Flexible designs for pivotal clinical trials

Vlad Dragalin, RSU-SDS-BDS-GSK

FDA/Industry Workshop

Session: Flexible Designs – Are We Ready Yet?

Washington, D.C., September 14-16, 2005

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Declaimer The views expressed in this presentation are

not necessarily those of PhRMA

The views expressed in this presentation are not necessarily those of GlaxoSmithKline

The views expressed in this presentation are not necessarily my

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Acknowledgment Judith Quinlan for inviting me to work on this trial

GSK Clinical Team for compound SBx for giving me the opportunity to design this trial

Compound SBx

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Outline

Overview of adaptive designs

GSK experience

Details of Design

Points to Consider

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What are Adaptive Designs?

Adaptive Design

• uses accumulating data to decide on how to modify aspects of the study

• without undermining the validity and integrity of the trial

PROTOCOL

AMENDMENTS

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General Structure of Adaptive Designs An adaptive design requires the trial to be conducted in several

stages with access to the accumulated data

An adaptive design may have one or more rules:

Allocation Rule: how subjects will be allocated to available arms Sampling Rule: how many subjects will be sampled at the next stage Stopping Rule: when to stop the trial (for efficacy, for harm, for futility) Decision Rule: the final decision and interim decisions pertaining to

design change not covered by the previous three rules

At any stage, the data may be analyzed and subsequent stages redesigned taking into account all available data

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Adaptive Design Process

DecisionRule

New Patient

SamplingRule

StoppingRule

AllocationRule

Data

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GSK Experience PoC Study in Neuropathic Pain:

Three-stage adaptive design: p-values combination test Allocation Rule: drop the “loser” Stopping Rule for efficacy/futility Sampling Rule: timing of the 2nd/3rd stage depends on data

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Background

Compound SBx lead indication in Psychiatry (anxiety & depression) secondary indications in Neuropathic pain, RLS & FMS

Objectives : To establish superiority of SBx dose(s) versus placebo

Confirm efficacy (and durability of response) 8 week treatment, but expect treatment effect at 2 weeks correlation between early and late treatment effects

Establish safety profile Establish dose-response

Strategic Aim: pivotal quality to potentially support registration

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Study Designs Last thing we want is to get to the end only to discover

no doses are effective OR we missed obtaining a significant result because our original assumptions

were too optimistic

Standard Dose Ranging Design known entity, but lacks flexibility

Adaptive Design Potential savings in terms of both resource and time if there are clear signs

that SBx does not work Allows for addition of more patients to a promising dose

Protects against underestimate of variance Potential to get to decision quicker, e.g. 5 - 9 months Full data package on doses of interest Statistical validity maintained

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Team Concerns Regulatory acceptance as a pivotal quality study

statistical rigor is maintained Thought EU feedback may delay study start up

concerns proving unfounded: design accepted by EMEA CPMP after one F2F meeting

Patients may be enrolled before you can adapt the study performed simulations use electronic data capture

GSK inexperience (e.g. protocol development, electronic data capture) may delay study start

Unequal information on all doses

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Details of the DesignPrimary Endpoint:

Primary Goal:

Target Difference:

STDeviation:

Type I error:

Power:

Traditional Dsgn:

Adaptive Dsgn:

Efficacy Bndry:

Futility Bndry:

Inflation Factor:

PI-NRS change from Baseline at 8thW of treatment

Comparison of three SBx doses (LD, MD, HD) with Plb

1.3 units

2.1 units

= 0.05 (adjustment for multiplicity = 0.05/3 = 0.017)

90%

4 parallel groups - 72 patients/per arm (total 288)

3 stage inverse-normal combination test

O’Brien-Fleming type

nominal levels: (0.0006, 0.014, 0.0235)

nominal levels: (0.5, 0.5)

1.025 - maximum 75 patients/arm

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1 2 3 4 115 6 7 8 9 10 Month

Enrollment Period

1st Stage Data

Plb

MDLD

HD

3rd IA2nd IA1st IA

Randomization

CROCRO

0 8w2w

1st Stage

Decisions:

