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ERDO - a framework to select an appropriate randomization procedure for clinical trials.

ABSTRACT: Randomization is considered to be a key feature to protect against bias in randomized clinical trials. Randomization induces comparability with respect to known and unknown covariates, mitigates selection bias, and provides a basis for inference. Although various randomization procedures have been proposed, no single procedure performs uniformly best. In the design phase of a clinical trial, the scientist has to decide which randomization procedure to use, taking into account the practical setting of the trial with respect to the potential of bias. Less emphasis has been placed on this important design decision than on analysis, and less support has been available to guide the scientist in making this decision.We propose a framework that weights the properties of the randomization procedure with respect to practical needs of the research question to be answered by the clinical trial. In particular, the framework assesses the impact of chronological and selection bias on the probability of a type I error. The framework is applied to a case study with a 2-arm parallel group, single center randomized clinical trial with continuous endpoint, with no-interim analysis, 1:1 allocation and no adaptation in the randomization process.In so doing, we derive scientific arguments for the selection of an appropriate randomization procedure and develop a template which is illustrated in parallel by a case study. Possible extensions are discussed.The proposed ERDO framework guides the investigator through a template for the choice of a randomization procedure, and provides easy to use tools for the assessment. The barriers for the thorough reporting and assessment of randomization procedures could be further reduced in the future when regulators and pharmaceutical companies employ similar, standardized frameworks for the choice of a randomization procedure.

SUBMITTER: Hilgers RD

PROVIDER: S-EPMC5715815 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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ERDO - a framework to select an appropriate randomization procedure for clinical trials.

Hilgers Ralf-Dieter RD Uschner Diane D Rosenberger William F WF Heussen Nicole N

BMC medical research methodology 20171204 1

<h4>Background</h4>Randomization is considered to be a key feature to protect against bias in randomized clinical trials. Randomization induces comparability with respect to known and unknown covariates, mitigates selection bias, and provides a basis for inference. Although various randomization procedures have been proposed, no single procedure performs uniformly best. In the design phase of a clinical trial, the scientist has to decide which randomization procedure to use, taking into account ...[more]

PMID: 29202708

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Project description:BackgroundRandomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial.MethodsWe survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice.ResultsRestricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size.ConclusionsThe choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.

Project description:BackgroundThis study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function, as well as social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting up to 90 min were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs.ResultsInterviews (N = 36) were conducted with caregivers of children age 0-2 years (n = 8) and 3-7 years (n = 7) and child/caregiver dyads with children age 8-11 years (n = 15) and 12-17 years (n = 6). Children/caregivers identified pain, short stature, impacts on physical functioning, and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n = 9/14, 64%) and an improvement in limb proportion (n = 11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12-17. Some children aged 8-11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a 7-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N = 12 interviews with caregivers of children age 0-11 (n = 9) and adolescents age 12-17 (n = 3).ConclusionsAchondroplasia impacts physical functioning and emotional/social well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12-17 years and caregiver-report is recommended for age 0-11 years.

Project description:Selecting motor strategies in daily life tasks requires a perception of the task requirements as well as of one's own physical abilities. Age-related cognitive and physical changes may affect these perceptions. This might entail that some older adults select inappropriate movement strategies when confronted with daily-life motor tasks, which could lead to balance loss or falls. We investigated whether older adults select motor strategies in accordance with their actual physical ability. Twenty-one older adults were subjected to a stepping down paradigm, in which full-body kinematics of selected and reactive behavior were recorded. Stepping down from a curb can be done with either (1) a relatively low effort but more balance threatening heel landing, or (2) a more controlled but more demanding toe landing. The probability of selecting a toe landing grows with an increase in curb height. We determined the curb height at which participants switched from heel to toe landing during expected stepping down over different heights as an indicator of their perceived ability. During an unexpected step down trial, participants encountered a step down of 0.1 m earlier than expected, because part of the walkway was removed and covered by a black cloth. We evaluated participants' actual physical ability from the reactive behavior, with performance defined as the reduction in kinetic energy between the peak value after landing and the onset of the next step. To unravel whether the selected motor strategies corresponded with actual physical ability, the ability to recover from the unexpected step down was correlated to the height at which the participants switched movement strategy. The switching height was not correlated to the ability to recover from an unexpected step down (ρ = 0.034, p = 0.877). This finding suggests that older adults do not select their movement strategy in stepping down based on their actual abilities, or have an imprecise perception of their actual abilities. Future research should evaluate whether inappropriate motor strategy selection in a stepping down paradigm can explain accidental falls in older adults.

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ERDO - a framework to select an appropriate randomization procedure for clinical trials.

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ERDO - a framework to select an appropriate randomization procedure for clinical trials.

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