Rumination 5 - The Lost Month
Rumination 5 – The Lost Month
May 13, 2007
You may have noticed discussions of clinical trials and patients circumventing them in both the popular (e.g., Wall Street journal, May 4, page A15) and in the scientific literature (news@nature.com, doi:10.1038/news061218-14; Nature Medicine 1/31/2007, doi:10.1038/nm0207-111b; Nature 446:474, 3/29/2007). To make a long story very short, these articles describe a conflict between the perceived needs of the patient population and the need for definitive clinical trials. The patients, who know they are dieing, want the right to take whatever drugs they feel might possibly help them; the FDA is concerned that some of these drugs might harm them further; and the supporters of clinical trials worry that the patient population they need might vanish.
Now that I find myself involved in a clinical trial, I am beginning to understand the frustration of the patients and some of the causes of that frustration. My sympathies, as a life-long scientist, were originally on the side of the clinicians running the clinical trials. While I still retain all my sympathy in support of their objectives, I also see how many unnecessary and easily avoided problems contribute to patient unrest. Problems that are irrelevant to the scientific objectives. I’ll use me as an example.
On April 3rd I had a PET scan that showed a metastasis in my liver. On April 11th, after the radiologist’s report was available, I met with the oncologist, Dr. Hodi at Dana-Farber (DFCI). I had already reviewed the literature and knew that of all the clinical trials of drugs for melanoma metastases only two were relevant for my mucosal melanoma (one at Sloan Kettering in NY and the other by Dr. Hodi). I readily agreed to sign up for his trial of Glivec (imatinib). He told me that it would take about three weeks for the samples of my tumor to be sent to Oregon to a lab that could determine whether my tumor was c-kit active, because the drug was specific for c-kit tumors. No other options were discussed.
After three weeks were up, during which I received no communication from DFCI, I sent e-mail to the research nurse at DFCI on Wednesday, May 2, and was told that the results from the lab were not back but were expected that Friday, or Monday the latest. I heard nothing from DFCI, so the following Wednesday (May 9th) I left voice mail for Dr. Hodi. We caught up with each other the next day.
It was an interesting conversation both because of what I learned and because of the facts I could connect thereafter. What I learned was that:
1. There was a considerable, but unspecified, delay in getting the samples from pathology and sending them off to the lab.
2. That the lab in Oregon was the only lab in the country qualified to do the complete gene expression profile with particular expertise/emphasis on c-kit.
3. That the lab has promised at least preliminary results by Friday or Monday (the 14th).
4. That a new PET scan will be done when I start the drug and again four weeks later to assess whether the drug had any effect.
I pointed out that a month has gone by during which my tumor was busy growing without any active intervention. When I asked Dr. Hodi why I had not been started on the drug a month ago, I was informed that the drug company will not provide the drug until after the c-kit sensitivity was confirmed. When I suggested to Dr. Hodi that he could have written a prescription for the drug at the time. He said that melanoma was not an approved use for the drug (it is approved for several other cancers) and that the insurance company might not have paid for it. I asked whether it would not have been appropriate for him to at least discuss the issue with me at the time, he said that without the c-kit information there would be no evidence that the drug would do any good. We left it at that.
It took me a day or two to realize how Kafkaesque this all is (in addition to being emotionally draining). Let’s go back to the time immediately after the PET scan when we elected to consider Glivec as the primary option. It is a clinical judgment to decide whether the drug may help. If it is unlikely to help, there is no point considering the clinical trial, particularly since I had made it clear that I did not intend to pursue any therapy with less than a 30% chance of success because of the side effects. Dr. Hodi thought that since it was a mucosal melanoma, there was a 30% chance that Glivec would be beneficial. Although I did not realize it at the time since no alternative was mentioned, there were, in fact, two options: Start the drug now or wait for the lab results. What is the rationale behind waiting for the test results? Thinking it over, I conclude that there are two contributing factors: The first is the clinical trial protocol end point: does the drug stops the tumor from growing. An unintended consequence of this prima facie reasonable end point is that the size of the tumor at the time of starting the trial is of no consequence to either the study or to the company supplying the drug. Consequently, no hurry. The second is that the requirement for prior testing saves the drug company money, since they do not have to supply the drug to patients without clear evidence that the drug is appropriately targeted. (I do not know, but will be interested to find out, whether the drug company would be willing to include patients in the study if they have purchased and used the drug while the lab work was being done.)
From the patients’ perspective this is all backwards. Nothing in the study protocol would be jeopardized by giving the patient the drug immediately. The correlation among gene expression, the drug, and tumor stasis/regression is just as valid whether the lab data is available at the end or the beginning of the four week drug-taking period. The cost argument is also rather spurious because it is not appropriate in the context of a phase II trial to value the drug at its market price; rather it should be valued at the incremental cost of producing it, which is a tiny fraction of the market price which has to include development costs. Last, but hardly least from the patient’s perspective, is the fact that a month out of a rather short life expectancy (in my case about a year with a large standard deviation) will be saved by starting the drug immediately, so that if it turns out that the drug does not help, or the side effects are too onerous, there is time to try an alternative before it is too late. If the drug does work, the residual tumor load is significantly smaller.
Given the mind set that such protocols display, is it any wonder that the patients are restive, dissatisfied, and seek alternatives? To add insult to injury, they are then vilified in the scientific press by the proponents of clinical trials. If, instead, those critics would support the tracking of those seeking to use unproved drugs and the monitoring of their experience by competent clinicians, the resulting data have the potential of providing valuable clues for the direction of future research. That such an effort would require some investment by FDA and NIH is obvious; their disinterest in doing so is equally obvious. Ensuring that the best interests of clinical trial participants take priority over everything except the validity of the results should be the task of the IRBs (Institutional Review Boards), but recent articles have suggested that they are often not up to the task.
I must confess that I, even as knowledgeable researcher, feel abused by the system; I profoundly sympathize with those less knowledgeable and more terrified of the system than I am. They deserve the medical research community’s compassion and support and they are not getting it. No wonder there is such a burgeoning interest in alternative therapy and avoiding clinical trials.
It should not be necessary for me to add as I stated in a previous rumination (and it is a sad commentary on our society that it is indeed necessary), that calls from malpractice lawyers will most definitely not be welcome and will, in fact, be resented. What is needed is pressure on government agencies and drug companies to ensure prompt and appropriate care of patients in the time interval from their being considered for enrolment until the protocol actually starts. If there is a consumer organization or smart lawyer who can figure out how to require inclusion of appropriate wording into all clinical trial contracts/grants, I would be delighted to help them in any way I can.
The bottom line is that I have been deprived of a month that I can never get back. If the drug works, I am unnecessarily left with a tumor that has had the time to grow bigger (just how much bigger we won’t know until the next PET scan). If it does not work, or if the side effects are intolerable, that was a month in which a different therapy could have been explored. What is frustrating and infuriating is that there is not the slightest scientific justification for the delay – it is simply a consequence of “the system”.
As I am sure all of you who have traveled on business have observed, it is far easier on the one who travels, than on the spouse who remains behind. Therefore, it is not surprising that Katherine is far more upset, angry, and ready to clutch at any straw than I am. I predict that without changes in how the clinical trial system is run and how experimental drugs are made available to terminal patients and how the results are evaluated, the patient revolt we have seen to date is just the beginning. Without meaningful change, the pharmaceutical industry and the biomedical research community will deservedly bear the brunt of the frustration and anger of the public and the members of the research community will have no one but themselves to blame for the inevitable consequences. Unfortunately, it is the patients and their families that will needlessly suffer the most, both physically and mentally.
