Delta Inflation, Optimism Bias, and Uncertainty in Clinical Trials.

The phenomenon of delta inflation, in which design treatment effects tend to exceed observed treatment effects, has been documented in several therapeutic areas. Delta inflation has often been attributed to investigators' optimism bias, or an unwarranted belief in the efficacy of new treatments. In contrast, we argue that delta inflation may be a natural consequence of clinical equipoise, that is, genuine uncertainty about the relative benefits of treatments before a trial is initiated. We review alternative methodologies that can offer more direct evidence about investigators' beliefs, including Bayesian priors and forecasting analysis. The available evidence for optimism bias appears to be mixed, and can be assessed only where uncertainty is expressed explicitly at the trial design stage.

Ethical Considerations and Equipoise in Cancer Surgery.

The changing landscape of cancer surgery requires ongoing consideration of ethical issues to ensure patient-centered care and fair access to treatments. With technological advancements and the global expansion of surgical interventions, healthcare professionals must navigate complex ethical dilemmas related to patient autonomy, informed consent, and the impact of new technologies on the physician-patient relationship. Additionally, ethical principles and decision-making in oncology, especially in the context of genetic predisposition to breast cancer, highlight the importance of integrating patient knowledge, preferences, and alignment between goals and treatments. As global surgery continues to grow, addressing ethical considerations becomes crucial to reduce disparities in access to surgical interventions and uphold ethical duties in patient care. Furthermore, the rise of digital applications in healthcare, such as digital surgery, requires heightened awareness of the unique ethical issues in this domain. The ethical implications of using artificial intelligence (AI) in robotic surgical training have drawn attention to the challenges of protecting patient and surgeon data, as well as the ethical boundaries that innovation may encounter. These discussions collectively emphasize the complex ethical issues associated with surgical innovation and underscore the importance of upholding ethical standards in the pursuit of progress in the field. In this study, we thoroughly analyzed previous scholarly works on ethical considerations and equipoise in the field of oncological surgery. Our main focus was on the use of AI in this specific context.

Rapid qualitative analysis of recruitment obstacles in the FORVAD (Posterior Cervical Foraminotomy surgery versus Anterior Cervical Discectomy surgery in the treatment of cervical brachialgia) randomised, controlled trial.

BACKGROUND: The number of surgical trials is increasing but such trials can be complex to deliver and pose specific challenges. A multi-centre, Phase III, RCT comparing Posterior Cervical Foraminotomy versus Anterior Cervical Discectomy and Fusion in the Treatment of Cervical Brachialgia (FORVAD Trial) was unable to recruit to target. A rapid qualitative study was conducted during trial closedown to understand the experiences of healthcare professionals who participated in the FORVAD Trial, with the aim of informing future research in this area. METHODS: Semi-structured interviews were conducted with 18 healthcare professionals who had participated in the FORVAD Trial. Interviews explored participants' experiences of the FORVAD trial. A rapid qualitative analysis was conducted, informed by Normalisation Process Theory. RESULTS: Four main themes were generated in the data analysis: (1) individual vs. community equipoise; (2) trial set-up and delivery; (3) identifying and approaching patients; and (4) timing of randomisation. The objectives of the FORVAD trial made sense to participants and they supported the idea that there was clinical or collective equipoise regarding the two FORVAD interventions; however, many surgeons had treatment preferences and lacked individual equipoise. The site which had most recruitment success had adopted a more structured process for identification and recruitment of patients, whereas other sites that adopted more "ad hoc" screening strategies struggled to identify patients. Randomisation on the day of surgery caused both medico-legal and practical concerns at some sites. CONCLUSIONS: Organisation and implementation of a surgical trial in neurosurgery is complex and presents many challenges. Sites often reported low recruitment and discussed the logistical issues of conducting a complex surgical RCT. Future trials in neurosurgery may need to offer more flexibility and time during set-up to maximise opportunities for larger recruitment numbers. Rapid qualitative analysis informed by Normalisation Process Theory was able to quickly identify key issues with trial implementation so rapid qualitative analysis may be a useful approach for teams conducting qualitative research in trials. TRIAL REGISTRATION: ISRCTN, ISRCTN reference: 10,133,661. Registered 23rd November 2018.

