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

Pediatric Drug Research: Food and Drug Administration Should More Efficiently Monitor Inclusion of Minority Children (09/26/2003, GAO-03-950}

-------------------------Indexing Terms-------------------------
REPORTNUM: GAO-03-950
TITLE: Pediatric Drug Research: Food and Drug Administration Should More Efficiently Monitor Inclusion of Minority Children
DATE: 09/26/2003

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Report to Congressional Committees:

United States General Accounting Office:

GAO:

September 2003:

Pediatric Drug Research:

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

Pediatric Drug Research:

GAO-03-950:

GAO Highlights:

Highlights of GAO-03-950, a report to the Committee on Health,
Education, Labor and Pensions, U.S. Senate, and the Committee on
Energy and Commerce, House of Representatives

Why GAO Did This Study:

Drug effectiveness and adverse events can vary between children and
adults and among racial and ethnic groups. The Food and Drug
Administration (FDA) is authorized under the pediatric exclusivity
provision to grant drug sponsors 6 months of additional exclusive
marketing rights for conducting clinical drug studies in children. The
Best Pharmaceuticals for Children Act of 2002 (BPCA) expanded this
provision to require FDA to take into account the adequacy of minority
representation in pediatric exclusivity studies. BPCA also directed
GAO to evaluate the representation of minorities in such studies. GAO
examined the extent to which minority children are represented,
whether drugs that treat diseases disproportionately affecting
minority groups are studied under the provision, and FDA�s monitoring
of the representation of minority children in the studies. GAO
reviewed related FDA documents, FDA requests for pediatric studies and
final study results, and interviewed FDA officials and other experts.

What GAO Found:

Compared with the proportions of children from racial and ethnic
minority groups in the U.S. population, smaller proportions of
children from minority groups were included in the pediatric clinical
drug studies requested by FDA before the enactment of BPCA that GAO
reviewed. However, FDA required, and drug sponsors included, larger
proportions of African American children in clinical studies for
hypertension drugs because there is evidence that hypertension is more
prevalent and more severe among African Americans. Furthermore, FDA
has requested that forthcoming studies for certain drugs include
larger proportions of minority children.

Studies of some drugs that may be used to treat diseases or conditions
that disproportionately affect minorities have been completed and
additional such studies have been requested by FDA. From January 4,
2002, through March 6, 2003, FDA granted additional exclusive
marketing rights to four drugs that may be used to treat conditions
such as hypertension, type II diabetes, and sickle cell anemia�
conditions or diseases that disproportionately affect minority
children. During that time, FDA also issued written requests for
studies of six drugs for these conditions.

FDA does not have a system in place to serve as a single source of
data to allow the agency to efficiently determine the extent of
participation of children by racial and ethnic group under the
pediatric exclusivity provision. GAO found that some study reports
submitted to FDA from drug sponsors did not specify the race and
ethnicity of all study participants. Across all the studies for drugs
granted additional exclusive marketing rights that GAO reviewed, 86
percent of study participants were identifiable by race or ethnicity,
but the race or ethnicity of 14 percent of study participants was
unknown. In January 2003, FDA issued draft guidance recommending that
drug sponsors use standard definitions for race and ethnicity in drug
studies. However, drug sponsors are not required to use these
definitions. FDA has also begun to develop an agencywide system to
monitor demographic characteristics of study participants, such as
age, sex, and race.

FDA agreed with the GAO recommendation to specify the categories that
sponsors should use to report minority representation as well as GAO�s
findings regarding the efficiency of its data collection systems. FDA
expressed concerns about the GAO comparison of the proportion of
minorities in drug studies to their proportion in the U.S. population.
However, FDA had previously used the methodology GAO employed in its
analyses of adult study participants.

What GAO Recommends:

GAO recommends that FDA specify that drug sponsors use the standard
racial and ethnic group definitions described in FDA�s January 2003
draft guidance to identify study participants. FDA concurred with the
recommendation.

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.

[End of section]

Contents:

Letter:

Results in Brief:

Background:

Smaller Proportions of Minority Children Were in Studies for Additional
Marketing Exclusivity Requested before BPCA:

Drugs of Importance to Minority Children Are Being Studied in Response
to Pediatric Exclusivity Provision Requests:

FDA Monitoring of Data on Minority Representation Needs Improvement:

Conclusions:

Recommendation for Executive Action:

Agency Comments and Our Evaluation:

Appendix I: Scope and Methodology:

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

Appendix III: Comments from the Food and Drug Administration:

Appendix IVGAO Contact and Staff Acknowledgments:

GAO Contact:

Acknowledgments:

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:

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:

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:

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:

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:

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.[Footnote 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.[Footnote 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 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.[Footnote 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.[Footnote 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 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.[Footnote 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
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.

Results in Brief:

Compared with the proportions of children from racial and ethnic
minority 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.

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 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.

