practical implementation of multi-arm multi-stage trials mahesh parmar director
DESCRIPTION
Practical Implementation of Multi-Arm Multi-Stage Trials Mahesh Parmar Director MRC Clinical Trials Unit. Structure of presentation. MAMS Designs MAMS application in STAMPEDE Issues in implementation Conclusions. MAMS Designs MAMS application in STAMPEDE Issues in implementation - PowerPoint PPT PresentationTRANSCRIPT
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Implementation of MAMS 1 Mahesh Parmar, Feb-2010
Practical Implementation of Multi-Arm Multi-Stage Trials
Mahesh ParmarDirector
MRC Clinical Trials Unit
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Implementation of MAMS 2 Mahesh Parmar, Feb-2010
Structure of presentation
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 3 Mahesh Parmar, Feb-2010
1. MAMS Designs
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 4 Mahesh Parmar, Feb-2010
Why Multi-Arm, Multi-Stage trials?
• More often than not ‘new’ is not better
• Academia 624 NCI sponsored phase III trials (Arch. Int Med, 2008) ~30% of trials ‘statistically significant’ ~40% of trials ‘new’ therapy preferred
• Industry Agents successful at phase I: only 10-20% receive a
marketing authorisation Success rate of phase III trials ~30-40%
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Implementation of MAMS 5 Mahesh Parmar, Feb-2010
Why Multi-Arm, Multi-Stage trials?
• Typical (academic) Phase III trial Hundreds or thousands of patients 5 to 10 years from idea to result Hundreds of research staff Cost millions in development Years of investment from the key players
• High chance of finding new treatment is not superior
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Implementation of MAMS 6 Mahesh Parmar, Feb-2010
Principles of a New Strategy
• Need better mechanism than single arm phase II trial to decide
• Test as many new promising treatments as possible in the same timescale maximise potential for a “positive trial”
• Potential to discontinue unpromising arms quickly and reliably
• Start to randomise as quickly as possible
• Multi-Arm, Multi-Stage (MAMS) trials
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Implementation of MAMS 7 Mahesh Parmar, Feb-2010
Activity (phase II stages)
• Asks the question Are there reasons why we should not continue
testing this treatment?
• Testing for a lack-of-activity Emphasis not testing for activity but for lack-of-
activity or lack-of-sufficient-benefit
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Implementation of MAMS 8 Mahesh Parmar, Feb-2010
Activity phase II stages
• Assume definitive outcome measure is most clinically relevant eg overall survival in cancer trials
• In Activity Stages focus on an earlier outcome measure eg “failure-free survival” (FFS) in cancer trials
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Implementation of MAMS 9 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
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Implementation of MAMS 10 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Stage 1 accrual
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
Intermediate analyses 1
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Implementation of MAMS 11 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
Intermediate analyses 1
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Implementation of MAMS 12 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Intermediate analyses 1
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
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Implementation of MAMS 13 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Intermediate analyses 1
Yes
Yes
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
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Implementation of MAMS 14 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Intermediate analyses 1
Yes
Yes
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
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Implementation of MAMS 15 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Intermediate analyses 1
Yes
Yes
No
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
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Implementation of MAMS 16 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Yes
Yes
No
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
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Implementation of MAMS 17 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
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Implementation of MAMS 18 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
Intermediate analyses 2
Final analyses
Stage 3 accrual
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Implementation of MAMS 19 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
Intermediate analyses 2
Yes
Yes
Stage 3 accrual
Final analyses
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Implementation of MAMS 20 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Final analyses
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
(N/A)
Intermediate analyses 2
Yes
Yes
No
Stage 3 accrual
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Implementation of MAMS 21 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Final analyses
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
(N/A)
Insufficient activity
Intermediate analyses 2
Yes
Yes
No
No
Stage 3 accrual
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Implementation of MAMS 22 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Intermediate analyses 1
Final analyses
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
(N/A)
Insufficient activity
Sufficient activity
Intermediate analyses 2
Yes
Yes
No
No
Yes
Stage 3 accrual
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Implementation of MAMS 23 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Control
Primary analysis
Intermediate analyses 1
Final analyses
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
(N/A)
Insufficient activity
Sufficient activity
Intermediate analyses 2
Yes
Yes
No
No
Yes
Stage 3 accrual
Primary analysis
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Implementation of MAMS 24 Mahesh Parmar, Feb-2010
Multi-Arm, Multi-Stage Trials
R
A
N
D
O
M
I
S
E
Test 1
Test 2
Test 3
Test 4
Con-trol
Eligible patient
Yes
Yes
Yes
Yes
Yes
Stage 1 accrual
Control
Sufficient activity
Insufficient activity
Sufficient activity
Sufficient activity
Control
Primary analysis
Secondary analysis
Secondary analysis
Primary analysis
Intermediate analyses 1
Final analyses
Yes
Yes
No
Yes
Yes
Stage 2 accrual
Control
Sufficient activity
(N/A)
Insufficient activity
Sufficient activity
Intermediate analyses 2
Yes
Yes
No
No
Yes
Stage 3 accrual
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Implementation of MAMS 25 Mahesh Parmar, Feb-2010
Advantages of MAMS
• Fewer patients • Less overall time
Randomised from the start Concurrent (not sequentially) No delay between phase II and phase III Fewer applications for finance and approvals
• one grant application• one protocol• one CTA submission (per country)• one ethics submission (per country)• one R&D approval (per site)
Saves many years!