The death of a neurotrauma trial lessons learned from the prematurely halted randomized evaluation of surgery in elderly with traumatic acute subdural hematoma (RESET-ASDH) trial.

Introduction: Acute subdural hematoma (ASDH) due to traumatic brain injury (TBI) constitutes an increasing global health problem, especially in the elderly population. Treatment decisions on surgical versus conservative management pose a neurosurgical dilemma. Large practice variation exists between countries, hospitals, and individual neurosurgeons, illustrating the presence of 'clinical equipoise'. The RESET-ASDH trial aimed to address this dilemma but was terminated prematurely due to insufficient patient recruitment. Research question: What factors may have contributed to the premature discontinuation of the RESET-ASDH trial? Materials and methods: The RESET-ASDH was a multicenter randomized controlled trial (RCT) comparing functional outcome at 1 year after early surgery or an initial conservative treatment in elderly patients (≥65 years) with a traumatic ASDH. Logs of registry data, medical-ethical approval timelines and COVID-19 related research documents were analyzed. Furthermore, non-structured interviews with involved clinical research personnel were conducted. Results: The concept of clinical equipoise was broadly misinterpreted by neurosurgeons as individual uncertainty, hampering patient recruitment. Also, the elderly target population complicated the inclusion process as elderly and their informal caregivers were hesitant to participate in our acute surgical trial. Moreover, the COVID-19 pandemic added additional hurdles like delayed medical-ethical approval, a decline in eligible patients and repeated trial halts during the peaks of the pandemic. Discussion and conclusion: The premature termination of the RESET-ASDH study may have been related to the trial's methodology and target population with an additional impact of COVID-19. Future acute neurosurgical trials in elderly may consider these challenges to prevent premature trial termination.

Testing new anticancer drugs before curative locoregional therapies: MDICT 2024 recommendations.

Advances in the treatment of cancer have resulted in improved outcomes for patients, but improving the cure rate is a major unmet need. While testing new anticancer drugs in the earliest settings may be attractive as the chance of benefit may be greatest, it is also a setting where researchers must ensure patients are not harmed, by either over or undertreatment, or denial of timely standard curative treatments. The Methodology for the Development of Innovative Cancer Therapies Taskforce (MDICT) meets immediately before the ESMO-Targeted Anticancer Therapies (ESMO-TAT) meeting, usually held annually in Paris, France, to address questions that are considered important for early academic clinical trials. The focus of the MDICT 2024 was on early, signal-seeking phase clinical trials of new drugs conducted in the neoadjuvant (NEO) setting (NEO-ECTs) rather than pivotal confirmatory NEO trials (NEO-CONFs), which are typically phase III in design. Recommendations encompass four key concepts: patient engagement, reviewing risk-benefit ratio and clinical/ethical equipoise, the requirement for a randomization to reduce bias and allow robust conclusions to be drawn, and the selection of appropriate endpoints. The careful design of NEO-ECTs will allow the testing of new anticancer treatments in earlier disease settings where activity is hoped to result in higher cure rates, while also ensuring that patients are not harmed by delays to curative/definitive treatments nor by long-term or late-onset toxicity and morbidity. Additional research and investigation are required to further define and refine robust endpoints for use in this setting, including imaging, tissue and blood based endpoints.

Causal inference in the absence of positivity: The role of overlap weights.