Background:

Congress passed the pediatric exclusivity provision as part of the Food
and Drug Administration Modernization Act of 1997 to address a long-
standing concern about the low percentage of prescription medications
on the market that had been tested and approved for use in children.
BPCA, which reauthorized the pediatric exclusivity provision, also
included a requirement that FDA take into account adequate
representation of race and ethnicity in the development of patient
groups in pediatric drug studies. FDA is responsible for administering
the law and has procedures for ensuring the study of drugs in pediatric
patients as well as guidance that encourages (1) the inclusion of
children from minority groups and (2) the collection and analysis of
race-related study data. In this role, FDA must balance its policy of
minimizing the number of children exposed to a drug during clinical
trials with the need to maintain adequate sample sizes, including
adequate representation of minority children, for effectively assessing
a drug.

Improvements Resulting from the Pediatric Exclusivity Provision:

In May 2001, we testified before the Senate Committee on Health,
Education, Labor and Pensions that, since enactment of the pediatric
exclusivity provision, both the numbers of new drugs studied in
children and the number of therapeutic classes these drugs represent
have substantially increased.[Footnote 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 evaluations of a drug's safety and
effectiveness in children of various ages.[Footnote 7] BPCA
reauthorized and expanded the provision for 5 more years through
October 1, 2007.

FDA Procedures for Ensuring the Study of Drugs in Pediatric Patients:

The process for obtaining exclusive marketing rights can be initiated
either by a drug sponsor or by FDA. A sponsor may submit a proposal to
FDA to conduct drug studies. If FDA officials believe that studying a
drug may produce health benefits for children, FDA issues a formal
written request to the drug sponsor that includes, among other things,
the type of studies to be conducted, the study design and goals, and
the formulations and age groups to be studied. As of March 31, 2003,
FDA had issued 272 written requests for pediatric studies. Of these,
220 were issued in response to sponsors' proposals. FDA may issue a
written request without the sponsor's proposal if FDA identifies a need
for pediatric data. FDA has issued 52 written requests without
sponsors' proposals. A written request may require more than 1 study of
a drug; the 272 requests covered 631 studies, and could involve more
than 37,150 pediatric patient participants if they were all completed.
Regardless of the final study results, if FDA determines that the data
submitted fairly responds to the written request and the studies were
conducted properly, it will grant the sponsor 6 months of additional
exclusive marketing rights. From enactment of the pediatric exclusivity
provision in 1997 through April 30, 2003, FDA granted an additional 6
months of additional exclusive marketing rights for 74 drugs. Sponsors
are not required to include minority children in studies for pediatric
exclusivity.

Findings from these studies have led to labeling changes for pediatric
use for 50 drugs. For example, a study of fluoxetine (an
antidepressant) confirmed its effectiveness to treat major depressive
disorders in children 8 to 17 years of age and obsessive-compulsive
disorder in children 7 to 17 years of age. In addition, studies for a
new asthma drug--montelukast--led to new information on dosing and a
new oral formulation permitting its use in children from the ages of 12
months to 5 years.

FDA also has a process in place to encourage pediatric studies of drugs
that manufacturers choose not to conduct. For drugs on which the patent
or exclusive marketing rights have expired, commonly referred to as
off-patent drugs, the National Institutes of Health (NIH) in
collaboration with FDA annually develop a list of drugs for which
pediatric studies are needed and publish it in the Federal
Register.[Footnote 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,[Footnote 9] to test the drug
with funds raised from the private sector.

Evidence Shows That Drug Effectiveness and Toxicity Can Vary among
Racial and Ethnic Groups:

An important reason to include minorities in pediatric drug studies is
to examine the effect of race or ethnicity on the disposition and
effects of drugs in children. In adults, the activity of some drug-
metabolizing enzymes varies with race or ethnicity.[Footnote 10] For
example, one commonly prescribed drug used to treat gastric conditions,
esomeprazole (Nexium), is partly metabolized by the CYP2C19 enzyme.
Studies have shown that from 15 to 20 percent of Asians lack the enzyme
CYP2C19. As a result, some Asians metabolize the drug poorly and
require lower doses because their bodies do not clear the drug as
rapidly as individuals with this enzyme.[Footnote 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.[Footnote 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
enzyme (ACE) inhibitors, and central nervous system agents
(antidepressants and antipsychotics).[Footnote 13]

FDA's Efforts to Account for Minority Children in Clinical Drug
Studies:

BPCA requires that FDA take into account adequate representation of
children from ethnic and racial minority groups when issuing written
requests to drug sponsors. FDA regulations have required that in new
drug applications, "effectiveness data (safety data) shall be presented
by gender, age, and racial subgroups and shall identify any
modifications of dose or dose interval needed for specific
subgroups."[Footnote 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.[Footnote 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.

Limitations of Pediatric Drug Studies:

According to FDA officials, FDA's policy is to minimize the number of
children exposed to a drug during clinical studies, while maintaining
an adequate sample size to draw clinically meaningful conclusions. Most
pediatric studies for extension of exclusive marketing rights are
designed to give health care providers information on the appropriate
dosage or formulation of a drug in a pediatric population.[Footnote 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.

