I’ve written numerous times about veterinary stem cell therapies, and I’ve been quite critical about the proliferation of such interventions in veterinary medicine. This is not because I don’t see great hope in stem cell therapies, for I do. But to be clear, I’ll repeat what I’ve said before on the subject:

One of the hottest, most fashionable new therapies for a wide range of ailments in veterinary patients is stem cell therapy. There is extensive theoretical and laboratory work in animals and humans to indicate a variety of effects of these cells, and there is good reason to believe that clinical benefits may be possible. Unfortunately, there is no agreement about what these cells do in living animals and how they do it, and there is very little clinical research evidence to support any one of the many different commercial stem cell therapies marketed for dogs and cats. Leading researching in human and veterinary stem cell therapies caution that our knowledge about these cells and what they do is too preliminary to justify claims that they are safe or effective in real patients. I am hopeful that safe and effective stem cell therapies will one day be available, but so far none have proven themselves and using them is still a gamble.

Veterinary stem cell research: Is this the best we can do?

Vet Stem’s stem cell therapy and Chemaphor’s Oximunol join forces

Selling veterinary stem cell therapies: Medivet’s dodgy advertising

Stem cell therapy: Still an uncontrolled experiment on our pets

Veterinary stem cell therapies discussed at Fully Vetted blog

Stem Cell Researchers Caution Against Using Unproven Stem Cell Therapies

Most media coverage of stem cell therapies is unfailingly positive, and the difficulties of developing and validating a complex set of entirely new therapeutic practices are generally glossed over. So I was pleased to see some mention of these challenges and uncertainties in a recent article at Philly.com. As usual, the notes of caution come from stem cell researchers themselves, who certainly cannot be viewed as an ignorant or reflexively negative source on the subject. The reality is that the very scientists who will hopefully one day bring us revolutionary new therapies based on stem cells are those who see most clearly that commercial stem cell therapies currently marketed are insufficiently understood and not yet proven safe and effective to a reasonable standard.

The article tells the story of Bernie, a pit bull abandoned on a hot roof who suffered severe burns to his paw pads. The veterinarian who treated him was concerned the burns would not heal with conventional wound therapy, so he obtained a compassionate use dispensation from the FDA to try a stem cell therapy not licensed for use in dogs and marketed by Celavet, Inc, a company apparently run by one of the veterinarian’s clients. According to the company, the cells it markets are taken from fetal dogs and cats but have some of the properties of embryonic stem cells, which should enable them to grow into mature cells of any type, including skin. Bernie’s wounds healed, and the case was lauded as an example of a miraculous recovery credited to stem cell therapy.

Of course, I have discussed many times why anecdotes about individual patients aren’t reliable evidence of the safety or efficacy of a particular treatment. In the Philly.com article, researchers from the University of Pennsylvania discusses why this story should not be taken as proof of the usefulness of this therapy.

The stem cells may not have been necessary for Bernie’s recovery, said John Gearhart, director of the University of Pennsylvania’s Institute of Regenerative Medicine and one of the first to isolate human embryonic stem cells.

From examining the company’s literature and pictures of the dog’s paws, he concluded that the new skin was unlikely to have been made from the stem cells. The cells may have helped to produce a protective covering, but Bernie’s paws in the after pictures are most likely covered in his own skin.

“Ultimately, was this animal helped or harmed?” Gearhart asked. “That’s the key question.”

Penn dermatology professor George Costarelis had the same skeptical reaction to the images before and after treatment. In the before pictures, he noted that the dog still had some skin around the wounds and this might have been capable of slowly growing slowly over the injured site.

The stem cells may have covered the wound temporarily, Costarelis said, but he agreed that they probably had been rejected and replaced with the dog’s own skin.

“I’m skeptical this is any different from what would have happened if the dog had good wound care” without stem cells. With no controlled studies, he said, it’s impossible to know.

Such sensible caveats are seldom found in mainstream media coverage of cases like this, and are never mentioned in the advertising materials that promote veterinary stem cell therapies. So while the use of this experimental therapy may be appropriate in such desperate circumstances, the outcome should not be used to fan the flames of public enthusiasm for as yet unproven stem cell treatments. As Dr. Gearhart put it,

The publicity surrounding stem cells has made the public “nuts,” he said. Desperate people contact him all the time, the most emotional of whom are seeking treatments for their animals. “There’s a long history, from the animal side of things,” he said, “of clinics popping up that take advantage of folks.”

He also points out that Celavet did not profit from the use of its product for Bernie, so one cannot criticize the motives of the company. But heartwarming stories like this are the core marketing tool for all unproven and outright bogus medical therapies, and even though they are ultimately unreliable, they are emotionally very compelling. It is up to scientists like Gearhart and Costarelis, and to us as veterinarians, to point out that stories like this do not justify widespread sale or use of such therapies before they have met appropriate standards of scientific scrutiny. Ultimately, the risks of bypassing proper study are greater than the potential benefits.

