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Implementation of the Pediatric Exclusivity Provisions

Statement of

Janet Woodcock, M.D.
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services


the Senate Committee on Health, Education, Labor, and Pensions

May 8, 2001


Mr. Chairman and Members of the Committee, I am Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA or the Agency). I appreciate the opportunity to discuss FDA's role with respect to implementation of the pediatric exclusivity provisions.

In 1997, as part of the Food and Drug Administration Modernization Act (FDAMA) (Pub. L. 105-115), Congress enacted a new provision that provides marketing incentives to manufacturers who conduct studies of drugs in children. This law, which provides six months exclusivity in return for conducting pediatric studies, is commonly known as the pediatric exclusivity provision.

From the inception of this program the industry has responded enthusiastically to the incentives offered in the pediatric exclusivity provision. FDA continues to believe that this program holds the promise of significantly expanding children's access to and safe use of important therapeutics.

The report, required by statute, on the experiences under the pediatric provision was submitted to Congress in January 2001. As described in the report, the pediatric exclusivity provision has been highly effective in generating pediatric studies on many drugs and in providing useful new information in product labeling. Some categories of drugs and some age groups remain inadequately studied, however, despite the new incentives. I will address these issues and update the Agency's progress in implementing the pediatric provision.


Children suffer from both child specific diseases and diseases that also occur in adult populations. In both cases, children, by necessity, are often treated with the same drugs as those used to treat adults. Even today, only a small fraction of all drugs marketed and used as therapies for children in the United States (U.S.) has been studied in pediatric patients, and a majority of marketed drugs are not labeled, or are insufficiently labeled, for use in pediatric patients. Safety and effectiveness information for the youngest pediatric age groups is particularly difficult to find in product labeling. This is a particular concern as it is this youngest population that is undergoing marked physiologic and developmental changes which are affected by drug therapies. The absence of pediatric testing and labeling poses significant risks for children. Without appropriate testing and labeling, inadequate dosing is likely to occur. Inadequate dosing information exposes pediatric patients to the risk of adverse reactions that could be avoided if such information were provided in product labeling and may reduce the benefits that could be gained if the therapy were properly dosed. In addition, pediatric patients may be denied the ability to benefit from therapeutic advances because physicians choose to prescribe existing, less effective medications in the face of insufficient information about the use of a new medication in the pediatric population. The failure to produce drugs in dosage forms that can be used by young children (e.g., liquids or chewable tablets) also can deny them access to important medications.

FDA implemented a number of largely voluntary measures in the early 1990s to encourage the submission of pediatric labeling information. These failed to produce significant increases in pediatric labeling. In August 1997, FDA proposed a regulation that would require manufacturers of new and marketed drugs and biological products to conduct pediatric studies in some circumstances.

In November 1997, Congress enacted FDAMA, which contains the provision establishing economic incentives for conducting pediatric studies. The pediatric exclusivity provision provides six months of exclusivity to be attached to any existing exclusivity or patent protection on a drug for which FDA has requested pediatric studies and where the manufacturer has conducted such studies in accordance with the requirements of the provision.

After the passage of FDAMA, FDA finalized its regulation requiring pediatric studies for new drug and biologic applications in some circumstances (Pediatric Rule) (Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule (63 Federal Register 66632; December 2, 1998).

The Pediatric Rule, proposed in 1997, finalized in 1998, and effective on April 1, 1999, requires that manufacturers of certain new and marketed drugs and biological products conduct studies to provide adequate labeling for the use of these products in children. Under this regulation, FDA can require pediatric studies of a new drug or biological product if the product is likely to be used in a "substantial number of pediatric patients" or would provide a "meaningful therapeutic benefit" to pediatric patients over existing treatments. FDA also can require pediatric studies of marketed drugs if either of these conditions applies and inadequate labeling could pose significant risks. The term "meaningful therapeutic benefit" is defined as a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population (Title 21, Code of Federal Regulations "314.55(c)(5)). FDA considers the term "substantial number of patients" to mean 50,000 pediatric patients in the U.S. with the disease or condition for which the drug or biological product is indicated (63 Federal Register 66636).

Although the incentive provided by the pediatric exclusivity provision was expected to result in the submission of pediatric studies for many drugs, the Agency issued the final Pediatric Rule to complement the pediatric exclusivity provision and help ensure that future drug and biologic applications would include pediatric studies when they are warranted.


The Agency has implemented the pediatric exclusivity provision according to the requirements of FDAMA by:

  • publishing a list of drugs for which pediatric information may be beneficial;
  • working with sponsors to develop and issue Written Requests for pediatric studies;
  • reviewing submitted studies;
  • making exclusivity determinations; and,
  • submitting a Status Report to Congress in January 2001.