Smaller Proportions of Minority Children Were in Studies for Additional
Marketing Exclusivity Requested before BPCA:

Compared to their proportions in the U.S. population, smaller
proportions of children of racial and ethnic minority groups were
included in the clinical drug studies we reviewed for additional
exclusive marketing rights that FDA requested before BPCA took effect.
However, for hypertension drugs where differences in racial response
have been documented in adult drug studies, FDA required, and drug
sponsors included, larger numbers of children from specific racial and
ethnic groups. Most of FDA's written requests for studies that have
been issued since BPCA took effect required drug sponsors to report the
number of racial and ethnic minorities in their final study results. In
addition, some requests required drug sponsors to analyze the effects
of race and ethnicity or increase minority representation for certain
drugs where differences in racial response have been documented in
adult drug studies.

The Proportions of Children in Racial and Ethnic Minority Groups in
Clinical Studies for Exclusive Marketing Rights Were Lower Than Their
Proportions in the U.S. Population:

Compared with their proportions in the U.S. population, smaller
proportions of African American, Hispanic, and Asian children were
included in clinical studies for the drugs that were granted 6 months
of additional exclusive marketing rights by FDA from January 4, 2002,
through March 6, 2003. Across all clinical studies for the 23 drugs we
examined, 7 percent of pediatric patients were African American, 5
percent were Hispanic, and 1 percent were Asian. Most pediatric
patients were Caucasian--69 percent--and the race and ethnicity were
unknown for 14 percent. Compared with the frequency distribution of
African American and Hispanic children under 18 years of age for the
U.S. population as a whole in 2000, the proportions of these two groups
included in clinical drug studies were 8 and 12 percentage points
lower, respectively, than their proportions in the U.S. population. The
proportion of Asian children in clinical drug studies was 2 percentage
points lower than their proportion in the U.S. population (see table
1). (See app. II for the number of children in racial and ethnic groups
included in clinical studies for drugs granted additional exclusive
marketing rights from January 4, 2002, through March 6, 2003.):

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:

Race/ethnicity: African American; Number in clinical studies: 488;
Percentage in clinical studies: 7; Percentage in U.S. population under
age 18: 15.

Race/ethnicity: Asian; Number in clinical studies: 94; Percentage in
clinical studies: 1; Percentage in U.S. population under age 18: 3.

Race/ethnicity: Caucasian; Number in clinical studies: 4,783;
Percentage in clinical studies: 69; Percentage in U.S. population under
age 18: 69.

Race/ethnicity: Hispanic; Number in clinical studies: 355; Percentage
in clinical studies: 5; Percentage in U.S. population under age 18: 17.

Race/ethnicity: Other; Number in clinical studies: 272; Percentage in
clinical studies: 4; Percentage in U.S. population under age 18: NA.

Race/ethnicity: Unknown; Number in clinical studies: 960; Percentage in
clinical studies: 14; Percentage in U.S. population under age 18: NA.

Race/ethnicity: Total; Number in clinical studies: 6,952; Percentage in
clinical studies: 100; Percentage in U.S. population under age 18:
104[A].

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.

[End of table]

Pediatric Studies for Hypertension Drugs Included More Children of
Racial and Ethnic Minority Groups:

FDA required that sponsors increase representation of children of
ethnic and racial minority groups in clinical studies for drugs used to
treat diseases that disproportionately affect children in such groups
or where evidence from studies on adults suggests that for certain
classes of drugs differences in metabolism or response for racial or
ethnic groups exist. For example, because hypertension is more
prevalent and more severe in African Americans than in Caucasians, and
adult responses to some hypertension therapies appear to be different
in African American and non-African American populations, FDA's written
requests for these drugs require that the patient recruitment protocol
be designed to ensure a mixture of African American and non-African
American patients. Therefore, in pediatric clinical studies for three
cardiovascular drugs used to treat hypertension, African American
children represented 22 percent of study participants (see table 2).

Race/ethnicity: African American; In clinical studies for 3 drugs when
mixed race required: 22; Numbers in percent: In all other clinical
studies: 6; In U.S. population under age 18: 15.

Race/ethnicity: Asian; In clinical studies for 3 drugs when mixed race
required: 1; Numbers in percent: In all other clinical studies: 1; In
U.S. population under age 18: 3.

Race/ethnicity: Caucasian; In clinical studies for 3 drugs when mixed
race required: 54; Numbers in percent: In all other clinical studies:
70; In U.S. population under age 18: 69.

Race/ethnicity: Hispanic; In clinical studies for 3 drugs when mixed
race required: 17; Numbers in percent: In all other clinical studies:
4; In U.S. population under age 18: 17.

Race/ethnicity: Other or unknown; In clinical studies for 3 drugs when
mixed race required: 6; Numbers in percent: In all other clinical
studies: 19; In U.S. population under age 18: NA.

Race/ethnicity: Total; In clinical studies for 3 drugs when mixed race
required: 100; Numbers in percent: In all other clinical studies: 100;
In U.S. population under age 18: 104[A].

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.

