As I’ve mentioned previously, in the last four years I have continued my clinical practice while also working for Loyal, a biotechnology company pursuing FDA approval of drugs to extend health lifespan in dogs. There is little overlap between my SkeptVet activities and my work at Loyal, and of course my writing here doesn’t represent the official position of the company on anything. But I do like to share here some of the science and publications on aging that I work on at the company. Sadly, that tends to draw the attention of those irritated by my advocacy for science-based veterinary medicine.
Recently, there was a large amount of publicity surrounding a milestone on the road to potentially getting our first drug approved at Loyal. While this drew mostly positive interest, I was accosted on the SkeptVet Facebook page by a follower of the “holistic veterinarian” Dr. Judy Morgan. Dr. Morgan’s fan asked me to respond to a FB Live video briefly discussing (or “ranting about,” in Dr. Morgan’s own characterization) the press coverage of Loyal’s work.
I eventually had to block this fan’s account for personal abuse, and I don’t generally bother to respond to trolls since their comments are typically ignorant and disingenuous, and their minds are firmly closed. Dr. Morgan’s fan wanted to set up a “debate” between us, a common tactic among alternative medicine advocates that mistakes theatrical performance for substantive exploration of evidence-based science. As I explained to her on FB, “science isn’t about public debate or performance, its about evidence. [Dr. Morgan] can say what she likes, and support it with whatever evidence she has, and I can do the same, and everyone can evaluate her claims and support for themselves…How we sound or look on video talking to each other isn’t useful or relevant, it’s just theater.”
However, there are some pretty significant misconceptions and misrepresentations of science and the drug approval process generally in Dr. Morgan’s video, and I thought it might be useful to take the opportunity to respond to those and, hopefully, give everyone a clearer picture of how those processes work and how science gives us the best chance at finding therapies that provide meaningful, beneficial impact on the health and wellbeing of our pets.
What Was the Fuss About?
The announcement and associated publicity concerned something called Reasonable Expectation of Efficacy (RXE). This is a standard for supporting evidence that the FDA sets for veterinary drugs as part of the process of pursuing conditional approval. Since the regulatory system is complex and not something vets or pet owners often know much about (I certainly didn’t before becoming involved in this project!), I thought I’d start with a brief outline of how it works. The official explanation and detains can be found on the FDA web site.
Any medicine intended to treat disease in animals must be approved by the FDA. This is to ensure that these medicines are both safe and effective. Of course, as I’ve said many, many times, nothing is ever perfectly safe or always effective, and medicine is about balancing the benefits of a treatment against the potential risks, all in the light of the available scientific evidence and the frustrating, but inevitable, uncertainty about these. Having FDA approval means that a significant degree of scientific evidence at multiple levels is available to support the specific claims of safety and efficacy made for a prescription drug. This is not perfect, but it’s a great deal better than what is available for treatments that don’t go through this process (including supplements and nearly all forms of “alternative” medical treatments).
In the case of the typical FDA approval process, the agency requires several types of supporting evidence for safety and effectiveness. This includes pre-clinical research, that is studies done in test tubes or lab animals showing how a drug works and what biological effects it has. Such studies are an important part of demonstrating what we call “biologic plausibility,” the existence of an explanation for how something works that is consistent with established scientific knowledge.
Therapies such as homeopathy or “energy medicine” (such as Reiki) lack biologic plausibility because there is no scientific rationale for how they might work; they can only work if much of what we know about basic physical, chemistry, and biology is wrong. While scientific knowledge isn’t always completely correct, the basic knowledge that is the foundation for most of the successful medicine and technology in use today is pretty unlikely to be completely wrong. Clinical studies of these implausible therapies don’t make much sense and are often misleading.
Once there is good evidence for the underlying biology of how a drug might work, then a company seeking approval has to test it directly in the species it is intended for. If the drug is being developed for dogs, then studies must be done in dogs to understand how the drug works and what risks it may have. Sometimes this involves studies in laboratory dogs, often beagles, but it may also involve research in companion dogs. These studies have to comply with rigorous guidelines for methodology and to control various types of bias and error, so they are usually stronger evidence than studies not performed under such guidelines.
