Burdens on research imposed by institutional review boards: The state of the evidence and Its implications for regulatory reform

Milbank Quarterly

Volumn 89, Issue 4, 2011, Pages 599-627

  Silberman, George ^a,b,c   Kahn, Katherine L ^a,b,c  

^a RAND CORPORATION   (United States)

^b Cancer Policy Group LLC   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

clinical trials; government regulations; Institutional review board; research costs; research ethics

Indexed keywords

CERTIFICATION; CLINICAL RESEARCH; COST; DECISION MAKING; ETHICS; HUMAN; INSTITUTIONAL REVIEW; INSTITUTIONAL REVIEW BOARD; MEDLINE; PRIORITY JOURNAL; PRODUCTIVITY; PUBLIC HEALTH SERVICE; RELIABILITY; RESEARCH; RESEARCH SUBJECT; REVIEW;

ETHICS COMMITTEES; ETHICS COMMITTEES, RESEARCH; HEALTH SERVICES RESEARCH; HUMAN EXPERIMENTATION; HUMANS; ORGANIZATIONAL POLICY; PATIENT SELECTION; QUALITY ASSURANCE, HEALTH CARE; RESEARCH SUBJECTS; UNITED STATES;

EID: 84555178455     PISSN: 0887378X     EISSN: 14680009     Source Type: Journal    
DOI: 10.1111/j.1468-0009.2011.00644.x     Document Type: Review

References (71)

