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Office of Generic Drugs FY 2016 Regulatory Science Research Report

Office of Generic Drugs FY 2016 Regulatory Science Research Report

Director's Message

Research Topics:


Director’s Message

Kathleen Uhl, M.D.In 2016, the Office of Research and Standards (ORS), a sub-office of the Office of Generic Drugs, continued its efforts to support the regulatory science program established under GDUFA. FDA awarded contract and grant funding to 16 new and 38 ongoing extramural projects in FY2016.

Awards were made in the following five regulatory science priority areas:

  • Post-market evaluation of generic drugs
  • Equivalence of complex drug products
  • Equivalence of locally acting products
  • Therapeutic equivalence evaluation and standards
  •  Computational and analytical tools

ORS managed a total of 87 extramural projects in 2016, as many projects awarded in previous years continued into 2016. This report describes the updates to ongoing activities from projects awarded in previous years as well as the new awards that were made in FY2016. Publications and specific regulatory outcomes from different project areas can be found in the different subsections of this report.

Significant research accomplishments in 2016 include the first demonstration that clinical dermal open-flow microperfusion is a viable approach for bioequivalence evaluation of a topical locally-acting dermatological product. In addition, the results of two bioequivalence studies with lamotrigine immediate release tablets, conducted in patients with epilepsy under clinical conditions, supported the validity of the FDA bioequivalence standards. As a result, the American Epilepsy Society rescinded its 2007 position statement opposing generic substitution of antiepileptic drugs and acknowledged in a statement that drug formulation substitution with FDA-approved generic products reduces cost without compromising efficacy.

We thank our external collaborators for the many scientific achievements made through our research program in 2016. We are excited to continue our work with industry, academia, and other government agencies to further generic drug regulatory science research in 2017, and enhance access to safe and affordable generic drugs for the American public. 


Division of Therapeutic Performance

The Division of Therapeutic Performance (DTP) in ORS facilitates development of generic drug products through pre-ANDA communications with potential applicants about therapeutic equivalence of their proposed generic products. Research in DTP focuses on equivalence for complex and locally-acting drug products.

In the past decade, generic drug use has risen exponentially, but the switch from brand-name to generic drugs, however, has moved more slowly for locally-acting and complex drug products, because the assessment of bioequivalence (BE) is less amenable to traditional plasma pharmacokinetic (PK) methods. Unlike orally-absorbed dosage forms, where the rate and extent of drugs delivered systemically can be compared by blood sampling, the rate and extent of drugs delivered locally or of products with unique formulation features is considerably more challenging to measure and compare.

Consequently, traditional approaches for demonstrating BE do not assess therapeutic equivalence for certain classes of drugs, including locally-acting drug products applied to the skin, mucosal surfaces of the pulmonary tree, gastrointestinal (GI), and genitourinary tracts, ophthalmic and otic products, as well as drugs that have been engineered based on more recent technological advances such as nano-products, liposomal products, and long-acting injectable products with unique formulation characteristics. Research facilitates the development of regulatory recommendations for developing generic versions of these complex drug products. 


Division of Quantitative Methods and Modeling

The Division of Quantitative Methods and Modeling (DQMM) in ORS provides expertise in advanced quantitative methods for the generic drug program and conducts quantitative-based GDUFA regulatory science activities. 

DQMM research activity advances several key tool sets:

  • Physiological based pharmacokinetic (PBPK) models
  • Pharmacometrics for generic drugs
  • Analysis of Big Data for generic drugs

PBPK models mechanistically describe drug release and absorption for oral and non-oral drug products. These models allow DQMM scientists to drive key decisions about regulatory standards and product specifications. Models of the non-oral routes of delivery are critical in evaluating new bioequivalence approaches for complex products.

Pharmacometrics for generic drugs use tools that characterize the variability and pharmacodynamics (PD) effects of drugs to aid decisions about the best way to establish bioequivalence. Quantitative analysis is critical to decisions about optimal BE study design; sensitivity of pharmacodynamics (PD) endpoints; selection of PK metrics, such as partial AUC (pAUC), for BE assessment; and definition of Narrow Therapeutic Index (NTI) drugs.

Methods based on the emergence of Big Data, such as analytics for equivalence of complex mixtures, risk-based models, systems pharmacology, business process models, and post marketing surveillance, inform decisions across the generic drug program.