Biomarker-Based Bayesian Adaptive Designs for Targeted ... · Adaptive Designs for Targeted Agent...
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Biomarker-Based Bayesian
Adaptive Designs for Targeted
Agent Development –
Implementation and Lessons
Learned from the BATTLE TrialJ. Jack Lee, Suyu Liu, Nan Chen
Department of Biostatistics
University of Texas
M. D. Anderson Cancer Center
PremiseMany new targeted agents and many more potential
combination therapies.
Unfortunately, success rate for oncology drug
development is very low.
Targeted agents do not work for all patients.
Are there markers to guide the choice of treatments?
How to treat patients best in the trial?
How to gauge the treatment effect?
– response rate, disease stabilization, improved survival
Limited patient population enrolled in clinical trials
Time is of the essence.
How to best identify markers, gauge treatment
efficacy, and treat patients in a clinical trial?
Phase I Phase II Phase III
Traditional Drug Development
I
I
II
I
II
II
II
III
III
One dose, Schedule
A few doses/schedules
Multiple doses/schedules
Traditional Drug Development
Traditional Drug Development
Biomarkers - Evolution of Knowledge in NSCLC
Pao and Girard, Lancet Oncology 2010
How to Test Treatment Effect, Marker Effect, and
their Combined Effect (Interaction)?
crizotinib
erlotinib
trastuzumab
FTI ?
PLX4032?
?
?
?
?
Tier 1 evidence: Assign pts to treatments – single arm confirmation trials?
Tier 2 evidence: Randomized trials?
Tier 3 evidence: Single arm screening trials? Randomized screening trials?
Randomized Phase II Trial for Testing 5-Gene
Signature of Paclitaxel Sensitivity in Breast Cancer
Ito et al., Cancer Science 2011
Est. Path RR: 30% 80%
Actual Path RR: 21% 36%
(N=11)(N=56) (N=19)
Lesson:
We think we know but often we really don’t –
Need clinical trials to confirm or refute the hypothesis.
Goals for Biomarker-Based Adaptive Designs
Identify prognostic and predictive markers for targeted agents– Prognostic markers
markers that associate with the disease outcome regardless of the treatment: e.g., stage, performance status
– Predictive markers
markers which predict differential treatment efficacy in different marker groups: e.g., In Marker (-), tx does not work
but in Marker (+), tx works
Test treatment efficacy– Control type I and II error rates
– Maximize study power for testing the effectiveness between treatments
– Group ethics
Provide better treatment to patients enrolled in the trial– Assign patients into the better treatment arms with higher probabilities
– Maximize total number of successes in the trial
– Individual ethics
BATTLE (Biomarker-based
Approaches of Targeted Therapy
for Lung Cancer Elimination)Patient Population: Stage IV recurrent non-small cell lung cancer (NSCLC)
Primary Endpoint: 8-week disease control rate (DCR)
4 Targeted treatments, 11 Biomarkers
200 evaluable patients
Goal:– Test treatment efficacy
– Test biomarker effect and their predictive roles to treatment
– Treat patients better in the trial based on their biomarkers 1. Zhou X, Liu S, Kim ES, Lee JJ. Bayesian adaptive design for targeted therapy development in lung cancer - A step toward personalized medicine (Clin Trials, 2008).
