Iacobelli - Budapest 27-4-2016

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27 April 2016
Massimo Iacobelli, MD
CONFIDENTIAL
Clinical trials with adaptive design
in the paediatric population
Pediatric Drug Development Conference
27-28 April, 2016 - Budapest, Hungary

“The beginning is the most important part of the work.”
Plato, The Republic, 380 BC
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The Typical Drug Development Process

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Changing the Paradigm for the Development of New Therapies
Models of drug development
Cathie Spino et al. Changing the Paradigm for the Treatment and Development of New Therapies
for FSGS. Front Pediatr. 2016; 4: 25

Clinical trials planned with an adaptive design
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In some instances studies can be planned with a so‐called adaptive
design involving design modifications based on the results of an
interim analysis.
• Such a design has the potential to speed up the process of drug
development or can be used to allocate resources more efficiently
without lowering scientific and regulatory standards.
Adaptive designs would be best utilized for clinical trials in areas
where it is necessary to cope with difficult experimental situations.
• Investigation of drugs for the treatment of children or rare diseases is
a difficult task.
• A single phase II/III combination trial may be justified if such an
approach is more efficient to display the totality of available
information that can be derived from a limited number of patients.
Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive
design. CHMP. 18 October 2007

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• From PhRMA White Paper (2006):
By adaptive design we refer to a clinical study design that uses
accumulating data to decide how to modify aspects of the study as
it continue, without undermining the validity and integrity of the
trial
• From EMA Reflection Paper (2007)
A study design is called “adaptive” if statistical methodology allows
the modification of design element (ie sample size, randomization
ratio, number of treatment arms) at an interim analysis with full
control of type I error.
• From FDA Guidance for Industry (2010)
An adaptive design clinical study is defined as a study that include
a prospectively planned opportunity for modification of one or
more specified aspects of the study and hypotheses based on
analysis of data (usually interim data) from subjects in the study.
Definitions of Adaptive Design

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• The definition of Adaptive design allows a wide range of possible
adaptations, some more acceptable than others.
• At interim data review, subsequent stages of the study can be
redesigned taking into account all available data
• The design allow modifications (at interim analysis):
• updates to the maximum sample size,
• study duration,
• treatment group allocation,
• dosing, number of treatment arms,
• or study endpoints.
• When adaptive designs are used properly, efficiencies can be obtained:
o a smaller sample size,
o a more efficient treatment development process,
o an increased chance of correctly answering the clinical question
of interest,
o reduced time for completing clinical development.
Adaptive design clinical trials
Kairalla JA et al. Adaptive trial designs: a review of barriers and opportunities. Trials 2012; 13:145

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• However, improper adaptations can lead to biased studies.
• Protocol changes should not be ad hoc, but ‘by design’, based
on pre‐specified decision rules.
• For each type of adaptation, researchers must ensure that:
• the type I error rate is controlled,
• the trial has a high probability of answering the research
question of interest,
• and equipoise is maintained .
• Adaptive design requires to define and apply (at interim
analysis) some rules:
• Allocation rules
• Sampling rules
• Stopping rules
• Decision rules

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Traditional setting
Adaptive setting
Study 1
Phase II
Placebo
Dose B
Placebo
Dose A
Dose A
Dose B
Phase II
Interim analysis
Adaptive design should reduce
the time of clinical development
Phase III
Final results
Variable, depending from
interim results
Modify sample size,
randomization,
allocation, parameters
Study 2
Phase III

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Managing adaptive design studies
Adaptive design for clinical trials
Chow & Chang, Orphanet Journal of Rare Diseases 2008; 3:11
Prospective adaptations
• Adaptive
randomization
• Early stopping
• Dropping the losers
• Sample size re‐
estimation
• Other
Implemented by
study protocol
Concurrent adaptations
• Inclusion/Exclusion
criteria
• Evaluability criteria
• Dose/regimen,
treatment duration
• Hypotesis
• Study endpoints
• Other
Retrospective adaptations
• Statistical analysis
changes (made before
database lock or
unblinding of treatment
codes
Implemented by
protocol amendments
Implemented by
regulatory reviewer’s
consensus

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Summary of different types of adaptive designs

Confirmatory clinical trials planned with an adaptive design
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In all instances the interim analysis and the type of the anticipated
design modification (change of sample size, discontinuation of
treatment arms, etc.) would need to be described and justified in the
study protocol.
• Adaptations to confirmatory trials introduced without proper
planning will render the trial to be considered exploratory.
Assessment of results from clinical trials involves, amongst other
issues, a full discussion of potential sources of bias.

Scientific Basis for Independent Substantiation
• Unanticipated, undetected, systematic bias
• Inherent variability in biological systems producing a positive
trial by chance alone (1 in 40)
• Results at one center may be dependent on site or
investigator specific factors
• Rare that favorable efficacy results due to fraud

The importance of confidentiality of interim results
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In trials that have had interim analyses, it is possible to assess
patient demography and to estimate the size of the treatment effect
from the data collected before, and after, the interim analysis and
check these for consistency.
• Substantial discrepancies with respect to the types of patients
recruited and / or results obtained will raise concern: it will be
difficult to interpret the conclusions from the trial if it is
suspected that the observed discrepancies are a consequence
of (intentional or unintentional) dissemination of the interim
results.
• This problem is usually of even greater importance in situations
where treatments cannot be fully blinded or the assessment of
results incorporates some subjective element.