Finally, if the evidence to this point shows the drug is likely to be safe and effective for its intended purpose, a clinical trial is performed. This is the “randomized controlled trial” or RCT that people most often associate with medical science, even though it is only one part of a much more comprehensive testing process. In an RCT, ideally some dogs are given the new drug and others are given a placebo (a “fake” drug which does nothing at all), and everyone involved is “blinded” so they don’t know which is which. The details vary with the specific drug being tested, but again the standards for how these RCTs must be conducted to gain FDA approval are very specific and quite high, so the results are pretty good quality evidence.
This process often takes many years and is very expensive to complete. This is a problem because it makes it harder for veterinarians to get new and properly tested therapies. The system in most countries, and certainly in the U.S., is set up so that private companies are responsible for paying the costs of developing and testing new drugs, and so they aren’t likely to do so unless they think they can make back the money invested in this. Lots of interesting political debates could be had over whether a different system would be better, but that’s beyond the scope of this blog, and frankly nothing about this is likely to change here any time soon.
The FDA recognizes that vets can’t get many treatments that have met the high standards of the typical approval process, and so it allows some compromises to make useful therapies available to vets and their patients. We are, for example, allowed to use drugs approved for humans “off-label,” meaning in ways they were not tested and approved for. Many of the treatments vets use have been tested thoroughly for safety and efficacy in humans but not in dogs or cats. While this increases the potential risks when we use them in these species, often this is still better than the alternative of having no treatment for a given problem, or having treatments that haven’t even been scientifically validated in any species.
The FDA also doesn’t regulate some treatments much at all. The rules governing dietary supplements are especially lax (and violated all the time with little consequence), so it is much faster and more profitable for companies to make supplements than develop prescription drugs. Sadly, this has led to a booming and lucrative industry (highly favored by alternative medicine advocates like Dr. Morgan) selling products that may be claimed to be safe or effective even when there is little to no real evidence that these claims are true.
A more recent change in the FDA approval system has been the pathway of conditional approval. Under this approach, new drugs must meet all the same requirements for proving safety, manufacturing quality, environmental impacts, and so on as under full approval. However, if a product is targeting a serious health problem with no existing effective treatments (which is clearly the case for aging), and if the RCT needed for full approval is complex and likely to take a long time (again, this is clearly true for drugs intended to extend healthy lifespan), then a drug can be made available to vets for use while that RCT is being conducted.
In order to do this, the company must provide sufficient evidence that the product is likely to be effective (aka reasonable expectation of efficacy or RXE) along with the usual evidence for safety and other components of approval. Several products have been made available to vets under this pathway, including medications for heart disease, pancreatitis,anemia, and epilepsy.
The big news in the press that prompted Dr. Morgan’s “rant” on FB was that the FDA granted this RXE approval for one of Loyal’s products. The support for this approval included four years of pre-clinical research and 2,300 pages of data and documentation, so it is a pretty robust standard even prior to the completion of the final RCT. The product has not yet been approved, and it is not expected to be available for at least another year even if it eventually achieves this approval. However, the milestone was pretty significant since the FDA has never before granted RXE status (or approval of any kind) for a drug intended to treat the mechanisms and consequences of aging. Ultimately, this has the potential to open up an entire new area of preventative medicine, though there is a long way yet to go towards this goal.
Who is Judy Morgan?
Dr. Morgan is a self-described “holistic” veterinarian. She was in clinical practice for many years, and since retiring she has focused exclusively on selling products, books, and educational courses on her web site as well as a variety of other educational and advocacy activities. She is quite typical of the alternative medicine advocates I have written about many times. She promotes Traditional Chinese Veterinary Medicine (TCVM), homeopathy, raw diets, innumerable untested supplements, and a wide range of dubious or disproven tests and treatments. She is also deeply suspicious of science-based veterinary medicine, condemning conventional diets and ranting about the dangers of conventional drugs, vaccines, parasite preventatives, and other mainstream medical tools.
Her educational courses often touch on longevity and geriatrics, and she clearly has an interest in these areas. However, her advice is largely unscientific, and she makes numerous false claims about the “proven” benefits of raw diets, TCVM, supplements, and so on. Anyone who suggests vets should choose supplements and foods for maintaining health or treating disease based on supporting “elements” such as Fire, Wood, and Water, or on “balancing” mystical energies like Yin and Yang, cannot be taken very seriously when commenting on science and scientific medicine.