How to analyze data when there is violation of the positivity assumption? Several possible solutions exist in the literature. In this paper, we consider propensity score (PS) methods that are commonly used in observational studies to assess causal treatment effects in the context where the positivity assumption is violated. We focus on and examine four specific alternative solutions to the inverse probability weighting (IPW) trimming and truncation: matching weight (MW), Shannon's entropy weight (EW), overlap weight (OW), and beta weight (BW) estimators. We first specify their target population, the population of patients for whom clinical equipoise, that is, where we have sufficient PS overlap. Then, we establish the nexus among the different corresponding weights (and estimators); this allows us to highlight the shared properties and theoretical implications of these estimators. Finally, we introduce their augmented estimators that take advantage of estimating both the propensity score and outcome regression models to enhance the treatment effect estimators in terms of bias and efficiency. We also elucidate the role of the OW estimator as the flagship of all these methods that target the overlap population. Our analytic results demonstrate that OW, MW, and EW are preferable to IPW and some cases of BW when there is a moderate or extreme (stochastic or structural) violation of the positivity assumption. We then evaluate, compare, and confirm the finite-sample performance of the aforementioned estimators via Monte Carlo simulations. Finally, we illustrate these methods using two real-world data examples marked by violations of the positivity assumption.

Consultations about randomised controlled trials are shorter and less in-depth for socioeconomically disadvantaged patients compared to socioeconomically advantaged patients: qualitative analysis across three trials.

BACKGROUND: Patients from socioeconomically disadvantaged backgrounds are underserved in randomised controlled trials, yet they experience a much greater burden of disease compared with patients from socioeconomically advantaged areas. It is crucial to make trials more inclusive to ensure that treatments and interventions are safe and effective in real-world contexts. Improving how information about trials is verbally communicated is an unexplored strategy to make trials more inclusive. This study examined how trials are communicated verbally, comparing consultations involving patients from the most and least socioeconomically disadvantaged areas. METHODS: Secondary qualitative analysis of 55 trial consultation transcripts from 41 patients, sampled from 3 qualitative studies embedded in their respective UK multi-site, cancer-related randomised controlled trials. Patients living in the most and least socioeconomically disadvantaged areas, defined using English Indices of Multiple Deprivation decile scores, were purposively sampled. Analysis was largely thematic and drew on the constant comparison method. RESULTS: Recruiters communicated clinical uncertainty in a similar way for patients living in different socioeconomic areas. Consultations with disadvantaged patients were, on average, half the duration of those with advantaged patients, and tended to involve recruiters providing less in-depth explanations of trial concepts, used phrasing that softened trial arm risks, and described trial processes (e.g. randomisation) using informal or metaphorical phrasing. Disadvantaged and advantaged patients differed in the concerns they expressed; disadvantaged patients voiced fewer concerns and asked fewer questions but were also less likely to be invited to do so by recruiters. CONCLUSION: Interactions about trials unfolded in different ways between patients living in different socioeconomic areas, likely due to both patient- and recruiter-related factors. We present considerations for recruiters when discussing trials with patients from socioeconomically disadvantaged backgrounds, aimed at enhancing trial communication. Future research should examine disadvantaged patients' and recruiters' experiences of verbal trial communication to inform guidance that addresses the needs and preferences of underserved groups.

Fluidity of Equipoise in a Multi-Centred Pilot RCT: Influences on Clinician Decision-Making in Offering Trial Entry.

OBJECTIVES: The embedded Qualitative Process Evaluation (QPE) within the CSTICH- Pilot RCT explored facilitators and barriers to recruitment within the Pilot. This study reports a secondary analysis of the overarching theme of Fluidity of Equipoise and the influences on individual and community clinical equipoise around the use of Emergency Cervical Cerclage (ECC). STUDY DESIGN: RCT recruitment assumes clinical equipoise and is defined as genuine uncertainty about an intervention. The ability of trial recruiters to convey this equipoise is also key to participant recruitment and fully informed consent. This exploratory qualitative process evaluation used semi-structured interviews with healthcare professionals (HCPs) involved in trial recruitment. Interviews were audio-recorded, transcribed, and analysed using codebook thematic analysis. RESULTS: 23 HCPs were interviewed. Clinical equipoise around the use of ECC was variable and influenced by a multitude of factors including: (1) obstetric history; (2) gestation; (3) standard site practice, and (4) HCPs previous experiences of ECC. We have interpreted this variability as 'fluidity of equipoise'. CONCLUSIONS: Clinical equipoise around complex pregnancy related conditions was fluid and influenced by the complexities of obstetric histories and gestation at presentation. Equipoise of HCPs involved in trial recruitment should be considered carefully as it can impact the nuances of recruitment, particularly in more challenging trials such as CSTICH-2. Study-specific documents and training can be used to increase staff and patient awareness of uncertainty in the evidence base for interventions under investigation. Further research is needed around the potential consequences of equipoise fluidity.

