Trials for Pediatrics and Proteins Under Debate

Legislation designed to encourage pharmaceutical companies to underwrite research on drug use in children requires Congressional reauthorization this year, generating talk of revising the system. Research sponsors say the current incentives are working fine and are needed to encourage more studies, but generic drug makers and some health care providers claim that added exclusivity for brands drives up the cost of medicines.

Jill Wechsler

Efforts to make prescription drugs more affordable also is spurring a campaign to authorize the FDA to establish a pathway for approving generic or follow-on versions of biotech therapies. Amidst the debate over costs and exclusivity, the need for clinical trials on follow-on biologics is emerging as a key issue.

Spurring research in children

Incentives and requirements for pediatric studies expire September 30, 2007, and pressure is building to extend these programs. The Best Pharmaceuticals for Children Act (BPCA) grants an added six-months exclusivity to manufacturers that conduct postmarket research likely to generate new labeling on correct drug use in children. This 10-year-old policy is hailed as a great success, having generated some 800 studies that have resulted in labeling changes for more than 100 drugs.

The legislation also established a program at the National Institutes of Health (NIH) to underwrite pediatric research on drugs with expired patents that do not draw manufacturer support, but this has been less productive.

In addition to the BPCA "carrot," the Pediatric Research Equity Act (PREA) of 2004 provides a "stick" to spur research by giving FDA authority to require pediatric studies of some drugs under development. Sen. Chris Dodd (D-CT), who is the main proponent of both programs, has also introduced legislation providing incentives for developing medical devices designed for children.

The campaign to maintain incentives for pediatric studies has generated debate over a number of provisions. BPCA and PREA both have to be reauthorized every five years, and sponsors claim that uncertainty about the incentives deters some research. However, Dodd and most policy makers want to maintain the five-year sunset on the exclusivity program, but support legislation sponsored by Sen. Hillary Clinton (D-NY) to make the PREA pediatric rule permanent. At a hearing held by the Senate Health, Education, Labor and Pensions (HELP) Committee in March, Richard Gorman, MD, of the American Academy of Pediatrics (AAP) backed additional changes to increase transparency of pediatric study results and FDA's process for managing the research and exclusivity awards.

The main issue, though, is whether the current six-month exclusivity program provides a big windfall to marketers of blockbuster drugs. Patient advocates, generic drug makers, and some medical groups want to reduce exclusivity to three months, particularly for products with sales over $1 billion or other thresholds. Democrats added such a change to legislation to continue the prescription drug user fee program. That provides critical support for the FDA drug approval process and is considered "must pass legislation" before it expires this fall.

Gorman of AAP advised that any such change should be carefully analyzed to ensure it does not reduce the number of drugs studied in children. Dodd backed exclusivity for blockbuster drugs, despite industry cautions that "if it's not broke, don't fix it."

Trials costly

Support for reauthorizing BPCA and PREA comes from a Government Accountability Office (GAO) report issued in March that documents the success of BPCA in spurring industry-sponsored pediatric research and important drug labeling changes. From 2002 to 2005, the legislation prompted FDA to issue more than 200 written requests for pediatric studies, and sponsors agreed to conduct the requested research on 173 of them.

Although most of the studies were still ongoing, the program produced more than 50 exclusivity determinations during that period, and most (87%) of those exclusivity awards led to labeling changes for drugs that treat a wide range of diseases, including some life-threatening conditions for children.

However, GAO noted that the FDA process of approving labeling changes resulting from the studies was often lengthy and cumbersome.

Moreover, the analysts were critical of the NIH program to fund research on those drugs that fail to draw industry sponsorship. FDA had requested that the nonprofit Foundation for NIH study nine drugs that industry declined to take on, but only one research project may result. The problem is that NIH calculated it would cost more than $40 million to study six of the nine drugs and the Foundation had raised only $1 million for the program through 2005. The high cost of pediatric clinical trials appears to be taking a toll on the program.

A March report from the Tufts Center for the Study of Drug Development documents a sharp rise 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 increase research expenditures. And problems recruiting child volunteers for desired studies prompt sponsors to try to renegotiate the scope of requested research with FDA.

An article by Duke University researchers published in the Journal of the American Medical Association in February similarly reported that pediatric studies for nine drugs cost from $5 million to $44 million. The article concluded that the pediatric exclusivity program may over-compensate a few companies that conduct pediatric research on blockbusters, but that most products gaining exclusivity realize only modest returns on their investment.

The rise in research costs and user fees on pediatric study applications provides ammunition for those who claim that a reduction in exclusivity will curb industry enthusiasm for tackling pediatric study proposals, especially on small-market drugs. However, Congressional leaders appear intent on curbing any windfalls for drug makers from this program.

Trials for follow-ons

In addition to limiting exclusivity for pediatric studies, 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. However, this more contentious issue may take more than a few months to resolve. A key issue is whether clinical trials are needed to bring a follow-on to market.

Innovator drug firms claim that any biologic produced by a different company must submit data from clinical studies to demonstrate "sameness" and rule out clinically significant differences. Generic firms maintain that advances in analytical testing can ensure comparability and safety of similar versions of large molecules. This is important, they maintain, because the resulting market competition will greatly reduce the cost of important therapies for patients.

FDA officials say that 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 at a hearing in March held by the House Oversight and Government Reform Committee.

Such research requirements could range from small pharmacokinetic studies to larger randomized trials. However, if clinical trials are not needed, Woodcock commented, it may be unethical to require them. FDA requested additional clinical testing for Sandoz' Omnitrope follow-on, but not as much as provided originally by the innovator.

A related issue is whether the manufacturer of a follow-on product could submit enough clinical trial evidence for the new drug to be rated therapeutically equivalent to an innovator biologic. Documenting comparability is quite challenging, but "ensuring interchangeability is essentially impossible," commented former FDA official Jay Siegel, now with Johnson & Johnson, at a hearing before the Senate HELP Committee.

Even with many added studies, Omnitrope did not get a therapeutically equivalent rating from FDA. To demonstrate substitutability, Woodcock said that the follow-on sponsor may need studies showing that repeated switches between the innovator and the follow-on has no negative effects on patients.

FDA envisions a case-by-case approach to testing and evaluating comparability of follow-ons, similar to the approach adopted by European regulators for "biosimilars."

FDA is developing long-awaited guidance to clarify what data it recommends for developing new versions of fairly well-characterized biologics, such as human growth hormone and insulin. Evaluation of follow-ons will be complex and time-consuming, but Woodcock says FDA has the expertise to make the hard decisions that will arise, as policies governing follow-ons gradually evolve over the next decade.

While policy makers have agreed on many of the core issues related to follow-on approvals, continued debate on exclusivity and testing may delay adoption.

Jill Wechsler is the Washington editor of Applied Clinical Trials (301) 656-4634 jwechsler@advanstar.com