随机对照实况试验的概念、设计和实施

随机对照实况试验由于所纳入的受试者和干预过程接近临床实践的真实状况,其效应量接近或与临床实践真实情况相似,冈此其疗效效应量用于评估患者的疗效较之辨析性研究更加准确。由于其特点是干预措施和过程可变,符合包括中医药和针灸在内的临床治疗特点,因而日益受到国内中医药界的极大兴趣和关注。实际上,随机对照实况试验也适合于比较采用临床路径和不采用临床路径管理患者的效果。本文介绍了随机对照实况试验的原理和概念,并通过举例说明其设计要点。     

Real-world experiences with generating real-world evidence: Case Studies from PCORI's pragmatic clinical Studies program

BackgroundOver the last decade, randomized studies evaluating outcomes of health care interventions conducted in real-world settings—often termed “pragmatic trials”—have come to be seen as an important means of obtaining relevant, actionable evidence to guide health care decisions. Despite extensive writing on methodological considerations in pragmatic trial design, limited information exists regarding the practical and logistical challenges encountered in carrying out rigorous randomized evaluations in highly representative, real-world contexts.MethodsThe Patient Centered Outcomes Research Institute (PCORI) convened an expert panel in 2017 to examine common tradeoffs in study design and implementation through 3 “case studies” of in-progress, PCORI-funded pragmatic trials. This paper summarizes the findings of this panel, using the 3 examples to illustrate common implementation challenges encountered in pragmatic trials.ResultsInvestigators aimed to generate highly generalizable findings that could address real-world clinical decisions; however, practical considerations required that each study incorporate traditionally “explanatory” elements to achieve a “fit-for-purpose” approach to design and implementation. Within individual studies, efforts to balance pragmatic versus explanatory perspectives often involved multiple, diverse aspects of trial design and implementation, and the aspects of design and implementation where investigators reported encountering such tradeoffs varied across the three cases we examined.ConclusionsEfforts to generate rigorous evidence that is generalizable to “real-world” practice require continuous and iterative efforts to balance “pragmatic” and “explanatory” perspectives. In each study examined, these tradeoffs were guided both by an overriding effort to maintain pragmatism and practical considerations that varied depending on the research question and study context.     

The acute respiratory distress syndrome network controversy: lessons and legacy

PURPOSE OF REVIEW: Several of the Acute Respiratory Disease Syndrome Network clinical trials embrace a clinical trial design that evaluates contrasting strategies, one or both of which represents only a segment of standard practices. Such a trial design has engendered ethical controversy regarding the value of such trials and their ability to protect human subjects. During the past year, commentators have continued to reflect on the significance of such trials. RECENT FINDINGS: Several authors have reflected on the ethical significance of the standard of care in clinical trial design and have offered a framework for determining control group selection in critical care trials. Other authors have written on methodologic issues and approaches to determine whether control groups are reflective of standard practices. Surveys have been performed to determine the impact and hence the relevancy of the Acute Respiratory Disease Syndrome Network tidal volume trial on clinical practice. SUMMARY: The controversy related to and the impact of the Acute Respiratory Disease Syndrome Network clinical trial design on clinical practice offer an opportunity to explore the trade-offs between explanatory and pragmatic types of clinical trials. Such discussions will lead to a clearer understanding of the value of both types of clinical trials and the optimal ethical conduct of such trials.     

Pragmatic clinical trials at the National Institute of Nursing Research

Background

Pragmatic clinical trials are used to test the efficacy of interventions in a real-world clinical practice setting.

