Medical Device Daily Washington Editor

The FDA last week released another clutch of guidances under the Critical Path Initiative, with the goal to push clinical trials along without incurring undue danger to trial subjects or in post-approval commercial use.

Dubbed the Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) initiative, the accompanying press release notes that the agency wants to “leverage existing oversight done by private entities to accomplish the agency's risk-minimization goals.” Underlying much of the impetus behind these guidances is the increased use of multi-center trials and the related burden on institutional review boards (IRBs).

Janet Woodcock, PhD, deputy commissioner for operations at the FDA and the chair of the HSP/BIMO steering committee, unveiled the initiative during the annual meeting of the Drug Information Association (Horsham, Pennsyl-vania), held at the Georgia World Congress Center in Atlanta. The initiative includes two final guidances, one each on the subjects of centralized IRBs and clinical trial data monitoring boards (DMBs), as well as a draft guidance on a process for referrals to the agency for pediatric clinical trials.

Other items in progress include a set of rules for clinical trials conducted outside the U.S., registration requirements for IRBs, and an update on adverse event reporting to IRBs, which the agency said is also a response to a “major trend toward multicenter trials.”

The guidance for centralized IRBs reminds of “substantial growth in the amount of clinical research generally, the number of multicenter trials and the size and complexity of late-stage clinical trials,” a trend that has placed “considerable burdens” on sponsors and clinical investigators as well as IRBs.

The agency said it wants to cut out the “unnecessary duplication of effort, delays and increased expenses” incurred by these trials, giving the example of multiple IRB reviews of consent forms. The hope is that “greater reliance on a centralized IRB review process” could cut down on delays and reduce the burden on IRBs, an idea said to be “consistent with the requirements of existing IRB regulations.”

One of the elements that a centralized IRB will have to incorporate into its work will be “the local context of the research” engendered by “sensitivity to community attitudes and the ability to ascertain the acceptability of proposed research in terms of institutional commitments.”

To that end, central IRBs must document “in meeting minutes or other records how it considered relevant local factors for the various communities” that serve as study sites. IRBs will also have to write procedures that “describe how it will perform its initial and continuing review [of] responsibilities at remote sites.”

This guidance seems to suggest the formation of a new kind of IRB, perhaps a “super-IRB,” with an expanded membership adequate to oversee numerous trials.

In an e-mail response to questions posed by Medical Device Daily, Woodcock declined to comment on such a possibility.

The guidance for data monitoring boards points out that DMBs are not currently required in the exception of trials conducted in emergency care settings in which informed consent is either impractical or impossible.

However, safety concerns may suggest the use of a DMB when a treatment regime is novel, when existing data suggest safety problems or when “favorable or unfavorable early results might ethically require termination of the study before its planned completion.”

The practicality of DMBs also is addressed, with the agency commenting that such a committee would not have much opportunity to do its work for a trial of short duration. Still, the FDA insists that short-term trials with “important safety concerns” might call for “special mechanism . . . to permit DMC evaluation and input.” Another approach would be the intermittent conduct of a clinical trial to allow data review “before an additional cohort of participants would be enrolled.” The guidance also points out that “a DMB can help assure scientific validity (and perception of such) of the trial.”

As for the composition of a DMB, the guidance says that most “are composed of clinicians with expertise in relevant clinical specialties and at least one biostatistician.” On the other hand, for any trial “with unusually high risks or with broad public health implications,” a sponsor might do well to include a medical ethicist with clinical trial experience, and some trials might also benefit from the inclusion of other specialists, such as toxicologists and epidemiologists. The guidance also comments that “[p]rior DMB experience is important when considering the committee as a whole.”

As for how many sites and/or subjects a study would have to encompass before the FDA would want to see a DMC for oversight, Woodcock told MDD that it “would really depend on the setting and the risk.” However, she indicated that the history of the sponsor would not be a factor in the agency's interest in the use of a DMB.

The referral of pediatric trials to the FDA is made possible by the inclusion of subsection 50.54 to 21 CFR Part 50. This would allow the commissioner of the FDA to overrule an IRB decision to suspend a pediatric clinical trial if the commissioner concludes “that the clinical investigation, in fact, satisfies the conditions” of the three previous subsections of Part 50 despite an IRB's conclusion to the contrary. The open comment period on this draft ends July 10.

Alternately, the commissioner could approve the trial if the trial “presents a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children,” and if the trial fulfills two other requirements. They are that the trial will be “conducted in accordance with sound ethical principals; and adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.”

This draft guidance notes that the paperwork requirements for IRBs would be minimal because the explanation for an IRB's refusal “will already be part of the IRB meeting minutes,” and notes that “only a very small percentage (approximately five per year) are expected to refer a clinical investigation to FDA.”

Woodcock declined to respond to a question from MDD concerning what prompted the agency to allow sponsors to appeal to the commissioner to override IRB decisions.