Design considerations for randomised trials in orthopaedic fracture surgery

In the hierarchy of research designs, the results of randomised controlled trials are considered the highest level of evidence. Randomisation is the only method for controlling for both known and unknown prognostic factors between comparison groups. However, there are a number of challenges to conducting trials to evaluate surgical interventions. These include patient and surgeon preferences, inability to blind surgeons and difficulties blinding patients, difficulties in obtaining adequate sample sizes, and a lack of standardisation of surgical procedures. In this paper we address these issues and offer potential solutions within the context of conducting fracture trials in orthopaedics. Careful planning can help identify methodological issues, promote adaptive study designs, and lower the risk of bias to objectively assess new or existing surgical therapies.     

Ethical considerations in neuroclinical trials

Ethical decision making in clinical trials has become increasingly emphasized at many levels of the review process.Ethical concepts applicable to Neuroctinical Trials (NCT) are reviewed. The discussion is directed towards ethical concerns that investigators must consider and justify prior to Institutional Review Board (IRB) submission. Risk-benefit analysis, methodology (randomization; placebo; design) and consent (informed; deferred; waived) are reviewed and Office for Protection from Research Risk (OPRR) guidelines are described.Our confusions: Investigators proposing NCT face increasing ethical scrutiny by IRBs. Attention to ethical issues early in trial planning process is recommended.     

Fundamentals of randomized clinical trials in wound care: Design and conduct

The care for chronic and acute wounds is a substantial problem around the world. This has led to a plethora of products to accelerate healing. Unfortunately, the quality of studies evaluating the efficacy of such wound care products is frequently low. Randomized clinical trials are universally acknowledged as the study design of choice for comparing treatment effects, as they eliminate several sources of bias. We propose a framework for the design and conduct of future randomized clinical trials that will offer strong scientific evidence for the effectiveness of wound care interventions. While randomization is a necessary feature of a robust comparative study, it is not sufficient to ensure a study at low risk of bias. Randomized clinical trials should also ensure adequate allocation concealment and blinding of outcome assessors, apply intention‐to‐treat analysis, and use patient‐oriented outcomes. This article proposes strategies for improving the evidence base for wound care decision making.     

Methods and design considerations for randomized clinical trials evaluating surgical or endovascular treatments for cerebrovascular diseases

OBJECTIVE: The results of clinical trials affect the practice of surgery and endovascular therapy for cerebrovascular diseases. The purpose of this report is to review the basic components of the designs and methods for randomized clinical trials and to describe the influence of those components on the interpretation of trial results. METHODS: The goal of an optimal clinical trial of a new procedure is to provide the most objective and rigorous evaluation of the safety and effectiveness of that procedure. Anything in the design, performance, or analysis that impairs such an assessment decreases the ability of the trial to achieve its goal and answer the research question. To highlight the components of a clinical trial, this report uses examples of Phase III clinical trials that have influenced the practice of cerebrovascular surgery and endovascular therapy in the past three decades, including the International Cooperative Study of Extracranial/Intracranial Arterial Anastomosis, the North American Symptomatic Carotid Endarterectomy Trial, the Asymptomatic Carotid Atherosclerosis Study, the Prolyse in Acute Cerebral Thromboembolism II study, and the International Subarachnoid Aneurysm Trial. RESULTS: The research question (objective) of the trial must be clearly defined, with an objective measure of efficacy and a specified quantitative difference to define the superiority of one intervention over another, in a relatively homogeneous patient population. Allocation concealment, randomization with or without stratification, and blinding (or masking) are important strategies to prevent differences in the study populations that could adversely affect the conclusions of the study. The primary end point must correspond to the specific aims of the trial. It should be objectively defined, quantifiable, reliable, and reproducible. Commonly defined end points in surgical trials include changes from baseline illness or disease severity scores, morbidity and mortality rates, and relative risks of reaching an end point with time. The statistical methods used for interim and final analyses are important. The effects of dropouts, crossovers, and missing data should be understood in the context of the final analysis. Additional concepts, such as intention-to-treat analysis and use of actual versus predicted outcomes, are important with respect to interpretation of the final results of the study. CONCLUSION: The neurosurgical and neuroendovascular communities are currently planning or conducting several clinical trials to evaluate new procedures for the treatment of cerebrovascular diseases. It is hoped that a better understanding of the components of clinical trials will facilitate the design and implementation of effective studies.     

Health-economic evaluation in implant trials: design considerations

In today's world, demonstration of the safety, efficacy, and quality of a new treatment strategy is no longer sufficient in many countries for market entry and reimbursement in the public healthcare system. This implies that new implants in orthopedic and orthopedic trauma surgery not only must be shown to lead to better medical outcome compared with the standard of care implant, but also must be shown to exhibit "good value" for the money for the public health-care system based on sound economic data from health-economic studies. The purpose of this article is to elucidate a framework for health-economic aspects alongside implant trials, with the assumption that the new implant is more costly but potentially better than the control implant. Cost-effectiveness, cost-utility, and cost-benefit studies are suitable for the assessment of the health-economic value of a new implant. The following criteria should be considered for a health-economic study design in the context with an implant: i) it should state medical benefits of the new implant compared with the control implant; ii) it should precise the type of health economic study; iii) it should define the methodological approach, perspective of the study, and types of costs; iv) if necessary, it should state discount costs and/benefits; and v) a sound sensitivity analysis should be included. Furthermore, close cooperation between researchers, clinicians, and health economists is essential.     

History of randomized clinical trials in neurosurgery

The randomized clinical trial is a treatment evaluation technique that has been available in clinical research since 1946. Its first application in neurosurgery seems to have occurred in 1960 by McKissock and colleagues. Neurosurgery has been slow to adopt the technique, particularly in the evaluation of surgical therapy, but its use has increased in recent years.     

Ethical considerations for innovations and clinical trials

The ethical imperative to improve practice through innovation and research finds justification in the requirements of physicians to help patients, minimize the harms of treatment and disease, and to bring the benefits of scientific medicine to those suffering from illnesses for which satisfactory treatment has not yet been developed. This article discusses the values and principles that underlie clinical trials; the need for evidence-based knowledge; the difference between research and therapy; the ethical duty to improve care through research; the challenge of conflict of interest; the relevance of clinical equipoise; the need for research review and postapproval monitoring; and the value of disseminating results to research subjects, colleagues, and the public. Public confidence and willingness to participate in clinical trials will continue if the ethical standards set by professional, government, and international bodies are met.     

Efficient designs: factorial randomized trials

As an alternative to conducting multiple parallel group randomized controlled trials, the factorial design is an efficient means of evaluating multiple interventions. This review highlights when it is appropriate to conduct a factorial trial, considers the structure and nomenclature of factorial designs, and discusses various methodological considerations, including sample size calculation, the role of statistical interactions between different interventions, and statistical power. Several pertinent examples in orthopaedics and medicine are used to highlight the key concepts.     

A primer on randomized controlled trials

Randomized Clinical Trials are held as the gold standard for quantifying the effect of an intervention across two or more groups. In such a trial an intervention is randomly allocated to one of two groups. The benefit of such a trial lies in its ability to establish nearly comparable groups of subjects in all manner except for the effect of the intervention. As such, the effect of a given intervention may be attributed solely to the intervention and not to any other extraneous factor. In the following editorial, we will discuss several issues that are important for understanding how to conduct and interpret randomized trials: choosing the study population, choosing the comparison group, choosing your outcome, study design, data analysis, and issues of inference. This editorial is intended to make the reader an educated consumer of such trial designs.