Congress passed the pediatric exclusivity provision as part of the Food and Drug Administration Modernization Act of 1997 to address a long- standing concern about the low percentage of prescription medications on the market that had been tested and approved for use in children. BPCA, which reauthorized the pediatric exclusivity provision, also included a requirement that FDA take into account adequate representation of race and ethnicity in the development of patient groups in pediatric drug studies. FDA is responsible for administering the law and has procedures for ensuring the study of drugs in pediatric patients as well as guidance that encourages (1) the inclusion of children from minority groups and (2) the collection and analysis of race-related study data. In this role, FDA must balance its policy of minimizing the number of children exposed to a drug during clinical trials with the need to maintain adequate sample sizes, including adequate representation of minority children, for effectively assessing a drug. In May 2001, we testified before the Senate Committee on Health, Education, Labor and Pensions that, since enactment of the pediatric exclusivity provision, both the numbers of new drugs studied in children and the number of therapeutic classes these drugs represent have substantially increased. We reported that hundreds of studies were being done on drugs that are important to pediatric patients because the drugs treat a variety of diseases or conditions that afflict children. Some were tests on relatively small numbers of pediatric patients to determine the correct dose for a specified age group, while other tests were on larger numbers of pediatric patients and were more complex and costly evaluations of a drug’s safety and effectiveness in children of various ages. BPCA reauthorized and expanded the provision for 5 more years through October 1, 2007. The process for obtaining exclusive marketing rights can be initiated either by a drug sponsor or by FDA. A sponsor may submit a proposal to FDA to conduct drug studies. If FDA officials believe that studying a drug may produce health benefits for children, FDA issues a formal written request to the drug sponsor that includes, among other things, the type of studies to be conducted, the study design and goals, and the formulations and age groups to be studied. As of March 31, 2003, FDA had issued 272 written requests for pediatric studies. Of these, 220 were issued in response to sponsors’ proposals. FDA may issue a written request without the sponsor’s proposal if FDA identifies a need for pediatric data. FDA has issued 52 written requests without sponsors’ proposals. A written request may require more than 1 study of a drug; the 272 requests covered 631 studies, and could involve more than 37,150 pediatric patient participants if they were all completed. Regardless of the final study results, if FDA determines that the data submitted fairly responds to the written request and the studies were conducted properly, it will grant the sponsor 6 months of additional exclusive marketing rights. From enactment of the pediatric exclusivity provision in 1997 through April 30, 2003, FDA granted an additional 6 months of additional exclusive marketing rights for 74 drugs. Sponsors are not required to include minority children in studies for pediatric exclusivity. Findings from these studies have led to labeling changes for pediatric use for 50 drugs. For example, a study of fluoxetine (an antidepressant) confirmed its effectiveness to treat major depressive disorders in children 8 to 17 years of age and obsessive-compulsive disorder in children 7 to 17 years of age. In addition, studies for a new asthma drug—montelukast— led to new information on dosing and a new oral formulation permitting its use in children from the ages of 12 months to 5 years. FDA also has a process in place to encourage pediatric studies of drugs that manufacturers choose not to conduct. For drugs on which the patent or exclusive marketing rights have expired, commonly referred to as off- patent drugs, the National Institutes of Health (NIH) in collaboration with FDA annually develop a list of drugs for which pediatric studies are needed and publish it in the Federal Register. FDA may select a drug from this list, issue a written request to the manufacturer that holds the approved application for the drug, and, if the manufacturer does not respond within 30 days, forward the written request to NIH to issue a contract to conduct the study. In fiscal year 2003, HHS announced that NIH would set aside $25 million from its budget to conduct pediatric studies of off-patent drugs from this list. Similarly, if FDA issues a written request for a drug that is on-patent but the drug sponsor declines to test the drug in children, FDA can ask the Foundation for the National Institutes of Health, which supports the mission of NIH, to test the drug with funds raised from the private sector. An important reason to include minorities in pediatric drug studies is to examine the effect of race or ethnicity on the disposition and effects of drugs in children. In adults, the activity of some drug-metabolizing enzymes varies with race or ethnicity. For example, one commonly prescribed drug used to treat gastric conditions, esomeprazole (Nexium), is partly metabolized by the CYP2C19 enzyme. Studies have shown that from 15 to 20 percent of Asians lack the enzyme CYP2C19. As a result, some Asians metabolize