Patient Expectations of Benefit in Early-phase Trials: Ethics Issues in Informed Consent 


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Instead of trying to dissuade patients from expressing hope or positive attitude, we might work with them to make sure they are planning for all possible outcomes.

—Kevin P. Weinfurt, PhD

It has been found that many patients in early-phase oncology trials believe their chance of benefit to be much higher than estimates derived from historical data.1-3 In a recently reported study in Journal of Clinical Oncology, Kevin P. Weinfurt, PhD, of Duke Clinical Research Institute, and colleagues attempted to discern whether patients’ expectations differed according to how questions about expected benefit were asked during the process of obtaining informed consent.4

Study Details

Of 213 patients enrolled in phase I or II trials in three U.S. tertiary care centers who were invited to participate in the study, 171 (80%) agreed. These 171 patients were randomly assigned to one of three groups corresponding to three queries about expectations: “frequency type,” “belief type,” or both.

A frequency-type probability refers to relative frequency of an event in a given population—eg, “On average, 5 of every 100 patients will have a response to experimental treatment.” A belief-type probability refers to an individual’s attitude toward a future event—eg, “I am 90% confident that I will be one of the people who respond to the experimental treatment.” 

Patients in the “belief” (or “confidence”) group (n = 56) were asked, “How confident are you that the experimental therapy will control your cancer (0% to 100%)?” Those in the “frequency” group (n = 55) were asked, “If 100 people were to participate in this study, how many could be expected to have their cancer controlled as a result of the experimental therapy?” Those in the combination group (n = 60) first answered the “belief” question, discussed the answer with the interviewer, and then were asked the “frequency” question; the answer to the latter was the response of interest in this group, with the investigators hypothesizing that discussion of the first response would lower expectations as reflected in the response to the frequency question.

Overall, patients had a mean age of 60 years. Most were men (58%), white (82.5%), married/partnered (74%), living with others (89%), and participating in a clinical trial for the first time (68%). Almost all (95%) had ECOG performance status of 0 or 1. Most patients had some college (22%) or were college graduates (43%). Monthly income level brackets with more than 10% of the population were $2,000 to $2,999 (16%), $3,000 to $3,999 (11%), $5,000 to $5,999 (11%), and $8,000 or more (19%). Sixty-seven percent of patients were enrolled in phase I trials, and 33% in phase II trials.

Higher Expectations in ‘Confidence’ Group

Expectation of benefit differed significantly by question type (P < .001). The confidence group exhibited a mean expectation of benefit of 64.4 ± 22.3, significantly higher than the 51.6 ± 25.9 (P = .01) and 43.1 ± 27.1 (P < .001) values in the combination and frequency groups, respectively.

Contrary to the investigators’ hypothesis, expectation reflected in the combination group’s response to the frequency question was (nonsignificantly) higher than that in the frequency group. Mean expectations were slightly but nonsignificantly higher among participants in phase II trials (56.5 vs 51.7). A noteworthy finding was that 34% of patients in the confidence group selected an answer of 50, a clustering not observed in the other groups.

Expectations of patients in the confidence and frequency groups were also analyzed according to patient characteristics elicited using various survey measures. Patient aptitude for numbers was assessed using the Subjective Numeracy Scale and a single item assessing understanding of a statement of aggregate probability. The Quality of Informed Consent measure was used to assess understanding of elements of informed consent in clinical research. The Life Orientation Test-Revised measured patients’ optimism, and the Daily Spiritual Experiences Scale and Organizational Religousness–Short Form were used as measures of patients’ spirituality and religiousness.

Associated Factors

On these analyses, patients with higher belief-type expectations tended to prefer information expressed in nonquantitative terms (r = –0.19, 95% confidence interval [CI] = –0.19 to –0.36, on the numeracy preference subscale), had poorer knowledge about research/objective understanding of informed consent information (r = –0.21, 95% CI = –0.38 to –0.03, on Quality of Informed Consent objective score), greater dispositional optimism (r = 0.20, 95% CI = 0.01 to 0.37, on Life Orientation Test-Revised measure), and reported more spiritual thoughts and feelings in daily life (r = 0.22, 95% CI = 0.03 to 0.38, on Daily Spiritual Experiences scale). The only factor correlated with higher frequency-type expectations was poorer knowledge about research/objective understanding of informed consent information (r = –0.27, 95% CI = 0.27 to –0.51, on Quality of Informed Consent objective score).

As noted by the investigators, the finding that belief-type questions elicit a higher expectation of benefit from an experimental treatment (ie, greater confidence in a good personal outcome) may reflect a patient’s taking the opportunity to voice optimism about outcome. For example, patients may believe that personal feelings of confidence are less vulnerable to being called inaccurate than are knowledge claims about what proportion of patients are likely to benefit from treatment. Many patients value optimism, and a belief-type probability statement affords greater opportunity to express that optimism.

Ethical Implications

It was also the case that expectations elicited by frequency-type questions were higher than would be expected based on the chance of benefit suggested by historical data. As noted by the investigators, the ethical implications of such “therapeutic misestimation” depend on the reasons for the misestimation: “Such reasons might include difficulty understanding quantitative information during the consent process, encoding the gist of rather than the verbatim characteristics of information during disclosure, or trying to voice an optimistic attitude rather than express true understanding of the chances of success. More research is needed on the relative impact of factors leading to misestimation of frequency-type probabilities.”

With regard to the patients’ high belief-type expectations, the investigators stated, “[O]ur findings shift the focus of ethical concern in informed consent for clinical trials to issues other than disclosure, such as whether it is morally acceptable for patients to be optimistic, whether such optimism is beneficial, or whether it represents a cognitive bias that makes patients vulnerable and diminishes the quality of their informed consent.” They noted that they currently are conducting studies to address these issues.

As concluded by the investigators, “[T]hese findings show that the process of obtaining genuinely informed consent in early-phase clinical trials is more complex than has been understood previously, and they suggest the need to continue investigations of how best to advance the science of medicine while maintaining respect for patients who participate in these trials.” ■

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Disclosure: Among the authors of the JCO report, Dr. Herbert I. Hurwitz has been a consultant for Genentech/Roche, sanofi-aventis, Regeneron Pharmaceuticals, and Bayer Pharmaceuticals; has received honoraria from Genentech/Roche and Bayer; and has received research funding from Genentech/Roche, sanofi-aventis, Bristol-Myers Squibb, Tracon Pharmaceuticals, and Ascenta Therapeutics. None of the other authors reported any potential conflicts of interest.

References

1. Meropol NJ, Weinfurt KP, Burnett CB, et al: Perceptions of patients and physicians regarding phase I cancer clinical trials: Implications for physician-patient communication. J Clin Oncol 21:2589-2596, 2003.

2. Daugherty C, Ratain MJ, Grochowski E, et al: Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 13:1062-1072, 1995.

3. Cox AC, Fallowfield LJ, Jenkins VA: Communication and informed consent in phase 1 trials: A review of the literature. Support Care Cancer 14:303-309, 2006.

4. Weinfurt KP, Seils DM, Lin L, et al: Research participants’ high expectations of benefit in early-phase oncology trials: Are we asking the right question? J Clin Oncol 30:4396-4400, 2012.


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