This page will guide the aquaculture pioneer new animal drug sponsor through the first steps of opening an Investigational New Animal Drug (INAD) file and the New Animal Drug Approval (NADA) process. The steps to aquaculture drug approval are the same as those for any animal drug approval. That information is repeated here for your convenience. Additionally, there is specific information regarding environmental considerations and requesting authorization for investigational animals to enter the human food supply. Information about incentives applicable to aquaculture drug approval is also included.
For assistance in navigating the approval process, please email CVM.ONADE.PM@fda.hhs.gov.
NOTE: For sponsors seeking approval for an aquaculture drug that will be a copy of a previously approved drug, this is a generic new animal drug. Please contact the Division of Generic Animal Drugs at CVMDGADMGT@fda.hhs.gov. You may also refer to Abbreviated New Animal Drug Applications for more information on the generic new animal drug approval process.
As a first step, we strongly encourage aquaculture new animal drug sponsors to review CVM GFI #61: Special Considerations, Incentives, and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species.
Target Animal Safety and Effectiveness
In the Target Animal Safety (TAS) technical section, the sponsor must show that the new animal drug is safe for the target animal(s) when it is used according to the label. 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.
In the Effectiveness technical section, the sponsor must show that the new animal drug works in the target animal(s) when it is used according to the label. The goal of a standard effectiveness study is to make sure the drug will do what it is expected to do when it is used under the conditions of use proposed by the sponsor.
CVM GFI #61: Special Considerations, Incentives, and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species provides additional information for developing the Target Animal Safety and Effectiveness technical sections for aquaculture sponsors.
In general, a study should be randomized, masked, and well-controlled. The statistical analysis model should take into consideration the study design. A summary of sample size estimation should be provided in the study protocol so that CVM will know whether the study is adequately powered. Sample size refers to the number of experimental units, which can be individual fish or tank of fish, depending on the randomization of animals to the treatment groups, the route of drug administration, and other factors. We encourage you to submit the protocol for concurrence before you conduct the study.
To facilitate CVM’s review, a data submission should include a README file; the protocol and the final study report (FSR) should include section numbers, section titles, and PDF bookmarks. More details can be found in CVM GFI #197: Documenting Electronic Data Files and Statistical Analysis Programs.
Human Food Safety
A sponsor must provide scientific data or information to demonstrate that the residues of new animal drugs in the edible tissues of treated animals are safe. For new animal drugs used in food-producing animals, the human food safety evaluation ensures that the food derived from treated animals is safe for human consumption. CVM assesses the human food safety from the perspectives of microbial food safety, toxicology, and residue chemistry.
The general principles for evaluating human food safety are described in GFI #3: General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food Producing Animals.
Microbial Food Safety
One part of CVM’s overall safety assessment is a determination of microbial food safety in which CVM factors whether the drug is:
- regularly considered to have properties that would exert antimicrobial resistance pressure on bacteria of public health concern,
- used to treat zoonotic gastroenteritis or other bacterial disease in humans,
- under development to treat a bacterial disease in humans, and
- approved for a bacterial disease in a food-producing animal species.
Based on responses to the above, CVM will determine if a sponsor needs to submit for review any microbial food safety-related information. Our recommendations on how sponsors may address potential food safety hazards and characterize their risk to human health can be found on page 6 of GFI #3: General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food Producing Animals.
The toxicology section reviews safety data on the new animal drug, which is usually provided in the form of toxicity studies in laboratory animals. A standard set of studies are designed to evaluate the adverse effects and to establish the no-observed-effect levels (NOELs)/no-observed-adverse-effect levels (NOAELs) of the new animal drugs. A general toxicology testing approach is outlined in GFI #149 (VICH GL33): Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: General Approach to Testing. Review of toxicity studies and other toxicology information results in the establishment of an acceptable daily intake (ADI), and/or acute reference dose (ARfD); based on the ADI and/or ARfD, safe concentrations of the total drug residues in edible tissues of treated animals are calculated. Chronic ingestion of the drug residues at and below the ADI is considered to be safe (reasonable certainty of no harm) to human consumers. In addition to the general testing approach, CVM also accepts alternative approaches when such approaches are scientifically justified.
Sponsors can find additional details on page 7 of GFI #3: General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food Producing Animals.
