On this page:
- Novel Approaches
- Continuous Manufacturing and Other Advanced Manufacturing Technologies
- Flexibilities in the Review Process
- Legislative Authorities
- Communication with Stakeholders to Increase Transparency and Predictability
- Research to Support Approval
The FDA’s Center for Veterinary Medicine (CVM) protects and promotes public health by ensuring that animal drug products are evaluated for safety and effectiveness; manufactured under quality standards; and properly labeled. While CVM evaluates new animal drug products according to existing laws and regulations that define the critical regulatory standards for approval (e.g., substantial evidence of effectiveness, reasonable certainty of no harm), CVM has flexibility in how these standards are met.
CVM does more than review animal drug applications. Promoting public health also requires the Agency to take steps that can help facilitate access to safe, effective, and innovative products, that can address existing, novel, and emerging animal health challenges. CVM takes a proactive approach to ensuring we have the tools and flexible processes to bring these innovations to the market.
CVM is committed to the identification and use of novel approaches to bring innovative products to the market while meeting regulatory standards. The typical process for demonstrating drug effectiveness is conducting a clinical trial; however, there are other ways to prove an animal drug works and alternative study designs to use when the standard design doesn’t fit the situation.
For example, CVM evaluated a range of data sources that demonstrate the safety of ThyroKare in dogs, a drug used to treat hypothyroidism, as an alternative to conducting laboratory animal studies. These sources included (1) a comprehensive review of publicly available literature on the use of levothyroxine in dogs; (2) pharmacovigilance data for ThyroKare that were voluntarily reported to the sponsor when it was previously marketed as an unapproved drug; and (3) reports to an animal poison control center of accidental overdoses of natural or synthetic thyroid hormone products in dogs.
Some other examples include:
- In 2014, CVM approved Folltropin, the first drug that relied on a systemic review of the literature and meta-analysis for the determination of effectiveness. On March 15, 2023, CVM updated its Guidance for Industry #106 entitled, “The Use of Published Literature in Support of New Animal Drug Approvals” to include information on multiple uses of the scientific literature to encourage continued use of this kind of innovative approach.
- In 2018, CVM approved Experior (lubabegron Type A medicated article), the first animal drug that when fed to beef cattle under specific conditions results in less ammonia gas released as a by-product of their waste. The drug sponsor collected data in special environmental chambers where gas emissions could be contained and accurately measured. These studies indicated that the product partially reduces ammonia gas emissions from manure from an individual animal or a pen of animals in semi-controlled conditions in enclosed housing.
- In 2022, CVM approved Solensia (frunevetmab injection), the first monoclonal antibody approved for use in any animal species. Because of the current limitations inherent in studies designed to evaluate the effectiveness of drugs intended to control chronic pain in cats, a weight of evidence approach was used to determine the effectiveness of Solensia. In a pilot study and confirmatory study, three clinical assessments were included that measured different aspects of pain associated with osteoarthritis in cats. In both studies, the owner’s and veterinarian’s assessments agreed that Solensia reduced pain associated with osteoarthritis more than the control; however, the confirmatory effectiveness study did not achieve success as defined by the protocol. In this case, CVM determined that the overall trend of the results in both studies supports the drug’s effectiveness and the weight of the evidence demonstrated that Solensia is effective at controlling pain associated with osteoarthritis in cats.
Continuous Manufacturing and Other Advanced Manufacturing Technologies
One of today’s most important tools for modernizing the animal pharmaceutical industry is a process known as continuous manufacturing. This advanced form of manufacturing transforms the traditional, step-wise manufacturing processes into a single system that’s based on modern process monitoring and controls. CVM supports and encourages the adaptation of advanced manufacturing technologies for animal drug products and encourages any sponsor interested in incorporating advanced manufacturing to meet with CVM to discuss the best regulatory filing strategy for the process. CVM held a public meeting on this topic in 2022 to hear from animal drug sponsors on use of advanced manufacturing technologies and how CVM and assist them in adopting these technologies. Advanced manufacturing is still new and developing. Harnessing the full potential of these innovations will require us to invest time and resources in developing scientific standards and policy and supporting implementation.
Flexibilities in the Review Process
CVM’s scientists regularly look for ways to move regulatory science forward and identify and fill gaps. For example:
- CVM recognizes that there are many critical drugs used by veterinarians that are not approved. CVM published a review of the scientific literature on the safety of one such drug, potassium bromide, in 2012. This innovative approach enabled a drug company to complete the target animal safety standard without performing prospective animal studies, supporting the conditional approval of KBroVet in January 2021.
