France's competitiveness in global pharmaceutical research: The situation is improving.

AIMS: The French pharmaceutical companies' association (LEEM) biennially carries out a study on the attractiveness of France in pharmaceutical clinical research. This study aims to measure France's global competitiveness for international clinical trials (CT) and assess its strengths and areas of excellence. METHODS: A descriptive and comparative analysis was conducted using the data from both the ClinicalTrials.gov registry for the 2015-2019 period and those reported in a national web-based database (OSCAR) involving the major pharmaceutical companies operating in France in 2018-2019. OSCAR allows to describe the administrative authorization and starting process for all drug trials conducted in France. RESULTS: Among 8607 worldwide drug trials initiated in 2019, 34.3% (n=2.954) were funded exclusively by pharmaceutical companies (52.1% in France). On average, France was involved in 10.5% of all global industrial CTs launched over 2018-2019, still ranking in the 4th position among European countries. Early-phase trials represented 17.3% of trials conducted by the drug companies in France, versus 25% in Germany and 29% in United Kingdom. Oncology remains an area of excellence in France with 18.7% of all worldwide CTs conducted in this therapeutic area over the study period involving at least some French centres, ranking France 2nd among European countries. The median of total deadline before the first patient inclusion of 204 days in 2018-2019 with no marked improvement as compared to 2016-2017 period. However, the delay getting initial trial authorization was slightly reduced and an overall deadline of 167 days was observed for CTs entered the pilot phase initiated recently by the European regulation. CONCLUSION: After ten difficult years, areas of excellence, such as oncology and rare diseases and more recently, the outstanding mobilization for the COVID-19 research, have enabled France to maintain its pharmaceutical research. Furthermore, a set of additional decisions would strengthen this position in the next years.

Clinical added value of drugs: An empirical survey of French transparency committee opinions.

OBJECTIVES: To identify criteria used by French health authorities to assess the clinical added value (ASMR) of drugs seeking reimbursement. METHODS: We conducted a systematic review of the opinions of the transparency committee (TC) of the French national authority for health (HAS) between March, 2014 and October, 2016 in ten therapeutic areas. TC opinions content was coded and analysed using descriptive statistics and logistic models. RESULTS: The database comprised 160 opinion texts, which included ASMR assessments using a 5 level scale (1=highest ASMR 5=no ASMR). Main elements that were linked with ASMR 1,2,3,4 as compared to ASMR 5 were appraisal of the medical need, population size (<5000 patients), and clinical relevance of the evaluated results. The factors associated with ASMR 4 as compared to ASMR 1-3 were the safety profile and clinical relevance of the results. However, the factors associated with ASMR level varied according to the therapeutic area considered. CONCLUSIONS: The assessment of the drug ASMR conducted by the French transparency commission of the HAS appears to be at least in part determined by criteria (medical need, population size) which reflect the burden of the disease but not reflect the ASMR of the medicine assessed. Other criteria used for the assessment of ASMR are not clearly defined and depend on the therapeutic domain. The lack of sufficient clarity and consistency in assessment of ASMR complicate the decision making process for drug development. Moreover, this situation can be a barrier for a harmonized process of ASMR assessment at European level.

[Attractiveness of France for international clinical research: 8th survey conducted by Leem (French association for pharmaceutical companies)]. / Attractivité de la France pour la recherche clinique internationale : résultats de la 8e enquête du Leem.

The Leem (French association of pharmaceutical companies) has conducted the eighth survey on attractiveness of France for clinical research. It serves to measure France's global competitiveness for international clinical trials and assess its strengths and areas of excellence. It also highlights the potential for progress and emerging trends at a time when the regulatory environment in France and Europe is undergoing change. This survey has been updated every two years since 2002 using the same methodology. It assesses the current status of research undertaken in France by the pharmaceutical industry between January 1st 2014 and December 31st 2015. Thirty companies (62% of the French market) have participated in this 8th survey which involved 3474 centers (versus 2860 in 2014) and 16,622 patients (versus 14,634 in 2014) enrolled in France across 586 clinical trials (versus 613 in 2014). This survey shows a reduction in the number of phase I and phase II trials. It also confirms that the studies conducted in France are primarily concerned with oncology (45%). Despite improvements across hospital contracts times (due to the adoption of the sole agreement) and performance indicators in trials (such as the number of patients enrolled by center), trial setup times in France are still overly lengthy (with stable times by French authorities). Ensuring that clinical research remains a priority issue for country is crucial for patients because of rapid access to innovation but also for the vitality of the French economy. Constructive dialogue with stakeholders on the subject of clinical research is essential to enhance the attractiveness of France and to improve the continuum between research, innovation and care.

What strategy should France implement for H2020?