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Interim analyses always introduce the possibility of damaging the
integrity of a trial.
• To minimise these risks, three important issues need to be
considered during the planning stage of the study:
• is there a need to perform any interim analysis?
• is the number of interim analyses justified? and
• is the information flow carefully described and controlled?
• In general, interim data should be provided by an independent
statistician to an independent decision‐making committee (DMC
or DSMB); sponsor involvement is discouraged.

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 Data Monitoring Committee nesds to be independent (IDMC),
non‐sponsor controlled to protect study integrity.
 Responsible for review of interim analysis of unblinded data
and adaptive decision making in accordance with a well
specified adaption plan
 Most important is to describe in the IDMC charter:
 Who will perform the interim analysis,
 the implementation of the adaptation plan,
 Who receive access to interim results,
 How access will be provided

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Lancet.
2012
7;379:
1301‐9

• HSCT has become the standard of care for many patients with
defined congenital or acquired disorders of the hematopoietic
system, or with solid tumors
• Althoug HSCT offer the only cure available for many diseases,
the procedure remains limited by regimen‐related toxicities,
with significant morbidity and mortality:
• Hepatic Veno‐Occlusive Disease (VOD)
• Graft versus Host Disease (GVHD)
• Mucositis
• Transplantation‐related infections
Regimen Related Toxicities (RRT)
Copeland EA. Hematopoietic Stem Cell Transplantation. N Engl J Med 2006;354:1813-26.

Hepatic Veno‐Occlusive Disease (VOD)
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• 7 months old, with AML M7, t(1;22)
• Bu/Cy – HSCT (d0)
• d+10/11: weight gain increased,
hepatomegaly
• d+12: respiratory failure
• d+13: hyperbilirubinemia
• d+15: renal failure
• d+26: death due to MOF
Clinical Diagnosis of VOD:
Hepatomegaly (painful), jaundice, ascites,
weight gain ( > 5%), onset < d+35 post
HSCT, other causes absent
Incidence:
8-20% of HSCT (more frequent in children)
Outcome:
Overall mortality is 4 times higher in HSCT
patients who develop VOD;
Severe VOD (with Multi-Organ Failure) in
about 1/3 of VOD cases, with death
approaching 85%
Treatment:
No treatments available

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Confirmatory clinical trial of defibrotide
Study EBMT Pediatric Prevention study (EudraCTA 2004‐
000592‐33)
Countries Austria, Czech Rep, France, Germany, Ireland, Israel,
Italy, Sweden, Switzerland, The Netherlands, UK
Number of centers 28
Indication Prevention of VOD in HSCT patients
Number patients 360
Age Pediatric (>6 months <18 years old)
Design Randomised, controlled study
Doses Defibrotide iv 25 mg/kg/day, 30d from conditioning (or
until hospital dicharge, min 14d)
Status Completed
Lancet. 2012 7;379: 1301‐9

Eligible pediatric patients
Control Arm (n = 176)
No prophylaxis for VOD
Randomization (n = 356)
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Prophylaxis Arm (n = 180)
Defibrotide 25 mg/kg/d iv
VOD No VODNo VOD VOD
Follow up until D+180 post HSTC
Conditioning
EU Pediatric Prevention Trial
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 As the true incidence of VOD in this population was unknown, the trial
incorporated a planned adaptive interim analysis to be reviewed by an
independent DSMB
 The primary and secondary efficacy analysis at 0.05 significance level,
based on:
 Intent‐to‐Treat (ITT) population: all randomized patients in the DF
prophylaxis and in the control group.
 Per‐protocol’ (PP) population: only non‐dropouts with no serious
protocol violations.
Serious protocol violations are:
 Registration of a patient after the start of conditioning
 Violation of the treatment dose (25mg/kg/d)
 Violation of the schedule (less than three times a day)
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Statistical AnalysisStatistical Analysis

The sample size estimate was based on the primary endpoint of the binary
outcome of VOD incidence by Day+30 post‐SCT.  The VOD rate for the
Control Arm was estimated to be 30%, with a 15% VOD incidence in the DF
Prophylaxis Arm.  Assuming a one‐sided level of significance at 0.025,
power of 80%, and 10% drop‐outs, 135 patients per group were required.
Because the incidence of VOD in children was unclear at the time the
study was designed, the protocol incorporated one pre‐specified adaptive
interim analysis, based on available data and following the algorithm of
Denne (Denne 2001), to be reviewed by an independent DSMB, consisting
of one statistician and three physicians) when 120 patients in each group
were assessable for the primary efficacy endpoint.
The sponsor remained blinded to the interim results; results were available
only to an independent statistician and DSMB.
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Statistical Analysis: Study Protocol and SAPStatistical Analysis: Study Protocol and SAP

