From an Idea to the Marketplace: The Journey of an Animal Drug through the Approval Process
STARTING POINT: An idea
FINISH LINE: An approved animal drug on the market
Many of us may not be familiar with the path to the finish line, so let’s break it down to see how an animal drug makes the journey from being an idea to a product on the market.
- Drugs
- Drug Sponsor
- Approved New Animal Drug
- Major and Minor Species
- Conditional Approval and Indexing
A Brief Summary of the Drug Approval Process
- The Beginning: The Idea
- The First Steps: Open Communication
- The Puzzle Pieces
- The End: The Puzzle is Complete
Over-the-Counter versus Prescription versus Veterinary Feed Directive Animal Drugs
Helpful Definitions
CVM – Center for Veterinary Medicine
FDA – Food and Drug Administration
FFDCA – Federal Food, Drug, and Cosmetic Act
NADA – New Animal Drug Application
OMUMS – Office of Minor Use and Minor Species Animal Drug Development
ONADE – Office of New Animal Drug Evaluation
Drugs
To understand the journey, we need to understand the term “drugs.” The Federal Food, Drug, and Cosmetic Act (FFDCA) defines the term “drugs” to include, among other things, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” (See Section 201(g)(1)(B) & (C) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 321(g)(1)(B) & (C)].)
The intended use of a product determines if it’s a drug. Here are a few examples to illustrate this concept:
- When a company sells bottled water for people to drink as a beverage, the water is not a drug. But if the company sells those same bottles of water as a cure for cancer in dogs, then the water is a drug under the FFDCA because the intended use is to cure a disease (cancer) in dogs.
- When a company sells formaldehyde for a car manufacturer to use to make automotive parts, it’s not a drug. But when a company sells formalin—a solution of formaldehyde—for a fish biologist to use to kill external parasites on finfish, it’s a drug under the FFDCA because the intended use is to treat a disease (parasitism) in fish.
- When a company sells a product claiming it makes cows ovulate at the same time, the product is a drug. Although it’s not treating or preventing a disease in the cows, the product’s intended use is to change how their bodies function, which makes it a drug under the FFDCA.
The FFDCA gives the U.S. Food and Drug Administration (FDA) the legal authority to approve and regulate drugs for both people and animals. A drug intended for use in animals is called a new animal drug. FDA’s Center for Veterinary Medicine (CVM) approves and regulates new animal drugs.
CVM is made up of six offices that work together to approve new animal drugs and monitor the drugs after they are on the market. The Office of New Animal Drug Evaluation (ONADE) is the “pre-approval office,” meaning that it is the lead office for reviewing the information about a new animal drug before it is approved.
Drug Sponsor
Now, let’s define “drug sponsor.” For the purpose of this article, a drug sponsor is the entity responsible for collecting all the information about a new animal drug and submitting this information to CVM for review.
Who can be a drug sponsor? Any organization, or even one person, can be a drug sponsor. For example, scientific research groups; government agencies, such as the U.S. Department of Agriculture; and academic organizations, such as colleges and universities, can all be drug sponsors. But typically, drug sponsors are pharmaceutical companies.
Together, CVM and the sponsor guide the drug through the approval process.
Approved New Animal Drug
We also need to understand what it means for a drug to be an approved new animal drug. An approved animal drug is one that has gone through the New Animal Drug Application (NADA) process and has received CVM’s stamp of approval.
Just as high school seniors who want to attend college must go through the college application process, drug sponsors who want to make and sell animal drugs must go through the NADA process. A high school senior uses a college application to formally ask a school for acceptance. The college application tells the senior’s story, including all the information about the student’s extra-curricular activities and grades in high school. Likewise, a drug sponsor uses a NADA to formally ask CVM to approve a new animal drug. The NADA tells the drug’s story and contains all the information about the drug.
CVM’s approval of the NADA means the animal drug is safe and effective when it is used according to the label.
“Safe” includes safety:
- To the animal; and
- Of food products made from the treated animal, if the drug is for use in food-producing animals.
“Effective” means the drug consistently does what it is expected to do.
CVM’s approval also ensures that the drug’s strength, quality, and purity are maintained from batch to batch and that the drug’s labeling is truthful, complete, and not misleading.
