Transcript 20151210PROactivePioglitazone_BladderCax

Journal Club
Erdmann E, Harding S, Lam H, Perez A.
10-Year Observational Follow-Up of PROactive: a randomized cardiovascular
outcomes trial evaluating pioglitazone in type 2 diabetes.
Diabetes Obes Metab. 2015 Nov 23. doi: 10.1111/dom.12608.
Faillie JL, Hillaire-Buys D.
Examples of how the pharmaceutical industries distort the evidence of drug
safety: the case of pioglitazone and the bladder cancer issue.
Pharmacoepidemiol Drug Saf. 2015 Nov 30. doi: 10.1002/pds.3925. [Epub
ahead of print]
2015年12月10日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
Thiazolidinedione
Muraglitazar
(Bristol-Myers Squibb )
pioglitazone and other active TZDs have been shown
to bind to the outer mitochondrial membrane protein
mitoNEET with affinity comparable to that of
pioglitazone for PPARγ.
mitogen-activated
protein kinases
GRE, glucocorticoid response element; PPARγ, peroxisome proliferator-activated
receptor γ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor.
bind to the outer mitochondrial membrane protein mitoNEET
Nature Reviews Nephrology 8:445-58, 2012
Matsuda index = 1.9 → 3.6
John J. Nolan, Bernhard Ludvik, Patricia Beerdsen, Mary Joyce, and Jerrold Olefsky:
Improvement in Glucose Tolerance and Insulin Resistance in Obese Subjects Treated with
Troglitazone N Engl J Med 331:1188-1193, 1994.
ピオグリタゾン
Bays H, Mandarino L, DeFronzo RA. J Clin Endocrinol Metab. 89:463-78, 2004. を日本人向けに描画
ピオグリタゾンの心血管イベント発症に対する影
対象：大血管障害の既往を有する2型糖尿病患者
響
514 of 2605 patients in the pioglitazone group and 572 of 2633
Stroke既往
大血管障害既往（5,238例）
心筋梗塞既往（2,445例）
（984例）
patients in the placebo group had at least one event in the primary
Hard endpoints
MACE
MI
ACS
Stroke
評価項目
composite
endpoint (HR 0·90,
95% CI 0·80–1·02,
p=0·095).
The
main
総死亡
●
secondary
endpoint
was the composite of all-cause mortality, non-fatal
心血管死
●
myocardial
infarction,
and stroke.
301 patients
in the pioglitazone
心筋梗塞
●
●
●
group
in the placebo
脳卒中 and 358●
● group reached this endpoint (0·84,●0·72–
0·98,
ACS p=0·027).
●
Hard
endpoints1）
リ
ス
ク
低
下
率
（%）
0
MACE2）
16%
0
10
NNT=48
20
p=0.027
MI3）
18%
0
28%
10
NNT=46
10
NNT=46
20
p=0.02
20
MIの既往を有
ACS3）
0
37%
0
10
NNT=44
10
NNT=21
20
MIの既往を有
20
脳卒中の既往を有
30
30
30
30
40
40
40
40
50
50
50
50
p=0.045
Stroke4）
47%
30
p=0.035
40
50
p=0.009
1）Dormandy JA. et al.: Lancet, 366, 1279, 2005 2）Wilcox R. et al.: Am Heart J, 155:712, 2008
3）Erdmann. E. et al.：J.Am.Coll.Cardiol., 49,1772,2007 4） Wilcox R. et al.: Stroke, 38,865,2007.
Primary end point
Lancet 2005; 366: 1279–89
PROactive試験における癌患者発生率
アクトス群(n=2605)
イベント例数
新生物
患者例数
プラセボ群(n=2633)
イベント例数
患者例数
p
118
112
(4%)
117
113
(4%)
NS
103
97
(4%)
103
99
(4%)
NS
結腸直腸癌
16
(1%)
15
(1%)
0.834
肺癌
15
(1%)
12
(1%)
0.544
膀胱癌
14
(1%)
6
(<1%)
0.069
膀胱癌(除外後)§
6
(<1%)
3
(<1%)
0.309
造血器癌
6
(<1%)
10
(<1%)
0.327
乳癌
3
(<1%)
11
(<1%)
0.034
47
(2%)
46
(2%)
0.876
悪性新生物‡
その他
‡：症例の中には複数種の腫瘍も認められている
§：盲検解除後に検討した例
There was no difference in the overall incidence of malignant neoplasms. There were some imbalances in the
incidence of individual tumours. There were more bladder tumours (14 vs six) and fewer cases of breast cancer
(three vs 11) reported in the pioglitazone group compared with placebo.
