Pediatric Drug Research: Substantial Increase in Studies of Drugs
for Children, But Some Challenges Remain (08-MAY-01,		 
GAO-01-705T).							 
								 
Children are subject to many of the same diseases as adults and  
are often treated with the same drugs. However, only about 25	 
percent of drugs used today have been labeled for pediatric	 
patients. The lack of pediatric testing and labeling can place	 
children at risk of under- or overdosing, and the lack of	 
age-appropriate formulations, such as liquids or chewable	 
tablets, can result in improper administration of drugs. The	 
pediatric exclusivity provision of the Food and Drug		 
Administration Modernization Act of 1997 has been successful in  
encouraging drug sponsors to generate needed information about	 
how drugs work in children. A wide range of drugs are being	 
studied in many therapeutic areas. The infrastructure for	 
conducting pediatric trials has also been greatly strengthened,  
which should help to support continued progress. While a number  
of drug labels have been changed to incorporate findings from	 
research conducted under the pediatric exclusivity provision,	 
label changes typically occur long after the Food and Drug	 
Administration has granted the extension of market exclusivity.  
In addition, there continues to be little incentive to conduct	 
pediatric research on off-patent drugs. 			 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-01-705T					        
    ACCNO:   A00964						        
  TITLE:     Pediatric Drug Research: Substantial Increase in Studies 
             of Drugs for Children, But Some Challenges Remain                
     DATE:   05/08/2001 
  SUBJECT:   Children						 
	     Drugs						 
	     Pharmaceutical industry				 
	     Pharmacological research				 

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GAO-01-705T
     
Testimony Before the Committee on Health, Education, Labor and Pensions, U.
S. Senate

United States General Accounting Office

GAO For Release on Delivery Expected at 9: 30 a. m. Tuesday, May 8, 2001
PEDIATRIC DRUG

RESEARCH Substantial Increase in Studies of Drugs for Children, But Some
Challenges Remain

Statement of Janet Heinrich Director, Health Care- Public Health Issues

GAO- 01- 705T

Page 1 GAO- 01- 705T Pediatric Drug Research

Chairman Jeffords, Ranking Member Kennedy, and Members of the Committee:

I am pleased to be here today to discuss the pediatric exclusivity provision
of the Food and Drug Administration Modernization Act of 1997 (FDAMA).
Children are subject to many of the same diseases as adults and are often
treated with the same drugs. However, only about 25 percent of drugs in use
today have been studied and labeled for pediatric patients. Doses for
children are often merely adjusted for their smaller weight, but there are
many other differences in children that can affect how drugs act in the
body. The lack of pediatric testing and labeling can place children at risk
of under- or overdosing, and the lack of age- appropriate formulations, such
as liquids or chewable tablets, can result in improper administration of
drugs. To help address these concerns, FDAMA authorized 6 months of
additional marketing exclusivity for drugs tested by manufacturers and other
sponsors for use in children, and placed a sunset date of January 1, 2002,
on the provision. 1

To assist the Committee in evaluating the pediatric exclusivity provision,
Chairman Jeffords, you, and Senator Dodd asked us to provide information on
some of the initial results of this provision. Today, I would like to focus
on (1) the number and types of drugs being studied, (2) whether these
studies have resulted in useful new information for using drugs in children,
and (3) two remaining challenges to achieve the objective of providing
better information on drugs commonly used in children.

To address these issues, we met with representatives of the Food and Drug
Administration (FDA), the National Institute of Child Health and Human
Development (NICHD) of the National Institutes of Health (NIH), the
Pharmaceutical Researchers and Manufacturers of America (PhRMA), the Generic
Pharmaceutical Association (GPhA), the American Academy of Pediatrics (AAP),
the National Organization of Rare Disorders (NORD), and Public Citizen, a
consumer advocacy organization. We examined the statute, FDA?s list of drugs
for which pediatric information may be beneficial, and FDA?s January 2001
report to Congress on the pediatric

1 Drug manufacturers or other drug sponsors may obtain marketing exclusivity
through patents or by compliance with the requirements of the Orphan Drug
Act (P. L. 97- 414) or Drug Price Competition and Patent Term Restoration
Act (P. L. 98- 417). In addition to drug manufacturers, sponsors can include
government agencies, health care institutions, individual physician-
investigators, and others.