- In 2018, CVM published a Federal Register notice seeking comments on how to improve the standard design of heartworm effectiveness studies. CVM recognized the limitations of the current recommended laboratory and field effectiveness studies for heartworm preventatives for use in dogs and sought stakeholder input on alternative approaches to these study designs that would reduce the limitations of such studies while also ensuring that the studies generate data to support substantial evidence of effectiveness. On November 9, 2022, the FDA issued draft Guidance for Industry (dGFI) #276 entitled, “Effectiveness of Anthelmintics: Specific Recommendations for Products Proposed for the Prevention of Heartworm Disease in Dogs.” The draft guidance provides specific recommendations for the effectiveness evaluation of drugs intended for the prevention of heartworm disease in dogs, including recommendations on how to establish product effectiveness, better assess effectiveness under actual conditions of use and select heartworm isolates used in laboratory studies. The FDA considered the comments received in response to the 2018 notice in creating dGFI #276. The FDA requested public comment on the draft guidance and is now in the process of revising the draft guidance document.
Veterinary Innovation Program (VIP)
Veterinary regenerative medicine products (e.g., stem cells) and intentional genomic alterations (IGAs) in animals are fast-growing sectors of the animal health and agricultural industries and an active area of animal health research. The FDA initiated the Veterinary Innovation Program (VIP) in 2019 to facilitate advancements in development of these types of innovative animal products. The goals of the VIP are to provide greater certainty in the regulatory process, encourage development and research, and support an efficient and predictable pathway to market for cell- and tissue-based products and IGAs in animals. As of August 2023, there were more than 50 products enrolled in the VIP.
Intentional Genomic Alterations (IGAs) in Animals
IGAs in animals have potentially significant and broad applications to advance animal and human health including development of animal models of human disease, human pharmaceutical production, production of organs/tissues for xenotransplantation, improved animal health/husbandry and enhanced food production. Given the unique nature and evolving science associated with these products, the FDA uses a science- and risk-based review approach to assess the type and amount of information needed to support approval.
In December 2020, CVM approved a first-of-its-kind intentional genomic alteration (IGA) in a line of domestic pigs, referred to as GalSafe pigs, which may be used for food or human therapeutics. This is the first IGA in an animal that the CVM has approved for both human food consumption and as a source for potential therapeutic uses. This approval underscores the success of the FDA in modernizing our scientific processes to optimize a risk-based approach that advances cutting-edge innovations in which consumers can have confidence. The GalSafe pigs were the first products approved under the VIP, demonstrating the impact of this initiative in supporting the sponsor throughout the product review process.
In March 2022, the FDA announced its first low-risk determination for enforcement discretion for an IGA in an animal for food use. The low-risk determination was for the marketing of products, including food, from two genome-edited beef cattle and their offspring after the FDA determined that the IGA does not raise any safety concerns. The IGA results in the equivalent genotype (genetic make-up) and short-hair coat trait seen in some conventionally bred cattle, known as a “slick” coat. This action demonstrated the agency’s ability to identify low-risk IGAs that don’t raise concerns about safety, when used for food production and helped pave the way for animals containing low-risk IGAs to more efficiently reach the marketplace. The FDA posted a webinar about this risk-based review process for IGAs in animals that may pose low risk.
Another resource the agency recently posted is an animal biotechnology webinar intended to help developers understand what data CVM expects them to submit for their product. To accomplish this, CVM prepared hypothetical case studies outlining the risk questions CVM poses for specific types of products. The webinar describes the hypothetical products and provides information on CVM’s oversight process, which entails a science- and risk-based approach with various levels of review (ranging from no review of data, to review of data addressing relevant risk factors, to full review) based on a product’s risk; as well as the data expectations for submissions.
In May 2023, the FDA announced the availability of a webinar for developers who are interested in learning more about the process of requesting an Investigational Food Use Authorization (IFUA) for animals with investigational IGAs. An IFUA permits edible tissues (such as meat, milk, eggs, honey) from animal species treated with investigational products to be used for food. IFUAs are helpful to developers because they allow animals (or their products) to be used for food instead of being wasted. The webinar covers what an IFUA is; when it is appropriate to make an IFUA request; the types of data and information the FDA reviews in support of an IFUA request; three case study examples that cover different types of scenarios where developers of IGAs in animals might request IFUAs; and administrative procedures that developers of IGAs in animals follow when submitting an IFUA request.
To view these webinars and other related resources, see the Center for Veterinary Medicine (CVM) Animal Biotechnology Products Resource Center.
Animal Cells, Tissues, and Cell- and Tissue-Based Products
In 2015, CVM published Guidance for Industry #218, Cell-Based Products for Animal Use, to clarify the regulatory pathway for different types of cellular products. In October 2022, CVM published additional guidance on good manufacturing practices (Guidance for Industry #253) and donor eligibility for animal cell- and tissue-based products (Guidance for Industry #254). To help animal owners, veterinarians, researchers, and the public with access to information on clinical field studies investigating the use of these products in veterinary patients, CVM maintains a listing of Clinical Field Studies for Animal Cells, Tissues, and Cell- and Tissue-Based Products.