What’s the “Rant” About?
Most of Dr. Morgan’s video has nothing to do with Loyal’s products or the related media coverage. She spends much of her time talking about the work of a Japanese scientist on apoptosis inhibitor of macrophages (AIM), a protein supposedly being developed into a dietary supplement or injectable medicine to prevent or treat kidney disease and extend lifespan in cats (a set of claims that are themselves pretty dubious, and which I will try to find the time to talk about someday).
Unfortunately, she doesn’t make the transition very clear when she switches from talking about the Loyal RXE coverage and other subjects, and she repeatedly talks about a “vaccine” for aging, although neither Loyal nor the Japanese scientist she discusses are developing a vaccine. This may just be a sloppy shorthand for anything injectable, or a superficial reading of the media coverage (one web site does describe the AIM product as a “vaccine,” though the actual company web site makes it clear that is not what is being developed.) However, since she does spend a fair bit of her time talking about the dangers of vaccines (while still claiming to support them), I think this is part of the obvious effort she is making with this video to cast these products in a suspicious light for her viewers, many of whom are likely as distrustful of vaccines as she is.
Dr. Morgan begins the video by suggesting that she isn’t impressed by the RXE approval and she is “gonna wait ten years and see what the reports are” before even considering using this or any other drug treatment for aging. This is part of a consistent theme throughout the video– suspicion of scientific evidence and a preference for anecdotes to evaluate medical treatments. At one point, she actually says, “one of the great ways to find out what side-effects can be seen is social media.” ???? In her view, “if people are reporting the same side-effect time after time after time” then this is a reliable indicator of the safety of a drug. This ignores the well-established unreliability of anecdotal evidence (as the saying goes, the plural of ‘anecdote’ is not ‘data’).
She clearly doesn’t understand the role of pre-clinical evidence, not only because she recommends therapies that fail to show basic biologic plausibility, but because she acts as if any use of a drug without a comprehensive RCT is a dangerous experiment. With regard to conditionally approved drugs, she says, “When you go to your vet the day this thing hits the market, your dog is part of that clinical trial, you are saying, Yes, I am going to let my dog be part of that science experiment…it might have some serious side-effects that we don’t know about.”
One could claim that she is simply demanding the highest form of evidence for medical treatments, except that clearly she is comfortable using supplements, diets, and alternative therapies that have never been shown to be safe or effective through clinical trials. What is more, she explicitly admits she would never participate in a clinical trial because she thinks they are too dangerous: “I will not sign my dogs up for clinical trials. I know somebody has to somewhere but it’s not gonna be me.” Instead, she has the bizarre but common belief that scientific evidence is unreliable but if we have enough anecdotes then we can know what therapies are safe or effective. That is the sort of fundamental misunderstanding underlies so much of alternative medicine, and it makes her judgements on specific interventions unreliable.
Consistent with this approach, she often makes false claims about the risks of lack of efficacy of treatments based on anecdotal reports collected online. For example, she claims that isoxzoline parasite preventatives “have killed hundreds of thousands of animals” based on such reports, which is a demonstrably untrue exaggeration (e.g. 1, 2, 3). She also argues that the allergy treatment lokivetmab (a.k.a. Cytopoint) commonly ceases to work because of anti-drug antibody formation (for which there is no substantive evidence) and that there are “tons of side-effects” but the company “[doesn’t] have to report the side-effects that are seen once the drug is used widely,” which is again completely untrue.
Bottom Line
None of the drugs Loyal is developing have been approved for use by the FDA, so of course no one is claiming they have been proven to be safe and effective yet. Having strong scientific evidence at all levels is the whole purpose of going through the prescription drug approval process rather than just launching a longevity supplement, which is a much faster and easier way to get a product to market with minimal scientific evidence. More evidence is needed, and it is being generated.
However, it is clear that better scientific evidence is not really what Dr. Morgan is concerned about. She already believes she can extend lifespan and healthspan with therapies that don’t have any meaningful scientific support, such as raw diets, supplements, and TCVM. And she repeatedly rejects the evidence when it is favorable to treatments she believes are dangerous base don anecdote or just simple prejudice against “injections” and “chemicals” and so on.
