(M1030-06-34) In Vitro Permeation Test Outlier Data Evaluation during Bioequivalence Assessment of Abbreviated New Drug Applications

Purpose: The Agency recommends In Vitro Permeation Test (IVPT) studies to demonstrate bioequivalence (BE) for certain topical products (liquid-based and/or other semisolid products). Currently, according to Guidance for Industry “In Vitro Permeation Test Studies for Topical Drug Products Submitted in Abbreviated New Drug Applications (ANDAs)”, there is no recommendation provided for handling outliers (e.g., the exclusion of aberrant data) in IVPT studies. Outlier occurrences are frequently observed in IVPT studies and may impact BE assessment. The purpose of this survey is to collect the ANDAs of reporting outlier data in IVPT studies and to summarize the general considerations and understanding of how outlier data impacts the determination of BE. Additionally, to identify easily avoidable deficiencies related to outlier issue in IVPT study.

Methods: Data from in-house ANDAs for a total of nineteen (19) topical drug products, including different dosage forms such as cream, gel, lotion and ointment, submitted from 2013 to 2023, were studied. The drug products include Doxepin hydrochloride, Ivermectin, Luliconazole, Metronidazole (Oxymetazoline hydrochloride, Ozenoxacin, Penciclovir, Pimecrolimus, Calcipotriene, Flourouracil, Tazarotene Acyclovir, Dapsone, Diclofenac sodium, Clindamycin phosphate, Halobetasol propionate, Crisaborole, Calcipotriene and Tacrolimus. For each of these ANDAs, the following information was collected: the presence of outlier data, the reason for outlier issue and statistical analysis of the outlier data. The identification of outlier data is categorized into subjective and objective criteria.  Subjective outlier is classified as outlier based on experimental or protocol errors or any observed aberrant value of flux or permeation profile. Objective outlier is classified as outlier data based on any pre-specified criterion in predetermined protocol (e.g., using statistical outlier tests like Dixon’s Q outlier test or Dean Dixon test and Grubbs outlier test).

Results: Out of a total eighty-four (84) ANDAs, forty-one (41) applicants performed IVPT studies, which were in line with their respective product specific guidance at the time of ANDA submission. Among these, 36.6% [fifteen (15) ANDAs] were identified as having outlier issues in IVPT studies. Out of the 15 identified ANDAs, 40% [six (6) ANDAs] fall under subjective criteria for outlier, 60% [nine (9) ANDAs] can be classified as objective criteria for outlier. The reason why 6 ANDAs were identified as having subjective criteria for outlier issue is due to high flux profile (intra donor or inter donor) altered permeation profile, or protocol error. For the other 9 ANDAs classified as objective criteria for an outlier, the identification method of outlier and outlier exclusion criteria was pre-specified in the IVPT protocol. Regardless of outlier classification, statistical analysis using scaled average bioequivalence (SABE), or average bioequivalence (ABE) approach was conducted for data from IVPT studies by including and excluding outlier data. Out of 15 ANDAs, 67% [ten (10) ANDAs] met the BE criteria irrespective of inclusion or exclusion of outlier data. SABE or ABE statistical approach analyses is robust to the influence of typical variations in individual donor or replicate data values. Therefore, diffusion cells should typically not need to be replaced unless there are specific concerns about the validity or availability of the data from the diffusion cell(s). Four (4) out of 15 ANDAs, 27% met the BE criteria when outlier data was excluded and failed to meet the BE criteria when outlier data was included, 3 were classified as subjective outlier and 1 as an objective outlier. One ANDA (7%) failed to meet the BE criteria when outlier data was excluded and met the BE criteria when outlier data was included. The deficiency sent by the Agency in the failed IVPT studies due to outlier issues was to reconduct the IVPT study. The applicant in these cases redeveloped their respective IVPT methods including significant changes like dose application without occlusion, avoiding overhydration of skin prior to dosing, wipe off the dose at certain timepoint and including photographic evidence at each step in conducting the IVPT study.

Conclusion: In general, the Agency has not considered excluding aberrant data solely based on a statistical outlier test for a pivotal IVPT study data analysis. The outlier data in IVPT studies is assessed using a case-by-case strategy considering the totality of evidence available during ANDA assessment. The outlier data issue can be controlled using and executing well-developed IVPT method, well controlled method development and method validation procedures, etc. The applicants are encouraged to seek Agency’s support regarding specific questions related to IVPT method development by submitting product development meetings, pre-submission meetings, controlled correspondences, etc. Further investigation is necessary to better understand the relationship causing numerical anomalies in IVPT studies and to establish objective statistical criteria that can support the removal of outliers within an IVPT dataset. The critical approach to data analysis regarding outlier issue in IVPT studies would improve the quality of generic topical products for American public health.