ICH E9 (R1) 臨床試験のための統計的原則〜中間事象に対するストラテジー

*$)& 3 ྟচࢼݧͷͨΊͷ౷ܭతݪଇɹิҨͷ֓ཁɾࣄྫ   ྟচࢼݧʹ͓͚ΔFTUJNBOEͱײ౓෼ੳ ྟচӸֶݚڀʹ͓͚Δใࠂͷ࣭޲্ͷͨΊͷ౷ܭֶͷݚڀձ ୈճݚڀूձ ࠤ౻ढ़ଠ࿕ ৫ా఩࿕ தాඒ௡ࢠ

*$)&ͱ͸Կ͔ʁ 2 ྟচࢼݧͷͨΊͷ౷ܭతݪଇʢಠཱߦ੓๏ਓҩༀ඼ҩྍػث૯߹ػߏʣɺIUUQTXXXQNEBHPKQJOUBDUJWJUJFTJOUIBSNPOZJDIIUNM w *$)ͷ߹ҙʹج͖ͮɺྟচࢼݧʹ͓͚Δ౷ܭతݪଇʹ͍ͭͯهࡌͨ͠΋ͷ w ঝೝ৹ࠪͷͨΊͷࢿྉͰ͋Δ͕ɺҰൠతͳྟচࢼݧʢ؍࡯ݚڀ΋ؚΉʣʹ΋ద༻Մೳ w ྟচࢼݧ͔ΒಘΒΕΔ݁ՌͷภΓΛ࠷খʹ͠ɺਫ਼౓Λ࠷େʹ͢Δ͜ͱΛ໨ඪͱ͢Δ

*$)& 3 ͱ͸Կ͔ʁ 3 ಠཱߦ੓๏ਓҩༀ඼ҩྍػث૯߹ػߏɺIUUQTXXXQNEBHPKQJOUBDUJWJUJFTJOUIBSNPOZJDIIUNM w *$)&ͷิҨʢิॿతͳࢿྉʣ w ྟচࢼݧͷܭըɺσβΠϯɺ෼ੳͦͯ͠ղऍΛ໌ྎʹ͢Δ͜ͱΛ໨తʹ͍ͯ͠Δ w
*$)ͷ࠷ऴ߹ҙ͸͞Ε͍ͯΔɻ೔ຊͰ͸·ͩن੍΁ͷऔΓೖΕΒΕ͍ͯͳ͍ w ਖ਼ࣜͳ೔ຊޠ༁͸ଘࡏ͠ͳ͍ w ωοτʹ͋Δ೔ຊޠ༁͸ݹ͍ w τϨʔχϯάϚςϦΞϧ͕ຊจΑΓΘ͔Γ΍͍͢

ࠓճͷษڧձͷΩʔϫʔυ 4 தؒࣄ৅ &TUJNBOE ετϥςδʔ ײ౓෼ੳ

தؒࣄ৅ʹରԠ͢ΔͨΊͷετϥςδʔ *$)& 3 ྟচࢼݧͷͨΊͷ౷ܭతݪଇɹิҨͷ֓ཁɾࣄྫ   ྟচࢼݧʹ͓͚ΔFTUJNBOEͱײ౓෼ੳ ࠤ౻ढ़ଠ࿕ ௕࡚େֶපӃྟচݚڀηϯλʔ TIVOUBSPTBUP!OBHBTBLJVBDKQ !4IVOUBSPPP

͜ͷηΫγϣϯͰѻ͏಺༰ 6

ཧ૝తͳྟচࢼݧʢ3$5ʣ 7 *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ͳ͠ɺࢼݧ׬਱
தؒࣄ৅ͳ͠ɺࢼݧ׬਱ #BTFMJOF NPOUIT ࣏ྍΛׂΓ෇͚ΒΕͨױऀ͕ɺׂΓ෇͚ΒΕ࣏ͨྍΛ९क͠ɺதؒࣄ৅͕ൃੜͤͣɺࢼݧΛ׬਱ ׂΓ෇͚ͨ   ࣏ྍ ࣮ࡍͷ࣏ྍ Ξ΢τΧϜ ަབྷҼࢠ w ࣏ྍΛϥϯμϜʹׂΓ෇͚Δ͜ͱͰɺަབྷҼࢠͱ࣏ྍͱ ͷؔ܎Λ੾Δ w ׂΓ෇͚࣏ͨྍͷޮՌΛόΠΞεͳ͘ޮՌΛਪఆͰ͖Δ w ͜ͷঢ়گͰ͸ɺׂΓ෇͚࣏ͨྍޮՌ࣮ࡍͷ࣏ྍޮՌ ࣏ྍޮՌͰ͸ͳ͘ɺׂΓ෇͚࣏ͨྍͷޮՌ*55F ff FDU