Hopefully, veterinarians and dog owners with a genuine interest in aging and in prolonging healthy lifespan will be interested in any new tools that are developed to achieve this. Hopefully they will critically evaluate the strengths and limitations of the scientific evidence as we all should for all of the therapies we use. However some, and I suspect Dr. Morgan will be one, will automatically reject any pharmaceutical as a safe and effective way of extending healthspan regardless of the evidence because it doesn’t fit their fundamentally unscientific philosophy. That’s fair enough, of course, but those folks shouldn’t try to claim that this rejection is really about holding out for more and better evidence if this is obviously inconsistent with their other claims and practices.
To me, the onus is on proponents of a new Rx or supplement is to design/execute a trial that finds a net benefit in some group of people or pets before routine use. The Limit of Efficacy decided by the FDA should not be negotiable. NNTreat and NNHarm should be calculated and available to the public or the public will lose confidence in the FDA like veterinarians have lost confidence in usda vaccine conditional use approval.
In the perfect world, of course, we wouldn’t stop there. Multiple large, high-quality clinical trials in different populations with different investigators and sponsors and with different biases are ultimately needed to provide the strongest possible evidence for any therapy. The question is how much evidence is enough for what degree of confidence, and how much are we willing to do to get it?
The higher the standard, the fewer approved treatments are available and the more people will turn to unapproved treatments with even less evidence. Conditional approval is a compromise–less evidence for efficacy than standard approval (though the same evidence is required for safety), but the treatment is available sooner for conditions that currently have no effective approved treatment. Is the lower standard of evidence for efficacy worth exchanging for earlier availability of the treatment? That will probably depend on how things work out for each drug. If the final RCT for full approval supports efficacy, then we will have made the right decision and the drug will be helping patients 4-5 years earlier. If the full approval RCT doesn’t confirm the RXE findings for efficacy, we won’t have done harm (because, again, the evidence for safety is the same in both pathways), but we will not have actually helped patients as we had expected.
Overall, the balance between these two outcomes over multiple drugs will be needed to decide if the pathway is a net benefit for patients. If most drugs fulfill the prediction based on RXE, then there will be a net benefit from the pathway, and if not then likely it will not be worth continuing. Time, and evidence,e will tell.
I am a long time reader and was pleasantly surprised to learn about your involvement with Loyal, as they were a company I was broadly skeptical of given the lack of publicly available information around their work.
Based on my general understanding of veterinary drug development I would expect to have significantly more information about their approach beyond a vague biological target at this stage in development.
I realize there are likely IP issues at play, but I can’t help but think they are being purposefully obfuscatory to generate hype around a product which is less innovative than they’re leading on.
Do you have any idea on when we might expect more data?
Thanks and keep up the great work!
Thanks for the comment.
We are absolutely committed to transparency and to publication of our research data, including both positive or negative findings, as quickly as possible. The field efficacy studies for the FDA will take about 4 years, and the first of those has just begun this month, so it will be quite a while before that is analyzed and published. However, we have published the results of our observational study evaluating instruments for measuring frailty and quality of life, key components of healthspan. There are also papers currently in review based on our preclinical studies, which will hopefully be published soon.
You are correct that there are some limits to how much detail we can offer prior to FDA approval. For one thing, we aren’t allowed to say anything that might be taken as an efficacy or safety claim for our drugs until the FDA approves the data and the specific language. Also, as you say, we cannot simply tell everyone what the drugs are and how they work at a stage at which much larger, better funded companies could potentially simply steal our ideas and run with them. Hopefully, we are nearing a point where that risk is sufficiently low that we can offer more detail publicly on the mechanisms of action of our products in development.
Of course, we don’t actually have any products available yet, so we aren’t asking anyone to use our drugs without providing detailed information about safety and efficacy. If we are successful at achieving conditional approval, then of course the evidence supporting safety and efficacy will be publicly available for vets and dog owners to evaluate before deciding whether to use the products. Since we are hoping to reach that stage in the next 1-2 years, we will be making additional details available as quickly as possible over that timeframe.