Since the September 8, 2015 publication of the notice of proposed rulemaking ("NPRM") proposing several significant changes to the Federal Policy for the Protection of Human Subjects (the "Common Rule") in the Federal Register, the Department of Health and Human Services ("HHS") Office of Human Research Protections ("OHRP") has received sharp criticism from many in the U.S. research community. OHRP has received over 500 comments on the proposed changes from industry stakeholders, most of them critical, including a recent comment from the Council on Government Relations ("COGR") questioning many of the NPRM's key proposed revisions. In addition, at a town hall meeting regarding the NPRM (the "Town Hall Meeting") on October 20, 2015 by HHS, members of several major research institutions were in attendance and provided HHS and the other agencies involved in the promulgation of the Common Rule with further criticism.

HHS has responded to some of this criticism already. While the initial deadline for comment submission under the NPRM was December 7, 2015, many interested parties expressed concern that the timeframe was not sufficient to meaningfully read and understand the proposed changes and adequately respond to the nearly ninety questions posed by HHS regarding the modifications. In response, HHS announced on November 25, 2015 that the notice and comment deadline would be extended an additional 30 days to January 6, 2016. Please see our previous article regarding the proposed rule, available here.

Background

The proposed changes to the Common Rule would be the first modifications since its promulgation in 1991. HHS, in conjunction with 15 other Common Rule agencies, stated that the objective of these revisions is modernize the federal policy on human subjects research and to align the Common Rule with many changes and advances that have taken place in the research industry in the last two decades. While industry stakeholders agree that the Common Rule needs to be modified to fit technological and other advances that have occurred in the clinical research landscape, the industry response so far to the NPRM has not been positive. Comments criticizing the NPRM have come from research institutions, investigators, universities, physicians, institutional review boards ("IRBs") and patients, among others.

Industry Criticisms

Most of the comments received by HHS to date harshly criticize what are considered some of the key proposed changes to the Common Rule. Perhaps the most significant of these comments came on December 8, 2015 from COGR, an association of 190 research universities and their affiliated academic medical centers. COGR is very influential in the clinical research industry due to the fact its members conduct over $60 billion in research and development annually.

In COGR's 48-page comment on the NPRM, the association highlighted their key concerns with the proposed changes and responded to each of the 88 questions posed by HHS in the NPRM. COGR expressed concern that the proposed changes would subject research institutions to "astronomical costs for policies that are not aimed at improving human subjects protections, but rather represent misguided means to reduce investigators' workload." COGR further recommended that HHS drop from the Final Rule any elements appearing in the NPRM "that are underdeveloped (i.e., the decision tool, consent template, the Secretary's safeguards and the Secretary's list of minimal risk research)" and instead see that these are "developed independently" of the Final Rule, with separate comment from industry stakeholders. COGR feels that many of the changes in the NPRM would lead to a significant increase in burden, delay, ambiguity and cost at the expense of valuable research, all without increasing protections for human subjects.

Finally, COGR expressed disappointment and concern that controversial policies previously proposed or implemented by the National Institutions of Health ("NIH") dominate the NPRM despite strong opposition from many industry players who provided well-reasoned feedback on these controversial policies during the Advance Notice of Proposed Rulemaking ("ANPRM") comment period for the Common Rule in 2011.

Below is a summary of some of the main concerns expressed by COGR as well as other institutions, physicians, investigators and IRBs, in both formal commentary and during the Town Hall Meeting.

Mandate for a Single IRB in Multi-Site Studies. One of the most noteworthy changes outlined in the NPRM was the requirement that all institutions participating in cooperative research studies utilize a single IRB as the reviewing body for the study. The federal funding agency or the lead institution would be responsible for selecting the single IRB. A cooperative study could still be reviewed by an institution's individual IRB, though the results of such review would not be binding or enforced by OHRP.

According to COGR, the mandate for multi-site studies is "destined to create a bureaucratic quagmire for investigators and institutions." Those institutions that are selected to serve as the single IRB would undoubtedly face significant additional costs due to the increased workload that would accompany serving as the reviewing body for multiple locations. COGR noted that because many institutional IRBs are not appropriately staffed or equipped to administratively support the review of a study involving a significant number of sites, central review for multi-site studies is likely to disproportionately fall to major research institutions with large research programs. In addition, it would be necessary for the reviewing IRBs to develop reliance agreements between the central IRB and the collaborating research sites. The development and subsequent negotiation of these agreements, according to COGR, is likely to be a costly endeavor. Resolving issues of liability and indemnification and establishing the necessary documentation requirements between institutions would also add time, cost and effort to the review process that may result in significant delays to research. 

