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Changing the Common Rule to Facilitate Multisite Research and Establish an Appeals Process

Policy Date: 10/30/2012
Policy Number: 20129

Abstract

The Code of Federal Regulations (45 CFR 46), known as the Common Rule, governs ethics, safety, and oversight of human research and delegates authority to institutional review boards (IRBs) at research institutions. The regulations are seen as imposing a variety of seemingly burdensome bureaucratic procedures. Specifically, multisite research must be approved by each site’s IRB, which may result in conflicting requirements that threaten the internal and external validity of the research. In addition, the Common Rule does not require that the researcher always be allowed some form of appeal of an IRB decision. These problems have led to perceptions of distrust and unfairness in the IRB process and raised questions about the legitimacy and viability of the human research protection system. The US Department of Health and Human Services is currently preparing to revise the Common Rule, and a policy in favor of making a single IRB the lead agency in multisite reviews and requiring IRBs to implement an independent appeal process of an IRB decision will enable APHA to contribute to the public comment on these two topics.

Problem Statement

The American Public Health Association supports the Principles of the Ethical Practice of Public Health, one of which holds that “[p]ublic health institutions should protect the confidentiality of information that can bring harm to an individual or community if made public. Exceptions must be justified on the basis of the high likelihood of significant harm to the individual or others.”[1] However, this principle is not linked to any essential public health service and does not mention public health research. Rules and regulations concerning the protection of participants in federally sponsored research are contained in the Code of Federal Regulations (45 CFR 46), known as the Common Rule because 15 separate federal departments and agencies adopted these regulations as the uniform standards for the protection of human subjects.[2] The Common Rule, in turn, authorized the creation of institutional review boards (IRBs) to review, determine, and ensure that proposed research can be conducted at an institution within the constraints set forth by the IRB and by other institutional and federal requirements.

Unfortunately, the regulations have imposed a variety of seemingly burdensome bureaucratic procedures that place unnecessary requirements on researchers conducting studies that pose few physical or psychological risks.[3] Several public health organizations have indicated concerns about the current system. The Council of State and Territorial Epidemiologists has called for clearer guidance on whether or not certain public health activities are subject to IRB review.[4] The Joint Policy Committee of the Societies of Epidemiology noted that changing the Common Rule could better protect human subjects while facilitating research and reducing burden, delay, and ambiguity for investigators. They were particularly interested in having the Common Rule explicitly define “research” and what research activities fall under the purview of the Common Rule, as well as the difference between research and public health “practice.”[5]

The Illinois White Paper documented “mission creep” or goal displacement in the IRB system, contending that the focus on procedures and documentation for minimal risk studies displaces thoughtful consideration of difficult ethical questions in complex clinical trials.[6] As a result, potentially productive research is discouraged or self-censored to the detriment of society.[7] This is supported by empirical studies[8,9] suggesting that perceptions of distrust and unfairness in the IRB process, especially for minimal risk research, raise questions about the legitimacy and viability of the entire system.[10]

The aim is to lessen the burden on researchers while maintaining adequate protection for research participants, especially those involved in minimal risk studies.

A review of 52 studies from the PubMed database and a supplemental bibliographic search showed that IRBs operated at different levels of efficiency and that IRBs presented with identical protocols requested different and even competing revisions.[11] Some IRB decisions were found not to conform to federal policy guidelines.

In summary, review of multisite research by several local IRBs is likely to be burdensome. A report on multisite studies in health services research attributed variation in IRB decisions to, among other factors, the influence of institutional or professional culture and regional thinking.[12]

One epidemiological case-control interview study included patients from nine hospitals. All nine hospital IRBs insisted that the epidemiologist obtain a signed informed consent form identical to those used for inpatient clinical trials before beginning interviews. Three of the hospitals required that the epidemiologist contact patients only after they returned a card or letter to the physician who invited them to participate, and three requested that copies of the signed consent form be included in patients’ hospital record. These requirements tend to reduce the participation rate, thereby limiting the validity of the epidemiological study.[13]

Studies of multisite research at Veterans Administration facilities have revealed variations in approval decisions as well as requirements for protocol revisions that required changes to preserve the study’s internal validity but threatened its external validity by reducing the number and types of participating facilities and patients.[14,15]

A comparison of IRBs at six medical schools revealed differences in the timeliness and consistency of IRB reviews of medical education research across institutions that may hinder multi-institutional research and slow evidence-based medical educational reform.[16]

According to federal regulations, institutional officials may not approve research that has been disapproved by an IRB. Since IRBs are autonomous entities making binding decisions,[17] many do not allow researchers to formally appeal a decision. A researcher may want to appeal on the grounds that the required modifications to the protocol or informed consent form might threaten the internal and external validity of the proposed research, that the research does not pose more than a minimal risk to participants, or that the investigation is public health practice and does not require IRB review. In short, the IRB approval process lacks “checks and balances.”[18]

