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Special cardiac safety
concerns
Shari L. Targum, MD, MPH, FACC
Medical Officer
U.S. Food and Drug Administration
Detecting cardiac safety signals
– Common, drug-related: can detect in placebo-controlled,
clinical trials, compare to background rate
–
Rare, severe, drug-related: sometimes detected in clinical trials (e.g.,
Stevens-Johnson) or via
• risk biomarkers (e.g., QT prolongation) or
• epidemiologic studies (e.g., case-control)
–
Spontaneous events ↑ rate with drug: single event usually not
interpretable; detect via
• large enough controlled trial
• compare to background rate
• epidemiologic study (large hazard ratio)
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QT prolongation and risk of arrhythmia
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QT interval
• Variable-- heart rate, autonomic tone, time of
day
• Can be prolonged due to:
– heart disease (e.g., congestive heart failure)
– electrolyte abnormalities (e.g., hypokalemia)
– drugs (e.g., quinidine).
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Torsade de pointes (TdP)
Rare, but life-threatening. Might not be detected
in a drug development program.
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Background
– Drug withdrawals due to QT risk for nonantiarrhythmic drugs (e.g., cisapride,
terfenadine)
– How to evaluate TdP risk in drug
development (e.g., prior to marketing)?
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QT as a safety biomarker:
• Era of the “Thorough QT” (TQT) study
• Threshold for potential clinical importance set
very low (10 msec)
• “Negative study” → routine phase 3 monitoring
• Failure to rule out 10 msec → heightened
phase 3 monitoring
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QT Study Characteristics
• Characterize QT effects of the drug under near
“worst case” scenario
– Exposure at supratherapeutic concentrations
– ECG sampling at peak concentrations
(drug/metabolites)
– Sufficient duration of dosing/sampling to
characterize effects
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Some concerns about QT studies
• TQT studies difficult and expensive
• QTc relationship to risk (arrhythmia) not
constant
• Unknown public health consequences of
compounds removed from pharmaceutical
pipeline
• Interest in alternative approaches to assess
proarrhythmic risk.
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SCIPA (Comprehensive In Vitro
Proarrhythmia Assay) Initiative
1. in vitro drug effects, multiple cardiac
channels + in silico reconstruction of electrical
effects;
2. confirmation using human stem cell-derived
cardiomyocytes.
Undergoing validation at this time.
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Drug-induced Valvulopathy
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Weight loss and “Fen-phen”…
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Appetite suppressants
• Fenfluramine (1973): approved for short-term
use
– racemic mixture*- increased serotonin, associated
with depression
• Dexfenfluramine (1996)* thought to be “safer”
• Fen-Phen: never approved, widely used offlabel for long-term management
*withdrawn in 1997
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Case-control study in Europe: odds ratio 23.1
associated with use > 3 months.
24 women, no prior heart disease, mean treatment duration 11 months.
Fenfluramine and dexfenfluramine voluntarily withdrawn on Sept. 15, 1997
Source: Bhattacharyya et. al. Lancet 2009; 374: 577-85
Diabetes drugs and cardiovascular risk
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Cardiovascular risk and diabetes drugs
• Diabetes drugs approved based on glycemic
control (hemoglobin A1c)
• Diabetics have increased cardiovascular risk
• Concerns that some medications increase
cardiovascular risk (and little information)
• Need to show that treatment doesn’t result in
unacceptable risk (e.g., non-inferiority)
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Cardiovascular (CV) risk and diabetes drugs
• Guidance evaluating cardiovascular risk in new
antidiabetic therapies to treat type 2 diabetes
(2008)
– Design Phase 2/3 trials to allow meta-analysis
– Blinded CV endpoint adjudication committee
– Include higher risk patients (e.g., elderly, renal
impairment)
– Prespecified upper bound
• May need adequately powered cardiovascular
outcome study.
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Defining acceptable cardiac risk and
diabetes drugs
Acceptable and unacceptable cardiovascular risk
awith a reassuring point estimate
Upper bound of 95% confidence interval
for risk ratio or hazard ratio
Conclusion
>1.8
Inadequate to support approval
>1.3 but <1.8a
Postmarketing cardiovascular trial(s)
needed to show definitively <1.3
<1.3a
Postmarketing cardiovascular trial(s)
generally not necessary
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Detecting cardiac safety signals
– Common, drug-related: detect in placebocontrolled, clinical trials of appropriate
duration
– Rare, severe, drug-related: detect via
• risk biomarkers (e.g., QT prolongation)
• epidemiologic studies (e.g., valvulopathy)
– Spontaneous events ↑ rate with drug: single
event usually not interpretable; detect via
• large enough controlled trial
• Meta-analysis (e.g., diabetes drugs)
Cardiac Safety-related Groups
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Cardio-Oncology
• Several oncology drugs associated with cardiac
toxicity (e.g., anthracyclines, trastuzumab,
tyrosine kinase inhibitors)
• Interest in assessing and mitigating
drug/radiation-induced cardiovascular risk
• New interest group (American College of
Cardiology), journal (Cardio-Oncology),recent
FDA public workshop (22 September 2016)
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Cardiac Safety Research Consortium
• Launched in 2006 through an FDA Critical Path
Initiative Memorandum of Understanding with
Duke University to support research into the
evaluation of cardiac safety of medical products.
• Industry-academia-government effort
• Think tanks, research projects, publications
• Further information: cardiac-safety.org
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