The

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

'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 Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regu ...

, 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 A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

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 trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s by the

Institutional Review Board An institutional review board (IRB), also known as an independent ethics committee (IEC), ethical review board (ERB), or research ethics board (REB), is a committee at an institution that applies research ethics by reviewing the methods proposed ...

* Drug susceptibility to

abuse Abuse is the act of improper usage or treatment of a person or thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, ...

* Proposed labeling (

package insert A package insert is a document included in the package of a medication that provides information about that drug and its use. For prescription medications, the insert is technical, providing information for medical professionals about how to pr ...

) and directions for use Exceptions to this process include voter driven initiatives for

medical marijuana Medical cannabis, medicinal cannabis or medical marijuana (MMJ) refers to Cannabis (drug), cannabis products and cannabinoid, cannabinoid molecules that are prescription drug, prescribed by physicians for their patients. The use of cannabi ...

in certain states.

Before trials

To legally test the drug on human subjects in the United States, the maker must first obtain an

Investigational New Drug The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical industry, pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug inte ...

(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 effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

Clinical trials

Since the 1962 Kefauver–Harris Amendment, new drugs are statutorily required to demonstrate both safety and effectiveness through ''substantial evidence'' for approval. The amendment defines ''substantial evidence'' as "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof."Food, Drug, and Cosmetic Act, Section 505; 21 USC 355] This standard lies at the heart of the regulatory program for drugs. Data for the submission must include those from one or more rigorous clinical trials. Due to the plural "adequate and well-controlled investigations" in the statute, FDA has interpreted the substantial evidence requirement as requiring at least two adequate and well-controlled clinical trials, each convincing on its own. However, in 1997, Congress passed an amendment, expressly granting FDA authority to consider other types of confirmatory evidence along with one adequate and well-controlled clinical investigation for approval. 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 In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

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

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 and consumers 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.” Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the United States. 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, then the FDA rejects the application by sending the applicant a ''Refuse to File'' letter, which explains where the application failed to meet requirements. Where the application cannot be granted for substantive reasons, the FDA issues a Complete Response Letter. Assuming the FDA finds the NDA acceptable, a ''74-day letter'' is published. 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 A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows: The biologics license application is a request for permission to introduce, or deliver for introduction, a biologic product into inters ...

(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 drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

s that have already been approved via an NDA submitted by another maker are approved via an

Abbreviated New Drug Application An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drug. The ANDA is submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, ...

(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 Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...

calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...

, and

hyaluronidase Hyaluronidases are a family of enzymes that catalyse the degradation of hyaluronic acid. Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on the enzyme reaction products. The three main types of hyaluroni ...

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. 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.

References

External links