(T1330-10-69) Evaluation of Applications for Topical Semisolid Drug Products with In Vitro Permeation Test and In Vivo Bioequivalence Study with Pharmacokinetic Endpoints

Purpose: To demonstrate bioequivalence (BE) for topical semisolid drug products, the Agency has been recommending “characterization-based approaches” as an alternative to comparative clinical endpoint BE study. A typical characterization-based BE approach for a topical semisolid drug product recommends the same physicochemical and structural (Q3) attributes and equivalent rate of drug release based upon an acceptable in-vitro release test (IVRT) if the test product contains no significant difference in inactive ingredients or in other aspects of the formulation relative to the reference standard (RS) that may significantly affect the local or systemic availability of the active ingredient. Depending on the complexity of the drug product, other studies that may be recommended as part of a characterization-based BE approach include a biorelevant test, such as in-vitro permeation test (IVPT) (typically recommended to mitigate the risk of failure mode related to local availability) and/or in-vivo BE study with pharmacokinetic (PK) endpoints (typically recommended to mitigate the risk of failure mode related to systemic availability). During BE assessment of abbreviated new drug applications (ANDAs), there were challenges in the various aspects of the IVPT studies, based on the submitted data. The present research is designed to understand the fundamental issues in the submitted IVPT studies which resulted in increased assessment cycles, compared to in-vivo BE study with PK endpoints.

Methods: The data were collected from submitted ANDAs for 3 topical semisolid drug products containing both an IVPT study and in-vivo BE study with PK endpoints. The study design, method validation and study outcome in both IVPT and in-vivo BE study with PK endpoints were evaluated. Further evaluation of identified deficiency comments was carried out to understand the potential root causes for the relevant challenges of the IVPT and in-vivo BE study with PK endpoint from the submitted data, as applicable. In addition, due to inherent variability associated with the skin, the variability [e.g., %CV, coefficient of variation using within subject/donor variability (sWR) of RS] of IVPT and in-vivo BE study with PK endpoints (with replicate study design) was evaluated to understand the impact of the same in the outcome of respective BE studies.

Results: Based on the BE assessment of in-house ANDAs (n=20) for 3 semisolid drug products, 50 % ANDAs had adequate in-vivo BE studies with PK endpoints in the first assessment cycle. While 45 % of ANDAs had minor deficiencies (e.g., missing raw data, missing information on dosing technique, clarification on sample repeats, clarification on wipe off time/procedure, bioanalytical method, etc.) for in-vivo BE study with PK endpoints after the first assessment cycle. In contrast, based on the analysis of the submitted IVPT study data, all of the in-house ANDAs were deemed inadequate in the first assessment cycle due to deficiencies which include but are not limited to study design, method validation (e.g., sensitivity and selectivity studies), and pivotal study. Out of these identified deficiencies during the BE assessment; uninterpretable/zig-zag flux profiles that results into substantial high variability, aberrant data, lack of discrimination for validation studies, and insufficient number of donors/replicates are some of the key issues which resulted in re-development or re-conduct of IVPT studies. In comparison of the intra-donor/subject variability (% CV) between IVPT and in-vivo BE study with PK endpoints, a wider range of variability for IVPT endpoints [i.e., maximum flux (J_max) and total cumulative amount (AMT)] was noted compared to in-vivo BE study with PK endpoints [i.e., maximum plasma concentration (C_max) and area under the curve (AUC_last)].

Conclusion: Overall, the in-vivo BE study with PK endpoints in the generic topical semisolid drug product applications had a higher adequacy rate in the first assessment cycle as compared to the IVPT studies. The inadequacy of the IVPT studies resulted in an increased number of assessment cycles. The possible sources of the observed variability for IVPT endpoints could be the inherent variability associated with the drug product or a lack of adequate control during the conduct of the IVPT studies. Careful considerations of fundamentals of IVPT method development and validation, with well-controlled conduct of IVPT studies will lead to successful pivotal studies while considering the above-mentioned observations. Proactive considerations will ultimately expedite the assessment process and availability of high-quality affordable generic topical semisolid drug products to the American people.

Acknowledgements: DISCLAIMER: The present work reflects the views of the author(s) and should not be construed to represent U.S. FDA’s views or policies.