தؒࣄ৅͕ى͜ΔͱͲ͏ͳΔ͔ʁ 8 ׂΓ෇͚ͨ   ࣏ྍ ࣮ࡍͷ࣏ྍ Ξ΢τΧϜ ަབྷҼࢠ ͍ͨΔͱ͜ΖͰόΠΞεܦ࿏͕Ͱ͖Δ தؒࣄ৅
$2ͱ߹͏ޮՌΛ໌֬ʹɻԿΛਪఆ͍ͨ͠ͷ͔ʁ &TUJNBOE &TUJNBOEͷߏ੒ཁૉ தؒࣄ৅ʹର͢Δετϥςδʔ

&TUJNBOEͷߏ੒ཁૉʢ&TUJNBOEBUUSJCVUFTʣ 9 & 3 ʹ४ͨ͡ &TUJNBOEͷߏ੒ཁૉ ߟ͑΍͍͢   &TUJNBOEͷߏ੒ཁૉ ఆٛ
5SFBUNFOU ࣏ྍܭը ؔ৺ͷ͋Δ࣏ྍܭըͱൺֱରর 1PQVMBUJPO ର৅ूஂ $2ͷղܾΛ໨ඪͱ͍ͯ͠Δूஂ 7BSJBCMF Ξ΢τΧϜఆٛ $2Λߟ͑ɺରॲ͢ΔͨΊͷױऀҰਓͻͱΓ͔Βऔಘ͢Δม਺ ର৅ͷதؒࣄ৅ ࣏ྍ։࢝ޙʹൃੜ͠ɺղऍ΍Ξ΢τΧϜͷଘࡏʹӨڹ͢Δࣄ৅ 1PQVMBUJPOMFWFM TVNNBSZ ूஂϨϕϧͷཁ໿ ఆ࣏ٛͨ͠ྍ৚݅Λൺֱ͢ΔͨΊͷཁ໿ࢦඪ 0UIFSJOUFSDVSSFOU FWFOUT ্ͰఆΊ࣏ͨྍํ਑ɺର৅ूஂɺΞ΢τΧϜఆٛʹ൓ө͍ͯ͠ͳ͍தؒࣄ৅ 1IBN5. 5XFFE$% $BSQFOUFS+3 ,BIBO#$ /VOO"+ $SPPL". FUBM3FUIJOLJOHJOUFSDVSSFOUFWFOUTJOEF fi OJOHFTUJNBOETGPSUVCFSDVMPTJT USJBMT$MJO5SJBMT0DU r

$2͔Β&TUJNBOEετϥςδʔ΁ 10 $2 ݚڀ໨త தؒࣄ৅ ࣏ྍํ਑ ର৅ूஂ ม਺ ͲͷΑ͏ʹதؒࣄ৅ΛऔΓѻ͏͔ʁ &TUJNBOEετϥςδ
w ࣏ྍํ਑ετϥςδʔʢ5SFBUNFOUQPMJDZTUSBUFHZʣ w Ծ૝ετϥςδʔʢ)ZQPUIFUJDBMTUSBUFHZʣ w ෳ߹ετϥςδʔʢ$PNQPTJUFTUSBUFHZʣ w ࣏ྍԼετϥςδʔʢ8IJMFPOUSFBUNFOUTUSBUFHZʣ w ओཁ૚ετϥςδʔʢ1SJODJQBMTUSBUVNTUSBUFHZʣ

࣏ྍํ਑ετϥςδʔʢ5SFBUNFOUQPMJDZTUSBUFHZʣᶃ 11 w தؒࣄ৅ͷൃੜͱ͸ແؔ܎ʹɺ࣏ྍޮՌΛఆٛ͢Δ ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜɺࢼݧ్த୤མ தؒࣄ৅ͳ͠ɺࢼݧ్த୤མ
#BTFMJOF NPOUIT ϨεΩϡʔ ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͯ͠΋ɺ࠷ऴ؍࡯·Ͱ௥੻ ࢼݧ్த୤མͨ͠ͱ͜Ζ·Ͱͷ৘ใͰɺ   ࠷ऴ؍࡯࣌ͷσʔλΛิ׬ #BTFMJOF NPOUIT ϨεΩϡʔ ͜Ε·Ͱͷࢼݧ ࣏ྍํ਑ετϥςδʔ ࠷ॳʹׂΓ෇͚ΒΕ࣏ͨྍͱ   ͦͷͱ͖ͷूஂ৘ใͷΈͰɺ   *55Λఆٛ ಉҙఫճ ಉҙఫճ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ

