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How will CER impact IRBs? Inquiring minds want to know
Experts offer clues
Whenever the research enterprise is pushed into a new direction, some different ethical issues and considerations arise. Experts say this likely will be the case as more research institutions engage in comparative effectiveness research (CER), as well.
But how might CER affect IRBs and change IRB deliberations?
Here are some issues that might arise and expert opinion on the impact:
• CER trials might enroll participants with comorbidities and who are frail and elderly. What are the ethical considerations of this change?
One issue that might arise with CER is that study populations sometimes will match the general patient population, including patients who are elderly, frail, and have comorbidities. These types of patients often do not meet the exclusion criteria in placebo-controlled, randomized CTs.
This might raise questions with IRBs, but they should look at the big picture when discussing risks for these types of study populations, says Mark S. Roberts, MD, MPP, president of the Society for Medical Decision-Making and a professor of medicine, health policy, and management and industrial engineering at the University of Pittsburgh School of Medicine. Roberts also is chief of the section of decision sciences and clinical systems modeling in the department of medicine at the University of Pittsburgh.
"I think IRBs need to become a little less worried about doing studies of research in frail populations because we need to know more about what happens with frail populations," Roberts says.
Clinical trials often eliminate participation by patients with cancer, renal failure, and heart disease, and yet those are the kinds of patients doctors see, he adds.
"You need some way to understand how a drug will react in those people," Roberts says. "Many of us think research trials need to be much more general in their populations."
CER will include more frail populations, and this might raise issues for IRBs, says Joel Kupersmith, MD, chief research and development officer for the Department of Veterans in Washington, DC. Kupersmith is a member of the Federal Coordinating Council for Comparative Effectiveness.
"We'll need a question that needs to be examined, applying the usual ethical principals to it," he says. "And if we decide the research can answer the question, the next issue is whether it is feasible to do this research when it's more complicated because of patients having a lot of comorbidities."
What Roberts would like is for IRBs to deliberate about how to best expand entry criteria in studies, to include broader groups of people.
"They need to understand the whole point of clinical trials is to improve decision making in treating that disease," he says. "If most people with that disease don't look like the clinical trial, but look like the people the clinical trial eliminated, then it doesn't really help much."
There are a number of trials conducted today that are not placebo-controlled, including trials for new asthma and hypertension treatments, because it would be unethical to have a placebo arm when there already is an accepted treatment, Roberts notes.
• Will informed consent and equipoise be different with CER?
New methodologies, more frail study populations, and other issues associated with comparative effectiveness research also could affect what future IRBs want in CER informed consent documents.
IRBs will play a role in adjusting informed consent for CER studies, as needed, says Caleb Alexander, MD, assistant professor in the department of medicine at the MacLean Center for Clinical Medical Ethics of the University of Chicago Hospitals.
"IRBs will need to consider the importance of equipoise in the context of having two treatments that are being compared," he says. "It would be important to be sure the equipoise exists between these treatments."
With comparative effectiveness research, there might be some fine-tuning of the concept of equipoise.
For example, if a majority of clinicians prescribe treatment A for a particular disease because they feel it is superior to treatments B and C, would a comparative effectiveness trial comparing the three treatments have true equipoise? Would there be genuine uncertainty regarding the comparative therapeutic merits of each arm of the study?1
The New England Journal of Medicine addressed this very question 20 years ago in a paper that found that requiring investigators to have no treatment preference throughout the course of a trial presents nearly insurmountable obstacles to the ethical completion of a controlled trial.1
The paper further suggested that an alternative concept of equipoise could be based on the present controversy in the clinical community over the preferred treatment.
Therefore, this alternative view of equipoise might pose informed consent challenges for IRBs and would, at least, require boards to require investigators to conduct extensive analyses of various treatments' findings before proposing a clinical trial that compared several treatments head-to-head.
The research established clinical equipoise as an uncertainty in the community at large rather than for an individual, explained Mark S. Schreiner, MD, chairman of the Committee for the Protection of Human Subjects at the Children's Hospital of Philadelphia.
"[Freedman] posited that it was ethical for an investigator to proceed with a trial even if convinced that one treatment was better — provided that there was uncertainty in the community," he says. "The history of clinical trials has shown nothing if not that investigators' biases are frequently proved incorrect."