Blood On Tap, Part 2: An Ethical Dilemma in Emergency Research

"Ethics is not the process of giving 'correct' answers. Neither is it allowing everyone's opinion to stand unchallenged. It is the process by which we test either some, most, or all of what we do against the reasons that we do it."
-John Freeman, MD

By the time you read this, paramedics of the Denver Health Paramedic Division will have randomized the first patients into a nationwide prehospital study of the oxygen-carrying blood substitute Polyheme. The study is groundbreaking, historical and utterly impossible without a vital piece of legislation known as 21 CFR 50.24, an exception to the requirement of informed consent in medical research. The Polyheme trial will be another chapter in the widening debate over the ethics of risk and informed consent in emergency medical research. This is an up-close look at the history and roots of the controversy as some of the experts face off over an issue with far-reaching implications in the future of emergency medicine.

Bad Blood

Possibly the most difficult question to ask of history is, "What if?" It's difficult to say if the seemingly minor 1996 amendment to the code of federal regulations known as 21 CFR 50.24 would have made much of a stir if it hadn't gotten off to such a bad start. If the first few research studies conducted under the new waiver of informed consent had gone off without a hitch, the alteration may have gone unnoticed by anyone outside of the medical research community. But it didn't work that way.

March 31, 1996. The scientific community was surprised to learn that Baxter Healthcare Corporation was halting its phase III trauma study of the oxygen-carrying blood substitute Hemassist after enrolling just 112 patients. The product, which had already showed promise in multiple phase II studies, had not demonstrated the lifesaving potential that researchers had predicted. Instead, the patients who received Hemassist had demonstrated a mortality rate that not only exceeded Baxter's predictions, but far exceeded the mortality rates of patients in the control group who had received whole blood.

In all, 24 of the 50 patients who received Hemassist died. These numbers would have been merely an unfortunate footnote in emergency research if not for one critical distinction: None of the patients had consented to be involved in the study. Baxter's Hemassist study was the first research ever conducted under the new federal regulation allowing some emergency research to be exempted from the requirement of informed consent.

Hemassist's failure launched a swarm of negative press and brought CFR 50.24 into the spotlight. The media wanted to know, "How could this happen?" An Associated Press headline proclaimed "Blood Trials Done Without Consent." Websites devoted to warning the public of becoming guinea pigs popped up, and reporters unfairly compared the research to barbaric studies conducted by the Third Reich during World War II.

The shockwave of bad press sent Baxter Healthcare's stock plummeting and eventually led Baxter to withdraw Hemassist from all clinical trials, costing the company an estimated $500 million.

All predictions had been that the trial would be a perfect debut for the new exception to informed consent rule. A product that had proved itself in multiple phase II studies would be given to critically ill trauma patients who could not possibly provide informed consent. It was the type of study for which 50.24 was designed. What could go wrong?

The Rule (In a Nutshell)

When I say "the rule," I am specifically referring to the Code of Federal Regulations Title 21, Volume One, Part 50.24, which provides the first exception to a long-standing rule requiring informed consent of all human participants in medical research. The authors of 50.24 (as it is known in research circles) didn't offer the exception lightly.

Specifically, researchers must meet seven qualifications before conducting a study under a waiver of informed consent. An independent review board (IRB) must agree that the proposed study meets the following criteria before approval can be granted to waive a patient's right to voluntary, informed consent:

1. Research subjects must be in a life-threatening situation, where available treatments are unproven or unsatisfactory and the collection of scientific evidence is necessary to determine the safety and effectiveness of a particular intervention.

2. It must not be feasible to obtain informed consent before administering the intervention.

3. Based on preclinical data, participation in the research must hold a reasonable potential of direct benefit to the subject.

4. The clinical study could not practically be carried out without the waiver of informed consent.

5. A length of time must be defined by which researchers will attempt to obtain documented, informed consent from the patient or a representative.

6. There must be public disclosure of the study within the community where the study is to take place, as well as public consultation before the study is initiated.

7. An independent data-monitoring committee must provide ongoing oversight of the clinical trial.

After reading the list of protections afforded to the general public through the guidelines of 50.24, one might be tempted to ask, "What's the big deal?" Make no mistake about it: Informed consent is a big deal in medical research. To understand why folks take patient consent so seriously, we need to take a look back at some of medicine's painful lessons from the past.

The Origins of Consent

October 1946, Nuremberg, Germany

The world listened in shock and horror as the Nuremberg trials uncovered the brutal inhumanity of 20 Nazi physicians who performed research on concentration camp prisoners. In light of the enormity of the moral and ethical crimes of the 20 physicians, the tribunal decided that a code of ethics that centered on the rights of patients was needed, in addition to the Hippocratic Oath that already bound the doctors who stood trial.

The result was the Nuremberg Code-a 10-point document that defined the commonly accepted protections afforded to human subjects in medical research today. The first principle of the Nuremberg Code begins: "The voluntary consent of the human subject is absolutely essential."

It would be easy to argue that the moral lessons taught by the gross malevolence of Nazi physicians were so painfully obvious they fail to serve us in modern medicine. Several examples of more recent medical wrongdoings suggest that might be a dangerous conclusion, and moral lessons, once taught, are easily forgotten.

Tuskegee Syphilis Study (1932-1972)

For 40 years, 399 poor black males from Macon County, AL, were offered free meals and burial insurance to participate in research to treat their syphilis infections. In truth, the researchers purposefully withheld proven treatments such as penicillin to monitor the disease's progress. Over a hundred of the participants died from syphilis-related ailments prior to the study's termination under media scrutiny.

U.S. Human Radiation Experiments (1944 - 1974)

During the cold war, thousands of research participants were exposed to dangerous levels of radiation to gather safety data on the effects of the atomic bomb and to develop treatments for cancer patients. Subjects included prisoners, soldiers, the gravely ill and 54 mentally impaired children, who were intentionally fed radioactive breakfast cereal.

