Rumination 24. Building Destructive Empires

Rumination 24. Building Destructive Empires
By
Thomas P. Vogl
September 27, 2009

Sutent was a roaring success for me initially. The scans two months after starting Sutent showed stable disease and the side effects were minimal. So, of course, we continued the Sutent with scans scheduled two months later (September 2). Unfortunately, a funny thing happened on the way to the forum. In mid-August, two days before the Agricultural Fair that we were scheduled to work for four days, my bi-weekly labs showed that my LDH (a non-specific liver function measure) jumped almost 50% from two weeks before. Curious, but not alarming. The next day (after spending the day setting up for the fair), I spiked a fever and thought, probably correctly, that I had a virus at a most inopportune time. By the next day I had what was most likely my first ever attack of acute hepatitis with all the classic symptoms except jaundice accompanied by just a little pain, mainly discomfort. Ten days later we did the scheduled scans and there were significant changes in the liver. So, in preparation to switching to a new experimental regimen, a PD-1 inhibitor (more below), we discontinued the Sutent. Within 24 hours the symptoms had markedly decreased and within three days they were gone. I also discovered that the fatigue, for which Sutent is famous, had been sneaking up on me so slowly that I did not notice, after having been absent (as far as I could tell) the first few weeks of treatment. What a pleasant surprise to have the hepatitis gone and my energy back!

Last week I met with Dr. Hodi and Laurie Chiambalero, the research nurse on the Phase 1b PD-1 study. It was a delightful, positive meeting in which we covered all the bases. The drug, MDX-1106, will be infused every two weeks at 10mg/Kg, the dose considered optimal (see http://www.asco.org/ASCOv2/Meetings/Abstracts&vmview=abst_detail_view&confID=55&abstractID=34904) and, aside from occasional scans, there will be no reason for additional trips to Boston. After the first infusion, for which I elect to stay in Boston overnight just in case of untoward side effects, infusions will all be one day trips. So far, only twenty patients have been recruited into the study so relatively little is known about side effects other than that there is no discernible pattern to date. Since I worked with Laurie on another study with Dr. Shapiro, I feel very comfortable working with her and Dr. Hodi. I have decided, however, that if this study does not help me, I will not participate in any further studies unless there is biological evidence that the drug is relevant to my tumor's deranged pathway(s).

The reason I feel relatively optimistic about this very new drug, is that (briefly) it binds a receptor (PD-1) on the surface of the melanoma cells. This binding blocks the activation of a protein that would otherwise be activated and inhibit the function of T-cells, a component of the immune system that could destroy the abnormal tumor cells. The English language is inimical to double negatives, so it has a great deal of difficulty in dealing with immunology, which is full of them. So another way of explaining what the PD-1 inhibitor does is that by inhibiting production of a protein that inhibits T-cell attacks on the cancer cells, it disinhibits the functioning of the immune system.

Since my immune system has clearly been doing a pretty good job of keeping the tumor progressing far slower than expected, suppressing this obstacle to allowing the full force of my immune system to act against the tumor suggests that the results will be encouraging. This assumes, of course, that my tumor produces this protein, and that we do not know. We shall see.

Added in proof: The astounding positive results of PLX4302 (a BRAFV600E inhibitor) on metastatic melanoma (http://www.medicalnewstoday.com/articles/152309.php ) were announced a few days ago. Slides from my tumor are being tested for this mutation. Results in a few weeks.

However, the PD-1 study will not start for another few weeks. The reason for that brings me to the the title of this Rumination.

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I asked when the study would begin, and I was told that the IRB (Institutional Review Board) paperwork still needed some i's dotted and t's crossed. Probably an unnecessary delay, but OK. I then asked where (which of three infusion facilities at DFCI) the infusion will take place and was told that this was also an IRB decision. To me, that was the last straw, so I will vent my frustration and anger at IRB misfeasance here. For my many readers who may not be aware of the history of IRBs, IRBs were created by Congressional mandate (see, e.g., http://en.wikipedia.org/wiki/Institutional_review_boardhttp://en.wikipedia.org/wiki/Institutional_review_board

for the laudable purpose “to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study “ Each facility (hospital, research institution, university) establishes its own independent IRB that must follow the guidelines/rules mandated by FDA and NIH.

Unfortunately, but essentially inevitably, this laudable purpose has been perverted to generate a bureaucracy that, de facto, functions to protect its local institution using patient protection as a club to expand its empire and exert ever increasing control over the research enterprise by non-scientist/non-physician administrators, and, equally important to protect the organization from adverse publicity and law suits. (I won't mention the for profit rent-an-IRB scams further.) Only rarely do administrators value the goal of their institution over their own aggrandizement and CYA (Cover Your Ass)– those select few are worth their weight in platinum. The literature is rife with examples. The example I encountered is probably typical. Consider the three infusion facilities at DFCI. Either they are of equal quality and competence, in which case the choice among them is completely irrelevant to protecting “the rights and welfare of patients”, or they are unequal in some way relevant to patient protection in which case the IRB, to fulfill its mandate, should tell doctors to only assign patients to the best one and be raising hell with the hospital administration to correct shortcomings in the others. In neither case is it appropriate for the IRB to assign patients to a particular infusion facility. It is a failure of top management to curb the mission creep and power enhancement that is the personal goal of every administrator and manager in every institution, public or private.