࣏ྍํ਑ετϥςδʔᶄ 12 ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͯ͠΋ɺ࠷ऴ؍࡯·Ͱ௥੻ ࢼݧ్த୤མͨ͠ͱ͜Ζ·Ͱͷ৘ใͰɺ   ࠷ऴ؍࡯࣌ͷσʔλΛิ׬
#BTFMJOF NPOUIT ϨεΩϡʔ ࣏ྍํ਑ετϥςδʔ ಉҙఫճ w ิ׬ํ๏͸೉͍͠ w ऴ຤Πϕϯτʢࢮ๢ʣͷ৔߹ɺͲ͏͢Δ͔ w ͦ΋ͦ΋ิ׬͢Δ΋ͷͱ͸ʁ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ w ࣏ྍࣗମͷޮՌͰ͸ͳ͘ɺ࣏ྍʹׂΓ෇͚ΒΕͨͱ͖ͷ૯߹తͳޮՌΛਪఆ͢Δ w ࣏ྍதࢭͱࢼݧதࢭͱΛ۠ผ͢Δ w தؒࣄ৅͕ൃੜͯ͠΋࠷ऴ؍࡯·Ͱ௥੻͢Δ w Ͳ͏ͯ͠΋ܽଌ͕ग़Δ৔߹ɺ౷ܭֶతख๏Λ༻͍ͯิ׬͢Δ

Ծ૝ετϥςδʔʢ)ZQPUIFUJDBMTUSBUFHZʣ 13 w தؒࣄ৅͕ى͖ͯͳ͍͜ͱΛԾఆͯ͠ɺ࣏ྍޮՌΛఆٛ w ྙཧతͳཧ༝͔ΒϨεΩϡʔ͕ඞཁ͕ͩɺϨεΩϡʔΛ࢖Θͳ͔ͬͨ৔߹ͷ࣏ྍޮՌΛ஌Γ͍ͨ w ͍ͭ͘΋ͷԾ૝ঢ়ଶΛఆٛͰ͖Δ w ͦͷԾ૝ঢ়ଶʹྟচతͳҙຯ͕͋Δ͔͸ৗʹݕ౼͢Δ
ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͨ͠ͱ͜Ζ·Ͱͷ৘ใͰɺ   ࠷ऴ؍࡯࣌ͷσʔλΛิ׬ #BTFMJOF NPOUIT ϨεΩϡʔ Ծ૝ετϥςδʔ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ w ࠞ߹ޮՌϞσϧΛ༻͍ͯղੳ͢Δ͜ͱ͕ଟ͍ w ʢ͜Ε͸ैདྷͷ*55Ͱͷղੳͱͯ͠ඪ४తͳํ๏ʣ

ෳ߹ετϥςδʔʢ$PNQPTJUFTUSBUFHZʣ 14 w தؒࣄ৅ͷൃੜΛΤϯυϙΠϯτͷఆٛʹऔΓೖΕΔ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ ױऀ ױऀ ױऀ
தؒࣄ৅ͳ͠ ྟচతʹҙຯͷ͋Δਖ਼ͷมԽ w தؒࣄ৅ൃੜྟচతʹҙຯͷ͋ΔෛͷมԽ w ೋ஋σʔλͰ΋Մ w ॱҐσʔλͰ΋Մ w ෳ߹ΤϯυϙΠϯτ w ແ૿ѱੜଘظؒ w XJOSBUJP #BTFMJOF NPOUIT ϨεΩϡʔ ෳ߹ετϥςδʔ தؒࣄ৅ͳ͠ ྟচతʹҙຯͷ͋ΔෛͷมԽ w ऴ຤Πϕϯτ΋͏·͘ѻ͑Δ w ܽଌ΋ى͜ΓͮΒ͍

࣏ྍԼετϥςδʔʢ8IJMFPOUSFBUNFOUTUSBUFHZʣ 15 w தؒࣄ৅͕ى͖Δ·ͰͷظؒΛΤϯυϙΠϯτͷఆٛʹऔΓೖΕΔ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͨ͠ͱ͜Ζ·Ͱͷ৘ใΛ༻͍Δ #BTFMJOF NPOUIT
ϨεΩϡʔ ࣏ྍԼετϥςδʔ ͜ͷظؒͷ৘ใ΋ར༻ w ྫͱͯ͠ɺൃੜ཰ͰධՁ w ϙΞιϯճؼϞσϧʢෛͷೋ߲ճؼʣͰɺޮՌࢦඪΛਪఆ w ϋβʔυ͕࣏ྍظؒத͸มԽ͠ͳ͍͜ͱΛԾఆ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ

ओཁ૚ετϥςδʔʢ1SJODJQBMTUSBUVNTUSBUFHZʣ 16 w ؔ৺ͷ͋Δ૚ʹରͯ͠ͷΈͷ࣏ྍޮՌΛߟ͑Δ ײછ঱ ײછ঱ ϫΫνϯະ઀छ܈ ϫΫνϯ઀छ܈ ྫɿϫΫνϯ઀छޙͷײછ঱ൃ঱ྫΛର৅ʹॏ঱౓΁ͷ༧๷ޮՌΛධՁ͍ͨ͠ ॏ঱ͷׂ߹
ॏ঱ͷׂ߹ ױऀ தؒࣄ৅ΛൃੜޙͷΞ΢τΧϜʹ஫໨ #BTFMJOF NPOUIT ओཁ૚ετϥςδʔ ओཁ૚ ࣮ࡍʹײછ͔ͨ͠Ͳ͏͔Ͱͳ͘ɺ   જࡏతʹײછ͠͏Δ૚Λର৅ʹ͢Δ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ

ετϥςδʔͷ੔ཧ 17 ݚڀ໨త ؔ৺ͷ͋Δ࣏ྍ಺༰ .BMMJODLSPEU$) #FMM+ -JV( 3BUJUDI# 0`,FMMZ. -JQLPWJDI*
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ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶃ 24 w ຫੑด࠹ੑഏ࣬ױʢ$01%ʣʹର͢ΔࡎʹΑΔݻఆ༻ྔϨδϝϯ͸༻ྔͰ͸ݕ౼͞Ε͍ͯͳ͍ w ٵೖεςϩΠυɺ௕࣌ؒ࡞༻ੑ߅ίϦϯༀʢ-"."ʣɺ௕࣌ؒ࡞༻ੑЌܹࢗༀʢ-"#"ʣ w ओཁධՁ߲໨ɿ$01%૿ѱͷ೥ؒൃੜ཰ w ࣏ྍதࢭޙ΋σʔλऔಘ
ࡎซ༻ʢٵೖεςϩΠυЖHʣ ࡎซ༻ʢٵೖεςϩΠυЖHʣ ࡎซ༻" ࡎซ༻# ݚڀܭըॻΑΓҾ༻ 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP (MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP7FSZ4FWFSF$01%/&OHM+.FE+VM r

ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶄ 25 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM
r &/%10*/54   "DPNQSFIFOTJWFGSBNFXPSL BTEFTDSJCFEJO SFDFOUSFHVMBUPSZHVJEFMJOFT XBTVTFEUPQSPWJEF DMBSJUZJOUIFEFTDSJQUJPOPGFTUJNBUFTPG USFBUNFOUF ff FDU JODMVEJOHUIFIBOEMJOHPG QPUFOUJBMMZDPOGPVOEJOHFWFOUT TVDIBT USFBUNFOUEJTDPOUJOVBUJPOT   &BDIBQQSPBDIJTEFOPUFECZBEJ ff FSFOU lFTUJNBOEzBUBSHFUPGFTUJNBUJPOUIBUJODMVEFT UIFBOBMZTJTQPQVMBUJPOBOEUIFFOEQPJOU WBSJBCMFPSWBSJBCMFTBOEQSFTQFDJ fi FTUIFXBZJO XIJDIUIFTFDPOGPVOEJOHFWFOUTXJMMCFIBOEMFE JOUIFBOBMZTJT ࣏ྍதࢭͳͲͷજࡏతͳަབྷࣄ৅ͷऔΓѻ͍Λؚ Ή࣏ྍޮՌͷਪఆ஋ͷهड़Λ໌֬ʹ͢ΔͨΊʹɺ ࠷ۙͷن੍ΨΠυϥΠϯʹهࡌ͞Ε͍ͯΔแׅత ͳ࿮૊ΈΛ࢖༻ͨ͠ɻ   ֤Ξϓϩʔν͸ɺҟͳΔʮFTUJNBOEʯʹΑͬͯࣔ ͞ΕΔɻ&TUJNBOEͱ͸ɺղੳूஂͱΤϯυϙΠϯ τม਺ΛؚΉਪఆର৅Ͱ͋Γɺղੳʹ͓͍ͯ͜Ε Βͷަབྷࣄ৅ΛͲͷΑ͏ʹѻ͏͔Λ͋Β͔͡Ίن ఆ͢Δɻ ֓೦ͷઆ໌͕ඞཁ

ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶅ 26 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM
r &TUJNBOE આ໌ ղੳର৅ूஂ & 3 Ͱͷ &TUJNBOE 1SJNBSZ FTUJNBOE & ffi DBDZ ࣮ࡍͷ९कঢ়گʹؔ܎ͳ͘ɺݚڀظؒத͸ϥϯμϜԽ͞ Ε࣏ͨྍ͕ܧଓ͢ΔͱԾఆͨ͠৔߹ͷɺ͢΂ͯͷඃݧऀ ʹ͓͚ΔϥϯμϜʹׂΓ෇͚ΒΕ࣏ͨྍޮՌ NPEJ fi FE*55 Ծ૝ ࣏ྍԼ "EEJUJPOBM FTUJNBOE "UUSJCVUBCMF ೜༰ੑ·ͨ͸༗ޮੑͷܽ೗ͳͲͷཧ༝ʹΑΔϥϯμϜԽ ͞Εͨ౤ༀͷதࢭΛ޷·͘͠ͳ͍݁ՌͱΈͳ࣏ͨ͠ྍ ޮՌ NPEJ fi FE*55 ෳ߹ ࣏ྍԼ 5SFBUNFOU QPMJDZ ϥϯμϜԽ͞Ε࣏ͨྍ͕ܧଓ͞ΕΔ͔Ͳ͏͔ʹؔ܎ͳ ͍ɺϥϯμϜʹׂΓ෇͚ΒΕ࣏ͨྍޮՌ *55 ࣏ྍํ਑ 1FSQSPUPDPM ݚڀܭըॻ͔Βͷେ͖ͳҳ୤͕ͳ͍ूஂʹ͓͚Δ࣏ྍ ޮՌ 114 NPEJ fi FE*55ඃݧऀ͕ϥϯμϜׂΓ෇͚͞Ε࣏ͨྍΛதࢭ͢ΔલʹಘΒΕͨσʔλͷΈΛར༻͢Δ*55 & 3 ʹͩ͜ΘΒͣɺݚڀͰ஌Γ͍ͨ͜ͱΛ&TUJNBOEʹ͢Δ

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r શ෦ॻ͚ΔΘ͚͸ͳ͍ αϓϦʹ·Θ͢

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rͷ5BCMFΛվม ໨త ݚڀܭըॻʹهࡌ͞Εͨݚڀ໨తʢؔ৺ͷ͋Δྟচ՝୊ʣ ࣏ྍ ؔ৺ͷ͋Δհೖ·ͨ͸࣏ྍ &45*."/% ղੳ ର৅ूஂ ղੳର৅ूஂ ؔ৺ͷ͋Δྟচ্ͷٙ໰ͷର৅ूஂ ूஂϨϕϧͷཁ໿ͷର৅ͱͳΔྟচࢼݧࢀՃऀC ม਺ ධՁ߲໨ ؔ৺ͷ͋Δྟচ্ͷٙ໰ʹରॲ͢ΔͨΊʹɺݸਓϨϕϧͰଌఆ͞ΕΔ߲໨ ม਺͕ղੳ࣌ͲͷΑ͏ʹѻΘΕΔ͔ தؒࣄ৅ͷऔΓѻ͍ ܽଌ஋ͷऔΓѻ͍ wதؒࣄ৅ ετϥςδʔB wதؒࣄ৅ ετϥςδʔB ֤ʑͷதؒࣄ৅ʹ͍ͭͯهࡌ͢Δɺཧ༝΋͋Δͱྑ͍ ܽଌ஋ͷ୅ೖ๏ͱͦͷલఏͱͳΔԾఆ ײ౓෼ੳܽଌ஋ͷҟͳΔରॲ๏ ूஂϨϕϧͷཁ໿ࢦඪ ղੳख๏ ࣏ྍͨ͠৔߹ɺ͠ͳ͔ͬͨ৔߹ɺ͋Δ͍͸ೋ܈ؒͷࠩͷධՁͷج൫ͱͳΔ   ධՁ߲໨ͷཁ໿ࢦඪ ౷ܭྔʢਪఆྔʣ͕ײ౓෼ੳͰͲͷΑ͏ʹਪఆ͞ΕΔ͔ɿ   ਪఆྔ͝ͱʹ͓͔ΕΔҟͳΔԾఆख๏ B& 3 Ͱنఆ͞ΕΔετϥςδʔʹ͸࣏ྍํ਑ɺԾ૝ɺෳ߹ɺԾ૝ɺओཁ૚ετϥςδʔ͕͋Δɻ Cղੳର৅ͷ܈͕ෳ਺ଘࡏ͢Δ৔߹͸ ྫଟ܈ࢼݧʹ͓͚Δൺֱରরूஂ ɺ͜͜Ͱఆٛͯ͠΋ྑ͍ɻ

