Medical ethics, children, and chelation therapy for autism

I’ve said it before, and I’ll say it again. J.B. Handley, that bull-in-a-china-shop general in the mercury militia who detests me intensely, is about as ignorant as they come when it comes to science and clinical trials. Yesterday, he provided yet more evidence of his cluelessness in his latest piece posted to that repository for all things antivaccine, Age of Autism.

Mr. Handley’s all in a lather because the Associate Press published a story yesterday about a proposed NIH-sponsored clinical trial of chelation therapy for autism entitled Fringe autism treatment could get federal study. Because the AP story actually got it (mostly) right, Mr. Handley was sufficiently enraged to be moved to write an open letter to Carla Johnson, the AP reporter who wrote the story. It’s the usual assortment of faux wounded self-righteousness that we’ve come to expect from Mr. Handley, and I won’t dwell on this aspect of Handley’s rant. That’s just his usual schtick. What caught my attention was this passage referring to the proposed NIH study described in the AP article:

Do you really think the NIH fund studies because parents are desperate? No, they fund studies because compelling anecdotal evidence leads them to believe that more work should be done to see if the anecdotes can be extrapolated to a broader conclusion to benefit more kids. This is how science progresses.

My irony meter fried every single circuit in response to seeing Mr. Handley pontificate on “how science progresses.” (I seem to go through a lot of them whenever I dare to load my browser with the morass of logical fallacies and bad science that is AoA.) If Mr. Handley had a single clue about how science progresses, he would have realized three years ago that science has left his pet belief that it’s somehow, some way got to be the vaccines causing autism behind and has moved on to more fruitful avenues of investigation. Indeed, the only thing keeping the vaccine/autism myth alive is the lobbying of true believers like Handley. It’s certainly not scientists. Handley’s also being either incredibly naïve, disingenuous, or ignorant. (Take your pick.) The reason is that the NIH is almost certainly not considering funding this study because of “compelling anecdotal evidence” supporting chelation therapy. That’s because there is none. It’s almost certainly funding this study precisely because Handley’s “desperate parents” have become loud and vocal, resulting in political pressure being applied.

Sadly, although I wish it weren’t the case, because NIH is funded by the federal government, it can be coopted by powerful woo-friendly legislators, like the antivaccinationist- and quackery-friendly Representative Dan Burton (R-IN). Indeed, I had thought that this particular monstrosity of a study had been killed off once and for all about a year ago. I guess that, like so many studies of “alternative” methodologies, it’s a zombie study. Kill it, and it rises from the grave to eat you. Of course, in a democracy, because the NIH is funded by our tax dollars, it needs to be accountable to the voters through the legislature for how it spends its research dollars. The upside of this is that the research priorities of the NIH will usually mirror the priorities of the electorate, for the most part. The downside of this is that political pressure from small, vocal, activist fringe groups can influence the NIH to undertake research and studies whose scientific basis is, to put it kindly, not up to the usual high quality that most NIH study sections demand of NIH-funded research. Some of these studies are even sometimes downright unethical.

My guess is that the genesis of this particular highly unethical and scientifically dubious trial was very similar to that of another much larger and similarly highly unethical and scientifically dubious trial a a few years ago: just that sort of political pressure. I’m referring to the infamous Trial to Assess Chelation Therapy (TACT) for coronary artery disease (CAD). That massive boondoggle came about through in spite of its initial rejection by scientific board reviewing it, which quite correctly pointed out that there was insufficient preclinical data and no compelling scientific rationale to think that the trial would be positive, particularly in light of several randomized clinical trials in the 1990s that failed to find an therapeutic effect against cardiovascular diseaes above placebo attributable to chelation therapy. Thanks to Dan Burton, however, this trial also rose from the dead to suck the blood of American taxpayers to the tune of $30 million, an incredible sum of money for bad science and an unethical clinical trial. (I know, I know. I’m mixing my zombie and vampire metaphors. Just go with it; I’m on a roll.) Indeed, the TACT trial is not the only previous large clinical trial to have come about thanks to woo-friends in high places. There was also the infamous and even more scientifically dubious trial of the Gonzalez therapy, which involves a panoply of woo that includes dozens of supplements a day, a special diet, and coffee enemas, for pancreatic cancer.

