Part IV of this blog ended by observing that the NIH-funded trial of the “Gonzalez regimen” for cancer of the pancreas,† to have begun in March, 1999, was in trouble almost as soon as it started. As originally designed, it was to have been a randomized, controlled trial comparing gemcitabine, the standard chemotherapy, to the “Gonzalez regimen” of pancreatic enzymes, “supplements,” twice-daily coffee enemas, and other purported methods of “detoxification.” By June, 1999, according to Dr. John Chabot, the Columbia University surgeon acting as Principal Investigator (PI) of the trial, only 3 of the first 50 potential subjects had agreed to be randomized, and none of the three met the eligibility criteria. By January, 2000 it had become clear that the trial would not accrue a sufficient number of subjects if it remained randomized, because almost all of the potential subjects were intent on being in the “nutritional,” ie, the Gonzalez arm.
Trouble with Randomizing
The investigators at Columbia therefore decided to change the protocol to a “single-armed, non-randomized case-cohort study where patients will only be enrolled in what was the nutritional arm.” Paradoxically, PI John Chabot had recently explained, at the 1999 Comprehensive Cancer Care Conference of James Gordon’s Center for Mind-Body Medicine, why this would not be a scientifically sound design:
Would it be possible to allow patients to choose what arm of the trial they want to be on?
Giving individualized treatment in a non-random fashion is more realistic than randomizing, but unfortunately, randomizing was necessary to maintain the validity and integrity of the study in the face of traditional criticism.
Language similar to Chabot’s gratuitous, final phrase has become a staple gesture used by academic researchers speaking to “CAM” audiences. It appears to answer the perpetual special pleading of IMC advocates by passing the buck to unnamed “traditional critics,” as if the issue were not really one of “validity and integrity.” Chabot himself later admitted to being one of those critics, at a 2001 meeting of the White House Commission on Complementary and Alternative Medicine Policy, chaired by Gordon:
The vast majority of people who call with interest are only interested in alternative medicine approaches. Patients who express interest in this protocol are generally healthier than the overall population of patients that I see in my practice with advanced pancreatic cancer. The way this protocol, and, I suspect, many are designed, the patients who meet the eligibility criteria are clearly healthier than the general population of advanced pancreatic cancer patients.
One has to be very careful coming to any conclusions comparing these patients with the general population of pancreatic cancer patients.
I will stop at my third observation. The effects of psychosocial support and delivering hope to these patients is not insignificant. In the absence of a blinded, randomized trial, separating these effects from the physiologic and pharmacologic effects will be a major challenge in trial design.
Trouble with Regulators
It was not long after the protocol was changed that the trial began to draw the attention of the federal Office of Human Research Protections (OHRP). In 2002, a determination letter from the OHRP to Columbia stated:
OHRP finds that the informed consent documents reviewed and approved by the Institutional Review Board (IRB) for this study did not list the risk of death from coffee enemas.
The 2002 OHRP letter listed 7 additional complaints, but each of these was “redacted” from the public copy. We would love to know what they were. In 2003 the OHRP sent another determination letter to Columbia, revealing problems that the agency itself likely did not recognize as being as worrisome as they were. Among them:
(1) Department of Health and Human Services (HHS) regulations at 45 CFR 46.110(b)(2) permit use of expedited procedures for review of minor changes to previously approved research during the period for which approval is authorized. OHRP finds that the CUHS institutional review board (IRB) employed expedited procedures to review changes that exceed this limitation. On January 20, 2000, the CUHS IRB received a request from the principal investigator to approve an amendment to the protocol that included eliminating the randomization and adding a patient questionnaire. It appears that approval of this amendment was done in an expedited manner.
(3) OHRP finds that the informed consent documents reviewed and approved by the CUHS IRB for this study failed to adequately address the following elements required by HHS regulations at 45 CFR 46.116(a)(1):
(a) An explanation of the purposes of the research. The IRB-approved protocol stated that “primary endpoint is survival….” However, the informed consent document stated that “the purpose of this research study is to determine whether enzyme-nutritional therapy is as effective as a drug called gemcitabine for treating pancreatic adenocarcinoma.”