[End of table]

FDA Written Requests Issued since BPCA Require Sponsors to Increase
Minority Representation for Certain Drugs:

For some written requests issued since BPCA took effect, FDA required
sponsors to increase the participation of minority children.
Specifically, 4 of the 22 written requests for such studies directed
sponsors to increase the proportion of minority children participants
or to analyze the effects of race and ethnicity. In 11 of the 22
requests, FDA directed drug sponsors to report the representation of
pediatric patients of ethnic and racial minority groups when submitting
final study results, but did not request that sponsors include a
particular proportion of minority children or analyze the effects of
race and ethnicity. The remaining 7 written requests made no mention of
race or ethnicity.

FDA's four study requests that directed sponsors to increase the
proportion of minority children participants or to analyze the effects
of race or ethnicity took varied approaches. One written request by FDA
required that the sponsor include a mixture of African American and
non-African American patients for a study of a drug used to treat
hypertension. Two other requests, for diabetes drugs, required the
study sponsors to ensure that 50 percent of the study populations were
composed of African American, Native American, and Hispanic patients
because of a greater prevalence of diabetes in these groups. In the
fourth written request, for a drug used to prevent bone loss, FDA
required that the study sponsor examine potential demographic
covariates, such as race.

Drugs of Importance to Minority Children Are Being Studied in Response
to Pediatric Exclusivity Provision Requests:

Some drugs that may be used to treat diseases or conditions that
disproportionately affect children of racial and ethnic minority groups
are being studied under the pediatric exclusivity provision. In
response to FDA written requests, drug sponsors are conducting or have
completed pediatric studies on drugs that might be used to treat
hypertension, type II diabetes, sickle cell anemia, and other
conditions that disproportionately affect minorities.

From January 4, 2002, through March 6, 2003, FDA granted exclusive
marketing rights or issued written requests for studies of 10 drugs
that might be used to treat diseases or conditions that
disproportionately affect minority children. Specifically, 4 of the 23
drugs for which FDA granted additional exclusive marketing rights might
be used to treat diseases or conditions that are more prevalent in
minorities, such as asthma and hypertension (see table 3). In addition,
6 of the 22 written requests for new studies that FDA issued to drug
manufacturers during this period also included treatments for diseases
or conditions disproportionately affecting minorities, such as type II
diabetes, hypertension, sickle cell anemia, HIV, and hepatitis B.

Disease/condition: Asthma; Estimated prevalence among selected racial
and ethnic groups: Asthma prevalence of 82/1,000 in African American
children compared to 76/1,000 in Hispanic and 65/1,000 in Caucasian
children.[A]; Drug(s): Budesonide; Study status: Exclusive rights
granted.

Disease/condition: Diabetes mellitus (type II diabetes); Estimated
prevalence among selected racial and ethnic groups: National age-
adjusted rates for all types of diabetes show that it is more frequent
in African Americans and Hispanics than Caucasians.[B] In addition, one
study found that over 70 percent of type II diabetes cases among
children were in African Americans.c; Drug(s): Metformin, Pioglitazone;
Study status: Written request issued (both).

Disease/condition: Hepatitis B; Estimated prevalence among selected
racial and ethnic groups: Age-adjusted rates of Hepatitis B in African
Americans are more than 2.5 times greater than in Hispanics and 4.5
times greater than in Caucasians.[D]; Drug(s): Adefovir; Study status:
Written request issued.

Disease/condition: HIV infection and AIDS; Estimated prevalence among
selected racial and ethnic groups: Prevalence rate of 1.4/100,000
African American children was 7 times greater than in Hispanics and 14
times greater than in Caucasians and Asians.[E]; Drug(s): Tipranavir;
Study status: Written request issued.

Disease/condition: Hypertension; Estimated prevalence among selected
racial and ethnic groups: A study found that a sample of African
American children in California had higher blood pressure than
Caucasian children.[F]; Drug(s): Losartan, Quinapril, Fosinopril,
Metoprolol; Study status: Exclusive rights granted (first three).
Written request issued (for Metoprolol).

Disease/condition: Sickle cell anemia; Estimated prevalence among
selected racial and ethnic groups: Occurs in 1 out of every 700 African
American births, 1 of every 46,622 Hispanic births, and 1 of every
158,127 Caucasian births.[G]; Drug(s): Hydroxyurea; Study status:
Written request issued.

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.

[End of table]

FDA Monitoring of Data on Minority Representation Needs Improvement:

FDA does not have a system in place to serve as a single source of data
to allow the agency to efficiently determine the extent of minority
enrollment in drug studies under the pediatric exclusivity provision.
Further, we found that some study reports submitted to FDA from drug
sponsors did not specify the race and ethnicity of study participants.
For example, in the completed studies for the 23 drugs granted
additional exclusive marketing rights that we examined, the race or
ethnicity of 86 percent of study participants was identified, but study
sponsors did not specify the race or ethnicity of 960 children, or 14
percent of the studies' populations. Recently, FDA issued draft
guidance to improve drug sponsors' reporting of racial and ethnic
minority representation data, and FDA is planning to develop a database
to monitor demographic variables in drug trials across the agency.

