One More Time: Clinical
Research Is Not Clinical Care
By
Leonard Zwelling
The latest issue of The
New Yorker has a story that chilled me to the bone while bringing up 20
year old memories.
http://www.newyorker.com/magazine/2015/12/07/bacteria-on-the-brain
The story is called Bacteria
On The Brain by Emily Eakin. It relates the story of Drs. Paul Muizelaar
and Randolph Schrot, two neurosurgeons from The University of California at
Davis who wanted to test a novel idea in the therapy of glioblastoma multiform
(GBM). It was an old idea in a novel setting. They wished to use bacteria
injected into the sites of otherwise untreatable brain cancers to stimulate an
immune response against the malignant cells. The subsequent brain abscess was
treatable though the GBM was not. This is really a concept dating back to the
1800’s and Coley’s toxin.
The good doctors (and they are painted as first-class
neurosurgeons) tried the approach on three patients. None did very well. The
doctors had no animal data supporting their proposal and had minimal IRB
support as they called what they were doing innovative treatment. The reason
this was being done was that the patients were desperate and had no other
options.
This reminded me of the pleas I used to hear from the MD
Anderson faculty about patients needing phase 1 drugs despite not being
perfectly eligible for the open trial du
jour. No one needs a phase 1 drug. Phase 1 drugs are highly experimental
and the trial design only recently has included efficacy as a quantifiable end
point. But even the most risky of phase 1 trials have some laboratory data to
back up the proposed protocol. Labeling a clinical intervention innovative
treatment seems to transcend the need for scientific rationale, a protocol, an
IRB or any other oversight, at least for these neurosurgeons.
What is so telling about the article is the old excuses.
It’s not really research. They did it with the best of intentions. The patients
were no worse off than they would have been (except for the huge hospital bills
incurred while the patients were comatose on an ICU). And, of course, the
ever-popular, the only reason the docs got caught is that the press got wind of
what they were doing. In this case it was the Sacramento Bee that broke the story of what these two neurosurgeons
were doing to patients without any scientific or ethical underpinnings.
UC Davis did settle two of the patient law suits.
Discussions ensued about why innovative therapy is less regulated than
research. Again, these arguments fall upon intent. Patients (human subjects,
really) need protection from researchers who are in it for their own glory, but
not from doctors who just want to help patients. This is sheer poppycock as it
is very difficult to distinguish a well-meaning physician from a self-serving
and megalomaniacal one who hides behind “innovative treatment” in lieu of the
proper IRB oversight.
Toward the end of her article, Eakins describes the arduous
path trod by Duke researchers to successfully treat brain tumors with polio
virus. This was a 21-year journey and was done “the right way.” Did some
patients die because the proposed therapy was not ready for clinical
application? Probably. But when the clinical trials were done, the success observed
was certain and the mechanism understood.
All of this brought back my memories of having tried as a
Vice President to convey to well-meaning and enthusiastic faculty, that the
rules governing clinical research could not be by-passed even for their
“superior” clinical judgment. Clinical judgment is for individual patient care
where only the result in the one patient counts. Clinical research is to
generate generalizable knowledge. The patients are human subjects, not patients
and the doctors are not caregivers but investigators. When you do clinical
research in 2015 in the United States, that is what you sign up for. Now, as
then, I understand why passionate, caring doctors don’t like the IRB and all
its rules. Too bad. The times when the lack of oversight have led to abuse of
human subjects are over. This is the price we pay to make sure the people are
protected from us and the data derived are of widely applicable use.
At he very end of the article, Muizelaar still does not
understand why the rules exist and can only think in terms of the individual
patient, even if that patient is himself. What is clear is that he was never
going to be a useful clinical investigator no matter how great his surgical
skill. The skills to be a great doctor and a great investigator do not
necessarily overlap.
Most of the physicians doing clinical research in academic
medicine are very well trained. Whether any of them have been well-trained in
the rules governing clinical research is another matter. It may be time that
all of the organizations certifying physicians add mandatory training in clinical
research for those wishing to do it.
Clinical research is simply not clinical care. Patients on
protocols are human research subjects first with special privileges and
considerations that must be afforded them. Infrastructures supporting clinical
research should be equally informed and adequately funded. This is not an
option.
With the proliferation of stock deals at academic centers
bringing true conflict of interest to the front door as institutions have high
stakes in the success or failure of drugs they both own and test, it is more
imperative than ever that someone of authority watch the store whether clinical
research or innovative therapy is being offered.
