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But is bioavailability sufficiently monitored by FDA for generic products on the market?
Dating back to the FDA Safety and Administration Act of 2012 (FDASIA), Congress had taken a more critical look at FDA inspection practices generally, and the specific problem of fewer inspections of manufacturing sites outside the US than inside it. A 2010 GAO report had found that 40% of domestic manufacturers had been inspected, but only 11% had been during 2007-2009 (not all manufacturers have to inspected all the time; and since then FDA has instituted a risk-based evaluation process to target certain sites). Now, HHS’ Office of Inspector General has found that FDA is getting closer to parity in US/non-US “surveillance” (routine) inspections; in FY2013, 57% of inspections were of non-US facilities. However, the parity based on risk evaluation is still to be met, as well as comparable “depth and rigor” of the inspections.
The OIG report, FDA Has Made Progress on Oversight and Inspections of Manufacturers of Generic Drugs, also looked at “preapproval” inspections, which are supposed to occur when FDA reviewers evaluating new drug applications request them. Preapproval inspections have increased more than 60% between 2011 and 2013. (There is a lot more to these inspections than simply counting the number of them: FDA can do combined preapproval and surveillance inspections, and can request documentation in lieu of an inspection—and the risk-based criteria kick in as well.) Overall, OIG recommends that FDA perform all preapproval inspections for which its reviewers request, and ensure compliance with required registration information of generics manufacturers.
There have been some headline-generating failures of generics manufacturers to meet FDA standards and in this context it’s worth noting that of the four sites that received “multiple enforcement actions” during 2013, all were in India (an “action” can include barring import of product to the US). The questionable quality standards of Indian manufacturers has been called out by, among others, Roger Bate of the American Enterprise Institute, but in a more recent report, “Generics Substitution, Bioequivalence Standards … Complex Issues Facing the FDA,” he and his coauthors highlight varying quality standards among all generics manufacturers. “The OIG report is about one very specific question, which indeed FDA has done well in addressing. Namely it has ramped up inspections in the field and as a result has found problems, notably in India. That does NOT mean the medicine supply is better/safer,” he says. There should be tighter control of bioavailability (the rate at which the active ingredient’s concentration peaks in the bloodstream) and more random surveillance of generic drugs on the market. The poor degree of standardization of bioavailability in small-molecule generic drugs also raises questions on how well FDA will be able to regulate interchangeability in biosimilars.