In this interview, NewsMedical speaks with Karen Greenwood, who shares practical advice for early-stage animal health companies navigating FDA CVM processes.
What is the biggest regulatory challenge early-stage animal health companies face?
The biggest regulatory challenge for an early-stage company with a promising idea, but limited experience in the industry, is understanding what they do not know.
There is plenty of guidance from regulatory agencies outlining the major steps—how to demonstrate efficacy, what types of safety studies are needed, and the requirement for a CMC (Chemistry, Manufacturing, and Controls) section that shows consistent drug production.
However, what these documents don't address are the smaller decisions made early in development that can lead to either significant problems or successes later in the program.
For example, if a company selects a particular model for a proof-of-concept or efficacy study, that decision may limit the language of the eventual product claims, especially if the claim is not clearly aligned with the study design. Another common issue is that early-stage companies often underestimate the time and effort required for CMC work, particularly the manufacturing side.
In animal health, this becomes a rate-limiting step. A specific quality of the drug must be achieved before pivotal safety and effectiveness studies can be conducted. This timing issue contrasts with human health, where manufacturing is not usually rate-limiting. As a result, companies entering animal health from the human health sector often fail to recognize the urgency of initiating this work early. It is critical to begin the process right away.
How can conditional approval be used strategically by smaller sponsors?
The FDA Center for Veterinary Medicine (CMV) has an expanded conditional approval process—referred to as XCA. It is particularly useful for small companies, as well as for larger ones with eligible projects. Unlike other conditional approval pathways, XCA includes products intended for large markets, meaning those that treat a significant number of animals, not just minor use or emergency cases.
To qualify for XCA, a product must address a serious or life-threatening disease or condition, or an unmet medical need in animals or humans. Additionally, the effectiveness study must be particularly complex or difficult.
This complexity must be intrinsic—for example, the treatment may need to be administered over a long period, or the disease may be rare—making the study inherently hard to conduct. The agency will not accept studies that are only difficult due to poor or unnecessarily complicated design.
The safety and manufacturing requirements are the same as those for full approval, which ensures that pet owners and farmers can be confident in the safety and quality of the product. However, the product may be approved with only a "reasonable expectation of effectiveness," which means there is sufficient evidence to indicate that it likely works, but without a full efficacy study.
The pivotal studies can be time-consuming and expensive. The conditional approval process allows smaller companies to begin selling the product and use the resulting revenue to fund the pivotal effectiveness trial. Companies are given five years to complete this study, which should be sufficient even for the most complex clinical conditions. This approach provides considerable flexibility.
What makes demonstrating a reasonable expectation of effectiveness particularly challenging?
The challenge is largely tied to the same factors that make a product eligible for XCA in the first place. Typically, there is no established laboratory model for the disease.
In the field, the condition may be rare or may require a long treatment duration. As a result, companies often lack pilot study data, since generating that data can be time-consuming. This introduces a greater degree of uncertainty compared to diseases or treatments for which efficacy can be more readily assessed.
On the positive side, full statistical significance is not required to demonstrate a reasonable expectation of effectiveness. The data simply needs to trend strongly in the right direction. This makes the process somewhat more manageable. Furthermore, studies under XCA can be conducted using pilot drug batches rather than fully validated registration batches, allowing companies to begin development earlier.
It is essential to engage with the FDA CVM early in the process to confirm that your approach to demonstrating reasonable expectation of effectiveness aligns with their expectations. Otherwise, there is a risk of reaching the end of your studies only to find that the agency disagrees with your conclusions, leading to significant delays and disappointment.
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The company can distribute a drug, but then has five years to complete the efficacy study. Please can you explain the ethics behind this?
The typical path involves conducting a study on perhaps 20 animals instead of 200, but still obtaining a clear signal that the drug is effective. At that point, the risk-benefit balance is considered. Full safety data is already available, so there is confidence that the product will not cause harm.
The disease being treated must be one for which there is an unmet need—meaning there is currently no treatment available—so having some treatment is better than none. Alternatively, it could be a life-threatening condition, where having a treatment option is critical.
You weigh the strength of the available evidence suggesting the drug will be effective against the consequences of making patients wait another five years while a full study is conducted.
These products are clearly labeled as conditionally approved, and veterinarians should explain this to pet owners. The name of the drug even includes a "-CA1" suffix to indicate that it is the first conditionally approved claim. This marking appears directly on the label, so it is visible at a glance. There is nothing hidden about the approval status.
For example, one conditionally approved drug was developed for treating anemia in cats. While there are existing products, they are not very effective. This new option offers a better approach, giving veterinarians an additional tool for treatment. So, the system provides an ethical and transparent framework.
