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DEFINITY®
Perflutren Lipid Microsphere Injectable SuspensionFDA Advisory Committee
Microbubble Contrast Agents
Washington DCJune 24, 2008
Clinical and Post-marketing SafetyMichael Main, MD
Medical Director, Echocardiography LaboratorySaint Luke’s Mid-America Heart InstituteKansas City, MO
Non-clinical SafetySimon Robinson, PhD
Senior Director Pre-Clinical DiscoveryLantheus Medical ImagingBillerica, MA
Overview
• Clinical trials– Special population and placebo controlled studies provide value
in understanding safety, as exemplified by DEFINITY trials• Non-clinical safety studies
– Animal models can be useful at different stages of development to demonstrate safety, as shown with DEFINITY studies when compared to clinical trials
• Post-marketing safety surveillance– Going beyond spontaneous reporting, large retrospective
database mining is valuable to demonstrate and understand the safety of contrast agents, as exemplified by DEFINITY
• Overall, the data show DEFINITY enhanced echocardiography provides a diagnostic test with a positive benefit-risk profile
3
DEFINITY Background
• Approved in U.S. in 2001 following extensive non-clinical and clinical programs
–“for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.”
• Vial contains PFP and blend of three endogenous lipids (one conjugated to MPEG) that is activated by rapid agitation
• DEFINITY dosing I.V. bolus and infusion (1.3ml max) over 30-60 sec
• According to AMR data, approximately 2 million patients have been dosed since product launch
Clinical Safety
DEFINITY Clinical Trials
• 48 pre and post-approval clinical trials – 26 echocardiography,12 abdominal US (liver, kidney), 8 special
safety assessment/PK, 2 retrospective safety evaluation– 27 in NDA; 40 in EU Marketing Authorization Application; 8 post-
MAA• 5 pivotal studies in echocardiography (359 DEFINITY treated;
42 placebo subjects)• 3 pivotal studies in abdominal US (309 DEFINITY treated)
• 3,985 subjects – 3,616 with at least one dose of DEFINITY – 369 placebo
DEFINITY has been extensively studied in clinical trials
40 Studies (MAA)(40 completed)2951 Subjects
3 in Healthy Subjects60 Healthy Subjects
Placebo16 Subjects
DEFINITY44 Subjects
37 Trials in Subjects2891 Subjects
7 Placebo Trials224 Subjects
6 Echocardiography218 Subjects
1 Radiology6 Subjects
37 Trials in Subjects2667 Subjects
Echocardiography1381 Subjects(359 pivotal)
Radiology1122 Subjects(302 pivotal)
Other164 Subjects
11 Post Marketing Studies(8 completed, 3 ongoing)
1034 Subjects
51 Studies(48 completed, 3 ongoing)
3985 Subjects
Placebo184 Subjects
Definity848 Subjects
Definity On-going~593 Subjects
Data N/A
DEFINITY Clinical Trials
Adverse Events in Clinical Trials
• Serious Adverse Events–Total 34 - all reported as “unrelated” to DEFINITY
• 8 (0.2%) fatal outcomes all >24 hr after DEFINITY administration
– All occurred at least 35 hours after DEFINITY dosing (35 hours, 4, 5 (2), 7, 12 (2) and 15 days)
– All >58yo with underlying medical conditions and/or complications from surgical procedures
» Except 33-year old man with heart transplant
– Most had serious cardiac illnesses and/or cancer
• Frequency of SAEs in clinical trials ~1%
Adverse Events in Clinical Trials
• Adverse Events – fully evaluated in 2,951 subjects in 40 studies (MAA studies)
–26% subjects had at least one AE –7.6% AE were reported as drug related–The most common drug related AEs (>1%)
• Fatigue, headache, dyspnea, back pain, nausea, flushing, and dizziness
• No dose response relationship found with either bolus or infusion
Adverse Events in Placebo Controlled Clinical Trials • Placebo-Controlled Studies
– 126 AE in 224 placebo subjects (56%) – 259 AE in 543 DEFINITY subjects (48%)– Profile of AEs are the same
No clear difference between placebo and dosed groups
• Rest-Stress Placebo-Controlled Studies – 106 AE in 168 placebo subjects (63%) – 194 AE in 345 DEFINITY subjects (56%)– 125 AE in 516 rest only subjects (24%)
AEs attributable to stress procedures, not DEFINITY
Safety in Pivotal Studies
• AE rates DEFINITY-treated subjects in all pivotal studies – 85/359 (24%) in pivotal echocardiography– 77/309 (25%) in pivotal radiology
• AE rates in placebo-controlled pivotal echocardiography studies:
– 11/42 (26%) in placebo; 49/169 (29%) in DEFINITY group; no significant difference
• AE Profile in pivotal studies is consistent with other DEFINITY studies
• No significant difference in AE rates between DEFINITY and placebo patients
Overall Cardiovascular Evaluation • ECG parameters
– PI describes 221 subjects with 64 (29%) >30msec increase in QTc– Analysis performed for EMEA approval with aggregate data
