ABSTRACT
Adaptive designs are increasingly used in clinical trials. The Drug Information Association's Adaptive Design Scientific Working Group (ADSWG) works to foster collaboration among regulatory agencies, academia, and pharmaceutical and biotech companies to further the science of adaptive clinical development. The ADSWG Survey Subteam has collected data on the usage of adaptive designs in clinical research from multiple sources, including a recent ADSWG survey regarding the perception and usage of adaptive designs in academia and industry for studies between 2008 and 2011, as well as barriers to usage; a literature review examining publications of adaptive design methodology and usage between 2000 and 2011; and a trial registry review of adaptive design references from 1996 to 2011. The comprehensive results of the ADSWG 2012 survey are provided in this article with comparisons to our previous 2008 survey, the literature and registry reviews, and recent surveys carried out by the US Food and Drug Administration (FDA) and the European Medicines Agency. Results of the ADSWG 2012 survey illustrate that industry and academia are showing more enthusiasm for adaptive trials, accompanied by an increase in the number of trials using designs described as less well understood in the FDA draft guidance on adaptive designs, published in 2010. The increased use of these methods in exploratory trials is consistent with the FDA draft guidance. The survey also identified several examples of successful marketing applications supported by confirmatory trials utilizing adaptive designs that were considered, at least at the time of the draft guidance, as less well understood. While some of the technological barriers to adaptive design usage identified in the 2008 survey are now less common, there are several important persistent barriers to usage. Organizations can help overcome these barriers through education, preplanning, and early engagement in discussions with the regulators.
ABSTRACT
In this paper, the authors express their views on a range of topics related to data monitoring committees (DMCs) for adaptive trials that have emerged recently. The topics pertain to DMC roles and responsibilities, membership, training, and communication. DMCs have been monitoring trials using the group sequential design (GSD) for over 30 years. While decisions may be more complicated with novel adaptive designs, the fundamental roles and responsibilities of a DMC will remain the same, namely, to protect patient safety and ensure the scientific integrity of the trial. It will be the DMC's responsibility to recommend changes to the trial within the scope of a prespecified adaptation plan or decision criteria and not to otherwise recommend changes to the study design except for serious safety-related concerns. Nevertheless, compared with traditional data monitoring, some additional considerations are necessary when convening DMCs for novel adaptive designs. They include the need to identify DMC members who are familiar with adaptive design and to consider possible sponsor involvement in unique situations. The need for additional expertise in DMC members has prompted some researchers to propose alternative DMC models or alternative governance model. These various options and authors' views on them are expressed in this article.
ABSTRACT
AIMS: Patients with atrial fibrillation (AF) consider the related symptoms disruptive to their quality of life (QoL). This study aimed to evaluate the impact of the control of symptomatic paroxysmal AF (PAF) on QoL. METHODS AND RESULTS: Patients with symptomatic PAF were treated for 48 weeks with open-label flecainide acetate controlled release (Flec CR). Quality of life was assessed by SF-36 and Atrial Fibrillation Severity Scale scores at baseline, Week 12 (W12), W24, and W48. Of the 229 treated patients, 217 were analysed for QoL (123 with controlled and 94 with uncontrolled symptomatic PAF at inclusion). The controlled group had a similar or better QoL (SF-36) at baseline compared with a reference population (significantly better for: physical functioning, bodily pain, and physical component). The uncontrolled group had an inferior QoL (significantly worse for: role physical, general health, vitality, role emotional, social functioning, mental health, and mental component). When treated with Flec CR, the controlled group baseline QoL scores were maintained and the uncontrolled group scores were improved to a level comparable to the controlled group scores. Safety findings reflect the known clinical safety profile of flecainide acetate. CONCLUSION: In this study, patients with uncontrolled symptomatic PAF at baseline had an inferior QoL to those with controlled symptomatic PAF. Following treatment with controlled-release flecainide acetate, their QoL improved to a level comparable to controlled patients.
