Support for science

One way to address quality and safety concerns, said Winkle, is for "the ge-nerics industry step up to the plate" and support efforts to "strengthen the science underpinning FDA regulatory decisions." FDA researchers are examining the effects of excipients on bioavailability and new sequential designs for bioequivalence (BE) studies that may require fewer subjects to test highly variable drugs. Even with added resources, though, CDER is limited in its ability to support research projects, Winkle noted. FDA's Critical Path Initiative seeks industry collaboration on several research projects such as studies to support the development of generic products using metered-dose inhalers, topical drugs, and other challenging dosage forms.

Other parties are weighing in with further examinations of these issues. The National Institute on Neurological Disorders and Stroke at the National Institutes of Health aims to address the controversial question of whether new generic anticonvulsants may pose safety problems for some patients by studying the pharmacokinetic results of patients who have reported problems with generic drugs. The goal is to determine whether any measurable difference exists between responses to brand and generic products.

heart problems of patients prescribed Plavix with those experienced by patients using Eli Lilly (Indianapolis) and Daiichi Sankyo's (Tokyo) Effient (prasugrel). Through pharmacogenetic assessments, the study will identify patients who can metabolize Plavix normally who would fare well with a generic drug, and the smaller group who should be allowed to stay with the expensive brand prasugrel.

The results of such research can help the public understand the meaning of BE and confidence intervals. One way for sponsors to address anecdotal claims about varying responses to generic products, Buehler suggested, is to add another reference arm to BE studies to examine more conclusively whether differences appear between multiple lots of the reference product.

Review pile-up

Although some manufacturers support such analysis, they are more focused on how FDA can improve the generic-drug approval process. Generic-drug makers complain that it still takes almost two years, on average, to gain approval of an abbreviated new drug application (ANDA), and that backlogs in pending applications continue to rise. OGD receives more than 800 ANDAs per year (up from about 350 in 2002) and approves about 600; the result is more than 1600 pending applications. Congress stipulated that OGD receive an extra $10 million in its 2010 budget, but the office needs another 100 staffers to clear the backlog and perform all its functions as required, Buehler acknowledged. An obvious solution is to establish a user-fee program for generics, but so far negotiations have failed to establish a viable fee system. Last year, the Obama administration proposed a $36-million fee program for generics, which was more than double previous levels, but industry opposed the plan and Congress dropped it.

Sharfstein emphasized at the GPhA meeting that reducing the backlog of generic-drug applications was a top priority for FDA's leadership, but that a user-fee program was needed to achieve this goal. At that meeting, both Sen. Orrin Hatch (R-UT) and Rep. Henry Waxman (D-CA) agreed on the need for increased funding for OGD and for generic-drug user fees. The funding would expedite the review process for generics, said Hatch, and speed consumer access to medicines. Waxman noted that a user-fee program should come with "real accountability" on the length of review processes and on transparency on regulatory decisions.

Industry leaders say they're willing to reopen negotiations in what they now regard as a congenial environment at FDA. The agency's progress in responding to citizen petitions within a new six-month timeframe and in dealing with 30-month stays is encouraging manufacturers to map out performance metrics that could form the basis of a fee program. "But we want some value for what we're paying," said Bill Marth, president of Teva North America. This could include specified consultations on the development of complex dosage forms and timely plant inspections, as well as quicker application approvals.

At the October 2009 GPhA meeting, Buehler reported on various initiatives to make OGD more responsive and more efficient than before. The microbiology review team has been expanded, and a new team structure for the BE review staff has improved its performance. Added funds may support another chemistry-review division in the coming year, Buehler said. Almost all ANDAs are adopting FDA's Question-based-Review (QbR) system, and a QbR for microbiology is in the works. CDER's 21st-century review process, which focuses on improving application reviews for new drugs, may help generic-drug applicants by freeing up new drug reviewers for consultations on complex generic products.

A key issue for OGD staff is inconsistent quality in ANDAs. Manufactures frequently present different data in different sections of an application and fail to fully justify in-process parameters and proposed product specifications. Complete and coordinated applications would help OGD review and assess ANDAs in the first review cycle and save time and money on all sides.