24 12 28 EU ICH ICH DSUR DSUR
EU E2F 20121228 1
... 4 1.1... 4 1.2... 5 1.3 DSUR... 5 1.4 DSUR PSUR... 7 1.5 DSUR... 7... 7 2.1 DSUR... 7 2.2 DSUR... 8 2.3 DSUR... 8 2.4 DSUR... 9 2.5 DSUR... 9 2.6... 10 2.7 DSUR... 11 DSUR... 13 3.1... 14 3.2... 14 3.3... 14 3.4... 16 3.5... 16 3.6... 17 3.7... 19 3.8... 22 2
3.9... 23 3.10... 23 3.11... 24 3.12... 24 3.13... 24 3.14 DSUR... 24 3.15... 25 3.16... 25 3.17... 26 3.18... 27 3.19... 28 3.20... 29 DSUR... 29... 30 A... 30 B... 30 C... 30 3
1. DSUR EU ICH EU DSUR Investigational New DrugINDIND Annual Report EU Annual Safety Report 1 DSUR A * 1.1 * 2 3,4 ethics committees ICH 1 DSUR 2 3 The Development Safety Update Report DSUR: Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials: Report of CIOMS Working Group VII, Geneva 2007. 4 ICH Topic E6 R1. Guideline for Good Clinical Practice. http://www.ich.org/lob/media/media482.pdf 4
DSUR ICH 1.2 DSUR 1 4 1 2 3 ** 4/ DSUR DSUR DSUR 1.3 DSUR DSUR 5 DSURDSUR 5 5
DSUR ] 6 expanded access program particular patient use INDsingle patient INDs treatment INDs DSUR in vitro DSUR ICH E8 General Considerations for Clinical Trials Current Step 5 17 July 1997. http://www.ich.org/lob/media/media484.pdf 6
1.4 DSUR PSUR ICH PSUR DSUR DSUR PSUR PSUR DSUR DSUR PSUR DSUR PSUR 1.5 DSUR DSUR / DSUR 7 SAR 2. 2.1 DSUR DSUR DSUR DSUR 2.4.2 7 ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. October 1994 http://www.ich.org/lob/media/media436.pdf 7
2.2 DSUR * DSUR *DIBD DSUR DIBD DIBD DSUR DSUR DIBD PSUR DSUR DSUR PSUR PSUR IBD DSUR DSUR PSUR DSUR DSUR DSUR 60 2.3 DSUR DSUR 8 DSUR 8 IND IND 8
2.4 DSUR 2.4.1 *DSUR DSUR * DSUR 2.4.2 DSUR DSUR DSUR DSUR DSUR 2.5 DSUR DSUR 9
DSURDSURDSUR8.5 1DSUR 2DSUR DSUR DSUR DSUR A+X+Y+Z DSUR A + X, Y, Z A DSUR A + B DSUR A + B DSUR A B X, Y, Z X + Y + Z DSUR 2.6 IBDSUR 7.1 IB 10
IB 9 DSUR DSUR IB IB DSUR 2.7 DSUR 2.7.1 DSUR DSUR DSUR ectd DSUR ectd 2.7.2 DSUR 1. 2. 3. 4. 9 EU Summary of Product CharacteristicsSmPC 11
5. 6. 6.1 6.2 7. 7.1 7.2 7.3 8. 8.1 8.2 8.3 8.4 8.5 9. 10. 11. 12. 13. 14. DSUR 15. 16. 17. 18. 18.1. 18.2-19. 20. DSUR 12
3. DSUR DSUR DSUR DSUR : ; DSUR 18 DSUR 19 IB 13
3.1 : DIBD IBD DSUR DSUR 3.2 3.3 *DMC * 3.4 14
10 3.15 : o o o o o o o : o o o o 10 15
3.4 IB * DSUR 3.5 * * B : o ; ; o 16
1 / ; ; ; first visit of first patient; FVFP B 3.6 DSUR 6.1 6.2 serious adverse events; SAE DSUR 17
SAE 3.6.1 B 2-4 ; DIBD 18
3.6.2 PSUR DSUR 3.7 DSUR7.17.3 DSURSAR DIBD adverse drug reactions; ADRs DSUR SARSAE DSUR /Medical Dictionary for Regulatory Activities MedDRA Preferred Term 19
SAE 3.7.1 3.7.2 SAR B SAR System Organ ClassSOC SAR SAR SAR 20
