oversight

Pediatric Drug Research: Food and Drug Administration Should More Efficiently Monitor Inclusion of Minority Children

Published by the Government Accountability Office on 2003-09-26.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                 United States General Accounting Office

GAO              Report to Congressional Committees




September 2003
                 PEDIATRIC DRUG
                 RESEARCH
                 Food and Drug
                 Administration Should
                 More Efficiently
                 Monitor Inclusion of
                 Minority Children




GAO-03-950
                                                September 2003


                                                PEDIATRIC DRUG RESEARCH

                                                Food and Drug Administration Should
Highlights of GAO-03-950, a report to the       More Efficiently Monitor Inclusion of
Committee on Health, Education, Labor
and Pensions, U.S. Senate, and the              Minority Children
Committee on Energy and Commerce,
House of Representatives




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


www.gao.gov/cgi-bin/getrpt?GAO-03-950.

To view the full product, including the scope
and methodology, click on the link above.
For more information, contact Janet Heinrich
at (202) 512-7119.
Contents


Letter                                                                                     1
               Results in Brief                                                            4
               Background                                                                  6
               Smaller Proportions of Minority Children Were in Studies for
                 Additional Marketing Exclusivity Requested before BPCA                  11
               Drugs of Importance to Minority Children Are Being Studied in
                 Response to Pediatric Exclusivity Provision Requests                    14
               FDA Monitoring of Data on Minority Representation Needs
                 Improvement                                                             16
               Conclusions                                                               18
               Recommendation for Executive Action                                       18
               Agency Comments and Our Evaluation                                        19

Appendix I     Scope and Methodology                                                     21



Appendix II    The Number of Children by Racial and Ethnic
               Group in Studies for Drugs Granted Exclusive
               Marketing Rights                                                          23



Appendix III   Comments from the Food and Drug Administration                            25



Appendix IV    GAO Contact and Staff Acknowledgments                                     29
               GAO Contact                                                               29
               Acknowledgments                                                           29


Tables
               Table 1: Children, by Racial and Ethnic Group, in Clinical Studies
                        for Drugs Granted Additional Exclusive Marketing Rights,
                        January 4, 2002, through March 6, 2003                           12
               Table 2: Children, by Racial and Ethnic Group, in Clinical Studies
                        for Three Drugs for Which FDA Required Mixed Race
                        Participation, and for All Other Drugs Granted Additional
                        Exclusive Marketing Rights, January 4, 2002, through
                        March 6, 2003                                                    13



               Page i                                     GAO-03-950 Pediatric Drug Research
Table 3: Estimated Prevalence of Diseases or Conditions in
         Minorities That May Be Treated by Drugs for Which FDA
         Issued Written Requests or Granted Exclusive Marketing
         Rights, January 4, 2002, through March 6, 2003                                   15
Table 4: Children of Racial and Ethnic Groups, by Drug Class, in
         Clinical Studies for Drugs Granted Exclusive Marketing
         Rights, January 4, 2002, through March 6, 2003                                   24




Abbreviations

ACE               angiotensin converting enzyme
AIDS              acquired immunodeficiency syndrome
BPCA              Best Pharmaceuticals for Children Act
DIDR              Demographic Information and Data Repository
FDA               Food and Drug Administration
HHS               Department of Health and Human Services
NICHD             National Institute of Child Health and Human Development
NIH               National Institutes of Health
HIV               human immunodeficiency virus
NDA               new drug application
sNDA              supplemental new drug application



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Page ii                                             GAO-03-950 Pediatric Drug Research
United States General Accounting Office
Washington, DC 20548




                                   September 26, 2003

                                   The Honorable Judd Gregg
                                   Chairman
                                   The Honorable Edward M. Kennedy
                                   Ranking Minority Member
                                   Committee on Health, Education, Labor and Pensions
                                   United States Senate

                                   The Honorable W.J. “Billy” Tauzin
                                   Chairman
                                   The Honorable John D. Dingell
                                   Ranking Minority Member
                                   Committee on Energy and Commerce
                                   House of Representatives

                                   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.1 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.2 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



                                   1
                                    R. Roberts and others, “Pediatric Drug Labeling: Improving Safety and Efficacy of
                                   Pediatric Therapies,” Journal of the American Medical Association, vol. 290, no. 7 (2003).
                                   2
                                    Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, §111, 111
                                   stat. 2296, 2305. Drug manufacturers may obtain marketing exclusivity through patents,
                                   patent term extensions to compensate for regulatory delays, approval of drugs containing
                                   new chemical entities, or approval of orphan drugs.



