Science

Prove the scientific consensus and win a prize: A time-dishonored PR ploy used by cranks, quacks, and pseudoscientists (Robert F. Kennedy Jr. edition)

Science-Based Medicine - February 20, 2017 - 3:36am
Last week, antivaccine activist Robert F. Kennedy, Jr. teamed up with Robert De Niro to issued a challenge to provide one scientific study that proves thimerosal in vaccines is safe, with a cash prize of $100,000. They thus joined a long line of antivaxers, creationists, and climate science denialists offering money to "prove" the scientific consensus. Science doesn't work that way.
Categories: Science

Corrigendum. The Week in Review for 02/19/2017

Science-Based Medicine - February 19, 2017 - 11:59am
More poorly done acupuncture studies. Burzynski eats just desserts. Italians like homeopathy. New Jersey is going after Oregon. And more
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Spinal Manipulation for Back and Neck Pain: Does It Work? Annotated.

Science-Based Medicine - February 17, 2017 - 3:07am
Spinal Manipulation for Back and Neck Pain: Does It Work? You would think it does if you read the article but not if you actually read the literature.
Categories: Science

Turning chiropractors into primary care physicians via Legislative Alchemy

Science-Based Medicine - February 16, 2017 - 1:00am
Via the magic of Legislative Alchemy, chiropractic lobbyists are trying to to convince state legislators to expand chiropractic scope of practice so they can rebrand as primary care physicians.
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Regulating Health Care Products

Science-Based Medicine - February 15, 2017 - 8:25am
How should we optimally regulate health care products to protect consumers? A conversation with the Acting Chairman of the FTC.
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Natural Remedies for Diabetes: Plavinol, Glucopure

Science-Based Medicine - February 14, 2017 - 3:00am
There is not enough evidence to support using dietary supplements in the treatment of diabetes. There is preliminary evidence that some herbs lower blood sugar by a modest amount, but it would be foolish to think they could replace conventional treatment of diabetes.
Categories: Science

In 2017, are antivaxers winning?

Science-Based Medicine - February 13, 2017 - 3:00am
The election of Donald Trump as President has emboldened antivaxers, because they quite rightly sense that he is one of them. His inauguration as President, combined with other trends, have led observers to ask the question: Are antivaxers winning, or will 2017 be the year of the antivaxer?
Categories: Science

Corrigendum. The week in review for 02/12/2017

Science-Based Medicine - February 12, 2017 - 6:52pm
The week in review. Chiropractic and stroke. Integrative Medical doctors don’t trust vaccines. Death from medical marijuana. Shilajit: compost or mulch oozing from Himalayan rocks. India goes full Tuskeegee with AIDS. And more
Categories: Science

Robert F. Kennedy, Jr. promotes an awful epidemiology study linking vaccines and neurological conditions from…Yale?

Science-Based Medicine - February 12, 2017 - 12:12am
Donald Trump's new BFF Robert F. Kennedy, Jr. has never seen a lousy study linking vaccines to bad things that he didn't like. This is no exception. Oddly enough, this study was funded and carried out by a lawyer and an investment banker, with the help of an eminent Yale pediatrician. Not surprisingly, thanks to a combination of p-hacking and not controlling for a very obvious confounder, it doesn't show what RFK Jr. thinks it shows.
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Vaginal Seeding: To Swab or Not to Swab Your Newborn Baby

Science-Based Medicine - February 10, 2017 - 9:00am
More mothers are requesting vaginal seeding, but does the evidence support this potentially risky intervention?
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Radiolab Presents: Ponzi Supernova

Radiolab Podcasts - February 10, 2017 - 12:45am
Madoff speaks.  Investigating the world's largest con with the team behind @Audible_com's #PonziSupernova.
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Do anti-inflammatory drugs effectively treat spinal pain?

Science-Based Medicine - February 9, 2017 - 9:00am
While anti-inflammatory drugs are commonly used to treat back pain, a new review suggests that they may not provide meaningful benefits to most people.
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Russian Academy of Sciences Calls Homeopathy Pseudoscience

Science-Based Medicine - February 8, 2017 - 7:49am
That homeopathy is pure pseudoscience is not news. Its basic principles are essentially magic, and the preparation of homeopathic products is indistinguishable from brewing a magic potion. Its two core principles, as the commission states, are a priori dogma - that like cures like, and that diluting substances out of existence leaves behind their magical essence. Science has progressed over two centuries since these ideas were invented, and they remain just as much pseudoscience as they every were - more, in fact, because the more we learn about chemistry, biology, and physics the less plausible homeopathy becomes.
Categories: Science

Re-thinking Antioxidant Supplementation for Macular Degeneration

Science-Based Medicine - February 7, 2017 - 3:00am

Age-related macular degeneration (AMD) is a leading cause of blindness. Known risk factors include smoking, obesity, hypertension, high intake of vegetable fat, and low dietary intake of antioxidants and zinc. The AREDS (Age-Related Eye Disease Study) trial was designed to test whether supplementation with an antioxidant formula could slow the progression of the disease. In 2001 the results of the trial were published in the Archives of Ophthalmology.  They found that a mixture of vitamin C, vitamin E, beta-carotene, zinc, and copper significantly slowed the progression of disease in patients with moderate to severe age-related macular degeneration. It was a large multicenter double-blind study.

There was concern about possible harm from certain ingredients in the original formulation (beta-carotene was associated with lung cancer in smokers, and zinc in high doses was known to cause adverse effects), so a subsequent study, AREDS2, was done. It tested the effects of various changes in the formulation: removing beta-carotene, reducing the amount of zinc, and adding lutein/zeaxanthin or omega-3 fatty acids. The results, published in 2013, found that there was no additional benefit from the changes.

I wrote about AREDS in 2010, with an update on AREDS2 in 2014  I was skeptical then, and I am even more skeptical now that more information has come to light about the trials.

The response

Most clinicians accepted the results of AREDS and recommended that patients with moderate to advanced AMD take a supplement mixture. There was no evidence that patients with mild AMD would benefit, and there was no suggestion that supplements could prevent the disease from developing in the first place. Not everyone followed the actual evidence. Eye vitamin preparations were taken by people who had no evidence-based justification for taking them. And many of the eye vitamins on the market were different from the AREDS mixtures.

A Cochrane review considered the strength of the evidence to be “moderate,” concluding:

People with AMD may experience delay in progression of the disease with antioxidant vitamin and mineral supplementation. This finding is drawn from one large trial conducted in a relatively well-nourished American population. The generalisability of these findings to other populations is not known. Although generally regarded as safe, vitamin supplements may have harmful effects.

Was the AREDS trial actually negative?

Dr. Daniel Seigel accused the AREDS investigators of distorting their findings.  He said they promoted a nonsignificant result into a conclusive recommendation. The original study design called for 4 tests, none of which was statistically significant. “One, testing the effect of zinc on progression to advanced AMD, achieved a level of significance defined by the investigators as suggestive.” Essentially, the results were negative. They then restricted their analysis to a sub-group and “featured a combined treatment group which in secondary analysis broke the boundary of statistical significance, thereby disregarding the primary analysis in which neither treatment was significant.” They then made a conclusive recommendation based on these inconclusive findings. Dr. Seigel points out that a negative result would have been more in line with the majority of other studies in which antioxidant supplements have failed to prevent diseases.

In a letter to the editor in the Archives of Ophthalmology, Ambati and Ambati cautioned against “misplaced enthusiasm.” They said the benefit of these supplements is questionable, some of the ingredients may be harmful, and the study’s methodology is flawed.  The researchers failed to correct for post hoc analysis. When the proper corrections are made, “The effect of the combination treatment on loss of visual acuity, the only endpoint that truly matters to patients…is even less compelling at a similarly corrected P=.24.”

Another professor of ophthalmology, Cynthia J. Mackay, published a devastating critique on her website  She claims that the study results were actually negative, that the researchers went back and changed the research design after the study was completed, that they arbitrarily threw out all patients with mild AMD from the study, and the definition of “success” was changed from “preventing vision loss and progression” to “preventing AMD events.” She said,

The only people who supposedly “benefitted” from this drug are people who have intermediate AMD in one eye, and advanced AMD in the other. No other type of patients had any benefit. Even if a doctor accepts the results of this study, he should only recommend this drug to this small subgroup of patients.

She also pointed out that there was conflict of interest, that there was no rationale for choosing the particular ingredients in AREDS, that all the ingredients were known to cause serious problems, and that the doses are far above recommended amounts.

The manipulation of the data amounts to what Norbert Kerr, writing in Personality and Social Psychology Review,  called HARKing: Hypothesizing After the Results are Known.

Conflicts of interest

The AREDS study was funded in part by Bausch and Lomb, and many of the investigators had ties to the company. One of the AREDS study authors, Dr. Ferris, holds a patent for the AREDS formulation with Bausch and Lomb and earns royalties, and he did disclose this conflict of interest in a few published papers; yet in many of the papers he co-authored reporting AREDS data, he neglected to report it. Out of 48 AREDS reports, only 8 include any mention of conflicts of interest. While this doesn’t necessarily mean the studies are biased, a conflict of interest statement is standard practice, and one can only wonder why it was selectively omitted from most of these reports. One article explains that Dr. Ferris invented the patent, but it is owned by Bausch and Lomb, and he has assigned his interest in the patent to the United States Government and received government compensation.  A Freedom of Information request disclosed that Dr. Ferris has personally earned $1.8 million from the Bausch and Lomb patent. Such payments to federal employees are allowed under a U.S. law designed to encourage transfer of technology from government to industry. Isn’t $1.8 million worth mentioning in a financial disclosure? An article on Medscape criticized this and similar conflicts of interest.

Do genotypes matter?

Emerging evidence suggests that the response to antioxidants varies with the patient’s genotype.

In the original AREDS study, only patients who had category 2 though 4 disease (minimal, intermediate, and advanced) were enrolled in the trial. Category 1 patients who were thought to be at low risk of AMD were enrolled in a separate study to evaluate the effect of antioxidant supplements on cataract progression. In a Jan 26, 2017 article in the Journal of Vitreoretinal Diseases, 3 doctors (Awh, Zanke, and Kustra) re-analyzed data from that trial and genotyped the subjects.

Here’s what they concluded:

On average, antioxidant treatment has no impact on the development of intermediate AMD in patients without AMD. However, antioxidant treatment may increase the risk of developing intermediate AMD in patients with low genetic risk and may reduce the risk of developing intermediate AMD in patients with high genetic risk.

This would seem to support the idea of selectively prescribing eye vitamins for patients without AMD based on genetic testing, but the authors cautioned,

Pending validation studies, physicians, and patients should be mindful of the unproven benefit, and the potential risk, of antioxidant supplementation for most patients without AMD.

