Are You Informed About Informed Consent?

This is Part One of a two-part series focusing on the clinician’s role in clinical trials. Part Two will explore the ethics of recruiting patients for Phase 1 trials.

In July of 2007, trials for a gene-based intervention for arthritis were temporarily suspended following the death of Jolee Mohr, a participant. Although investigations by both the Food and Drug Administration and the company resulted in findings that the investigational treatment was not at fault and the trial has been restarted, some questions were raised about the nature of the informed consent and the role the patient’s community-based physician played in her recruitment.

At one time, clinical trials in the United States were almost entirely within the purview of the academic medical center (AMC). In 1991, 80% of industry money for clinical trials went to AMCs.¹ By 2007, the community physician was getting nearly 77% of the spending for clinical investigations.²

In both instances, in the United States, the Institutional Review Board (IRB) takes the lead in approving the outlines of a protocol and making sure these meet the various legal, ethical, and regulatory requirements.

“The IRB serves as an arm of the Office for Human Research Protection [OHRP], of [the Department of Health and Human Services] and is charged with local oversight in institutions involved in human subject research,” says Elan Czeisler, director of the IRB for New York University Medical Center in New York City. “They are charged with both the review and oversight of research and ensure that they comport with safeguards enacted by legislation and regulations in place to protect research subjects.”

One major concern for physicians thinking about participating in a clinical trial is in the area of informed consent.

“According to federal statute, informed consent has to be an educational process and not just a form people sign,” says Eric Matteson, MD, chair of the division of rheumatology at the Mayo Clinic in Rochester, Minn. “Research subjects have to voluntarily decide to participate in research and it is important that they clearly understand everything about the trial, including the very substantial risk that is sometimes involved.”

Informed Consent in Clinical Trials Different from Regular Practice

Informed consent in a clinical trial differs greatly from the informed consent obtained before surgery. One of the aspects least understood by both subject and investigator is the focus of the interventions.

“It has to be made unambiguously clear that what they are to receive is not clinical care,” says Paul Romain, MD, chief of rheumatology at the Cambridge Health Alliance in Cambridge, Mass. “There is a loss of the physician’s ability to make decisions that personalize the intervention. The goal of the research is to produce scientifically valid results and that means adhering to the predetermined research protocol.”

In clinical practice, prescribing a drug or suggesting a procedure is done with the assumption that it most likely will benefit the patient. This assumption is not present in clinical trials.

One of the concerns voiced in aftermath of Mohr’s death was the issue of the bond between a patient and physician and how it might influence the subject’s decision. The normal trust that a patient puts in the doctor may lead to problems with informed consent if the doctor/researcher is not very careful.

“Patients and physicians often have a disproportionate belief in the likelihood that the intervention will benefit the subject-patient,” says Dr. Romain. “Data show that subjects in a study often do not appreciate the blinded nature of whether they get placebo or active treatments. They assume the doctor is likely to do what is best for them, not fully understanding that the decisions are being made on what is best for the trial.”

This can be especially troublesome if the subjects are not fully aware of how the randomization process may affect their treatment and its impact on disease. For example, giving a placebo in a trial assessing the impact of a medication on rheumatoid arthritis could result in additional damage to the joint.

A similar concern relates to whether subjects know how their care in a trial differs from the standard of care. The trial may require multiple X-rays when usual practice only suggests one. Information on risks that are added because of the study’s requirements need to be included.

Goal Is Not Individualized Care

The goal of a trial is to produce generalizable knowledge, whereas the goal of clinical medicine is to produce individualized care. They are two very different objectives, and the differences need to be thoroughly explained as part of the informed consent process.

Size and complexity of the consent form can be another significant difference. It is not unusual to find consent forms that run to 10 or 15 pages outlining every possible concern in often legalistic language. This was brought out following Mohr’s death.

“In the clinic, the consent form largely focuses on things that are common or important,” says Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego. “In clinical trials, they may include a laundry list of things that a reasonable person may not understand. It becomes a balancing act to communicate what are important risks while allowing the potential research subject to see the entire breadth of what the company’s lawyers think needs to be said.”

In community settings, the researchers may have little control over the content of the informed consent. The IRB for a particular study gives approval for the form and there is little an individual researcher can do to change it. Thus, one of the important early decisions is whether the researcher is comfortable with the form.

“The informed consent form, in one sense, should be viewed as documenting the important elements of the conversation that you had with the potential subject, reminding the investigator of details that they might have otherwise forgotten and giving the subject a record of those details both before and after they sign,” says Dr. Romain.

All of the experts interviewed agreed that informed consent first requires assessment of the potential subject and their ability to consent. “Informed consent begins with the assessment of the patient’s ability to understand before they are even offered the opportunity to become a research participant,” says Dr. Kavanaugh. “There must be freedom from coercion, competence, and the ability to understand the ramifications of entering the study.”

There must also be equitable access to the study by populations such as the elderly, those who are pregnant, and ethnic minorities.

“One of the more challenging ethical challenges faced by IRBs is to ensure that investigators adhere to the principle of justice, specifically equitable access,” says Dr. Czeisler. “The investigator should make every effort to distribute the benefits associated with clinical research in an equitable manner and to not exclude people simply because they are non-English speakers or educationally or economically disadvantaged.”

Time may be the best way to assure that informed consent is both fully informed and valid consent. Personal contact—taking the time to explain the terminology and the goals of the study—makes it possible to fulfill the requirements of informed consent. This process is even more important for potential subjects with poor educational achievement.

Regulations require that all forms used in trials be written to a sixth- or eighth-grade reading level. However, that may not be clear enough for patients to comprehend fully, and the researchers should also make sure the subject understands the jargon being used.

“Standard literacy is very different from health literacy,” says Dr. Romain. “People do not always know much about how their bodies work and cannot easily appreciate what the implications are of different side effects and interventions.”

Structured interventions such as audio-visual presentations or brochures have not been shown to be effective in achieving informed consent. However, most of the experts agreed that questionnaires can find holes in a subject’s understanding. Allowing subjects to take the forms home and discuss them with their family and friends is useful as well.

“The most meaningless question an investigator can ask is, ‘Do you understand?’ ” says Dr. Matteson. “That isn’t really a question, but rather a statement designed to get a yes. You gauge understanding by having them repeat in their own words the various concepts as you both go through the protocol.”

Kurt Ullman is a freelance writer based in Indiana.

References

1. Getz KA. AMCs rekindling clinical research partnerships with industry. Boston: CenterWatch, 1999.
2. Thompson CenterWatch. State of the Clinical Trials Industry. Boston: CenterWatch, 2007.