Using Equipoise to Determine the Radiographic Characteristics Leading to Agreement on Best Treatment for Thoracolumbar Burst Fractures Without Neurologic Deficits.

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVES: Our goal was to assess radiographic characteristics associated with agreement and disagreement in treatment recommendation in thoracolumbar (TL) burst fractures. METHODS: A panel of 22 AO Spine Knowledge Forum Trauma experts reviewed 183 cases and were asked to: (1) classify the fracture; (2) assess degree of certainty of PLC disruption; (3) assess degree of comminution; and (4) make a treatment recommendation. Equipoise threshold used was 77% (77:23 distribution of uncertainty or 17 vs 5 experts). Two groups were created: consensus vs equipoise. RESULTS: Of the 183 cases reviewed, the experts reached full consensus in only 8 cases (4.4%). Eighty-one cases (44.3%) were included in the agreement group and 102 cases (55.7%) in the equipoise group. A3/A4 fractures were more common in the equipoise group (92.0% vs 83.7%, P < .001). The agreement group had higher degree of certainty of PLC disruption [35.8% (SD 34.2) vs 27.6 (SD 27.3), P < .001] and more common use of the M1 modifier (44.3% vs 38.3%, P < .001). Overall, the degree of comminution was slightly higher in the equipoise group [47.8 (SD 20.5) vs 45.7 (SD 23.4), P < .001]. CONCLUSIONS: The agreement group had a higher degree of certainty of PLC injury and more common use of M1 modifier (more type B fractures). The equipoise group had more A3/A4 type fractures. Future studies are required to identify the role of comminution in decision making as degree of comminution was slightly higher in the equipoise group.

What Factors Influence Surgeons in Decision-Making in Thoracolumbar Burst Fractures? A Survey-Based Investigation of a Panel of Spine Surgery Experts.

STUDY DESIGN: Cross-sectional survey study. OBJECTIVE: To investigate factors affecting decision-making in thoracolumbar burst-fractures without neurologic deficit. METHODS: A 40-question survey addressing expert-related, economic, and radiological factors was distributed to 30 international trauma experts. Descriptive statistics were used to assess the impact of these factors on operative or non-operative management preferences. RESULTS: Out of 30 experts, 27 completed the survey. The majority of respondents worked at level 1 trauma centers (81.5%) within university settings (77.8%). They were primarily orthopedic surgeons (66.7%) and had over 10 years of experience (70.4%). About 81% found distinguishing between A3 and A4 fractures relevant for decision-making. Most experts (59%) treated A3 fractures non-surgically, while only 30% treated A4 fractures conservatively. Compensation systems did not influence treatment recommendations, and hospital measures promoting surgeries did not significantly affect distribution. Radiological factors, such as local kyphosis (25/27), fracture comminution (23/27), overall sagittal balance (21/27), and spinal canal narrowing (20/27), influenced decisions. CONCLUSION: Incomplete burst fractures (A3) are predominantly treated non-surgically, while complete burst fractures (A4) are primarily treated surgically. Compensation, third-party incentives, and outpatient care did not significantly impact decision-making. Radiological factors beyond the AO Spine thoracolumbar classification system seem to be essential and warrant further evaluation.

Predictive Algorithm for Surgery Recommendation in Thoracolumbar Burst Fractures Without Neurological Deficits.

