[Couldn't ever imagine this trail would ever be allowed to come to anything.]
A GREAT OPPORTUNITY LOST
For June 22, 2008
Many readers have asked what happened to the National Institutes of Health-sponsored clinical trial of the Gonzalez regimen, the one that used orally administered enzymes for the treatment of pancreatic cancer?
In the 1980s, Nicholas Gonzalez, MD, was a disciple of Robert A. Good, MD, PhD, director of Sloan-Kettering Institute, New York. With Good's encouragement, he began a project (while still a Cornell medical student) to evaluate the enzyme treatment of cancer promoted by William Donald Kelley, DDS, of Grapevine, Texas.
Gonzalez felt this treatment was beneficial and eventually opened an office in Manhattan to treat patients using this protocol. He presented 25 of his best cases to the NCI's Division of Cancer Treatment (DCT) in July 1993. The pilot study was published in 1999 in the journal Nutrition and Cancer (Gonzalez 1999). Because of the positive findings of this pilot study, first the National Cancer Institute and then the National Center for Complementary and Alternative Medicine (NCCAM) proposed a formal clinical trial of the method.
A decade ago, hopes were high and this trial was promoted as a sterling example of how conventional and alternative medicine could work together for the good of patients, by seeking the truth about the relative merits of various contesting treatments. For example, John Chabot, MD, of the Herbert Irving Comprehensive Cancer Center of Columbia University, and Dr. Gonzalez spoke from the same podium at the 1999 Center for Mind-Body Medicine conference. It seemed like a transcendent moment.
The National Institutes of Health (NIH) awarded a grant of $1.4 million to Dr. Gonzalez. Alas, this clinical trial ran into trouble almost as soon as it was launched in March 1999. The trial was originally designed to randomize 90 pancreatic cancer patients to receive either gemcitabine (Gemzar) chemotherapy or a large daily dose of orally administered pancreatic enzymes. But the key word was 'randomize' – patients were to be randomly assigned to one or the other group by the computer equivalent of a coin toss. However, most people who were attracted to this trial wanted the enzyme therapy, and not a 50-50 chance of getting chemotherapy. So in the end only three eligible patients agreed to be randomized in this fashion.
Sensing an approaching impasse, in 2000, NIH intervened to change the design. According to a government statement of the time:
"The design of the trial is now changing to a single-armed, non-randomized case-cohort study where patients will only be enrolled in what was the nutritional arm. Researchers plan to compare patients on the Gonzalez regimen to a concurrently accrued group of patients being treated with gemcitabine, although such comparisons are known to be difficult because patients selected for the newer or older treatments may not be entirely comparable."
In fact, the 'de-randomization' of the trial was a major blow to its credibility. I was on a panel of government advisors that was asked to endorse this decision. In a conference call a representative of the US Food and Drug Administration (FDA) stated clearly that his agency would not accept the results of any trial that was not fully randomized. Yet the NIH strongly recommended the change and the panel in question voted in favor of changing the protocol for pragmatic reasons.
I will not attempt to trace the deterioration of this trial in the next few years. Simply put, after the "honeymoon" phase of 1999-2000, there came a period of increasing tension between Dr. Gonzalez and the Columbia University investigators. Dr. Gonzalez claimed that after Columbia was chosen as the site of the trial, "the money went into their bank account, all of it, never to be seen again" (personal communication, June 19, 2008). He also claims that he wasn't adequately compensated for his treatment of the patients.
The newly non-randomized trail was supposed to accrue between 72 and 90 participants within the first three years. But it dragged on and on, with insufficient recruitment and a growing atmosphere of disagreement. Finally, in 2007 the trial was suspended. Its entry at www.clinicaltrials.gov states: "This study is ongoing, but not recruiting patients." In fact, the trial in its current incarnation is unlikely ever to start up again.
According to Columbia's own Web site, the Irving Center diagnoses and treats 3,500 cancer cases per year. I find it amazing that Columbia University could not recruit 72 to 90 suitable participants over 8 years. But that was not the limit of potential patients. There could also be referrals from other centers.
Each year, more than 37,000 Americans are diagnosed with pancreatic cancer and 34,000 die of this disease. Many people are eventually told that they have the kind of incurable, inoperable disease that was targeted in this trial. Yet NCI and Columbia University between them apparently could not find 70 people to fill the trial, even though about a quarter of a million such patients were diagnosed with this cancer in the US during the period in question.
