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Initiatives to improve the safety of drugs after they are marketed arose from the recognition that rare potentially serious adverse drugs reactions (ADRs) are usually identified only after a drug is in clinical use. One has only to recall the example of phocomelia in newborns from exposure to thalidomide, a drug not approved for use in the U.S. at the time but used widely elsewhere from 1957 to 1961 to treat morning sickness in pregnant women and that caused congenital malformations in over 10,000 children (Vargesson, 2015). As a result of this tragedy and other ADRs, many countries have developed postmarketing surveillance systems to identify ADRs and to determine their prevalence and impact.

Approaches to drug safety have evolved in response to increased recognition of three important principles. First, the safety and efficacy of a drug are not fixed at the time of its approval but must be reassessed over its life cycle. Second, drug safety after marketing is affected not only by rare ADRs but also (and perhaps more importantly) by increased risk of common events not recognized initially as ADRs (e.g., myocardial infarction with rofecoxib). Third, strategies that mitigate risk effectively can allow drugs with serious adverse effects to remain on the market (e.g., use of thalidomide for multiple myeloma).

Counterfeit, substandard, and adulterated drugs; incorrect or unsafe clinical use; overdose; and accidental exposure to drugs also impact drug safety (Figure 8–1). This chapter focuses on efforts to improve drug safety by identifying and managing risks associated with the drug and its appropriate use in clinical practice after it is marketed, and on subsequent reevaluation of the drug’s risk-benefit ratio. Many countries implement variations of the approaches we describe; for simplicity, we describe the U.S. system.

Figure 8–1

Postmarketing drug safety is affected by many factors intrinsic to the drug itself and the way it is used.



ADR: adverse drug reaction

CI: confidence interval

DSC: drug safety communication

FAERS: FDA Adverse Event Reporting System

HR: hazard ratio

HRT: hormone replacement therapy

ICSR: individual case safety report

IOM: Institute of Medicine

RCT: randomized controlled trial

REMS: risk evaluation and mitigation strategy


Landmark Laws That Improved Drug Safety

Three landmark laws in the U.S. have been enacted in response to public health disasters. These laws focused on improving evidence of preclinical safety, clinical efficacy, and postmarketing safety, respectively.

  1. The Food, Drug, and Cosmetic Act of 1938 was passed in response to the death of more than 100 patients who received a preparation of sulfanilamide elixir with diethylene glycol as a solvent (Paine, 2017). The legislation required that manufacturers test new drugs for toxicity ...

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