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CLINICAL TRIAL DESIGN/ANALYSIS GUIDANCE FOR CDRH REVIEWERS

This article was originally published in The Gray Sheet

Executive Summary

CLINICAL TRIAL DESIGN/ANALYSIS GUIDANCE FOR CDRH REVIEWERS should be developed by FDA, the Committee for Clinical Review recommends in a report released March 5. The guidance development is one of six recommendations made in the report for improving device application content and the review of the submissions by FDA's Center for Devices and Radiological Health. The recommendations are based on the committee's review of 29 premarket approval applications, 510(k)s, and investigational device exemption applications. The committee, informally known as the Temple group, says it would "be useful to develop written guidance for reviewers on what to look for in reviewing a study...It is often helpful, particularly to new reviewers, to have a checklist of considerations to guide their reviews." The committee adds that all reviewers and supervisors at CDRH's office of device evaluation "should receive training in the theoretical and practical aspects of study design and analysis" in order to "increase attention to these issues and to assure that guidance is properly applied and communicated." The committee suggests that because of the "ingrained" submission deficiencies that were uncovered in its review, it may be some time before results are produced by any corrective actions. "The problems of study design, conduct and analysis we observed are sufficiently widespread to suggest that they are ingrained and will not be altered overnight." The committee adds: "Many device manufacturers, and perhaps many of their investigators, are unfamiliar with the use of, or do not believe there is need for, clinical studies of rigorous design in the evaluation of medical devices." The group recommends an "evolutionary" approach to changing submission standards, with pending applications being held to existing standards. Additional FDA actions recommended by the committee include greater use of the agency's scientific advisory committees. The group notes that in comments on a draft version of the report, several advisory panel chairs "sought greater participation in the design and monitoring of clinical trials. For important devices, this assistance could be extremely valuable to CDRH." The committee also suggests that the device center could "improve the instructions it gives to advisory committees on their authority to refuse to accept inadequate data as a basis for recommending approval." CDRH already has efforts under way that address several of the committee's recommendations. The agency highlights this fact in a March 5 "Talk Paper" on the report, stating that the committee's findings "validate several steps that CDRH is taking to improve the quality of clinical studies." For example, the group recommends "early interaction between reviewers and sponsors" on study design. At an advisory panel meeting in February, ODE Acting Director Alan Andersen called for early identification of study endpoints and indicated that a symposium on trial design would be held later in the year ("The Gray Sheet" Feb. 15, I&W-5). The committee comments that "it would be especially useful to conduct workshops to consider the appropriate use of" historical controls since they are used extensively in device clinical studies. Another recommendation being addressed is the committee's call for manufacturer guidance on submissions. The group urges creation of guidance on "design and analysis of studies in general and for specific device classes, and on format and content of submissions." Principles incorporated in the documents should include: statement of a clear hypothesis, ability of studies to test the hypothesis (through use of appropriate endpoints, control groups, and sample populations), and data analysis methods, the group suggests. CDRH plans to develop a document outlining general principles of study design and currently has several guidances on specific device types in the works ("The Gray Sheet" March 1, I&W-1). The committee also says that CDRH should provide "consistent and reliable advice" throughout the testing and review process. "If CDRH agrees that a design and approach is acceptable, it should expect to accept the resulting study as appropriate unless new knowledge alters that conclusion." The committee adds that the device center "should consider refusing to file applications containing studies whose design is clearly inadequate." In early November, Andersen told a Regulatory Affairs Professionals Society meeting that the device center would like to institute "quality thresholds" for the filing of applications so that time is not wasted reviewing poor submissions ("The Gray Sheet" Nov. 9, I&W-2). Andersen also acknowledged the need for the device center to adhere to agreements on study design unless the adequacy of the studies is called into question by new information. A final recommendation made by the committee is greater integration of biostatisticians into the review process. Biostatisticians' "increased participation in the review process, from IDE to PMA and 510(k), is an essential component of constructive interaction with sponsors and more comprehensive evaluation of marketing submissions," the report states.
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