For those of us who work in the clinical research field, the last two days have been quite exciting. At long last, the Notice of Proposed Rulemaking for the Common Rule is here, and the field is alive with talk of the proposed changes and the various ways in which the changes would impact the conduct of research in the U.S.
To recap the events, on Wednesday, September 2, the U.S. Department of Health and Human Services (“HHS”), along with fifteen other federal departments and agencies, released an unofficial version of a Notice of Proposed Rulemaking (“NPRM”) for the Federal Policy for the Protection of Human Subjects, known as the Common Rule. (HHS’s Common Rule regulations are found at 45 C.F.R. Part 46, Subpart A.) The NPRM can be found here. An official version of the NPRM is scheduled to be published in the Federal Register on September 8. Comments will be due 90 days after the NPRM is published in the Federal Register (which will be on or about December 7).
To aid our own analysis of the NPRM, we created a redline of HHS’s current Common Rule regulations at 45 C.F.R Part 46, Subpart A against the proposed regulations in the NPRM. In case it is helpful to you as you digest and analyze the NPRM, you can download a copy of this redline here.
Along with many others, we have been reviewing the NPRM and the lengthy accompanying commentary with great interest, and we will be providing clients with our analyses of particular topics addressed by the NPRM in the coming weeks. In the meantime, we wanted to share our high level comments regarding some of the key changes that the NPRM would implement if adopted:
- Informed Consent. The NPRM proposes changes to the informed consent requirement that are aimed at ensuring a prospective subject has sufficient information, presented in an accessible manner and format, to allow the individual to make a well-informed decision about participating in research. Informed consent forms would be required to present the consent elements outlined in the NPRM before providing any other information, and any information provided that is not required under the NPRM would need to be included in an appendix to the consent form. The NPRM clarifies, however, that if a HIPAA authorization were compounded with a consent form, the elements of authorization would be required to be in the consent form itself, not an appendix. Another particularly significant proposed change is a requirement that the final version of informed consent forms for federally supported clinical trials be posted on a publicly available federal website within 60 days after the trial is closed to recruitment. Finally, new elements of informed consent have been proposed for research involving identifiable private information and, as discussed further below, for broad consent to the storage, maintenance, and secondary research use of biospecimens or identifiable private information.
- Secondary Research Involving Biospecimens or Identifiable Information. The NPRM would expand the definition of “human subject” to include biospecimens, whether or not individually identifiable, thus requiring oversight and informed consent for the storage, maintenance, and secondary research use of all biospecimens. However, secondary research involving stored biospecimens or identifiable private information is proposed to be exempt from the full requirements of the Common Rule assuming that the exemption is “recorded” as proposed in the NPRM, that “broad consent” has been obtained according to the NPRM’s standards, that other standards proposed to protect biospecimens and identifiable information outlined in the NPRM are applied, and that limited IRB review confirming the procedures for obtaining broad consent occurs. The NPRM proposes to require specific elements of broad consent to ensure individuals are fully informed about the use of their biospecimens or identifiable private information in future studies. Under the NPRM, the Secretary of HHS would publish templates for broad consent that would include the required elements of consent (and, if used, would not need to be reviewed by an IRB). Additionally, the NPRM proposes supplemental waiver conditions for research involving biospecimens. In addition to the existing criteria, waiver of consent for biospecimens research may only occur where (1) there are compelling scientific reasons for the research use of the biospecimens and (2) the research could not be conducted with other biospecimens for which informed consent was or could be obtained. If an individual refused to consent to the storage or maintenance of biospecimens or identifiable information, an IRB would not be permitted to waive consent for the storage or future use of those materials. Under this new, more stringent waiver standard, the circumstances in which a waiver could be granted by an IRB for biospecimens research would be extremely rare.
