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Background: Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures., Methods: We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples., Results: Over a range of 5½ years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias., Conclusions: For the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP.

Purpose: To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time., Methods and Materials: A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey., Results: Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments., Conclusion: An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey was performed among pharmaceutical companies that are based in France or that have affiliates in France. The survey concerned international phase II and III clinical studies carried out in 2002 and 2003. Ten pharmaceutical companies representing 36% of the French market completed the survey. 134 trials were analysed in total. France recruited 8.3% of the overall number of patients recruited, and 15.0% of those recruited within Europe. France was within the overall mean with regard to the percentage of active centres (78.5% versus 79.5%) and the percentage of patients evaluable according to protocol (86.8% versus 87.3%). In contrast, France ranked within the last third of analysed countries with respect to the speed of recruitment (1.5 versus 1.9 patients/centre/month), and the number of queries per observation (16.8 versus 10.9). The analysis of the qualitative indicators of performance showed that, although the perception of pharmaceutical companies towards the quality of French medicine and administrative authorities is positive, France notably needs to improve the productivity of its clinical research in order to enhance its attractiveness for the pharmaceutical sponsors of clinical trials.

This paper concerns the statistical work carried out with respect to clinical trials conducted for regulatory purposes. Although the general quality of such work has improved markedly over recent years and is now generally high, a number of shortcomings remain. A few of these arise from failure to follow well established statistical practice. Rather more arise from a poor understanding of areas of known statistical disagreement and from the unsatisfactory use of newer and more advanced techniques. Inadequacies in reporting statistical work are commonplace. Examples of all these shortcomings are provided and emphasis is placed on the value of a statistical contribution to overall summaries such as the clinical expert report.