New Challenge for Academic Medical Centers: Role of Central/Commercial IRBs
By Barry B. Bercu, M.D.
and Ernest D. Prentice, Ph.D.
Barry B. Bercu, M.D., is Affiliate Professor of Molecular Pharmacology and Physiology and Professor Emeritus of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, Fla.
Ernest D. Prentice, Ph.D., is Associate Vice Chancellor for Academic Affairs and Professor of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Neb.
Barry B. Bercu, M.D., e-mail email@example.com
The institutional review board (IRB) plays an invaluable role in the review and oversight of research involving human subjects. It is imperative that the rights and welfare of research subjects be respected and protected from unnecessary risks and harm. The process of IRB oversight is guided by regulations and ever-evolving government-issued guidance documents. Thus, researchers, as well as IRBs, are challenged by a myriad of escalating requirements necessary to carry out ethically-based research. Research protection enterprises within academic medical centers (AMCs) have not always kept up with the growing demands required in a highly competitive research and development (R&D) environment. This manuscript will address benefits and drawbacks as AMCs consider whether to utilize central IRBs (CIRBs), either for-profit (commercial) CIRBs or not-for-profit CIRBs in the review and oversight of multicenter clinical trials.
Beginning in the 1990s, the pharmaceutical and biotechnology industries dramatically increased funding devoted to R&D. The proliferation and complexities of multicenter clinical trials concomitantly increased, which, in turn, required many more research participants. Given the race to bring new products to market and the bureaucratic impediments that often exist in AMCs, it is not surprising that there has been a continual migration of clinical research away from AMCs. In the U.S. in 1994, 70 percent of clinical trials were conducted at academic sites; in 2005, 41 percent; and in 2008, only 34 percent of these trials were at academic sites.1 In another more recent study done by the Tufts Center for the Study of Drug Development, only about one-third of global Food and Drug Administration-regulated clinical trials were conducted by independent, community-based investigators whereas by 2012, it was over one half.2 In the same study, the proportion of Principal Investigators based in North America has declined steadily from 84 percent in 1996 to 61 percent in 2012. While there are those who would argue that clinical trials should not be indigenous only to AMCs, that point of view ignores the financial reality for most AMCs. Commercially sponsored research is a very reasonable way to generate revenue through overhead charges in academic settings. However, as the above statistics indicate, AMCs are losing out to the private sector.
Academic Versus Central IRBs
It is clearly desirable for many, if not most, AMCs to aggressively seek commercial funding to improve their research infrastructure, create clinical research units for multicenter pharmaceutical and device studies and ultimately attract more funding. On the positive side, this could expose more faculty members to clinical research in academic environments where a rather small percentage of clinical faculty members actually engage in research. One factor, however, that affects an AMC’s ability to attract commercially sponsored research is IRB efficiency, which too often is deficient when compared to nonprofit CIRBs and, especially, commercial IRBs. Many AMCs simply do not allocate sufficient resources to adequately support their IRBs and productive faculty members are hard pressed to find the time to serve on such a labor-intensive board. In addition, it is simply not cost-effective or tenable in today’s environment to have multiple IRB reviews of the same multicenter clinical trial.3 Although it is important for sponsors to continue to use both academic and community-based investigators/institutions, it would be unfortunate in the long term if the academic enterprise were to be further excluded because of its own internal bureaucratic issues.
There are compelling reasons for AMCs to seriously consider using CIRBs in addition to their own internal IRBs. These include lowered cost and improved efficiency as they relate to the development and marketing of new drugs and devices — vital elements for the U.S. to effectively compete in a global economy. The FDA, various associations and more recently the U.S. Department of Health and Human Services through the advanced notice of proposed rulemaking (ANPRM) on revisions to the Common Rule for protection of human research subjects have explicitly stated the need for change in the current academic IRB system.4,5,6 This system admittedly is outdated and too often inefficient in meeting the needs of the pharmaceutical industry, particularly with regard to IRB review of multicenter clinical trials. Indeed, the federal government already has taken some corrective steps by creating the following CIRBs: National Cancer Institute Pediatric Oncology CIRB in 2004; Veterans Administration CIRB in 2008; NCI Adult CIRB in 2011. In addition, various networks, such as NeuroNext, utilize their own CIRB for review of in-network clinical trials. These not-for-profit CIRBs, as well as commercial IRBs, have become increasingly essential in meeting Pharma demands that IRB review be more efficient and cost-effective.