The Agency also has made organizational changes to support the implementation of the pediatric exclusivity provision, including assembling a Pediatric Team and creating a Pediatric Advisory Subcommittee. The Subcommittee has been convened four times since its creation to address broad ethical and scientific issues related to pediatric drug development.

Finally, the Agency has published several guidances to facilitate the implementation of the exclusivity provision:

  • Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act (original July 1998; updated September 1999)
  • Pediatric Oncology Studies in Response to a Written Request (Draft June 2000)
  • General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products (Draft November 1998)

In addition, the Agency also has produced a guidance ICH-E11, Clinical Investigation of Medicinal Products in the Pediatric Population (December 2000), developed at the international level, to address pediatric studies.

Current Program Operations

FDA has in place a Pediatric Team that coordinates all of the pediatric exclusivity activities. The Pediatric Team coordinates with the individual drug review divisions and assists with the review of the Written Requests by the Pediatric Implementation Team (PdIT). PdIT is composed of individuals from various disciplines within the Agency and members of the Pediatric Team. The Pediatric Team serves as a resource for the entire Agency for pediatric issues and maintains both the databases relevant to exclusivity activities and Web based communications.

After a Written Request is issued, a sponsor will work with the review division to begin studies in accordance with the Written Requests. These may be amended or proceed as requested by FDA. Implementing the requirement in "505A(d), Federal Food, Drug, and Cosmetic Act (FD&C Act), that pediatric studies be reported in accordance with FDA's filing requirements, the Agency requires that pediatric studies submitted for exclusivity be submitted as new drug applications (NDA) or as supplements to the sponsor's approved or pending NDA, with proposed labeling. When the sponsor completes the studies requested in the Written Request, these are submitted to the appropriate review division. Thus, there are, in effect, two review processes. There is a review to determine if the elements of the Written Request are included in the submission. There is also the review of the supplement or NDA which follows the Agency's standard drug review process. The division responsible for the drug being studied, initially reviews the submission to determine if the terms of the Written Request have been satisfied. The division presents its findings to the Pediatric Exclusivity Board (PEB). This board is composed of individuals from the Agency. Based on the information provided by the division, the PEB either makes an exclusivity determination or requests additional information. Within 90 days of a sponsor's request for a pediatric exclusivity determination, FDA makes a determination if the studies fairly respond to the terms of the Written Request. If the determination is that the sponsor's submission satisfies the Written Request, the six months pediatric exclusivity is granted at that time. Thus, the six months exclusivity for the active moiety could be granted even before the review of the submitted labeling changes. It should be noted that this does not mean the supplement or the NDA is approved or that it is guaranteed approval. The reviewing division must still approve the change. In conjunction with the review of the change, labeling changes also are determined.

List Publication

Section 505A(b), FD&C Act, required FDA, after consultation with experts in pediatric research, to develop, prioritize, and publish an initial list of approved drugs for which additional pediatric information may produce health benefits in the pediatric population. The initial list was developed as required and published on May 20, 1998. The list contained all drugs approved for use in adults for indications that occur in the pediatric population.

FDA also prioritized the list. To be included on the initial priority list the drug had to meet one of the following criteria:

  • The drug product, if approved for use in the pediatric population, 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; or,
  • The drug had to be widely used in the pediatric population, as measured by at least 50,000 projected uses per year; or,
  • The drug was in a class or for an indication for which additional therapeutic or diagnostic options for the pediatric population are needed.

The list has been updated annually as required by the statute. A drug need not appear on the priority section of the list to be eligible for pediatric exclusivity and FDA has generally issued Written Requests for pediatric studies without regard to a moiety's appearance on the list. FDA has issued Written Requests to products not on the list because the rapid development and approval of new products does not always coincide with the preparation of the annual list. In addition, a drug is removed from the priority list when the product has been studied and adequately labeled for use in the pediatric population.

Written Requests

Section 505A, FD&C Act, authorizes exclusivity for those pediatric studies submitted in response to a "Written Request" from the Secretary. A manufacturer that receives a Written Request is under no obligation to conduct a study. A manufacturer that submits a pediatric study, however, is not eligible for pediatric exclusivity unless the study was submitted in response to a Written Request, and it is determined that the study fairly responds to the Written Request.

