Transcript Slide 1

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Dose Response in Early Phase Studies
Professor Andy Grieve
SVP Clinical Research Methodology
ClinResearch / ADDPLAN
Cologne, Germany
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Outline
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Motivation
First-in-Human Studies
Determining the MTD in Oncology Studies
Phase 2b Dose-Response/Finding/Selection Designs
The Slow Pace of Translation of Methodological
Development into Practice.
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Motivation – MISG (UK)
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MISG Forums
1.
2.
3.
4.
5.
6.
7.
Imaging In Cardiovascular Drug Development - 2007
Early access to Medicines - 2007
Benefit-Risk Decision Analysis - 2008
Safety Biomarkers - 2008
Personalised Medicines - 2009
Widening Access To Medicines Via Reclassification - 2009
Clinical Trial Design - 2010
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Questions to be Addressed by the Forum
1. Under what circumstances are the
‘standard’ designs of exploratory trials
not fit for purpose, not generating
adequate information for a well
informed decision on whether to
progress to confirmatory
development?
2. Is there a role for novel clinical trial
designs in the exploratory arena? If
so, is it possible to define factors
which influence whether to select a
standard, or a novel approach for a
given experimental situation?
3. To what degree would improving the
scope, conduct and / or efficiency of
exploratory development have the
potential to decrease failure rate of
confirmatory studies, and potentially
reduce regulatory requirements for
confirmatory development?
4. What are the hurdles to
implementation of novel clinical
trial designs in exploratory or
confirmatory development, and
how can these be overcome?
5. What opportunities exist for
further methodological research
into novel clinical trial designs in
exploratory and confirmatory
development?
6. What is the role of regulatory
agencies in guiding or
encouraging the use of novel
designs in exploratory or
confirmatory development?
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Question To Be Addressed by APG
Question 1.
Under what circumstances are the ‘standard’ designs
of exploratory trials not fit for purpose, not generating
adequate information for a well informed decision on
whether to progress to confirmatory development?
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Northwick Park and First in Human Studies
Pre-Clinical Safety and Phase I Safety
Royal Statistical Society Working Party
Statistical Issues in ‘First-in-Man’ Studies
TGN – Northwick Park & Phase I
Terms of Reference
"To review statistical design considerations for 'first in man' studies with
particular reference to monoclonal antibodies and the wider class of new
biologicals and biotechnologies .
In particular to consider the following issues
1. What statistical theory, for example as covered by the subjects of decision
analysis and experimental design, implies about ethical and logical design
of first in man studies
2.
What data are currently available regarding safety of first in man studies
and what can be done to facilitate their use in guiding trial design
3. What statistical practice, in particular as regards future appropriate
collection and dissemination of data, can contribute to improving ethical
decision making in first in man studies. "
RSS Working Party Members
Dr Dipti Amin, Senior Vice-President, Global Medical & Regulatory Affairs , Quintiles Limited
Professor R.A. Bailey, Professor of Statistics, Queen Mary, University of London
Professor Sheila M. Bird FFPH, Principal Scientist/Statistician, MRC Biostatistics Unit, visiting
professor at Department of Statistics and Modelling Science, University of Strathclyde
Dr Barbara Bogacka, Reader in Probability and Statistics, Queen Mary, University of London
Mr Peter Colman+, Senior Consultant Statistician, Pfizer Global R+D, Statistical Applications
Dr Andrew Garrett, Vice President Biostatistics, Quintiles Limited
Professor Andrew Grieve, Professor of Medical Statistics, King’s College London
Professor Sir Peter Lachmann, FRS, FMedSci, Emeritus Professor of Immunology, University of
Cambridge
Professor Stephen Senn*, Professor of Statistics, University of Glasgow
* Chairman
+ Representative of Statisticians in the Pharmaceutical Industry (PSI)
RSS Recommendations:
21 in 4 Themes
Generic issues
Preparatory work before first in man
Content of protocols (including design)
Risk and information sharing for social good
and reporting standards
Content of Protocols
 Justification of relevant quantities
 proper interval, dose step, safety, expected number of
adverse events etc
 Statistical justification of sample size
 Justification of design
 Detailed description of intended analysis
 Design and analysis should reflect realistic PK models
 Plan for blood sampling etc to based on pre-clinical
studies
 True informed consent: ‘open protocol, hidden allocation’
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TGN 1412 – Northwick Park Catastrophe
