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  6. Q&A for Developers of Animal Cells, Tissues, and Cell- and Tissue-Based Products (ACTPs)
  1. Cell and Tissue Products for Animals

Q&A for Developers of Animal Cells, Tissues, and Cell- and Tissue-Based Products (ACTPs)

What is an ACTP?

“ACTP” is an acronym for animal cells, tissues, and cell- and tissue-based products. In these Qs and As, when referring to the term “ACTP”, we are referring to an ACTP that is intended to diagnose, cure, mitigate, treat, or prevent disease in animals or is intended to affect the structure or any function of a recipient animal. ACTPs require FDA approval, conditional approval, or index-listing to be legally marketed.

What are examples of ACTPs?

Examples include cells and tissues such as:

  • Stem cells (including those consisting of mesenchymal stem cells, induced pluripotent stem cells, or embryonic stem cells)
  • Precursor and progenitor cells
  • Differentiated cells
  • Stromal vascular fraction
  • Bone marrow aspirate concentrate
  • Amnion, amniotic membrane, and/or amniotic fluid
  • Whole and homogenized tissues
  • Blood and blood-derived products (such as platelet-rich plasma and autologous conditioned serum)
  • Conditioned media
  • Exosomes

What FDA Guidances are available for ACTPs?

The following guidances are available for ACTPs:

Are there FDA resources available concerning ACTPs?

Resources include:

Is my product regulated by FDA or USDA?

Animal cells and tissues may be subject to regulation by FDA and/or USDA. FDA’s Center for Veterinary Medicine (CVM) and USDA’s Center for Veterinary Biologics work together concerning the regulatory oversight of a product. We encourage you to contact us early in product development and prior to opening a file to determine which agency will regulate your product. Send your questions to AskCVM@fda.hhs.gov.

See FDA’s webpage on Animal Biologicals for additional information.

How does FDA determine if a product is regulated as a device?

You can refer to FDA’s webpage on Animal Drugs Marketed as Animal Devices for more information. You can also refer to GFI #218 "Cell-Based Products for Animal Use" for information on the regulation of ACTPs. If you have questions about the status of your product, you are encouraged to contact FDA’s Center for Veterinary Medicine (CVM) at AskCVM@fda.hhs.gov.

I am developing an ACTP. When is the best time to contact FDA?

We encourage you to contact FDA as early as possible in the development of your product. Engagement with FDA early in your research and development is especially important for ACTPs, as these are novel products that often have unique scientific considerations. We can help you determine the regulatory requirements that apply to your product.

Opening a file with FDA early in your product research and development enables you to take part in on-going discussions with FDA. You may establish a Veterinary Master File (VMF) to engage in early product development discussions with FDA as you work toward determining the precise product and indication that you wish to pursue. If you have determined the precise product and indication and are ready to submit information to FDA to support approval, you can open an investigational file (INAD). You can reach out to FDA’s Center for Veterinary Medicine (CVM) Project Management Team at CVM_PM_Biotech@fda.hhs.gov for help determining what file type is most appropriate for your stage of development and to understand the requirements for each file type.

Can I develop similar products for both human and animal use?

Yes. If you are developing products intended for both human and animal use, this will involve oversight from both FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Veterinary Medicine (CVM). We encourage you to reach out to both Centers early in the development process. Data intended to support the ACTP approval may be generated during preclinical development of the human product. Before you generate data in the target species, you can meet with CVM to discuss your development plan.

My laboratory provides a service to veterinarians by processing autologous animal cells or tissues and returning them to the veterinarian for use in a patient animal. Is this regulated by FDA?

ACTPs intended to diagnose, cure, mitigate, treat, or prevent disease in animals, or affect the structure or any function of the recipient animal, are generally regulated as ACTPs by FDA. Persons performing operations (such as processing, packaging, holding, testing, analyzing, or labeling) required to produce an ACTP are considered manufacturers. This includes persons operating in a laboratory setting. Manufacturers of ACTPs are subject to the same regulatory requirements as manufacturers of other products. 

Do I need to open a file with FDA before I conduct a study in client-owned animals using an investigational ACTP?

Yes. To ship your investigational ACTP, you must comply with the regulations for an investigational exemption in Title 21 Code of Federal Regulations (CFR) § 511.1(b). These regulations require you to submit to FDA a notice of claimed investigational exemption (NCIE) before conducting your study. You can do this by opening an investigational file with FDA and providing certain information about the study and investigators. FDA can help you establish the file and understand the regulatory requirements associated with conducting clinical studies.

What are the user fees associated with opening and holding a file with FDA and are there fee waivers available?

An Investigational New Animal Drug (INAD) file is subject to an annual sponsor fee. A Veterinary Master File (VMF) is not subject to user fees.

You can find information on fee waivers, including the Significant Barrier to Innovation waiver, in GFI #170 "Animal Drug User Fees and Fee Waivers and Reductions."

    What are some of the scientific considerations for ACTPs?

