FDA Answers Your Questions about Fish Drugs

1.   What’s a drug?

Federal law (the Federal Food, Drug, and Cosmetic Act) defines the term “drug” to include “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.”

Let’s take a more practical look at the definition from an aquaculture perspective. A drug (the “article”) can, for example, be something that is intended to treat a fish disease or intended to affect the structure or function of a fish’s body. A product’s intended use determines whether it’s a drug or not.

When the intended use of formalin—a solution of formaldehyde—is to fix a biopsy sample from a fish, it isn’t a drug because the intended use is to preserve the tissue for future study. But when the intended use of formalin is to kill external parasites on finfish, it’s a drug because the intended use is to treat parasitism. Because, in this case, the intended use of formalin is to treat a disease, it’s a drug under federal law.

Now, let’s look at the other part of the definition about a drug affecting the structure or function of a fish’s body. When the intended use of tricaine methanesulfonate, or MS-222, is to immobilize fish, it’s a drug because the intended use is to change how the fishes’ bodies function. When the intended use of oxytetracycline hydrochloride is to mark the otoliths of finfish fry and fingerlings for future identification, it’s a drug because the intended use is to affect the structure of the fishes’ bodies (their otoliths, in this case).

 2.   What’s an approved new animal drug?

Several drugs are FDA-approved for use in fish, but what does that mean?

Approved new animal drugs have gone through the New Animal Drug Application (NADA) process, or for generic animal drugs, the Abbreviated New Animal Drug Application (ANADA) process. In a nutshell, the process involves the drug sponsor—typically a drug company—collecting safety, effectiveness, and other information on the intended use of an animal drug. The sponsor then submits this information to FDA in the NADA or ANADA application. If the application meets the approval requirements, the agency approves the new animal drug. FDA approves the drug only for the specific intended uses listed on the drug’s label.

The aquaculture industry, drug companies, and government agencies created public partnerships to support research on fish drugs with the hope that this research will lead to the availability of more legally marketed fish drugs. The public partners conduct studies on the safety and effectiveness of a fish drug. The information goes into a Public Master File (PMF) that, as the name suggests, is available to the public. Rather than conduct all its own studies, a drug company can use the information in a PMF to help satisfy FDA’s approval requirements, thereby reducing both the time and cost of completing the NADA process. This gives companies more incentive to pursue approval of a fish drug, especially when the market for that drug is small.

FDA maintains an online searchable database, called “Animal Drugs @ FDA  ,” that lists approved new animal drugs, including fish drugs.

 3.   What does FDA’s approval provide?

FDA’s approval of an animal drug ensures that:

·  The drug is safe and effective when used according to the label;

·  The drug’s strength, quality, and purity are consistent from batch to batch; and

·  The drug’s labeling is truthful and complete.

If the drug is for food-producing animals, such as fish intended for human consumption, FDA’s approval also ensures that food made from treated animals is safe for people to eat.

FDA continues to monitor an approved animal drug after it’s on the market to make sure that:

·  The drug remains safe and effective. Sometimes, the agency’s post-approval monitoring uncovers safety and effectiveness issues that were unknown at the time of approval;

·  The quality and consistency of the manufacturing process are maintained; and

·  The labeling remains truthful and complete.

 4.   What’s a conditionally approved new animal drug?

Did you use AQUAFLOR-CA1 when it was “conditionally approved”? Were you unsure what that meant? It meant that AQUAFLOR-CA1 went through the Conditional New Animal Drug Application (CNADA) process. This process has the same approval requirements as the NADA process except FDA conditionally approves the drug before the effectiveness requirement is complete. FDA’s conditional approval ensures the drug is safe and that there’s a reasonable expectation of effectiveness when used according to the label.

The drug company’s conditional approval is effective for one year, and can be renewed annually for up to four additional years. During this time, the company can legally market the drug while collecting the remaining effectiveness data. When the company completes the effectiveness requirement, FDA can finish its review and, if appropriate, approve the application for full approval. Conditional approval is available only for drugs forminor species or minor uses in a major species.