To ensure that studies eligible for pediatric exclusivity provide meaningful safety and effectiveness information on the use of the drug in relevant pediatric age groups, a Written Request addresses, among other things, the type of studies to be performed, study design, appropriate study age groups, and clinical endpoints. These issues have been discussed internally and by the Pediatric Advisory Subcommittee. The Written Requests cover a range of studies. Each Written Request usually has contained more than one study request and, as of April 1, the types of studies requested in the 188 issued Written Requests have included the following:


137 (33%)
123 (30%)
36 ( 9%)
82 (20%)
38 ( 9%)

A study for efficacy is designed to show that the drug will work for its intended use. A safety study would show that the drug used at a certain drug level is safe for its intended use and determines risk. Both safety and efficacy studies may require controlled clinical trials. A PK (pharmacokinetic) study measures the levels of the drug in a person's blood and the general rate of absorption, distribution and elimination. A PD (pharmacodynamic) study will study the action of the drug on the body and how the body will react to the drug.

To help focus on issuing Written Requests for studies that manufacturers were interested in conducting, FDA asked interested sponsors to submit a Proposed Pediatric Study Request (PPSR). In some cases, FDA has issued Written Requests to sponsors on its own initiative. These include active moieties for which no PPSR has been received and FDA believes that the pediatric information is needed for the product.


The pediatric exclusivity provision has been highly effective in providing pediatric information for many drugs. In general, the industry's response has been vigorous and the public health benefits have been extensive.

Pharmaceutical Industry's Response

The response from the pharmaceutical industry to the pediatric exclusivity provision has been vigorous. Between the publication of the guidance in July 1998 and April 1, 2001, there has been the following activity in the pediatric program:


Proposals from sponsor
FDA-issued Written Requests for pediatric studies
Written Requests that have Proposed Pediatric Study Requests
Incomplete letters (issued instead of a Written Request in response to a Proposed Pediatric Study Requests)
Amendments to the Written Requests (usually the result of negotiation between FDA and sponsor)
Number of products with submitted pediatric studies
Number of products granted pediatric exclusivity

The Written Requests cover a broad range of diseases and conditions, including a number of life-threatening conditions and very common childhood illnesses. A complete list of the active moieties can be found at www.fda.gov/cder/pediatric/ wrlist.htm. The Written Requests have included drugs that treat such diseases as HIV, juvenile rheumatoid arthritis, seizures, diabetes, hypertension, gastroesophageal reflux, obsessive compulsive disorder, allergies, and fever.

Sponsors have indicated that they have conducted, or will conduct, 80 percent or more of the studies that FDA has requested. In contrast, before enactment of the pediatric exclusivity provision, few of the pediatric studies requested by FDA were completed. Over a six-year period between 1991 and 1996, drug sponsors promised to complete 71 postmarketing pediatric studies yet only 11 were completed.

Public Health Benefit

The purpose of encouraging pediatric studies is to provide needed pediatric efficacy, safety and dosing information to physicians in product labeling. Of the 28 drugs granted pediatric exclusivity, 18 drugs have newly approved labeling for pediatric use. Labeling changes are expected approximately 6-12 months after the studies have been submitted.

Of the 18 drugs whose labels have already been changed four were new molecular entities for which pediatric labeling was available at the time of initial approval. The 14 remaining marketed products now have complete labeling in the relevant pediatric population.

Studies of six of these 18 products resulted in identification of significant changes in dosing or adverse events either specific to or newly defined in the pediatric population.

With the first 18 new pediatric labels, we have identified the following significant information if drugs are to be used safely in children:

  • Midazolam (Versed) - higher risk of serious life threatening situations in children with congenital heart disease and pulmonary hypertension who need lower doses than predicted to prevent respiratory compromise;
  • Propofol (Diprivan) - increased mortality when used for pediatric ICU sedation;
  • Gabapentin (Neurontin) - need to use higher doses in children less than five years of age in order to control seizures and new adverse events such as hostility and aggression identified in children less than 12 years old;
  • Fluvoxamine (Luvox) - inadequate dosing of adolescents leading to ineffective therapy or no effect for Obsessive Compulsive Disorder while girls ages 8-11 years were being potentially overdosed;
  • Etodolac (Lodine) - recognition of a need for a dose two to three times (in mg/kg) the dose used in adults for effective treatment of childhood arthritis;
  • Sevoflurane (Ultane) - new precaution about the potential of the product to cause seizures in children without a previous history of such.

There have been a number of drugs (five), however, for which more than a year has passed since pediatric exclusivity was granted and for which no label changes have yet been finalized. Label changes for these products are still pending.