                                   Page 1                                               GAO-03-950 Pediatric Drug Research
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.3

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.4
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



3
 U.S. General Accounting Office, Pediatric Drug Research: Substantial Increase in
Studies of Drugs for Children, But Some Challenges Remain, GAO-01-705T (Washington,
D.C.: May 8, 2001).
4
 Pub. L. No. 107-109, § 18, 115 Stat. 1408, 1423. The pediatric exclusivity provision sunset on
January 1, 2002. BPCA, which took effect on January 4, 2002, reauthorized the provision
through October 1, 2007. BPCA, § 8, 115 Stat. 1414.




Page 2                                                 GAO-03-950 Pediatric Drug Research
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, 2003.5 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



5
 We collected clinical study participation data for three racial groups (African American,
Asian, and Caucasian) and one ethnic group (Hispanic) because these categories were
commonly used in the clinical study documents that were submitted to FDA for exclusive
marketing rights. The term pediatric study is defined as including at least one clinical
investigation and may include studies on the absorption, distribution, metabolism, and
excretion of a drug in pediatric age groups in which a drug is expected to be used.




Page 3                                               GAO-03-950 Pediatric Drug Research
                   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.


                   Compared with the proportions of children from racial and ethnic minority
Results in Brief   groups in the U.S. population, smaller proportions of children from
                   minority groups participated in clinical drug studies for additional
                   exclusive marketing rights that FDA requested before BPCA took effect. In
                   clinical studies for the 23 drugs granted 6 months of additional exclusive
                   marketing rights from January 4, 2002, through March 6, 2003,
                   approximately 7 percent of study participants were African American, 5
                   percent were Hispanic, and 1 percent were Asian, whereas these groups
                   comprised 15, 17, and 3 percent, respectively, of U.S. children under 18
                   years of age in 2000. However, FDA required, and drug sponsors included,
                   larger proportions of minority children in studies for hypertension drugs
                   because there is evidence suggesting a difference in drug metabolism or
                   response in adult minority groups. Specifically, hypertension is more
                   prevalent and more severe in African Americans, and African American
                   children represented 22 percent of pediatric study participants in studies
                   for three hypertension drugs. Similarly, FDA written requests for certain
                   drugs issued since BPCA took effect require sponsors to increase minority
                   representation. Specifically, in 4 of the 22 requests FDA required sponsors
                   to increase the number of minorities in the study or analyze the effects of
                   race and ethnicity for drugs that may affect minority groups differently. 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, and 7 written requests made no
                   mention of race or ethnicity.

                   Some drugs that may be used to treat diseases that disproportionately
                   affect minorities are being studied under the pediatric exclusivity
                   provision. During the period January 4, 2002, through March 6, 2003, FDA
                   granted exclusive marketing rights for four drugs and issued written
                   requests for pediatric studies of six drugs that may be of particular
                   importance to children in minority groups. For example, drug sponsors are
                   either conducting or have completed studies on drugs to treat children
                   with hypertension, type II diabetes, and sickle cell anemia—conditions or
                   diseases that disproportionately affect children of racial and ethnic
                   minority groups.




                   Page 4                                      GAO-03-950 Pediatric Drug Research
FDA does not have a system in place to serve as a single source of data to
allow the agency to efficiently determine the level of participation of
children by racial and ethnic group under the pediatric exclusivity
provision. In addition, FDA lacks standard definitions for study sponsors
to use in reporting racial and ethnic group participation in studies, and
sponsors have reported these data using their own definitions for racial
and ethnic groups. 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. FDA has taken action to start to
address these issues. In January 2003, FDA issued draft guidance
recommending that sponsors of drug studies use the definitions for race
and ethnicity that the Department of Health and Human Services (HHS)
has adopted for data collection and reporting systems funded or supported
by HHS. However, FDA’s guidance is not legally binding on clinical study
sponsors. FDA has also begun to develop an agencywide system to
monitor demographic variables, such as race, age, and sex in clinical
studies.

