Medical Device Daily Washington Editor

FDA has issued a draft guidance for diagnostic and medical device clinical trials and takes on a few bones of contention with industry along the way, including the meaning of the phrase “least burdensome.“ However, the agency also indicates that it is unfriendly toward a sponsor's training of doctors and other providers participating in those clinical trials unless the sponsor is willing to do the same for doctors in routine practice. This, the guidance indicates, applies even to studies engaged prior to the pivotal clinical trial.

FDA offers an interesting caveat early in the guidance, stating that “even with a well-planned design, the study may not yield the results expected or necessary to demonstrate safety and effectiveness,“ adding that a sponsor may have to “re-assess their goals . . . and conduct additional studies“ to demonstrate safety and efficacy. Whether that's intended as a signal that the stand-alone pivotal trial will become a less common species is difficult to parse, but industry might be inclined to read it as such, given that even though much of the emphasis at the agency's Center for Devices and Radiological Health has been on the 510(k) channel, observers have awaited some signal about a formal toughening of the PMA mechanism.

The draft also says that a trial should account for variability in “the performance of the device when used by practitioners of varying expertise.“ Later in the guidance, however, FDA says that if the sponsor intends to offer no training to practitioners in real-world use, providers engaging in the trial “should not be specifically trained in the use of the device“ as a means of ensuring “that the study reflects real-world conditions.“

A substantial portion of the 56-page guidance deals with implantable devices, including a passage addressing exploratory studies. FDA says that it may require “continued animal testing of implanted devices at six months, two years and three years after implant“ even as the pivotal trial is underway.

One of the more interesting aspects of the guidance is that it reintroduces the boilerplate pertaining to the standard of “least burdensome,“ a bit of phrasing that had been omitted from a number of documents issued by the agency over the past year and a half. The guidance goes into some detail about the precise meaning of the phrase, however. FDA says that the principal of “least burdensome“ is described as “a successful means of addressing a pre-market issue that involves the most appropriate investment of time, effort and resources on the part of industry and the FDA.“

The draft guidance notes that it applies to both therapeutic and diagnostic devices as well as those dealing with purely “aesthetic“ considerations. However, the guidance does not apply to humanitarian device exemption studies or to companion diagnostics, which were the subject of a separate draft guidance published in July (Medical Device Daily, July 15, 2011).

On the subject of site selection, the guidance says that a sponsor of a clinical trial should “consider diversity of sites in terms of investigator or operator experience,“ saying that surgeons at tertiary care sites “may have more specialized experience than those at a community hospital.“ FDA says that selecting only referral sites for a study “could lead to a biased assessment of device performance.“

FDA took on a topic of considerable interest to industry in addressing clinical study endpoints, and although this was not the primary point to be made in this portion of the guidance, it may jump out more at device makers than other features of this section of the guidance, even though the topic is not unexplored. The draft guidance says that if a trial is underway “when the understanding of science or medicine changes ... the relevance of particular endpoints, outcomes or measurements may change,“ in which case the sponsor is advised to consult with the agency as to “the best possible course of action.“

In the portion of the guidance deals specifically with diagnostics, the draft indicates a long-standing concern about the “variability in the performance of persons interacting with the device,“ which the agency says can create a need to conduct additional studies to remedy. Another source of bias might be the effects of sequential readings, which has been a matter of concern for reviewers at the radiological devices branch for some time. One potential fix for the sequential problem is, as might be expected, a wash-out period during which a reviewer has time to forget what he or she saw from that patient's other scans.

The draft guidance is open for comment for 90 days from the Aug. 15 date of publication.

Also dated Aug. 15 is an FDA guidance on factors to consider when making risk-benefit determinations for devices under review, including both PMAs and 510(k)s. One interesting portion of the document indicates that “engineering tests that are able to challenge the device under worst-case conditions“ are still applicable despite some of the distaste among advocacy groups for the use of bench tests in lieu of clinical trials.

This draft guidance offers a worksheet for sponsors to employ in anticipating the agency's perspectives on risk and benefit, but also offers some examples, including those involving a diagnostic that was only equivalent to the standard of care, but less invasive. This draft guidance is also open for feedback for 90 days.

Deadlines set for obsolete device filings

FDA announced in the Aug. 16 edition of the Federal Register that another three pre-amendment class III devices have received a deadline for PMA or product development protocols (PD) as a condition of continued marketing. In the most recent example prior to this, the agency gave a deadline for manufacturers to file such applications for cranial electrotherapy stimulators (Medical Device Daily, Aug. 10, 2011).

The latest batch of pre-amendment devices to be addressed are ventricular bypass (assist) devices, pacemaker repair or replacement materials, and female condoms. Perhaps the most interesting passage of all in the FR announcement is that the agency has “concluded that there is little or no interest in marketing these devices“ because of an absence of applications of any kind for any of the three in the past five years. The FR notice states that FDA has no record that the ventricular bypass device was ever marketed, whereas the pacemaker repair category was no longer marketed as of 1992. The female condom, the statement notes, was last marketed in the 1930s.

The regulation goes into effect Aug. 23, the FR statement notes, and interested parties have 90 days past that date to file a PMA or a PDP.