New drug application
|Regulation of therapeutic goods in the United States|
The Food and Drug Administration's 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 the drug (good manufacturing practice [GMP]) and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?
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.
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. 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: The drug is tested for both efficacy and safety in a larger sample pool. The majority of 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 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 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 are toxic and technically not "safe" in the usual sense.
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 clinical tests, what the ingredients of the drug formulation are, results of animal studies, how the drug behaves in the body, and how the company manufactures, processes and packages it. 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.
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.
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. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.
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. 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. 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, because these products were already approved when legislation to regulate biotechnology medicines 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 to be approved. In July 2003, the Sandoz generics unit of Novartis filed, and the FDA accepted, an ANDA for a "follow-on" version of Pfizer's brand-name human growth hormone (Genotropin) 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.
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.
- Food, Drug, and Cosmetic Act, Section 505; 21 USC 355]
- 21 CFR 201.5: Labeling Requirements for Prescription Drugs and/or Insulin
- "Daily Med:Current Medication Information". Retrieved October 10, 2007.
- Liberti L, McAuslane JN, Walker S (2011). "Standardizing the Benefit-Risk Assessment of New Medicines: Practical Applications of Frameworks for the Pharmaceutical Healthcare Professional". Pharm Med 25 (3): 139–46. doi:10.1007/BF03256855.
- Kathie Clark (December 15, 2009). "Updates from the Regulators:FDA". The eCTD summit.
- FDA, CDER Office of Generic Drugs
- 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