Mandated Postmarket Studies

Another ''tool'' that the FDA uses to achieve its surveillance and risk assessment goals are mandated postmarket studies, conducted under either PMA conditions of approval (for Class III products) or FDAMA (Section 522) authorities. A sponsor may be required to perform a post-approval study as a condition of approval for a PMA [Title 21 CFR Part 814(a)(2)]. The study questions may relate to longer-term performance of an implant, or focus on specific safety issues that may have been identified during review of the product for which additional information is felt to be needed, postmarket. Results from these studies may be included as revisions to the product's labeling (including patient- and clinician-related material).

In addition to the PMA authority for Class III products, the agency may, under Section 522, impose postmarket study requirements on certain devices. The latter provision, originally mandated in 1990 under SMDA, allows the agency, under its discretion and for good reason, to order a manufacturer of a class II or class III device to conduct a postmarket study if the device: (1) is intended to be implanted in the human body for more than one year; (2) is life-sustaining or life-supporting (and used outside a device user facility); or (3) failure would reasonably be likely to have serious adverse health consequences. Although this discretionary authority overlaps the PMA postapproval authority for some products (e.g. PMA Class III implants), it effectively extends FDA authority to cover non-PMA products as well (i.e. those subject to premarket notification). Unless there are unusual circumstances, the Section 522 authority is typically reserved for the latter.

Prior to issuing an order, the FDA will discuss the public health concern with the firm. The concern may arise from questions about a product's long-term safety, about performance of a device in general use or involving a change in user setting (e.g. professional to home use), or notable AEs. Upon receiving an order, the firm has up to 30 days in which to submit their study plan and, by statute, studies are limited to 3-year patient follow-up (or longer if agreed to by the firm). (The FDA soon plans to issue a regulation clearly specifying the requirements for a study plan, conduct, and follow-up.)

The FDA has issued guidance on criteria used in considering order issuance as well as possible study approaches (October, 1998; http:// html). Briefly, the criteria include: the public health issue must be important; other postmarket mechanisms cannot effectively address the issue; the study must be practicable (i.e. feasible, timely, not cost-prohibitive); and the issue is of high priority. The possible study approaches vary widely (designed to capture the most practical, least burdensome approach to produce a scientifically sound answer) and include: a detailed review of complaint history and the literature; non-clinical testing of the device; telephone or mail follow-up of a patient sample; use of registries; observational studies; and, rarely, randomized controlled trials.

Generally speaking, these mandated postmarket studies (both via PMA conditions of approval and Section 522) require the participation of both firms and the clinical community. Problems, however, may arise in the conduct of these studies if, for instance, it is difficult to recruit physician investigators or accrue patients or if industry lacks incentive. These issues particularly resonate with rapidly evolving technologies, where rapid device evolution may make studies of prior models obsolete by the time they are completed.

Although there may be difficulties in study conduct, an example of a Section 522 study reveals the authority's public health importance and its risk assessment role. In 1991, FDA scientists demonstrated that it was possible for polyurethane to break down under laboratory conditions to form 2,4-toluenediamine (TDA). TDA had been shown to be an animal carcinogen. Prior to this it was thought that breakdown could only occur at very high temperatures and pH extremes. The firm that manufactured polyurethane foam-coated breast implants ceased sales in 1991 and agreed to a clinical study under Section 522. The study involved comparing TDA levels in urine and serum samples from women with and without the implants. Although minute amounts of TDA were found in the majority of women with the implants, the increase in cancer risk was determined to be vanishingly small (1 in 1 million) (Hester et al., 1997; DoLuu et al., 1998). The FDA issued a public health correspondence (FDA Talk Paper) on the results and their reassuring implications (Food and Drug Administration, 1995).

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