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Choosing primary endpoints for clinical trials of health care interventions.

ABSTRACT: The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health outcomes. It is therefore crucial that the chosen endpoints are meaningful to the clinicians, patients and policymakers that are the end-users of evidence generated by these trials. The choice of endpoints may be improved by understanding their characteristics and properties. This narrative review describes the evolution, range and relative strengths and weaknesses of endpoints used in late phase trials. It is intended to serve as a reference to assist those designing trials when choosing primary endpoint(s), and for the end-users charged with interpreting these trials to inform practice and policy.

SUBMITTER: McLeod C

PROVIDER: S-EPMC6881606 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Choosing primary endpoints for clinical trials of health care interventions.

McLeod Charlie C Norman Richard R Litton Edward E Saville Benjamin R BR Webb Steve S Snelling Thomas L TL

Contemporary clinical trials communications 20191112

The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health outcomes. It is therefore crucial that the chosen endpoints are meaningful to the clinicians, patients and policymakers that are the end-users of evidence generated by these trials. The choice of endpoints may be improved by understanding their characteristics and properties. This narrative review describes the evolution, range ...[more]

PMID: 31799474

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Project description:BackgroundIncreasing the attractiveness of primary care careers is a key step in addressing the growing shortage of primary care physicians. The purpose of this review was to (1) identify interventions aimed at increasing the proportion of undergraduate medical students choosing a primary care specialty, (2) describe the characteristics of these interventions, (3) assess the quality of the studies, and (4) compare the findings to those of a previous literature review within a global context.MethodsWe searched MEDLINE, EMBASE, ERIC, CINAHL, PsycINFO, The Cochrane Library, and Dissertations & Theses A&I for articles published between 1993 and February 20, 2015. We included quantitative and qualitative studies reporting on primary care specialty choice outcomes of interventions in the undergraduate medical curriculum, without geographic restrictions. Data extracted included study characteristics, intervention details, and relevant outcomes. Studies were assessed for quality and strength of findings using a five-point scale.ResultsThe review included 72 articles reporting on 66 different interventions. Longitudinal programs were the only intervention consistently associated with an increased proportion of students choosing primary care. Successful interventions were characterized by diverse teaching formats, student selection, and good-quality teaching. Study quality had not improved since recommendations were published in 1995. Many studies used cross-sectional designs and non-validated surveys, did not include control groups, and were not based on a theory or conceptual framework.DiscussionOur review supports the value of longitudinal, multifaceted, primary care programs to increase the proportion of students choosing primary care specialties. Isolated modules or clerkships did not appear to be effective. Our results are in line with the conclusions from previous reviews and add an international perspective, but the evidence is limited by the overall low methodological quality of the included studies. Future research should use more rigorous evaluation methods and include long-term outcomes.

Project description:BackgroundGiven the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion.ResultsSimulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity.ConclusionsIn a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

Project description:ImportanceMany interventions that are important to the health care of patients are not subject to regulation by the US Food and Drug Administration (FDA) or comparable regulatory bodies in other nations.ObjectiveTo determine whether specialty journals that publish trials of primarily nonregulated health care interventions require prospective registration and whether the prospective registration policies are associated with the publication of prospectively registered trials, trials with adequately registered outcomes, and trials with primary outcomes consistent with the registered primary outcomes.Design and methodsPubMed was searched daily, from March 18, 2016, to September 17, 2016, for nonregulated intervention randomized clinical trials. The search included all journals in the Clarivate Analytics Science Citation Index Expanded categories of behavioral sciences, nursing, nutrition and dietetics, psychology, rehabilitation, and surgery. Trials of interventions not subject to FDA regulation were included. One investigator extracted journal registration policy and trial registration status. Two investigators independently extracted trial registration and publication characteristics.Main outcomes and measuresFor journals, the main outcome was the trial registration policy. For trials, the main outcomes were prospective registration, adequacy of outcome registration, and concordance of registered with published primary outcomes.ResultsIn total, 953 nonregulated intervention trials published in 254 journals were identified. Prospective registration was required for publication by 29 (11.4%) of 254 journals, and an additional 12 journals (4.7%) had conditional date-based requirements. Only 189 (19.8%) of the 953 trials were registered prospectively, including 33 of 98 published in journals with prospective registration policies as compared with 156 of 855 in journals without policies (33.7% vs 18.2%; P = .004). Among the 17 journals that required prospective registration and had at least 2 included trials, none had a prospective registration of more than 50%. In journals with policies, only 3 of 98 trials included primary outcomes consistent with prospectively, adequately registered outcomes, as compared with 34 of 852 trials in journals without policies (3.1% vs 4.0%; P = .62).Conclusions and relevanceFew journals in behavioral sciences or psychology, nursing, nutrition and dietetics, rehabilitation, and surgery require prospective trial registration, and those with existing registration policies rarely enforce them; this finding suggests that strategies for encouraging prospective registration of clinical trials not subject to FDA regulation should be developed and tested.

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Choosing primary endpoints for clinical trials of health care interventions.

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Choosing primary endpoints for clinical trials of health care interventions.

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