STUDY DESIGN: Predictive algorithm via decision tree. OBJECTIVES: Artificial intelligence (AI) remain an emerging field and have not previously been used to guide therapeutic decision making in thoracolumbar burst fractures. Building such models may reduce the variability in treatment recommendations. The goal of this study was to build a mathematical prediction rule based upon radiographic variables to guide treatment decisions. METHODS: Twenty-two surgeons from the AO Knowledge Forum Trauma reviewed 183 cases from the Spine TL A3/A4 prospective study (classification, degree of certainty of posterior ligamentous complex (PLC) injury, use of M1 modifier, degree of comminution, treatment recommendation). Reviewers' regions were classified as Europe, North/South America and Asia. Classification and regression trees were used to create models that would predict the treatment recommendation based upon radiographic variables. We applied the decision tree model which accounts for the possibility of non-normal distributions of data. Cross-validation technique as used to validate the multivariable analyses. RESULTS: The accuracy of the model was excellent at 82.4%. Variables included in the algorithm were certainty of PLC injury (%), degree of comminution (%), the use of M1 modifier and geographical regions. The algorithm showed that if a patient has a certainty of PLC injury over 57.5%, then there is a 97.0% chance of receiving surgery. If certainty of PLC injury was low and comminution was above 37.5%, a patient had 74.2% chance of receiving surgery in Europe and Asia vs 22.7% chance in North/South America. Throughout the algorithm, the use of the M1 modifier increased the probability of receiving surgery by 21.4% on average. CONCLUSION: This study presents a predictive analytic algorithm to guide decision-making in the treatment of thoracolumbar burst fractures without neurological deficits. PLC injury assessment over 57.5% was highly predictive of receiving surgery (97.0%). A high degree of comminution resulted in a higher chance of receiving surgery in Europe or Asia vs North/South America. Future studies could include clinical and other variables to enhance predictive ability or use machine learning for outcomes prediction in thoracolumbar burst fractures.

The Influence of Comminution and Posterior Ligamentous Complex Integrity on Treatment Decision Making in Thoracolumbar Burst Fractures Without Neurologic Deficit?

STUDY DESIGN: A prospective study. OBJECTIVE: to evaluate the impact of vertebral body comminution and Posterior Ligamentous Complex (PLC) integrity on the treatment recommendations of thoracolumbar fractures among an expert panel of 22 spine surgeons. METHODS: A review of 183 prospectively collected thoracolumbar burst fracture computed tomography (CT) scans by an expert panel of 22 trauma spine surgeons to assess vertebral body comminution and PLC integrity. This study is a sub-study of a prospective observational study of thoracolumbar burst fractures (Spine TL A3/A4). Each expert was asked to grade the degree of comminution and certainty about the PLC disruption from 0 to 100, with 0 representing the intact vertebral body or intact PLC and 100 representing complete comminution or complete PLC disruption, respectively. RESULTS: ≥45% comminution had a 74% chance of having surgery recommended, while <25% comminution had an 86.3% chance of non-surgical treatment. A comminution from 25 to 45% had a 57% chance of non-surgical management. ≥55% PLC injury certainity had a 97% chance of having surgery, and ≥45-55% PLC injury certainty had a 65%. <20% PLC injury had a 64% chance of having non-operative treatment. A 20 to 45% PLC injury certainity had a 56% chance of non-surgical management. There was fair inter-rater agreement on the degree of comminution (ICC .57 [95% CI 0.52-.63]) and the PLC integrity (ICC .42 [95% CI 0.37-.48]). CONCLUSION: The study concludes that vetebral comminution and PLC integrity are major dterminant in decision making of thoracolumbar fractures without neurological deficit. However, more objective, reliable, and accurate methods of assessment of these variables are warranted.

The impact of feedback training on prediction of cancer clinical trial results.