Table 1 summarizes characteristics contrasting academic and commercial IRBs. One of the driving forces for pharmaceutical sponsors in the determination to use commercial IRBs is the considerable cost savings and efficiencies when dealing with hundreds of single sites in a multicenter clinical trial. These types of randomized clinical trials remain the gold standard in drug development as pharmaceutical companies attempt to bring their products to the consumer. It is also important to emphasize that multiple reviews of the protocol may create scientific bias and an undesirable variability in evaluation. Certainly, there is an expensive duplication of effort, inefficient use of time and resources and, ultimately, delays in implementation of research.7,8
It is understandable, on the other hand, as summarized in Table 2, that AMCs have multiple reasons to be cautious in their decision making as they consider adding CIRBs, in particular, commercial IRBs, as a complementary addition to their Human Research Protection Program (HRPP), as suggested in a recent survey.9 One of the concerns for many AMCs is the loss of revenue for IRB review, which is usually over $2,000 per protocol and is paid for by the sponsor. However, this loss can be partially recovered by incorporating an administrative processing fee for the institution’s IRB staff time and effort. Furthermore, there could be significant financial benefit to the AMC because of the increased overhead income through earlier initiation of a study, which may allow for more participant recruitment prior to the sponsor’s defined total enrollment quota. This could result in increased institutional revenue based on the contractual arrangement of per subject income and also more revenue for procedures performed by the AMC.
Many other concerns, also included in Table 2, were raised by respondents at AMCs in another survey. For this survey, 60 IRBs were contacted, which represented every fourth one on the list of the top 240 institutions based on NIH funding.10 Based upon the above-mentioned concerns, as well as ongoing debate within both the regulatory and research community, it is clear that the administrative leadership of AMCs should carefully evaluate both functional and legal ramifications and make certain that any decision to use a CIRB addresses all identified concerns. Ultimately, the AMC needs to be assured that the AMC-CIRB oversight partnership works for the institution.
Table 3 summarizes the perspective of the sponsors, which is also very important to consider. If they collectively determine the cost is too great to deal with many single-site IRBs and this current trend continues, this could be to the detriment of the AMCs. Indeed, there are many indications that the pharmaceutical, biotech and medical device industries are adopting cost-saving measures, which include pressuring some AMCs to use the sponsor’s commercial IRB of choice. It is likely that such pressure will increase in frequency across AMCs. A possible exception may be for institutions that have nationally recognized physicians who the industry considers important to be involved as an investigator in their clinical trial.
D.K. Nelson proactively addressed the question of an AMC use of commercial IRBs.11 He reported results of a pilot study done at the University of North Carolina (UNC) at Chapel Hill where during a six-month interval, the quality of eight commercial IRBs was systemically evaluated. All eight IRBs were accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP). There were no negative outcomes. UNC now has 16 executed contracts with AAHRPP-accredited commercial IRBs for Phase I – IV clinical trials. UNC investigators currently have the flexibility of using any one of the 16 commercial IRBs designated by the sponsor for review of the clinical trial instead of using the UNC IRB. This system obviously decreases the workload of the UNC IRB, although under the contract, there is still a provision for shared oversight.
From the individual faculty member investigator to senior level administrators, U.S. AMCs should explore the opportunity to partner with both nonprofit CIRBs and commercial IRBs in order to remain competitive. By providing cost-effective and efficient oversight, CIRBs enhance the academic community’s ability to initiate and complete clinical research and, in the public’s interest, get needed drugs, biologics and medical devices to the marketplace sooner. While this manuscript purports many benefits to AMCs as they consider adding one or more CIRBs, it must be emphasized that the AMC and IRB leadership must carefully weigh what is currently best for their own institutions; circumstances may not yet be right for use of a CIRB. However, at the same time, it is likely that AMC use of CIRBs, including commercial IRBs, will increase in the future. Therefore, it is recommended that AMCs monitor trends across the U.S. and ensure that their own institution takes appropriate and timely measures to remain competitive. Even if an AMC provides adequate resources in support of its own IRB, it may not be sufficient to satisfy sponsor demands for efficiency and cost reduction.
The authors wish to acknowledge the editing and research assistance of Jennifer Kucera, MS, CIP, IRB Administrator at UNMC, in the preparation of this manuscript.
