(????????TF??????(2006?5?)???)

1
??????????
????????? ????????????? 11???? 2007?11?15?
???????? ?? ??????????? ????????? ?? ??
2
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• ????????
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• (1)????????
• -?????????-
• (2)????????
• -????????-
• 3. ?????????????

3
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• ????????
• ?????
• (1)????????
• -?????????-
• (2)????????
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• 3. ?????????????

4
?????????????????????? ? ??????????????????????
?????????
????????? ??????????????T?? ????????????????
T (????????)
(Iwashita-Tamamuro model)
Innovation in Living Time
????? ????????????
? ?
E (??)
???????????? ?????????? ?????? ????????
V
???????????
C (??)
??????
?????????? (ex.?????????????etc.)
?????(V) ECT ?????????????????????????
(????????TF??????(2006?5?)???)
5
????????
()
(??)
()
30
20
10
0
-10
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
2004
???????
???????
1961 ???????
????????????????????????????? ???
???????????????????
?1????????????????1980?????68SNA??81????93SNA???
?2??????????1968???????
6
???????????
??
??
19501990??
1950
?????????
????? ????
?????????????
????????????
???? ????
????????????????????
2000
????????
HMG-CoA ACE???
??????????????????????????
????????
?????????? ???????????
1990??
??????? ????????
1990
?????
H2?????? ß??????
PCR?
1983
NSAID
1973 DNA?????
??? ????? ???? ?????????????
??????????
?????? ??????
1950
?????????
20??
7
Chronology of b-lactam Antibiotics
1930
1940
1950
1960
1970
1980
1990
2000
benzylpenicillin 1947
amoxicillin 1966
penicillin 1929/1940
piperacillin 1980
ampicillin 1952
Penicillin
methicillin 1960
ceftriaxone ceftazidime 1983
cephazolin 1971
cefotaxime cefmetazole 1980
cefpirome 1993
cephalosporin C 1948
Injectable Cephalosporin
cefotiam 1981
latamoxef 1982
cefdinir 1991
cephalexin 1969
cefcapene 1997
cefixime 1987
Oral Cephalosporin
cefuroxime 1988
Year Year of the First Launch () Discovery
8
Chronology of Other Antibiotics
1930
1940
1950
1960
1970
1980
1990
2000
tetracycline 1984
Tetracycline
rifampicin 1968
linezolid 2000
sulfamethoxazole /trimethoprim 1976
vancomycin 1959
Others
norfloxacin 1984
levofloxacin 1993
chloramphenicol 1949
gatifloxacin 1999
ofloxacin 1985
streptomycin 1949
gentamycin 1966
ciprofloxacin 1987
tobramyin 1974
Quinolone
Aminoglycoside
amikacin 1976
clarithromycin 1990
erythromycin 1953
Macrolide
azithromycin 1991
telithromycin 2001
Year Year of the First Launch
9
Chronology of Cardiovascular Agents
1950
1960
1970
1980
1990
2000
nitrendipine 1971
amlodipine 1983
Ca Antagonist
nifedipine 1967
Angiotensin II Antagonist
nicardipine 1973
verapamil 1962
nilvadipine 1979
candesartan 1990
diltiazem 1968
losartan 1986
non-peptide ARB 1979
eprosartan 1989
delapril 1980
teprotide 1965/69
valsartan 1990
alacepril 1978
ACE Inhibitor
imidapril 1982
captopril 1976
cilazapril 1980
enalapril 1978
Year Year of the First Patent Application ()
Discovery
10
Chronology of Gastrointestinal Agents
1950
1960
1970
1980
1990
2000
roxatidine 1979
burimamide 1969
cimetidine 1972
famotidine 1979
H2 Blocker
ranitidine 1976
nizatidine 1980
pantoprazole 1983
omeprazole 1978
H Pump Inhibitor
lansoprazole 1984
rabeprazole 1986
Year Year of the First Patent Application
11
Chronology of Cholesterol-lowering Agents
1960
1970
1980
1990
2000
clofibrate 1961
gemfibrozil 1969
bezafibrate 1982 (Launched)
lovastatin 1979
compactin 1974
fluvastatin 1982
pravastatin 1980
cerivastatin 1988
simvastatin 1980
HMG-CoA reductase inhibitor
Year Year of the First Patent Application
12
Chronology of Anti-diabetic Drugs
1950
1960
1970
1980
1990
2000
insulin 1923
tolbutamide 1956
troglitazone 1988
PPARc receptor 1990
pioglitazone 1991
rosiglitazone 1991
Thiazolidinedione
Year Year of the First Patent Application ()
First Patent Approved, () Discovery
13
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14
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15
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2000??
1991?
1968?
1982?
1956?
H2???????????????????????
H. pylori ?????
????????????????
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??????????
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?????
???????
??????? (Sippy)??
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????????No.20(????????? 2004.7)??????????
16
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??????HS??????17?? ??????????? 2015??????????
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17
???????????????????? ??????????????(1983?1999)
100
(95)
(92)
(90)
(85)
(87)
90
(81)
(88) (87)
80
(83) (77)
(76)
70
(72)
(67)
60
(52)
???
(49)
50
(36)
40
(24)
0-14?(n1229) 15-29?(n11841)
30-44?(n43595) 45-59?(n107921)
60-74?(n135949) ???(n1500,??????)
30
??
(10)
20
10
0
?
0
5
10
15
18
????????????????????????????????????????????QOL
??????????
4???QOL???????
????????QOL??? ????????? ??????????Wilcoxons
signed-ranks test (plt0.05, plt0.01)
???????????????????
19
????????????
20
??????????????????(ex.?)??????????????? ?
?????????
2015
2005
2010
2020
2025
?????????????
?????
87
71
60
DDS?????????? In silico ??????????????
????PGx??????
??????????? ???????????
????
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3
11
20
????????????????? ???????????????
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1
415
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35
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4
57
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??????????????????????????????????
??????? BioJapan2007
21
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???? ??????
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????
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22
???????????????(???? ????)
??????? ?????????? ?????? ????????
23
????????
24

