The Ethics of “CAM” Trials: Gonzo (Part II)

Laetrile and the Politics of NIH-Sponsored trials of “Alternative Cancer Treatments”

Part I of this blog ended by asking how, in light of the implausible and arduous nature of the “Gonzalez regimen” for cancer of the pancreas, and the unconvincing “best case series,” the NIH could ever have decided to fund a trial of it.† This entry will begin to answer that question. In so doing it may seem to veer from the original subject, but hold on to your seats: what you’ll find here is a piece of the treasure map that leads to the Mother Lode of Fool’s Gold that is government-sponsored “CAM” research.

All historical accounts of the encroachment of implausible claims into the research agenda of the NIH must begin with Laetrile. By that is meant all implausible claims, not merely those having to do with cancer. Elsewhere we have traced the history of “chelation therapy” for coronary artery disease, and have shown that its origins as a political movement, eventually leading to an unethical, $30 million, 2000 subject NIH trial, were intimately associated with people and organizations advocating Laetrile—the most lucrative health fraud ever perpetrated in the United States. In that essay we offer evidence that the creation of the NCCAM itself was at least partly attributable to the history of Laetrile and its advocates. Several good histories or partial histories of the Laetrile debacle are available online, including here, here, here, here, here, and here. The best,¹ but one that does not seem to be available online, is by the recently deceased dean of historians of American quackery, James Harvey Young.

If Young were still alive, I suspect that he would agree that the NCI’s decision in the late 1970s to fund a trial of Laetrile to settle the matter “once and for all,” in the words of Director Arthur Upton,¹ was a mistake. The initial attempt to solicit case reports from Laetrile-prescribing physicians yielded only a tiny fraction of the cases that the NCI had expected. Nevertheless, the sum of information thus generated, together with what was already known about Laetrile, should have convinced the NCI to go no further. The NCI, however, arrived at the opposite conclusion, in part because it had no idea how to evaluate such cases, as Douglas Stalker explained in his 1995 article cited in Part I of this blog. The eventual prospective trial, an uncontrolled but well-performed case series, was headed by the Mayo Clinic cancer researcher Charles Moertel, who had been the first to call for a Laetrile study. It showed, beyond any reasonable doubt, that Laetrile was both dangerous and a complete failure.

Hard-core Laetrile advocates rejected that finding, as expected after Laetrile kingpin Robert Bradford had brought an unsuccessful lawsuit attempting to block the study before it was completed, and after disparaging statements made by other advocates before it had begun.¹ ² Upon publication of Moertel’s report in 1982, Bradford opined:

The whole thing is a put-up deal to discredit Laetrile. It was a phony test, and I’m not surprised at the results.¹

That was the opinion of Laetrile advocates in general and, although stated with less vehemence, of a few apologists in academia. Even Linus Pauling, who had become a crank in his old age, wrote an opposing letter to the New England Journal of Medicine.² Notwithstanding those opinions, some think that the Moertel study was the prototype for demonstrating the social value of trials of implausible medical claims (IMC). The late NCCAM Director Stephen Straus, for example, in attempting to refute our fellow blogger Wally Sampson’s arguments against the NCCAM’s agenda, claimed in 2001 that the demand for Laetrile had “abated markedly only after competent studies showed it to be ineffective.”

The Early Courtship of an Odd Couple: Quackery and EBM

In fact, the demand (or at least the supply, and hence the public health menace) had abated markedly in 1979, after the Supreme Court’s decision in the Rutherford case had upheld the FDA’s decision to regulate Laetrile as a “new drug.” That ruling, for practical purposes, made Laetrile illegal.¹ ² In the history of Laetrile, however, we can detect both roots of the political “CAM” movement—in the virulent, paranoid, but well-organized and well-funded Laetrile advocacy organizations, virtually every one of whose principals was a member of the arch-right-wing John Birch Society—and the more subtle harbingers of what would become Evidence-Based Medicine’s (EBM) self-imposed, if unwitting failure to reckon with implausible claims. Those harbingers can be found, for instance, beginning on p. 16 of FDA Commissioner Donald Kennedy’s Decision in 1977 to declare Laetrile a “new drug”:

1. Objective Evidence of Effectiveness

The courts have thus determined that, as a matter of law, no ‘general recognition’ of a drug’s effectiveness can exist absent adequate and well-controlled clinical investigations…. There are no clinical investigations of Laetrile’s effectiveness, published or otherwise…

There is…an apparent lack of public understanding of what the required studies consist of and why they are required. The Commissioner will thus include in this opinion a discussion of what adequate and well-controlled studies are and why they are needed.

That language must have seemed utterly reasonable at the time, particularly in the context of a much larger statement that included overwhelming evidence against Laetrile. It is now clear, however, that IMC advocates eventually came to view access to taxpayer-sponsored trials of their pet claims as a right of citizenship—not as a decision rightfully based on scientific promise. In this era of EBM and its tunnel-vision for controlled clinical trials to the near-exclusion of all other evidence, the words of the Commissioner, of Moertel , and of a few other scientists at the time could be interpreted as an invitation to such folly.