One of the therapies that has arisen within conventional veterinary medicine, but which shares many of the worrisome features of an alternative approach, is stem cell therapy. Though it is a plausible intervention with promising preclinical evidence to support investigating its possible clinical benefits, it remains an unproven and inadequately investigated form of treatment. As a result, it is currently legal for human use in the U.S. only under very restricted conditions.  Unfortunately, many people seek such therapies in other countries with less robust laws and regulations protecting the public, through so-called “medical tourism.” And since the same strong public health laws rarely apply to our veterinary patients, stem cell therapies are aggressively marketed in the U.S. despite having even less evidence to support their use than is available for human medical uses.

I have written about this marketing and about the concern researchers in human stem cell therapies have expressed about the premature clinical use of inadequately tested stem cell treatments. Some of these researchers have recently reiterated their cautions about medical tourism and stem cell therapies, and their arguments are just as applicable to the domestic market in veterinary stem cell treatments.

Master Z, Resnik DB. Stem-cell tourism and scientific responsibility.EMBO Rep. 2011 Jul 29.

With a few exceptions—such as the use of bone-marrow haematopoietic cells to treat leukaemia—novel stem-cell therapies are often unproven in clinical trials. Even well-proven therapies can lead to tumour for­mation, tissue rejection, autoimmunity, permanent disability and death. The risks of unproven and unregulated therapies are potentially much worse…

Any medical innovation is ethically responsible when it is based on animal studies or other research that guarantee evidence of safety and clinical efficacy. Adequate measures must also be taken to protect patients from harm, such as clinical monitoring, follow-up, exclusion of indi­viduals who are likely to be harmed or are unlikely to benefit, use of only clinical-grade stem cells, careful attention to dosing strategies and informed consent.

The authors also address the issue of educating patients and doctors about the inadequate evidence for most stem cell therapies and the dangers of employing these therapies without a clear understanding of their risks and benefits. Their conclusions, however, are disappointing for those of us involved in such educational efforts, regarding both stem cell therapy and other kinds of unproven or even disproven methods.

Educating patients about the risks of unproven therapies can also help to address the problem of stem-cell tourism. However, education too has significant limitations, since many people will remain ignorant of the dangers of unproven therapies, or they will simply ignore warnings and prudent advice. For many years, cancer patients have travelled to foreign countries to receive unconventional and unproven treatments, despite educational campaigns and media reports discussing the dangers of these thera­pies. Since the 1970s, thousands of patients have travelled to cancer clinics in Mexico to receive medical treatments not available in the USA.

Education for physicians on the dangers of unproven stem-cell therapies can be helpful, but this strategy also has limitations, since many will not receive this education or will choose to ignore it. Additionally, responsible physicians might still find it diffi­cult to persuade their patients not to receive an unproven therapy, especially when con­ventional treatments have failed. The history of cancer treatment offers important lessons here, since many oncologists have tried, unsuccessfully, to convince their patients not travel to foreign countries to receive questionable treatments.

Given the lack of impact educational efforts often have on patient and clinician behavior, another possible method for limiting the potential harm of inadequately tested therapies is regulatory oversight requiring a reasonable degree of scientific evidence before such therapies can be marketed outside of the clinical research and compassionate use contexts. This has worked to prevent much inappropriate use of stem cell therapies in humans in the U.S., though the practice of medical tourism is a way around such regulations. Regulations on veterinary therapies are far less restrictive, and this has both benefits and costs. Lax regulation makes investigating novel therapies easier and cheaper, which may lead to more rapid and affordable development of new therapies. However, the same loose regulatory environment also subjects pets and their owners to unproven therapies which may not benefit them and may even be harmful. In any case, regulation is often not an especially effective way of constraining the use of therapies not supported by reasonable scientific evidence.

The recommendation these authors make for reducing stem cell tourism involves denying essential materials to practitioners overseas who use unproven stem cell therapies. This is, obviously, not relevant to the issue of veterinary stem cell therapies marketed in the U.S. What is relevant is the fact that leading researchers into stem cell therapies for humans, those scientists most likely to believe in the promise of such therapies because they have made investigating them their life’s work, are consistent in warning against the premature clinical use of these treatments without adequate supporting research evidence. Caution about such therapies seems prudent when even their advocates recommend it.

