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Regulatory Guidance Documents on Adaptive Designs: An Industry Perspective
Abstract
Adaptive designs have the potential to be a transformative methodology in clinical drug development, but acceptance by regulatory agencies is a prerequisite for their broader adoption and success, especially in the context of confirmatory studies. Both FDA and EMA have published guidance documents focusing on adaptive designs, which have been neither discouraging nor clearly supportive of the approach in their assessments and recommendations. As a result, the interpretation of the regulatory position on adaptive designs also has been mixed, with some citing the guidance documents as evidence that health authorities do not accept adaptive designs, while others mentioning the same documents as indication that regulators support their use in drug development, when properly planned, conducted, and analyzed. This chapter reviews and discusses the two main regulatory documents on adaptive designs issued by the time this book was published: the reflection paper by EMA (Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan (draft CHMP/EWP/2459/02, 23-Mar-2006), 2007) and the draft guidance by FDA (Adaptive design clinical trials for drug and biologics draft guidance, 2010). Reactions from the biopharmaceutical industry to both documents, collated by industry trade groups, are also presented and discussed.
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In clinical studies that address dose-finding objectives, the use of trial designs that allow adaptations based upon accruing unblinded data have much potential to introduce added efficiency and to improve the decision making process, compared to traditional designs. In this paper we consider the processes by which such adaptations may be made. Conventions for interim data monitoring and decision making, particularly with regard to restricting access to data, have largely evolved based upon the needs in Phase III nonadaptive studies; as such, they may not be an ideal fit for adaptive dose-ranging studies, because of the different natures of the trials, their placement in the drug development process, and the objectives of the monitoring. In this paper, we specifically discuss what processes for interim monitoring, analysis, decision making and implementation, might be advantageous and appropriate for adaptive dose-ranging studies, and then illustrate how processes were implemented and carried out in a particular case study.
Poor dose-regimen selection remains a key cause of the high attrition rate of investigational drugs in confirmatory trials, being directly related to the escalating costs of drug development. This article is a follow-up to the first white paper put forward by the PhRMA Working Group (WG) on Adaptive Dose-Ranging Studies (Bornkamp et al. 2007). It presents results and conclusions from a new round of simulation-based evaluations conducted by the WG, proposing a new set of recommendations to improve the accuracy and efficiency of dose-finding in clinical drug development.
A PhRMA Working Group on adaptive clinical trial designs has been formed to investigate and facilitate opportunities for wider acceptance and usage of adaptive designs and related methodologies. A White Paper summarizing the findings of the group is in preparation; this article is an Executive Summary for that full White Paper, and summarizes the findings and recommendations of the group. Logistic, operational, procedural, and statistical challenges associated with adaptive designs are addressed. Three particular areas where it is felt that adaptive designs can be utilized beneficially are discussed: dose finding, seamless Phase II/III trials designs, and sample size reestimation.
Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.
Pharmaceutical Research and Manufacturers of America (PhRMA) has formed a Working Group on Adaptive Designs. The group aims to contribute to a constructive dialogue on adaptive designs by engaging statisticians, clinicians, and other stakeholders in academia, regulatory agencies, and industry. Hopefully this will facilitate broader consideration and implementation of these designs. The papers that follow in this issue comprise the Full White Paper of the group and summarize its findings and recommendations from its first year of activity.
The purpose of this study was to assess the impact of phase II dose-selection strategies on the likelihood of success of phase III clinical programs, comparing both traditional and adaptive approaches. We evaluated the impact of the phase II approach to dose selection (including traditional, design-adaptive, and analysis-adaptive approaches), the sample size used in phase II, the number of doses studied in phase II, and the number of doses selected to advance into phase III on the probability of demonstrating efficacy, of demonstrating a lack of toxicity, of phase III trial success, and on the probability of overall success of the combined phase II/phase III programs. The expected net present value was used to quantify the financial implications of different strategies. We found that adaptive dose allocation approaches (in particular, the Bayesian general adaptive dose allocation method) usually outperformed other fixed dose allocation approaches with respect to both probability of success and dose selection. Design-adaptive approaches were more efficient than analysis-adaptive approaches. The allocation of additional resources into phase II improved the probability of success in phase III and the expected net present value. Bringing two doses forward into phase III testing also increased the probability of success and improved the expected net present value. The overall probability of success in phase III ranged from 35% to 65%, consistent with recent industry experience. This success rate could likely be improved with additional investment in phase II, the use of design-adaptive dose-finding designs when possible, increasing the power of phase III trials, more explicit consideration of toxicity concerns, and better dose selection.
Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan (draft CHMP
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