New drug application
Encyclopedia
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:
(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 for approval include new molecular entities or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side-effects.
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 (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 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. 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.
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. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.
Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD
format.
, 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 drug
s 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 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 animal
s 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 device
s 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.
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
through which drug sponsors formally propose that the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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 drugDrugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
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 insertPackage insertA package insert or prescribing information is a document provided along with a prescription medication to provide additional information about that drug.-Responsible agencies:In the United States, the Food and Drug Administration determines the requirements...
) appropriate, and what should it contain?
- Are the methods used in manufacturing (Good Manufacturing PracticeGood Manufacturing Practice"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...
, 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 DrugInvestigational New Drug
The United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...
(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 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.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-blindDouble-blindA blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
, placeboPlaceboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
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 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. 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.
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. A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.
Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD
ECTD
The electronic Common Technical Document is an interface for the pharmaceutical industry to agency transfer of regulatory information.The content is based on the Common Technical Document format....
format.
Requirements for similar products
BiologicsBiologics
A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...
, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application
Biologic License Application
As defined by the US FDA, a Biologic License Application is: Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product...
(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
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
s 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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
, glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
, calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
, and hyaluronidase
Hyaluronidase
The hyaluronidases are a family of enzymes that degrade hyaluronic acid.In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1.-Use as a drug:...
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
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
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 animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s 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 device
Medical device
A medical device is a product which is used for medical purposes in patients, in diagnosis, therapy or surgery . Whereas medicinal products achieve their principal action by pharmacological, metabolic or immunological means. Medical devices act by other means like physical, mechanical, thermal,...
s 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
Toothbrush
The toothbrush is an oral hygiene instrument used to clean the teeth and gums that consists of a head of tightly clustered bristles mounted on a handle, which facilitates the cleansing of hard-to-reach areas of the mouth. Toothpaste, which often contains fluoride, is commonly used in conjunction...
) do not require any approval at all.
See also
- Drug developmentDrug developmentDrug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
- Inverse benefit lawInverse benefit lawThe Inverse Benefit Law states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively a drug is marketed...
- Investigational New DrugInvestigational New DrugThe United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...
, FDA application to start clinical trials - Kefauver Harris AmendmentKefauver Harris AmendmentThe U.S. Kefauver Harris Amendment or "Drug Efficacy Amendment" is a 1962 amendment to the Federal Food, Drug, and Cosmetic Act.It introduced a requirement for drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval...
, a 1962 amendment to the Federal Food, Drug, and Cosmetic Act (e.g. to also require evidence of efficacy). - Regulation of therapeutic goodsRegulation of therapeutic goodsThe regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency...
, Rules in different countries.