Separately, in 1998 the National Institutes of Health adopted a policy requiring all research proposals applying for NIH funding to include children in studies and to follow standards to ensure ethical treatment of young study subjects.

These actions have vastly increased the number of clinical trials and the number of young participants involved in clinical studies. Such developments have raised a host of ethical and operational issues related to clinical trial procedures and policies that continue to challenge policy makers.

Stimulating studies
By most counts, the pediatric exclusivity policy established by the FDA Modernization Act of 1997 (FDAMA) has been a major success. As of March 2002, FDA had received 300 proposed pediatric study requests from manufacturers and had issued 241 “written requests” for such studies, which FDA says could potentially involve more than 32,000 children. As a result of reports from these studies, the agency granted exclusivity to 56 drugs and gained pediatric labeling for 31 of them. FDA considers 9 of the 31 pediatric labels to provide “significant changes” for dosing, safety, or use. In addition, studies show that certain products are not recommended for pediatric use.

To continue the program past its five-year “sunset” date at the end of last year, Congress approved the “Best Pharmaceuticals for Children Act” (BPCA), which was signed into law in January 2002. It extends the program until 2007 and contains numerous initiatives to further encourage pediatric research. A key provision permits FDA to collect user fees for reviewing pediatric supplements, which will allow the agency to consider these “priority” supplements that merit speedy assessment.

The BPCA also authorizes the federal government to fund pediatric studies for drugs and other medical products that lack patent protection or sufficient sales to prompt private sector research. A major shortcoming of the voluntary pediatric program is that many therapies—antibiotics, off-patent products, orphan drugs—offer little financial incentive for a sponsor to conduct additional studies on children. The legislation provides $200 million to support research on such therapies by NIH and calls for FDA to develop a list of approved drugs that could benefit from additional pediatric studies that industry is unlikely to undertake.

The legislation also calls for FDA to establish a new Office of Pediatric Therapeutics in the Commissioner’s office to coordinate all FDA pediatric issues and activities. This office will oversee the Office of Pediatric Drug Development and Special Initiatives in the Center for Drug Evaluation and Research (CDER), which was established last September. Dianne Murphy, who formerly headed CDER’s pediatric team, directs the current CDER office, which will have more resources from user fees to oversee an expanding number of pediatric clinical trials.

Other provisions in the bill aim to facilitate pediatric studies by calling for sponsors to submit to FDA plans for conducting pediatric research during the IND (investigational new drug) study phase. The legislation creates a Pediatric Pharmacology Advisory Committee and adds language to encourage studies on neonates and on minority groups. Congress also includes provisions in BPCA to encourage research on cancer therapies for children, building on FDAMA provisions that FDA clarified in a guidance published in June 2000. BPCA calls on the National Cancer Institute to develop preclinical models for evaluating pediatric cancer therapies and to coordinate NIH research in this area. FDA and NIH will report to Congress next January on how these and other initiatives further patient access to new pediatric cancer therapies.

Keeping the rule
In addition to providing incentives for industry to study new drugs in children, FDA also finalized its “Pediatric Rule” in 1998, which authorizes the agency to require sponsors to submit pediatric data in all new drug applications (NDAs). Industry has objected that the FDAMA exclusivity provisions make the rule unnecessary, but FDA and pediatric researchers believe that having the rule on the books encourages voluntary action. Even though the agency has not had to use the rule to require specific pediatric studies for new drugs, the policy has provided a basis for FDA to deny suitability petitions for new dosage forms of existing products without pediatric data.

The need for the rule and its relationship to the exclusivity program sparked a heated debate a few months ago when FDA proposed to suspend it for two years while reevaluating how it is affected by BPCA. FDA proposed such action to delay a court ruling on a lawsuit filed two years ago by free-market advocacy organizations challenging FDA’s authority to mandate pediatric studies. FDA said that it feared the court would kill the pediatric rule altogether, but critics considered the suspension plan a move by FDA to gut the policy. A group of U.S. senators called for legislation to codify FDA’s authority to require companies to test medical products on children. In response, FDA backtracked and issued a Federal Register notice [Federal Register, 67 (79), 20071 (24 April 2002)] asking interested parties to address several issues that it will have to consider in implementing BPCA.