AQUAFLOR-CA1 was the first ever conditional approval of a drug. FDA conditionally approved AQUAFLOR-CA1 for the control of mortality in catfish due to columnaris disease associated with Flavobacterium columnare. [The “CA1” after the name indicated that the drug was conditionally approved (CA) and that it was the first (1) conditionally approved application for this product.] In April 2012, FDA fully approved AQUAFLOR to control mortality due to columnaris disease associated with Flavobacterium columnare in all freshwater finfish, including catfish. (Note the lack of “CA1” after the drug name now that it’s fully approved for this use.)

Currently, there are no conditionally approved fish drugs.

 5.   Is the approval/conditional approval process the only legal pathway to the marketplace for a new animal drug?

No, some animal drugs can take a different pathway called indexing. Indexed animal drugs are technically unapproved but still legally marketed for some minor species.

You may know about, or have even used, the two indexed drugs for ornamental fish: OVAPRIM (salmon gonadotropin releasing hormone analog + domperidone) and AQUACALM (metomidate hydrochloride). Both drugs are currently on FDA’s Index of Legally Marketed Unapproved New Animal Drugs for Minor Species, referred to simply as “the Index.” A drug listed on the Index can be legally marketed for a specific use in certain minor species.

Indexing is allowed for drugs for:

·  Non-food-producing minor species, such as ornamental fish. These animals don’t produce food for people to eat; and

·  Early life stages of a food-producing minor species, such as oyster spat (immature oysters). Because people don’t generally eat oyster spat, a drug to treat a disease in spat can be indexed, but a drug to treat a disease in adult oysters, which people commonly eat, cannot be indexed.

Indexing a drug is a three-step process that includes a review of the drug’s safety and effectiveness by a panel of qualified experts outside FDA. All members of the expert panel must agree that, when used according to the label, the drug’s benefits outweigh the risks to the treated animal. If FDA agrees with the panel, the drug is added to the Index.

CVM’s Office of Minor Use and Minor Species Animal Drug Development maintains the Index.

6.   How can I find out if an animal drug is legally marketed?

To find out if an animal drug is legally marketed, look at the drug’s label for a specific number and statement. FDA assigns a unique, six-digit number to every approved, conditionally approved, and indexed animal drug. Examples include:

You should not confuse these numbers with a National Drug Code (NDC) number, which are also sometimes listed on a drug’s label. FDA assigns a unique, ten-digit NDC number to a drug to serve as its universal identifier. The presence of an NDC number on a drug’s label does not mean the drug is FDA-approved or legally marketed.

 7.   What’s the difference between a finished drug product and an active ingredient?

You may wonder why 35% PEROX-AID, an approved fish drug with hydrogen peroxide as the active ingredient, is different than another source of hydrogen peroxide.

In the context of an approval, conditional approval, or Index listing, the term “drug” refers to the final drug product. The final drug product includes both active and inactive ingredients.

An active ingredient is the pharmacologically-active component responsible for achieving the drug’s intended purpose—for example, to treat a disease or to change the structure or function of the body. A drug may have one or more active ingredients. Inactive ingredients are all other components of the final drug product, such as coloring and flavoring substances, preservatives, and binding agents.

When FDA approves a drug, the agency is approving the final drug product, not the active ingredient alone.

Now let’s take another look at 35% PEROX-AID. This approved final drug product, which contains a specific concentration of hydrogen peroxide, was shown to be consistently manufactured to ensure its strength, quality, and purity. The final drug product was also shown to be safe and effective to control mortality due to certain fungal and bacterial fish diseases. Another hydrogen peroxide product, even at the same concentration, isn’t the same as 35% PEROX-AID. Unapproved hydrogen peroxide products may not be safe or effective to treat fish diseases, and the quality and consistency of the manufacturing process cannot be assured.

 8.   What’s the difference between an approved new animal drug and a drug that has an INAD exemption?

You’ve probably heard that theU.S. Fish & Wildlife Service’s Aquatic Animal Drug Approval Partnership (AADAP) Program  is the sponsor of an INAD for the fish sedative AQUI-S® 20E (eugenol), and several other drugs, but you may be confused by what that means.

First, let’s define “INAD.” The acronym stands for Investigational New Animal Drug. An “INAD exemption” allows a drug sponsor to ship the investigational drug for research purposes.

