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When is it rational to participate in a clinical trial? A game theory approach incorporating trust, regret and guilt.

Djulbegovic B, Hozo I - BMC Med Res Methodol (2012)

Bottom Line: By asking current patients "to sacrifice for the benefit of future patients" we risk subjugating our duties to patients' best interest to the utilitarian goal for the good of others.The more that a researcher believes the experimental treatment will be successful, the more incentive the researcher has to abuse trust.By varying all variables in the Monte Carlo analysis we found that, on average, the researcher can be expected to honor a patient's trust 41% of the time, while the patient is inclined to trust the researcher 69% of the time.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Evidence-based Medicine and Health Outcome Research, Clinical Translational Science Institute and Department of Internal Medicine, University of South Florida, Tampa, FL, USA. bdjulbeg@health.usf.edu

ABSTRACT

Background: Randomized controlled trials (RCTs) remain an indispensable form of human experimentation as a vehicle for discovery of new treatments. However, since their inception RCTs have raised ethical concerns. The ethical tension has revolved around "duties to individuals" vs. "societal value" of RCTs. By asking current patients "to sacrifice for the benefit of future patients" we risk subjugating our duties to patients' best interest to the utilitarian goal for the good of others. This tension creates a key dilemma: when is it rational, from the perspective of the trial patients and researchers (as societal representatives of future patients), to enroll in RCTs?

Methods: We employed the trust version of the prisoner's dilemma since interaction between the patient and researcher in the setting of a clinical trial is inherently based on trust. We also took into account that the patient may have regretted his/her decision to participate in the trial, while a researcher may feel guilty because he/she abused the patient's trust.

Results: We found that under typical circumstances of clinical research, most patients can be expected not to trust researchers, and most researchers can be expected to abuse the patients' trust. The most significant factor determining trust was the success of experimental or standard treatments, respectively. The more that a researcher believes the experimental treatment will be successful, the more incentive the researcher has to abuse trust. The analysis was sensitive to the assumptions about the utilities related to success and failure of therapies that are tested in RCTs. By varying all variables in the Monte Carlo analysis we found that, on average, the researcher can be expected to honor a patient's trust 41% of the time, while the patient is inclined to trust the researcher 69% of the time. Under assumptions of our model, enrollment into RCTs represents a rational strategy that can meet both patients' and researchers' interests simultaneously 19% of the time.

Conclusions: There is an inherent ethical dilemma in the conduct of RCTs. The factors that hamper full co-operation between patients and researchers in the conduct of RCTs can be best addressed by: a) having more reliable estimates on the probabilities that new vs. established treatments will be successful, b) improving transparency in the clinical trial system to ensure fulfillment of "the social contract" between patients and researchers.

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Two-way sensitivity analysis of the prisoner’s dilemma trust game of clinical trials. The effect of the probability of treatment success on: a) the patient’s trust of the researcher (whether to enroll in the trial), b) researcher’s inclination to honor the trust. At the intersection, the two strategies are identical. The dot shows the baseline values of the model. Color fields indicate the optimal strategy for each player.
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Figure 2: Two-way sensitivity analysis of the prisoner’s dilemma trust game of clinical trials. The effect of the probability of treatment success on: a) the patient’s trust of the researcher (whether to enroll in the trial), b) researcher’s inclination to honor the trust. At the intersection, the two strategies are identical. The dot shows the baseline values of the model. Color fields indicate the optimal strategy for each player.

Mentions: (9)p1−rEUStd−EUExp+1−eRU3−U2+EUExp−1−eRU3−U2≥EUStd−1−sRU1−U4The solution of the tree under the baseline values shown in Table 1 produced a disconcerting result: the most rational behavior for the patient is to not trust and to not enroll in the RCT [Expected value (EVtrust) = 45 vs. EVno_trust = 50]. From the researcher’s point of view, the strategy with the highest expected utility was associated with “Abuse Trust” Expected value(EVhonor_trust) = 65 vs. EVabuse_trust = 66].The analysis was sensitive to most assumptions about the utilities related to the success and failure of therapies that are tested in RCTs. Figure 2 displays the results of the patient’s and researcher’s strategy over all possible values of the success of experimental and standard treatments. Under the baseline assumption of the model, the most rational strategy for the patient is not to trust and for the researcher to abuse this trust. It can also be seen that the higher the probability that the experimental treatment will be successful, the more incentive the researcher has to abuse the patient’s trust. However, for the wide range of success of experimental treatments, the most rational strategy is still for the patient to trust, despite the possibility that the researcher may not honor it: the likelihood of obtaining successful treatment appears to justify putting oneself in a vulnerable position. Figure 3 shows the two-way sensitivity analysis for p (probability that the researcher will honor trust) vs. r (probability of randomization). Under typical randomization of 50%, in the trust model, unlike in the equipoise model, the most rational strategy for the researcher and patient is not to cooperate. The researcher has incentive to honor trust only when the probability that a patient’s chance of being randomized to the experimental treatment is ≥61%. On the other hand, the patient should rationally exercise his/her trust only if the probability that the researcher will honor the trust is ≥67%. We also observed two other interesting results: under our assumption that regret is not greater than guilt, neither the patient’s regret nor the researcher’s potential guilt affected the analysis. In addition, the results were not affected by the patient’s utility related to the success of experimental treatment (it would have to be >100% in order to override any patient’s concern about trustworthiness of the researcher) (Results not shown).


