Rumination 12 - Stable is Good

Rumination 12. Stable is Good

by

Thomas P. Vogl

March 19, 2008

Last week I had a repeat PET scan that reported "stable disease". That is, in the two months that had elapsed since the previous scan little had changed.  There were a few new spots in the liver but some of the old spots had faded; there was a new suspicious spot in my neck, too small to classify, but the lymph node in my chest showed decreased activity. So officially, I am "stable", a condition not common with melanoma which is notorious for its aggressive behavior. Overall life expectancy statistics for metastatic melanoma are usually quoted as five to eight months and/or 14% survival after five years. Ah, well, in any case I am still asymptomatic after 15 months so I have nothing to complain about. We'll repeat the scan in May and continue AZD-1152 infusion every two weeks until then.

Scientifically, the interesting question, at least to me (I note a lack of interest on the part of the PI of the study whom I have not seen since I signed up on the dotted line early in January) is the source of the stability. The drug company's take, since they are continuing me on the study, is that it is their drug. Maybe it is, maybe it is a contributing factor, and maybe it is irrelevant. After all, I had an extended period of stability last Spring and Summer without AZD-1152. Since then I have increased my intake of omega-3 fats (fish oil and flax oil), doubled my intake of Celebrex (a COX-2 inhibitor) regarding both of which there are published indications that they may help suppress melanoma; and I have started taking selenium supplement, a known immune system stimulator.  My suggestion that we take a look at my immunoglobulin levels and T-cells fell on deaf ears. After all, the study protocol is to determine maximum safe dosage – let's focus on that and not look at anything else – an attitude that I strongly suspect is fostered by the sponsoring drug company that is footing the bill.

Meanwhile, back at the farm, the lab in my basement to process blood samples has had two dry runs and a production run. I sent samples to John Viator at the the University of Missouri on Monday last, so that John can check for melanocytes in the circulation.

My concerns about the design and conduct of clinical trials has been simmering for years. It has been brought to a head by the experience of a friend who also has metastatic melanoma, with a brain metastasis that, mirabile dictu, disappeared and has remained gone for over a month after a short course of Ipilimumab (Ipi). This surprising (to put it mildly) result appears to be the direct reason for a new study protocol for patients with metastatic melanomas in the brain. Yet this patient is being denied further access to Ipi because, since her Ipi treatment a long-standing and very slow growing intestinal carcinoid tumor was discovered and removed.

She has been denied further Ipi treatment, even as a compassionate use patient, because the protocol says 'no other cancer'. If her carcenoid had been known earlier, she would have been denied her successful treatment. Now that her carcenoid is known (and removed) she is being denied further treatment. How Kafkaesque!  How absurd can it get?

I call your attention to a recent, highly relevant paper Observational Research, Randomised Trials, and Two Views of Medical Science by Jan P. Vandenbroucke in PLoS Med 5(3): e67 doi:10.1371/journal.pmed.0050067 available on line: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050067 or http://tinyurl.com/3xoxc8 that points out the limitations of the randomized double blind clinical trial and its stultifying effect on scientific discoveries. I found the paper particularly interesting because when I was at the National Academy of Sciences in the mid 1970s the idea of double blind trials was being introduced and much discussed. The issues raised in this paper were on the table at that time and many of us were quite concerned that in the headlong dash to anoint the double blind clinical trial as the gold standard, the baby was being thrown out with the bathwater.

I will stick my neck out and predict that of the 12 patients to be recruited under this new study of brain metastases, (Clinical Trial NCT00623766) only one (+/- 1) will show a positive result. I base this on the fact that a much larger trial of Ipi had less than 10% response rate and there is no sound reason to believe that the response rate for brain metastases will be any different. My friend just happens to be one of the lucky ones whose melanoma is highly sensitive to Ipi. Her other melanoma metastases also went away. The problem is that the management of the drug companies are all looking for blockbuster drugs in line with the success they had with antibiotics for infectious diseases.

Folks, it ain't going to happen with cancer. Cancer is the result of heterogeneous, highly individualized mutations and/or epigenetic changes. One drug will never fit all, even for sub-types of a particular cancer. What the drug companies apparently are just beginning to acknowledge (kicking and screaming) is that they have to focus on finding markers that identify which drug will help which patient, not look for a drug that will help a high percentage of all patients. It is my opinion that this will never happen effectively, nor will we get humane compassionate use of experimental drugs, nor will we get honest, complete and prompt reporting of the results of clinical drug trials as long as the drug companies control the trials. So, I am trying to do my small part by proposing a solution. The letter that follows, is addressed to my Senator, Ted Kennedy who is the Chairman of the Committee on Health, Education, Labor and Pensions, as well as to Congressman Henry Waxman (D-CA) and  Edward Markey (D-MA) who introduced the Fair Access to Clinical Trials (FACT) Act (H.R. 3196). I urge you to write to them and to your Congressmen to support my idea or to present yours. In fairness to patients, our trust in the medical community, and to the advancement of medical science, we cannot permit the present system continue.