For administrative purposes, CVM assigns an INAD file number in the beginning of the approval process. The sponsor then uses the INAD file as a way to correspond with CVM. For example, the sponsor uses the file to communicate with CVM before treating fish. Before treated fish can enter the food supply, the sponsor must ask CVM for permission and have the center grant a “food use authorization.” Before granting the food use authorization, CVM makes sure that treated fish are safe for people to eat.

When conducting studies under the INAD exemption, researchers follow a specific study protocol as well as certain procedures for reporting results, problems, and other information to the sponsor. All information is submitted to CVM as part of the INAD file. For any study done under the INAD exemption, the drug is for investigational use only—it’s not approved, or if the drug is approved for other intended uses, it’s not yet approved for the intended use under investigation.

In the case of AQUI-S® 20E, fishery professionals can legally obtain the drug by working with AADAP under the program’s INAD exemption. Fishery professionals who cooperate with AADAP and comply with all investigational procedures, food use authorization conditions, and reporting requirements can legally use the fish sedative for research purposes.

Let’s revisit the question about the difference between a drug and an active ingredient. The active ingredient in AQUI-S® 20E is eugenol, but the food use authorization granted under AADAP’s INAD exemption has a very narrow and specific scope and doesn’t cover all eugenol-containing products. Although clove oil contains eugenol, clove oil isn’t the same as AQUI-S® 20E. Clove oil is not part of the food use authorization nor is it approved. CVM has concerns about the potential of some components of clove oil to cause cancer (seeGuidance for Industry 150 for more information).

9.   What should I do if I experience a problem with a fish drug?

Problems with any drug, approved or not, include adverse drug events and product defects. Adverse drug events are undesired side effects associated with a drug or a lack of effect (the drug doesn’t do what it’s supposed to do). Adverse drug events also include unfavorable reactions in people who handle the drug. Product defects are problems such as defective packaging or abnormal appearance of the drug.

CVM encourages veterinarians, fish health specialists, fishery biologists, hatchery managers, researchers, and animal owners to report adverse drug events and product defects with approved animal drugs to the drug company. The Federal Food, Drug, and Cosmetic Act requires drug companies to submit all reports of problems that they receive to FDA. The required reporting of adverse drug events and product defects allows CVM’s Office of Surveillance and Compliance to more easily identify and correct problems with approved animal drugs.

For unapproved animal drugs, you can voluntarily report adverse drug events and product defects to FDA.Information for fisheries on how to report adverse drug events is available on CVM’s website.

 10. What are FDA’s concerns about unapproved animal drugs? Why should I care?

The term “unapproved animal drugs” means animal drugs illegally marketed in the U.S. that haven’t been approved, conditionally approved, or indexed by FDA. The agency has serious concerns about unapproved animal drugs because they potentially put the health of animals and people at risk. These drugs are not reviewed by FDA and may not meet the agency’s strict standards for safety, effectiveness, and quality. Unapproved animal drugs also may not be labeled or advertised appropriately or truthfully.

With no FDA review of an animal drug, there’s no way for veterinarians, fishery biologists, animal owners and others to know if a drug is safe and effective or if its manufacturing process is adequate to maintain the drug’s quality and consistency from batch to batch. Also, because there are no requirements to report adverse drug events and product defects for unapproved animal drugs, CVM’s Office of Surveillance and Compliance may not be able to easily identify and correct problems with these drugs.

 11. What about products I hear referred to as “low regulatory priority”?

CVM has identified a number of unapproved products used in aquaculture that have been called “low regulatory priority” when used in fish intended for human consumption. These products should more appropriately be considered low-risk products. These products are not approved. However, CVM has determined that exposure of fish to these products, as outlined in FDA’s Fish and Fishery Products Hazards and Controls Guidance, are unlikely to result in a risk to human health if people consume the fish.

Keep in mind that just because CVM has determined that these are low-risk products doesn’t mean they are FDA-approved or that CVM has determined that they are safe and effective for fish. Also keep in mind that in the future, CVM can take a different position on the use of any low-risk product. CVM’s primary goals are to protect public health and encourage sponsors to pursue approval of drugs that will meet the therapeutic and production needs of the aquaculture industry.

Hopefully, this article answers many of your questions about aquaculture and FDA. If you have more questions or would like more information, please contact CVM’s Communications Staff at 240-276-9300 orAskCVM@fda.hhs.gov.

(Source FDA)