OGD Revision of BE Guidance – What Does it Mean for Product Development and Approved Products?

How does the Office of Generic Drugs (OGD) make a determination to revise an existing bioequivalence (BE) guidance?  What happens to the requirements for drug product under development or those products that are approved when a BE guidance is revised? These questions were addressed by Dr. Robert Lionberger and Dr. Larissa Lapteva in a session at the GPhA Fall Tech Conference.

When you look at the FDA’s Product-Specific BE Guidance page (here),   you can see many new product-specific recommendations, but there are also many revised recommendations. In the latest update to the list, there were 42 new Guidance documents and 18 revisions to previously issued Guidance documents.

According to Dr. Lapteva’s presentation, there are a number of reasons Guidance documents may be revised.  Her slide below outlines may of the issues:

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Interesting enough, in the Q&A session, we found that, when a Guidance is revised post-approval of an application, the decision as to whether to require the sponsor of the approved application to provide additional information or perform new studies is dictated by an increased reporting level of adverse events, report of lack of effectiveness, or lack of equivalence.  The decisions are made on a case-by-case basis and, as science advances, there may be instances where pending or proposed applicants may have to comply with the new requirements but previously approved products may not.  Again, this would be dictated by the impact on public health associated with the new information on the product that may come from the reference listed drug (RLD) product or the other types of information identified above.

If a product is in development, it is possible that a revision in a BE guidance may require either additional work or new BE studies prior to ANDA approval.  One example that was given related to where new information became available regarding a food effect previously not identified on the RLD which resulted in FDA asking sponsors of pending ANDAs to perform a food effect study (see slide below).

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OGD will evaluate the information that comes from the RLD holder, new scientific evidence that becomes available to FDA, or as a result of some of the research projects or studies that OGD has commissioned under GDUFA.

Whether you are in product development, planning to start a study, have a pending ANDA, or have an approved ANDA, the industry needs to pay attention when a product-specific Guidance is revised to determine if they may have to perform additional work and or supply additional data to the Agency.  In most cases, according to the two OGD presenters at the GPhA meeting, when additional work or data might be needed, OGD will typically write a letter to the applicant providing its rationale for determining that a potential safety or efficacy issue may exist with the previous Guidance and outline the necessary information or studies that they believe is required for resolution.