One of the themes of SBM has been, since the very beginning, how the paradigm of evidence-based medicine discounts plausibility (or, perhaps more appropriately, implausibility) when evaluating whether or not a given therapy works. One of our favorite examples is homeopathy, a therapy that is so implausible on a strictly scientific basis that, for it to work, huge swaths of well-established science supported by equally huge amounts of experimental and observational evidence would have to be found to be all in serious error. While such an occurrence is not per se impossible, it is incredibly unlikely. Moreover, for scientists actually to start to doubt our understanding of chemistry, biochemistry, pharmacology, and physics to the point of thinking that our understanding of them is in such serious error that homeopathy is a valid description of reality, it would take a lot more than a bunch of low-quality or equivocal studies that show no effect due to homeopathy detectably greater than placebo.

On Friday, Kim Atwood undertook an excellent discussion of this very issue. What really caught my attention, though, was how he educated me about a bit of medical history of which I had been completely unaware. Specifically, Kim discussed the strange case of John Lykoudis, a physician in Greece who may have discovered the etiology of peptic ulcer disease (PUD) due to H. pylori more than a quarter century before Barry Marshall and Robin Warren discovered the bacterial etiology of PUD in 1984. One reason that this story intrigued me is the same reason that it intrigued Kimball. Lykoudis’ story very much resembles that of many quacks, in particular Nicholas Gonzalez, in that he claimed results far better than what medicine could produce at the time, fought relentlessly to try to prove his ideas to the medical authorities in Greece at the time, and ultimately failed to do so. Despite his failure, however, he had a very large and loyal following of patients who fervently believed in his methods. The twist on a familiar story, however, is that Lykoudis may very well have been right and have discovered a real, effective treatment long before his time.

Kimball is right to point out that discoveries require context. Medicine can be prone to dogma. Of that, there is no doubt. Sometimes, physicians resist challenges to prevailing medical dogma. Of that, too, there is no doubt. However, reading the story of John Lykoudis, I couldn’t help but wonder the full context of his activities and efforts to convince the Greek medical authorities of the 1950s and 1960s that he was on to something. It also allows me to indulge myself in a bit of my surgical training, the bulk of which, ironically enough, occurred during the time period when the discoveries of Warren and Marshall were first revolutionizing the treatment of PUD and becoming increasingly accepted in the 1990s. When evaluating a story like that of Dr. Lykoudis and why he was unable to convince the medical profession of 50 years ago that his findings had merit, it’s very important to understand (1) the prevailing notion at the time of PUD etiology and, even more importantly, (2) how PUD was diagnosed and treated in the 1950s and 1960s.

Throughout most of the 20th century, PUD was thought to be caused by stress and dietary factors. The primary treatment for disease that had not yet developed complications was bed rest and prescription of bland diets. Towards the mid-20th century it became increasingly appreciated that gastric acid is a major factor in the etiology of PUD, and increasingly antacids, then later H₂ receptor antagonists like cimetidine and ranitidine, and then still later proton pump inhibitors like omeprazole. Cimetidine and ranitidine were the mainstays of PUD treatment when I was a medical student and a resident. For complicated PUD that either was not adequately managed by drugs, sometimes surgery would be necessary. Endless were the discussions and arguments among surgeons fo the time what operation was best for PUD management, a Bilroth I or Bilroth II, vagotomy and pyloroplasty, and, at the time I was finishing my residency, the highly selective vagotomy. Then, of course, there were the discussions of what to do in the case of a bleeding ulcer that couldn’t be stopped using endoscopy or what operation to perform in the case of a perforated ulcer.

One must also remember that in the 1950s and 1960s, the diagnosis of PUD was much different than it was even in Marshall and Warren’t time in the 1980s. That’s because in the 1970s and 1980s fiberoptic endoscopy became the dominant method of diagnosing PUD. Not only did it allow for direct visualization of the ulcer, but it also allowed for potential therapy without laparotomy. More relevant for purposes of this discussion, endoscopy allows isolation of the H. pylori that causes PUD. Prior to that, the methods of diagnosis were not as accurate. In general, PUD would be diagnosed by history, physical, and then an upper GI X-ray series, in which the patient would swallow barium-containing slurries, after which fluoroscopy would visualize the stomach and duodenum.

Consequently, if you imagine yourself back in the 1950s and 1960s, the time when Dr. Lykoudis practiced, the diagnosis of PUD was less certain than it was in the 1980s. Unless it was severe, it might not even show up on upper GI series, given the limitations of the imaging technology of the time. It wasn’t always possible to distinguish between gastritis and true PUD. Consequently, a lot of diagnosis and treatment of PUD in pre-endoscopy times ended up being a lot more empiric than it is now. The diagnosis was arrived at clinically, and it was symptomatic relief that was used as the main measure of treatment success.

