Waiver of consent
“By signing below, you are agreeing...”
If you’ve ever figured out how to support a proposal you like by voting ‘no’ for the corresponding proposition on the ballot, you should have an easy time understanding what is involved in obtaining a waiver of consent. Most of us can’t do either. But Guy L. Clifton, MD, professor and holder of the Nancy, Clive, and Pierce Runnells Distinguished Chair in Neurosurgery at The University of Texas Health Science Center at Houston (UTHealth) Medical School, tackled the complex and thorny issue of consent and its impact on clinical trials in subjects with severe brain injury. His efforts helped remove a major obstacle for researchers in emergency medicine and enabled more critically injured patients to benefit from cutting-edge science.
“Science had been changing over a period of about 15 years. We had all these new cardiac and neurological treatments, but the treatment windows were getting shorter and shorter. Many of the therapies under study had to be applied within a matter of hours – in some cases, a matter of minutes. We had to have a new consent mechanism to move forward,” says Clifton.
That was his situation in 1994 when he was trying to carry out clinical trials of hypothermia, a cooling technique, in patients with severe brain trauma. Clifton’s research suggested that lowering the body temperature to 33 degrees Celsius might reduce brain swelling, a possible fatal consequence of head trauma. But hypothermia had to be administered within six hours of injury. Clifton’s potential subjects were often injured in car accidents. They were both unconscious – a frequent result of severe brain injury – and alone. Locating a family member to give consent for the patient to be treated with hypothermia often took so long that it was too late to administer the cooling therapy.
“You could not do the time-sensitive research,” says Paula Knudson, special advisor to the provost and executive vice president for research at UTHealth, who worked closely with Clifton on the waiver issue.
Clifton decided to take on the challenge of untangling the issues and dealing with the entities and people that determine policy on patient consent in clinical trials. “Like anything else in life, you don’t give up,” he observes.
Dr. Clifton goes to Washington
“There were lots of phone calls, lots of trips,” Clifton recalls. Knudson says, “He (Clifton) was incredible. He and I gave testimony in Washington and lots of senators sent legislative aides to hear what we had to say.“
Knudson herself “mobilized the Institutional Review Board (IRB) community,” in Clifton’s words, alluding to the institutional review boards, the bodies in all research institutions designated to approve, monitor and review research involving human beings and committed to protecting the rights and welfare of research subjects.
Clifton petitioned the U.S. Department of Health and Human Services (DHHS). “There was pressure from the NIH, from me, from the IRB,” he notes. A tremendous boost to the cause was provided by D.A. Henderson, M.D., assistant secretary of the DHHS. “D.A. Henderson got involved in this on our side, and he managed to get an exception into the Congressional Record,” Clifton says.
A Federal Register notice of July 20, 1995, permitted Clifton’s study – specifically and solely – to proceed using waiver of consent under what were termed “strictly limited circumstances.”
Democracy and medicine
They were past the first hurdle: showing that the research cannot be done without a waiver.
But another key provision of the regulations governing waivers of consent is community consultation. The researchers’ due diligence must include taking the issue to the public. “We had to see if the public found our use of waiver acceptable,” Clifton explains.
Clifton and Knudson gave talks at breakfast meetings and community centers, being sure to give a balanced presentation of the facts. “We had to be very careful. We said, ‘There are unknowns here.’ And there was an IRB person with us.
“Usually between 20 and 40 people came to these meetings. They asked good questions. We pointed out that 56 percent of the patients we were talking about ended up dead, vegetative or dependent, and that we had not seen any real improvement in outcome in 20 years. We also pointed out that our lab data was very strong and that hypothermia was among the most promising options we had for treating these patients. We conducted the community consultation in the ‘robust manner’ required, and we documented everything,” Clifton says.
“The people in Washington had expected there to be an outcry. But 95 percent of the public we consulted felt that the study was ‘something that should be done.’ I can think of only two cases in which someone voiced a strong objection. As it turned out, speaking to the public was something I enjoyed doing. I didn’t think I would.”
Refocusing the argument
According to Clifton, “The regulations regarding informed consent had been in place since WWII. The intent of the framers was to protect patients from inappropriate research being conducted without their knowledge, but the regulations as they were interpreted would have prevented much promising emergency research from being conducted.“
Knudson, who has devoted a significant portion of her career to the consent issue, injects another point into the debate. “What does ‘informed consent’ really mean in these situations? These patients are critically ill. Even if they are conscious, do they really understand what they are signing?” As she puts it, she is “married to the proposition” that informed consent in a grave emergency is a flawed concept. “A farce, really,” she adds.
The results in the first year of the hypothermia study established that experimental treatments that required immediate application in comatose patients could not be tested without the ability to use waiver of consent.
When it became clear that emergency research could not be conducted if informed consent was always required, the consent issue was transformed.
“Taking the condition of the patient and the circumstances into account put the risk in perspective; it was an immense change,” Clifton explains.
Decisions and data
On October 2, 1996, federal action revised the Code of Federal Regulations – specifically the provisions of 45CFR46 – to permit the use of waiver of consent in emergency research under carefully defined circumstances and with specific requirements.
Clifton’s article, Waiver of Consent in Studies of Acute Brain Injury, (Journal of Neurotrauma, 2002) co-authored by Knudson and Marilyn McDonald, executive assistant to Clifton, reported that in the last 32 months of the study, completed with the option to use waiver of consent, an average of 127 patients a year were enrolled. The study also produced unique data documenting the effect of consent procedures on accrual, time to treatment and minority enrollment. More patients were enrolled and hypothermia was able to be induced sooner when waiver was permitted. And although one of the objections to waiver of consent was that it violated the rights of minorities in particular, the reverse was true: minority enrollment was increased.
A new approach to research
“The hypothermia study broke it open,” says Clifton. “We were the first in the country to conduct trials with waiver of consent. We established that such research could be conducted safely – that the regulations were workable – and importantly that the public understood and accepted the use of waiver of consent.”
Clifton’s hypothermia trials are completed now. “We learned that we have to start cooling very early. We have found that even then hypothermia is not effective for patients with brain injury without blood clots. We have found that there is a strongly protective effect in those with blood clots. This will do it!”