It should be noted that two of the authors disclosed a conflict of interest: they both own shares in a company that markets genetic tests for AMD.

Should prescription be guided by genotype?

It’s probably too early to say. The American Academy of Ophthalmology does not support the routine use of genetic testing, citing bias in the data analysis.   The validity of the genotype studies was questioned in an editorial in Ophthalmology. 

Deceptive marketing

A 2015 study examined 11 of the top-selling ocular nutritional supplements in the US and found that the majority of products were not identical to the formulations tested in the AREDS or AREDS2 trials.  Only 4 out of the 11 contained equivalent dosages. They found evidence of misleading marketing. All the individual supplements claimed to “support,” “protect,” “help,” or “promote” vision and eye health, but none specified that there is no proven benefit in using nutritional supplements for primary prevention of eye disease.

Inappropriate use

In an abstract presented at the ARVO Annual Meeting in September 2016, Ellingson and Ambati reported that 73.5% of patients taking eye vitamins did not meet AREDS criteria, and only 29.6% of those taking eye vitamins were taking a preparation identical to the AREDS formulation. They calculated an adjusted NNT (number needed to treat) of 220, and they calculated the direct cost of inappropriate vitamin use as between $218,000 and $657,000 per quality adjusted life year. They also noted that 86% of patients who were active smokers were unaware that beta-carotene might increase their risk of lung cancer.

Standard of care?

Many ophthalmologists, and the manufacturers of eye vitamins, would have us believe the standard of care is to recommend AREDS formulas for patients with moderate to severe AMD.  In my opinion, there is good reason to question that recommendation. The evidence is from a single flawed study.

The AAO Preferred Practice Pattern Guidelines say supplements “should be considered,” rather than employed routinely. They rate it as “discretionary,” a category they use when there is low-quality evidence or when the evidence suggests that desirable and undesirable effects are closely balanced. The Veterans Administration noted the poor-quality analysis, pointing out that the 6% absolute risk reduction comes from a post-hoc analysis.

Conclusion: questions remain

With all the questions that have been raised about the evidence, and the fact that it hinges on a single study, I don’t think we can strongly recommend AREDS-type supplements for anyone. Patients who meet the AREDS study criteria can be offered the supplements with acknowledgement of the uncertainty, and they can work with their ophthalmologists to arrive at a shared informed decision. Patients who do not meet the AREDS criteria should not take the supplements, and there is no justification for taking supplements that do not match the AREDS formulations. There is an intriguing possibility that genetic analysis might identify some patients without AMD who could prevent or delay the development of the disease by taking an AREDS-type formula, but it’s too early to base clinical recommendations on that yet.

Categories: Science

Donald Trump versus the FDA: Is the standard of evidence for drug approval actually too low, not too high?

Science-Based Medicine - February 6, 2017 - 3:00am

There are good things and bad things about holding the Monday slot on this blog. One of the good things is that I tend to have more time to come up with material. However, one of the drawbacks of holding the Monday slot is that a lot of studies and news stories are published on Monday that I’d normally like to write about but can’t because by the time I see them my post is done. Then I have to wait until the following Monday, by which time something new has usually intervened, a shiny bright object to attract my attention from last Monday’s story, which, by the time I’m ready to write about it is old news. True, I can write about such stories on my not-so-super-secret other blog (and frequently do), but sometimes I like to provide the greater exposure this blog provides.

So it was last Monday that Jonathan Kimmelman & Carole Federico published a commentary in Nature entitled Consider drug efficacy before first-in-human trials. I thought it an important topic considering the speculation over who will be pointed FDA Commissioner by President Trump. As I discussed three weeks ago and a New York Times article published yesterday discusses, Donald Trump’s three most likely picks for FDA Commissioner (that I knew of at the time) all favor loosening drug approval standards and could very well undo decades of safeguards. Two are cronies of technolibertarian Peter Thiel. Of these two, one (Jim O’Neill) believes that the FDA shouldn’t have to require evidence of efficacy, only safety, before approving drugs and devices for the market. (Apparently the free market will sort it all out.) The other (Balaji Srinivasan) believes that a “Yelp for drugs” would do a better job than the FDA in assuring drug safety. (Apparently he’s never actually spent much time reading online ratings systems.) The third candidate (Scott Gottlieb) is the closest thing I’ve ever seen to a bona fide, honest-to-goodness pharma shill, who called the early termination of a multiple sclerosis drug study “an overreaction,” even though three participants had died, defended the off-label marketing of Evista, and, when he was Deputy Commissioner of the FDA, harassed underlings when FDA scientists rejected Pfizer’s osteoporosis drug candidate Oporia, forecast to earn $1 billion a year.

Srinivani appears to be no longer in the running, thanks to his rookie mistake of not taking down his Twitter account before meeting with President Trump, allowing some of the dumber things he said about using the Uber model or the Yelp model for online reviews of drugs to be brought to light. However,. There’s now a new candidate, Joseph Gulfo, executive director of the Lewis Center for Healthcare Innovation and Technology at Fairleigh Dickinson University, the author of Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances and the former President and CEO of the medical device firm MELA Sciences. More on him later, but you can see from the title of his book that his philosophy is from the same mold as O’Neill’s and Srivinasan’s, but, unlike them, appears a bit more grounded in reality, although he appears to share O’Neill’s and Srivinasan’s unshakeable belief that the FDA is far too strict.

When Dr. Oz met Donald Trump: Somehow this photo just seems appropriate for every post I do about Donald Trump and medical science.

Basically, no matter who is finally chosen by the Trump administration to run the FDA, it is clear that the mandate will be to decrease regulation. Indeed, just last week President Trump told a gathering of pharmaceutical executives, “We’re going to get the approval process much faster.” The only question, thus, will be by how much. If it’s O’Neill or Srivinasan, I’d expect a push towards a radical overhaul of the FDA. If it’s Gulfo or Gottlieb, I’d expect a less radical, but still highly deregulatory, approach. Add to that President Trump’s recent executive order mandating that federal agencies eliminate two regulations for every new regulation they issue, as well as a legislative agenda designed to “decrease regulatory burden,” and under this administration we will almost certainly see a loosening of drug approval standards, all in the name of “fostering innovation.” It’s a process that actually began before Donald Trump with the passage in the waning days of the Obama administration of the misbegotten 21st Century Cures Act, which promised to get the cures flowing from industry by authorizing the FDA Commissioner to develop a framework decreasing the level of evidence needed for drug and device approval. That’s why this Nature commentary is so important now. It argues for a higher standard before even allowing a drug to be tested for the first time in humans, thus going very much against the prevailing sentiment in Washington right now.

A disaster in a”first in human” drug trial

Kimmelman and Federico begin by describing an incident to illustrate the problem. It’s not an example from the US, but it is a good starting point to discuss the dangers of “fast-tracking” new drugs:

On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.

The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.

When thinking about drug approval, most people focus on phase III clinical trials, which are large randomized, double-blinded (when possible) trials designed to test the efficacy of an experimental drug versus placebo and/or existing drugs. However, phase III trials are only the culmination of the process of pre-approval drug development. Long before that there is preclinical research in chemistry, cell culture, and laboratory animals. Only when there is deemed to be sufficient evidence of promise does an experimental drug advance to phase I trials, also known as “first in human” trials. Incidents like the one above are one reason why I view “right-to-try” laws with such alarm, as such laws require nothing more than that a drug has passed phase I tests to be eligible for a patient to use them outside of a clinical trial.

Be that as it may, the French medicines safety agency (ANSM) ordered an investigation and re-examination of the data provided by the drug company Bial, based in Trofa, Portugal, had supplied to the French ethics panel—in essence, the French version of what we in the US call the Institutional Review Board (IRB). This re-examination resulted in a report, with the following findings:

The report notes that the 63-page Investigator Brochure describing the trial included fewer than two pages of evidence that the drug had the desired pharmacological activity. It identified only two studies presented as evidence for efficacy, both problematic. In one, Bial had data for a different marketed drug showing it was more effective than Bial’s drug at relieving pain in animals, but did not include that information in a summary figure. Both preclinical studies showed only “moderate” positive effects. Moreover, Bial’s drug had been tested at a range of doses in mice that made it impossible to estimate the most likely effective dose in humans.

Press coverage following the tragedy quoted independent experts concluding that there was little evidence to support a trial, and that at least five other drugs designed to act in a similar way had been tested in people without success.(Bial maintains that toxicities were not predictable and that it has followed all human-testing norms. We approached the company for more information about the event for the purposes of this Comment but received no response.)

This incident is a good way to start a discussion about just how much preclinical evidence for a compound is enough to justify a first-in-human (FIH) clinical trial.

Efficacy versus safety in clinical trials

Kimmelman and Federico are bioethicists who have studied the ethics of first-in-human (FIH) and early-phase drug research for more than a decade. They wrote this editorial because they are concerned that there is a lack of emphasis on the efficacy of drug candidates observed in pre-clinical research during decisions about whether to advance a drug candidate to FIH clinical trials. They call for “infrastructure, resources and better methods to rigorously evaluate the clinical promise of new interventions before testing them on humans for the first time,” noting that more than half of all drugs that reach later stage trials (Stage II and III) fail because they do not demonstrate efficacy, going on to write:

Today, the evaluation of preclinical evidence is especially important. Favoured picks for the next commissioner of the US Food and Drug Administration (FDA) are likely to lower the current requirements that a drug must demonstrate efficacy in humans before entering the market. If so, low standards for launching clinical trials in the United States could result in ineffective drugs being approved, while also decreasing incentives.

Regulators in Europe and North America evaluate safety before human trials can proceed, but they do not currently demand evidence for potential efficacy. At a workshop of the US National Academy of Sciences in September, Robert Temple, a veteran at the FDA’s Center for Drug Evaluation and Research, said that the agency largely left it to drug sponsors to evaluate their rationale that an experimental drug was likely to work. “I can’t think of any cases where [FDA has] said you can’t do this [phase I] study because we’re just too sceptical.” The European Medicines Agency (EMA) — Europe’s drug regulator — is similarly silent about the evaluation of clinical promise, even in proposed revisions to guidelines prompted by the Bial affair.

I’d say that Kimmelman and Federico are, if anything, understating the case. Lowering drug approval standards with respect to efficacy would not only be likely to result in more ineffective drugs being approved, but, if coupled with a generalized anti-regulatory push and an attitude to approve more drugs, likely to lead also to a decrease in safety standards as well, as the two are coupled. Think of it this way. We accept high levels of toxicity in chemotherapy drugs because they treat a deadly disease, but would never tolerate toxic side effects as serious to treat, for instance, a headache. Perfect safety is never possible in any drug, but must always be weighed against efficacy and the seriousness of the condition for which the drug is to be marketed. If efficacy is overestimated or de-emphasized, then considerations of the benefit-risk ratio will be skewed.

