The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial drug candidates proceed through the entire multi-year process of drug development, concluding with an approved NDA, if successful.
The goals of the NDA are to provide enough information to permit FDA reviewers to establish the complete history of the candidate drug. Among facts needed for the application are: Patent and manufacturing information Drug safety and specific effectiveness for its proposed use(s) when used as directed Reports on the design, compliance, and conclusions of completed clinical trials by the Institutional Review Board Drug susceptibility to abuse Proposed labeling (package insert) and directions for use
Exceptions to this process include voter driven initiatives for medical marijuana in certain states.
Before trials
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. 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. Often the "new" drugs that are submitted for approval include new molecular entities or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side effects.
Clinical trials
The legal requirement for approval is "substantial" evidence of effectiveness demonstrated through controlled clinical trials. This standard lies at the heart of the regulatory program for drugs. Data for the submission must come from rigorous clinical trials.
The trials are typically conducted in three phases: 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.
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 actual application
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. The prescribing information is widely available on the web, from the FDA, 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.” Currently, the FDA decision process lacks transparency, however, efforts are underway to standardize the benefit-risk assessment of new medicines. 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.