Cardiovascular Outcome TrialsHow is Benefit-Risk Appropriately

Balanced with Respect to

Cardiovascular Outcomes?

Sanjay Kaul, MD, FACC, FAHA

Division of Cardiology

Cedars-Sinai Medical Center

Los Angeles, California, USA

“There is a tendency to make the measurable important,

rather than the important measurable”

Robert S. McNamara

Current Models for Benefit-Risk Assessment

• General models

Principle of Three, TURBO, etc., (not highly valuable)

• Simple models

Number needed to treat (NNT)/Number needed to harm (NNH)

or incremental net benefit (INB) that incorporate utility

functions, including patients preferences

• MCDA (Multi-criteria decision analysis)

The most sophisticated and highly valued model

• An ‘HTA-like’ model based on quality of life measures (QALYs), etc.

• Bayesian models

Institute Study on the Current Status of Benefit-Risk

Assessment among Companies and Agencies

(N=9/23 pharma companies, 10/13 regulatory agencies)

Companies

• Purely qualitative (4/9)

• Semi-quantitative (4/9)

• Fully quantitative (1/9)

Agencies

• Purely qualitative (6/10)

• Semi-quantitative (4/10)

• Fully quantitative (0/10)

Dr Neil McAuslane, Director of the Institute for Regulatory Science

CMR International, 2008

Low enthusiasm for quantitative approaches

Decision

Factor

Evidence and

Uncertainties

Conclusions and

Reasons

Analysis of Condition

Current Treatment Options

(unmet clinical need)

Benefits (efficacy from RCTs)

Risks (from RCTs, SAE reports)

Risk Management (REMS)

Benefit Risk

Summary Assessment

Qualitative Framework for Benefit/Risk Analysis

FDA’s Five-Item Grid Proposal (PDUFA V)

“Qualitative science grounded in quantitative data and dependent upon judgment”

http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM329758.pdf

Strength

of evidence

Assessing Drug SafetyKey Elements in Decision Making

Seriousness

& magnitude

of adverse

event

Safer

alternatives

& patient

preference

9Critical

(death, Q-MI, disabling stroke,

major bleeding)

8

7

6 Important, but not critical(recurrent ischemia, recurrent

hospitalization, restenosis / TVR,

silent /biomarker MI, groin hematoma)

5

4

3Informative, but not important

(surrogate markers: LDL, BS/A1C, BP,

CRP, PVCs, creatinine)

2

1

Grading Importance of Outcomes

How to Assess the Tradeoff Between Efficacy (Reduced Atherothrombotic Events) and

Safety (Increased Bleeding) of Vorapaxar?

• Subjectively assess separate analyses of safety and efficacy

- NNT vs NNH (favorable BR balance: NNT < NNH)

- Assumes equivalence of primary efficacy and safety endpoint

• A formal, weighted composite safety and efficacy endpoint

- Would require weights based on patient- and physician-determined

value judgments (difficult to assess; done a priori)

• Net clinical benefit analyses (NCO, NACE)

- Combines efficacy and safety into one composite endpoint

- Assumes each component is equivalent

Endpoint Placebo Vorapaxar HR (95% CI) P value ARDNNT/

NNH (-)

CVD/MI/Stroke/UCR (PEP) 12.4% 11.2% 0.88 (0.82-0.95) 0.001 1.2% 83

CVD/MI/Stroke (SEP) 10.5% 9.3% 0.87 (0.80-0.94) <0.001 1.2% 83

MI 4.8% 4.1% 0.85 (0.76-0.95) 0.005 0.7% 143

GUSTO Moderate/Severe

bleeding 2.5% 4.1% 1.67 (1.43-1.94) <0.001 -1.6% -63

Clinically significant

bleeding11.1% 15.7% 1.46 (1.35-1.57) <0.001 -4.6% -22

Intracranial Hemorrhage 0.5% 0.9% 1.91 (1.36-2.69) <0.001 -0.4% -250

CVD/MI/Stroke/UCR/GUSTO

Moderate/Severe bleed

(NCO)

12.2% 11.7% 0.95 (0.89-1.02) 0.142 0.5% -

Vorapaxar in Stabilized CAD & PAD (TRA 2OP) Benefit-Risk (BRAT) in Overall Cohort (N=26,449)