When is it rational to participate in a clinical trial? A game theory approach incorporating trust, regret and guilt.

Djulbegovic B, Hozo I - BMC Med Res Methodol (2012)

Two-way sensitivity analysis of the prisoner’s dilemma trust game of clinical trials. The effect of the probability of treatment success on: a) the patient’s trust of the researcher (whether to enroll in the trial), b) researcher’s inclination to honor the trust. At the intersection, the two strategies are identical. The dot shows the baseline values of the model. Color fields indicate the optimal strategy for each player.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473303&req=5

Figure 2: Two-way sensitivity analysis of the prisoner’s dilemma trust game of clinical trials. The effect of the probability of treatment success on: a) the patient’s trust of the researcher (whether to enroll in the trial), b) researcher’s inclination to honor the trust. At the intersection, the two strategies are identical. The dot shows the baseline values of the model. Color fields indicate the optimal strategy for each player.
Mentions: (9)p1−rEUStd−EUExp+1−eRU3−U2+EUExp−1−eRU3−U2≥EUStd−1−sRU1−U4The solution of the tree under the baseline values shown in Table 1 produced a disconcerting result: the most rational behavior for the patient is to not trust and to not enroll in the RCT [Expected value (EVtrust) = 45 vs. EVno_trust = 50]. From the researcher’s point of view, the strategy with the highest expected utility was associated with “Abuse Trust” Expected value(EVhonor_trust) = 65 vs. EVabuse_trust = 66].The analysis was sensitive to most assumptions about the utilities related to the success and failure of therapies that are tested in RCTs. Figure 2 displays the results of the patient’s and researcher’s strategy over all possible values of the success of experimental and standard treatments. Under the baseline assumption of the model, the most rational strategy for the patient is not to trust and for the researcher to abuse this trust. It can also be seen that the higher the probability that the experimental treatment will be successful, the more incentive the researcher has to abuse the patient’s trust. However, for the wide range of success of experimental treatments, the most rational strategy is still for the patient to trust, despite the possibility that the researcher may not honor it: the likelihood of obtaining successful treatment appears to justify putting oneself in a vulnerable position. Figure 3 shows the two-way sensitivity analysis for p (probability that the researcher will honor trust) vs. r (probability of randomization). Under typical randomization of 50%, in the trust model, unlike in the equipoise model, the most rational strategy for the researcher and patient is not to cooperate. The researcher has incentive to honor trust only when the probability that a patient’s chance of being randomized to the experimental treatment is ≥61%. On the other hand, the patient should rationally exercise his/her trust only if the probability that the researcher will honor the trust is ≥67%. We also observed two other interesting results: under our assumption that regret is not greater than guilt, neither the patient’s regret nor the researcher’s potential guilt affected the analysis. In addition, the results were not affected by the patient’s utility related to the success of experimental treatment (it would have to be >100% in order to override any patient’s concern about trustworthiness of the researcher) (Results not shown).

Bottom Line: By asking current patients "to sacrifice for the benefit of future patients" we risk subjugating our duties to patients' best interest to the utilitarian goal for the good of others.The more that a researcher believes the experimental treatment will be successful, the more incentive the researcher has to abuse trust.By varying all variables in the Monte Carlo analysis we found that, on average, the researcher can be expected to honor a patient's trust 41% of the time, while the patient is inclined to trust the researcher 69% of the time.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Evidence-based Medicine and Health Outcome Research, Clinical Translational Science Institute and Department of Internal Medicine, University of South Florida, Tampa, FL, USA. bdjulbeg@health.usf.edu

ABSTRACT

Background: Randomized controlled trials (RCTs) remain an indispensable form of human experimentation as a vehicle for discovery of new treatments. However, since their inception RCTs have raised ethical concerns. The ethical tension has revolved around "duties to individuals" vs. "societal value" of RCTs. By asking current patients "to sacrifice for the benefit of future patients" we risk subjugating our duties to patients' best interest to the utilitarian goal for the good of others. This tension creates a key dilemma: when is it rational, from the perspective of the trial patients and researchers (as societal representatives of future patients), to enroll in RCTs?

Methods: We employed the trust version of the prisoner's dilemma since interaction between the patient and researcher in the setting of a clinical trial is inherently based on trust. We also took into account that the patient may have regretted his/her decision to participate in the trial, while a researcher may feel guilty because he/she abused the patient's trust.

Results: We found that under typical circumstances of clinical research, most patients can be expected not to trust researchers, and most researchers can be expected to abuse the patients' trust. The most significant factor determining trust was the success of experimental or standard treatments, respectively. The more that a researcher believes the experimental treatment will be successful, the more incentive the researcher has to abuse trust. The analysis was sensitive to the assumptions about the utilities related to success and failure of therapies that are tested in RCTs. By varying all variables in the Monte Carlo analysis we found that, on average, the researcher can be expected to honor a patient's trust 41% of the time, while the patient is inclined to trust the researcher 69% of the time. Under assumptions of our model, enrollment into RCTs represents a rational strategy that can meet both patients' and researchers' interests simultaneously 19% of the time.

Conclusions: There is an inherent ethical dilemma in the conduct of RCTs. The factors that hamper full co-operation between patients and researchers in the conduct of RCTs can be best addressed by: a) having more reliable estimates on the probabilities that new vs. established treatments will be successful, b) improving transparency in the clinical trial system to ensure fulfillment of "the social contract" between patients and researchers.

Show MeSH
Related in: MedlinePlus