Two other important factors that the center considers during the NADA process are:
- The drug’s impact on the environment; and
- The safety of the people who will give the drug to the animal or who may come in contact with the drug.
Major and Minor Species
A new animal drug can be for companion (pet) animals, such as dogs, cats, and horses; or for food-producing animals, such as cattle, pigs, and chickens. A new animal drug can also be for minor species or for a minor use in a major species. CVM classifies horses, dogs, cats, cattle, pigs, chickens, and turkeys as the seven major species. All other animals, such as fish, ferrets, and goats, are minor species. A minor use in a major species is the use of a drug in one of the seven major species for a condition that occurs:
- Infrequently and in only a small number of animals each year; or
- In a limited part of the country and in only a small number of animals each year.
For example, the use of a drug to control pain in dogs with bone cancer is a minor use in a major species because relatively few dogs get bone cancer each year.
If the drug is for a minor species or a minor use in a major species, both ONADE and the Office of Minor Use and Minor Species Animal Drug Development (called “OMUMS” for short) are involved in the review process. Learn more about minor species and minor uses by visiting these webpages: Lions and Tigers and Bears! OMUMS! and Minor Use/Minor Species.
Conditional Approval and Indexing
Besides the standard NADA process, two additional pathways to the marketplace are available for drugs used in animals, depending on the situation. These two pathways are:
- Conditional approval. This pathway is available only for some drugs for use in a minor species or in a major species under special circumstances.
- Indexing. This pathway is available only for drugs for certain minor species.
Learn more about conditional approval and indexing by visiting these webpages: Conditional Approval Explained: A Resource for Veterinarians and Drug Indexing.
Common Misconceptions
Now, we need to clear up some common misconceptions about the drug approval process.
Misconception: The drug approval process starts with CVM.
Truth: The drug approval process starts with the drug sponsor. The sponsor conducts initial research on a potential new animal drug, and if the research is promising, the sponsor contacts CVM to start discussions about the drug and the approval process.
Misconception: CVM tells the drug sponsor which new animal drugs to research and develop.
Truth: The drug sponsor decides which new animal drugs to research and develop for possible approval. CVM and the sponsor discuss what information is needed to get a drug approved.
Misconception: CVM tests a new animal drug for safety and effectiveness.
Truth: The drug sponsor is responsible for testing a new animal drug for safety and effectiveness. CVM reviews the results of the tests to determine if the drug is safe and effective and meets the approval requirements.
A Brief Summary of the Drug Approval Process
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The drug sponsor collects information about the safety and effectiveness of a new animal drug. The sponsor may need to conduct studies to get this information. For any studies that are performed, the sponsor analyzes the results.
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Based on the collected information, the drug sponsor decides if there is enough proof that the drug meets the requirements for approval. The sponsor must prove that the drug is safe and effective for a specific use in a specific animal species. If the drug is for food-producing animals (like cows or chickens), the sponsor must also prove that it’s safe for people to eat food from treated animals, such as meat, milk, and eggs.
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If the drug sponsor decides the drug meets the requirements for approval, the sponsor submits a New Animal Drug Application (NADA) to CVM. The NADA includes all the information about the drug and the proposed label.
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A team of CVM personnel, including veterinarians, animal scientists, biostatisticians, chemists, microbiologists, pharmacologists, and toxicologists, reviews the NADA. If the center's team agrees with the sponsor’s conclusion that the drug is safe and effective when it is used according to the proposed label, CVM approves the NADA and the drug sponsor can legally sell the drug.
The Longer Version
ADUFA – Animal Drug User Fee Act
CVM – Center for Veterinary Medicine
INAD – Investigational New Animal Drug
NADA – New Animal Drug Application
ONADE – Office of New Animal Drug Evaluation
The Beginning: The Idea
The journey to drug approval begins with the drug sponsor having an idea about a new compound. Perhaps this new compound has certain qualities that may make it a useful drug to treat bovine respiratory disease in cattle. The sponsor researches and develops the new compound and conducts initial (“pilot”) laboratory studies on it for a specific use (called an “indication”) in a specific animal species (called the “target animal species”). In the example above, the indication is the treatment of bovine respiratory disease and the target animal species is cattle. If the results of the pilot studies are promising and there is a potential market for the drug, the drug sponsor contacts CVM to officially start the drug approval process.