悪性新生物の全体的な発生率に差は認められなかった。個々の腫瘍の発生率のいくつかの不
均衡があった。プラセボと比較してピオグリタゾン群で膀胱腫瘍（14対6）が多く、乳がんは
（3対11）有意に低下していた。
Dormandy J.A. et al:Lancet ,366,1279,2005.
PROactive試験における癌患者発生率
アクトス群(n=2605)
イベント例数
膀胱癌
プラセボ群(n=2633)
患者例数
14
イベント例数
患者例数
6
(1%)
(<1%)
5
p
0.069
0.040
非盲検化される前にデータ安全性モニタリング委員会は、外部専門家（S·コーエン：ネブラスカ大学医療セ
ンター、Dフィリップス：癌研究英国の研究所）による20膀胱例を検討を実施。
20例
9例
3例
ｱｸﾄｽ：14例
ﾌﾟﾗｾﾎﾞ:6例
ｱｸﾄｽ：6例
ﾌﾟﾗｾﾎﾞ:3例
ｱｸﾄｽ：2例
ﾌﾟﾗｾﾎﾞ:1例
ランダム化の1年以内発生
喫煙、曝露が、家族歴、以前の腫瘍、尿路感染症等
発がんリスク上昇因子あり
11例
6例
ｱｸﾄｽ：8例
ﾌﾟﾗｾﾎﾞ:3例
ｱｸﾄｽ：4例
ﾌﾟﾗｾﾎﾞ:2例
Dormandy J.A. et al:Lancet ,366,1279,2005.
In the overview of PROactive data published in 2009, Dormandy and colleagues anecdotally mentioned that, in
the placebo group, one case in fact showed a benign histology. (Hillaire-Buys D: Lancet 378:1543-44, 2011)
膀胱癌の発生リスク（pioglitazone投与歴有無での比較）
（%）
累
積
膀
胱
癌
発
症
率
3
ピオグリタゾン投与歴あり（Pio）
ピオグリタゾン投与歴なし（None）
2
二重盲検期間
カプランマイヤー法
HR 0.98（95%CI 0.55-1.77）
p=0.959
PROactive
追跡観察期間
最短
Lancet 366:1279–89, 2005.
最長
投与歴あり
1
投与歴なし
0
例数
Pio 2,783
None 2,455
0
2,323
1,971
1,824
1,464
1,526
1,206
1,000
2,000
3,000 （日）
ランダム化からの期間
PROactive
開始時
ピオグリタゾン
n=2,605
プラセボ
n=2,633
PROactive終了後
追跡開始時
ピオグリタゾン
n=1,820
プラセボ
n=1,779
追跡観察6年
非 TZD
n=1,449
ピオグリタゾン
n=246
他 TZD
n=144
非 TZD
n=1,497
ピオグリタゾン
n=179
他 TZD
n=127
プラセボ群に割り付けられた患者のうち試験終了後にピオグリタゾンが投与された179名は投与歴ありとして解析した。
Spanheimer R.；ADA 72th Scientific Sessions,2012, Philadelphia.
People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive
(PROspective pioglitAzone Clinical Trial In macro Vascular Events) was a landmark study of secondary cardiovascular
disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular
outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with
type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term
exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and
tolerability characteristics associated with pioglitazone therapy in PROactive.
As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for
placebo) and weight gain (mean change of +3.8 kg vs −0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was
consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7%
vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart
failure, and absolute rates of macro-vascular events and mortality were similar to those in the placebo group. Liver
function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic
function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more
cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus
placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs
2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment
limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by
good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.
Drug Saf. 2009;32(3):187-202. doi: 10.2165/00002018-200932030-00002.