So what would it have taken to demonstrate, given the technology of the time, that Dr. Lykoudis’ treatment was effective? It would have taken pretty much what it would take today, minus the use of endoscopy. Consequently, we could envision a clinical trial in which standard of care at the time (bland diet, antacids, etc.) was tested against the standard of care plus Dr. Lykoudis’ antibiotic regimen. The design would be simple: Two groups, one receiving standard of care plus placebo, one receiving standard of care plus antibiotics. Alternatively, although it probably wouldn’t be considered ethically acceptable now, back in the 1960s, it probably would have been considered ethical to do an alternative study, directly comparing the then standard of care to Dr. Lykoudis’ antibiotic regimen. Whichever design were chosen, before entry in the study, each patient would have to undergo upper GI to document the presence of PUD and measure its severity. They would also have to undergo upper GI at the end of the study to document healing. Throughout the study, pain scores would be measured, and patient outcomes tracked to see what proportion of patients end up requiring surgery for their PUD and which proportion can go back to eating a regular diet. Unfortunately, Dr. Lykoudis didn’t have data anywhere near that level of rigor.

On the other hand, what I’m describing above is the equivalent of what we would call today a phase III clinical trial. In general, phase III trials aren’t started without preliminary data. But what sort of preliminary data are usually needed to provide adequate scientific justification for a phase III trial? Today, we require preclinical evidence in the form of cell culture and animal studies, as well as lesser levels of clinical evidence, such as smaller trials like phase I or phase II trials. The preclinical data provide scientific justification and plausibility, and the human data bolster that. Of course, we can’t apply today’s standards to the science of 50 years ago. Back then, the methodology and ethics of randomized clinical trials were not as advanced and well-worked out as they are today.

So what happens if we look at Dr. Lykoudis’s story and whether he might have had enough data to justify a large phase III-like clinical trial in the time in which he was practicing? By today’s standards, he probably did not. As Kimball pointed out, although plausibility does not mean understanding the mechanism, it does mean that there should be a potentially plausible mechanism, as there does not exist, for example, for homeopathy. The concept that there might be a bacterial cause of PUD is not, on the surface, incredibly implausible. But was it plausible enough to justify a clinical trial of the sort that Dr. Lykoudis proposed? What would it take? This is what Dr. Lykoudis proposed:

In 1967, Lykoudis succeeded in getting the attention of the Prime Minister’s office. His correspondence with the Minister of Health on 21 August, 1967, a sad document indeed, is revealing. He registers his frustration that medications with apparently no effect on PUD were approved, whereas Elgaco was repeatedly rejected. He proposes, in essence, a phase III trial: 100 PUD patients to be treated at a State hospital by the eminent professors, 50 with conventional treatment and 50 with Elgaco. ‘Their refusal to approve it is understandable, but their refusal to test it is not!’ he writes.

A not unreasonable assertion. Unfortunately, as Kimball pointed out, the technology to isolate and culture H. pylori didn’t exist at the time. Absent that, providing strong evidence for a bacterial etiology for PUD would require an obvious and strong response to antibiotics in the form of unambiguous symptom relief and healing documented on followup upper GI imaging studies. Even if Lykoudis had had that, he would have been unable to culture the organism responsible for PUD, which would have left scientists in a quandary. Response to antibiotics is storngly suggestive of an infectious etiology, but, absent an organism, one can never determine for sure whether it is in fact a bacteria causing a disease or the antibiotic has an activity other than its ability to kill bugs, an additional activity. For example, erythromycin increases GI motility. Thus, in the context of the time, it’s not surprising that Lykoudis’ ideas were considered highly implausible, and it would have required very strong evidence to make the idea seem plausible.

Steve Novella made a cogent observation:

But taken at face value, I think the real lesson is that process is more important than whether or not one turn’s out to be correct. Science is about process.

The problem with Lykoudis is that his behavior was indistinguishable from the myriad quacks and charlatans that existed then and exist today. That in hind sight one turned out to be on the right track is not all that surprising, and their contemporaries should not be faulted for their inability to predict the future.

The question is – what did Lykoudis do to convince the scientific community of his claims. Did he perform carefully controlled double-blind placebo-controlled trials? Did he attempt to enlist the help of a microbiologist to try to isolate the organism? Or did he just expect people to take his word for it?

What did he do to deserve being taken seriously? Being right in the hindsight of history is not enough.

