Blood substitute study raises consent questions

Community education makes the difference

In emergency medicine and critical care, clinical trials are difficult to conduct. The unpredictable and time-sensitive nature of these specialties means that controlled, randomized, clinical trials are difficult, sometimes impossible to design.

For example, in most situations, prior informed consent for new emergency procedures cannot be obtained because the patient’s condition is life-threatening and must be treated immediately, or the patient is unconscious and unable to consent.

To encourage carefully monitored research into new life-saving interventions, federal regulations provide an exception to the rule requiring patients be given informed consent before they are enrolled in clinical trial.

To be eligible for the exemption, investigators must demonstrate that:

  • patients who would be included in the trial face a life-threatening situation;
  • currently available treatments are unproven or unsatisfactory;
  • consent from the patient would not be feasible because of the patient’s condition, and because treatment must be initiated before an appropriate representative can be reached;
  • research cannot reasonably be conducted otherwise;
  • risks and benefits of the experiment are considered reasonable in light of the patient’s condition and what is known about other therapies;
  • participation in the research holds the potential for direct benefit of the subject.

If these conditions are met, federal regulations also require investigators to develop methods to publicly communicate information about the study in the community where it will be conducted, to publish the results of the study once it is complete, to use an independent data safety monitoring board, and have the protocol approved by the U.S. Food and Drug Administration.

PolyHeme, for example

One such protocol is now under way at 20 medical centers nationwide. Paramedics working for these centers will be administering an experimental blood substitute to patients in the field who meet certain criteria.

PolyHeme, a substitute blood product manufactured by Evanston, IL-based Northfield Laboratories, is made from chemically modified hemoglobin derived from human blood and is designed to be an alternative to transfused blood in the treatment of acute blood loss.

According to information published by the manufacturer, PolyHeme is universally compatible and does not require blood typing prior to its use. And, unlike stored donated blood, which can only be stored for 28-42 days, the experimental product has an estimated shelf life of 12 months under refrigerated conditions.

If proven effective, PolyHeme could dramatically improve outcomes for trauma patients. Donated blood cannot be carried on ambulances because of problems with storage and the need to match a patient’s blood type. People who suffer severe blood loss in the field are normally given transfused saline to maintain blood volume and pressure during their transport to a medical facility. An oxygen-carrying blood substitute however, could better maintain blood-oxygen levels and help reduce the incidence of hemorrhagic shock.

PolyHeme has been previously tested in surgical patients and used during in-hospital resuscitations, with no reported adverse events.

But investigators believe it is essential to test the product in emergency patients to determine how they will respond.

The problem, however, is that patients who suffer severe blood loss in the field are unable to give informed consent prior to participation in a study. Often, the patients are unconscious. But even if they are not, paramedics cannot take time out from performing lifesaving procedures to explain the potential risks and benefits.

The research is just one example of studies being conducted under the 1996 federal exemption from consent regulations for research into emergency, lifesaving procedures.

Critics fear abuse

Some patient advocates say the exception is unethical because it permits experimentation on human subjects without their prior consent.

The study "is another one along that slippery slope that’s essentially demolishing your individual right not to become experimental subjects unless you give prior, voluntary, informed, comprehending consent," Vera Sharav, president of the New York-based Alliance for Human Research Protections, told the Associated Press on Feb. 20.

But many medical ethicists say there are important characteristics of emergency care that warrant exemptions to standard research practices.

"Emergency medicine and critical care are the two areas most in need of clinical research, but it is very difficult to conduct study protocols in this setting," says Norman Fost, MD, MPH, director of the Program in Medical Ethics at the University of Wisconsin-Madison Medical School.

Emergency and critical care specialists frequently don’t have the time to design and conduct randomized clinical trials of new procedures or therapeutics. Yet they often want to employ innovative new therapies if they believe they offer their patients the best chances of survival and recovery. Clinicians frequently try new therapies on an ad hoc basis with little or no supervision.

For many years, prior to the increased emphasis on "evidence-based medicine," physicians frequently tried untested treatments on patients in a variety of settings — particularly in emergency medicine and critical care.

