FasterCures Comments on Federal Policy for the Protection of Human Subjects
Jerry Menikoff, M.D., J.D.
Office for Human Research Protections
U.S. Department of Health and Human Services
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Re: Federal Policy for the Protection of Human Subjects, Notice of Proposed Rulemaking
Dear Dr. Menikoff,
FasterCures welcomes the opportunity to provide comment on the notice of proposed rulemaking (NPRM) for the Federal Policy for the Protection of Human Subjects (i.e., the Common Rule) that was published in the Federal Register on September 8, 2015 (Docket ID: HHS-OPHS-2015-0008). FasterCures, a center of the Milken Institute, is a non-profit, non-partisan action tank driven by a singular goal – to save lives by speeding up and improving the medical research system. We work with all stakeholders – academia, patient groups, philanthropies, industry, and government – to identify and implement opportunities to enhance research efficiencies across all disease types. Our commitment to expanding patients’ roles in medical research is embodied in our Patients Count program, which aims to harness the science of patient input. Our reputation as a successful collaborator and partner has been illustrated through our active involvement in recent policy efforts, such as the 21st Century Cures initiative in the U.S. House of Representatives and the Patient-Focused Drug Development initiative at the Food and Drug Administration (FDA).
Given that the Common Rule was first implemented over 20 years ago to establish a system of protections for human participants in research,  FasterCures supports the NPRM’s stated goal “to modernize, simplify, and enhance the current system of oversight.” The research enterprise and the role of patients have evolved over the past decades. The time has come to update the rule, and the NPRM proposes changes to almost every aspect. As we will discuss below, there are many reforms that are straightforward, common-sense improvements that will streamline the system while maintaining protections provided for research participants. The federal government should work to implement those reforms as quickly as possible. There are a series of proposals, however, that are highly complex and, in some instances, seem to be working at cross purposes. These would have uncertain impacts on patients/participants and the overall research enterprise. We want to ensure that the changes made are effective. For that reason, FasterCures recommends that there is a commitment to a deliberative, inclusive, transparent process to work with all stakeholders to advance the issues and come to the best possible conclusion for patients/participants and the overall research enterprise.
The Common Rule establishes a regulatory framework to ensure that research involving human participants is done to the highest ethical standards, balancing responsibilities to the individual and to society as a whole. The Belmont Report, issued in 1979, established an ethical framework for research that is still broadly accepted, and any changes to the Common Rule should maintain an appropriate relationship among the three ethical principles established by that report: Respect for Persons, Beneficence, and Justice.  In addition, changes should be meaningful in that they will clearly improve protections while not improperly impeding valuable research or adding overly burdensome costs. This is a challenging task, and many of the issues being addressed in the NPRM do not have simple answers. We thank the Office for Human Research Projections (OHRP) and its federal partners for working diligently over many years to grapple with these complex issues in service of the research enterprise and, ultimately, in service of patients in need.
The NPRM seeks to undertake a comprehensive update of the entire set of regulations. Given the breadth, our comments will address a subset of changes being proposed. We will focus on perhaps the most significant proposed change, the treatment of biospecimens in research. We will then discuss a set of proposed reforms to streamline the regulatory process. We will close with general comments on the NPRM and a suggested path forward.
Use of biospecimens in research:
The most significant change proposed by the NPRM is the re-definition of “human subjects” to include biospecimens (§___.101, §___.102), regardless of identification status (i.e., whether or not the specimen is tagged with a person’s name or unique identifier). The NPRM and associated commentaries from the OHRP and the National Institutes of Health (NIH) state that the driving motivation for this change is to enhance the ethical principle of Respect for Persons by requiring researchers to seek consent from participants for all uses of biospecimens regardless of their identification status. This would be a change to the current Common Rule, which does not require consent for secondary research using non-identified biospecimens because of the minimal risk to the individual and benefit to society of the secondary research.
