Winter (Volume 28, Number 4)
Reflections on Ethical Medical Research
By Philip A. Baer, MDCM, FRCPC, FACR
“Only one rule in medical ethics need concern you - that action on your part which best conserves the interests of your patient.”
– Dr. Martin H. Fischer
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I started thinking about this topic recently when two
seemingly unrelated events occurred in close proximity:
the closure of the only clinical research trial in which I
was still actively participating, and my wife and I choosing
to see a recently released documentary called "Three Identical
Strangers."
For twenty-five years, I was a principal investigator in a
variety of Phase 2, 3 and 4 trials and registries. NSAID and
COXIB trials were common initially, including SUCCESS-1
(celecoxib vs. naproxen), MORE (meloxicam vs. placebo), a
trial of enteric-coated vs. plain naproxen, VIGOR (rofecoxib
vs. naproxen), and the pivotal Phase 3 trials for a Canadian-developed topical NSAID, diclofenac in DMSO (Pennsaid).
VIGOR provoked anxiety as it was an adverse-event
driven trial, which would end when a certain number
of patients had experienced upper GI bleeds. One of my
twelve VIGOR patients had a fortunately mild bleed event
while on naproxen, which fit with the study hypothesis that
rofecoxib would be safer. Unfortunately, cardio-vascular
events tilted in the other direction, starting the cascade of
events which would lead to the withdrawal of rofecoxib and
other COX-2 inhibitors and multiple lawsuits. Prominent
Canadian rheumatology researchers were ensnared in the
resulting publicity, including Dr. Claire Bombardier, VIGOR’s
lead author. I was a tiny minnow and escaped any attention.
Later, I participated in a variety of trials in rheumatoid
arthritis (RA) for agents which failed, as well as early trials
of a biologic known then as D2E7, now more familiar to
the world as adalimumab. For 15 years, I was an investigator
in the Canadian BioTRAC registry following patients with
RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA)
on either infliximab, golimumab or ustekinumab. This trial
survived through 2 corporate mergers, ultimately enrolling
3,000 Canadian patients and generating multiple poster
presentations and 1 ACR podium presentation for me personally,
before closing in mid-2018.
Over time, trial participation has become more onerous
on patients and investigators, in my opinion. The availability
of proven agents in many rheumatic diseases make placebo-controlled trials difficult to justify in the Canadian
setting. Consent forms are longer and harder to fully comprehend,
adverse event documentation is more exacting,
research ethics boards demand greater information, and
the requirement for record retention has increased to 25
years. That is a long time to contemplate for someone in
mid-career or later, as I find myself now. I don’t think I will
initiate any new trials at my site going forward.
Why are research requirements so exacting? One has
only to look at the historical record of human experimentation
to see why so much protection is needed for human
research subjects. We recall easily the horrors of Nazi medical
experiments, leading to the Nuremberg Code (1947),
the Declaration of Geneva (1948) and the more familiar
Declaration of Helsinki (1964, last amended in 2013). However,
despite these statutes, failures to protect human subjects
have occurred more recently, even in countries such
as Canada and the United States.
Google “Tuskegee Syphilis Study” for a particularly heinous
example. Started in 1932 by the US Public Health Service,
poor African-American men in Alabama were offered
free medical care in a study designed to determine the
natural history of untreated syphilis. The patients were not
apprised of their diagnosis. Even after penicillin was known
to be an effective treatment, it was not provided. The study
carried on until 1972, when a whistleblower came forward
and the study ended. The study toll included numerous men
who died of syphilis, forty wives who contracted the disease,
and 19 children born with congenital syphilis. This study
led to the establishment in the US of the Office for Human
Research Protections (OHRP) to oversee clinical trials.
Familiar study requirements became mandatory, including
informed consent, communication of diagnosis, and accurate
reporting of test results, as well as institutional review
boards (IRBs) including laypeople, which were mandated to
review study protocols and protect patient interests, ensuring
that study patients are adequately informed.
Closer to home, I remember my psychiatry rotation as a
medical student at the Allan Memorial Institute at McGill.
The institute was located in Ravenscrag, the former hilltop
mansion of Sir Hugh Allan, a Canadian railroad and shipping
baron of the 1800s. While we found the place a bit eerie,
we did not know at the time that patients hospitalized
there in the 1950s and 1960s had been unknowing participants
in experiments conducted as part of the CIA’s MK
Ultra project. This was directed at the Allan by Dr. Donald Ewen Cameron, a prominent psychiatrist and one-time
president of both the Canadian and American Psychiatric
Associations. Subjects received LSD, high-intensity electroconvulsive
therapy and “psychic driving” treatment, often
while in drug-induced comas. The MK Ultra project did not
end until 1973. Some Canadian victims received compensation
in 1992, but many did not.
Which brings me full circle to the movie "Three Identical
Strangers." As a father of twins, I have always been interested in
stories about twins, triplets and higher-order multiple births.
Without spoiling the movie, which I highly recommend, the
story revolves around identical triplets, adopted out to 3 different
families in New York state in 1961, and unaware of the
existence of their siblings until chance intervened in 1980.
At that point, they experienced their 15 minutes of fame, but
the future featured tragedy, as well as the discovery that their
adoption had been part of a scientific study gone rogue, akin
in its own way to the studies I outlined above.
Next time you wonder why enrolment of patients in clinical
trials has become much more rigorous, the answer lies
in the failings of scientific researchers not very far removed
from the present.
Philip A. Baer, MDCM, FRCPC, FACR
Editor-in-chief, CRAJ
Scarborough, Ontario
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