French Jardé's law and European regulation on drug trials: Harmonization and implementation of new rules.

Jardé's law, concerning research studies in humans, was enacted in March 2012 but did not come into force until November 2016. This delay is largely explained by the adoption of a European regulation on clinical trials on medicinal products that will probably not be applicable until October 2018. In addition to covering the respective areas of the French and European legislation, the round table provided an opportunity to discuss the principal measures that will apply to future research, particularly those concerning the operational procedures of the ethics committees and the national committee for research in humans, as well as measures relating to the management of serious adverse effects, more specifically in phase I studies in subjects not presenting with any disorder. This round table also enabled the formulation of recommendations to better anticipate the practical difficulties that the regulatory changes might engender. Finally, we highlight the numerous challenges in terms of training that these important regulatory changes impose and the absolute necessity to best adapt the restrictions to those that are planned in numerous other European countries so that France remains competitive in terms of clinical research and so that French patients may continue to benefit rapidly from the most innovative treatments.

The European "clinical trial" regulation; relationship with the Jardé Act: a Giens workshop.

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency.

Fever control using external cooling in septic shock: a randomized controlled trial.

RATIONALE: Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. OBJECTIVES: To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. METHODS: In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. MEASUREMENTS AND MAIN RESULTS: Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). CONCLUSIONS: In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.

How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed?

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription.

Prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome.

OBJECTIVE: Right-to-left shunting across a patent foramen ovale may occur in acute respiratory distress syndrome as a result of pulmonary hypertension and positive-pressure mechanical ventilation. The shunt may worsen the hypoxemia. The objective of our study was to determine the prevalence, clinical implications, and prognosis of patent foramen ovale shunting during acute respiratory distress syndrome. DESIGN: Prospective study. SETTING: Medical intensive care unit of a university hospital in Créteil, France. PATIENTS: Two hundred three consecutive patients with acute respiratory distress syndrome. INTERVENTIONS: Patent foramen ovale shunting was detected by using transesophageal echocardiography with modified gelatin contrast. Moderate-to-large shunting was defined as right-to-left passage of at least 10 bubbles through a valve-like structure within three cardiac cycles after complete opacification of the right atrium. In 85 patients without and 31 with shunting, the influence of the positive end-expiratory pressure level on shunting was studied. MEASUREMENTS AND RESULTS: The prevalence of moderate-to-large patent foramen ovale shunting was 19.2% (39 patients). Compared to those in the group without shunting, the patients in group with shunting had larger right ventricle dimensions, higher pulmonary artery systolic pressure, and a higher prevalence of cor pulmonale. Compared to patients without shunting, patients with shunting had a poorer Pa(O(2))/Fi(O(2)) ratio response to positive end-expiratory pressure, more often required prone positioning and nitric oxide as adjunctive interventions, and had fewer ventilator-free and intensive care unit-free days within the first 28 days. CONCLUSIONS: Moderate-to-large patent foramen ovale shunting occurred in 19.2% of patients with acute respiratory distress syndrome, in keeping with findings from autopsy studies. Patent foramen ovale was associated with a poor oxygenation response to positive end-expiratory pressure, greater use of adjunctive interventions, and a longer intensive care unit stay.

[The Jardé law: What does change]. / La loi Jardé : ce qui change.

The Jardé law has been voted in 2012 but was only enforced in November 2016, after the publication of its decree. Introduction of non-interventional researches in the scope of the "researches involving human beings" and random allocation of ethics committees are the main novelties of the new law. Global consent, which authorizes future researches on existing data without informing the study participant, has also been introduced. Submission of collections of biological samples and genetic studies on existing samples have been simplified. CNIL has revised the rules of data protection ("Reference Methodologies").

Informed consent for and regulation of critical care research.

PURPOSE OF REVIEW: Critical care is a special area in which research needs to take place, because of the severity of the diseases which are treated there, but it is also a place where research faces a lot of hurdles and difficulties. The main cause of difficulties is the consent issue, as most patients cannot consent for themselves. Recently, all national legislations in the countries of the European Union have been modified to include the provisions of directive 2001/20. RECENT FINDINGS: This review article provides a summary of the recent literature concerning the issue of consent for clinical care research such as how the surrogate consent reflects the view of the patient and how time consuming and inaccurate can be the consultation of a community before the start of a trial with a waiver of consent. Another hurdle to research is the rigidity of our legislations concerning clinical research, especially the absence of a simplified way for low or no-risk research. This article shows how this situation is potentially deleterious and how it could ultimately forbid low-risk research. SUMMARY: Critical research remains a domain in which research on patients is difficult and controversial. Regulation can be difficult to implement, largely inadequate or uselessly complicated. Intensive care physicians need to keep pressure on politicians and lawmakers to constantly explain the necessity and specificities of critical care research.

Non-interventional research and usual care: definition, regulatory aspects, difficulties and recommendations.

Non-interventional research is an essential approach to gathering data in different situations and it often complements other research methodologies, such as biomedical research and research aimed at evaluating usual care. Yet the legislative framework for this type of research is nonexistent, and this void poses a number of problems for non-interventional researchers, including an absence of any guarantee of quality and therefore of reliability, a limited recognition of the research beyond our borders, cumbersome administrative procedures, and a lack of visibility. In light of the growing demand for data, particularly in post marketing authorisation for drugs, which largely relies on non-interventional methods, the Round Table participants have issued a set of proposals for a future legislative framework for this type of research.

[Research on "usual" care: new French legislation]. / La recherche portant sur les soins courants: une nouvelle catégorie de recherche clinique autorisée par la loi.