The First Steps: Open Communication
The key to a smooth journey to drug approval is open and early communication between the drug sponsor and CVM. The drug sponsor starts this communication by contacting ONADE to open an INAD file, discuss ADUFA fees, and discuss the development plan for the new animal drug. The sponsor may first contact ONADE simply to talk about the best ways to share scientific information about a promising new animal drug.
INAD stands for Investigational New Animal Drug. Typically, the drug sponsor opens an INAD file in the beginning of the drug approval process. The sponsor then uses the file as a way to correspond with CVM throughout the journey.
ADUFA stands for the Animal Drug User Fee Act. Originally passed in 2003, ADUFA authorizes CVM to collect fees from drug sponsors to support the center’s review of animal drugs. A similar “user fee” system was created in 1992 for drugs for people. Learn more about ADUFA by visiting the following webpage: Animal Drug User Fee Act (ADUFA).
A development plan discussion is usually held early in the drug approval process. As part of the development plan, ONADE and the drug sponsor discuss, and generally agree on, the information needed to get the drug approved, including the number and types of studies that may be required and the overall design of each study.
The Puzzle Pieces
Let’s think of the drug approval process as a puzzle. Before starting the puzzle, the drug sponsor has to figure out the dosage form of the drug and the dosage regimen that will be on the drug’s label.
The dosage form is the drug’s physical form when it comes out of the manufacturing facility. There are several types of dosage forms, including oral and injectable. A drug given by mouth is an oral dosage form. Tablets and capsules are two variations of an oral dosage form. A drug that is injected under the skin, into muscle, or into a vein is an injectable dosage form. A solution is a common injectable dosage form.
The dosage regimen includes:
- How much of the drug to give (the dose);
- How often to give it (the frequency);
- How long to give it (the duration); and
- How to give it (the route of administration). Various routes of administration include injecting the drug under the skin, into muscle, or into a vein; giving the drug by mouth; or applying the drug topically to the skin.
The Major Technical Sections
The five major technical sections are the biggest pieces of the drug approval puzzle:
- Target Animal Safety;
- Effectiveness;
- Human Food Safety;
- Chemistry, Manufacturing, and Controls; and
- Environmental Impact.
Target Animal Safety
The drug sponsor must show that the drug is safe to the target animal species when it is used according to the label. (The target animal species is the specific animal species that the drug will be used in.) To prove the drug’s safety, the sponsor typically conducts a target animal safety study in a small number of healthy animals.
The two goals of a standard target animal safety study are:
- To identify any harmful side effects of the drug; and
- To establish a margin of safety for the drug. The margin of safety is usually determined by testing the drug at higher-than-labeled doses for a longer-than-labeled time period in the target animal species. The drug’s margin of safety is like a “cushion” or “safety net” to make sure the drug will be safe when it is used in animals that may be sick or sensitive to the drug.
During the study, the sponsor collects safety information on the drug by:
- Examining the animals;
- Observing their behavior;
- Looking at the results of their blood tests; and
- Looking at their tissues and organs both grossly (with the naked eye) and under a microscope.
For some drugs, there may be additional safety questions that may not be answered in a standard target animal safety study. For example, if the drug might be used in pregnant mares, CVM may ask the sponsor for information on the safety of the drug in breeding horses. The center may sometimes ask the sponsor to conduct a special case study, for example, a study done in a specific dog breed that may be extra-sensitive to the drug. An injection site irritation study is a common special case study that CVM usually requires for a drug that is injected into a food-producing animal. This type of study shows how injecting the drug affects the skin and muscle of treated animals.
The drug sponsor also collects safety information on the drug during any effectiveness studies that are done.
Effectiveness
The drug sponsor must show that the drug works in the target animal species when it is used according to the label. One way for sponsors to prove that the drug is effective is by conducting a field study. In a field study, all the animals in the study have the disease or condition that the drug will be used for. For example, if the drug will be used to treat urinary tract infections (UTIs) in dogs, a dog must have a UTI to be in the field study. The goal of the field study is to make sure the drug will do what it is expected to do when it is used under normal (“field”) conditions and according to the label.
