Revisiting Bioequivalence

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  • 12/11/2013

As we inch closer to biosimilars in the US, we need to remember that similar does not mean identical – and that means paying close attention to bioequivalence.

MedPage Today reports that FDA-funded studies are underway that may lead the FDA to stiffen its bioequivalence rules for generic anti-epileptic drugs (AEDs) and others with so-called narrow therapeutic indices.

These studies examine drug pharmacokinetics in epilepsy patients and under chronic dosing -- could show that some current generic AEDs vary enough to put patients at risk. My eldest son has Juvenile Myoclonic Epilepsy (JME), and I can attest to the problems with therapeutic substitution from personal experience.

The FDA has shown a willingness to modify its rules if, indeed, the evidence is there, said Barry Gidal, PharmD, of the University of Wisconsin, at a press briefing held at the American Epilepsy Society (AES) annual meeting. "We're bringing the evidence."

Current bioequivalence regulations allow some variation in generic drug pharmacokinetics relative to the original branded drug. In particular, the lower boundary for 90% confidence intervals in measures of bioavailability can be as low as 80% of the mean for the branded drug, and the upper boundary can be as high as 125% of the branded drug mean.

Under current FDA rules, single-dose studies in healthy volunteers are adequate to show bioequivalence. He said that this poses two problems: drug availability and metabolism may be different in patients than in healthy people, and it may also be different with chronic dosing.

The issue of real-world generic equivalence is not confined to AEDs. Immunosuppressants are another drug class with narrow therapeutic indices, and an FDA-funded study of tacrolimus bioequivalence is also underway.

Another view of the bioequivalence issue was provided by another University of Cincinnati study led by Lisa Garrity, PharmD -- a survey of Cincinnati-area pharmacists about their knowledge and experience with generic AEDs.

Garrity and colleagues obtained responses to a one-page questionnaire from 30 retail pharmacists who had a mean of 15.6 years in practice (SD 8.8). Of these, 20 reported having no specific education about possible issues with generic AEDs when switching from one manufacturer to another.

Responses indicated that 22 believed that switching from a branded version to a generic could cause problems, but only 18 said that issues could arise when switching between generic versions of the same drug. Per Garrity, "I think these [types of switches] should be equally concerning.”

Another problem with the current system is the lack of transparency regarding generic drugs' pharmacokinetics. Data from manufacturers' FDA submissions are not readily available.

Can you say INN?


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.

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