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Dear  :

I am writing to you to propose a solution to the problems arising from patients' lack of  access to new drugs under current compassionate use rules and the problem of  inadequate disclosure of the results of drug trials by the drug companies.

The public's loss of confidence in traditional medicine and the increasing appeal of alternative medicine and quack treatments for terminal diseases, especially cancer, is a direct consequence of terminally ill patients' inability to receive a sympathetic and fair hearing for compassionate use of experimental drugs from the drug companies that control the process. The continuing stream of press reports that documents drug companies' failure to report fairly and promptly on the results of clinical trials, particularly if they are disappointing results that are likely to reduce the value of the drug companies' stock, exacerbates the problem and decreases the public's and the patients' confidence in medicine. These problems are also documented in medical publications, e.g., the New England Journal of Medicine  [NEJM 357:2219 (November 29, 2007)]. The rejection by the Supreme Court of review of the U.S. Court of Appeals the for D.C. Circuit (No. 04-5350) denying access to experimental drugs to the terminally ill, throws the problem back into the legislative arena. 

This letter is written to request that you actively address these issues which impact on so many families and to suggest a cost-effective solution.

I recommend that drug companies continue to propose clinical trials to the FDA, as is the current practice.  However, instead of the drug companies then taking control of the trials (i.e. choice of Principal Investigator (PI), patients, protocol, etc.), the FDA, after an initial positive review, would, through a Memorandum of Understanding (MoU), task the relevant institute at the NIH to convene a panel of intramural and extramural scientists and clinical investigators to review the trial protocol submitted by the drug company and, as needed, propose changes with respect to end point(s), sample size, statistical methods, etc., to ensure that the study is both clinically relevant and scientifically and statistically sound. (Far too many of the studies appear to have end points designed to influence the drug companies stock price rather than clinical relevance.)  The recommendations of this panel shall be binding on the study.  (Of course, the drug company would have the option of withdrawing from the study and canceling its application.) 

The FDA, in consultation with the NIH and the drug company would then determine the cost of the study, and the drug company shall deposit that amount of money in a pool established solely for that purpose; all funds in the pool to be applied solely to fund clinical trials.  Then, the FDA transfers to NIH funds from the pool and NIH (not as at present, the drug companies) selects the Principal Investigators (PI) and institutions at which the clinical trials will be carried out. In effect, NIH sponsors the studies using the pool as the source of funds. Under this arrangement, there is no change in tax burden and at most a negligible increase in cost to the drug company. The drug company's role in the execution of the trials shall be strictly limited to providing the drug for the trials and for any NIH approved compassionate use. 

Patient selection as well as decisions relating to compassionate use of the drug shall reside solely within the purview of the PIs in consultation with, and with the approval of, the NIH.

It shall also be the responsibility of the NIH to ensure prompt, accurate, and complete publication of study results. I recommend that further phases of drug study not be permitted to begin until the publication of the results of the prior phase.

To ensure cost neutrality, it would be prudent in initial years for the drug companies to deposit an extra 15% into the pool with the understanding that any balance left in the pool at the end of the year will be returned to the drug companies not on the basis of cost accounting of each study but on the basis of the fraction of the total pool that each company provided. In subsequent years, FDA can adjust this percentage based upon experience in prior years. That way, if one study runs a little over budget and another a little under, the total moneys in the pool will cover the discrepancies.  It will also serve to ensure that the money that each company deposits in the pool is clearly understood to be for overall clinical trials and not in direct payment for any specific trial. Any payments to PIs, physicians, and institutions are made by NIH, not by a drug company, in order to ensure the avoidance of any possibility of conflict of interest and to maintain transparency.

A word on my background. I am a retired research scientist who has spent much of his life in biomedical research with over 150 publications in the peer reviewed literature (see http://upislandeggs.com/Tpv-CV.htm).  I am also a patient with metastatic melanoma currently participating in a Phase I clinical trial (for my experience with my disease, please see http://upislandeggs.com/Ruminations.htm).

If there is anything I can do to assist you in this matter, please do not hesitate to call upon me.

                                                Sincerely,