We are recommending that FDA revise the format of its written requests to
specify 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.

In commenting on a draft of this report, FDA concurred with our
recommendation and reported that it has already begun to implement it.
FDA also reaffirmed the importance of testing drugs used to treat children
in clinical studies of that population and agreed that the agency needed to
improve the efficiency of its system for tracking demographic information
about study participants. However, 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 FDA and we found
that the information needed for such comparisons was not available.
Further, FDA has previously used the methodology we employed in its


Page 5                                      GAO-03-950 Pediatric Drug Research
                         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. Our
                         report does not make any recommendations about the preferred study
                         populations for any clinical drug trial. Third, FDA noted that the race or
                         ethnicity of a high percentage of study participants was identified even
                         before BPCA was enacted. While our findings agree with that assessment,
                         we believe that FDA should have been able to identify the race or ethnicity
                         of every study participant.


                         Congress passed the pediatric exclusivity provision as part of the Food
Background               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.


Improvements Resulting   In May 2001, we testified before the Senate Committee on Health,
from the Pediatric       Education, Labor and Pensions that, since enactment of the pediatric
Exclusivity Provision    exclusivity provision, both the numbers of new drugs studied in children
                         and the number of therapeutic classes these drugs represent have
                         substantially increased.6 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


                         6
                         GAO-01-705T.




                         Page 6                                       GAO-03-950 Pediatric Drug Research
                              evaluations of a drug’s safety and effectiveness in children of various
                              ages.7 BPCA reauthorized and expanded the provision for 5 more years
                              through October 1, 2007.


FDA Procedures for            The process for obtaining exclusive marketing rights can be initiated
Ensuring the Study of         either by a drug sponsor or by FDA. A sponsor may submit a proposal to
Drugs in Pediatric Patients   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.




                              7
                               More recently, FDA officials reported that the pediatric exclusivity provision has
                              stimulated pediatric clinical studies resulting in improved understanding of drugs
                              prescribed in pediatric medicine, important dose changes, and improved safety for children
                              taking certain drugs. See R. Roberts and others, “Pediatric Drug Labeling: Improving Safety
                              and Efficacy of Pediatric Therapies.”




                              Page 7                                               GAO-03-950 Pediatric Drug Research
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.8 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,9 to test the drug
with funds raised from the private sector.




8
 The purpose of this list is to promote studies of pharmaceuticals in pediatric populations
that would normally not be studied under the pediatric exclusivity provision. These include
drugs that do not have specific patent protection or exclusive marketing rights that could
be prolonged under BPCA.
9
 Originally established by Congress as the National Foundation for Biomedical Research,
the Foundation was incorporated in 1996 as a nonprofit organization funded through
private donations. In 1998 Congress changed its name to the Foundation for the National
Institutes of Health.




Page 8                                               GAO-03-950 Pediatric Drug Research
Evidence Shows That Drug     An important reason to include minorities in pediatric drug studies is to
Effectiveness and Toxicity   examine the effect of race or ethnicity on the disposition and effects of
Can Vary among Racial        drugs in children. In adults, the activity of some drug-metabolizing
                             enzymes varies with race or ethnicity.10 For example, one commonly
and Ethnic Groups            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.11 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.12 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