Benefit-risk balance not favorable for the overall cohort

Vorapaxar in TRA 2OPBenefit-Risk in Proposed Label Population* (N=16,856)

Endpoint Placebo Vorapaxar HR (95% CI) P value ARDNNT/

NNH (-)

CVD/MI/Stroke/UCR (PEP) 11.4% 9.8% 0.82 (0.74-0.90) <0.001 1.6% 63

CVD/MI/Stroke (SEP) 9.0% 7.4% 0.78 (0.70-0.88) <0.001 1.6% 63

MI 5.3% 4.4% 0.83 (0.72-0.95) 0.005 0.9% 111

GUSTO Moderate/Severe

bleeding2.0% 3.0% 1.54 (1.24-1.90) <0.001 -1.0% -100

Clinically significant

bleeding10.2% 14.8% 1.48 (1.35-1.63) <0.001 -4.6% -22

Intracranial Hemorrhage 0.4% 0.5% 1.44 (0.87-2.40) 0.160 -0.1% -

CVD/MI/Stroke/UCR/GUSTO

Moderate/Severe bleed

(NCO)

11.5% 10.3% 0.89 (0.82-0.98) 0.017 1.2% 83

Benefit-risk balance favorable for proposed label population

*History of MI and without prior stroke or transient ischemic attack (post hoc subset)

Vorapaxar in TRA 2OPTreatment Effect According to Eligibility Criterion

• Benefit driven by treatment effect in CAD stratum

• No heterogeneity of treatment effect in CAD and PAD strata

PopulationEnrollment

Criterion

Proposed

Label

Approved

Label

CAD stratum

(>2-52 wks post-MI)0.83 (0.76-0.92) 0.82 (0.74-0.90) 0.82 (0.74-0.90)

CVD stratum 1.02 (0.84-1.23) No No

PAD stratum 0.95 (0.79-1.14) No 0.87 (0.71-1.06)

Overall 0.88 (0.82-0.95) 0.82 (0.74-0.90) 0.83 (0.76-0.90)

Vorapaxar in TRA 2OPBenefit-Risk in Post-MI or PAD Patients Without

a History of Stroke or TIA (FDA Label, N=20,170)

Benefit-risk balance favorable for the cohort

Endpoint Placebo Vorapaxar HR (95% CI) ARD NNT

CVD/MI/Stroke/UCR (PEP) 11.8% 10.1% 0.83 (0.76-0.90) 1.7% 59

CVD/MI/Stroke (SEP) 9.5% 7.8% 0.80 (0.73-0.89) 1.7% 59

CV death 2.8% 2.4% 0.86 (0.71-1.03) 0.4% -

Myocardial Infarction 6.4% 5.4% 0.82 (0.73-0.93) 1.0% 100

Moderate/Severe bleeding 2.4% 3.7% 1.55 (1.30-1.86) -1.3% -77

Clinically significant bleeding 10.9% 15.5% 1.47 (1.35-1.60) -4.6% -22

Intracranial Hemorrhage 0.4% 0.6% 1.46 ( 0.92-2.31) -0.2% -

Endpoint Placebo Vorapaxar HR (95% CI) P value ARDNNT/

NNH (-)

CVD/MI/Stroke/UCR (PEP) 19.9% 18.5% 0.92 (0.85-1.01) 0.072 1.4% -

CVD/MI/Stroke (SEP) 16.4% 14.7% 0.89 (0.81-0.98) 0.018 1.7% 58

MI 10.3% 9.2% 0.88 (0.78-0.99) 0.033 1.4% 71

GUSTO Moderate/Severe

bleeding 5.8% 7.6% 1.36 (1.18-1.57) <0.001 -1.9% -56

Clinically significant

bleeding14.6% 19.5% 1.41 (1.29-1.54) <0.001 -4.9% -21

Intracranial Hemorrhage 0.4% 1.1% 2.52 (1.48-4.29) <0.001 -0.7% -143

Vorapaxar in ACS (TRACER Trial) Benefit-Risk in Overall Cohort (N=12,944)

Benefit-risk balance not favorable for the overall cohort

Benefit-Risk Balance in TRA 2OP (Approved Label)1000 Patients Treated with Vorapaxar Instead of Placebo

Vorapaxar vs placebo

Benefit

• 17 ischemic endpoints prevented

- 10 MIs

Risk

• 13 excess GUSTO Mod/Severe bleedsor

• 46 excess clinically significant bleeds- 12 GI bleeds

Does the evidence favor Class I (benefit >>> risk)

recommendation for vorapaxar in stabilized ACS/PAD?

