Category: Clinical Pharmacology
Purpose: Therapeutic equivalence requires both pharmaceutical equivalence and bioequivalence between the generic and innovator drug products. As injectable solutions, establishing bioequivalence could be straightforward under CFR 320.22(b)(1) for generic low molecular weight heparin (LMWH) drug products. However, as their active ingredient is a complex mixture of oligosaccharides, a scientifically rigorous multifaceted approach is required to establish active ingredient sameness of LMWH between the test and reference products. An in vivo pharmacodynamic (PD) study is one of the studies recommended in the product-specific guidance (PSG) for the demonstration of active ingredient sameness between test and reference products for LMWH injectable drug products such as Enoxaparin Sodium Injection and Dalteparin Sodium Injection. According to the PSG for these two drug products, the recommended PD study design is a single-dose, two-way crossover in vivo fasting study in normal healthy males and nonpregnant females, general population. The recommended PD endpoints to measure are anti-Xa activity and anti-IIa activity in plasma, with equivalence being based on anti-Xa activity while anti-IIa activity serves as supportive evidence of active ingredient sameness. Deficiencies in PD studies for LMWH Abbreviated New Drug Applications (ANDAs) are often observed and may result in additional review cycle(s) and delay ANDA approval. A survey of deficiencies related to ANDAs for LMWH products indicates the majority to be related to bioanalytical issues. The current study examines and summarizes common bioanalytical deficiencies in PD studies for LMWH ANDAs and identifies multiple deficiencies that are less common but specific to the bioanalytical assay. This study will assist the generic pharmaceutical industry in improving their LMWH ANDA submission quality through the identification of deficiencies that may delay approval of this set of ANDAs.
Methods: We conducted a survey of all in-house ANDAs for LMWH drug products except those that are refuse-to-receive or withdrawn. Deficiencies from these ANDAs were collected and placed into 4 major categories: general deficiencies (e.g., missing/incomplete documents), study method deficiencies, method validation deficiencies, and repeat analysis deficiencies.
Results: Among the LMWH ANDAs surveyed, 64.7% of them had deficiencies issued. The most common category of deficiencies is general deficiencies, which include incomplete or missing documents such as standard operating procedure(s) [SOP(s)] for method validation and/or analytical repeat analysis (52.9% of ANDAs); missing 100% numerical raw data (41.2% of ANDAs); and discrepancy in information among study protocol, study report, and summary tables (23.5% of ANDAs). For the study method category, the most common deficiency is missing details including but not limited to testing procedure, reagent used, and species source (11.8% of ANDAs). For the method validation category, common deficiencies include: 1) missing or inadequate stability study data to cover storage conditions of study samples, stock solutions and/or working solutions used in the pivotal PD study (47.1% of ANDAs) and 2) missing validation data to support assay robustness under hemolytic and lipemic conditions, or no documentation indicating if samples were hemolyzed or lipemic at the time of analysis (17.6% of ANDAs). For the repeat analysis category, many deficiencies are related to samples identified for repeat due to above upper limit of quantitation (AULOQ) and involve: 1) missing information such as original values, dilution factor used, and activity of the dilution quality control (DQC) (17.6% of ANDAs); 2) missing explanation for why reassay values of AULOQ samples were markedly lower than upper limit of quantitation (11.8% of ANDAs); and 3) the dilution factor or activity of DQC validated in pre-study method validation does not cover that of AULOQ samples in the pivotal study (11.8% of ANDAs). Other common repeat analysis deficiencies include: 1) reason for reassay and/or final reported value was not per repeat analysis SOP and 2) repeat analysis identification or reporting criteria is not clearly and objectively pre-specified in the SOP (17.6% of ANDAs).
In addition to the common deficiencies listed above, there are multiple other deficiencies that are less common, but specific to the bioanalytical assay. For example, if commercial analytical kits are used in the PD study and there are lot-to-lot changes in analytical kits between the method validation and the pivotal PD study, then partial validation data supporting the changes are not provided. Another example of a less common deficiency is the lack of justification for the use of non-compendial method of anti-Xa and anti-IIa activity measurement such as clotting time rather than the use of a compendial method such as an amidolytic assay.
Conclusion: A PD study is one of the battery of studies to demonstrate active ingredient sameness between test and reference LMWH drug products. Deficiencies related to this type of PD study are often observed in the review process and many could be prevented by providing complete information. An LMWH ANDA application with improved submission quality will help reduce PD study-related deficiencies and hence accelerate the approval of LMWH generic drug products.