Bad medical ideas often start with good intentions. Most doctors are interested in preventing and treating disease, and some diseases are particularly challenging. Some rise to this challenge, forming clever hypotheses and finding accurate ways to test them, but others aren’t so successful. Sometimes, hypotheses are too implausible to be worth spending much time on. Sometimes, the method used to test a hypothesis is simply not valid.
This story begins on the website Age of Autism. AoA is one of the homes of the antivaccination movement and gives a lot of time to those who still believe that vaccinations and other “toxins” cause autism. The site is full of remarkably paranoid rants. When Chicago Tribune journalist Trine Tsouderos won an excellence in health care journalism award, AoA accused the CDC and Trib of having “bought” the award. They are boosters of every unproven and implausible “treatment” for autism, such as chelation, hyperbaric oxygen, and chemical castration through lupron injections. Recently, they provided a platform to Dr. Andrew Wakefield, the physician who’s Lancet paper drawing a link between autism, vaccinations, and gut disorders, was formally withdrawn by the journal’s editors. Due to accusations of scientific and ethical misconduct, he is likely to lose his license to practice medicine in England.
So it came as no surprise to see one of their writers hyping a study in progress that is testing oral enzymes for the treatment of autism. In the piece, Theresa Conrick incorrectly implies that the existence of this study is vindication for both the autism-gut hypothesis and for Wakefield’s behavior.
In 1998 Dr. Andrew Wakefield published a paper in the prestigious medical journal the Lancet. In this study, he claimed that the measles, mumps, rubella (MMR) vaccine caused observable changes to children’s intestines which eventually lead to autism. The study led directly to falling vaccination rates in the UK, an increase in vaccine-preventable disease, and helped launch the modern antivaccination movement in North American and Europe. The study, as it turned out, was so fraught with conflicts of interest and poor science that several of the authors dropped their association with it, and it was eventually withdrawn from the journal. Wakefield himself was lambasted by England’s General Medical Council for his unethical behavior associated with the study, and will likely lose his license to practice medicine.
Wakefield’s hypothesis about autism and gastrointestinal disease was never terribly plausible to begin with, and despite the retraction of his original study, there persists a belief in many parts of the autism community that the gut is somehow implicated in the development and treatment of autism. Wakefield still has many zealous adherents and dietary therapies for autism have grown in popularity. Jenny McCarthy attributes much of her purported success with her child to severe dietary restrictions which she recommends for others. So far, however, there is no good body of literature supporting any connection between gut disease, diet, and autism. A new study aims to change that.
According to the hyperbolic language of Age of Autism, you would think that the very existence of this study exculpates Wakefield and vindicates all of the pseudo-experts’ opinions about the causes of autism. But what is behind Age of Autism’s excitement?
The study is designed to evaluate the affect of “CM-AT”, made by Curemark, LLC, on the symptoms of autism in children. CM-AT is an enzyme with a proprietary delivery system that is supposed to help digest proteins.
There are a number of conditions for which orally ingested enzymes can be used. Lactose deficiency, a common condition in which someone can’t digest the primary sugar in milk, can be treated effectively by taking lactase with dairy meals. People with pancreatic damage can take pancreatic enzymes to help them digest certain carbohydrates, fats, and proteins. Assuming that CM-AT actually breaks down proteins in vivo, what hypothesis underlies its use in autism?
According to the brief description at ClinicalTrials.gov:
Treatment is based upon the observation that many children with autism do not digest protein.
I’m unsure what literature supports this assertion. They do of course give references, but the reference are in large part either irrelevant to the hypothesis or of very poor quality. For example, one study looked at the co-occurrence of certain medical problems and autism, including GI problems, but the study failed to compare these rates to non-autistic children. Another looked at parental reports of abnormal stools in autistic kids. Neither of these gives a particularly strong foundation for a study of proteases in autism. Yet another study extensively quotes the work of Andrew Wakefield, the doctor who was censured in England for his unethical work. But the most interesting study is one done by Wakefield himself.
