Clinical equipoiseAttend Spring Meetings on Development topics from Apr Comment and engage with experts. Although I would alter the order of rcy above and give a slightly testosterone patch angle to the arguments. So any design RCT or not that leaves subjects without treatment in presente of 'clinical equipoise' would be un ethical. In this situation, as David reminds us, Equipoise in rct can be the most fair way of assigning treatment, equipoise in rct that after applying all reasonable targeting criteria, a lottery gives everyone equipoiae same chance.
Clinical equipoise - an overview | ScienceDirect Topics
Clinical decisions in reproductive medicine are often made in uncertainty. To reduce uncertainty and to improve clinical decision-making, RCTs are increasingly called upon. A key concept underpinning the ethics of RCTs is equipoise. Here, we aimed to dissect the basic reasoning behind the concept of equipoise and we proposed a line of thinking delineating under which conditions it is ethical to design and execute an RCT. This might prevent a priori negative trials, reduce research waste and aid in the design of meaningful ones.
It is these trials that will provide insight on how to safely and effectively assist subfertile couples. Subfertility, defined as a failure to conceive after 12 months of unprotected intercourse, affects up to 1 in 10 couples who aim to get a child and manifests itself as an acute and unanticipated life crisis Gnoth et al. Subfertility creates overwhelming stress and tests coping strategies as it is unforeseen and lasts for an undetermined length of time Wirtberg et al.
The inability to conceive carries a high psychological burden and couples may exceed their physical and mental boundaries to achieve the desired pregnancy. Reproductive medicine aims to assist these couples. This would be a trivial pursuit if there was certainty on how to effectively assist subfertile couples, but the truth is that many clinical decisions are made in uncertainty because of a lack of comparative data on effectiveness on both group and individual level Farquhar et al.
In the absence of these data, personal preferences then start to play a role and this, in turn, may not always lead to the best decisions. To improve clinical decision-making, the concept of critical appraisal was introduced by David Sackett in the mids, later referred to as evidence-based medicine Sackett et al. Evidence-based medicine aims to de-emphasize intuition and clinical experience as sufficient ground for clinical decision-making and stresses the appraisal of evidence from clinical research next to pathophysiologic reasoning.
The highest level of evidence in clinical research would be generated by aggregated evidence of RCTs Guyatt et al. Standards detailing how to execute and perform RCTs have well been set Schulz et al. So, at present, the why and the how of performing RCTs are no longer a matter of debate, and as a consequence, an increasing amount of RCTs is performed each year. In the Lancet published a series of five reviews assessing research waste at its several stages: Although the series has provoked discussion and is on the agendas of several key players, many steps still have to be made.
To help researchers, clinicians and policymakers in establishing research priorities, we here address the question under what conditions an RCT should be performed. The key concept in this is equipoise Fried, Equipoise refers to a state of regarding two treatments as an equal bet in prospect Edwards et al. Since , there is an ongoing debate on whether equipoise can be limited to an individual doctor being genuinely uncertain or whether equipoise refers to uncertainty in the medical community at large, a state also known as clinical equipoise Freedman, ; Lilford and Jackson, Also, if clinical equipoise is accepted as the state in which we are allowed to randomize patients, it is debated how to deal with personal preferences and believes of the clinician and the patient who are relevant in the choice between treatments Lilford, ; Miller and Brody, ; Hey and Truog, In our opinion, the basic reasoning behind the concept of equipoise is missing in this debate, and we will make the argument that the interaction between pathophysiological processes and mechanisms and observational data is of paramount importance in assessing whether one is in equipoise.
To do so, we will delineate three scenarios framing the balance between the understanding of the pathophysiological processes underlying a disease and observational data gathered in the population on the basis of the biological plausibility behind the effect of an intervention. If certain pathophysiological processes or mechanisms have—beyond doubt—identified the cause of a disease, it has traditionally been assumed that correction of these processes will cure the patient. This may well be the case, but obviously any positive effect of a treatment overcoming the pathophysiologic hurdle should be observed before this treatment can be routinely implemented.
If a treatment works exactly as it was expected from the pathophysiologic reasoning and overcomes a large gap between treated and non-treated patients, a single observation can be sufficient to provide evidence of the efficacy of a treatment Glasziou et al. If this is followed by multiple observations confirming the initial observation, an RCT is not needed and is even unethical to perform.
An example of such an intervention is IVF leading to the birth of Louise Brown in , the first test tube baby. Her mother, Lesley Brown was sterile since her—diseased—fallopian tubes had been surgically removed Steptoe and Edwards, In this case, it is clear that Louise Brown could only have been conceived by IVF and never by natural conception.
When the first case report on the success of IVF was followed by multiple reports of similar events, it was apparent that IVF was a causal treatment for women with surgically removed or blocked tubes that otherwise would have no chance to conceive.
If biological plausibility behind the effect of an intervention is absent, the a priori chances that this treatment is effective are low. Bayesian logic dictates that in these situations, it is unlikely to detect any meaningful difference in an RCT. Such trials should not be performed. Examples are trials in which homeopathic interventions are randomized. Effectiveness of these interventions is not underpinned by any pathophysiological data, and the probability of the treatment being effective is zero.
Another explicit example is a trial in which intercessory praying for IVF was evaluated. In , an RCT was published that assessed the potential effect of intercessory prayer, i. In this trial, Korean women were randomized between receiving intercessory praying and conventional IVF Cha and Wirth, This RCT should not have been performed since there is no pathophysiologic reasoning behind the effect of intercessory praying on pregnancy rates.