the drug poorly and require lower doses because their bodies do not clear the drug as rapidly as individuals with this enzyme. Also, compared with Caucasians, certain Asian groups are more likely to require lower dosages of a variety of different antipsychotic drugs used to treat mental illness. Research in adults over the past several decades has further characterized significant differences among racial and ethnic groups in the metabolism, clinical effectiveness, and side-effect profiles of many clinically important drugs. These differences in response to drug therapy can be traced to differences in the distribution of genetic traits that produce these differences among racial and ethnic groups. These naturally occurring variations in the structures of genes, drug metabolism enzymes, receptor proteins, and other proteins that are involved in drug response affect how the body metabolizes certain drugs, including cardiovascular agents (beta- blockers, diuretics, calcium channel blockers, angiotensin coverting enzyme (ACE) inhibitors, and central nervous system agents (antidepressants and antipsychotics). BPCA requires that FDA take into account adequate representation of children from ethnic and racial minority groups when issuing written requests to drug sponsors. FDA regulations have required that in new drug applications, “effectiveness data (safety data) shall be presented by gender, age, and racial subgroups and shall identify any modifications of dose or dose interval needed for specific subgroups.” Other FDA guidance encourages the participation of racial and ethnic groups in all phases of drug development, recommends collection of race-related data during research and development, and recommends the analysis of the data for race-related effects. FDA officials told us that if there is scientific evidence documenting possible mechanisms causing variation in drug response in minorities, such as a higher or lower prevalence of a specific drug metabolizing enzyme or drug receptor, then FDA’s written request will require the study sponsor to increase minority representation in the study. The officials told us that it is particularly important to consider racial differences in pediatric patients under two circumstances: (1) when there is a possible difference in drug metabolism or response demonstrated in adult clinical studies or documented in the scientific literature or (2) if a drug is used to treat a disease that disproportionately affects minorities. Absent these conditions, the officials told us that FDA does not require that sponsors include particular numbers or proportions of minority children in its studies. According to FDA officials, FDA’s policy is to minimize the number of children exposed to a drug during clinical studies, while maintaining an adequate sample size to draw clinically meaningful conclusions. Most pediatric studies for extension of exclusive marketing rights are designed to give health care providers information on the appropriate dosage or formulation of a drug in a pediatric population. As a result, most pediatric clinical drug studies generally are on a smaller scale than the clinical studies drug sponsors conduct to gain FDA approval to market a new drug. FDA officials told us that both the small number of patients in most pediatric studies as well as the fact that most studies seek to determine the appropriate dosage and safety for pediatric patients have precluded any definitive conclusions about racial or ethnic differences in drug response among children. No completed studies under the pediatric exclusivity provision to date have led to findings or labeling changes specific to any racial or ethnic group. Compared to their proportions in the U.S. population, smaller proportions of children of racial and ethnic minority groups were included in the clinical drug studies we reviewed for additional exclusive marketing rights that FDA requested before BPCA took effect. However, for hypertension drugs where differences in racial response have been documented in adult drug studies, FDA required, and drug sponsors included, larger numbers of children from specific racial and ethnic groups. Most of FDA’s written requests for studies that have been issued since BPCA took effect required drug sponsors to report the number of racial and ethnic minorities in their final study results. In addition, some requests required drug sponsors to analyze the effects of race and ethnicity or increase minority representation for certain drugs where differences in racial response have been documented in adult drug studies. Compared with their proportions in the U.S. population, smaller proportions of African American, Hispanic, and Asian children were included in clinical studies for the drugs that were granted 6 months of additional exclusive marketing rights by FDA from January 4, 2002, through March 6, 2003. Across all clinical studies for the 23 drugs we examined, 7 percent of pediatric patients were African American, 5 percent were Hispanic, and 1 percent were Asian. Most pediatric patients were Caucasian—69 percent—and the race and ethnicity were unknown for 14 percent. Compared with the frequency distribution of African American and Hispanic children under 18 years of age for the U.S. population as a whole in 2000, the proportions of these two groups included in clinical drug studies were 8 and 12 percentage points lower, respectively, than their proportions in the U.S. population. The