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FDA Plans Studies into Problems Affecting Complex Generic Drugs

Posted 25 March 2015 | By Alexander Gaffney, RAC

FDA Plans Studies into Problems Affecting Complex Generic Drugs

The US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) is preparing to fund studies to develop models to better evaluate generic drugs, including modified-release drugs and several popular oral anticoagulants.


The study, announced on 24 March 2015 on the federal government's website, is intended "to develop pharmacometric modeling and simulation tools for generic drug substitutability evaluation and post marketing risk assessment," FDA wrote in its grant proposal.

"The goal is to develop pharmacometic approaches (including clinical trial simulation and clinical use/substitution simulation) that will aid [FDA's Office of Generic Drugs (OGD)] in the evaluation of post-market risk and the interpretation of post-market adverse event reports or product substitution complaints."

The grant is being made under the auspices of the Generic Drug User Fee Act (GDUFA), a component of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. GDUFA was passed by legislators in an attempt to bolster FDA's ability to review generic drug products, as well as to improve the regulatory science it uses to assess generic drugs.

The agency has suffered from several generic drug problems in recent years, including bioequivalence problems between some generic products and the drugs they referenced, known as their "Reference Listed Drugs" (RLDs). In plain terms, the generic drugs were not sufficiently "generic" to the original drugs, and FDA was forced to pull them off the market. Affected drugs have included generics of the antidepressant Wellbutrin XL, the ADHD drug Concerta and potentially the blood pressure drug Toprol XL.

In the wake of those scandals, in February 2014 FDA began to plan series of major studies into the safety and quality of generic drugs using money made available to it by GDUFA.

A Focus on Problematic Generics

FDA's newest study is a part of that larger effort, and intends to focus on some of the issues which caused generic drug bioequivalency problems in the past, the agency explained in its grant proposal.

"This study will focus on risk-based methodology on generic equivalents of RLDs that may be most susceptible to 'with cause' switching issues (e.g., modified release oral dosage forms or 'patient perception' of switching issues where differences in efficacy or safety can be readily perceived in clinical practice (e.g., anticoagulants)," FDA wrote.

The study will place an emphasis on studying modified-release drugs with "complex release profiles"—a category of drug FDA called the "most susceptible to excipient effects and subject-by-formulation interactions."

"They often have high inter- and intra-subject variability," FDA added.

Another focus of the study will be non-vitamin K antagonist oral anticoagulants, including apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto). FDA said it wants its study to determine which NOACs are "most likely to encounter switching issues, and least likely to demonstrate post-marketing bioinequivalence."

The grant anticipates a three-year program worth up to $750,000.

A separate grant announcement made by FDA on 20 March 2015 noted the agency will also study the bioequivalency of metered-dose inhalers (MDIs) in a two-year contract worth up to $1.6 million.

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