Special article
Clinical equipoise and systematic reviews of randomized controlled trials
Equipoise clínico y revisiones sistemáticas de ensayos clínicos aleatorizados controlados
Ferrán Catalá-Lópeza,b,c,
, Diana González-Bermejoa, César de la Fuente Honrubiaa, Diego Macías Saint-Geronsa
Corresponding author
a División de Farmacoepidemiología y Farmacovigilancia, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain
b Fundación Instituto de Investigación en Servicios de Salud, Valencia, Spain
c Departamento de Medicina, Universidad de Valencia/Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Valencia, Spain
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However, there are many examples in the scientific literature that show how the information provided in the publications is often poor, and often have serious methodological problems.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">4,5</span></a> Certain factors may prevent a clinical trial being considered valid from a clinical practice perspective, such as: asking irrelevant questions or questions that have already been answered, implementation of inadequate designs and methods (e.g., incorrect selection of the patient sample, poor randomization methods, use of inaccurate response variables, inappropriate choice of treatment or comparator) or an incomplete research report.</p><p id="par0015" class="elsevierStylePara elsevierViewall">From a clinical bioethics perspective, an important aspect that affects the design and planning of the trial is that there must be reasonable doubts about the efficacy or safety of the interventions to be evaluated. Specifically, in situations where it is known that an intervention is better than another, it would not be justifiable to start the study because patients in a group would be exposed to a treatment that is known to be less effective (or safe) and thus, not fulfilling the clinical <span class="elsevierStyleItalic">equipoise</span> principle.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This article briefly introduces the clinical <span class="elsevierStyleItalic">equipoise</span> concept, and its relation to the role that systematic reviews and meta-analyses can have in the planning, design and evaluation of a controlled clinical trial is discussed, arguing its importance in clinical research through some examples.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">The clinical <span class="elsevierStyleItalic">equipoise</span> concept<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">6–12</span></a></span><p id="par0025" class="elsevierStylePara elsevierViewall">The knowledge generated through clinical research, particularly through randomized controlled clinical trials, should serve to reduce uncertainties about the relative effects of different treatments.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In 1963, Sir Austin Bradford Hill wrote that for a clinical trial to be acceptable from a bioethical standpoint, it should be possible to give each patient selected any of the treatments under evaluation.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">7</span></a> In principle, if I know that an experimental treatment (A) is superior to another (B), conducting a clinical trial would not be justified, since it would be required to give the patient the clinical treatment A. However, if reasonable doubts were raised about which treatment is better (or worse), more (or less) safe, each patient should have the same chance of receiving each treatment. Therefore, the inclusion of patients in one study and the randomized allocation to different intervention groups could only be accepted in this state of “ignorance (or uncertainty)” in which treatments should be indifferent.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In 1987, Freedman<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">6</span></a> proposed the concept of clinical <span class="elsevierStyleItalic">equipoise</span> as a fundamental ethical principle for the design and implementation of randomized and controlled clinical trials. A clinical <span class="elsevierStyleItalic">equipoise</span> situation would be given (indeterminacy or clinical balance) when in the scientific community there is no agreement on which of the different treatment alternatives or options may be more effective or safer for patients participating in the study. In other words, there is the same uncertainty about the effects of the different treatments.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In principle, conducting a new trial would only be justifiable if the clinical <span class="elsevierStyleItalic">equipoise</span> scenario is met. In other words, to determine the suitability of the study before its start, none of the interventions under assessment (experimental and control treatment) should be higher or lower relative to the other intervention in relation to its benefits and/or risks. Although this principle may seem clear and intuitive, it should be recalled that the interpretation of scientific evidence is complex on many occasions, and may be subject to significant limitations, biases and some degree of subjectivity by those who interpret the information.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> The clinical <span class="elsevierStyleItalic">equipoise</span> situation may be different for each research question and will depend on the information available for each intervention under evaluation. On the one hand, it has been argued that for randomization to be ethically acceptable, the clinician or investigator should completely ignore what is the best treatment for a patient (individual perspective).<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> On the other hand, it has been argued that the clinical <span class="elsevierStyleItalic">equipoise</span> should reflect the collective uncertainty of the medical community regarding the treatment (for example, reflected in the clinical practice guidelines),<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> rather than the individual's clinical uncertainty. The 2 perspectives agree that the uncertainty as to the most effective treatment is the main motivation necessary for the study to be considered ethically acceptable.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Relevance of the systematic review and meta-analyses to help clarify the clinical equipoise</span><p id="par0045" class="elsevierStylePara elsevierViewall">Clinical <span class="elsevierStyleItalic">equipoise</span> would not be met if there is substantial evidence showing that a treatment has an efficacy significantly higher (or lower) than another option or alternative. Therefore, to help define this uncertainty, it would be necessary to have a synthesis of rigorous and comprehensive scientific evidence that would serve to inform decision-making, beyond just expert opinions (and/or study sponsors), which are generally susceptible to potential biases. As an important clinical epidemiology contribution, systematic reviews and meta-analyses of clinical trials can serve to identify areas where there is significant uncertainty regarding the effects among health interventions.