So the answer is, sadly, that political pressure from the woo brigade can result in the NIH acting contrary to good science and even medical ethics to fund scientifically dubious studies if enough people (or, more importantly, enough of the right people) apply pressure or threaten its budget. It’s exactly the sort of pressure that was applied in the early 1990s by Senator Tom Harkin (D-IA) to “persuade” the NIH to start the embryonic Office of Unconventional Medicine when the scientific leadership saw no reason why there needed to be a separate office to fund such research. Harkin then helped nurse its development into the current $120+ million a year money pit for bad science that has become the NIH National Center for Complementary and Alternative Medicine (NCCAM). Clearly, Ms. Johnson understood that this study is driven far more by politics than scientific merit, as she AP storygets it correct right from the beginning:

Pressured by desperate parents, government researchers are pushing to test an unproven treatment on autistic children, a move some scientists see as an unethical experiment in voodoo medicine.

Unethical voodoo medicine is a beautiful term to describe this study, for reasons I’ll explain in a moment.

The treatment removes heavy metals from the body and is based on the fringe theory that mercury in vaccines triggers autism — a theory never proved and rejected by mainstream science. Mercury hasn’t been in childhood vaccines since 2001, except for certain flu shots.

But many parents of autistic children are believers, and the head of the National Institute of Mental Health supports testing it on children provided the tests are safe.

“So many moms have said, `It’s saved my kids,'” institute director Dr. Thomas Insel said.

For now, the proposed study, not widely known outside the community of autism research and advocacy groups, has been put on hold because of safety concerns, Insel told The Associated Press.

As well it should be put on hold. In any case, this is sad to see. Dr. Insel apparently doesn’t quite understand the difference between testimonials and real anecdotal evidence with clinical observations that are as objective as possible. In fact, it disturbs me greatly that anyone who would say something so utterly boneheaded is actually the head of a major NIH institute.

But, why, you ask, do I call this study unethical? It should be very obvious. One cardinal rule of human subjects research enshrined in the Common Rule, which governs all federally funded human subjects research, is that vulnerable populations must be protected by an additional level of ethical constraints. Usual vulnerable populations include prisoners, the mentally disabled, or–yes–children. The reason, of course, is that prisoners can be coerced, that the mentally disabled may have impaired decision-making capabilities that interfere with their ability to give informed consent, and that children cannot under law give informed consent What all this means is that, both ethically and legally, the bar is set much higher for any human subjects research that is to be carried out on children, and it’s hard to imagine a population more vulnerable and needing such protection than autistic children. The science must be even more compelling than for adults, and the experimental design must be bulletproof. Reading the article and from what I know from some of my colleagues, my guess is that the Institutional Review Board (IRB) reviewing the proposed chelation study is having some serious reservations about the safety and risk-benefit ratio of the proposed study.

As well it should.

Normally, at most institutions, any clinical trial protocol that is submitted for approval usually goes through two committees, a Scientific Review Board (SRB) and the IRB. The SRB is generally charged with evaluating the study for soundness of its scientific rationale, how compelling the evidence supporting the hypothesis to be tested is, how well the clinical trial is designed, and how rigorous the proposed statistical analysis is, as well as whether the investigator proposing it has the skills to carry it out well. If any of these aspects of the trial is dinged by the SRB, the trial won’t even make it to the IRB, which is charged with making sure that the human subjects are protected and that the trial design is ethical. Again, when the subjects are children, the IRB is supposed to be utterly ruthless in quashing any potential problem with patient safety.

So why is this trial so bogus? It’s bogus to its very core because its very core, the hypothesis that it is designed to test, is not supported by good science. That hypothesis is that autism is in fact a form of mercury poisoning is the basic hypothesis being tested here, with the corollary being that chelation can remove that excess mercury and alleviate the symptoms of autism. Neither the main hypothesis, nor its corollary is supported by compelling evidence. Indeed, it doesn’t even have biological plausibility going for it, as it in essence postulates that some sort of mercury exposure (from those evil vaccines, naturally) caused some sort of brain damage in infants that led to autism months to years later. Even if mercury in vaccines did cause damage leading to autism, that such damage could be reversed months or even several years later by chelation defies scientific plausibility based just on biology alone.

