Clinical equipoiseThe ethics of clinical research requires equipoise--a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically obliged to offer that treatment. The current understanding of this requirement, which entails that the investigator have no "treatment preference" throughout the course of the trial, presents nearly insuperable obstacles to the ethical commencement or completion of a controlled trial and may also contribute to the termination of trials because of the failure to enroll enough patients. I suggest an alternative concept of equipoise, which would be based on present or imminent controversy in the clinical community over the preferred treatment. According to equipoise and the ethics of clinical research summary concept of "clinical equipoise," the test cypionate and masteron is satisfied if there is genuine uncertainty within the expert medical community--not necessarily on the part of the individual investigator--about the preferred treatment.
Equipoise and the ethics of clinical research. - PubMed - NCBI
AMA Journal of Ethics. December , Volume 17, Number Malone is a primary care doctor in the student health clinic at a large research institution, and one of her patients, year-old Charlie, was just diagnosed with stage 4 non-small-cell lung cancer. The five-year observed survival rate is 1 percent and the current standard of care is chemotherapy. The Food and Drug Administration has just approved a promising new drug called MX for clinical trials.
A medical school classmate of Dr. Promising early-phase investigations suggest that patients receiving the new drug are improving and, based on this information, Dr. Malone thinks Charlie would probably be a good candidate for the drug. There is no guarantee that Charlie would be randomized to the experimental arm of the trial, but Dr. Malone and Charlie are hopeful that he would improve. As a result, Charlie enrolls. After some weeks, he has shown no improvement, and, while it may be too early to tell, Dr.
Malone begins to wonder whether he was in fact randomized to the control treatment arm. Malone feels responsible for possibly giving him false hope. She is aware of another clinical trial from which Charlie might benefit and is unsure whether she should voice her suspicions to Charlie, which might prompt him to leave the study, or keep her concerns to herself. In its canonical formulation, clinical equipoise stipulates that a randomized controlled trial RCT is only ethical insofar as there exists, at the outset, a state of genuine uncertainty in the community of medical experts about the relative therapeutic merits of every arm in the trial .
In other words, if clinical equipoise holds, then all arms are equally likely to be beneficial and all are consistent with competent medical care. This conception of clinical equipoise—as rooted in the uncertainty of the community of medical experts—emerged in response to an earlier and perhaps more intuitive conception, proposed by Charles Fried. Fried had argued that a physician-investigator could ethically enroll her patients in an RCT so long as she individually was in the state of equipoise—that is, she had no justified belief that one arm of the study was any better than the others.
In other words, if she was perfectly indifferent about which treatment arm was best, then she could enroll her patients in the trial and leave their assignments to chance . However, critics were quick to point out that this state of individual equipoise—and therefore the ethical acceptability of enrolling research participants—was too fragile.
Malone is experiencing . Yet whatever the reason for her change in belief, as soon as she was no longer indifferent, she would be ethically prohibited from encouraging future patients to enroll in the study.
More to the case at hand, it would also obligate her to encourage any of her patients who were already enrolled in the study to withdraw. In response to the fragility of individual equipoise, Benjamin Freedman proposed the concept of clinical equipoise.
Under the principle of clinical equipoise, individual physicians may have beliefs about the superiority of one treatment over another in an RCT, but the trial is still ethical so long as there is no consensus in the community of medical experts. As Freedman put it:. Shifting the uncertainty about the better treatment from the individual to the medical community made for a far more robust epistemic threshold, one more accommodating to carrying out RCTs.
If there is a state of clinical equipoise at the start of the trial, then a physician may ethically enroll her patients. Importantly, this remains an ethically justifiable action even if she has a suspicion that a patient of hers has been allocated to the supposed inferior arm, since the existence of clinical equipoise entails that the medical experts as a group do not yet know which arm is better.
A saga from oncology, which parallels Dr. The New York Times published a story in describing the plight of two cousins who were enrolled in an RCT comparing dacarbazine, the marginally effective standard treatment, to a promising new drug, vemurafenib, for the treatment of BRAF-mutated metastatic melanoma .
One cousin received dacarbazine and succumbed to his cancer. As the author of the Times story noted, there was considerable disagreement about the ethical acceptability of this RCT. Vemurafenib had achieved an 81 percent response rate in early-phase melanoma trials for patients with the requisite BRAF-mutated tumors . Therefore, some physicians argued, RCTs were unethical because vemurafenib was clearly superior to the standard of care for this patient population .
Proponents of the RCTs argued that, despite the dramatic response rate in the early-phase studies, clinical equipoise could not be overturned on the basis of a surrogate endpoint i. Therefore, an RCT employing clinical endpoints was still needed to definitively determine which treatment was superior .
This controversy points to a subtle but important dimension of clinical equipoise: If, at the outset of the trial, sufficiently robust evidence exists to rule out the possibility that the two treatments are clinically equivalent, then the trial is unethical.
However, if this robust evidence does not exist, then the trial can still be ethical. Given that high response rates in early-phase oncology trials can regress in subsequent studies, it is reasonable to think that clinical equipoise had not yet been overturned in the case of vemurafenib.
And, as it turned out, the observed response rates with vemurafenib did regress considerably over the course of testing: There are also legitimate concerns that promising results on surrogate endpoints such as response rate or sometimes even clinical endpoints do not straightforwardly support conclusions of superior clinical effectiveness .
