Shann Williams has 10 years of experience managing clinical trials. She is a Sr. Director of Operations and the program director of the statistical and clinical coordinating center of the Transplantation Group for the division-wide consolidated coordinating center sponsored by the National Institute of Allergy and Infectious Disease (NIAID). In addition, Shann serves as Rho’s project management operational service leader, an internal expert sharing project management best practices, processes and training.
On January 18, the Department of Health and Human Services (HHS) announced revisions to the Common Rule. The intent of the revisions is to enhance protection for research participants while reducing the administrative burden associated with oversight. This article provides background on the Common Rule, discusses the purpose of the revisions, provides a summary of the changes including which proposals from the review period were not incorporated, and discusses some anticipated impact of the final rule. Stakeholders will need to be compliant by January 19, 2018.
Background
In 1991, the Federal Policy for the Protection of Human Subjects, generally referred to as the Common Rule, was released. The original rule was based heavily on the Belmont Report of 1974 that sought to outline:
- The boundaries between biomedical/behavioral research and the accepted routine practice of medicine.
- The role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects.
- Appropriate guidelines for the selection of human subjects for participation in such research.
- The nature and definition of informed consent in various research settings.
The last revision took place in 2005. Notice of proposed revisions to the Common Rule was published in September 2015 and more than 2100 comments were received, and some proposed changes were not adopted in the final rule.
The Common Rule applies to research using human subjects conducted or supported by HHS or 15 other federal agencies. Pharmaceutical industry studies not conducted or supported by HHS may still fall under similar and largely redundant FDA regulations (e.g. 21 CFR 50, 21 CFR 54, 21 CFR 56). Further, studies conducted or supported by HHS that need to comply with IND regulation would be subject to both the Common Rule and FDA regulations (for example, a study that will support changes to the label for an approved product).
Revision Purpose
According the rule summary, the revision is “intended to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. These revisions are an effort to modernize, simplify, and enhance the current system of oversight.”
Research involving human subjects has grown and developed substantially over the last two decades. The revision cites examples of developments that include the increasing number and type of clinical trials, the use of electronic health data and other electronic data elements, as well as large data combined with more sophisticated analytical techniques. These advances were not being matched by a comprehensive oversight system. Per the revision, “The sheer volume of data that can be generated in research, the ease with which it can be used to identify individuals were simply not possible, or even imaginable, when the Common Rule was first adopted.” The revision also references the President’s Precision Medicine Initiative as a consideration for proposed changes with the central tenant that participants in research should be active partners and not merely passive subjects.
Summary of Changes
The revision to the Common Rule includes the following:
- Enacts new policies for what research subjects should be informed of during the informed consent process. New requirements include:
- A statement added to the consent form regarding whether a subject’s biospecimens – even if non-identified – may be used for commercial profit and whether the subject will or will not share in this profit.
- Whether or not clinically relevant research results will be disclosed to subjects and, if so, how they will be disclosed.
- Requires that one version of the informed consent form used during enrollment be posted for studies conducted or supported by the federal government on a federal website no later than 60 days after last patient, last visit. Responses to the revision suggested using Clinicaltrials.gov as the website to post these forms, but the federal website that will be used has not been determined.
- Creates an expectation that informed consent forms include a succinct summary at the beginning of the document that includes information that would be most important to the person considering participation in the study such as potential benefits and risks, alternative treatments they should consider, and the purpose of the research. According to Jerry Menikoff, Director of the Office of Human Research Protections (OHRP) at HHS, “Over the years, many have argued that consent forms have become these incredibly lengthy and complex documents that are designed to protect institutions from lawsuits, rather than providing potential research subjects with the information they need in order to make an informed choice about whether to participate in a research study. We are very hopeful that these changes and all the others that reduce unnecessary administrative burdens will be beneficial to both researchers and research participants.”
- Allows obtaining a broad consent from subjects for unspecified future research as an option for investigators and requires that 12 elements be included (6 of these are specific to a broad consent).
- Identifies new categories of research that may be exempt from a full IRB review based on the study’s risk profile.
- Requires that multi-center research use a single IRB for research that takes place within the United States. This will become effective 3 years after publication of the final rule in 2020.
