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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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Model of clinical research according to the trust version of the prisoner’s game dilemma. The inset shows the equipoise model; e-success of experimental treatment; s-success of standard treatments. R-regret; G-guilt; U1 to U4: the patient’s utilities related to treatment success or failure; V1-V4: the researcher’s utilities related to treatment success or failure; Exp Rx- experimental treatment; Std Rx- standard treatment NA- not applicable (see text for details).
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Figure 1: Model of clinical research according to the trust version of the prisoner’s game dilemma. The inset shows the equipoise model; e-success of experimental treatment; s-success of standard treatments. R-regret; G-guilt; U1 to U4: the patient’s utilities related to treatment success or failure; V1-V4: the researcher’s utilities related to treatment success or failure; Exp Rx- experimental treatment; Std Rx- standard treatment NA- not applicable (see text for details).

Mentions: A dilemma whether to enroll in an experimental trial vs. opting for more established treatments can come in the various alternatives. Sometimes, patients themselves may insist on receiving hoped-for but inadequately tested and potentially harmful experimental treatments[25,26]. However, obtaining such treatments would be difficult without the cooperation of a researcher/physician who would need to agree to prescribe such an intervention outside of the clinical trial at the potential risk of professional and personal liability. In addition, these treatments are rigorously controlled by the regulatory agencies such as the Food and Drug Administration [27]. The dilemma can present in the context of participating in phase I, II or III trials. Therefore, one can potentially create many models depending on the specifics of the situation for an individual patient and/or a researcher. We choose to illustrate a dilemma facing investigators and patients by highlighting tension that is commonly encountered in clinical research: should a researcher offer a new, experimental treatment within the context of an RCT, or should he/she offer this promising treatment that is unproven, yet available, outside of the trial [28]? Figure 1 illustrates our model. We believe that the model captures most generic clinical research situations and certainly those that have provoked extensive writings in the medical and ethical literature. [2,29-31]


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)

Model of clinical research according to the trust version of the prisoner’s game dilemma. The inset shows the equipoise model; e-success of experimental treatment; s-success of standard treatments. R-regret; G-guilt; U1 to U4: the patient’s utilities related to treatment success or failure; V1-V4: the researcher’s utilities related to treatment success or failure; Exp Rx- experimental treatment; Std Rx- standard treatment NA- not applicable (see text for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Model of clinical research according to the trust version of the prisoner’s game dilemma. The inset shows the equipoise model; e-success of experimental treatment; s-success of standard treatments. R-regret; G-guilt; U1 to U4: the patient’s utilities related to treatment success or failure; V1-V4: the researcher’s utilities related to treatment success or failure; Exp Rx- experimental treatment; Std Rx- standard treatment NA- not applicable (see text for details).
Mentions: A dilemma whether to enroll in an experimental trial vs. opting for more established treatments can come in the various alternatives. Sometimes, patients themselves may insist on receiving hoped-for but inadequately tested and potentially harmful experimental treatments[25,26]. However, obtaining such treatments would be difficult without the cooperation of a researcher/physician who would need to agree to prescribe such an intervention outside of the clinical trial at the potential risk of professional and personal liability. In addition, these treatments are rigorously controlled by the regulatory agencies such as the Food and Drug Administration [27]. The dilemma can present in the context of participating in phase I, II or III trials. Therefore, one can potentially create many models depending on the specifics of the situation for an individual patient and/or a researcher. We choose to illustrate a dilemma facing investigators and patients by highlighting tension that is commonly encountered in clinical research: should a researcher offer a new, experimental treatment within the context of an RCT, or should he/she offer this promising treatment that is unproven, yet available, outside of the trial [28]? Figure 1 illustrates our model. We believe that the model captures most generic clinical research situations and certainly those that have provoked extensive writings in the medical and ethical literature. [2,29-31]

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