- Excluded Research. The NPRM proposes to “exclude” from the regulations certain activities that would currently meet the definition of research and, if involving human subjects, would be covered by the regulations. These proposed exclusions are based on clarification that the nature of the activity is not in fact “research” or recognition that conducting the activity inherently poses low risk or risks that are already adequately protected outside of the Common Rule, for example by the HIPAA regulations or by existing oversight structures other than an IRB. The exclusions offer potential solutions to age-old debates (e.g., the evasive line between research and quality improvement) as well as a more precise application of the protections of the Common Rule keyed to risk.
- Exempt Research. The NPRM proposes eight “exemptions” (declining to perpetuate the “excused” terminology used in the ANPRM). The proposal includes new categories, while revamping and broadening certain existing exemptions and shifting others to the “excluded” bucket. The stated goal is “to better calibrate the level of review to the level of risk involved in the research.” The proposed exemptions require varying degrees of ancillary protection: all require documentation and certain exemptions must be supplemented with privacy safeguards, broad consent, and limited IRB review depending on the degree of risk posed by the research. Several of these protections have been added in exchange for broadening an existing exemption (for example, certain survey research that is currently subject to IRB review under the Common Rule may be exempt under the NPRM assuming that proposed privacy standards are applied). Significantly, the NPRM moves away from the registration and auditing process contemplated in the ANPRM, introducing a safe-harbor option for institutions that elect to employ an exemption determination tool developed by a federal agency or institute. Providing accurate information to the decision tool would be presumed to result in an appropriate exemption determination. Administrative review by the IRB will not be required. Institutions will be faced with policy decisions as to whether to adopt such a tool when it becomes available and who within the institution should be authorized to employ it. The proposed rule envisions investigators making their own exemption determinations, however, only by use of the available decision tool.
- Single IRB Review. The NPRM proposes to mandate reliance on a single IRB for all domestic multi-site research, except when additional IRB review is legally required (e.g., FDA-regulated device trials) or when the federal funding agency (if any) determines that use of a single IRB is not appropriate for the study. The reviewing IRB would be selected by the funding agency or, if there is no federal funder, by the lead institution conducting the research. Any local or additional IRB review conducted would have no regulatory status or authority. To address long-expressed concerns about liability and regulatory enforcement vis-à-vis external IRBs, the NPRM proposes to make IRBs directly responsible for complying with the regulations. Also, “reliance agreements” would now be required as a matter of regulation and would have to set forth the respective compliance responsibilities of the relying institution and the reviewing IRB. Assuming the NPRM is adopted, institutions will need to develop significant new relationships, systems, and processes for ensuring compliance if they wish to participate or continue participating in multi-site research. A particular challenge will be development of mechanisms to assure appropriate attention to compliance with local law, regulations, and other local requirements affecting the research.
- Continuing Review. In an effort to reduce the burden of complying with the Common Rule when doing so arguably does not enhance human subject protections, the NPRM would generally eliminate the requirement for continuing review for studies undergoing expedited review and for other studies in which the only remaining research procedures are data analysis or accessing follow-up clinical data from standard of care procedures. Continuing review would also not be required for certain secondary research use of biospecimens or identifiable private information that is subject to limited IRB review. Note that, assuming the NPRM were adopted, if an IRB conducts continuing reviews when it is not required to do so under these provisions, the IRB would be required to document the rationale for doing so and retain the rationale in the IRB’s records.
- Non-Federally Funded Trials. In order to further the goal that all research, regardless of funding, is conducted in accordance with accepted ethical principles, the NPRM would extend the application of the Common Rule to “clinical trials” conducted at institutions that receive support for non-exempt, non-excluded human subjects research, regardless of the funding for the particular clinical trial. However, as an exception to this general rule, clinical trials that are already subject to FDA regulations would not be subject to the Common Rule (assuming no federal funding). Also, it is important to note that this extension of the Common Rule would apply only to “clinical trials,” which, by definition, would generally include only research studies in which human subjects are prospectively assigned to interventions in the context of biomedical or behavioral health research (e.g., higher risk research, such as surgical trials, which may not currently be regulated).