FDA's bioequivalence rules are out of date and need to be modernised

Economist Roger Bate of the American Enterprise Institute and collaborators claim​ in the journal Trends in Pharmacological Sciences​ that the non-bioequivalence problem affects drugs to treat depression, organ rejection, heart disease and many other conditions and diseases.

"The regulations for assessing the quality of generic drugs and their bioequivalence to innovator products are outdated and need to be substantially modernised,"​ they write, pointing out that the review criteria have remained largely unchanged since the 1980s despite the increasing complexity of medicinal products.

In particular, the researchers note that while FDA guidance acknowledges that the rate of drug absorption is a critical factor in determining bioequivalence, some measurements of this have been "traditionally ignored" by the FDA.

The paper cites a number of examples of cases in which a switch from an innovator to generic drug has led to adverse effects, including drug such as levothyroxine, epilepsy drugs, immuno-suppressants used in transplant patients, the antidepressant bupropion and attention-deficit hyperactivity disorder (ADHD) treatment methylphenidate.

One of the primary reasons behind the issue is that there is a lack of transparency of bioequivalence data collected by the FDA, according to Bate, who would like the agency to start by making public the bioequivalence information it routinely requires from all generic manufacturers.

With data in hand, physicians could then make a judgment whether two supposedly bioequivalent products are actually interchangeable. A federally-funded trial into the effects of switching between generic products would also be desirable, according to the study authors, who note it is possible for two generic drugs to both be equivalent to the innovator but not to each other.

"A switch from an innovator drug to a generic drug, or switching from one generic to another, is not a benign process, as there is substantial clinical, professional judgment involved," he says. "In some instances these decisions should be better informed."​

The increasingly globalised and fragmented market for pharmaceutical ingredients - as well as finished dosage manufacturing - can lead to variations in production particularly in countries with lower levels of regulatory oversight and "poor enforcement of weak laws,"​ Bate adds.

The study poses a number of questions intended to stimulate debate into the issue, asking whether products that lose their AB bioequivalence rating should remain on the market, if manufacturers with a history of GMP failures be allowed to receive additional FDA approvals, and whether labelling laws be changed to note the country of origin of drug products.