New Drug Application

To legally test the drug on human subjects in the U.S., the maker must first obtain an Investigational New Drug (IND) designation from FDA.[5] This application is based on nonclinical data, typically from a combination of in vivo and in vitro laboratory safety studies, that shows the drug is safe enough to test in humans.[5] Often the "new" drugs that are submitted for approval include new molecular entities[6] or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side effects.

The legal requirement for approval is "substantial" evidence of effectiveness demonstrated through controlled clinical trials.[7] This standard lies at the heart of the regulatory program for drugs. Data for the submission must come from rigorous clinical trials.[5]

The trials are typically conducted in three phases:[5]

• 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.[5]

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 side effects.

Many approved medications for serious illnesses (e.g., cancer) have severe and even life-threatening side effects. Even relatively safe and well understood OTC drugs such as aspirin can be dangerous if used incorrectly.

The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information.[8] The prescribing information is widely available on the web, from the FDA,[9] drug manufacturers, and frequently inserted into drug packages. The main purpose of a drug label is to provide healthcare providers with adequate information and directions for the safe use of the drug.

The documentation required in an NDA is supposed to tell "the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.”[2] Currently, the FDA decision process lacks transparency, however, efforts are underway to standardize the benefit-risk assessment of new medicines.[10] Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the U.S.

Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD format.[11]

Once the application is submitted, the FDA has 60 days to conduct a preliminary review, which assesses whether the NDA is "sufficiently complete to permit a substantive review." If the FDA finds the NDA insufficiently complete (reasons can vary from a simple administrative mistake in the application to a requirement to re-conduct testing), then the FDA rejects the application by sending the applicant a Refuse to File letter, which explains where the application failed to meet requirements.[12] Where the application cannot be granted for substantive reasons, the FDA issues a Complete Response Letter.

Assuming the FDA finds everything acceptable, they decide if the NDA needs a standard or accelerated review, and communicates acceptance of the application and their review choice in another communication, known as the 74-day letter.[13] A Standard Review implies an FDA decision within about 10 months while a Priority Review should complete within 6 months.[14]

Biologics, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application (BLA), rather than an NDA. The manufacture of biologics is considered to differ fundamentally from that of less complex chemicals, requiring a somewhat different approval process.

Generic drugs that have already been approved via an NDA submitted by another maker are approved via an Abbreviated New Drug Application (ANDA), which does not require all of the clinical trials normally required for a new drug in an NDA.[15] Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law.[16] However, a handful of biologic medicines, including biosynthetic insulin, growth hormone, glucagon, calcitonin, and hyaluronidase are grandfathered under governance of the Federal Food Drug and Cosmetics Act, because these products were already approved when legislation to regulate biotechnology medicines later passed as part of the Public Health Services Act.

Medications intended for use in animals are submitted to a different center within FDA, the Center for Veterinary Medicine (CVM) in a New Animal Drug Application (NADA). These are also specifically evaluated for their use in food animals and their possible effect on the food from animals treated with the drug.

• Drug development
• Inverse benefit law
• Investigational New Drug, FDA application to start clinical trials
• Kefauver Harris Amendment, a 1962 amendment to the Federal Food, Drug, and Cosmetic Act (e.g. to also require evidence of efficacy)
• Regulation of therapeutic goods, rules in different countries.

• Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563
• Chapter 11: Prescription Drug Product Submissions in: Fundamentals of US Regulatory Affairs, Eighth Edition 2013 Archived March 4, 2016, at the Wayback Machine
• Novel Drug Approvals for 2021