Other commenters have echoed COGR's concerns over the single IRB mandate. Many commenters raised concerns that the mandated single IRB would lack the appropriate expertise and understanding of local issues and local populations to effectively review the protocol as it relates to a specific institution. State-specific requirements may necessitate additional local review and site specific changes to informed consent, although, according to the NPRM, this local review would not be binding or enforced by OHRP.

During the Town Hall Meeting, attendees raised concerns about the internal beliefs and values of particular institutions at which multi-site research was being conducted and how these beliefs will be considered by the single IRB. One attendee raised concerns about Catholic institutions and their compliance with the Ethical and Religious Directives ("ERDs"). Issues such as birth control under the ERDs may require entities to alter the protocol and informed consent in ways that differ from the original protocol reviewed by the single IRB and utilized at all other sites. When questioned whether religious entities could modify protocol that was being used uniformly at other sites in a multi-site study, HHS stated that a site has the right not to participate in research based on its internal values. Any changes to a protocol or a consent form by a single institution would have to be done in conjunction with the single IRB and the single IRB would need to approve such changes.

Additionally, commenters emphasized that individual institutions would still presumably be responsible for conducting institution level reviews. Commenters felt that issues such as privacy, electronic record keeping and pharmacy and nursing procedures are all best evaluated in a setting that is aware of institutional policies, practices and history. Therefore, investigators would still be burdened with submitting protocols to their own local institutions, and local institutions would still need to perform extensive internal reviews. This would undoubtedly result in questions regarding the role and responsibility of the institution versus the review of the single IRB.

Informed Consent for Biospecimens. The NPRM proposed to expand the definition of "human subject" to include biospecimens, whether or not the specimens contain identifiable information. The current regulations define a human subject as "a living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual or identifiable primary information." Biospecimens are often used for continued research unrelated to the purpose for which they were originally collected (a "secondary use"), and it is often possible to extract DNA from biospecimens to obtain individually identifiable data. The NPRM took the position that secondary use without consent should be prohibited because research subjects should have control over the circumstances in which personal information can be derived from their specimens.

Additionally, the NPRM proposed to allow researchers to obtain a one-time broad consent for the storage or maintenance of biospecimens for secondary use in subsequent research studies. The secondary use of non-identifiable biospecimens for research that generates information already known about the individual, such as validation tests and research to develop specific diagnostic tests, would be excluded from the Common Rule.

In its comment, COGR criticized what it called the NPRM's blatant disregard for other federal research guidelines. COGR stated that "of significant concern is what we perceive to be a lack of balance among the ethical principles articulated in the Belmont Report. In particular, we are concerned that the proposed treatment of biospecimens inappropriately emphasizes the principle of respect for persons (autonomy), with seemingly little regard for beneficence and justice." It is COGR's position that this imbalance between the Belmont principles would have a significant negative impact on research involving biospecimens, to the detriment of society at large, all while providing little increase in individual autonomy.

COGR noted that broad consent for future use of biospecimens would greatly expand consent practices, particularly in non-research settings, and would require significant documentation and tracking on the part of health care providers. COGR expressed concerns that only the largest, wealthiest research hospitals would be able to afford the required infrastructure to track consent for biospecimens and that these infrastructure costs would likely come out of already limited research grants and funding. Research institutions often partner with large health systems, community hospitals and clinics that provide non-identified specimens. For many of these institutions, their primary mission is not research. Hospitals and clinics would have to train nurses and staff to obtain such consent, document the results and have a system in place to maintain the documentation for the time when an investigator with a protocol for biospecimen research requires access. With large health systems, the numerous potential entry points for patients seeking clinical care would require development of complex information management systems to track consent and withdrawal of consent processes. Many entities would not have the resources to implement these proposed changes, nor would it be part of their mission.