And I think that this is the key point. Science is a process. It is by its very nature constrained by what is known at any given time in history. In the context of Dr. Lykoudis’s time and given what was known then, it is not surprising that his idea would have encountered heavy resistance from the scientific orthodoxy of the time. Another issue to consider is regional variation in physicians’ attitudes. One example I like to use to illustrate this is the reaction of European physicians to the ideas of Ignaz Semmelweis. Semmelweis, as most readers will recall, first demonstrated that the high rate of puerperal fever in the obstetrics ward run by physicians was due to physicians not washing their hands after doing autopsies, going straight from the morgue to the delivery room. Semmelweis’ findings were far more favorably received in England, for example, than they were on the continent. It is possible, although by no means assured, that Lykoudis’ ideas might have been better received if he had lived in a different part of the world.

Here’s one final consideration. Science is performed by human beings. Although it is a process designed to overcome human biases, communicating the results of scientific research is subject to the same idiosyncracies to which any human communication is subject. Anyone who’s ever been to a scientific conference knows that. It is quite possible to be right and, to put it bluntly, to piss off the very scientists that need to be convinced so much that they harden their positions protecting the scientific consensus. One example is Semmelweis himself. Sherwin Nuland, in his book The Doctors’ Plague: Germs, Childbed Fever and the Strange Story of Ignac Semmelweis, suggested that if Semmelweis had communicated his findings more effectively and managed not to antagonize the medical establishment so thoroughly he might not have been marginalized and dismissed in the manner that he was. At the very least, he may not have been met with as much hostility. Galileo, although apparently not intentionally, alienated the Pope at the time by putting his words in the mouth of a character named Simplicio defending the Aristotelian Geocentric view in Dialogue Concerning the Two Chief World Systems. Reading between the lines, one can see echoes of this sort of antagonism in Lykoudis’s story. Indeed, Michael Phillips of St. Vincent’s Medical Center wrote in an letter to The Lancet:

I propose a less dramatic metaphor: medicine is a marketplace of ideas, with sellers and buyers. Sellers (innovators with new ideas) advertise their intellectual property to potential buyers (other physicians). This buying public is highly sophisticated and sceptical. Quite correctly, physicians will only accept the highest quality new ideas because the lives of their patients are at risk. So physicians buy only when they see the hallmark of quality: publication in a respected peer-reviewed journal.

That in a nutshell explains the tragedy of John Lykoudis. He had a wonderful intellectual product: the insight that peptic ulcer disease is infectious, supported by the evidence that it can be cured with antibiotics. But he lacked the ability (or the training) to sell this insight to his colleagues. He was a retail trader who treated individual patients instead of targeting the wholesale market of other physicians.

Of course, this is the problem. Most physicians are not scientists, and many physicians are very prone to being swayed by anecdotal evidence. Without well-designed clinical trials based on the best basic and translational science available, way to validate or refute anecdotal data. I find Lykoudis’s story to be a cautionary tale. Whether he was correct and thus the true “Galileo” of H. pylori, rather than Warren and Marshall or whether he was just another crank, his story demonstrates that we scientists should be very careful to guard against excessive smugness. As has been repeated by many skeptics in many variants over the years, it is not sufficient to claim the mantle of Galileo as a persecuted martyr for science. You must also be right. Even though it is not clear whether, taken in the context of the time, Lykoudis was a crank or a misunderstood physician who was ahead of his time, Warren and Marshall’s vindication of his ideas that PUD is bacterial in etiology reminds us that not all who claim the mantle of Galileo are necessarily cranks. The vast majority usually are, but on very rare occasions we do see a real Galileo.

In September 2008 I wrote a post on Misleading Ads for Back Pain Treatment. with particular attention to the bogus claims for the DRX 9000.

The Canadian Broadcasting Company (CBC) show “Marketplace” has just done a scathing exposé of so-called nonsurgical spinal decompression treatment with machines like the DRX 9000 and of some of the unscrupulous practitioners who offer it.  Between the hidden camera footage and the weasel words of the chiropractor they interview, it’s quite entertaining.

For a number of reasons, well-argued many times here on SBM, it would be beneficial to American citizens if the National Center for Complementary and Alternative Medicine (NCCAM) were abolished. This does not seem to be in the cards anytime soon. Here, then, are my suggestions for making the Center less dangerous and less of a marketing tool for pseudomedicine than it has been since its inception. Some suggestions might even make the Center somewhat useful. They are listed in order of priority. The Center should:

1. Abandon all unethical trials, beginning with the Trial to Assess Chelation Therapy (TACT, which is under the joint auspices of the NHLBI). This should be done in a very public manner. The reasons for abandoning the TACT, in summary, are as follows.

