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

 Under $120 M

$120 M - $199 M

$200 M - $399 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 6-

month 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