BUSINESS OVERVIEW 6 Obtaining the pharmaceutical establishment license directly, U.S. Biological Products Development Process either as distributor “exploitant” or as manufacturer, requires The process required by the FDA before a biological product may the submission of a request file specific to each of the two be marketed in the United States generally involves the following: qualifications with the ANSM, and only granted after review and evaluation by the ANSM, usually after verification that the • completion of non-clinical laboratory tests and animal studies company has adequate premises, the necessary personnel and according to GLP, and applicable requirements for the humane an adapted structure with satisfactory procedures for carrying use of laboratory animals or other applicable regulations; out the proposed pharmaceutical activities, in particular • submission to the FDA of an application for an IND, which must pharmaceutical supply and pharmacovigilance. become effective before human clinical trials may begin; We currently entrust CMOs with the manufacturing and release • performance of adequate and well-controlled human clinical by a qualified person of clinical batches and intend to continue trials according to the FDA’s regulations, commonly referred relying on CMOs for the production of our commercial batches. to as GCPs, and any additional requirements for the protection of human research subjects and their health information, to Declarations of Financial Interests establish the safety and efficacy of the proposed biological Act No. 2011-2012 of December 29, 2011 aiming at strengthening product for its intended use; health safety of medicinal and health products, as amended (and • submission to the FDA of a BLA for marketing approval that its implementing decrees), introduced into French law some includes substantive evidence of safety, purity and potency provisions regarding transparency of fees received by some from results of non-clinical testing and clinical trials; healthcare professionals from industries. These provisions have • satisfactory completion of an FDA inspection of the been recently extended and redefined by Order No. 2017-49 of manufacturing facility or facilities where the biological product January 19, 2017. Act No. 2011-2012 also reinforced the French is produced to assess compliance with GMP, to assure that the anti-gift rules on which the changes made by Order No. 2017- facilities, methods and controls are adequate to preserve the 49 wil l enter into force after the publication of implementing biological product’s identity, strength, quality and purity and, measures, which is expected to occur by July 1, 2018. if applicable, the FDA’s current good tissue practices, or GTPs, Regulatory Framework in the United States for the use of human cellular and tissue products; In the United States, biological products, including gene therapy • potential FDA audit of the non-clinical and clinical trial sites that products and medical devices are subject to regulation under generated the data in support of the BLA; and the Federal Food, Drug, and Cosmetic Act, or FD&C Act, and • FDA review and approval, or licensure, of the BLA. the Public Health Service Act, or PHS Act, and other federal, state, local and other national statutes and regulations. Both the Where a gene therapy study is conducted at, or sponsored by, FD&C Act and the PHS Act and their corresponding regulations institutions receiving NIH funding for recombinant DNA research, govern, among other things, the testing, manufacturing, safety, prior to the submission of an IND application to the FDA, a efficacy, labeling, packaging, storage, record keeping, distribution, protocol and related documentation is submitted to and the study export and import, reporting, approval, advertising and other is registered with the NIH Office of Biotechnology Activities, promotional practices involving biological and medical device or OBA, pursuant to the NIH Guidelines for Research Involving products. Recombinant DNA Molecules, or NIH Guidelines. Compliance with the NIH Guidelines is mandatory for investigators at institutions FDA approval must be obtained before marketing of biological receiving NIH funds for research involving recombinant DNA; products. The process of obtaining regulatory approvals and however, many companies and other institutions not otherwise the subsequent compliance with appropriate federal, state, local subject to the NIH Guidelines voluntarily follow them. Institutions and national statutes and regulations require the expenditure of that receive NIH funding also are potentially subject to review by substantial time and financial resources, and regulatory approval the NIH Office of Biotechnology Activities’ RAC; the RAC will is not guaranteed. only publicly review clinical trials if the trials cannot be evaluated by standard oversight bodies and pose unusual risks. The FDA works closely with the NIH and its RAC, which makes recommendations to the NIH on gene therapy issues and engages The clinical trial sponsor must submit the results of the preclinical in a public discussion of scientific, safety, ethical and societal tests, together with manufacturing information, analytical data, issues related to proposed and ongoing gene therapy protocols. any available clinical data or literature and a proposed clinical The FDA and the NIH have published guidance documents with protocol, to the FDA as part of the IND. Some preclinical respect to the development and submission of gene therapy testing may continue even after the IND is submitted. The IND protocols. automatical ly becomes effective 30 days after receipt by the GENSIGHT BIOLOGICS – 2017 Registration Document– 89