While research ethics are the primary drivers of the Common Rule’s provisions, they cannot be divorced from the practical implications of the regulation. The challenge is obviously how to strike this balance so that there is a 360-degree view taken. For a biospecimen to be available for research, the NPRM’s proposal will require a consent record to be established and maintained regardless of the identification status of the specimen itself. This record will need to be passed from institution to institution as the specimens are used in research studies. This consent record will, by definition, contain sensitive personal information about the research participant and her health status, and therefore will require a very high level of information security and administrative oversight. The NPRM proposes new broad consent processes intended to facilitate secondary research by limiting the need for Institutional Review Board (IRB) review of secondary research using biospecimens that were collected with broad consent that explicitly requests consent for all future secondary research (§___.104, §___.116). There have been important innovations in obtaining and tracking informed consent electronically using mobile devices that could reduce the administrative burden of this proposal. However, it is not known how quickly such systems could be universally deployed, or if it would be appropriate to apply them to every type of research study involving human participants. While the NPRM’s requirement for consent for use of non-identified biospecimens is intended to enable participants to have more control over their specimens, it is possible that the accompanying proposal to allow a broad consent agreement for use of those specimens could result in such vague consent documents that patients would actually be less empowered to know what they are agreeing to. The NPRM states that the government will develop and promulgate a broad consent template at a future date. The exact nature of this template will be critical for the community to fully understand the implications of these aspects of the NPRM. A further example of how proposals in the NPRM appear to be working at cross-purposes, §___.111(a)(8), appears to disincentivize returning results to study participants. Biospecimens collected using the broad consent template could be used in secondary research without additional IRB review. However, if the researcher wants to return results to participants, the study would need to be reviewed by the IRB. If a goal of the NPRM is to empower research participants, could this be a disincentive to return results?
It is critical that both the benefits and costs of any change to regulation are considered. The near- and long-term impacts on the day-to-day practice of research stemming from the NPRM’s proposed change to the use of biosamples can’t be predicted with certainty, but have been estimated by the NPRM and by members of the research community. Based on the comments submitted to the Common Rule’s Advanced Notice of Proposed Rulemaking (ANPRM) and the NPRM public comments submitted to date, it appears that many research institutions and professional societies are concerned that maintaining a consent record for all biospecimens could:
- Increase the cost of collecting biospecimens and maintaining specimen repositories, thereby disincentivizing proof-of-concept, retrospective secondary research studies.
- Have an especially negative impact on the collection of biospecimens during clinical care, as compared to collection in a research environment. (There are practical and ethical questions related to the ability to obtain meaningful consent during a clinical encounter.)
- Reduce the collection of biospecimens from underserved populations. (Clinics and community hospitals serving poor populations are chronically underfunded and could be hard-pressed to support the administrative burden of the new consent record system.)
The NPRM states that the change to the rule regarding biospecimens is to enhance the ethical principle of Respect for Persons. If the above three outcomes were to occur, the other two ethical principles, Beneficence and Justice, could be negatively affected:
- Beneficence could be affected by reducing benefits to society (due to delayed or forgone research), and by increasing risks to participants (due to the need to maintain a broadly disseminated consent record containing highly sensitive personal information, increasing the chances of a data breach).
- Justice could be affected by the potential for fewer biospecimens being collected from underserved populations, reducing their ability to participate in and benefit from medical research.
It is surprising that the NPRM does not propose a change requiring consent for use of non-identified data in secondary research, as it does for biospecimens. While data are not physically extracted from a research participant in the way that a biospecimen is, their ability to represent a person is just as significant as that of a physical specimen. In many respects, data are much more powerful research tools because they can be easily shared and compared/combined with other data in ways that a physical specimen cannot (e.g., medical records, genome sequence data). The NPRM proposal would create a double standard, one for biospecimens and another for data. The value of biospecimens lies in the data contained within them, so it is not clear why a more stringent standard would apply to the material than to the data it contains. The NPRM’s different treatment of data and biospecimens underscores the complexity of the issue and suggests that more analysis and deliberation involving all stakeholders are required before implementing this proposed change to the Common Rule.
