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An adaptive design is defined as a strategy that allows modifications to the trial without undermining its validity and integrity. By utilizing the results accumulating in the trial, clinical researchers can modify the trial’s course following pre-specified rules. Compare with the traditional fixed design, the adaptive design is often more flexible, efficient, informative, and ethical. It often makes better use of resources such as time and money and can be applied across all phases of clinical research. The FDA has published some adaptive trial design guidance documents covering wide-ranging and important topics.
Fig.1 Schematic of a traditional and adaptive clinical trial design (Pallmann, 2018)
Traditionally clinical trials were often conducted as prescribed by the design. Once the trials are finished, the data are analyzed according to a pre-specified analysis plan. This design is straightforward but inflexible as it does not include any desirable changes during the trial. Adaptive designs have been described as a flexible alternative. Based on analyses of accumulating data, the adaptive designs allowed scheduled interim reviews of the data and pre-specified changes to the trial’s course. At the same time, the design also maintains the validity and integrity of the trial.
Pre-planned changes that an adaptive design may involve the sample size, doses, the allocation ratio of patients to trial arms, etc. The adaptive design also allows the identification of patients most likely to benefit and the focus of recruitment efforts on them. In addition, clinical trials can be stopped at an early stage if they are lack efficacy. For adaptive design, preserving integrity and validity is crucial. All the pre-planned changes are based on the results from interim data analyses. The data are repeatedly examined to ensure that they are analyzed correctly and in accordance with good clinical practice at every stage. The adaptive design also needs to ensure that test data and processes are not corrupted.
The flexibility is the biggest feature of adaptive design and it is a gateway to provide patients with more effective trials. In adaptive clinical trial design, recruitment to futile treatment arms may stop early and require fewer patients to ensure an equally high chance of getting the right answer. An underpowered trial may be prevented and fewer patients may be randomized to a less promising treatment or dose. The patient population most likely to benefit from treatment may be identified and treatment effects can be estimated more accurately. The adaptive design permits a better understanding of the dose-response or dose–toxicity relationship, which helps determine a safe and effective dose for clinical use. Meanwhile, Definitive conclusions may be drawn earlier so that the novel effective medicines can be made available more quickly to a larger group of patients who did not participate in the trial.
Although adaptive designs have obvious benefits in many cases, they are still far from established in practice. There are a variety of reasons including a lack of expertise or experience, concerns about the attitudes of funders and regulators, or more fundamentally practical challenges and restrictions on specific types of adaptive design. Another major reason why clinical investigators are seldom inclined to adaptive design is that they don't know when the adaptive design is applicable and what they can accomplish. The clinical investigators also don't know the practical implications of adaptive design and how to interpret and report the results of adaptive design. Although there are some practical obstacles in the way of a good adaptive design trial, clinical investigators are encouraged to use pre-planned opportunities to make design changes in clinical trials.
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