1. Bell, J., J. Whiton, and, S. Connelly,. 1998. Final Report Evaluation of NIH Implementation of Section 491 of the Public Health Service Act, Mandating a Program of Protection for Research Subjects. Report prepared under National Institutes of Health contract, NO1-OD-2-2109. Washington, DC: U.S. Department of Health and Human Services.
2. Bureau of Medical Services. 1966. Clinical Investigations Using Human Beings as Subjects. Circular no. 38, June 23.
3. Burman, W., P. Breese, S. Weis, N. Bock, J. Bernardo, and, A. Vernon,. 2003. Tuberculosis Trials Consortium: The Effects of Local Review on Informed Consent Documents from a Multicenter Clinical Trials Consortium. Controlled Clinical Trials 24 (3): 245-55. (Pubitemid 36570376)
4. Byrne, M.M., J. Speckman, K. Getz, and, J. Sugarman,. 2006. Variability in the Costs of Institutional Review Board Oversight. Academic Medicine 81 (8): 708-12. (Pubitemid 44167309)
5. Camacho L.H., L. Marubio, M.A. Purdom, D. Leonard, D.S. Hong, S. Moulder, S.R. Pilat, and, R. Kurzrock,. 2007. Improving the Institutional Submission and Approval Process for Clinical Research Protocols in Oncology. Journal of Clinical Oncology 25 (12): 1632-33. (Pubitemid 46733099)
6. Caplan, A.L., 1984. Inconsistency, Idiosyncrasy, and IRBs. IRB: Ethics & Human Research 6 (2): 10-12.
7. Catania, J.A., B. Lo, L.E. Wolf, M.M. Dolcinin, L.M. Pollack, J.C. Barker, S. Wertlieb, and, J. Henne,. 2008. Survey of US Human Research Protection Organizations: Workload and Membership. Journal of Empirical Research on Human Research Ethics 3 (4): 57-69.
8. Chaney, E., L.G. Rabuck, J. Uman, D.C. Mittman, C. Simons, B.F. Simon, M.M. Ritchie, M. Cody, and, L.V. Rubenstein,. 2008. Human Subjects Protection Issues in QUERI Implementation Research: QUERI Series. Implementation Science 15 (3): 10.
9. Clark, S., A.J. Pelletier, B.E. Brenner, D.M. Lang, R.C. Strunk, and, C.A. Camargo,. 2006. Feasibility of a National Fatal Asthma Registry: More Evidence of IRB Variation in Evaluation of a Standard Protocol. Journal of Asthma 43 (1): 19-23.
10. Dilts, D.M., and, A.B. Sandler,. 2006. Invisible Barriers to Clinical Trials: The Impact of Structural, Infrastructural, and Procedural Barriers to Opening Oncology Clinical Trials. Journal of Clinical Oncology 24 (28): 4545-52. (Pubitemid 46630949)
11. Dilts, D.M., A.B. Sandler, M. Baker, S.K. Cheng, S.L. George, K.S. Karas, S. McGuire, G.S. Menon, J. Reusch, D. Sawyer, M. Scoggins, A. Wu, K. Zhou, and, R.L. Schilsky,. 2008. Development of Clinical Trials in a Cooperative Group Setting: The Eastern Cooperative Oncology Group. Clinical Cancer Research 14 (11): 3427-33.
12. Dinan M.A., K.P. Weinfurt, J.Y. Friedman, J.S. Allsbrook, J. Gottlieb, K.A. Schulman, M.A. Hall, J.K. Dhillon, and, J. Sugarman,. 2006. Comparison of Conflict of Interest Policies and Reported Practices in Academic Medical Centers in the United States. Accountability in Research 13 (4): 325-42.
13. Dyrbye, L.N., M.R. Thomas, A.J. Mechaber, A. Eacker, W. Harper, F.S. Massie Jr., D.V. Power, and, T.D. Shanafelt,. 2007. Medical Education Research and IRB Review: An Analysis and Comparison of the IRB Review Process at Six Institutions. Academic Medicine 82 (7): 654-60. (Pubitemid 47013349)
14. Dziak, K., R. Anderson, M.A. Sevick, C.S. Weisman, D.W. Levine, and, S.H. Scholle,. 2005. Variations among Institutional Review Board Reviews in a Multisite Health Services Research Study. Health Services Research 40 (1): 279-90. (Pubitemid 40229360)
15. Emanuel, E.J., A. Wood, A. Fleischman, A. Bowen, K.A. Getz, C. Grady, C. Levine, D.E. Hammerschmidt, R. Faden, L. Eckenwiler, C.T. Muse, and, J. Sugarman,. 2004. Oversight of Human Participants Research: Identifying Problems to Evaluate Reform Proposals. Annals of Internal Medicine 141 (4): 282-91. (Pubitemid 39089129)
16. Federman, D.D., K.E. Hanna, L. Lyman, D.L. Azarnoff, T. Beauchamp, T. Stoltzfus Jost, P.A. King, R.J.A. Little, J. McNulty, A.N. Petersen, B.W. Ramsey, L. Villa-Komaroff, and, F.M. Visco, eds. 2003. Committee on Assessing the System for Protecting Human Research Participants. Responsible Research: A Systems Approach to Protecting Research Participants. Washington, DC: National Academies Press.