2. Kim ES, Herbst RS, Wistuba II, Lee JJ, et al, Hong WK. The BATTLE Trial: Personalizing Therapy for Lung Cancer. (Cancer Discovery, 2011)
Biomarker Groups by Molecular Pathway
• EGFR marker group• Mutation
• Gene copy number, high polysomy/ amplification
5 Marker Groups
Based on 2005 data
Hierarchial-based
1
• KRAS/BRAF marker group
• Mutations (KRAS and BRAF)2
• VEGF marker group
• VEGF expression
• VEGFR-2
3
• RXR/Cyclin D1 marker group
• RXR , ,
• Cyclin D1 exp/amp
4
Inadequate tissue/ no markers
present
5
EGFR
Mutation - Sequencing
Copy Number - FISH
High Polysomy Amplification
Deletion 746E-750A
CTG858CGG (L858R) CTG858 Wild-Type
Exon 21
Exon 19
KRAS/BRAF
KRAS Mutation - Sequencing
BRAF Mutation - Sequencing
TCG446TTG (S446L)TCG446 Wild-Type
GGT12TGT(G12C) GGT12CGT(G12R)
Exon 11
Codon 12
Biomarker analysis performed in
Thoracic Molecular Pathology Research Lab
VEGF/VEGFR-2
VEGF - IHC
VEGFR-2 - IHC
RXR/Cyclin D1
Cyclin D1 - IHC
CCND1 - FISH
RXRs - IHC
Amplification
RXR
RXR
RXR
Summary of Marker Group Assignment and
Treatment Randomization
• Randomized open-label phase II
• 250 patient enrollment
• Initial “equal” followed by “adaptive” randomization
• Novel clinical design
EGFR KRAS VEGFRXR/
CycD1None Total
Erlotinib
Vandetanib
Erlotinib+
Bexarotene
Sorafenib
Total
Tre
atm
en
ts
Marker Groups
5 marker groups
Marker Group assignment was based on:
1. Results of the individual biomarkers
2. Higher ranking biomarker took precedence
4 treatments
Treatment assignment was based on:
1. Equal randomization initially
2. Adaptive randomization based on marker group and
posterior probability
BATTLE Schema
Erlotinib SorafenibVandetanib Erlotinib + Bexarotene
Randomization:
Equal Adaptive
Primary end point: 8 week Disease Control (DC)
Umbrella Protocol
EGFR KRAS/BRAF
VEGF RXR/CyclinD1
Core BiopsyBiomarker
Profile
Bayesian Hierarchical Probit Model
1 if 0
0 otherwise
Pr( 1) Pr( 0)
ijk
ijk
jk ijk ijk
zy
y z
2
2
~ ( , 1), for 1,...,
~ ( , ), for 1,...,5
~ (0, ), for 1,...,4
ijk jk jk
jk j
j
z N i n
N k
N j
• Notation
-- ith : subject, i=1 , ..., njk
-- jth : treatment arm, j=1 , …, 4
-- kth : marker group, k=1 , …, 5
-- yijk: 8-week progression-free survival status: 0(no) vs 1(yes)
-- zijk : latent variable
-- jk : location parameter
-- j : hyper-prior on jk
-- jk : disease control rate (DCR)
-- 2,2 : hyper-parameters control borrowing across MGs
within and between treatments
• Probit model with hyper prior (Albert et al, 1993)
ER is applied in the first stage for model developmentAR will be applied after enrolling at least one patient in each (Treatment x MG) subgroup.Adaptively assign the next patient into the treatment arms proportional to the marginal posterior disease control rates.
set a minimum RR to 10% to ensuring a reasonable probability of randomizing pts in each arm
Suspend randomization of a treatment in a biomarker group if – Probability(DCR > 0.5 | Data) < 10%
Declare a treatment is effective in a biomarker group if – Probability(DCR > 0.3 | Data) > 80%
ˆ ˆ/ ( )jk wk
w
Equal Randomization (ER) Followed By
Adaptive Randomization (AR)
Adaptive Randomization (AR) vs.
Equal Randomization (ER)Consider two treatments, binary outcome
First n pts equally randomized (ER) into TX1 and TX2
After ER phase, the next patient will be assigned to
TX1 with probability , where
1 1 2 2
1 1 2 2 2 1
ˆ ˆ, or
Pr( ), Pr( )
B p B p
B p p B p p
1 1 2/( )B B B
Note that the tuning parameter
– = 0, ER
– = , “play the winner”
Continue the study until reaching early stopping
criteria or maximum N
1 1 2ˆ ˆ ˆ/( )p p pAR rate to TX 1=
Demo 1
Adaptive vs. Fixed Randomization
Korn and Freidlin (JCO 2011)
– Compare AR versus FR in two-arm trials using simulations.
– AR has no benefits over FR if accrual rate is the same.
– If using AR can increase the accrual rate, use a fixed 1:2
randomization in favor of the experimental arm.
Berry (JCO 2011)
– I agree with their calculations, but not with their conclusion.
– Greatest potential for adaptive randomization is in multi-
armed Trials.
– Adaptive designs promise shorter cancer drug development
and better identification of responding patient populations.
– Adaptive trials have disadvantages that must be considered
along with the potential advantages.