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Implementation of MAMS 26 Mahesh Parmar, Feb-2010
Advantages of MAMS
• Fewer patients • Less overall time• Increased flexibility• Reduced costs
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Implementation of MAMS 27 Mahesh Parmar, Feb-2010
2. MAMS application in STAMPEDE
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 28 Mahesh Parmar, Feb-2010
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
0-4
5-9
10-1
415-1
920-2
425-2
930-3
435-3
940-4
445-4
950-5
455-5
960-6
465-6
970-7
475-7
980-8
485+
Age at diagnosis
Nu
mb
er
of
case
s
0
200
400
600
800
1,000
Rate
per
10
0,0
00
popu
lati
on
Male cases
Male rates
• Most common male cancer UK diagnosis: 34,000 in 2005
UK deaths: 10,000 in 2006
Global deaths: 250,000 in 2000
• Rising rates of diagnosis Aging population, awareness, PSA
screening
• Modest treatment effect = big impact
Impact
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Implementation of MAMS 29 Mahesh Parmar, Feb-2010
• Urgent need to improve outcomes for men starting hormone therapy with prostate cancer Median survival ~4 years Median failure-free survival ~2 years
• No new therapies improving survival for this group of men for many years
Needs in prostate cancer
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Implementation of MAMS 30 Mahesh Parmar, Feb-2010
Design rationale
• Many interesting agents Different classes and modes of action
• No obvious reason to choose one Many used in later stages of disease Don’t want to choose arbitrarily
• Quicker and efficient to use MAMS design
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Implementation of MAMS 31 Mahesh Parmar, Feb-2010
Trial Design
R
A
N
D
O
M
I
S
E
Androgen suppression (AS)A
AS + zoledronic acidB
AS + docetaxelC
AS + celecoxibD
AS + zoledronic acid + docetaxelE
AS + zoledronic acid + celecoxibF
Control arm
R
A
N
D
O
M
I
S
E
Hormone Therapy (HT)A
HT + zoledronic acidB
HT + docetaxelC
HT + celecoxibD
HT + zoledronic acid + docetaxelE
HT + zoledronic acid + celecoxibF
Control arm
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Implementation of MAMS 32 Mahesh Parmar, Feb-2010
Trial Design Stages
Stage Outcome MeasuresPrimary Secondary
Pilot Safety Feasibility
Activity I-III Failure-free survival Overall survival(phase II) (PSA-driven) Toxicity
Skeletal-related events
Efficacy IV Overall survival Failure-free survival(phase III) Toxicity
Skeletal-related eventsQuality of life
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Implementation of MAMS 33 Mahesh Parmar, Feb-2010
Design Assumptions: for all stages
• Pairwise comparison of each research arm against control
• Hazard ratios for design
•10% improvement in FFS: 50 to 60% at 2 yr
Overall survival
Failure-free survival
Null (H0) 1.00 1.00
Alternative (HA) 0.75 0.75
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Implementation of MAMS 34 Mahesh Parmar, Feb-2010
Significance level and power
StagePrimary Outcome
Significance Level
Power
I FFS 0.50 95%
II FFS 0.25 95%
III FFS 0.10 95%
IV OS 0.025 90%
Overall - 0.013 85%
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STAMPEDE Joint TSC/IDMC Meeting 35 Matt Sydes, 20-July-2009
Cutpoints in STAMPEDE
95% power
95% power
95% power
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Implementation of MAMS 36 Mahesh Parmar, Feb-2010
3. Issues in implementation
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 37 Mahesh Parmar, Feb-2010
Groups to convince – 1
• Medical community Mostly seen by urologists Trial treatments need to be given by oncologists
• Would it appear complex in clinics? Or in MDT meetings?
