"For a topical solution drug product, in vivo bioequivalence may be waived if the inactive ingredients in the product are qualitatively (Q1 ) identical and quantitatively (Q2 ) essentially the same compared to the listed drug. In this setting, quantitatively essentially the same means that the amount/concentration of the inactive ingredient(s) in the test product cannot differ by more than + 5 percent of the amount/concentration of the listed drug. Where a test solution differs in Q1 and/or Q2 from the listed drug, in vivo BE may be waived, provided the sponsor submits evidence that the difference does not affect safety and/or efficacy of the product at the time a waiver is requested." Quoted from FDA draft guidance "Topical Dermatological Drug Product NDAs and ANDAs - In Vivo Bioavailability, Bioequivalence, In Vitro Release, and Associated Studies. The last sentence says that in vivo BE may be waived if Q1 and/or Q2 are different from RLD, but sponsor must submit evidence that difference doesn’t affect safety and/or efficacy. What are some examples of evidence that the FDA would be looking for to verify safety and/or efficacy?
Good question and I must say I am not sure. For openers, some form of clinical trial data that say that (Q1) and (Q2) have been explored (say in the original NDA or supplements) over sufficient ranges to make it clear that efficacy and /or safety were not affected over wide range. Say, clinical trials were conducted and the efficacy and safety were shown to be functions of log of dose and the proposed formulation differs by only 10% in concentration. That would certainly be enough to get a waiver.
Could be that similar data, showing that log dose was shown in animal experiments would be sufficient evidence (using biomarkers of pharmacological activity) if it the drug is well known from a mechanism of action point of view.
Both clinical (and or animal) data would need to be shown for the active mouthy as well as all of the other inactive components of the new formation.
gets harder from there.
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