Regulatory requirements biomarkers

Documentation on assumptions should address those assumptions implicit in the pharmacokinetic or pharmacodynamic model and the statistical methodology chosen to evaluate the data. It should also state the assumed sensitivity of the parameters required to define the model relative to the data space being evaluated as well as any preconceived notions regarding biomarkers or surrogate markers evaluated as responses or covariates in the analysis. Hypotheses should be defined based on what was held a priori as true before the study or analysis, what was developed from preliminary or exploratory data analysis, and what would constitute a difference or equivalence in an effect or outcome, hi some instances the criteria for difference as opposed to equivalence can be defined from a statistical viewpoint independent of the actual study design. This approach does not always confer regulatory acceptance, however. 

The qualification of novel DILI biomarkers will require application to biospecimens obtained from many different patient populations treated with many different drugs, both those that cause clinically important DILI and those that cause elevations in traditional liver chemistries but do not cause clinically important liver injury. It is important that pharmaceutical companies start now to archive samples and link these specimens to the relevant liver safety data. Ideally, liver safety data management tools should be standardized across the industry to facilitate the precompetitive collaborations on biomarker validation and qualification, such as eDISH (Watkins et al., 2011). Formal biomarker validation and qualification will warrant significant time to obtain regulatory-endorsed exploratory status via Letters of Support. 

Integration of biomarkers into clinical protocols requires incorporation of biomarker analysis into one of the study objectives. For novel biomarkers this is typically achieved by including an exploratory objective that examines the feasibility of measuring the biomarkers in the study population. Within the protocol a summary of preclinical or translational evidence for the biomarkers should be provided. When available, biomarker qualifications or letters of support from regulatory authorities should be referenced. A schedule of events describing when samples for biomarker analysis should be collected in context with all other clinical visits and tests should be included. When special collection, processing, or storage considerations are required, a separate... 

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