What Impact Will Globalization Have on Bridging Studies Katsuyoshi Shimatani J-Clin, Pfizer K. Shimatani/ K-H Symposium/ October 22-23, 2001 1 Number of Consultation for Bridging Studies Successful cases: >20 300 Number of applications 250 Number of consultations for BS 200 150 100 50 0 1997 1998 1999 2000 Kikoh Mr. Mori (07 October 2001) K. Shimatani/ K-H Symposium/ October 22-23, 2001 2 Drug Approved Through the Use of Overseas Data (1) (NCE) Indication of Drug Erectile dysfunction Alzheimer's disease Influenza Depression, Panic disorders Allergy Breast cancer Influenza Breast cancer Bronchial asthma Migraine Date of Approval Overseas Data for January 1999 October 1999 December 1999 August 2000 August 2000 December 2000 December 2000 April 2001 June 2001 June 2001 K. Shimatani/ K-H Symposium/ October 22-23, 2001 Evaluation Evaluation Reference Reference Evaluation Evaluation Evaluation Reference Reference Evaluation 3 Drug Approved Through the Use of Overseas Data (2) (NCE) Year Number of Approvals Approvals with Overseas Data Total Evaluation Reference 1999 39 3 (7.7%) 2 (5.1%) 1 (2.6%) 2000 39 4 (10.3%) 3 (7.7%) 1 (2.6%) 2001* 13 4 (25%) 2 (8.3%) 2 (16.7%) Total 91 11 (11.1%) 7 (6.6%) 4 (4.4%) *: as of October 1 K. Shimatani/ K-H Symposium/ October 22-23, 2001 4 Were the objectives of the bridging study achieved? Was study duplication minimized? Studies not done in Japan for CCDP Phase II: 1 Phase III: 5 Long term study: 3 Special study: 3 K. Shimatani/ K-H Symposium/ October 22-23, 2001 5 Were the objectives of the bridging study achieved? Was the time-lag (drug-lag) between J and W reduced? Time difference of approval between J and W Erectile dysfunction: Alzheimer’s disease: Influenza: Allergy: Breast cancer: Migraine: Average 11 M 36 M 15 M 55 M 65 M 111 M, 52 M 49 M K. Shimatani/ K-H Symposium/ October 22-23, 2001 6 Observations in Bridging Studies (1) Are 20 successful consultations and 11 approval drugs in 3 years sufficient numbers? The drug-lag has shortened but has not disappeared “Bridging” is broadly defined Would it be better to define bridging more narrowly? Most of the drugs that have been approved are ones that meet special medical needs K. Shimatani/ K-H Symposium/ October 22-23, 2001 7 Observations in Bridging Studies (2) Dosage differences There are no set results for determining dosage in bridging studies Should dose response studies be conducted using the same dosage range as that used in the West, or a dosage range that is one step lower? Japan is said to use lower dosages than the West, but is it really that the dosages are scientifically low, or is this simply a matter of culture/ custom? K. Shimatani/ K-H Symposium/ October 22-23, 2001 8 Observations in Bridging Studies (3) Bridging is intended to mainly pursue similarity only, but has it been possible to adequately obtain the information required for Japanese prescribers and patients? Is it necessary to re-confirm efficacy of the drugs in Japanese? There are a lot of cases in which extrinsic factors have been a bigger problem than intrinsic factors K. Shimatani/ K-H Symposium/ October 22-23, 2001 9 Observations in Bridging Studies (4) There are therapeutic areas for which bridging is difficult The use of placebo in psychiatry It is necessary to have a large sample size in order to calculate the true end points in CV area Conducting only 1 bridging study is very risky. Depending on the therapeutic area, reproducibility may be low. Wise way to use overseas data should be considered in order to reduce duplication K. Shimatani/ K-H Symposium/ October 22-23, 2001 10 Bridging Study Benefits 1. Drugs for which it would be difficult to obtain approval based only on the Japanese data have been approved through the use of overseas data 2. The duplication of clinical data has been minimized through the use of overseas data 3. The time required for development has been reduced With the introduction of the new GCP 4. The quality of Japanese clinical studies has improved 5. Awareness of clinical studies has