Research on standard or usual care is defined by the law to cover assessments of standard care, except for drug treatments but including medical devices. It involves research about basic health care that uses standard procedures and products. Authorization by the relevant authority (DGS or Afssaps) is not required; the only application is made to a new Comité de protection des personnes. This committee is more closely related than in the past to the institutional review boards and ethics committees required for international publications. Committee approval is required to begin the study. Patients must be informed. Their consent is not mandatory, but they may object to participating in the study.

[New legislation about clinical research involving "usual care": reminder of recent problems]. / Nouvelle législation portant sur les soins courants: rappel des difficultés passées.

OBJECTIVE: The regulatory framework of clinical research in France was recently modified substantially, in part to transpose into French law directive 2001/20/EC of the European Parliament and Council, which concerns only drug trials. The revision also covered research on "human beings" (Public Health L. 2004-806, 2006-450), on biological samples (revision of bioethics, L. 2004-800) and on data (the so-called CNIL act, L. 2004-801). The value of this set of texts (statutes, decrees, and regulations) is that it diversifies and clarifies the different forms of clinical research. METHODS: This article describes the painful progression of important public health studies, most often with "academic" sponsors. RESULTS: The 5 studies described here managed to overcome a variety of obstacles posed by the pre-2004 regulations. COMMENTS: To understand the new provisions, it is useful to recall the difficulties, imprecision and inaptness of the earlier regulations.

Ethics and research in critical care.

BACKGROUND: The past few years have witnessed several controversies regarding the ethics of conducting research involving critically ill patients, and such research is ethically challenging. DISCUSSION: Research ethics is a changing field, one that is influenced by empirical data, contemporary events, and new ideas regarding aspects of clinical trial design and protection of human subjects. We describe recent thoughts regarding several aspects of research ethics in the critical care context. CONCLUSION: The ability of the research community to conduct research ethically and to maintain public trust would benefit from heightened awareness to the principles and requirements that govern such research.

Effects of vertical positioning on gas exchange and lung volumes in acute respiratory distress syndrome.

OBJECTIVE: Supine position may contribute to the loss of aerated lung volume in patients with acute respiratory distress syndrome (ARDS). We hypothesized that verticalization increases lung volume and improves gas exchange by reducing the pressure surrounding lung bases. DESIGN AND SETTING: Prospective observational physiological study in a medical ICU. SUBJECTS AND INTERVENTION: In 16 patients with ARDS we measured arterial blood gases, pressure-volume curves of the respiratory system recorded from positive-end expiratory pressure (PEEP), and changes in lung volume in supine and vertical positions (trunk elevated at 45 degrees and legs down at 45 degrees ). MEASUREMENTS AND RESULTS: Vertical positioning increased PaO(2) significantly from 94+/-33 to 142+/-49 mmHg, with an increase higher than 40% in 11 responders. The volume at 20 cmH(2)O measured on the PV curve from PEEP increased using the vertical position only in responders (233+/-146 vs. -8+/-9 1ml in nonresponders); this change was correlated to oxygenation change (rho=0.55). End-expiratory lung volume variation from supine to vertical and 1 h later back to supine, measured in 12 patients showed a significant increase during the 1-h upright period in responders (n=7) but not in nonresponders (n=5; 215+/-220 vs. 10+/-22 ml), suggesting a time-dependent recruitment. CONCLUSIONS: Vertical positioning is a simple technique that may improve oxygenation and lung recruitment in ARDS patients.

B-type natriuretic peptide and weaning from mechanical ventilation.

OBJECTIVE: Cardiac function and volume status could play a critical role in the setting of weaning failure. B-type natriuretic peptide (BNP) is a powerful marker of cardiac dysfunction. We assessed the value of BNP during the weaning process. DESIGN, SETTING AND PATIENTS: One hundred and two consecutive patients considered ready to undergo a 1-h weaning trial (T-piece or low-pressure support level) were prospectively included in a medical intensive care unit of a university hospital. Weaning was considered successful if the patient passed the trial and sustained spontaneous breathing for more than 48 h after extubation. INTERVENTIONS: Plasma BNP was measured just before the trial in all patients, and at the end of the trial in the first 60 patients. RESULTS: Overall, 42 patients (41.2%) failed the weaning process (37 patients failed the trial and 5 failed extubation). Logistic regression analysis identified high BNP level before the trial and the product of airway pressure and breathing frequency during ventilation as independent risk factors for weaning failure. BNP values were not different at the end of the trial. In nine of the patients in whom the weaning process failed, it succeeded on a later occasion after diuretic therapy. Their BNP level before weaning decreased between the two attempts (517 vs 226 pg/ml, p=0.01). In survivors, BNP level was significantly correlated to weaning duration (rho=0.52, p<0.01). CONCLUSIONS: Baseline plasma BNP level before the first weaning attempt is higher in patients with subsequent weaning failure and correlates to weaning duration.

[The mission of the Committee for Personal Protection (CPP) in France: neither ethical, nor scientific?]. / La mission des Comités de protection des personnes en France: ni éthique, ni scientifique?

In France, research on human beings was first organized (and legally authorized) in 1988 by a law (so called Huriet-Séruclat). Since then, the specific mission of research ethics committees (RECs) has been heavily disputed. The legislator explained that the role of RECs is neither ethic nor scientific. It is << to control that the research protocol has been drafted according to the law >>. Of course, this is clearly at odds with the common practice of RECs in France and abroad as well. The assessment of the benefit/risk balance and of the << pertinence >> of the protocol cannot be achieved without a clear understanding of its scientific rationale. Origin of this French << cultural exception >> is to be found in the historic context of the elaboration of the law, back in the mid Eighties.