If that sounds farfetched, consider the Authors’ Conclusions in the abstract of the 2006 Cochrane Review of “Laetrile Treatment for Cancer”:

The claim that Laetrile has beneficial effects for cancer patients is not supported by data from controlled clinical trials. This systematic review has clearly identified the need for randomised or controlled clinical trials assessing the effectiveness of Laetrile or amygdalin for cancer treatment.

That astonishing statement is due to the singular blind spot in EBM’s “evidence” calculus, as originally discussed here and here. The abstract of the Cochrane Review for Laetrile, without any apparent sense of irony, also offers this:

OBJECTIVES: The aim of this review was to assess the alleged anti-cancer effect and the possible harms of Laetrile as a sole or adjunctive therapy in cancer treatment.

SELECTION CRITERIA: Randomized clinical trials (RCTs) and non randomized controlled clinical trials (non-RCTs).

MAIN RESULTS: No RCTs or non-RCTs were found, so no abstraction of outcome data could be performed in this systematic review.

The absurdity of the marriage of EBM and IMC is again exposed. It seems plain—but not, apparently, to the Cochrane authors and like-minded EBM puppets. Can they really believe that absent “RCTs or non-RCTs” there is no basis upon which to judge “the alleged anti-cancer effect and the possible harms of Laetrile as a sole or adjunctive therapy in cancer treatment?” Laetrile is one of the most well-considered quack claims in history. The evidence against it, even without considering Moertel’s study—its extreme biological implausibility, its persistence having been an obvious matter of lucrative health fraud, its advocates having been sociopathic criminals, its “miraculous” cures having been revealed as illusory, its ineffectiveness and risk of cyanide toxicity having been demonstrated in prospective animal studies performed by real scientists and by numerous unfortunate cases of desperate cancer sufferers—is overwhelming.

One of the authors of the Cochrane Laetrile review was Edzard Ernst, whose enigmatic views are illustrated by that review and by his previously quoted, perfectly fallacious dismissal of “a priori plausibility,” which stand in sharp contrast to his considerable insight into the process of IMC advocacy:

A[n]…important point relates to a repetitive pattern in the scientific investigation of “bogus” therapies. Proponents first manage to mobilize supporters to campaign in their favor. This brings financial gain. When skeptics ask about the evidence, the burden of proof is swiftly put on their shoulders, and the lack of evidence is made to look like a “conspiracy” of orthodoxy against the alternative. If scientists then decide to rigorously test the method, its proponents would celebrate this as a breakthrough for their method. Again, this amounts to financial gain. Subsequently, a study may prove that the method is ineffective. Proponents now claim that the research was flawed, did not adhere to their protocol, or was wrongly analyzed. The press coverage yet again brings financial gain. This pattern repeats itself with depressing regularity, e.g., when Laetrile or Di Bella’s cancer cure were promoted.

Ernst is absolutely correct about that “repetitive pattern.” Then how can he ignore its obvious conclusions? One is that scientists should NOT “decide to rigorously test [a ‘bogus’] method” other than for the same reason that they propose to test any other method: that there is genuine scientific promise. In particular, noisy, obnoxious, and even well-funded and politically-connected advocacy is, in the absence of scientific promise, a terrible reason to decide to rigorously test a method. That lesson is the legacy of the NCI’s Laetrile trial and why we can now judge it to have been a mistake. Another obvious conclusion is that emotional advocacy—by scientifically-naive individuals who, for various reasons not relevant to natural processes, believe in the IMC in question—must count against the prior probability of the claim being valid. Douglas Stalker called that a “source reason for prior probability ranking” and gave several examples.

The Odd Couple Ties the Knot

I cannot, in this entry or even in several, present a comprehensive history to convince you, dear readers, of my assertion about Laetrile and government-sponsored IMC research in the U.S. It is my hope that someone with more time and historical savvy than I have, perhaps the scholarly heir to James Harvey Young, will eventually do that. Instead I’ll offer a few more clues next week—no, more than clues: compelling, albeit incomplete pieces of evidence. I’ll present them not according to chronology, but in such a way as to induce each to help explain the next to be discussed, and so on. Forgive me if that doesn’t work.

That’s all for now; important houseguests have arrived: Andrea and Enriqueta. This blog may require 4 parts or more.

The W^5/2 will appear over the weekend.

1. Young JH. Laetrile in Historical Perspective. In: Young JH. American Health Quackery. Princeton, Princeton Univ. Press 1992, pp. 205-55

2. Bross IDJ; Pauling L; Culbert ML. Laetrile. NEJM 1982;307(2):118-19

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†The “Gonzalez Regimen” Series:

1. The Ethics of “CAM” Trials: Gonzo (Part I)

2. The Ethics of “CAM” Trials: Gonzo (Part II)

3. The Ethics of “CAM” Trials: Gonzo (Part III)

4. The Ethics of “CAM” Trials: Gonzo (Part IV)

5. The Ethics of “CAM” Trials: Gonzo (Part V)

6. The Ethics of “CAM” Trials: Gonzo (Part VI)