Pediatric Drug Research: Food and Drug Administration Should More Efficiently Monitor Inclusion of Minority Children
Published: 2003-09-26T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: While children can be stricken with many of the same diseases afflicting  adults and are often treated with the same drugs, only about one-third of  drugs in use today have been studied and labeled for pediatric use. A drug  used to treat children that has not been tested or labeled for pediatric use  may place children at risk of under- or overdosing, and when age- appropriate formulations of the drugs do not exist, such as liquids or  chewable tablets, the drug may be improperly administered to children. To  help address these concerns, in 1997 Congress passed a law that gives  sponsors 6 months of additional exclusive marketing rights for their  products in return for conducting clinical drug studies in children,  commonly known as the pediatric exclusivity provision. The Food and  Drug Administration (FDA), the federal agency that approves drugs for  marketing, is responsible for administering the law and has procedures for  ensuring the study of drugs in pediatric patients. Specifically, if FDA  officials believe that studying a drug may lead to health benefits for  children, FDA issues a formal “written request” for clinical drug studies in  pediatric patients to the drug sponsor. If the sponsor agrees to comply  with the terms of the written request and submits final study results to  FDA that meet the terms of the request, FDA will grant the sponsor 6  months of additional exclusive marketing rights. Pediatric drug research  has increased substantially since the enactment of the pediatric exclusivity  provision.
FDA officials are concerned that drug effectiveness and adverse effects  can vary among children from different racial and ethnic groups. Although  FDA has requested race and ethnicity data on subjects in clinical drug  trials, no formal evaluations have assessed the extent to which children of  different racial and ethnic groups are represented in clinical studies of  new drugs, thus the extent to which these drugs have been tested on  children in minority groups is unknown. Concern exists that if children  from racial and ethnic minority groups are not included in adequate  numbers in clinical studies of drugs, the administration of the drugs to  children in these groups may result in atypical responses or unexpected  side effects. In addition, no formal evaluations have assessed the extent to  which drugs that were studied under the pediatric exclusivity provision  may be used to treat diseases or conditions that disproportionately affect  minority children.
To ensure that children of racial and ethnic minority groups are included  in clinical studies for new drugs, the Best Pharmaceuticals for Children  Act of 2002 (BPCA) expanded the pediatric exclusivity provision to  require, among other things, that FDA “take into account adequate  representation” of children from racial and ethnic minority groups when  negotiating written protocols with the study sponsors of pediatric drugs.  In addition, the act required that we study the adequacy of minority  representation in studies covered by the pediatric exclusivity provision. As  agreed with the committees of jurisdiction, we addressed the following  questions: (1) to what extent are children of racial and ethnic minority  groups represented in clinical studies for drugs granted exclusive  marketing rights, (2) are drugs that are used to treat diseases that  disproportionately affect racial and ethnic minority groups being studied  for safety and effectiveness in children under the pediatric exclusivity  provision, and (3) does FDA have appropriate management systems to  monitor the representation of children of racial and ethnic groups in  studies submitted for additional exclusive marketing rights?
To answer these questions, we reviewed recently completed and requested  pediatric studies for inclusion of children from racial and ethnic minority  groups and FDA’s data systems, regulations, and guidance used to  implement the pediatric exclusivity provision. To quantify the  participation of racial and ethnic groups in completed pediatric clinical  studies, we reviewed FDA pediatric study documents and collected data  about racial and ethnic group representation in study participants for the  23 drugs that were granted additional exclusive marketing rights during  the period January 4, 2002, through March 6, 2003. All of the studies for  these drugs had been requested by FDA before BPCA took effect on  January 4, 2002, and thus were not subject to the expanded pediatric  exclusivity provisions under the law. The time lag between an FDA written  request and a sponsor’s submission of final study results ranges from 1 to  4 years. To determine the representation and reporting requirements that  FDA required drug sponsors to follow concerning the participation of  racial and ethnic minorities in pediatric studies since BPCA took effect,  we reviewed the 22 written requests for pediatric drug studies that FDA  issued from January 4, 2002, through March 6, 2003. To determine if drugs  used to treat conditions disproportionately affecting minorities are being  studied, we obtained data on the prevalence of selected diseases or  conditions that disproportionately affect minorities. We then examined the  list of drugs for which FDA had either issued study requests or granted  additional exclusive marketing rights from January 4, 2002, through   March 6, 2003, to determine if any of the drugs may be used to treat these  diseases or conditions. To evaluate FDA’s monitoring of data on  demographic traits, such as race, in drug studies, we reviewed relevant  documents and interviewed FDA officials. We also interviewed  pharmacology experts and pediatric clinicians, including members of the  American Academy of Pediatrics and the Pharmaceutical Research and  Manufacturers of America. (For additional information on our  methodology, see app. I.) We conducted our work from October 2002  through September 2003 in accordance with generally accepted  government auditing standards.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: Improvements Resulting from the Pediatric Exclusivity Provision
paragraphs: 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.
section_title: FDA Procedures for Ensuring the Study of Drugs in Pediatric Patients
paragraphs: 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.
section_title: Evidence Shows That Drug Effectiveness and Toxicity Can Vary among Racial and Ethnic Groups
paragraphs: 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).
section_title: FDA’s Efforts to Account for Minority Children in Clinical Drug Studies
paragraphs: 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.
section_title: Limitations of Pediatric Drug Studies
paragraphs: 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.
section_title: Smaller Proportions of Minority Children Were in Studies for Additional Marketing Exclusivity Requested before BPCA
paragraphs: 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.
subsections: section_title: The Proportions of Children in Racial and Ethnic Minority Groups in Clinical Studies for Exclusive Marketing Rights Were Lower Than Their Proportions in the U.S. Population
paragraphs: 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.)
section_title: Pediatric Studies for Hypertension Drugs Included More Children of Racial and Ethnic Minority Groups
paragraphs: 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).
section_title: FDA Written Requests Issued since BPCA Require Sponsors to Increase Minority Representation for Certain Drugs
paragraphs: 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.
section_title: Drugs of Importance to Minority Children Are Being Studied in Response to Pediatric Exclusivity Provision Requests
paragraphs: 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.
section_title: FDA Monitoring of Data on Minority Representation Needs Improvement
paragraphs: 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.
subsections: section_title: There Is No Single Source of Data about Minority Representation
paragraphs: 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.
section_title: Reporting of Minority Representation Data Is Not Standardized
paragraphs: 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.
section_title: FDA Is Taking Steps to Improve Data Management
paragraphs: 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.
section_title: Conclusions
paragraphs: 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.
section_title: Recommendation for Executive Action
paragraphs: 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.
section_title: Agency Comments and Our Evaluation
paragraphs: 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.
section_title: Appendix I: Scope and Methodology
paragraphs: 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.
section_title: Appendix II: The Number of Children by Racial and Ethnic Group in Studies for Drugs Granted Exclusive Marketing Rights
paragraphs: 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.
section_title: Appendix III: Comments from the Food and Drug Administration
section_title: Appendix IV: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Acknowledgments
paragraphs: Gloria E. Taylor, Sharif Idris, George Bogart, and Elizabeth T. Morrison  also made major contributions to this report.