On June 25, 2018, the Association of Accessible Medicines (AAM) submitted comments to Docket FDA-2017-N-6644: Generic Drug User Fee Amendments Reauthorization of 2017; Regulatory Science Initiatives; Public Workshop and provided some very interesting and relevant comments and suggestions.  The full text of the AAM comments can be found here, but here is a peek into the basket of suggestions.

Certainly, the Regulatory Science Initiatives emanating out of GDUFA I and II have begun to change the requirements for certain complex products.   The success, to date, translates into many more products reaching the market which were previously stalled by the inability to develop acceptable bioequivalence requirements or characterization criteria for complex generic products.  Working together with academic institutions and companies, the FDA has begun to evaluate alternate methods to address some of the issues that have been keeping certain generics out of the hands of the public for years (one example is acyclovir ointment and cream that now has an in vitro path to approval rather than a bioequivalence study with clinical endpoints, which was not only costly but also had a very low chance of success).  AAM’s comments seek to provide the Agency with additional avenues for study in the following areas (again, these are briefly summarized and some points are combined here, please see the above-referenced link for further and more specific details).

Orally Inhaled Products – Continue evaluation of in vitro pK tests, as well as establish the relevance of the various in vitro tests required to both help support and streamline future requirements.

In-Vitro Methods – Use of in vitro methods to determine immunogenicity of peptide products (continue study).

Biowaivers – Many products are not systemically absorbed.  The FDA made significant progress in establishing in vitro bioequivalence requirements for a number of products that meet this criteria by imposing qualitative and quantitative sameness requirements and supportive in vitro testing.  AAM suggests the “[d]evelopment of methods to enable biowaivers for modified release oral products that act locally in the GI tract.”

Global Reference Product – This is a rather ambitious ask, as the FDA has continually held firm on testing requirements against a US-approved reference listed drug product.  Perhaps moving to a global reference product would permit certain products to come to market faster, especially if they are first approved in another country.

CQAs – Here the AAM is asking the FDA to recognize that there is batch-to-batch variation in the reference listed drug and they want the FDA to carefully consider that variance when setting more clinically relevant specification for the generic counterpart.

Human Factors Considerations for Sameness – This is a tough one as well.  How different can a complex generic product (especially a drug/device combination product) be, and still be considered to be the same as the reference listed drug product?  AAM asks for further research and evaluation of the impact of “external critical design attributes” to ANDA sameness.

Identifying In Vitro Alternatives to Clinical Endpoint Studies – We all know that BE studies with clinical endpoints are the least sensitive, accurate, and reproducible method for establishing bioequivalence. AAM asks FDA to establish meaningful in vitro testing to replace the time consuming and costly BE study with clinical endpoints.

Drug Product Formulation – In my words, it means finding an acceptable means to end “The Price is Right” game that generic manufacturers must play when attempting to establish quantitative (Q2) sameness to the brand name products.  The FDA’s Inactive Ingredient Database (IID), while improving, is far from optimal and analytical methods do not always take into account the loss of inactive ingredients in the formulation.

While the AAM has a lot of good advice, the question is – can the science be found to provide the answers to these age-old questions such that the assurance of bioequivalence can be relied upon by the Agency and healthcare professionals?  Let’s hope for timely solutions to some of these perplexing issues.