• Previous multi-arm trials Excellent recruitment to: FOCUS – colorectal cancer – 5 arms ICON5 – ovarian cancer – 5 arms
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Implementation of MAMS 38 Mahesh Parmar, Feb-2010
Groups to convince – 2
• Men with prostate cancer Involved patient groups Two patients on Trial Management Group Very positive opinions Patient involvement has been excellent for trial
• Two-part PIS General information (few pages) – prior to randomisation Arm-specific information
• All before randomisation or• Only relevant one after randomisation (few pages)• Patient choice – as informed as patient would like to be
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Implementation of MAMS 39 Mahesh Parmar, Feb-2010
Groups to convince – 3
• Funding bodies• Regulatory and ethical committees• Hospital governance
• Potential for conservative reviewers No precedent for such approaches
• Approved – after a bit of ‘discussion’
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Implementation of MAMS 40 Mahesh Parmar, Feb-2010
Groups to convince – 4
• Industry partners 3 industry partners in STAMPEDE All keen on design because… Not primarily comparing their drugs head to head Efficient design Early “get-out” if agent not so beneficial
• More companies = more negotiations More contracts More time …
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Implementation of MAMS 41 Mahesh Parmar, Feb-2010
Recruitment
• How many patients are required?• Total N dependent on:
Observed accrual rates Observed event rates
• Do we have the predicted mix of patients? # arms recruiting in each Activity & Efficacy Stage
• Likely 2300 to 3600 patients Over 5.5 to 7.5 years
• Faster recruitment: Requires more patients Takes less time
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Implementation of MAMS 42 Mahesh Parmar, Feb-2010
STAMPEDE Accrual
0
300
600
900
1200
1500
1800
2100
Cum
ulat
ive
rand
omis
atio
ns
Oct
-05
Jan
-06
Jul-
06
Jan
-07
Jul-
07
Jan
-08
Jul-
08
Jan
-09
Jul-
09
Jan
-10
Jul-
10
Jan
-11
Jul-
11
Oct
-11
Date of randomisation
Observed Expected
There are many successful accrual scenarios for recruitment toSTAMPEDE in the Statistical Design Document. One is shown here.
Pilot phase Activity Stage I Activity Stage II
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Implementation of MAMS 43 Mahesh Parmar, Feb-2010
Pilot Phase
• Assessing safety & feasibility Particularly for the combination arms
• Target: 210 patients in 18 months Limited centres
• Completed: Oct-2005 to Spring-2007 On schedule
• IDMC recommended continuing all arms None stopped because of clear safety signals
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Implementation of MAMS 44 Mahesh Parmar, Feb-2010
Stage 1
• Completed ahead of schedule
• IDMC recommended continuation of all arms
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Implementation of MAMS 45 Mahesh Parmar, Feb-2010
Hurdles
1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive6. Vioxx7. Increased number of stages8. Continuity of staff9. Pilot phase
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Implementation of MAMS 46 Mahesh Parmar, Feb-2010
Funding – main grant
• Outline Application to MRC – May 2001 Accept for Full Application Novel design & novel drugs vs conservatism Advised to submit to CTAAC instead New at time – for cancer trials, incl. MRC funds
• Outline Application to CTAAC – November 2001 Accept for Full Application
• Full Application to CTAAC – November 2002 Accepted for partial funding – Feb 2003 Agreements/funding needed from industry partners
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Implementation of MAMS 47 Mahesh Parmar, Feb-2010
Funding – industry partners
• Novartis – zoledronic acid Research grant Free drug Drug distributed to sites
• Sanofi-Aventis – docetaxel Research grant Discounted drug (buy 1, get 2 free) Sites to buy drug & claim back
• Pfizer – celecoxib Free drug Research grant, including distribution costs
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Implementation of MAMS 48 Mahesh Parmar, Feb-2010
Negotiations
• Discussions required in many trials• More difficult if many companies?