• ???????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ?????????????????????????????????????????????????
• (G????????/?????????????? 1989?1??)

25
???????????(??)
??
19501990??
1950
??
?????????
????? ????
?????????????
????????????
???? ????
????????????????????
2000
????????
HMG-CoA ACE???
??????????????????????????
????????
?????????? ???????????
1990??
??????? ????????
1990
?????
H2?????? ß??????
PCR?
1983
NSAID
1973 DNA?????
??? ????? ???? ?????????????
??????????
?????? ??????
1950
?????????
20??
26
????????????????????VOCATION
2025 ??????50?
??
1990??
2023 ????
2021 ?????
2019 ??????????
???? ?????
2019 ??????
2019 ???
2017 ???????
2014 ???????????
?????????
????? ????
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????????????????????
2000
????????
????/??????????????????????????
?????????? ???????????
27
????????

• ????????
• ?????
• (1)????????
• -?????????-
• (2)????????
• -????????-
• 3. ?????????????

28
?????????(1)

• 1983. 5 ???????????????
• 1984. 3 FK506??(????????)
• 1984.12 ????? ?????
• 1985. 4 ????(????)???????
• 1986. 8 ??????(?????)?FK506 ????????
• 1987. 6 ??????(?????)?FK506???? ??

29
?????????
????
??????????
30
?????????
???????? ????????????????????
??????????????????????
?
?
31
????????????????????? (1960-1980)
32
????????????????????? (1981-2000)
FK463 (1994) antifungal
33
????????
34
MLR (Mixed Lymphocyte Reaction)
spleen cell
spleen cell
X ray
responder
stimulator
35
(No Transcript)
36
??????
???
37
FK506??????????in vitro??????????
IC50 (nM)
????? ???
???????? ?????T???? IL-2?? IL-3?? IFN-??? IL-2???
?? ??????????
?? ??? ?? ??? ?? ?? ???
FK506 0.2 0.3 0.068 0.3 0.05 0.14 1400
???????? 14 24 7 32 0.2 9.9 800
38
?????????????
??
??????? 1995?4? ????????
1997?3? ?????????? 1997?9? ???????
2000?1? ?????? 2001?2? ?????????
?? 2003?11? ???????(?) 1996?1?
??
39
?????????(2)

• 1988. 9 Prof. Starzl, FK506 non-commercial IND
  ??
• 1989. 2 FK506???????????-rescue??
• ???Pittsburgh?FK506???????
• 1989.10 NY Times, FK506????????
• 1989.10 ??????(?????)
• 1990. 5 ??????FK506?????
• 1990. 6 ??????????
• 1990.7 ??????????
• 1990.9 ???????????
• 1990.8 ????????
• 1991.8 ?1?FK506????(Pittsburgh)
• 1991.12 ????????
• 1992.2 ????? ????(?????9?)

40
?????????(??)

• Wonder Drug (Prof. Thomas Starzl)
• Fujitoxin (Sir Roy Calne)

41
?????? ?????????????????