Human Food Safety
This puzzle piece is only for drugs intended for food-producing animals. When a food-producing animal is treated with a drug, residues of the drug may be present in or on food products made from that animal. Food products made from treated animals must be safe for people to eat. To show that the food products are safe, a drug sponsor usually conducts what are called human food safety studies. The goal of these studies is to make sure the level of drug residues in or on food products made from treated animals will not harm people.
If the drug is an antibiotic intended for food-producing animals, the sponsor also conducts human food safety studies to assess how likely it is that antibiotic-resistant bacteria will enter the food supply in or on food products made from treated animals. All animals normally have bacteria in and on their bodies. When an animal is treated with an antibiotic, all the bacteria in and on that animal are also exposed to the drug. Some of the exposed bacteria may become resistant, meaning that the antibiotic, and possibly similar antibiotics, may no longer work against those bacteria.
Resistance to antibiotics is a growing public health concern for both people and animals, and antibiotic-resistant bacteria that enter the food supply may add to the problem.
There are four slices of the human food safety puzzle piece:
- Toxicology: By looking at detailed information about the drug in laboratory animals, toxicologists at CVM determine the “acceptable daily intake,” or “ADI.” The ADI is the largest amount of the drug in a person's diet that is not harmful even if he or she consumes that amount every day.
- Residue Chemistry: Residue chemists at CVM evaluate several characteristics of the drug, including:
- How the animal's body gets rid of it.
- How the animal's body breaks it down; and
- Where the drug goes in the animal's body;
Based on this information, along with the ADI, the residue chemists set the tolerance for the drug in the edible tissues of treated animals. The tolerance is the highest level of drug residues legally allowed to be in or on food products made from treated animals. Eating food that contains even the highest legal level of drug residues (meaning, at the full tolerance) will not exceed the ADI and is safe for the consumer.
Based on the tolerance, the residue chemists also set the withdrawal period. The withdrawal period is the time from when the animal was last treated with the drug to when the animal can be slaughtered for food or the animal’s milk or eggs can go to market. The withdrawal period allows for drug residues in the edible tissues of the treated animal to get to levels that are at or below the tolerance. If the withdrawal period is followed, food products made from the treated animal are safe to enter the food supply. - Microbial Food Safety: To determine if an antibiotic can be safely used in food-producing animals, CVM’s microbiologists first look at the drug’s ability to cause bacteria to become resistant. Second, the microbiologists look at the impact of that resistance on public health, and if the impact is potentially negative, they determine if the risk is acceptable.
- Analytical Method: CVM’s scientists make sure the drug sponsor develops appropriate and accurate methods for measuring residues in a specific edible tissue (for example, liver, kidney, or milk). These methods are used to test the tissue to make sure the drug residues aren’t above the legal tolerance.
Chemistry, Manufacturing, and Controls
In the Chemistry, Manufacturing, and Controls (CMC) technical section, the drug sponsor describes the plan for making the drug. This plan includes:
- What ingredients will be used to make the drug;
- Where the ingredients will come from;
- Where the drug will be made;
- How it will be made;
- How it will be packaged;
- How it can be stored (under what conditions); and
- How long it can be stored (this is important in determining the drug’s expiration date).
A big portion of the CMC puzzle piece is looking at what tests the drug sponsor will use to make sure the drug is high-quality and safe. Another important part is deciding when FDA’s investigators should inspect the manufacturing facilities where the drug is made. When an inspection is needed, FDA’s investigators work with scientists at CVM to make sure the manufacturing facilities are using the correct equipment and methods to consistently produce a high-quality and safe drug.
Environmental Impact
CE – Categorical Exclusion
CVM – Center for Veterinary Medicine
EA – Environmental Assessment
EIS – Environmental Impact Statement
FONSI – Finding of No Significant Impact
NEPA – National Environmental Policy Act
Under the National Environmental Policy Act (NEPA), CVM must consider how the environment will be affected if the center approves an animal drug. To do this, the center requires that drug sponsors prepare an Environmental Assessment (EA). This assessment describes how much drug is expected to get into the environment and its potential environmental effects.
