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 pre-clinical data, typically from animal studies, that shows the drug is safe enough to be tested in humans.
Often the "new" drugs that are submitted are not new molecular entities, but old medications that have been modified.
The legal requirement for approval is "substantial" evidence of efficacy demonstrated through controlled clinical trials. This standard lies at the heart of the regulatory program for drugs. It means that the clinical experience of doctors, the opinion of experts, or testimonials from patients, even if they have experienced a miraculous recovery, have minimal weight in this process. Data for the submission must come from rigorous clinical trials.
The trials are typically conducted in three phases:
The legal requirements for safety and efficacy 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 are toxic and technically not "safe" in the usual sense.
Many approved medications for serious illnesses (i.e. 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. 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 doctors 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 formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the U.S.
Recently, the FDA has mandated that NDAs submitted electronically should be done in the eCTD format in place of the previous eNDA standard. The transition has been successful with the promise of reduced review times. To date, the FDA has received over 30,000 submissions in the eCTD format (of those, over 8,300 have been related to NDAs) .
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. 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. Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law. 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, which appears to be because these products were already approved when legislation aimed at regulating biotechnology medicines was later passed as part of the Public Health Services Act.
Biologic medicines governed under the Federal Food Drugs and Cosmetics Act has been an area of considerable confusion and dispute for the FDA, because under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, a "generic" need not be an exact duplicate of the brand-name original in order to be approved. In July 2003, the Sandoz generics unit of Norvartis filed, and the FDA accepted, an ANDA for a "follow-on" version of Pfizer's brand-name human growth hormone (Genotropin) that that Sandoz named Omnitrope using the 505(b)(2) pathway. The application was submitted following lengthy discussions with the FDA and contained preclinical, clinical, and comparability data, as well as literature references to the FDA's original decision on Pfizer's Genotropin. But on September 2, 2004, the FDA told Sandoz that the Agency was unable to reach a decision on whether to approve the company's application for Omnitrope. Frustrated with the FDA's failure to give them a decision on Omnitrope, Sandoz then sued the FDA in U.S. District Court in Washington, D.C., citing a statutory requirement that the FDA is required by law to act on drug applications within 180 days. On May 30, 2006, Judge Ricardo Urbina ruled in favor of Sandoz on the Omnitrope case in a very strongly worded opinion, calling the FDA's repeated delays "egregious" writing that there was absolutely no excuse for a delay that was nearing 1,000 days, and effectively ordered the FDA to give the company a response. Following that lawsuit, the FDA approved Omnitrope. With Omnitrope's approval, the FDA stated that the law governing generics permits approvals like Omnitrope's because they aren't technically forbidden, "as long as the current state of science allows the evaluation necessary to support approval," which is what the the FDA wrote in its response to Pfizer's petition against Omnitrope's ANDA. Since then, the Governors of several different states have also petitioned the FDA for guidelines on generic insulin.
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.
Medical devices are approved by a variety of methods depending on the class of the device. A Pre-market Application (PMA) largely equivalent to an NDA is required for class III devices, and a 510(k) approval that shows the device is equal to or better than a predicate device already on the market is required for class II devices. Class I medical devices (such as a toothbrush) do not require any approval at all.