Residue chemistry studies assess the quantity and nature of the residues in edible tissues (meat, milk, eggs, and honey) derived from animals treated with new animal drugs. Sponsors seeking approval of new animal drugs for use in animals intended for human consumption address the residue chemistry component as part of the drug approval process.
CVM’s recommendations on how to design various studies to address the residue chemistry component can be found on page 16, Table 3 of GFI #3: General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food Producing Animals.
CVM’s recommendations regarding study design that will facilitate the universal acceptance of the generated residue depletion data to fulfill the national/regional requirements for drugs intended for use in aquatic food-producing species can be found on GFI #257: Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Species: Marker Residue Depletion Studies to Establish Product Withdrawal Periods in Aquatic Species.
Sponsors may propose scientifically justified alternative approaches to address the residue chemistry component of the drug approval process. Proposals will be evaluated through a review process. We encourage sponsors to contact the Division of Human Food Safety to discuss their plans.
Chemistry, Manufacturing, and Controls
How a drug is manufactured is essential to determining and preserving the identity, strength, quality, and purity of the drug. For this reason, sponsors must demonstrate that their specific manufacturing process and manufacturing sites will consistently produce a safe and effective commercial drug. Sponsors provide this information for the final formulation (i.e., the formulation intended for marketing) in the Chemistry, Manufacturing, and Controls (CMC) technical section.
For example, sponsors provide detailed information about the manufacturing process, dosage form, formulation, container closure system, and analytical controls to demonstrate their capabilities for commercial manufacturing. Specific studies (e.g., mixing, stability, batch manufacturing) are provided to demonstrate the commercial manufacturing consistently produces a drug with the same quality attributes as the drug demonstrated to be safe and effective in clinical studies. Other studies may be needed to support statements on the drug product label (e.g., in-use stability and instructions for preparation of the drug for administration).
The information in the CMC technical section is compared to what was used to manufacture the investigational new animal drug used in safety and effectiveness studies and serves as the basis for evaluating future manufacturing changes after the drug is approved. Consequently, the sponsor’s responsibilities for reporting manufacturing information to CVM is a long-term commitment for the life of the product.
Facilities used for the manufacture of drugs are required by law to meet Current Good Manufacturing Practice (CGMP). CGMP inspections of manufacturing facilities ensure that the drug sponsor’s procedures are being followed and that the facilities’ quality systems are appropriately maintained. Facilities are subject to routine inspections throughout the life of the product.
Sponsors can find additional details at Chemistry Manufacturing and Controls (CMC) Guidances for Industry (GFIs). Sponsors should meet with the Division of Manufacturing Technologies to discuss CMC considerations for their specific drug product.
Under the National Environmental Policy Act (NEPA), the Center for Veterinary Medicine (CVM) must evaluate whether Agency actions will have significant environmental impacts. In the context of new animal drugs, Agency actions include investigational studies under an investigational new animal drug (INAD) file, requests for eligibility for indexing, and approval of new animal drug applications (NADA). Therefore, in accordance with the Food and Drug Administration’s (FDA) NEPA implementing regulations your request for Agency action must include either an environmental assessment (EA) or a claim of categorical exclusion (CE) from the requirement to prepare an EA [21 CFR 25.15(a)].
In general, preparation of an EA is required (21 CFR 25.20) for any proposed action that does not meet the criteria for a categorical exclusion, or if extraordinary circumstances (21 CFR 25.21) indicate that any specific proposed action that ordinarily would be categorically excluded may significantly affect the quality of the human environment. Actions that meet the criteria of categorical exclusion are listed in 21 CFR 25.33. For new animal drugs used in aquatic species, the environmental exposure may not be limited, increasing the possibility that environmental concerns may exist. Therefore, CVM may request additional information (e.g., predicted environmental concentrations) to help with the evaluation of extraordinary circumstances. If extraordinary circumstances exist, an EA would need to be prepared for the proposed action (21 CFR 25.21).
We recommend sponsors of aquaculture drugs begin work on the Environmental Impact technical section early in the development process to avoid unnecessary delays in completing this technical section. We also recommend that you meet with the appropriate Environmental Team to discuss your proposed drug if potential environmental concerns exist or if preparation of an EA is needed.