Pioglitazoneと膀胱癌発現リスクに関する主な研究報告（1）
調査名又は
掲載雑誌名
アクトス投与による膀胱癌発症リスク
ハザード比（95%信頼区間）
引用された
データベース
1.2（0.9‐1.5）
カルフォルニア州
の医療保険
データベース
CNAMTS2）
1.22（1.05‐1.43）
フランス医療保険
データベース
（SNIIRAM）
Hepatology3）
0.95（0.70‐1.29）
KPNC1）
1.305（0.661‐2.576）
Diabetes Care4）
1.83（1.10‐3.05）
BMJ5）
Br J Clin Pharmcol6）
台湾国民健康
保険登録
データベース
主解析
1.16（0.83‐1.62）
プロペンシティ・
スコアを用いた解析
1.22（0.80‐1.84）
1）Lewis JD et al.； Diabetes Care ,34,916,2011.
2）Neumann A.;Diabetologia,55,1953,2012
3）Chang C.H. et al；Hepatology. 2011 Dec 2.
英国医療保険
データベース
（GPRD）
4）Tseng C.H.et.al.; Diabetes Care,35,2,278,2012
5）Azoulay L.et.al.；BMJ,2012
6）Li Wei et al；Br Clin Pharmacol,2012
Pioglitazoneと膀胱癌発現リスクに関する主な研究報告（2）
調査名又は
掲載雑誌名
JNCI1）
Diabetes Metab J2）
膀胱癌発現リスク
SU薬使用例（41,396
例）に対するチアゾリ
ジン薬使用例（18,459
例）のハザード比
ケース･コントロール
試験における
膀胱癌症例（329例）
と非膀胱癌症例（658
例）のピオグリタゾン
の使用率比較
多変量解析における
ピオグリタゾン使用歴
のオッズ比
0.93
（95%CI: 0.68-1.29）
膀胱癌症例 6.4%
非膀胱癌症例 15.0%
（p<0.001）
引用された
データベース
英国実地診療
データベース
（THIN）
韓国Yonsei大学
Severance病院
データベース
2.09
（95%CI: 0.260-16.814）
1）Mamtani R.et al.;JNCI, 104,18,1411,2012
2）Song S Ok.;Diabetes Metab J,36,371,2012
KPNC研究：ピオグリタゾンと膀胱癌発現リスク
（5年間と8年間の中間解析結果比較）
5年間
ピオグリタゾン使用
総補正後HR*
（95%CI）
1.17（0.92-1.49）
ピオグリタゾン使用開始からの期間
8年間
総補正後HR*
（95%CI）
1.07（0.87-1.30）
減っている！
1.5年未満
1.17（0.79-1.74）
3.5年未満
0.96（0.74-1.24）
1.5-3年
1.37（0.91-2.06）
3.5-6.5年
1.07（0.77-1.48）
3年超
1.27（0.89-1.82）
6.5年超
1.19（0.78-1.80）
1年未満
0.83（0.55-1.26）
1.5年未満
0.78（0.57-1.05）
1-2年
1.40（0.92-2.13）
1.5-4年
1.15（0.87-1.53）
2年超
1.44（1.03-2.02）
4年超
1.62（0.96-2.74）
4年超
1.30（0.91-1.86）
p=0.03
Test for trend
p=0.24
1-10,500mg
1.02（0.71-1.47）
1-13,000mg
0.89（0.67-1.20）
10,501-28,000mg
1.18（0.80-1.75）
13,001-35,000mg
0.98（0.71-1.35）
>28,000mg
1.43（0.96-2.12）
>35,000mg
1.25（0.91-1.74）
ピオグリタゾンによる累積治療期間
Test for trend
累積投与量
*補正項目： 年齢、性、人種、他の糖尿病治療薬、喫煙、他の膀胱の状況、収入、心不全、他の癌、腎機能不全、
HbA1c、糖尿病罹病期間。 8年間解析では、KPNC研究登録後の期間も含む。
Lewis JD et.al.: http://clinicaltrials.gov/ct2/show/NCT01637935?term=KPNC&rank=1
Pioglitazone and bladder cancer risk:
a multipopulation pooled, cumulative exposure analysis
A
Association of cumulative
days of exposure (per 100
days) to pioglitazone with
bladder cancer incidence
within centres and
combined across centers
and combined across
centres in (a) men and (b)
women, with adjustment
for age, calendar year, and
ever exposure to
pioglitazone (logetransformed axis and
whiskers). (a) The absence
of ever exposure events in
Rotterdam prevented
convergence and hence is
excluded from the plot. (b)
The absence of ever
exposure events in
Manchester prevented
convergence and hence is
excluded from the plot.
