Regulation of therapeutic goods in the United States

The New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration (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?

To legally test the drug on human subjects in the U.S., the maker must first obtain anInvestigational New Drug (IND) designation from FDA. This application is based on pre-clinical data, typically from animal studies after P1, that shows the drug is safe enough to be tested in humans.Before trials

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 efficacy demonstrated through controlled clinical trials.^[1] 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 (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.^[2] The prescribing information is widely available on the web, from the FDA,^[3] 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 formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. Currently, the decision process for FDA approval lacks transparency; however, efforts are underway to standardise the benefit-risk assessment of new medicines.^[4] 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 will assess whether the NDA is “sufficiently complete to permit a substantive review”. If the NDA is found to be insufficiently complete (and reasons for this can vary from a simple administrative mistake in the application to a requirement to reconduct much of the testing), then the FDA rejects the application with the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed to meet requirements.^[5]

Assuming that everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter.^[6] A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.^[7]

Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD format.^[8]

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.^[9] Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law.^[10] 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 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 aNew 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) clearance that shows the device is “substantially equivalent ” to a predicate device already on the market is required for class II devices. In general, Class I medical devices (such as a toothbrush) do not require any approval at all.

See also

• 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.

References