Adaptive Methods: When and How Should They be Used in Clinical Trials?

Abstract

-Adaptive clinical trial designs are defined as designs that use data cumulated during trial to possibly modify certain aspects without compromising the validity and integrity of the said trial. Compared to more traditional trials, in theory, adaptive designs allow the same information to be generated but in a more efficient manner. The advantages and limits of this type of design together with the weight of the constraints, in particular of a logistic nature, that their use implies, differ depending on whether the trial is exploratory or confirmatory with a view to registration. One of the key elements ensuring trial integrity is the involvement of an independent committee to determine adaptations in terms of experimental design during the study. Adaptive methods for clinical trials are appealing and may be accepted by the relevant authorities. However, the constraints that they impose must be determined well in advance.

Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology

“…By the end of 2010, more than 850 positive opinions for orphan medicinal product designation had been adopted from the 1235 applications that have been reviewed since 2000 by the Committee for Orphan Medicinal Products (COMP) . Protocol assistance for orphan medicinal products is also a strong incentive because it provides an excellent opportunity by optimizing research and development, reducing uncertainties in regulatory outcomes and accelerating the time taken for the approval of a marketing authorization application.…”

“…As shown by Bashaw [2] and described in the next chapter, the French Medical Pharmacology has a large experience to use tools and principles able to enhance these data using translational analysis in the application of orphan drug designation and during the drug development programme. By the end of 2010, more than 850 positive opinions for orphan medicinal product designation had been adopted from the 1235 applications that have been reviewed since 2000 by the Committee for Orphan Medicinal Products (COMP) [13]. Protocol assistance for orphan medicinal products is also a strong incentive because it provides an excellent opportunity by optimizing research and development, reducing uncertainties in regulatory outcomes and accelerating the time taken for the approval of a marketing authorization application.…”

The Adaptive designs CONSORT Extension (ACE) Statement: A checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

“…Well designed and conducted AD trials allow researchers to address research questions more efficiently by allowing key aspects or assumptions of ongoing trials to be evaluated or validly stopping treatment arms or entire trials on the basis of available evidence [15,18,20,21]. As a result, patients may receive safe, effective treatments sooner than with fixed (non-adaptive) designs [19,[22][23][24][25]. Despite their potential benefits, there are practical challenges and obstacles to the use of ADs [18,[26][27][28][29][30][31][32][33].…”

“…The systematic tendency for the treatment effect estim from their 'true values' including the statistical properti rates) to deviate from what is expected in theory (e.g., nominal error rate) Operational bias Occurs when knowledge of key trial-related information changes to the conduct of that trial in a manner that bi conclusions made regarding the benefits and/or harms treatments Statistical bias Bias introduced to the study results or conclusions by t as a result of changes to aspects of the trial or multiple accumulating data from an ongoing trial Subpopulation(s) Subset(s) of the trial population that can be classified b characteristics of participants that are thought to be as treatment response (e.g., genetic markers or biomarke Adaptation outcome(s) Outcome(s) used to guide trial adaptation(s); they may from the primary outcome(s) Box 3 summarises some types of ADs and cites examples of their use in randomised trials. The motivations for these trial adaptations are well discussed [15,18,22,25,[34][35][36][37]. Notably, classification…”

“…Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome For each group, the numbers of participants who were randomly assigned, received intended treatment, and we analysed for the primary outcome and any other outcome used to inform pre-planned adaptations, if applicable Where the full statistical analysis plan and other relevant documents can be accessed Funding 25 Sources of funding and other support (such as supply of drugs), role of funders Note: 1 Hopewell et al 2008 [139,140]; 2 Ioannidis et al 2004 [141]; "X« Y" means original item Y has been renumbered to X; "X«" means item reordering resulted in new item X replacing the number of the original item X; "see expanded E&E text for clarification" means the wording of the item remains unchanged but we clarify additional considerations for ADs in the E&E text. Sample sizes for the proposed adaptive design.…”