chapter  3
48 Pages

Chapter 3

ByShayne C. Gad

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).