17. Finch, S.A., S.L. Barkin, R.C. Wasserman, N. Dhepyasuwan, E.J. Slora, and, R.D. Sege,. 2009. Effects of Local Institutional Review Board Review on Participation in National Practice-Based Research Network Studies. Archives of Pediatrics & Adolescent Medicine 163 (12): 1130-34.
18. Goldman, J., and, M.D. Katz,. 1982. Inconsistency and Institutional Review Boards. JAMA 248 (2): 197-202. (Pubitemid 12078157)
19. Gordon, B.G., A. Kessinger, S.L. Mann, and, E.D. Prentice,. 2003. The Impact of Escalating Regulatory Requirements on the Conduct of Clinical Research. Cytotherapy 5 (4): 309-13. (Pubitemid 37264998)
20. Govindarajan, R., J.W. Young, C.L. Harless, and, L.F. Hutchins,. 2007. Barriers to Clinical Trials Vary According to the Type of Trial and the Institution. Journal of Clinical Oncology 25 (12): 1633-34. (Pubitemid 46733100)
21. Gray, B.H., R.A. Cooke, and, A.S. Tannenbaum,. 1978. Research Involving Human Subjects. Science 201 (4361): 1094-1101.
22. Green, L.A., J.C. Lowery, C.P. Kowalski, and, L. Wyszewianski,. 2006. Impact of Institutional Review Board Practice Variation on Observational Health Services Research. Health Services Research 41 (1): 214-30.
23. Greene, S.M., and, A.M. Geigen,. 2006. A Review Finds That Multicenter Studies Face Substantial Challenges but Strategies Exist to Achieve Institutional Review Board Approval. Journal of Clinical Epidemiology 59 (8): 784-90. (Pubitemid 43975723)
24. Greene, S.M., A.M. Geigen, E.L. Harris, A. Altschuler, L. Nekhlyudov, M.B. Barton, S.J. Rolnick, J.G. Elmore, and, S. Fletcher,. 2006. Impact of IRB Requirements on a Multicenter Survey of Prophylactic Mastectomy Outcomes. Annals of Epidemiology 16 (4): 275-78.
25. Gunsalus, C., E. Bruner, N. Burbules, L. Dash, M. Finkin, J.P. Goldberg, W.T. Greenough, G.A. Miller, M.G. Pratt, M. Iriye, and, D. Aronson,. 2007. The Illinois White Paper: Improving the System for Protecting Human Subjects: Counteracting IRB Mission Creep. Qualitative Inquiry 13: 617-49.
26. Harding, T., and, M. Ummel,. 1989. Evaluating the Work of Ethical Review Committees: An Observation and a Suggestion. Journal of Medical Ethics 15 (4): 191-94. (Pubitemid 20096241)
27. Helfand, B.T., A.K. Mongiu, C.G. Roehrborn, R.F. Donnell, R. Bruskewitz, S.A. Kaplan, J.W. Kusek, L. Coombs, and, K.T. McVary,. 2009. Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Randomized, Controlled Surgical Trial. Journal of Urology 181 (6): 2674-79.
28. Hirshon, J.M., S.D. Krugman, M.D. Witting, J.P. Furuno, M.R. Limcangco, A.R. Perisse, and, E.K. Rasch,. 2002. Variability in Institutional Review Board Assessment of Minimal-Risk Research. Academic Emergency Medicine 9 (12): 1417-20. (Pubitemid 35416537)
29. Humphreys, K., J. Trafton, and, T.H. Wagner,. 2003. The Cost of Institutional Review Board Procedures in Multicenter Observational Research. Annals of Internal Medicine 139 (1): 77. (Pubitemid 38124625)
30. Infectious Diseases Society of America. 2009. Grinding to a Halt: The Effects of the Increasing Regulatory Burden on Research and Quality Improvement Efforts. Clinical Infectious Diseases 49 (3): 328-35.
31. Jester, P.M., S.J. Tilden, Y. Li, R.J. Whitley, and, W.M. Sullender,. 2006. Regulatory Challenges: Lessons from Recent West Nile Virus Trials in the United States. Contemporary Clinical Trials 27 (3): 254-59.
32. Kimberly, M.B., K.S. Hoehn, C. Feudtner, R.M. Nelson, and, M. Schreiner,. 2006. Variation in Standards of Research Compensation and Child Assent Practices: A Comparison of 69 Institutional Review Board-Approved Informed Permission and Assent Forms for 3 Multicenter Pediatric Clinical Trials. Pediatrics 117 (5): 1706-11. (Pubitemid 46071401)
33. Kozanczyn, C., K. Collins, and, C.V. Fernandez,. 2007. Offering Results to Research Subjects: US Institutional Review Board Policy. Accountability in Research 14 (4): 255-67.
