(M0930-10-67) Past-to-Present Comparison of Repeat Analysis-Related Observations in Pharmacokinetic Bioequivalence Studies Submitted in Abbreviated New Drug Applications

Purpose: Study sample repeat analyses are frequently observed in pharmacokinetic (PK) bioequivalence (BE) studies submitted in Abbreviated New Drug Applications (ANDAs). As presented in the 2016 American Association of Pharmaceutical Scientists Annual Meeting and Exposition (poster #03W1230), a survey of ANDAs assessed in 2015 indicated that many deficiencies related to repeat analysis were avoidable. In the current study, a similar survey was conducted on ANDAs assessed in fiscal year 2022, where the incidences and common deficiencies for repeat analysis were investigated and compared to those identified in 2015. The findings in the current study will assist the generic pharmaceutical industry to further improve ANDA submission quality.

Methods: A survey was conducted on original ANDAs assessed in fiscal year 2022 (October 2021 to September 2022) that contained in vivo PK studies. For each ANDA, the reasons for repeat analysis (i.e., repeat codes) reported in the repeat analysis summary tables and the deficiencies related to repeat analysis issued during the first cycle of ANDA assessment were collected. The collected repeat codes were classified into the following categories: PK repeat, above upper limit of quantification (ULOQ), internal standard (IS) variation, incomplete analysis (including instrument malfunction and handling exigency), positive pre-dose, truncated calibration curve (CC), and miscellaneous. Among the ANDAs surveyed, the number of ANDAs containing a given repeat code was determined. The deficiencies related to repeat analysis were classified as either code-specific or general (i.e., not related to a specific repeat code). Further, for the code-specific deficiencies, the deficiency rate for each repeat code was calculated as follows (using "above ULOQ” as example): Deficiency Rate for Above ULOQ = Number of ANDAs with deficiencies related to Above ULOQ repeats / Total number of ANDAs reporting repeat analysis due to Above ULOQ. The survey results were then compared to those of 2015.

Results: Data from a total of 398 ANDAs (versus 764 in 2015) were collected for fiscal year 2022. Among these ANDAs, 385 (96.7%, versus 96.9% in 2015) reported repeat sample analysis. As with ANDAs assessed in 2015, IS variation was the most frequently reported repeat code in fiscal year 2022. In the current study, the percentage of ANDAs under each repeat code, in the order of decreasing frequency, were as follows: IS variation (90.7% vs. 83.6% in 2015), incomplete analysis (58.0% vs. 62.6% in 2015), above ULOQ (44.2% vs. 54.5% in 2015), positive pre-dose (38.9% vs. 27.9% in 2015), poor chromatogram (34.7% vs. 33.5% in 2015), miscellaneous (15.6% vs. 24.5% in 2015), truncated CC (13.1% vs. 9.6% in 2015), and PK repeat (5% vs. 32.5% in 2015). Overall, the Agency issued deficiencies (code-specific and/or general) related to repeat analysis for 12.7% of the ANDAs examined in this study, compared to 33.5% in 2015. The percentage of repeat analysis-containing ANDAs that had the code-specific deficiencies decreased from 16.89% in 2015 to 8.57% in fiscal year 2022; and those with general deficiencies decreased from 28.24% in 2015 to 6.23% in fiscal year 2022. For the code-specific deficiencies, the deficiency rate for some repeat codes remained similar between two surveys (e.g., for above ULOQ, the deficiency rate was 6.0% in 2015 and 6.8% in fiscal year 2022). On the other hand, the deficiency rate for some repeat codes decreased (e.g., the deficiency rate for poor chromatogram was 19.5% in 2015 vs. 5.8% in fiscal year 2022). Regarding the code-specific deficiencies, while the common deficiencies remained largely unchanged, there were some deficiencies that became more prevalent as compared to 2015. For example, for above ULOQ, the most common deficiency in fiscal year 2022 (8.3% vs. 0.8% in 2015) was a request to the applicant to provide an explanation regarding the reassay concentration being markedly lower than ULOQ after correction for dilution factor. The frequency of the most common general deficiencies observed in 2015, including incomplete or no numerical raw data (24.7% in 2015 vs. 2.1% in fiscal year 2022), as well as incomplete or missing repeat analysis-related SOP(s) effective at the time of repeat analysis (4.3% in 2015 vs. 1.8% in fiscal year 2022), has decreased.

Conclusion: The overall deficiency rate related to repeat analysis has decreased from the 2015 study to the present study, likely due to improved repeat analysis-related SOPs (e.g., pre-defined clear and objective repeat analysis criteria in SOPs, and better SOP implementation/compliance), as well as more complete submission of information (e.g., raw data, chromatograms, additional details, etc.) to support the repeat analysis. Continued improvement of ANDA submission quality for repeat analysis will further help decrease repeat analysis-related deficiencies and facilitate generic drug approval.