An INAD file is the investigational file under which studies to document the safety and effectiveness of a new animal drug are conducted. Studies under an INAD file can be used to support a New Animal Drug Application (NADA). The regulations regarding INADs are in 21 CFR 511.
The new animal drug application (NADA) process is a systematic way to document the safety, effectiveness, and proper manufacturing to support approval of the new animal drug.
The recommended approval pathway is the phased review process, where a sponsor submits data and information supporting technical section requirements for incremental review under the INAD file. CVM recommends using the phased review process, because this process allows for greater CVM and sponsor interaction that is critical to the development of new, innovative products. Additional information about the approval process can be found at the links below.
The regulations for New Animal Drug Applications are in 21 CFR Part 514.
An overview of the animal drug approval process is at: From an Idea to the Marketplace: The Journey of an Animal Drug through the Approval Process.
A CNADA is used to seek conditional approval of a new animal drug. A conditionally approved product has met all the requirements to support the full approval of the new animal drug except for a demonstration of “substantial evidence of effectiveness.” For a CNADA, the applicant must demonstrate a “reasonable expectation of effectiveness.” A conditionally approved product allows the applicant to legally market the new animal drug for up to 5 years, provided FDA approves the required annual renewal requests, while the applicant continues to collect the effectiveness data needed to meet the “substantial evidence” standard for full approval.
Aquaculture drugs are eligible for the conditional approval pathway because they are new animal drugs intended for use in minor species criteria. For information regarding CVM’s processes for determining conditional approval eligibility, please see CVM ONADE’s P&P 1243.5704 Process for Eligible Sponsors to Obtain Conditional Approval.
For more information about INADs, NADAs, and CNADAs, please visit New Animal Drug Applications.
Indexing is an alternative to the approval process available for drugs intended for use in certain minor species. It provides legal marketing status, which means indexed drugs, while considered unapproved, can be legally marketed in the U.S. The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index) is limited to:
- new animal drugs intended for use in a minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food-producing animals; and
- in a hatchery, tank, pond, or other similar contained man-made structure in an early, non-food life stage of a food-producing minor species, where safety for humans is demonstrated in accordance with the standard of section 512(d) (including, for an antimicrobial new animal drug, with respect to antimicrobial resistance).
The review process for indexed drugs includes an integrated process of FDA and qualified expert panel review. There are three submissions that must be successfully completed to add a drug to the Index. They include:
- Requesting determination of eligibility for indexing;
- Proposing a qualified expert panel to evaluate the target animal safety and effectiveness of the drug; and
- Requesting addition to the Index.
Once a drug is added to the Index, there are reporting requirements that are similar to an approved drug. These include submission of annual indexed drug experience reports, reporting adverse drug events, and submission of distributor statements (if one is being used).
To learn more about indexing, please see Drug Indexing.
Public Master Files are files that contain publicly available studies or other non-proprietary information intended to support drug approvals. Drug sponsors can use the information in PMFs to support their approvals.
For information on public research partners and public work completed for aquaculture drugs please refer to Public Master Files (PMFs) Supporting Applications for Minor Use and Minor Species Drugs.
The Animal Drug User Fee Act (ADUFA) and its amendments, amended the Federal Food, Drug, and Cosmetic Act (FFDCA) and authorized FDA to collect fees for certain animal drug applications, and for the establishments, products, and sponsors associated with these and previously approved animal drug applications, in support of the review of animal drugs.
Aquaculture drug sponsors are all eligible for Minor Use Minor Species fee waivers. Specific information is available in CVM GFI #170: Animal Drug User Fees and Fee Waivers and Reductions.
Note that waivers from annual fees must be requested annually. The first fee for which you will typically request a waiver is the annual sponsor fee once you establish a file with us.
Information about user fees is available at: Animal Drug User Fee Act (ADUFA).
For waiver related questions, please contact: CVMADUFA@fda.hhs.gov.
If you are a non-U.S. firm, you will need a U.S. Agent. Please keep in mind that your U.S. Agent must either reside in the U.S. or maintain a place of business in the U.S. The U.S. Agent cannot use a post office box as an address. The U.S. Agent cannot use just an answering service. They must be available to answer the phone or have an employee available to answer the phone during normal business hours. Your U.S. Agent must make all submissions to CVM on your behalf.
