The Code of Federal Regulations has defined narrow therapeutic index (NTI) drugs as those having less than 2 - fold difference in median lethal dose and median effective dose or have less than a 2 - fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood. However, there is lack of clear objective set of heuristics to define NTI. Having a clear objective definition is critical from regulatory and industry points of view. The CFR alludes to consider NTI as a factor during bioequivalence (BE) evaluation. There are several publications highlighting the negative impact on efficacy and safety if switching occurs between brand and generic forms of NTI drugs. Furthermore, the Advisory Committee for Pharmaceutical Sciences (ACPS) recommended in April 2010 meeting that the FDA should develop a list of NTI drugs with clear specialized criteria and the current BE standards are not sufficient for NTI drugs. This highlights the importance of development of precise, objective criteria for assessing the BE for NTI drugs. The objective of this research is to utilize principles of pharmacokinetics (PK), pharmacodynamics (PD) and steepness of PK/PD relationship to propose quantitative metrics to identify NTI drugs and propose BE criteria to better understand the difference between brand and generic drugs. Simulations as well as published literature information for NTI drugs will be utilized for analysis. Qualitative aspects including the severity of disease and reversibility of adverse events will be incorporated in the decision tree. The decision tree will be evaluated for sensitivity and specificity by applying to approved NTI and non NTI drugs. Followed by evaluation of BE criteria based on statistical comparison of therapeutic goalposts (proportion of patients exceeding and proportion of patients below the therapeutic window) for the brand and the generic drug. In addition, different criteria for PK bioequivalence will be evaluated to determine which PK bioequivalence criteria should be chosen to satisfy a given criteria for therapeutic bioequivalence between brand and generic. This step will involve simulations of PK and PD of approved brand and generic drugs considered as NTI. The deliverables from this research will be a) decision tree that will incorporate both qualitative and quantitative features for deciding whether a drug belongs to NTI or not b) bioequivalence criteria for NTI drugs incorporating information from PK and therapeutic window of approved brand and generic drugs.

Public Health Relevance

The aim of this research is to utilize pharmacometric approaches to propose objective criteria to designate narrow therapeutic index (NTI) drugs. The project will also evaluate if alternate criteria are necessary for approving a NTI generic to enhance public health.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Maryland Baltimore
United States
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