• Stop arm for futility• 49.5%

• Stop arm for efficacy• 2.9%

• Stop the study for futility• Stop arm(s) for safety • Determine Randomization• Determine timing of 2nd IA(based on 80% Cond. Power)

Timing by 80% CP

GSK GSK Steering Steering

CommitteeCommittee

GSK GSK Steering Steering

CommitteeCommittee

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1 2 3 4 115 6 7 8 9 10 Month

Enrollment Period

1st Stage Data

PlbMDHD

3rd IA2nd IA1st IA

Randomization

CROCRO

0 8w2w

2nd Stage

2nd Stage Data

GSK GSK Steering Steering

CommitteeCommittee

Decisions:

• Stop arm for futility• 13.1%

• Stop arm for efficacy• 47.6%

• Stop the study for futility• Stop arm(s) for safety • Determine Randomization• Determine timing of 3rd IA(based on 80% Cond. Power)

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1 2 3 4 115 6 7 8 9 10 Month

Enrollment Period

1st Stage Data

PlbMD

3rd IA2nd IA1st IA

Randomization

CROCRO

0 8w2w

3rd Stage

2nd Stage Data

GSK GSK Steering Steering

CommitteeCommittee

3rd Stage Data

Final Analysis

• Overall p-value • Estimate of TRT eff.• Confidence Interval

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Interim Analyses: Data

For each armat each stage

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Interim Analyses: Test

Null Hypothesis:

Estimate of mean 8thW endpoint:

Standardized Test Statistics:

Reduced Variance:

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Multiplicity Adjustment Due to interim analyses

O’Brien-Fleming stopping for superiority nominal levels: (0.0006, 0.014, 0.0235)

Stopping for futility nominal levels: (0.5, 0.5)

Due to multiple comparisons Holm procedure at each stage

Due to adaptive design Inverse normal p-value combination rule

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Design PropertiesDifference -0.2 0.0 0.2 0.5 1.0 1.3 1.5

Power 0.001 0.008 0.033 0.171 0.678 0.898 0.936

AvSS 42.7 51.2 59.4 68.4 66.3 56.7 50.5

AvSS 2ndStage

29.9 29.8 29.6 29.0 26.4 23.2 20.7

AvSS 3rdStage

29.9 29.7 29.2 28.0 23.0 18.5 15.4

Pr. Reach2nd Stage

0.368 0.505 0.629 0.796 0.949 0.971 0.967

Pr. Reach3rd Stage

0.224 0.374 0.541 0.728 0.704 0.495 0.359

Difference -0.2 0.0 0.2 0.5 1.0 1.3 1.5

Power 0.001 0.008 0.033 0.171 0.678 0.898 0.936

AvSS 42.7 51.2 59.4 68.4 66.3 56.7 50.5

AvSS 2ndStage

29.9 29.8 29.6 29.0 26.4 23.2 20.7

AvSS 3rdStage

29.9 29.7 29.2 28.0 23.0 18.5 15.4

Pr. Reach2nd Stage

0.368 0.505 0.629 0.796 0.949 0.971 0.967

Pr. Reach3rd Stage

0.224 0.374 0.541 0.728 0.704 0.495 0.359

Parallel 4 arm Dsgn: 72 per arm

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Points to Consider

Logistics issues pertaining to traditional group-sequential designs also pertain to adaptive designs

Establish an IDMC (charter, contracts) for pivotal trials

Have adaptation performed by an independent third party with no conflict of interest issues

During interim adaptation, unblind only data that are necessary to be unblinded

Patient recruitment is not interrupted

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Points to Consider Adaptation entails careful planning at the protocol design stage

Every detail of the statistical design and analysis that can be fixed in advance is described in the study protocol:

number of interim analyses information rates stopping guidelines tests

Depending on the information rates, the interim analysis is scheduled. The time of the IA is unknown to the investigators.

On IA a snapshot of the DB is made (“soft close”). All available data are used for IA.