beaBridgingStudy.pps

2001/10/22,2nd kitasato-harvard symopium,japanese experience on bridging studies through pmdecs reviews of ndas,national institute of health sciences pmdec (pharmaceuticals and medical devices evaluation center) evaluation division ii yasuhiro fujiwara md, phd,standard disclaimer,“this is not an official mhlw/pmdec guidance or policy statement. no official support of endorsement by mhlw/pmdec is intended or should be inferred.”,the drug regulatory process in japan,clinical trials consultation (opsr) adr report review (pmdec) gcp compliance inspection domestic (opsr) overseas (pmdec) pmdec review expert panel meeting (pmdec) pharmaceutical affairs and food sanitation council (pafsc) meeting (mhlw) licensing/approval decision (minister of health, labor, and welfare),出来薬剤内訳（薬効群）,抗悪性腫瘍薬 循環器官用薬 代謝性医薬品 抗生物質 化学療法剤 眼科耳鼻科用薬 抗薬,呼吸器官用薬 解熱鎮痛消炎薬 中枢神経用薬 剤 泌尿生殖器官用薬,2001会議（大分）機構 森 課長,drugs approved with a prospectively conceptualized bridging strategy during clinical development,as of october 22, 2001 fexofenadine approved on september 22, 2000 oseltamivir approved on december 12, 2000 anastrozole approved on december 22, 2000 sumatriptan approved on june 20, 2001 zolmitriptan approved on june 20, 2001,time from nda submission to approval note: not time clock !,fexofenadine 14.0 months oseltamivir 4.7 months (priority review) anastrozole 13.3 months sumaltriptan 10.7 months zolmitriptan 15.5 months,type of bridging study,fexofenadine : randomized placebo-controlled double-blind dose-finding study (allergic rhinitis n=310) oseltamivir : randomized placebo-controlled double-blind phase iii study (n=316) anastrozole : randomized phase ii study (n=31) clinical pharmacological study (healthy n=48) sumaltriptan : randomized placebo-controlled double-blind dose-finding study (n=274) zolmitriptan : randomized placebo-controlled double- blind dose-finding study (n=289),common complete clinial data package,pk/pd study,japan,us or eu,pk/pd study,bridging study,bridging corresponding study,therapeutic confirmatory long-term administration special population,fexofenadine,急回成功塩酸,申請 11年7月29日 承認 12年9月22日 効能効果： 性鼻炎、蕁麻疹 国内通常実施実薬対照第相比較試験 効能省略事例 通年性性鼻炎、申請当初提出 第相用量検索試験（10 vs 60 vs 120mg bid） 用量 反応性為、 申請後、新、季節性性鼻炎患者対象 二重盲検用量比較試験（ vs 60 vs 120mg bid） 実施、成功。,公開版 非臨床臨床試験成績等関資料 p393 抜粋,pharmacokinetics (fexofenadine) - healthy male volunteer -,japanese,overseas,japanese/overseas,公開版 非臨床臨床試験成績等関資料 p404 抜粋,seasonal allergic rhinitis (fexofenadine),公開版 非臨床臨床試験成績等関資料 p407 抜粋,tss (total symptom score) sneezing rhinorrhea itchy or watery eyes,慢性蕁麻疹関 後付試験妥当性,慢性蕁麻疹、第相用量検索試験 試験位置付、 試験開始当初念頭 。 医薬品機構相談踏、 先立解析計画書追加、 本試験試験位置付。 （公開版審査報告書 ）,公開版 非臨床臨床試験成績等関資料 p395 抜粋,公開版 非臨床臨床試験成績等関資料 p396 抜粋,chronic urticaria (fexofenadine),公開版 非臨床臨床試験成績等関資料 p399 抜粋,change of mean pruritus score,試験妥当性,症例選択基準除外基準 併用薬等治験環境（次：外因性要因参照） 評価尺度、主要評価項目評価（解析）方法 患者間変動大 （投与前症状分布及投与前後変動分布） 薬剤投与期間 検討判断,外因性要因説明重視 extrinsic factors (esp. difference in medical practice) are important,審査、内外診療、教科書、総説等示、診断検査方法、薬物療法、他治療法国内海外差異認示求、内外経口抗薬臨床使用実態調査、内外差示求。 （公開版審査報告書 ）,can histamin-induced wheal and flare reaction (in healthy volunteers) be a bridging study?,no 審査、monroe述（j allergy clin immunol 99:s798-806, 1997）、誘発皮内反応試験、用量反応関係瀬踏行試験、性鼻炎慢性蕁麻疹抗薬臨床的有効性予測、種抗薬臨床的有効性比較用考、皮内反応試験単独試験用判断。 （公開版審査報告書 ） 専門協議判断妥当 （公開版審査報告書 ）,sumatriptan,酸,申請 12年8月2日 承認 13年6月30日 効能効果： 片頭痛 国内通常実施実薬対照第相比較試験 省略事例,公開版 非臨床臨床試験成績等関資料 p290 抜粋,pharmacokinetics (sumatriptan tablet),公開版 非臨床臨床試験成績等関資料抜粋, tablet,japan,overseas,primary efficacy endpoin consisted of the percentage of responders，defined any patients who，at 4 hours after ingesting study drug, reported improvement in headache intensity to mild (grade 1) or pain-free level (grade 0) from a pretreatment level of moderate (grade 3) or severe (grade 4).,anastrozole,extrapolation of foreign clinical data to japan: anticancer drugs,western：,phasestudy （, selection of starting dose）,phasestudy （ antitumor efficacy ）,domestic：,phasestudy （, selection of