proportion of Asian children in clinical drug studies was 2 percentage points lower than their proportion in the U.S. population (see table 1). (See app. II for the number of children in racial and ethnic groups included in clinical studies for drugs granted additional exclusive marketing rights from January 4, 2002, through March 6, 2003.) FDA required that sponsors increase representation of children of ethnic and racial minority groups in clinical studies for drugs used to treat diseases that disproportionately affect children in such groups or where evidence from studies on adults suggests that for certain classes of drugs differences in metabolism or response for racial or ethnic groups exist. For example, because hypertension is more prevalent and more severe in African Americans than in Caucasians, and adult responses to some hypertension therapies appear to be different in African American and non-African American populations, FDA’s written requests for these drugs require that the patient recruitment protocol be designed to ensure a mixture of African American and non-African American patients. Therefore, in pediatric clinical studies for three cardiovascular drugs used to treat hypertension, African American children represented 22 percent of study participants (see table 2). For some written requests issued since BPCA took effect, FDA required sponsors to increase the participation of minority children. Specifically, 4 of the 22 written requests for such studies directed sponsors to increase the proportion of minority children participants or to analyze the effects of race and ethnicity. In 11 of the 22 requests, FDA directed drug sponsors to report the representation of pediatric patients of ethnic and racial minority groups when submitting final study results, but did not request that sponsors include a particular proportion of minority children or analyze the effects of race and ethnicity. The remaining 7 written requests made no mention of race or ethnicity. FDA’s four study requests that directed sponsors to increase the proportion of minority children participants or to analyze the effects of race or ethnicity took varied approaches. One written request by FDA required that the sponsor include a mixture of African American and non- African American patients for a study of a drug used to treat hypertension. Two other requests, for diabetes drugs, required the study sponsors to ensure that 50 percent of the study populations were composed of African American, Native American, and Hispanic patients because of a greater prevalence of diabetes in these groups. In the fourth written request, for a drug used to prevent bone loss, FDA required that the study sponsor examine potential demographic covariates, such as race. Some drugs that may be used to treat diseases or conditions that disproportionately affect children of racial and ethnic minority groups are being studied under the pediatric exclusivity provision. In response to FDA written requests, drug sponsors are conducting or have completed pediatric studies on drugs that might be used to treat hypertension, type II diabetes, sickle cell anemia, and other conditions that disproportionately affect minorities. From January 4, 2002, through March 6, 2003, FDA granted exclusive marketing rights or issued written requests for studies of 10 drugs that might be used to treat diseases or conditions that disproportionately affect minority children. Specifically, 4 of the 23 drugs for which FDA granted additional exclusive marketing rights might be used to treat diseases or conditions that are more prevalent in minorities, such as asthma and hypertension (see table 3). In addition, 6 of the 22 written requests for new studies that FDA issued to drug manufacturers during this period also included treatments for diseases or conditions disproportionately affecting minorities, such as type II diabetes, hypertension, sickle cell anemia, HIV, and hepatitis B. FDA does not have a system in place to serve as a single source of data to allow the agency to efficiently determine the extent of minority enrollment in drug studies under the pediatric exclusivity provision. Further, we found that some study reports submitted to FDA from drug sponsors did not specify the race and ethnicity of study participants. For example, in the completed studies for the 23 drugs granted additional exclusive marketing rights that we examined, the race or ethnicity of 86 percent of study participants was identified, but study sponsors did not specify the race or ethnicity of 960 children, or 14 percent of the studies’ populations. Recently, FDA issued draft guidance to improve drug sponsors’ reporting of racial and ethnic minority representation data, and FDA is planning to develop a database to monitor demographic variables in drug trials across the agency. There is no single data source at FDA to allow the agency to tabulate the overall numbers of racial and ethnic minorities in clinical studies. For example, to quantify the participation of racial and ethnic groups in studies for the 23 drugs granted additional exclusive marketing rights since January 2002, FDA had to extract and tally race data from about 50 separate final study reports that included nearly 7,000 children. Final study results submitted to FDA from sponsors do not always fully describe the race and ethnicity of children who participated in clinical drug studies. In addition, FDA has not established uniform definitions