Different pace Different contracts Different comments on protocol
• Flagged plans for future discussions International expansion planned All agreements made with UK affiliates
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Implementation of MAMS 49 Mahesh Parmar, Feb-2010
Changes in CTU Personnel
Continuity
3 Project Leads
5 Trial Managers
7 Data Managers
3 Patients/Consumer representatives
3 Statisticians (including the original 2!)
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Implementation of MAMS 50 Mahesh Parmar, Feb-2010
Future hurdles
1. Recruitment rates2. Contracts revisited3. Moving through MAMS stages4. Dropping arms5. Completing recruitment6. Adding arms
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Implementation of MAMS 51 Mahesh Parmar, Feb-2010
5. Issues in intermediate analyses
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 52 Mahesh Parmar, Feb-2010
Moving through stages
• IDMC review interim data Safety and activity data Recommendations to TSC and TMG
• Education & training For all committees Trust in relationships Hypothetical examples
Trials
Unit
Trials
Unit
DMC: Data Monitoring Committee
TSC: Trial Steering
Committee
Participating centres
DMC feedback to TSC & TSC response to DMC
via Trials Unit
DMC feedback to TSC & TSC response to DMC
via Trials Unit
Report from Trials Unit
Question & Feedback
Trial expert panels
Sponsor/ Funder
Report from Trials Unit
Question & Feedback
TMG: Trial Management
Group
TMG: Trial Management
Group
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Implementation of MAMS 53 Mahesh Parmar, Feb-2010
Moving through stages
• Face-to-face meeting between TSC and IDMC
• Discussion of different scenarios
• Agree a lengthy communication plan – including timelines Between IDMC and TSC To Centres To Participants To Regulators Changes in randomisation programme etc…
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Implementation of MAMS 54 Mahesh Parmar, Feb-2010
Dropping arms or agents
• If combination arm stopped for lack of sufficient effect Should “single” agent arm stop too?
• If single agent arm stopped for lack of sufficient effect Should combination arm stop too?
• Training and discussion
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Implementation of MAMS 55 Mahesh Parmar, Feb-2010
Adding new arms
• Could an extra arm be added? Promising agents could be added later! “Rolling trial” or “roundabout design”? Use same approach as for other arms, but delayed
• Implementing in STAMPEDE Considering abiraterone Application to CTAAC (CRUK) approved Company considering proposal
• Design should be appealing to funders and industry Pre-existing network of recruiting sites Saves ~3 years
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Implementation of MAMS 56 Mahesh Parmar, Feb-2010
6. Conclusions
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. Conclusions
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Implementation of MAMS 57 Mahesh Parmar, Feb-2010
Conclusions
• Multi-arm, multi-stage trials are Being done in a number of other cancer types Feasible Efficient Supported by patients, clinicians, funders,
companies
• STAMPEDE Is recruiting well Is running well
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MAMS Trials for GSK 58 Mahesh Parmar, Nov. 2010
References – MAMS trials
• Royston P, Parmar MKB, Qian W Novel Designs for Multi-Arm Clinical Trials with Survival Outcomes, with an Application in Ovarian Cancer. Statistics in Medicine 2003;22: 2239 – 2256.
• Barthel FM-S, Royston P, Parmar MKBA menu-driven facility for sample size calculation in multi-arm, multi-stage randomised controlled trials with a survival-time outcome. The Stata Journal 2007 (submitted)
• Parmar MKBSpeeding up the Evaluation of New Agents in Cancer. J.Natl.Cancer Inst. 100 (17):1204-1214, 2008.
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MAMS Trials for GSK 59 Mahesh Parmar, Nov. 2010
References - STAMPEDE
• Sydes MR, MKB Parmar, ND James et alIssues in applying multi-arm multi-stage (MAMS) methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 10 (39), 2009.
• James ND, Sydes MR, Clarke NW et alSTAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer -- A Multi-Arm Multi-Stage Randomised Controlled Trial. Clinical Oncology 20 (8):577-581, 2008.
• James ND, Sydes MR, Clarke NW et alSystemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU.Int 103 (4):464-469, 2009.
