8 Preclinical studi t es include labor a atory r evaluation of product chemistry r and formulation, as well as in vitro and animal studi t es to assess the potential for adverse events and in some cases to establ a ish a rationale for therapeutic use. The conduct of preclinical studi t es is subj u ect to federal regulations and requirements, including GLP regulations for safety/toxicology studi t es. An IND sponsor must subm u it the results of the preclinical tests, together with manufact f ur t ing information, analytical data, any availabl a e clinical data or literature and plans for clinical studi t es, among other things, to the FDA as part of an IND. Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue afte f r the IND is subm u itted. An IND automatically becomes effe f ctive 30 days afte f r receipt by the FDA, unless before that time, the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, subm u ission of an IND may not result in the FDA allowing clinical trials to commence. Clin l ical Trials The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supe u rvision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subj u ects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedur d es, subj u ect selection and exclusion criteria and the parameters to be used to monitor subj u ect safety and assess effi f cacy. Each protocol, and any subs u equent amendments to the protocol, must be subm u itted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institut t ion at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonabl a e in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subj u ect or his or her legal representative, and must monitor the clinical trial until completed. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may subm u it data from the clinical trial to the FDA in suppor u t of an NDA or BLA. The FDA will accept a well-designed and well-conducted foreign clinical study t not conducted under an IND if the study t was conducted in accordance with GCP requirements and the FDA is able to validate the data through an onsite inspection if deemed necessary. Clinical trials in the United States generally are conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap. • Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affe f cted patients who are initially exposed to a single dose and then multiple doses of the product candidate. The primary purpos r e of these clinical trials is to assess the metabol a ism, pharmacologic action, side effe f ct tolerabi a lity and safety of the drug. r • Phase 2 clinical trials involve studi t es in disease-affe f cted patients to determine the dose required to produce the desired benefits. At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effe f cts and safety risks are identifie f d and a preliminary r evaluation of effi f cacy is conducted. • Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the effe f ctiveness of the product for its intended use, its safety in use and to establ a ish the overall benefit/risk relationship of the product and provide an adequate basis for product approval. These trials may include comparisons with placebo and/or other comparator treatments. The duration of treatment is ofte f n extended to mimic the actual use of a product during marketing. Post-appr a oval trials, sometimes referred to as Phase 4 clinical trials, may be conducted afte f r initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA or BLA. Progress reports detailing the results of the clinical trials, among other information, must be subm u itted at least annually to the FDA and written IND safety reports must be subm u itted to the FDA and the investigators for serious and unexpected suspected adverse events, findings from other studi t es suggesting a significant risk to humans exposed to the drug, r findings from animal or in vitro testing that suggest a significant risk for human subj u ects and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.