In a notice on the CDER webpage today, FDA published 32 new draft bioequivalence recommendation documents and revised 19 previously published recommendations. The list of new draft guidance documents contained two powder for inhalation products (dry powder Inhalers, [DPI]) which represent what the FDA would term “complex products”.
The two DPI recommendations, one for salmeterol xinafoate and one for tiotropium bromide, provide detailed recommendations for in vitro testing, pharmacokinetic testing requirements, as well as comparative clinical pharmacodynamic studies. They also provide recommendations that the test and reference products be qualitatively (Q1) and quantitatively (Q2) the same and provides additional device requirements and data to be used to support sameness.
In addition, to continue a long trend in recommendations for topical products, the FDA has provided firms with the opportunity for an in vitro or in vivo option for docosanol topical cream (brand name Abreva) used for cold sores. The in vitro option recommends the test product to be Q1 and Q2 to the reference product and have the same physicochemical characteristics. If the product is not Q1 or Q2 or it cannot match up with the characteristics of the reference product, then the Agency recommends a bioequivalence study with clinical endpoints to also include a placebo arm if the Q1 or Q2 difference cannot be justified. Because, like acyclovir cream and ointment, the product efficacy is on the marginal side, the number of subjects needed to establish equivalence is likely to be very large and the likelihood of success is not great, most firms would, therefore, likely choose the in vitro option. This is another in a string of in vitro recommendations for establishing bioequivalence for topical products that present potential challenging in vivo testing.
FDA also published revisions for previously issued recommendations on 19 different products, including 8 for ophthalmic products. The ophthalmic products recommend in vitro (waiver options) or, in some instances, an in vivo option to establish bioequivalence.
We have posted about the problem associated with BE recommendation revisions and their mpact on applications pending submission, those currently pending at the Agency, or on approved applications previously, so we won’t go into that again. However, we will implore the Agency to include a revision history on the BE recommendations when a change is made to assist the industry in better understanding where and what changes are being proposed.