Of the 1,870 ongoing cancer clinical trials in the world, 531 are phase I clinical trials designed to verify the safety of experimental cancer treatments and procedures for use in humans.
As these trials may not directly benefit potential participants, it is especially important that cancer patients are well informed of the potential risks, potential benefits, medical procedures, and time commitments involved in the study before they agree to participate.
The health care professionals who are involved in the process of informed consent are charged with the tremendous responsibility of ensuring that potential trial participants understand the different aspects of the trial.
Christopher Daugherty tackles these complex issues in his article entitled "Informed Consent, the Cancer Patient, and Phase I Clinical Trials" in Ethical Issues in Cancer Patient Care (Kluwer Academic Publishers, 2000). In this chapter, he elucidates the history and evolution of informed consent in the last few decades.
Daugherty uses this history as a basis for a discussion about consenting patients in phase I cancer clinical trials and presents thought-provoking conclusions about how much trial participants truly understand about their participation.
Experts in medical ethics grapple with the task of establishing a definition of informed consent, a concept that continues to evolve as clinical research progresses in new directions. Daugherty generally defines informed consent as a "process of communication" between a potential participant and an investigator regarding the experimental treatment or procedure to be examined in a research study.
Most health care professionals incorporate the following five elements into this communication process with the patient:
Disclosure involves informing patient of the potential risks and benefits of the trial procedures and alternative methods of treatment for their condition besides participation in the study. This aspect of informed consent also includes conveying the experimental nature of the research to the patient and emphasizing the participant’s freedom to withdraw from the trial at any point without jeopardizing his or her future access to medical care.
Comprehension, the second element of a legally valid informed consent, requires that patients have a "substantial" understanding of the information disclosed to them by the investigator.
The issue of comprehension in informed consent has been surrounded by controversy in the last few years. Certain health care professionals believe that patients should understand all of the information presented to them, and they want to disclose as much information as possible to patients.
Other health care practitioners believe that "there is no guarantee that everyone’s interests and needs [would] be served" should this approach be used by those involved in getting informed consent from patients. Faden and Beauchamp believe that such disclosures would be too long and would be ineffective in achieving substantial patient understanding. Rather, they would like to refocus the discussions on informed consent and devise ways to create more effective communication between the investigator and potential participant.
The last three aspects of informed consent relate to patients’ ability to make an autonomous, thoughtful decision about their participation in a research study. While potential participants are evaluated for their emotional and mental capacity to give informed consent, they should also be free from coercion or influence from health care practitioners who may have a "conflict of interest" as health care workers and investigators in the study.
Origins of Informed Consent
In elucidating the origins of the process of informed consent, Daugherty notes that the concept of informed consent has often been erroneously attributed to the Nuremberg Code. He states that the Nuremberg Code specifically responds to the crimes against humanity perpetrated on people in Nazi concentration camps during World War II. He points out that the Nazi physicians who committed these atrocities did not have their victims’ therapeutic benefit in mind as they conducted their research.
Instead, Daugherty traces the first legal use of the term "informed consent" to a California Supreme Court case in 1957. The court ruled that no patient can be subjected to "medical intervention without having been given prior ‘informed consent.’"
Daugherty also notes that in a 1947 letter, the Atomic Energy Commission stated the need for "informed consent" in response to an investigator’s request to report declassified data from federally sponsored radiation research on cancer patients. Thus, the concept of informed consent began to permeate the field of medical research in the 1950s and 1960s.
The concept of informed consent was only in its infancy when Harvard anesthesiologist Henry Beecher published an important article in the New England Journal of Medicine in 1966. In this groundbreaking article, Beecher detailed 22 clinical trials carried out in the 1950s and 1960s that violated the rights of human subjects. The trial designs and procedures Beecher described jeopardized the health of the participants, who were often completely unaware of the risks such biomedical research posed to them.
Two of the studies described by Beecher involved the use of cancer patients in cancer clinical research. At one study site, later identified as the Jewish Chronic Disease Hospital, hospitalized patients were injected with malignant cells from cancer patients to evaluate the body’s immune response to cancer. The participants were elderly and debilitated patients without cancer. They were told that they would be injected with "some cells." The word "cancer" was never mentioned.
Another study described by Beecher involved a mother who consented to a transplant of melanoma from her terminally ill daughter ". . .in the hope that the production of tumor antibodies might be helpful in the treatment of the cancer patient." The researchers intended to withdraw serum from the mother and administer it to the patient. Unfortunately, the daughter died 1 day after the transplantation was complete. The tumor implant was removed from the mother 24 days later. The mother died about 1 year later from diffuse melanoma that had metastasized from the tumor implant.
