Wednesday October 2nd - Thursday October 3rd, 2002 New Ohtani Hotel, Tokyo

1. 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

2. The 3rd Kitasato University - Harvard School of Public Health Symposium Current Situation of Regulatory and Clinical Environment • 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

3. 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 terms of the scientific evaluation of the data

4. 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 simply not comparable

5. 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.

6. The 3rd Kitasato University - Harvard School of Public Health Symposium Bridging Strategies Issues: Regulatory Bodies, Statistical concerns Comments: • 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

7. 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 global studies - how can we achieve this?

8. 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?

9. 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?

10. The 3rd Kitasato University - Harvard School of Public Health Symposium • 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 sub-populations 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?

11. The 3rd Kitasato University - Harvard School of Public Health Symposium • 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 the the additional requirements of each region.

12. The 3rd Kitasato University - Harvard School of Public Health Symposium • 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?