45&1ͷ&TUJNBOEΛߟ͑Δ 29 ໨త ౶೘ප͕ͳ͍աମॏ·ͨ͸ංຬͷ੒ਓʹ͓͍ͯɺηϚάϧνυൽԼ஫NHͷܧଓ౤༩͸ମॏݮগͷҡ࣋ʹͲͷΑ͏ͳޮՌΛ༩͑Δ͔ʁ ࣏ྍ ηϚάϧνυൽԼ஫NHͷܧଓ౤༩ɺϓϥηϘ౤༩ &45*."/% ղੳ ର৅ूஂ ղੳର৅ूஂ
౶೘ප͕ͳ͍աମॏ·ͨ͸ංຬͷ੒ਓ ࣏ྍΛ։͔࢝ͨ͠Ͳ͏͔ʹ͔͔ΘΒͣɺ࣏ྍΛແ࡞ҝʹׂΓ෇͚ΒΕͨ͢΂ͯ ͷࢀՃऀ ม਺ ධՁ߲໨ ମॏʢXFFL ʣ XFFL͔ΒͷମॏͷมԽྔʢओཁධՁ߲໨͸XFFLͷมԽྔʣ தؒࣄ৅ͷऔΓѻ͍ ܽଌ஋ͷऔΓѻ͍ ᶃ࣏ྍ୤མɾதࢭɾϨεΩϡʔ ࣏ྍํ਑ετϥςδʔ   ˠதؒࣄ৅ʹؔΘΒͳ͍࣏ྍͷޮՌʹؔ৺͕͋Δཧ༝   ᶄ࣏ྍ୤མɾதࢭɾϨεΩϡʔ Ծ૝ετϥςδʔ   ˠதؒࣄ৅͕ͳ͘ɺ࣏ྍΛܧଓͨ͠ͱԾఆͨ͠ޮՌʹؔ৺͕͋Δཧ༝ ᶃಉ͡܈಺ͷଟॏ୅ೖ๏ͰXFFLͷ஋Λิ׬ɻ   ᶄXFFL͔Βͷ৘ใΛར༻ɻதؒࣄ৅͕ൃੜͨ͠৔߹ɺͦͷલͷ࣌఺·Ͱ ͷ৘ใΛར༻ɻ ूஂϨϕϧͷཁ໿ࢦඪ ղੳख๏ ฏۉ஋ ᶃ"/$07"ɿ܈ͱXFFLͷཁҼɻ   ᶄ܁Γฦ͠ଌఆͷͨΊͷࠞ߹ޮՌϞσϧɿ܈ɺXFFLɺXFFLͷཁҼɻࢀՃ ऀ͝ͱʹωετɻແߏ଄ͷڞ෼ࢄߦྻΛར༻ɻ

&TUJNBOEΛҙࣝͨ͠ݚڀܭը 30 3BUJUDI# #FMM+ .BMMJODLSPEU$ #BSUMFUU+8 (PFM/ .PMFOCFSHIT( FUBM$IPPTJOH&TUJNBOETJO$MJOJDBM5SJBMT1VUUJOHUIF*$)& 3
*OUP 1SBDUJDF5IFS*OOPW3FHVM4DJ.BS rͷ'JHVSFΛվม ݚڀ໨తͷఆٛ Bҙࢥܾఆऀͷಉఆ w ݚڀ݁ՌΛ୭͕ར༻͢Δͷ͔ʁ w ୭͕ݚڀͷ੒൱ΛܾΊΔ͔ʁ ɹ&TUJNBOE͕มΘΔ Cݚڀ໨తͷఆٛ w ҙࢥܾఆऀͷ஌Γ͍ͨ͜ͱΛ޿͘ݕ౼͢Δ w ݕ౼ʹ͸ɺϥϯμϜׂΓ෇͚͢Δ࣏ྍɺױऀ ूஂɺΤϯυϙΠϯτɺ͞·͟·ͳ࣌ؒʢ؍ ࡯ظؒɺ࣏ྍظؒɺ४උظؒ౳ʣ΋ؚΊΔ &TUJNBOEͷఆٛ BՄೳੑͷ͋Δதؒࣄ৅Λಉఆ w ؍࡯ظؒ಺ʹൃੜ͢ΔՄೳੑͷ͋Δ தؒࣄ৅Λ͢΂ͯϦετΞοϓ͠ɺൃ ੜՄೳੑ΋ࣔ͢ w όΠΞεʹ͍ͭͯ΋ݕ౼͢Δ C࣏ྍܭըͷఆٛ w ݚڀʹ͓͚Δ࣏ྍܭըͷৄࡉΛఆٛ ͢Δ w தؒࣄ৅΋ؚΊͨޮՌΛ஌Γ͍͔ͨ ݕ౼͢Δ D&TUJNBOEͷఆٛ w Cͷ࣏ྍܭըʹج͖ͮɺதؒࣄ৅ͷ छྨ͝ͱʹετϥςδʔΛݕ౼͢Δ w தؒࣄ৅ͱετϥςδʔΑΓɺର৅ ूஂͱม਺ͱཁ໿ࢦඪΛܾΊΔ w ݚڀ໨త͕FTUJNBOEͱ߹க͍ͯ͠Δ ͔֬ೝ͢Δ B&TUJNBOEʹ༗༻ͳσʔλ C୤མΛ๷͙ํ๏ σʔλͷऔΓѻ͍ CओͱͳΔਪఆྔ BܽଌϝΧχζϜͷԾఆ ղੳܭը Dײ౓෼ੳͷਪఆྔ EαϯϓϧαΠζ