However, the World Health Organization recommends that IRBs have written procedures that specify how a researcher may request a reconsideration of the decision, either by the IRB itself or by another entity.[19] The Canadian Tri-Council Statement, which is the equivalent of the Common Rule, provides for the establishment of an appeals process. The Tri-Council Statement specifies that after all reconsiderations have been fully exhausted and a final decision issued, a researcher may initiate an appeal to an ad hoc or permanent appeals committee. It also specifies that members of the review board that made the original decision are not to be included as part of the appeals committee. Further institutions may share appeals committees under a formal letter of agreement between the institutions.[20]

Proposed Recommendations Statement

To facilitate multisite research, the following changes should be made to the Common Rule:

• Make one IRB of record for domestic multisite research studies the regulatory default and identify criteria for selecting the lead IRB that include the home institution of the principal investigator, which IRB has the requisite expertise to review the study, and where the preponderance of research participants will be located, as well as criteria for resolving disputes among participating IRBs that might include ethnic, racial, and native communities or vulnerable population that would have difficulty with language describing the protocol and informed consent.

• Require IRBs to implement an independent appeal process of an IRB decision.

Until the Common Rule is changed, public health departments should enter into collaborative agreements with universities, hospitals, and health systems that cover IRB reviews of multisite research.

Opposing Arguments/Evidence

Two arguments were part of the feedback to the Department of Health and Human Services (DHHS) Advanced Notice of Proposed Rule Making (ANPRM), as follows.

First, many institutions currently have legal language pertaining to their liability associated with research activities that could conflict with a federal mandate to allow another institution to be responsible for a study’s human research protections. In addition, it would be difficult for a single IRB to consider local issues at other sites that might be relevant for a protocol and informed consent.[21] However, some institutions have created collaborative agreements covering multisite research that would legally allow an IRB at another institution to be the IRB of record (see alternative strategies below).[22,23]

Second, investigators should have the option to resubmit to another IRB panel if they are unhappy with the results of their first review. However, it would be institutionally burdensome and highly politicized to have a specific appeals IRB, and this approach is not recommended.[24] But, as pointed out above, both the World Health Organization[19] and the Canadian Tri-Council Statement[20] call for a written formal appeal process that is reasonable in scope and that does not involve the original reviewers, who should properly recuse themselves from the appeal process.

Alternative Strategies

One alternative strategy is to continue to rely on voluntary collaborating agreements between research institutions that identify an IRB of record based on criteria that include the home institution of the principal investigator, which IRB has the requisite expertise to review the study, and where the preponderance of research participants will be located.[22] These institutions may include universities, hospitals, regional health care systems, and state health departments.[23] This strategy may be effective in some cases but still requires researchers outside the collaborative network to submit to multiple IRBs.

Another strategy is to continue to follow the peer review model similar to that used by scientific journals. In this model, IRBs invite researchers to respond to their questions, concerns, and suggestions for improving the proposal either before or after initially approving a protocol.[25] A journal editor may have the original reviewers consider the resubmission or select a new reviewer to gain an independent opinion. Currently, when a researcher requests that an IRB reconsider required changes to the protocol or consent form, the IRB chair may ask some IRB members, or even the full IRB, to address the issue. IRB members who participated in the original decision may or may not recuse themselves. Unlike a rejected journal manuscript, however, a rejected research proposal cannot readily be sent to another IRB. According to the American Association of University Professors, an appeals process would not only protect researchers against arbitrary decisions by IRBs; it would also help IRBs by building credibility among researchers.[26]

Action Steps

Therefore, APHA:

• Recommends that DHHS revise the Common Rule to make one IRB of record for domestic multisite research studies the regulatory default.

• Recommends that DHHS identify criteria for selecting the lead IRB and resolving disputes among participating IRBs that might include ethnic, racial, and native communities that would have difficulty with language describing the protocol and informed consent.

• Encourages public health departments to enter into collaborative agreements with universities, hospitals, and health systems that cover IRB reviews of multisite studies to facilitate such research.

• Calls on DHHS to revise the Common Rule to require (and research institutions to create) an appeals process that specifies how a researcher may request a reconsideration of an IRB decision and excludes individuals who participated in the original decision.