Page 2 GAO- 01- 705T Pediatric Drug Research

exclusivity provision. 2 We also examined supporting documents provided by
FDA, as well as those provided by the other groups we contacted. We
conducted our work from March through April 2001 in accordance with
generally accepted government auditing standards.

In brief, since enactment of the pediatric exclusivity provision, both the
numbers of drugs studied in children and the therapeutic classes they
represent have substantially increased. Hundreds of studies are being done
on drugs that are important to pediatric patients. Some are tests on
relatively small numbers of pediatric patients to determine the correct dose
for a specified age group. Others are more complex and costly evaluations of
a drug?s safety and effectiveness in children of various ages. While there
has been some concern that exclusivity may be sought and granted primarily
for drugs that generate substantial revenue, most of the drugs studied are
not top sellers, and less than 1 in 10 generates revenues of more than $1
billion a year. As of April 1, 2001, 28 drugs had been granted marketing
exclusivity extensions, and research results have provided new and useful
information about how drugs work in children, which have been incorporated
into labels for 18 drugs. However, challenges remain to ensure that the
results of pediatric research are expeditiously incorporated into drug
labels, and that incentives are provided to encourage pediatric studies of
off- patent drugs widely used in children.

According to the American Academy of Pediatrics, only about a quarter of all
approved drugs marketed in the United States have had clinical trials
performed involving pediatric patients. FDA?s January 2001 report to
Congress on the pediatric exclusivity provision noted that evidence from
several studies conducted since 1973 showed that between 71 and 81 percent
of drugs were inadequately labeled for use in pediatric patients. According
to the legislative history of FDAMA, several factors appear to have
contributed to the lack of pediatric studies. Drug companies indicated that
they had little incentive to perform pediatric studies on drugs they
intended to market primarily to adults and that these drugs would provide
little additional revenue from use in children. Companies also said they
were concerned about liability and malpractice issues and

2 The Pediatric Exclusivity Provision, January 2001 Status Report to
Congress, Department of Health and Human Services, U. S. Food and Drug
Administration. Background

Page 3 GAO- 01- 705T Pediatric Drug Research

the difficulty of attracting enough pediatric patients for studies because
of the small number of children with a particular disease.

Previous FDA efforts to address the problem of inadequate pediatric testing
and drug labeling information had been unsuccessful. For example, in 1994
FDA tried to encourage sponsors to provide more pediatric information and
conduct new studies. However, it did not require sponsors to conduct new
pediatric studies, and pediatric use information did not substantially
increase.

In 1997, the Congress recognized the importance of learning more about how
drugs work in children by including in FDAMA a financial incentive for
pharmaceutical manufacturers and drug sponsors to conduct pediatric studies
and submit the results to FDA. The pediatric exclusivity provision offered 6
months of additional marketing exclusivity for drugs tested by manufacturers
and other sponsors for use in children. This provision also required FDA to
develop, prioritize, and publish an annual list of approved drugs for which
new pediatric information may produce health benefits in the pediatric
population. FDA?s initial priority list, issued in May 1998, was developed
based on recommendations from experts in pediatric research from the
American Academy of Pediatrics, PhRMA, GPhA, the National Institutes of
Health, the Pediatric Pharmacology Research Units Network, 3 the U. S.
Pharmacopoeia, and several others. To be included on FDA?s priority list, a
drug had to meet one of the following criteria:

 The drug would be a significant improvement compared to marketed products
labeled for use in the treatment, diagnosis, or prevention of a disease in
the relevant pediatric population.

 The drug is widely used in the pediatric population, with at least 50,000
projected uses per year.

 The drug is in a class or for an indication for which additional
therapeutic or diagnostic options are needed for pediatric patients.

The process for obtaining the pediatric exclusivity extension usually begins
when a sponsor submits a proposal to conduct pediatric studies to FDA. 4 If
FDA officials believe the studies will provide useful information,

3 In 1994, NICHD established a network of Pediatric Pharmacology Research
Units (PPRUs) to facilitate and conduct pediatric drug trials that can
improve pediatric labeling of new and existing drugs.

