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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 FDAs 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 GAOs 
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 FDAs 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).

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:

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.

[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]

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.

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:

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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