a EudraCT 11 b c d e f g h / i / j MedDRA k l / B 3.7.3 DIBD DSUR SAE SOC SAE 11 EudraCT 21
SAE B 3.8 3.8.1 12 * 3.8.2 3.8.3 DSUR DSUR 12 ICH E3 CIOMS VII 22
3.8.4 ICH E2D IND 3.8.5 DSUR / DSUR DSUR // DSUR / DSUR 2.5 3.9 * *registriesactive surveillance programmes 3.10 23
3.11 3.12 in vivo in vitro 3.18 3.13 3.14 DSUR DSUR DSUR DSUR DSUR 24
3.15 3.16 DSUR SAR SAR a SOCb c DSUR 18 DSUR 18 25
DSUR 18 13 US IND 14 US IND US IND 3.17 DSUR DMC 3.18 13 US IND FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing and Controls Information, May 2003. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07 0567.pdf 14 US Code of Federal Regulations 21 CFR 312.23 a 3iv ; revised April 2009. http://frwebgate.access.gpo.gov/cgi-bin/get-cfr.cgi 26
3.18 DSUR DSUR / 3.18.1 o o QTQT/QTc o o o o o 27
3.18.2 / * DSUR 3.19 * 28
ICH E2E C 3.20 DSUR DSUR DSUR 1 2 3 4 5 6 7 DSUR 3.16 29
US IND US IND US IND 4 A B C 30
A ICH CIOMS ICH DSUR ICH CIOMS / 1. CIOMS VI 2. / CIOMS VI / 3. ICH E2F 4. CIOMS VII DSUR 5. CIOMS VII DSUR DIBD 31
/ 6. ICH E6 7. CIOMS 8. EU Volume 9A : 9. EU Volume 9A 32
/ 10. CIOMS VII 11. CIOMS VII investigational medicinal product 12. EU Directive 2001/20/EC 13. CIOMS VII 14. EU Volume 9A 33
/ 15. ICH E2E / 16. CIOMS VI 17. ICH E6 R1 18. ICH E6 34
/ 35
B [] ID FVFP FVFP = DSUR ID / / 36
/ * * 37
* * 38
ID ID/ EudraCT SAR -------- -------- ------- -------- -------- -------- -------- -------- -------- // SAR 39
SAE 2009 12 31 [] 18 4 7 2 9 2 4 1 9 2 3 1 2 2 4 7 2 2 4 7 40
C 2012 2014 C1 C2 C1 DSUR 2012 19 1. Z 20mg/kg/ 60mg/kg/ 100mg Z 30 6.7% 0127 0.9mg/dL 1.8mg/dL 0139 1.0mg/dL 1.9mg/dL dipstick 2+24 21 41
8.2 18.1 100mg 28 119 50mg 72 Z 100mg Z 50mg 1248 1624 egfr/ 24 0.5mg/dL 30% egfr 25% 2. KR-102 60mg/kg/ 8 60mg/kg/ 102 Z 50mg 102-03714 ALT AST 2.7 2.3 8.2 18.1 Z 16 28 42
X Y 102-037 Z Cmax 50mg 8 Z Z 148 102-037 4 16 12481624 ALTAST DSUR 2013 19 1. * Z 100mg 30 6.7% 100mg Z 201 50mg 60 8.3% 43
25mg 62 8.1%10mg 59 5.1% 1.25 1.5 61 10% 50mg 60 1.7%25mg 62 0 10mg 59 1.7% 1.5 61 3.3% 8.2 18.1 Z 202 204 124 122448 egfr 24 2. * Z 60mg/kg/ 149 0.7%14 2.5 ALT AST 201 Z 2/1811.1%8.2 1/611.6% 102-037 Cmax 44
3. * Z NO 201 2/811.1% Z 201-119201-212 10mg 25mg Z DSUR 2014 19 1. * Z 100mg 50mg 25mg 10mg 7.8%6.8%5.8% 1.251.5 6.3%50mg 25mg 10mg 1.5%0.5%1.9% 1.5 2.7%8.2 18.1 45
50% <0.6mg/dL 301141248 egfr 3+ 24 2. * Z ALTAST 301141248 3. * Z NO Z 21 21/6323.3% 1.4% 4. * 8.1 8.2 46
301 47
C2: 19 Z Z X 48
X * Z 301 20mg/kg/ 60mg/kg/ egfr 141248 2+ 100mg 24 1.251.5 50mg 25mg 10mg 7.8% 6.8% 5.8% 6.3% 1.5 50mg 25mg 10mg 49
1.5%0.5%1.9% 2.7% 50% <0.6mg/dL 8.2 18.1 * KR-102 60mg/kg/ ALTAST 301 141248 ALTAST 60mg/kg/ * Z Z NO 21 21/632 50
3.3% 1.4% * Z 301 51