Beecher’s work on these two cases and the 20 other studies described in his article shocked the medical community, leading to tighter regulations in government-sponsored clinical research in the 1960s and 1970s.
Daugherty notes that other such discussions ultimately resulted in the creation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. This committee’s recommendations led to the measures that are currently used to protect the rights of research subjects: the formal institutional review process and the use of informed consent.
What Motivates Patients
As a large number of clinical trials relate to cancer care, Daugherty focuses the rest of his chapter on analyzing the factors that motivate cancer patients to participate in studies that do not offer them a direct therapeutic benefit.
Specifically, Daugherty addresses debates about the level of patient understanding of clinical trials by examining studies that investigated the motivations and perceptions of participants in phase I cancer clinical trials.
Dr. Sjoerd Rodenhuis and his colleagues in the Netherlands conducted the first of these studies. They explored the motives of 48 patients with advanced-stage cancer who agreed to participate in a phase I clinical trial. The informed consent process for this study involved three different sessions that included the patient, the family, and health care professionals.
After these three sessions, 10 cancer patients who agreed to participate in the study were separately interviewed to determine how well they recalled the information disclosed in the informed consent process, what motivated them to participate in the trial, and whether they were content with their decision.
The investigators determined that eight of the 10 patients were adequately informed. However, four of these eight patients appeared to have an incomplete understanding of the intent of the trial, as they objected to being considered the "subject of an experiment."
These four patients stated that potential therapeutic benefit largely motivated them to participate in the study, and one other patient felt similarly. The husbands of three patients strongly encouraged them to take part in the study. In particular, the spouses urged these three patients to "grab at their last straws."
The remaining two patients could not point to a specific motivation and stated that they were complying with the expectations of their personal physician.
It should be noted that seven of the 10 patients also spontaneously stated during their treatment that they were interested in furthering the progress of science.
Based on these data, the investigators concluded that along with potential therapeutic benefit, influence from loved ones was a large factor in motivating advanced cancer patients to participate in clinical trials.
US Survey Study
Daugherty and his colleagues at the University of Chicago designed and executed a similar pilot study in which they surveyed 30 cancer patients who had agreed to participate in trials at that institution. Of the patients surveyed, 85% cited "possible therapeutic benefit" as their main motivation for participation in the trial; 11% said they participated because of influence from or trust of physicians; and 4% said they were pressured into participation by their families.
A full 93% of the patients stated that they understood all or most of the information disclosed to them in the informed consent process. However, only one third of this group was able to state the objective of the trial, and only the more educated patients were able to state the general purpose of phase I clinical trials.
This suggests that the level of the information presented in the consenting process about the purpose of the study was inaccessible to many participants.
Based on these findings, the authors concluded that while altruistic feelings are present in the patients, their main motivation for participation stems from the perceived prospect of potential therapeutic benefit. In addition, Daugherty suggests that the patients capable of understanding the idea of dose escalation may have ignored this information because it was inconsistent with their hopes for potential therapeutic benefit.
Another interesting finding of this study was that many patients stated that alternatives to participation in the trial were omitted from the consenting process, although all written consent documents included such information.
Daugherty believes that the patients’ hopes for therapeutic benefit may reflect the beliefs of the physicians involved in the design and execution of these trials. Their study also involved a survey of oncologists involved in clinical trials. The oncologists were found to have high expectations about the investigational agent’s potential therapeutic benefit for trial participants.
Overall, the lack of patient comprehension about the objective of the trial and the prevalence of potential perceived benefit of trial participation suggest that further discussion of these issues is essential.
New Methods Needed
The results of these studies suggest that there is a discrepancy between what cancer patients believe they understand based on informed consent procedures and what they actually understand about the clinical trial in which they participate.
To alleviate this problem and other difficulties in informed consent procedures, Daugherty suggests that researchers explore novel ways of obtaining informed consent. The author along with his collaborators recently conducted a study of an approach termed "cohort-specific informed consent," which involves a consent form that can be adjusted as a trial progresses.
Thus, while great progress in the fields of medical ethics and clinical research has been made since the 1950s and 1960s, the discussion surrounding the issue of informed consent remains quite active. Finding solutions to these ethical issues is not trivial, and researchers should continue to explore methods of refining this procedure to ensure that the rights of patients remain well protected.