Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Telemedicine: what framework, what levels of proof, implementation rules.

The concept of telemedicine was formalised in France in the 2009 "Hospital, patients, health territories" (loi hôpital, patients, santé, territoire) law and the 2010 decree through which it was applied. Many experiments have been carried out and the regulatory institutions (Ministry, Regional Health Agency [Agence régionale de santé, ARS], French National Health Authority [Haute autorité de santé, HAS], etc.) have issued various guidance statements and recommendations on its organisation and on the expectations of its evaluation. With this background, the round table wanted to produce recommendations on different areas of medical telemonitoring (the role of telemonitoring, the regulatory system, the principles for assessment, methods of use and conditions for sustained and seamless deployment). Whilst many studies carried out on new medical telemonitoring approaches have led to the postulate that it offers benefit, both clinically and in terms of patient quality of life, more information is needed to demonstrate its impact on the organisation of healthcare and the associated medico-economic benefit (criteria, methods, resources). Similarly, contractual frameworks for deployment of telemonitoring do exist, although they are complicated and involve many different stakeholders (Director General fo the Care Offering [Direction générale de l'offre de soins, DGOS], ARS, HAS, Agency for Shared Health Information Systems [Agence des systèmes d'information partagés de santé, ASIP], French National Data Protection Commission [Commission nationale informatique et libertés, CNIL], French National Medical Council [Conseil national de l'Ordre des médecins, CNOM], etc.) that would benefit from a shared approach and seamless exchange between the partners involved. The current challenge is also to define the conditions required to validate a stable economic model in order to promote organisational change. One topical issue is placing the emphasis on its evaluation and operation. Access to patient data, particularly data from the health insurance funds and the use of these data, may enable the process to be more effective. In addition, the budgetary non-fungibility of the various financial envelopes for the different areas of work, restricts the consolidation of financial impact. Funding methods will need to be adapted to this new distribution of roles, both at the centre of the healthcare system and in the industrial ecosystem. All of these changes will help the leaders of our healthcare system to bring this new ambition closer to all of the people working in the health economy.

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.

[Attractiveness of France for international clinical trials in 2012: 6(th) survey assessed by Leem (French association of pharmaceutical companies)]. / État des lieux 2012 de l'attractivité de la France pour la recherche clinique internationale : 6(e) enquête du Leem.

Since 2002, the Leem (French Association of Pharmaceutical Companies) has conducted a survey every two years to update the attractiveness of France for international clinical trials. Thirty companies (68% of the French market) have participated in this 6(th) survey which involved 79 countries, a greater number of Phases I/II, II and III studies (420 versus 352 in 2010), a relatively stable number of included patients (246,895 versus 249,704 in 2010) and a greater number of centers (32,965 versus 24,337 in 2010). The evolution of time-lines for the go-ahead by French Authorities is heterogeneous (shorter time-lines by the French National Agency of Drug and Health Products Safety [ANSM] but longer time-lines by Research Ethics Comittees [CPP]). The time-lines for first hospital contracts remain stable. France ranks at an average position among European countries in regards to quantitative and qualitative data, and its state-of-art in early stages is still recognized. Its good performance in oncology and orphan diseases are major assets of competitiveness.

[France, an attractive country for international clinical research: 2010 survey assessed by Leem (French association of pharmaceutical companies)]. / Place de la France dans la recherche clinique internationale : enquête 2010 du Leem France et recherche clinique internationale.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey is performed every two years among pharmaceutical companies that are based in France or have affiliates in France. Twenty-nine companies (72% of the French market) including 10 newly participants, have participated in the current survey which included 328 international phase II and III clinical studies, 79 countries, 24,337 centres and 249,704 patients (included in 2008/2009). France (291 patients/million inhabitants) ranked among the best European recruiters in second position behind Scandinavia. Since 2008, protocols are still to be given the go-ahead by French Authorities (Afssaps and CPP) within 60 days, in accordance with European directive. The continuation of reduction in deadlines for hospital contracts is encouraging and highlights the positive effect of CeNGEPS. French state-of-art is well recognized in Oncology/Hematology and Orphan disease which could be an example to improve the competitiveness of France in other key therapeutic areas such as Alzheimer's disease and Immuno-Inflammation.

