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 define equipoise in medicine each arm in a trial. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically boldenone effects and side effects to offer that treatment. The current understanding of this requirement, which entails that define equipoise in medicine 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 define equipoise in medicine the termination of trials because of the failure to enroll enough patients. I suggest an alternative concept of equipoise, which would eqhipoise based on present or imminent controversy in the clinical community over the preferred treatment. According to this concept of "clinical equipoise," the requirement is satisfied medicinw 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
Clinical equipoise exists when the overall benefit or harm offered by the treatment to a patient is uncertain. Clinical equipoise requires ethical conduct when performing clinical trials that involve assigning patients to different treatment arms. If the outcome of a treatment is known, such a trial has not been encouraged as it could introduce bias. In an ideal situation, the principle of clinical equipoise is recognized, avoiding preferential treatment of one intervention against another.
If not followed, it could lead to bias and dilemma in deciding which patient should belong to the arm and which arm of the trial is significantly outperforming the other arm.
It is unethical to conduct clinical trials on a drug whose efficacy has been clearly established, as the result cannot be generalized to other populations. There is also ethical impact of uncertainty, which should be justifiable when making a randomized or double-blind selection in trial design.
The efficacy of the test drug or the efficacy in a different population should not be known. Documented information suggests that equipoise should be the decision of the physician who determines whether a patient should participate in a clinical trial. Results generated by methodological bias must be supported with a mechanism to reduce the bias, as many trials are known culprits of this unacceptable conduct . Cohen, in Clinical Pharmacology During Pregnancy , Richard Chin, Bruce Y.
Prior to a trial, clinical equipoise exists, that is, investigators do not know which treatments are superior. However, as the trial progresses, increasing evidence may suggest that one study group is responding or doing much better than another.
Is it then ethical to keep assigning patients equally to all study groups? Are you then denying patients effective treatment? Moreover, wouldn't assigning more patients to the effective treatment group then reduce your required sample size? Response adaptive randomization addresses these questions by continuously updating assignment probabilities based on response of the different groups to their respective treatments.
This method will increase the chance of subsequent patients being assigned to effective treatment groups. To utilize response adaptive randomization, treatment responses need to be relatively rapid and easily measurable.
Slow, delayed, equivocal, and subjective responses do not lend themselves well to this allocation design. Examples of response-based randomization techniques include although these examples assume only two Study Arms A and B, adapting them for more than two study arms is simple:. The play the winner rule is similar to the urn randomization design, except that the previous patient's response to treatment determines what types of balls to add to the container.
If the first patient is assigned to Study Arm A and has a favorable response i. This makes it more likely to draw Study Arm A for the next patient. Every time a patient improves, add m balls of that study group to the container. Every time a patient fails to improve or worsen, add m balls of the other study group to the container. This method weighs the probabilities so that Study Arms that demonstrate successes have a higher likelihood of being selected.
This design is similar to the play the winner design, except that treatment failures lead to dropping balls from the container. In this design, the container holds three types of balls: If the patient has an unfavorable response i.
If the next draw for the next patient yields an Immigration ball, add a Study Arm A ball and a Study Arm B ball to the container Immigration balls keep the container from becoming depleted. So in general, treatment success means keep the same number of balls, and treatment failure means removing a ball of that study group. Doubly adaptive biased coins: This randomization scheme also uses the equivalent of a coin flip but weights the coin flip based on both the characteristics and responses of the different study groups.
One potential problem with adaptive randomization is potential time effects, that is, some patient characteristics and responses change over time. The characteristics initially may seem unbalanced but over the course of time actually be balanced or vice versa.
Trying to keep them balanced may be similar to herding cats. Response to treatment can oscillate as well. Patients may respond to a treatment early on but later become unresponsive or vice versa.
Timothy Beukelman, Hermine I. Central to the concept and ethical implications of RCTs is clinical equipoise. This is defined as honest professional disagreement among expert clinicians about the preferred treatment.
Clinical equipoise is widely regarded as an ethical requirement for the design and conduct of RCTs. Underlying clinical equipoise is the norm that no patient should be randomized to treatment known or thought by the expert clinical community to be inferior to the established standard of care.
Excellent arguments for when placebo trials are appropriate have been presented by Freedman and colleagues. The net therapeutic advantage of standard treatment has been called into question by new evidence. There are increasing arguments about abandoning the requirement of clinical equipoise for randomized clinical trials. Skolnick, in Handbook of Neuroemergency Clinical Trials , As such, the use of DSMBs has become a focal point of assessment by regulatory authorities.
Three concepts appear central for DSMB functionality: In a clinical trial, equipoise exists when there is a lack of evidence for choosing one treatment strategy over another.
The principle of clinical equipoise can be defined as the state or condition at the start of a trial where clinical equipoise regarding the merits of the particular regimens to be tested exists and the trial is designed in manner to make it reasonable to expect that, if the trial is successfully conducted, clinical equipoise will be disturbed.
