implement active surveillance of specific drugs and diseases as needed in a variety of settings.

Other federal partners in the drug safety system (VA and the Centers for Medicare and Medicaid Services, CMS, in particular) also use automated databases and should work with CDER, as appropriate, to accomplish the goal of improved formulation and testing of drug safety hypotheses for the entire drug safety system. As will be described in Chapter 7, CDER and its federal partners in the drug safety system will need increased resources to accomplish these goals.

Confirmatory Studies

Passive surveillance, epidemiologic research with administrative databases, and active surveillance can be used to answer many drug safety questions. When they do not provide definitive answers, they can sometimes provide guidance for the development of further studies or provide sufficient information to narrow the uncertainty about drug-related risks and benefits and guide regulatory actions and the decisions of patients and providers. In some instances, full-scale observational studies or clinical trials will be required to answer key questions, particularly if the outcome of interest is common in the patients taking a drug. Such studies are often expensive and time-consuming, but they provide valuable information that less rigorous studies cannot provide. For example, the Women’s Health Initiative (WHI) and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) cost an estimated $725 million and $125 million, respectively, but provided valuable evidence about efficacy and safety.

Although $125 million seems like a lot of money, 28.4 percent of the adult population, or about 65 million men and women, of the United States have high blood pressure (Fields et al., 2004), and more than half of them are taking medications for it (Hajjar and Kotchen, 2003). The annual costs of two of the blood-pressure medications used in ALLHAT are about $547 for amlodipine (a calcium-channel blocker) and $83 for chlorthalidone (a low-dose diuretic) (The Medical Letter, 2004). Demonstration that low-cost and older drugs, such as diuretics, are the most effective first-line treatment for high blood pressure can improve health outcomes and save money. ALLHAT also helped to resolve uncertainty about the safety profile of the calcium-channel blockers.

There is no realistic mechanism to ensure that important phase 4 clinical trials are done. As discussed in Chapter 2, some phase 4 studies to be conducted by the drug sponsor are agreed on at the time of drug approval, but for various reasons, many of those studies are never completed. FDA has no authority to compel the completion of these studies, and industry could



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