B. Columbia, British
Columbia; Exp., exposed:
FE, fixed effects; RE,
random effects; Unexp.,
unexposed
Centre
Scotland
Finland
Events
Unexp. Exp.
543
23
Person-years
Unexp.
Exp.
711,917
38,586
RR [95% CI]
0.92 [0.83,1.02]
1,028
18
1,142,875
30,086
1.07 [0.98, 1.16]
B. Columbia
367
15
305,647
6,234
1.13 [1.01, 1.26]
CPRD
447
31
430,869
32,276
0.97 [0.91, 1.03]
Manchester
24
1
40,547
2,072
1.10 [0.87, 1.39]
FE: Q test p=0.03
1.01 [0.97, 1.05]
RE Model:
1.02 [0.94, 1.10]
0.75
1.00
1.25
1.50
Observed outcome
B
Centre
Scotland
Events
Unexp. Exp.
216
15
Person-years
Unexp.
Exp.
626,114
32,991
RR [95% CI]
1.03 [0.95, 1.12]
Finland
280
3
1,177,338
22,275
0.98 [0.75, 1.29]
B. Columbia
89
1
267,959
4,177
1.19 [0.78, 1.80]
CPRD
112
9
369,985
25,214
0.97 [0.85, 1.10]
Rotterdam
10
1
15,238
585
1.02 [0.69, 1.50]
FE: Q test p=0.88
1.01 [0.95, 1.08]
0.75
1.00
1.25
1.50
Observed outcome
Diabetologia DOI 10.1007/s00125-014-3456-9 posted online 3 December 2014
JAMA. 2015;314(3):265-277.
In the subset of
persons receiving a
new diagnosis of
diabetes at cohort entry
(n = 59 070), there was
no evidence of
increased risk of
bladder cancer with
short- or long-term
pioglitazone use
(eTable 5 in the
Supplement).
JAMA. 2015;314(3):265-277.
JAMA. 2015;314(3):265-277.
JAMA. 2015;314(3):265-277.
ピオグリタゾン、膵癌と前立腺癌リスク増？
http://www.m3.com/clinical/journal/15675
JAMA. 2015;314(3):265-277.
Diabetes Obes Metab. 2015 Nov 23.
DOI: 10.1111/dom.12608
Aims
PROactive evaluated pioglitazone for secondary
prevention of macrovascular events in patients
with type 2 diabetes and pre-existing
macrovascular disease. A 10-year, observational
follow-up of patients completing PROactive
investigated whether trends of cardiovascular
benefit with pioglitazone and imbalances in
specific malignancies persisted over time.
Methods
Macrovascular endpoints and malignancies were
compared based on original randomization to
pioglitazone or placebo and “Any” versus “No
pioglitazone use” for bladder and prostate cancer.
the primary endpoints
all-cause mortality,
myocardial infarction
[MI], cardiac
intervention, stroke,
major leg amputation,
leg revascularization
the 2ndary endpoints
death, MI, stroke
**Calculated using only male patients
†Excludes two cases of breast cancer in male patients in the pioglitazone group. When both male and female patients were included in the analysis, the relative
risk was 1.14 [0.53–2.46] for the 10-year observational period and 0.70 [0.37–1.33] for the combined period.CI=confidence interval; N/A=not available.
Figure 1
Figure 2. Kaplan-Meier curve of time to all-cause mortality.
A) 10-year observational period only.
B) Combined PROactive double-blind and 10-year observational period
Figure 2. Kaplan-Meier curve of time to all-cause mortality.
