BUSINESS OVERVIEW 6 FDA, unless the FDA places the clinical trial on a clinical hold During all phases of clinical development, regulatory agencies within that 30-day time period. In such a case, the IND sponsor require extensive monitoring and auditing of al l clinical and the FDA must resolve any outstanding concerns before activities, clinical data and clinical trial investigators. Annual the clinical trial can begin. The FDA may impose clinical holds progress reports detailing the results of the clinical trials must on a biological product candidate at any time before or during be submitted to the FDA. Written IND safety reports must be clinical trials due to safety concerns or non-compliance. If the FDA promptly submitted to the FDA, the NIH and the investigators imposes a clinical hold, studies may not recommence without FDA for serious and unexpected adverse events, any findings from authorization and then only under terms authorized by the FDA. other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinical ly Clinical trials involve the administration of the biological important increase in the rate of a serious suspected adverse product candidate to healthy volunteers or patients under the reaction over that listed in the protocol or investigator brochure. supervision of qualified investigators, generally physicians not The sponsor must submit an IND safety report within 15 calendar employed by or under the study sponsor’s control. Clinical trials days after the sponsor determines that the information qualifies are conducted under protocols detailing, among other things, for reporting. The sponsor also must notify the FDA of any the objectives of the clinical trial, dosing procedures, subject unexpected fatal or life-threatening suspected adverse reaction selection and exclusion criteria, and the parameters to be used within seven calendar days after the sponsor’s initial receipt of to monitor subject safety, including stopping rules that assure the information. Phase I, Phase I I and Phase I I I clinical trials may a clinical trial wil l be stopped if certain adverse events should not be completed successfully within any specified period, if at all. occur. Each protocol and amendments to the protocol must be The FDA or the sponsor or its data safety monitoring board may submitted to the FDA as part of the IND. Clinical trials must suspend a clinical trial at any time on various grounds, including a be conducted and monitored in accordance with the FDA’s finding that the research subjects or patients are being exposed regulations comprising the GCP requirements, including the to an unacceptable health risk. Similarly, an IRB can suspend requirement that all research subjects provide informed consent. or terminate approval of a clinical trial at its institution if the Further, each clinical trial must be reviewed and approved by an clinical trial is not being conducted in accordance with the IRB’s IRB at or servicing each institution at which the clinical trial will requirements or if the biological product has been associated with be conducted. An IRB is charged with protecting the welfare and unexpected serious harm to patients. rights of study participants and considers such items as whether the risks to individuals participating in the clinical trials are Sponsors of clinical trials of investigational products are minimized and are reasonable in relation to anticipated benefits. required to register on clinicaltrials.gov, a National Institute of The IRB also approves the form and content of the informed Health website registry database, and disclose certain clinical consent that must be signed by each clinical trial subject or his or trial information. Information related to the product, patient her legal representative and must monitor the clinical trial until population, phase of investigation, study sites and investigators, completed. Clinical trials also must be reviewed by an institutional and other aspects of the clinical trial is then made public as part of biosafety committee, or IBC, a local institutional committee that the registration. Sponsors are also obligated to discuss the results reviews and oversees basic and clinical research conducted at of their clinical trials after completion. Disclosure of the results of that institution. The IBC assesses the safety of the research and these trials can be delayed until the new product or new indication identifies any potential risk to public health or the environment. being studied has been approved. Competitors may use this publicly-available information to gain knowledge regarding the In some cases, the FDA may condition approval of a BLA for progress of development programs. a product candidate on the sponsor’s agreement to conduct The NIH and the FDA have a publicly accessible database, the additional clinical trials after the product’s approval. In other Genetic Modification Clinical Research Information System which cases, a sponsor may voluntarily conduct additional clinical trials includes information on gene transfer studies and serves as an post-approval to gain more information about the product. electronic tool to facilitate the reporting and analysis of adverse Post-approval clinical trials, sometimes referred to as Phase IV events on these studies. clinical trials, may be conducted after initial marketing approval. These clinical trials are used to gain additional information from Concurrent with clinical trials, companies usual ly complete the treatment of patients in the intended therapeutic indication, additional animal studies and must also develop additional particularly for long-term safety follow-up. The FDA recommends information about the physical characteristics of the biological that sponsors observe subjects for potential gene therapy-related product as wel l as finalize a process for manufacturing the delayed adverse events for a 15-year period, including a minimum product in commercial quantities in accordance with GMP of five years of annual examinations followed by ten years of annual requirements. To help reduce the risk of the introduction of queries, either in person or by questionnaire, of study subjects. adventitious agents (unwanted viruses or bacteria), with use of 90 – GENSIGHT BIOLOGICS – 2017 Registration Document