If CVM determines that the drug will not significantly impact the environment based on the information in the EA, the center writes what is called a “Finding of No Significant Impact,” or “FONSI” for short. If CVM determines that the drug will significantly impact the environment, the center writes an Environmental Impact Statement (EIS).
Learn more about environmental impact considerations by visiting the following webpage: Environmental Impact Considerations.
A drug sponsor can ask CVM for a “categorical exclusion," or “CE” for short. A CE means that the drug falls into a legally-defined category that is unlikely to affect the environment. If the center grants a CE, the sponsor does not have to prepare an EA.
Two examples of when the center typically grants a CE are:
- A drug for companion animals, like cats and dogs. Because a drug for companion animals is given to one animal at a time (as opposed to a herd or flock of animals), not much of the drug is likely to get into the environment; and
- A slight change to an already-approved animal drug if the change will not increase how much drug is used or how much will get into the environment.
The Minor Technical Sections
The two minor technical sections are smaller pieces that fit into the puzzle after the five bigger pieces are complete or almost complete. These are:
- All Other Information; and
- Labeling.
All Other Information
The All Other Information technical section includes all information about the drug that the drug sponsor did not submit as part of the major technical sections. The sponsor typically collects this information from:
- Published scientific literature;
- Foreign experience, if the drug is approved in a country outside the United States; and
- Studies that were conducted but not completed at the time the sponsor submitted the major technical sections.
Labeling
The term “labeling” includes all the information on the:
- Immediate container – this is the container that the drug itself comes in. Vials, bottles, syringes, and packets are immediate containers. For a drug that is in animal feed, the immediate container is the feed bag.
- Package insert – this is usually attached to the immediate container. The package insert is typically written for veterinarians who will prescribe or give the drug to animals.
- Outer packaging – this is what the immediate container comes in. For example, if a vial is packaged in a carton, the carton is the outer packaging.
- Shipping label – this is put on the larger container that is shipped from the manufacturing facility to identify the container’s contents. For example, the container may hold 12 cartons, with each carton holding one vial.
- Client information sheet – this is written for pet owners to let them know what to expect when giving the drug to their pets, including what side effects to look for. Not every approved drug for companion (pet) animals has a client information sheet.
In the Labeling technical section, CVM reviews the exact language and formatting that will be on each piece of labeling. As part of the review, CVM makes sure the labeling includes all necessary information to use the drug safely and effectively and the risks associated with the drug. The center also makes sure the labeling is truthful, complete, and not misleading.
The Last of the Puzzle Pieces
The Freedom of Information Summary
The Freedom of Information (FOI) Summary is a public document describing the safety and effectiveness information that supports CVM’s decision to approve the new animal drug. It includes summaries of studies that were done and explains the basis for the center’s approval.
Learn more about FOI Summaries by visiting the following webpage: Freedom of Information (FOI) Summaries for Approved Animal Drugs.
The End: The Puzzle is Complete!
CVM approves the NADA if the information submitted by the drug sponsor meets the requirements for approval. After CVM approves the drug, the center publishes a notice of approval in the FEDERAL REGISTER. The new animal drug has now completed its journey through the approval process, and the drug sponsor can legally sell the drug.
Over-the-Counter versus Prescription versus Veterinary Feed Directive Animal Drugs
CVM – Center for Veterinary Medicine
NADA – New Animal Drug Application
OTC Drug - Over-the-Counter Drug
Rx Drug - Prescription Drug
VFD Drug - Veterinary Feed Directive Drug
The approval process is the same for any new animal drug, whether it’s an over-the-counter (OTC), prescription (Rx), or veterinary feed directive (VFD) drug. All must go through the NADA process, but one difference between these three categories of animal drugs is whether CVM has determined that veterinary oversight is required for the safe and effective use of the drug. If the center determines that adequate “directions for use” can be written on the drug’s label in such a way that a non-veterinarian can use the drug safely and effectively, then it can be marketed as OTC. If not, then the drug must be marketed as either Rx or VFD.