(b) A complete description of the procedures to be followed, and identification of any procedures which are experimental.
(i) The protocol included an evaluation of nutritional status by a “subjective global assessment” questionnaire and a questionnaire regarding quality of life. These assessments were not mentioned in the informed consent document.
(ii) The informed consent document referred to the alternative regimen as “pancreatic proteolytic enzyme therapy” or “enzyme-nutritional therapy” and throughout referred to the study as involving “treatment” and “therapy.” The only treatment or therapy available on the protocol was gemcitabine; therefore it appears that the experimental procedures were not accurately described in the informed consent document.
Corrective Action: OHRP acknowledges that the informed consent document will be revised to state the purpose of the study more directly, to refer specifically to the questionnaires and assessments noted above, and replace the words “treatment” and “therapy” with the term “experimental regimen” or similar. OHRP finds that these corrective actions adequately address the above finding and are appropriate under the CUHS FWA.
(4) HHS regulations at 45 CFR 46.116 require that informed consent information be in language understandable to the subject or the subject’s legally authorized representative. OHRP finds that the informed consent document approved by the CUHS IRB for this study appeared to include complex language that would not be understandable to all subjects, such as alleviating, persist, emesis, anorexia, myalgias, arthralgias, transient intolerance, abdomen and pelvis.
A Troubling Case History
Readers who know something about both human studies ethics and the nature of the Gonzalez regimen will have sensed, while reading the charges quoted above, the pungent aroma of rat. This blog will discuss the ethics of the trial at length, but first it will summarize the experience of an unsuspecting artist in his 40s, the father of two boys, who was diagnosed in March of 2002 with cancer of the pancreas and made the mistake of submitting himself to the trial. The story can be told only because a friend of the patient, mathematician Susan Gurney, wrote and published it in the Scientific Review of Alternative Medicine:
My friend’s wife was a believer in homeopathic medicine. She and others in her community suggested that he look into a protocol run by Nicholas Gonzalez, MD….His protocol was being funded by the National Institutes of Health and the National Center for Complementary and Alternative Medicine and implemented at Columbia Presbyterian. My friend’s surgeon [Dr. Chabot] was one of the investigators.
…my friend decided that the Gonzalez protocol seemed to offer the most hope for survival…[he] arranged to meet with Dr. Gonzalez during the 2 weeks that followed his recovery from surgery to determine whether or not he was eligible for the trial. He was encouraged when he was found to be acceptable. Dr. Gonzalez told him that in order to meet the criteria one had to be still strong enough to follow an arduous regimen…
During this time I also investigated the Gonzalez protocol. I had obtained a copy of an article by Michael Specter in the February 5, 2001 issue of the New Yorker magazine. The article seemed to indicate that although this protocol had been funded by the NIH, there was some debate as to its value by physicians at Columbia Presbyterian. I was disturbed to read that Dr. Gonzalez had been successfully sued and that New York State had made attempts to remove his license…I placed a call to Dr. Chabot’s office. It was not returned.
Dr. Gonzalez advised my friend to have fillings from his teeth removed by a dentist in Connecticut, which he did on April 16. He had just begun the vitamin and enzyme protocol, which was very time-consuming…His wife was by that time already extremely busy obtaining all the pills and food that were required for the Gonzalez regimen.
That same day I called Karen Antman, MD, head of oncology at Columbia Presbyterian…she said that my friend had been offered many different treatment options, and had chosen the Gonzalez one. She encouraged me to do further research.
On April 17 I once again called Dr. Chabot’s office and spoke with his secretary, saying that I had some questions about the Gonzalez trial. I was informed that I should speak to Michelle Gabay, the nurse who was running the protocol…[but] she had no answers to my questions about Gonzalez protocol results.
