1. Special cardiac safety concerns
Shari L. Targum, MD, MPH, FACC
Medical Officer
U.S. Food and Drug Administration

2. 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)
Detecting cardiac safety signals

3. QT prolongation and risk of arrhythmia

5. 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).

6. Torsade de pointes (TdP)
Rare, but life-threatening. Might not be detected in a drug development program.

7. Background
Drug withdrawals due to QT risk for non-antiarrhythmic drugs (e.g., cisapride, terfenadine)
How to evaluate TdP risk in drug development (e.g., prior to marketing)?

8. 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

9. 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

10. 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.

11. 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.

12. Drug-induced Valvulopathy

13. Weight loss and “Fen-phen”…

14. 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 off-label for long-term management
*withdrawn in 1997

15. Case-control study in Europe: odds ratio 23.1
associated with use > 3 months.
Case-control study in Europe which showed an odds ratio of 23.1 associated with use > 3 months.

16. 24 women, no prior heart disease, mean treatment duration 11 months.
Combination not approved by FDA; but total # prescriptions exceeded 18 million.
24 women with no history of HD, who developed cardiac symptoms or murmur. Mean duration rx about 11 months.
Fenfluramine and dexfenfluramine voluntarily withdrawn on Sept. 15, 1997

17. Source: Bhattacharyya et. al. Lancet 2009; 374: 577-85
Dasatinib also associated with pulmonary hypertension, possibly via PDGF.
Source: Bhattacharyya et. al. Lancet 2009; 374:

18. Diabetes drugs and cardiovascular risk

19. 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)

20. 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.

21. 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

22. Detecting cardiac safety signals
Common, drug-related: detect in placebo-controlled, 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)

23. Cardiac Safety-related Groups

24. 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)

25. 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