Informed consent should be process, not ending point
The Institute of Medicine (IOM) of the National Academies in Washington, DC, has called for some major changes in IRBs and research, including suggestions that research grants and sponsors, as well as research institutions, put more money into the process of protecting human subjects. In a report titled "Responsible Research: A Systems Approach to Protecting Research Participants," the Committee on Assessing the System for Protecting Human Research Participants has outlined the legislative, regulatory, and institutional changes that are needed in order to gain public trust in the ethics of human subjects research.
One of the major changes promoted in the report is that federal legislation be passed requiring human subjects protection for all research projects involving human volunteers, regardless of funding source or research setting, and for institutions engaging in research to establish human research participant protection programs (HRPPP).
The report’s emphasis on this change has support in two bills introduced in Congress this year. One bill, introduced Oct. 4, 2002, by Sen. Edward M. Kennedy (D-MA), is the Research Revitalization Act of 2002 (S.3060), and the other is the Human Research Subject Protections Act of 2002 (HR 4697), introduced May 9, 2002, by Rep. Diana DeGette (l-CO). Both bills would require all research to follow human subjects protection regulations.
The Senate bill would require accreditation for all IRBs, establish rules for financial conflict of interest for IRB members, and allow IRB expenses to be charged as direct costs on federal grants. Conflicts-of-interest rules would be strengthened, and regulations would be written to create a model ethics-training program for investigators.
The House bill would require informed consent and require all human subject research to be conducted in accordance with the common rule and the vulnerable-population rules. The House bill was referred May 17, 2002, to the House subcommittee on health, and the Senate bill was referred Oct. 4, 2002, to the Senate committee on health, education, labor, and pensions.
These programs would send the message to staff, researchers, and the public that high ethical research standards are a top consideration from the institutional CEO on down, says Daniel D. Federman, MD, chair of the committee that wrote the IOM report. Federman is the senior dean for alumni relations and clinical teaching and the Carl W. Walter distinguished professor of medicine and medical education at Harvard Medical School in Boston. "That sounds like nothing new, but it is," he says. "To have a CEO on record insisting on high standards is not universal."
The key point of the IOM report is that human research protection must take place within an entire system so that institutions are actively involved in overseeing the process, says Timothy Stoltzfus Jost, JD, who is on the committee and is the Robert L. Willett Family Professor of Law at the Washington and Lee University School of Law in Lexington, VA. "There was a concern of the committee and of people who talked with us that IRBs are overloaded, overstressed, and are asked to do too many things," Jost says. "Because of that, they are losing the most important and original focus on research human protection and making sure research is conducted ethically."
IRB members and others interviewed by the committee often reported having too many responsibilities and too few resources, Federman says. Some IRBs, consisting of eight to 10 people, have 3,000 protocols to handle, and that seems a stretch, Federman notes.
With an HRPPP in place, an institution would then need to provide the financial and personnel resources necessary for IRBs to adequately monitor human subjects protection, and different boards should handle some of the IRB’s other responsibilities, the report says.
Increased resources could be sought from both the institution and from the funding sources of the proposed research, Jost says. "One of the most important messages of our report is that if an institution asks for a research grant and the sponsor says, We’ll give you the grant, but we’re not going to give you any indirect costs,’ then the institution should say, No, we have to cover our costs if we do research,’" he says. "If the sponsor isn’t willing to pay for IRB protection, then the research shouldn’t be done because the ultimate consequence of it not happening is we’ll continue to have scandal after scandal and perhaps death after death — although those are rare events — and other injuries as well."
Some might argue that if sponsors and funding sources are forced to pay for the IRB and other indirect costs then the total funds available for research will be more limited, Federman says. However, no one has a comprehensive idea about the total amount of research that is under way, and no one knows how many people are experiencing harm as a result of the research, he notes. "Absent that information, I recommend that enhanced support, including financial support for human subject protection, is a good idea now, and the government should be collecting comprehensive data on the total amount of research and harm to subjects," Federman says.
One way to reduce the work overload of IRBs would be for the institution to put the responsibility for full scientific review and conflicts of interest into the hands of separate committees that would then share their findings with the IRB as part of the review process.
Soon after the report was issued in October, critics, including the Alliance for Human Research Protection (AHRP) in New York charged that this proposition was flawed because it suggested that institutions be responsible for self-monitoring their conflicts of interest, which critics claim is one of the major problems with the current system of research review and protection.
"Conflicts of interest are at the root of most of the ethical/legal violations in medical research," according to a statement issued Oct. 3 by AHRP in response to the IOM report. "There are high financial stakes to speed up clinical trials — but there are neither effective enforcement mechanisms nor meaningful penalties."
Federman says the committee could see no reason institutions couldn’t handle reviews of individual conflicts of interest, which include instances when an investigator holds stock in a company for which he or she is conducting research. However, institutional conflicts of interest should be handled by a group of senior faculty, investigators, and ethics and community participants, he says. "We think it’s mandatory that institutional conflicts-of-interest committees have not only outside members, but, to a degree, an outside board," Federman explains. "I know we’ve already received some criticism that this is not tough enough."
But there probably isn’t a practical way to have conflict-of-interest committees that are completely outside the research institution, he adds.
Another chief recommendation in the report is that IRBs be given a new name that reflects their more focused role in protecting human subjects. The report suggests IRBs be called Research Ethics Review Board or Research ERB. The Research ERB’s objective should be to obtain consensus in approving research protocols, rather than majority control, the report says.
With a stronger mandate and more time and resources to focus on ethics and protecting human subjects, the Research ERB should make certain that investigators obtain informed consent as an ongoing process, rather than merely obtaining signatures on a form that often is bloated with language designed to insulate the institution from liability, the report states.
"Informed consent needs to be a dialogue between participant and investigator," says Daniel L. Azarnoff, MD, president of D.L. Azarnoff Associates and senior vice president of clinical and regulatory affairs at Cellegy Pharmaceuticals in South San Francisco, CA. "The dialogue should be about a variety of things related to potential risks and benefits of the trial or the procedures that they’re asking the participant to undergo," he says. "And the dialogue shouldn’t stop because as the trial proceeds, new information becomes available that may require continuing the discussion with the participant."
For example, if during a trial there is an increase in a particular adverse event, then this needs to be discussed with enrolled volunteers, he says. "It needs to be discussed with all subjects about whether the new risk warrants their wanting to continue with trial participation," Azarnoff explains.