• The TACT was conceived and approved not because of any scientific or medical promise, but because of pressure from a powerful demagogue in Congress, Rep. Dan Burton (R-IN). Burton was acting on behalf of a tiny, fringe group of physicians whom the editor of Chest and Archives of Internal Medicine had correctly called “pseudoscientific zealots” whose practices were “an abuse of the physician’s freedom of choice.” Barely 15 years later, TACT literature emanating from the NIH renamed the same practitioners “respected experts.” Their organization, the American Association for Advancement in Medicine (ACAM), actively lobbied for the TACT.
• The TACT Principal Investigator (PI) made numerous false statements in his application for the grant and in his subsequent protocol submission, the effect of which was to give the erroneous impression that chelation is a promising treatment for coronary artery disease. I believe that those false statements constitute scientific misconduct. If the PI had offered an accurate review of the existing literature, any scientific review board or IRB worth its salt would have refused to approve the trial. In the event, the “Special Emphasis Panel” that the NCCAM convened to review the application included the very practitioner who, as President of the ACAM, had been instrumental in securing Rep. Burton’s influence. That practitioner was also named, in the application that he reviewed, as a member of a TACT committee, and would shortly thereafter become a TACT investigator. This is a violation of the NIH conflict of interest policy.
• We have shown, and both the federal Office of Human Research Protections (OHRP) and the University of Miami IRB have acknowledged, that the TACT proceeded with a misleading consent form—so misleading that any change now, more than 6 years after the trial began, couldn’t possibly reverse the damage already done. Misleading statements in the consent form included a strong implication that the study drug was the relatively less dangerous calcium-sodium ETDA, not the very dangerous disodium EDTA used in the trial. The consent form also failed to state important risks, including death.
• Almost 2 years ago the FDA withdrew its approval for disodium EDTA, which it had previously approved only for emergency treatments of digitalis toxicity and hypercalcemia. The FDA cited the dangers of the drug, including recent deaths associated with unapproved uses by ACAM members. Thus there is now no point in studying this drug because it is, for practical purposes, illegal.
• We also showed, and the OHRP and U. Miami IRB also agreed, that many of the investigators in the TACT have criminal records, histories of discipline by state medical boards, histories of membership in IRBs disciplined by the FDA, and other indications of incompetent practices or worse. They are the pseudoscientific zealots mentioned above. I have argued on SBM that at least 2 deaths of human subjects in the TACT can be attributed to incompetent care at the hands of such investigators.
• The TACT protocols, including far-too-biased investigators, inadequate blinding methods, multiple primary and secondary endpoints, and more (discussed here), are so tainted that whatever the reported outcome, it is unlikely that it will solve the very problem that it was intended to solve. The outcome will likely be equivocal, but even if it is reported as confirming or disconfirming, either conclusion will almost certainly be rejected by those who disagree.
•  This suggestion—to abandon the TACT—isn’t really optional, although I am not so naïve as to think that NIH policy-makers will agree. It is not optional because the TACT violates numerous tenets of internationally recognized human studies ethics and numerous articles of the U.S. Federal Code of Regulations, and those violations are not retroactively remediable. As Henry Beecher wrote in his seminal article on human studies ethics, “an experiment is ethical or not at its inception; it does not become ethical post hoc…”

Thus to continue the trial, now that such violations are known, is not an ethically viable option for the NIH. Nor should the NIH succumb to political pressure framed as the “legislative mandate” of the NCCAM, which is its usual justification for such mischief. The reason is found in the Helsinki Declaration:

Physicians should consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.

The NCCAM should also publicly address the horribly unethical trial of the Gonzalez regimen for cancer of the pancreas, even though that trial is over. It was spawned by much the same political pressure as was the TACT, it involved NIH-sponsored torture of hapless subjects, and its disconfirming outcome has done nothing to dissuade Gonzalez himself or his champions, including Burton and long time NCCAM advisee (and “Harkinite”) Ralph Moss.

Finally, the NCCAM must reconsider one of its recurrent public justifications for such trials: popularity. I have written about this several times (including in both the TACT article linked above and the Gonzalez regimen series here on SBM, also linked above) so I won’t go into detail here. In summary, “popularity”—which is almost always exaggerated, as it was in both of those cases—is a weak basis for a human trial: it should not trump a lack of scientific promise, and it never trumps welfare of individual subjects.

2. Stop using its public information function as an advertisement for fanciful, implausible claims. That it does this is apparent from even a passing glance at its website, but if examples are sought I refer you to a previous discussion.

3. Start using its public information function for some good, such as informing citizens that homeopathy is nonsense, or that those who claim a vaccine-autism link are both wrong and dangerous. It needs to confront the longstanding, close affiliation between “CAM” proponents and antivax hysteria.

4. Stop putting the cart before the horse by giving grants to medical schools to create “integrative medicine” centers, and stop promoting puff treatments of “CAM” for medical students.

5. Stop funding studies of “CAM” use and popularity, and begin trying to find out why it is that some people are drawn to implausible treatments, even in the face of compelling, contradictory evidence. Such investigations might begin by looking at the work of Beyerstein and Alcock, for example.

That’s it for now.