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INTRODUCTION

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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 discussion of an approach to the diagnosis of drug-induced disease, an overview of the new drug approval process in the United States, monitoring of drug safety postapproval, and the suggested role for the ­medical toxicologist in the discovery, reporting, and prevention of ADEs.

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ADEs are defined as untoward effects or outcomes associated with use of a drug. In this chapter, the word “drug” will be used for a pharmaceutical product and includes prescription and nonprescription medications, and dietary supplements.

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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. 45).

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HISTORY OF THE UNITED STATES DRUG APPROVAL PROCESS

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The evolution of drug product regulation in the United States has generally 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 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 twentieth century in the United States. Relatively recent changes in US drug approval law further changed drug review timelines and prioritization of drug application reviews. Most recently, specific provision of the FDA authorization has designated certain medication classes, such as antimicrobials, to receive extended patent protection as an incentive to develop new medications in an area where growing antibiotic resistance is on the rise and has become a public health concern.

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Examples of the pre-1900—or preregulation—marketed products include aspirin containing heroin sold as cough syrup and wine with cocaine to enhance sales of the alcoholic beverage. There was no legal requirement for systematic testing of products to determine content or the presence of possible adulterants in product formulations. The Pure Food and Drug Act of 1906 required pharmaceutical manufacturers to meet a standard for the concentration and purity of the drugs they marketed. However, the burden of proof was on the FDA to show that the drug was incorrectly labeled or that the ...

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