                             10
                              An FDA review of demographic data for 185 new molecular entities approved between
                             January 1, 1995, and December 31, 1999, found that labeling for 45 percent of the drugs
                             contained a statement that race may affect how a patient responds to the drug, although in
                             only 8 percent were any differences in response related to race described. For this small
                             subset of drugs, information on differences in the drugs’ effects among racial and ethnic
                             groups noted that 50 percent were related to how drugs are processed in the body, 39
                             percent were related to efficacy, and 11 percent were related to safety. However, only one
                             drug label, for a drug used to treat hypertension, recommended a change in dosage based
                             on racial differences. It recommended that physicians increase the initial dose for African
                             American patients. See B. Evelyn and others, FDA, Office of the Commissioner, Office of
                             Special Health Issues, Participation of Racial/Ethnic Groups in Clinical Trials and Race-
                             Related Labeling: A Review of New Molecular Entities Approved 1995-1999 (Rockville,
                             Md.: 2001). http://www.fda.gov/cder/reports/race_ethnicity/race_ethnicity_report.htm
                             (downloaded Oct. 29, 2002).
                             11
                              H. Xie and others, “Molecular Basis of Ethnic Differences in Drug Disposition and
                             Response,” Annual Review of Pharmacology Toxicology; Vol. 41 (2001), 815-850, and
                             R. Weinshilboum, “Inheritance and Drug Response,” New England Journal of Medicine,
                             vol. 348 (2003), 529-537.
                             12
                              Institute of Medicine, Unequal Treatment: Confronting Racial and Ethnic Disparities in
                             Health Care (Washington, D.C.: 2002).




                             Page 9                                               GAO-03-950 Pediatric Drug Research
                           enzyme (ACE) inhibitors, and central nervous system agents
                           (antidepressants and antipsychotics).13


FDA’s Efforts to Account   BPCA requires that FDA take into account adequate representation of
for Minority Children in   children from ethnic and racial minority groups when issuing written
Clinical Drug Studies      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.”14 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.15

                           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.



                           13
                             There are over 100 examples in the medical literature in which inherited individual traits
                           that contributed to atypical, exaggerated responses to drugs or to unusual effects or
                           ineffectiveness of drugs. See for example, V.J. Burroughs, R.W. Maxey, and R.A. Levy,
                           “Racial and Ethnic Differences In Response to Medicines: Towards Individualized
                           Pharmaceutical Treatment,” Journal of the National Medical Association, vol. 94, no. 10,
                           Supplement (2002).
                           14
                             21 C.F.R. 314.50 (d)(5)(v) and (vi) (a) (Content and format of an application for approval
                           to market a new drug).
                           15
                            Food and Drug Administration, Guideline Format and Content of Clinical and
                           Statistical Sections of an Application (Rockville, Md.: July 1988); Food and Drug
                           Administration, Population Pharmacokinetics (Rockville, Md.: 1999); Food and Drug
                           Administration, Content and Format of the Adverse Reactions Section of Labeling for
                           Human Prescription Drugs and Biologics (draft) (Rockville, Md.: 2000).




                           Page 10                                               GAO-03-950 Pediatric Drug Research
Limitations of Pediatric   According to FDA officials, FDA’s policy is to minimize the number of
Drug Studies               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.16 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
Smaller Proportions        of children of racial and ethnic minority groups were included in the
of Minority Children       clinical drug studies we reviewed for additional exclusive marketing rights
                           that FDA requested before BPCA took effect. However, for hypertension
Were in Studies for        drugs where differences in racial response have been documented in adult
Additional Marketing       drug studies, FDA required, and drug sponsors included, larger numbers of
                           children from specific racial and ethnic groups. Most of FDA’s written
Exclusivity Requested      requests for studies that have been issued since BPCA took effect required
before BPCA                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.




                           16
                            FDA officials told us that about one-third of the studies requested under the pediatric
                           exclusivity provision are for efficacy.




                           Page 11                                               GAO-03-950 Pediatric Drug Research
The Proportions of          Compared with their proportions in the U.S. population, smaller
Children in Racial and      proportions of African American, Hispanic, and Asian children were
Ethnic Minority Groups in   included in clinical studies for the drugs that were granted 6 months of
                            additional exclusive marketing rights by FDA from January 4, 2002,
Clinical Studies for        through March 6, 2003. Across all clinical studies for the 23 drugs we
Exclusive Marketing         examined, 7 percent of pediatric patients were African American, 5
Rights Were Lower Than      percent were Hispanic, and 1 percent were Asian. Most pediatric patients
Their Proportions in the    were Caucasian—69 percent—and the race and ethnicity were unknown
U.S. Population             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.)