References

1. Public Health Leadership Society. Principles of the Ethical Practice of Public Health. Available at: http://www.apha.org/NR/rdonlyres/1CED3CEA-287E-4185-9CBD-BD405FC60856/0/ethicsbrochure.pdf. Accessed May 30, 2012.
2. Office of the Secretary, US Department of Health and Human Services. Human subjects research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators. Available at: http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf. Accessed February 1, 2012.
3. Emmanuel EJ, Menikoff J. Reforming the regulations governing research with human subjects. N Engl J Med. 2011;365(12):1145–1150.
4. Hodge JG, Gostin LO. Public health practice vs. research: a report for public health practitioners including cases and guidance for making distinctions. Available at: http://www.cste.org/pdffiles/newpdffiles/CSTEPHResRptHodgeFinal.5.24.04.pdf. Accessed January 31, 2012.
5. Joint Policy Committee, Societies of Epidemiology. Re: comments on 45 CFR 46, letter to Jerry Menikoff, MD, JD, Office of Human Research Protections, October 26, 2011. Available at: http://www.regulations.gov/#!documentDetail;D=HHS-OPHS-2011-0005-1066. Accessed February 1, 2012.
6. Gunsalus C, Bruner E, Burbules N, et al. The Illinois White Paper: Improving the system for protecting human subjects: counteracting IRB mission creep. Available at: http://www.primr.org/uploadedFiles/PRIMR_Site_Home/Resource_Center/Articles/11.%20Illinois%20Whitepaper.pdf. Accessed February 8, 2012.
7. Gunsalus CK, Bruner EM, Burbules NC, et al. Creep in the IRB world. Science. 2006;312(5779):1441.
8. Keith-Spiegel P, Koocher GP, Tabachnick B. What scientists want from their research ethics committees. J Empir Res Hum Res Ethics. 2006;1(1):67–82.
9. Ashcraft MH, Krause JA. Social and behavioral researchers' experiences with their IRBs. Ethics Behav. 2007;17:1–17.
10. Fost N, Levine RJ. The dysregulation of human subjects research. JAMA. 2007;298(18):2196–2198.
11. Silberman G, Kahn KL. Burdens on research imposed by institutional review boards: the state of the evidence and its implications for regulatory reform. Milbank Q. 2011;89(4):599–627.
12. Gold JL, Dewa CS. Institutional review boards and multisite studies in health services research: Is there a better way? Health Serv Res. 2005;40(1):291–308.
13. Cann CI, Rothman KJ. IRBs and epidemiologic research: how inappropriate restrictions hamper studies. IRB. 1984;6(4):5–7.
14. Petersen LA, Simpson K, SoRelle R, Urech T, Chitwood SS. How variability in the institutional review board process affects minimal-risk health services research. Ann Intern Med. 2012;156(10):728–735.
15. Rose AJ, Petrakis BA, Callahan P, Mambourg S, Patel D, Hylek EM, Bokhour BG. Organizational characteristics of high- and low-performing anticoagulation clinics in the Veterans Health Administration. Health Serv Res. 2012;47(4):1541–1560.
16. Dyrbye LN, Thomas MR, Mechaber AJ, et al. Medical education research and IRB review: an analysis and comparison of the IRB review process at six institutions. Acad Med. 2007;82(7):654–660.
17. Centers for Disease Control and Prevention. Procedures for protection of human research participants. Available at: http://www.cdc.gov/od/foia/manuals/procphrp.pdf. Accessed May 29, 2012.
18. Ceci SJ, Bruck M. Do IRBs pass the minimal harm test? Perspect Psychol Sci. 2009;4(1):28-29.
19. Standards and operational guidance for ethics review of health-related research with human participants. Available at: http://whqlibdoc.who.int/publications/2011/9789241502948_eng.pdf. Accessed May 29, 2012.
20. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada. Tri-Council Policy Statement: ethical conduct for research involving humans. Available at: http://www.pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf. Accessed February 1, 2012.
21. American Lung Association. Comment on notice: Human subject research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators. Available at: http://www.regulations.gov/#!documentDetail;D=HHS-OPHS-2011-0005-0833. Accessed February 1, 2012.
22. Clemson University. Collaborative agreements: institutional review boards. Available at: http://media.clemson.edu/research/compliance/irb/hssc-signed-cooperative-agreement.pdf. Accessed May 29, 2012.
23. Florida Department of Health. Human Research Protection Program: multiple IRB review. Available at: http://flpublichealthethics.net/. Accessed May 29, 2012.
24. Center for Biomedical Ethics, Stanford University Medical School. Comment on notice: Human subject research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators. Available at: http://www.regulations.gov/#!documentDetail;D=HHS-OPHS-2011-0005-0640. Accessed February 1, 2012.
25. Noah L. Deputizing institutional review boards to police (audit?) biomedical research. J Legal Med. 2004;25(3):267–293.
26. American Association of University Professors. Comments in reply to Human subjects research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators. Available at: http://dataprivacylab.org/projects/irb/aaup.pdf. Accessed May 29, 2012.