Design
Questions
1. Why 6 + 2
2. Why four doses?
3. Why the chosen dose ratios?
4. Why simultaneous treatment in cohorts
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Efficiency of Different Designs
Royal Statistical Society’s Working Party on
Statistical Issues in First-in-Man JRSSA, 2007
© Andy Grieve
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First-in-Human Studies
Examples Presented to CHM Clinical Trials Expert Advisory Group
■ “13.2 Determination of the Sample Size. No formal statistical
testing will be performed and hence no formal sample size
calculation was carried out for this exploratory study.” (14
patients in each of 5 groups)
■ “6.15. Statistical considerations A maximum of 10 patients will
be enrolled into the trial and all evaluable patients will be
included in any analyses. Formal statistical analyses is not
possible in this small cohort of diverse patients, therefore data
analyses will be descriptive in nature”
■ “9.2 Determination of the Sample Size. Only descriptive
statistical methods will be used and therefore no formal sample
size determination is necessary. The sample size is sufficient to
achieve the aims of the study”
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Determining the MTD in Oncology Studies
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Determining MTD in Oncology Studies
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Continual Reassessment Method (CRM)
●
CRM assesses a dose-response relationship
—
—
●
based on accruing data of the trial
allows investigators to make decisions based on a continually updated
dose-response model
recommended for use in dose response trials in early clinical
development by both FDA and EMA
Standard 3+3 Method
 Dose levels (Fibonacci), DLT escalation scheme specified
# Patients with DLT
0/3
1/3
1/3 + 0/3
1/3 + (1/3, 2/3 or 3/3)
2/3
3/3
Next Dose Level
 To next level
3 more patients at this level
 To next level
Stop: choose previous level
Stop: choose previous level
Stop: choose previous level
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Problems with 3+3 design
 MTD is not defined – Prob ( DLT | MTD) = * ?
 It has a high chance of picking an ineffective dose – (MTD < ) –
O’Quigley et al (1990)
 It doesn’t utilise all of the toxicity data – only the information
from the last 3 or 6 patients (cf up-and-down)
 It has poor operating characteristics
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Determining MTD in Oncology Studies
■
Continual Reassessment Method (CRM)
●
CRM assesses a dose-response relationship
—
—
●


based on accruing data of the trial
allows investigators to make decisions based on a continually updated
dose-response model
recommended for use in dose response trials in early clinical
development by both FDA and EMA
Has wider applicability than just oncology
2 Examples
Example 1: Infant Sedation During
Cardiac Cathetrisation – Determine ED90
Stopped by
Independent
Committee
Dose
0.6 mg kg -1
F S F F F F F F F F F S F F F
1.0
0.5 mg kg -1
Starting
Dose
0.4 mg kg -1
0.9
F
0.8
0.7
0.3 mg kg -1
0.6
0.5
0.2 mg kg -1
0.4
0.3
0.1 mg kg-1
0.2
0.1
0.0
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Example 2: Dose-finding study
of ibuprofen in patent ductus arteriosus
 Study designed to find the minimum effective dose regimen
(MEDR) of IBU (one course) required to close ductus arteriosus
in preterm infants.