The FDA also helps support innovative product development by using legislative authorities designed to increase drug availability for minor animal species or minor uses in major species while ensuring critical standards are still met. One way the agency does this is through the conditional approval pathway for new animal drugs. Established as part of the Minor Use and Minor Species (MUMS) Animal Health Act in 2004, conditional approval allows a drug company to legally market a drug for use in a minor species, such as ornamental fish, ferrets, sheep, goats or honey bees, or for a use in a major species (horses, dogs, cats, cattle, pigs, turkeys and chickens) afflicted with an uncommon disease or condition (minor use) after proving the drug is safe and that there is reasonable expectation that it will be effective.
This program has helped facilitate development and approval of certain innovative canine cancer drugs. For example, in January 2017, the FDA conditionally approved the first drug to treat lymphoma in dogs, and this drug became the first conditionally-approved companion animal drug to achieve full approval in July 2021. In January 2021, the FDA conditionally approved the second drug and first oral tablet to treat lymphoma in dogs. The ability to utilize the MUMS conditional approval pathway enabled access to critical treatments for lymphoma in dogs before evaluation of all of the effectiveness data typical for a full approval had been completed. In December 2021, FDA conditionally approved a drug for the treatment of chemotherapy-induced diarrhea in dogs. While it is not a cancer drug itself, this new medication provides veterinarians and pet owners with a needed tool to help control the side effects of chemotherapy for dogs undergoing some cancer treatments.
As part of the Animal Drug User Fee Act (ADUFA) reauthorization in 2018, Congress expanded FDA’s authority to grant conditional approval to include certain animal drugs for use in major species for some diseases or conditions for which effectiveness would prove otherwise particularly difficult to obtain. Expanded conditional approval has the potential to incentivize drug development and provide veterinarians with legally marketed new animal drugs to fill treatment gaps for serious or life-threatening diseases or conditions. To-date, FDA has conditionally approved four new animal drugs under the expanded conditional approval authority. The four drugs conditionally approved under this expanded pathway are providing veterinarians and pet owners early access to therapies for serious, unmet and life-threatening diseases, specifically for epilepsy, heart failure, acute pancreatitis, and anemia associated with chronic kidney disease.
Communication with Stakeholders to Increase Transparency and Predictability
CVM takes a collaborative approach to working with its industry stakeholders to increase regulatory transparency and provide a more predictable pathway to approval. CVM regularly engages in dialogues with organizations that represent the animal drug industry and more targeted animal drug sectors. CVM also invites drug companies to meet periodically with us as part of portfolio overview meetings to share projections of their upcoming projects. Drug companies can meet with FDA early in drug development to discuss the regulatory pathway and work with CVM on solutions to challenges specific to their drug.
While communication with each drug company is a valuable tool, the FDA can often best communicate to the industry through guidance providing the Agency’s best and current thinking on how to navigate aspects of the approval process. In October 2021, the FDA published four significant final guidance documents that point specifically to our commitment to innovative approaches. The guidance documents provide pathways for drug sponsors to use new approaches like adaptive study designs, real world evidence and biomarkers to establish drug effectiveness and more detailed guidance on how to leverage data collected from foreign countries to support the US approval.
Research to Support Approval
In keeping with the goals of reducing, replacing, and/or refining the use of animals in research, CVM is conducting a study at its research facility to validate an alternative in-vitro dissolution model approach for bioequivalence studies for certain animal drugs. If this study validates the bioequivalence model, this alternative approach will provide animal drug sponsors with a scientifically sound method to demonstrate bioequivalence of certain drugs that does not require that dogs be euthanized as part of the study.
FDA laboratories continue to investigate and define parameters for the culture and characterization of cellular based new animal drugs (including stem cells) to inform the development and evaluation of these products. CVM is engaged in cooperative research and discovery agreements (CRADAs) with corporate partners to develop a human intestine on-a-chip model that incorporates a multiple species bacterial microbiome for use in evaluating the potential impact of human consumption of animal drug residues in food derived from treated animals, and to develop physiologically-based in-silico models for the evaluation of new animal drug oral bioavailability and pharmacokinetics. CVM also collaborates with university experts to investigate the potential use of intestinal organoids on the evaluation of new animal drugs. CVM is also partnering with multiple stakeholders in a research collaboration agreement (RCA) to develop a research protocol utilizing validated endpoints that can reliably measure pain in piglets with the goal that it can be used by drug sponsors to support the approval of new animal drugs.
CVM’s flexible, collaborative and proactive approach to the regulation of animal drugs has facilitated the availability of critically needed drugs for conditions like heart failure, hypertension, cancer, epilepsy, and pain and brought a number of generic animal drugs to market to enhance competition and drive innovation. These approaches have also facilitated the introduction of novel technologies with One Health impacts beyond animal health like reduction in gas emissions from an animal’s waste and IGAs in animals that produce biopharmaceuticals used in the production of human drugs.