There Is No Single Source of Data about Minority Representation:

There is no single data source at FDA to allow the agency to tabulate
the overall numbers of racial and ethnic minorities in clinical
studies. For example, to quantify the participation of racial and
ethnic groups in studies for the 23 drugs granted additional exclusive
marketing rights since January 2002, FDA had to extract and tally race
data from about 50 separate final study reports that included nearly
7,000 children.

Reporting of Minority Representation Data Is Not Standardized:

Final study results submitted to FDA from sponsors do not always fully
describe the race and ethnicity of children who participated in
clinical drug studies. In addition, FDA has not established uniform
definitions for reporting racial and ethnic minorities in drug studies.
In reviewing the study results for the 23 drugs granted additional
exclusive marketing rights from January 4, 2002, through March 6, 2003,
we found wide variation in how study sponsors presented and defined
data regarding minority participation. Study sponsors reported minority
representation according to non-standard definitions, which were often
ambiguous. For example, one study classified its 200 participants as
"mostly Caucasian" and included no further data on the remaining
population. Similarly, in studies included in three applications
involving more than 1,500 children, sponsors only identified the number
of Caucasian patients and did not identify the racial or ethnic groups
of non-Caucasian children. Across all studies for drugs granted
exclusive marketing rights from January 4, 2002, through March 6, 2003,
the race or ethnicity of 960 children, or about 14 percent of all study
participants, was unknown. Eighty-six percent of study participants
were identified by race or ethnicity. Further, we could identify the
specific race or ethnicity for only 30 of the 268 subjects classified
as "other" in study reports. FDA officials told us that they do not
know which populations are included in the "other" category and that it
likely includes children whose race was not determined.

FDA Is Taking Steps to Improve Data Management:

Recently, FDA has begun to take steps to address data management
issues. In January 2003, FDA issued draft guidance for
industry[Footnote 17] 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.[Footnote
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.[Footnote 19] DIDR is
part of FDA's response to a congressional report requesting that FDA
monitor the representation of women in clinical studies.[Footnote 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.

Conclusions:

To have optimal effectiveness for all children, a drug should be tested
in clinical studies that include pediatric patients representing the
full range of population groups likely to receive the drug once it is
marketed. In addition to age, genetic factors related to race and
ethnicity may play important roles in the variability of patients'
responses to a drug. Pediatric clinical drug studies with sufficient
representation of minority groups are necessary to detect the presence
or absence of differences in responses to certain drugs. The changes
under BPCA to the pediatric exclusivity provision require that FDA take
into account the adequate representation of children of racial and
ethnic minorities in written requests for drug studies. However, it is
too early to tell whether FDA's written requests issued since enactment
of BPCA will result in better reporting or a broader mix of
participants. Currently, FDA is unable to accurately determine whether
and to what extent minority groups are accounted for in final study
results because it does not require sponsors to use uniform
definitions. Though FDA's draft guidance on standard definitions for
reporting race and ethnicity is helpful, sponsors will not be obligated
to use these categories to identify study participants unless FDA
requests that they do so. The standardized collection of demographic
data, such as race and ethnicity, would help ensure that FDA's
forthcoming DIDR will have the required data needed to evaluate the
risks and benefits of a drug in specific demographic groups.

Recommendation for Executive Action:

To help the agency more efficiently monitor the participation of
children of racial and ethnic groups in studies for additional
exclusive marketing rights, we recommend that the Commissioner of FDA
specify in written requests that study sponsors must use the racial and
ethnic categories described in FDA's January 2003 draft guidance to
identify study participants in their reports to the agency. FDA can
refuse to grant 6 months of additional exclusive marketing rights under
the pediatric exclusivity provision for sponsors that do not fairly
respond to FDA's written requests.

Agency Comments and Our Evaluation:

FDA comments on a draft of this report reaffirmed the importance of
clinical studies of drugs used to treat children. FDA agreed that the
agency needed to improve the efficiency of its system for tracking
demographic information about study participants. FDA also agreed with
our recommendation and reported that it has already begun to implement
it.

FDA raised concerns about three aspects of our draft report. First, FDA
was critical of our comparison of the proportions of minority children
study participants to the proportions of minority children in the
population. FDA commented that it would have been more appropriate for
us to compare the proportions of minority children in clinical drug
studies with the proportions of minority children with the specific
condition each drug is intended to treat. We agree that such a
comparison would have been useful, but both we and FDA found that the
information needed for such comparisons--the racial and ethnic group
distributions of children with many of the specific conditions treated
by the drugs studied for additional exclusive marketing rights--was not
available. Further, FDA has previously used the methodology we employed
in its analyses of adult study participants.[Footnote 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 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:

Signed by Janet Heinrich:

[End of section]

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.[Footnote 22] However, the clinical studies included in the
NDAs or sNDAs submitted during this period were conducted before the
effective date for the Best Pharmaceuticals for Children Act of 2002
because the time lag between when FDA issues a written request for a
pediatric study and when sponsors submit final study results ranged
from 1 to 4 years. To assess the extent to which FDA required drug
sponsors to take into account the adequate representation of children
of racial and ethnic groups in clinical studies for drugs for which
written requests have been issued since BPCA took effect, we reviewed
the 22 written requests issued for pediatric drug studies by FDA from
January 4, 2002, through March 6, 2003.