• ??
• 1.???life-threatening patients
• 2.FK506????????????
• 3.FK506????????????
• 4.????????
• 5.???????????????CyA???
• Rescue?????FK506??????????????
• 1.??????????????????
• 2.??????????????
• 3.?????????FK506??????????

42
FK506??????Pittsburgh?????

• 1. ??????????????????
• positive POC study????????
• compassionate use???????????
• 2. ????????academic???
• - ???
• - Health authority
• 3. ???????innovative therapy??????
• ???????

43
(No Transcript)
44
?????????(3)

• 1991?12? ????????
• 1992?2? ????? ????(?????9?)
• 1993?4? ????????(6???)
• 1994?4? ????????(6???)
• 1994?10? ?????
• 1997?4? ?????????
• 2003? ???67???

45
?????????????

• 1992?????????????????????
• ???????4????
• ???2?????????
• 1993? ?????
• 10???(???????1)
• 2002? ?????????????
• (???????) 30??

46
??????????????????(??)


47
FK506???? Chemical Genetics???????

• ?????? Dr.Schreiber
• ??????????
• FK506?????
• FKBP???

FK506
48
FK506(??????)??????????????
49
????????

• ????????
• ?????
• (1)????????
• -?????????-
• (2)????????
• -????????-
• 3. ?????????????

50
Fujisawa Case

• 1st Stage (before 1980) Low Risk - Low Return
• Export Business, Open of Rep. Office
• 2nd Stage (1980-) Medium Risk-Medium Return
• JV, Minority Participation
• 3rd Stage (1990-) High Risk-High Return
• Full-fledged Subsidiary (RD, Production,
  Marketing Sales)

51
Fujisawa Case1980

• USA Europe
  Asia
• FPC(NY) London Office ????
• (77??.6?) (78??.4?) (62??.30?)

52
Fujisawa Case1985
USA Europe Asia
FSK(50) Klinge Pharma(28) ????
(81??.85?20M) (83,85?DM100M) ??????
Lyphomed(26) London Office(4?) (83??.3?)
(85??.85?60M) CRC-Europe(85??.3?)
PMP (Chemical)
(81??.85?10M)
FPC(2?)
53
Fujisawa Case1991
USA Europe Asia
Fujisawa USA Fujisawa GmbH (1991) ????
(90??.91?310M) Klinge Pharma (80) ????
PMP(Chemical) (??DM150M) (89??.19?)
(??20M) Fujisawa Ireland(90??)
Fujisawa Holland
(87??.??)
London Office
CRC-Europe
??????????? (89??.5?)
54
Fujisawa Case1999
USA Europe Asia
Fujisawa Healthcare Fujisawa GmbH (??) ????
(98??.99?390M) (??DM210M) (??30M)
FRIA(RD) Klinge Pharma (91) ????
(20?) (??300M) (??\0.2B)
PMP (Chemical) Fujisawa Ireland(200?) ????
(??30M) Fujisawa Holland(??) ?????
London Office (93??.3?)
CRC-Europe
???????????(20?)
55
Lyphomed Story
1981 Lyphomed Starts Business
1985 First Equity Participation (22.5)
followed by three major share-ups
1987- 88 GMP Problems
1989 TOB
1990 Integrated into Fujisawa USA
1991- 94 FDA Problems
1997 Divestiture of Generic Business
56
Generic Products Problem
1988/7 The Dingle Subcommittee
1989 Quad Pharmaceutical
1991/2 Investigation of Lyphomed
1991/3 House Energy Commerce/Oversight Subcommittee
1991/11 FDA 483
1992/2 The Independence Report
1992/3 FDA Fraud Policy (AIP)
1993/8 Corrective Action Plan
1993-94 Assay Validation Task Force, Product/Process
Validation Task Force
1993/11 GMP Inspection (Grand Island Plant)
1994/6 GMP Inspection (Melrose Park Plant)
1994/7 Removal from AIP
57
Major Requirements of FDAApplication Integrity
Policy
a) Voluntary withdrawal of fraudulent applications
b) Voluntary recall of products covered by fraudulent applications
c) Full cooperation with FDA during the Validity Assessment
d) Identification of all individuals who were or may have been
involved or associated with the fraudulent acts
e) Conduct a credible internal review of all approved and pending ANDAs to supplement FDAs own independent comprehensive
investigation
f) Submit a written Corrective Action Operating Plan to FDA,
describing Fujisawas commitment and procedures to preclude
further instances of violation, including a comprehensive ethics training program for all employees
58
Corrective Actions Implemented By Fujisawa USA,
Inc. in order to Rehabilitate the Company
GMP Improvement Initiatives
Management FUSA hired new Vice Presidents of
Manufacturing, Q.A. Regulatory Affairs Operations