The main question is whether the new BPCA program for funding research on therapies that manufacturers decline to study provides a better way to obtain pediatric labeling information than FDA’s attempt to coerce such action by manufacturers under the pediatric rule. Proponents of retaining the rule point out that the BPCA “gap” provision still does not extend to biologics and certain antibiotics, and that resources to support government-funded pediatric research rely on continued Congressional appropriations. FDA is asking whether there is redundancy in its pediatric research policies and what approaches might best help the agency acquire pediatric labeling information:

• What changes are needed to integrate the BPCA and the pediatric rule more effectively?
• Are there differences in the criteria to request studies of already approved drugs under the exclusivity program and the pediatric rule, and which criteria are more appropriate?
• What provisions in the exclusivity program could apply to biological products?
• How should FDA deal with provisions in BPCA and the rule for recommending changes in product formulation?

Continuing controversies
Another highly contentious issue is whether the pediatric exclusivity program harms the public by delaying for six months when a new generic drug can come to market. Generics manufacturers have complained that pediatric patent extensions boost expenditures on prescription drugs by billions and provide windfalls for innovator firms that spend relatively small amounts to fund pediatric studies. Attempts by some innovator firms to use pediatric labeling issues to further delay generic drug entry led to loud debate on the issue.

In the end, compromise language was added to BPCA to permit a new generic drug on the market without full pediatric labeling, provided it states that the generic product is not labeled for pediatric use. The legislation also clarifies the relation between pediatric exclusivity extensions and the 180-day exclusivity provided to the first generic drug to come to market.

Congress will revisit this and other issues in coming years with support from an extensive cost-benefit analysis of the pediatric exclusivity program by the General Accounting Office (GAO). BPCA calls for GAO to assess by October 2006 the benefits of added pediatric labeling compared with costs in the form of higher expenditures caused by delayed generic competition:

• Number and importance of pediatric drugs tested and not tested under the exclusivity program.
• Economic costs based on higher expenditures by Medicaid and other government programs; sales of innovator drugs during six-month exclusivity periods; and loss of revenue by the generic drug industry and retail pharmacies.
• Benefits to consumers and the health-care system from added pediatric labeling as seen in decreased hospitalizations, reduced medical errors, fewer physician visits, lower health insurance premiums, lower treatment costs, and less missed time from school and work.
• Nature of pediatric studies for each drug granted exclusivity, including number of study sites, number of children involved in studies, and estimated cost of studies.
• Expansion of public and private pediatric research capability related to the program.
• Role of government in implementing program, including processing written requests and developing priority research lists.

FDA examined the economic impact of the pediatric incentive program on the public in its January 2001 Report to Congress, providing a base for GAO’s analysis. With many promising therapies being produced by molecular biology, a key issue for FDA and the research community to address is the need for pediatric dosing information for biologics. Another thorny issue is how to encourage manufacturers to study new uses of an approved drug in children if a sponsor can gain only one six-month pediatric exclusivity extension. FDA actions to implement BPCA and to re-evaluate the pediatric rule may be affected by court decisions and further congressional action.

SIDEBAR: Pediatric Research Issues

The significant increase in the number of children participating in clinical trials continues to raise ethical and procedural concerns. Congress addressed some of these issues in the Children’s Health Act of 2000, which requires all research involving children that is funded or regulated by the Department of Health and Human Services to comply with federal standards for research on children established by the “Common Rule.” FDA issued a rule last year (April 2001) to implement these provisions. It calls for institutional review boards (IRBs) to review study protocols that include children to ensure that they adopt safeguards to protect young research participants.

The Institute of Medicine (IOM) is examining these issues further in a study on research policies and “best practices” related to research involving children. This two-year study required by BPCA will address:

• Process for obtaining informed consent and assent from children and their parents or legal representatives.
• How well participants in pediatric studies and their guardians understand direct benefits and risks of study involvement.
• Definition of “minimal risk” related to healthy and ill child study participants.
• Whether regulations and policies should vary for children of different ages (for example, teenagers and infants).
• Appropriateness of payments to children, parents, or legal representatives for participation in research.
• Role of IRBs in monitoring compliance with regulations related to pediatric studies.

—Jill Wechsler, Washington Editor