    The scientific considerations that impact development of ACTPs are related to the biologic nature of these products. These considerations include, but are not limited to, the following:

    • Characterization
      • In contrast to most conventional drugs that are chemically synthesized and have a known structure, most ACTPs are complex mixtures that are not easily identified or characterized. Each product is likely to have a unique set of characteristics that define the product and its risk profile. For example, the donor-recipient relationship (autologous, allogeneic, xenogeneic), cell or tissue type (embryonic stem cell, mesenchymal stem cell, induced pluripotent stem cell, etc.), and processing and manipulation (culture expansion, reprogramming, intentional genomic alterations, etc.) are influential ACTP characteristics that impact safety, effectiveness, and quality of the product.
    • Variability
      • As biologically-derived products, ACTPs are often highly variable in nature, which can impact the safety, effectiveness, and quality of the product. For example, cells donated from different donors may have different growth rates, secretion profiles, or gene expression, which may result in differences in potency and clinical outcomes. Considerations associated with variability in ACTPs include uniform donor selection, controlled manufacturing processes and procedures, potency assays, and comparability of multiple batches.
    • Donor eligibility
      • ACTPs are often produced from cells and tissues procured from donor animals. This presents a risk for transmission of diseases from the donor to the recipient. Considerations associated with selection of donors include health and screening assessments of donors, risk assessments for exposure to disease agents, and disease agent testing programs.
    • Safety
      • Many ACTPs are transplants of cells or tissues and as such may cause immune reactions. Some ACTPs may also cause ectopic tissue formation or tumors. Some ACTPs may distribute widely in the body or to unintended locations, which may cause adverse events. The specific safety risks are dependent on the unique characteristics of the product and factors such as biodistribution and cell survival.
    • Mechanism of action
      • ACTPs are most often evaluated for use in regenerative medicine applications because of their promise for functional repair of tissues; however, the mechanism of action of many ACTPs is likely multifactorial and not yet well understood. Mechanism of action may vary based on the type of ACTP and may impact the expected clinical effect of the product, relevant target population, and potency assay and effectiveness study design.

    What manufacturing standards apply to ACTPs?

    ACTPs are required to meet Current Good Manufacturing Practice (GMP) as described in 21 CFR parts 210 and 211. See CVM GFI #253 Current Good Manufacturing Practice for Animal Cells, Tissues, and Cell- and Tissue-Based Products and CVM GFI #254 Donor Eligibility for Animal Cells, Tissues, and Cell- and Tissue-Based Products. Although the current good tissue practice (GTP) in 21 CFR part 1271 only apply to human cellular and tissue-based products, the principles described in GTP can provide a basic reference for the handling of cells and tissues used in the manufacture of ACTPs.

    Is conditional approval an option for my ACTP?

    ACTPs may be eligible for conditional approval under certain circumstances. Conditional approval requirements may be difficult to meet for most ACTPs due to the novel nature of the products, the inter-related nature of safety, effectiveness, and manufacturing, and the current state of the science. If you are a developer of an ACTP, contact FDA early in the development process to discuss the feasibility of this pathway for your product.

    For an explanation of conditional approval, including eligibility criteria, see the Center for Veterinary Medicine’s webpage, "Conditional Approval Explained: A Resource for Veterinarians", and GFI #261 “Eligibility Criteria for Expanded Conditional Approval of New Animal Drugs.”

    What is FDA doing to facilitate development of ACTPs?

    FDA has multiple initiatives to facilitate development of ACTPs. In October 2018, FDA launched the Veterinary Innovation Program, or VIP, to foster development and research of ACTPs and other biotechnology products. Benefits of the VIP include, but are not limited to, the option for pre-investigational development meetings, pre- and post-review feedback for technical section submissions, and the ability to stop the review clock for major technical section submissions.

    FDA also has a program devoted to ACTP research, which serves to inform FDA’s regulatory approach and answer scientific questions. Publications from this research program include journal articles on topics such as:

    Additionally, FDA engages in outreach to stakeholders by attending and presenting at professional group meetings and conferences. FDA has previously spoken at conferences including the North American Veterinary Regenerative Medicine Association, Scientific Liaison Coalition, American Veterinary Medical Association, and the International Society of Cell and Gene Therapy. In October 2021, FDA posted a pre-recorded webinar on the development of ACTPs to provide information and examples on current good manufacturing practice related to preserving cellular function and integrity, ensuring consistency of the process and product, preventing contamination, selecting appropriate donors and preventing transmission of disease.

    What is the Veterinary Innovation Program (VIP), and how do I enroll my product?

    The FDA Center for Veterinary Medicine’s (CVM) Veterinary Innovation Program, or VIP, is for certain intentional genomic alterations (IGA) in animals and ACTPs. The goal of the VIP is to facilitate advancements in development of innovative animal products by providing greater certainty in the regulatory process, encouraging development and research, and supporting an efficient and predictable pathway to market for ACTPs and IGAs in animals.

    We recommend you contact CVM as early as possible in the development process if you are interested in participating in the VIP for your product.

    Are there incentives available for sponsors developing ACTPs for minor species or minor uses in major species (MUMS)?

    Yes. Refer to the Center for Veterinary Medicine’s Minor Use/Minor Species webpage for information on MUMS incentives. 

    Does FDA evaluate environmental impacts of ACTPs?

    Under the National Environmental Policy Act (NEPA), FDA must evaluate all major actions it takes to determine whether they will have a significant impact on the human environment. Under FDA’s regulations, major actions include actions on new animal drug applications, thus NADAs require submission of either an environmental assessment (EA) or a claim of categorical exclusion (CE) from the requirement to prepare an EA (21 CFR 25.15(a)). ACTPs intended for use in non-food animals may qualify for a claim of CE, for both investigational use under 21 CFR 25.33(e) and the new animal drug application (NADA) under 21 CFR 25.33(d)(1), unless extraordinary circumstances indicate the action would significantly affect the environment (21 CFR 25.21). ACTPs intended for use in food animals may qualify for a CE for the investigational use of the drug under 21 CFR 25.33(e) and the NADA if they meet the criteria of a CE listed under 21 CFR 25.33. If the action does not meet the criteria for a claim of CE or extraordinary circumstances exist (21 CFR 25.21), then an EA may need to be prepared. The scope of an EA for the use of ACTPs will depend on the intended use and what target animal species is being proposed.

    For more information on environmental impact considerations at FDA Center for Veterinary Medicine (CVM), visit Environmental Impact Considerations.

    How do I contact FDA with questions about ACTPs?

    All inquiries can be sent to AskCVM@fda.hhs.gov.

     

     
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