Clinical importance of MIs? Fatal vs nonfatal

? Q-wave vs non-Q wave MI

? Heart failure/LVSD, arrhythmia, SCD

Clinical importance of Bleeds? Hospitalizations

? Resource utilization

How is Bleeding Different from a MI?Variable Weights Based on Perception of “Utility”

CAD

MI risk Bleeding risk • MIs are part of the disease,

incompletely prevented by

therapy

• Can’t count the MIs that

are prevented

• All MIs are not created equal

(clinical importance varies)

• Spontaneous major bleeding

is unusual, bleeding

unequivocally caused by Rx

• Events are easy to count

• Bleeding causes panic

• Increased LOS and cost

Asymmetry in assessment of benefit-harm (bleeding > MI)

How is Bleeding Different from a Stroke?Variable Weights Based on “Utility”

A Fib

Stroke risk Bleeding risk • Embolic strokes are part of

the disease, incompletely

prevented by therapy

• Can’t count the strokes that

are prevented

• Strokes usually associated

with long-term effects

• Spontaneous major bleeding

is unusual, bleeding

unequivocally caused by Rx

• Events are easy to count

• Bleeding causes panic

• Consequences are typically

finite

Asymmetry in assessment of benefit-harm (bleeding>>stroke)

Physicians: bleeding: stroke risk: 4:1

Patients: bleeding: stroke risk: 10:1

Benefit-Risk in Drug & Device DevelopmentAsymmetry in Assessment of Efficacy & Safety

• RCTs• Anticipated, prespecified• Adequate power• Adjudicated• Precisely measured and

quantified (P values)

Efficacy• Non-clinical data, PK/PD studies,

meta-analyses, observational databases, AERS/Sentinel

• RCTs: limited exposure, narrow population

• Unanticipated, not prespecified • Not adjudicated (after the fact)• Delayed/late onset events

missed (after withdrawal)• Not precisely measured and

quantified (r/o unacceptable risk)

Safety

O’Neill RT, Drug Information Journal 2008;42;235–245

Assessing Drug Safety Post-Approval Lessons from Vioxx, Avandia and Meridia

CharacteristicRofecoxib

(Vioxx)

Rosiglitazone

(Avandia)

Sibutramine

(Meridia)

Date of approval 5/20/1999 5/25/1999 11/22/1997

Approval outcome Pain control Glycemic control Weight loss

Indication- Osteoarthritis

- Acute pain in adults

- Dysmenorrhea

- Type 2 DM in

conjunction with

diet and exercise

- Obesity

BMI>30kg/m2

BMI>27kg/m2 + CRF

Warnings, precautionsGI side effects,

renal diseaseClass III/IV CHF

Uncontrolled HTN,

CVD, CHF, arrhythmia

Post-marketing safety trialVIGOR

(N=8,076; 9m)

RECORD

(N=4,447)

SCOUT

(N=10,000; 3.8y)

Safety signal Excess CV risk ? CV risk Excess CV risk

Post-approval

regulatory actionWithdrawn

9/29/2004

Restricted access

10/8/2010

Withdrawn

10/8/2010

Meta-analysis

(N=10)

(+ 4 updates)

Prospective RCT

(N=1)

RECORD

Epidemiologic

(28 studies)

Rosi vs. con

Pio vs. con

Rosi vs. Pio

Post hoc/RCT

(N=3)

BARI-2D

ACCORD

VADT

Cardiovascular

Effects of

Rosiglitazone

• Large exposure (309 MACE)

• HR >1.3 r/o for all events except MI

• Favorable lean on mortality

• Burdened by study design and

conduct issues that preclude

reassuring estimates

• Inconsistent and fragile evidence

• Methodological limitations

• Results not reliable or replicable

• Good for raising questions, not settling them • Weak associations (OR<1.5-2.0)