To determine whether drugs used to treat conditions or diseases
disproportionately affecting minorities are being studied under the
pediatric exclusivity provision, we obtained data on the prevalence of
selected diseases or conditions that disproportionately affect
minorities and examined the list of drugs for which FDA has either
granted exclusive marketing rights or issued study requests from
January 4, 2002, through March 6, 2003, to determine if any of these
drugs may be used to treat these diseases or conditions. We compiled
data on the estimated prevalence of the diseases and conditions by race
and ethnicity from the National Centers for Health Statistics, National
Center of HIV, STD, and Tuberculosis Prevention, and research in
scientific journals reporting the prevalence of these diseases and
conditions in minority children. We interviewed National Institutes of
Health officials, pharmacology experts, and pediatric clinicians,
including members of the American Academy of Pediatrics and the
Pharmaceutical Research and Manufacturers of America to gain their
perspectives on the representation of minorities in drug studies and
the study of drugs of importance to these populations.

To evaluate FDA's management of pediatric clinical study data on
minority representation and its guidance to sponsors on reporting such
data, we reviewed FDA's policies, guidance, and rules for inclusion and
reporting of minority representation in drug studies. We interviewed
FDA officials within the Office of Counter-Terrorism and Pediatric Drug
Development to determine how they interpret and implement these
policies for the pediatric exclusivity program. We spoke with officials
in the Office of Women's Health who were responsible for establishing a
database to monitor demographic variables to determine how an
agencywide demographic database might affect the monitoring of minority
participation in drug studies. We also reviewed FDA's response to a
congressional request to develop an agencywide demographic
database.[Footnote 23]

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

[End of section]

Appendix II: The Number of Children by 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.

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: A; Indication: Allergic Rhinitis; African American: 6; Asian: 0;
Caucasian: 46; Hispanic: 0; Other: 5; Unknown: 398; Total: 455.

Drug: B; Indication: Allergic Rhinitis; African American: 47; Asian: 2;
Caucasian: 146; Hispanic: 0; Other: 24; Unknown: 0; Total: 219.

Drug: C; Indication: Allergic Rhinitis; African American: 51; Asian: 0;
Caucasian: 222; Hispanic: 0; Other: 33; Unknown: 0; Total: 306.

Drug: D; Indication: Cancer; African American: 0; Asian: 0; Caucasian:
30; Hispanic: 0; Other: 0; Unknown: 45; Total: 75.

Drug: E; Indication: Cancer; African American: 13; Asian: 4; Caucasian:
151; Hispanic: 10; Other: 7; Unknown: 0; Total: 185.

Drug: F; Indication: Cancer; African American: --; Asian: --;
Caucasian: 26; Hispanic: --; Other: --; Unknown: 112; Total: 138.

Drug: G; Indication: Cancer; African American: 1; Asian: 0; Caucasian:
12; Hispanic: 6; Other: 5; Unknown: 0; Total: 24.

Drug: H; Indication: Cardiovascular; African American: 3; Asian: 3;
Caucasian: 172; Hispanic: 0; Other: 9; Unknown: 0; Total: 187.

Drug: I; Indication: Cardiovascular; African American: 0; Asian: 0;
Caucasian: 311; Hispanic: 6; Other: 2; Unknown: 0; Total: 319.

Drug: J; Indication: Cardiovascular; African American: 2; Asian: 6;
Caucasian: 203; Hispanic: 0; Other: 3; Unknown: 24; Total: 238.

Drug: K; Indication: Hypertension[A]; African American: 52; Asian: 5;
Caucasian: 152; Hispanic: 35; Other: 9; Unknown: 0; Total: 253.

Drug: L; Indication: Hypertension[A]; African American: 50; Asian: 3;
Caucasian: 54; Hispanic: 21; Other: 8; Unknown: 0; Total: 136.

Drug: M; Indication: Hypertension[A]; African American: 33; Asian: 0;
Caucasian: 125; Hispanic: 48; Other: 21; Unknown: 0; Total: 227.

Drug: N; Indication: Ophthalmologic; African American: 3; Asian: 2;
Caucasian: 89; Hispanic: 0; Other: 40; Unknown: 0; Total: 134.

Drug: O; Indication: Ophthalmologic; African American: 3; Asian: 2;
Caucasian: 89; Hispanic: 0; Other: 40; Unknown: 0; Total: 134.

Drug: P; Indication: Psychiatric; African American: 16; Asian: 49;
Caucasian: 265; Hispanic: 34; Other: 12; Unknown: 0; Total: 376.

Drug: Q; Indication: Psychiatric; African American: 6; Asian: 0;
Caucasian: 1,101; Hispanic: 0; Other: 4; Unknown: 249; Total: 1,360.

Drug: R; Indication: Psychiatric; African American: 52; Asian: 4;
Caucasian: 391; Hispanic: 48; Other: 23; Unknown: 0; Total: 518.