My friend was determined to try as hard as he could to maintain the regimen, which is extremely difficult. He had been told that pain might be an indication that the tumors were being dissolved, and that he could expect weight loss as he was detoxifying his body. I saw him on April 26, when he told me that he was in more pain. It was obvious that he had lost a significant amount of weight. In the next few weeks he was to describe himself to his mother as looking like “a concentration camp victim from Auschwitz.”
He was having difficulty sleeping. Whether this was because of coffee enema stimulation or because he was experiencing ever-increasing pain and stress, I do not know…but [he] said that he was going to stick with this regimen until the next appointment, when he would get the results. He was determined to give it his utmost effort.
I told him that I was going to attend the annual conference of the American Society of Clinical Oncology (ASCO) and would report on other options to him. Once at ASCO, I learned quickly and definitively that the Gonzalez protocol was a fraud; no mainstream doctors believed it was anything else and they were surprised that anyone with education would be on it.
During the following month, my friend lost 30-40 pounds and became so weak that he could no longer walk his dog around the block. The pain was becoming unbearable, and he was eager to be evaluated and have another scan.
My friend was not scanned until Sunday, June 2, when he received bad news. The tumors had progressed. The Gonzalez regimen had not worked.
On Monday he made an appointment with Dr. Sherman, the oncologist at Columbia Presbyterian…
By this time my friend was extremely thin and weak. He was given prescriptions for pain medication and chemotherapy, and scheduled for additional intravenous therapy the following week.
….He felt better in June,…[but although he] started eating regular food and sipping concentrated food supplements, he was unable to gain weight and did not show an obvious early response to his 3 chemotherapy treatments…
Over the Fourth of July weekend…his lungs filled with fluid. He was rushed to [the] hospital….Over the course of that month he stabilized somewhat, but he continued to weaken. He went home on July 26, intending to talk to his doctor, who had been away that week. He did not live to have the conversation.
By Sunday, hospice care was called in and he died a few days later, in the early morning of August 1, 2002. That he died was not surprising, as pancreatic cancer is a terminal disease. That he died as quickly and brutally as he did, however, is tragic.
We had [had] many conversations about treatment options…but the Gonzalez protocol quickly overwhelmed him; first by being impossibly time-consuming and then by being so physically debilitating. Had he realized this in early April, he would have had a real chance to examine his options. But once the decision was made to begin the Gonzalez protocol, with the apparent support of those involved in his care at Columbia Presbyterian, he became committed to it.
By remaining neutral about the Gonzalez regimen, physicians at Columbia Presbyterian who place patients in this trial effectively preclude them from starting other options, because of the demands it places on patients and their families. If physicians believe they are truly being neutral by not fully explaining the Gonzalez protocol’s nature to cancer patients, it is they who are in denial.¹
Physicians may quibble slightly with Ms. Gurney’s assessment, noting that the course of her friend’s illness—the pain, weakness, insomnia, weight loss, and early death—was entirely consistent with that of untreated cancer of the pancreas alone. That is true, but it is still possible that his particular course was made worse by the arduous regimen. There is no denying that his pain could have been largely mitigated, that he would have had more useful time during his last few months if he hadn’t been on the Gonzalez regimen, and that he would have had a better chance of responding to standard treatment or to a rational nutritional regimen if these had begun earlier.
Troubles with Human Studies Ethics
“A Clinically Competent Medical Person”?
It is also clear that some of the medical practices reported by Ms. Gurney amounted to incompetent nonsense. An example was Gonzalez’s having instructed the patient to have his fillings removed, almost certainly to relieve presumed mercury poisoning from dental amalgams—a common “CAM” canard (was that part of the protocol?). Also included were Gonzalez’s having told the patient that “pain might be an indication that the tumors were being dissolved, and that he could expect weight loss as he was detoxifying his body.”