A) 10-year observational period only.
B) Combined PROactive double-blind and 10-year observational period
Results
Of 4873 patients completing PROactive, 74% entered the
follow-up. During follow-up (mean 7.8 years), there were no
statistically significant differences in the primary (all-cause
mortality, myocardial infarction [MI], cardiac intervention,
stroke, major leg amputation, leg revascularization) or main
secondary (death, MI, stroke) endpoints for subjects
originally randomized to pioglitazone and placebo, except for
leg amputations during follow-up (4.1% pioglitazone, 5.6%
placebo; HR=0.74 [95%CI0.55–0.99]; p=0.046). During
follow-up, the incidence of total malignancies was similar
between groups; bladder cancer was reported in 0.8% of
patients (n=14) in the pioglitazone versus 1.2% (n=21) in the
placebo group (RR=0.65 [95%CI0.33–1.28]), and prostate
cancer was reported in 44 (3.7%) men in the pioglitazone
versus 29(2.5%) men in the placebo group (RR=1.47
[95%CI0.93–2.34]).
Conclusions
The trends of macrovascular benefits of
pioglitazone compared with placebo during
PROactive did not persist in the absence of
continued pioglitazone during this 10-year followup. Trends of decreased bladder cancer and
increased prostate cancer were observed in the
pioglitazone group during follow-up; however,
these imbalances should be interpreted with
caution due to limitations of the observational
study design.
Message
Pioglitazoneで膀胱癌はこの研究では最終的に
は有意差なし（実数では減ってきている）。
心血管イベントは止めると低下しない。
心血管イベントについてはpioglitazoneではっ
きりとさせる追試の大規模試験があればよかっ
たのであろう。
Number of Patients who were Prescribed
an Oral Hypoglycemic Agent in our Center
Metformin*
Sulfonylurea
DPP-4 inhibitor
SGLT2 inhibitor
Thiazolidinedione
Glinide
Alpha-glucosidase inhibitor*
One patient may received several agents.
In type 2 diabetic patients, combination use with insulin has been approved if the
indication of the agent is “type 2 diabetes mellitus” or the combination has been
specifically approved.
*: In type 1 diabetic patients, combination use with insulin may be accepted.
Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University
インスリン抵抗性改善薬 処方状況
pioglitazone
年度
2009
2010
2011
2012
2013
2014
528
433
352
374
465
568
2012
2013
2014
actos
303
273
220
metformin
%
25.1
22.9
20.0
22.1
23.6
27.6
1535
1155
1210
882
897
910
%
73.1
61.0
68.9
52.1
45.6
44.2
generic liovelLD liovelHD
0
153
0
0
222
5
121
218
28
経口血糖
降下薬
2100
1892
1757
1693
1967
2057
合計
456
500
587
(重複を含む)
埼玉医科大学総合医療センター 内分泌・糖尿病内科
韓国系アメリカ人による集団訴訟から
2012年12月26日、トヨタはカリフォルニア中部連邦地方裁判所における集団訴訟で、
原告側と11-14億ドルの支払いで和解に同意した。これまでの総費用は約30億ドルにのぼる
https://ja.wikipedia.org/wiki/トヨタ自動車の大規模リコール
Pharmacoepidemiol Drug Saf. 2015 Nov 30. doi: 10.1002/pds.3925
The firms' behavior in the pioglitazone bladder
cancer affair has already been criticized.
(i) the wrong pharmacological presentation of pioglitazone as a
selective peroxisome proliferator-activated receptor γ (PPAR γ)
agonist whereas it belongs to the dual PPAR γ/α agonists, a
class that has been associated with bladder tumors;[1]
(ii) the mistaken number of bladder cancer cases in the placebo
group of the PROactive trial hiding a statistically significant risk
of bladder cancer;[2] or
(iii) the alleged lack of reporting of post-marketing bladder cancers
to the FDA.[3]
In the context of one of the first pioglitazone lawsuits, the US
District Court for the Western District of Louisiana made
accessible through its website the 68-page legal memorandum
of sworn testimonies supporting the arguments against the
firm.[4]
unknown examples of the firms' poor conduct
These documents reveal unknown examples of
the firms' poor conduct regarding drug safety
assessment and management of pioglitazone.