                            Table 1: Children, by Racial and Ethnic Group, in Clinical Studies for Drugs Granted
                            Additional Exclusive Marketing Rights, January 4, 2002, through March 6, 2003

                                                                Number in       Percentage in          Percentage in U.S.
                                Race/ethnicity             clinical studies    clinical studies   population under age 18
                                African American                        488                  7                               15
                                Asian                                    94                  1                                3
                                Caucasian                              4,783                69                               69
                                Hispanic                                355                  5                               17
                                Other                                   272                  4                            NA
                                Unknown                                 960                 14                            NA
                                Total                                  6,952               100                           104a
                            Sources: FDA and Department of Commerce.

                            Notes: GAO analysis of final study reports for the 23 drugs granted additional exclusive marketing
                            rights; and U.S. Bureau of Census, Census 2000 Summary File 1, “Total Population by Age and Sex
                            for the United States: 2000.”

                            NA means not applicable.
                            a
                            Individual entries do not sum to 100 percent because the Department of Commerce, in collecting
                            U.S. Census data, permitted individuals to report that they belonged to multiple race groups.
                            Consequently, the total of all race groups exceeds the population total.




                            Page 12                                                    GAO-03-950 Pediatric Drug Research
Pediatric Studies for        FDA required that sponsors increase representation of children of ethnic
Hypertension Drugs           and racial minority groups in clinical studies for drugs used to treat
Included More Children of    diseases that disproportionately affect children in such groups or where
                             evidence from studies on adults suggests that for certain classes of drugs
Racial and Ethnic Minority   differences in metabolism or response for racial or ethnic groups exist.
Groups                       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).

                             Table 2: Children, by Racial and Ethnic Group, in Clinical Studies for Three Drugs
                             for Which FDA Required Mixed Race Participation, and for All Other Drugs Granted
                             Additional Exclusive Marketing Rights, January 4, 2002, through March 6, 2003

                                                                                    Numbers in percent
                                                          In clinical studies for
                                                           3 drugs when mixed        In all other clinical   In U.S. population
                                 Race/ethnicity                    race required                  studies         under age 18
                                 African American                             22                        6                     15
                                 Asian                                         1                        1                      3
                                 Caucasian                                    54                       70                     69
                                 Hispanic                                     17                        4                     17
                                 Other or unknown                              6                       19                     NA
                                 Total                                       100                     100                  104a
                             Sources: Department of Commerce and FDA.

                             Notes: GAO analysis of 23 new drug applications (NDAs) or supplemental new drug applications
                             (sNDAs) and FDA medical officer reviews and Department of Commerce, Bureau of the Census,
                             Census 2000 Summary File 1, “Total Population by Age and Sex for the United States: 2000.”

                             NA means not applicable.
                             a
                             Individual entries do not sum to 100 percent because the Department of Commerce, in collecting
                             U.S. Census data, permitted individuals to report that they belonged to multiple race groups.
                             Consequently, the total of all race groups exceeds the population total.




                             Page 13                                                      GAO-03-950 Pediatric Drug Research
FDA Written Requests        For some written requests issued since BPCA took effect, FDA required
Issued since BPCA Require   sponsors to increase the participation of minority children. Specifically, 4
Sponsors to Increase        of the 22 written requests for such studies directed sponsors to increase
                            the proportion of minority children participants or to analyze the effects of
Minority Representation     race and ethnicity. In 11 of the 22 requests, FDA directed drug sponsors to
for Certain Drugs           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
Drugs of Importance         disproportionately affect children of racial and ethnic minority groups are
to Minority Children        being studied under the pediatric exclusivity provision. In response to
                            FDA written requests, drug sponsors are conducting or have completed
Are Being Studied in        pediatric studies on drugs that might be used to treat hypertension, type II
Response to Pediatric       diabetes, sickle cell anemia, and other conditions that disproportionately
                            affect minorities.
Exclusivity Provision
Requests                    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.