I’ve written a bit about “integrative” veterinary cancer care previously and how it is often marketed with claims that are unsupported by evidence. A recent example of this is a post  on the Huffington Post blog in which a prominent CAVM advocate suggests that his conversion from skepticism to belief in alternative medicine is due in part to his realization that a therapy he judged to be quackery actually works. In reality, the therapy is still unsupported by anything stronger than anecdote and personal opinion.

Such unproven therapies are often marketed on the basis of claims that conventional therapies for the same problems are useless, or do more harm than good, and so it makes sense to try alternatives even if they don’t have good evidence behind them. This is an argument commonly made about chemotherapy and alternative cancer therapies, and it is made explicitly in the comments following the HuffPo article.

Fortunately, today Dr. David Gorski at Science-Based Medicine has posted a thorough and cogent response to the bogus claim that chemotherapy is useless. He does a great job of explaining both the value and the limitations of chemotherapy as well as pointing out the weaknesses of the evidence CAM advocates use to support their claims about chemotherapy. I encourage every to have a look at Dr. Gorski’s article.

The American Veterinary Medical Association (AVMA) and the American Animal Hospital Association (AAHA) recently released a set of Canine and Feline Preventative Healthcare Guidelines. The primary reason for doing so seems to be evidence from several surveys that suggest the demand for veterinary services has decreased in the last 10 years despite a significant increase in the population of dogs and cats in the United States. The surveys indicate that some of the reason for this decline is the increasing reliance of pet owners on the Internet for pet healthcare information, and the lack of awareness of the importance of preventative healthcare for pets.

I certainly agree that preventative healthcare is extremely important, and that reliance on the Internet as a source of information in lieu of professional veterinary care is a mistake. And as a general practitioner, I strongly believe that evidence-based guidelines are indispensible. Such resources have made evidence-based medicine practical for busy primary care clinicians without the time, skills, or energy to critically evaluate the medical literature themselves on an ongoing basis. Such tools would be of great benefit to veterinary medicine, and creating them is one of the goals of the Evidence-Based Veterinary Medicine Association (EBVMA), which I am involved with.

However, it is important that such guidelines be constructed in a way that is truly based on objective scientific evidence. If they are simply a way of promulgating the opinions of individual experts, they will constitute a quite low level of evidence justifying specific clinical practices. If they are not explicit and formal about the primary research evidence they are based on, it is impossible to judge whether they represent an evidence-based assessment or merely opinion, and this will reduce their reliability. And it is important that such guidelines be free from undue influence or bias of individuals or groups with potential conflicts of interest that could compromise the integrity of the evidence gathering and assessment process or the ultimate content of the guidelines.

The difference between truly evidence-based guidelines and opinion-based guidelines is a bit like the difference between a systematic literature review and a narrative or traditional literature review. Systematic reviews use explicit, predetermined criteria to identify and evaluate the primary research relating to a specific, focused question in order to allow a summary with as little bias as possible which can be replicated by others to check its validity. A narrative review is an informal search of the literature, usually covering a broader and less clearly defined subject than a systematic review. In a narrative review, the methods for finding and assessing the primary research literature may not be formally established or fixed in advance, and there is a strong likelihood that the opinions and biases of the reviewer will influence what research is examined and how it is evaluated and weighted in drawing conclusions. Narrative reviews can be useful, but they are a lower level of evidence than systematic reviews and less reliable due to the high risk of bias.

The new preventative guidelines published by the AVMA and AAHA appear to be much more like a narrative review. Despite being promoted as evidence-based, they are really a summary of previous consensus statements and other forms of expert opinion. The topic covered is broad and not clearly defined, the criteria or methods for selection and evaluation of the scientific literature are not stated, and there appears to be a high risk of bias in the content. The effort was also sponsored, and presumably funded, by the Partnership for Preventative Pet Healthcare. This organization, established in July, 2011, is a consortium of 16 organizations, including the AVMA and AAHA as well as 13 corporations selling veterinary products and services. Obviously, this presents the appearance, and the very real risk, of a conflict of interest that has to be considered in evaluating the content of the guidelines.

Many of the guidelines seem quite reasonable to me as a primary care veterinarian. It is hard to object to the idea that pets should have regular checkups, that veterinarians should consider medical health, nutrition, behavior, infectious and zoonotic diseases, and other important issues when evaluating pets, and that veterinarians should communicate clearly with clients and keep good records.

However, even these apparently obvious and sensible guidelines ought to be supported by reasonable and explicit scientific evidence, if possible. Plausibility is an important factor to consider in evaluating a healthcare practice, but it isn’t the end of the line. There is some evidence, for example, that in apparently healthy humans annual physical examinations may not have any real benefits in disease prevention, and the subject is the subject of some debate and controversy. And while it seems reasonable to assume that screening tests are always a good thing that can aid in prevention of illness, I’ve discussed before why this isn’t necessarily true (here and here). So simply because the recommendations seem reasonable, it is not enough to simply assume they are appropriate without looking for supporting evidence. There is a government agency, the U.S. Preventative Services Task Force, devoted entirely to evaluating the evidence and making recommendations concerning preventative healthcare for humans because it is recognized in human medicine that such recommendations ought to be based evidence-based.