Kimmelman and Federico go on to argue that commercial interests “cannot be trusted to ensure that human trials are launched only when the case for clinical potential is robust.” While I accept that this is true, I also can’t help but note that commercial interests also do not want to spend boatloads of money carrying out clinical trials on experimental drugs unlikely to be shown to be efficacious and safe. When a new drug fails phase III clinical trials, it’s a huge loss to a company, both in terms of development costs and in terms of the loss of projected revenue from sales of the drug, which explains why Scott Gottlieb was so upset when the FDA rejected Oporia. No, I’m not being sucked in to Jim O’Neill’s fantasy that the free market will guarantee drugs that are safe and effective. I’m just noting that the situation is…complicated. There are competing incentives, both regulatory and financial. Nor do I disagree that commercial interests should be trusted to ensure that the preclinical evidence is robust and bulletproof before launching a clinical trial. Rather, I’m emphasizing again that lowering the standards would shift the incentives to make it more worthwhile to pharmaceutical companies to see what they can get a way with.

What is to be done?

It’s certainly true that very few FIH trials have resulted in disastrous outcomes like the one in France. Indeed, it’s noted that in Europe only 2 out of 3,100 FIH trials overseen by the European Medicines Agency since 2005 have had disasters like the one in France and that serious harm and that the record in the US is similarly good. However, Kimmelman and Federico are correct to point out:

But, even if individual participants are not harmed, trials of ineffective therapies place burdens on society. Drug development is costly, in terms of money and people. Patients, healthy volunteers and experts involved in testing a dud treatment are not available for more promising ones. Expenses wasted on ineffective therapies and uninformative trials result in higher drug prices. Investigators, host institutions and sponsors have a responsibility to consider all this before embarking on new research programmes.

Moreover, researchers have ethical obligations to “assure that the risks to subjects are reasonable in relation to the anticipated benefits”, according to FDA guidance. Such regulators explicitly delegate these appraisals to ethics review committees.

Basically, the problem is that drug developers can, in essence, cherry pick favorable preclinical evidence in order to make their case that a clinical trial should be allowed. The other problem is that regulatory agencies will accept weak evidence of efficacy in animal models. Basically, the three questions that have to be answered in assessing whether preclinical evidence justifies a FIH trial:

  1. What is the likelihood that the drug will prove clinically useful? (In other words, have other similar drugs worked? What drugs already exist for the disease and how well do they work?)
  2. Assume the drug works in humans. What is the likelihood of observing the preclinical results? (How robust and reproducible are the preclinical data? How large are the effects observed? Do the animal models used reflect human disease well enough?)
  3. Assume the drug does not work in humans. What is the likelihood of observing the preclinical results? (How do we know that the preclinical observations aren’t due to random variation and bias?)

To address these questions and existing problems, the authors propose the following:

  • Require drugs sponsors to include negative results from animal studies in documents submitted to investigators and ethics committees. This is similar to the approach of All Trials in that greater transparency is recommended. Just as drug companies should have to report the results of negative preclinical trials, it only makes sense to apply the same standard to preclinical evidence submitted to support a FIH clinical trial. It’s even suggested that an additional way to discourage data cherry-picking would be to require that drug sponsors sign a statement testifying that the clinical and preclinical evidence presented on clinical promise is complete and unbiased.
  • Encourage reviewers to consider a broad base of evidence in assessing the probability that a drug will prove clinically useful: for example, how have other drugs in the same class performed in trials? One important part of any application, be it for a grant or for approval of a clinical trial is the “Background and Significance” section. That is the part of the application where the applicant summarizes the existing evidence base supporting the application, discusses shortcomings in current knowledge and potential controversies, and makes the case for the significance of what is proposed before presenting the applicant’s own preliminary data supporting the proposal. It’s very easy to cherry pick studies that are positive and leave out studies that are negative. If the reviewer examining the application is not very familiar with the field, he could easily be unaware of the information left out. Similarly, it makes sense not to consider a drug in isolation. If another member of the class of drugs as an experimental drug being considered for a clinical trial failed its clinical trials, it’s important to make a case for why this experimental drug is different, why this drug is expected to succeed where the others in its class failed.
  • Allow trials to proceed only after careful vetting of the preclinical evidence by independent experts. See above. Basically, in order to detect cherry picking and evaluate the evidence with a hard, cold eye, you need reviewers who are truly experts in the field and who have no vested interest in whether the FIH clinical trial proceeds or not.

Of course, all of this would require more investment. For example a new centralized FIH system is proposed:

Instead, we suggest the creation of a centralized FIH advisory system that combines ethical and scientific review. Several precedents exist. The Recombinant DNA Advisory Committee (which reviews new gene-transfer protocols) has assessed evidence of both risk and efficacy since it began reviewing human gene-transfer studies in 1989. Further examples of centralized, expert review of clinical trials in the United States include the SMART IRB Reliance Platform at the National Center for Advancing Translational Sciences; the National Cancer Institute’s Central IRB; and the Office for Human Research Protections’ ‘407 review process’for certain paediatric trials.

The FIH advisory mechanism we envision would consist of subcommittees that specialize in clinical areas (for example, neurodegenerative disease, cancer and cardiovascular disease). Advisory-committee assessments would, like most of the above examples, be included in materials presented to physician–investigators and local ethics committees.

The authors anticipate some criticisms. For example, setting up a system like this would cost money. Their response is that such a review system might actually decrease cost and burden to the pharmaceutical companies, through the prevention of clinical trials unlikely to show a positive result by insuring a more sound basis for late-stage clinical trials, thus offsetting the cost at least partially.

Another anticipated criticism is exactly the sort of argument several of Trump’s candidates for FDA Commissioner make, namely that such a system could prevent truly promising candidates from being tested. Of course, I can’t help but point out that I’d be hard pressed to consider a candidate to be “truly promising” if the preclinical evidence supporting it is weak and or the effect size of the compound is small in animal models. The authors note:

However, we are not arguing that the preclinical evidence must be strong, rather that it be examined critically to inform ethical judgement. For diseases in which robust preclinical evidence is impossible — for instance, where animal models are clearly inadequate as in many neurodegenerative disorders — a limited suggestion of clinical promise might be enough to justify trials for a relatively benign drug candidate aimed at a great unmet medical need.

In other words, as I mentioned above, we need to look critically at all the evidence for new drugs and put it in the context of the seriousness of the disease, whether effective therapies already exist, and existing science and evidence.

Joseph Gulfo: Use biomarkers, not overall survival, to show drug efficacy

As I’ve discussed before, much of philosophy behind the Trump administration’s approach to the FDA seems to be based on a technolibertarian fantasy that, if only the “heavy hand” of government regulation were removed from entrepreneurs and industry, the cures would flow and the free market would sort out which drugs do and don’t work. That is not surprising, given that Peter Thiel, who’s never met a regulation he didn’t hate, appears to be having an outsized influence on whom Trump will nominate for FDA Commissioner, so much so that, ironically, I’m actually hoping for the pharma shill to be chosen rather than the Thiel cronies who want, in essence, to dismantle the FDA. The FDA could survive Scott Gottlieb (indeed, it already has). I don’t know if it could survive Jim O’Neill or Balaji Srinivasan. But what about Joseph Gulfo, whom I haven’t discussed before?

Joseph Gulfo.

Joseph Gulfo doesn’t (quite) fit the mold of the Thiel cronies and was dismissive of Scott Gottlieb, even saying, “If you want safe snake oil, Jim O’Neill’s your man.” He also believes that the FDA should require evidence of efficacy before approving a drug. The problem is, though, that he defines “efficacy” differently from how the FDA does. Basically, he redefines efficacy by using a lower standard of evidence. In a WSJ editorial written in November, A Trumpian Cure for the FDA’s Chronic Lethargy, he explains:

The first change involves returning the FDA to its original role under the law. That is to prevent snake oil from getting on the market by ensuring that the only drugs approved for sale have demonstrated biological activity in fighting a disease and can be labeled for safe use. The FDA would no longer require approvals based on long-term health outcomes—a practice that dissuades development and increases the complexity, cost and duration of clinical trials.

This argument sounds at least semi-reasonable on the surface, but has huge holes in it, as you will see. You will also see that there is at least one area where Gulfo does fit in with the Thiel crony contingent:

This revision would pave the way for products proven safe and effective to be made available to determine which are most beneficial for individual patients. Patients and their physicians, not the FDA, need to make private health decisions; the Internet of Things would ensure that they have the best information to make these choices.

What is it with this touching faith in technology to fix all the problems in drug development that so many share?

But let’s get back to what, specifically, Gulfo means by returning the FDA to its original role:

The way to return the FDA to its proper role is to pass legislation that defines effectiveness categories for the agency, such as:

How the drug affects biomarkers, such as the lowering or raising of blood-test parameters associated with disease, e.g., glucose levels, blood coagulation parameters, and cancer proteins. How it affects clinical signs and symptoms, e.g., blood pressure, tumor-shrinkage, pain, fever and infection. How it affects disease modification, e.g., prevents joint damage, relapses of multiple sclerosis or migraines. And how it affects long-term outcomes, e.g., survival, stroke and heart attack.

These categories would form the basis of approval, and the labels would be color-coded so that physicians and patients know precisely the nature of the clinical evidence used to prove that the drugs are effective and what to expect when using them.

Yes, he wants to color code FDA-approved drugs based on the level of evidence—because there’s no way that can go wrong, right? In a more recent interview, Gulfo makes similar arguments.

None of this is a new debate, actually. In oncology, for instance, we’ve been debating over whether drugs should have to show a benefit in overall survival (OS) in order to be approved for at least two decades. Cancer therapies are generally evaluated using a number of endpoints. The most commonly used include OS and progression-free survival (PFS). OS is what it sounds like: How long do patients survive their cancer after diagnosis? Period. It’s hard for an endpoint to be more objective than that: Either the patient is alive or he is dead. This number is usually expressed in terms of median survival, which is the period of time after which half of the patients under study are still alive and half have died. This includes all causes, not just cancer. If a patient with cancer under study dies of a heart attack that is not related to his cancer or his cancer treatment, that counts. Traditionally, OS has been the “gold standard” endpoint in measuring the efficacy of a cancer therapy, because the primary goal has been to prolong survival, the ideal case being prolonging survival to the point where it is indistinguishable from life expectancy if the patient never had cancer in the first place. PFS is survival without progression; i.e., how long the patient with cancer survives before his or her tumor starts measurably growing again or metastasizes. While PFS is often measured as well as OS, it’s generally considered less useful because it is entirely possible for a treatment to prolong PFS without prolonging OS. This sort of result can happen when the treatment is effective at shrinking a tumor or slowing its growth but its toxicities can result in death. Thus, PFS can improve with no improvement in OS.

