BUSINESS OVERVIEW 6 preclinical testing stage. Preclinical tests, also referred to as No. 2001/20/EC of the European Parliament and of the Council non-clinical studies, include laboratory evaluations of product of April 4, 2001 relative to the implementation of good clinical chemistry, toxicity and formulation, as well as animal studies to practices in the conduct of clinical trials on medicinal products assess the potential safety and activity of the product candidate. for human use, or Clinical Trials Directive. Each country of the Preclinical tests must comply with the laws and regulations and European Union had to implement this Directive into national law other requirements, including GLP, in each jurisdiction in which by eventually adapting it to its own regulatory framework. they are conducted. The Clinical Trials Directive has been amended by Regulation (EU) Clinical trials involving human beings are typically conducted in No. 536/2014 of the European Parliament and of the Council of three sequential phases that may overlap or be combined: April 16, 2014 on clinical trials on medicinal products for human • Phase I. The biological product is initial ly introduced into use, adopted on April 16, 2014 and published in the Official healthy human subjects and tested for safety, dose tolerance, Journal of the European Union on May 27, 2014 (the “Clinical Trials absorption, metabolism, distribution and excretion. In the Regulation”). case of some products for severe or life-threatening diseases, The Clinical Trials Regulation entered into force on June 16, 2014 especial ly when the product may be too inherently toxic to and will take effect six months after the publication of the notice ethical ly administer to healthy volunteers, the initial human referred to in Article 82(3). To our knowledge, this notice has not testing is often conducted in patients. been published yet. Until the Clinical Trials Regulation comes • PhaseII. The biological product is evaluated in a limited patient into effect, all clinical trials performed in the European Union are population to identify possible adverse effects and safety risks, required to be conducted in accordance with the Clinical Trials to preliminarily evaluate the efficacy of the product for specific Directive. targeted diseases and to determine dosage tolerance, optimal European law establishes a system of prior authorization under dosage and dosing schedule. which the sponsor may not start a clinical trial until a specific ethics • Phase III. Clinical trials are undertaken to further evaluate committee has issued a favorable opinion and the competent dosage, clinical efficacy, potency and safety in an expanded authority of the relevant Member State has not informed the patient population at geographical ly dispersed clinical trial sponsor of any grounds for non-acceptance. The authorization sites. These clinical trials are intended to establish the overall and oversight of clinical trials remains the responsibility of each risk/benefit ratio of the product and provide an adequate basis Member State. for product labeling. Regulatory Authorization/Approval Required for the Conduct of a Clinical trials may, at times, be necessary after marketing in order Clinical Trial in France to explain certain side effects, explore a specific pharmacological In France, the Clinical Trials Directive has been notably effect, or obtain additional data that is more precise. A regulatory implemented by Act No. 2004-806 of August 9, 2004 relative authorization is required for the conduct of clinical trials. to the public health policy, as amended, and by Decree No. 2006- The regulatory authorities may block the protocols for clinical 477 of April 26, 2006, modifying the title of the French Public trials suggested by the companies that apply to test products, Health Code, or PHC, on research involving human beings, this suspend them, or require significant modifications in them. for al l categories of products concerned: medicinal products, Moreover, the patient must be kept informed of the objective, medical devices, biological products, ATMP, etc. the methodology, and the time period of the research, as wel l French Order No. 2016-800 of June 16, 2016 on research as of the anticipated benefits, constraints, and foreseeable risks involving human beings and Act No. 2012-300 of Mach 5, 2012r resulting from the administration of the products that are the (or “Loi Jardé”) related to biomedical research involving human object of the clinical trials. The information communicated is beings have recently adapted French law to the new provisions of summarized in a written document delivered to the patient prior Clinical Trials Regulation. France adopted several changes to the to any administration of products, and the latter must confirm his laws and regulations on clinical trials since then. or her agreement to participate in the clinical trial by signing an informed consent form. The main French provisions applicable to the conduct of clinical trials are the following: Government Regulation in the European Union • Decree No. 2017-884 of May 9, 2017 modifying some Regulatory Authorization/Approval Required for the Conduct of a regulatory provisions on research involving human beings; Clinical Trial in the EU • Order of May 3, 2017 establishing the list of researches Regarding medicinal products, requirements for the conduct of referred to in Article L.1121-1, 2°, of the French Public Health clinical trials are currently provided for in the European Directive Code; GENSIGHT BIOLOGICS – 2017 Registration Document– 85