Recommendations for the design of Phase 3 pharmaceutical trials that are more informative for patients,clinicians, and payers

BackgroundPharmaceutical pragmatic clinical trials (PCTs) are designed to provide the type of evidence that is desired by patients, clinicians and payers but too often missing from traditional regulatory trials.PurposeThis paper presents framework for designing pragmatic trials incorporating evidence desired by post-regulatory decision makers while remaining within acceptable standards for regulatory approval.MethodsFollowing a stakeholder meeting convened in May of 2009 to identify gaps in information collected in Phase 3 trials, CMTP staff and the authors drafted recommendations for Pragmatic Phase 3 Pharmaceutical Trials. This draft was circulated first to technical working group members for their comments. After revising the document based on these comments, it was distributed electronically to other select experts and then made available for public comment. The final version of the EGD appears on the CMTP website.ResultsThe process resulted in a set of 10 recommendations for conducting Phase 3 trials that met regulatory needs while addressing information important to physicians, patients, payers, and policy-makers. These recommendations encompassed three primary areas: generalizability from the trial participants to the clinical population of interest; effectiveness relative to active comparators; and consistently measured relevant outcomes for coverage and treatment decisions.LimitationsWhile stakeholders were involved throughout the process, not all recommendations will meet the needs of all stakeholders.ConclusionsPragmatic trial design need not be deferred until a product is in widespread use. Incremental movement toward the more pragmatic design of Phase 3 trials is desirable.     

A questionnaire-based survey of participants' decisions regarding recruitment and retention in a randomised controlled trial - lessons learnt from the SCoRD trial

Successful recruitment and retention on trials is critical to ensuring that adequate power is conferred, results are generalisable and trials are completed within the allocated time and resources. Nested within an existing pragmatic randomised controlled trial a process evaluation was conducted to explore the reasons for a much higher than anticipated recruitment (120% of required sample size) and retention rate (96% completed follow-up). A questionnaire was designed to ascertain patient's views on reasons affecting consent and retention. 148 patients still enrolled in the trial at their final follow-up were either given or mailed a questionnaire of which 102 were returned (69%). 96% rated the written information as very or somewhat important in their decision to consent. Verbal information given to them by the operating surgeon was considered very or somewhat important by 86% and the relative inconvenience was rated as important by 79% of patients. Reasons for consenting for a large proportion of patents were the wish to help in research which may benefit others in the future and the perception that this was an important and relevant study. There was also some evidence that patients weighed up the demands with the potential benefits to them. High levels of satisfaction were expressed with trial personnel and trial procedures. The inclusion of a trial process evaluation such as the one presented here is an efficient method for gathering information of participants' decisions regarding recruitment and retention in a trial and can help to inform the successful planning of future trials.     

Behavioral headache research: methodologic considerations and research design alternatives

Behavioral headache treatments have garnered solid empirical support in recent years, but there is substantial opportunity to strengthen the next generation of studies with improved methods and consistency across studies. Recently, Guidelines for Trials of Behavioral Treatments for Recurrent Headache were published to facilitate the production of high-quality research. The present article compliments the guidelines with a discussion of methodologic and research design considerations. Since there is no research design that is applicable in every situation, selecting an appropriate research design is fundamental to producing meaningful results. Investigators in behavioral headache and other areas of research consider the developmental phase of the research, the principle objectives of the project, and the sources of error or alternative interpretations in selecting a design. Phases of clinical trials typically include pilot studies, efficacy studies, and effectiveness studies. These trials may be categorized as primarily pragmatic or explanatory . The most appropriate research designs for these different phases and different objectives vary on such characteristics as sample size and assignment to condition, types of control conditions, periods or frequency of measurement, and the dimensions along which comparisons are made. A research design also must fit within constraints on available resources. There are a large number of potential research designs that can be used and considering these characteristics allows selection of appropriate research designs.     

Sample size calculations for the design of cluster randomized trials: A summary of methodology

Cluster randomized trial designs are growing in popularity in, for example, cardiovascular medicine research and other clinical areas and parallel statistical developments concerned with the design and analysis of these trials have been stimulated. Nevertheless, reviews suggest that design issues associated with cluster randomized trials are often poorly appreciated and there remain inadequacies in, for example, describing how the trial size is determined and the associated results are presented. In this paper, our aim is to provide pragmatic guidance for researchers on the methods of calculating sample sizes. We focus attention on designs with the primary purpose of comparing two interventions with respect to continuous, binary, ordered categorical, incidence rate and time-to-event outcome variables. Issues of aggregate and non-aggregate cluster trials, adjustment for variation in cluster size and the effect size are detailed. The problem of establishing the anticipated magnitude of between- and within-cluster variation to enable planning values of the intra-cluster correlation coefficient and the coefficient of variation are also described. Illustrative examples of calculations of trial sizes for each endpoint type are included.     

