FDA user fee renewal addresses drug shortages, new drug development

March 1, 2012

Every 5 years, Congress is called on to reauthorize a series of user fees that support FDA oversight of drugs and medical products. The Prescription Drug User Fee Act (PDUFA) and similar measures authorizing fees to fund a number of FDA regulatory programs have become increasingly vital for maintaining the agency's ability to maintain an efficient approval process for new therapies.

Key Points

Every 5 years, Congress is called on to reauthorize a series of user fees that support FDA oversight of drugs and medical products. The Prescription Drug User Fee Act (PDUFA) and similar measures authorizing fees to fund a number of FDA regulatory programs have become increasingly vital for maintaining the agency's ability to maintain an efficient approval process for new therapies.

This must-pass bill, however, creates a ready legislative vehicle for policy-makers to add on a host of pet FDA-related measures (see http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+Now/New-user-fee-renewal-legislation-will-include-new-/ArticleStandard/Article/detail/740587).

Last month, biomedical companies, providers, medical researchers, and FDA officials made the case for renewing user fees in hearings before the House Energy and Commerce (E&C) health subcommittee. Commissioner Margaret Hamburg, MD, explained the importance of reauthorizing PDUFA and legislation to spur pediatric drug labeling; Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER), addressed drug shortages and the need for new fees for generic drugs and biosimilars; and Jeffrey Shuren, MD, director of the Center for Devices and Radiological Health (CDRH), outlined a hard-fought agreement on the medical device user fee program (MDUFA).

SAFETY AND SHORTAGES

The most likely addition to the drug user fee package are measures enhancing FDA controls over the global drug supply chain, including stiffer import controls, more inspections of foreign manufacturers, and added requirements to help prevent drug shortages. Congress is expected to adopt some version of the drug safety legislation authored by Rep. John Dingell (D-Mich.), as both Democrats and Republicans want to boost inspections of foreign operators to level the playing field for US firms, and new user fees for generic drugs would provide necessary funding.

The legislators also backed proposals that require manufacturers to inform FDA earlier about situations likely to lead to drug shortages and to authorize fast FDA review of applications seeking to bring short-supply medicines to market. Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children's Research Hospital in Memphis, Tenn., described how drug shortages caused real difficulties in treating patients and urged enactment of legislation to enhance FDA's ability to combat and prevent these situations.

Dr Woodcock mapped out FDA efforts to prevent and alleviate shortages of critical medicines, noting that generic drug user fees will help get substitutes for short-supply products on the market more quickly. Generic drug-makers, in turn, highlighted a new voluntary program to provide more information on shortages of sterile injectible products.

MORE DRUGS FOR CHILDREN

Dr Greene also emphasized that drug shortage legislation should address the need for critical drugs for children. This concern fits efforts to reauthorize legislation that supports the testing of drugs for children as part of the PDUFA approval process. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are both up for 5-year renewals and have strong support from health professionals, researchers, and pharma companies. However, some reform proposals undermine incentives in the program for drug manufacturers to conduct necessary pediatric studies and could stymie the reauthorization process.

Pharmaceutical companies oppose many of these changes, particularly any reduction in the extra 6-months exclusivity they receive for conducting requested studies, or new penalties for failing to complete such research on schedule. Yet, there's support for providing FDA with additional tools for dealing with research delays. Under current policy, FDA's only "stick" to compel a sponsor to complete a requested study is to deem the product misbranded and pull it from the market, which no one wants to do. Authorizing civil monetary penalties seems a more effective way to improve compliance with pediatric study requests. At the same time, FDA officials acknowledge that often there are good reasons for pediatric research to take longer than anticipated, and that the agency should be able to grant deferrals when warranted.

Another strategy for accelerating development of pediatric labeling is for pharma companies to plan for studies in children earlier in the drug development process. The American Academy of Pediatrics (AAP) wants sponsors to submit proposed pediatric study plans at the end of phase 2, instead of waiting until application submission to outline study design, objectives, end points, and a timeline for completion. The pediatricians also want more studies to include neonates as well as older children. There's general agreement among researchers and sponsors that PREA requirements for pediatric studies should be made permanent, but the physicians support the Democratic position that the exclusivity provisions authorized by the BPCA should continue to be re-evaluated every 5 years.

In addition to providing more information on therapies for children, legislators are rolling out numerous proposals to spur development of critical therapies, including antibiotics to combat drug resistance and therapies for rare conditions. For example, there's bipartisan backing for the Spending Reductions through Innovations in Therapies (SPRINT) Act; it would provide $50 million to fund public-private partnerships doing research on critical conditions, such as Alzheimer's disease. However, both FDA and pharmaceutical companies are leery of bills that would prevent FDA from seeking necessary clinical data to approve a new drug, an approach backed by smaller biotech firms and patient groups as a way to achieve more certainty for drug development.

FDA's response is that several recent drug approval decisions illustrate that it can be flexible on setting data and study requirements for important experimental therapies. And the PDUFA V agreement includes a number of changes in FDA operations to facilitate new drug development. The updated program provides additional funding to support the validation of biomarkers, broader use of patient-reported outcomes, and use of innovative clinical trial designs that promise to enhance clinical evaluation.

CONFLICTS AND DISCLOSURE

Another drug development issue is whether to loosen conflict-of-interest (COI) requirements and raise caps on COI waivers to make it easier to appoint key experts to FDA advisory committees. Democrats and consumer groups object that permitting scientists with industry ties to serve on these important committees might undermine the panels' independence and impartiality.

Republicans and manufacturers claim that the current rules are too rigid and delay approvals when advisory panels have trouble filling their slots. They have support from orphan drug advocates who agree that FDA should only have to meet the financial disclosure rules that apply to all other federal agencies and not face added restrictions, which are particularly troubling in specialized research fields with a limited number of key scientists. Diane Dorman, vice president of the National Organization for Rare Disorders (NORD), told the House E&C panel that the current COI rules have created a system that is "out of balance" because "conflict avoidance"-and not unique expertise-is the primary driver of who serves on advisory committees.

However, Commissioner Hamburg said that the current COI policy is not a problem, and that it doesn't need a "legislative fix." Those comments differ from Dr Hamburg's testimony last year that the COI rules made it difficult to find sufficiently qualified individuals to serve on advisory committees.

Inadequate disclosure of clinical trial results could be another thorny issue. Some Democrats want to expand required postings on the http://clinicaltrials.gov/ website to include data from registered trials for drugs that are never approved. The rationale is that important information can be gleaned from dropped studies, but pharma companies oppose mandating disclosure of often-sketchy clinical results.

One issue that appears off the table is an overhaul of requirements for establishing Risk Evaluation and Mitigation Strategies (REMS). Pharma companies have complained that the proliferation of REMS programs delays new drug approvals, and providers and pharmacists find multiple REMS requirements confusing and burdensome. FDA has responded by scaling back the program, as seen in guidance adopted last year that pulls most MedGuides out of REMS and greatly reduces the need for REMS assessments. As part of the PDUFA V agreement, FDA says it will work to standardize formats for those REMS deemed necessary and do more to measure the program's impact.

And finally, there's debate about revising FDA's mission statement to emphasize the agency's important role in facilitating healthcare innovation and in creating jobs. Dr Hamburg noted at the E&C hearing that FDA would have trouble factoring jobs creation into decisions on new product approvals. "It will get very complicated and, frankly," she said, "I think it would be quite inappropriate."

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