A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines.

OBJECTIVES: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe. STUDY DESIGN AND SETTING: This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no." RESULTS: Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials. CONCLUSIONS: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.

Estudios postautorización de tipo observacional en España: impacto de la regulación del año 2002 / Studies postauthorization of type observacional in Spain: impact of the regulation of the year 2002

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The effect of the European Clinical Trials Directive on published drug research in anaesthesia.

The clinical indications for anaesthetic drugs are developed through peer-reviewed publication of clinical trials. We performed a bibliometric analysis of all human research papers reported in nine general anaesthesia journals over 6 years (n = 6489), to determine any effects of the 2004 European Clinical Trials Directive on reported drug research in anaesthesia originating from Europe and the United Kingdom. We found 89% studies involved patients and 11% volunteers. Of 3234 (50%) drug studies, 96% were phase IV (post-marketing) trials. Worldwide, the number of research papers fell by 3.6% (p < 0.004) in the 3 years following introduction of the European Clinical Trials Directive (5% Europe, 18% United Kingdom), and drug research papers fell by 12% (p < 0.001; 15% Europe, 29% United Kingdom). The introduction of the Clinical Trials Directive has therefore coincided with a decline in European drug research, particularly that originating from the United Kingdom. We suggest a number of measures researchers could take in response, and we propose a simplification of the application process for phase IV clinical trials, emphasising patient risk assessment.

Data from regulatory studies: What do they tell? What don't they tell?

Phase III studies of antiepileptic drugs (AEDs) are specifically designed to satisfy strict regulatory criteria. As they are conducted in protocol-restricted patient populations over short treatment periods and employ fixed study designs and dosing schedules, they are not fully representative of 'real-life' clinical practice. Therefore, in order to provide an overall assessment of clinical performance, regulatory studies must be backed up by post-marketing clinical experience. Phase IV studies provide information on a drug's performance in a setting more closely representing real clinical practice, with broader patient populations and a more flexible approach to individual treatment. Prospective long-term studies allow the determination of efficacy and safety (and cost-effectiveness) over extended treatment periods; these studies and audit data provide a means of assessing idiosyncratic side effects, unusual interactions and the effects of an AED in rare patient groups. By complementing regulatory evidence with real-life clinical experience, a comprehensive assessment of the risks and benefits of an AED can be made.

[The GCP directive--consequences for clinical drug research]. / GCP-direktivet--konsekvenser for klinisk laegemiddelforskning.

The contents and implications of the EU Directive on good clinical (research) practice (GCP) regarding drug trials are described. As of May 2003, clinical researchers in Denmark must have standard operation procedures, conduct monitoring, consider quality assurance, and expect inspections. The industry may be better prepared, but the Directive makes GCP part of the law and phase IV studies become subject to GCP. Patients will be assured the same quality in trials irrespective of the industry or investigator being the sponsor and may look forward to quality improvement of drug trials.

Guidelines for the implementation of drug utilization observation (DUO) studies in psychopharmacological therapy. The "Phase IV Research" Task-Force of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP).

The task-force on Phase-IV-Research of the Association for Neuropharmacology and Pharmacopsychiatry (AGNP) has developed guidelines for the implementation of scientifically sound drug utilisation observation studies (DUO studies). These guidelines have been adopted by the executive committee as the position of the association. DUO studies are prospective pharmacoepidemiological studies, by which prescription, illness, and patient data of individual patients are collected without interference with the routine course of treatment. They can answer questions on the interaction of treatment modalities with positive and negative treatment outcome. Scientific standards require that there is a study protocol which describes the epidemiological, statistical, procedural, and quality assurance methodology and states who is responsible for what. As such studies can violate data protection regulations or can be used for sales instead of scientific purposes, consultation of an ethics committee is recommended.

[Methodological analysis of phase IV clinical trials performed in hospital based on the Huriet Law ]. / Analyse méthodologique des essais cliniques de phase IV entrepris à l'hôpital après la loi Huriet.

Since the implementation of the 'Huriet law', drugs in phase IV clinical trials are handled by the pharmaceutical Department of the 'Hôpital Neuro-Cardiologique' (Lyon, France). The methodology of these trials is assessed by using a special assessment grid which enables a score for each protocol, with a maximal score of 20 and a minimal one of minus 20. Although many limitations could be advanced, results of this study show that, among 39 assessed trials, 13 trials had weak methodology (score < or = 0), 16 are middle-quality trials (score between 0 and 10) whereas 10 trials only can be considered as having a strong methodology (score > 10). So, a fairly large number of the organized phase IV trials have debatable quality. Moreover, their objective is questionable, that is essentially promotional, in spite of the 'Huriet law' and Persons Protection Committees.