In this study, Wakefield reported that he had discovered “new variant of inflammatory bowel disease is present in this group of children with developmental disorders.” This was a number of years before his famously retracted study in which he blamed the MMR vaccine for autism, the same study for which he was censured. Before that controversy, a discussion in the journal Histopathology criticized Wakefield’s work, and practically accused him of lying about his methodology:
Sir: The histopathology proforma used for scoring of intestinal biopsies in the paper ‘Enterocolitis in children with developmental disorders’1 by Wakefield et al. receives detailed criticism in the Commentary, ‘Autistic enterocolitis, is it a histopathological entity?’,2 by MacDonald and Domizio. In his response Dr Wakefield states that ‘the proforma was designed by Professor A Dhillon of the Department of Histopathology, who with Dr A Anthony evaluated the sections for the purposes of completion of this proforma’.3
I neither designed the proforma being debated, nor was I a coauthor of the paper in which the proforma was published.
Given Wakefield’s subsequent troubles I find it curious that Curemark chose to cite this study in support of their work.
I spoke to Dr. William E. Gannon Jr. who is directing the study for Curemark. He has decades of experience running clinical trials. He reported to me that he is aware of the challenges sometimes associated with research into autism treatments and has worked closely with Curemark and the FDA to make sure this phase III trial is done right. He has been in continuous contact with study sites to make sure they stay on protocol and avoid inappropriate release of preliminary results.
But it would appear he is being hamstrung by Curemark, who is pumping up CM-AT before the phase III results are available. Their website currently links to a BusinessWeek article about the product:
“One of the most promising treatments in this category is a drug called CM-AT made by a startup called Curemark. Dr. Joan Fallon, the company’s founder and CEO, observed that many autistics show a strong preference for foods high in carbohydrates and low in protein. A diagnostic test revealed that some autistic children lack enzymes that digest protein. As a result, these children produce fewer of the essential amino acids that are the building blocks for brain development and neuroreception. Fallon believes this deficiency is linked to the most severe symptoms of autism, and she says an early observational study of CM-AT, an orally ingested powder that delivers protein-digesting protease, showed “significant improvements.” Curemark is enrolling patients in phase III clinical trials at 10 to 12 site the largest autism trial to date.” (emphasis mine)
Where did she get these ideas? What evidence supports this hypothesis? Who is Dr. Joan Fallon?
First, Fallon is not a doctor; she is a chiropractor. She is not exactly widely published in the medical literature. In 2005 she put a piece in Medical Hypotheses (a controversial journal, to say the least) in which she “hypothesizes” that the antibiotic Augmentin may be responsible for autism. She applied for a patent to use the commonly available laxative lactulose to treat autism. And she’s promoted the idea that autism is somehow related to the gut. None of her ideas really hang together. Is autism caused by a failure of protein digestion? By an antibiotic? By toxic ammonia levels? Whatever the cause, she seems to be looking for a profitable cure. I’m not sure that she can patent lactulose, but she apparently found a substance she can patent—CM-AT, a proteolytic enzyme in a novel delivery system.
There are a number of things I find disturbing about this study. While it appears to be well-run, it fails to conform to an important scientific and ethical standard: plausibility. According to the Helsinki Declaration protecting human research subjects:
12. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.
Fallon and Curemark have not convinced me that there is any science that would justify their study. It’s certainly reasonable to take some risks based on sound science, but in this case, all that underlies this study is a handful of very questionable studies. Citing literature to justify your research is not just some bureaucratic hurdle to leap; it is fundamental to the ethical design of clinical trials. There is no reason to expect that delivering an oral protease to children with autism should improve symptoms of autism. There is no putative mechanism by which this should work, despite the speculations of the chiropractor CEO of the company that makes the product.
Given the low plausibility of the hypothesis, even positive results, should they be found, must be interpreted with a high index of suspicion. The statistics underlying the study of implausible hypotheses tell us that positive results are often due to chance or problems with study design rather than the drug being tested. This is not an esoteric technical detail. This is a study being done on child subjects whose parents have been led to believe this treatment may help. There is no reason to believe this is so. Perhaps some day if there are convincing preliminary studies, the current one would be justified. At this point, though, it is simply another questionable study built on a foundation of bad science.