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Innovative designs of point-of-care comparative effectiveness trials.

ABSTRACT: One of the provisions of the health care reform legislation in 2010 was for funding pragmatic clinical trials or large observational studies for comparing the effectiveness of different approved medical treatments, involving broadly representative patient populations. After reviewing pragmatic clinical trials and the issues and challenges that have made them just a small fraction of comparative effectiveness research (CER), we focus on a recent development that uses point-of-care (POC) clinical trials to address the issue of "knowledge-action gap" in pragmatic CER trials. We give illustrative examples of POC-CER trials and describe a trial that we are currently planning to compare the effectiveness of newly approved oral anticoagulants. We also develop novel stage-wise designs of information-rich POC-CER trials under competitive budget constraints, by using recent advances in adaptive designs and other statistical methodologies.

SUBMITTER: Shih MC

PROVIDER: S-EPMC4639459 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Innovative designs of point-of-care comparative effectiveness trials.

Shih Mei-Chiung MC Turakhia Mintu M Lai Tze Leung TL

Contemporary clinical trials 20150619 Pt A

One of the provisions of the health care reform legislation in 2010 was for funding pragmatic clinical trials or large observational studies for comparing the effectiveness of different approved medical treatments, involving broadly representative patient populations. After reviewing pragmatic clinical trials and the issues and challenges that have made them just a small fraction of comparative effectiveness research (CER), we focus on a recent development that uses point-of-care (POC) clinical ...[more]

PMID: 26099528

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Project description:BackgroundAdaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation.MethodsUsing two large critical care trials (ADRENAL.Clinicaltrialsgov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR.Clinicaltrialsgov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05.ResultsAcross all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O'Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became increasingly underestimated as the number of interims increased.ConclusionsThis study confirms the right adaptive design can reach the same conclusion as a fixed design with a much-reduced sample size. The efficiency gain associated with an increased number of interims is highly relevant to late-phase critical care trials with large sample sizes and short follow-up times. Systematically exploring adaptive methods at the trial design stage will aid the choice of the most appropriate method.

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Innovative designs of point-of-care comparative effectiveness trials.

Publications

Innovative designs of point-of-care comparative effectiveness trials.

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