The Secretary’s Advisory Committee on Human Research Protections (SACHRP) recommended the Department of Health and Human Services consider a new interpretation of “engaged in research,” which is key to whether entities are required to follow Common Rule regulations.

The committee also recommended ways to provide a clearer definition of what is meant by Common Rule agency “support” of research.

“Engaged in research” is mentioned only once in the Common Rule, which states that “each institution engaged in research that is covered by [the Common Rule] shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements of this policy” (45 C.F.R. §46,103(a)).

Between 2008 and 2011 OHRP issued three guidances to help institutions and individuals determine whether they were “engaged in research.”

“This guidance is confusing and at times is inconsistent,” Mark Barnes, co-chair of SACHRP’s subcommittee on harmonization, told the full committee July 20.

SACHRP recommended OHRP adopt “an entirely new definition” of “engaged in research” that would “focus OHRP jurisdiction and attention, and the attention of researchers, research institutions and cognizant [institutional review boards (IRBs)] on those entities (and their researchers) that control the primary features of study design, conduct data analysis, and communicate generalizable results to the larger scientific and public communities.”

“SACHRP acknowledges that adopting an entirely new definition of ‘engaged in research’ will require substantial effort by OHRP staff, and a process of engagement with the regulated community in order to refine application of the standard in various common scenarios, and to formulate meaningful guidance,” the committee said. “SACHRP believes, however, that given the confusion that has attended the application of the current guidances and given the increased prevalence of single IRB review and of ‘decentralized trials’ involving multiple service providers to trials, this effort is needed, and will be needed even more acutely in years to come.”

In addition, SACHRP recommended the new guidance be accompanied by multiple scenarios and their reasonable interpretation under the new standard, and that the regulated community be solicited to nominate scenarios for inclusion in the new interpretive guidance.

SACHRP further recommended that in the new guidance, “OHRP adopt a procedural standard that would respect a reasonable determination by a research institution or cognizant IRB as to whether an entity is “engaged in research.” “Under this procedural approach, if that determination is reasonable and if its rationale of that determination is documented contemporaneously, then OHRP, as a regulatory matter, would afford that determination a presumption of validity, and would not second-guess that determination,” the committee recommendation said.

SACHRP said the standard should be: “A party is ‘engaged in research’ if it (or its employees, staff, or agents) has a key role in designing the research, conducting the research, analyzing and interpreting the results, or gaining informed consent from human subjects.”

“In SACHRP’s view, this standard would firmly place the burden of ensuring that research supported by federal funding rests on the entities and persons that are actually in charge of the research in question. It would simultaneously eliminate from the ‘engaged in research’ scope those parties whose roles are peripheral to the research and/or whose activities are pre-determined and directed in their entirety by those who are ‘engaged in research’ under this new definition.”

SACHRP noted that in applying the revised definition, “research institutions, researchers and IRBs would need to determine those entities that are in direct control of the research, as opposed to those entities that are merely implementing the design and plan provided by others. One factor, though not definitive in all cases, would be the status of prime awardee or subawardee of federal funds used to support the research. Indeed, the Common Rule applies to entities that receive federal funding for human subjects research and that exercise intellectual authority over that research, thus aligning closely with the standards that should apply to what entities are ‘engaged in research’ for Common Rule purposes.”

“Except in the case of a truly ‘pass-through’ entity (such as the central entity of a recognized consortium that merely funnels federal funds to other entities actually designing and conducting research), it would appear that in the vast majority of cases, responsibility for adherence to the Common Rule standards in implementing a research design would certainly include awardees and subawardees,” SACHRP said. “Those awardees and subawardees, in turn, typically bind their own vendors to adhere to study design and to comply with applicable law, including human subjects research standards, and moreover have duties under federal grants principles to select vendors with care, and to monitor vendors’ performance, which would include adherence to the contract scope of work and any quality standards embedded in the contract. These processes and duties regularly occur independent of any [Federalwide Assurance (FWA)] obligations of the vendor.”

The committee noted that some vendors now deemed to be engaged in research “balk at any contractual obligation that they file an FWA and meet all its regulatory requirements. This vendor aversion to filing an FWA can result in difficulty to secure vendors or contractors for research projects. On the other hand, it may be that with a more clear contractual obligation that binds vendors to human subjects research standards, some vendors may also balk at agreeing to those standards.” SACHRP concluded that, with either approach, “some vendors – perhaps many – may not be pleased with being bound to any such standards, with or without an FWA in place.”