• Confounding

• Prespecified hypothesis in 1 study

• MI risk not validated

• Hypothesis generating at best

• Post hoc nonrandomized

observations challenge

interpretability

• ODE/CDER/FDA

• ACCF/AHA

• US FDA restricts marketing

No risk risk

• OSE/CDER/FDA

• ADA/EASD

• EMA suspends marketing

Rosiglitazone and Cardiovascular EventsDivergence of Opinion

Insufficient evidence to either incriminate or exonerate rosiglitazone

Regulatory Approval for Diabetes TherapiesPrimary Criterion: Glycemic Control (HbA1c)

• HbA1c and vascular risk- UKPDS: ↑ vascular risk when HbA1c >5.5%

- ADVANCE: ↑ microvascular risk >6.5%: ↑ CVD risk >7.0%

• Intensive glycemic control (Type 1 DM)- Moderate quality evidence of microvascular benefit (DCCT x6.5y)

- Moderate quality evidence of macrovascular benefit (DCCT x6.5y

plus EDIC x10y)

• Intensive glycemic control (Type 2 DM) - Moderate quality evidence for microvascular benefit (UKPDS x10y)

- Low quality evidence for macrovascular benefit (UKPDS x20y)

- No evidence of micro or macrovascular benefit ( ACCORD,

ADVANCE, VADT)

Treatment HbA1c Lipids Weight BS CHF CV event

Sulfonylureas ~1% +/- +/-

Metformin* ~1% LDL (10mg%) +/- +/- +/- ? (obese)

Acarbose ~0.5% +/- +/- ? +/- ?

Rosiglitazone** ~1% LDL, HDL TG +/- 2-fold ?

Pioglitazone** ~1% LDL, HDL,

TG +/- 1.5-fold ?

Nateglinide ~0.5% +/- +/- ? ?? ??

Repaglinide ~1% +/- +/- ?? ??

DPP-4 inhibitors ~1% ? +/- +/- ? No

GLP-1 agonists ~1% LDL, TG, HDL +/- ?? ??

SGLT2 inhibitor ~0.7% LDL, HDL,TG +/- ?? ?

Comparison of Oral Antidiabetic Therapies

Bolen et al, Systematic Review. Ann Int Med 2007;147:386-99; Ann Int Med 2011

*Lactic acidosis, GI side effects; ** fractures, macular edema (case reports), ? bladder cancer

2008 FDA Diabetes GuidanceRecommendations

• Primary evidence for regulatory approval: glycemic control

• Demonstrate that therapy will not result in an unacceptable increase in CV risk (noninferiority)

• Phase 2/3 design should permit a pre-specified meta-

analysis of major cardiovascular events (MACE)

• Independent committee should prospectively and blindly adjudicate MACE

• Trials should include patients at increased risk for cardiovascular disease (advanced CVD, CKD, elderly)

• Trial duration(s) should be longer than 3-6 months to obtain enough events and provide long-term data (~2yrs)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm

2008 FDA CVOT GuidanceRuling Out Excess CV Risk: Two-Step Approach

Trial

phase

“Reassuring”

Point Estimate

0 1 2

Hazard ratio

No. of

Events

Patient

Exposure

Screening

(Premarketing, Stage 1)<1.262122 2500 x 2y

1.81.3

<0.91

<0.53

Premarketing 122 2500 x 2y

Pre- + post-

marketing*122 2500 x 2y

*Using O’Brien-Fleming adjustment

Goal is to rule out 6 excess events/1000 PY from a baseline of 20 events/1000 PY

Confirmatory

(Postmarketing, Stage 2) <1.11611 6000 x 5y

Present Landscape of CVOT in Type 2 DM N~150K, 18 Trials (N~170K, 20 Trials)Name of trial Drug Estimated enrollmentSAVOR TIMI-53* Saxagliptin 18206