Imagine if the NCI and NIH, sponsors of the trial, had released a series of press releases, or launched a vigorous advertising campaign, whose purpose was to inform the American public about the availability of this non-toxic dietary treatment for cancer. They could probably have populated a dozen such trials! It seems to me that the basic difficulty was a lack of genuine interest or enthusiasm on the part of the academic participants.
At the same time, the trial came under tremendous pressure from doctors and
compliant journalists who opposed the testing of alternative treatments.
Sometimes this opposition was little more than a hatchet job.
It was unfortunate that, as time progressed, most of the medico-political support for the trial drained away. At the time of its initiation, some of its prominent supporters included not just members of Congress, but Drs. Ernst Wynder, head of the American Health Foundation, New York; William Fair, MD, chairman of urology at Memorial Sloan-Kettering Cancer Center, New York; Karen Antman, MD, professor of medicine and pharmacology at Columbia's medical school, and director of Columbia's Irving Comprehensive Cancer Center; Michael A. Friedman, deputy director of the National Cancer Institute; Wayne Jonas, MD, director of the Office of Alternative Medicine (now the National Center for Complementary and Alternative Medicine); and John Paul Jones III, research vice president of the giant Proctor & Gamble company.
What a difference a decade makes! Wynder and Fair died soon afterwards; Antman and Friedman moved to even more prestigious jobs; Jonas was replaced by a new NCCAM director, who was indifferent (if not downright hostile) to the project; and Jones retired from P&G. By 2007, Gonzalez himself had become "One Man Alone" – ironically, the title of his 1990 monograph on the program's developer, William Donald Kelley, DDS. One hundred years after John Beard, DSc, of the University of Edinburgh, first proposed the treatment of cancer with pancreatic enzymes, this plausible approach still lacks a rigorous clinical trial in humans.
Because of the radically different interpretations being put forward about
the trial, Dr. Gonzalez submitted the dispute for adjudication to the Office for
Human Research Protection (OHRP), a branch of the Department of Health and Human
Services. On February 25, 2008 OHRP sent a letter to Steven Shea, MD, Vice
President and Dean of the Columbia Center, which is now available online.
This letter from the OHRP confirms some of Dr. Gonzalez's accusations concerning the conduct of this failed trial. The most surprising government finding was as follows: "We note that Columbia University Medical Center (CUMC) found that for 40 of 62 subjects it appeared that informed consent was not documented with a signed written consent form prior to the initiation of research activities involving human subjects." Read that over-nearly two-thirds of the participants were not even properly informed of the risks and benefits of participation in the trial!
There were other irregularities as well. The OHRP requested of Columbia's dean: "Please provide us with a corrective action plan that addresses the above determinations by March 21, 2008." The letter does not state whether or not any corrective plan has been proposed.
Dr. Gonzalez alleges much more widespread malfeasance on the part of his
erstwhile academic collaborators. It certainly seems that the OHRP charges,
although mildly phrased, confirm that all was not as it should have been at
Columbia. Given the fact that two-thirds of the subjects did not give proper
informed consent - responsibility for which rested entirely with Dr. Chabot and
Columbia - one wonders exactly what prospective patients were told about the
relative merits of the two arms of the trial. I understand that at least one
Congressman, Dan Burton (R-IN), has taken an interest in the failure of this
once-promising trial. It is certainly time for a full-scale Congressional
investigation of this failure - of what exactly went wrong and, in the broader
sense, whether the public is getting the truth about the potential benefits of
alternative treatments for cancer.
NOTE: The formal title of the trial was "A Phase III Study of Gemcitabine Compared With Pancreatic Enzyme Therapy Plus Specialized Diet (Gonzalez Regimen) in Treating Patients Who Have Stage II, Stage III or Stage IV Pancreatic Cancer." The principal investigator was the aforementioned Dr. Chabot. The project number was P30-CA13696.
--Ralph W. Moss, Ph.D.
OHRP letter to Dr. Shea:
Gonzalez's Web site:
Gonzalez and Chabot spoke on same podium:
Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer. 1999;33(2):117-24.
Irving Center's Web site:
"Little more than a hatchet job." See for example my discussion of Washington Post article:
Trial still listed at clinicaltrials.gov:
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