BUSINESS OVERVIEW 6 biological products, the PHS Act emphasizes the importance of potent, or effective, for its intended use, and has an acceptable manufacturing control for products whose attributes cannot be purity profile, and whether the product is being manufactured precisely defined. The manufacturing process must be capable of in accordance with GMP to assure and preserve the product’s consistently producing quality batches of the product candidate identity, safety, strength, quality, potency and purity. The FDA and, among other things, the sponsor must develop methods for may refer applications for novel biological products or biological testing the identity, strength, quality, potency and purity of the products that present difficult questions of safety or efficacy to final biological product. Additionally, appropriate packaging must an advisory committee, typically a panel that includes clinicians be selected and tested and stability studies must be conducted and other experts, for review, evaluation and a recommendation to demonstrate that the biological product candidate does not as to whether the application should be approved and under what undergo unacceptable deterioration over its shelf life. conditions. The FDA is not bound by the recommendations of U.S. Biological Product Review and Approval Processes an advisory committee, but it considers such recommendations carefully when making decisions. During the biological product After the completion of clinical trials of a biological product, FDA approval process, the FDA also will determine whether a REMS approval of a BLA must be obtained before commercial marketing is necessary to assure the safe use of the biological product. If of the biological product. The BLA must include results of product the FDA concludes REMS is needed, the sponsor of the BLA development, laboratory and animal studies, human studies, must submit proposed REMS; the FDA will not approve the BLA information on the manufacture and composition of the product, without REMS, if required. proposed labeling and other relevant information. In addition, under the Pediatric Research Equity Act, or PREA, a BLA or Before approving a BLA, the FDA wil l inspect the facilities at supplement to a BLA must contain data to assess the safety and which the product is manufactured. The FDA will not approve the effectiveness of the biological product for the claimed indications product unless it determines that the manufacturing processes in al l relevant pediatric subpopulations and to support dosing and facilities are in compliance with GMP requirements and and administration for each pediatric subpopulation for which adequate to assure consistent production of the product within the product is safe and effective. The FDA may grant deferrals required specifications. For a gene therapy product, the FDA for submission of data or full or partial waivers. Unless otherwise also wil l not approve the product if the manufacturer is not in required by regulation, PREA does not apply to any biological compliance with the GTPs. The GTPs are FDA regulations that product for an indication for which orphan designation has been govern the methods used in, and the facilities and controls used granted. The testing and approval processes require substantial for, the manufacture of human cel ls, tissues, and cel lular and time and effort and there can be no assurance that the FDA will tissue based products, or HCT/Ps, which are human cells or tissue accept the BLA for filing and, even if filed, that any approval will be intended for implantation, transplant, infusion, or transfer into a granted on a timely basis, if at all. human recipient. The primary intent of the GTP requirements is Under the Prescription Drug User Fee Act, or PDUFA, as to ensure that cell and tissue based products are manufactured amended, each BLA must be accompanied by a user fee. The in a manner designed to prevent the introduction, transmission FDA adjusts the PDUFA user fees on an annual basis. PDUFA and spread of communicable disease. FDA regulations also also imposes an annual program fee on prescription biologics. require tissue establishments to register and list their HCT/Ps Fee waivers or reductions are available in certain circumstances, with the FDA and, when applicable, to evaluate donors through including a waiver of the application fee for the first application screening and testing. Additionally, before approving a BLA, the filed by a small business. Additionally, no user fees are assessed FDA will typically inspect one or more clinical sites to assure that on BLAs for products designated as orphan drugs, unless the the clinical trials were conducted in compliance with IND study product also includes a non-orphan indication. requirements and GCP requirements. To assure cGMP, GTP and GCP compliance, an applicant must incur significant expenditure Within 60 days fol lowing submission of the application, the of time, money and effort in the areas of training, record keeping, FDA reviews a BLA submitted to determine if it is substantially production and quality control. complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly Notwithstanding the submission of relevant data and information, reviewable at the time of submission and may request additional the FDA may ultimately decide that the BLA does not satisfy its information. In this event, the BLA must be resubmitted with the regulatory criteria for approval and deny approval. Data obtained additional information. The resubmitted application also is subject from clinical trials are not always conclusive and the FDA may to review before the FDA accepts it for filing. Once the submission interpret data differently than we interpret the same data. If the is accepted for filing, the FDA begins an in-depth substantive agency decides not to approve the BLA in its present form, the review of the BLA. The FDA reviews the BLA to determine, FDA will issue a complete response letter that usually describes among other things, whether the proposed product is safe and all of the specific deficiencies in the BLA identified by the FDA. GENSIGHT BIOLOGICS – 2017 Registration Document– 91