FDA Should Clarify Real-World Evidence Criteria, HHS Advisory Panel Says

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By Jeannie Baumann

An HHS advisory panel wants the FDA to clarify when the use of real-world data constitutes a clinical investigation that would be subject to the agency’s regulations.

The recommendation from the Health and Human Services Secretary’s Advisory Committee on Human Research Protections (SACHRP) was part of commentary about a draft guidance document the Food and Drug Administration released last summer on the use of real-world evidence to support regulatory decision making for medical devices. SACHRP approved several recommendations May 26, the last day of the committee’s first two-day meeting in 2017.

Questions of whether and how to incorporate real-world evidence into the FDA’s regulatory decision-making process have gained momentum over the past several years on Capitol Hill, at the agency level, and in health policy circles. Congress’s latest bill to revise and extend FDA user fees ( S. 934), still under consideration, and the 21st Century Cures law ( Pub. L. 114-255) to spur biomedical innovation both direct the FDA to expand the use of real-world evidence in regulatory decision making.

“The current version of the draft guidance does not provide sufficient information to be of utility to sponsors, investigators and [institutional review boards], and because of the limited fact patterns does not provide objective criteria for determining whether a given clinical investigation needs an [investigational device exemption],” the SACHRP commentary said.

The FDA defines real-world evidence as “information on health care that is derived from multiple sources outside typical clinical research settings, including electronic health records (EHRs), claims and billing data, product and disease registries, and data gathered through personal devices and health applications.”

The move to consider sources other than randomized clinical trials has been controversial at times. Public Citizen said such a change would weaken the FDA’s standards for approving the medical products administered in patients. But former FDA Commissioner Robert Califf, a key figure promoting real-world evidence, rejected the notion these activities were incompatible with randomized clinical trials or compromised the safety and efficacy of approved products.

The FDA released draft guidance last July to establish the criteria to help determine if real-world data sources “are of sufficient quality to potentially generate valid scientific evidence” for medical devices. SACHRP applauded the agency’s effort to address what it described as difficult and important issues while encouraging the FDA to think more broadly.

SACHRP recommended the FDA should provide the regulated community with clear, objective criteria that IRBs and other regulated parties can use to determine:

  •  when research is a clinical investigation, and if it is, when it is significant risk and needs an investigational device exemption,
  •  when the investigational device is non-significant risk and can proceed under the abbreviated IDE requirements, and
  •  when it is exempt from the IDE requirements.
The comment period on the draft guidance ended Oct. 25. SACHRP first considered the draft guidance at its previous meeting in October and didn’t reconvene until May 25.

SACHRP recommendations aren’t binding, but they are forwarded to the HHS secretary’s office for the advisement of any human subject-related policymaking issues.

New Implementation Date?

SACHRP also called on the federal government to push back the January 2018 implementation date for final revisions to the Common Rule.

The new rule marked a major overhaul of the regulations that protect research subjects with new requirements for informed consent, new activities that will be exempt from the regulations, and several other changes. Top HHS administrative officials are reviewing the Jan. 19 rule, putting in a holding pattern these changes and cutting by at least half the amount of time institutions have to comply with the changes. Jerry Menikoff, director of the HHS Office for Human Research Protections, indicated at the meeting the HHS is considering pushing back the implementation date.

In a recommendation about compliance and transition provisions on the final rule, SACHRP asked HHS Secretary Tom Price to “take notice of considerable uncertainty in the research community about whether the final rule will take effect on January 19, 2018, as published, or will be delayed or modified by executive or congressional action.”

The committee asked to move the implementation date to one year from when any periods of uncertainty are over and three years for a provision to require single IRB review of multisite studies. These dates would mirror the original plan that gave institutions one and three years, respectively, to come into compliance.

Elyse Summers, president and chief executive officer of the Association for the Accreditation of Human Research Protection Programs, also called for a delay. Implementing the new rule requires substantial costs in staff time, information technology upgrades, institutional policy creation, and education efforts, she said.

“Given that it is anything but clear whether the new rules will remain intact, it seems particularly egregious, not to mention unrealistic, to expect organizations to have essentially two systems of human research participant protection in place with a toggle switch that can be flipped for full compliance on Jan. 19, 2018,” Summers said during the May 25 public comment portion of the SACHRP meeting.

Incidental Findings

The committee also approved a final document on incidental findings in research, or “discoveries of individual-level findings that are unrelated to the goals of the study.”

“The usual construct of an incidental finding is a directly actionable (clinically or otherwise) finding that needs to be provided to the subject in a timely manner,” the SACHRP recommendation said.

At the same time, the committee said, research ethics require investigators to avoid undue harm to subjects. “[T]o the extent that the return of incidental findings to subjects could lead to harm or discomfort, there must be consideration of whether it is appropriate to return such findings,” SACHRP said.

The recommendation said federal research agencies should acknowledge that incidental findings aren’t individual research results because incidental findings are less of a research issue and more of a clinical one.

“This will ensure flexibility in the consideration of whether and how to return incidental findings, and will make clear that IRBs and institutions are not out of compliance if they do not address returning incidental findings,” recommendation said.

The document is the last in a four-part series of recommendations on the sharing of study data and results and builds on previous recommendations about the public release of data, the return of general study results to subjects, and the return of individual study results to subjects.

SACHRP’s next meeting is scheduled for July 25-26 in Rockville, Md.

To contact the reporter on this story: Jeannie Baumann in Washington at jbaumann@bna.com

To contact the editor responsible for this story: Randy Kubetin at RKubetin@bna.com

For More Information

More information on SACHRP's May 25 to May 26 meeting is available at http://src.bna.com/pqc. The FDA draft guidance on real-world evidence for medical devices is available at http://src.bna.com/pqd.

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