 Study run in two
independent groups (20
per group)
 PMA 27-29 weeks : 80%
closure
 PMA < 27 weeks
 50% closure
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Ibuprofen loading dose (mg/kg)
10
15
20
Allocated Success/
Dose
Failure
10
2/1
5
0/1
15
3/0
10
2/1
15
2/1
15
2/0
10
1/0
15
3/0
10
1/0
Prior estimated probabilties of success
0.6
0.8
0.9
0.95
0.481
0.683
0.812
0.891
0.370
0.544
0.682
0.787
0.539
0.744
0.861
0.925
0.512
0.717
0.840
0.915
0.467
0.667
0.799
0.882
0.500
0.703
0.829
0.903
0.519
0.723
0.845
0.914
0.553
0.757
0.870
0.931
0.567
0.771
0.880
0.938
.2
1
2
3
4
5
6
7
8
9
Patients
(n)
3
1
3
3
3
2
1
3
1
0
Cohort
Probability
.4
.6
.8
5
1
Example 2: Dose-finding study
of ibuprofen in patent ductus arteriosus
1
2
3
4
5
Cohort
6
7
8
9
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Determining MTD in Oncology Studies
■
BUT
■
Identified 1235 trials designed to find the MTD in a
PUBMED search between 1991 & 2006
Of these 1215 used the “3 + 3” or variants
Only 20 (less than 1/60) used the CRM or variants
■
■
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Phase 2b DoseResponse/Finding/Selection Designs
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Phase 2b Dose Response/Finding/Selection Designs
1st Example
■ Development in osteoarthritis
■ 1st Cycle - pla, 80 mg, 120 mg, 160 mg (x2)
● All 3 doses better than placebo, no differences between them
● Doses based on pre-clinical data
■ 2nd cycle - pla, 40mg, 80 mg, 120 mg (x4)
● All 3 doses better than placebo, no differences between them
■ 3rd Cycle – pla, 2.5 mg, 10mg, 40mg
(x 64)
● 2.5mg not different from placebo
■ More Efficient
● wide range of doses, smaller numbers of patients per group
● followed by one large parallel group study focusing on the
doses showing promise in exploratory study.
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Phase 2b Dose Response/Finding/Selection Designs
2nd Example -1st Cycle
Headache Response Rate
0.8
0.6
0.4
0.2
0
Placebo
5 mg
20 mg
30mg
40mg
80mg
Dose
All doses significantly different from Placebo
2
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Phase 2b Dose Response/Finding/Selection Designs
2nd Example - 2nd Cycle
Headache Response Rate
0.8
0.6
0.4
0.2
0
Placebo
5 mg
20 mg
30mg
40mg
80mg
Dose
20mg, 30mg significantly different from Placebo,
5 mg not significant – 16x increase in dose
2
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Comparison Between Successful and Unsuccessful
Phase II Programs
Initial Dose Finding Unsuccessful More Studies Required
Study
1
2
Initial
Dose
Range
4
1
Total Dose
Range
Examined
64
4
3
4
6
4
16
8
Median
4
12
Initial Dose Finding
Successful
Study
1
2
Dose
Range
Examined
40
8
3
4
5
Median
4
10
4
8
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Phase 2b Dose Response/Finding/Selection Designs
Response
Standard Design
Dose
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Phase 2b Dose Response/Finding/Selection Designs
Response
Placebo + 4 doses available where to put them ?
Dose
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Phase 2b Dose Response/Finding/Selection Designs
Response
Choose Many Doses & Adapt
Dose
■ Increase # of
doses
■ Adapt to steep
part of dose
response curve
■ Concentrate on
estimation rather
than comparing
individual doses
to placebo
■ Use of Bayesian
Methods
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Phase 2b Dose Response/Finding/Selection Designs
Choose Many Doses & Adapt
Invention Reinvented, McKinsey Perspectives on Pharmaceutical R&D 2010
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Phase 2 Adult
Dose Response/Finding/Selection/Ranging Designs
10% Random sample of 340 Studies from Clinicaltrials.gov
60.0%
50.0%
40.0%
20.0%
10.0%
0.0%
>=6
5
19992004 2005Start of Study
2007
4
3
20082010
2
Number of Doses
% of Studies
30.0%
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Phase 2 Adult
Dose Response/Finding/Selection/Ranging Designs
10% Random sample of 340 Studies from Clinicaltrials.gov
Ratio of Maximum to Minimum Dose
10000.0
1000.0
100.0
10.0
1.0
0
1
2
3
4
5
6
7
Number of Doses
8
9
10
11
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Phase 2 Adult
Dose Response/Finding/Selection/Ranging Designs
Mean Ratio of Maximum to Minimum Dose
10% Random sample of 340 Studies from Clinicaltrials.gov
10
9
8
7
6
5
4
3
2
1
1999-2004
2005-2007
Start of Study
2008-2010
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Deficiencies in Clinicaltrials.gov
■
Incompleteness
■
Missing information
■
■
■
numbers of arms
Individual dose level
Accessibility
■
■
■
Limited abaility to download information
20 fields are available
Does not include information on treatment arms and dose
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Play-the the-Winner Rule
Zelen (J Am Statis Ass, 1969)
 Treatment assignment
depends on the
outcome of previous
patients - Response
adaptive assignment
 When response is
determined quickly
 1st subject: toss a
coin, H = Trt A, T = Trt
 Advantage: Potentially more
patients receive the better
treatment
 Disadvantage: Investigator
knows the next assignment
TRT A :
SSF
TRT B :
Patient
SSSF
SF
123
4 5 6 7 8 9 ......