INTRODUCTION: Funders must make difficult decisions about which squared treatments to prioritize for randomized trials. Earlier research suggests that experts have no ability to predict which treatments will vindicate their promise. We tested whether a brief training module could improve experts' trial predictions. METHODS: We randomized a sample of breast cancer and hematology-oncology experts to the presence or absence of a feedback training module where experts predicted outcomes for five recently completed randomized controlled trials and received feedback on accuracy. Experts then predicted primary outcome attainment for a sample of ongoing randomized controlled trials. Prediction skill was assessed by Brier scores, which measure the average deviation between their predictions and actual outcomes. Secondary outcomes were discrimination (ability to distinguish between positive and non-positive trials) and calibration (higher predictions reflecting higher probability of trials being positive). RESULTS: A total of 148 experts (46 for breast cancer, 54 for leukemia, and 48 for lymphoma) were randomized between May and December 2017 and included in the analysis (1217 forecasts for 25 trials). Feedback did not improve prediction skill (mean Brier score for control: 0.22, 95% confidence interval = 0.20-0.24 vs feedback arm: 0.21, 95% confidence interval = 0.20-0.23; p = 0.51). Control and feedback arms showed similar discrimination (area under the curve = 0.70 vs 0.73, p = 0.24) and calibration (calibration index = 0.01 vs 0.01, p = 0.81). However, experts in both arms offered predictions that were significantly more accurate than uninformative forecasts of 50% (Brier score = 0.25). DISCUSSION: A short training module did not improve predictions for cancer trial results. However, expert communities showed unexpected ability to anticipate positive trials.Pre-registration record: https://aspredicted.org/4ka6r.pdf.

Physician Approaches to Antithrombotic Therapies for Recently Symptomatic Carotid Stenosis.

BACKGROUND: Whereas the beneficial effect of antiplatelet therapy for recurrent stroke prevention has been well established, uncertainties remain regarding the optimal antithrombotic regimen for recently symptomatic carotid stenosis. We sought to explore the approaches of stroke physicians to antithrombotic management of patients with symptomatic carotid stenosis. METHODS: We employed a qualitative descriptive methodology to explore the decision-making approaches and opinions of physicians regarding antithrombotic regimens for symptomatic carotid stenosis. We conducted semi-structured interviews with a purposive sample of 22 stroke physicians (11 neurologists, 3 geriatricians, 5 interventional-neuroradiologists, and 3 neurosurgeons) from 16 centers on four continents to discuss symptomatic carotid stenosis management. We then conducted thematic analysis on the transcripts. RESULTS: Important themes revealed from our analysis included limitations of existing clinical trial evidence, competing surgeon versus neurologist/internist preferences, and the choice of antiplatelet therapy while awaiting revascularization. There was a greater concern for adverse events while using multiple antiplatelet agents (e.g., dual-antiplatelet therapy (DAPT)) in patients undergoing carotid endarterectomy compared to carotid artery stenting. Regional variations included more frequent use of single antiplatelet agents among European participants. Areas of uncertainty included antithrombotic management if already on an antiplatelet agent, implications of nonstenotic features of carotid disease, the role of newer antiplatelet agents or anticoagulants, platelet aggregation testing, and timing of DAPT. CONCLUSION: Our qualitative findings can help physicians critically examine the rationale underlying their own antithrombotic approaches to symptomatic carotid stenosis. Future clinical trials may wish to accommodate identified variations in practice patterns and areas of uncertainty to better inform clinical practice.

Practical psychiatry: On therapeutic equipoise - Principles of a balanced approach to psychiatric treatments.

OBJECTIVE: There are many burgeoning treatments, and a large range of therapeutic options for 21st century psychiatry. This paper briefly comments upon considerations for balancing treatment to suit the patient, their illness, and their milieu. CONCLUSIONS: Therapeutic equipoise, for psychiatric care, is an aspiration rather than a position easily achieved. In day-to-day clinical practice, there will be unexpected demands and barriers that cannot always be accommodated or surmounted. Psychiatrists can work collaboratively with patients, carers, and colleagues in conceptualising and care-planning to avoid extremes of therapeutic hubris and despair, and to adapt evidence-based care more effectively so that it is suited to the patient and their circumstances.

Ethics of Adaptive Designs for Randomized Controlled Trials.