for reporting racial and ethnic minorities in drug studies. In reviewing the study results for the 23 drugs granted additional exclusive marketing rights from January 4, 2002, through March 6, 2003, we found wide variation in how study sponsors presented and defined data regarding minority participation. Study sponsors reported minority representation according to non-standard definitions, which were often ambiguous. For example, one study classified its 200 participants as “mostly Caucasian” and included no further data on the remaining population. Similarly, in studies included in three applications involving more than 1,500 children, sponsors only identified the number of Caucasian patients and did not identify the racial or ethnic groups of non-Caucasian children. Across all studies for drugs granted exclusive marketing rights from January 4, 2002, through March 6, 2003, the race or ethnicity of 960 children, or about 14 percent of all study participants, was unknown. Eighty-six percent of study participants were identified by race or ethnicity. Further, we could identify the specific race or ethnicity for only 30 of the 268 subjects classified as “other” in study reports. FDA officials told us that they do not know which populations are included in the “other” category and that it likely includes children whose race was not determined. Recently, FDA has begun to take steps to address data management issues. In January 2003, FDA issued draft guidance for industry recommending that study sponsors collect and report racial and ethnic representation using definitions developed by the Office of Management and Budget, which HHS adopted for use in HHS funded and sponsored data collection and reporting systems. FDA stated in its draft guidance that using uniform categories would enhance the consistency and comparability of data across studies and other HHS agencies, as well as promote the early identification of differences in physiological response among racial and ethnic groups. FDA’s draft guidance recommended that sponsors collect race and ethnicity data for clinical study participants using five racial groups (African American/Black, American Indian/Alaska Native, Asian, and Native Hawaiian/Other Pacific Islander, and White) and two ethnic groups (Hispanic/Latino and not Hispanic/Latino). However, FDA guidance is not legally binding for either FDA or the sponsor. In addition, FDA has started to develop an agencywide system called the Demographic Information and Data Repository (DIDR) to electronically manage information regarding demographic characteristics of clinical trial participants, including age, sex, and race. DIDR is part of FDA’s response to a congressional report requesting that FDA monitor the representation of women in clinical studies. The conference report accompanying FDA’s 2002 appropriations identified a $500,000 increase in funding for FDA’s Office of Women’s Health to begin work on this system. FDA officials told us that it would be several years before the system is operational. To have optimal effectiveness for all children, a drug should be tested in clinical studies that include pediatric patients representing the full range of population groups likely to receive the drug once it is marketed. In addition to age, genetic factors related to race and ethnicity may play important roles in the variability of patients’ responses to a drug. Pediatric clinical drug studies with sufficient representation of minority groups are necessary to detect the presence or absence of differences in responses to certain drugs. The changes under BPCA to the pediatric exclusivity provision require that FDA take into account the adequate representation of children of racial and ethnic minorities in written requests for drug studies. However, it is too early to tell whether FDA’s written requests issued since enactment of BPCA will result in better reporting or a broader mix of participants. Currently, FDA is unable to accurately determine whether and to what extent minority groups are accounted for in final study results because it does not require sponsors to use uniform definitions. Though FDA’s draft guidance on standard definitions for reporting race and ethnicity is helpful, sponsors will not be obligated to use these categories to identify study participants unless FDA requests that they do so. The standardized collection of demographic data, such as race and ethnicity, would help ensure that FDA’s forthcoming DIDR will have the required data needed to evaluate the risks and benefits of a drug in specific demographic groups. To help the agency more efficiently monitor the participation of children of racial and ethnic groups in studies for additional exclusive marketing rights, we recommend that the Commissioner of FDA specify in written requests that study sponsors must use the racial and ethnic categories described in FDA’s January 2003 draft guidance to identify study participants in their reports to the agency. FDA can refuse to grant 6 months of additional exclusive marketing rights under the pediatric exclusivity provision for sponsors that do not fairly respond to FDA’s written requests. FDA comments on a draft of this report reaffirmed the importance of clinical studies of drugs used to treat children. FDA agreed that the agency needed to improve the efficiency of its system for tracking demographic information about study participants. FDA also agreed with our recommendation and reported