(n=672) indicates no difference in change from baseline between placebo and DEFINITY groups
• Premature ventricular beats– Retrospective evaluation of 75 subjects exposed to a variety of US
imaging protocols indicates DEFINITY did not produce premature beats
– US PI recommends Mechanical Index of < 0.8• Systemic Arterial Pressure (from all Registration studies)
– Frequency of transient hypertension or hypotension < 1% • No associated clinical sequelae
Clinical trials did not reveal evidence of systemic or hemodynamic compromise
Electrocardiogram (ECG Analysis in 672 Subjects)
Change category Placebo Definity Dosed
Total Subjects with ECG Data 191 (100%) 481 (100%)
Increase ≥30 msec 34 (18.6%) 77 (16.9%)
Decrease ≥30 msec 47 (25.7%) 92 (20.2%)
Both increase and decrease 0 1 (0.2%)
Number (%) of Subjects with Percent Changein ECG Parameters ≤10% from Baseline
Ventricular rate 106 (57.9%) 268 (58.6%)
PR interval 138 (78.4%) 344 (78.2%)
QRS interval 137 (75.3%) 355 (77.7%)
QT interval 160 (87.4%) 378 (82.9%)
QTc interval 126 (68.9%) 313 (68.6%)
Overall Cardiovascular Evaluation • ECG parameters
– PI describes 221 subjects with 64 (29%) >30msec increase in QTc– Analysis performed for EMEA approval with aggregate data (n=672)
indicates no difference in change from baseline between placebo and DEFINITY groups
• Premature ventricular beats– Retrospective evaluation of 75 subjects exposed to a variety of US
imaging protocols indicates DEFINITY did not produce premature beats
– US PI recommends Mechanical Index of < 0.8• Systemic Arterial Pressure (from all Registration studies)
– Frequency of transient hypertension or hypotension < 1% • No associated clinical sequelae
Clinical trials did not reveal evidence of systemic or hemodynamic compromise
Assessment of Immune Response
• In a high dose safety study (50 l/kg) involving 12 healthy and 12 COPD subjects
– No meaningful change: • IgA, E, G, and M, (blood)• Total complement (CH50)• Tryptase and histamine
– Transient increase C3a with 50 L/kg DEFINITY– No anaphylactoid responses observed
Independent immunologist concluded complement activation is not causing mast or basophil cell activation
Safety Evaluation in Special Patient Populations
• COPD Patients– Prospective study
• 12 COPD and 12 healthy subjects - bolus DEFINITY (50 L/kg). • Lung clearance of PFP rapid (t ½ 1-2 min) and similar in both groups• No SAEs were reported• AEs were reported 7/12 for COPD and 4/12 for healthy group• DEFINITY related AE’s 1/12 for COPD vs 3/12 for healthy group
– Integrated Summary of Safety Analyses• 46 of 765 patients in 12 echocardiography studies were identified with
COPD• AEs were reported in 29.3% of COPD vs 32.5% non-COPD• DEFINITY related AEs: 7.6% in non-COPD and 6.5% in COPD patients
AE frequency not increased in COPD patients and no new AE types observed
Safety Evaluation in Special Patient Populations
• Mechanical Ventilation Study (n=38) – No clinically significant abnormalities reported
• Arterial O2 saturation, temperature, ETCO2 BP, HR, CVP, PCWP• Heart Failure Study (n=211)
– No SAEs observed– Overall incidence of new-onset AE was not statistically different between
DEFINITY and Placebo treated patients• Acute Myocardial Infarction Study (n=100)
– One SAE, mild chest pain, 2 days after dosing• Not drug related
– New-onset AE rate observed in subjects with acute MI was low (14%)• 5% Drug related AE
AE rate not increased in Special Patient population and no new AE types observed
Peer-Reviewed Publications:Safety Information
• Clinical Studies: 52 publications described DEFINITY use– 23,772 patients
• 21,573 echocardiography• 2,199 radiology
– Four publications and 1 case report provide safety data (n=1836)• DEFINITY was generally well tolerated• AE rates reported are similar to clinical trial rates
– One SAE reported (<0.1%); patient recovered• 83 yo female: sepsis, AF, hypovolemic, pacemaker, CAD, DM, GI bleed,
meningitis• Developed hemodynamic instability, respiratory distress, rapid AF 3 min post
dosing• Presumptive treatment for anaphylaxis with Benadryl, sepsis with antibiotics
and hypovolemia with fluids
Clinical Trial Perspective
• Overall Clinical Findings– Low SAE rate (1%) despite patient population with multiple co-morbidities
including cardiac and oncologic diseases– No dose response relationship noted for AEs
• Placebo Controlled Studies– Demonstrated majority AE were not DEFINITY related– AE rate is higher in rest/stress studies but similar between placebo and
DEFINITY groups• Special Studies
– AE rate not increased in Special Patient Populations (COPD, mechanical ventilation, acute MI, HF)
– No increase in cardiovascular effects• Efficacy