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ݚڀܭըॻ΁ͷ&TUJNBOEͷهࡌᶄ 32

ݚڀܭըॻɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌ 33 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff
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ICH E9 (R1) 臨床試験のための統計的原則〜中間事象に対するストラテジー

ICH E9 (R1) 臨床試験のための統計的原則〜中間事象に対するストラテジー

Shuntaro Sato

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*$)& 3 ྟচࢼݧͷͨΊͷ౷ܭతݪଇɹิҨͷ֓ཁɾࣄྫ   ྟচࢼݧʹ͓͚ΔFTUJNBOEͱײ౓෼ੳ ྟচӸֶݚڀʹ͓͚Δใࠂͷ࣭޲্ͷͨΊͷ౷ܭֶͷݚڀձ ୈճݚڀूձ ࠤ౻ढ़ଠ࿕ ৫ా఩࿕ தాඒ௡ࢠ

$)& 3 ͱ͸Կ͔ʁ 3 ಠཱߦ੓๏ਓҩༀ඼ҩྍػث૯߹ػߏɺIUUQTXXXQNEBHPKQJOUBDUJWJUJFTJOUIBSNPOZJDIIUNM w $)&ͷิҨʢิॿతͳࢿྉʣ w ྟচࢼݧͷܭըɺσβΠϯɺ෼ੳͦͯ͠ղऍΛ໌ྎʹ͢Δ͜ͱΛ໨తʹ͍ͯ͠Δ w

ࠓճͷษڧձͷΩʔϫʔυ 4 தؒࣄ৅ &TUJNBOE ετϥςδʔ ײ౓෼ੳ

தؒࣄ৅ʹରԠ͢ΔͨΊͷετϥςδʔ *$)& 3 ྟচࢼݧͷͨΊͷ౷ܭతݪଇɹิҨͷ֓ཁɾࣄྫ   ྟচࢼݧʹ͓͚ΔFTUJNBOEͱײ౓෼ੳ ࠤ౻ढ़ଠ࿕ ௕࡚େֶපӃྟচݚڀηϯλʔ TIVOUBSPTBUP!OBHBTBLJVBDKQ !4IVOUBSPPP

͜ͷηΫγϣϯͰѻ͏಺༰ 6

ཧ૝తͳྟচࢼݧʢ3$5ʣ 7 *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ͳ͠ɺࢼݧ׬਱

தؒࣄ৅͕ى͜ΔͱͲ͏ͳΔ͔ʁ 8 ׂΓ෇͚ͨ   ࣏ྍ ࣮ࡍͷ࣏ྍ Ξ΢τΧϜ ަབྷҼࢠ ͍ͨΔͱ͜ΖͰόΠΞεܦ࿏͕Ͱ͖Δ தؒࣄ৅

&TUJNBOEͷߏ੒ཁૉʢ&TUJNBOEBUUSJCVUFTʣ 9 & 3 ʹ४ͨ͡ &TUJNBOEͷߏ੒ཁૉ ߟ͑΍͍͢   &TUJNBOEͷߏ੒ཁૉ ఆٛ

$2͔Β&TUJNBOEετϥςδʔ΁ 10 $2 ݚڀ໨త தؒࣄ৅ ࣏ྍํ਑ ର৅ूஂ ม਺ ͲͷΑ͏ʹதؒࣄ৅ΛऔΓѻ͏͔ʁ &TUJNBOEετϥςδ

࣏ྍํ਑ετϥςδʔʢ5SFBUNFOUQPMJDZTUSBUFHZʣᶃ 11 w தؒࣄ৅ͷൃੜͱ͸ແؔ܎ʹɺ࣏ྍޮՌΛఆٛ͢Δ ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜɺࢼݧ్த୤མ தؒࣄ৅ͳ͠ɺࢼݧ్த୤མ

࣏ྍํ਑ετϥςδʔᶄ 12 ױऀ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͯ͠΋ɺ࠷ऴ؍࡯·Ͱ௥੻ ࢼݧ్த୤མͨ͠ͱ͜Ζ·Ͱͷ৘ใͰɺ   ࠷ऴ؍࡯࣌ͷσʔλΛิ׬

ෳ߹ετϥςδʔʢ$PNQPTJUFTUSBUFHZʣ 14 w தؒࣄ৅ͷൃੜΛΤϯυϙΠϯτͷఆٛʹऔΓೖΕΔ *$)& 3 5SBJOJOH.BUFSJBM.PEVMFΛࢀߟ ױऀ ױऀ ױऀ

࣏ྍԼετϥςδʔʢ8IJMFPOUSFBUNFOUTUSBUFHZʣ 15 w தؒࣄ৅͕ى͖Δ·ͰͷظؒΛΤϯυϙΠϯτͷఆٛʹऔΓೖΕΔ ױऀ ױऀ தؒࣄ৅ͳ͠ɺࢼݧ׬਱ தؒࣄ৅ൃੜͨ͠ͱ͜Ζ·Ͱͷ৘ใΛ༻͍Δ #BTFMJOF NPOUIT