Number of Non-RespondersTrue
Response
Rate
FR 1:1
[N=132]
FR 1:2
[N=153]
AR
[N=140]
Cntl Exp
0.2 0.05 115.5 137.7 118.7
0.2 0.1 112.2 132.6 117.3
0.2 0.2 105.6 122.4 112.0
0.2 0.3 99.0 112.2 103.5
0.2 0.4 92.4 102.0 92.9
0.2 0.5 85.8 91.8 81.1
0.2 0.6 79.2 81.6 68.9
0.2 0.7 72.6 71.4 56.5
0.2 0.8 66.0 61.2 44.0
0.2 0.9 59.4 61.0 31.4
AR: Randomization probability bounded at 0.9.
Percent of RespondersTrue
Response
Rate
FR 1:1
[N=140]
AR
[N=140]
FR 1:1
[N=153]
FR 1:2
[N=153]
AR
[N=153]
Cntl Exp
0.2 0.05 12.9 15.2 13.5 10.0 15.6
0.2 0.1 15.3 16.2 15.7 13.3 16.5
0.2 0.2 20.0 20.0 20.0 20.0 20.0
0.2 0.3 25.0 26.0 25.0 26.6 25.9
0.2 0.4 30.5 33.7 31.1 33.3 34.1
0.2 0.5 35.8 42.1 37.0 40.0 42.7
0.2 0.6 41.1 50.8 42.7 46.6 51.6
0.2 0.7 46.4 59.6 48.4 53.3 60.5
0.2 0.8 51.7 68.6 54.1 60.0 69.6
0.2 0.9 57.0 77.2 59.8 66.6 78.3
AR: Randomization probability bounded at 0.9.
Three-Arm Trials: FR versus ARTrue Response
Rate
Fixed Ratio Randomization
(1:1:1)
Adaptive Randomization
[Bound 0.9]
CntlExp
1
Exp
2
Pr(resp)
%
[N=171]
# of Non-
Responders
[N=171]
Rejection
Rate
[N=171]
Pr(resp)
%
[N=183]
Pr(resp)
%
[N=183]
# of Non-
Responders
[N=183]
% on
Control
[N=183]
% on
Exp1
[N=183]
% on
Exp2
[N=183]
Rejection
Rate
[N=183]
0.2 0.05 0.05 10.0 153.9 0 10.7 11.6 161.8 43.7 28.1 28.2 0
0.2 0.1 0.1 13.3 148.2 0 13.8 14.0 157.4 39.6 30.2 30.2 0
0.2 0.2 0.2 20.0 136.8 0.10 20.0 20.0 146.4 33.3 33.3 33.3 0.10
0.2 0.3 0.3 26.7 125.4 0.52 26.6 27.2 133.2 27.8 36.1 36.1 0.53
0.2 0.4 0.4 33.3 114.0 0.90 33.6 35.4 118.3 23.2 38.4 38.4 0.90
0.2 0.5 0.5 40.0 102.6 0.99 40.6 44.0 102.5 19.9 40.0 40.0 0.99
0.2 0.6 0.6 46.7 91.2 1.00 47.5 52.9 86.3 18.0 41.0 41.0 0.99
0.2 0.7 0.7 53.3 79.8 1.00 54.4 61.7 70.0 16.5 41.7 41.7 1.00
0.2 0.8 0.8 60.0 68.4 1.00 61.3 70.7 53.6 15.5 42.2 42.2 1.00
0.2 0.9 0.9 66.7 57.0 1.00 68.2 79.7 37.1 14.7 42.6 42.6 1.00
0.2 0.3 0.5 33.3 114.0 0.97 34.4 36.3 116.5 23.8 32.7 43.5 0.98
0.2 0.4 0.6 40.0 102.6 0.99 41.3 44.7 101.1 20.3 35.7 44.0 0.99
0.2 0.4 0.8 46.7 91.2 1.00 48.9 56.0 80.6 18.5 32.3 49.2 1.00
0.2 0.1 0.6 30.0 119.7 1.00 32.0 38.6 112.2 28.3 20.0 51.7 1.00
0.2 0.2 0.4 26.7 125.4 0.78 27.3 28.5 130.8 28.7 28.7 42.6 0.83
0.2 0.2 0.6 33.3 114.0 0.99 35.1 39.9 110.0 25.2 25.2 49.6 1.00
0.2 0.2 0.8 40.0 102.6 1.00 42.6 53.7 84.8 21.9 21.9 56.2 1.00
Allocation % on Exp. Arm vs. # of
Patients Accrued, No Early Stopping
0 50 100 150
2040
6080
100
Number of Patients Accrued
Allo
catio
n R
ate
on E
xp.