 The adaptive interim analysis assessed the conditional power for
achieving a statistically significant result on the primary endpoint in
favor of DF Prophylaxis by end of the study with the initial sample size.
 If the conditional power was less than 30%, the DSMB could
recommend stopping the study for futility;
 if the conditional power was less than 80%, the DSMB could
recommend recalculating the final sample size required to achieve
conditional power of at least 80% (Denne 2001).
 Stop the trial if statistically significant superiority of Defibrotide over
the Control Arm with respect to the primary endpoint had been
achieved at a one‐sided 0.01% (or 0.0001) level of significance (if the
study is not stopped at this stage, a one‐sided 2.49% (or 0.0249) level
of significance would be used for the final analysis).
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Adaptive Interim Analysis: Study Protocol and Statistical
Analysis Plan for the Interim Analysis
Adaptive Interim Analysis: Study Protocol and Statistical
Analysis Plan for the Interim Analysis

DSMB Charter
• The DSMB, composed of three expert
haematologists and one statistician,
prepared a charter that detailed two
meetings to be performed during the
course of the trial for the review of patient
data.

The DSMB convened twice during the course of the study, at pre‐
specified intervals.
The first meeting reviewed safety and mortality after the enrolment
of the first 120 patients; the DSMB identified no safety concerns and
recommended that the study continue to enroll.
The second meeting was the adaptive interim analysis, which was
conducted after 240 patients had been randomized and followed for
at least 30 days post‐SCT.
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Adaptive Interim AnalysisAdaptive Interim Analysis

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Adaptive Interim Analysis: ResultsAdaptive Interim Analysis: Results
Second DSMB Meeting
• The original sample size estimated that 135 patients per group were
required.
• Using a denominator of 119 and 118 in the DF Prophylaxis and Control Arms,
respectively, the incidence of VOD in the DF Prophylaxis Arm equaled 12%
and that in the Control Arm equaled 21%.
• Both arms appeared well‐balanced for all criteria
• The conditional power for the study equaled 60%.
• The calculated sample size required for an 80% conditional power equaled
180 randomised patients per group.
• The company was not provided with this information (and statistical analysis)
until after database lock for the final analysis.

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Adaptive Interim Analysis: ResultsAdaptive Interim Analysis: Results
Conclusions of the DSMB (from the written minutes of that meeting) :
• There are no significant safety concerns regarding drug administration at
this time. There is no evidence of clinical futility.
• Results to date were thus considered satisfactory, with performance of the
DF Prophylactic Arm consistent with prior phase 2 data and the Control
Arm with a priori protocol assumptions.
• It was therefore recommended that the study continue to accrue.
• The sample size of the study should be increased to an evaluable sample
size of 180 patients per arm (assuming the same drop out rate as
anticipated in the protocol), to achieve an 80% conditional power for
detecting a statistically significant benefit to Defibrotide over control with
respect to the primary endpoint.

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Defibrotide
Prophylaxis
Control P value
Hepatic VOD
CICR (95% CI)
(a)
12% (22/180)
0.13 (0.08,0.19)
20% (35/176)
0.20 (0.15,0.27)
0.0488(b)
Final Analysis
Primary end‐point, Incidence of VOD
Intent‐To‐Treat Analysis: all randomised patients
(a) Confidence Interval Estimation by ln Transformation
(b) P-value of Z test
Comparison against the defibrotide arm for the primary efficacy analysis was
performed using a cumulative competing risk approach where death not due
to VOD, discontinuing the study due to an adverse event, and receipt of
second transplant due to transplant failure, were considered competing risks
(3 pts DF, 2 pts control).
Prevention of VOD in Pediatric HSCT

Allogeneic SCT DF Prophylaxis
(n = 122)
Control
(n = 117)
P value
Acute GvHD by D+100 47% (57) 65% (76) 0.005*
 GvHD Grade 1 25% (30) 28% (33)
0.003**
 GvHD Grade 2 15% (18) 26% (30)
 GvHD Grade 3 4% (5) 8% (9)
 GvHD Grade 4 3% (4) 3% (4)
* P-value from Chi-Square Test for incidence if GvHD by D+100
** P-value from Wilcoxon Test for Grading of GvHD by D+100
*** P-value from Chi-Square Test for incidence if GvHD by D+180
Chronic GvHD by D+180 13% (16) 15% (17) 0.751***
Prevention of VOD in Pediatric HSCT
Secondary end‐point, Graft versus Host Disease
Intent‐To‐Treat Analysis: all randomised patients

Conclusions
The Adaptive design is useful in case of difficulties in defining
sample size of confirmatory trials. It should be used for in other
cases to optimize clinical development.
Adequate procedures and protocol specifications are needed to
ensure that the sponsor maintain the confidentiality of interim
results
Importance of role and experience of Data Monitoring Committee

Iacobelli - Budapest 27-4-2016

Iacobelli - Budapest 27-4-2016

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