                            Page 14                                      GAO-03-950 Pediatric Drug Research
Table 3: Estimated Prevalence of Diseases or Conditions in Minorities That May Be Treated by Drugs for Which FDA Issued
Written Requests or Granted Exclusive Marketing Rights, January 4, 2002, through March 6, 2003

                                       Estimated prevalence among selected racial and
 Disease/condition                     ethnic groups                                                     Drug(s)             Study status
 Asthma                                Asthma prevalence of 82/1,000 in African American         Budesonide                  Exclusive rights granted.
                                       children compared to 76/1,000 in Hispanic and 65/1,000 in
                                                           a
                                       Caucasian children.
 Diabetes mellitus                     National age-adjusted rates for all types of diabetes show Metformin                  Written request issued.
 (type II diabetes)                    that it is more frequent in African Americans and Hispanics Pioglitazone              Written request issued.
                                                          b
                                       than Caucasians. In addition, one study found that over
                                       70 percent of type II diabetes cases among children were
                                                              c
                                       in African Americans.
 Hepatitis B                           Age-adjusted rates of Hepatitis B in African Americans are Adefovir                   Written request issued.
                                       more than 2.5 times greater than in Hispanics and 4.5
                                                                         d
                                       times greater than in Caucasians.
 HIV infection and AIDS                Prevalence rate of 1.4/100,000 African American children          Tipranavir          Written request issued.
                                       was 7 times greater than in Hispanics and 14 times
                                                                              e
                                       greater than in Caucasians and Asians.
 Hypertension                          A study found that a sample of African American children          Losartan            Exclusive rights granted.
                                       in California had higher blood pressure than Caucasian            Quinapril           Exclusive rights granted.
                                                 f
                                       children.                                                         Fosinopril          Exclusive rights granted.
                                                                                                         Metoprolol          Written request issued.
 Sickle cell anemia                    Occurs in 1 out of every 700 African American births, 1 of        Hydroxyurea         Written request issued.
                                       every 46,622 Hispanic births, and 1 of every 158,127
                                                         g
                                       Caucasian births.
Sources: FDA and publications identified below.
                                                         a
                                                         L.J. Akinbami and K.C. Schoendorf, “Trends in Childhood Asthma Prevalence, Health Care
                                                         Utilization, and Mortality,” Pediatrics, vol. 110, no. 2 (2002), 315-322.
                                                         b
                                                          Age-adjusted rates from the National Center for Chronic Disease, Diabetes Public Health Resources,
                                                         available at http://www.cdc.gov/diabetes/statistics/index.htm#prevalence (downloaded Apr. 11, 2003).
                                                         c
                                                          A study in Arkansas found that 74 percent of type II diabetes in children was in African Americans.
                                                         C. Scott and others, “Characteristics of Youth-onset Noninsulin-dependent Diabetes Mellitus and
                                                         Insulin-dependent Diabetes Mellitus at Diagnosis,” Pediatrics, vol. 100, no.1 (1997), 84-91.
                                                         d
                                                         Age-adjusted rates from the National Health and Nutrition Examination Survey III (1988-1994) in
                                                         G.M. McQuillan and others, “Prevalence of Hepatitis B Virus Infection in the United States: The
                                                         National Health And Nutrition Examination Surveys, 1976 through 1994,” American Journal of Public
                                                         Health, vol. 89, no. 1 (1999), 14-18.
                                                         e
                                                          Based on a total of 175 AIDS cases reported in children aged 13 and younger in December 2001,
                                                         from National Center for HIV, STD and TB Prevention,
                                                         http://www.cdc.gov/hiv/stats/hasr1302/table18.htm#tab18 (downloaded Apr. 11, 2003).
                                                         f
                                                         M.L. Cruz and others, “Insulin Sensitivity and Blood Pressure in Black and White Children,”
                                                         Hypertension, vol. 40, no. 1 (2002), 18-22.
                                                         g
                                                         A. Ashley-Koch, Q. Yang, and R.S. Olney, “Sickle Hemoglobin (Hb S) Allele and Sickle Cell Disease:
                                                         A HuGE Review,” American Journal of Epidemiology, vol. 151, no. 9 (2000), 839-845.




                                                         Page 15                                                      GAO-03-950 Pediatric Drug Research
                             FDA does not have a system in place to serve as a single source of data to
FDA Monitoring of            allow the agency to efficiently determine the extent of minority enrollment
Data on Minority             in drug studies under the pediatric exclusivity provision. Further, we
                             found that some study reports submitted to FDA from drug sponsors did
Representation Needs         not specify the race and ethnicity of study participants. For example, in
Improvement                  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 Source    There is no single data source at FDA to allow the agency to tabulate the
of Data about Minority       overall numbers of racial and ethnic minorities in clinical studies. For
Representation               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.