Streamlining the Common Rule:
Many aspects of the NPRM are proposals to streamline the Common Rule and are intended to enhance the research enterprise, balance regulatory oversight with risk, and maintain an appropriate relationship among the Belmont Report’s three ethical principles. The intent of these reforms is to enable researchers and IRBs to focus their efforts where they will most benefit research study participants and the overall medical research enterprise. We will comment on a subset:
- Requiring that informed consent documentation presents key information relevant to study participants up front (§___.116) will reverse the trend of highly complex documentation that many perceive to be focused on protecting research institutions instead of effectively informing study participants.
- Establishing a new set of research that is excluded from the Common Rule and streamlining review of work that is subject to the regulation will relieve regulatory burden. Most IRBs are staffed by volunteers with other full-time jobs. Their time should be directed at reviewing the “hard” cases (e.g., complex studies with the potential for significant risk to the participants) and should not be burdened with the review of activities that are not research, or are very low risk. Several NPRM proposals would streamline IRB responsibilities, enhancing their ability to protect research participants and maintain the integrity of the system:
- The NPRM creates a set of activities that are excluded from the Common Rule (§___.101) due to the fact that they are not research (e.g., oral history, journalism, public health surveillance) or are very low risk (e.g., surveys, publically available information acquired for non-research purposes). This new category is especially beneficial to IRB workloads and to advancing research because, unlike exempt activities, excluded activities do not need IRB confirmation of their excluded status.
- Eliminating the requirement for continuing IRB review of certain studies that have transitioned to a phase of minimal risk to participants (e.g., data analysis only) (§___.109) will free up IRBs to focus on novel and higher risk studies.
- To facilitate exemption determinations, the NPRM also proposes that the federal government develop a “decision tool to assist in exemption determinations” (§___.104). Assuming that correct information was provided, if the tool determines that a study is exempt, no further review by an IRB will be required. The NPRM does not provide detail on how this decision tool will be developed, and it seems that there could be unintended negative consequences if implemented poorly. We recommend that the federal government undertake a transparent and inclusive process with ample opportunity for both researchers and research participants to weigh in on how the tool should be developed and employed before this aspect of the NPRM is implemented in regulation.
- Using single IRBs for multi-site research studies has the potential to reduce unnecessary administrative burden and could be especially helpful for rare diseases, which have small patient populations spread widely across the globe. There are exciting developments in multi-site IRBs and common data platforms to support multi-site research, and we are pleased to see the NPRM’s promotion of these efficiencies. However, moving from the current voluntary use of single IRBs to the NPRM’s regulatory mandate that all domestic, multi-site studies use single IRBs (§___.114) requires that the new system be effectively designed and resourced prior to implementation:
- The requirement that the federal funding agency select the IRB is an important safeguard to ensure a high quality of review across all studies.
- To facilitate implementation, we recommend that the government explore expansion of federally funded, disease-specific central IRBs akin to the National Cancer Institute’s Central IRB. The government should also redouble its work with IRBs, research institutions, and the public to develop uniform guidance to maintain consistency across institutions and studies.
- Given the diverse views on the merits of a single IRB mandate (as opposed to the current voluntary system where the context of each study drives the decision), and the complexity of implementing the system were it to become part of the Common Rule, we recommend additional consideration by the broader community before final implementation.
Additional comments and path forward:
We support the proposal to modify the Common Rule to fill gaps that currently enable some research studies with human participants to operate outside the regulation (§___.101). However, we note that there is still an apparent lack of harmonization between the Common Rule and the FDA’s regulations governing clinical trials. In the NPRM, there are numerous instances where more disharmony could be introduced, particularly with regard to consent provisions, some exemptions, and waiver conditions. The medical research enterprise would benefit from fully harmonized regulation of studies involving human participants, and the NPRM seems to make the regulatory setting even more complex.