that it has already begun to implement it. FDA raised concerns about three aspects of our draft report. First, FDA was critical of our comparison of the proportions of minority children study participants to the proportions of minority children in the population. FDA commented that it would have been more appropriate for us to compare the proportions of minority children in clinical drug studies with the proportions of minority children with the specific condition each drug is intended to treat. We agree that such a comparison would have been useful, but both we and FDA found that the information needed for such comparisons—the racial and ethnic group distributions of children with many of the specific conditions treated by the drugs studied for additional exclusive marketing rights—was not available. Further, FDA has previously used the methodology we employed in its analyses of adult study participants. Second, FDA was concerned about what it regards as the implications of our finding that the proportions of minority children in pediatric studies requested by FDA before the passage of BPCA were less than their proportions in the general population. FDA incorrectly suggested that we advocate that “the percentage of children in each clinical drug trial would or should track the percentage of children in the general population.” Our report does not make any recommendations about the preferred study populations for any clinical drug trial. Further, we did not disagree with FDA’s current policy requiring larger proportions of children from racial and ethnic minority groups when a studied drug treats a condition that disproportionately affects minorities or when it is known from adult studies that the effects of a drug may be different in persons from different racial or ethnic groups. Third, FDA noted that the race or ethnicity of a high percentage of study participants was identified even before BPCA was enacted. Our findings agree with that assessment—we reported that the race or ethnicity of study participants was identified for 86 percent of study participants—but we believe that FDA should have been able to identify the race or ethnicity of every study participant. FDA’s written comments are reprinted in appendix III of this report. FDA also provided technical comments, which we considered and incorporated where appropriate. We are sending this report to the Commissioner of FDA and to other interested persons. We will also provide copies to others upon request. In addition, the report will be available at no charge on GAO’s Web site at http://www.gao.gov. If you or your staffs have any questions about this report, please contact me at (202) 512-7119. Another contact and major contributors to this report are listed in appendix IV. To assess the extent to which children of racial and ethnic groups are represented in clinical studies for drugs granted exclusive marketing rights, we reviewed data for the 23 drugs that were granted exclusive marketing rights from January 4, 2002, through March 6, 2003. For these 23 drugs, we determined the total number of children in four racial and ethnic groups enrolled in each study from Food and Drug Administration summary documents, and new drug applications (NDA) or supplemental new drug applications (sNDA) submitted to FDA for this time period. We collected clinical study participation data for three racial groups (African American, Asian, and Caucasian) and one ethnic group (Hispanic) because drug sponsors commonly used these categories. However, the clinical studies included in the NDAs or sNDAs submitted during this period were conducted before the effective date for the Best Pharmaceuticals for Children Act of 2002 because the time lag between when FDA issues a written request for a pediatric study and when sponsors submit final study results ranged from 1 to 4 years. To assess the extent to which FDA required drug sponsors to take into account the adequate representation of children of racial and ethnic groups in clinical studies for drugs for which written requests have been issued since BPCA took effect, we reviewed the 22 written requests issued for pediatric drug studies by FDA from January 4, 2002, through March 6, 2003. To determine whether drugs used to treat conditions or diseases disproportionately affecting minorities are being studied under the pediatric exclusivity provision, we obtained data on the prevalence of selected diseases or conditions that disproportionately affect minorities and examined the list of drugs for which FDA has either granted exclusive marketing rights or issued study requests from January 4, 2002, through March 6, 2003, to determine if any of these drugs may be used to treat these diseases or conditions. We compiled data on the estimated prevalence of the diseases and conditions by race and ethnicity from the National Centers for Health Statistics, National Center of HIV, STD, and Tuberculosis Prevention, and research in scientific journals reporting the prevalence of these diseases and conditions in minority children. We interviewed National Institutes of Health officials, pharmacology experts, and pediatric clinicians, including members of the American Academy of Pediatrics and the Pharmaceutical Research and Manufacturers of America to gain their perspectives on the representation of minorities in drug studies and the study of drugs of importance to these populations. To evaluate FDA’s management of pediatric clinical study data on