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
Payers and PBMs also are examining generic-drug quality and efficacy to support prescribing decisions when new generic drugs
come to market. In anticipation of generic versions of the sanofi aventis (Paris) and Bristol-Myers Squibb (New York) anticlotting
drug Plavix (clopidogrel) in two years, Medco has launched a large observational study comparing deaths and
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
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.
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.