Such claims are similar to those that the New York State Board for Professional Medical Conduct had described in its Findings of Fact in 1994:
For all patients A through F, the Hearing Committee found that Respondent failed to correctly interpret signs and symptoms of disease progression…, in some cases attributing symptoms of cancer progression to non-compliance with his protocol.
The Hearing Committee…finds that Respondent’s treatment of Patients A through F was incompetent within the meaning of New York State Education Law Section 6530 (5) in that it demonstrated a lack of requisite skill and knowledge.
…the Hearing Committee sought both training appropriate for Respondent’s practice, the vast majority of whose patients have some form of cancer, and experience in a setting that would acquaint Respondent with the broader aspects of practice, including the entire cycle of death and available palliative aspects of treatment of the terminally ill.
The 1998 Consent Order agreed:
In the treatment of all the patients in this case, the Respondent demonstrated that he lacked the basic understanding of the disease from which all the patients were suffering. For example, in the case of Patient C, the Respondent describe the Patient as being stable, doing fine or in a rebuilding process, when the Patient was suffering increasing pain and showing other symptoms which demonstrated the marked progression of her disease. In the case of Patient F, the Patient showed symptoms such as progressive inflammation, crusting and weeping of the breast and increased pain, which were the result of metastatic disease, but which the Respondent attributed to toxicity and a repair and rebuilding process.
The Review Board sustains the Hearing Committee’s Determination ordering the Respondent to undergo retraining in oncology.
Relevant human studies treatises stipulate certain qualifications for investigator/practitioners. The Helsinki Declaration is explicit:
Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.
The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.
The Belmont Report requires that IRBs consider the practices of the pertinent physician, with the implication that those practices meet acceptable standards of care:
Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.
The NIH also has certain requirements for investigator/practitioners, although these are more difficult to find. According to the 2001 Request for Applications (RFA) for another NCCAM-sponsored trial:
Biographical sketches for all key investigators must be provided. In addition, applications must name a Senior Investigator for each trial site in the consortium that will be responsible for on-site clinical and scientific implementation, direction and management of the trial protocol….Senior Investigators must have substantial experience in the treatment and management of CAD and in the design, implementation and evaluation of clinical trials.
If we change “CAD” to “cancer of the pancreas,” it seems likely that similar requirements should have applied to Gonzalez (the trial corresponding to the RFA quoted above is also in violation of those requirements, but that is another story).
The New York Board’s opinions quoted above should have been part of the deliberations of any committee—the scientific review group at the NIH or the Columbia Institutional Review Board (IRB), for example—charged with passing judgment on the trial. We can safely assume that either Gonzalez’s history was not made available to those committees or, if it was, that the committees reneged on their responsibilities.
Uninformed Consent, Inappropriate Subject Selection, and Lack of Clinical Equipoise
We have already seen, in the OHRP’s determination letters of 2002 and 2003, that until at least 2003 the Gonzalez trial’s consent information was woefully inadequate. I wonder if the new one is any better. In 2003, using the Gonzalez regimen as an example, I argued that the information offered to prospective subjects of trials of implausible claims is likely to be misleading:
Plausibility also figures in informed consent language and subject selection. How many subjects who are not wedded to “alternative medicine” would be likely to join a study that independent reviewers rate as unlikely to yield any useful results, or in which the risks are stated to outweigh the potential benefits? Are informed consents for such studies honest? In at least one case cited in the following paragraph, the answer is “no.” Nor may subjects who prefer “alternative” methods be preferentially chosen for such research even if they seek this, because “fair subject selection requires that the scientific goals of the study, not vulnerability, privilege, or other factors unrelated to the purposes of the research, be the primary basis for determining the groups and individuals that will be recruited and enrolled” (Emanuel et al. 2000).
