Posts Tagged ‘clinical trials’
By: Leopold Kong, PhD
Human research in the United States in the form of clinical trials and other scientific studies has been regulated by Institutional Review Boards (IRBs) since 1974 after the passage of the National Research Act. The initial policies were inspired by the Nuremberg Code, a set of international research ethics principles developed in the aftermath of the second world war when Nazi medical officers conducted large-scale human experimentation atrocities. Policies that regulate IRBs in the United States are codified in the Common Rule, which mandates requirements such as membership qualifications and guidelines for protections of certain vulnerable research subjects. Although the Common Rule has not been modified since 1991, the changing face of medical research has led to recent proposals to improve the efficiency, accountability and qualification of IRBs. What has motivated change? The following situations may be illustrative.
In November 2015, the consumer advocacy group Public Citizen, and the American Medical Student Association contacted the Office for Human Research Protections (OHRP) to criticize two studies on how longer-than-21-hour shifts of first-year medical students may affect 30-day patient mortality rates. Public Citizen noted that even though the studies forced new residents to work “dangerously long shifts”, placing all involved in danger, they were readily approved by IRBs. Similarly, IRBs approved a study on the hazards of pediatric exposure to lead paint, in which researchers did not clearly reveal to households that they detected high levels of lead in their homes, resulting in neurological problems for at least one child. Also, a publication last year in the European journal Acta Informatica Medica found that only 26.5% of individuals in IRBs correctly answered 11 simple True or False questions designed to test understanding of study design and ethics. Part of the problem may be research fatigue since, according to OHRP, there are only about 3,500 registered IRBs that review more than 675,000 research protocols annually. Inefficiencies in the review process may further exacerbate the situation.
Late last year, Kathy Hudson and Francis Collins, the Deputy Director for Science, Outreach and Policy at the National Institutes of Health (NIH), and the Director of the NIH, respectively, published a Perspective in the New England Journal of Medicine on the proposed revisions to the Common Rule. In order to bring the Common Rule into the 21st century, the revisions will focus on implementing broad biospecimen consent, enhanced privacy safeguards, streamlined IRB review, and requirements for more agencies to follow the Common Rule. One of the more interesting and key revisions to improve review efficiency, the requirement for a single IRB (sIRB) for multisite studies, will be implemented on May 25, 2017. The rest of this essay focuses on this proposed change.
The time it takes for a clinical trial protocol to be reviewed by an IRB depends on the type of review, and varies from location to location. For example, a protocol can be deemed exempt, which might take only 1-2 weeks of review, expedited, which might take a few weeks longer, or be required for full review, which would take even longer. Re-evaluations are required if the protocol is sent through expedited or full reviews every year, after any changes to the method, or after any adverse event in the study. The review generally evaluates proof of human subjects’ training, consent, recruitment materials, and data collection instruments, as well as individual conflicts of interests, all of which may depend on the specific population studied and local restrictions. However, clinical trials are increasingly spread across multiple sites in order to recruit enough people for their studies. Under the current rule, each site must conduct local reviews of the same protocol independently of each other, potentially causing delays due to unneeded redundancies. “The problem that this [proposed sIRB] policy was trying to solve was that we were seeing delays and complications in moving research forward in a way that wasn’t providing commensurate protections for human research participants,” said Carrie D. Wolinetz, NIH associate director for science policy, to Bloomberg BNA.
From December 3, 2014 to January 29, 2015, the NIH received 167 comments from individual researchers, academic institutions, IRBs, advocacy groups, scientific societies, healthcare organizations, Tribal National representatives and members of the general public on the sIRB proposal. Many of the comments were highly positive and supportive of the revision. For example, the Federation of American Societies for Experimental Biology (FASEB), which represents over 120,000 researchers across 27 scientific societies, stated that “[t]his change would facilitate collaborative review arrangements and reduce the obstacles that investigators encounter when embarking on multi-center projects.” David M Pollock, the president of the American Physiological Society, added further support, commenting that the current rule results in “lack of uniformity” while the proposed changes may reduce administrative burden, and improve efficiency and quality of review.
However, many of the comments displayed reservations and harsh criticism. For example Harry W. Orf representing Massachusetts General Hospital was skeptical that the costs to move into the sIRB system would outweigh the benefits, commenting “there is currently little research or data to demonstrate that these potential benefits will materialize.” In much stronger terms, Curtis Meinert from the Johns Hopkins Bloomberg School of Public Health stated,” [t]he expectation is that the change will save money. Good luck on that. The reality is that the change will increase costs given what IRBs of record have to do to acquire the necessary assurances and certifications. The expectation also is that the single IRB will shorten the time to start, good luck on that one also.” Meinert and others, including the Human Subjects Protection Branch at Walter Reed Army Institute of Research, pointed out that the time it takes to start a study is mainly determined by other factors such as the time it takes for investigators to agree on a protocol, not IRB review. Meinert also warns that, “A likely unintended effect of the one IRB requirement is to further diminish the means and incentives for individual investigators to propose and initiate multicenter studies..” Finally, some communities also viewed the revision as a threat to local autonomy and representation. For example, Bill John Baker, the Principal Chief of the Cherokee Nation, commented, “Tribal IRB members have firsthand knowledge of local tribal customs, cultural values, and tribal sensitivities. If Tribal IRB members are not able to participate […] our citizens are affected by persons who are not sensitive to their distinctive needs.”
Analysis of all comments made regarding sIRB by the Council on Government Relations indicated that 51% opposed the proposal while 42% supported it and 6% offered qualified support. Interestingly, most commercial IRBs, which might be more favorably biased towards the needs of industry sponsors, supported this change. A breakdown of the numbers indicates that while the majority of advocacy groups, professional societies, disease registries and individual researchers supported the change, 89% of universities and medical centers, the organizations that are directly involved with clinical trials and representing thousands of researchers and medical support staff, opposed it. “The spirit of the changes are well intended, but it fails to address the fact that roles and responsibilities of the IRB have expanded beyond those initially dictated when the use of IRBs were first formed“ says Annika Shuali, certified clinical research coordinator at the University of Virginia.
Clearly, reforms are needed to update the aging IRB system. In theory, centralization through the sIRB may improve efficiency. However, in practice, the complexities and details of conducting clinical trials at specific sites such as resolving individual conflicts of interest, being compliant with local regulations, and accounting for the specific rights of certain populations make centralization extremely difficult. To address these site-specific issues, local IRB’s may still need to be in place, but now required to communicate to the sIRB, potentially increasing administrative burden, which undermines the original motivation to streamline review. Hopefully, the sIRB revision to be implemented next year will be further revised to address the critiques from the majority of the community.
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