New legislation introduced in the US House of Representatives seeks a government investigation into the US Food and Drug Administration's (FDA) review of complex generic pharmaceuticals to consider whether the agency is in need of new regulatory authority.

Background

The bill, the Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015, was introduced on 24 March 2015 by Rep. Michael Burgess (R-TX), a former physician and member of the House Energy and Commerce Committee.

The bill would require the government's internal oversight body, the Government Accountability Office (GAO), to assess whether FDA has adequate oversight over "nonbiologic complex drugs" (NBCDs).

"A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known," explained the authors of a January 2014 paper in the Journal of the American Association of Pharmaceutical Scientists (AAPS).

The drugs, experts say, fall into a regulatory gap of sorts. They're more complex than the typical generic drugs regulated by FDA under its 505(j) abbreviated new drug application (ANDA) pathway, but less complex (and generally ineligible to use) FDA's biosimilar pathway under Section 531(k) of the Federal Food, Drug and Cosmetic Act.

One of the key regulatory problems is the difficulty with which NBCDs are manufactured. "The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation," the authors of the AAPS paper explained.

Another problem: "FDA has refused to define these complex drugs as distinct from normal, small molecule medicines," former FDA Deputy Commissioner Scott Gottlieb wrote last year in Forbes. "That has forced the agency to rely on less information in approving these complex copies than it probably would like."

The Bill

Burgess' bill directs GAO to take a critical look at FDA's "current regulatory pathway for reviewing generic versions" of NBCDs.

Some of these drugs may represent "unique challenges" to the development and approval of equivalent generic drugs, the bill observes. FDA standards may therefore need to be "significantly different" to accommodate those challenges.

Questions GAO is supposed to answer include:

• What degree of characterization of the proposed generic version and the reference product should be required in order to determine the safety and effectiveness of the generic version?
• What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product?
• What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product?
• What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product?
• Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product.
• Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.

GAO is also asked to recommend whether FDA is in need of new regulatory authority under section 505(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act) to more properly regulate NBCDs.

GAO has two years in which to create its report.

Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015

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