Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

Outpatient healthcare and clinical trials in the care pathway: Organisational and regulatory aspects and tools.

Clinical research in outpatient healthcare, particularly in general practice, which is the first line of contact with the population, is now a public health issue. However, this type of research has specific characteristics that differentiate it from clinical research conducted in a hospital setting and requires an adaptation of its conditions of practice: in terms of organisation, the development of research in outpatient healthcare relies on the appropriation of its fundamentals by the investigators, which implies their presentation, upstream, from the initial cycle, and the participation of practitioners in training modules adapted to research in primary care, such as those already organised by several GIRCI (Groupement Inter régional de la Recherche Clinique et de l'Innovation [French Interregional Clusters for Clinical Research and Innovation]). To compensate for the fragmented nature of their location, on the model of the EMRCs (équipes mobiles de recherche clinique [mobile clinical research teams]) in oncology, mobile research teams should enable general medical practices to participate in clinical trials. This presupposes, on the one hand, the allocation of earmarked funding to ensure the sustainability of a base of dedicated personnel and, on the other hand, the impetus of a national dynamic through the setting up of a multi-organisation thematic institute for "research in primary care" associated, at the operational level, with a national scale investigation network supported by a platform of excellence. The use of digital tools and innovations (telemedicine; data collection via connected tools; e-consent; electronic signature) which make it possible to digitise and relocate all or part of the research procedures for both the participant and the investigation teams. An adaptation of the legal framework in order to bring the place of research closer to the patient and not the other way round, which means moving the equipment and investigations closer to the patient. Taking into account the acceptability of the patient, thus limiting the disruption that may be caused by his or her participation in a research protocol and motivating the practitioner by valuing his or her contribution and providing all the guarantees of scientific relevance and independence of practice. In view of the contextual analysis, positive feedback and the availability of organisational and digital support points facilitating the delocalisation and digitisation of the conduct of research activity as close as possible to the patient and his or her doctor, the round table concluded that opportunities exist today which favour the development of clinical research in general practice. It is important to seize this opportunity and make the most of it without delay.

[Organising an investigation site: a national training reference document]. / Organiser un site investigateur : un référentiel national de formation pédagogique.

OBJECTIVE: Several surveys have shown a declining performance of French investigators in conducting clinical trials. This is partly due to insufficient and heterogeneous investigator training and site organisation. A multidisciplinary group was set up to propose solutions. We describe the tools developed to improve study site organisation. RESULTS: This working group was made up of clinical research experts from academia, industry, drug regulatory authorities, general practice, and consulting. Methods and tools were developed to improve site organisation. CONCLUSIONS: The proposed tools mainly focus on increasing investigators' awareness of their responsibilities, their research environment, the importance of a thorough feasibility analysis, and the implementation of active patient recruitment strategies. These tools should be able to improve site organisation and performances in conducting clinical trials.

Clinical trials and E-health: impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research.

Within the last few years, new technology has come to play an important part in our professional and private daily environment. Healthcare has not escaped this progressive mutation with computers reaching the bedside. Clinical research has also shown growing interest in these new tools available to the clinical investigator, the patient, as well as to specialist departments for diagnosis and follow-up of patients, and to the different professions in clinical research. If the use of new technology seems to make life easier, by centralizing data or by simplifying data-sharing between different teams, it is still a matter of private data which must remain reliable, confidential and secure, whether it is being used in ordinary healthcare or in academic or industrial research. The aim of the round table was to estimate the impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research. First, an inventory was made of the development of these new technologies in the healthcare system. The second point developed was identification of expected benefits in order to issue guidelines for their good use and hazard warnings in clinical trials. Finally, the impact of these new technologies on the investigator as well as the project manager was analysed.

Collections of human biological samples for scientific purposes. Why do current regulation need to be clarified and how?

The collection of human biological samples is of major importance for future research in France and Europe. In recent years, new regulatory procedures have been designed to monitor these activities; but they are somewhat complex and some clarifications are needed. The law needs also to be amended. The definition of biobanking activities should be clarified, and regulatory procedures, including consultation of the Ethics Committee, declarations to the Ministry of Research and the protection of personal data, should be simplified. It is also of great importance to correctly define the modalities in which Biobanks are granted their authorisations. The role of Ethics Committees regarding the evaluation of information and the consent procedures should also be clarified, particularly when samples from children are used, or when the samples are used for genetic analyses. As well as scientific and public health aspects, the storage of human biological samples may also have important economic consequences. It is hence crucial to adapt the procedure for submitting patents, particularly when several public or private partners are working together. The possible changes to both French and European laws planned in the next months would be an ideal time to introduce these changes.

