Issues on Late Medication Improvement in Japan.

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Issues on Late Medication Improvement in Japan. Masahiro Takeuchi Hajime Uno Fumiaki Takahashi. Plot. Presentation Clinical Trial Environment Late Research and development Pattern Factual Issues and Potential Methodologies Wellbeing Issues Conclusion. Presentation. ICH - Broadly useful
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Issues on Recent Drug Development in Japan Masahiro Takeuchi Hajime Uno Fumiaki Takahashi

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Outline Introduction Clinical Trial Environment Recent R&D Trend Statistical Issues and Potential Approaches Safety Issues Conclusion

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Introduction ICH - General Purpose Unification of fundamental documentation and its organizations for NDA accommodation E5 Guideline : Extrapolation of remote clinical information Avoidance of superfluous clinical trials New GCP Guideline Quality affirmation of clinical trial information Simultaneous Global Drug Development Better medications in an opportune manner

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Regulatory Environment Review time various sanction drugs by use of E5 rule

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Clinical Trial Environment in Japan

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Current Situation in Japan Clinical Trial Costs: Very High Numbers of Clinical Trials: Diminishing

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Costs of Clinical Trials in Japan Average expense per understanding every year Relative expense per quiet Presentation by Dr. Uden at 3 rd Kitasato-Harvard Symposium, 2002

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No. of Initial Clinical Trial Notifications

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Location of Clinical Trials led by Japanese Companies Even Japanese organizations conduct clinical trials in remote nations

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Speed of Clinical Trials in Japan

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Domestic organizations direct their clinical trials outside of Japan High cost to lead clinical trials Slow speed of clinical trials Hollowing out of Clinical Trials

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Recent R&D Trend From spanning to worldwide studies Importance of essential science

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Concept: Avoidance of Unnecessary Clinical Trials Bridging studies Foreign information New Regions Simultaneous worldwide studies US EU ASIA

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Issues to be indicated Intrinsic components Extrinsic elements Intra variability >> Inter variability Conduct of a proposed clinical trial among areas Difference in Medical Practice - Different study outline - Different unfriendly occasion reporting framework

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Intrinsic elements (Influence of Genotype) Fukuda et. al.(2000) explored whether the attitude of venlafaxine was influenced by the CYP2D6 genotype. # subject=36 blue(*10/*10) = 6 red(*1/*10,*2/*10)=13 orange(*1/*1,*1/*2,*2/*2)=16 green(others)=1 may influence adequacy and security – modification of dose

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Mixture of Target Disease Population DNA small scale exhibit: NEJM,2002 - Target Population: diffuse substantial B-cell lymphoma - Efficacy : anthracycline chemotherapy - 35% - 40% - blend of target malady populace Gene expression: -gathered target populace -obviously characterized target sickness populace

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Mixture of Target Disease Population DNA smaller scale cluster: NEJM,2002 Cox relapse Gene-expression marks: 4 particular quality expression marks score by the 4\'s mix marks

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Extrinsic elements Different therapeutic practice Ex: Depression Trials US and EU : Placebo Controlled Trial Japan : Non-inadequacy Trial or Placebo Controlled Relapse Trial

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3 Major Studies

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Lessons Intrinsic elements: outline (stage I and II) Importance of essential science Clear meaning of an objective populace - P450 data: explore singular variety w.r.t. viability and wellbeing - pharmacogenomics: conceivably distinguished individual qualities - surrogate markers: speedy discovery of adequacy distinctive edges of profile - PPK examination: examination of conceivable components

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Lessons Extrinsic variables R ealization of conductivity of an arranged trial Regulatory perspectives: New GCP execution administrative science hone – relies on upon structure of a survey framework Design viewpoints: study outline: diverse therapeutic practice free information checking panel Simulation concentrates presumably assume a critical part for future forecast

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Statistical Issues and Potential Approaches How can insights assume a part in extrapolation of remote clinical information?

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Statistical Issues Intrinsic components Clearly characterized target populace intra-variability >> between variability Randomization Scheme Statistical Issues: Definition of similitude Statistical test versus point estimation Variability inside of a district Required example size?

