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.

Generics and substitution modalities: proposed methods for the evaluation of equivalence, traceability and pharmacovigilance reporting.

The use of generics results in savings for the budget of the health insurance, and no player of health could question seriously the principle. The generic drug of a reference medicinal product defines itself as a drug having the same qualitative and quantitative composition in active ingredients, the same dosage form and the bioequivalence with this reference medicinal product was demonstrated by appropriate studies of bioavailability. It is the right to switch granted to the pharmacists in 1999 that is at the origin of the real development of these specialties on the French pharmaceutical market. Nevertheless, about 10 years later, it seems that the system in place does not offer all the necessary securities with regard to pharmacovigilance, notably for the products with narrow therapeutic margin. By strengthening and/or by completing the role played by the health care professionals and the public institutions concerned, it is highly possible to improve the robustness of the system. Also, the recent arrival in Europe of the biosimilars, similar molecules but not bioequivalent to biological products, cause an even more tricky specific situation than that of the generics because of their nature, of the difficulty to manufacture them, and of the risk of immunogenicity. If the substitution is not permitted in several European countries including France, the other issues can appear especially in case of interchangeability requiring also, the reinforcement of certain measures.The various aspects are described in this article with concrete proposals on how the current system can be made safer, both for the generics and the biosimilars.

Risk management and monitoring methods for the future mother, embryo, fetus, and post-natal consequences.

Data required to asses the risk of a new drug regarding the normal course of pregnancy as well as embryo, fetal and neonate development, are often missing when a new product is launched. In such a situation, a risk management plan is to be developed by the industrial and validated by regulatory authorities. This risk management plan is to take into account the data benefits on the drug and its potential therapeutic use by women as being of childbearing age. The obtaining of post licence human data is to be built on many players, both private and public, involved in the data collection and evaluation. The setting up of such a network would allow them to join together and optimize their action by standardizing the data collected and their follow up. This should help to generate or rapidly respond to an alert, to conduct collaborative pharmacovigilance pharmacology studies.

Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study.

This prospective long-term cohort study investigated the incidence of malignancies in severe psoriasis patients treated with cyclosporine. A total of 1252 patients were followed prospectively for up to 5 y. Malignancies were recorded prospectively. Incidence rates for malignancies were compared with the general population using standardized incidence ratios. The effect of duration of exposure to cyclosporine and to previously administered anti-psoriatic treatments on the incidence of malignancies was investigated using Poisson regression models. The mean age of patients was 43 y and on average, patients received cyclosporine for 1.9 y. Malignancies were diagnosed in 47 patients (3.8%), 49% of them had skin malignancies. The standardized incidence ratio in the study cohort was 2.1 as compared with the general population. The higher incidence of malignancies was attributed to a 6-fold higher incidence of skin malignancies, most of which were squamous cell carcinoma. The incidence of nonskin malignancy overall was not significantly higher in this study than in the general population. Duration of exposure to cyclosporine, exposure to psoralen and ultraviolet A, exposure to methotrexate, and exposure to immunosuppressants showed a significant effect on the incidence of nonmelanoma skin malignancies. In conclusion, treatment of psoriasis with cyclosporine is associated with an increased risk of nonmelanoma skin cancer. Patients treated for more than 2 y with cyclosporine were shown to have a higher risk. In addition, exposure to psoralen and ultraviolet A and to other immunosuppressants was shown to contribute to the overall risk.