Tre
atm
ent
(%)
AR
ER
P1 = 0.2
P2 = 0.4
Allocation % on Exp. Arm vs. # of
Patients Accrued, With Early Stopping
0 50 100 150 200 250
2040
6080
100
Number of Patients Accrued
Allo
catio
n R
ate
on E
xp.
Tre
atm
ent
(%)
AR
ER
P1=0.2
P2=0.4
Simulation – Scenario 1
One effective treatment for MG 1-4, no effective treatment
for MG 5, adaptive randomization (AR), with vague
prior
MG 1 MG 2 MG 3 MG 4 MG 5
TX 1 0.8 0.3 0.3 0.3 0.3
TX 2 0.3 0.6 0.3 0.3 0.3
TX 3 0.3 0.3 0.6 0.3 0.3
TX 4 0.3 0.3 0.3 0.6 0.3
Simulation Results, Scenario 1
(with early stopping)
Conventional Design
Simon’s optimal two-stage design in each of the 4 x 5 = 20 trt x MG combinations
H0: p p0 vs. H1: p p1
p0 = 0.3, p1 = 0.5, = 0.20, 1- = 0.80
n1 = 6, r1 = 1, n = 20, r = 7,
Total N up to 20 x 20 = 400
MG 1 MG 2 MG 3 MG 4 MG 5
Erlotinib
Sorafenib
Vandetanib
Erlotinib +
Bexarotene
Registration
Biomarker
Information
(Determine
MarkerGroup)
Evaluate at
8 Week
And determine
Response
Adaptive
Randomization
Assign
Treatment
Clinical Visits
Patient
Follow Up
Visits
Off Study
InformationBiopsy
Two Weeks Eight Weeks
Schematic Diagram to run the web based
“BATTLE” application
Report
s
Medical History
Physical Exams
Lab Tests
Diagnostic
Procedures
Drug
Compliance
Concomitant
Medications
Adverse
Events
Sample
Collection
Tumor
Measurements
Adaptive
Randomization
(R Code, Web Svc)
Web
Inte
rface
SQL 2005 DatabaseCORe
Menu
Randomization ProcessPatient Consented and
Registered in Database
Information sent to
Surgical Team for biopsy
Biopsy sent to Thoracic
Molecular Path Lab
Randomization of
Patient to Trial
Biomarker results entered
into database
Research Nurse Notified
Automatically
Patient Consented to
Appropriate Trial
Randomize
BATTLE Timeline and Accrual
• Patients Enrolled 341
• Randomized 255
• Evaluable 244
Late 2004: Grant Planned
Mid 2005: Grant Submitted
April 2006: Grant Approved
Nov 2006: Trials Activated- 1st pt
Oct 2009: Trials completed accrual!
2004 2005 2006 2007 2008 20092007 2009
Accrual
0
50
100
150
200
250
300
350
1 4 7 10 13 16 19 22 25 28 31 34
Est. reg
Est. rand
Cum. reg
Cum. rand
Study Accrual and Randomization
Time (months)
Pati
en
ts E
nro
lled
341
255
BATTLE Accrual Summary
Trial activation: November 2006
Last patient enrolled: October 2009
Total patients registered 341
Total patients randomized 255
Total patients with 8-wk DC status 244
Patients equally randomized 95 (39%)
Patients adaptively randomized 149 (61%)
Patients with complete markers 203 (83%)
Patients w/o complete markers 41 (17%)
Registration and Randomization of
Patients
Total RegisteredN = 341
Total Randomized (N = 255)Equal Randomization (N = 97, 38%)
Adaptive Randomization (N = 158, 62%)
ErlotinibEqual (N = 25)
Adaptive (N = 33)
VandetanibEqual (N = 23)
Adaptive (N = 29)
