Understanding the Scientific Issues Embedded in the Generic Drug Approval Process

Report of the American Society of Transplantation Conference on Immunosuppressive Drugs and the Use of Generic Immunosuppressants

“…In 1970, the FDA established the Abbreviated New Drug Application (ANDA) as a mechanism for the review and approval of generic versions of drug products that had been approved between 1938 and 1962 (1,5). For drugs approved after 1962, manufacturers of generic products were required to submit complete safety and efficacy data.…”

“…Neither of these approaches was acceptable because of the expense incurred in undertaking clinical studies and the lack in many cases of published data. In 1984, the Drug Price Competition and Patent Term Restoration Act focused on modifying and accelerating the ANDA procedure and gave the FDA statutory authority to approve generic versions of innovator products approved after 1962 as safe and effective (1,(5)(6)(7). The revised ANDA process does not require manufacturers to include preclinical or clinical data establishing the safety and efficacy of the active ingredients (1,5) because these data were previously documented during the approval process for the innovator product.…”

“…Bioequivalence refers to the absence of a significant difference in the rate and extent to which the active ingredients in pharmaceutical equivalents become available at the site of drug action in the body when administered under similar experimental conditions (1,(8)(9)(10). The surrogate clinical endpoints for bioequivalence studies are based upon pharmacokinetic parameters of the active ingredient for rate and extent of absorption, Tmax, Cmax, and AUC.…”

“…They should be older than 18 years of age and represent a reasonable representation of different ages, ethnicities, and gender (1,8,14,15). Performing initial bioequivalence studies in healthy volunteers is a safe stepwise approach to generic drug testing, and does not preclude further testing in the target population.…”

“…Although the approval process has been in place for more than 30 years, generic substitution remains a topic of heated debate among health care professionals, members of the pharmaceutical industry, consumers, and government officials. These debates are often fueled by a lack of understanding of the mechanics of the generic drug approval process and the scientific rigor underpinning the methodology (1). At the core of this controversy is whether the current FDA standards regulating bioequivalence are restrictive enough to ensure that generic formulations of critical dose drugs are clinically equivalent to their brand name counterparts.…”