Monday, July 23rd 2012

Research At Your Peril

A physician can’t employ novel, potentially dangerous, treatments on you, even with your permission, without crossing off Institutional Review Board approval. The IRB critique process is designed to weight the risk/benefit of the proposed study and assure appropriate informed consent of the subjects. And in the case of new drugs or devices, the physician can’t do it without running through the Food & Drug Administration.

And so the confusion out at UC-Davis right now, involving the chair of neurosurgery, is likely to grab some attention.

In 2008, [UC-Davis neurosurgery chair Dr. J. Paul Muizelaar and his colleague Dr. Rudolph J. Schrot] proposed treating a glioblastoma patient with bacteria applied to an open wound to “attack the tumor,” then later withholding antibiotics and letting the bacteria do its work.

Schrot contacted the FDA but ultimately was cautioned that animal studies were needed first.

Back at UC Davis, IRB chairman [Dr. John] Anderson…was also skeptical. Anderson told Schrot in an email that denying this patient the treatment would be “likely devastating to this family,” but that he believed the FDA and UC Davis “won’t allow this product to be used in humans without further testing,” internal documents reveal.

Despite the initial roadblock, Muizelaar and Schrot “strongly believed that the intervention with intentional wound infection was promising for patients who otherwise faced certain death,” according to [a letter from Harris A. Lewin UC-Davis' vice chancellor of research]

[...]

Between October 2010 and March 2011, the physicians went forward with three procedures on humans with malignant brain tumors, surgically introducing probiotics into their open head wounds.

[...]

Schrot got IRB permission to move forward on Patient No. 1 with a “one-time procedure” that was “not associated with any research aim,” the letter states.

University documents show that the physicians believed they had been given the go-ahead for all three surgeries, but officials later determined that they had been misinformed or were misunderstood by the doctors.

Muizelaar and Schrot stressed to The Bee that all three patients, in consultation with their families, gave their consent.

[...]

In the case of Patient No. 1, the investigation found, Schrot had made an “incorrect statement” about restrictions on the bacteria’s use, leading IRB staff to incorrectly conclude that such review was not necessary, Lewin told the FDA.

As for Patients 2 and 3, the university found that treating them with an “unapproved biologic” amounted to human-subjects research – and thus required prior review and approval.

The idea of infections stemming cancer progression is hardly unprecedented and is reported in the literature for everything from lung cancer to bone cancers. Indeed, even intentional infections in cancer patients have a history. And, although two recent relatively large retrospective studies from 2009 and 2011 failed to show post operative infections improved survival in GBM, the issue remains equivocal with more anecdotal reports supporting the idea that infections may promote an immunologic response against the tumor itself.

Much of the issue seems to center on the idea of these bacteria as a ‘biologic’. If what Drs. Muizelaar and Schort did constituted ‘research’ of a biologic then there is likely real trouble ahead and much, if not all, of UC-Davis’ federal research funds, from all sources, could be at risk. It probably bodes well that if the University thought there was something wrong going on here that they self reported it and potentially did so in a relatively timely fashion.

I’m not going to jump to conclusions here. Although two patients seems to have had poor outcomes, potentially related to the treatment, it seems very plausible that this is a matter of bureaucratic misunderstanding. I understand the idea behind IRBs and the reasoning of a level of paternalism that most bioethicists feel patients need,

Arthur Caplan, director of medical ethics at New York University’s Langone Medical Center, said that desperate people are especially vulnerable and need added protections.

“If you’re dying, you’re kind of like reaching out to anything that anybody throws in front of you,” said Caplan, who recently left the University of Pennsylvania’s Center for Bioethics to assume the New York post.

“That’s why so many people over the years are pursuing quack cures in Mexico and all kinds of questionable treatments,” he said, speaking in general terms. “They’re not able to think straight because they’re at death’s door.”

Caplan said that institutional review boards are often misunderstood, with many people believing that such strenuous oversight is “a lot of bureaucracy to get in the way of trying something to save lives.”

In reality, he said, the committees are an essential safeguard for research subjects, who may not get an unbiased view on a researcher’s consent form of the study’s risks vs. benefits.

Maybe the informed consent portion should be the sole purview of the IRB. It is true that the ‘informed’ in informed consent can be a matter of contention, there is very often a wide discrepancy in information between a provider and patient. However, if Drs. Murzelaar and Schort, provided a reasonable view of the risks versus very potential benefits to these patients, even if the use of the bacteria actually under law fell to the FDA for permission, I would be inclined to step back, take a very libertarian view and think much unnecessarily is being made of the situation.

I’m sure fuller details are to follow. It is unfortunate that this is playing out so publicly at present.

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