DEVICE CLINICAL STUDIES SHOULD BE "OVERDESIGNED"

DEVICE CLINICAL STUDIES SHOULD BE "OVERDESIGNED" to account for the likelihood that some data will be invalidated, Richard Chiacchierini, director of the Division of Biometric Sciences in FDA's Center for Devices and Radiological Health, said, at an FDA/industry teleconference on clinical trials Jan. 27. "Very many medical device manufacturers will design a study on the margin of adequacy," Chiacchierini remarked. "If you have a marginally designed study and something goes wrong, you've probably wasted everything." The teleconference was cosponsored by CDRH and the Food and Drug Law Institute.

In "every study I've ever been involved in, and I think anyone who has ever done a study will recognize this, something always goes wrong" that will invalidate some data. Chiacchierini said that if a sponsor develops "an overdesigned study" with "some safety factors" such as a "higher level of control" or a "higher level of treatment assignment," then even if "something goes wrong" that would invalidate some of the data, "you probably have a salvageable claim."

The second in a series of quarterly CDRH teleconferences, the Jan. 27 event followed up on a Sept. 27 clinical trials workshop and was intended to more broadly disseminate FDA policy on device studies "to the 50 participating "download" sites.

During the teleconference, Chiacchierini and Susan Alpert, director of CDRH's office of device evaluation, reiterated many of the points made in a draft of a general device clinical study guidance document released at the September workshop ("The Gray Sheet" Oct. 4, p. 6). For example, they highlighted use of appropriate control groups, factors to consider in calculating sample size and appropriate definition of a study hypothesis and clinical endpoints.

Addressing one specific area of concern, Chiacchierini said that FDA would "like to see more balance among study sites," with "approximately equal numbers [of patients] at sites if you can do that." Having a large majority of patients at only a few of the study sites creates "a potential for huge bias," he explained.

Chiacchierini also took issue with a comment that patients should only be randomized when there is no knowledge that the new device is preferable to the control. The assumption that an unapproved device is the standard of care and therefore preferable "is one that history has proven to be wrong in numerous instances," he said.

FDA participants were asked to, discuss situations in which it is acceptable to modify a device during clinical study. Alpert responded that "in device development, we clearly recognize that [products] are constantly being improved upon and tinkered with." She added, however, that changes should be made only when device design is "stable enough" and "mature enough" that the modifications "are not going to significantly impact on safety and effectiveness." If changes do affect safety and effectiveness, and the "device we started with is not the device that a company wants to take to the market," then data gathered in the study "may not apply," Alpert said.

Commenting on the pace of 510(k) decisions, Jacobson noted that the backlog of pending 510(k)s has been dropping in the first few months of fiscal year 1994 (beginning Oct. 1). The FDAer cited statistics for November, when 503 510(k)s were received and 546 cleared.

The next CDRH teleconference, scheduled for May 12, is expected to focus on 510(k) issues. Topics that may be addressed include premarket notification data requirements and the 510(k) backlog. At a Jan. 25 conference in Washington, D.C., CDRH Office of Compliance Director Ronald Johnson fielded questions on other 510(k)-related issues such as the need for submissions for device changes and the agency's 510(k) rescission policy.

The live teleconference projected a highly polished and professional image, with a news desk-like set and smooth transitions between the three segments on study design, study conduct, and data analysis.

The conference wrapped up with a prerecorded "CDRH News Update" anchored by "CDRH Reporter" James Addams, who introduced presentations by device center Director Bruce Burlington, Deputy Director for Regulations and Policy Joseph Levitt and Deputy Director for Science Elizabeth Jacobson.

Burlington noted that the FDA hiring freeze has been lifted and CDRH is "hiring to its allocated [full time equivalent] ceiling" ("The Gray Sheet" Jan. 17, p. 4). The fiscal 1994 budget increase serves as "a downpayment that will help deal with the backlog" but is not sufficient to eliminate it, he added.

On the issue of device user fees, Levitt remarked that the funds would help the agency accomplish three main goals: eliminating 510(k) backlog, establishing a predictable time frame for application review, and having "the proper support systems in place so that the program works smoothly and in a user friendly Wily to manufacturers."