Ruminations 15: Lawyers 10, Science 1

Rumination 15. Lawyers 10, Science 1

By

Thomas P. Vogl

August 4, 2008

The experiment that I proposed in Rumination 14, to get infused weekly instead of bi-weekly, (back issues are archived at http://upislandeggs.com/Ruminations.htm) was, as I predicted, turned down. The primary and overriding reason is that any deviation from an approved protocol must be reviewed and approved by the IRB (Institutional Review Board) of the hospital performing the study, the IRB of the drug company whose drug is being used, and the FDA. The excuse for this bureaucratic excess is that it is in place to protect the patients on the studies. I do not dispute that patients on studies (and otherwise) require and deserve protection. They also deserve to have the maximum possible information/data extracted from the experimental treatment in which they have volunteered to participate. Even more do they deserve, as long as the primary objective of the study is met, to have the option of modifying the treatment to explore the possibility of enhancing the benefit to the patient.  Ascertaining whether the experimental treatment is of benefit to the patient and, if it is not, discontinuing the treatment not because it is doing harm but simply because the patient has better things to do with his/her time (including exploring other potentially beneficial therapeutic options) is also a significant benefit, as is the scientific goal of ascertaining why the patient is doing well for reasons other than the experimental treatment.

I am a concrete example that may illustrate the problem. Of the 91 patients with solid tumors in the AZD-1152 trial, only two (me and a woman with lung cancer) exhibited no progression of disease – our diseases are stable. Patients with cancer occasionally exhibit stable disease without treatment. The standard explanation is that their immune systems are responding appropriately to the disease.  Consequently, there is a very real question whether AZD-1152 is actually effective in a few percent of the population because of the specifics of the genetics of our tumor or whether the drug is ineffective in solid tumors given the dose limitations imposed by side effects.  This is not an academic question.  If a trial drug is working, the patients should certainly stay on it. If their stability is unrelated to the drug, then it would be far better for them to try a different regimen, sooner rather than later when their natural defenses which are keeping the disease stable start to crumble.  The patients, of course, have no basis for making such a decision and their oncologists are prevented by the bureaucratic red tape from ever finding out.  In my case, the experiment I proposed was both simple and safe: Give the infusion every week instead of every other week and check the white cell count twice as often. If it starts to drop significantly, discontinue the experiment.  Since my count dropped only once, after the first infusion, and then only slightly, the risk in my case is minimal, not zero, but minimal. Other patient’s white counts have/will react differently but individual differences are not taken into account in the early trials, which, in my opinion, is one of the principal reasons so many expensive Stage III trials fail.

It is only since I have become personally involved that I have realized how absurd the IRB system has become since its initiation for patient protection. A large part of the problem is the amazing reliance that has developed  on the legal fiction of ‘informed consent’; the paper work for which consume the IRBs (and whose primary function is to protect the pharmaceutical industry, hospitals, and doctors from lawsuits). The reality is that the typical patient, even the very well educated and informed one, does not have either the background or the technical knowledge to perform the scientific evaluation that is required to give *informed* consent, that is, knowledgably concur that the experiment to be performed on him/her can reasonably be expected to bestow a perceived benefit that overrides the risks. Only the lawyers who wrote the rules for the IRBs can persuade themselves that giving informed consent and signing an informed consent form are in any way a comparable activities or indicative of the same mind set. The correspondence is pure fiction. The reality is that the patient is told about possible benefits and adverse effects orally and then told to take the form home and read it or, if you prefer and want to get started - a delay may jeopardize your slot in the study - just sign here.

In the July 18, 2008, issue of Science, page 324, is an amazing example of the absurd damage to science and scientific progress that the current IRB implementation has brought on. It is reported that a respected team of scientists at the University of Tokyo have been forced to retract a paper because “it apparently failed to obtain informed consent from tissue donors or from their IRB. Observers believe the problem stems in part from guidelines that do not sufficiently explain how to handle samples collected before Japan established informed consent procedures.”  Now I am not suggesting that IRB rules and regulations should not have teeth. However, retraction is a totally inappropriate remedy for any cause other than scientific error or fraud. As it stands, readers of the journal will know only that the paper has been retracted and will assume that it contains erroneous data or misleading conclusions, when that is not the case. This cuts the heart out of what the archival record means in science and illustrates the potential for, and the reality of, abuse of power inherent in IRBs. It punishes the scientific community, not the ‘perpetrators’.

On a different note, I was reliably informed that the experiment of treating weekly instead of bi-weekly had been performed in Holland (the home country of the developer of the drug) and that they found that some fraction (I have no idea what fraction) of the patients developed leucopenia on the weekly treatment, which is why they opted for the bi-weekly protocol.  That may well be true, but is that a good reason not to try it on a patient (me) who had only the mildest leucopenia in response to the first treatment and never thereafter? Particularly, since the weekly trial could be stopped at any time? Further, the weekly infusion was not on patients with stable disease. Yet further, in that the same dose was given to all patients irrespective of their weight.  Still further, since the trial has officially been terminated and only the few patients who are stable are, by courtesy, continuing to receive the drug – but of course only under the conditions imposed by the original protocol, now discontinued because it did not work. And beyond all that, that rarity, the proposed experiment is on a patient, me, who can give meaningful informed consent. The lawyers win, patients and science loses, and all asses are covered. Sic transit gloria mundi.