I mention this distinction because several years ago, the FDA approval for Avastin to treat metastatic breast cancer was revoked because it had been based on studies showing improvements in PFS but later studies failed to show an improvement in OS in a later study. I discussed the case in detail in 2010, if anyone’s interested. The point is that short term surrogate markers often don’t correlate with long term health outcomes. Sometimes they do. For instance, pathologic complete response (pCR) of breast cancer to chemotherapy (in which a tumor melts away completely, so that not even a single cell is detected when the area where the tumor was is resected) does correlate with long term survival, so much so that the FDA proposed allowing the use of pCR as a surrogate endpoint in clinical trials for the accelerated approval of drugs targeting breast cancer, although more recent work has suggested caution and pointed out that only in certain subtypes of breast cancer does the surrogate endpoint of pCR appear to predict OS.

Yes, again, it’s complicated. John LaMattina over at Forbes.com points out the major holes in Gulfo’s plan:

Let’s take Alzheimer’s Disease (AD). Just last week, Lilly reported very disappointing results for its AD drug, solanezumab, which failed in a long-term clinical trial. The drug was essentially safe, but it just didn’t work. Under Dr. Gulfo’s plan, solanezumab would have been approved years ago based on its effects on biomarkers and millions of desperate people would have taken it in the hopes that it would have halted or delayed the consequences of this ravaging disease. Furthermore, the healthcare system would have paid at least hundreds of millions, if not billions, of dollars for what essentially is a placebo. Under the Gulfo Plan, patients would have felt betrayed and cheated had they been taking an ineffective drug for five years or more, regardless of whatever color was on the label.

Didn’t Gulfo criticize Gottlieb as someone who’d approve a bunch of “safe snake oil”? Well, that’s basically what Gulfo’s plan would do—and likely to an even greater extent! That’s not all:

Furthermore, the importance of demonstrating real-world effectiveness is not just limited to AD drugs. There are drugs that were believed to be the ultimate answer for treating heart disease–the CETP inhibitors, developed by Pfizer, Roche and Lilly–that simultaneously raised “good cholesterol” (HDL) and lowered “bad cholesterol” (LDL). By totally remodeling one’s lipid profile, these drugs were hoped to be the answer in preventing heart attacks and strokes. Again, the Gulfo proposal would have had these drugs on the market for years before long-term cardiovascular outcome studies showed that not only were these drugs ineffective in reducing cardiovascular disease, but that they could actually be harmful despite the fact that these drugs more than doubled HDL levels and, in combination with statins, lowered LDL levels by 50-60%. Such activity was unprecedented and had heart patients and cardiologists very excited. Had these drugs been approved based solely on lipid modulation, their sales also would have been in the billion-dollar range. Yet, they ultimately offered no benefit to patients.

Yes, as LaMattina notes, not all drugs that shrink tumors prolong survival (Avastin for breast cancer) and not all drugs that lower blood glucose prevent the end complications of diabetes. Just because a drug changes your biomarkers doesn’t necessarily mean it’s improving your health. Yes, shortcuts are tempting. What researcher wouldn’t want to be able to do a two year trial based on surrogate endpoints and biomarkers instead of a ten year trial looking at long term health outcomes if the surrogate endpoints and biomarkers predict the long term health benefits? The problem is that, far more often than people like Gulfo seem to think, they don’t.

Food and Drug Administration building.

The FDA is almost certainly going to go in the wrong direction

Kimmelman and Federico lay out a persuasive case that there is insufficient attention paid to the robustness of preclinical evidence by the FDA and European regulatory agencies and that something should be done to correct this problem. Unfortunately, here in the US under President Trump, we are poised to go in exactly the wrong direction, thanks to a faith-based belief in the almighty power of the free market and an unrelenting hostility to even justified government regulation. No matter whom Trump appoints as FDA Commissioner, we can expect the level of clinical evidence necessary to approve drugs to become less rigorous, at least as much as current law allows, and we might even see legislation passed to make the approval of drugs even easier, in essence building on what the 21st Century Cures Act did. A new FDA Commissioner could undo regulation in several ways without Congressional approval though; e.g., by interpreting existing regulations as loosely as possible, so that requirements for certain clinical trials—especially large-scale ones that can take years and involve thousands of patients—can be weakened or eliminated. Ironically, the most effective way to speed up drug approval would be to add staff, not cut it; yet there’s no sign that the Trump administration has plans to do that.

I concede that a reasonable argument can be made for a drug that impacts surrogate endpoints but not long term health outcomes if it significantly improves patient quality of life. In oncology, for instance, it is sometimes argued that if a drug improves PFS, but not OS, it should be approved if it improves patient quality of life. (Unfortunately, in the case of Avastin, the evidence for improved quality of life was very weak.) However, that is not the primary argument being made by Gulfo, and it’s not the argument being made by any of Trump’s other candidates known to be under consideration for FDA Commissioner. All of them, particularly the Silicon Valley contingent under the thrall of Peter Thiel seem to think that an overly strict FDA is the key impediment to innovation, when in fact it is primarily the limits of our knowledge. Computer developers control the hardware and software. Medical researchers do not have that advantage, but technolibertarians keep making simplistic analogies to computer development when discussing drug development.

If the preclinical evidence requirements for efficacy are already too low, then lowering the clinical requirements for efficacy (e.g., by approving drugs based only on biomarker changes) will be an even bigger disaster than I thought before, because more ineffective drugs would be approved. Given that no drug is completely safe, the approval of such drugs could then result in harm and expense with no benefit. No one, least of all I, is saying that the FDA is perfect or that there aren’t ways of streamlining the FDA approval process, even though it is already fast compared to European agencies. Moreover, the FDA has already started to adapt to new science by incorporating biomarkers and new trial designs for precision medicine into its approval process. Dramatically decreasing the bar that new drugs have to clear to be approved is not the answer to developing treatments and cures for deadly diseases. It’s as though the Trump administration assumes that more and faster drug approvals will translate into better health when they would be unlikely to benefit patients and more likely to result in more expense and harm.

Categories: Science

Corrigendum: The week in review for 01/29/2017

Science-Based Medicine - February 5, 2017 - 11:55pm

A 1000 Points of Pseudo-Medicine

Selections from Society for Science-Based Medicine Points of Interest with comments.

Not every article and study that pops up my feeds in the world of pseudo-medicine is worthy of a complete blog post. But they need to be noticed and commented upon. Duty Calls.

What’s the Harm

The harm continues.

Two chemists walk into a bar
The first one says “I’ll have some H2O.”
The second one says, “I’ll have some H 2O2.”
Then he dies.

Back in 2012 I wrote Blonde Blood: Hydrogen Peroxide (H2O2 )Infusions about using H2O2 intravenously. Hydrogen Peroxide is also a recommended as an oral nostrum for treating cancer and a variety of other diseases, thanks in part to

The growing naturopathic health industry has promoted the use of hydrogen peroxide in treating a wide variety of medical conditions.

I mean, hydrogen peroxide is just water with an extra-oxygen, right? Just like Drano is half salt (Na) and half water (H0). How could that understanding of chemistry lead to any harm? Or so saith the hydrogen peroxide providing pseudo-medical provider. Hydrogen peroxide is just a concentrated source of oxygen. And oxygen is good for you.

Nope.

It is not such a good idea to ingest hydrogen peroxide, as chemist number 2 referenced above failed to realize and is confirmed in: Outcomes After High-Concentration Peroxide Ingestions. Hydrogen peroxide kills:

In the 10-year study period, 41 of 294 patients (13.9%; 95% confidence interval 10.2% to 18.4%) with symptoms after high-concentration peroxide ingestion demonstrated evidence of embolic events, and 20 of 294 (6.8%; 95% confidence interval 4.2% to 10.3%) either died or exhibited continued disability

The embolism is from H2O2 producing gas resulting in a gas embolism, and gas where it doesn’t belong is a known complication of drinking H2O2 .

Patients also had damage to the esophagus and stomach due to the caustic nature of hydrogen peroxide that was not fatal but can be very debilitating.

29.3 % were drinking the H2O2 for therapeutic reasons, the rest unintentional or for self-harm.

Good rule of thumb: anything that can bleach hair is unlikely to be good for you.

FDA Finds Poison In Homeopathic Teething Remedies.

The FDA confirmed this week variable levels of deadly nightshade (you might guess from the name it is a poison) in some children’s teething nostrum that may have killed 10 children. The result?

I have noted many times in the past that pseudo-medical providers never respond to the potential of patient harm by altering practice. They ignore the precautionary principle

that if an action or policy has a suspected risk of causing harm to the public, or to the environment, in the absence of scientific consensus (that the action or policy is not harmful), the burden of proof that it is not harmful falls on those taking that action.

Almost every time.

The song remains the same. One company that makes the product is NOT doing a recall and National Center for Homeopathy called the FDA’s warnings “arbitrary and capricious” and due to

groups interested in seeing homeopathy destroyed continue to hammer away at the system – making exaggerated claims that create misunderstandings about and limit consumer access.

Suggesting children not take deadly nightshade is arbitrary and capricious. Welcome to CAM world.

If you under the impression that pseudo-medical providers are interested in the safety of you and yours, think again.

You learn in medical school that licorice root contains

Glycyrrhetic acid, the active metabolite in licorice, inhibits the enzyme 11-ß-hydroxysteroid dehydrogenase enzyme type 2 with a resultant cortisol-induced mineralocorticoid effect and the tendency towards the elevation of sodium and reduction of potassium levels.

Resulting in a rare form of hyperaldosteronism. I would never expect to see a case, as who can consume that much licorice, a vile flavor at best? People taking supplements, that’s who:

Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department..

A 65-year-old woman with a background of myalgic encephalitis, who was taking alternative medicines and dietary supplements, presented with hypokalaemia and hypertension. After a thorough history it became apparent that this was most likely secondary to regular consumption of liquorice tea.”

Myalgic encephalitis, by the way, is an English term for Chronic Fatigue Syndrome.

Acupuncture

More information to support the overwhelming studies that point to acupuncture being no better than placebo aka worthless was released this week with Moderators of acupuncture effectiveness in breast cancer survivors: Randomized clinical trial (RCT)..