4 Drugs do not have to be on FDA?s priority list in order for FDA to
consider a sponsor?s proposal.

Page 4 GAO- 01- 705T Pediatric Drug Research

the agency issues a formal written request for sponsors to conduct the
studies. FDA also issues written requests without sponsor proposals. The
written request addresses, among other things, the type of studies to be
performed, study design, appropriate study age groups, and clinical
endpoints. The sponsor then decides whether to conduct studies requested by
FDA. Once the sponsor submits the results of the studies to FDA, the agency
generally has 90 days to determine whether the completed studies reported
meet the terms of the written request and were conducted properly. 5 If FDA
officials determine that the sponsor?s efforts were sufficient, the 6- month
marketing exclusivity extension is granted.

There has been a substantial increase in pediatric drug research compared to
the very limited amount of such research before enactment of FDAMA. As of
April 1, 2001, FDA had issued 188 written requests covering 155 drugs
already on the market and 33 new drugs not yet approved. About 73 percent of
the written requests were for drugs that treat anti- inflammatory,
cardiovascular, anti- viral, oncology, neurology, or endocrine diseases or
conditions.

A written request can ask for more than one study of a drug, and the 188
requests include 414 studies involving potentially more than 23,200 children
as research subjects. Of the 414 studies requested, 33 percent were to
examine drug safety and efficacy in pediatric patients, about 30 percent
were to examine both a drug?s safety and its pharmacokinetics, or how it is
absorbed, distributed, and eliminated from the body. Another 20 percent of
the studies were to examine only a drug?s safety in pediatric patients, and
about 9 percent were to study both pharmacokinetics and pharmacodynamics, or
how different individuals, such as children at various stages of
development, respond to a drug.

Precise data on study costs is not publicly available. The estimates we were
provided vary considerably. Officials at NICHD, which has conducted many
pediatric drug studies, said costs vary depending on the number of children
participating and type of drug being studied. They estimated that a safety
and efficacy study may cost between $1 million and

5 When FDA and the sponsor have a written agreement on a study?s protocol,
FDA has 60 days to review the study results and decide whether they were
conducted properly. Substantial Increase

in the Number of Drug Studies in Children

Page 5 GAO- 01- 705T Pediatric Drug Research

$7.5 million, while the cost of a pharmacokinetic study can range from
$250,000 to $750,000 per age group. Limited data provided by PhRMA suggested
higher study costs, ranging from under $5 million to more than $35 million.
Another study indicated that, based on a survey of drug companies, the cost
of pediatric studies averaged $3.87 million per written request. 6

As of April 1, 2001, 28 drugs had been granted marketing extensions based on
research conducted in accordance with FDA?s written requests. The drugs
granted extensions treat a variety of diseases or conditions that afflict
children. Table 1 provides some overall population information on the
prevalence of diseases in pediatric patients that may be treated by some of
the drugs granted market extensions.

Table 1: Prevalence of Diseases That May Be Treated by Drugs Granted
Marketing Extensions

Condition Estimated pediatric prevalence Drug

Generalized anxiety disorder 486,000 Buspirone Epilepsy 354,000 Gabapentin
Obsessive- compulsive disorder 268,000 Fluoxetine

Fluvoxamine Insulin- dependent diabetes (Type 1) 137,000 Insulin glargine

Metformin Juvenile rheumatoid arthritis 30,000 to 50,000 Etodolac

Oxaprozin Hypertension 36,000 Bisoprolol

Enalapril HIV infection and AIDS 5,600 Abacavir

Lamivudine Note: Figures are for patients under age 18 except for diabetes,
which includes patients under age 20, and HIV, which includes patients under
age 13.

Source: GAO analysis of data from the Centers for Disease Control, NIH, the
Surgeon General of the United States, the Arthritis Foundation, and the 2000
U. S. Census.

There has been some concern that exclusivity may be sought and granted
primarily for drugs that generate substantial revenue. Our analysis found
that sales revenue varied widely for the 155 approved drugs for which FDA
has issued written requests. 7 As shown in figure 1, while 7.7 percent of
the

6 The Pediatric Studies Incentive: Equal Medicines for All , Christopher-
Paul Milne, Tufts Center for the Study of Drug Development, April 2001. 7
Since a drug sponsor is not required to conduct studies based on a written
request, it is possible that some of the 155 drugs are not part of ongoing
studies.

