European regulators' views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials.

Development of novel therapies for Duchenne muscular dystrophy (DMD) are driving the need for more efficient ways of detecting changes in disease- progression in DMD [1]. However, medicines' approval must be based on outcome measures that are acceptable from a regulatory perspective. In this article, European regulators provide an update on the recent regulatory consideration of a new endpoint (Stride Velocity 95th Centile (SV95C)) that could be used in therapeutic DMD trials. This new endpoint aims to quantify a patient's ambulation directly, reliably and continuously in a home environment with a wearable device.

[Future Perspective of Pharmacoepidemiology in the "Big Data Era" and the Growth of Information Sources]. / Perspectiva futura de la farmacoepidemiología en la era del "Big data" y la expansión de las fuentes de información.

The arrival of new drug into the market requires many years of previous research along with the need of continuous evaluation throughout the lifetime of the drug. This warrants pharmacoepidemiological research which may be defined as the study of the use and the effects of drugs in large populations. Nowadays this type of research seems more feasible thanks to the massive expansion of the information sources and data (e.g: clinical patient registries, electronic medical records). However there is a risk of information overload, fragmented evidence and given the enthusiasm aroused by the "Big Data", it must be emphasized that its nature is mainly observational, and therefore subject to bias and confusion. The application of epidemiological methods in this scenario seems essential for any analysis. In short, the management and use of these data sources to generate useful information expansion is the next challenge for the application of research methods in modern pharmacoepidemiology.

[Clinical-Epidemiological Profile of Patients Initiating Intensive Statin Therapy for the Secondary Prevention of Vascular Disease in Spain]. / Perfil clínico-epidemiológico de pacientes que inician terapia intensiva con estatinas para la prevención secundaria de enfermedad vascular en España.

BACKGROUND: The new recommendations regarding the utilization of high potency statins (intensive therapy) for the treatment of cardiovascular disease have been based on the extrapolation of data coming from clinical trials. The objective is to describe the clinical-epidemiological profile of statin therapy users for the secondary prevention of cardiovascular disease in Spain and to examine the predictors for intensive therapy initiation. METHODS: Cross-sectional study from a sample of 88,751 patients aged ≥45 years-old with previous cardiovascular disease which initiated statin therapy between 1st January 2007 to 31st December 2011. Dose treatments >40 mg simvastatin daily (or equivalent dose if different statin) were considered intensive therapy treatment. Multivariable logistic regression models were built for dependent summary variables to examine the association between and the intensive therapy utilization (vs low-moderate intensity therapy). RESULTS: 16,857 adult patients receiving a first prescription of statin for the secondary prevention of cardiovascular diseases were identified. Predictors for intensive therapy initiation were year of statin prescription, male gender (adjusted OR: 1.70; 95% CI: 1.44-2.00), age >75 years-old (1.39; 1.15-1.69), previous history of coronary artery disease (1.71; 1.44-2.04), previous history of transient ischemic attack (1.24; 0,97-1.59), smoking (1.62; 1.34-1.95), hypertension (1.41; 1.20-1.65) and recent use of fibrates (2.32; 1.27-4.26). CONCLUSIONS: The onset of intensive therapy with statins in secondary was determined by the type of vascular event and age (>75 years-old in which the risk benefit balance could be controversial). No statistically significant differences were found according to the LDL-c levels.

The placebo arm in clinical studies for treatment of psychiatric disorders: a regulatory dilemma.

BACKGROUND: The use of placebo in clinical trials, and, related to this, ethical and feasibility aspects, are often debated. However, regulatory authorities must ensure that only new drugs with a positive benefit/risk would be granted a marketing authorization. It is therefore not surprising that they often put forward the need for placebo control in clinical trials in an area where many trials fail, and assay sensitivity is not self-evident. To illustrate the complexity that regulatory authorities encounter when faced with the registration dossier of products in the main psychiatric therapeutic areas, Major Depressive Disorder (MDD) and schizophrenia, the trial outcome for products receiving an opinion in the EU during the past 15 years were reviewed. DATA SOURCE: European Public Assessment Reports and registration files. RESULTS: A total of 45 studies qualified for analysis. For the indication MDD 38% of the studies (10/26) were recorded as failed, and another 15% (4/26) as negative. For schizophrenia, these figures were 16% (3/19) and 11% (2/19). Further exploration of the trials in MDD revealed an inconsistent pattern in terms of magnitude of placebo- and drug-mediated response (i.e. similar studies with consistent placebo response provided different treatment outcomes). CONCLUSION: From a regulatory perspective the dilemma of a priori exclusion of the placebo arm in clinical trials in the domains of depression or schizophrenia cannot be solved at this time as long as factors influencing trial variability are not better identified or understood. This counts in particular for MDD where the added drug effect is not consistent across trials with almost identical inclusion criteria. Unfortunately, this trend has not changed over the past 15 years. However, all efforts should be taken to optimize the clinical development of drugs in the psychiatric domain, and improve the intrinsic quality of the clinical trials in order to allow for a different viewpoint.

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

BACKGROUND: Thorough 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. METHODS: In 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. RESULTS: The 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. CONCLUSION: The 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.

Albuminuria as a surrogate marker for drug development: a European Regulatory perspective.

Clinical trials with surrogate end points generally require smaller sample sizes and shorter duration than those with clinical outcomes. However, in practice, surrogate end points are likely to result in less comprehensive conclusions than 'outcome' end points as they sometimes reflect only partial aspects of complex phenomena. A number of conditions help to establish the validity of a particular variable as predictive of clinical outcome. This article discusses to what extent albuminuria fulfills these requisites in two particular clinical scenarios: prevention of renal deterioration and prevention of cardiovascular disease.