minority representation and its guidance to sponsors on reporting such data, we reviewed FDA’s policies, guidance, and rules for inclusion and reporting of minority representation in drug studies. We interviewed FDA officials within the Office of Counter-Terrorism and Pediatric Drug Development to determine how they interpret and implement these policies for the pediatric exclusivity program. We spoke with officials in the Office of Women’s Health who were responsible for establishing a database to monitor demographic variables to determine how an agencywide demographic database might affect the monitoring of minority participation in drug studies. We also reviewed FDA’s response to a congressional request to develop an agencywide demographic database. We conducted our work from October 2002 through September 2003 in accordance with generally accepted government auditing standards. We obtained the number of children by race or ethnic group who participated in the clinical drug studies for the 23 NDAs or sNDAs for exclusive marketing rights in our sample by reviewing the portions of final study reports that provide information on the demographic representation in the study. Table 4 represents the number of children of racial and ethnic groups, by drug class, in clinical studies for drugs granted exclusive marketing rights from January 4, 2002, through March 6, 2003. It is important to recognize that the FDA written requests outlining the study design for the 23 NDAs or sNDAs that we examined preceded the passage of BPCA on January 4, 2002. The time between when FDA issued written requests for pediatric studies and sponsors conducted and submitted final study results for FDA review and approval ranged from 1 to 4 years. Gloria E. Taylor, Sharif Idris, George Bogart, and Elizabeth T. Morrison also made major contributions to this report.

Summary: Drug effectiveness and adverse events can vary between children and adults and among racial and ethnic groups. The Food and Drug Administration (FDA) is authorized under the pediatric exclusivity provision to grant drug sponsors 6 months of additional exclusive marketing rights for conducting clinical drug studies in children. The Best Pharmaceuticals for Children Act of 2002 (BPCA) expanded this provision to require FDA to take into account the adequacy of minority representation in pediatric exclusivity studies. BPCA also directed GAO to evaluate the representation of minorities in such studies. GAO examined the extent to which minority children are represented, whether drugs that treat diseases disproportionately affecting minority groups are studied under the provision, and FDA's monitoring of the representation of minority children in the studies. GAO reviewed related FDA documents, FDA requests for pediatric studies and final study results, and interviewed FDA officials and other experts. Compared with the proportions of children from racial and ethnic minority groups in the U.S. population, smaller proportions of children from minority groups were included in the pediatric clinical drug studies requested by FDA before the enactment of BPCA that GAO reviewed. However, FDA required, and drug sponsors included, larger proportions of African American children in clinical studies for hypertension drugs because there is evidence that hypertension is more prevalent and more severe among African Americans. Furthermore, FDA has requested that forthcoming studies for certain drugs include larger proportions of minority children. Studies of some drugs that may be used to treat diseases or conditions that disproportionately affect minorities have been completed and additional such studies have been requested by FDA. From January 4, 2002, through March 6, 2003, FDA granted additional exclusive marketing rights to four drugs that may be used to treat conditions such as hypertension, type II diabetes, and sickle cell anemia--conditions or diseases that disproportionately affect minority children. During that time, FDA also issued written requests for studies of six drugs for these conditions. FDA does not have a system in place to serve as a single source of data to allow the agency to efficiently determine the extent of participation of children by racial and ethnic group under the pediatric exclusivity provision. GAO found that some study reports submitted to FDA from drug sponsors did not specify the race and ethnicity of all study participants. Across all the studies for drugs granted additional exclusive marketing rights that GAO reviewed, 86 percent of study participants were identifiable by race or ethnicity, but the race or ethnicity of 14 percent of study participants was unknown. In January 2003, FDA issued draft guidance recommending that drug sponsors use standard definitions for race and ethnicity in drug studies. However, drug sponsors are not required to use these definitions. FDA has also begun to develop an agency-wide system to monitor demographic characteristics of study participants, such as age, sex, and race. FDA agreed with the GAO recommendation to specify the categories that sponsors should use to report minority representation as well as GAO's findings regarding the efficiency of its data collection systems. FDA expressed concerns about the GAO comparison of the proportion of minorities in drug studies to their proportion in the U.S. population. However, FDA had previously used the methodology GAO employed in its analyses of adult study participants.