How Safe Are We? Health Canada and Drug Safety - Joel Lexchin MD School of Health Policy and Management, York University Emergency Department ...
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How Safe Are We?
Health Canada and Drug
Safety
Joel Lexchin MD
School of Health Policy and Management, York
University
Emergency Department, University Health
Network
Points to Cover • Limitations of clinical trials & drug safety • Adverse drug reaction reporting • Funding for drug safety • New drugs and safety • Drugs removed because of safety issues • Communicating about drug safety
Efficacy
Trials
• Trials
to
get
drugs
approved
for
marke7ng
are
designed
and
run
by
drug
companies
– Want
to
prove
efficacy
&
therefore
exclude
pa7ents
where
factors
could
confound
ability
to
see
if
drug
works
– Short
term
&
won’t
see
safety
issues
that
occur
with
prolonged
use
– Won’t
detect
rare
side
effects
(typically
anything
occurring
in
fewer
than
1:1500
people)
– Some7mes
safety
issues
are
hidden
by
companies
Exclusion criteria mean most
patients don’t qualify for efficacy
Trials
•Drug intervention trials often
exclude individuals due to
concomitant medication use,
medical comorbidities, female
sex, and socioeconomic statusShort-Term Testing & Small Patient
Numbers
16 new active substances launched in Canada
1990-2000
• Small numbers of patients, e.g., when risperidone
marketed 2 published trials with 1-49 patients and one
with 49-99 patients
• Out of 129 published trials
– 34% 26 weeks
– E.g., no olanzapine trial longer than 26 weeks
Lexchin. Can Fam Physician 2002;48:1487-92Lack of Publication - SSRIs &
Childhood Depression
Published data for Combined published
paroxetine, sertraline, and unpublished data
venlafaxine for paroxetine, sertraline,
venlafaxine, citalopram
• Some evidence of efficacy
• Not efficacious
• Little or no evidence of
• Small possible risk of
harm suicidal ideation and/or
serious adverse events
Whittington et al. Lancet 2004;363:1341-5How
Does
Health
Canada
Evaluate
Safety
in
Approving
New
Drugs?
Drug company Health Canada Outcome
submission
•Market
•Basic chemistry authorization
•Laboratory data •Product
•Animal studies monograph =
•Clinical trials Product
•Manufacturing Information
information •Summary
Basis of
DecisionSafety
Informa7on
in
Summary
Basis
of
Decision
Documents
• 161
SBDs
issued
from
Jan.
1
2005
to
April
30,
2012
– 456
individual
clinical
trials
Absent
Unclear
Present
No.
Clinical
trials
Withdrawal
rate
248
200
8
456
given
Sta7s7cal
435
2
0
437
significance
between
withdrawal
rate
for
new
drug
and
comparator
given
ADRs
vs.
Prescrip7ons
Year
No.
of
outpa7ent
No.
of
reported
ADRs
prescrip7ons
1998
254,187,000
4,663
2011
524,952,000
41,923
107%
increase
799%
increase
Why are the number of reported ADRs going up so much faster than
the number of prescriptions?Deaths Due to ADRs (US & EU) • Lazarou 1998 – 106,000 deaths in hospital per year from ADRs • Ins7tute for Safe Medica7on Prac7ces 2011 – 128,000 deaths per year from ADRs • European Commission 2008 – 100,800-‐197,000 deaths annually in EU • No good Canadian data
Resource Distribution: Drug
Approval vs. Drug Safety
Approves new drugs
Approves new drugs
Monitors safety of drugsHealth
Canada
Expedited
Approval
Op7ons
Program
Year
Time
in
review
Provisions
created
process
(days)
Priority
review
1996
180
Effec7ve
treatment
for
serious,
life-‐threatening
or
severely
debilita7ng
disease
&
no
drug
currently
marketed;
Significant
increase
in
efficacy
and/or
significant
decrease
in
risk
for
a
disease
not
adequately
managed
No7ce
of
1998
200
Earlier
access
to
promising
new
Compliance
with
drugs
for
serious,
life
condi7ons
threatening
or
severely
debilita7ng
diseases
based
on
surrogate
endpoints;
postmarket
trials
required
Safety
Differences
Between
Standard
&
Priority
Review
Times
Standard review =
300 days
Priority review =
180 days
Difference does not
seem to be due to
mechanism of action
of drug or condition
it is approved to
treat
!Safety
Differences
Between
Standard
Review
&
NOC/c
Review
Standard review =
300 days
NOC/c review =
200 days
Curves significantly different, p = 0.0113, Log rank (Mantel-Cox) testDrugs Removed for Safety Reasons as a Percent NAS Approved in Five-‐Year Periods, 1990-‐2009
No. of Withdrawn Products Don’t Tell the
Whole Story
• Cisapride
– Withdrawn in 2000, late 1990s among top 40
prescribed drugs in Canada
• Vioxx
– Withdrawn in 2004, in 2003 10th most widely
prescribed drug in Canada (January – Sept.
