Download DAPT: Safety findings, and FDA`s General Approach to

DAPT: Safety findings, and FDA’s General
Approach to Safety Findings
Cardiovascular Research Technologies (CRT) 2015
February 24, 2015
Ellis F. Unger, M.D.
Director
Office of Drug Evaluation-I
Office of New Drugs
Center for Drug Evaluation and Research (CDER)
US FDA
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I have no financial interests in any drug or
medical device.
Ellis F. Unger, M.D.
Director
Office of Drug Evaluation-I
Office of New Drugs
Center for Drug Evaluation and Research (CDER)
US FDA
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…However, in patients with a drug-eluting stent, the overall death
rate was higher among those receiving 30 months of dual
antiplatelet therapy compared to those receiving 12 months
(2.0% vs. 1.5% respectively), explained by an increase in noncardiovascular deaths (1% vs. 0.5%; HR 2.2, p=0.002). The
most frequent causes of non-cardiovascular death were cancer
(34 vs. 17 deaths) and trauma (8 vs. 2 deaths) for 30 months
and 12 months of therapy, respectively. The increase in overall
mortality was observed in the clopidogrel cohort (2.2% vs. 1.5%,
respectively) but not the prasugrel cohort (1.6% vs. 1.6%). It should
be noted that in other large clopidogrel trials, increases in risk of
non-cardiovascular death have not been observed. Outcomes in
patients receiving bare metal stents are still being evaluated.
FDA will continue to evaluate the information from this trial and
other available data, and will communicate again when our
evaluation is complete.
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Mortality in DAPT
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Safety Findings in Clinical Trials:
Does FDA simply accept study findings on
their face?
• Adverse event terms (called ‘preferred
terms’) are analyzed by computer algorithms
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Many seemingly identical preferred
terms are tabulated separately:
– cardiac failure
– cardiac failure, acute
– cardiac failure, chronic
– cardiac failure, congestive
– cardiopulmonary failure
– left ventricular failure
– ventricular failure.
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• More examples:
– pulmonary edema
– acute pulmonary edema
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Tabulation of safety findings in clinical trials:
‘Pulmonary edema’ is separated from…
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Tabulation of safety findings in clinical trials:
…’Acute pulmonary edema!’
Yes…this is crazy!
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Thus, FDA will conduct its own analyses of the
preferred safety terms (52,299 here)
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Thus, FDA will conduct its own analyses of the
preferred safety terms (52,299 here)
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Thus, FDA will conduct its own analyses of the
preferred safety terms (52,299 here)
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Multiplicity
• Given that we’re always interested in certain
safety issues, multiplicity is a problem, for
example:
–
–
–
–
–
Myocardial infarction
Death (cardiovascular and all-cause)
Congestive heart failure
Cancer
Suicide/suicidality
• The possibility of detecting a false positive
finding is in important issue.
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Recent Safety
Findings in the
Cardiovascular
Arena – Not
Substantiated:
1. Prasugrel and
cancer from
TRITON TIMI 38
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Prasugrel and cancer findings not substantiated
in TRILOGY ACS:
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Prasugrel and cancer findings not substantiated
in TRILOGY ACS:
“The frequency of new, nonbenign neoplasms in
the overall treated population did not differ
significantly between the prasugrel group and
the clopidogrel group (1.9% vs. 1.8%, P =
0.79)….”
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2. Dabigatran and Acute MI - From RE-LY
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Dabigatran and MI
From Mini Sentinel, 5/13/14
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Dabigatran and MI
From Mini Sentinel, 5/13/14
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Bottom Line: Many cardiovascular drugs we
regulate are for prevention!
- drugs for hypertension and dyslipidemia to
prevent stroke and MI
- anticoagulants in AF to prevent stroke
- antiplatelet agents after ACS, +/- stent to
prevent cardiovascular events
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Bottom Line: FDA will make the public aware
of emerging safety signals, and investigate
fully.
Patients do not adhere to preventive
therapies for a variety of reasons.
It is critical that we do not alarm the public
about safety signals under evaluation!
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Thank you!
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