starting dose ） bridging study pharmacokinetic studies,phase study （ overall survival rate,）,phasestudy （ antitumor efficacy ） bridging study pharmacokinetic studies,postmarketing phase study ( at least two studies ),approval,approval,reference,based on ich e5 (ethnic factors in the acceptability of foreign clinical data), although phase iii studies conducted overseas may be used to satisfy this requirement, in general at least one study must be conducted in japan,time from nda submission to approval - oncology drugs -,before pmdec establishment （march 1991june 1997） median 38.8 months （29.1 77.0) （11 drugs） after pmdec establishment （july 1997 - ） median 14.5 months （3.926.5） （15 drugs),申請 11年11月19日 承認 12年12月22日 （13.3月） 効能効果： 閉経後乳癌 試験（国内後期第相試験） 若干難点、 合技一本、 国内通常必要後期第相試験本本 省略事例,（）,審査、申請者国内薬効確認試験後期第相試験（ (1033jp/0027)）、本剤有効性海外試験同程度確認試験、試験complete clinical data package位置試験如何知見得申請者側十分検討行問題考。、本剤有効性海外試験同程度検証症例数設定含試験計画明確判断考。 （公開版審査報告書）,complete clinical data package 審査解釈,（）,国内海外本薬薬物動態及薬理作用検証試験閉経後乳癌対象実施適切審査判断専門委員同意。 （公開版審査報告書 ）,extrapolation of foreign clinical data to japan: anticancer drugs,western：,phasestudy （, selection of starting dose）,phasestudy （ antitumor efficacy ）,domestic：,phasestudy （, selection of starting dose ） bridging study pharmacokinetic studies,phase study （ overall survival rate,）,phasestudy （ antitumor efficacy ） bridging study pharmacokinetic studies,postmarketing phase study ( at least two studies ),approval,approval,reference,based on ich e5 (ethnic factors in the acceptability of foreign clinical data), although phase iii studies conducted overseas may be used to satisfy this requirement, in general at least one study must be conducted in japan,potential strategies for incorporating preexisting overseas data into development in japan: example 1., overseas phase i data: starting dose calculations for japanese phase i studies may be based upon the overseas experience. for instance, an abbreviated phase i study in japan may begin at a dose level that is below the mtd (as determined overseas) but above the (overseas) starting dose. the exact starting level in the japanese phase i study will differ for each drug, based on the available data.,potential strategies for incorporating preexisting overseas data into development in japan: example 2., overseas phase ii data from studies using the new drug as a single agent may be substituted for a late phase ii study. the other supporting japanese phase ii study(ies) must have been conducted in an acceptable manner (in particular, study sizes must have been sufficiently large). the dose route and schedule of the overseas study should be the same as those used in the japanese study(ies).,potential strategies for incorporating preexisting overseas data into development in japan: example 2 (contd)., when there is a difference between the doses used in the overseas study and in the japanese studies, the sponsor must be able to demonstrate that the difference in dosing will not result in a difference in clinical effect. data to support such an assertion should be based on comparisons of the the results from appropriately designed and well-conducted pk/pd studies conducted both within and without japan.,potential strategies for incorporating preexisting overseas data into development in japan: example 3., overseas phase iii comparative study data may provide data regarding the safety of chronic dosing (e.g., studies of hormonal agents or of adjuvant therapy, etc.) in the preapproval setting. careful consideration should be given to the potential impact upon the study outcomes (and the ability to extrapolate these results to japan) of extrinsic factors, such as variations in treatment patterns, standards of care, etc.,potential strategies for incorporating preexisting overseas data into development in japan: example 4., data from an overseas phase iii comparative study may also be submitted as one of the required postmarketing phase iii studi