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MAMS Trials for GSK 60 Mahesh Parmar, Nov. 2010
Software and wokshop
• Free software available Design MAMS trials Available from MRC CTU Implemented in Stata
• CTU Workshop in February 2011 Design and analysis of MAMs trials Advanced Issues in Design and Analysis of Trials
with Time to Event Outcomes
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MAMS Trials for GSK 61 Mahesh Parmar, Nov. 2010
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Implementation of MAMS 62 Mahesh Parmar, Feb-2010
Other MAMS trials
• ICON 6 3-arm, 4-stage trial in 2nd line ovarian cancer
using progression-free survival as the intermediate outcome measure
• AML 16 5-arm, 2-stage trial in acute myeloid leukaemia
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Implementation of MAMS 63 Mahesh Parmar, Feb-2010
Conclusions
• MAMS trials are Feasible Efficient Supported by patients, clinicians, companies
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Implementation of MAMS 64 Mahesh Parmar, Feb-2010
Contacts
Matthew Sydes
T +44 (0)20 7670 4798
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Implementation of MAMS 65 Mahesh Parmar, Feb-2010
Extra slides
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Implementation of MAMS 66 Mahesh Parmar, Feb-2010
Trial Initiation 6 trial arms
Pilot PhaseRecruit 210 patients
Recruitment continues to control arm + other
research arms in next stage
Due to safety issues or a lack of feasibility, accrual may stop to one or more research arms
IDMC review
Key IDMC = Independent Data Monitoring Committee
FFS = Failure Free survival
(Total ~210 pts)
Trial Stage - Pilot
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Implementation of MAMS 67 Mahesh Parmar, Feb-2010
Trial Stage - Efficacy Stage I
Efficacy Stage I
Recruit until 113 control arm FFS events (Total ~1200 pts)
IDMC review
Accrual may be stopped in any research arm for safety or lack of efficacy
HR=1.00
Key IDMC = Independent Data Monitoring Committee
FFS = Failure Free survival
Recruitment continues to control arm + other
research arms in next stage
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Implementation of MAMS 68 Mahesh Parmar, Feb-2010
Trial Stage - Efficacy Stage II
Efficacy Stage II
Recruit until 216 control arm FFS events (Total ~1800 pts)
IDMC review
Key IDMC = Independent Data Monitoring Committee
FFS = Failure Free survival
Accrual may be stopped in any research arm for safety or lack of efficacy
HR=0.92Recruitment continues to
control arm + other research arms in next stage
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Implementation of MAMS 69 Mahesh Parmar, Feb-2010
Trial Stage - Efficacy Stage III
Key IDMC = Independent Data Monitoring Committee
FFS = Failure Free survival
Efficacy Stage III
Recruit until 334 control arm FFS events (Total ~2300 pts)
IDMC review
Accrual may be stopped in any research arm for safety or lack of efficacyHR=0.89
Recruitment continues to control arm + other
research arms in next stage
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Implementation of MAMS 70 Mahesh Parmar, Feb-2010
Trial Stage – Efficacy Stage IV
Efficacy Stage IV
Recruit until 405 control arm deaths (Total ~3200 pts)
Main Analyses
(1) Overall survival in arms recruiting in Efficacy Stage IV
(2) Secondary outcome measures in arms recruiting in Efficacy Stage IV
(3) All outcome measures in all 6 arms involved in trial (regardless of
when recruitment stopped)
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Implementation of MAMS 71 Mahesh Parmar, Feb-2010
Statistical Issues
• Pair-wise comparison of each research vs control
• Randomisation ratio (A:B:C:D:E:F) = 2:1:1:1:1:1 Two control arm patients for every research arm patients Efficient for power