Reporting of Minority        Final study results submitted to FDA from sponsors do not always fully
Representation Data Is Not   describe the race and ethnicity of children who participated in clinical
Standardized                 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


                             Page 16                                      GAO-03-950 Pediatric Drug Research
                          know which populations are included in the “other” category and that it
                          likely includes children whose race was not determined.


FDA Is Taking Steps to    Recently, FDA has begun to take steps to address data management
Improve Data Management   issues. In January 2003, FDA issued draft guidance for industry17
                          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.18 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.19 DIDR is part of FDA’s response
                          to a congressional report requesting that FDA monitor the representation




                          17
                           See Food and Drug Administration, A Guidance for Industry: Collection of Race and
                          Ethnicity Data in Clinical Trials (Rockville, Md.: January 2003)
                          http://www.fda.gov/cber/gdlns/racethclin.htm (downloaded Jan. 28, 2003).
                          18
                           See Department of Health and Human Services, A Policy Statement on Inclusion of Race
                          and Ethnicity in DHHS Data Collection Activities (Washington, D.C.: October 1997).
                          19
                            In a prior report, we recommended that FDA develop management tools to ensure that
                          the collection, presentation, and analyses of data related to sex differences are addressed
                          and monitored. See U.S. General Accounting Office, Women’s Health: Women Sufficiently
                          Represented in New Drug Testing, but FDA Oversight Needs Improvement, GAO-01-754
                          (Washington, D.C.: July 6, 2001).




                          Page 17                                              GAO-03-950 Pediatric Drug Research
                     of women in clinical studies.20 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
Conclusions          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
Recommendation for   of racial and ethnic groups in studies for additional exclusive marketing
Executive Action     rights, we recommend that the Commissioner of FDA specify in written
                     requests that study sponsors must use the racial and ethnic categories



                     20
                      The conference report for the 2002 FDA appropriations act expressed concern that FDA
                     has paid insufficient attention to gender-based research and directed the agency to develop
                     an agencywide database focused on women’s health activities to include demographic data
                     on clinical trials. See H.R. Conf. Rep. No. 107-275, at 82-83 (2001) (accompanying Pub. L.
                     No. 107-76, making appropriations for Agriculture, Rural Development, Food and Drug
                     Administration, and Related Agencies programs for the Fiscal Year Ending September 30,
                     2002, and for other purposes).




                     Page 18                                              GAO-03-950 Pediatric Drug Research
                     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
Agency Comments      clinical studies of drugs used to treat children. FDA agreed that the agency
and Our Evaluation   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.21

                     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



                     21
                      For example, see B. Evelyn and others, Participation of Racial/Ethnic Groups in
                     Clinical Trials and Race-Related Labeling: A Review of New Molecular Entities Approved
                     1995-1999.




                     Page 19                                           GAO-03-950 Pediatric Drug Research
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.




Janet Heinrich
Director, Health Care—Public Health Issues




Page 20                                      GAO-03-950 Pediatric Drug Research
             Appendix I: Scope and Methodology
Appendix I: Scope and Methodology


             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.1 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


             1
              We classified as “other” any study participants that were specified by some other race or
             ethnicity. If no race was indicated, we classified those participants as “unknown.” For
             example, one study classified its 200 participants as “mostly Caucasian” and included no
             further data on the remaining population. We classified the entire study population as
             unknown.




             Page 21                                               GAO-03-950 Pediatric Drug Research
Appendix I: Scope and Methodology




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.2

We conducted our work from October 2002 through September 2003 in
accordance with generally accepted government auditing standards.




2
 “Response to Congressional Request on FY 2002 Funding to Develop an Agency-wide
Database Focused on Women’s Health Activities,” Conference Action, Pub. L. No. 107-76,
FDA, June 2002.




Page 22                                            GAO-03-950 Pediatric Drug Research
              Appendix II: The Number of Children by
Appendix II: The Number of Children by
              Racial and Ethnic Group in Studies for Drugs
              Granted Exclusive Marketing Rights


Racial and Ethnic Group in Studies for Drugs
Granted Exclusive Marketing Rights
              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.




