STARTING POINT: An idea
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.
To understand the journey, we need to understand the term “drugs.” The Federal Food, Drug, and Cosmetic Act (FFDCA) defines the term “drugs” as “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.”
In plainer language, a drug (the “article”) is something that treats a disease or changes the structure or function of the body. Some drugs, such as insulin, do both – treat a disease and change the structure or function of the body. Insulin given to a cat with diabetes treats a disease (diabetes mellitus) and changes the cat’s body by allowing cells to take up glucose, commonly called “blood sugar,” from the blood. Other drugs only change the structure or function of the body. For example, in the routine animal husbandry practice called “heat synchronization,” a compound is given to a group of cows to make them ovulate at the same time. Although this compound is not treating a disease in the cows, it is still a drug because it changes how their bodies function.
The FFDCA gives the U.S. Food and Drug Administration (FDA) the legal authority to approve and regulate drugs for both people and animals. If a drug is for use in animals, it is called a new animal drug. New animal drugs are approved and regulated by FDA’s Center for Veterinary Medicine (CVM).
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. The 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, like fish, ferrets, and goats; or for minor uses in a major species, like a rare disease in horses. If the drug is for a minor species or a minor use in a major species, the Office of Minor Use and Minor Species Animal Drug Development (called “OMUMS” for short) is also involved in the review process.
Now, let’s define “drug sponsor.” 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.
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 if it is used according to the label.
“Safe” includes safety:
“Effective” means the drug consistently and uniformly does what it is supposed to do.
CVM’s approval also ensures that the drug’s strength, quality, and purity are consistent from batch to batch, and that the drug’s labeling is appropriate and truthful.
Two other important factors that CVM considers during the NADA process are:
Besides the standard NADA process, two additional pathways to the marketplace are available for some animal drugs for minor species or minor uses in a major species. These two pathways are conditional approval and indexing. Learn more about minor species, minor uses, conditional approval, and indexing by visiting the following websites: http://www.fda.gov/AnimalVeterinary/ResourcesforYou/AnimalHealthLiteracy/ucm189540.htm ; and
Now, we need to clear up some common misconceptions about the drug approval process.
Misconception: The drug approval process starts with CVM.
Misconception: CVM tells the drug sponsor which new animal drugs to research and develop.
Misconception: CVM tests a new animal drug for safety and effectiveness.
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 (BRD) in cattle. The sponsor researches and develops the new compound and conducts initial (“pilot”) 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 for the treatment of BRD 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 key to a smooth journey to drug approval is open and early communication between the drug sponsor and CVM. The drug sponsor initiates 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 contact ONADE simply to share scientific information about a 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. For example, the sponsor uses the INAD file to notify CVM before:
ADUFA stands for the Animal Drug User Fee Act of 2003. Under ADUFA, drug sponsors must pay CVM a “user fee” to review each NADA. A similar “user fee” system was created in 1992 for drug sponsors that make and sell drugs for people. Learn more about ADUFA by visiting the following website: http://www.fda.gov/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/default.htm .
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.
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 categories of dosage forms, including oral and injectable. A drug given by mouth is an oral dosage form. Tablets and capsules are two types 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 type of an injectable dosage form.
The dosage regimen includes:
The Major Technical Sections
The five major technical sections are the biggest pieces of the drug approval puzzle:
Target Animal Safety
The two goals of a standard target animal safety study are:
During the study, safety information on the drug is collected by:
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 females, CVM may ask the sponsor for information on the safety of the drug in breeding animals. CVM 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.
Safety information on the drug is also collected during any effectiveness studies that are conducted.
Human Food Safety
When a food-producing animal is treated with a drug, chemical residues of the drug may be present in or on food products made from that animal. Chemical residues include small amounts of leftover drug, or parts of the drug that are not completely broken down by the animal’s body. One goal of the human food safety studies is to make sure the level of chemical residues in or on food made from treated animals will not harm people.
All animals normally have bacteria in and on their bodies. When an animal is treated with a drug, 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 drug, and possibly similar drugs, will no longer work against those bacteria.
Drug resistance in people and animals is a growing public health concern, particularly resistance to antimicrobial drugs. Antibacterial drugs, commonly called antibiotics, are one category of antimicrobial drugs. Antibiotic-resistant bacteria that enter the food supply may add to drug resistance in people. A second goal of the human food safety studies is to minimize the number of antibiotic-resistant bacteria that enter the food supply in or on food products made from treated animals.
There are four slices of the human food safety puzzle piece:
Chemistry, Manufacturing, and Controls
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.
EAs are available to the public at the following website: http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/EnvironmentalAssessments/default.htm .
If CVM decides that the drug will not have a significant impact on the environment based on the information in the EA, CVM writes what is called a “Finding of No Significant Impact,” or “FONSI” for short. If CVM decides that the drug will have a significant environmental impact, CVM writes an Environmental Impact Statement (EIS).
Both FONSIs and EISs are available to the public at the following website: http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/EnvironmentalAssessments/ucm072419.htm .
A drug sponsor may ask CVM for a waiver from having to prepare an EA. This waiver is called a “categorical exclusion," or “CE” for short. A CE means that the drug falls into a legally-defined category that is unlikely to cause a significant environmental impact. If CVM grants a CE, the sponsor does not have to prepare an EA.
Two examples of when CVM typically grants a CE are:
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
In the Labeling technical section, CVM looks at the complete labeling in its final form. CVM makes sure the labeling provides all the necessary information to use the drug safely and effectively, including the risks associated with the drug. CVM also makes sure the labeling is not false or misleading.
The Last of the Puzzle Pieces
Electronic copies of the FOI Summaries for approved animal drugs are located online at the following website: http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/default.htm .
If an electronic copy of the FOI Summary is not available online, a hardcopy can be requested in writing. For more information on how to make a written request to CVM for an FOI Summary, please see the following website:
The NADA is approved if the information submitted by the drug sponsor:
After the drug is approved, a notice of approval is published 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.
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. Rather than a New Animal Drug Application, drug sponsors of generic animal drugs submit an Abbreviated New Animal Drug Application (ANADA) to CVM. The application is “abbreviated” because generic copies of brand name animal drugs go through a shortened drug approval process. This shortened approval process was established in 1988 by the Generic Animal Drug and Patent Term Restoration Act (GADPTRA).
For a generic animal drug to be approved, the information in the ANADA must show that the generic copy is identical to the approved brand name drug in:
The information in the ANADA must also show that the generic copy is:
Also, the labeling for the generic copy must match the labeling for the approved brand name animal drug, although the generic copy may use a different trade name.
Similar to the “user fee” system for brand name animal drugs, drug sponsors for generic animal drugs must pay CVM a fee to review each ANADA. The “user fee” system for generic animal drugs was established in 2008 by the Animal Generic Drug User Fee Act (AGDUFA).
Learn more about GADPTRA and AGDUFA by visiting the following websites:
Whether the drug is a brand name animal drug or a generic copy, 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 assuring 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.