Although acupuncture produced significant improvements from baseline to follow-up in insomnia symptoms, fatigue, and QOL, these improvements did not differ from sham.

Although there was the suggestion of efficacy in subgroup analysis, if you look up worthless in the OED you will find one definition to be subgroup analysis. Also, gullible is not in the dictionary.

Interestingly the less severe the patients depression, the better the response to acupuncture. They say it was due to more available serotonin. Uh huh.

Turns out, the less severe the depression, the greater the response to placebo.

A more appropriate conclusion would not be it is because of serotonin but that acupuncture is placebo.

Still, as is always the case,they suggest more studies need be done. No.

Another recurrent theme is that there is no acupuncture, a unique intervention, but there are as many acupunctures as there are practitioners. Since acupuncture is a placebo it doesn’t matter where the needles are placed or the style used. Yet another example in A comparative study on the effects of systemic manual acupuncture, periauricular electroacupuncture, and digital electroacupuncture to treat tinnitus: A randomized, paralleled, open-labeled exploratory trial..

They were all the same; the kind of acupuncture doesn’t matter as acupuncture is all placebo.

Some other acupuncture studies of note.

Evidence-based therapy for tendinopathy of the knee joint : Which forms of therapy are scientifically proven?.

No reasonable data are available for the treatment of tendinopathy in the knee region by acupuncture, fascial therapy or cryotherapy.

Reasonable data. I love the term, especially as the methodologies of acupuncture studies, and other pseudo-medicine, usually results in unreasonable data. As an example this week may I offer The effect of auricular acupressure on nausea and vomiting caused by chemotherapy among breast cancer patients..

As is so often the case, intervention vs usual control. A study that guarantees a postive result. And it was. People are apes and are a calmed by touch and compassionate interaction, as long as in deference to a million years of evolution, you will not attempt to pick fleas off him. You do not to add pseudo-scientific ear pressure to be a good nurse and provide patient support.

Supplements

Unlike most pseudo-medicines, there is not necessarily zero prior plausibility that herbs will be ineffective. Still, there is often no reason to suggest they should be effective. The indications for herbs are many and the rational lost in the mists of time. This shows up in the almost random way herbs are evaluated. And often found wanting.

In Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. they found.

Limited evidence could be found for pine bark extract and Gingko biloba. The other herbal preparations showed no efficacy in the treatment of ADHD symptoms and …no concrete recommendations for use can be made so far..

Vaccination

It is always a nice reminder that vaccines work. Middle school vaccine mandate cut whooping cough 53%. It is good to vaccinate the vectors and those most at risk for infection.

And not just for the benefit the person receiving the vaccination. Use of the HPV vaccine has been associated with the decrease in vaccine stains in unvaccinated women. That benefit has now been demonstrated in the HPV vector, er, I mean unvaccinated men: Human Papillomavirus Prevalence in Unvaccinated Heterosexual Men After a National Female Vaccination Program

A 78% lower prevalence of 4vHPV genotypes was observed among younger male subjects. These data suggest that unvaccinated men may have benefited from herd protection as much as women from a female-only HPV vaccination program with high coverage.

Herd immunity. It works.

Homeopathy

Denial. More than a river in Iran.

In Effect of Homeopathy on Pain Intensity and Quality Of Life they found

This study could not show any significant effect of homeopathy on primary dysmenorrhea in comparison with placebo. Considering the possible effect of the homeopath and the homeopathic remedies prescribed on the results of such interventions, further studies are needed to help us arrive at a conclusion.

LOL. No, I do not think we need further studies to know that water will not help any symptom but thirst. And, as I mentioned aboce, you do not need to add pseudo-science to be a compassionate provider.

Despite being useless and even dangerous, homeopathy use is expected to grow: Global Homeopathy Product Market: Increasing Demand for Dilutions to aid Revenue Rise at 18.2% CAGR 2016–2024, says TMR. They say

Of the key product varieties in the market, the segment of dilutions is expected to achieve the most promising share in the market’s valuation by the end of forecast period, retaining its dominant position with over 35% of the market by 2024

As I understand it, water is anticipated to be the kind of homeopathic product with the biggest growth potential. As in

Homeopathy Product Market (Product Type – Tincture, Dilutions, Biochemics, Ointments, and Tablets.

The homeopathy theme song? Money for Nothing by Dire Straits

Now look at them yo-yo’s that’s the way you do it
You make you dilutions at Borion
That ain’t workin’ that’s the way you do it
Money for nothin’ and checks for free

In the Literature

Some papers of note.

A systematic review and meta-analysis of complementary and alternative medicine in asthma..

…there was limited evidence on the effectiveness of CAM in adult asthma as most CAMs were only assessed in a single trial. CAMs with multiple trials provided null or inconsistent results.”

You know the rule, over time studies with better methodologies show decreasing effect. Reproducibility is even more a problem when the intervention is based on a fantasy.

It is curious how culture can result in the most curious of studies, such as Effect of Vocalization of the Holy Quran With and Without Translation on Pregnancy Outcomes: A Randomized Clinical Trial..

Why do such a study?

The harmonious tone of the Holy Quran is a type of mystic music, which contributes to the secretion of endorphins by affecting the brain and stimulating alpha waves. Therefore, it enhances the stress threshold, removes negative emotions, creates a sense of relaxation, and improves the immune system.

and so help with the stress of pregnancy. Did it work? Nope.

Based on the results of this study, despite the lower prevalence of preterm labor and caesarean section in the intervention groups as compared to the control group, no statistically significant effect was seen. This was apparently due to the small sample size.

Small sample size? Or perhaps an ineffective intervention.

Legal and Legislative

Physical therapists are winning their suit for the right to practice their form pseudo-science, dry needling:

A North Carolina federal judge on Monday denied a bid to dismiss a lawsuit against the North Carolina Acupuncture Licensing Board accusing it of trying to stifle competition from physical therapists, saying the therapists’ antitrust claims were sufficient to proceed.

Acupuncturists are under the delusion that there is something special about their intervention and want to prevent others from doing it. There isn’t. But with most of the major medical institutions wallowing in the pseudo-medical integrative clinics, why shouldn’t physical therapists get their piece of the magical pie?

Remember to go to Summary Pending Legislation 2017 to keep abreast of the pseudo-scientific legislative shenanigans in your state.

Saudi Arabia bans training on Reiki therapy. Why ban reiki? Not for religious reasons like Catholics.

The Saudi National Centre for Complementary and Alternative Medicine warned early in January of the negative effects of Reiki on patients who could neglect their modern medical treatment and face serious health complications for believing that such alternative medicine could heal serious illnesses.

Weird. Doesn’t the Saudi National Centre for Complementary and Alternative Medicine know they are supposed to promote pseudo-medicine? It is what the NCCIH does. Talk about not understanding their job. Perhaps Betsy DeVos has a Saudi Arabian twin?

Weirdness

Perspectives from Patients and Healthcare Providers on the Practice of Maternal Placentophagy. Placentophagy. Eating placentas. Not for vegans, I would suppose. They conclude

Most providers and patients have heard of placentophagy but are unsure of its benefits and/or risks. Further research examining the potential therapeutic efficacy and/or risks of placentophagy is needed.

Benefits. Of auto-cannibalism? There aren’t any. Placentophagy is touted for postpartum depression, based on anecdotes.  Still, the most disgusting clinical trials are suggeted:

Despite these challenges, Marraccini and Gorman underscore the importance of continued research on human placentophagy, as well as the importance of clinician awareness and openness in discussing placentophagy with their patients. Given the growing interest, further studies investigating the physiologic response and related benefits or adverse effects to hormones and minerals present in placenta capsules is warranted.

Ewwwwwwww. Placenta capsules.

Categories: Science

Elemonics – Nothing but a dance and a tune

Science-Based Medicine - February 5, 2017 - 4:33pm

Pictured: the Mike Adams scientific method.

Elemonics – a term coined by Mr Mike Adams (The Health Ranger) to propose a “new” concept (hypothesis) he has been promoting since the “Truth on Cancer Symposium 2016” in October last year. The term appears to come from the combination of the words ‘element(s)’ and ‘harmonics’ or similar. Since his introduction of this concept, via a live presentation, at the aforementioned symposium, elemonics appears to have generated significant interest in the Complementary, Alternative, and Integrated-Medicine (CAM) media in a relatively short space of time, with numerous websites and blogs linking to Mr Adams’ articles and video uploads on his symposium presentation in a few short months. Both Mr Adams and many in the CAM media appear convinced that this is a major scientific breakthrough that will usher in a vast number of medical and other scientific applications. So is there anything to elemonics? The answer, as some chemists may say, is that apparently considerable entropy is being generated for a vacuum. In simple English: much talk and excitement about nothing. In fact, elemonics as a hypothesis it is quite meaningless and pure pseudoscience.

For those familiar with Mr Adams’ claims on elemonics, the reader can skip ahead to the section entitled: “Shat the sciences say” to avoid a brief reference and summary on the topic.

The song and dance

Mr Adams’ first Natural News/cite> article on elemonics was entitled “Health Ranger to unveil revolutionary scientific synthesis of atomic physics and musical harmonics” which appeared a few days after his live presentation on this topic at “Truth on Cancer Symposium 2016”. A second more recent article was published on Natural News entitled “Now you can HEAR chemistry: Health Ranger translates molecules into music in stunning video demonstration that will blow your mind (and your ears)” with Mr Adams as the main author thereof as well. There is also a video copy of his symposium presentation which is quite popular in many of the CAM media and blogs. Lastly, Mr Adams (or a business partner) appears also have moved very quickly to commercially capitalize on elemonics as can be seen via the following advertisement:” Upgrade your hydration with the Echo Elemonics hydrogen infusion machine.” Whatever ones opinion, both Mr Adams and many in the CAM industry (which include a few its key proponents and spokesman) have shown strong support for elemonics. It is clear that collectively they believe that Mr Adams has achieved a genuine and “stunning” breakthrough in the sciences via elemonics; and if not them, then certainly Mr Adams’ supporters and fans certainly do based on their feedback on Natural News.

A summary, after review of the available information, shows that the central tenets of elemonics start with quantum mechanics, as given by Mr Adams’ opening statements, in his first article:

All matter — which includes everything in the Table of Elements — is nothing more than organized vibrations…The SPDF orbitals of electrons at the atomic level, for example, are nothing but vibratory probability clouds.

