The 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. The goals of the NDA are to provide enough information to permit FDA reviewers to establish the following:
* Is the drug safe and effective in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?
* Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?
* Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?
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 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.
Clinical trials
The legal requirement for approval is "substantial" evidence of efficacy demonstrated through controlled clinical trials. [Food, Drug, and Cosmetic Act, Section 502; 21 USC 355] ] 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:
*Phase 1: The drug is tested in a few healthy volunteers to determine if it is acutely toxic.
*Phase 2: Various doses of the drug are tried to determine how much to give to patients.
*Phase 3: The drug is typically tested in double-blind, placebo controlled trials to demonstrate that it works. Sponsors typically confer with FDA prior to starting these trials to determine what data is needed, since these trials often involve hundreds of patients and are very expensive.
*(Phase 4): These are post-approval trials that are sometimes a condition attached by the FDA to the approval.
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 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. [21 CFR 201.5: Labeling Requirements for Prescription Drugs and/or Insulin] The prescribing information is widely available on the web, from the FDA, [Cite web|url=http://dailymed.nlm.nih.gov/dailymed/about.cfm|title=Daily Med: Current Medication Information|accessyear=2007|accessmonthday=October 10] 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)[cite web]
author=eCTDBlog.com
year=2008
title=FDA, 30,000 eCTDs and Counting!
publisher=eCTDBlog.com
accessdate=2008-07-07
url=http://www.ectdblog.com/2008/07/fda-30000-ectds-and-counting.html] .Requirements for similar products
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. [ [http://www.fda.gov/cder/ogd/ FDA, CDER Office of Generic Drugs] ] Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law. [ [http://pubs.acs.org/cen/coverstory/8038/8038biogenerics2.html Rouhi, A.M. "Beyond Hatch-Waxman: Legislative action seeks to close loopholes in U.S. law that delay entry of generics into the market" Chem & Eng News 80(38):53-59] ] 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 [ [http://www.iht.com/articles/2006/04/25/business/biotech.php Heuser, Stephen, "Ruling budges logjam on generic biotech drugs", "International Herald Tribune", April 26, 2006.] ] . 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 [ [http://www.nytimes.com/2007/01/11/business/11insulin.html?ex=157680000&en=c5f684f9d90ffc70&ei=5124&partner=permalink&exprod=permalink Saul, Stephanie; "Bridling at Insulin's Cost, States Push for Generics"; "The New York Times", January 11, 2007.] ] .
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.
References
ee also
*Regulation of therapeutic goods
*Investigational New Drug
*Kefauver Harris Amendment
*Active ingredient
*Drug development
*Clinical trial
*Food and Drug Administration (FDA)
*European Medicines Agency (EMEA)
*Ministry of Health, Labour and Welfare (Japan)