CAROLINA Linagliptin 6000

CARMELINA Linagliptin 8300

TECOS Sitagliptin 14000

EXAMINE* Alogliptin 5380

NCT01703208 MK-3102 4000

EXSCEL Exenatide 14000

REWIND Dulaglutide 9622

LEADER Liraglutide 9340

SUSTAIN 6 Semaglutide 3297

ELIXA Lixisenatide 6000

ACE Acarbose 7500

GRAND 306 Fasiglifam 5000

DEVOTE Insulin Degludec 7500

DECLARE TIMI-58 Dapagliflozin 27000

CANVAS Canagliflozin 4335

CANVAS-R Canagliflozin 5700

CREDENCE Canagliflozin 3627

EMPA-REG OUTCOME Empagliflozin 7000

NCT01986881 Ertugliflozin 3900

* Completed trial

Alogliptin vs placebo

Benefit

• HbA1C (-0.36%)- HR 0.96 (-0.88% = HR 0.911)

• Weight loss (+0.06kg)

• BP lowering (neutral) 2

• Lipid profile (neutral) 3

Risk

• CHF signal (RR 1.19)4

1Diabetologia 2009, 2BMJ 2009, 3CTT Meta-analysis, Lancet 2010, 4NEJM 2013

Potential CV Effects of DPP-4 Inhibitors Modeling Projection Based on Intermediate Outcomes

Expected MACE benefit: 0.96 x 1.00 x 1.00 = 0.96

(4% risk reduction in MACE4 vs 19% risk increase in CHF4 )

Saxagliptin vs placebo

Benefit

• HbA1C (-0.20%)- HR 0.98 (-0.88% = HR 0.911)

• Weight loss (-0.50kg)- ? Impact on CV outcomes

• BP lowering (neutral) 2

• Lipid profile (neutral) 3

Risk

• CHF signal (RR 1.27)4

1Diabetologia 2009, 2BMJ 2009, 3CTT Meta-analysis, Lancet 2010, 4NEJM 2013

Potential CV Effects of DPP-4 Inhibitors Modeling Projection Based on Intermediate Outcomes

Expected MACE benefit: 0.98 x 1.00 x 1.00 = 0.98

(0% risk reduction in MACE4 vs 27% risk increase in CHF4 )

SGLT2 inhibitors

Benefit

• Effective glycemic control

(-0.66% HbA1c c/w placebo)

• hypoglycemia (-SU, insulin)

• Weight loss (-1.8Kg)

• BP lowering (-4.5 mmHg)

Risk

• Mycotic genital infection (OR 5.0)

• UTI (OR 1.4)

• Polyuria, nocturia, dysuria

• Volume depletion, thirst, ↑ Hct

• Dyslipidemia (↑ LDL, non-HDL)

SGLT2 Inhibitors for Treatment of Diabetes

Balancing Benefits and Risks

Uncertainty about CV & renal effects, bone health, malignancy

Adapted from Vasilakou et al, Ann Intern Med 2013;159;262-274

GLP-1 agonists

Benefit

• Effective glycemic control

(-0.6-1.0% HbA1c c/w placebo)

• hypoglycemia (-SU)

• Weight loss (-2.9kg)

• BP lowering (-3.6/-1.4mmHg))

• Lipid profile (improved)

Risk

• Heart rate (↑)

• ↑ Hypoglycemia (+SU)

GLP-1 Agonists for Treatment of Diabetes

Balancing Benefits and Risks

Uncertainty about CV effects, pancreatitis, malignancy

Implications for Drug SafetyAs Seen Through Rosi-Colored Glasses

• Life cycle evaluations

Conditional approval contingent on demonstration of efficacy & safety in phase III/IV trials

• Regulatory authority

Empower FDA to “enforce” post-marketing studies, labeling changes, and stringent REMS

• Resource allocation

Increase FDA funding to develop comprehensive post-marketing surveillance

• Registration of clinical trials

• Approvable endpoint

Disease-oriented surrogate endpoint vs. patient-oriented health outcome benefit

• Analytical standards (Diabetes CV Guidance)

Ruling out an unacceptable harm should be driven by clinical relevance >> trial feasibility

Avoiding partial unblinding to preserve data confidentiality and trial integrity

• Determine efficacy validly

• Detect risks prudently

• Do both in a timely and efficient way

Drug Approval ProcessKey Attributes

Is the drug development and approval

process meeting these goals?