Dear e-drug colleagues, I am sending you this draft essay for the Side Effects
of Drugs Annual not only because I think it will interest many of you, but
because I would also appreciate any suggestions for improving it. AH
Andrew,
Thanks for sending on a copy of your article. I have showed it to several
other members of the Canadian Adverse Reaction Advisory Committee.
It was well written and made several good points - such as the potential
benefits of submitting signals re: ADRs to wider scientific review (how
about urgent RCTs as well?)
From a practicing clinician and pharmepi's point-of-view, my plea would
be for much more rigorous critical appraisal of the data at hand re:
ADR's prior to any policy decision. To use your examples, for instance:
1. Cotrimoxazole is an extremely useful and cost-effective antibiotic. It
is one of the first line choices for many conditions listed in our
provincial antibiotic guidelines. TMP alone is unproven and much more
expensive here in Canada. As the Jick paper stated, although co trimox
clearly has increased risk of serious skin reactions, in the overall
scheme of things compared to other antibiotics, it is very safe. For
instance, the elderly are much more likely to die of C difficile diarrhea
than cotrimos-related SJS. A recent NEJM article put the cotrimos-related
serious skin reactions at 1 in 6 million incidence - at least some number
extremely rare. GPs may manage rash, but they tend not (at least here) to
manage the type of rash that could be fatal. We have so far advised that
an alert reminding docs about the skin reactions and what to look for be
issued but the drug not be restricted.
2. the 3rd generation contraceptives. I am still trying to get the
original studies, but as I understand teh situation all 3 studies were
case control in design, or atleast nonexperimental (? one cohort). If so,
it would be impossible no matter what matching or adjustments were done
in analysis to avoid the original prescribing bias (why did these women
get the 3rd generation drugs instead of the other OC's? Was it because
they were believed safer and therefore prescribed to those women who
smoked or had other unmeasured risk factors for venous t-embolism.
Diagnostic suspicion bias is a major problem - everyone believes that OCs
are assoc. with venous thromboembolism. As well confirmation of clot is a
big problem in most centres. Short of venogram and duplex ultrasound,
most methods are relatively inaccurate. Jim Douketis and a few of us have
a paper submitted that reviews how lowsy the studies on OCs and HRT and
thromboembolism really are. It will be very interesting to add these 3
new ones to the brew!
In general, I think that a systematic assessment of ADR data is needed.
Now that I sit on CADRAC, I realize how terrible a lot of the case report
data is - often impossible to make much of, even if further info is
requested. We should not take a totally risk averse stance otherwise no
therapies would ever be used (although maybe nobody would smoke or drink
either - a thought!). Policy in this area really needs to be tempered by
the strength of the signal of ADR, the potential harm presented by the
ADR, the benefit of the medication compared to others available, and the
contribution of confounders. Medicolegal practices unfortunately have not
caught on to this larger picture either.
my 2 cents' worth,
Regards, anne