Erlotinib+ BexaroteneEqual (N = 21)
Adaptive (N = 15)
SorafenibEqual (N = 26)
Adaptive (N = 72)
Reasons not randomized (N = 86)-Concurrent illness/Poor PS (N = 51)
-Not biopsied/other (N = 21)
-Alternate or No Tx (N = 14)
Demo 2
37
BATTLE Results: Disease Control in % (n)
EGFR KRAS VEGFRXR/
CycD1None Total
Erlotinib 35% (17) 14% (7) 40% (25) 0% (1) 38% (8) 34% (58)
Vandetanib 41% (27) 0% (3) 38% (16) NA (0) 0% (6) 33% (52)
Erlotinib +
Bexarotene55% (20) 33% (3) 0% (3) 100% (1) 56% (9) 50% (36)
Sorafenib 39% (23) 79% (14) 64% (39) 25% (4) 61% (18) 58% (98)
Total 43% (87) 48% (27) 49% (83) 33% (6) 46% (41) 46% (244)
Tre
atm
en
ts
Marker Groups
AACR Presentation: http://app2.capitalreach.com/esp1204/servlet/tc?cn=aacr&c=10165&s=20435&e=12587&&m=1&br=80&audio=false
Posterior Probabilities for DCRs
BATTLE Results: Disease Control %
[Probability(DCR > 30%) > 0.8]
EGFR KRAS VEGFRXR/
CycD1None Total
Erlotinib35%
[0.66]
14%
[0.14]
40%
[0.85]0%
38%
[0.67]34%
Vandetanib41%
[0.92]
0%
[0]
38%
[0.75]NA
0%
[0]33%
Erlotinib +
Bexarotene
55%
[0.99]
33%
[0.54]
0%
[0]100%
56%
[0.92]50%
Sorafenib39%
[0.76]
79%
[1.00]
64%
[1.00]25%
61%
[1.00]58%
Total 43% 48% 49% 33% 46% 46%
Tre
atm
ents
Marker Groups
EGFR and KRAS Marker Groups
EGFR Group
35%39%41%
0
10
80
20
40
30
60
70
50
Erlotinib
Vandetanib
Erlotinib + Bexarotene
Sorafenib
90
55%
Achie
ved 8
week D
C (
%)
100
Primary Endpoint: Overall DCR at 8 weeks was 46%
N =17 27 20 23
KRAS Group
14%
79%
0
33%
7 3 3 140
10
80
20
40
30
60
70
50
90
100
N =
EGFR Group- mutation
- copy number
KRAS Group- KRAS mutation
- BRAF mutation
EGFR and KRAS Mutations:
Novel Discovery Findings
KRAS Mutation
0
10
80
20
40
30
60
70
50
90
Achie
ved 8
week D
C (
%)
100
22%
37%
56%
61%
+ - + - + - + -
EGFR Mutation
+ -+ -+ -+ -
23%
64%
0
10
80
20
40
30
60
70
50
90
100
Erlotinib Vandetanib Erlotinib + Bexarotene Sorafenib
71%
29%
Erlotinib Sorafenib Erlotinib Sorafenib
N = 7 45 13 67 N = 9 43 18 62
Individual Biomarkers for Response
and Resistance to Targeted Treatment:
Exploratory Analysis
Drug Treatment Biomarker P–value DC
Erlotinib EGFR mutation 0.04 Improved
Vandetanib High VEGFR-2 expression 0.05 Improved
Erlotinib +
BexaroteneHigh Cyclin D1 expression 0.001 Improved
EGFR FISH Amp 0.006 Improved
Sorafenib EGFR mutation 0.012 Worse
EGFR high polysomy 0.048 Worse
Did AR work?
Prob(RAND)
AV
E(a
rm=
=1
)
0.0 0.2 0.4 0.6 0.8
0.0
0.2
0.4
0.6
0.8
1.0
Randomized to Arm 1
Prob(RAND)
AV
E(a
rm=
=2
)
0.0 0.2 0.4 0.6 0.8
0.0
0.2
0.4
0.6
0.8
1.0
Randomized to Arm 2
Prob(RAND)
AV
E(a
rm=
=3
)
0.0 0.2 0.4 0.6 0.8
0.0
0.2
0.4
0.6
0.8
1.0
Randomized to Arm 3
Prob(RAND)
AV
E(a
rm=
=4
)
0.0 0.2 0.4 0.6 0.8
0.0
0.2
0.4
0.6
0.8
1.0
Randomized to Arm 4
What are the DCRs in ER vs. AR?
DCR
– in ER = 52% (N=95)
– in AR = 42% (N=149)
What a bummer !?
Why?