Drug: S; Indication: Psychiatric; African American: 0; Asian: 0;
Caucasian: 367; Hispanic: 0; Other: 0; Unknown: 89; Total: 456.

Drug: T; Indication: Psychiatric; African American: 86; Asian: 8;
Caucasian: 583; Hispanic: 72; Other: 19; Unknown: 43; Total: 811.

Drug: U; Indication: Other; African American: 18; Asian: 1; Caucasian:
86; Hispanic: 26; Other: 1; Unknown: 0; Total: 132.

Drug: V; Indication: Other; African American: 5; Asian: 2; Caucasian:
15; Hispanic: 5; Other: 1; Unknown: 0; Total: 28.

Drug: W; Indication: Other; African American: 41; Asian: 3; Caucasian:
147; Hispanic: 44; Other: 6; Unknown: 0; Total: 241.

Total; African American: Drug: 488; Asian: Drug: 94;
Caucasian: Drug: 4,783; Hispanic: Drug: 355; Other: Drug: 272; Unknown:
Drug: 960; Total: Drug: 6952.

Percentage of children in clinical studies; African
American: Drug: 7; Asian: Drug: 1; Caucasian: Drug: 69; Hispanic: Drug:
5; Other: Drug: 4; Unknown: Drug: 14; Total: Drug: 100.

Percentage of U.S. population under age 18;
African American: 15; Asian: 3; Caucasian: 69; Hispanic: 17; Other:
NA; Unknown: NA; Total: 104[B].

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.

[End of table]

[End of section]

Appendix III: Comments from the Food and Drug Administration:

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service:

Food and Drug Administration Rockville MD 20857:

September 5, 2003:

Janet Heinrich:

Director, Health Care-Public Health United States General Accounting
Office 441 G Street, NW:

Washington, DC 20548:

Dear Ms. Heinrich:

Please find the enclosed comments from the Food and Drug Administration
on the GAO draft report entitled, PEDIATRIC DRUG RESEARCH: Food and
Drug Administration Should More Efficiently Monitor Inclusion of
Minority Children (GAO-03-950). The Agency provided extensive technical
comments directly to your staff.

We appreciate the opportunity to review and comment on this draft
report before its publication as well as the opportunity to work with
your staff in developing this report.

Signed by Mark B. McClellan, M.D., Ph.D
Commissioner of Food and Drugs

Enclosure:

General Comments By The Department of Health And Human Services' Food
and Drug Administration on GAO' S Draft Report PEDIATRIC DRUG RESEARCH:
Food and Drug Administration Should More Efficiently Monitor Inclusion
of Minority Children (GAO-03-950:

FDA appreciates the opportunity to comment on GAO's draft report that
focuses additional attention on the area of needed research of drugs
used to treat children. Our general comments are as follows:

General Comments:

1. Support of Clinical Studies of Pharmaceuticals in Children: FDA
appreciates and concurs fully with the interest of GAO and the Congress
in assuring that all of the children of the United States benefit
appropriately from the significant advances taking place in medicine.
For children to benefit from these advances, practitioners and parents
need to know when and how best to use these medicines in the different
stages of childhood. To do this, well-designed, ethically conducted,
clinical trials are needed to give the community the information
required to make appropriate health care decisions. For too long,
practitioners and parents have had to treat children without the type
of safety, efficacy, and dosing information in children that are
routinely available for adults. FDAMA and BPCA have gone a long way in
rectifying this situation. To fully meet our obligations to our
children in this respect, FDA and HHS fully support the bipartisan
legislation now before Congress regarding pediatric studies of
pharmaceuticals.

2. Agreement on Need for More Efficient Tracking System: FDA currently
monitors the inclusion of racial and ethnic minorities in pediatric
studies and has been systematically compiling this information since
January 4, 2002, when the BPCA was signed into law. However, FDA agrees
with the GAO that the current system used to track the demographic
information on study participants needs to be made more efficient and
less resource intensive. FDA is in the process of developing improved
knowledge management capabilities to track sub-population
participation in clinical trials and to track variability in response,
both in terms of efficacy and safety, to medications by people of
different racial and ethnic groups.

3. Doing What is Scientifically Rational and Ethically Appropriate: Two
of the three determinations Congress directed the GAO to make under the
BPCA are: 1) to determine the extent to which children of ethnic and
racial minorities are adequately represented in studies, and 2) to
determine whether drugs used to address diseases that
disproportionately affect racial and ethnic minorities are being
studied for their safety and effectiveness. FDA believes these two
issues are inherently interconnected. In several areas throughout the
document GAO comments on the "smaller proportion" of minorities in the
studies when compared with the proportion of children from racial and
ethnic minority groups in the U.S. population. While this might be
factually correct, FDA questions whether this is the metric by which
one should determine if children in minority ethnic and racial
populations are "adequately
benefiting" from this legislation. FDA believes there is no scientific
or public health rationale to expect or mandate that the percentage of
children in EACH of these trials would or should track the percentage
of children in the general population.