Intention to treat analysis,compliance, drop-outs and how to deal with missing data in clinical research: a review

Abstract

Background: Pragmatically, intention to treat (ITT) analysis has become the 'gold standard' for analysing the results of clinical trials. Despite its popularity and wide use, ITT is not without its critics, controversies and misunderstandings. To perform an ideal ITT requires a full set of data, where all patients providing data are followed, independent of any protocol deviation. However, most of the time, clinicians and researchers are faced with non-compliance and drop-outs. Thus, researchers should be familiar with the concepts associated with ITT and strategies to deal with missing data.

Objectives: The objective of this review is to clarify and summarise the important aspects of ITT limitations, and contributions to clinical research. In addition, the concepts of effectiveness and efficacy will be discussed in the context of randomised controlled trial (RCT) analysis. This will help clinicians and researchers to have a greater understanding of ITT and apply this knowledge when designing, evaluating, and reporting RCTs.

Conclusions: Depending on the objective of the trial, different approaches to data analysis could be used. If the trial's objective is purely explanatory, an 'as treated' or 'per protocol' analysis could be a reasonable option. Nevertheless, it is advised that these approaches are not reported on their own because of their susceptibility to bias when estimating treatment effects. If the objective of the trial is pragmatic, that is, it addresses the effectiveness of a specific treatment in real life (clinical setting), an ITT should be the primary analysis.     

Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 3: Design considerations

Ongoing safety monitoring of clinical trials of investigational treatments must operate at levels that range from the minute and detailed - namely, mathematical treatment of trial data - to the philosophical and societal - namely, ethical concerns for individuals and populations. Between those two poles lies a realm of environmental and pragmatic considerations that reflect the goals, biases, risk-tolerance, and constraints of study sponsors and organizers. These factors, while more difficult to quantify or, at times, to justify, also have a meaningful impact on the approach to safety monitoring and the resulting actions and outcomes. This paper considers the influence and interaction of two such factors, study design and statistical framework, on continuous safety monitoring procedures. Group sequential designs have been generally preferred for clinical trials over continuous sequential designs because of practical considerations. The group means and greater time for deliberation when using a group sequential procedure, as opposed to a continuous sequential procedure, can improve the quality of the analyses with minimal loss in sensitivity. However, undertaking any sequential analysis within a frequentist framework provokes considerable theoretical and practical difficulties. Continuous monitoring with a likelihood based method, on the other hand, has the advantages that all available information, including new data, can be used; sample sizes need not be fixed; and decisions can be made at any time without statistical penalty, irrespective of trial design. Such responsive statistical rules are needed to provide guidance to the human beings charged with trial monitoring.     

What's Next for Acute Heart Failure Research?

Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either “inpatient” or “ED‐based.” Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high‐priority research areas.     

Evaluating the benefit of clinical trials to future patients

Large, multicenter clinical trials are expensive to design and to carry out. In spite of the magnitude of expenditures for such endeavors during the past two decades, little attention has been given to evaluating the impact of findings from these trials on those who are expected to benefit from them, i.e., future patients to whom trial findings apply. The implications of failure to demonstrate that results from these large medical experiments have been accepted by medical practitioners and policy makers and applied appropriately to patients must be of concern to all advocates and practitioners of controlled trials. Of the 20 evaluation studies reviewed in this paper, 6 were directed at assessing dollar benefits to the patient or to society. The remaining 14 studies were concerned primarily with physician knowledge and acceptance of trial findings. Investigators and sponsors of each large trial have a responsibility to develop an evaluation strategy during the planning phase of the trial, to publicize findings from the trial, to evaluate the impact of the findings on future patients, to act in response to the results of the evaluation, and to foster integration of findings into patient care policy.     

