ABSTRACT
Gad Consulting Services, Cary, North Carolina, U.S.A.
INTRODUCTION
Toxicologists in the pharmaceutical and medical device industries have as their
prime responsibility the identification of any potential risks associated with
therapeutics that their employers intend to take to market and into potential
clinical use. In almost all cases, toxicologists in industry (although they may
possess an individual expertise in one or more target organ systems) must per-
form as generalists, evaluating a compound for a broad range of adverse effects.
Many of the standardized experimental designs that serve for detecting whether
such effects are present (so-called regulatory toxicology studies) are subject to
regulatory mandate and review. This fact and the usual restraints of timing and
cost has historically limited and guided what is done to identify cardiotoxic
agents, including the determination that an effect exists, at what dose levels, and
occasionally to determine whether the effect is reversible. Since the early 2000s,
experience with postmarket identification of cardiovascular adverse effects of
drugs (not limited to those for cardiovascular indications) and medical devices in
patients using these products has dictated a series of changes to the preclinical
evolution of potential products prior to late-stage clinical development. While
changes have been made in the collection or analysis of data to address specific
concerns that arise, such as the exposure of the potential for induction of valvular
heart disease by fenfluramine (Table 1), such changes are limited in nature to
either conducting additional studies or adding measures or means of analysis to
existing study designs. More importantly, such concerns have lead to additional
test requirements as well as modifications to existing study designs. Tests now
required or recommended are both in vitro and in vivo, and will be considered in
these contexts (Table 2).
