095: A Survey of Pharmacodynamic Biomarkers Bioanalysis in 20 Biologics License Applications Approved for Enzyme Replacement Therapy Indications

Statement of Purpose, Innovation or Hypothesis: The purpose is to survey the landscape of pharmacodynamic (PD) biomarkers in the regulatory submissions of enzyme replacement therapy (ERT) products and their method validation profiles. Evaluation of the current state of PD biomarkers bioanalysis can inform future best practice.

Description of Methods & Materials: Twenty BLAs from 1990 - 2023 for ERT products were reviewed for their PD biomarkers and analyzed. PD biomarkers were stratified into groups (Yes/Yes, No/Yes, Yes/No, and No/No) dependent on the combination of two criteria they met: Listed in their product’s label (USPI); Had a bioanalytical method validation report. Whereas the Yes/No and No/No groups were not amenable for analysis, the validation parameters for each biomarker of the Yes/Yes and No/Yes groups were analyzed for the following: The 7 key analytical parameters (accuracy, analytical measurement range (AMR), parallelism, precision, selectivity, specificity, stability) mentioned in the Critical Path (CP) Institute’s Points to Consider Document (2019) and if they were evaluated in their reports; Concordance of method validation with the recommendations in “Bioanalytical Method Validation Guidance for Industry” (2018); Types of endpoints and context of use (COU) of PD biomarkers in clinical studies; Relationship between COU and tested parameters; Relationship between PD biomarkers, clinical studies, COU, endpoints, bioanalytical methods, and parameters.

Data & Results: From 20 BLAs, 22/35 PD biomarkers belonged to either the Yes/Yes and No/Yes groups for analysis, specifically 13/35 and 9/35 respectively. Each of the 22 biomarkers assessed a subset of those 7 key analytical parameters, ranging from 2 parameters for 1 biomarker to 7 parameters for 1 biomarker. Across all 22 biomarkers, the number of biomarkers tested for each of the 7 key analytical parameters varied between the Yes/Yes and No/Yes groups respectively: accuracy (13,8), precision (13,9), AMR (11,8), parallelism (9,5), selectivity (10,4), specificity (13,6), and stability (11,7). Compared to the recommendations for validation parameters, the tested parameters demonstrated variability in adherence. The parameter(s) with the highest adherence were as follows; Yes/Yes (accuracy, precision, specificity) and No/Yes (precision). The parameter(s) with the lowest adherence was parallelism and selectivity for the Yes/Yes and No/Yes group respectively. In both groups, the most used endpoint type of PD biomarkers was secondary endpoint (12/13, 7/9) while the least used endpoint type was tertiary endpoint (4/13, 4/9). The most used context of use (COU) type in both groups were PD response, (13/13, 9/9) while the least used type was safety (4/13,2/9) and dosing (4/13, 3/9). The relationship between the COU and tested parameters varied depending on the COU type. In the Yes/Yes group, the most tested parameter(s) for all COU types was accuracy, precision, and specificity, while the least tested was parallelism (PD response &efficacy) and selectivity (safety & dosing). In the No/Yes group, the most tested parameter was precision for 3/4 COU types while for dosing it was AMR and parallelism. The least tested parameter was selectivity for all COU types. The relationship between PD biomarkers, clinical studies, COU, endpoints, bioanalytical methods, and parameters conveyed heterogeneity.

Interpretation, Conclusion or Significance: The survey results conveyed heterogeneity in biomarker bioanalysis and further work is necessary to develop best practice.

Disclosures: The findings and conclusions in this poster reflect the views of the authors and should not be construed to represent FDA’s views or policies. Dr. Yunghon Lee’s fellowship was supported through the Oak Ridge Institute for Science and Education (ORISE).

Citations/References:

Additional Information/Authors: N/A