Multiplicity is the concern that with multiple looks at the safety profile when multiple types of adverse events are likely to be present, bias may occur during the interim review of adverse events observed in each study arm. There are events that may result from the disease being treated or as a result of the intervention itself. Well-defined and regulatory-specified definitions should be adhered to and in special circumstances events of special interest identified.
For example, individuals with cerebrovascular disease are at an elevated risk of other vascular events e. Thus, a specific case of myocardial infarction in a participant in a trial of a new neuroprotectant may not be readily attributed to the new therapy. A DSMB, however, will regularly review the number of myocardial infarctions observed in each study arm.
If an imbalance between groups emerges, concerns will arise that some of the myocardial infarctions may be due to the therapeutic intervention rather than to the disease itself. Because a potentially large number of adverse event categories may be observed and compared between the study arms, the interpretation of safety findings by the DSMB must be sensitive to the issues of multiplicity.
The DSMB also needs to be concerned that adequate adverse event reporting occurs and that investigators do not under-report such results due to their viewing these as being related to the underlying disease. In this way the DSMB has to be assured that adequate site monitoring and reporting is occurring in an accurate and timely manner. Knowledge of unblinded interim comparisons from a clinical trial is not necessary for those conducting or those sponsoring the trial; further, such knowledge can bias the outcome of the study by inappropriately influencing its continuing conduct or the plan of analyses.
In the context of interim data evaluation and the results of interim analyses, these should generally not be accessible by anyone other than DSMB members.
Sponsors should establish procedures to ensure the confidentiality of the interim data to reduce any potential bias. These three factors, equipoise, multiplicity, and bias, must be carefully considered and weighed in both formulating the DSMB charter and while executing the responsibilities of the DSMB. One of the most important types of bioethical research has been conceptual analysis. Although frequently undervalued and even dismissed, conceptual analysis has been essential to advancing bioethics and, indeed, advancing clinical research.
One key example is the development of the justification for randomized controlled trials RCTs. This was termed equipoise. First, it suggested that the ethical justification of clinical trials depended on the views of individual physicians. If a clinician knows, or has good reason to believe, that a new therapy A is better than another therapy B he cannot participate in comparative trials of therapy A versus therapy B. Ethically, the clinician is obligated to give therapy A. A significant advance was made in by Benjamin Freedman when he distinguished theoretical equipoise from what he called clinical equipoise: Theoretical equipoise exists when, overall the evidence on behalf of two alternative treatment regimens is exactly balanced.
Because of its fragility, theoretical equipoise is disturbed as soon as the investigator perceives a difference between the alternatives—whether or not any genuine difference exists. Freedman's advance was to make a careful distinction between theoretical equipoise and clinical equipoise. Clinical equipoise occurs not when the belief of a clinician is in precise balance or when the accumulated evidence is evenly split; rather, clinical equipoise refers to the balance in the views of the community of researchers: Each side recognizes that the opposing side has evidence to support its position, yet each still thinks that overall its own view is correct.
There exists … an honest professional disagreement among expert clinicians about the preferred treatment. Clinical equipoise exists when the data are unclear—that is, when there is no consensus among the experts. Clinical equipoise is compatible with an individual investigator or a clinician having a preference or bias for one treatment or another. The insight of Freedman is that equipoise is a communal or social, not an individual, phenomenon.
Although Freedman's insight may seem subtle and even trivial, it has been very powerful because it has made clear that the justification of a clinical trial does not depend on any individual's views. Clinical equipoise , for all its own problems, has provided the clearest articulation of the ethical justification for randomized controlled trials and the strongest response to those who argue that physicians cannot ethically enroll patients in randomized clinical trials.
A second example of the importance of conceptual analysis may be found in the issue of coercion, undue inducement, and exploitation. These are critical concepts for research ethics. Coerced consent is involuntary and therefore not valid. Consent rendered in response to undue inducements also is thought to be invalid:. Payment in money or in kind to research subjects should not be so large as to persuade them to take undue risks or volunteer against their better judgment.
Payments or rewards that undermine a person's capacity to exercise free choice invalidate consent. Yet these three concepts are frequently confused and conflated and even mixed up with other concepts, such as misunderstanding or deception:. It is difficult to avoid coercing subjects in most settings where clinical investigation in the developing world is conducted. African subjects with relatively little understanding of medical aspects of research participation, indisposed toward resisting the suggestions of Western doctors, perhaps operating under the mistaken notion that they are being treated, and possibly receiving some ancillary benefits from participation in research, are very susceptible to coercion.
Table clarifies the proper definitions of coercion, undue inducement, exploitation, and other concepts with which they are confused. Undue inducement is the irresistible million dollar offer to do something too risky. This should be contrasted with exploitation, which involves giving too little. These conceptual distinctions are more than merely philosophical casuistry.