutic benefit, FDA approves them for testing in humans. Clinical trials consist of three phases: Phase 1 is used to determine toxicity and safe dose levels; Phase 2 assesses drug efficacy using small-scale trials; and Phase 3 further evaluates efficacy and monitors adverse responses using large-scale trials. Figure 1 illustrates the new drug development and testing process. Figure 1: New Drug Development and Testing Process ‘re-ClInical Clinical Phase 1 Phase Phase 2 3 effectiveness. FDA Approval Verify effectiveness, monitor adverse reactions from . flange: 1-3 Years Average: 18 Months Range: 2 Months 7 Years Average: 24 Months Range: 2-10 Years Average: 5 Years New Drug Application Submitted FDA Time: 30-Day Safety Review Page 4 GAO/HRD-93-17 Women in Prescription Drug Teclting - _ _ .._ _. “. ..-...-.. 1---------- B-2 4 3 8 9 0 F D A a p p ro v edsru g sb e fo reth e y a re m a rk e te fo d r p u b l i uc s ep ri n c i p a l l y b a s e od n te s ti n gre s u l tsre p o rte di n n e w d ru ga p p l i c a ti o nAsn.3a p p l i c a ti o n c o n ta i n as ,m o n og th e rth i n g sa, s u m m a ry o f th e d ru g ’s te s ti n gh i s to rya n d d a tafro m c l i n i c atril a l s i, n c l u d i nthge d i s tri b u ti oonf d ru gtri a l p a rti c i p a n ts b y g e n d earn da g e A. n F D A re v i e wte a ms c ru ti n i z ethse d a tafro m s p e c i fi c te c h n i c av il e w p o i n tots e v a l u a th te e d ru g ’ss a fe tya n de ffi c a c yIn. a d d i ti o n to re v i e w bs y c h e m i s atsn dp h a rm a c o l o g iFsDtsA p, h y s i c i a en vs a l u a te c l i n i c atril a l re s u l ts -i n c l u d i th n ge d ru g ’s th e ra p e u tiacn da d v e rsee ffe c ts . S ta ti s ti c i a ne sv a l u a th te e d e s i g nfos r e a c hc o n tro l l eddru gtri a l ,th e v a l i d i ty o f th e s ta ti s ti c aa ln a l y s easn, dth e c o n c l u s i oonfss a fe tya n de ffi c a c by a s e d o n th e s tu d yd a ta T. h ere v i e wte a md e te rm i n ewsh e th e th r eevidence s u p p o rts th e d ru gm a n u fa c tu re cr’s l a i mth a tth e d ru gi s s a fea n de ffe c ti v e u n d e thr e c o n d i ti o no sf u s ere c o m m e n d ien dth e p ro p o s el da b e l i n g . F D A P o l i c yE x c l u d e s W o m e on f C h i l d b e a ri n g I’o te n t,i aF l ro m E a rl yT ri a l s .-_----.I- -.- _-- O n eo f F D A ’S p o l i c i eosn c l i n i c ad lru gte s ti n gp re c l u d ewso m e no f c h i l d b e a ripnogte n ti afro l m p a rti c i p a ti ni ng P h a s e1 a n de a rl yP h a s 2e tri a l s .4T h i sp o l i c w y a s i m p l e m e n teto da v o i de x p o s i nagfe tu s to a d ru g th a th a sn o ts a ti s fi epdre l i m i n a srya fe tya n de ffi c a c te y s ti n gW. o m e on f c h i l d b e a ripnogte n ti aal re p e rm i tte dto p a rti c i p a iten tri a l so n c ee v i d e n c e o f a d ru g ’se ffe c ti v e n e isnsh u m a n i ss o b ta i n eadn dd a taa re a v a i l a bfro l em re p ro d u c ti vs etu d i e os f a n i m a lths a th a v ee x a m i n ewdh e th e th r e d ru g c a u s ebsi rth d e fe c tsF.D A i s re e v a l u a ti intsgp o l i c yo n th e e x c l u s i oo nf w o m e no f c h i l d b e a ripnogte n ti ai ln th e e a rl yp h a s eosf d ru gte s ti n gT. h i s re p o rtd o e sn o ta d d re sths e a p p ro p ri a te n eo sf ths i s p o l i c yN. o r d o e sth e re p o rtc o n ta i sn ta ti s ti c os n fe m a l ere p re s e n ta ti ionnP h a s e1 d ru gtri a l s . -..--- G & o r-re l a te d D i ffe re n c e s i n R w p o n s eE x i s tfo r S o m eD ru g s E v i d e n coef th e i m p o rta n coef g e n d e r-re l a atenda l y s ei nsd ru gte s ti n gi s m o u n ti ni gn h e a l thre s e a rc hF .o re x a m p l we i, th p ro p ra n o l (a o l b e ta b l o c k ecr o m m o n luys e dto tre a th y p e rte n s i oa nb ,n o rm ah le a rtrh y th m s , a n da n g i n am), e na n dw o m e nte n dto re s p o n dd i ffe re n tl yW. h e nm e na n d w o m e ni n g e si td e n ti c ad lo s e os f p ro p ra n o l oa l h, i g h ecr o n c e n tra ti o nf th e d ru gw i l l re m a i ni n th e b l o o dl e v e l 8s h o u rsl o n g ei rn w o m e nth a n i n m e n . W o m e n p’sh y s i o l o g i dc iaffel re n c e(bs o d yc o m p o s i ti osnu, c ha s s m a l l e r “ A d ru gm a n u fa c tu re m ru s st u b m iat n e wd ru ga p p l i c a ti re o