Transcript 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

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
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
2
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
3
Outline
 Overview of adaptive designs
 GSK experience
 Details of Design
 Points to Consider
4
What are Adaptive Designs?
Adaptive Design
PROTOCOL
•
uses accumulating data to
decide on how to modify
aspects of the study
•
without undermining the
validity and integrity of the
trial
AMENDMENTS
5
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
6
Adaptive Design Process
Decision
Rule
Sampling
Rule
New
Patient
Data
Stopping
Rule
Allocation
Rule
7
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
8
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
9
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

10
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
11
Details of the Design
Primary Endpoint: PI-NRS change from Baseline at 8thW of treatment
Primary Goal: Comparison of three SBx doses (LD, MD, HD) with Plb
Target Difference: 1.3 units
STDeviation: 2.1 units
Type I error: a = 0.05 (adjustment for multiplicity a = 0.05/3 = 0.017)
Power: 90%
Traditional Dsgn: 4 parallel groups - 72 patients/per arm (total 288)
Adaptive Dsgn: 3 stage inverse-normal combination test
Efficacy Bndry: O’Brien-Fleming type
nominal levels: (0.0006, 0.014, 0.0235)
Futility Bndry: nominal levels: (0.5, 0.5)
Inflation Factor: 1.025 - maximum 75 patients/arm
12
CRO
1st Stage
GSK
Steering
Committee
Randomization
0
8w
2w
HD
MD
LD
Plb
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)
1st Stage Data
Timing by
80% CP
1st IA
1
2
3
4
5
2nd IA
6
7
8
3rd IA
9
10
11
Month
Enrollment Period
13
CRO
2nd Stage
GSK
Steering
Committee
Randomization
0
8w
2w
HD
MD
Plb
Decisions:
2nd Stage Data
• 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)
1st Stage Data
1st IA
1
2
3
4
5
2nd IA
6
7
8
3rd IA
9
10
11
Month
Enrollment Period
14
CRO
3rd Stage
GSK
Steering
Committee
Randomization
0
8w
2w
MD
Plb
2nd Stage Data
Final Analysis
• Overall p-value
3rd Stage Data • Estimate of TRT eff.
• Confidence Interval
1st Stage Data
1st IA
1
2
3
4
5
2nd IA
6
7
8
3rd IA
9
10
11
Month
Enrollment Period
15
Interim Analyses: Data
For each arm
at each stage
16
Interim Analyses: Test
Null Hypothesis:
Estimate of mean
8thW endpoint:
Reduced Variance:
Standardized Test
Statistics:
17
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
18
Design Properties
-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 2nd
Stage
29.9
29.8
29.6
29.0
26.4
23.2
20.7
AvSS 3rd
Stage
29.9
29.7
29.2
28.0
23.0
18.5
15.4
Pr. Reach
2nd Stage
0.368
0.505
0.629
0.796
0.949
0.971
0.967
Pr. Reach
3rd Stage
0.224
0.374
0.541
0.728
0.704
0.495
0.359
Difference
Parallel 4 arm Dsgn: 72 per arm
19
Points to Consider
 Logistics issues pertaining to traditional groupsequential 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
20
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.
21