One might infer from the GAO report that GAO advocates that sponsors
should enroll children of racial or ethnic minorities in these studies
in the same proportion seen in the general population. Using the
general population as the comparator is not the correct metric to
assess minority children's "adequate" representation in the particular
diseases being studied.

For example, it is not scientifically appropriate to enroll a majority
percentage of Caucasian subjects in trials for diseases that
predominately affect African Americans (e.g., sickle cell disease). A
trial that enrolls predominately African American patients for this
disease would be scientifically appropriate, even if other minority
groups were not included. In contrast, it would be equally
inappropriate to enroll a specified percentage of African Americans in
a trial for a disease that is prevalent in Ashkenazi Jews of eastern
European descent, such as Tay-Sachs disease.

An accurate assessment of the extent to which children of ethnic and
racial minorities are adequately represented in studies cannot be
obtained by using averages referencing the general population. To
effectively assess whether these children are adequately represented in
studies, the more appropriate comparison would be to the number of
minority children in the population with the specific disease being
studied.

In addition, there is a lot FDA already knows about the approved drugs
being studied for pediatric indications that guide decisions about drug
effect based on race and ethnicity, and even more that we are learning
through pharmacogenomics. Race and ethnicity may serve as a crude
predictor of disease and drug response in medical practice because we
know that some genes and propensities can cluster in this way. There
are however times where race or ethnicity is not an accurate means of
determining genetic factors that may influence a drug's activity in
individuals. The GAO report does not fully address this fundamental
medical fact, nor does it acknowledge that there is a lot already known
from studies in adults about bow drugs affect minority groups, and that
this knowledge is used to make decisions about the inclusion of
minority children in studies for pediatric exclusivity in ways that
limit the overall number of children that are exposed to experimental
drugs in clinical trials.

FDA believes it has ensured representation of racial and ethnic groups
in diseases where these groups are disproportionately affected by the
disease. FDA does ask for increased representation of ethnic and racial
minority populations in studies of treatments for these diseases where,
based on scientific knowledge and, often, adult experience with the
drug, specific populations are disproportionately affected either by
the disease or by safety concerns with the drug. However, FDA believes
it is scientifically unjustified to specify that specific percentages
of certain ethnic or racial groups be included in studies when the
disease being treated or safety concerns with
the test product do not affect any particular ethnic or racial
population differently from the general population.

FDA believes that the effort to enroll specific populations in a trial
needs to be a careful decision made on a drug-by-drug basis, and should
be based on current knowledge of the drug and/or disease. This practice
should be preserved because it constitutes good science, good medicine,
and good ethics.

4. High Level of Reporting Even Before BCPA Enacted: FDA would like to
point out that sometimes the summary of the report fails to reflect
much of the substance of the more detailed text, especially the fact
that all of the drug studies that GAO evaluated were based on Written
Requests issued prior to the passage of the BPCA. GAO does note,
however, that 86 percent of study participants were identified by race
or ethnicity in these studies even before BPCA was enacted. FDA notes
that in the studies of the 23 drugs reviewed by, FDA calculated that 90
percent of study participants were identified by race or ethnicity, and
that the race or ethnicity of only 10 percent of study participants was
unknown, even though this was not yet a requirement. This was based on
a total number of 7002 participants, of which race or ethnicity was not
identified for 723 participants.

5. Comment on GAO Recommendation: GAO recommended that FDA require drug
sponsors to use the standard racial and ethnic group definitions
described in FDA's January 2003 draft guidance to identify study
participants. FDA's guidance documents do not establish legally
enforceable rights or responsibilities and do not bind the public or
FDA. However, if FDA believes that the use of the categories in
reporting pediatric study results provides information necessary to
adequately label the drug for pediatric use, it can, in the written
request or in the written agreement, describe the racial and ethnic
categories the sponsor must use in data collection and presentation to
the agency.

In fact, as a result of the mandate in the BPCA to "take into account
adequate representation of children of ethnic and racial minorities,"
FDA began including a standard statement in all written requests issued
after April 2002. The statement reads as follows: "In addition, the
reports are to include information on the representation of pediatric
patients of ethnic and racial minorities." After the issuance of draft
guidance for industry, Collection of Race and Ethnicity Data in
Clinical Trials, and as of August 2003 FDA began including the
following statement in all written requests: "In addition, the reports
are to include information on the representation of pediatric patients
of ethnic and racial minorities. All pediatric patients enrolled in the
study (s) must be categorized using one of the following designations
for race: American Indian or Alaska Native, Asian, Black or African
American, Native American, Native Hawaiian or Pacific Islander or
White. For ethnicity one of the following designations must be used:
Hispanic/Latino or Not Hispanic/Latino."

[End of section]

Appendix IV GAO Contact and Staff Acknowledgments:

GAO Contact:

Martin T. Gahart, (202) 512-3596:

Acknowledgments:

Gloria E. Taylor, Sharif Idris, George Bogart, and Elizabeth T.
Morrison also made major contributions to this report.

FOOTNOTES

[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.

[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.

[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.

[6] GAO-01-705T.

[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."

[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.

[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).

[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).

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

[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).

[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).

[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.

[22] 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.

[23] "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.

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