Adaptive Designs to Demonstrate Risk Reduction in Cardiovascular Outcome Trials

A Case Study of the EXAMINE Trial

Cyrus Mehta Ph.D. and Lingyun Liu Ph.DCytel Inc., Cambridge MA

FDA and Industry: September 23, 2014 2

• Multicenter randomized double blind placebo controlled study of Alogliptin a DPP4 inhibitor

• Designed to rule out excess risk of CV outcomes in very high risk T2DM patients

• Primary Endpoint: composite of first occurrence of CV death, MI or stroke (MACE)

• FDA Guidance: estimate upper bound of 95% RCI for the hazard ratio of Alogliptin/Placebo• if < 1.8: submit pre-marketing NDA for alogliptin• if < 1.3: CV safety demonstrated

The EXAMINE Trial

FDA and Industry: September 23, 2014 3

EXAMINE: Group Sequential Design

1.8

1.3

1

80 100 125 150

550 650

550 650

• O’Brien-Fleming spending function

• Sample size: 5400

• Events: 150 for 1.8 and 650 for 1.3

• Enrolment 2 years

• Trial duration 4.25 years

• 94% power for 1.8 for true HR=1

• 91% power for 1.3 for true HR=1

Only 53% power to claim superiority if true HR=0.85

FDA and Industry: September 23, 2014 4

EXAMINE: Study Results

Non-

inferiority HR 1.8

Non-

inferiority HR 1.3

Superior

ity HR 1

83 100 125 150

550 650

550 650

• Total enroll: 5383

• IA1: 83 events• Upper bound of RCI: 1.51• Submitted NDA

• IA2: 550 events• HR: 0.96• Upper bound RCI: 1.17• Stopped to claim non-inferiority

• White et. al. published in NEJM

Trial could have continued to 650 events in hopes of showing superiorityWhy stop at 550 and accept a non-inferiority claim?

FDA and Industry: September 23, 2014 5

Trial was underpowered for Superiority

Hazard Ratio 80% Power 90% Power

Events Sample Size Events Sample Size

0.8 631 5253 845 70340.85 1189 9644 1592 12913

0.9 2829 22377 3787 29954

0.95 11933 92116 15975 123317

Deterrents to an up-front superiority design• Don’t know what HR to target• HR = 0.8 unlikely• HR > 0.85 leads to very large trial with high risk of failure

Sample size requirements for a trial powered to show superiority(assumes 2 years accrual and 3 additional years of follow-up)

FDA and Industry: September 23, 2014 6

• SAVOR-TIMI Trial (NEJM 2013)• Designed up front for superiority• Planned for 1040 events and 16,500 patients• 85% power to detect HR=0.83• O’Brien-Fleming boundary at 50% information

• After enrolling 16,492 patients with 2.1 years median follow-up and 1222 MACE events, the trial failed to show superiority

• Could have designed a smarter trial!

The Risks of Powering Up-Front for Superiority

FDA and Industry: September 23, 2014 7

• Power for non-inferiority with 650 events and 5400 patients

• At interim analysis (IA-550), re-power for superiority by increasing the number of events and sample size provided:1. NI criterion is met (RCI bound < 1.3)2. CP(Sup) is in a “promising zone”

Less risky to allow switching from NI to Superiority objective at interim analysis

FDA and Industry: September 23, 2014 8

Decision Rules at Interim Analysis

IA at 550 events

NI criterion met (RCI <1.3)

Compute CP(Sup)

CP(Sup) < 20%

Terminate and claim NI

CP(Sup) ≥20%

Switch to Adaptive Design

NI criterion not met

Final Analysis at 650

Test for NI and Sup

FDA and Industry: September 23, 2014 9

The Path to an Adaptive Switch

IA at 550 events

NI criterion met (RCI <1.3)

Compute CP(Sup)

CP(Sup) < 20%

Terminate and claim NI

CP(Sup) ≥20%

Switch to Adaptive Design

NI criterion not met

Final Analysis at 650

Test for NI and Sup

FDA and Industry: September 23, 2014 10

Switch to Adaptive Design

Unfavorable Zone 20%<CP(Sup)<50%

Go to 650 events

Promising Zone50%≤CP(Sup)<90%

Increase events to 1300Incr sample size to 10,800

Go to 650 events

Criteria for adaptive increase of events and sample size

FDA and Industry: September 23, 2014 11

Zones for Decision Making to Claim Superiority after NI Boundary is Crossed

Stop and claim NI: CP(sup)<20%

Unfavorable Zone: 20% ≤CP(sup)<50%Carry on with no change

Promising Zone: 50% <CP(sup)≤90%Double the events and sample size

Favorable Zone: CP(sup)>90%Carry on with no change

FDA and Industry: September 23, 2014 12

• Since promising zone starts at 50% conditional power, no special adjustment needed for the adaptive increase in events (Chen, DeMets and Lan, 2004)

• Thus one can use the classical RCI for a group sequential superiority trial

where D is the number of MACE events at the final analysis (here 650)

No adjustment necessary for adaptation

Dα 2

ln(HR) c

FDA and Industry: September 23, 2014 13

Results: If IA-550 is in Promising Zone

0.8 0.85 0.9 0.95 10

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Hazard Ratio

Pow

er

FDA and Industry: September 23, 2014 14

Operating Characteristics if HR=0.85

• NI claim is assured• Sup claim has good prospects too

• 40% chance at IA with 550 events• 0.12x0.37= 4% chance at 650 events (no adaptation)• 0.11*0.96=11% chance at 1300 events (adaptation)

• If adaptation occurs, 96% chance of showing Sup

FDA and Industry: September 23, 2014 15

Operating Characteristics if HR=1

• NI claim has at least 90% power (per design) with 76% chance of early stop• Very little (<2%) chance of showing superiority• Only 2% chance of expanding the trial by doubling sample size and events

FDA and Industry: September 23, 2014 16

• All design details are included in DMC charter• DMC buys into design at the kick-off meeting, but

reserves right to exercise clinical judgment• Although the trial is expanded only if the IA at 550

events shows promise of superiority:• Actual interim decision should only be conveyed on

need to know basis (to drug supply and IVRS teams)• Investigators may be told only that this adaptive design

has a maximum sample size of 13,000 patients and possibility of showing superiority

• Double blind design also important to avoid bias

Operational Considerations

FDA and Industry: September 23, 2014 17

• No anti-glycemic agent has shown protection to CV risk

• Huge up-side to being the first on the market• Traditional superiority design requires:

• large up-front commitment of resources• considerable optimism about underlying HR

• SAVOR-TIMI example underscores the risks• Start with modest expectations and expand

only if interim results are promising

Concluding Remarks