The initiation of Horizon 2020--the European Union's 8th Framework Programme for Research and Innovation, allotted a budget of 79 billion euros--provides an opportunity to review France's participation in previous Framework Programmes. Indeed, French participation does not match either its scientific importance or its financial investment. While France contributed 16.5 to 17% of the EU's 7th Framework Programme research budget, its return through the funding of coordinated projects in which French teams are participating stands at around 12.5 to 13%, a shortfall of 600 million euros. Although the situation depends on the type of activity, French participation in clinical research appears to be smaller than that of its neighbours, with fewer responses to European calls for proposals. While France has many assets, which include the assured funding of clinical research, structured thematic networks and the initiation of major national programmes, it suffers from the dilution of resources due to France's regional development policy, the lack of multidisciplinarity and the ignorance of both the medical and scientific community and the institutions to which they belong as to how Horizon 2020 actually works. We propose three types of strategy to encourage proposals for coordinated clinical research projects or projects involving French teams, and to help in the drawing up of applications: Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. Recognise the value of European actions to influence the European landscape and change mentalities. Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application. • Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. • Recognise the value of European actions to influence the European landscape and change mentalities. • Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application.

Medico-economic evaluation of health products in the context of the Social Security Financing Act for 2012.

The participants in round table 6 of the Giens Workshops 2012 drafted recommendations based on the collective interpretation of important elements of the decree concerning the medico-economic evaluation of health products published a few days earlier (02 October 2012). The medico-economic evaluation (MEE), becomes an additional determinant for fixing the prices of health products by the Health products economic committee (Comité économique des produits de santé, CEPS) via the hierarchisation of treatment strategies, and thus modifies the market access conditions. Limiting the analysis to medicinal products and medical devices for which a major, important or moderate improvement in the medical service rendered (ASMR) or of the expected service (ASA) has been requested and presenting a significant budget impact on the Social Security expenses, excludes health products with ASMR or ASA with a lower level requested which often create complex price fixing problems and often have a major budget impact. This latter concept remains to be defined in detail. The MEE envisaged for the first registration must include the need to confirm or refute the initial hypotheses especially concerning the actual position in the therapeutic strategy at the time of renewal of the registration. For the first registration, the conventional reference to European prices guaranteeing a minimum price to innovative medicinal products, the medico-economic models submitted by the industry to the French Drug Authority (Haute autorité de santé, HAS) must be used to guide the compilation of new data to be requested at the time of the registration renewal and to negotiate the level of the discounts in the framework of a price-volume agreement, if applicable. The MEE will allow comparing the result of the analysis to the model hypothesis at the time of the renewal of the registration, which may contribute to the renegotiation (either up or down) of the price of health goods. The costs related to obtaining new data must be controlled. In order for the MEE to allow confirming the relationship between the price requested and the benefit expected, the group privileges the definition of reference values with an indicative and non-normative value, likely to evolve with time rather than a threshold. Concerning the evaluation procedure: the time to market access must not be lengthened; while the possibility of regular meetings between the industry and the HAS is recommended to avoid methodological divergences. A transitory period should allow the implementation of the entire evaluation procedure which must also take into account the specificities of health products registered before the 3 October 2013.

[Not Available]. / La mise en place des cohortes en France : pourquoi, pour qui, comment et avec quels moyens ?

A cohort is a group of individuals sharing some characteristics, followed longitudinally. Essential tools of epidemiology, these studies provide pieces of evidence of the relationship between an exposition and outcomes in order to guide public health policies. In France, many cohorts have been conducted over the past few years. Sometimes, initiated by independent research teams (e.g. E3N) but more often, either requested by health authorities in a global public health plan (e.g. MEMENTO in the Alzheimer plan) or conducted to investigate a safety issue (e.g. France Coag). Besides, post authorization studies often consist in prospective cohorts. Because of objectives, designs and governance arrangements diversity; participants questioned whether it was interesting for researchers, regulators and industrials to use this epidemiological tool. Some findings about difficulties met in cohorts' establishment have been shared by each other. In order to make cohorts more efficient, participants have made some recommendations.

[Not Available]. / La mise en place des cohortes en France : pourquoi, pour qui, comment et avec quels moyens ?

A cohort is a group of individuals sharing some characteristics, followed longitudinally. Essential tools of epidemiology, these studies provide pieces of evidence of the relationship between an exposition and outcomes in order to guide public health policies. In France, many cohorts have been conducted over the past few years. Sometimes, initiated by independent research teams (e.g. E3N) but more often, either requested by health authorities in a global public health plan (e.g. MEMENTO in the Alzheimer plan) or conducted to investigate a safety issue (e.g. France Coag). Besides, post authorization studies often consist in prospective cohorts. Because of objectives, designs and governance arrangements diversity; participants questioned whether it was interesting for researchers, regulators and industrials to use this epidemiological tool. Some findings about difficulties met in cohorts' establishment have been shared by each other. In order to make cohorts more efficient, participants have made some recommendations.

[How to optimize the carrying out and the development of post-registration studies]. / Optimiser la réalisation et l'utilisation des études post-inscription.

Studies conducted in real clinical practice on drug prescription, drug use and consequences on patients and on the organizational scheme of treatments establish the basis of the evaluation of commercialized drugs when seeking renewal of their insurance coverage, anticipated reevaluation or safety issues. Time has come now for pharmaceutical companies to write a critical report on the operating procedures identifying the issues of the various operation phases (i.e.: conception, study conduct, use and interpretation of results). The report put forth various optimization axes through 17 concrete measures. Those measures concern several domains including the communication with Health Authorities, the necessity of specific methodological recommendations, a better involvement of partners, the improvement of the access to health databases, a better understanding of budget constraints, and more transparency in the evaluation process as well as in the interpretation of results.