Subtopic 2 (Pharmacometric M&S for Generic Drug Substitutability Evaluation and Post- Marketing Assessment of small molecule) A Model- and Systems-Based Approach to Efficacy and Safety Questions Related to Generic Substitution The Office of Generic Drugs (OGD) occasionally receives reports from patients, physicians and/or professional organizations about the therapeutic INequivalence of marketed generic drugs. Frequently, there is little scientific evidence to conclusively support a rationale for problems following generic substitution. Given that a 2009 study by OGD demonstrated that the average difference in Cmax and AUC between generic and innovator products was 4.35% and 3.56%, respectively for 2,070 bioequivalence products conducted between 1996 and 2007, this raises the question of whether these bioINequivalence (BIN) signals are real or perceived. However, generic drugs can be complex because of things like input-rate sensitivity in pharmacodynamics (e.g., hypotension related to nifedipine) following oral administration or different mechanisms of extended release for once-a-day oral formulations (e.g., with methylphenidate). Therefore, it is critical to have a process in place to assess purported therapeutic INequivalence. The broad goal of this research strategy is to define a process whereby the OGD can specifically evaluate the potential BIN of approved generic products in patients under clinical use conditions during the post-marketing period, and investigate purported adverse drug reactions arising from generic substitution. It is essential that a scientifically rigorous workflow be established to challenge the notion that generic drugs don't work as well as reference drugs. The results of this research will help to instill confidence in the American public about the quality of generic drugs and the willingness of FDA to use an evidence-based approach to investigate claims of BIN. We are proposing a mechanistic and quantitative research strategy using modeling and simulation techniques that moves from assessing pharmaceutical equivalence (i.e. quality), through bioequivalence (i.e., biopharmaceutical performance) and on to therapeutic equivalence (i.e., clinical efficacy and safety profile), that is a risk-based, comprehensive and pragmatic approach to addressing issues of post-market risk of generic drugs, and interpretation of post- market adverse event reports or product substitution complaints using systems biology principles. It is intended that the research strategy represent a workflow and analysis for the Office of Generic Drugs (OGD) to systematically investigate purported BIN arising from generic drug substitution. Our approach would be conducted as a pilot study in close collaboration with scientists and clinicians in OGD who would help identify high-risk generic substitution situations for evaluating the quality and consistency of the research strategy.