Intervention Fidelity in Pain Pragmatic Trials for Nonpharmacologic Pain Management: Nuanced Considerations for Determining PRECIS-2 Flexibility in Delivery and Adherence

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, “flexibility in delivery” and “flexibility in adherence,” address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate.PerspectiveThis article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable.     

The Necessity for Clinical Reasoning in the Era of Evidence-Based Medicine

Clinical decisions are increasingly driven by evidence-based recommendations of guideline groups, which aim to be based on the highest quality knowledge—randomized clinical trials (RCTs) and meta-analyses. Although RCTs provide the best assessment of the overall value of a therapy, high-quality evidence from RCTs is often incomplete, contradictory, or absent even in areas that have been most exhaustively studied. Moreover, the likelihood of the success or failure of a therapy is not identical in all the individuals treated in any trial because therapy is not the only determinant of outcome. Therefore, the overall results of a trial cannot be assumed to apply to any particular individual, not even someone who corresponds to all the entry criteria for the trial. In addition, the potential for bias due to financial conflicts remains in many guideline groups. Guidelines are key sources of knowledge. Nevertheless, limitations in the extent, quality, generalizability, and transferability of evidence mean that we clinicians must still reason through the best choices for an individual because even in the absence of full and secure knowledge, clinical decisions must still be made. Clinical reasoning is the pragmatic, tried-and-true process of expert clinical problem solving that does value mechanistic reasoning and clinical experience as well as RCTs and observational studies. Clinicians must continue to value clinical reasoning if our aim is the best clinical care for all the individuals we treat.     

Should data and safety monitoring boards share confidential interim data?

Consider the following situation: Two clinical trials are underway, closely related in terms of the interventions being compared and the target populations. In preparing for a planned interim analysis, the statistician for trial 1 finds that the results support a recommendation to stop the trial early. Should the statistician ask the investigators for trial 2 to make interim results of their trial available to the data and safety monitoring board (DSMB) for trial 1? If so, in what form? Would the answers change if the trial 1 results showed a strong but not convincing trend? What is the obligation of the trial 2 investigators to respond to such a request? What role do the two DSMBs have, either in initiating a request or in agreeing to respond to it? In this article, we examine this situation in some detail, having faced it occasionally in our own experience with clinical trials and DSMBs. The chief argument in favor of sharing data is that data from trial 2 are obviously relevant to the question being addressed by trial 1 and therefore ought to be available to those who must interpret the results from that trial. On the other hand, there are several reasons for not sharing interim data. For example, sharing is incompatible with the independence of the trials; the time for synthesizing evidence from both trials is after the two teams of investigators have presented the full analysis and interpretation of their separate trials. For this and other conceptual and practical reasons we conclude that it is better, in most cases, for DSMBs to consider only information that has already been made public in some form.     

The Role of Plasma Transfusion in Pre-Hospital Haemostatic Resuscitation

Traumatic haemorrhage remains a major cause of preventable death and early haemostatic resuscitation is now a mainstay of treatment internationally. Recently, 2 randomized control trials (RCTs) - PAMPer (Prehospital Air Medical Plasma) and COMBAT (Control of Major Bleeding After Trauma), evaluating the effect of pre-hospital use of plasma on mortality provided conflicting results, raising important questions on the role of plasma resuscitation in pre-hospital environment. Both PAMPer (n = 501 patients) and COMBAT (n = 144 patients) trials were pragmatic RCTs that evaluated the effect of pre-hospital plasma transfusion (two units) versus standard of care on 28/30 days mortality in trauma patients who presented with clinical signs of haemorrhagic shock (defined as hypotension or tachycardia). The PAMPer trial showed that plasma transfusion reduced 30-day mortality compared with standard of care (23% vs 33%, 95% confidence interval -18.6; -1.0%; P = 0.03), while COMBAT trial showed no difference in 28-day survival. The post-hoc analyses of the 2 trials have suggested that the benefit of pre-hospital plasma transfusion may be greater for patients who are coagulopathic, have blunt injury and have a transport time from the scene of injury to the hospital of >20 minutes. In this review we evaluate strengths and limitations of the two trials and their differences and similarities, which may explain the conflicting results, as well as provide directions for future trials to better define the target population that would most benefit from pre-hospital plasma resuscitation. Further, considering the logistical challenges of carrying any blood components on an aircraft, cost/safety of plasma, and the scarcity of universal blood group donors, there is a need for a health economic evaluation of pre-hospital plasma transfusion in trauma patients, prior to this intervention becoming universal.     