Performing this kind of trials is a waste of time, resources and effort, effective treatments are withheld to the patients and they are exposed to possible side effects. Even more importantly, raising false hope to subfertile couples is morally abject. If biological plausibility behind the effect of an intervention is uncertain and one is thus in doubt whether the proposed intervention might have a positive effect, observational data might be helpful to decide if an RCT is necessary.
Treatment effects may be observed in cohorts, cases or pilot studies. If multiple clinical observations show a negative effect of a treatment, like death or, in our field, irreversible infertility, RCTs should not be performed. If multiple observations show a positive or no effect of a treatment, we are in equipoise.
The same condition is met if some cohorts show a positive effect, while others show a negative effect. These interventions should all be subjected to RCTs to provide evidence of their effectiveness before introduction to routine clinical practice. ICSI leads to higher fertilization rates compared to IVF—physiological plausible and epidemiological data show a positive effect—which lead to the idea that this technique may also generate higher pregnancy rates than conventional IVF van Rumste et al.
A multicenter RCT assessing this topic indeed showed a higher fertilization rate per oocyte inseminated after ICSI than after IVF, but pregnancy rates per cycle were not higher, thus arguing against the expanded role of ICSI in non—male factor infertility Bhattacharya et al. This trial countered the hypothesis that the higher fertilization rates observed in ICSI treatments would translate to higher pregnancy rates and provided the evidence not to introduce ICSI in couples with non—male factor infertility.
Thus, if there is uncertainty on the biological plausibility behind the effect of an intervention and observational data suggest that a treatment might work, we are in equipoise and it is ethical to perform an RCT to test the effectiveness of a new intervention. Many interventions of which the biologic plausibility is uncertain and for which evidence of effectiveness is lacking are already applied on a wide scale.
These treatments should not have been introduced in clinical medicine in the first place but have become part of medicine. In these cases, RCTs can serve to debunk bad medicine. An example is the administration of progesterone in women with a history of unexplained recurrent miscarriage. Despite the lack of clear pathophysiologic or observational data, progesterone is prescribed by many clinicians. The trial showed that progesterone therapy did not result in a higher rate of live births among women with a history of unexplained recurrent miscarriage; and therefore, this treatment should be abolished.
Trials to debunk bad medicine might be regarded as fulfilling a policing function and are therefore ethical to perform.
The paradox however is that these trials, which are the most urgent ones to do, are also the ones for which recruitment of patients is the most difficult, especially if the interventions we want to debunk have been applied by the majority of clinicians and for a long period of time. It is then difficult for many to realize and to accept that what is regarded as common practice is based on hardly anything.
As a consequence, patients experience randomization as decreasing their chances of success. Decent counseling of patients by dedicated doctors is of utmost importance in these trials. Since our basic reasoning rests heavily on the biological plausibility behind the effect of an intervention, we feel the need to add a few remarks on the role of biologic plausibility. First, we have framed our description of what typifies biologic plausibility in the setting of scientific medicine, in which biological hypotheses are generated and after thorough fundamental research rejected or not.
It follows that types of medicine that do not fulfill these criteria are not part of scientific medicine. An example of this is acupuncture. The mechanisms behind the effect of acupuncture are based on the so-called chi and body meridians, of which existence there is no scientific evidence Kaptchuk, Second, researchers may be so convinced of their own beliefs and reasoning that they shift from uncertain biologic plausibility to known biologic plausibility, even when scientific data underpinning this shift are absent.
An example of this is the biologic plausibility of dehydroepiandrosterone DHEA supplementation for women with low ovarian reserve. Proponents of administrating DHEA argue that an RCT is not needed, since the androgen dependency of follicle growth and development is well established Gleicher, Although androgen dependency of follicle growth is indeed well established, there is limited understanding of how DHEA metabolizes to androgens and subsequently regulates follicular development and whether administrating this precursor of testosterone would stimulate follicle recruitment Prizant et al.
The biological plausibility therefore remains uncertain and should be mapped to Scenario 3. Thus, a well-powered, well-designed RCT is needed. Third, data on the pathophysiological processes or mechanisms of a disease may be well established but not taken into account. PGS has been offered in routine clinical practice for more than two decades now. With this procedure, aneuploid embryos are discarded after a single-cell analysis.
It is thought that the transfer of embryos with such aneuploidies does not result in live birth Wilton, Yet, the phenomenon of mosaicism, i. If the existing data on biological plausibility had been seriously taken into account from the beginning, then RCTs would have preceded instead of followed routine clinical application, and women would not have been offered this costly and harmful addition to their IVF treatment Mastenbroek and Repping, Now, the first generation of PGS techniques has been abandoned and replaced by new methods that use a different timing and different methods for the analysis.
And again, these PGS methods are introduced on a vast scale in routine clinical practice without proper RCTs, while the biological plausibility is certainly not beyond doubt Mastenbroek and Repping, ; Greco et al.
As a consequence of performing RCTs in the absence of equipoise, subfertile couples are exposed to non-effective and often costly interventions and time, effort and money are wasted. We all should be aware that couples with infertility belong to a vulnerable group that will do anything for a pregnancy Nap and Evers, We should perform carefully designed RCTs when equipoise is reached or to debunk non-tested interventions that have crept into regular practice. Manuscript drafting and preparation of the final manuscript were done by all authors.
Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. Equipoise and the RCT M. Abstract Clinical decisions in reproductive medicine are often made in uncertainty. Increasing value and reducing waste in biomedical research regulation and management.
Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: A randomised controlled trial. Does prayer influence the success of in vitro fertilization-embryo transfer?