Transcript Points for Discussion - kitasato

WORKSHOP 4: KEY COMMENTS FROM THE
PANEL DISCUSSION
The 3rd Kitasato University - Harvard School of Public
Health Symposium
Wednesday October 2nd - Thursday October 3rd, 2002
New Ohtani Hotel, Tokyo
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The 3rd Kitasato University - Harvard School of Public Health Symposium
Current Situation of Regulatory and Clinical Environment
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Comments:
Is Bridging one way? Answer is No:
– Some sponsors are actually already using Asian data in
submissions outside Asia to support foreign filings
Reduction in number of clinical trials? Answer is No:
– The number of clinical trials in Japan at the moment is actually
increasing
The costs are very expensive:
– The cost of running a clinical trial in Japan is estimated as 2.5-5
times higher than in the US
The speed is slow but catching up:
– The speed of clinical trials in Japan is improving and now
catching up with the West
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The 3rd Kitasato University - Harvard School of Public Health Symposium
Approval procedure is not transparent;

Comment:
There is a missing middle ground between the ICH-E5
guideline and the practical implementation of a clinical trial

Responses:
– Quite deliberately the ICH-E5 guidelines are actually very
general, but maybe we should be looking to add some
further clarity around the details, to attempt to cover
some of this ‘middle ground’
– We have already seen that Pharmaceutical companies are
able to run studies multi-nationally so, maybe, we are
already in a position to add some clarity around
practicalities of running these multinational studies
– However, maybe there is still some framework missing in
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terms of the scientific evaluation of the data
The 3rd Kitasato University - Harvard School of Public Health Symposium
Bridging Studies
Issues: Definition of ethnicity, Intrinsic factors, Extrinsic factors

Comment:
– What is the definition of ethnicity?
– Mixed ethnicity clearly complicates the clinical trials
situation, so how should we deal with this in drug
development? (Remembering that genotype is very
important.)

Responses:
– The definition of ethnicity must remain ambiguous, since
we have to look at the ‘visible’ variability. But let us focus
on the details of extrinsic factors since it is primarily
these that result in individual variability
– In defining ethnicity we must consider extrinsic factors in
terms of medical practice, whether it will be possible for
Japan to participate in studies where there will be ethnic
comparisons, or whether medical practices are simply4
not comparable
The 3rd Kitasato University - Harvard School of Public Health Symposium
Bridging Studies
Issues: Industry perspective

Comments:
– Industry seems to have reached a conclusion on how to
utilise bridging studies. Basically, the industry
perspective is that if we have a good drug we need to
make it available as soon as possible, and bridging is
one way that we can achieve this, through removal of
duplication.
– Hopefully through these strategies, and through utilising
data from all over the world, we should be able to reduce
costs and also increase efficiency of clinical trials
– However, it is hoped that the scale of these studies will
diminish over time
– We also need to recognise that there are differences in
terms of types of drugs used in different countries.
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The 3rd Kitasato University - Harvard School of Public Health Symposium
Bridging Strategies
Issues: Regulatory Bodies, Statistical concerns
Comments:
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It is also good to see that review time of these strategies
has been accelerated.
It depends upon the type of bridging study. However, one of
the statistical challenges is how to quantify the amount of
uncertainty around the PK results, in order to be confident
that the data are similar to the foreign data collected. How
confident do we need to be about the dose response?
How should we decide, for phase III trials, whether the
results do or do not corroborate external data and whether
the dose is correct or not in the new region. Particularly, the
existence of differing concomitant medications can confuse
the interpretation of these results
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The 3rd Kitasato University - Harvard School of Public Health Symposium
Global Studies
Issues: Regulatory acceptance, Public health care, Medical
practice, Surrogate markers

Comments:
– Currently many bridging studies are done as phase IIB
studies with the aim of skipping phase III
– However, if we consider the future of global simultaneous
development of a drug, if Japan is to catch up with other
countries, then the current method of bridging is likely to
be a barrier towards achieving this

Responses:
– In terms of PK we could consider a single site for direct
comparison of PK profiles, or we could run the same
protocol at separate sites in order to compare ethnicity.

Comment:
– Our current target is to move from bridging studies to 7
global studies - how can we achieve this?
The 3rd Kitasato University - Harvard School of Public Health Symposium

Responses:
– But we need to focus more on genetic differences.
– Phase IIa can play a major role in providing rationale for
the differences in PK and can be used to provide
information that can be utilised for global studies.
– In terms of surrogate markers, do we need to always
validate these markers? Would a pilot study be beneficial
prior to joining a global study? This can potentially have
a great impact. But maybe we don’t always need to
validate these markers?
– Also in terms of being able to participate in a global
study can we be sure that the interpretation of the
protocol in each of the regions will be the same?
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The 3rd Kitasato University - Harvard School of Public Health Symposium
Design Issues
Clinical aspects, Statistical aspects;

Comments:
– And how will we be able to estimate an appropriate
sample size for these studies?
– Can we further broaden the scope from simply Japan to
other Asian countries?
– In the future, from the perspective of developing a drug
for ALL humans, perhaps we should conduct global
development programs, but also have some regional
supportive studies.
– Further, as opposed to independent review in every
region would it be possible to move to a situation of a
centralised review across regions?
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The 3rd Kitasato University - Harvard School of Public Health Symposium
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Responses:
– The ICH-E5 informal discussion group has discussed the
possibility that a guideline be produced for how many
patients will be required from each region
– But it is still not clear about how different subpopulations should be considered.
– Further, there are issues in terms of data management;
not having a single database, or not using visit based
CRF’s in each region can present logistical problems.
Will the investigators always be happy to complete the
CRF in the requested way? Will they always be happy
with the form structure?
– How do we deal with different languages between
countries?
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The 3rd Kitasato University - Harvard School of Public Health Symposium
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Comment:
– What should we do with the differing regulatory
requirements that are in place at the moment?

Responses:
– Are different regulators going to require additional data
in their own specific region? This may result in report
duplication for different regions of the world…
– An integrated global study is quite different from
integrated global development
– How should we approach regulators to ask the question
‘ this is what I’ve already got - what else do you need as
evidence that this drug is “good”’?
– Looking at drug development from the perspective of a
single protocol, we may need to consider intrinsic and
extrinsic factors and the way that they may impact upon
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the the additional requirements of each region.
The 3rd Kitasato University - Harvard School of Public Health Symposium
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Responses:
– How should we assess safety data on a global basis?
– How should we use pharmacogenomics?
– In the situation where a very large study will be required
to demonstrate non-inferiority, superiority etc, if this
study is run globally, do we really need a bridging study
to support a development program?
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