• Randomisation centrally Computer based algorithm Minimisation with an additional random element 7 stratification factors for balancing groups
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MAMS Trials for GSK 72 Matt Sydes, Oct-2009
Phase II studies of single agent
Phase II studies of combinations
Phase III trials of combinations
R1
R1
R1C
R2
R2
R2C
R3
R3
R3C
A – Traditional approach
B – MAMS design
Phase II studies of single agent
R1
R2
R3
C R1 R2 R3
MAMS: Phase II/III trial of combinations
Time
Notes
C = control arm; R1 = research arm R1; R2 = Research arm R2; R3 = research arm R3
Assumes that single agent studies would be carried out before combination studies
Assumes that phase II studies require smaller numbers of patients and so smaller number of centres. Therefore, phase II studies of different agents may be carried out concurrently
Assumes that phase III trials require larger numbers of patients and a network of centres that can only run one trial at a time: therefore, phase III trials of different agents must be carried out sequentially
MAMS design rolls phase II assessment of combinations into the same trial as the phase III assessment of effectiveness
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Implementation of MAMS 73 Mahesh Parmar, Feb-2010
Impact of accrual rates
Accrual/Year
Total pts Duration (yrs)
Difference in pts
Difference in length
350 2960 8.5 -451 20 months
500 3411 6.8 0 0
750 4046 5.4 635 -17 months
Assuming: median FFS=24m, median OS=48m, 6 arms recruiting at each stage
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Implementation of MAMS 74 Mahesh Parmar, Feb-2010
Assumptions in STAMPEDE
• Broad eligibility spectrum Patients starting hormone therapy
• Newly metastatic• New & locally advanced• Previously treated & relapsing
Assume more patients are M0 than M1 Failure-free survival (FFS): median = 2 years Overall survival (OS): median = 4 years
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Implementation of MAMS 75 Mahesh Parmar, Feb-2010
Traditional Approach
Phase II
Phase III
A B C
Multi-arm, Multi-stage
A B C
Phase II = 50 pts, Phase III = 600pts
4*50 + 4*300 = 1400
Traditional vs MAMS
50+600=650
+50=700+600=1300
+50=1350+600=1950
Total
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STAMPEDE Joint TSC/IDMC Meeting 76 Matt Sydes, 20-July-2009
Continue Stop
Estimated Treatment Effect (HR)
1.000.75 (Favours experimental) (Favours control)
1-sided 75% CI around 0.92
End of Stage
II if HR >0.92
A+B
B
A
x
x
x
Example
Stop A
Stop A+B
Stop B
Action?
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STAMPEDE Joint TSC/IDMC Meeting 77 Matt Sydes, 20-July-2009
Continue Stop
Estimated Treatment Effect (HR)
1.000.75 (Favours experimental) (Favours control)
1-sided 75% CI around 0.92
End of Stage
II if HR >0.92
A+B
B
A
x
x
x
Example
Action?
Continue A
Continue A+B
Continue B
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STAMPEDE Joint TSC/IDMC Meeting 78 Matt Sydes, 20-July-2009
Continue Stop
Estimated Treatment Effect (HR)
1.000.75 (Favours experimental) (Favours control)
1-sided 75% CI around 0.92
End of Stage
II if HR >0.92
A+B
B
A
x
x
x
Example
Requires exploration and intra-arm comparisons
Stop A
Stop A+B
Continue B
Action?
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STAMPEDE Joint TSC/IDMC Meeting 79 Matt Sydes, 20-July-2009
Continue Stop
Estimated Treatment Effect (HR)
1.000.75 (Favours experimental) (Favours control)
1-sided 75% CI around 0.92
End of Stage
II if HR >0.92
A+B
B
A
x
x
x
Example
Continue A
Continue A+B
Continue B
Action?
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STAMPEDE Joint TSC/IDMC Meeting 80 Matt Sydes, 20-July-2009
Continue Stop
Estimated Treatment Effect (HR)
1.000.75 (Favours experimental) (Favours control)
1-sided 75% CI around 0.92
End of Stage
II if HR >0.92
A+B
B
A
x
x
x
Example
Action?
