Narrow Therapeutic Index Drugs: FDA Experience, Views, and Operations.

The U.S. Food and Drug Administration (FDA) has defined narrow therapeutic index (NTI) drugs as "those drugs 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.

Analysis of imprecision in incurred sample reanalysis for small molecules.

Over the years, incurred sample (IS) reanalysis (ISR) has become a tool to confirm the reliability of bioanalytical measurements. The recommendation for ISR acceptance criterion for small molecules is at least 67% of ISR samples that have reanalyzed concentrations within 20% of their original concentrations when normalized to their means. To understand the relevance of the ISR acceptance criterion and sample size requirements, simulated ISR studies evaluated the probability of ISR studies passing the acceptance criterion (ISR pass rate) as a function of IS imprecision and sample size.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product.

Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration.

Background: In the US, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the generic formulation provides the same rate and extent of absorption as (ie, is bioequivalent to) the innovator drug product. Thus, most orally administered generic drug products in the US are approved based on results of one or more clinical bioequivalence studies.

Objective: To evaluate how well the bioequivalence measures of generic drugs approved in the US over a 12-year period compare with those of their corresponding innovator counterparts.

Bioequivalence approaches for highly variable drugs and drug products.

Over the past decade, concerns have been expressed increasingly regarding the difficulty for highly variable drugs and drug products (%CV greater than 30) to meet the standard bioequivalence (BE) criteria using a reasonable number of study subjects. The topic has been discussed on numerous occasions at national and international meetings. Despite the lack of a universally accepted solution for the issue, regulatory agencies generally agree that an adjustment of the traditional BE limits for these drugs or products may be warranted to alleviate the resource burden of studying relatively large numbers of subjects in bioequivalence trials.