- Enforces regulatory compliance for IRBs that are not operated by a Federal Wide Assurance holding institution. Previously the rule held that institutions holding the FWA would be held responsible, thus increasing the reluctance of clinical sites to use a central IRB.
- Alleviates the need for IRB continuing review of ongoing research for studies that were under expedited review, those studies that have completed study interventions and are in analysis, or are in observational follow-up combined with standard of care.
The final rule did not adopt several proposals being considered during the advanced notice of proposed rulemaking time period, including:
- Requiring that non-identified biospecimens be subject to the Common Rule and require consent to be obtained for such specimens as well as imposing further restrictions under which a waiver of consent could be obtained for biospecimen research. The proposed changes that received the most comments were regarding how the rule would impact biospecimens including the expanded definition of “human subject”.
- Requiring that this policy expand to cover clinical trials that are not federally funded
- Enforcing standard privacy practices for identifiable health information and biospecimens
- Adding a list of activities that would meet the definition of “minimal risk” to provide more clarity around this definition
- Requiring that the study exemptions to IRB review be documented and determined in a specific way (e.g., using a specific tool)
Predictions, Questions, and Things that Remain to Be Seen
- The Common Rule document includes projections for quantitative savings and qualitative benefits from years 2017 – 2026. One theme of the NPRM public comments which led to the abandonment of the more controversial proposed changes in this final rule was the lack of details or as the Administrative Procedure Act calls them “terms or substance.” The comments discussed a lack of quality deliverables as well as ambiguity around underlying tools, templates and concepts. The revision cites examples of these not available for public comment at the time of the proposed rule-making: 1) broad consent templates; 2) standards for privacy protection; 3) list of eligible expedited procedures; and 4) study exemption decision tool. Time will tell if the streamlined nature of the final rule as compared to the proposed changes will result in measurable deliverables and the projected quantitative & qualitative benefits.
- In an ideal execution of the new rule, the requirement for multi-site U.S. research to use a single IRB would reduce costs and expedite the research. Notably, the NIH also recently issued their policy on the use of a single IRBs for these types of studies. However, we’ve had first-hand experience following this recent mandate. Some clinical sites have been reluctant or unable to relinquish control over their research to a central IRB authority. We have some studies that have had to go through both a central IRB and institutional site IRBs thereby increasing the study costs and timelines in direct contradiction to the goal of the revision. Since the requirement change for the central IRB not held by a FWA-holding institution be in compliance with the rule will not be made effective until next year, there seems to be high potential that there will be increased costs and burden in the short-term.
- In the same vein of thought, some clinical site IRBs may continue their current practices for full- and continuing reviews regardless of whether those studies meet the revised definition of being exempt from requiring them. Hopefully the changes will provide long-term benefits as more clinical sites become comfortable implementing the revisions and amending their institutional guidelines.
- It is possible that institutions that support Common Rule-only, IND-only, and Common Rule/IND regulated projects will develop policies that generally assure compliance to both the CR and FDA regulations irrespective of which formally applies to any given study.
- Providing study subjects their clinically relevant data has been a topic of discussion and an area of vested interest for some time now. This is certainly a reasonable expectation for study subjects and one that the clinical research community wants to provide. The new rule does not require data to be provided to subjects, but the requirement to tell subjects whether they will receive this data may encourage the clinical research community to move in that direction more quickly. However, there has been very little in terms of generally accepted methods or best practices in the absence of a formal guidance. In order to draft the appropriate consent form language per the updated rule, study-specific decisions will need to be made earlier during the protocol development phase which will impact CRF and database development as well as potentially have study design and randomization schema impacts. Discussions will need to take place around what data is deemed to be “clinically relevant” (e.g., should all data for a given subject be provided or just this subset?), how distributing this data to study subjects may impact blinding considerations, appropriate timing of data sharing (e.g., after LPLV or after that specific subject completes the study), HIPAA considerations, providing the same data to their primary care providers, format and medium of the data to be shared, among many others factors for consideration. The research community will need to start discussing these impacts to ensure the statement included in the informed consent form will accurately convey the intent.
- In addition, it is uncertain what opinions are held by the new presidential administration and what impact those opinions might have.
- With regard to informed consent changes, there is clearly a desire to make ICFs easier for subjects to read, so they fully understand the benefits and risks of participation. While the final rule sets that expectation, implementation of these changes will determine whether they provide the intended benefit.