These additional dimensions of uncertainty and variability in clinical development must be factored into judgments of clinical equipoise. In retrospect, it appears that the vemurafenib skeptics may have been right to insist on RCTs: Returning now to Dr.
However, since this is based on preliminary data, there should be considerable uncertainty around the 40 percent estimate. This uncertainty can be represented formally with wide 95 percent confidence intervals, ranging from 15 to 65 percent, say. In other words, we are very confident that the true response rate of MX lies somewhere between 15 percent and 65 percent. Since there is typically much more evidence about the standard treatment, there will also be less uncertainty around this estimate e.
We can thus establish that there ought to be a state of clinical equipoise: Furthermore, since the interval for MX does not fall below the interval for standard treatment, then both are consistent with competent medical care. If we assume the RCT is using an equal allocation ratio, then there was a 50 percent chance that Charlie would get assigned to the MX arm.
Malone observes that he is not responding to therapy, it is now a slightly better bet that he is in the control arm. But this is still far from certain.
Charlie may be a late responder, or the new drug may just not be effective for him. A valid RCT requires that, until the study is complete, we do not know the arm of the trial in which Charlie is enrolled. Additionally, the existence of clinical equipoise explains why it is ethically acceptable to let Charlie continue in the study. Clinical equipoise should also alleviate some of the guilt that Dr. Clinical trials necessarily involve uncertainty about the effectiveness of new agents.
Indeed, this is why we do research—to reduce uncertainty. Moreover, it is a necessary scientific feature of RCTs that some patient-subjects are exposed to what is later discovered to be an inferior treatment. Yet, this does not mean that the hope of an effective treatment that Dr. Malone offered to Charlie was false.
On the contrary, clinical equipoise ensures that the hope was justified—Charlie would be equally likely to benefit regardless of whether he enrolled in research. At the same time, it is the nature of research that the possibility of dramatic patient benefit greatly surpassing the expectations with the standard of care can only be a hope.
If there had been certainty that he would see incredible benefit from the experimental drug, then the RCT would have been unethical to begin with.
At the same time, participants must recognize that the experimental agent may also turn out to be harmful compared to the standard treatment. Indeed, robust safety data about an experimental intervention typically only becomes available in late-phase trials and rare adverse events are typically detected in monitoring after the drug has been brought to market.
Malone does not have an ethical obligation, flowing from considerations of beneficence, to encourage him to withdraw from the study. Yet to say that beneficence is not a dominating principle in this case is not the same as saying that it does not apply. So let us now consider the logical inverse of this obligation: Malone to encourage him to withdraw from the study. As the scenario stipulates, she knows that there are other trials going on and suspects that Charlie could do better in one of those.
Or can she justify encouraging him to withdraw from study A and consider enrolling in study B? There is, however, an ethical tension between Dr. And if too many patients drop out of the study, that fact itself can be sufficient to determine whether the experimental agents are effective. If so, then Dr. After all, study B is also asking an important research question, and study B needs participants too! Unfortunately, we do not live in a world of limitless resources for research.
Once recruitment on a study has ended, dropouts might not be able to be replaced. Given that research risks for trial participants and research costs for society are supposed to be offset in part by the scientific knowledge generated which will hopefully help future patients , every lost data point, in effect, worsens the ethical profile of the trial by increasing the likelihood of a faulty inference and contributes to inefficiency across the research enterprise .
Consistent inefficiencies in research can also diminish public trust in the value of medical research. Further, as the vemurafenib case showed, experimental agents can generate promising results in early phases of research, only to lose some of their promise in later phases.
Moreover, according to one recent study, there is only about a 1 in 10 chance that a new agent entering clinical testing will be proven to be effective . Although the prospect that a struggling patient-subject may benefit in a different trial can be a tantalizing one, it must be considered realistically, in the broader context of the scientific process and in the long view of evidentiary standards for determining what constitutes an innovation.
Therefore, in discussing future options, Dr. Malone should explicitly explain this dilemma to Charlie, acknowledging his absolute right to withdraw and switch to the other study if he so chooses since he may not share her commitment to improving the care of future patients. She should also discuss the realities of experimental medicine, explaining that research is uncertain by nature, and that the majority of new drugs fail in development .
Once that is said, if the shift from study A to study B can still be supported by a sound argument—explaining why switching to study B offers a better prospect of a good outcome than continuing on in study A and how switching still does not guarantee that Charlie will receive the experimental drug—then this expression of patient-centered care and beneficence might mitigate worries about scientific validity and efficiency.
But the burden of proof should fall heavily on this explanation. In closing, we should acknowledge the critical perspective that sees clinical equipoise as, at best, an inappropriate standard for ethical research  and, at worst, an incoherent concept . In its place, critics have proposed that informed consent can do the proverbial heavy lifting in research ethics.
That is, so long as a patient-subject is informed of, understands, and accepts the risks of participation, the research is likely ethically acceptable. Although it would take us too far afield here to canvass the various arguments and counterarguments in this debate , it is worth noting that the ethical analysis of Dr. Her feelings of guilt, for example, are rooted in the fact that she is not in a state of individual equipoise.
Malone should not feel guilty because enrolling was his autonomous decision , the concept of clinical equipoise illuminates precisely why this guilt is misplaced: When she presents a patient the option of enrolling in a study, she can honestly inform him or her about the state of her beliefs.