I want to state quite clearly that I do not blame any individual physicians or teaching hospitals for this state of affairs. None of them wanted this absurd system foisted upon them. However, some blame does accrue to them collectively. If they, collectively, announced that unless the system was appropriately modified they will conduct no further clinical trials, the system would be changed within months. But who will volunteer to take the responsibility for herding cats?

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I was recently asked on what evidence I based my decision to take celecoxib (Celebrex, a COX-2 inhibitor) and the omega-3 fatty acids (fish and flax oil). Since this is a very reasonable question, I thought it appropriate to replicate my answer in these Ruminations. The COX-2 / omega-3 story is complicated since they interact in their biochemistry via the prostaglandin pathways. My choice was also based on my genetics.

Let me begin with the science by providing a bibliography of some of the more relevant papers. I have copies of most of them if anyone is interested enough to read them. Otherwise, the titles will suffice to suggest the basis of my decision:

A. Bundschere et al., Antiproliferative and proapoptotic effects of rapamycin and celecoxib in malignant melanoma lines. Oncology Reports 19: 547 - 553 (2008)

C. Lee et al., Expression of cyclooxygenase-2 and peroxisome  proliferator-activated receptor gamma during malignant melanoma progression. J. Cutaneous Path. (2008) doi:10.1111/j.1600-0560.2007.00939.x

S. K. Lee. et al., Vitamic C suppresses proliferation of the human melanoma cell SK-MEL-2 through inhibition of COX-2 expression and the modulation of insulin-like growth factor II (IGF-II) production. Cell. Physiol. 216: 180 - 188 (2008)

 Kast, R.E., Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications. Med. Oncol. 24: 1-6 (2007)

K. Muller-Decker et al., The cyclooxygenase-2 mediated prostaglandin  signaling is causally related to epithelial carcinogenesis. Mol. Carcinog. 46: 705-710 (2007)

 J-C Marshall et al., The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. J. Carcinog. 6: 17 doi:10.1186/1477-3163-6-17 (2007)

J. C. Marshall et al., The use of a cyclooxygenase inhibitor (Nepafenac) in an ocular and metastatic animal model of uveal melanoma. Carcinogenesis 28: 2053 - 2058 (2007)

F.J. Lejeune et al., Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase inhibitor. Melanoma Res. 16: 263-265 (2006)

K. S. Wilson, Cyclooxygenase-2 inhibition and regression of metastatic melanoma. Melanoma Res. 18(?): 465-466 (2006)

K. S. Wilson, et al., Clinical activity of Celecoxib in metastatic melanoma. Cancer Invest. 24: 740 -746 (2006)

S. Xia et al., Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids. PNAS 103: 12499-12504 (2006)

 Y. Denkins et al., Role of w-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J. Lipid Res. 46: 1278 - 1284 (2005)

C. Denkert et al., Expression of cyclooxygenase-2 in human malignant melanoma. Cancer Res. 61: 303 - 308 (2001)


The COX-2/ Omega-3 story is particularly relevant in my particular case for two reasons that, until I thought about it, I had previously always thought were unrelated.

I have had a life-long affliction from hereditary polymorphic light eruptions (PMLE). My mother had a mild case, I have a severe case, and one of my daughters has an intermediate case.  In the past, if I spent 15 minutes in the sun, three days later I would break out in typical PMLEs.  Several very competent dermatologists have tried to help over the years, including a course of PUVA (psoralen & UV light), but nothing helped. Until I started taking omega-3 supplements. With the usual dose, the PMLEs decreased significantly in severity and on the double dose I am now taking they have disappeared completely.

I also have hereditary colonic polyps (not polyposis).  Both my parents died of colon cancer. I had my first polyp removed at age 40 and few harvested every couple of years since, until I started taking 200 mg/day of Celebrex about 7 years ago. Since then, not a single polyp in three scopings.  If 200 mg/day will completely suppress the colonic precancerous lesions, might my melanoma also have similar pathways, given my genotype? 400 mg/day is the clinically accepted maximum dose so why not see if that will help, given that I have no cardiovascular risk factors. (The Celebrex also does a great job keeping my lumbago/sciatica under control.)

That is why I concluded that it would be prudent to increase my intake of both omega-3 fatty acids and COX-2 inhibitor. Neither can do me significant harm. Given my genetics, I think that they are likely to do me some good by reducing tumerogenesis.  That is why I proposed the experiment to Dr. Shapiro to increase the frequency of AZD-1152 for one cycle to see if it makes a difference. It may well be, given that AZD-1152 at the accepted tolerable dose has not been a success in over 90% of solid tumor patients, that my stability derives from the omega-3 / Celebrex in collaboration with my immune system and not the AZD-1152.  It would be nice to find out, but given the rules under which the IRBs and FDA have chosen/been forced to operate, it will not happen. So, I really have no meaningful choice but to stay on the current regimen and travel to Boston every other week for two days for infusion, even though that effort may have no bearing on my well being and it would be so easy to find out whether or not it does.  Alas, we will probably never know.