The Office for Human Research Protections recently cited Columbia University for failure to describe serious risks on the consent form of its “Gonzalez” protocol for cancer of the pancreas, funded by the NCCAM (OHRP 2002). The study proposes to compare the arduous “Gonzalez” method, which is devoid of biological rationale, to gemcitabine, an agent acknowledged by the investigators to effect “a slight prolongation of life and a significant improvement in . . . quality of life.” Nevertheless, a letter from Columbia to prospective subjects states, “it is not known at the present time which treatment approach is best [sic] overall” (Chabot 1999). The claim of clinical equipoise, or uncertainty in the expert medical community over which treatment is superior–necessary to render a comparison trial ethical–is not supported by the facts (Freedman 1987).
Ms. Gurney’s article provides additional, compelling evidence that the Gonzalez protocol did not meet the standard of clinical equipoise:
…at ASCO, I learned quickly and definitively that the Gonzalez protocol was a fraud; no mainstream doctors believed it was anything else and they were surprised that anyone with education would be on it.
The “mainstream doctors” of the American Society of Clinical Oncology must be judged representatives of the pertinent “expert medical community.”
I am aware that “clinical equipoise,” as a prerequisite for a trial being judged ethical, has been challenged. Nevertheless, the challenges do not impinge upon the points made here, nor have they resulted in a consensus opinion that “clinical equipoise” no longer be considered a requirement for a trial.
There are many other reasons that the Gonzalez trial is unethical, but I will limit this discussion to three more: scientific reasons, the fallacy of popularity, and the need for independent review.
Science and Ethics
There is a consensus, among those who consider human studies ethics, that a study must be scientifically sound in order to be ethical. According to the Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS; Geneva, Switzerland:1993. Quoted here):
Scientifically unsound research on human subjects is ipso facto unethical in that it may expose subjects to risks or inconvenience to no purpose.
The Helsinki Declaration agrees:
Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.
There is no body of basic science or animal experimentation that supports the claims of Gonzalez.
Emanuel and colleagues, writing in JAMA in 2000, asserted:
Examples of research that would not be socially or scientifically valuable include clinical research with…a trifling hypothesis…
I assert that highly implausible claims ought to be viewed as “trifling hypotheses.”
The Fallacy of Popularity
Virtually all of the research agenda of the NCCAM has been justified by the assertion that implausible claims that are popular require research, merely because people are using them. Referring to the opinions of the late NCCAM Director Stephen Straus, Science Magazine wrote in 2000:
Scientific rigor is sorely needed in this enormously popular but largely unscrutinized field….Most of these substances and treatments have not been tested for either safety or efficacy.
As surprising as it may be to some, however, a method’s popularity may not supercede the interests of individual trial subjects. According to the Helsinki Declaration:
In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.
The Belmont Report agrees:
Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to the subject, if any, and the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight.
The U.S. Code of Federal Regulations is unequivocal:
The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. (CFR §46.111)
The Requirement for Independent Review
As explained by Emanuel and colleagues:
Investigators inherently have multiple, legitimate interests—interests to conduct high-quality research, complete the research expeditiously, protect research subjects, obtain funding, and advance their careers. These diverse interests can generate conflicts that may unwittingly distort the judgment of even well-intentioned investigators regarding the design, conduct, and analysis of research.
…[thus] for much of clinical research, review should be done by a full committee of individuals with a range of expertise who have the authority to approve, amend, or terminate a study.
Emanuel and colleagues suggested that it is IRBs that provide such independent reviews, but we have already shown that IRBs can only be expected to act according to the information made available to them by the investigators. We have shown, in addition, that the “expert medical community” need be involved in such independent reviews. Individuals with the requisite expertise may or may not be members of the pertinent IRB.
Next Week: Politics Makes for Bad Science (Redux), and the Regrettable (Non-)Outcome of the Gonzalez Trial
1. Gurney S. Socially Harmful but Unapparent Effects of the NCCAM-Columbia University-Gonzalez Protocol. Sci Rev Alt Med 7 (2):74-77 (Fall/Winter 2003-4)
†The “Gonzalez Regimen” Series: