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When urgency to cure beats research ethics, bad things happen

Editor’s note: Just for your edification, here’s a “bonus” post. True, you might have seen this recently elsewhere, but it’s so appropriate for SBM that I couldn’t resist sharing it with those of you who might not read the other source where this was published recently. :-)

I’ve written a lot about Stanislaw Burzynski and what I consider to be his unethical use and abuse of clinical trials. Before that, I used to regularly write about Mark Geier and his unethical use and abuse of IRBs and clinical trials. Both doctors use their own IRBs stacked with their own cronies to rubberstamp scientifically and ethically dubious studies. Mark Geier got away with it for years. Stanislaw Burzynski got away with it for decades and, apparently, is still getting away with it to some extent. (His IRB is chaired by an old Baylor crony of his from the 1970s, and he has been cited for numerous problems with his IRBs.) I’d like to contrast how their unethical research, in which Mark Geier and his son David subjected autistic children to chemical castration with Lupron to decrease testosterone levels and allegedly make mercury easier to chelate (to them mercury was bound by testosterone, something that doesn’t happen under physiological conditions but requires organic solvents) and Stanislaw Burzynski administered an unproven cancer chemotherapy (antineoplastons) to hundreds of patients over the years and charged them for it, compares to a recent case in the news.

The case has been mentioned by PZ Myers. It happened that it involves the same sort of tumors that Stanislaw Burzynski claims to be able to cure, namely brain tumors. It happened at the University of California Davis (UC Davis) and involved two very prominent neurosurgeons there, a former head of the department Dr. J. Paul Muizelaar and Dr. Rudolph J. Schrot, who were found to have violated university’s faculty code of conduct with their experimental work. When you read this part of the story, you’ll shiver. At least, I did:

The procedure in question involved three patients described in documents only as Patients 1, 2 and 3 – two middle-aged women and one man who had a common enemy: glioblastoma.

For anyone unlucky enough to be diagnosed with the highly malignant brain tumor, the prognosis is dismal. Median survival is less than 15 months.

Muizelaar and Schrot called their novel approach “probiotic intracranial therapy,” or the introduction of live bowel bacteria, Enterobacter aerogenes, directly into their patients’ brains or bone flaps. The doctors theorized that an infection might stimulate the patients’ immune systems and prolong their lives.

The first patient lived about 5 1/2 weeks. The second survived another year, an outcome that buoyed the doctors and seemed to bolster their theory, they said.

The institutional trouble began in March 2011, when a newly diagnosed third patient developed sepsis, became unresponsive and died two weeks after being deliberately infected. The university’s first internal investigation soon followed.

As a cancer scientist and surgeon myself, my first thought here was: Who on earth thought this was a good idea? Let me put it this way. What Muizelaar and Schrot were doing was intentionally causing bacterial meningitis. In cancer patients! You know, patients whose immune systems are often compromised to begin with! To be honest, on the surface, Burzynski’s antineoplastons have more biological plausibility than this. Thirty years ago, I could say that they were at least drugs and therefore might have had some activity against cancer.

The concept that inducing an inflammatory reaction might help “prime” the immune system to counter cancer is not a new idea. In general, however, it’s not a good idea to use bacteria that could cause potentially life-threatening infections. The CNS is generally viewed to be an immune “privileged” site, meaning that the immune system doesn’t function the same way there as it does in the rest of the body. Immune privilege was first observed when it was noted that tissue grafts that would be rapidly rejected if grafted to the skin or other sites would survive a long time when grafted into the CNS. The original thought was that this meant the CNS was somehow cut off from the immune system by the blood-brain barrier, its lack of draining lymphatics, and the apparent inability of cells known as microglia to function as immune cells. However, recently this concept has been reevaluated in light of new data that show that the CNS is neither isolated nor passive in its interactions with the immune system, but that doesn’t change the observation that the immune system functions somewhat differently in the CNS. In any case, gut bacteria are in general not expected to be in the CNS, and bacterial meningitis can be really nasty. It’s also not that difficult to induce meningitis. Remember the outbreak of fungal meningitis from contaminated steroid injections last year?

Apparently, Muizelaar based his idea on an apparent observation in among neurosurgeons that postoperative infection was associated with better survival in patients with glioblastoma. However, the data supporting this particular association is, to put it kindly, mighty thin, a retrospective study. What Muizelaar apparently did was to place an enteric (gut) bacteria, Enterobacter aerogenes, into the open wound and bone flap after surgery in order to produce a wound infection. E. aerogenes tends not to be pathogenic except in patients who have compromised immunity, such as the elderly, infants, and, yes, cancer patients.

It’s instructive to read some of the PDFs included with the article, such as the report of the UC Davis investigation of Dr. Muizelaar and of Dr. Schrot. It reveals a bit of the complexity of doing investigations like this and, more importantly, why Drs. Muizelaar and Schrot went too far and how they gamed the system. He started with a consultation to the Bioethics Consultation Committee, which, after a lengthy debate, concludes that the practice “may be seen as consistent with the customs and practices of medicine.” However, the committee thought that the procedure required more oversight than it could provide, and suggested that the protocol should be reviewed by the IRB. So Dr. Schrot submitted a full application to the IRB in which he admitted that further preclinical work was needed but argued that in this patient the benefit/risk ratio was favorable. On what evidence? Who knows? I don’t have the IRB application. Dr. Schrot also discussed the procedure with the Center for Biologics Evaluation and Research at the FDA and was told that “animal studies will be necessary prior to entering into the clinic with your proposed therapy.” In addition, he was told that “these animal studies must show not only safety, but also establish a reasonable proof of concept in order for this investigational therapy to be introduced into patients.” In other words, the FDA told them to do the preliminary work first.

In the meantime, Drs. Muizelaar and Schrot submitted an NIH grant application for the animal studies. It was not well received by the study section, which characterized it as having “low translational impact with seriously flawed methodology and statistical analysis.” The summary statement concluded, “There is absolutely no feasibility evidence in support of this project” and comments that it has a “low translational impact since it is very unlikely that any IRB or the FDA will allow the introduction of Enterobacter aerogenes directly into patients.”

Here’s where things get interesting. The FDA had told Dr. Muizelaar that he and Dr. Schrot could proceed with their “innovative treatment” if the bacteria were available locally. No doubt this was because the FDA is a federal agency and doesn’t have jurisdiction if everything happens within one state. (It’s the same issue with Stanislaw Burzynski, actually.) If it was not available locally and had to go through the investigational new drug (IND) process, then more animal work was required, as the CBER stated. It turns out that a graduate student had some Enterobacter aerogenes from ATCC, and that’s what was used on these patients.

What follows then is wrangling between Dr. Muizelaar and the university. Dr. Muizelaar went to the Chief Medical Officer Al Siefkin and told him that the IRB had told Dr. Schot that the proposed procedure wouldn’t be considered research. In any case, both gave the impression that they were “shopping” for approval, and, although probably not lying, being a bit selective in what they told various parties involved in the approval process. As the news report notes:

Among the university’s findings, detailed in reports, email correspondence, interviews and regulatory documents:

  • A former top administrator said he believed the doctors went “shopping for approval” and were “doing all they could to get around” the formal approval process. A physician who served on the research oversight board said the surgeons seemed to be “gaming” the system to bypass any institutional rejection or skepticism of their plans.
  • Muizelaar and Schrot did not complete a study on rats before they began treating the three human patients, despite an FDA directive in 2008 that “animal studies will be necessary prior to entering into the clinic with your proposed therapy,” according to an email to Schrot from an FDA official. When asked by a compliance investigator why animal trials were not done first, Schrot allegedly responded that such testing would take “10 years … his entire career,” one internal review states. The investigator found Schrot’s “eagerness to proceed” to be concerning and his actions “reckless.”
  • One university investigator questioned whether the doctors ever would have been able to get federal approval of their concept. According to one report, Schrot’s grant application to the National Institutes of Health to study the bacterial treatment was rejected, with NIH commenting in 2009 that “(t)his is a very poorly developed scientific proposal that lacks feasibility.” The NIH thought it unlikely that university or federal regulators would allow the introduction of live bacteria directly into patients, the report states.

Ultimately, the procedures were done on three patients. Particularly disturbing is the consent forms that were drawn up, which basically said that there was no evidence that this would work but that the surgeons wanted to do it anyway. While technically that is accurate, one has to wonder how much coercion the patients might have felt and how free they felt they could say no. After all, they all had horrible diseases with a median survival of less than 15 months expected. As this editorial points out, patients also weren’t told everything:

Despite the absence of any FDA approval or IRB review, the neurosurgeons proposed their treatment, to Terri Bradley. The consent form she and her daughter signed appears straightforward. It made clear that the infection the surgeons were deliberately introducing into Bradley’s brain “may be totally ineffective.” It then laid out the many serious risks, including “further neurological deterioration … paralysis, coma or death.” The women were told the procedure did not have FDA approval.
Faced with the alternatives presented and the near certainty of death, not surprisingly, the Bradleys signed.

Here’s what the Bradleys weren’t told. They were not told that the FDA hadn’t just failed to approve the procedure their physicians were pushing, federal officials had told the doctors specifically not to perform the procedure until they had conducted animal studies. The Bradleys were not told that the doctors had bypassed the university’s IRB process or that the IRB had previously told the doctors not to perform their “experimental” procedures on human patients.

In other words, the “informed consent” provided was every bit as much misinformed consent as what antivaccinationists and “health freedom” activists advocate for.

The end result was one patient living less than six weeks, another surviving two weeks, and the second patient, the “success story” living over a year. However, the family of that patient, Terri Bradley, didn’t view it as a “success.” Indeed, Mrs. Bradley required at least one operation to “clean out” her infected head wound and directly administer antibiotics. Indeed, her daughters reported that the infected wound had begun to smell bad. True, this patient did apparently have some tumor shrinkage. As I read about the tumor shrinkage, thoughts of Stanislaw Burzynski came to mind, as did the observation that three patients are too few to say anything and that one sees longer-than-expected survival in cancer patients with homeopathy (i.e., treatment with nothing but water). In any case, despite the doctors’ thinking that Ms. Bradley had benefited, she did not:

“Patient 2 did not experience significant functional benefit,” investigators concluded, “and upon her death … recurrences of the tumors and chronic infection of the brain were identified.”

Shockingly, even after this almost certainly treatment-related death, Drs. Muizelaar and Schrot convened an ad hoc ethics committee and presented them with a proposal to proceed with five additional patients. According to this report, the ad hoc committee concurred with the proposal and recommended continuing clinical activities with the understanding that they would develop an IRB-approved protocol as soon as possible.

In the end, this case demonstrates just how much oversight is needed on human subjects research and just how disturbing what “brave maverick doctors” like Stanislaw Burzynski, Mark Geier, and, yes, Drs. Muizelaar and Schrot do can be. The problem, of course, is that the line between research and trying something “innovative” (or truly innovative without the scare quotes) is not always clear, nor is the line between research and making a “last ditch” effort to save a patient’s life. It also speaks to the inherent conflict between the desire of a doctor to save lives and the need to do rigorous research in order to determine whether what the doctor does actually does save lives. As a physician, it’s very easy to develop a tunnel vision and believe that your latest idea is something that will work, that will save lives, if only those unimaginative clods would see what you see. Also, in the service of the goal of saving lives, it becomes progressively easier to justify cutting ethical corners, as Drs. Muizelaar and Schrot appear to have done. It’s very easy to start to view the system designed to protect human subjects as obstacles to be overcome rather than the patients’ advocate.

You know how they say that the road to hell is paved with good intentions? I can’t think of a better example in medicine than a case like this.

Posted in: Cancer, Clinical Trials, Medical Ethics

Leave a Comment (30) ↓

30 thoughts on “When urgency to cure beats research ethics, bad things happen

  1. Jim says:

    Aww, you worried the little guys are taking away daddy’s market share?
    Dont worry, you guys still have the casualties in your favor.. Keep on spinning

    1. Calli Arcale says:

      Did you even read the article? Or did you conclude that people doing something “alternative” HAD to be good, as long as it takes market share away from “mainstream” medicine? Do you have even the slightest clue that you are supporting someone cheating and lying to get permission to carry out a totally insane experimental therapy that not only didn’t work, it actually killed one patient and made things much worse for the other two? And that they are now trying to do it on more patients? Would you like E. coli smeared into a deep head wound just because it’s alternative? Seriously?

  2. windriven says:

    Oh puhleeze – are you rolling out the pharma-shill gambit? Lame. Lame.

    These guys thought squirting poop into people’s brains was a good idea* … and proceeded to give it a roll without, apparently, any work with animal models. I guess you think squirting poop in people’s brains is a good idea too.

    *I expect wild applause for burying 23 variations of the obvious joke formula and not putting a single one to print. But Jimmy boy sorely tempted me.

    1. weing says:

      Maybe for those that have s**t for brains, it’s normal, even good?

      1. windriven says:

        Damn weing, only 22 variations left! :-)

        1. weing says:

          I tried to hold back. I really did.

        2. Chris says:

          I just thought “Jim” was a joke unto himself.

          And I am just unresponsive to the horror of surgeons skipping IRB, animal studies and going full poop in the brain.

        3. Chris says:

          I thought “Joe” was a joke onto himself.

          Also, I am kind of of in shock of the thought of surgeons using neither an IRB or animal studies, but going straight to poo on brain. The whole concept is horrible. And quite close to this take on fecal transplant:
          http://leftbrainrightbrain.co.uk/2010/12/09/bring-the-crazy-fecal-transplant/

        4. Chris says:

          Okay, first it was 503 error, and then a duplicate comment! This is my fourth attempt to replay to windriven’s August 26, 2013 at 10:04 pm comment. Since I am one of those “special” folks that get to have each and every one of my comments moderated, I trust only one will get through. So here it is, again:

          I thought “Joe” was a joke onto himself.

          Also, I am kind of of in shock of the thought of surgeons using neither an IRB or animal studies, but going straight to poo on brain. The whole concept is horrible. And quite close to this take on fecal transplant:
          http://leftbrainrightbrain.co.uk/2010/12/09/bring-the-crazy-fecal-transplant/

        5. Chris says:

          Sometimes I really hate this system. Five attempts, and I get “503″, “duplicate” and then nothing. It hates me. Sixth attempt and then I am walking to the grocery store to get bread and cat food. Here goes, again my response to windriven’s August 26, 2013 at 10:04 pm comment:

          I thought “Joe” was a joke onto himself.

          Also, I am kind of of in shock of the thought of surgeons using neither an IRB or animal studies, but going straight to poo on brain. The whole concept is horrible. And quite close to this take on fecal transplant:
          http://leftbrainrightbrain.co.uk/2010/12/09/bring-the-crazy-fecal-transplant/

  3. Not only do we see the regular updates on Burzynski, but we get the dreadful midwestern oncologist and neck surgeon, then the west coast horrifying neurosurgeons. Turns out Mondays are Sociopathic Doctor of the Week day.

    Actually, It’s good to see these issues on SBM. I think it’s easy to take it for granted that doctor’s are following rules of ethics and laws, which isn’t always the case. From a patient’s point of view, it does highlight a real problem with oversight, though. You don’t see a lot of articles on commercial pilots that just decide to ignore the FAA rules for years…

    1. Young CC Prof says:

      You make a very good point, and part of the difference is that pilots work in front of the whole world. The air traffic controllers know where they are. If anything goes wrong, the cockpit recorders know exactly what they said.

      This a bit of a problem in education as well. Most of the time, a teacher is the only professional in the classroom. You can ask the students if the teacher is doing a good job, but they aren’t well qualified to judge. You can occasionally observe each other’s classes, but that’s not the same as working together day in and day out. So, when it comes time to hire, promote, and fire, information about who the good teachers are is tougher to come by than we’d like.

      Also, I imagine that flying a plane is a bit more routine than being a doctor, particularly in some specialities. The pilot has to adjust to weather or other unexpected problems, but for the most part, the schedule says where you’re going and air traffic control tells you when you can leave and how to get there. When a doctor first sees a new patient, it’s a total mystery, and first he needs to figure out what city to fly to.