Page 6 GAO- 01- 705T Pediatric Drug Research

drugs covered by written requests had sales exceeding $1 billion in 1999,
53.5 percent had sales under $120 million in 1999. Another 14.8 percent of
the drugs had sales that were more than $120 million but less than $200
million.

Figure 1: U. S. Sales of 155 Drugs Issued Written Requests Under the
Pediatric Exclusivity Provision

0 10

20 30

40 50

60 Above $1 B $400 M - $1 B

$200 M - $399 M $120 M - $199 M Under $120 M

53.5 14.8

11.7 12.2 7.7

Percent of drugs

Source: GAO analysis of FDA data and sales revenues of the top 200 selling
prescription drugs in 1999 as compiled by IMS Health Inc.

Research conducted under the pediatric exclusivity provision is providing
new and useful information about whether and how drugs work in children. As
of April 1, 2001, labels for 18 of the 28 drugs granted marketing extensions
had been changed to incorporate findings from research conducted to obtain
the extensions. Some of these label changes Studies Have Led to

Better Labeling and Infrastructure

Page 7 GAO- 01- 705T Pediatric Drug Research

include new statements that the drug can be used for younger children or for
a new use. Other label changes provide additional and more specific guidance
regarding the effective dose or additional warnings about adverse events in
children or information on related medications. In addition to making label
changes, sponsors for three drugs developed new formulations that are easier
to administer to children.

A few examples will help illustrate the new information derived from these
studies.

 Ibuprofen: this commonly used drug to reduce fever had no dosing
information for children under 2 years of age. Studies in thousands of
infants established a safe and effective dose in infants and children from 6
months to 2 years.

 Ranitidine: studies in neonates provided accurate dosing information for
safer and more effective use of this drug in the management of reflux of
stomach contents- a life- threatening event in seriously ill neonates- and
the label now says the drug can be prescribed to newborns and 1- montholds.

 Fluvoxamine: studies with this drug, used to treat children with obsessive
compulsive disorder, indicated that the dose in adolescents may need to be
as high as in adults but may need to be lower for girls ages 8 to 11 years.

 Etodolac: study results allowed for indication on the label that the drug
can be used to treat juvenile rheumatoid arthritis in children 6 to 16 years
old.

 Midazolam: studies with this drug, used as a sedative, led to a new oral
formulation for use in infants and children. In addition, the study results
showed that this drug has a high risk for an adverse event in children with
congenital heart disease and pulmonary hypertension.

Experts agree that, since FDAMA, there also has been significant growth in
the infrastructure necessary to conduct pediatric studies. For example,
NICHD has expanded the number of PPRUs from 7 to 13. 8 These units, located
in children?s hospitals and academic research centers specializing in
pediatric research, have conducted an increasing number of pediatric drug
studies. Prior to FDAMA, the PPRU Network had conducted 17 studies in
collaboration with drug sponsors. By 2000, the PPRUs were

8 NICHD provides full or partial funding for investigators and researchers,
and pharmaceutical companies pay the clinical costs of individual pediatric
studies.

Page 8 GAO- 01- 705T Pediatric Drug Research

conducting 73 pediatric drug studies in collaboration with drug sponsors.
The pharmaceutical industry also has increased its capacity to conduct
pediatric studies since enactment of FDAMA. According to a recent survey,
contract research organizations, which conduct pediatric trials for drug
sponsors, are working on over 100 pediatric studies involving 7,000
patients. 9 In addition, two of the largest contract research groups have
established pediatric- specific research ventures, which collectively can
call on the services of 500 doctors with pediatric training and nearly 2000
investigators.

While the new information generated by the increasing number of pediatric
studies has resulted in a variety of benefits, the cost of granting
additional market exclusivity can be very large. The cost to the public of
providing the brand named drugs with an additional 6 months of market
exclusivity presents a delay in consumer access to lower- cost generic
drugs. Delaying access to lower cost generic drugs increases health care
spending overall and may be particularly burdensome for those without
prescription drug coverage that must pay for the drugs out- of- pocket. FDA
estimates that the delay in availability of generic drugs could increase
national drug spending by about one half of one percent, or on average about
$695 million per year over a 20- year period. 10 The Agency did not attempt
to develop a quantitative estimate of cost savings from improved health
outcomes at this time.