The problem is widespread. The most famous CYA case was a study of the effect of maintaining the prescribed sterility actions in emergency situations (in this case placing central lines) on subsequent complications. A study at one hospital in the mid-West, when they assigned a staff member (I believe a nurse) to accompany a team and remind them of sterile procedures showed a marked decline in complications. When they asked NIH for grant support to try this at other hospitals before a general recommendation was made (after all an additional staff member costs money and their presence must be cost effective) the NIH Office of Human Subjects Research (OHSR, the NIH IRB that covers grant applications) said that they could not do this without obtaining the informed consent of the patients. Picture this: a seriously ill patient in the Emergency Department or the ICU must be asked to sign a waver to allow a nurse to remind the doctor to wash his/her hands! National publicity and ridicule eventually reversed this bizarre decision. Unfortunately, the incident did nothing to change the behavior of IRBs or of the OHSR. Delays of significant research projects by IRB hairsplitting and nit-picking continue unabated. As my example from DFCI illustrates, such intrusive incursions are ubiquitous. It may not be killing research by the death of one thousand cuts, but it certainly slows research, and wastes enormous amounts of time and money. What has happened to staying within the stated mandate, let alone using a modicum of common sense?

Have any of you ever seen, let alone read, a consent form that can pass IRB muster? I have in front of me copies of the two consent forms I signed for the PD-1 study. The main one, which is consent to the study, runs 26 single spaced pages. (Think about the median reading competence of the U.S. population!) Reasonably enough, the first three pages outline the purpose of the study and alternative treatments for the patient's condition. The next six pages are devoted to explaining the screening and the protocol including explanations of what EKGs, urine tests, blood tests, etc. involve. The last 16 pages are devoted to a laundry list of what can conceivably go wrong without any attempt to put these events into perspective or to inform the reader what is known about the incidence of these events to prior patients. Does this not serve far more to protect the institution, no matter what may happen, rather than meaningfully inform the patient? Now, particularly in Phase I trials, the number of prior patients may be small and the data scanty. None the less, is this not the kind of information needed to allow an informed consent?

The other consent form I signed runs only ten pages to allow for for the collection of a few additional tubes of blood for immunological studies. What is particularly fascinating and worrying is that this immunologic study is the primary basic research component of the study -- can the efficacy of this drug be predicted from the patient's immunologic status and can the effect of the drug on patients be monitored by changes in their immunologic status? Some obvious questions: Why is this not a part of the original consent and should any patients not agreeing to this be allowed in the study? Having already agreed to blood draws in the primary consent form, does it really need ten more pages of boiler plate to allow the draw of a few more tubes? What a fantasy world of philosophical theory the IRBs live in at what cost to society with consent forms written to protect the institution and providers rather than inform of the patient.

A similar fate for similar reasons has befallen HIPAA. HIPAA started as a drive to force standardization on medical insurance claim forms (which never happened). Added were attempts to increase electronic transactions and, in the process protect patient's medical records from inadvertent or malicious disclosure to others. See http://www.hipaaps.com/main/background.html for an overview. In a nutshell, HIPAA ended up saying that the patient has control (in a sense, ownership) over his/her medical record and may dictate to whom they may or may not be disclosed. Enter the bureaucracy and the empire building CYA administrator. When I asked Dr. Hodi to give me copies of all the reports (Labs, radiology, etc.) as soon as they were received, either in person, by FAX, or e-mail, I was informed that the local HIPAA administrator has decreed that all patient requests for such information must come through the Medical Records Department (which, of course, is his bailiwick). To ensure that this will happen, he has decreed that all printing and e-mailing from the DFCI computer system will be monitored and that any printing or e-mail of any medical record is essentially prohibited and exceptions will be investigated and have to be justified. For empire building, what a great ploy using the fear of large fines as club; for CYA it is an ideal excuse for the most arcane restrictions that require lots of staff to oversee – see my budget and my empire grow; for doctor-patient communication, what a disaster.

Equally horrifying is the unintended but pernicious influence of HIPAA on research. If patient data can be shared only under an immense bureaucratic paperwork burden, it most often will not be shared, vital data/information becomes unavailable, and the whole point of the enterprise, improving patient care, is slowed if not stopped cold. All this because in our society, personal medical information is considered in the same light as information on personal sexual activity was viewed in Victorian England. My personal view on the matter is that if anyone in the world can benefit by reading my medical record, they are welcome to do so. If this requires publication of my record in the New York Times, sure, go ahead. Given the national obsession with medical privacy, I am not suggesting that HIPAA be scrapped. Rather, I suggest that individuals have the right to waive or opt-out of HIPAA. People are allowed to waive trial by jury even in capital cases, and to waive many other rights conferred by law if they choose to do so and if in so doing no one else is harmed. Why not HIPAA?

I am also very curious as to why the senior clinical investigators, who bring their institutions both prestige and a copious flow of direct and overhead funds, have chosen to roll over and play dead in response to this assault upon their time, energy, and patients. As a group within their own institution, and nationally through their organizations such as ASCO (American Society for Clinical Oncology), they have considerable power and clout, if only they would choose to exercise it. A lobbyist to Congress would be useful. A more immediate need is a publicist to inform the general public of what the interference of these hair-splitting, nitpicking bureaucrats are doing to delay their care, intrude upon the doctor-patient relationship, slow down finding desperately needed treatments, and use up money that could be used for research. A very important role for the publicist should be to regularly publicize IRB and HIPAA absurdities. A little ridicule would go far to rationalize the behavior of both IRBs and HIPAA administrators.

I end with a plea to those of my readers who are lawyers or who have friends who are lawyers: Could one of you please come up with a blanket waiver for patients who wish to exempt their medical records from HIPAA safeguards. Of course, the institution and providers releasing those records must be held harmless in perpetuity for that release. It would also be necessary that the document requires the immediate release of the information as it is generated, lest the institution generates further paperwork obstacles to the prompt release of information.

The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm

and my e-mail address at the bottom of the page at http://upislandeggs.com/

(I use this circumlocution to suppress spam).