There is also the question of whether the AVMA and AAHA can truly be both objective advocates for best clinical practices and also lobbying organizations for veterinarians. Both organizations have historically been more interested in defending the prerogatives of the profession and pleasing their own constituencies than in promoting or policing evidence-based standards of care for veterinary medicine.

AVMA has failed to clearly and consistently defend science-based veterinary medicine and challenge unscientific practices. I wrote earlier this year, for example, about the AVMA’s Model Veterinary Practice Act, which is being revised, and how the weak language concerning alternative veterinary practice could be improved to more clearly identify that most CAM is not consistent with established science or the curriculum taught in most veterinary schools. Instead, the AVMA chose to eliminate any mention of scientific validity in describing CAM. As a membership organization, the AVMA must follow the wishes of its members, and so it is unlikely to be able to effectively advocate for a standard of care that would threaten the practices of any significant number of members.

Similarly, I find it difficult to take seriously the claim that AAHA supports scientific, evidence-based medicine in the face of their recent e-newsletter which lauds the benefits of veterinarians working with animal communicators and previous owner education pieces promoting decidedly non evidence-based practices.

Undoubtedly, some will characterize these new guidelines as at least partially targeted at generating income for veterinarians and others with a financial stake in veterinary healthcare. That is a difficult accusation to defend against given that the guidelines were sponsored primarily by corporations who sell products and services which the guidelines recommended. This is especially true when there is an absence of explicit and good quality evidence provided to support the recommendations. Recommending continuous, year-round broad-spectrum parasite and flea prevention for all dogs and cats regardless of individual risk factors, for example, does not seem consistent with an objective evaluation of the evidence, but it does seem consistent with the objectives of the sponsoring organizations who market parasite and flea preventatives.

I don’t doubt the individual integrity of the members of the committee that drafted the guidelines. I have often pointed out that bias rarely involves straightforward dishonesty or malfeasance, and that we cannot simply dismiss arguments on the basis of the presumed financial motives of those making them. As a clinician and advocate for science-based medicine, I deal every day with pet owners and critics of mainstream veterinary medicine who are suspicious of the role of money in the veterinary profession. The best defense against such suspicions is a transparent assessment of the scientific evidence supporting our practices, and a lot of my efforts are directed at illustrating why the evidence clearly supports conventional, scientific medicine far more than most of the proposed alternatives. So I would have liked to see these guidelines produced in a manner that made them truly evidence-based, with appropriate controls for bias, financial and otherwise, so that I could enthusiastically promote and defend them. As it is, while I think much of the content is reasonable and appropriate, the process and the details appear deeply flawed, which significantly reduces the reliability and value of the guidelines.

I also recognize that no organization and no process for developing consensus or general guidelines can be perfect, and I don’t wish to make the perfect the enemy of the good. However, there is another set of guidelines currently being developed which I think illustrate a superior, and truly evidence-based process that should be a model for future efforts of this kind.

The Veterinary Emergency and Critical Care Society (VECCS) has an ongoing project to establish  evidence-based guidelines for CPR in veterinary species. The Reassessment Campaign on Veterinary Resuscitation (RECOVER) project  seems to me an outstanding example of what a truly evidence-based process for establishing such guidelines should be. Criteria for selection and evaluation of the primary literature and focused clinical questions were established in advance, a formal process of grading the literature was
followed, and both the primary literature used and any potential conflicts
of interest were explicitly disclosed.

This project illustrates the potential for how such guidelines can be developed in an evidence-based way, avoiding many of the concerns that I think weaken the AVMA/AAHA guidelines. The former is much more like a systematic review and the latter more of a traditional narrative review. Both can be useful, but the systematic and explicit process of the RECOVER initiative is likely to lead to a more reliable end product, more useful and less subject to allegations of bias or hidden economic agendas.

Hopefully, more focused and evidence-based guidelines will become available to general practice veterinarians in the future. I believe this will significantly improve the quality of veterinary care available to pets. But this benefit can only be realized, and pet owners can only be made to have confidence in their veterinarians’ recommendations, if transparent and truly evidence-based processes are utilized to develop such guidelines. I think the RECOVER initiative is an excellent model for such a process, and I hope it will illustrate how an evidence-based approach can be practical and can provide the most effective clinical tools and also the best defense against suspicious about the motives or integrity of the veterinary profession.