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Based on the definition of the Cochrane<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">13</span></a> manual, a systematic review “aims to bring together all the empirical evidence that meets the pre-established eligibility criteria, in order to answer a specific research question. It uses systematic and clear methods which are chosen in order to minimize bias, thus providing more reliable results from which to draw conclusions and make decisions. Many of the systematic reviews contain meta-analysis, the application of statistical methods to summarize the results of independent studies. By combining information from all relevant studies, a meta-analysis achieves better estimates of the effects on healthcare compared to those derived from the individual studies included in a review. It also allows to investigate the consistency of evidence and explore the differences between studies”. Therefore, systematic reviews and meta-analyses are essential tools to generate, summarize, consolidate and give access to the best scientific evidence accurately and reliably in an ever-changing health care environment. They also help provide the ethical and scientific rationale for any new study to be conducted in human populations. In this sense, systematic reviews and meta-analyses that are carried out properly and are presented with the desirable level of detail, can be used to help identify methodological deficiencies and gaps in the existing literature, and should serve to help assess the need and relevance of any potential study.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The idea of using the accumulated evidence from systematic reviews and meta-analysis to inform the design and implementation of new clinical trials is not new. However, to date, there are only a few evaluations that help us to assess the real role of systematic reviews and meta-analyses in the planning and design of new studies.</p><p id="par0060" class="elsevierStylePara elsevierViewall">An evaluation conducted on trials financed from public funds by the UK's <span class="elsevierStyleItalic">National Institute for Health Research Health Technology Assessment-Programme</span> was recently published.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> From the cohort of funded clinical trials in the period 2006–2008, the authors identified that although most of the studies (37; 77%) referred to a systematic review in the proposal, less than half (20; 42%) used the information contained in the systematic review for the design or planning of the new study. The main areas that used the systematic reviews were: the selection or definition of the outcome variable measured in the trial (7 of 37; 19%), the calculation of sample size (7; 19%), duration of follow-up (8; 22%) and the approach adopted to describe adverse events (9; 24%). In contrast, a small number of studies justified the choice of comparator from a systematic review (6; 16%).</p><p id="par0065" class="elsevierStylePara elsevierViewall">Since it was introduced in the 1990s, the meta-analyses cumulative technique to calculate, retrospectively, summary estimates of the effects of interventions on the basis of results from similar clinical trials whenever an additional test was incorporated into the series of studies, the importance of this procedure as a method of evaluation in <span class="elsevierStyleItalic">research on research</span> has become clear. Through a systematic review of cumulative meta-analysis of clinical trials evaluating the effects of health interventions, Clarke et al.,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a> identified 50 cumulative meta-analysis illustrating a variety of topics and noted that a considerable number of meta-analyses would have served to reduce uncertainty (or help ensure clinical <span class="elsevierStyleItalic">equipoise</span>) if this source of knowledge had been taken into account before a new trial. They also identified examples where the inclusion of results from new clinical trials with a small sample size does not help resolve uncertainties with the knowledge available. Among the examples identified, the systematic review and meta-analyses of Fergusson et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a> on the use of aprotinin in cardiac surgery from 64 placebo-controlled randomized clinical trials stand out (1987–2002). In this study,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a> the authors found that the beneficial results of antifibrinolytic drug (versus placebo) in reducing the need for perioperative transfusion remained stable over time from the study No. 12 (published in June 1992), showing that a large number of subsequent trials (including more than 7600 additional patients) provided answers to questions already resolved a decade earlier. In another systematic review and cumulative meta-analysis conducted by Ker et al.,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a> which included 129 clinical trials controlled with placebo or other comparator (reporting period 1972–2011) it was also observed that the reduction of bleeding and subsequent transfusion requirement associated with the use of tranexamic acid during surgery had been clearly established a decade earlier. However, the drug's effects on the risk of death and thromboembolic events were not known in 2011, because studies published to date had been too small to provide conclusive answers.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In short, systematic reviews and meta-analyses of existing scientific evidence can help clinicians, patients, researchers and sponsors to make more informed decisions about the appropriateness of conducting new studies. They can help to inform the design and planning studies which guarantee the clinical <span class="elsevierStyleItalic">equipoise</span> from existing research information, allowing us to identify more effective interventions early on in clinical practice, helping to justify the selection of appropriate comparators where there is reasonable uncertainty.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">18</span></a> They also allow for the interpretation of new study results in the context of existing knowledge. The CONSORT statement's preparation and rationale document (<a id="intr0010" class="elsevierStyleInterRef" href="http://www.consort-statement.org/">http://www.consort-statement.org/</a>) already argued that biomedical research should be based on a thorough knowledge of the literature, according to the Helsinki declaration. Similarly, the need for a new study should be justified in the introduction, ideally including an explicit reference to a systematic review of similar studies (or a declaration of absence of such studies, if applicable). As revealed in the medical literature, there is still considerable room for improvement in the implementation of systematic reviews and meta-analyses to guide the clinical research agenda and funding of the same considering the already existing knowledge. All this would help reduce inefficiencies resulting from unjustified research, avoid unnecessary suffering for patients and, ultimately, increase the value of scientific research to improve the health of the population.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">5,19–21</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Note</span><p id="par0075" class="elsevierStylePara elsevierViewall">The opinions expressed by the authors in this paper do not necessarily reflect those of the institutions they work for.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conflict of interests</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "The clinical equipoise concept" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Relevance of the systematic review and meta-analyses to help clarify the clinical equipoise" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Note" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of interests" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-03-23" "fechaAceptado" => "2015-04-09" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Catalá-López F, González-Bermejo D, de la Fuente Honrubia C, Saint-Gerons DM. <span class="elsevierStyleItalic">Equipoise</span> clínico y revisiones sistemáticas de ensayos clínicos aleatorizados controlados. 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