Editing New Drug Application (section)

==Clinical trials==
Since the 1962 [[Kefauver–Harris Amendment]], new drugs are statutorily required to demonstrate both safety and effectiveness through ''substantial evidence'' for approval. The amendment defines ''substantial evidence'' as "evidence consisting of adequate and well-controlled investigations, including [[clinical trial|clinical investigations]], by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof."<ref name='FDCA'>Food, Drug, and Cosmetic Act, Section 505; 21 USC 355]</ref><ref>{{cite web |title=Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products |archive-url=https://web.archive.org/web/20200830074933/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products |url-status=dead |archive-date=August 30, 2020 |website=www.fda.gov |publisher=FDA |language=en |date=27 January 2020}}</ref>
This standard lies at the heart of the regulatory program for drugs. Data for the submission must include those from one or more rigorous clinical trials.<ref name="fda2018-3"/>

Due to the plural "adequate and well-controlled investigations" in the statute, FDA has interpreted the substantial evidence requirement as requiring at least two adequate and well-controlled clinical trials, each convincing on its own. However, in 1997, Congress passed an amendment, expressly granting FDA authority to consider other types of confirmatory evidence along with one adequate and well-controlled clinical investigation for approval.<ref>{{cite web |title=Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical |archive-url=https://web.archive.org/web/20240226073253/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical |url-status=dead |archive-date=February 26, 2024 |website=www.fda.gov |publisher=FDA |language=en |date=30 November 2023}}</ref>

The trials are typically conducted in three phases:<ref name=fda2018-3/>
* Phase 1: The drug is tested in 20 to 100 healthy volunteers to determine its safety at low doses. About 70% of candidate drugs advance to Phase 2.
* Phase 2: The drug is tested for both efficacy and safety in up to several hundred people with the targeted disease. Some two-thirds of candidate drugs fail in Phase 2 clinical trials due to the drug not being as effective as anticipated.
* Phase 3: The drug is typically tested in several hundred to several thousand people with the targeted disease in [[double-blind]], [[placebo]] controlled trials to demonstrate its specific efficacy. Under 30% of drug candidates succeed through Phase 3.
* Phase 4: These are [[postmarketing surveillance]] trials in several thousand people taking the drug for its intended purpose to monitor efficacy and safety of the approved marketed drug.<ref name=fda2018-3/>

The legal requirements for safety and effectiveness have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs have [[adverse event|adverse]] [[side effect]]s.