While the pediatric exclusivity provision is working better than previous
efforts to stimulate pediatric drug research, two important challenges
remain. First, the law does not ensure that research results are
incorporated into labels in a timely manner for drugs that are already on
the market once marketing extensions have been granted. Second, the law
provides no incentive to conduct pediatric research on drugs for which
patents and marketing exclusivity have expired.

The statute requires that FDA decide whether to grant the 6- month marketing
exclusivity within 90 days of receiving research results. The decision must
be based solely on whether the research meets the terms of

9 The Pediatric Studies Incentive: Equal Medicines for All , Christopher-
Paul Milne, Tufts Center for the Study of Drug Development, April 2001. 10
The Pediatric Exclusivity Provision, January 2001 Status Report to Congress,
Department of Health and Human Services U. S. Food and Drug Administration,
pages 15 through 17. Challenges for Label

Changes and OffPatent Research Remain

Page 9 GAO- 01- 705T Pediatric Drug Research

the written request. The sponsor is required to submit proposed label
changes with the study results, but the decision to grant the extension is
not contingent on reaching agreement with FDA on label changes.

Because it usually takes much longer than 90 days - often a year- to
evaluate study results and negotiate label changes with manufacturers, drugs
may be granted an additional 6 months of marketing exclusivity before
appropriate label changes have been determined. We found that it took on
average more than 9 months for FDA and sponsors to agree on label changes
for the 18 drugs granted exclusivity that have had label changes. This is
slightly faster than FDA?s goal of reviewing other, similar changes to
approved drug labels within 10 to 12 months. FDA officials told us that five
drugs have gone for more than a year without label changes after the sponsor
was granted exclusivity extension. In some cases, FDA officials said they
have had substantial difficulty in getting drug manufacturers to incorporate
unfavorable pediatric research results into drug labels.

We found a difference of opinion on whether a marketing extension should be
contingent on label changes. Some officials we interviewed suggested that
drug manufacturers should be required to incorporate results into label
changes within 1 year. Others have suggested that the 6month marketing
extension be contingent on agreement on label changes based on the pediatric
study results. PhRMA officials told us that the current requirement provides
their members with a degree of certainty that they will receive an
additional 6- months exclusivity when they successfully complete the
pediatric studies requested by FDA. They have suggested some policy changes
to ensure that label changes are agreed to more quickly after pediatric
studies are completed.

Another remaining challenge is obtaining research and label changes for
drugs on which the patent or marketing exclusivity has expired. The
pediatric exclusivity provision was not designed for off- patent drugs and
provides no incentive for drug sponsors to conduct research on these
products. According to FDA, patents have expired for many drugs that are
widely used in children but lack pediatric information in their labeling.
FDA?s analysis of 1994 data found that 6 of the 10 drugs most commonly
prescribed for children were off- patent. In addition, only 9 of the 180
offpatent drugs on FDA?s May 2000 list of priority drugs for pediatric
research have been issued written requests. Although NICHD has conducted
some pediatric research on off- patent drugs, there is no mechanism to
ensure that the findings are incorporated into drug labels. Currently, only
a drug sponsor can apply for a label change. NIH officials told us they
believe that

Page 10 GAO- 01- 705T Pediatric Drug Research

academic and NIH researchers should be allowed to assume the drug sponsor
role to negotiate with FDA to incorporate research findings into labels for
off- patent drugs.

The pediatric exclusivity provision has been successful in encouraging drug
sponsors to generate needed information about how drugs work in children. A
wide range of drugs are being studied in many therapeutic areas. The
infrastructure for conducting pediatric trials also has been greatly
strengthened, which should help to support continued progress. While a
number of drug labels have been changed to incorporate findings from
research conducted under the pediatric exclusivity provision, label changes
typically occur long after FDA has granted the extension of market
exclusivity. In addition, there continues to be little incentive to conduct
pediatric research on off- patent drugs.

This concludes my prepared statement. I will be happy to answer any
questions that you may have.

For future contacts regarding this testimony, please call Janet Heinrich,
Director, Health Care- Public Health Issues, at (202) 512- 7119. Other
individuals who made contributions to this statement include Paul Cotton,
John Hansen, Claude Hayeck, Julian Klazkin, and Gloria Taylor.

(290048) Concluding

Observations GAO Contact and Acknowledgements
*** End of document. ***