Over the course of time, we have all seen multiple revisions of FDA’s ANDA bioequivalence (BE) Guidance documents in draft or final form.  In some instances, the FDA makes relatively minor changes, but, in others, they ask for significant revisions in collection of data, metrics, and sometimes study designs.  For instance, FDA may ask for a fed study where none was previously required.  Sometimes the FDA will revise a BE Guidance to require a fully replicate design where previously they asked for a standard 2-way crossover design, like they recently did for Cyclosporine Capsule products.  For modified-release products, FDA has often required the addition of multiple partial Area Under the Curves (AUCs) to required BE metrics like they did for the methylphenidate extended-release products.   These changes are typically precipitated by increased knowledge of the product performance by FDA, resulting in a tightening of requirements that are necessitated by that new evaluation, to further assure that the generic products perform like that of the brand name product upon which they rely for approval.

We all know that the science of bioequivalence continues to evolve and advance and that changes are sometimes needed to further assure therapeutic equivalence of generic products, and thus, support the public’s confidence in the substitutability of generic medications.

The changes in BE Guidance recommendations may occur prior to a firm submitting an ANDA, during the review of an ANDA, or even after an ANDA has been approved and marketed for a period of time (oftentimes, years after approval).  So how does a firm know what to do when a revision in the BE Guidance recommendation changes, especially since these Guidance documents represent the Agency’s current thinking and are not binding on the applicant as an alternate approach may be found acceptable?  This fact is noted in each Guidance document.  What is even more difficult on a firm’s decision is when a change is made to a draft BE guidance recommendation that has not yet been finalized.

There are obvious options for a firm once a revision has been made.

  • They can repeat the study using the new recommendations.
  • They can try to use the data captured in the original study to try to support the change (which, depending on the type of change, may be acceptable).
  • They can ignore the change.
  • They can propose an alternate approach (the one they used) with justification.

Clearly, revision of a BE Guidance just prior to ANDA submission can have an adverse impact on a firm’s filing.  Should they submit the ANDA with the study they performed based on FDA’s original recommendation?  What about for ANDAs already received by the Agency that now sit in the review queue?  Does a firm wait for FDA decide that the study needs to be repeated using the new recommendation or just go ahead and redo the study?  If a firm decides to wait, then it places itself in a position of delaying its potential approval.  And what about firms that have an approved application that is being marketed?  What triggers FDA’s decision to ask for a new study?

We are not entirely sure how FDA makes its decisions to revise a BE Guidance document, but we are clearly in the dark as to how and when the FDA decision to require firms to repeat BE studies using the revised recommendation are made.  I am sure that FDA will (as they have with certain products) tell a firm when it is absolutely necessary to repeat a study using a new BE recommendation, but FDA does not do this in all instances.  What are the criteria for FDA’s decision making process?  Does it stem from submitted reports of lack of therapeutic equivalence?  Adverse reactions?  Lack of effect?  How does the Agency decide when not to ask for a new study, either pre- or post-approval?  How does the FDA decide to receive or refuse-to-receive (RTR) an ANDA when a BE Guidance revises just prior to ANDA submission?  When will FDA decide that it is a review issue or that there is a need to issue an RTR letter?  These are some of the questions that industry has asked me.  I wonder what the FDA’s answers are?  If you have had experiences that you would like to share on how FDA has made such decisions based on issues you have faced, please let me know (r.pollock@LachmanConsultants.com) and I will share them (if you’d like) with our readers (blinded as to firm and drug, of course).  But right now, the only question I have is: What’s a mother to do?”