Is it the veterinarian’s responsibility to inform the pet owner that the drug is conditionally approved and that efficacy studies are still ongoing?
It is not necessarily the veterinarian’s legal responsibility to disclose that information in detail. Personally, I would expect my veterinarian to mention it. However, they are not required to read out a formal statement to the owner.
What they are legally obligated to do is follow the label precisely. In the United States, veterinarians are allowed to prescribe drugs off-label—for example, using drugs approved for other species, conditions, or even human medications in animals—when no suitable veterinary treatment exists.
For conditionally approved drugs, they are not allowed to use the product for anything other than the specific indication listed under its conditional approval. This restriction helps reduce risk because it ensures the drug is used only in the population for which it has shown likely benefit. It prevents the drug from being used inappropriately, where its effectiveness and safety have not been demonstrated.
How can real-world data support progression from conditional to full approval?
The primary path to full approval from conditional approval is the pivotal efficacy study—a tightly controlled, high-quality clinical trial that demonstrates the product’s effectiveness. However, during the conditional approval period, real-world data also plays an important role, particularly in evaluating safety.
While you may already have a strong understanding of the product’s safety profile, once it is available on the market, it will be used by many animals with diverse characteristics. These animals may have pre-existing conditions, be on different medications, consume different diets, or live in a wide range of environments. You’ll also encounter many breeds and individual responses. If any animal experiences an adverse event, it must be reported to both the manufacturer and the regulatory agencies.
That post-market data is included in the full approval submission. If any new safety concerns arise—something unexpected—that might trigger an additional safety study to investigate further. In other cases, it may simply lead to a new label warning, such as a caution not to use the product alongside a certain other medication.
In most cases we hope there are no surprises. But the system is designed to detect rare side effects that would not be visible even in relatively large pre-approval studies.
Does full approval occur after a period of market use without off-label issues?
To go from conditional to full approval, you need to conduct a full efficacy study. This study should be the same size as the one you would need to get full approval from the beginning—say, 200-250 animals. It must include both a control group and a treated group. You define in advance what kind of improvement you are expecting to see, and then you need to demonstrate a statistically significant benefit in the treated group.
Once that is done, you submit the study to the FDA CVM along with all the raw data. The FDA CVM then reanalyzes the data itself—it is a good cross-check of your results.
Assuming nothing unusual has happened while the drug’s been on the market, it can move forward to full approval.
As part of the submission, you also include an “all other information” section. This covers anything you know about the drug that has not already been submitted, including post-market experience. For example, you would report how many doses were sold and how many adverse events were reported. You want over-reporting rather than under-reporting, so all of that is reviewed.
Does a similar efficacy standard apply to drugs developed for humans, or is this approach unique to animal health?
In human health, under the FDA, there is a process called accelerated approval. It is quite similar to the conditional approval used in animal health, but with one major distinction: companies are not time-bound to complete a definitive efficacy study afterward.
For instance, this was the process used to authorize COVID-19 vaccines. The unfortunate reality of the pandemic—having a large number of sick individuals—meant the studies to support full approval could be completed relatively quickly, but allowing early access to the vaccine saved many lives.
There was an example a year or two ago involving a company that developed a drug for ALS. They conducted a follow-up study, which, tragically, showed that the drug did not work. As a result, it was pulled from the market, which was heartbreaking for the families involved.
In many other cases, companies never complete confirmatory studies, so it remains unknown whether the drug works as claimed. In that regard, I think the FDA CVM process is better. It allows five years to complete the efficacy studies, and if they are not completed within that timeframe, the product is removed from the market.
What unique hurdles arise when developing longevity products for animals?
This is a topic that I am very familiar with, as I used to work for Loyal, a company developing FDA-approved drugs to help dogs live longer. That was a wonderful experience, because no one ever says, "Oh no, we do not want dogs to live longer." When you say you are working on longevity drugs for humans, the reaction is often more hesitant—people ask whether it is really a good idea.
Longevity does come with significant hurdles. The first challenge is that death is not considered a disease from a regulatory standpoint. You die of something, but death itself is not classified as a disease.
This concept has been tested extensively in human health, where some attempted to convince the FDA otherwise, but were ultimately unsuccessful. As a result, selecting an appropriate claim for a longevity drug becomes somewhat tricky. It complicates the way you relate the drug’s mode of action to the extension of lifespan.
The second hurdle is that, if you are measuring lifespan, the study must continue until at least some of the participants die. These are, therefore, very long studies. The advantage is that, assuming your drug is safe, the control group lives out a normal lifespan, as they would have otherwise. The treatment group, ideally, lives longer. So, it is not like a typical disease study, where the control group may go without an improved treatment.
You must carefully consider the age of participants at the start of the study in relation to how long the study must run.