In the decades since the Common Rule was first instituted, there has been considerable innovation in the way that researchers interact with patients. Patients have transitioned from “passengers to co-pilots,” and the result has been an improvement in the entire enterprise. The rule’s use of “human subjects” in the context of research does not reflect these changes and the critical partnership needed between researchers and the people participating in studies. Replacing “subjects” with “participants” would more appropriately reflect and reinforce reality. However, we acknowledge that from a strict regulatory perspective, “participant” implies that the person has given explicit consent. The NPRM does contain appropriate exemptions and waivers for low-risk research so wholesale replacement of “subject” with “participant” throughout the Common Rule may not be appropriate. That said, the evolving relationship between researchers and study participants should be reflected in the Common Rule, and suggests yet another opportunity for a more inclusive, transparent process to address this, and the other especially complex issues raised in the NPRM.
Given that the NPRM is a proposed rule – one step away from becoming final regulation – it is notable that there are 87 questions for public comment, 13 more than were in the Common Rule’s ANPRM. The complexity of research with human participants is expected to lead to a very complex set of regulations. We thank the government for being so open about the outstanding questions that emerged from the interagency deliberations on the NPRM and for requesting the broader community’s feedback. However, it appears that the more complex proposals in the NPRM would benefit from additional discussion among the broader community before becoming a final rule.
Insuring that the Common Rule is up-to-date and meets the needs of an evolving research enterprise is a vitally important task, and we applaud the years of work by OHRP and its federal partners in this effort. Many of the proposed revisions are common-sense improvements, and the federal government should quickly incorporate them into the Common Rule. However, we have highlighted several proposals in the NPRM that are very complex:
- Processes for the collection and consent for use of biospecimens.
- Use of a web-tool to determine if a study is exempt from the Common Rule.
- Mandate for single IRB review of multi-site studies.
- Use of “participants” versus “subjects” in the Common Rule.
These proposals, and perhaps others, could benefit from an inclusive, transparent, and robust discussion among all constituencies, old and new (i.e., regulators, funders, researchers, as well as newly empowered patient communities). While helpful, we do not believe the NPRM’s 120-day comment period and associated town halls and webinars have provided sufficient opportunity for those outside of the federal interagency process to deeply explore the ethical and practical implications of the more complex proposals.
As a path forward, FasterCures recommends that OHRP consider updating the Common Rule in a step-wise manner, implementing the most straightforward proposals first. FasterCures would welcome the opportunity to work with OHRP to facilitate the necessary deliberations on the more complex proposals so that regulators and the community can move forward toward our common goals of increasing research efficiencies and accelerating development of disease cures. Thank you for the work that went into this and for the opportunity to comment.
FasterCures, a center of the Milken Institute
For more information:
• Read the Common Rule notice of proposed rulemaking: http://www.regulations.gov/#!docketDetail;D=HHS-OPHS-2015-0008
• View FasterCures' submitted comments: http://www.regulations.gov/#!documentDetail;D=HHS-OPHS-2015-0008-1970
 http://www.fastercures.org/programs/patients-count/ (Accessed Jan. 6, 2016).
 http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html (Accessed Jan. 6, 2016).
 The Belmont Report, http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html# (Accessed Dec. 7, 2015).
- Respect for Persons: Individuals should be treated as autonomous agents (i.e., having the right to self-govern), and individuals with diminished autonomy are entitled to protections.
- Beneficence: Maximize possible benefits, and minimize potential harms.
- Justice: Fair distribution of burdens and benefits of research across society.
 OHRP Webinar Series on the Common Rule NPRM, http://www.hhs.gov/ohrp/education/training/nprmwebinars.html (Accessed Dec. 12, 2015).
 Hudson, K. and F. Collins, “Bringing the Common Rule into the 21st Century,” N Engl J Med 2015, 373:2293-2296.
 For example, in their comments on the NPRM, the Health and Human Services Secretary’s Advisory Committee on Human Research Protections (SACHRP) finds that the requirement for broad consent under §___.104(f) is not a meaningful form of informed consent and recommends that a more ethical approach would be to replace it with a provision of notice of research practices, with an opt-out mechanism if a patient doesn’t want to participate. http://1.usa.gov/1OLhzQx (Accessed Jan. 5, 2016).
 Anderson, M. and K. McCleary, “From passengers to co-pilots: Patient roles expand,” Sci Trans Med 2015, 7:291fs25.