nq u e s ti nF gD A a p p ro v atol n v a rk ca t.n e w d ru gfo r h u m a un s ei n i n te rs ta tec o m m e rc e . ‘F IN ’sp o l i c ay p p l i eosn l ytu w o m e no f re p ro d u c ti cv ae p a b i l iatyn dm e d i c i n th e sa ta re n o td e s i g n to ed trra t, l i fe -th re a te n i nl l gn e s s eF sD. A a d o p te thd i sp o l i c lya rg e lby e c a u so ef a n a d v e rsderu gc x p c r i c n c e i n E u ro p ed u r i n gth e l a te 1 9 6 0ws h i c hc o n c e rn ered p o rtso f s e v e re d e fo rm i ti ei ns th o u s a n do sf b a b i e s b o rnto m o th c ruw h o h a dta k e nth e d ru gth a l i d o m i d ue r i n gp re g n a n cFyo. l l o w i nthge th a l i d o m i d e i n c .i d c nF t,D A i s s u egdu i d e l i nthe as ta tte m p tot p ro te c wt o m e na n dth e i ru n b o rno ffs p r i n gfro m th e p o s s i b hl ea rm fu el ffe c tso f n e wd ru g s . P a g e5 G A O /H B D - 9 3 - 1 7W o m e ni n P r e s c ri p ti o n D r u g T e s ti n g a B-243898 size and more fat, and the presence of endogenous [i.e., naturally occurring] sex steroid hormones) and other biological factors (including the presence of exogenous [e.g., ingested] sex steroid hormones) may influence their response to a drug. Gender-related effects in drug response due to the presence of naturally occurring hormones or use of oral contraceptives have particular relevance for women of childbearing age. Approximately a quarter of all women of childbearing age use oral contraceptives. Drug interactions with oral contraceptives can either decrease the effectiveness of the contraceptives or increase the toxicity of the other drug. For example, many drugs, such as those used to treat epilepsy, sometimes interact with oral contraceptives to make them less effective in preventing pregnancy. Conversely, certain drugs, such as antidepressants, have the opposite effect, interacting with oral contraceptives to increase their potency, sometimes to toxic levels. Likewise, interactions with estrogens, the principal female hormone, may affect drug disposition, thus requiring higher or lower dosages of prescription drugs. Principal Findings FDA Guidance Does Not Define Representation of Women in Drug Testing FDA has not issued specific guidance or criteria for drug manufacturers to use in determining the extent and sufficiency of female representation in Phases 2 and 3 drug trials. The agency’s clinical guidance recommends that the full range of those who will be taking the drug after approval be represented in drug testing. However, FDA has not defined the term ‘representative,” nor has it provided guidance to drug manufacturers for determining when sufficient numbers of women are included in clinical trials to detect gender-related differences in drug response. An industry survey showed that drug manufacturers are uncertain as to what FDA expects with regard to including representative numbers of women in clinical trials. FDA believes that specific guidance for determining the representation of women is not needed beca.use drug manufacturers generally include enough women in their trials. FDA officials base their belief on two surveys conducted in the 1980s on the extent of elderly representation in drug trials. In these surveys, one in 1983 and one in 1989, FDA found that for “Pharmaceutical Manufacturers Association, New Medicines In Development for Women (Washington, D.C., 1991). Page 6 GAO/HRD-93-17 Women in Prescription Drug Testing * -l*,,-*_-l..--.” .--.-._--..--_ --B-243898 most drugs, the representation of women reflected the gender distribution of the incidence of the corresponding disease in women. The agency also believes that the level of female representation was adequate to detect important gender-related differences in drug response. belief that specific guidance is not needed for determining the representation of women in drug testing is not reflected in the opinions and actions of the pharmaceutical industry. For example, the Special Populations Committee of the Pharmaceutical Manufacturers Association (PMA)~ found that the issue of how to best determine what is a representative proportion of women in clinical drug trials is unresolved. A 1991 survey by the committee concluded that there is no consensus on what FDA expects regarding the inclusion of women in drug