Abstract
In recent years, the use of adaptive design methods in pharmaceutical/clinical research and development has become popular due to its flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation. The flexibility and efficiency, however, increase the risk of operational biases with resulting decrease in the accuracy and reliability for assessing the treatment effect of the test treatment under investigation. In its recent draft guidance, the United States Food and Drug Administration (FDA) expresses regulatory concern of controlling the overall type I error rate at a pre-specified level of significance for a clinical trial utilizing adaptive design. The FDA classifies adaptive designs into categories of well-understood and less well-understood designs. For those less well-understood adaptive designs such as adaptive dose finding designs and two-stage phase I/II (or phase II/III) seamless adaptive designs, statistical methods are not well established and hence should be used with caution. In practice, misuse of adaptive design methods in clinical trials is a concern to both clinical scientists and regulatory agencies. It is suggested that the escalating momentum for the use of adaptive design methods in clinical trials be slowed in order to allow time for development of appropriate statistical methodologies.
Highlights
In pharmaceutical/clinical research and development, clinical trials are conducted for evaluation of safety and efficacy of a test treatment under investigation
Concluding Remarks In clinical trials, the flexibility of modifying study parameters is very attractive to clinical scientists, several scientific questions/concerns arise
What level of modifications to the trial procedures and/or statistical procedures would be acceptable to the regulatory authorities? Second, what are the regulatory requirements and standards for the review and approval process of clinical data obtained from adaptive clinical trials with different levels of modifications to trial procedures and/or statistical procedures of on-going clinical trials? Third, has the clinical trial become a totally different trial after the modification of the trial procedures and/or statistical procedures for addressing the study objectives of the originally planned clinical trial? These concerns should be addressed by the regulatory authorities before the adaptive design methods can be widely accepted in clinical research and development
Summary
In pharmaceutical/clinical research and development, clinical trials are conducted for evaluation of safety and efficacy of a test treatment under investigation. For design selection of the proposed dose escalation trial, a clinical trial simulation was conducted under the assumptions that (1) the total simulation runs is 5,000, (2) the initial dose is 0.3 mCi/kg, (3) the dose range is from 0.3 mCi/kg to 2.8 mCi/kg assuming that the MTD is at 2.5 mCi/kg with a total number of dose levels of 6, (4) algorithm-based 3+3 TER with and without de-escalation are considered, (5) maximum dose de-escalation allowed is 1, (6) CRM(n) with n = 1, 2, and 3 are considered, where n is the number of subjects per dose level, (7) logistic dose-toxicity model is assumed, (8) DLT rate at MTD is assumed to be 1/3 = 33%, (9) Bayesian approach with uniform prior is considered for estimation of the parameters of the dose-toxicity model, (10) number of doses allowed to skip is 0. The proposed two-stage seamless adaptive design is briefly outline below: Stage 1: This stage is a five-arm
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