ICH-E17:
Multi-Regional Clinical Trials –
a challenge and a chance
Armin Koch
Institut für Biometrie
Medizinische Hochschule Hannover
Carl-Neuberg-Str. 1
30625 Hannover
A brilliant approach
Instead of mingling around with a
set of studies in various regions or
a program in one region to be
acknowledged by other regulatory
agencies
(the ICH-E5 approach,
roughly speaking)
the idea is now to put one trial,
conducted in multiple regions, into
the centre of a new drug application
in (all) regulatory regions (the ICHE17 approach).
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Perception of regulatory work
with respect to assessment strategies
P < 0.05 (two-sided)
P ≥ 0.05 (two-sided)
It is more: formal proof of efficacy is required and there is need to check
whether the drug fits into the treatment context now in multiple regions.
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Fundamentals of assessment
"... we do not, as a rule, further
question eyewitness of an
experiment, but, if we doubt the
result, we may repeat the
experiment, or ask somebody else
to repeat it."
K. Popper, quoted from
Högel & Gaus (CCT 20, 511-518)
"... it has been FDA's position that
Congress generally intended to
require at least two adequate and
well-controlled studies, each
convincing on its own, to establish
effectiveness."
FDA: Guidance for Industry:
Providing Clinical Evidence of Effectiveness for
Human Drug and Biological Products
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Regulators, however, are supposed
to doubt (or, to critically challenge)
the results of clinical trials
(and will therefore usually search
for replication)!
Towards an MRCT-future
However, standards of evidence have changed:
• in former times (two-trials rule of the FDA) we had 2 (usually PBO
controlled) studies in the US and 2 (usually active controlled) studies
in the EU.
• nowadays assessment of efficacy and benefit/risk is based on one
world-wide pivotal study planned with an adaptive design intended to
justify licensing in all the ICH-regions.
In my understanding, in most instances the discussion about MRCTs
implicitly assumes that only one pivotal trial will be conducted.
If consistency / replication is considered important, nowadays
assessment of consistency and replication needs to be done within
instead of between studies.
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EU-guidance on applications with (i) meta-analysis and (ii) one pivotal trial:
may be prudent to plan for more than
one Phase III trial
 lack of pharmacological rationale
 new pharmacological principle
 Phase I / II limited or unconvincing
 history of failed studies or contradictory
results
 no effective treatment exists
 demonstrate efficacy in different subpopulations
/
co-medications
/
interventions / comparators
 need to address additional questions in
phase III
prerequisites for reliance on OPT
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internal validity: no indication for bias
external validity: population suitable for
extrapolation
clinical relevance: clinically valuable
treatment effect
degree of significance: 5% not
sufficient, narrow confidence interval
data quality
Internal consistency: similar effects in
pre-specified subgroups, w. r. to all
important endpoints
no center dominates the results
plausibility of hypotheses tested
CPMP/EWP/2330/99
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What we would like to see
Efficacy and safety of regorafenib for
advanced gastrointestinal stromal
tumours after failure of imatinib and
sunitinib (GRID): an international,
multicentre, randomised, placebocontrolled, phase 3 trial
George D Demetri, Peter Reichardt, Yoon-Koo Kang,
Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom,
and others
The Lancet, Vol. 381, No. 9863, p295–302
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The world "as is"
The Plato trial, comparing Ticagrelor to Clopidogrel in 18,000 patients with
ACS demonstrated superiority, but regional differences became obvious
from the results (pHet~0,05).
Is it wise to pretend that this is an American problem?
The dangerous impression of being in the
"comfort zone"
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Torn between two extremes
Everybody would love to assume that
observed differences are “a chance
finding”:
Multiple testing of subgroups w/o a plan
increases the T1E.
The subtle balance between:
increasing the type-1-error by means
of multiple testing in subgroups
and
overlooking important untoward effects
in subgroups
must be met and regulators need
confidence that there is no true
underlying „problem“.
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MRCTs are horribly informative:
The EGFR-mutation
Crossing survival as an
example for non-conclusive
overall outcome
EGFR mutation status in
the IPASS-trial comparing
Gefitinib to Carboplatin +
Paclitaxel in patients with
NSCLC.
(Mok et al. (2009))
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Free lunch?
No, best information comes at a price:
(S)
More negotiations with different RAs for the same study
(R)
Need to compromise with requirements from other RAs
(R)
No regulatory region has its own “significant” treatment effect
(R)
(Often) no external replication
(S)
Sample size needs to be allocated wisely to enable assessment of
regional consistency and consistency in other subgroups
(S)
“Light” increases in sample-size as reinsurance against increased
variability
(R/S) Upfront and post-hoc discussions about what “consistency of regions”
and effects in subgroups should mean
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Regarding compromising
Europe as a role-model:
•
National licensing for a long time
•
Old drugs not licensed in all countries
•
Different traditions to treat patients
•
Different co-medication
For a European trial:
• Acknowledge comparator after checking
evidence (or use legal route)
• Compromise with the endpoint after checking
evidence
• In order to plan studies that can generate
robust evidence, guidance is developed to
describe agreement between stakeholders.
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After external consultation
~ 800 comments (repetitive, slightly modified, new thoughts) were received
from a broad range of stakeholders.
Main areas of clarification needs:
1. Disentangle better ICH-E5 / ICH-E17 approaches,
2. Relevance of the overall treatment effect for planning sample-size, and
assessment,
3. Need to assess the role of intrinsic and extrinsic factors and general
consistency and implications for sample-size allocation,
4. Pooling of regions and the concept of pooled regional subpopulations
and role for decision making,
5. Early dialog to work on those areas of the trial, where regulatory
requirements differ.
6. Methodological implications of all this.
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EU-regulators‘ expectation
and confidence:
Expectation:
A number of difficulties and challenges have to
be resolved when MRCTs are supposed to be
primary source of evidence for drug licensing:
willingness to compromise and work on difficult
terms like consistency in line with proportionate
requirements for trials and assessment need to
be developed.
Confidence:
A strong group of experts with a sponsor-, a
regulatory- and a trialists-background will get it
right!
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