ओཁ૚ετϥςδʔʢ1SJODJQBMTUSBUVNTUSBUFHZʣ 16 w ؔ৺ͷ͋Δ૚ʹରͯ͠ͷΈͷ࣏ྍޮՌΛߟ͑Δ ײછ঱ ײછ঱ ϫΫνϯະ઀छ܈ ϫΫνϯ઀छ܈ ྫɿϫΫνϯ઀छޙͷײછ঱ൃ঱ྫΛର৅ʹॏ঱౓΁ͷ༧๷ޮՌΛධՁ͍ͨ͠ ॏ঱ͷׂ߹

ετϥςδʔͷ੔ཧ 17 ݚڀ໨త ؔ৺ͷ͋Δ࣏ྍ಺༰ .BMMJODLSPEU$) #FMM+ -JV( 3BUJUDI# 0`,FMMZ. -JQLPWJDI*

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶃ 18 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶄ 19 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶅ 20 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶆ 21 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶇ 22 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌᶈ 23 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶄ 25 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM

ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶅ 26 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM

ྫɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌᶆ 27 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM

&TUJNBOEΛߟ͑ΔςϯϓϨʔτ 28 ,BOH. ,FOEBMM." 3JCBVEP) 5JFSOFZ$ ;IFOH- 4NFBUPO- FUBM*ODPSQPSBUJOHFTUJNBOETJOUPDMJOJDBMUSJBMTUBUJTUJDBMBOBMZTJTQMBOT$MJO 5SJBMT+VO

45&1ͷ&TUJNBOEΛߟ͑Δ 29 ໨త ౶೘ප͕ͳ͍աମॏ·ͨ͸ංຬͷ੒ਓʹ͓͍ͯɺηϚάϧνυൽԼ஫NHͷܧଓ౤༩͸ମॏݮগͷҡ࣋ʹͲͷΑ͏ͳޮՌΛ༩͑Δ͔ʁ ࣏ྍ ηϚάϧνυൽԼ஫NHͷܧଓ౤༩ɺϓϥηϘ౤༩ &45*."/% ղੳ ର৅ूஂ ղੳର৅ूஂ

&TUJNBOEΛҙࣝͨ͠ݚڀܭը 30 3BUJUDI# #FMM+ .BMMJODLSPEU$ #BSUMFUU+8 (PFM/ .PMFOCFSHIT( FUBM$IPPTJOH&TUJNBOETJO$MJOJDBM5SJBMT1VUUJOHUIF*$)& 3

ݚڀܭըॻ΁ͷ&TUJNBOEͷهࡌᶃ 31 w *$).$MJOJDBMFMFDUSPOJD4USVDUVSFE)BSNPOJTFE1SPUPDPM $F4)BS1 Λࢀߟ w ྟচࢼݧͷݚڀܭըॻͷςϯϓϨʔτ w ݱࡏ։ൃத

ݚڀܭըॻ΁ͷ&TUJNBOEͷهࡌᶄ 32

ݚڀܭըॻɿ%.͕ͳ͍ංຬ੒ਓʹ͓͚ΔηϚάϧνυܧଓ౤༩ͷମॏҡ࣋ޮՌ 33 3VCJOP% "CSBIBNTTPO/ %BWJFT. )FTTF% (SFFOXBZ'- +FOTFO$ FUBM& ff

ݚڀܭըॻɿத౳঱Ҏ্ͷ$01%ʹର͢Δࡎซ༻ٵೖྍ๏ͷ༻ྔޮՌ 34 3BCF,' .BSUJOF['+ 'FSHVTPO(5 8BOH$ 4JOHI% 8FE[JDIB+" FUBM5SJQMF*OIBMFE5IFSBQZBU5XP(MVDPDPSUJDPJE%PTFTJO.PEFSBUFUP 7FSZ4FWFSF$01%/&OHM+.FE+VM

&TUJNBOEΛܾΊΔͨΊͷڞಉ࡞ۀ 35 ݚڀ໨తɾ&TUJNBOEɾσβΠϯ ΈΜͳͰߟ͑Α͏ʂ ҩࢣɾҩֶݚڀऀ ੜ෺౷ܭՈɾӸֶऀ ͦͷଞؔ܎ऀ

ֶश͢ΔͨΊͷಓඪ 36 w *$)& 3 "EEFOEVN&TUJNBOEBOETFOTJUJWJUZBOBMZTJTJODMJOJDBMUSJBMT/PW"WBJMBCMFGSPNIUUQTXXXJDIPSHQBHFF ff i DBDZ HVJEFMJOFTɹʲΦϦδφϧʳ