Steffen Thirstrup

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN)

BackgroundThorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states.MethodsIn order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey.ResultsThe ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising.ConclusionThe list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.

Opening the white boxes: the licensing documentation of efficacy and safety of psychotropic medicines for children.

The objective of the present study was to explore the available evidence in a regulatory agency on the safety and efficacy of two types of psychotropic medicine frequently prescribed to children and adolescents.

General Practitioners' and Hospital Physicians' Preference for Morphine or Oxycodone as First‐Time Choice for a Strong Opioid: A National Register–Based Study

The aim of this study was to characterize first‐time oxycodone and morphine prescriptions in outpatients by type of prescriber and naivety in regard to strong opioids. All prescriptions for morphine and oxycodone in Denmark reported to the National Register of Medicinal Product Statistics in 2010 were analysed. If a patient had not had a prescription filled for the same drug within the last 2 years, the prescription was defined as a first‐time prescription. Patients who had not received a prescription for strong opioids for 6 months prior to the date of redemption were classified as strong opioid naive. The odds ratio (OR) was calculated to investigate whether general practitioners (GPs) and hospital physicians had similar preferences for oxycodone over morphine for strong opioid–naive patients. We included 69,110 first‐time prescriptions, of which 59,316 (86%) were for strong opioid–naive patients. Opioid‐naive patients received 79% of the first‐time prescriptions for morphine and 91% of the prescriptions for oxycodone. Hospital physicians had a greater preference for oxycodone over morphine than GPs (OR 1.34, 95% CI 1.29–1.39). However, GPs were responsible for approximately 61% of all first‐time prescriptions for both oxycodone and morphine for strong opioid–naive patients. In conclusion, oxycodone is to a great extent prescribed as the first‐choice strong opioid, and both GPs and hospital physicians seem to contribute to this prescribing pattern of strong opioids to outpatients.

A comprehensive approach to benefit-risk assessment in drug development.

Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit–risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data‐driven benefit–risk assessment method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval phase. The proposed benefit–risk assessment method involves eight successive steps: (1) establishment of the decision context, (2) identification of benefit and risk criteria, (3) weighting, (4) scoring, (5) evaluation of uncertainty, (6) calculation of weighted scores, (7) visualization, and (8) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit–risk evaluation approach offers comprehensive, data‐driven assessments that can facilitate decision processes. It employs descriptive statistical methods to highlight the clinically significant differences between drugs in clinical trials. The approach can be used in single as well as in multiple trials and provides clear diagrams as the basis for presentation and discussion of the results.

Data‐Driven Assessment of the Association of Polymorphisms in 5‐Fluorouracil Metabolism Genes with Outcome in Adjuvant Treatment of Colorectal Cancer

A major challenge in the assessment of medicines, treatment options, etc., is to establish a framework for the comparison of risks and benefits of many different types and magnitudes, a framework that at the same time allows a clear distinction between the roles played by the statistical analyses of data and by judgements based on personal experience and expertise. The purpose of this study was to demonstrate how clinical data can be weighted, scored and presented by the use of an eight‐step data‐driven benefit–risk assessment method, where two genetic profiles are compared. Our aim was to present a comprehensive approach that is simple to apply, allows direct comparison of different types of risks and benefits, quantifies the clinical relevance of data and is tailored for the comparison of different options. We analysed a cohort of 302 patients with colorectal cancer treated with 5‐Fluorouracil (5‐FU). Endpoints were cure rate, survival rate, time‐to‐death (TTD), time‐to‐relapse (TTR) and main adverse drug reactions. Multifactor dimensionality reduction (MDR) was used to identify genetic interaction profiles associated with outcome. We have been able to demonstrate that a specific MDR‐derived combination (the MDR‐1 group) of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms is associated with increased and clinically significant difference for cure and survival rates, TTD and probably also for TTR, which are seen as the most important endpoints. An inferior profile was observed for severe myocardial ischaemia. A probably inferior profile was seen for severe arthralgia/myalgia and severe infections. A clear superior profile was seen for severe mucositis/stomatitis. The proposed approach offers comprehensive, data‐driven assessment that can facilitate decision processes, for example, in a clinical setting. It employs descriptive statistical methods to highlight the clinically relevant differences between options.