In human health, for instance, studies are often conducted in 70-year-olds. This allows for a shorter study duration, since, statistically, some will pass away sooner. However, it also means the drug is being introduced at an advanced age, and these are not miracle drugs—they will not turn a 70-year-old into a 30-year-old overnight. The same thinking applies in animal health. How early do you begin dosing?
Additionally, lifespan varies widely among dog breeds. A Great Dane may live only six to eight years, while small breeds might live up to 22 years. So, you must design the study to accommodate a broad range of dog sizes and ages. Cats are less variable in this regard, which simplifies things somewhat.
Loyal is currently conducting a longevity study in dogs with 1300 participants—a very large number for an animal health study. They recently announced that enrollment has been completed, and the study is expected to last up to four years. It is a significant undertaking.
Why is early engagement with the FDA CVM so important?
The FDA CVM, as well as other regulatory agencies, generally prefers to work collaboratively with sponsors. This gives companies the opportunity to present their development strategy very early in the process and receive feedback on whether the plan is comprehensive and aligned with expectations.
Regulatory agencies cannot tell you how to develop your product—that is not their role. However, if you ask them specific questions, they can provide answers. Engaging with them early—sharing your planned approach and asking whether, for instance, Option A or Option B is more appropriate—can help ensure you do not overlook something important or make a costly mistake that would later require repeating studies.
How do regulatory strategies differ between large companies and startups?
The path to market is the same for all companies, and the regulatory standards are also consistent. That said, you may occasionally hear large companies suggest that they are held to a higher standard.
In my experience, having worked in both large and small organizations, larger companies simply have more resources. They have the funds to support thorough and comprehensive submissions with complete datasets at the time of approval. This level of preparation helps the commercial launch team and is feasible because large companies already have revenue-generating products, so they are not in a rush to get the new product approved.
For smaller companies, achieving regulatory milestones is critical. Both the FDA CVM and United States Department of Agriculture (USDA) allow rolling reviews, which means you can submit one section, receive feedback, and continue working on the other parts of your dossier. This incremental feedback serves as tangible evidence that the program is progressing and that regulatory risk is being reduced—something that is incredibly valuable when speaking with investors.
Small companies also tend to take a more minimalistic approach to product development initially. For example, a large company might choose to develop a soft chew with excellent palatability, making it easy for dogs to accept. A small company, lacking the time and resources for such refinement, may opt for a hard tablet or a basic flavored tablet. It may not be as appealing, but it is functional. A more refined product—such as a chewable or enhanced formulation—can always be developed later as a follow-up.
While the regulatory pathway itself remains the same, the strategic choices often differ. Smaller companies tend to favor simplicity and speed, while larger companies aim for polish and depth.
What advice do you have for choosing the correct product classification?
The United States has a more complex veterinary regulatory system than anywhere else I am aware of, due to the presence of three agencies that can approve veterinary products.
The FDA CVM regulates small molecules and biological, cell, or tissue products. Their definition includes any substance, other than food, intended to affect the structure or function of the body. The USDA handles vaccines and immunotherapeutics—anything that works via the immune system. Then there is the Environmental Protection Agency (EPA), which approves some topical antiparasitics, although that is a niche category.
In most cases, it is relatively straightforward to determine whether a product falls under the FDA or USDA. However, with some biological products, it is not always obvious.
To address this, a joint jurisdiction committee has been established. Sponsors submit a letter to the agency they believe should regulate their product—or the agency they would prefer—and explain their reasoning. If the classification is ambiguous, the agencies consult with each other and determine jurisdiction. It is generally an efficient process now, and engaging with the agencies early avoids surprises.
When should manufacturing and facility planning begin in development?
This is a key consideration. It is always a balance—you want to begin CMC (Chemistry, Manufacturing, and Controls) activities as early as possible, but you also want to ensure that you are not investing heavily before you have enough confidence in your product. CMC is expensive.
For small companies, there is tension between the desire to move quickly and the need to have sufficient supporting data before committing to major manufacturing expenses. That said, there is a great deal of work that can be done early to avoid complications later on.
For example, it is important to ensure that your product is stable in the intended formulation. Stability directly affects shelf life, and you want to be confident that the product can last at least two years on a veterinarian’s shelf, which greatly simplifies logistics. Start those studies early.
You also need to consider how you’ll deliver the correct dose to animals of different sizes. Will you need splitable tablets? Will it be an injection that delivers an exact dose? These kinds of practical design decisions should be addressed early in development.
Another critical step is identifying your potential commercial manufacturing partners as early as possible. If you plan to do pilot work at one facility and later transfer it to another for commercial production, that transfer process can take six months. It involves handing over technical documentation, setting up analytical assays, and more. If you have not planned for that timeline, you may find yourself spending six months doing nothing but waiting, and that can be frustrating and costly.