Willowbrook Hepatitis Study (mid 1950s - early 1970s)

Hundreds of severely mentally retarded children were purposefully infected with the hepatitis virus to study the disease's progression and to test new vaccines. Due to overcrowding, children were denied access to the Willowbrook institution unless their parents enrolled them in the study.

These are just a few examples in a long list of sad stories with a similar moral lesson: Voluntary informed consent of patients cannot be taken too seriously. In light of these studies, it is easier to understand why some medical ethicists insist that the requirement of truly informed consent is an absolute in medical research. Clearly, if we are to transgress upon this rule, we must do so with great caution.

The Heart of the Matter

As a clinical professor of bioethics and emergency medicine at The Medical College of Wisconsin, Dr. Arthur Derse is well versed in the ethical debate surrounding waivers of consent. From his office at the Center for the Study of Bioethics, Derse explained the rationale behind waivers of consent and why they remain of critical importance to the future of emergency research, with three important points of consideration.

"First of all, people will engage in non-research by just trying out experimental therapies," he says. "That happens frequently in clinical practice. Practitioners are trying new things all the time to see if they will help a particular patient. But as soon as we enroll patients into research studies, they fall under the federal regulations and magically become research subjects." Derse describes the waiver of consent as a way to systematize that process, regulate it and publicize the results, for better or worse, for the benefit of the medical community.

Derse's second argument speaks to the futility of advancing emergency medicine without this type of research.

"There is no other way to be able to move forward in emergency research," he says. "You can't get consent from people who are near death." To emphasize the point, he recalls his ED experience.

"We were giving calcium in the early 1980s because it was part of the protocol," he explains. "Why was it being done? Because everybody did it. We learned not to give it because we conducted clinical trials and found out it was killing people. The only way to do it was to enroll people in cardiac arrest into one of two protocols. You can't explain that to the family beforehand."

The third point in Derse's defense of 50.24 addresses the benefit of emergency research beyond the specifics of any particular outcome. "This [emergency research] benefits the community even when it doesn't benefit the individual. It still benefits the class of individuals who are at risk. Now other individuals will benefit because they won't be subject to this particular form of therapy."

What about 50.24's heavy emphasis on public notification and consultation? Critics feel the gesture does little to protect the public's interests. "Public notification means nothing," says Dr. Arthur Caplan, director of bioethics at the University of Pennsylvania. "I know people are enamored of it, but it means nothing."

Derse flatly disagrees. "I wouldn't say that community consultation just makes researchers feel good, because I've seen it work and been involved in several that were quite good. They worked because there were advertisements on the radio and TV, it was held at a major venue and folks from the community gave their input.

"Also, consider this aspect," he continues. "You couldn't have a Tuskegee with a community consultation requirement, or even with public notification, because people would say, 'No, this stinks.' So there is something beneficial to it."

Lessons of the Past

Clearly, there are a multitude of reasons to continue with emergency research under waivers of informed consent. However, one question continues to burn in my mind: Do we need to accept the fact that research interventions will occasionally fail to perform as expected? Will some research inevitably do more harm to the subjects involved than conventional treatment, or are there lessons to be learned from the Hemassist failure, that could prevent a future occurrence, or at least lessen the damage?

"I'm a bit of a pragmatist," explains Dr. Douglas Hansell, vice president of Medical Affairs for Biopure Corporation, a company also involved in oxygen therapeutic research. "I always try to learn from the past. Absolutely, [the Hemassist] experience is worth looking at, dissecting and trying to understand as best we can. But you also have to focus on the question of why you do research. You do research to answer a question. You hope to answer the question in a positive way, otherwise you wouldn't embark on it, but ultimately, you are answering a question."

Derse echoes the sentiment. "The lesson of the Hemassist trial is that you can follow a research protocol and still end up not benefiting patients. We do need a scientific basis to go forward on, but people need to understand that we have an experimental drug that might help. If it doesn't help, we're sorry, but we were trying everything.

"In retrospect, the Hemassist patients were disadvantaged by being involved in the protocol. They were probably much worse off than if they had nothing. You need to be careful. You can't sell something as having benefit until you know it has benefit, and you'll never know if it has benefit unless you do the research."

Burden of Responsibility

To operate under a waiver of consent in medical research, perhaps the first and most critical step is to recognize that we are traveling on sacred ground. Protecting the rights of humans to consent to their own participation as research subjects is a moral responsibility handed to each caregiver who participates in research. A waiver of consent does not allow us to disregard a patient's rights; it permits us to take stewardship of them. To accept that responsibility, we must recognize that the first rule of the Nuremberg Code was written to protect not only the patient, but also the integrity of the medical profession.

Jeff Long, a clinical research specialist who is currently working on the Polyheme trial at Denver Health Medical Center, sums up the importance of waivers of consent succinctly: "If you want to learn how to save dying patients, experiments may need to be done on those patients, and consent may not be possible. Either it is determined that we can't do the research anymore and we can't get any better at saving lives, or we go forward with 50.24 and make advances in medicine."

If we are to go forward, we must do so with great respect and compassion for the patients who place their trust in us as caregivers to act solely in their best interest. We cannot proceed without honest answers to the tough questions that need to be asked and a willingness to constantly test what we do against the reasons that we do it.

It is not enough to recognize the codes of ethics that bind us as medical professionals; we are also obligated to seek understanding of them. It is in the understanding of these guidelines, their origins and purpose, that we authentically serve our patients and protect the practice of medicine as a moral art. ƒÞ

Author's note: Baxter Healthcare representatives did not respond to numerous author requests for comment.

Bibliography

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