Mr Adams gives considerable focus to electron orbital theory in this opening. However, Mr Adams explanation of the quantum mechanics therein is actually very poor and suggests that Mr Adams may not really understand his subject matter particularly well. From there Mr Adams moves onto the atomic mass of elements and attempts to imply that an element’s mass (or more specifically its inverse mass) is related, or a determinant of, its chemical properties, particularly whether it is beneficial or detrimental to biological systems and general health. He subsequently attempts to relate these inverse elemental masses to acoustic frequencies use a conversion factor of 3520 Hz (which Mr Adams states is the A-note in music, roughly the pitch at 1:47 in this video); and hence his following attempt to relate this to the music notes on a 88-key keyboard. Thus an element can be represented via a musical tone given by 3520 Hz divided by its molecular mass in g/mol. This gives the highest pitched note for the lightest element, namely hydrogen (A-note), to ever-decreasing tones for heavier and heavier elements (D-note for carbon and right at the bottom of the musical scale for mercury). For molecules, Mr Adams represents them as a string of different notes starting at the highest tone (typically hydrogen at 3520 Hz for an organic) down to the lowest (carbon, Sulphur, or a metal – depending on which is the heaviest). Lastly, Mr Adams then proceeds to fit this all into a 4-note chord system (based on the four valence nature of a carbon atom). This allows Mr Adams to represent each molecule, or so he claims, as repeated music tunes. With this “foundation” set, Mr Adams then proceeds to claim that by listening to these simple musical tunes an individual can easily tell “acoustically” if a particular molecule or element sounds harmonious with the background four-note chord system (and so is beneficial) or out of harmony (and is so detrimental). Further, Mr Adams asserts a direct correlation between an elements chemical properties and its elemonics. Thus if an element or molecule is toxic (eg. Mercury, DDT, ect.) it will sound “bad”, but if it is “good/healthy” it will sound “pleasant”. Finally, Mr Adams also states that the acoustic elemonics tones not only serve an analytical purpose, but can also be used to directly manipulate the physical and chemical properties on any element.

As an aside, I found the information given by Mr Adams on elemonics a little challenging to follow. Mr Adams’ discussion around elemonics appeared to be poorly given and rather vague in that his arguments were not well developed and his discussion appeared to lack adequate information to be clearly coherent as a scientific discourse.

What the sciences say

However a review of established science shows that elemonics, as a hypothesis, runs afoul of a number of scientific fields.

First, matter (whether elements or molecules) is not “nothing more than organized vibrations.” In quantum mechanics, a particulate or entity (whether a molecule, a lone atom, their electron cloud, a single electron or photon, ect.) can actually be defined by a wave-function based on specific solutions to the Schrödinger equation. The Schrödinger equation can actually be viewed as a general or broad mathematical scaffold to solve any number of models simulating a variety atomic or molecular processes which also incorporate the quantized nature of energy. (Max Plank discovered that energy is not a continuum in nature when it comes to its magnitude, it actual comes in “bundles” or “energy elements” of discrete size – see the quantization of the energy.) Using specific models, such as: particle-in-a-box, the rigid-rotor, and the harmonic oscillator quantum mechanical solutions for the movement of a particle, the rotational and vibrational energies of a molecule respectively can be (and have been) found showing the discrete energy levels in each. For lone atoms, the s, p, d, and f atomic orbitals serve as good solutions to the orbital wave functions for the atom’s electrons and their energy levels in that atom. For molecules, the observer must employ molecular orbitals instead, such as the Sigma, Pi and non-bonding orbitals, to describe electron distribution and energies in the molecule. It should be noted that a detailed mathematic explanation of these solutions is beyond the scope of this article, and my own knowledge.

Second, Mr Adams’ assertion, in context of elemonics, that an element’s properties can be determined by its total atomic mass (or more specifically its inversed mass) is unfounded. Yes, he is correct in regards the periodicity of the period table of elements in that elements in the same period (ie. vertical column) tend to have similar chemical properties. But this periodicity is not determined by the element’s atomic mass, rather by the electron configuration in the outer valence orbitals of that element – as it is only the outer valence electrons that participate in chemical reactions. This also applies molecules as well and is also the reason why a molecule’s properties are determined by the electron configuration in its outer molecular orbitals (Sigma and Pi orbitals, ect.) instead of its atomic orbitals. This is classically illustrated by the properties of the elements sodium , carbon and nitrogen vs the molecule sodium cyanide; and elemental mercury vs thiomersal. To imply that a substance’s chemical properties (ie. element or molecule) are determined by its atomic mass (and resulting periodicity) is equivalent to saying a substances chemical properties are determine by its total electron content, which is completely false as only its outer orbital electrons are valent (able to combine with other atoms or molecules) in nature – and even then not all of them.

Third, Mr Adams’ method in determining what constitutes a harmonious tune and what constitutes an unharmonious tune (ie. good/beneficial vs bad/toxic) is purely subjective. This subjectivity falls into two categories. In the first category, the preference as to what is harmonious and what is not, is based solely on the preference of the individual observer, meaning that one observer will classify certain music tunes as “good” while another will classify it as “bad”. It is solely at the discretion of the observer (or listener in this case). In fact, given that music and its styles tend to be almost largely cultural constructs, there is likely to be a strong cultural bias to the elemonic’s acoustic results. For the second category, there is simply not a clear numerical quantification or definition as to good and bad. In other words, no quantified zero point with no qualified method of measurement; and if nothing is or can be accurately measure (ie. quantified) the entire process is subject to unlimited levels of bias and uncertainty. In essence, the premises of “good” and “bad” collapse as they are solely observer driven.

Fourth, Mr Adams has not proposed any mechanism by which elemonics operates, whether viable or otherwise. He simply states it as fact, as a given – the equivalent of a magician pulling a rabbit out of the hat shortly after the music starts. This is among the Health Ranger’s most significant failings in regards elemonics. In any field of science, a viable mechanism of action is essential. No mechanism … NO action. There are no ifs, ands, or buts about it. In chemistry, we have the formation of activated complexes during reactions with the shifting of molecular bonds between the reagents after they have come together (new bonds forming and old bonds breaking). This is also the situation when intermediates are formed from a single reaction molecule in a multi-set reaction process. In physics, when a container of water is heated, water molecules with higher kinetic energy (provided by the heat-source) pass that heat energy on by colliding with other less energetic “cooler” water molecules. (It is interesting to note that in terms of the field of force-particles, the thermal heat is passed between water molecules in their “collision” as a photon. This exchange then causes the equivalent of a recoil between the two water molecules based on the law of the conservation of momentum.) These are only two of an enormous collection of examples ranging from swinging pendulums, to the generation of x-rays, through to the photo-electric effect and even black holes. Mr Adams’ elemonic hypothesis lacks this most critical component. This is even more acute an issue if Mr Adams’ claim of manipulating the chemical properties of a substance with acoustical energy is taken as sincere.

Fifth, there is simply no way sound in the audible acoustic range can be used to transfer energy to a chemical reaction with adequate efficiency. To impact a chemical reaction or drive it with sound, the experimenter typically requires ultrasonic frequencies, even in the best of circumstance getting acceptable results tends to be challenging. Audible sound is simply too un-energetic, too low a frequency to influence a chemical reaction. This is clearly illustrated by Planck’s equation on electromagnetic radiation, in which the energy delivered by a photon of light is dictated by its frequency (the higher the frequency the greater the energy carried). The same would apply to acoustic frequencies and the phononic model for such a system. Consequently, the new Echo Elemonics hydrogen infusion machine advertised on Mr Adams’ Natural News website is unlikely to produce any benefits due to elemonics, as audible acoustic sound cannot significantly impact on the behavior on the hydrogen and oxygen atoms making up the water passing through it.

And “amazing” flights of pseudoscience follow

The flurry and flight of pseudo-science that follows (or could follow) from elemonics is likely to be quite notable as is clearly illustrated in the advertisement for same aforementioned new Echo Elemonics hydrogen infusion machine, advertised on Mr Adams’ Natural News website. This requires a direct quote therefrom to illustrate the point:

First, it infuses water with free hydrogen, yet without substantially altering the pH of the water in the process. In other words, it’s not an “alkaline water” machine. …”

And

In essence, Echo Elemonics is a water filter, a hydrogen infusion machine and an Elemonics infusion system, all in one. The result is clean, hydrogen infused water with a symphony of balanced trace elements.

Seriously? … Free hydrogen (locked in a volume of water)? … hydrogen infused water? … a symphony of balanced trace elements? And one query that arises from these claims: Are the advertisers now claiming molecular forms given by H3O, H4O, H6O …?

These are clear examples of pseudo-science run amok in which the proponents are both ignoring and violating a whole gauntlet of scientific laws. First, hydrogen has an extremely low level of solubility in water (like most gases) if we are assuming only a locked-in infusion type process. If they are claiming new molecular forms of “water” then they are suggesting water molecular “forms” that would be extremely thermodynamically unstable and have never been seen before in nature unless under the most extreme of conditions. In addition, they have also not proposed a viable mechanism for the formation of the new “forms” or the bonding configuration. Last, audible acoustic sound cannot influence the properties of any element or molecule, nor can it be used to manipulate matter on the atomic scale. In the end the aforementioned advertisement literally overflows with pseudo-science in places, and this is likely to be the repeated outcome from any future elemonic “application”.

At best, this is expensive music

In conclusion, although Mr Adams’ elemonics produces some interesting audible work and likely would produce some “pleasant” tunes; that is all it can do. It is devoid of many key requirements to qualify as even a low-tier scientific study, let alone a genuine and “stunning” major breakthrough. Thus, elemonics as a concept is both meaningless and poorly constructed. It is not real science; it is pseudo-science from beginning to end, even if it alludes to some real scientific content. The day of the lone maverick redefining entire scientific fields is centuries behind us now. Major advances are always built on the work of dozens or hundreds of others – modern science is simply too complex for any other possibility. Mr Adams overwhelmingly lacks the funds, skill, and expertise to match those on science’s cutting-edge and always will. Hopefully Mr Adams will take this into serious consideration for any science project he boldly embarks on in the future.

Categories: Science

Board Disciplinary Actions. What Naturopaths Really Do Not Want You To Know

Science-Based Medicine - February 3, 2017 - 3:33am

See No, Hear No, Speak No.

All states have a Medical Board that oversees the practice of medicine. In Oregon it is eponymous Oregon Medical Board and the

mission of the Oregon Medical Board is to protect the health, safety, and wellbeing of Oregon citizens by regulating the practice of medicine in a manner that promotes access to quality care.

Every quarter the OMB sends out a newsletter that includes Board Actions and there is a monthly Board Action Report. Both are available on the home page of the organization.

