Policy developments in regulatory approval.

Abstract

Although radical changes in drug regulation are rare (e.g., the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendment to the Act creating an effectiveness requirement), regulations and guidance do evolve significantly in the face of new problems and accumulating experience. Recent changes have been driven by the Food and Drug Administration Modernization Act (FDAMA), user fee legislation, the International Conference on Harmonization, recent safety related drug withdrawals, and concerns about trial ethics and investigator conflict of interest. FDAMA and guidance developed in response to it has helped circumstances in which FDA would rely on a single study to support effectiveness and the circumstances in which surrogate endpoints could support approval. An ICH Document 'Choice of control group and related design issues in clinical trials' focussed attention on the ethics of placebo controls (acceptable, even if there is existing therapy, when the placebo-treated patient will suffer no irreversible injury) and the design of 'equivalence' or 'non-inferiority' trials. There has been greatly increased attention to obtaining good dose-response information and to assessing need for modifying treatment in demographic (age, gender, race) and concomitant disease (renal or hepatic function abnormalities) subgroups, and in assessing drug-drug interactions. Other important trends are increasing reliance on non-U.S. data, increasing numbers of FDA-industry meetings during drug development, and new focus on risk assessment and risk management.