improved among investigators, sponsors, and others K. Shimatani/ K-H Symposium/ October 22-23, 2001 11 Bridging Study Transitions Retrospective bridging The bridging of similar aspects based on studies already conducted or underway in the West and Japan Prospective bridging The design and conduction of new studies in Japan that are similar to studies already conducted in the West Advanced bridging The design and conduction of new studies in both the West and Japan for the purpose of bridging K. Shimatani/ K-H Symposium/ October 22-23, 2001 12 Future options of clinical trials under Globalization 1. Advanced bridging studies 2. Global studies K. Shimatani/ K-H Symposium/ October 22-23, 2001 13 Advanced Bridging Studies (1) ( 1 ) Protocols of overseas studies should be designed aiming to bridge Japanese studies. Japan must input to overseas protocols. K. Shimatani/ K-H Symposium/ October 22-23, 2001 14 Advanced Bridging Studies (2) ( 2 ) Even if Japan start later, the NDAs can be simultaneous West Phase I Japan Phase II Phase III Phase I Phase II Simultaneous NDA This strategy could be applied for the therapeutic areas: No difference in medical practices End points already validated (precedent) Easy to get consistent results K. Shimatani/ K-H Symposium/ October 22-23, 2001 15 Global Studies Why Global Studies? 1) ICH recommend to avoid redundancy of clinical studies which have been already done in overseas However, MHLW/ Japanese prescribers need to see Japanese data 2) There are difficult areas to conduct clinical studies in Japan Small patient population (cancer and others) Mega-trial (cardiac events, bone fracture) Difficult to have consistent result (psychiatry and others) Global studies Simultaneous NDA K. Shimatani/ K-H Symposium/ October 22-23, 2001 16 Points to be discussed in Global studies Speed and Quality Sample size Similarity Dosage Study design Medical practice K. Shimatani/ K-H Symposium/ October 22-23, 2001 17 Speed and Quality Has the Japanese clinical trial environment improved? YES, but……. Collaboration with Asian Countries K. Shimatani/ K-H Symposium/ October 22-23, 2001 18 Collaboration with SMO 250 Target No of pts Actual No. of pts 200 No of sits (drug shipment) 150 100 50 K. Shimatani/ K-H Symposium/ October 22-23, 2001 Oct-00 Sep-00 Aug-00 Jul-00 Jun-00 May-00 Apr-00 Mar-00 Feb-00 Jan-00 Dec-99 Nov-99 Oct-99 Sep-99 0 19 Sample size/ Similarity Is it possible to reduce sample size? Is it necessary to prove efficacy only in Japanese patients? Bridging Global study Prove efficacy 1,000 1,000 Prove efficacy Similarity 400 W J Prove efficacy 200 Similarity K. Shimatani/ K-H Symposium/ October 22-23, 2001 20 Similarity K. Shimatani/ K-H Symposium/ October 22-23, 2001 21 Dosage From PK profile West L M H Japan option 1 L M H L M option 2 option 3 l conduct Phase IIa K. Shimatani/ K-H Symposium/ October 22-23, 2001 22 Study design/ Medical practice To allow some flexibility in designing of protocol in order to satisfy with local needs - Diagnosis - Primary endpoints - Severity - Secondary endpoints - Demography - Dosage K. Shimatani/ K-H Symposium/ October 22-23, 2001 23 Summary (1) Bridging studies minimize the duplication of studies and increase the chances of approval Differences in extrinsic factors are more important than intrinsic factors in bridging studies K. Shimatani/ K-H Symposium/ October 22-23, 2001 24 Summary (2) As an important alternative to bridging studies, we should think to conduct global studies. In particular, we should be aggressive in looking into this for therapeutic areas in which clinical studies are difficult to conduct in Japan alone. In such cases, we should be flexible in choosing sample sizes and protocol designs that will allow both the global objectives as well as the local objectives to be achieved. We need to explore options that would allow us to collaborate with other countries in Asia when conducting global studies K. Shimatani/ K-H Symposium/ October 22-23, 2001 25
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