Both Rx and VFD drugs require veterinary oversight to be used safely and effectively. The main difference between these two categories of animal drugs is whether the drug is used in or on animal feed. When the drug is for use in or on animal feed (a medicated feed), CVM approves it as a VFD drug. When the drug is not for use in or on animal feed, the center approves it as an Rx drug. Federal law makes it clear that VFD drugs are not Rx drugs. A VFD drug requires veterinary oversight without invoking state pharmacy laws for an Rx drug that are unworkable for medicated feed.
An Rx animal drug can be dispensed only by or on the lawful written order of a licensed veterinarian and must have the following statement on the label:
"Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian."
A VFD is a written order issued by a licensed veterinarian in the course of the veterinarian’s professional practice that authorizes the client (the owner or other animal caretaker) to obtain and use a VFD drug in or on animal feed. A VFD animal drug must have the following statement on the label:
‘‘Caution: Federal law restricts medicated feed containing this veterinary feed directive (VFD) drug to use by or on the order of a licensed veterinarian.’’
Learn more about VFD drugs by visiting the following webpage: Veterinary Feed Directive (VFD).
Generic Animal Drugs
AGDUFA – Animal Generic Drug User Fee Act
ANADA – Abbreviated New Animal Drug Application
CVM – Center for Veterinary Medicine
GADPTRA – Generic Animal Drug and Patent Term Restoration Act
After an approved brand name animal drug has been on the market for a specific number of years, another drug sponsor can start the approval process for a generic copy. (The approved brand name animal drug is also called the “reference-listed new animal drug product” or the “pioneer” animal drug.) Rather than the full New Animal Drug Application process that a brand name animal drug goes through, a generic animal drug goes through the Abbreviated New Animal Drug Application (ANADA) process. The process is “abbreviated” because the drug sponsor doesn't have to conduct new safety and effectiveness studies with the generic animal drug. The Generic Animal Drug and Patent Term Restoration Act (GADPTRA) established the approval process for generic animal drugs in 1988.
For CVM to approve a generic animal drug, the information in the ANADA must show that the generic copy has the same quality, performance, and intended uses as the approved brand name drug. The drug sponsor must prove to CVM that the generic copy is the same as the approved brand name animal drug in:
- Active ingredient;
- Strength;
- Dosage form; and
- Dosage regimen, including route of administration.
The information in the ANADA must also show that the generic copy is bioequivalent to the approved brand name animal drug. This means that the generic drug is absorbed by and performs the same way in the animal’s body as the brand name drug.
CVM requires that the generic drug be manufactured under the same strict manufacturing standards as the brand name drug. The manufacturing processes for the generic copy must consistently produce a product that is the same as the brand name animal drug in identity, strength, purity, and quality.
Also, the labeling for the generic copy must match the labeling for the approved brand name animal drug. The labeling may differ only in items that are specific to the generic drug, such as trade name, logo, and company name and address.
In 2008, the Animal Generic Drug User Fee Act (AGDUFA) established a “user fee” system similar to the system for brand name animal drugs. AGDUFA authorizes CVM to collect fees from drug sponsors to support the center’s review of generic animal drugs.
Learn more about GADPTRA and AGDUFA by visiting the following webpages: Generic Animal Drug and Patent Term Restoration Act (GADPTRA) and Animal Generic Drug User Fee Act (AGDUFA).
CVM’s Stamp of Approval
Whether the drug is a brand name animal drug or a generic copy or whether it’s an over-the-counter, prescription, or veterinary feed directive animal drug, CVM’s stamp of approval stands for safety and effectiveness when the drug is used according to the label. The rigorous journey through the drug approval process protects the health of both animals and people by ensuring that only safe, effective, and high-quality animal drugs make it to the market, while unsafe animal drugs and those that do not work are kept off.
Animal Drugs @ FDA
Animal Drugs @ FDA is a searchable online database that includes most FDA-approved and conditionally approved animal drugs. You can search this database in several ways, such as by the drug’s proprietary name (also known as the trade name or brand name) or active ingredient. Indexed animal drugs aren’t listed in Animal Drugs @ FDA.