Over recent decades, adaptive trial designs have been used more and more often for clinical trials, including randomized controlled trials (RCTs). This rise in the use of adaptive RCTs has been accompanied by debates about whether such trials offer ethical and methodological advantages over traditional, fixed RCTs. This study examined how experts on clinical trial methods and ethics believe that adaptive RCTs, compared to fixed ones, affect the ethical character of clinical research. We conducted in-depth interviews with 17 researchers from bioethics, epidemiology, biostatistics, and/or medical backgrounds. While about half believed that adaptive trials are more complex and may thus threaten autonomy, these respondents also expressed that this challenge is not insurmountable. Most respondents expressed that efficiency and potential for participant benefit were the main justifications for adaptive trials. There was tension about whether adaptive randomization in response to increasing information disrupts clinical equipoise, with some respondents insisting that uncertainty still exists and therefore clinical equipoise is not disrupted. These findings suggest that further discussion is needed to increase the awareness and utility of these study designs.

Is equipoise a useful concept to justify randomised controlled trials in the cultural context of Pakistan? A survey of clinicians in relation to a trial of talking therapy for young people who self-harm.

BACKGROUND: Clinical equipoise, also defined as the uncertainty principle, is considered essential when recruiting subjects to a clinical trial. However, equipoise is threatened when clinicians are influenced by their own preferences. Little research has investigated equipoise in the context of trial recruitment. METHODS: This cross-sectional survey sought clinicians' views (operationalised as 11 statements relating to treatments offered in a trial of a psychological intervention for young people) about equipoise and individual treatment preferences in the context of moral justification for recruiting young people at risk of self-harm or suicide to a randomised controlled trial (RCT) to evaluate the Youth Culturally Adapted Manual Assisted Psychological Intervention (Y-CMAP) in Pakistan. We compared the views of clinicians involved in Y-CMAP RCT recruitment to those of a sample of clinicians not involved in trial recruitment but treating similar patients, comparing their sociodemographic characteristics and the proportions of those in each group agreeing with each statement. RESULTS: There was a response rate of 96% (75/78). Findings showed that, during trial recruitment and before the RCT results were known, the majority of all responding clinicians (73.3%) considered Y-CMAP to be an effective treatment for young people at risk of self-harm or suicide. Although there was an acknowledgement of individual preferences for the intervention, there was near consensus (90%) on the need to conduct an RCT for reaching an evidence-based decision. However, there were no significant differences in the proportion of recruiting clinicians reporting a treatment preference for Y-CMAP than non-recruiting clinicians (31 (88.6%) versus 36 (90%), p = 0.566). A significantly higher proportion of non-recruiting clinicians (87.5%) as compared to (48.5%) in the trial (p = 0.000) stated that there may be other treatments that may be equally good for the patients, seemingly undermining a preference for the intervention. Those reporting a treatment preference also acknowledged that there was nothing on which this preference was based, however confident they felt about them, thus accepting clinical equipoise as ethical justification for conducting the RCT. There was a significant group difference in views that treatment overall is better as a result of young patients' participation in the Y-CMAP trial (p = 0.015) (i.e. more clinicians not involved in the trial agreed with this statement). Similarly, more clinicians not involved in the trial agreed on the perceived availability of other treatment options that were good for young people at risk of self-harm (p < 0.05). CONCLUSIONS: The paper highlights that clinicians in Pakistan accept the notion of clinical equipoise as an ethical justification for patient participation in RCTs. The need for conducting RCTs to generate evidence base and to reduce bias was considered important by the clinical community.

Explanatory and pragmatic trials in orthopaedics - Have we done the right studies?

Recent decades have seen marked advances in the quality of clinical orthopaedic trauma research, and with this has come a rise in the number of randomised clinical trials (RCTs) being conducted in orthopaedic trauma. These trials have been largely valuable in driving evidence-based management of injuries which previously had clinical equipoise. However, though RCTs are traditionally seen as the 'gold standard' of high-quality research, this research method is comprised primarily of two entities, explanatory and pragmatic designs, each with its own strengths and limitations. Most orthopaedic trials lie within a continuum between these designs, with varying degrees of both pragmatic and explanatory features. In this narrative review we provide a summary of the nuances within orthopaedic trial design, the advantages and limitations of such designs, and suggest tools which may aid clinicians in the appropriate selection and evaluation of trial designs.