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Practical Issues Extrinsic variables Conductivity of a proposed clinical trial Regulatory organizations Different restorative practice Statistical Issues: What ought to be appeared? Comparability: measurements reaction, viability Regulatory science Placebo reaction: how to appraise Different medicinal practice

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Kitasato-Harvard-Pfizer-Hitachi venture Under different settings, utilizing genuine information sets and reenactment methods, we are attempting to make sense of how to manage the imperative issues concerning outline and investigation of worldwide clinical trials. Task colleague [Kitasato] M. Takeuchi, X. M. Tooth, F. Takahashi, H. Uno [Harvard] LJ Wei [Pfizer] C. Balagtas, Y. Ii, M. Beltangady, I. Marschner [Hitachi] J. Mehegan The 6 th Kitasato-Harvard Symposium, Oct 24-25, 2005, Tokyo, Japan

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Global/Multi-national Trials Global trials include numerous locales/nations. Worldwide trials give us data about investigational medication overall at the same time. As to getting new medication regard, there is the way that every district/nation has its own administrative approach. A ton of factual issues for DESIGN , ANALYSIS and MONITORING of worldwide trials still remain. we are attempting to make sense of how to manage these issues, utilizing genuine information sets. Today’s talk is worried with the examination issues in regards to nearby induction .

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Questions Although a solitary synopsis of the treatment distinction crosswise over nations is vital, however neighborhood induction is likewise alluring. What would we be able to say in regards to the treatment contrast in one nation, for instance, in Japan (with ONLY 14 subjects)? Could we think about the treatment distinction got from “pooled analysis” as that in Japan? Should we trust the outcomes got from “by-nation analysis” ? Can we obtain the data from different nations? How to obtain data? → One of the testing factual issues

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An experimental Bayes methodology Fit Cox model to every nation Normal rough guess of MLE for the treatment distinction Fit a Normal-Normal various leveled model (next page) Get the back appropriation of and Confidence Set. : treatment contrast : covariate 1=treatment gathering 0=control gathering : gauge peril capacity for k - th nation : treatment distinction for k - th nation Get CI for Analysis model for neighborhood surmising One compelling Pooled Analysis (acquiring specifically) another amazing By-nation Analysis (getting NO data) Compromised methodologies in the middle of (obtaining data) Suppose Cox-model Fit the stratified Cox model (strata=country) Fit the Cox model to every nation Get CI for

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A typical ordinary various leveled model Distribution of irregular parameter of interest True treatment Difference in every nation Individual Sampling Density

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An ordinary typical progressive model Distribution of arbitrary parameter of interest True treatment contrast In every nation Normal Approx. of MLE Individual Sampling Density

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An ordinary typical various leveled model Empirical Bayes: Estimating UNKOWN hyper parameter utilizing watched information Distribution of irregular parameter of interest True treatment contrast In every nation Normal Approx. of MLE Individual Sampling Density

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A motivation behind why we picked a N-N model on EB There is a surely understood issue on EBCI: “Naive” EBCI neglects to accomplish their ostensible scope likelihood. “Naive” EBCI is built from the back circulation of with connecting to the evaluations to obscure However, since are arbitrary, the back difference ought to be The term under the square root is only a rough guess of the first term of RHS in above mathematical statement. There are a ton of writing concerning EB for a N-N model. A few hypotheses are accessible to revise “Naive” EBCI particularly for a N-N model. (Morris (1983), Laird & Louis (1987), Carlin & Gelfand (1990), Datta et al (2002), and so on.)  We connected the Morris’ remedy in the accompanying examination.

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Approximated probability/Posterior conveyance Pooled Analysis Empirical Bayes By-Country Analysis

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Simulation contemplates A little recreation study was led to assess the execution of this methodology under the Cox model. The quantity of nations and the example size in every nation were altered, assessed the scope likelihood and normal length of certainty interim were assessed in view of 10,000 cycles. Recreation plan : Parameter of interest (treatment contrast): Survival time of gathering A: Survival time of gathering B: Censoring time of both gatherings: Thus, created information for gathering A: produced information for gathering B: , the scope likelihood of 95% CI is computed

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Conclusion This experimental Bayes approach (Normal-Normal progressive model combined with typical rough guess of the treatment\'s estimator distinction) can be utilized as a part of a wide mixed bag of circumstances. From a reenactment study, the execution of this methodology was not terrible regarding both scope likelihood and length of CIs. As to RALES information, this examination gives shorter CIs and recommends that the treatment contrasts among every nation are toward the same course. In worldwide clinical trials, performing this sort of middle of the road investigation can be empowered as an arranged affectability examination no

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