trials. The survey showed that 56 percent of the major drug manufacturers responded that FDA reviewers had requested that they include women when designing their drug trials, but 44 percent said that the agency had made no such request. Further, 24 percent of drug manufacturers reported that they do not deliberately recruit representative numbers of women as participants in clinical drug tria.ls.7 FDA'S Unlike FDA, NIH, the principal federal agency that sponsors biomedical research, has issued a policy that requires its research project grantees, when designing their studies, to ensure that women are adequately represented. NIH requires that grantees include women in numbers appropriate to the incidence of the disease being studied. The agency is also developing a database to routinely monitor grantees’ compliance with this policy.8 Drug trials need to include enough women to detect clinically significant differences in response related to gender. However, female participation in “I’MA is a scientific and professional trade organization representing more than 100 pharm;rc!eut.icai firms that discover, develop, and produce most of the prescription drugs used in the United States. The ;Lssociation’s Special Populations Committee, composed of 12 clinical doctors from m&r researchbased drug manufacturers, was formed to study the issues involved in testing drugs in special populations, including women. %omc drug manufacturers may be developing drugs that would be used exclusively by men. “Although NIH announced its policy encouraging the inclusion of women in research study populal.ions in 1986 and guidance for implementation was published in 1989, the policy was not applied consistently before 1990. Further, NIH officials had taken little action to encourage researchers to analyzrcstudy results by gender. After NIH’s implementation of its policy became the subject of congressional hearings in 1990, NIH established the Office of Research on Women’s Health to ensure that future NIH-sponsored research appropriately addresses issues relating to women’s hcakh and that Ulere is appropriate participation of women in clinical research, especially in clinical trials. See National Institutes of Health: Problems in Implementing Policy on Women in Study Populat.ions (GAO/r-HRD-90-33, June 18,199O). Page 7 GAO/HRD-93-17 Women in Prescription Drug Testing b B-243898 II. ^.._.I.. .^_.._..._--._ - -.- the trials for some drugs may not be sufficient to identify such differences. FDA guidelines prescribe a format for presenting demographic characteristics of trial participants and allude to the need for analysis of effectiveness by gender.B The guidelines do not, however, provide explicit criteria for determining the level of female participation needed to detect potential differences in drug response, FDA officials believe that usually at least 250 women, regardless of the drug, are needed to detect significant gender-related differences in drug response. Women ire Not Proportionately Represented in Trials for Some Drugs Women were included in the clinical trials for all the drugs in our survey, but for about 60 percent of the drugs, women were under-represented in the trials. Our method of assessing whether women were underrepresented was to compare the proportion of participants in Phase 2 and 3 drug trials conducted in the United States that were women with the proportion of women among those persons with the corresponding disease or condition. This methodology uses the same criterion recommended by NIA and used by FDA in its 1983 and 1989 surveys. The rationale for this methodology is that unbiased random clinical trials should yield a test group that closely approximates the population of patients for whom the drug is intended. Using this methodology, we rated the participation of women for each class of drugs as comparable, moderate, or low. A clinical pharmacist assisted us in our analysis. As shown in table 1, of the 53 drugs in our survey, 23 percent had a low proportion and 40 percent had a moderate proportion of women. “1J.S.Department of Iiealth and knnan Services. Food and Drug Administration, Center for Drug Evaluation and Research. Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications,fuly Page 8 GAO/HRD-93-17 Women in Prescription Drug Testing