# Presentation: 757777

## DEFINITY®

**Perflutren Lipid Microsphere Injectable Suspension**
**FDA Advisory Committee****Microbubble Contrast Agents****Washington DC****June 24, 2008**

## Clinical and Post-marketing SafetyMichael Main, MDMedical Director, Echocardiography LaboratorySaint Luke’s Mid-America Heart InstituteKansas City, MONon-clinical SafetySimon Robinson, PhDSenior Director Pre-Clinical DiscoveryLantheus Medical ImagingBillerica, 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**

## 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**

## Slide 7

## 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%

**Notes:**
Simplified slide 

## 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***

**Notes:**
Simplified slide 

## 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**

**Notes:**
Simplified slide 

## 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**

**Notes:**
Some simplification added . Additional changes needed. No clear on points for some statements!

## 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 Change
in 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**

**Notes:**
Some simplification added . Additional changes needed. No clear on points for some statements!

## 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 1⁄2 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**

**Notes:**
Need to make points with this or don’t include

## 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

**Notes:**
Need to condense . To much text.

## 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

**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

## Disease Model Testing

**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 

**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**

## 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% **

## Multi-Center Safety Outcomes Database

**Main et al, JACC 08, submitted**
**Premier PerspectiveTM 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 3MTM 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

- 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 PerspectiveTM 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**