Practical characteristics of adaptive design in phase 2 and 3 clinical trials

摘要

Summary What is known and objective Adaptive design methods are expected to be ethical, reflect real medical practice, increase the likelihood of research and development success and reduce the allocation of patients into ineffective treatment groups by the early termination of clinical trials. However, the comprehensive details regarding which types of clinical trials will include adaptive designs remain unclear. We examined the practical characteristics of adaptive design used in clinical trials. Methods We conducted a literature search of adaptive design clinical trials published from 2012 to 2015 using PubMed, EMBASE , and the Cochrane Central Register of Controlled Trials, with common search terms related to adaptive design. We systematically assessed the types and characteristics of adaptive designs and disease areas employed in the adaptive design trials. Results and discussion Our survey identified 245 adaptive design clinical trials. The number of trials by the publication year increased from 2012 to 2013 and did not greatly change afterwards. The most frequently used adaptive design was group sequential design (n?=?222, 90.6%), especially for neoplasm or cardiovascular disease trials. Among the other types of adaptive design, adaptive dose/treatment group selection (n?=?21, 8.6%) and adaptive sample‐size adjustment (n?=?19, 7.8%) were frequently used. The adaptive randomization (n?=?8, 3.3%) and adaptive seamless design (n?=?6, 2.4%) were less frequent. Adaptive dose/treatment group selection and adaptive sample‐size adjustment were frequently used (up to 23%) in “certain infectious and parasitic diseases,” “diseases of nervous system,” and “mental and behavioural disorders” in comparison with “neoplasms” (6.6%). For “mental and behavioural disorders,” adaptive randomization was used in two trials of eight trials in total (25%). Group sequential design and adaptive sample‐size adjustment were used frequently in phase 3 trials or in trials where study phase was not specified, whereas the other types of adaptive designs were used more in phase 2 trials. Approximately 82% (202 of 245 trials) resulted in early termination at the interim analysis. Among the 202 trials, 132 (54% of 245 trials) had fewer randomized patients than initially planned. This result supports the motive to use adaptive design to make study durations shorter and include a smaller number of subjects. What is new and conclusion We found that adaptive designs have been applied to clinical trials in various therapeutic areas and interventions. The applications were frequently reported in neoplasm or cardiovascular clinical trials. The adaptive dose/treatment group selection and sample‐size adjustment are increasingly common, and these adaptations generally follow the Food and Drug Administration's ( FDA 's) recommendations.