U.S. Food and Drug Administration • Center for Drug Evaluation
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U.S. Food and Drug Administration • Center for Drug Evaluation
and Research |
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Drug Information |
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Summary Context: Few recent data are available from formal evaluations of approved new drug applications to address perceptions that racial and ethnic groups are under-represented in clinical trials of new drugs. This study reviews racial and ethnic group participation in clinical trials and race-related labeling for new molecular entities approved during a five-year period by the Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER). Objectives: The objectives of the study were to assess to what extent racial and ethnic groups participated in clinical trials of newly approved drugs and determine to what extent sponsors presented race-related information in the labeling approved for those products. Design: This was a retrospective review of FDA medical officers' reviews of clinical trial protocols and product labeling for 185 new molecular entities (NME's) approved by CDER between January 1, 1995, and December 31, 1999. Enrollment data were obtained from the reviews and tabulated according to race/ethnicity. The approved product labeling was searched for statements related to product testing in various racial/ethnic groups. All data were compiled and analyzed using Microsoft Access. Main Outcome Measures: This study quantifies the participation of racial/ethnic groups in clinical trials by year and therapeutic category. Additionally, the study categorizes labeling based on the types of effects described as related to race/ethnicity. Results: Racial and ethnic groups appear to participate in clinical trials to varying degrees. Blacks participated in trials to the greatest extent; however, their participation steadily declined from 12% in 1995 to 6% in 1999. Among trials known to be conducted only in the U.S., Black participation is comparable to their representation in the U.S. population. In all cases, participants designated as Hispanic appear to be far below their representation in the population. Some differences in participation for all racial and ethnic groups are seen when comparisons from year-to-year or among drug classes are made. Labeling for 45% (84/185) of the products contained some statement about race, although in only 8% (15/185) were differences related to race described. Fifty percent (50%) of the effects were pharmacokinetic, 39% were efficacy, and 11% were safety. One product label recommended a change in dosage based on racial differences. Conclusions: Racial and ethnic groups are participating in clinical trials of new drugs. Some product labeling contains references to evaluation for effects due to race/ethnicity. The majority of effects attributed to race were pharmacokinetic. Few products demonstrated differences in safety or efficacy effects, and one product label recommended changes in dosage based on racial effects. Background Responses to drugs can be altered by a wide variety of individual characteristics that affect the pharmacokinetics of a drug (differences in absorption, metabolism, distribution, excretion, or the presence of other drugs) or the patient's response to the drug (differences in co-existing illness, etiology of disease, or again, the presence of other drugs, etc.). In some cases these differences have been related to demographic characteristics, such as gender or race. Women, for example, are unusually susceptible to drugs that prolong the electrocardiograhic QT interval and the serious ventricular arrhythmia (Torsades de pointes) that can accompany this prolongation. They may also, because of their smaller size, have more adverse effects (e.g., edema with amlodipine) than men when both are given the same dose. There are documented racial differences as well. Caucasians are more likely than Asians to have abnormally low levels of an important liver metabolizing enzyme (cytochrome p450 2D6). Blacks respond poorly to several classes of antihypertensive agents (beta blockers, angiotensive converting enzyme (ACE) inhibitors, and angiotensin II antagonists) and appear to have a greater risk of angioedema when given ACE inhibitors. It is therefore important to include in drug development representation of the broad range of patients who will eventually receive the drug, including people of both genders, representatives of major racial/ethnic groups, and patients with a wide range of disease severity, concomitant illnesses, and use of concomitant treatments. Attention to potential racial and ethnic differences in response to drugs is part of a larger effort by the FDA to ensure that the safety and efficacy of drugs are adequately studied in people who represent the full range of patients who will receive them upon marketing. FDA guidelines and regulations encourage the participation of racial and ethnic groups in all phases of drug development, promote collection of race-related data during research and development, and recommend analysis of the data for race effects. Following is a brief summary:
Draft guidance documents on population pharmacokinetics and the adverse reactions and clinical sections of the labeling also consider subgroup issues as summarized below.
