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INTRODUCTION

This chapter will focus on drug-induced diseases that occur as expected or unexpected adverse drug events (ADEs), as a drug–drug interaction or an ADE causing an untoward drug–disease interaction. Also included in this chapter is a brief overview of the drug development process in the United States and specific aspects of the process that relate to the development of antidotes. In addition, a discussion of an approach to the diagnosis of drug-induced disease, monitoring of drug safety postapproval, and the suggested role for the clinical and medical toxicologists in the discovery, reporting, and prevention of ADEs.

Adverse drug events are defined as untoward effects or outcomes associated with use of any dose of a drug whereas an adverse drug reaction refers to harm from a therapeutic dose. In this chapter, the word “drug” will be used for a pharmaceutical product and includes prescription and nonprescription medications, and dietary supplements.

In the United States, all new prescription and nonprescription medications must be shown to be both safe and effective in order to achieve approval by the US Food and Drug Administration (FDA), a prerequisite for marketing and sale. Dietary supplements fall outside of this legal requirement (Chap. 43) and are regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA).

*Dr. Cantilena completed work on the chapter shortly before his tragic death.

HISTORY OF THE US DRUG APPROVAL PROCESS

The evolution of drug product regulation in the United States has for the most part, been reactionary; that is, most drug regulations were created in response to medicine-related disasters at various times in our history. Prior to 1900, there was no requirement for a drug or medical device manufacturer to demonstrate that the product actually worked (efficacy), was safe when used as directed, or was made to be within precise manufacturing specifications. In addition, no laws existed that required labeled claims on marketed drug products to be proven valid. Any product could be sold as a company desired and it was left to the consumer or health care professional to determine if the products actually worked and were safe. Initiation of medicinal product regulation and the overall evolution of the US drug law and regulations are closely linked to specific medical product disasters that occurred during the 20th century in the United States. Relatively recent changes in US drug approval law further changed drug review timelines and FDA prioritization of drug application reviews. Most recently, specific incentives to encourage the development of new antimicrobials and novel therapeutics that impart a significant improvement in the effectiveness or safety of drug treatment compared to existing or the current standard of care for the condition have been included in provisions of the FDA authorization legislation.28 These incentives include extended patent protection or a shortened FDA review timetable that comes with priority review designation.

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