Tuesday’s session of the Fiscal Year (FY) 2022 Generic Drug Science and Research Initiatives Public Workshop opened with a presentation by Michael Banks, Senior Vice President, Global Head Regulatory Affairs, Teva Pharmaceuticals discussing the global challenges to the development of complex generic drugs.  Dr. Banks challenged the regulatory bodies to move towards more standardized approaches and harmonization of certain aspect of regulatory review and requirements. He notes the progress made in mutual recognition (which was talked about when I was at the Agency and has just recently come to be) and suggested that the same level of acceptance needs to be made for regulatory application reviews.

Banks made a point that there needs to be more flexibility in the need for Q1 Q2 sameness in some instances and bemoaned the changing advice of regulatory authorities as applications move through the review process, (i.e., revision of product specific guidances which can add years to product development and can in some cases cause firms to abandon the project from their portfolio, or where the Q1 Q2 determination is refuted in the second or third FDA review cycle after OGD agreed to it in a controlled correspondence, which can also put a project back to square one in development).  He raised the following question “[I]f FDA has potential advice changes that could result in that generic being abandoned, how should the FDA weigh the risk of not having a generic against the supposed benefits of the new requirement(s)?”  This is an ongoing debate for which the FDA has not really provided a response.

Other presentations focused on the differences between US and EU approval processes for complex products, for example, inhalation products where the US uses the totality or weight of evidence approach requiring in vitro testing, pharmacokinetic testing, and pharmacodynamic testing, while the EU uses a step-wise approach – i.e., if in vitro testing supports therapeutic equivalence, the product is approved; if not ,move to the next stage, using pharmacokinetic testing for additional support; and if that meets requirements, then the product is approved; if not, then the firm must also provide pharmacodynamic testing to support approval. One of the most interesting issues came out of the Q&A session where Leslie Benet, Ph.D., Professor at the University of San Francisco, stated that the RLD inhaled product cannot demonstrate pharmacokinetic or pharmacodynamic equivalence from batch to batch, so how relevant is it to require PK and PD bioequivalence of the generic to the RLD if there is such difference from batch to batch for the RLD? A question that the FDA representative seemed to acknowledge this as a potential issue.

There was a lively debate regarding the use of foreign comparator products for bioequivalence testing.  The discussion outlined potential differences that may make acceptance of the concept more difficult than one would expect, and certainly the US is not ready to permit moving to this approach; the EU appears to be on the same footing.

The next session identified complex dosage forms and the research being conducted under the GDUFA program to help support alternate methodology to approved complex dosage forms.  Topical dermatological products demonstrate the complexity of applying one approach for all products as some products have excipients that make characterization more difficult and require additional research to facilitate generic drug development. As you can imagine, alternate approaches developed by one regulatory body without coordination and harmonization among other regulatory bodies can result in different requirements, ultimately making global harmonization more difficult.  Additional research activities were discussed by FDA and industry representations provided advice on needs for further research and guidance on complex API and complex products.

The afternoon session dealt with Drug/Device combination products and the areas of research that need to be further evaluated. FDA talked about using the pre-ANDA meeting or controlled correspondence to make a threshold determination that the proposed combination product could be submitted as ANDA.  Much of the discussions and presentations focused on the user interface as one of the most important comparisons, also comparative use human factors (CUHF) studies along with assessing required labeling differences, physical comparative evaluation of the test versus reference product, as well as a robust and complete comparative task analysis.  Comparative use human factor studies and employing the use-related risk analysis (URRA) if appropriate, to help assure that design differences do not introduce the potential for user “errors or critical tasks that could result in harm or compromised medical care”.   But FDA indicated that industry should remember that, even if your drug-device is found not to be eligible for submission of an ANDA, there are other regulatory options, like the 505(b)(2) application.

It is clear that all participants strongly support continued harmonization efforts to reduce global development cost and consistency in regulatory review and approval requirements. Again, all session are available here https://www.youtube.com/playlist?list=PLUQMK8d-t3D9d5MAJm_dGW8JznEm4Ur-R and FDA notes that PDFs of the slides will be available in 1-2 weeks on FDA’s website.