Important Note: There Are Two Different Everolimus Bioequivalence Guidance Recommendations – Be Careful Which You Rely Upon

In the most recent update of the bioequivalence (BE) recommendations, there is a new Guidance for the conduct of BE studies for Everolimus dated June 2016.  This specific Guidance covers the use of the drug in treating organ rejection (here).  A previous Guidance document (initially issued in March 2011 and then revised in June 2012) covers a different product where the indication is for oncology (here).

Both Guidance documents provide the exclusionary language and outline to which indication the recommendation applies.  The new Guidance provides for a fully replicated design and permits a scaled BE approach to the limits of variability of the reference listed drug (RLD) product, which, according to the Guidance, has “low-to-moderate within-subject variability.”  FDA also acknowledges in the new Guidance that this particular product has a narrow therapeutic range, and thus, mirrors other BE Guidances relative to drug products for organ rejection and notes that “sub-therapeutic concentration leads to serious therapeutic failures.”

Even though it is clear which Guidance should be used for which RLD, one must take care in making sure you have selected the appropriate Guidance to put you on the right track.  It is possible that an ANDA applicant that reads the old Guidance for the product for oncology may have thought, erroneously, that those recommendations might also apply to the organ rejection product despite the disclaimer in the original Guidance document.  One should always keep in mind that FDA has taken a more stringent position on many drugs, for narrow therapeutic index drug, as well as modified-release and/or complex products.  Do not assume that one recommendation for one product will always apply to another.  Perhaps a Controlled Correspondence to OGD would be in order, especially for an unusual situation such as this prior to FDA issuing a Guidance.