The Food and Drug Modernization Act (FDAMA) of 1997 also prompted FDA to examine issues related to the inclusion of racial and ethnic groups in clinical trials. Section 115 of the Act required the Secretary, "in consultation with the Director of the National Institutes of Health and the representatives of the drug manufacturing industry, review and develop guidance, as appropriate, on the inclusion of women and minorities in clinical trials..." FDA established the FDAMA Women and
Minorities Working Group to review and implement this section of FDAMA. In
a report issued on July 20,
1998, FDA's Office of Special Health Issues (OSHI) completed three projects that gathered and evaluated demographic data. The results of the first study were presented at the 2000 FDA Science Forum in a poster entitled "Special Populations: Testing and Labeling of New Drugs." The study examined NME's approved in 1995 and 1996.2 Results demonstrated that Black volunteers participated in studies for most drugs but participation by other racial and ethnic groups was low. Similar results were found in an FDA review of demographic data for NME's approved from January 1998 to June 1991. The results of the second study were presented at the 2001 FDA Science Forum in a poster presentation entitled "Race, Age, and Gender: A Review of Demographic Subgroups in Clinical Trials of FDA-Regulated Drugs and Biologics."3 The study examined the extent to which IND sponsors complied with the reporting requirements of the 1998 Demographic Rule and found that all required information was not submitted for 85% of IND protocols with data reported. Where race/ethnicity could be determined, Blacks represented 9% of the study participants. Hispanic/Latinos and the group consisting of Asians, Pacific Islanders, and Native Hawaiians each comprised 3%. Another 3% were designated as nonwhite, and less than 1% were American Indian and Alaska Natives. This report presents the results of the third OSHI study "Participation of Racial/Ethnic Groups in Clinical Trials and Race-Related Labeling: A Review of New Molecular Entities Approved 1995-1999." Objectives The objectives of this study were to assess the following: 1. To what extent racial and ethnic groups participated in clinical trials of drug products approved between 1995 and 1999 and 2. To what extent sponsors presented race-related information in the approved product labeling. Methods Data Sources and Collection Data for this study were obtained from two primary sources. Information about clinical trial enrollment data was obtained from FDA medical officers' reviews of 185 new molecular entities approved by CDER between 1995 and 1999.4 The reviews contained descriptions of 2,581 clinical trial protocols. The reviews were searched for FDA reviewers' descriptions of the race of study participants. Race categories used were those defined in the Office of Management and Budget Directive 15.5 Participation was quantified according to year of product approval and therapeutic class based on the FDA review division. The labeling at the time of product approval was reviewed to determine whether assessments of racial/ethnic differences were being communicated to practitioners. Exact wording from the label was captured. Labels describing racial differences were reviewed to determine the type of difference and whether the difference required a change in dosage for a particular racial/ethnic group. All data extracted were captured on a protocol extraction form and entered into a Microsoft Access database. An initial audit of each data field for 250 protocols assured the quality of the extracted data. A second audit was conducted for each data field for 100% of the protocols once the data were entered into the database. Analysis Race data were analyzed from clinical trial protocols described in FDA medical officer reviews of 185 NME's. Results Race/Ethnicity of Clinical Trial Participants Overall Participation A total of 493,347 individuals were described in the medical officers' reviews as being enrolled in the 2,581 clinical trials for all products examined in this study. Race could be determined from the medical officers' reviews for 53% of the participants (Fig. 1). Race could not be determined for the remaining 47%. Of those for whom race and ethnicity could be determined (n=263,704), 88% were White; 8% were Black; 1% were Asian, Pacific Islander, or Native Hawaiian; 3% were Hispanic/Latino; and less than 1% were American Indian or Alaska Native. It must be noted that the Hispanic/Latino ethnicity is applicable to people of several races. Therefore, the possibility exists that in instances in which NDA submissions reported race without regard to ethnicity, Hispanics may have also been included, and the current figures may represent an undercount of the Hispanic ethnic group (Fig. 2). Figure 1. Figure 2.
Of the 263,704 participants for whom race data were available, 75,357 of them were in trials known to be conducted only in the U.S. When evaluating those individuals, 83% were White; 13% were Black; 3% were Hispanic/Latino; 1% were Asian, Pacific Islander, or Native Hawaiian; and less than 1% were American Indian or Alaska Native. (Fig. 3). Figure 3.
Figure four presents a comparison of the average proportion of each race or ethnic group participating in total and in U.S. trials with their average representation in the U.S. population, across the years 1995-1999. Figure 4.
*Represents 15% of total participants and 70% of participants from trials known to be conducted in the U.S. Population Estimates Source: U.S. Census Bureau, 1995-1999. Participation by Year The proportion of clinical trial participants from each racial/ethnic group varied from year to year. Overall the participation of Blacks ranged from 12% in 1995 and steadily declined to 6% in 1999 (Fig. 5). Among trials known to be conducted only in the U.S., the representation of Blacks ranged from 18% in 1995 to 10% in 1999. Their representation occasionally exceeded their representation in the U.S. population. Hispanic representation appeared to be consistently well below their representation in the population (Fig. 6). Figure 5. Figure 6.
Participation by Drug Class Drug classes were defined according to the division within the agency responsible for the product review. The categories of products for each division and designated abbreviations are listed in Table 1. Overall, racial and ethnic groups appeared to have participated in lesser proportions in trials for neuropharmacological, pulmonary, and oncologic drug products and in greater proportions for special pathogen and anti-infective drug products (Fig. 7). No statistical analyses were done. In many instances in which nonwhite racial/ethnic groups appear to be underrepresented, there are substantial numbers of individuals whose race could not be determined. For example, race could not be determined for as many as 70% of those enrolled in the trials for the pulmonary/allergy products and 54% of those in trials for oncologic products. Table 1: Abbreviation Review Division/Drug Class FDA Review Division
Figure 7.