All of these individuals have extensive experience in their
respective areas in the pharma. Industry
In addition, they have also made changes to improve the management and structure in each of their respective organizations

59
Corrective Actions Implemented By Fujisawa USA,
Inc. in order to Rehabilitate the Company
GMP Improvement Initiatives
B. Assay Validations FUSA completed a major effort to validated all assays for active products
A total of 129 products at Melrose park and 153 products at Grand Island Were completed The cost of this effort was approximately 1.0 million
C. Product/ Process Validations A total of 136 products codes at Melrose Park ad 98 product codes at Grand Island were validated In addition, the Company completed 152 protocols validating equipment, processes and computer, software at both facilities The cost for this effort was in excess of 3.3 million
60
Corrective Actions Implemented By Fujisawa USA,
Inc. in order to Rehabilitate the Company
GMP Improvement Initiatives
Stability Programs
FUSA made a number of organization changes in the
stability area. Stability program SOPs have been
reviewed and revised to assure consistency
between al sites and compliance with FDA
guidelines. A common computer software program
was purchased for each manufacturing site as well
as Pharmaceutical Sciences and validated. An SOP
for conducting investigations and communicating
issues was developed and issued. An SOP for
handling out of specification results (based on
Barr decision) was developed and issues
Temperature and humidity storage conditions were
standardized for all locations. A new stability
storage chamber and retention sample room were
built in Grand Island (110,000). The testing
requirements for reconstitution time and
particulate matter were standardized and
stability sampling requirements were standardized.
61
Corrective Actions Implemented By Fujisawa USA,
Inc. in order to Rehabilitate the Company
GMP Improvement Initiatives
E. Facility and Process Capital Investments FUSA invested approximately 1.4 million from 1992-1994 to improve our facilities at Grand Island and Melrose Park.
F. Summary In total from 1992-1994, FUSA has directly invested approximately 12 million as part of completing its GMP rehabilitation with the FDA.
62
?????????
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04
Pfizer
Pfizer
91??
00 ??
Pharmacia
Pharmacia
Warner-Lambert
03 ??
95 ??
93 ??
Pharmacia Upjohn
Erbamont
Kabi
GD Searle
Pharmacia
85 ??
00??
Upjohn
Monsanto
Monsanto
Merck Co
Merck Co
04
84
51??
100????
Centocor
Banyu
Banyu
99 ??
Johnson Johnson
Johnson Johnson
DuPont ?????
61 ??
89 ??
Bristol-Myers
??
01
Janssen
Bristol-Myers Squibb
Bristol-Myers Squibb
Squibb
94 ??
02 ????
American Home Products
American Home Products
Wyeth
American Cyanamid
63
?????????
04
03
02
01
00
99
98
97
96
95
94
93
92
91
90
89
88
87
86
85
Glaxo
Glaxo Wellcome
95??
Glaxo SmithKline
SK Beckman
Wellcome
00 ??
89??
SmithKline Beecham
Beecham
Astra
AstraZeneca
93 ???????????
99 ??
ICI
Zeneca
Rhone-Poulenc
Rhone-Poulenc Rorer
95??
90 ??
Fisons
99 ??
Aventis
W.H.Rorer
Hoechst
Hoechst
sanofi? aventis
Marion
95 ??
acquisition of a majority holding
68
89
04??
Marion Merrell Dow
Roussel-Uclaf
Merrell Dow
Sanofi
Sanofi SI
Sanofi-Synthelabo
94
Prescription drug??
Sterling
Synthelabo
99??
JR Geigy
Ciba-Geigy
Ciba-Geigy
Novartis
Novartis
96 ??
70??
Ciba
Sandoz
Roche
Roche
94??
97 ??
90 ????
02 ??
Genentech
Syntex
Boehringer Mannheim
Chugai
64
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04
03
03
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98
97
96
95
94
93
92
91
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05?10? ??
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05?10? ??
??
????
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65
(No Transcript)
66
(No Transcript)
67
(No Transcript)
68
(No Transcript)
69
????????

• ????????
• ?????
• (1)????????
• -?????????-
• (2)????????
• -????????-
• 3. ?????????????

70
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50-40??(1017?)
40-30??
1000-500??(1014?)
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5000?????
60????(3??????????)
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71
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• ??(??/???)???????????
• ?????????????