– Demonstrated efficacy for Left Ventricular Opacification and Endocardial Border Delineation
DEFINITY has a positive benefit/risk profile in a variety of clinical settings and patient populations
Non-Clinical Safety
Safety Pharmacology and Toxicology; General Findings
• Cardiovascular Safety (dogs)– No cardiopulmonary effects at up to 25x clinical dose– Respiratory rate, PAP, AP and cardiac contractility effects at higher
doses
• Toxicology (rat and primate)– Clinical signs seen (15 X rat, 50X primate) high multiple clinical dose
consistent with cardiopulmonary effects– Effects influenced by dose rate
Safety margin consistent with safe clinical use at recommended dose levels
• Primate (150x clinical dose)– Clear clinical signs following high DEFINITY dose – No meaningful change in hematology parameters or plasma levels of
histamine, tryptase or complement (SC5b-9)– Abnormal electrocardiographic changes, including ST-T segment depression
followed by cardiac arrhythmias within 1 minute– Suggest transient myocardial ischemia not an anaphylactoid response
• Pig- Literature reports (Grauer et al 1996, Chantal et al 2005)– Clinical dose of DEFINITY
• mild and transient pulmonary artery pressure change• no change in Heart rate, systemic pressure, partial pressure of oxygen, or left
ventricular systolic function.
– Pulmonary intravascular macrophage make pig good for screening for possible risk but less valuable for mechanism studies
Non-clinical testing suggests frequent anaphylactoid mediated events at clinical dose are unlikely. Consistent with clinical experience
Mechanism Behind Clinical Signs
• Occlusion microcirculation– Examined by intravital microscopy in rat spinotrapezius muscle– Low proportion (1.2%) microspheres transiently (85% dislodged by
10 min) retained microcirculation– No detrimental effect regional microcirculation even at 40X clinical
dose
• Pulmonary hypertension model – Dogs administered sephadex microspheres to induce either
moderate (+15mm Hg) or severe(+30 mm Hg) acute pulmonary hypertension.
– DEFINITY 10X clinical dose did not influence cardiac or pulmonary
function.
Consistent with clinical testing in COPD subjects
Disease Model Testing
• Mechanical ventilation– DEFINITY (25X clinical dose) did not influence cardiopulmonary parameters
in mechanically ventilated anaesthetized dogs– Persistence of DEFINITY in the circulation was not changed by mechanical
ventilation
Consistent with clinical testing in mechanically ventilated patients
• Bioeffects– Literature reports of cellular and tissue effects with combinations of high
contrast agent/ high Mechanical Index and extended ultrasound exposure– Low dose of DEFINITY in combination with low Mechanical Index and short
durations of scan in any particular plane will mitigate the potential to produce microscale bioeffects.
Clinical findings have suggested no bioeffect issues with DEFINITY with ALARA approach
Disease Model Testing
Perspective
• Non-clinical / Early Clinical– Use disease models to assess theoretical risks with new
classes of agents (i.e. pulmonary hypertension, mechanical ventilation)
• Late Clinical–Use in vitro/in vivo models in support of clinical
observations from trials to help address identified issues• Post Marketing
–Use in vitro/in vivo systems to examine mechanisms/pathways involved in safety concerns identified from clinical usage
Post Marketing Experience
DEFINITY POST MARKETING SAFETY EVALUATION
• Post Marketing Spontaneous Reporting–In accordance with CFR
• Single-center Safety Outcomes Studies–Herzog et al, JAMA, 2008
–Kusnetsky et al, JACC, 2008
• Multi-center Safety Outcomes Database–Premier Perspective DB (submitted JACC, 2008)
Summary of Post Market Experience
• Studies– Approximately 2 million administered doses based on Arlington
Medical Resources database
• Use (approximate)– 60% resting and 40% stress echocardiography
– 67% inpatients and 33% outpatients
• Location– Majority of use in the USA
– Other regions include: Canada, EU, Australia & Latin America
Spontaneous SAE Reports
• December 2000 through December 2007– 277 patients with SAEs (~0.014%)
• 14 fatalities; 7 (within ~30 minutes of dosing)• Patients who died mostly critically ill and unstable
• Type– 91 serious cardiopulmonary events (61 cases, including data
through April 2008)– 106 serious hypersensitivity cases
Frequency of SAE appears low (~0.01%) and often occurs in medically complex patients
Spontaneous reports provide SAE profile but do not assess impact of pseudocomplications
Pseudocomplications
• Adverse events occurring in association with a medical procedure may be due to either the procedure or the underlying disease state (pseudocomplication) (Hildner et al, 1973; Hildner et al, 1982; Main et al 2007)