What have you learned from working on products that achieved full approval?
On a personal level, it is incredibly rewarding. I often meet people who mention that their dog used to have very itchy skin, and I ask, "Is it on Apoquel?" They say yes, and I can say, "That was one of mine." Knowing that the products my teams and I worked on are improving pets’ lives is deeply fulfilling.
I am particularly proud of Apoquel and Cytopoint, which treat atopic dermatitis, and the canine parvovirus monoclonal antibody, which is used to treat puppies already infected with parvovirus. That product is life-saving, especially since vaccinating effectively for parvovirus is complicated, and there will always be some puppies that contract the disease.
From a regulatory strategy perspective, what I have learned is that nothing runs smoothly. These projects can take anywhere from five to twelve years, depending on the complexity of the disease, the type of animal (companion or livestock), and how much must be learned during development. Nothing proceeds for that long without unexpected challenges.
You must be resilient and prepared for setbacks. It is important to remember that the goal is not just regulatory approval, but delivering a product that is safe, effective, and high quality. Sometimes, that means recognizing when a product must be discontinued. You may discover, for instance, that a molecule is not as safe as initially believed. That is disappointing, but it is far better to learn that during development so you can pivot to a safer alternative. Ultimately, that is how you succeed.
Can you share a time when a creative regulatory strategy made a real difference?
Some of the most creative regulatory milestones come with the first approval of a new kind of treatment, where you must figure out how to regulate something completely new.
The first veterinary monoclonal antibody is one example, or the European approval of stem cell therapy for lameness in horses. That brought a type of treatment that many believed worked—but had not been proven—into a regulated space where there is now real proof of benefit in a specific disease with specific cells. This opens the door for others to follow.
Another example is the USDA’s approval of an autologous vaccine for osteosarcoma in dogs. It is made using a sample from the dog’s own tumor to generate a vaccine tailored to that tumor’s antigens. Innovations like that really shift the industry. Once someone shows it is possible to get a regulated product like that approved, others might think, "We could do that for X or Y disease as well."
Of course, there are also smaller, clever innovations in almost every regulatory program. But the biggest leaps come from companies brave enough to say, “We are going to get an approval for…”—whatever new modality they have in mind.
How do you align scientific innovation with regulatory requirements?
Both companies and agencies want innovation to succeed. The key is understanding that agencies are bound by statutory constraints—laws that define what they are legally allowed to do. If you ask them to approve of something outside that framework, they simply cannot. It is not about resistance; it is about legality.
So, it is critical to look at your product—what kind of claim you are making, how you are treating the disease, the type of delivery method, etc.—and see how that fits within the existing legal and regulatory framework. Then explain that to the agency. That is going to help a lot.
You also need to anticipate what will concern them. If you are using a new delivery system, is it safe? How will you prove it is safe if it is meant to be used over an animal’s entire life? If you are developing something that long-acting, you must ask: what happens if the dog has a bad reaction? You must address those risks proactively.
Another thing: regulatory agencies always weigh risk versus benefit. So, if your product is new, it is more likely to be accepted if it is treating something serious—like cancer, where the animal might die without treatment—than something minor that is not life threatening. The higher the benefit, the more acceptable the risk.
Finally, regulatory agencies want innovation. The FDA CVM even has a Veterinary Innovation Program to support companies working on novel products, like cell therapies or gene-edited treatments. They provide extra help and discussions to figure out how to get those products approved.
Sometimes companies see regulators as adversaries, but that is not accurate. If you approach them in the right way, with the right attitude and a willingness to work within their framework, they are more likely to work with you to find a path forward, assuming your product is suitable for approval.
About Karen Greenwood
Karen Greenwood is a biochemist by training, with 36 years in the pharmaceutical industry, all dedicated to the field of animal health. Her career started with laboratory work in natural products and screen design and development, then moved to program leadership and project management, regulatory submissions and strategy.
Karen has experience in large and small companies, where she has worked on products from ideas to identification of lead molecules and the studies required to gain regulatory approval for companion and food animals. These products include small and large molecules. Products that gained approval include Apoquel®, Cytopoint®, Librela®, Solensia®, Slentrol® and the Canine Parvovirus Monoclonal Antibody. Recently she led achievement of Reasonable Expectation of Effectiveness technical section complete letters for two longevity projects at Loyal, LOY-001 and LOY-002, which involved development of a regulatory path to market for a novel indication.
She specializes in developing strategies for early-stage Animal Health companies that have great ideas but are unclear what steps to take next. She has experience authoring FDA submissions and working with the FDA CVM to identify creative paths for drug development.
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