 Analysis based on sequence
lengths
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An Example of a PTW Study
 Comparison of enoxaparin and
dextran 70 for the prevention of
venous thrombo-embolism
following digestive surgery.
 modified version of the basic
PTW design
 following 15 consecutive successes
a change of treatment automatically
took place. The treatment
sequences were regarded as nonended and handled as censored
(survival analysis)
 In total 231 patients were
included in a PTW design.
 The design allocated 140
patients to enoxaparin and 91
to dextran-70.
 A survival analysis detected a
significant difference (p<0.05)
in favour of enoxaparin
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Kaplan-Meier Estimates of Sequence Lengths
1.0
0.9
Dextran 70
Survivalship S(t)
0.8
Enoxaparin
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
Number of patients
© Andy Grieve
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Post-Operative Venous Thromboembolism
Other Literature Examples
■ Larsen et al (Pharm, Med, 1994)
■ Reirtsen et al (Scand J Gastroenterol, 1993)
■ Mowinckel et al (Eur J Surg, 1995)
■ Bjerkeset et al (World J. Surg.,1997)
■ Reirtsen et al (Scand. J. Lab. Invest,1998)
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Adaptive Dose-Response
Pfizer Example
 Biomarker:
 Inhibition of thrombin generation
 Literature Data:
 Clinical outcome (incidence of VTE and major bleeding
[MB]) for comparator anticoagulants
 Model:
 Linked biomarker response and clinical outcome for
comparators with an integrated PK-PD model
 Estimated Dose:
 Predicted VTE and MB dose-response for PD 0348292
based on its biomarker response
Richard Lalonde, Clinical Pharmacology, Pfizer Inc
Pharmaceutical Sciences World Congress, New Orleans, November 2010
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Predicted PD 0348292
Dose-Response Relationships for VTE & MB
Richard Lalonde, Clinical Pharmacology, Pfizer Inc
Pharmaceutical Sciences World Congress, New Orleans, November 2010
44
Adaptive Dose-Response
Pfizer Example
 6-arm randomized, parallel group study with
adaptive dose range based on interim dose decision
analyses of VTE and MB
 Start with 5 doses of PD 0348292 (0.1 to 2.5 mg QD)
 Eliminate PD 0348292 doses based on excessive VTE or
MB
 Add higher PD 0348292 doses (4 and 10 mg QD) if we
eliminate lower doses and MB rate acceptable
 Enoxaparin 30 mg BID as control
 Dose decision interim analyses (dose-response
regression model) after every 147 evaluable patients
 Total sample size of 1250 patients
Richard Lalonde, Clinical Pharmacology, Pfizer Inc
Pharmaceutical Sciences World Congress, New Orleans, November 2010
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Adaptive Dose-Response
Pfizer Example
 Study designed using M&S was approved by senior
management and conducted successfully
 Study met key objective
 Identified the dose equivalent to enoxaparin with good
precision
 Safely explored a 100-fold dose range to allow
characterization of dose-response relationship for
efficacy (vs ~ 4-fold dose range for competitors)
 ~1/3 sample size of traditional parallel group study
 Savings of 2750 patients
 Savings >$20M in trial costs
 Shortened development time by I year
Richard Lalonde, Clinical Pharmacology, Pfizer Inc
Pharmaceutical Sciences World Congress, New Orleans, November 2010
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The Slow Pace of Translation of
Methodological Development into Practice.