*excludes 229,643 (47%) whose race was not described in the medical officers' reviews. Label Review Findings Review of the 185 product labels revealed that 84/185 (45%) contained some type of statement related to race, which included statements that no studies were conducted, too few patients were studied, or no differences were seen. The 84 product labels contained a total of 98 references to race. Eleven products had multiple statements such as statements that no differences were found in efficacy and no pharmacokinetic studies were conducted. Thirty four percent (33/98) of the statements indicated that no studies had been conducted to determine if there were differences related to race/ethnicity. Eight percent (8/98) indicated that studies were inadequate to detect any racial differences. Thirty percent (29/98) of the statements indicated that no differences were found. Eighteen percent of the statements (18/98) indicated that differences related to race had been identified. Ten percent (10/98) of the statements indicated that there were similar racial responses. A summary of the labels with race statements is listed in Table 2. Table 2: Label Review Findings
When reviewing differences found in the label by the drug class, the greatest proportion of race-based differences occurred in cardio-renal products (8/22 or 36%), analgesics (2/13 or 15%), neuropharmacology (3/21 or 14%), and metabolic/endocrine (2/25 or 8%). No race/ethnicity-based differences were noted in the labels of oncologic, anesthetic, gastrointestinal, anti-infective, anti-viral, dermatological and dental, pulmonary and allergy, reproductive and urologic, or special pathogen drug products (Table 3). Table 3: Frequency of Race Differences by Drug Class
Fifteen product labels contained 18 statements about differences related to race/ethnicity. Of the 18 effects described, 50% (9/18) were pharmacokinetic, 39% (7/18) were efficacy, and 11% (2/18) were safety. Three product labels described more than one effect related to race. Ten product labels described differences for Blacks; one of those also described a difference for Hispanics. Five labels described differences for Asians. One product, an antihypertensive agent, recommended a change in the dosage based on racial differences: an increased initial dose for Black patients. Discussion Participation of Racial/Ethnic Groups Overall, during the five-year period examined, nonwhite racial/ethnic groups participated in clinical trials at various rates. No comparisons were done to determine the types and proportions of products approved that might provide insight into year-to-year differences. No comparison was done, for example, to determine whether more anti-infective or cardiorenal products were approved in years where these groups were present in larger numbers. Nonwhite racial/ethnic groups rate of participation varies by drug class. Label Reviews The review of the labels showed that half of the products contained race-related statements and indicates that many sponsors are aware of the need to look for race-based effects. Only a minority of drugs where race/ethnicity was assessed showed a difference based on race/ethnicity. The race effects described in the labeling were primarily pharmacokinetic differences. One product, an antihypertensive agent, recommended a different initial dosage for a specific racial group. Limitations of the Study The limitations of this study are listed below:
Conclusions and Recommendations This study implements, in part, the July 1998 FDAMA Working Group initiative to gather and evaluate demographic data. Overall participation by racial and ethnic groups was small; however, Black representation closely approximated their representation in the U.S. population. Hispanics appeared to be most underrepresented in comparison to their representation in the U.S. population; however, they might have been counted among other racial groups. Few product labels contained statements about whether the effect of race was known. Attention to race by CDER medical officer reviews is variable. The recently launched Clinical Review Template will be implemented over the next year and will facilitate consistency among reviews. The template is intended primarily to standardize the ordering and placement of topics within reviews. The section on Special Populations will discuss how many people of various racial/ethnic groups were exposed to the investigational product during clinical trials and how well the data were analyzed for differences between them. Additional studies using actual sponsor submissions may be needed to determine if FDA should provide additional guidance to industry regarding demographic subgroup analysis in NDAs. Additional studies may also be needed to determine whether the proportion of a racial subgroup's participation in clinical trials of specific drug classes was comparable to the prevalence of those diseases within racial groups. October 15, 2001 1 U.S. Department of Health and Human Services, Food and Drug Administration, "Investigational New Drug Applications and New Drug Applications, Final Rule," Federal Register, February 11, 1998; 63(8):6854-62. 2 Banks, D.B.; Toigo, T.A.; Carmouse, G.N Participation of Women in Clinical Trials 1995-1996. Special Populations: Testing and Labeling of New Drugs. Presented at the FDA Science Forum, February 15, 2000. 3 Evelyn, B., Toigo, T., Banks, D., Pohl, D., Gray, K., Robins, B., Ernat, J. "Women's Participation in Clinical Trials and Gender-Related Labeling: A Review of New Molecular Entities Approved 1995-1999." June 2001. 4 Medical officer reviews are documents in which the FDA officials responsible for oversight of specific products analyze the sponsors' data and explain their conclusions. 5 U.S. Office of Management and Budget, "Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity." Federal Register, October 30, 1997; 62(210): 58781-90. FDA/Center for Drug Evaluation and Research |
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emphasizes the importance of including analysis of
demographic subset data in new drug applications. 