Good clinical practice in developing countries: applying recommendations.

The recommendations for clinical research in developing countries were published in 2007 and the present article deals with issues which were not initially raised or discussed in depth. In particular, we discuss specific questions linked to trials conducted in developing countries with regard to informed consent, research project review by two ethics committees, standards of care, management of biological samples, study follow-up committees, notification of Serious Adverse Events, paediatric trials, and Contract Research Organizations.

Integrity of scientific data: transparency of clinical trial data.

The integrity of the data from clinical trials and of its use is an essential element of the scientific method, and of the trust one can have in this method. There are many examples of fraud, and they recur regularly. The objective of this round table was to work on the definition of fraud, on its recognition and prevention especially in the institutional system. Fraud involves an active decision to cheat, and ranges from trying to hide incompetence to wholesale invention of data, patients or studies. Its frequency is difficult to evaluate but might be as high as 1% of all studies or publications. Fraud can involve ethics (post-hoc IRB [institutional review board] approval, IRB requests not applied, lack of consent), or any of the steps from realisation to interpretation of studies or trials. Identification of fraud is made harder by the usual risk for the whistle-blowers, who must be protected. Seeking fraud is implicit in Good Clinical Practices (GCP) that all industry sponsors must apply, but that are less often applied by institutional sponsors. It might be useful to install procedures to detect fraud in studies, especially institutional. Various statistical methods can be used to identify unusual data patterns that could suggest fraud. Once fraud is identified, its management is often not foreseen. Here again, clear procedures or recommendations would be of help.

Integrity of Scientific Data: Transparency of Clinical Trial Data.

The integrity of the data from clinical trials and of its use is an essential element of the scientific method, and of the trust one can have in this method. There are many examples of fraud, and they recur regularly. The objective of this round table was to work on the definition of fraud, on its recognition and prevention especially in the institutional system. Fraud involves an active decision to cheat, and ranges from trying to hide incompetence to wholesale invention of data, patients or studies. Its frequency is difficult to evaluate but might be as high as 1% of all studies or publications. Fraud can involve ethics (post-hoc IRB [institutional review board] approval, IRB requests not applied, lack of consent), or any of the steps from realisation to interpretation of studies or trials. Identification of fraud is made harder by the usual risk for the whistleblowers, who must be protected. Seeking fraud is implicit in Good Clinical Practices (GCP) that all industry sponsors must apply, but that are less often applied by institutional sponsors. It might be useful to install procedures to detect fraud in studies, especially institutional. Various statistical methods can be used to identify unusual data patterns that could suggest fraud. Once fraud is identified, its management is often not foreseen. Here again, clear procedures or recommendations would be of help.

Adaptation of the application of good clinical practice depending on the features of specific research projects.

The conduct of clinical trials falls within a strict regulatory framework. The objective of the round table was to develop reasonable recommendations for the implementation of GCP according to the type of research and taking in account the risks and challenges related to this research. Two types of risks have been identified: those related to the characteristics of the research and those related to the impact of the study results. The group designed an evaluation table of these risks. The round table focused its investigations on 3 main themes: monitoring, the investigational medicinal product and undesirable effects. Three methods of monitoring adaptation were analysed in terms of advantages and disadvantages: the gradual approach, the central monitoring, monitoring on the basis of sampling. Examination of the investigational medicinal product focused on the medicinal product circuit. The group recommends using the following 'basic' decision-making tree, which takes three elements into account: 1) is it an investigational medicinal product?, 2) do the trial objectives and design require packaging specific to the research?, 3) is the risk of use higher than that in standard practice? Finally, adaptation of the implementation of GCP in terms of pharmacovigilance appeared very limited and could possibly be considered for the medicinal product, the subject of the research, which already holds a marketing authorisation, and for which the safety profile is well known; in this case, only simplified collection of non-serious adverse events may be envisaged, which may be implemented by designing and using a standard collection listing. The adaptation of the implementation of GCP is possible. This firstly takes into account the characteristics of the research: which objectives/which risks/which challenges. The options in terms of adaptation must be pre-defined, documented and justified; if necessary, they will also be re-assessed in the course of analysis.