Sometimes the reasons for the actions are obvious (inappropriate prescribing) and sometimes not so much (unprofessional behavior, what ever that might be). There are over 12,000 physicians in Oregon and but only a handful of actions, but I can find no statistics on the their work. It can’t be an easy job to oversee other physicians.  The actions induce a queasy curiosity about what it takes to kill a medical career and how ostensibly bright people can really mess up.  

Naturopaths have a similar board, the Board of Naturopathic Medicine. The BNM is a different website than the OMB. With a “Find a Physician (ND)” option as well as an “About Naturopathic Medicine” it as much more of partisan promoter of naturopathy as an oversight organization, despite their vision of

To protect the health, safety and welfare of the public in the matters of care provided by Naturopathic physicians in Oregon.

Which could only realistically be met by dissolving the organization and preventing the practice of naturopathy. But that’s me.

They do mention that their role is to

Must remain neutral as possible when carrying out regulatory functions

Which to my mind runs contrary to the boosterism that permeates the site.

But I wondered. What kind of actions does the Naturopathic Board take in response to practice complaints. The Medical Board, as a rule, is not involved with specific issues of malpractice and poor care. That is left to hospital peer review and the legal system.  The Medical Board tends to look at inappropriate opiate prescribing, moral turpitude,  and general unfitness to practice.  Moral turpitude.

Crimes involving moral turpitude have an inherent quality of baseness, vileness, or depravity with respect to a person’s duty to another or to society in general.

You have too go pretty low to meet that standard and show up in front of the Board, but perhaps not to be the POTUS.  The ‘T’ stands for turpitude?

Issues concerning individual patient/standard of care do not appear before the Board, and would not be issue for ND’s anyway as their white paper proudly states

There is no naturopathic-specific standard of care. Naturopathic doctors are taught and held to the same standards of care as conventional providers.

Um, no. Most “conventional providers” do not offer the breadth of pseudo-medicine that defines the practice of naturopathy and makes their vision just one of the many fantasies of naturopathy. But that is neither here nor there. Just what kind of issues does the board find worthy of intervention with its practitioners?

But first how to find those actions? Transparency and ease of use, at least in comparison to the Medical Board, is not the strong suit of site.

Unlike the Medical Board, there nothing on the home page.

The “Concern/Complaint” page does not have a search or results link.

If you go to the “Licensee Directory” page and search for an practitioner,  you will find a link for a malpractice claim (more a disciplinary action) if you have a specific ND in mind, but who wants to search through every ND to find a handful of actions?

So I sent an email to the Board asking where a summary statement could be found and they directed me to their newsletter. Of course. Just like the Medical Board.  So I looked a few.

2016- not out yet. Unlike the Medical Board they do not need to publish monthly updates. So we will see if any ND’s warranted a Board evaluation in the last year.

2015- no actions. A good year for Board. No transgressions. Or none reported.

2014 – 6 actions. 2 unknown 4 for inappropriate opiate prescribing.

2013- no newsletter. Another good year. Or none reported.

2012- 7 actions. 2 for opiate prescribing, 1 for treating minors, 1 for a DUI, 1 for a drug and firearm issue.

2011- 5 actions. One action, I would opine, sets a dangerous precedent for the ND Board.  To me it sounds like the reasoning could be applied to most ND practices, since they note the

continued practice of naturopathic medicine constitutes a serious danger to the health and safety of the public… and (he) did not use conventional, scientific or otherwise established methods to diagnose or treat the patients conditions…(and) presented himself as a medical specialist in diagnosing and treating difficult cases and conditions…

That’s Naturopathy in a nutshell. Based on the ND websites, virtually every ND could be reported to the Board using this opinion as the criteria. Given the usual pseudo-medical and pseudo-scientific grounding of standard naturopathic practice, it is hard to imagine how far off the map the practice of this ND must have been for another ND to find it wanting.

One action was for giving HcG at a weight loss clinic without first examining the patients and another for lying on the application about a prior battery and a DUI. The reasons for the rest of the actions are opaque

2010 – 6 actions

At this point I gave up on the specifics as reading these legal documents is not very interesting. But it gave me a flavor for what the board has done, fairly similar to the actions of the medical board, but more difficult to find. Not in the bottom of a locked filing cabinet, stuck in a disused lavatory with a sign on the door saying “Beware of the Leopard hard to find.  But not as easy as the OMB.

The Board meets 6 times a year. An outgoing board member notes that by

abiding by our statutes and providing appropriate care, we are maintaining a high standard for our profession so that our licenses are respected.

Cases come to the Board when someone has filed a complaint.
That someone can be a patient, family member, pharmacist or other provider.
Our investigator does an investigation and writes a report which DOES NOT INCLUDE THE NAME OF THE DOCTOR. Discussing these reports and deciding what to do makes up the bulk of our meetings.
If you have never been on the Board you will never know: how many cases are dismissed with NO action!  (bold in the original).

With several years with no newsletters, I do idly wonder how many cases HAD an action and I just can’t find them. Is absence of evidence evidence of absence?  Color me skeptical.

As part of the Great Legislative Mistake where the Oregon legislature gave ND’s the legal designation of primary care providers, they included a peer review committee.

“The Oregon Board of Naturopathic Medicine shall appoint a peer review committee consisting of five members. The peer review committee shall evaluate complaints against naturopathic physicians which are referred to it by the board, and make recommendations to the board regarding those complaints. The board exercises ultimate authority and control over all complaints considered by the committee, approving or disapproving the recommendations of the committee.”

Senate Bill 22 would remove that provision:

Repeals provision establishing peer review committee for purpose of evaluating complaints against naturopathic physicians and making recommendations to Oregon Board of Naturopathic Medicine about those complaints.

Why this is at the request of Governor Kate Brown for Board of Naturopathic Medicine I do not know and cannot find out from the site or Google. I am sure there is a perfectly good reason why, I just can’t think of one beyond removing an un-needed extra layer of bureaucracy.  Currently an investigator does an investigation and reports to the board where, as I read the bill, an investigator would report to the peer review committee who would then report to the Board.

It kind of makes sense.  You have the Board, consisting of 5 ND’s and two members from the public.  Add another committee with another 5 ND’s and you get? Nothing plus nothing is still nothing as far as protecting the public is concerned.

 

 

Categories: Science

Battles over non-medical exemptions to vaccination festering in state legislatures

Science-Based Medicine - February 2, 2017 - 1:00am

Bills to eliminate non-medical exemptions to school vaccination requirements are pending in state legislatures. Bills to add non-medical exemptions are pending as well. Some bills make harder to claim an exemption. Others discourage vaccination by requiring “misinformed consent.” Still others try to weaken the authority of public health officials to combat vaccine-preventable diseases. Today, we look at a number of bills currently before the state legislatures and how they might affect immunization of school children.

All states require students to have been vaccinated against certain diseases to attend school and all states allow medical exemptions to vaccination. Unfortunately, every state except three allows religious or personal belief exemptions, even though neither is constitutionally required. While West Virginia and Mississippi have allowed only medical exemptions for some time, California repealed its non-medical exemptions less than two years ago, over the strenuous objections of anti-vaccination groups.

Mississippi would have been eliminated from that list in 2017 had one of two bills passed. House Bill 1439 established a conscientious belief exemption to vaccination and House Bill 1457 recognized both religious and philosophical exemptions. Fortunately, both bills died in committee this week.

Senate Bill 52 and Assembly Bill 1810 would make New York the fourth state by repealing the religious exemption, leaving only medical exemptions. However, just across the border, a New Jersey bill would allow parents to exempt a child “for any reason,” effectively making the state’s existing religious exemption unnecessary. A Rhode Island bill would reinstate the personal belief exemption there.

Oklahoma allows parents to exempt a child merely by signing a statement “objecting to the immunization of the child.” Sen. Ervin Yen, a cardiac anesthesiologist, has introduced a bill eliminating this broad exemption, leaving only medical exemptions valid. A bill filed in Arkansas to do away with religious and philosophical exemptions was, unfortunately, withdrawn by its author.

In Iowa, a bill would add an exemption for children of parents who oppose immunization due to “personal conviction.” A Hawaii bill would add to the state’s religious exemption by permitting a philosophical exemption because, as the bill’s preamble says,

the legislature also finds that individuals may object to vaccines due to philosophical objections, which include concerned parents who want to wait until their child’s immune system is more functional.

They got one thing right. Waiting “until their child’s immune system is more functional” is certainly based on philosophy, not science.

If you find this sort of legislative “alternative facts” depressing, you will be cheered by a bill in Pennsylvania that relies on real facts. While retaining the religious exemption, the bill eliminates those based on “strong moral or ethical convictions.” The bill’s sponsor explains that the state has the second lowest vaccination rate in the country, but doing away with the philosophical exemption would reduce the number of non-medical exemptions by more than half.

Short of actually getting rid of non-medical exemptions, pending state legislation would make it more trouble to claim one, which can be an effective strategy in increasing vaccination rates.

Minnesota law allows parents to exempt their children from school immunization requirements based on “conscientiously held beliefs” by simply signing a notarized statement. Companion bills (House File 96 and Senate File 143) would require parents to specify which vaccines they want to exempt and to say why the exemption is sought. (It would be interesting to see if of the reasons had any basis in fact.) They would also need a statement from a physician verifying that he or she reviewed the risks and benefits of vaccines and would have to acknowledge that their child could be excluded from school during an outbreak.

Religious exemptions are currently allowed in New York, but there is no established protocol for claiming them. To remedy this, a bill directs the Commissioners of Health and Education to work together on rules for this and hopefully introduce some stringency in the matter.

Two bills have been filed in Texas to ensure parents realize the risks of not vaccinating their children. Texas permits “conscience” exemptions, “conscience” being defined as “including a religious belief.” Per House Bill 241, sponsored by a legislator who is an RN, to take advantage of the conscience belief, a parent would have to submit a form from a health care practitioner stating that the practitioner has provided the parent with “information on the risks and benefits of immunization.” As an alternative, under House Bill 126, a parent would have to complete an internet-based “immunization education module” that presents “evidence based information” consistent with that provided by the CDC. The state could charge a fee for developing and maintaining the module.

Similarly, in Connecticut, if House Bill 6971 passes, parents would be required to attend a science-based educational session regarding the efficacy and safety of vaccines if they sought a religious exemption from immunization for their children.

An Iowa bill takes a different tack by requiring some back up before a religious exemption can be claimed. Iowa law allows religious exemptions only when immunizations conflict with the tenets and practices of a “recognized religious denomination.” The bill adds a requirement that the religious leader of a local congregation where the exemption applicant is a member in good standing sign the application and state that the immunizations actually do conflict with the religion’s tenets and practices.

