Importance to FDA

The presence of generic drugs on the market helps to ensure availability of quality medicines at a lower cost to the American public.

FDA fosters the development of complex generic drug products in particular in our scientific work because complex products represent nearly one-third of brand drug products currently used but have less generic competition than non-complex drugs because they are harder to genericize.

Some factors considered when determining whether drugs are complex include whether the products contain complex active ingredients, complex formulations/dosage forms, and/or are delivered through complex routes of delivery or with complex drug-device combinations. Evaluations of complex generic drug products often require advanced analytical technologies to properly assess quality attributes, critical and advanced quantitative methods, and modeling and data analytics methodology to establish scientific standards that would ensure therapeutic equivalence in patients. FDA prioritizes research to develop methods and approaches for establishing the sameness and bioequivalence of generic complex drug products with these and other factors in mind. Research on complex drug products informs FDA’s development of guidance documents for industry addressed to generic drug developers, and review of applications.

Examples

FDA’s scientific work on complex generics includes:

• Developing physiologically based pharmacokinetic (PBPK) models for locally acting drugs and use of PBPK models to predict how formulation properties may affect the amount of drug available to have a therapeutic effect at a certain time after taking the drug.
• Applying quantitative clinical pharmacology approaches to address multiple challenges in bioequivalence studies, including defining appropriate standards for narrow therapeutic index (NTI) drugs and determining appropriate comparative clinical endpoints when needed. NTI drugs are products where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.
• Evaluating advanced analytical technology to enhance the information content (e.g., improved precision and accuracy) of data used to compare complex generics to their reference listed drugs. Using improved analytical technology for complex drugs with many attributes results in improved sensitivity and resolution and provides additional means to support a determination that generic versions are bioequivalent to the reference product.
• Identifying alternatives to comparative clinical endpoint bioequivalence studies for evaluating the bioequivalence of products containing certain locally acting oral drugs. FDA is currently conducting a study to validate use of an alternative approach for comparing canine oral dosage forms containing both locally and systemically acting active pharmaceutical ingredients. The results of this study will impact pre-approval generic animal drug applications and the evaluation of post-approval formulation changes for innovator and generic animal drug products.
• Establishing the Center for Research on Complex Generics to increase access to safe and effective complex generic drug products through collaborative research, training, and exchange. The center facilitates communication and information sharing among FDA, academia, and generic drug companies. It also will make complex analytical assays and pharmaceutical development expertise accessible to the generic industry to support more efficient development of high-quality complex generics.