Just b’cause it ain’t science, don’t mean it ‘taint so.
Phrenology, Four humors, You were cursed, Leeches, …
This blog is written for the general public, not for the pharma/device expert who is my typical target for my blog.
My wife’s cousin asked me to comment on an article he had come across. The article was Cetyl Mytistoleate: A Unique Natural Compound, Valuable in Arthritis Conditions by Drs. Charles Cochran and Raymond Dent, see http://www.tldp.com/issue/168/168cetyl.html. This article is similar to many similar articles I’ve seen. So any lessons learned here are applicable to other articles.
My summary: 1) The natural chemical, cetyl myristoleate, may work and <cure> arthritis. [Note: I will use the ‘<‘ and ‘>’ to indicate air quotes. That is, open scorn and disbelief.] 2) The logic and science of this article is completely and totally lacking. There is NO EVIDENCE that cetyl myristoleate provides any greater efficacy than a sugar pill (placebo). 3) My best guess (90% historical accuracy) is that it is very likely a vapid hope and a false promise. But in truth, I don’t know.
The article is published in something called the ‘Townsend Letter for Doctors and Patients’, the Examiner of Alternative Medicines. What first caught my eye was a line between the title and the authors “A Sponsored Article”. Unless I’m wrong, the two doctors paid to publish this piece. While this doesn’t invalidate what they say, this is not a piece from the Journal of the American Medical Association (JAMA) or the New England Journal of Medicine.
They introduce arthritis as being a complex disease with 100 causes and many variants. Nevertheless, they indicate that cetyl myristoleate (I’ll abbreviate it as CM), “shows great promise of making a great contribution in non-infective types of arthritis.” They then spend about 3/4 of a page talking about the discoverer of CM, Mr. Harry Diehl, a chemist at the National Institute of Health (NIH), in the division dealing with Arthritis. He couldn’t find anyone at the NIH interested in CM, nor could he find pharma support.
As a side note, in 1980, when I first entered pharma, one of the first projects our entire department worked on was an anti-arthritis compound called Fenbufen. It failed to gain acceptance by the FDA. As a pharma professional, it took a very large amount of money and effort to PROVE a drug works. In this case to demonstrate that it didn’t.
Harry Diehl’s proof? Mice don’t get arthritis. They also have natural CM. He ran a study in rats, which <demonstrated> that the rats given CM don’t get an artificial version of arthritis. Such animal testing is typically a necessary first part of any medical program. But you can NEVER stop there for the FDA, nor should you. Next is extensive toxicology – how poisonous and cancer/ulcer inducing the drug is. Actually, the industry is <requested> by the FDA to do many different animal toxicology testing (short, medium, long, and lifelong), a variety of reproductive testing (e.g., rat pups and the children of these rat pups), how readily the drug is absorbed and what it breaks down (metabolized) into, and what organ (e.g., skin, liver) the drug is absorbed into.
This all precedes human testing. And this is where the big bucks come in. Why? You need to run studies, with known controls and very rigorous methodology with hundreds, thousands, or tens of thousands of patients. Each patient will have many, many hour long visits at the doctor’s office. Why? Let me list some of the tests we did on the Fenbufen patients: grip strength with the blood pressure cuff, photographs and doctors assessments of the number of swollen joints, number of painful joints, range of motion sets of tests (e.g., how far can you bend your elbow, turn your head), and some subjective assessments (on a scale of 1 to 10 rate how painful …). To use a medical term, there was a shit bucket full of testing. This was done typically two times before and once every month or two for a year or two on treatment. Yes, tens of millions of dollars to run a trial or medical program. In those days, there was a slow learning curve on how to run a <correct> trial. For Fenbufen there was a dozen or two false starts before the <real> studies could begin. The FDA typically requires two <real> studies. In medicine these are called Phase IIIb trials.
The CM article’s proof? The author’s listed 6 testimonials. Testimonials are the weakest form of any proof. So weak they are totally disallowed by any credible scientist or FDA. Prior to the FDA, we had snake oil salesmen selling their elixirs based on ‘sworn testimonials’. The gold standard to prove that a pill or injection works is to run a double-blind, randomized, placebo-controlled trial.
A double-blind trial is where neither the pharmaceutical company, the doctors and their staff, nor the patients know which treatment they are receiving. One does this because it is trivial to get a HUGE bias where patients and the (paid) doctors will say they are getting better when they receive any <bona fide> treatment. There are many forms of this bias (e.g., many people get better over time; many people <fib> to help the friendly doctor; many people lie to themselves, doctors give clues that the treatment ‘should have helped’). Let me just say it is HUGE. Let me give a small example. I went to a doctor yesterday who asked how well a device has helped me. I asked what she meant, she suggested “Like a 100% improvement or 75% improvement.” Most people would have given a large-ish number, like 50% or 75%. I’m a bit unusual, I said 5 to 10%. She later showed me some objective measurements which indicated I was still severe, but without any baseline we had no way to see improvement.
How huge the knowledge-of-the-treatment bias is depends on the measurement. The more it is controlled/interpreted by patient or doctor the larger the bias is. An example of such a subjectively controlled assessment would be the first CM case study, Leona, who was able to play piano and has an increased range of motion. A more ‘objective’ measurement showed the her ‘nodular deformities have not changed noticeably’.
The randomized trial is easy. You can’t have the doctors select (consciously or unconsciously) which patient should receive the treatment. You don’t want a subgroup (e.g., Asian or female or sicker patients) to predominate the active group. By randomizing, you completely avoid this selection bias.
Placebo controlled is typically the gold standard. Placebo means no active treatment. One can ALWAYS give both the active and control patients a standard treatment. One then will determine if the drug adds anything to what is the typical standard of care. After the trial is over, one examines if the active treatment has ANY credible (i.e., non-zero or statistically significant) improvement. Please see my blogs 1-4 on my opinion of such analyses. The reason one doesn’t compare your active treatment with your competitor’s active treatment is that this is shooting yourself in the foot – big time. If the other treatment has ANY benefit, then you need a much, much bigger study to prove your treatment works. Let us assume that placebo had a 5 point improvement over time, the other company’s treatment had a 10 point improvement, and your drug had a 15 point improvement, then your study against only an active treatment would need FOUR times more patients (and doctors and time) than if you just compared yourself to placebo controlled study.
In sum, the article shows NO credible proof that the CM treatment works in humans. NONE. They have theoretical proof it might work, but one always has some type of biological or physiological reason to run expensive research programs. According to one article, 90% of drugs which enter human testing (i.e., proved safety and efficacy in animal testing) fail (e.g., prove toxic, prove to worsen, or don’t demonstrate any real improvement) and not demonstrate enough proof for the FDA. And that is a very good thing.