Why didn’t AR work better? Time drift. ER pts tends to have more– never smokers (28% vs 18%)
– PS=0 pts (13% vs 6%)
– Erlotinib naïve (58% vs 53%)
– Female (51% vs 44%)
Percent of patients eligible for trials– Only 1 trial: 21%
– Two trials: 35%
– Three trials: 31%
– All four trials: 14%
PI override (N=3, all progressed)
Actual outcomes changed by the final endpoint review committee (N=14)
AR started too late (~40%, ER) and not aggressive enough.
46
Equal versus Adaptive Randomization –
Population Drift
Trial Enrollment
Pro
port
ion o
f D
isease C
ontr
ol (D
C)
Oct
2006
Nov
2009
Equal Randomization
(N = 95)
DC = 52%
Adaptive
Randomization
(N = 149)
DC = 42%
If equal
randomization had
continued
DC = 37%
5%
Lessons Learned from BATTLE?Biomarker-based adaptive design is doable! It is well received by clinicians and patients.
Prospective tissues collection & biomarkers analysis provide a wealth of information
Treatment effect & predictive markers are efficiently assessed.
Pre-selecting markers is not a good idea. We don’t know what are the best predictive markers at get-go.
Bundling markers into groups, although can reduce the total number of marker patterns, is not the best way to use the marker information either.
Watch for time drift and avoid it.
AR should kicks in early & closely monitored.
AR works well only when we have good drugs and good predictive markers.
Discovery Platform versus
Confirmatory PlatformEarly phase of drug developing is about discovery and learning.
Adaptive design provides an ideal platform for learning.
Due to the large number of tests, the overall false positive rate may be large.
Results found in the discovery platform need to be validated in the confirmatory platform– Validation of treatment efficacy
– Validation of predictive markers
After narrowing down the biomarkers and treatments combination(s), validation trials can be more focused.– Traditional designs or innovative designs
BATTLE-2 SchemaProtocol enrollment
Biopsy performed
Stage 1:
Adaptive RandomizationKRAS mutation
Primary endpoint: 8-week disease control
N = 400
Erlotinib Erlotinib+AKTi MEKi+AKTi
Stage 2:
Refined Adaptive Randomization“Best” discovery markers/signatures
Principles• Better specific drugs
• Better specific targets
• No biomarker grouping
• Selection, integration and validation of novel predictive biomarkers
Sorafenib
Tools for Conducting
Bayesian / Adaptive Trials at MDAClinical Trial Conduct (CTC) Website
Secured web application for conducting
Bayesian clinical trials
Can be used to
– Register patients
– Log in key information for randomization
Baseline characteristics
Outcome (toxicity, efficacy)
– Randomize patients
Connect to statistical software via web services
– Capture endpoints for interim analysis
New Trial Request Form
Trial Information and
Administration
Design Methods
Patients Information Input
Pocock-Simon Design
Outcome based Adaptive
Randomization Trial
Monitoring Efficacy and
Toxicity
Multi-Center Supported
Clinical Trial Conduct (CTC) Website
(as of August 2011)
Adaptive Randomization 44
Pocock-Simon Design 42
CRM 29
One Arm Time-To-Event Monitoring 11
Equal Randomization 6
Efftox 1
Total trials 133
Total # of patients ~4,360
Software Toolshttps://biostatistics.mdanderson.org/SoftwareDownload/
Over 70 programs freely available
Adaptive Designs
for
Personalized Medicine
Are we there?
Are Bayesian adaptive designs useful for
the development of personalized medicine?
Absolutely!
Are Bayesian adaptive designs ready for
the prime time?
Getting there. Need more work on education,
software development, and implementation.
It is an exciting time for advancement in
medicine and statistics.
Adapt!Adapt! Adapt!
Summary
Adaptive designs enable us to continue to learn about the new agents’ activities and identify the predictive markers during the trial in order to apply this knowledge to better treat patients in real time.
It can increase the study efficiency, allow flexibility in study conduct, and provide better treatment to study participants. – Speed up drug development– A step towards personalized medicine
Extra steps need to be taken to ensure the integrity of study conduct, e.g., objective and timely evaluation of endpoints, monitoring AR continuously.
Roll up your sleeves! The proof of the pudding is in the eating. We need to do more such innovative trials to learn and to improve the trial designs and conduct so we can turn promise into progress.