Policymakers weigh incentives for pediatric studies and policies to allow generic versions of biotech therapies


Pediatric exclusivity program and generic biotech therapies as related to PDUFA IV.

Key Points

Legislation designed to encourage pharmaceutical companies to underwrite research on drug use in children (the pediatric exclusivity program) requires congressional reauthorization this year, which could open the door to policy changes. Many research sponsors say the current incentives are working fine and are necessary to encourage additional studies, but generic drug makers and some healthcare providers claim that added exclusivity for brands will drive up drug costs.

Efforts to make prescription drugs more affordable also are helping trigger a campaign to authorize FDA to establish a pathway for approving generic, or follow-on, versions of biotech therapies. Advocates for follow-on versions maintain that new competitive products will be more affordable than branded products, but the costs will depend, in part, on how much testing FDA would require and whether new treatments would be suitable substitutes for current treatments.


A March 2007 report by the Government Accountability Office (GAO) provides evidence of BPCA's positive impact. From 2002 to 2005, the legislation prompted FDA to issue 214 written requests for pediatric studies. A total of 173 requests were honored by drug sponsors, yielding more than 50 exclusivity determinations; most (87%) of those patent extensions led to labeling changes for pediatric use of drugs that treat a wide range of diseases, including some life-threatening conditions for children. During the program's 10-year history, FDA requests have resulted in approximately 800 studies by pharmaceutical companies, which have led to labeling changes for more than 100 drugs.

In addition to the BPCA "carrot," the Pediatric Research Equity Act (PREA) of 2004 provides a "stick" to prompt research by authorizing FDA to require pediatric studies of some drugs under development. That bill is also up for reauthorization and has broad support from Congress, drug manufacturers, and healthcare providers. Sen Christopher Dodd (D–Conn), who is the lead proponent of the pediatric research program, has also introduced legislation that would provide incentives for the development of medical devices designed for children.


The campaign to retain incentives for pediatric studies has generated debate over a number of provisions. BPCA and PREA both require reauthorization every 5 years, and sponsors claim that uncertainty about the incentives deters some research. Sen Dodd and most policymakers want to maintain the 5-year sunset on the exclusivity program, but they support a measure sponsored by Sen Hillary Clinton (D-NY) to make the PREA rule permanent.

At a hearing held by the Senate Health, Education, Labor, and Pensions (HELP) Committee in March, Richard Gorman, MD, a representative for the American Academy of Pediatrics (AAP), expressed support of permanent status for PREA but said that it would be useful to reevaluate the exclusivity program periodically to ensure that it strikes "the right balance" between producing critical pediatric information and providing appropriate rewards to manufacturers.

This speaks to the main issue under debate: whether the current 6-month exclusivity program provides a large windfall to marketers of "blockbuster" drugs. Patient advocates, generic drug makers, and some medical groups want to reduce exclusivity to 3 months, especially for products with sales of more than $1 billion.

An article by researchers at Duke University published in the Journal of the American Medical Association (JAMA) concluded that a few companies that conduct pediatric research on blockbuster drugs may be overcompensated by the pediatric exclusivity program, but that most manufacturers gaining product exclusivity realize only modest returns on their investment.


Besides the exclusivity and sunset issues, the need to reauthorize both BPCA and PREA together provides an opportunity to enact a coordinated legislative package that could improve the program. The GAO report described several flaws in current law, such as a lengthy and cumbersome FDA process for approving labeling changes resulting from the studies and too little research involving newborns. Dr Gorman urged additional revisions in the program to better inform patients and healthcare providers of the label changes resulting from pediatric studies and to increase the transparency of FDA's process for managing research and exclusivity awards.

Despite the overall achievements of the program, the high cost of pediatric clinical trials appears to be taking a toll on pediatric research. A March report from the Tufts Center for the Study of Drug Development documented a sharp increase in pediatric research costs from nearly $4 million in 2000 to $30 million in 2006, and a doubling in the time it took to conduct studies on children. FDA requests for more trials and longer studies are the main factors in boosting research expenditures, as are the difficulties associated with recruiting child volunteers. The argument has been made that any reduction in exclusivity will curb industry enthusiasm for tackling pediatric study proposals, especially on small-market drugs.

Despite some problems with the program, the studies generated by BPCA and PREA provide important information on how "children's differing metabolism, growth, and development and size have very large effects," Dr Gorman said. "Children are not just small adults."

According to Dr Gorman, much more research is still required as nearly two-thirds of drugs used in children are still not labeled for them, and nearly 80% of hospitalized children receive at least 1 drug prescribed off-label. "For children, off-label use is the rule, not the exception," he said, because of a continued scarcity in pediatric prescribing information.


Sen Dodd and his colleagues succeded in adding the pediatric research reauthorization provisions to legislation that would continue the prescription drug user fee program, which policymakers have moved through the Senate in an effort to gain approval before the program expires this fall.

Generic drug makers also would like the user fee bill to include a measure that authorizes FDA to approve follow-on versions of biotech therapies, an even more contentious issue that leading senators have agreed to tackle. The aim is to permit FDA to be able to approve similar biologics based on an abbreviated application that draws on test data developed by the innovator firm. The Hatch-Waxman Act established such a process for conventional drugs in 1984, but it does not apply to biologics regulated by the Public Health Service Act.

However, consulting firm Avalere Health, LLC, Washington, DC, estimated savings from the use of biogenerics of only $3.6 billion over 10 years. The analysts claim it will take years for manufacturers to develop, and for FDA to approve, new follow-ons, and that these products will cost more to test and produce than conventional generic drugs. Innovator drug firms say the additional costs are due to the requirement that any biologic produced by a different company be supported by data from clinical studies to demonstrate "sameness" and rule out clinically significant differences. These drug firms claim that if follow-ons are not interchangeable, physicians will be slow to prescribe them.

Manufacturers of generic drugs contend that advances in analytical testing can ensure comparability and safety of similar versions of large molecules and that resulting market competition will greatly reduce the cost of important therapies for patients.

FDA officials say the extent of additional studies should be based on the complexity of the product and its clinical use and experience. Clinical trials are not always the best way to assess product structural changes, some experts point out. "But some degree of clinical assessment of a new product's immunogenic potential will ordinarily be needed," said FDA deputy commissioner Janet Woodcock, MD, at a March hearing by the House Oversight and Government Reform Committee.

A related issue is whether enough clinical trial evidence could be provided by manufacturers of follow-on products to allow the products to be rated therapeutically equivalent to innovator biologics. Documenting comparability is quite challenging, but "ensuring interchangeability is essentially impossible," said former FDA official Jay Siegel, MD, currently with Johnson & Johnson, New Brunswick, NJ, at a hearing before the Senate Health Committee. Dr Woodcock said that to establish adequate substitution, the follow-on sponsor may need to conduct studies demonstrating that repeated switches between the innovator and the follow-on don't result in adverse effects.

FDA envisions a case-by-case approach to testing and evaluating comparability of follow-ons, similar to the policy adopted by European regulators for "biosimilars." FDA is developing long-awaited guidance to clarify which data it recommends be included when developing new versions of fairly well-characterized biologics, such as human growth hormone and insulin.

SOURCE Li JS, Eisenstein EL, Grabowski HG, et al. Economic return of clinical trials performed under the pediatric exclusivity program. JAMA. 2007;297:480–488.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.

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