Ethical Issues

Concerns have been raised about the increased number of children being enrolled in clinical trials and the ethical issues that poses. FDA is very aware of these ethical issues and concerns and has taken steps to assure the public that the protection of children who participate in clinical trials is of paramount concern. Pediatric Advisory Subcommittee meetings have addressed a number of these issues including:

  • children as volunteers vs. patients
  • placebo controlled trials
  • trial design and data analysis
  • subpart D of Health and Human Services" regulations
  • vulnerable pediatric populations

FDA's Office of Human Research Trials also participates in oversight of the involvement of children in clinical trials. In addition, on April 24, FDA published an interim rule Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products, 66 Federal Register 20589 (April 24, 2001). The rule is intended to bring FDA into compliance with the Children's Health Act of 2000 (Pub. L. 106-310) and to address the continued increases in the enrollment of children in clinical investigations because of the Pediatric Rule and the pediatric exclusivity provision. Specifically, the rule establishes additional safeguards for children in clinical trials and coordinates these regulations with other Health and Human Services regulations on human subject protection requirements for children enrolled in clinical trials.


In general, the pediatric exclusivity provision has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative initiative to date. There are still some issues to consider in reviewing the operation of the program.

Pediatric List

FDA is required to maintain a prioritized list of drugs for this program under "505A(b), FD&C Act. Section 505A, FD&C Act, does not require that a drug be on the priority list to qualify for pediatric exclusivity. In practice, FDA review divisions are now considering every proposal for pediatric studies under "505A, on its individual merits, regardless of whether the product is on the priority list. The incorrect assumption that inclusion on the priority list is necessary to obtain exclusivity has been a source of confusion to drug sponsors and others. Products that have not been studied in children after remaining on the priority list for the first five years of the program may never be studied for pediatric populations.

Second Six-Month Period of Pediatric Exclusivity

Section 505A(h), FD&C Act, which authorizes a second grant of exclusivity, is limited in scope. FDA understands that "505A(h) limits second extensions of exclusivity to a very limited set of drugs. Those drugs that have obtained three years of exclusivity for making a change in an already approved product, e.g., adding a new indication, if the application was supported by clinical trials, are the only drugs eligible.

Written Agreement

Because compliance with the terms of the Written Request is required for the exclusivity award, some drug sponsors expressed initial interest in Written Agreements to try to eliminate ambiguity in a Written Request and minimize the risk of loss of exclusivity based on a misinterpretation of the terms of the Written Request. When a Written Agreement is in place, the terms of both the Written Request and the Written Agreement must be satisfied before pediatric exclusivity can be awarded. The more details agreed to in the Written Agreement, the greater the chance that the final studies will fail to meet its terms. After initial efforts to develop Written Agreements, it became clear that to prevent any possible misinterpretation, a Written Agreement must become long and cumbersome. In practice, the Written Agreements make it harder rather than easier for sponsors to earn exclusivity, the Agency has negotiated fewer than five Written Agreements and completed only two.

Drugs For Which Sequential Pediatric Studies Are Necessary

Many drugs of importance to children need to be studied in more than one pediatric age group because size and maturation of body systems can affect both dosing and side effects. For some drugs, such as neurotropic drugs, heightened safety concerns about exposure of neonates, infants and young children to the drugs have dictated that studies in these age groups be deferred until additional information is available from animal studies, studies in older children, or wider use in adults. In these settings FDA has granted pediatric exclusivity upon completion of the studies in the older pediatric age groups.

Once pediatric exclusivity is granted for the studies conducted in older pediatric age groups, there is not an adequate incentive to conduct additional studies in the younger age groups. This has left some age groups, especially neonates, unstudied, even though the need for the drug in those age groups is great.

Drugs Lacking Exclusivity or Patent Protection

Sponsors of marketed products that have no remaining patent life or exclusivity have no economic incentive under the existing exclusivity provisions to study these products. Many such products, however, have important uses in children and have not been adequately studied. For example, dopamine is a very important drug used in the treatment of serious life-threatening conditions (i.e., hypotension, heart conditions). It will most likely not be studied due to the lack of exclusivity or patent protection. So, too, old antibiotics are ineligible for the pediatric exclusivity incentive because these were never eligible for patent listing or exclusivity. Many of these antibiotics have the potential to provide a significant clinical benefit in the pediatric population.


The incentives provided by the newly authorized pediatric exclusivity should continue to lead to significant advances in pediatric medicine.

Superior drug treatment information is expected to permit quicker recoveries from childhood illnesses, with fewer attendant hospital stays, physician visits and parental work days lost, but could increase certain prescription drug prices.

The increase in the number of pediatric clinical trials for FDA-regulated products clearly has resulted in information valuable for the use of drugs in the pediatric population. FDA wants to build on these improvements with more studies and new labeling information. There are still a large number of drug and biological products that are inadequately labeled for children. We want to persist until these are all studied.

FDA wants to work with Congress to ensure that the benefits of an incentive program continue as they consider the reauthorization of the pediatric exclusivity program.

Thank you for your interest in pediatric medicine and the health of children.