34. Larson, E., T. Bratts, J. Zanzwiger, and, P. Stone,. 2004. A Survey of IRB Process in 68 US Hospitals. Journal of Nursing Scholarship 36 (3): 260-64.
35. Levine, R.J., 1984. Inconsistency and IRBs: Flaws in the Goldman-Katz Study. IRB: Ethics & Human Research 6 (1): 4-6.
36. Mansbach, J., U. Acholonu, S. Clark, and, C.A. Camargo Jr., 2007. Variation in Institutional Review Board Responses to a Standard, Observational, Pediatric Research Protocol. Academic Emergency Medicine 14 (4): 377-80. (Pubitemid 46464032)
37. Marsh, J.L., W. McMaster, J. Parvizi, S.I. Katz, and, K. Spindler,. 2008. AOA Symposium. Barriers (Threats) to Clinical Research. Journal of Bone and Joint Surgery 90 (8): 1769-76.
38. McWilliams, R., J. Hoover-Fong, A. Hamosh, S. Beck, T. Beaty, and, G. Cutting,. 2003. Problematic Variation in Local Institutional Review of a Multicenter Genetic Epidemiology Study. JAMA 290 (3): 360-66. (Pubitemid 37430522)
39. Mosesso, V.N. Jr., L.H. Brown, H.L. Greene, T.A. Schmidt, T.P. Aufderheide, M.R. Sayre, S.W. Stephens, A. Travers, R.A. Craven, and, M.L. Weisfeldt,. 2004. Conducting Research Using the Emergency Exception from Informed Consent: The Public Access Defibrillation (PAD) Trial Experience. Resuscitation 61: 29-36. (Pubitemid 38481629)
40. NBAC (National Bioethics Advisory Commission). 2001. Ethical and Policy Issues in Research Involving Human Participants. Vol. I:Report and Recommendations of the National Bioethics Advisory Commission. Bethesda, MD. Available at (accessed December 8, 2010).
41. NIH (National Institutes of Health), Advisory Committee on Human Radiation Experiments (ACHRE). 1953. Group Consideration of Clinical Research Procedures Deviating from Accepted Medical Practice or Involving Unusual Hazard. ACHRE no. HHS-090794-A.
42. Paasche-Orlow, M.K., H.A. Taylor, and, F.L. Brancati,. 2003. Readability Standards for Informed-Consent Forms as Compared with Actual Readability. New England Journal of Medicine 348 (8): 721-26. (Pubitemid 36237042)
43. Pogorzelska, M., P.W. Stone, E.G. Cohn, and, E. Larson,. 2010. Changes in the Institutional Review Board Submission Process for Multicenter Research over 6 Years. Nursing Outlook 58 (4): 181-87.
44. Ravina, B., L. Deuel, A. Siderowf, and, E.R. Dorsey,. 2010. Local Institutional Review Board (IRB) Review of a Multicenter Trial: Local Costs without Local Context. Annals of Neurology 67 (2): 258-60.
45. Rogers, A.S., D.S. Schwartz, G. Weissman, and, A. English,. 1999. A Case Study in Adolescent Participation in Clinical Research: Eleven Clinical Sites, One Common Protocol, and Eleven IRBs. IRB: Ethics & Human Research 21 (1): 6-10.
46. Schneider, E.C., A.M. Epstein, J.L. Malin, K.L. Kahn, and, E.J. Emanuel,. 2004. Developing a System to Assess the Quality of Cancer Care: ASCO's National Initiative on Cancer Care Quality. Journal of Clinical Oncology 22: 2985-91. (Pubitemid 41103710)
47. Shah, S., A. Whittle, B. Wilfond, G. Gensler, and, D. Wendler,. 2004. How Do Institutional Review Boards Apply the Federal Risk and Benefit Standards for Pediatric Research JAMA 291 (4): 476-82. (Pubitemid 38129752)
48. Sherwood, M.L., F.J. Buchinsky, M.R. Quigley, J. Donfack, S.S. Choi, S.F. Conley, C.S. Derkay, C.M. Myer III, G.D. Ehrlich, and, J.C. Post,. 2006. Unique Challenges of Obtaining Regulatory Approval for a Multicenter Protocol to Study the Genetics of RRP and Suggested Remedies. Otolaryngology-Head and Neck Surgery 135 (2): 189-96. (Pubitemid 44142140)
49. Silverstein, M., M. Banks, S. Fish, and, H. Bauchner,. 2008. Variability in Institutional Approaches to Ethics Review of Community-Based Research Conducted in Collaboration with Unaffiliated Organizations. Journal of Empirical Research on Human Research Ethics 3 (2): 69-76.
50. Sobolski, G.K., L. Flores, and, E.J. Emanuel,. 2007. Institutional Review Board Review of Multicenter Studies. Annals of Internal Medicine 146 (10): 759. (Pubitemid 351640009)