However, with the recommended approach, “the obligation of prime awardee and subawardee institutions to monitor vendors implementing research designs and hold them to these research standards will be more apparent. Some institutions may find this to be a new and unwelcome burden and would prefer that OHRP bear this oversight burden through a complex array of FWAs,” the committee said.

“However, given OHRP’s limited enforcement and monitoring resources, depending on the FWA process to ensure human subjects protections by vendors unacquainted with those standards provides slender assurance of compliance,” SACHRP said. “As a formal matter, though, for all these many entities to have an FWA does, admittedly, give OHRP some increased leverage throughout the research enterprise, if OHRP had the resources and intent to use that leverage extensively, which it does not appear to have at the present time.”

SACHRP noted that under the recommended approach, “if the entity is assisting in designing the research, conducting the research or analyzing and publishing the results, and will have actual control of any of those aspects of the research, the entity would appropriately be regarded as ‘engaged in research’ and would be required under the new standard to have an active FWA and to comply with the FWA in all its aspects.”

However, because the proposed standard focuses on control of these aspects of research, it would militate against including as “engaged in research” consultants with defined deliverables, or community-based organizations (CBOs) that may assist in advising on research design, and/or assist in subject recruitment, but that do not make final determinations about study design or recruitment strategy, and whose leaders do not routinely expect publication credit for final results.

“This ‘non-engaged’ status would pertain even if the CBO and its leaders in any published results may merit acknowledgement in any publication for their defined contributions, or even may merit co-authorship under [International Committee of Medical Journal Editors (ICMJE)]  standards, if their involvement is sufficient to meet those standards but does not qualify as the requisite degree of ‘control’ under the proposed standard.”

SACHRP noted that under the existing OHRP guidance, “involvement of an entity in obtaining informed consent from a prospective research participant by itself subjects the involved entity to the status of being ‘engaged’ in the research study.”

SACHRP recommended that in guidance applying the proposed “engaged in research” standard, OHRP set “a general presumption that obtaining informed consent by itself would render an entity ‘engaged in research’ but that the guidance also “accommodate the possibility that an entity whose only involvement is to obtain informed consent in low-risk, non-interventional studies could be considered (but is not required to be considered) by the research institution and the cognizant IRB as not ‘engaged in research’ if in obtaining that consent, participants are offered meaningful and ready opportunities to engage in additional consent discussions with the primary research team, and if their access to that research team for this purpose is facilitated promptly by the entity that is seeking to obtain consent. Finally, the optional determination by an IRB or research institution that the third-party entity is not ‘engaged in research’ in this scenario would be regarded by OHRP as presumptively valid, if reasonable and its rationales documented,” the recommendation said.

SACHRP Examines Meaning of ‘Support’

When OHRP asked SACHRP to study “engagement” it also asked the committee to make recommendations on “what should be included in the concept of HHS support, besides funding of the research grant?”

OHRP has historically interpreted support to include, funding, the provision of identifiable private information, or other tangible support such as the provision of a study drug.

“The primary purpose of this SACHRP recommendation is to provide a clear definition of ‘support’ that will provide the regulated community, including HHS, with consistency in determining when research is supported by HHS, which in turn should ease administrative burden,” the committee said. “The easing of administrative burden must be appropriately balanced with providing appropriate protection to research subjects through application of the Common Rule. This recommendation does not address agencies other than HHS.”

SACHRP recommended that HHS “support” be defined as:

• the provision of funding or items of value (such as equipment or labor) for a research project; and,
• which has documented evidence of the support specific to the research study such as a grant, a service contract, letter of support, or a material transfer agreement.

The recommendation said that examples of factors that lead to specific research projects being HHS supported are documented:

• HHS funding for the specific research project;
• provision of equipment for the specific research project; or
• provision of HHS-held private identifiable data for the specific research project.

The recommendation added that “conduct or support that does not involve documentation such as a grant or services agreement … will lead to specific research projects not being HHS supported.”

“HHS should provide clear guidance on the meaning of support, so that institutions and other parties involved in the conduct of research can accurately determine when a given research project has HHS support or not,” SACHRP concluded.