Recently, the increasing risk of drug development has impelled pharmaceutical enterprises to improve ways of research and exploitation. Adaptive design has been proposed for decades. Although the theory of this design is not perfect, it has been recognized and applied worldwide as a decreasing risk of drug development to a certain extent. The traditional fixed design in western medicine isn’t entirely suitable for traditional Chinese medicine (TCM), while the adaptive design with integrity and variability features provides a new idea for TCM development. Hereby the application of adaptive design in TCM is regarded as an important procedure for promoting TCM modernization, and it has a wide prospective.
Due to the competition of new drug research and clinical requirement, speeding up drug development and marketing requires faster and more flexible clinical trial design that meets the ethical requirements. Different adaptive designs have emerged in clinical trials of different stages and purposes, for trial efficiency improvement. Adaptive design is more widely used in the field of oncology. Compared with traditional design, adaptive design is more complicated and requires higher level of methodology from researchers. Therefore, implementing adaptive design requires careful consideration and adequate preparation. This paper aims to summarize the design of adaptive methods used in different trial stages so as to provide reference for clinical research designers and implementers.
Randomization was the basis for the design and conduct of clinical trials. However, the traditional randomized controlled trials (RCTs) were often randomized in a fixed manner with unbalanced potential covariates, which spured researchers to develop a more flexible and practical randomization method. Thus, the adaptive randomization emerged as the time needed. In this paper, the application of adaptive randomization in clinical trials was introduced, and its key points of implementation, advantages and disadvantages were summarized. The development space of the adaptive randomization in clinical applications was also discussed, and it provided evidence for the development of the drug clinical trials in China.
Master protocol with adaptive design is a new complex innovative trial design that combines an adaptive treatment strategy and master protocol. It is more flexible and adjustable. In the complex clinical trial environment, the dynamics emphasized in this design are consistent with the idea of traditional Chinese medicine (TCM) syndrome differentiation and treatment. In this study, we summarized its concept, characteristics and advantages, and we also discussed its application in TCM clinical research. We hope this paper can provide more thinking and suggestions for TCM clinical trials.
The modern clinical research evaluation systems have increasingly emphasized the evaluation of individual patients' clinical characteristics, diagnosis and treatment plans, and complex intervention measures. Traditional randomized controlled trials evaluate fixed interventions and non-adaptive treatment plans, which cannot meet the needs of evaluating adaptive interventions. This has made researchers more inclined to explore an individualized and adaptive clinical trial design, and sequential multiple assignment randomized trial (SMART) has emerged as needed. This article introduces the principles, key elements, and implementation points of SMART design, further explores the limitations of the mismatch between traditional Chinese medicine clinical trial design and syndrome differentiation treatment, and proposes that SMART design can meet the needs of traditional Chinese medicine clinical trials to inspire researchers in designing their plans.
In recent years, investment in new drug development in China has surged; however, challenges such as difficulties in efficacy validation, high failure rates, and lengthy, costly clinical trials have been faced. The traditional model is insufficient for addressing these issues, necessitating innovation. Adaptive design (AD), particularly sequential multiple assignment randomized trials (SMART), has emerged as a flexible and efficient new pathway for drug development. This study focused on the two-stage design of SMART, analyzed its principles, and contrasted it with randomized controlled trials, group sequential designs, and crossover designs. The advantages of SMART are highlighted in terms of its precision in evaluating treatment strategies, minimizing sample waste, and enhancing the exploration of complex treatment pathways. Through case analyses, we demonstrated that SMART significantly improved clinical trial efficiency and the quality of treatment decisions, representing an innovative solution to the challenges of new drug development. This study aims to provide strategic references for clinical researchers and promote the adoption of adaptive designs in China, facilitating the efficient advancement of new drug development.
Sample size re-estimation (SSR) refers to the recalculation of the sample size using the existing trial data as original planned to ensure that the final statistical test achieved the pre-defined goals. SSR can enhance research efficiency, save trial costs, and accelerate the research process. Depending on whether the group assignment of the patients is known, SSR is divided into blinded sample size re-estimation and unblinded sample size re-estimation. Blinded sample size re-estimation can estimate the variance of the primary evaluation index through the EM algorithm or single sample variance re-estimation method, and then calculate the sample size. Unblinded sample size re-estimation can calculate the sample size by estimating the overall variance or therapeutic effect difference, but it needs to control the family wise type I error (FWER) rate. Cui-Hung-Wang method, conditional rejection probability method, P-value combination method, conditional error function, and promising zone are common methods used to control FWER. Currently, there are application examples of SSR methods. With the maturation of related theories and the popularization of methods, it is expected to be widely applied in clinical trials, especially in traditional Chinese medicine clinical trials in the future.