Phase

Who? Patients given drug for therapy

Why? Adverse reactions, patterns of drug utilization, additional indications discovered By whom? All physicians

M NDA Submission Average 12 months

N NDA Approved

FIGURE 5-6 The phases of drug development in the United States.

duration of therapy that will be required in practice. Thus, the most profound and overt risks that occur almost immediately after the drug is given can be detected in a phase 3 study if they occur more often than once per 100 administrations. Risks that are medically important but delayed or less frequent than 1 in 1000 administrations may not be revealed prior to marketing (e.g., COX-2 inhibitors). Consequently, a number of unanticipated adverse and beneficial effects of drugs are detectable only after the drug is used broadly. Many countries, including the U.S., have established systematic methods for the surveillance of the effects of drugs after they have been approved for distribution (see below).

Postmarketing Surveillance for Adverse Reactions

For idiosyncratic adverse reactions, current approaches to "safety assessment" in clinical trials are problematic. The relative rarity of severe idiosyncratic reactions (e.g., severe dermatological, hematological, or hepatological toxicities) poses an epidemiological challenge. It is clear that a risk of 1 in 1000 is not distributed evenly across the population; some patients, due to unique genetic or environmental factors, are at an extremely high risk, whereas the remainder of the population may be at low or no risk. In contrast to the human heterogeneity underlying idiosyncratic risk, the standard process of drug development, particularly preclinical safety assessment using inbred healthy animals maintained in a defined environment on a defined diet and manifesting predictable habits, limits the identification of risk for idiosyncratic adverse drug reactions in the human population. Understanding the genetic and environmental bases of idiosyncratic adverse events holds the promise of assessing individual rather than population risk, thereby improving the overall safety of pharmacotherapy.

Formal approaches for estimating the magnitude of an adverse drug effect are the follow-up or cohort study of patients who are receiving a particular drug, the case-control study, where the frequency of drug use in cases of adverse reactions is compared with controls, and meta-analyses of pre- and postmarketing studies. Cohort studies can estimate the incidence of an adverse reaction but cannot, for practical reasons, discover rare events. To have any significant advantage over the premarketing studies, a cohort study must follow at least 10,000 patients who are receiving the drug to detect with 95% confidence one event that occurs at a rate of 1 in 3300, and the event can be attributed to the drug only if it does not occur spontaneously in the control population. Meta-analyses combine the data from several studies in an attempt to discern benefits or risks that are sufficiently uncommon that an individual study lacks the power to discover them.

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