Considerations on what constitutes a 'qualified statistician' in regulatory guidelines.

International regulatory guidelines require that a 'qualified statistician' takes responsibility for the statistical aspects of a clinical trial used for drug licensing. No consensus on what constitutes a 'qualified statistician' appears to have been developed so far. The International Society for Clinical Biostatistics is issuing this reflection paper in order to stimulate a discussion on the concept.

Regulatory advice and drug development--a case study in negotiating with regulators.

Regulatory guidance on the development of drugs has existed for well over half a century in some territories. As drug development grew to become global so was born the need for harmonization. Beginning in the 1990 s, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) developed guidelines which were adopted by the Food and Drug Administration (FDA) in the U.S.A., the European Medicines Agency (EMA) in the European Union and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. These guidelines are generally not disease specific. A visit to the web sites of any of the aforementioned Agencies or, for that matter other regulatory agencies outside of these, will witness a plethora of additional/separate guidances, some of which are disease specific. In addition to such written guidances, more specific advice (for example, on a drug development program at the end of Phase II) may be requested from the Regulator. Despite the harmonization efforts expressed through ICH, the actual advice given by different regulatory authorities in practical situations, however, may be inconsistent. This paper will describe a case of seeking advice on a Phase III programme from the FDA and the EMA, obtaining different opinions and developing an innovative solution to satisfy both Authorities without necessarily extending development time significantly. The case is chronic kidney disease; the issues concern study design (non-inferiority, margin, etc.); the solution required a non-traditional design and associated sample size considerations. We conclude with some general advice on 'talking to the regulator'. This work was originally presented as a Poster at the Statistical Methods in Biopharmacy, 6th International Meeting, Paris, 21-22 September 2009.

Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry-sponsored clinical trials.

In this paper we set out what we consider to be a set of best practices for statisticians in the reporting of pharmaceutical industry-sponsored clinical trials. We make eight recommendations covering: author responsibilities and recognition; publication timing; conflicts of interest; freedom to act; full author access to data; trial registration and independent review. These recommendations are made in the context of the prominent role played by statisticians in the design, conduct, analysis and reporting of pharmaceutical sponsored trials and the perception of the reporting of these trials in the wider community.

Making available information from studies sponsored by the pharmaceutical industry: some current practices.

Since the web-based registry ClinicalTrials.gov was launched on 29 February 2000, the pharmaceutical industry has made available an increasing amount of information about the clinical trials that it sponsors. The process has been spurred on by a number of factors including a wish by the industry to provide greater transparency regarding clinical trial data; and has been both aided and complicated by the number of institutions that have a legitimate interest in guiding and defining what should be made available. This article reviews the history of this process of making information about clinical trials publicly available. It provides a reader's guide to the study registries and the databases of results; and looks at some indicators of consistency in the posting of study information.

The potential for bias in reporting of industry-sponsored clinical trials.

Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell. In 2005 an Editorial in Journal of the American Medical Association made clear that, so great was their concern about misleading reporting of industry-sponsored studies, henceforth no article would be published that was not also guaranteed by independent statistical analysis. We examine the precursors to this Editorial, as well as its immediate and lasting effects for statisticians, for the manner in which statistical analysis is carried out, and for the industry more generally.

A randomized controlled trial to compare steroid with cyclosporine for the topical treatment of oral lichen planus.

OBJECTIVE: To compare the effectiveness of cyclosporine solution versus triamcinolone acetonide in orabase in the treatment of oral lichen planus (OLP) in reducing signs and symptoms. STUDY DESIGN: One hundred thirty-nine biopsy-proven OLP patients were randomly assigned to cyclosporine (68) or steroid (71) applied onto the target lesion and affected areas. Assessments were at weeks 0, 2, 4, 8 by clinical scoring and grid measurement of the target lesion (reticulation, erythema, ulceration). Patients ranked severity of pain and burning sensation using visual analog scales. RESULTS: Although clinical response, pain, burning sensation, area of reticulation, erythema, and ulceration at week 4 were all worse in patients receiving cyclosporine than in those receiving steroid, the differences were not statistically significant. Large patient-to-patient variability was evident over the observation period, with little evidence of marked changes in levels over time in both treatment groups. CONCLUSION: Topical cyclosporine appears no more effective than steroid in the treatment of oral lichen planus.

Cardiac arrest and resuscitation epidemiology in Singapore (CARE I study).

OBJECTIVES: To describe the epidemiology of out-of-hospital cardiac arrest (OHCA) in Singapore, the emergency medical services (EMS) response, and to identify possible areas for improvement. METHODS: This prospective observational study constitutes phase I of the Cardiac Arrest and Resuscitation Epidemiology (CARE) project. Included were all patients with nontraumatic OHCA conveyed by the national emergency ambulance service. Patient characteristics, cardiac arrest circumstances, EMS response, and outcomes were recorded according to the Utstein style. RESULTS: From October 1, 2001, to April 30, 2002, 548 patients were enrolled into the study. Mean (standard deviation [SD]) age was 62.2 (17.9) years, with a male predominance (65.6%). A total of 59.8% of collapses occurred at home, 35.3% of arrests were not witnessed, and bystander cardiopulmonary resuscitation was present for 20.6%. Mean (SD) time from collapse to call received by EMS was 10.6 (13.1) minutes. Mean (SD) EMS response time was 10.2 (4.3) minutes. Mean (SD) time from call to defibrillation was 16.7 (7.2) minutes. Mean (SD) on-scene time was 9.9 (4.5) minutes. First presenting rhythm at the scene was asystole in 54.5%, pulseless electrical activity 22.9%, ventricular fibrillation 19.6%, and ventricular tachycardia 0.4%. Of all cardiac arrests, 351 had resuscitation attempted and were of cardiac origin. Among these patients, 17.9% had return of spontaneous circulation, 8.5% survived to hospital admission, and 2.0% survived to discharge. CONCLUSION: CARE I establishes the baseline for the evaluation of incremental introduction of prehospital Advanced Cardiac Life Support interventions planned for future phases. Continuing efforts should be made to strengthen all chains of survival. This represents the most comprehensive OHCA study yet conducted in Singapore.