      1. Yeah, it’s not an exact analogy…but these doctors were clearly working against FDA recommendations…In this case, is it really a matter of medicine not being routine? Or is it a matter of obvious infractions falling through the cracks of multiple oversight agencies?

      2. mho says:

        I liked the analogy,even if it isn’t quite dead-on.
        I think the benefit/risk ratio makes a difference between the two–in the case of the doctor, his reputation may eventually suffer, but he will not feel any physical pain from his disregard of the rules.

        The pilot, on the other hand, risks dying. Some of them still do flaunt the rules–there are far too many stories about pilots flying drunk or hungover.

        1. mho says:

          sorry, where’s that preview function when I need it? I didn’t make myself clear.

          The benefit/risk problem ultimately falls to the patient, whereas the pilot risks his own safety as well as his passengers.

          1. Chris says:

            Could be worse. Note my battle with the system above. Le sigh.

        2. Yes, that’s the point, to having professional or criminal consequences for people engaged in unethical activities that endanger others. You change the risk/benefit for the practitioner. But, what sanctions will these doctors face? Bad press for a few months, then they go back to normal? Will they loose their license? Will they face criminal charges?

          The oncologist in Michigan who allegedly gave chemo to patients who didn’t need it, was reported to the State Medical Board well before he was investigated for fraud…what was done by them? Nothing as far as I can see.

          What do we have to do to get a system in place that has adequate investigation and sanctions for doctors that are suspected of or are practicing in an unethical manner?

          Or is there such a system in place that I am missing?

          Or does the medical profession NOT have a concrete standard for unethical behavior. Is it all just a subjective, “well, it seemed like a good idea at the time, even if the FDA and other ethics advisors were saying, NO.”

  4. Carl says:

    Couldn’t they at least have killed the bacteria first? Wouldn’t that still cause an immune response of some level without the risk of a runaway infection? What about all that adjuvant stuff they use in vaccines? Wouldn’t that crank things up without doing something which sounds like a good way to murder a patient?

  5. Carl says:

    Couldn’t they kill the bacteria first? How about that adjuvant stuff they use in vaccines? Wouldn’t that have the desired immune effect without doing something which sounds like the conclusion of a TV murder mystery?

  6. Carl says:

    Well this thing has gone full crazy today.

  7. jkwlab says:

    Wow. Perhaps someone was skimming the Gut-Brain literature and twisted things to fit their own opinions? The ethics of this is shocking. I’ll use it for a case study for my students next semester.

  8. These brain cancer patients really are some of the most vulnerable people. They can very easily be convinced to try anything. God, you have to be so careful with them. A horrid tale.

  9. Stephen H says:

    I must admit that I read the article rather hastily, but I seem to have missed the bit saying “criminal investigation” and “suspended from all medical practice”.

    1. harryeagar says:

      Yeah, I wondered about that, too.

  10. Calli Arcale says:

    I’m not sure which part about this story horrifies me more: the fact that they were doing this or the fact that they have not yet been stripped of their licenses. I mean, this is downright appalling. And meanwhile, we have people wanting to cripple the regulatory system *even more*, in the name of “health freedom” and suchlike.

  11. I made a comment much like those of Mouse, Calli, et al, yesterday, but got some weird error message and lost it–the comment and my patience. Both of these docs is simply moving on without the slightest concern or remorse. It’s enough to make you go try some acupuncture, (well, not quite, but you can see how the average person might think so).

  12. Alia says:

    This was probably the worst moment for me to read this article. My father-in-law has recently undergone neurological surgery and 10 days later they discovered that the site is infected. He’s in terrible pain and he’s going to have another surgery today, so at the moment the thought of deliberately infecting brain with gut bacteria makes me want to scream out loud.

  13. Alia – Sorry to hear about your father. I hope the surgery goes well and he gets good results and relief from his pain.
    Michele

  14. Alia says:

    Thanks, Michele. I’m waiting to hear whether he finally had the surgery today or whether it will be delayed until tomorrow. As a coincidence, my own father also had a surgery today, but in his case it was really minor, just cataract removal, and he seems to be feeling well.

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