              Page 23                                        GAO-03-950 Pediatric Drug Research
                                            Appendix II: The Number of Children by
                                            Racial and Ethnic Group in Studies for Drugs
                                            Granted Exclusive Marketing Rights




Table 4: Children of Racial and Ethnic Groups, by Drug Class, in Clinical Studies for Drugs Granted Exclusive Marketing
Rights, January 4, 2002, through March 6, 2003

 Drug       Indication                          African American       Asian     Caucasian      Hispanic      Other       Unknown       Total
 A          Allergic Rhinitis                                      6         0             46            0            5       398         455
 B          Allergic Rhinitis                                    47          2           146             0        24             0        219
 C          Allergic Rhinitis                                    51          0           222             0        33             0        306
 D          Cancer                                                 0         0             30            0            0         45         75
 E          Cancer                                               13          4           151            10            7          0        185
 F          Cancer                                                —        —               26           —         —           112         138
 G          Cancer                                                 1         0             12            6            5          0         24
 H          Cardiovascular                                         3         3           172             0            9          0        187
 I          Cardiovascular                                         0         0           311             6            2          0        319
 J          Cardiovascular                                         2         6           203             0            3         24        238
                             a
 K          Hypertension                                         52          5           152            35            9          0        253
                             a
 L          Hypertension                                         50          3             54           21            8          0        136
                             a
 M          Hypertension                                         33          0           125            48        21             0        227
 N          Ophthalmologic                                         3         2             89            0        40             0        134
 O          Ophthalmologic                                         3         2             89            0        40             0        134
 P          Psychiatric                                          16        49            265            34        12             0        376
 Q          Psychiatric                                            6         0         1,101             0            4       249       1,360
 R          Psychiatric                                          52          4           391            48        23             0        518
 S          Psychiatric                                            0         0           367             0            0         89        456
 T          Psychiatric                                          86          8           583            72        19            43        811
 U          Other                                                18          1             86           26            1          0        132
 V          Other                                                  5         2             15            5            1          0         28
 W          Other                                                41          3           147            44            6          0        241
            Total                                               488        94          4,783           355      272           960        6952
            Percentage of children in
            clinical studies                                       7         1             69            5            4         14        100
            Percentage of U.S. population
                                                                                                                                             b
            under age 18                                         15          3             69           17       NA            NA        104
Sources: Department of Commerce and FDA.

                                            Notes: GAO analysis of 23 NDAs or sNDAs and FDA medical officer reviews; and U.S. Bureau of
                                            Census, Census 2000 Summary File 1, “Total Population by Age and Sex for the United States:
                                            2000.”

                                            NA means not applicable.
                                            a
                                            Drugs are those for which FDA required greater minority representation.
                                            b
                                            Individual entries do not sum to 100 percent because in collecting U.S. Census data, the Department
                                            of Commerce permitted individuals to report that they belonged to multiple race groups.
                                            Consequently, the total of all race groups will exceed the total population.




                                            Page 24                                                   GAO-03-950 Pediatric Drug Research
             Appendix III: Comments from the Food and Drug Administration
Appendix III: Comments from the Food and
Drug Administration




             Page 25                                           GAO-03-950 Pediatric Drug Research
Appendix III: Comments from the Food and Drug Administration




Page 26                                           GAO-03-950 Pediatric Drug Research
Appendix III: Comments from the Food and Drug Administration




Page 27                                           GAO-03-950 Pediatric Drug Research
Appendix III: Comments from the Food and Drug Administration




Page 28                                           GAO-03-950 Pediatric Drug Research
                  Appendix IV: GAO Contact and Staff
Appendix IV: GAO Contact and Staff
                  Acknowledgments



Acknowledgments

                  Martin T. Gahart, (202) 512-3596
GAO Contact
                  Gloria E. Taylor, Sharif Idris, George Bogart, and Elizabeth T. Morrison
Acknowledgments   also made major contributions to this report.




(290224)
                  Page 29                                     GAO-03-950 Pediatric Drug Research
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