[France, an attractive country for international clinical research: 2008 survey assessed by Leem (French association of pharmaceutical companies)]. / La France, un pays attractif pour la recherche clinique internationale : enquête 2008 du Leem.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey is performed every two years among pharmaceutical companies that are based in France or have affiliates in France. Nineteen companies (61.9 % of the French market) have participated in the current survey which included 385 international phase II and III clinical studies, 77 countries, 29,708 centres and 312,835 patients (included in 2006/2007). France (400 patients/million inhabitants) ranked among the best European recruiters in second position behind Scandinavia. Since 2006, France has improved administrative processes and reduced deadlines for hospital contracts. Protocols are now to be given the go-ahead by French Authorities (Afssaps and CPP) within 60 days, in accordance with European directive. Its performance in early phases, oncology/hematology and vaccines/anti-infectious contribute to the attractiveness of France in international clinical research.

[State of unmet medical needs in France in 2006: necessity of reinforcing research effort]. / Besoins médicaux non couverts en France en 2006: l'effort de recherche doit être poursuivi.

Leem (French Pharmaceutical Companies) realized an inventory of unmet medical needs in 2006 in France for 12 pathologies. All of them are considered as national public health priorities by the law of August 9th, 2004. Allied to the epidemiological projections, analyses concerned various stages and/or pathology forms, impact of guidelines in clinical practice, therapeutic strategies, marketed therapeutics and pharmacological products in an advanced phase of clinical development. With more than 100 products listed in clinical phase III or pre-registration/marketed for those pathologies, French Pharmaceutical Companies contribute, quasi exclusively, to the development of innovative pharmaceutical products to answer unmet medical needs. This study illustrates the necessity of French Government to support therapeutic innovation led by Pharmaceutical Companies in France.

[The attractive position of France in international clinical research: 2006 survey assessed by Leem (French pharmaceutical companies)]. / La France est un pays attractif pour la recherche clinique internationale: enquête 2006 du Leem.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey is performed every two years among pharmaceutical companies that are based in France or have affiliates in France. Initiated in 2006, the current survey was much more representative than the previous ones with 20 companies accounting for 61% of the French market. This survey included 352 international phase II and III clinical studies carried out in 2004 and 2005, 74 countries, 17 345 centres and 137 989 patients. France has participated to half of the overall number of international clinical trials. France ranked among the best European recruiters (0,19 patient/1000 inhabitants) at the second position behind Scandinavian countries, taking in account numbers of inhabitants. Protocols are now to be given the go-ahead by Ethics Committee (CCPPRB) within 60 days. With a high productivity in phase IIb and in oncology, France is still an attractive place to locate clinical research.

[A survey on the position of France in international clinical research as assessed by pharmaceutical laboratories]. / Attractivité de la France pour la recherche clinique internationale: une etude du Leem dresse un constat peu favorable et suggère des voies d'amélioration.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey was performed among pharmaceutical companies that are based in France or that have affiliates in France. The survey concerned international phase II and III clinical studies carried out in 2002 and 2003. Ten pharmaceutical companies representing 36% of the French market completed the survey. 134 trials were analysed in total. France recruited 8.3% of the overall number of patients recruited, and 15.0% of those recruited within Europe. France was within the overall mean with regard to the percentage of active centres (78.5% versus 79.5%) and the percentage of patients evaluable according to protocol (86.8% versus 87.3%). In contrast, France ranked within the last third of analysed countries with respect to the speed of recruitment (1.5 versus 1.9 patients/centre/month), and the number of queries per observation (16.8 versus 10.9). The analysis of the qualitative indicators of performance showed that, although the perception of pharmaceutical companies towards the quality of French medicine and administrative authorities is positive, France notably needs to improve the productivity of its clinical research in order to enhance its attractiveness for the pharmaceutical sponsors of clinical trials.

[Attractiveness of France for clinical trials: evaluation of laboratories and promoters]. / Attractivité de la France pour les essais cliniques: évaluation par les laboratoires promoteurs.

Questions have been raised regarding the attractiveness of France versus other countries for performing clinical trials. A questionnaire was sent to pharmaceutical companies with offices in France to assess their level of activity and to get information on the pros and cons of performing phase I-IV international clinical trials in France. Eleven companies, of large to medium size and representing 44% of the shared market returned answers. In 2001, they spent 131 million euros on clinical trials--53% for phase I-III, with a staff of 1469 (not including Contact Research Organisations)--and involved 21,000 investigators recruiting 98,000 patients on local budgets, and 2257 investigators recruiting 10,270 patients on international budgets. France ranked well as regards size of market or resource availability, with an intermediate rank as regards costs, access to patients and disease prevalence, and was weak with regard to speed of recruitment and quality of investigators. Ways of improving France's attractiveness will be discussed.