• DEFINITY is often used in patients with serious underlying heart disease and other co-morbidities
• Important to distinguish pseudocomplications from DEFINITY related effects to understand true adverse event rates
Risks with Alternative Diagnostic Modalities
• Cardiac angiography mortality rate ~1/1000• Exercise test mortality or MI rate ~1/2500• Lifetime rate of fatal malignancy from SPECT/ or RVG
1/1000 – 1/10,000• TEE causal mortality rate ~1/10,000• DEFINITY contrast echo estimated associated rate of
serious event ~1/10,000 and mortality ~1/100,000
Contrast echocardiography risk appears lower than commonly utilized alternatives
Single Institution Safety Assessment
• Herzog, JAMA 2008– Hennepin County Medical Center, Minneapolis, MN
• Study Design - retrospective– 12,975 DEFINITY enhanced echos – All AEs documented by nursing staff reviewed
• Electronic charts abstracted and relationship to DEFINITY adjudicated• Non-fatal complications attributable to stress testing excluded
• Results for AEs occurring within 30 min– AE rate 0.12%– SAE rate 0.03% – No fatalities
SAE frequency low and similar to spontaneous reporting
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Single Institution Safety Assessment
• Kusnetsky et al., JACC, 2008– St Luke’s Health System, Kansas City, MO
• Study design - retrospective– 18,671 echocardiogram patients identified from Jan 2005 - Oct 2007– 12,475 non-contrast echos; 6,196 DEFINITY enhanced echos– Vital status within 24 hours of echo reviewed from records
• Results: Mortality within 24 hours–Non-contrast 0.37%–DEFINITY enhanced 0.42% (p=0.6)
• DEFINITY patients had higher clinical acuity and more co-morbidity than non-contrast patients
No increased risk of fatality associated with DEFINITY Ambient short term (24 hour) mortality rate in hospitalized
patients undergoing echocardiography ~0.4%
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Multi-Center Safety Outcomes Database
• Main et al, JACC 08, submitted– Premier Perspective™ DB (hospital claims data) Jan 1, 02 - Oct 31, 07
• Study Design - retrospective– 4,300,966 resting transthoracic echo exams identified
• 4,242,712 non-contrast echos• 58,254 DEFINITY enhanced echos
– Analysis• Severity of illness and risk of mortality variables were calculated using
3M™ APR-DRG Software• All cause 1-day mortality available for all patients• Multivariate logistic regression compared 24 hour mortality for non-
contrast vs. DEFINITY, controlling for case mix & covariates
• Results–Mortality rates:
• 1.08% for non-contrast echos (n=45,789/4,242,712) • 1.06% for DEFINITY enhanced echos (n=616/58,254) (p=0.613)
–Multivariate logistic regression analysis• DEFINITY enhanced echocardiography was associated with a 24%
statistically significant reduction in mortality – Risk adjusted odds ratio = 0.76 (95% CI = 0.70-0.82)
Decreased risk-adjusted mortality rate observed in patients receiving DEFINITY
Background 1-day mortality rate of 1% among an inpatient population
Multi-Center Safety Outcomes Database
Post–Marketing Safety Summary
• Spontaneous Reporting–Demonstrated a low SAE reporting frequency (0.01%)
• Confounded by pseudocomplications
• Herzog report–Suggests low AE (0.12%) and SAE (0.03%) frequencies–SAE rate similar to spontaneous reporting
• Kusnetsky report and Premier Perspective™ DB– Indicate DEFINITY is used in patient population with high ambient
mortality rate (0.4 to 1%)
–No increased risk of fatality associated with DEFINITY
Perspective
• Low event frequency implies–Need extremely large subject population to quantify in prospective
studies–Need control/ background population to identify agent involvement
Based on our experiences, requires assessment of large institution / outcome databases
• Safety Surveillance Approaches–Database mining to identify safety in sub-populations–Evaluated periodically post approval for significant trends–Findings incorporated into Medical Association Guidelines–Appropriate safety information incorporated into product labeling
Summary
• Clinical trials– Special population and placebo controlled studies provide value in
understanding safety, as exemplified by DEFINITY trials• Non-clinical safety studies
– Animal models can be useful at different stages of development to demonstrate safety, as shown with DEFINITY studies when compared to clinical trials
• Post-marketing safety surveillance– Going beyond spontaneous reporting, large retrospective
database mining is valuable to demonstrate and understand the safety of contrast agents, as exemplified by DEFINITY
• Overall, the data show DEFINITY enhanced echocardiography provides a diagnostic test with a positive benefit-risk profile
38