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Implementation of adaptive methods in early-phase clinical trials.

ABSTRACT: There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor understanding from clinicians and reviewers into how the designs work, and how best to evaluate the appropriateness of a proposed design. These barriers are likely to be enhanced in the coming years as the recent paradigm of drug development involves a shift to more complex dose-finding problems. This article reviews relevant information that should be included in clinical trial protocols to aid in the acceptance and approval of novel methods. We provide practical guidance for implementing these efficient designs with the aim of augmenting a broader transition from algorithmic to adaptive model-guided designs. In addition we highlight issues to consider in the actual implementation of a trial once approval is obtained. Copyright © 2016 John Wiley & Sons, Ltd.

SUBMITTER: Petroni GR

PROVIDER: S-EPMC5003756 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Implementation of adaptive methods in early-phase clinical trials.

Petroni Gina R GR Wages Nolan A NA Paux Gautier G Dubois Frédéric F

Statistics in medicine 20160229 2

There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor und ...[more]

PMID: 26928191

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Project description:Rationale & objectiveAdaptive design methods are intended to improve the efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to determine the use of adaptive designs in dialysis clinical trials and quantify trends in their use over time.Study designWe completed a novel full-text systematic review that used a machine learning classifier (RobotSearch) for filtering randomized controlled trials and adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines.Setting & study populationsWe searched MEDLINE (PubMed) and ClinicalTrials.gov using sensitive dialysis search terms.Selection criteria for studiesWe included all randomized clinical trials with patients receiving dialysis or clinical trials with dialysis as a primary or secondary outcome. There was no restriction of disease type or intervention type.Data extraction & analytical approachWe performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data.Results57 studies, available as 68 articles and 7 ClinicalTrials.gov summaries, were included after full-text review (initial search, 209,033 PubMed abstracts and 6,002 ClinicalTrials.gov summaries). 31 studies were conducted in a dialysis population and 26 studies included dialysis as a primary or secondary outcome. Although the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.12% in 2009 to 0.43% in 2019, with a mean of 1.82%). Group sequential designs were the most common type of adaptive design method used. Adaptive design methods affected the conduct of 50.9% of trials, most commonly resulting in stopping early for futility (41.2%) and early stopping for safety (23.5%). Acute kidney injury was studied in 32 trials (56.1%), kidney failure requiring dialysis was studied in 24 trials (42.1%), and chronic kidney disease was studied in 1 trial (1.75%). 27 studies (47.4%) were supported by public funding. 44 studies (77.2%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic review.LimitationsWe limited our search to 2 databases (PubMed and ClinicalTrials.gov) due to the scale of studies sourced (209,033 and 6,002 results, respectively).ConclusionsAdaptive design methods are used in dialysis trials but there has been a decline in their relative use over time.

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Implementation of adaptive methods in early-phase clinical trials.

Publications

Implementation of adaptive methods in early-phase clinical trials.

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