For more information on how CVM’s ONADE interacts with U.S. agents, please see P&P 1243.2020: United States (U.S)-Based Employee and U.S. Agent Representation of Foreign Sponsors.
Sponsors are not required to work with a consultant. A sponsor new to animal drug approval may find it helpful to work with an experienced consultant. If you wish to have the consultant make submissions or otherwise contact the agency on your behalf, a G submission to the applicable file(s) (e.g., INAD), outlining those permissions, is required in addition to the consultant being registered for electronic submission.
Submissions are made using the CVM’s eSubmitter tool.
You will appoint someone (e.g., regulatory staff, a consultant, or U.S. Agent) to make submissions via CVM’s eSubmitter tool. CVM recommends a sponsor have two assigned stakeholders who are capable of making submissions.
You will also need to identify the responsible official associated with each submission.
eSubmitter is the electronic submission platform in which all submissions are made to the CVM.
Information about setting up eSubmitter and using eSubmitter to make electronic submissions is available at: CVM eSubmitter Program for Animal Drugs - Office of New Animal Drug Evaluation. Additional details are available through the “Resource Center” link at the bottom of the page.
The FDA Electronic Submissions Gateway (FDA ESG) is the conduit through which successful electronic submission of information to the CVM Electronic submission system (CVM ESS) for review and evaluation must occur. The FDA ESG is separate and distinct from the CVM ESS. The purpose of the FDA ESG is to provide a centralized, Agency-wide communications point for securely receiving electronic regulatory submissions. Stakeholders seeking to make electronic submissions to the CVM ESS must register separately both with the FDA ESG and the CVM ESS. Registration for both systems can be done simultaneously and may take at least 30 days.
FDA ESG: Registering with the FDA ESG includes several steps, including requesting a WebTrader account, and the process may take up to 30 days to complete. Some helpful resources for getting set up with FDA ESG include:
- Setting up a WebTrader Account Checklist
- ESG Chapter 2 Overview of The Registration Process
- ESG overview: Electronic Submissions Gateway
- ESG User Guide: User Guide
- Section IV and Appendix 3 of CVM GFI #108: Registering with CVM Electronic Submissions System
For FDA ESG and WebTrader support, contact: ESGHelpDesk@fda.hhs.gov.
CVM ESS: You can register with CVM ESS at the same time you register for the FDA ESG. Some helpful resources for getting set up with CVM ESS include:
For CVM ESS support, contact: email@example.com.
CVM eSubmitter: CVM eSubmitter is a free, question-based tool that allows animal drug sponsors to electronically and securely submit information to the center. Once you are registered with FDA ESG and CVM ESS, you can use the CVM eSubmitter tool to create and send submissions. Some helpful resources for getting started with CVM eSubmitter include:
- CVM eSubmitter program download
- CVM eSubmitter quick guide
- CVM eSubmitter Program for Animal Drugs—Office of New Animal Drug Evaluation
- CVM Recommended File Specifications for eSubmitter
- Getting Started with eSubmitter
For CVM eSubmitter support, contact: firstname.lastname@example.org.
A request to establish an Investigational New Animal Drug (INAD) file should be submitted through eSubmitter. The regulations regarding INADs are in 21 CFR 511.
General summary of the “INAD-A” eSubmitter template specific requirements:
- Screen: 6.0 Submission Type Code/Amendment Information
- Select “Establish INAD File (A), Other; Unclassified
- Select “Division of Food Animal Drugs (HFV-130)”
- Screen: 7.0 Product Description
- Populate required fields: “Does the drug product have a USP monograph?”, product established name and details such as product dosage form, Route of Administration (ROA) and Target Animal designations.
- For specific information on completing the product related information fields, please see CVM eSubmitter Product Book Quick Guide.
EI is defined as “data and /or information which uniquely describes the general attributes of the new animal drug.” We recommend that EI be submitted as part of the initial request to open an investigational new animal drug (INAD).
For more information regarding CVM ONADE’s processes for accepting and reviewing EI, please see CVM ONADE’s P&P 1243.2200 Submission and Review of Early Information (EI) to Presubmission Conferences and Protocol Review.
Yes. Please refer to CVM GFI #61: Special Considerations, Incentives, and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species for additional information and for a list of other guidance for industry (GFI) documents that can help to guide you through parts of the approval process. These documents provide guidance and give you an idea of what we typically see; however, you can propose alternative approaches.
