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Adaptive Designs in Clinical Trials
Some designs for clinical trial research, such as drug effectiveness research, allow for modification and make use of an adaptive design. Designs such as adaptive group-sequential design, n-adjustable design, adaptive seamless phase II—III design, drop-the-loser design, adaptive randomization design, adaptive dose-escalation design, adaptive treatment-switching design, and adaptive-hypothesis design are adaptive designs.
In conducting clinical trials, investigators first formulate the research question (objectives) and then plan an adequate and well-controlled study that meets the objectives of interest. Usually, the objective is to assess or compare the effect of one or more drugs on some response. Important steps involved in the process are study design, method of analysis, selection of subjects, assignment of subjects to drugs, assessment of response, and assessment of effect in terms of hypothesis testing. All the above steps are outlined in the study protocol, and the study should follow the protocol to provide a fair and unbiased assessment of the treatment effect. However, it is not uncommon to adjust or modify the trial, methods, or both, either at the planning stage or during the study, to provide flexibility in randomization, inclusion, or exclusion; to allow addition or exclusion of doses; to extend treatment duration; or to increase or decrease the sample size. These adjustments are mostly done for one or more of the following reasons: to increase the probability of success of the trial; to comply with budget, resource, or time constraints; or to reduce concern for safety. However, these modifications must not undermine the validity and integrity of the study. This entry defines various adaptive designs and discusses the use of adaptive designs for modifying sample size.
Adaptive Design Variations
Adaptive design of a clinical trial is a design that allows adaptation of some aspects of the trial after its initiation without undermining the trial's validity and integrity. There are variations of adaptive designs, as described in the beginning of this entry. Here is a short description of each variation:
Adaptive Group-Sequential Design. Adaptive group-sequential design allows premature termination of a clinical trial on the grounds of safety, efficacy, or futility, based on interim results.
n-Adjustable Design. Adaptive n-adjustable design allows reestimation or adjustment of sample size, based on the observed data at interim.
Adaptive Seamless Phase II—III Design. Such a design addresses, within a single trial, objectives that are normally achieved through separate Phase IIb and Phase III trials.
Adaptive Drop-the-Loser Design. Adaptive drop-the-loser design allows dropping of low-performing treatment group(s).
Adaptive Randomization Design. Adaptive randomization design allows modification of randomization schedules.
Adaptive Dose-Escalation Design. An adaptive dose-escalation design is used to identify the maximum tolerated dose (MTD) of a medication. This design is usually considered optimal in later-phase clinical trials.
Adaptive Treatment-Switching Design. An adaptive treatment-switching design allows investigators to switch a patient's treatment from an initial assignment to an alternative treatment because of a lack of efficacy or a safety concern.
Adaptive-Hypothesis Design. Adaptive-hypothesis design allows change in research hypotheses based on interim analysis results.
Sample Size
There has been considerable research on adaptive designs in which interim data at first stage are used to reestimate overall sample size. Determination of sample size for a traditional randomized clinical trial design requires specification of a clinically meaningful treatment difference, to be detected with some desired power. Such determinations can become complicated because of the need for specifying nuisance parameters such as the error variance, and the choice for a clinically meaningful treatment difference may not be straightforward. However, adjustment of sample size with proper modification of Type I error may result in an overpowered study, which wastes resources, or an underpowered study, with little chance of success.
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