2004: >360,000 prescriptions)
• Bextra
– Withdrawn in 2005, in 2004 >150,000
prescriptionsWithdrawals and Ques7ons • Valdecoxib and Sitaxentam – 20 days from NOC to first safety warning • Cerivasta7n, Lumiracoxib, Efalizumab – 23 to 62 days from safety warning to withdrawal • Calcitonin, Cekobiprole, Drotrecogin alpha, Grepafloxacin, Idebenone, Pergolide, Remoxipride, Tegaserod, Tolcapone, Troglitazone, Trovafloxacin, – All withdrawn without any prior safety warning – Were there prior concerns about safety
Number and Cause of Serious
Injuries and Deaths
Where is the cause of preventable drug
related injuries and deaths:
• Inadequate initial testing?
• Breakdown in postmarket surveillance?
• Physician prescribing errors?
• Poor patient compliance?
We don’t know because no one collects the
dataPostmarketing Studies, Canada • Health Canada can only require these from manufacturers when a drug has been given a Notice of Compliance with Conditions (NOC/c) • Only 1/14 drugs with new active ingredients approved with NOC/c
Status
of
Drugs
with
NOC/c*
Condi7ons
Fulfilled
(years)
Condi7ons
Not
Fulfilled
(years)
NOC/c
revoked,
0-‐2
2-‐4
4-‐6
>6
0-‐2
2-‐4
4-‐6
>6
suspended,
not
fulfilled,
removed,
product
removed
from
market
No.
of
7
16
7
6
3
4
2
8
8
drugs
61NOC/c for new products or new indications (45 separate products):
• 36 conditions fulfilled
• 17 conditions not fulfilled
• 8 revoked, suspended, conditions removed, product removed from market before
fulfilling conditions
*As of December 4, 2014Operating Early Warning System • Look for adverse events in vulnerable populations (pregnant/breastfeeding women, children, seniors, people taking multiple drugs) • Active monitoring system for adverse events known to be caused primarily by prescription drugs • No system for either of these
Monitoring Effects of Previous
Warnings
• Issues bimonthly Adverse Drug Reaction
Bulletin to doctors and others
• No method of monitoring use of Bulletin or
effect of information on drug prescribing/
use
• No method for monitoring effects of safety
warnings on Health Canada web page on
either prescribing or use of medicinesSafety Warnings May Not Help – Atypical
Antipsychotics
No Standards for Safety Issues • No standard for the length of time that it will take between the receipt of an ADR and when that ADR has been analyzed and posted on Health Canada’s website • Label changes for safety reasons can take over 2 years to be enacted
Conclusions • Premarket informa7on about drug safety is very limited for a variety of reasons • Unknown how Health Canada evaluates premarket safety informa7on • Postmarket pharmacosurveillance system is not adequately resourced • Drug safety withdrawals raise ques7ons about how Health Canada evaluates informa7on • Health Canada has poor 7melines for communica7ng drug safety informa7on & doesn’t assess effec7veness of its communica7ons
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