Continue A
Continue A+B
Continue B
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STAMPEDE Joint TSC/IDMC Meeting 81 Matt Sydes, 20-July-2009
Activity phase II stages
• At any time should be more intermediate events than definitive events
– eg more FFS events than deaths (OS)
• Therefore, more power for intermediate outcome measure at any time
• Design assumes:– To see an effect on OS you have to see an effect on FFS– Just because you see an effect on FFS does not mean that you
will see an effect on OS
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STAMPEDE Joint TSC/IDMC Meeting 82 Matt Sydes, 20-July-2009
Advantages of MAMS
• Fewer patients • Less overall time
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STAMPEDE Joint TSC/IDMC Meeting 83 Matt Sydes, 20-July-2009
Traditional Approach
Phase II
Phase III
A B C
Multi-Arm, Multi-Stage
A B C
Phase II = 50 pts, Phase III = 600pts
4*50 + 4*300 = 1400
Traditional vs MAMS
50+600=650+50=700
+600=1300+50=1350
+600=1950
Total
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STAMPEDE Joint TSC/IDMC Meeting 84 Matt Sydes, 20-July-2009
Traditional Approach
Phase II
Phase III
A B C
Multi-Arm, Multi-Stage
A B C
Phase II = 50 pts, Phase III = 600pts
4*50 + 4*300 = 1400
Traditional vs MAMS
50+600=650+50=700
+600=1300+50=1350
+600=1950
Total
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STAMPEDE Joint TSC/IDMC Meeting 85 Matt Sydes, 20-July-2009
Cutpoints in STAMPEDE
95% power
95% power
95% power
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STAMPEDE Joint TSC/IDMC Meeting 86 Matt Sydes, 20-July-2009
Cutpoints in STAMPEDE
95% power
95% power
95% power
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STAMPEDE Joint TSC/IDMC Meeting 87 Matt Sydes, 20-July-2009
4. General issues in implementation
1. MAMS Designs2. MAMS application in STAMPEDE3. Issues in implementation4. General issues in implementation5. Issues in intermediate analyses6. Conclusions
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STAMPEDE Joint TSC/IDMC Meeting 88 Matt Sydes, 20-July-2009
No intermediate outcome?
• Design depends on the use of an intermediate outcome
• What happens if no such outcome exists?
• Use the primary outcome, earlier in time– Lack-of-benefit analysis useful anyway– Applying this to a number of ongoing trials
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STAMPEDE Joint TSC/IDMC Meeting 89 Matt Sydes, 20-July-2009
How many arms?
• Could be many arms– From 2 to 10 or more
• Consider – Accrual rates– Rationale for inclusion– Adjust randomisation ratio
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STAMPEDE Joint TSC/IDMC Meeting 90 Matt Sydes, 20-July-2009
Arms to compare
• Different drugs– Classes of agent– Combinations of agents
• Same drug– Dose levels– Duration– Initiation time– Method of administration
• Non-drug therapy
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STAMPEDE Joint TSC/IDMC Meeting 91 Matt Sydes, 20-July-2009
Adding new arms
• Could an extra arm be added?– Promising agents could be added later!– “Rolling trial” or “roundabout design”?– Use same rules as for other arms, but delayed
• Exploring in STAMPEDE
• Design should be appealing to industry– Pre-existing network of recruiting sites– GSK?
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STAMPEDE Joint TSC/IDMC Meeting 92 Matt Sydes, 20-July-2009
Stopping for efficacy?
• Stopping rules specified for lack-of-benefit
• No formal stopping rules for efficacy– Early data looking for sufficient evidence of activity to support
continued investment– Could draw in usual conservative early stopping guidelines
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STAMPEDE Joint TSC/IDMC Meeting 93 Matt Sydes, 20-July-2009
STAMPEDE TMG
Current TMG members
Nick James Karen Sanders
Noel Clarke Rachel Morgan
David Dearnaley Richard Gracie
Max Parmar Jim Stansfeld
Matt Sydes John Dwyer
Malcolm Mason
John Anderson
Rick Popert
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STAMPEDE Joint TSC/IDMC Meeting 94 Matt Sydes, 20-July-2009
How long to get here?
• Oct 2000 = first discussion• Nov 2000 = first formal meeting• Oct 2005 = first patient randomised
• Why so long?– Some issues of design ie MAMS-specific issues– Some issues of collaboration– Some issues beyond control
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STAMPEDE Joint TSC/IDMC Meeting 95 Matt Sydes, 20-July-2009
Hurdles
1. Funding
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STAMPEDE Joint TSC/IDMC Meeting 96 Matt Sydes, 20-July-2009
Hurdles
1. Funding2. Finalising choice of drug
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STAMPEDE Joint TSC/IDMC Meeting 97 Matt Sydes, 20-July-2009
Changes in drugs
1st mtg = Nov 2000 1st appln = May 2001
Hormone therapy Hormone therapy
Mitoxantrone (MTZ) MTZ+pred
Docetaxel Docetaxel + pred
Prednisolone -
Stilboestrol Stilboestrol + aspirin
Estramustine Estramustine + aspirin
?Bisphosphonates (factorial) ?Bisphosphonates
?Herceptin -
?ECF -
?Strontium -
?Epirubicin -
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STAMPEDE Joint TSC/IDMC Meeting 98 Matt Sydes, 20-July-2009
Changes in drugs
1st appln = May 2001 2nd appln = ???