DIFFERENTIATING CHARACTERISTICS OF ACADEMIC AND COMMERCIAL IRBs
|CHARACTERISTIC||ACADEMIC IRB||COMMERCIAL IRB|
|Number of IRBs||4 or more (39% have only 1)||4 or more|
|Meeting frequency||usually each meets monthly||meets weekly or even 3X/week|
|Number of sites||one to a few||thousands|
|Number of multisite studies||>150||>5000|
|Number of IRB chairs||1 – 5+||2 – 5+|
|Number of staff||20 – 30+||100 – 200+|
|Review Process CROs, SMOs||multiple steps, generally slow; multiple redundant review of protocol||streamlined (point of contact person); efficient communication with single review of protocols|
|Chair and board members||frequent conflicting responsibilities; time compensation for chairs||focused responsibilities; chairs and board members compensated|
|Litigation and control issues||often high||balanced|
|Conflict of interest issues||significant, individual and institutional||less of an issue|
|Scientific expertise||not an issue except in small institutions||consultants available as needed|
|Local/community concerns||not a concern||not an issue for multisite clinical trials|
|Cost of research||increased significantly to sponsor||cost effective|
|trend for multisite clinical trials||decreasing||increasing|
|CRO=Contract research organization; SMO=Site management organization|
PERSPECTIVES/CONCERNS OF ACADEMIC MEDICAL CENTERS
|Local institutional IRBs reflect:|
|Local knowledge of subjects|
|Local knowledge of investigators|
|Concern for protection of “our own subjects”; heightened sense of moral obligation|
|Desire for local autonomy and comfort level|
|Concern about differences between various commercial central IRBs|
|Loss of revenue generated for IRB|
|Loss of control and legal liability|
|Local institutions have:|
|More scientific expertise and representation on the IRB|
|More expertise, e.g., in biosafety and radiation safety|
|Increased complexity of protocols|
|Increased number of subjects|
|Requirement to use CROs and SMOs|
|Desire for use of commercial IRBs, especially those that are HRPP accredited|
|Difficulties in interacting with multiple IRBs|
|Research is now global|
|Reduced overall cost|
|Legal issues resolved proactively prior to initiation of the first study with that particular commercial IRB|
|Reduced legal entanglements with multiple IRBs|
|Opportunity for review of draft protocols and informed consent documents|
|Efficiency for initial review and subsequent reviews (continuing, amendments, etc.)|
|No recruitment of any subjects at 20% – 25% of sites, particularly at AMCs, because of delays|
|CRO=Contract research organization; SMO=Site management organization; HRPP=Human research protection program|
1 More information on the Food and Drug Administration’s Bioresearch Monitoring Information System File (BMIS) is available at http://www.fda.gov/Drugs/InformationOnDrugs/ucm135162.htm.
2 Kaitin KI, editor (Research Analysts: Getz, K. and Lamberti, M.J.). “Global site landscape remains highly fragmented with variable performance,” Tufts Center for the Study of Drug Development Impact Report 2013; 15(2):1-4.
4 More information on the FDA’s guidance titled Using a Centralized IRB Review Process in Multicenter Clinical Trials Guidance for Industry (March 2006) is available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm.
5 “Alternative Models of the IRB Review, Workshop Summary Report, November 17-18, 2005” (National Institutes of Health, HHS Office for Human Research Protections, Association of American Medical Colleges, American Society of Clinical Oncology); National Conference on Alternative IRB Models: Optimizing Human Subject Protection, Nov. 19-21, 2006; available at https://www.aamc.org/download/75240/data/irbconf06rpt.pdf.
6 More information on the ANPRM is available in the Federal Register notice (76 Fed. Reg. 44,512, July 26, 2011), available at http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf.
7 Viswanathan, M., Ansari, M.T., Berkman, N.D. et al. “Methods Guide for Comparative Effectiveness Reviews: Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions,” available at http://www.effectivehealthcare.ahrq.gov/ehc/products/322/998/MethodsGuideforCERs_Viswanathan_IndividualStudies.pdf.
9 Flynn, K.E., Hahn, C.L., Kramer, J.M., Check, D.K., Dombeck, C.B., Bang, S., Perlmutter, J., Khin-Maung-Gyi, F.A., Weinfurt, K.P. “Using Central IRBs for Multicenter Clinical Trials in the United States,” Plos One 2013; DOI:10.1371/journal.pone.0054999; available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054999.
10 Klitzman, R. How Local IRBs View Central IRBs in the US. BMC Medical 2011;12-13; doi:10.1186/1472-6939-12-13; available at http://www.biomedcentral.com/1472-6939/12/13.
11 Nelson, D. K. “Streamlining IRB Review for Multi-Site Research: Results of a Randomized, Control Trial of Central Versus Local IRB Review,” PRIM&R’s 2013 Advancing Ethical Research Conference, November 2013, Boston.