Other commenters also expressed concern over the proposed revisions regarding biospecimens, particularly with regards to patient privacy and confidentiality. For example, one commenter expressed concern that if the specimen is de-identified, it would in turn become identified if someone had to contact the individual for consent to use the biospecimen in further research. In the town hall Meeting, concerns were also raised over the ability of institutions to obtain broad consent because it would be nearly impossible to elaborate on what types of research would be conducted on the biospecimens, especially since technology is likely to continue to develop and advance in the next five to ten years. Finally, commenters noted that biospecimens from underserved populations served by small community and minority servicing institutions would bear the greatest burden and would be subject to the greatest declines in supply of biospecimens for research, resulting in data sets that are less heterogeneous and further reducing adherence to the principles of justice and beneficence.

Changes to Informed Consent Forms for Research. The NPRM also proposed significant changes to informed consent documents, including proposing that all information required by the Common Rule must be presented first in the informed consent document. This includes the information that a subject would need to know to make an informed decision about whether to participate in the study. All other information provided to the subject by the principal investigator as part of the informed consent process must be attached in an appendix. Additionally, to increase transparency and accountability, the NPRM commentary proposed that consent documents for trials conducted or supported by a Common Rule agency must be posted on a public federal website within 60 days after the close of the trial's recruitment.

COGR supported the notion that consent forms should first provide essential information that a reasonable person would want to know in order to make an informed decision, with any additional information being provided in the appendix. However, other commenters and industry stakeholders expressed concern over this requirement because the question of what constitutes a "reasonable person" and what information they would want in order to make an informed decision on whether or not to participate in a research trial would come into play. What one participant may want to know, another may not. Factors that could sway an individual away from participating in a study may be included in the appendix, which under the NPRM does not need to be signed by the participant.

COGR did, however, express concerns over the requirement that the informed consent documents be posted to a federal website after the trial's recruitment. COGR did not believe that there was any utility in this provision as it creates a new administrative burden without providing any clear additional protections for research subjects or benefit to the public at large. Attendees at the town hall Meeting were also extremely critical of the online posting of informed consent documents because of the limited ability of the mandate to improve the quality of the informed consent form if they are submitted after the enrollment of study subjects. In a webinar on the NPRM, HHS suggested that this requirement would encourage those writing informed consent forms to "think about doing a better job" because the forms would be posted for the public to view. However, due to timing issues, such posting could provide outdated, erroneous or misleading information to anyone viewing the consent forms on the federal website.

The posting of an informed consent document is a one-time requirement under the NPRM. As a result, commenters noted that even if a modification to an informed consent form occurs after it has been posted, investigators would not be required to re-post an updated document. The value of posting an informed consent form is limited unless it is a "living" document of the most current version. According to comments, in a multi-center study, concerns will be raised over whose responsibility it will be to monitor for public commentary to the informed consent forms that are posted on the federal website. This could create a scenario where informed consent forms are essentially "crowdsourced," with unknown implications to the research process. Other commenters also expressed concern over the posting mandate, especially with the costs and potential liability associated with it. According to one commenter, the forms would likely have to be significantly redacted due to proprietary information of the research sponsor included on the informed consent form. The redaction would be time consuming and expensive, and because of the significant rules and regulations involved in such a redaction, investigators may not be qualified to complete the redaction themselves. This means that the general counsel or the IRB would likely bear the burden of this task, making the requirement more burdensome than anticipated.

Practical Takeaways

A common theme among many of the comments submitted on the NPRM thus far is that there is a significant imbalance between the costs and benefits of many of the proposed revisions to the Common Rule. Namely, commenters are wary that the extreme costs of many of these modifications provide little to no additional protections to human research subjects, which according to HHS was one of the main aims of the NPRM. Additionally, industry stakeholders are concerned that HHS has reduced investigators' administrative burden at the expense of shifting such burden to the research institutions, making the changes even more costly.

Despite the HHS extending the comment period for the NPRM by an additional 30 days, industry stakeholders have continued to submit comments requesting an additional extension to allow them to fully respond to all questions posed by HHS.

The changes outlined in the NPRM, if adopted as proposed, would require those participating in human subjects research to evaluate and revise many of their research processes, procedures and policies. The NPRM continues to seek public comment from industry stakeholders under the new extended comment period, which now closes on January 6, 2016. A copy of the NPRM can be found here, and a copy of the comment submitted by COGR can be found here.