After you have established the INAD, you can submit other requests, such as a pre-submission conference and a food use authorization (authorization to slaughter animals for human consumption).
A pre-submission conference is a meeting to discuss the proposed indication and requirements for drug approval. The regulation regarding pre-submission conferences is 21 CFR 514.5.
If you are going to request an aquaculture food use authorization, (requesting authorization for investigational animals to enter the human food supply) you will need to:
- propose the number of animals that you anticipate you will need to conduct studies,
- describe the drug and intended dose and duration
- propose a withdrawal period, and
- request a waiver of notification of slaughter, if applicable.
When proposing a withdrawal period, you should provide as much residue information as you have so our residue chemists can assign an appropriate investigational withdrawal period.
A waiver of notification of slaughter is only needed for aquaculture food use authorization requests when the species to be treated is catfish or a group of fish that includes catfish (e.g., finfish). If a waiver is not requested for catfish, you will have to report the date and place of slaughter of all investigational catfish to USDA/FSIS and us prior to sending the animals to slaughter.
It is important to note that the proposed conditions of use included in your request for a food use authorization should be the same as those included with your claim of categorical exclusion (CE) for the investigational use of the new animal drug. If the conditions of use are not the same, then you should contact CVM because a new claim of CE may be needed.
The shipment or delivery of a new animal drug within the United States (US) intended for clinical investigations requires the submission of an environmental assessment (EA) or a claim of categorical exclusion (CE) from the requirement to prepare an EA [21 CFR 511.1(b)(10)]. In most cases, a claim of CE will likely be appropriate. Therefore, if clinical investigations or any shipments of the drug have occurred within the US or are expected to occur prior to the new animal drug application (NADA) approval, then a claim of CE according to 21 CFR 25.33(e) should be submitted.
With a claim of CE, you must certify that to your knowledge, no extraordinary circumstances exist that may significantly affect the quality of the human environment as discussed under 21 CFR 25.21. For new animal drugs used in aquatic species, the environmental exposure may not be limited, increasing the possibility that extraordinary circumstances may exist for investigational use of the new animal drug. If extraordinary circumstances are identified, you should contact CVM because the submission of an EA may be needed.
If you have questions regarding the environmental requirements for the investigational use of a new animal drug, please contact CVM. For more information on CVM ONADE’s processes regarding this topic, please see P&P 1243.7220 Processing Environmental Impact Submissions for New Animal Drugs.
The information provided above only addresses the investigational use of the new animal drug. Before submitting your administrative NADA, a separate EA or claim of CE to satisfy the Environmental Impact technical section of the NADA is required. Additionally, if you intend to pursue a conditional approval, a separate EA or claim of CE for the conditional approval will be needed.
Yes. The New Animal Drug Regulations, Sections 21 CFR 511.1(b)(3), 21 CFR 511.1(b)(4) and 21 CFR 511.1 (b)(10) require the sponsor to submit specific information prior to each shipment or other delivery of the drug for clinical investigation in animals.
For more information on CVM ONADE’s processes regarding these notices, please see P&P 1243.4066 Notice of Claimed Exemption (NCIE).
Yes, there are several government programs that may be able to assist with some elements of drug approval for an aquaculture product through waivers of user fees and financial assistance. For example, the FDA/CVM Office of Minor Use and Minor Species (OMUMS) has programs that provide incentives including financial assistance through grants for minor species drugs, including aquaculture. Another public resource is Public Master Files (PMFs). These are files that contain publicly available studies or other non-proprietary information. For more information on PMFs, please see: Public Master Files (PMFs) Supporting Applications for Minor Use and Minor Species Drugs. Additionally, programs such as the US Department of Agriculture’s Minor Use Animal Drug Program (MUADP) and US Fish and Wildlife Services’ Aquatic Animal Drug Approval Partnership Program (AADAP), are involved in research to support aquaculture drug approvals.
- To learn more about OMUMS, please see: Minor Use/Minor Species.
- To learn more about MUADP, please see: MUADP - Home.
- To learn more about AADAP, please see: Aquatic Animal Drug Approval Partnership Program | U.S. Fish & Wildlife Service (fws.gov)
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