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The Slow Pace of Translation of Methodological
Development into Practice
■ Despite these advantages and recommendations, Bayesian
adaptive designs have not been widely adopted in practice
■ This could be in agreement with the previous report from
Altman and Goodman (JAMA 1994)
« Newer technical innovations still typically take 4 to 6 years before they
achieve 25 citations in the medical literature. »
Sylvie Chevret (Medical Computer Sciences and Biostatistics Dept, Hôpital
Saint-Louis, Paris) ISCB Montpellier, France,1st Sept 2010
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The Slow Pace of Translation of Methodological
Development into Practice
■ Bayes clinical trials have been recommended for the last two
decades
● From the early phase trials up to the phase III
● However, they have been reported poorly used in practice
● Possibly due to the usual time lag of the technical innovation spread This was confirmed in this study with only 3% of biostatistical papers
reaching 25 citations after publication, as compared to 15% of reviews
and 32% of clinical trial reports
Sylvie Chevret (Medical Computer Sciences and Biostatistics Dept, Hôpital
Saint-Louis, Paris) ISCB Montpellier, France,1st Sept 2010
Adaptive Confirmatory Interim Designs
Bauer & Koehne (Biometrics,1994)
General Strategy - >=1 adaptive interims
 Adaptation
reassessment of sample size
change of follow-up time
reallocation to treatment arms
choice of test statistic
dose-finding, e.g., in Phase I/II toxicity and efficacy studies
Combining Phase II/III studies (adaptive seamless phase
II/III designs)
Selection of endpoints, study population (sub-group analysis
or population enrichment designs)
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Procedure of Bauer & Köhne (1994)
p1
Stage 1:
0
a1
1
a0
rejection of
H0
acceptance of
H0
p1 p2
Stage 2:
0
1
ca
rejection of
H0
acceptance of
H0
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Review of Adaptive Interims
Bauer and Einfalt (Biometrical J, 2006)
 Identified 75 papers dealing
with adaptive designs : 19892004
 combination tests
 conditional error function
 did not consider Bayesian
approaches
14
12
Frequency
10
Bauer and Köhne 1994
Proschan and Hunsberger 1995
Bauer and Röhmel 1995
Cui 1999
Lehmacher and Wassmer 1999
missing
 Searched for “applied
papers” in SCI, SSCI,
IAHCI referring to at least
one of the 75 papers
 Identified 60 applied
medical papers
USA
Ukraine
UK
Slovak Republic
Netherlands
8
Italy
6
Germany
France
4
Czech Republic
Canada
2
Austria
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year
By: year and adaptive methodology
0
10
20
30
40
50
By: Country of corresponding author
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Bauer and Einfalt Conclusions
 Adaptive interims not widely used
 Methods used mainly in Germany
 Adaptations in practice are limited to sample size reassessment
 Sophistications – dropping treatment arms, modifying
endpoints etc have not entered medical literature
 Standard of presenting statistical methods poo
 pressures on space ?
 Mid-trial changes may impact negatively on the
“persuasiveness” of the results
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Adaptive Dose-Response
Pfizer Example
 Setting: Venous thromboembolism (VTE) prophylaxis
in patients undergoing an elective total knee
replacement
 PD 0348292: an oral direct factor Xa inhibitor
 Dose selection critical for an anticoagulant
 Under-dosing: increased risk of thrombosis
 Over-dosing: increased risk of bleeding
 Objective of Phase 2b dose-ranging trial
 Find a dose equivalent to the current standard of care,
enoxaparin 60 mg/day
Richard Lalonde, Clinical Pharmacology, Pfizer Inc
Pharmaceutical Sciences World Congress, New Orleans, November 2010
54
Altman and Goodman (JAMA 1994)
Newer Statistical Methods That may be Seen More Often In the Coming Years
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Conclusions
■ Too little thought is given to the purpose and appropriate
analysis of FIH studies
■ Despite considerable evidence to the contrary in efficient
designs to determine the MTD are being used
■ Choosing 2,3 or 4 doses in a phase II dose-response design
is potentially wasteful and counter productive
■ Consideration should be given to increasing the number of
doses, the range of doses and the analytic methods.
■ Efforts should be taken to encourage the speedy translation
of innovative methodology into practice