Undermining student immunization

On the other hand, a number of bills seek to undermine school immunization requirements. One way to do this is to prevent public health officials from questioning medical exemptions, no matter how dubious their provenance or rationale. In Mississippi, current law permits a local health official to refuse a medical exemption if, in his or her opinion, it would cause undue risk to the community. House Bill 1456 would have prevented further inquiry, making the physician’s decision absolute. (The bill died in committee.) As a public health official explained when a similar bill failed last year, the state feared that out-of-state physicians were sending in exemptions for children under dubious circumstances. Assembly Bill 1810, pending in New York, provides that a medical exemption signed by a physician, nurse practitioner or physicians assistant “shall prevail,” eliminating questions from local authorities.

Another way to undermine public health officials is to take away their authority to determine vaccination requirements. In New Hampshire, the commissioner of health can issue regulations regarding vaccination against diseases other than those specified by the legislature. House Bill 361 eliminates this provision, leaving immunization requirements within the sole discretion of the legislature. (As regular readers of SBM are aware, I tend to take a dim view of the scientific literacy of the average state legislator.) House Bill 362 prevents the legislature itself from establishing school immunization requirements for diseases that are “noncommunicable in a child care or school setting” including hepatitis B. Likewise, Rhode Island Senate Bill 47 prevents the department of health from setting vaccination standards for disease that aren’t transmitted “in the school environment” and requires the department to hold public hearings before making any further changes in the vaccination schedule.

Imposing onerous “misinformed consent” requirements on health care providers can discourage vaccination. In Oklahoma, the “Parental Rights Vaccine Act” bill (companion Senate Bill here) requires informed consent prior to vaccination, which is defined, as a minimum, as giving parents a Vaccine Information Statement and “information concerning” the National Vaccine Injury Compensation Program. Each of these requirements is superfluous because, as with any medical procedure, informed consent is already required before vaccination, federal law already requires that health care practitioners give patients a VIS on each vaccine prior to administration and each VIS already includes information on the Vaccine Injury Compensation Program (see, e.g., this meningitis VIS).

There is one particularly troubling addition to this “minimum” requirement for informed consent. The practitioner must make “available for review” the CDC’s “Epidemiology and Prevention of Vaccine-Preventable Diseases: Vaccine Excipient and Media Summary.” “Epidemiology and Prevention of Vaccine-Preventable Diseases” (known as the “pink book”) is a 512-page reference work on all things vaccine for health care practitioners. The “Vaccine Excipient and Media Summary” is one subpart of an appendix to the “pink book.” It is a chart of the ingredients in each vaccine. Not an explanation of why they are necessary, not a risk-benefit determination, not an indication of how much of each is actually in the vaccine. Just those scary-sounding chemical names, like “aluminum hydroxide” and “formaldehyde,” one after another.

It’s not hard to see where this is going. Taking vaccine ingredients out of context and misrepresenting them as harmful is a favorite tactic of the anti-vaccination crowd. So is overemphasizing risk.

Misinformed consent bills have also been filed in Texas and Oregon. In Texas (where one of the sponsors is a veterinarian, who should know better), in addition to providing risks and benefits and a copy of the VIS, the practitioner must tell parents about procedures available under the National Vaccine Injury Act to seek

possible recovery for unreimbursed expenses for certain injuries arising out of the administration of certain vaccines.

Practitioners must also provide a copy of the Vaccine Excipient and Media Summary to parents. Oregon Senate Bill 579 goes even further. The entire 512-page “pink book” must be made available for review, as well as notice of how to file a petition for a claim under the National Vaccine Injury Act. Anything to overwhelm parents with information most of them are not competent to interpret and to undermine confidence in vaccination by emphasizing the possibility of adverse reactions, however remote.

Finally, some physicians have decided not to see unvaccinated patients, a decision that recently received some support from the American Academy of Pediatrics. Texas House Bill 1070 would take away their right to make that decision, no matter what the circumstances, by prohibiting health care practitioners from refusing to provide services to a patient if he or she is unvaccinated for a particular disease. Penalties include withholding payments from public health insurance programs.

Well-funded anti-vaxx lobbyists

The anti-vaccination lobby is up and running, opposing any bill that eliminates exemptions, makes them harder to get or adds new vaccination requirements. They even oppose collecting more vaccination statistics, a position that belies their claims they are concerned only about vaccine safety.

I first learned about some of these bills in an email from the Alliance for Natural Health, an organization supported by the dietary supplement industry and physicians who eschew evidence-based medicine.

From there, I went to the National Vaccine (Mis)Information Center’sAdvocacy Portal,” an obviously well-funded effort that lists several dozen bills and facilitates lobbying by the NVIC’s flying monkeys. In fact, as far as I know, this is the only comprehensive list of vaccination bills publicly available anywhere, a sad commentary on the lack of resources for the science-minded. If we were really in the pocket of Big Pharma, it should have bought us a nice “advocacy portal” like the NVIC’s, where we could take the opposite position on these bills and have a fancy internet-based system for lobbying. Sadly, that’s not the case. Until we have resources to match groups like the NVIC and Alliance for Natural Health, please use your own resources to contact state legislators to let them know what you think about these bills.

Categories: Science

Communicating with the Locked In

Science-Based Medicine - February 1, 2017 - 8:09am

Undoubtedly one of the worst neurological syndromes we confront is the locked-in syndrome (LIS). This can result from a stroke or other brain damage in which the thinking part of the brain is intact and functioning – the patient is awake – but the brainstem is damaged so that their brain cannot communicate with the rest of their body. They are essentially paralyzed below the eyes. In LIS some eye movements and blinking are still retained. This may not sound like much but it enables them to communicate yes-and-no answers, which provides some connection to the outside world.

There is also a syndrome known as complete locked-in syndrome (CLIS) in which even eye movements are lacking. This can result from end stage amyotrophic lateral sclerosis (ALS), in which all muscle control is lost. Eventually even the eye muscles are lost and the patient has no motor function. There is currently no way to communicate with people in CLIS, but a new study hopes to change that.

Brain Computer Interface

The best hope for paralyzed patients is probably advances in brain-computer interface (BCI) technology. There have been some impressive advances in the technology for allowing brains to communicate with computers, and vice-versa. I wrote about such advances here in 2012, and progress has continued since.

Researchers, for example, have been able to train a monkey to operate a robotic arms with its thoughts alone. This advance has been replicated in humans, giving a patient with tetraplegia (complete paralysis of all four limbs) the ability to operate a prosthetic limb. People have also been trained to use the electrical activity of their brains to control a cursor on a computer screen, enabling them to type out full messages.

Computer processing power and software technology is more than up to the task, and will only improve. The real limiting factor technologically is producing a stable physical connection between the computer and the brain. Computer chips tend to get hot and need to be powered. Wires tend to form scar tissue and make infections more likely.

Researchers are experimenting with intravascular electrodes, which may solve some of the problems. Scalp surface electrodes are safer and more convenient, but lose a lot of information resolution because of the skull and other tissue between the electrodes and the brain.

At this point you are probably thinking – OK, if a monkey can control a robotic arm using its brain activity, and a person can control a computer cursor, then conveying a simple yes-no should be a piece of cake. Surprisingly, however, researchers so far have been unable to use BCI to convey such abstract information in subjects who are completely paralyzed.

The possible reasons for this are interesting. I seems to be due to the fact that the learning process requires some motor or sensory feedback. In patients with CLIS, there is no motor feedback. Their motor neurons are completely gone and their muscles have wasted away. Without this motor feedback they cannot learn to operate a BCI.

This is disappointing, but provides useful clues as to how current BCIs are functioning. The brain has plasticity, it can adapt to new inputs and outputs, but it apparently needs them to map its activity to new function. It is much more difficult to adapt to a computer interface using pure thought without the feedback.

The New Study

A study published in PLOS Biology looked at four patients with CLIS or entering CLIS due to ALS. They used functional near infrared spectroscopy (fNIS) to measure the oxygenation of blood in the frontal lobes of the brain. When the brain is active the neurons draw more oxygen from the blood, decreasing the oxygen concentration in the blood which can be measured using fNIS.

They trained the subjects using yes-no questions with a known answer, like the name of their spouse. The subjects were told to think “yes, yes, yes” or “no, no, no” for 15 seconds. Computer software then learned how to distinguish their fNIS activity in the two “yes-no” states. They also simultaneously recorded scalp-surface EEG. Once calibrated they tested the accuracy of this system with further yes-no questions with known answers. The authors report that they were able to achieve >70% accuracy with fNIS overall, which was statistically significant.

This is the first time statistically significant results were found in CLIS subjects with a BCI. However, I think the results should be considered preliminary. There were only four subjects, and the results are only modestly above chance. Outcomes varies from 60-70% and there did not appear to be a significant learning curve.

If these results are valid, they can still be useful. You can ask the patient a question 10 times, for example, and if they give one answer 8 out of those 10 times that is probably the answer they intend.

The Future

Of course I would like to see these experiments replicated, both exactly and with variations to see if the results can be improved. I would be less suspicious of the outcome if they were able to achieve >90% accuracy. Also, based upon prior studies, it seems that asking the patient to think other things might be more useful. For example, in one study using fMRI scans researchers were able to distinguish when an apparently comatose patient was asked to imagine themselves playing tennis vs walking around their home. But again, asking the patient to imagine a motor task may be problematic if they lack all motor feedback. This needs to be sorted out.

Also, researchers may have better luck with higher resolution imaging, such as brain surface or intravascular electrodes.

Part of the difficulty researchers are having is that they have no way of knowing what is actually happening inside the minds of these patients. Are they paying attention? Are they distracted by some pain or sensation? Maybe they have an itch or an ear worm. It is impossible to know where patients go mentally when they are completely paralyzed.

This is important research, however, and I anticipate how far and how quickly it will advance. We need better physical interfaces to have stable high-resolution connections to the brain. We have also been picking the low hanging fruit, such as motor function or interpreting the activity in the primary visual cortex. We may be able to use this to great effect, but what we really want is to be able to decode the abstract thinking of the brain. I don’t think we are anywhere near this ability. Interpreting abstract thoughts, even yes-no, will probably take much higher resolution and much more sophisticated software and calibration algorithms. We are not entering the Matrix yet.

One possibility, at least with ALS patients, is to begin teaching patients to use such an interface when they are diagnosed, and not waiting until they are near CLIS. They may have a year or two to train their brains, and to train the software, to communicate, while they still have motor feedback. By the time they are completely paralyzed they can slide seamlessly into the virtual reality of their BCI.

It’s both exciting and frustrating to be at the dawn of this new technology. There are exciting advances, and we can see the potential, but the real benefits are still out of reach.

Categories: Science

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