But it’s more than just scientific plausibility. In any normal trial, especially on children, there has to be good preclinical evidence supporting the hypothesis. There should, for instance, be animal models showing that mercury exposure does indeed cause autistic symptoms and that chelation therapy alleviates those symptoms. There should be cell culture and animal models showing a plausible physiological mechanism. (Throwing a bunch of thimerosal on neurons in cell culture then noting that some of them die doesn’t count. I could do that with bleach, but that wouldn’t prove that bleach causes autism.) Absent strong animal data, there should be high quality observational data in humans that support the hypothesis; for example, compelling, strong, and consistent evidence that autistic children do have higher mercury exposures and higher mercury levels indicative of chronic mercury poisoning. There are no such data, and the usual data presented as “evidence” that mercury poisoning causes autism is of such poor quality that they don’t deserve to be called “data.” Most of all, however, the drug to be used, DMSA, is not risk-free:

But the study was put on hold for safety concerns after an animal study, published last year, linked DMSA to lasting brain problems in rats. It remains under review, Insel told the AP.

I believe the article is referring to this study, which shows that DMSA can indeed alleviate the cognitive effects due to acute lead toxicity in rats. However, treating rats not poisoned with lead actually hurt them, producing cognitive effects as similar to those caused by higher levels of led exposure, suggesting that giving DMSA to children who do not actually have lead poisoning is likely to be a very bad idea. Indeed, the abstract concluded:

These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.

So let’s see. No known benefit for autistic children combined with an animal study that suggests that chelating a child with this drug when that child does not have elevated mercury levels in the blood and tissues could actually harm that child? Check. In essence, a risk-benefit ratio of infinity because the benefit is zero? Check. On the basis of human subjects protections and ethics alone, such considerations should have killed this trial dead, dead, dead for a good long time, if not forever. Unfortunately, however, so strong is the unfounded belief that mercury in vaccines causes autism, that even this risk may not be enough to stop this zombie from rising from the dead to feed on autistic children.

An unethical experiment in voodoo medicine indeed.

I realize that one rationale of the trial is that, if no difference were found between the DMSA group and the placebo group, such a result would “would counteract ‘anecdotal reports and widespread belief’ that chelation works,” which is what, indeed, the study outline asserts. Whoever wrote the study outline is charmingly naive. She clearly doesn’t know antivaccinationists very well. A negative trial would not in the least deter the mercury militia. Antivaccinationists would just say that it was the wrong drug, the wrong dose, or that the therapy wasn’t continued long enough.Then they’d demand another study. If that study were negative, they’d find reasons to discount it, too and demand another one. The ability of antivaccinationists to shift the goalposts is well nigh infinite, as David Kirby’s goalpost-shifting has demonstrated. No matter how many studies showed that chelation does not help autistic children, they’d still demand just one more.

And, if this article is any indication, the clueless and hapless Dr. Insel would give it to them, too, no matter how unethical.

ADDENDUM: Steve Novella has more. Money quote:

Therefore, such research is a waste. But it is more than a waste – it subjects the people in the study to the risks of medical research without any benefit to society. If the treatments are highly implausible, then the probability is there was no benefit to the subjects themselves either. Such research seems to be all expense and risk and no benefit.

This puts advocates of science-based and ethical medicine in a difficult position, however. It is hard to argue against doing research – more information always sounds like a good idea. Refusal to even research a question can easily be made by fanatics to seem like suppression of the truth. This can turn the public against those who are most sincerely advocating for their rights, ironically. This motivates some, like Insel, agree to do the research – but this is a sucker’s bargain. We have been there before – doing the research accomplishes nothing because the people who need to be convinced are not basing their conclusions on scientific evidence in the first place.

A sucker’s bargain indeed.

Kevin Leitch also weighed in. Money quote:

Let’s be clear. This study is being touted about for one reason and one reason only – to appease the anti-vaccine/autism groups. In the mainstream medical/scientific community (and notably in the toxicology community) it is well known that autistic kids aren’t toxic.