Generic alternatives to brand-name prescription medications are emerging as a dominant force in the global drug market as
an increasing number of prescription drugs lose patent protection. In the United States, approximately 110 drugs will go off-patent
between 2007 and 2010, creating opportunities for generic drug manufacturers to bring less expensive pharmaceutical equivalents
to market.1
The availability of generic drugs provides advantages to consumers because of the cost savings over brand-name equivalents,
resulting in increased accessibility to prescription drugs and increased compliance with drug regimens.2,3
Likewise, the importance of generics to the pharmaceutical industry continues to grow: In the U.S., generics comprised 63%
of all prescriptions dispensed in the 12 months ending June 2007, representing an increase of approximately 16% since 2001.1Understanding generics
(C SQUARED STUDIOS, CARTESIA, GETTY IMAGES ILLUSTRATION: PAUL A. BELCI)
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Generic, non-systemically absorbed products (e.g., dermal, otic, ophthalmic, intranasal, and inhalation products) are typically
approved for marketing after their therapeutic equivalence is demonstrated in clinical trials, where the efficacy of the generic
and marketed product is compared. In contrast, pharma companies planning to market systemically absorbed, generic, solid,
oral, immediate-release products (e.g., tablets and capsules) are not required to perform efficacy trials to support regulatory
approval of their product because the safety and effectiveness of the active ingredient have been previously established.
Rather, the generic product must demonstrate bioequivalence to the brand-name original. Bioequivalence trials are designed
to compare the release, absorption, and elimination of the active ingredient from two formulations of a product (i.e., the
unmarketed generic and corresponding brand-name product) and, if successful, demonstrate similarity between both within pre-established,
statistically defined, pharmacokinetic parameters.
Although there are core principles that guide the planning and implementation of bioequivalence trials, there are notable
variations in region-specific regulatory requirements for the design, conduct, and analysis of these studies. Understanding
differences in region-specific requirements is essential as the pharmaceutical industry trends toward globalization.
This becomes apparent when a bioequivalence trial intended to support registration of a generic drug in one region is managed
through a contract research organization (CRO) based in a second region and is conducted in a third region, requiring that
regulatory requirements issued by countries where the trial is conducted and where the test product is intended to be registered
both be satisfied.
Global undertaking
Geographical regions with considerable activity in the area of generic drug development include the United States, Canada,
the European Union, and India. Therefore, this article will discuss study design features reviewed in guidance documents issued
by the United States' FDA,4,5 Canada's Health Canada (HC),6,7 the EU's European Medicines Evaluation Agency (EMEA),8 and India's Central Drugs Standard Control Organization (CDSCO).9
We will provide an overview of bioequivalence trials designed to support approval of solid, oral, immediate-release drug products.
The guidance documents reviewed here primarily apply to studies of systemically absorbed drug products with uncomplicated
characteristics, excluding drug products with characteristics, such as nonlinear pharmacokinetics, long half-lives, high toxicity
or narrow therapeutic ranges.
Before a meaningful review of these guidance documents can be undertaken, it is important to understand the role they serve
in the design and implementation of bioequivalence trials. Guidance documents are intended to provide recommendations and
explanations on how to comply with the regulatory obligations put forward by the agencies. Guidance documents are not intended
to provide binding regulations; therefore, alternate study designs may be considered if supported by sound scientific rationale.
