While we are thankful for the FDA’s work on issuing bioequivalence guidance documents, we worry about the impact of the constant and sometimes significant revisions to previously issued draft or final bioequivalence guidance recommendations on the review and approval process.  It seems that we are not alone!

In remarks made at the November 27th FDA meeting “Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions”, David Gaugh, AAM’s Senior Vice President, Science and Regulatory Affairs, echoed the same concerns that we have raised in numerous blog posts and also provided recommendations for relieving some of the burden that these revisions place on the generic industry.  David’s remarks on this issue are provided below.

New and updated Guidances – FDA should continue to carefully consider the impact of revising existing draft and final guidances has on timely access, especially when changes involve products that are susceptible to a shortage. AAM believes FDA should permit generic sponsors to comply with new or updated standards as a post-market commitment to mitigate delays in access. As we all know, the approval standards for generic medicines are often an evolving process. Such standards may change throughout the lifecycle of a product. But revisions made, especially during the review process, adds uncertainty and significant additional time to the overall approval of a product. Therefore, FDA should have the flexibility to use available regulatory discretions to assess public health impact. For examples, when FDA publishes a new or updated guidance or otherwise imposes a new requirement after an ANDA is received, including compendial, labeling, and bioequivalence or other testing requirements, the agency should allow the sponsor to comply with the changes as a post-market commitment. This said, the exception being if the changes address an imminent safety or efficacy concern. This approach could potentially help to alleviate shortages by expediting the approval of needed generic medicines and providing the predictability that is necessary to support a timely market entry.

Generic firms with pending or approved applications, or those that have completed BE testing but have not yet submitted their application at the time of guidance revision often do not know what to do or what is expected of them when a revision to a BE guidance recommendation is posted by the Agency.  Should they commence another study, is the change relevant to their approved or pending or yet to be submitted application or product?  Would a passing study be acceptable if completed under the existing guidance?

David Gaugh addresses some of these issues in part of his prepared statement (full statement available here) relating to BE guidances.  Guidance revision can cause significant delays in bringing a generic drug to market and, in many cases, significantly increase the cost associated with the filing.  This month alone, 41 BE guidances have been revised.  I will say that some of the revisions lower the burden (i.e., provide for an in vitro option to establish bioequivalence), but most increase the burden substantially.  FDA needs to address this issue especially with the number of revisions that occur each month.  One of the goals of the Hatch-Waxman Act was to reduce duplicative unnecessary human testing.  FDA should take this into account in determining when and if a new study is essential for a product that may have already conducted acceptable BE testing according to an existing guidance.  The Agency should judge the clinical significance of increased testing on the ultimate approval determination.

While AAM suggested some alternatives, we are skeptical that FDA will move the needle in the direction that AAM suggests, as FDA has been historically extremely risk adverse when making most approval decisions.