51. Stair, T.O., C.R. Reed, M.S. Radeos, G. Koski, and, C.A. Camargo,. 2001. MARC Investigators. Multicenter Airway Research Collaboration. Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Clinical Trial. Academic Emergency Medicine 8 (6): 636-41. (Pubitemid 32522205)
52. Stark, A.R., J.E. Tyson, and, P.L. Hibberd,. 2010. Variation among Institutional Review Boards in Evaluating the Design of a Multicenter Randomized Trial. Journal of Perinatology 30 (3): 163-69.
53. Straight, T.M., 2009. Clinical Research Regulation: Challenges to the Institutional Review Board System. Clinics in Dermatology 27 (4): 375-83.
54. Sugarman, J., K. Getz, J.L. Speckman, M.M. Byrne, J. Gerson, and, E.J. Emanuel,. 2005. Consortium to Evaluate Clinical Research Ethics: The Cost of Institutional Review Boards in Academic Medical Centers. New England Journal of Medicine 352 (17): 1825-27. (Pubitemid 40570939)
55. Thomson, J.J., C. Elgin, D.A. Hyman, P.E. Rubin, and, J. Knight,. 2006. Research on Human Subjects: Academic Freedom and the Institutional Review Board. Academe 92 (5): 95-100.
56. US DHHS (U.S. Department of Health and Human Services). 1998. Office of Inspector General, Institutional Review Boards: A Time for Reform. OEI-01-97-00193.
57. US DHHS (U.S. Department of Health and Human Services). 2005. Protection of Human Subjects. Code of Federal Regulations Title 45, Part 46, Section 46.103. Available at (accessed September 23, 2011).
58. US DHHS (U.S. Department of Health and Human Services). 2009. National Institute of Health Data Book (NDB). Available at (accessed December 8, 2010).
59. US DHHS (U.S. Department of Health and Human Services). 2011. Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators, Advanced Notice of Proposed Rulemaking. Federal Register 46: 44512-31.
60. US GAO (U.S. General Accounting Office). 1996. Scientific Research: Continued Vigilance Critical to Protecting Human Subjects. GAO/HEHS- 96-72.
61. U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1978. Report and Recommendations: Institutional Review Boards. DHEW Publication no. (OS) 78-0008. Washington, DC: U.S. Government Printing Office.
62. Vick, C.C., K.R. Finan, C. Kiefe, L. Neumayer, and, M.T. Hawn,. 2005. Variation in Institutional Review Processes for a Multisite Observational Study. American Journal of Surgery 190: 805-9. (Pubitemid 41446509)
63. Vogeli, C., G. Koski, and, E.G. Campbell,. 2009. Policies and Management of Conflicts of Interest within Medical Research Institutional Review Boards: Results of a National Study. Academic Medicine 84 (4): 488-94.
64. Wagner, T.H., A. Bhandari, G.L. Chadwick, and, D.K. Nelson,. 2003. The Cost of Operating Institutional Review Boards (IRBs). Academic Medicine 78 (6): 638-44. (Pubitemid 36712588)
65. Wagner, T.H., A.M. Cruz, and, G.L. Chadwick,. 2004. Economies of Scale in Institutional Review Boards. Medical Care 42 (8): 817-23.
66. Wagner, T.H., C. Murray, J. Goldberg, J.M. Adler, and, J. Abrams,. 2010. Costs and Benefits of the National Cancer Institute Central Institutional Review Board. Journal of Clinical Oncology 28 (4): 662-66.
67. Wennberg, J., and, A. Gittelsohn,. 1973. Small Area Variations in Health Care Delivery. Science 182 (117): 1102-8.
68. White, M.T., and, J. Gamm,. 2002. Informed Consent for Research on Stored Blood and Tissue Samples: A Survey of Institutional Review Board Practices. Accountability in Research 9 (1): 1-16.
69. Whittle, A., S. Shah, B. Wilfond, G. Gensler, and, D. Wendler,. 2004. Institutional Review Board Practices Regarding Assent in Pediatric Research. Pediatrics 113 (6): 1747-52. (Pubitemid 38697986)
70. Wolf, L.E., J.A. Catania, M.M. Dolcini, L.M. Pollack, and, B. Lo,. 2008. IRB Chairs' Perspectives on Genomics Research Involving Stored Biological Materials: Ethical Concerns and Proposed Solutions. Journal of Empirical Research on Human Research Ethics 3 (4): 99-111.
71. Yawn, B.P., D.G. Graham, S.L. Bertram, M.J. Kurland, A.J. Dietrich, P.C. Wollan, E.C. Brandt, J.M. Huff, and, W.D. Pace,. 2009. Practice-Based Research Network Studies and Institutional Review Boards: Two New Issues. Journal of the American Board of Family Medicine 22 (4): 453-60.