They shared information with one another in published articles and at meetings, but it often took years to determine that treatments believed to be effective were, in fact, ineffective or bad or dangerous for some patients, he says.

Clinical trials, approved by an institutional review board and supervised by data safety monitoring boards, may actually offer patients with emergency conditions more protections — even without their informed consent — than they would enjoy outside a research protocol.

"Informed consent is a process, not a means to an end," Fost says.

Its purpose, he contends, is to prevent people from being enrolled in research that they would not want to be involved in if they were aware of the risks and benefits.

However, prior informed consent is not always necessary to accomplish these goals, Fost adds.

The federal regulations require investigators to publicize the research in the community and seek public input, he says. And the informed consent exemption only applies to emergency research in areas where there is not an effective treatment available.

In many cases, community members where such research takes place indicate that they would welcome the opportunity to have access to the experimental treatment, he continues.

Investigators at Denver Health Medical Center, one of the hospitals participating in the multicenter trial, designed an extensive public education campaign in advance of seeking permission to test the PolyHeme product, says Jeffrey Long, clinical research specialist and the PolyHeme study coordinator at that site.

"A team of representatives from Denver Health, including the principal investigator, co-investigators, emergency room physicians, EMS personnel, and representatives from our public relations department, and myself met with several local community groups and provided a 20-minute presentation, detailing the study design and federal regulations as well as previous experience with the product," he reports. "The presentation was followed by a question-and-answer period that lasted between 15 and 20 minutes."

At the meetings, the team provided an anonymous survey to be filled out and returned. In addition, they placed notices in several local publications and got local coverage of the proposed study on local TV stations and newspapers.

"We also created a web site and offered both a call-in number, as well as e-mail and mailing addresses for correspondence concerning questions and comments regarding the study," Long adds.

They developed print and radio advertising in both English and Spanish and scheduled the principal investigator, Ernest E. Moore, MD, to give a presentation before the city council that was then featured on public access television.

"The reaction during our community consultation was positive," Long recalls. "I was pleasantly surprised by the enthusiasm surrounding the trial that was witnessed during our community consultation efforts. Multiple attendees told us that, should the situation arise, they hoped the PolyHeme product would be available for them and their families."

In the event that community members did not want to participate in the study, they could let investigators know through one of the established avenues of communication and would be provided with a small bracelet to wear, indicating they refused participation.

"The regulations don’t require this measure to be taken; however, we felt obligated to provide everyone with the opportunity to express their wishes to refuse participation," Long says.

Fears that the federal exemption from informed consent requirements in emergency research would lead to a rash of no-consent protocols have proved to be unfounded, adds Fost.

Since its implementation, only 15 such studies have been approved.

Fost attributes this to the stringent requirements and some confusion among research sponsors and would-be investigators about what the requirements for community consultation and public disclosure really are, he adds.

The federal regulations are not specific about the extent of public information required and, thus many sponsors are wary of attempting such research, Fost claims. The result, he contends, is that many beneficial studies never get performed, leaving emergency critical care patients with fewer options.

"If this element of the exception requirements could be clarified, I think it might help sponsors and investigators feel more comfortable designing and proposing these protocols," he states.

To ensure they met the federal requirements for appropriate community education and consultation, Denver investigators spent more than five months planning and developing a communications strategy for dissemination of study information to the public and building a response mechanism for local community members, Long says.

"During this period, we met with or petitioned medical professionals, some of which previously attempted and/or conducted this type of research; local paramedics; various members of the local community and the Colorado Multiple Institutional Review Board, to name just a few," Long says. "Each provided insight into how to reach community members and address potential concerns."

The paramedic division played a crucial role by working as a part of the team developing the protocol and a strategy that would be easily understood by the public, he adds.

For investigators and coordinators planning other emergency trials, Long recommends first going over the federal exception regulations with a fine-tooth comb.

"Most important, you need to understand and meticulously adhere to FDA regulations in order to assure the protection of the rights and welfare of research subjects," he says. "Second, formulate a detailed plan and include the IRB in each step of that plan. Develop a collaborative relationship with your IRB, accept their criticism as positive, and solicit their feedback during the application and the community consultation and public disclosure period."