Some Closing Remarks

Scope of Symposium Simultaneous Worldwide Development Strategies & Pharmacogenomics: 6 Sessions –1. Overview: Drs. Yazaki; Fujiwara, Wu, Jang, Malhotra, Murasake, Ishigooka, Hayashi, Kato, Kuemer –2. New Challenges: Drs. Imura, Tanigawara, Takei, Boyle, Nagata, Shimatani –3. ICHE5: Drs. O’Neill, Farrell, Loew, Ferris, Lewis, Ono –4. More Conrete Plans/Actions based on ICH and APEC report: Drs. Takeuchi, Azuma, Iwasaki,hi,Wood –5. Pharmacogenomics: drug discovery/development based on genetic analysis: Drs. Kamataki, Nihira, Riddell, Rakin, Horii, Sasai, Gushima –6. Implementation of Global Development Programs: Drs. Doogan, Uden, Kurokawa, Gans

Excellent Presentations and Discussion Too little time to review each session Will try to synthesize discussions Much progress in evolution of ICH E5 issues and initial experience in bridging studies Important distinction between Bridging versus Simultaneous Global Strategies: –Bridging: serial, evaluating and expanding existing information for evaluation of risks/benefits of a drug in a new region –Simultaneous: concurrent studies; presumably all regions will benefit from each study Potential to shorten time needed for worldwide availability of effective new drugs Likely to require fewer resources => Bridging studies likely to be less needed as legacy drugs are evaluated more fully; simultaneous worldwide development will play a greater role.

Premise KEY PREMISE: Timely approval of effective drugs, and non-approval of drugs that are ineffective or unacceptably toxic are the goals. In some ways, these can be seen as competing with one another: the latter suggests extreme caution prior to approval. Yet delays in process may also delay the availability to the public of effective and safe drugs. This makes regulators role especially challenging.  We must maintain high standards yet constantly look for ways of expediting evaluation of drugs  Bridging studies are by their nature imply a sequential versus simultaneous development/evaluation strategy. Whenever possible, simultaneous studies will produce information more quickly and be beneficial to a broader audience since bridging studies really only intended to help the new region.

Many Remaining Challenges Group into 3 broad & overlapping categories: –Scientific –Regulatory –Infrastructure

Some Scientific Challenges Deeper understanding of ethnic differences in disease rates and responsiveness to treatment: explainability via genomic information will have substantial advantages in understanding the role of a new treatment Bridging Studies - when is a bridging study necessary? - how large should a PK bridging study be? - how large should a PK/PD study be? Simultaneous worldwide studies -one versus several simultaneous studies -minimal sample size per participating country? -2 primary endpoints that individual countries weigh differently with respect to approval? Pharmacogenomics: initial role: explaining apparent associations (eg, ethnicity) at a more causal level; identifying patient subgroups who are more/less likely to benefit from treatment or have an AE

Some Infrastructure Challenges -Greater engagement by physicians in trials - availability of physician time - appreciation of clinical research in academia - physician training in clinical research and issues - Familiarity in data management; QA/QC - adequate expertise - adequate time -Familiarity with working together in multicenter studies: common procedures, assay methods

Some Regulatory Challenges Challenges to regulators are formidable Need to reach common agreement on a study’s design, its conduct, and how it will be analyzed. Shortage of MO and statisticians limits both design of multinational trials as well as review of their results. –Numbers of MOSs/statisticians in regulatory agencies in Japan, Taiwan, Korea is woefully low. –Need to increase substantially and make the work challenging and interesting to attract and retain high quality physicians/statisticians.

Next Steps 1. Continued research into designs for and analyses of multinational trials and bridging studies: –a. how much evidence is needed about safety, efficacy, dose- response in each participating country? Will vary with disease, type of drug, knowledge of drug class, prior beliefs on whether treatment efficacy varies among subpopulations. –b. designing several trials that can be simultaneously conduct i. Study 1: Phase III; regions 1, 2, 3 ii. Study 2: Phase III (confirmatory); in regions 2,4,5 iii. PK substudies versus separate studies in same/other regions iv. How much flexibility in concomitant meds; criteria for dose modification based on side-effects, etc among participating countries 2. Pharmacogenomics: combine genetic information with other to see if apparent associations between ethnicity and outcome variables explainable by genetic information

Next Steps (continued) 3. Training: develop greater expertise in clinical research studies among academia physicians engaged in research 4. Regulatory: -increase number of medical officers and statisticians to improve quality and speed of review process -promote interactions among regulators from different countries (eg, Asian countries) in hopes of identify commonality in how bridging and simultaneous global studies can be conducted.

Thank you for attending and participating!!