Hormone therapy Hormone therapy
MTZ+pred MTZ+pred OR
Docetaxel + pred Docetaxel + pred
Stilboestrol + aspirin Stilboestrol + aspirin OR
Estramustine + aspirin Estramustine + aspirin
?Bisphosphonates ?Bisphosphonates
?Iressa
?Atrasentan
?Celecoxib
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STAMPEDE Joint TSC/IDMC Meeting 99 Matt Sydes, 20-July-2009
Changes in drugs
2nd appln = ??? Final appln = Nov 2002
Hormone therapy Hormone therapy
MTZ+pred OR -
Docetaxel + pred Docetaxel + pred
Stilboestrol + aspirin OR -
Estramustine + aspirin
?Bisphosphonates Zoledronic acid
?Iressa -
?Atrasentan -
?Celecoxib Celecoxib
Docetaxel + zoledronic acid
Celecoxib + zoledronic acid
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STAMPEDE Joint TSC/IDMC Meeting 100 Matt Sydes, 20-July-2009
Change in population
• Originally new M1 only• Expand to new M1 + new M0• Expand to new M1 + new M0 + relapsing
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STAMPEDE Joint TSC/IDMC Meeting 101 Matt Sydes, 20-July-2009
Hurdles
1. Funding2. Finalising choice of drug3. Discussions with pharma
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STAMPEDE Joint TSC/IDMC Meeting 102 Matt Sydes, 20-July-2009
Hurdles
1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive
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STAMPEDE Joint TSC/IDMC Meeting 103 Matt Sydes, 20-July-2009
EU Clinical Trials Directive
• May 2004• Many uncertainties over sponsorship• Application for regulatory approval
– Put in before new system to get CTA-rollover– Easier in old system?– Less easy not for old system trials
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STAMPEDE Joint TSC/IDMC Meeting 104 Matt Sydes, 20-July-2009
Hurdles
1. Funding2. Finalising choice of drug3. Discussions with pharma4. Funding (revisited)5. EU Clinical Trials Directive6. Increased number of MAMS stages
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STAMPEDE Joint TSC/IDMC Meeting 105 Matt Sydes, 20-July-2009
Increased stages
• Planned as two-stage trial (plus Pilot)• IDMC to meet annually• Therefore, plan more interim hurdles• Increased from 2 to 4 stages
– Required new program– -stage2- to -stagen-– Revise protocol
• Revised again in Summer 2007– -stagen- to -nstage-– Small decrease in number of required events
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STAMPEDE Joint TSC/IDMC Meeting 106 Matt Sydes, 20-July-2009
Changes in trial personnel
Name Involvement
Nick James TMG (CI)
Noel Clarke TMG
David Dearnaley TMG
Max Parmar TMG
Matt Sydes TMG
Sarah Meredith Moved on
Sharon Naylor Moved on
David Kirk Retired (TSC)
Clare Moynihan Moved on
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STAMPEDE Joint TSC/IDMC Meeting 107 Matt Sydes, 20-July-2009
1. Recruitment rates
Accrual/Year
Total pts Duration (yrs)
Difference in pts
Difference in length
350 2960 8.5 -451 20 months
500 3411 6.8 0 0
750 4046 5.4 635 -17 months
Assuming: median FFS=24m, median OS=48m, 6 arms recruiting at each stage
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STAMPEDE Joint TSC/IDMC Meeting 108 Matt Sydes, 20-July-2009
Key points – 1
• For many diseases we have many potential new treatments
• Majority are likely to prove no more effective than control
• We need to change the question we ask– How do we improve outcomes as rapidly as possible for this
disease?
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STAMPEDE Joint TSC/IDMC Meeting 109 Matt Sydes, 20-July-2009
Key points – 2
• Intermediate outcome can be very helpful– Need not be true surrogate– Often assume larger effect size on intermediate outcome
• MAMS trials speed evaluation of new treatments by testing many treatments at the same time and using lack of benefit analyses