Okay, once more with feeling – “generic” does not equal “identical.” That’s why the FDA wants to tighten the bioequivalence standards for generic drugs. Bravo!
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
According to the agency, although that methodology is "statistically rigorous" and accepted as a valid way to establish bioequivalence in most of the world, "many consumers and health professionals do not understand these statistical methods and the approval standards based on confidence intervals … Many wrongly assume that the FDA places the standards ... on the mean or average of the study data rather than the confidence intervals."
"Since the public seems to have a basic understanding of averages, the proposal to be discussed is for an additional criterion to be placed on the geometric mean (average or point-estimate) of the data limiting it to 90-111 percent." The agency surveyed 12 years of generic approvals and found that only approximately 2 percent to 3 percent of approved generic drugs would not have passed with the additional criteria.
According to a report in the Pink Sheet, “There is regulatory precedent in the definition of narrow therapeutic ratio, where drugs that meet certain parameters of median lethal dose and median effective dose are required to have careful titration and patient monitoring. But that definition is not necessarily clinically practical, FDA states, because the relevant parameters are not always available during drug development. Thus, the agency is asking the advisory committee whether it should consider CD drugs to be a distinct class, and how it should be defined. The agency also wants to know whether if the current bioequivalence standards are appropriate for CD drugs.”
The agency has already set up specific requirements for one drug product, asking manufacturers of generic versions of Sanofi-Aventis's insomnia drug Ambien CR (zolpidem) to compare partial AUCs over clinically relevant time intervals. An appendix considers the role of partial AUC for generics of modified-release methylphenidate products as well.
Its good news that the FDA is taking a strong stance in favor of the public health – because there will be many who seek to undermine this important initiative.
In the words of John Stuart Mill,
“One person with a belief is equal to a force of 99 who have only interests.”
Navigating the therapeutic narrows
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