Nurses' unique roles in randomized clinical trials.

Nurses are in an ideal position to promote patients' awareness of the role played by clinical trials in the advancement of health science and the subsequent improvement of patient care. The history of clinical trials and the four phases of clinical trials are described. Nurses' professional roles in clinical trial participation, such as helping the patient to identify open clinical trials and acting as clinical interpreter and patient advocate during the patient's participation in a trial, are detailed. Professional considerations that must be addressed by the nurse are reviewed and include ensuring that the trial has received approval from an Institutional Review Board for the participation of human subjects; that the responsibilities of participation are congruent with the nurse's personal values and workplace obligations; and that once engaged, the nurse can make the commitment to sustain participation in the trial. Most important, the nurse must keep the patient's needs and values uppermost in mind during the evaluation of potential clinical trials. Nurses have a critical role to play in the promotion of clinical trials, the recruitment of patients for clinical trial participation, the education of the patient and family, and the clinical care and support of patients throughout their participation in clinical trials.     

A preliminary study comparing the use of cervical/upper thoracic mobilization and manipulation for individuals with mechanical neck pain

Objectives:Neck pain is routinely managed using manual therapy (MT) to the cervical and thoracic spines. While both mobilizations and manipulations to these areas have been shown to reduce neck pain, increase cervical range of motion, and reduce disability, the most effective option remains elusive. The purpose of this preliminary trial was to compare the pragmatic use of cervical and thoracic mobilizations vs. manipulation for mechanical neck pain.Methods:This trial included 20 patients with mechanical neck pain. Each patient was randomized to receive either mobilization or manipulation to both the cervical and thoracic spines during their plan of care. Within-group analyses were made with Wilcoxon signed-rank tests and between-group analyses were made with Mann–Whitney U.Results:There were no between-group differences for any of the dependent variables including cervical active range of motion (CAROM) (P = 0.18), deep cervical flexion (DCF) endurance (P = 0.06), numerical pain rating scale (NPRS) (P = 0.26), the neck disability index (NDI, P = 0.33), patient-specific functional scale (PSFS, P = 0.20), or the global rating of change (GROC) scale (P = 0.94). Within-group results were significant for all outcome variables (P<0.001) from initial evaluation to discharge for both groups.Discussion:These findings were consistent with other trials previously conducted that applied the MT techniques in a pragmatic fashion, but varied from previous trials where the treatment was standardized. A larger experimental study is necessary to further examine the differences between mobilization and manipulation for neck pain.     

Clinical trials of classical homeopathy: reflections on appropriate research designs

The growing popularity of complementary medicine has been accompanied by a call for controlled clinical studies to examine the efficacy and validity of its various methods. The difficulties encountered in applying the evaluation methods of conventional medicine to complementary medicine are the result of the different paradigms underlying these two methods of medicine, and the differences in the healing process. This paper attempts to bridge the gap between these two approaches and to suggest a possibility to use conventional research methodology in clinical studies of classical homeopathy. Two methods are described. One is the randomization into a placebo or a treatment group after an individual remedy is chosen for each patient. This method requires an experienced homeopath and is reproducible only by the same homeopath in the same population. On the other hand, the expected success rate will be high. Another method is prescribing and treating according to so-called keynotes, a set of symptoms known to respond to a particular remedy that must be present in a patient in order to elicit a reaction from the remedy. This method is more suitable to a conventional design of a clinical study and is reproducible by anyone. Yet the expected success rate is much lower. Some general design issues that may have a particular impact on clinical trials of classical homeopathy are discussed, including the need for sufficiently powered trials to detect relatively small effects, strategies to deal with patient preference and embracing the use of "active-control" pragmatic trial designs.