We discuss here the most relevant pieces of
information.
The Hidden and Untruthful Animal Data
Since the marketing of the drug, the firm's explanation for the bladder cancers
found in the male rats exposed to pioglitazone was the “crystalluria hypothesis,”
that is, that bladder cancers were due to the formation of irritant microcrystals in
the bladder, secondary to a pH change that only occurs in rats. The lawsuit
document shows that the firm pushed this explanation knowing its lack of
sustainability. As explained by the expert Dr Jennifer Southgate, animal data did
not provide clear evidence of the alleged change in urine pH, nor show a clear
correlation between the presence of microcrystals and cancer. Furthermore, the
observed type of cancer (transitional cell cancers) did not correspond to the
type expected with this kind of irritation (squamous cell cancers).[4] As it has
also been discussed elsewhere,[5] this rather supports that occurrence of
bladder cancer is not specific to rats and can also affect humans. Moreover, the
lawsuit document indicates that, for the authorization of pioglitazone in 1999,
the firm omitted to report to the FDA one kidney tumor and occurrences of
simple hyperplasia in exposed rodents.
The Hidden Cohort Study Analysis
When pioglitazone was authorized in 1999, regulators asked the firm to conduct
a post-marketing study to address the concerns raised about bladder cancer in
pre-marketing animal studies. Thus, a prospective cohort study based on a
Californian healthcare plan, the Kaiser Permanente Northern California, was
started in 2003 (4 years later) for a duration of 10 years. In 2009, its third interim
analysis (from 2003 to 2008) showed an increased risk of bladder cancer for
patients using pioglitazone for more than 2 years (hazards ratio (HR) = 1.4, 95%
confidence interval (CI): 1.03–2.0). These results were transmitted (1 year later)
to the FDA, which issued an alert on its website in September 2010, and they
were finally published in 2011.[6] In order to address confounding by
race/ethnicity, smoking, or duration of diabetes, the firm performed an additional
nested case–control analysis of the cohort using data retrieved by telephone
interviews.[6] The lawsuit document shows that its results, by nature less
subject to residual confounding, indicated in fact “even higher risks and across
more populations,” but they were not disclosed to the FDA nor published by the
firm, which alleged in court that data collection was biased.[4]
The Hidden Disproportionality Signal
Published in 2011, an analysis of the FDA adverse event reporting system
database found that, between 2004 and 2009, bladder cancers were 4.3-fold
more frequently reported with pioglitazone than with other antidiabetic drugs
(this is called a “disproportionality” analysis).[7] These types of results are
usually considered as pharmacovigilance signals that urge further
investigations. The lawsuit documents indicated that, as of 2005, the firm had
conducted a similar disproportionality study whose primary analysis showed a
statistically significant 190% increase of bladder cancer reports with
pioglitazone. At this time, the firm transmitted non-significant secondary
disproportionality analyses to the FDA but not the primary significant one.[4]
The “Ghost” Meta-analysis Study
During the revaluation of pioglitazone by the European Medicine Agency in
2011, the firm was asked to conduct a meta-analysis from its clinical trial
database. Involving about 22 000 patients, there were 19 cases in the
pioglitazone group versus seven in the comparator group, resulting in an HR of
2.64 (95%CI: 1.11–6.31, p = 0.029).[8] Lawsuit documents prove that the data
to conduct this meta-analysis were available to the firm from as early as 2004
and demonstrated that the firm intentionally never analyzed it. For instance, an
expert hired by the firm to conduct a meta-analysis of pioglitazone clinical trials
on cardiovascular outcome was expressively told not to use the data to assess
the bladder cancer risk.[4] Meta-analysis of clinical trials is commonly
considered as the type of study with the highest level of evidence. As Dr David
Kessler, former commissioner of the FDA, confirmed, these data should have
been provided to the FDA as of 2004 and would have resulted in a warning
about bladder cancer risk for humans being added to the drug label 7 years
earlier than it actually was. It is interesting to note that the re-analysis of the
PROactive trial data, removing the mistaken bladder cancer case in the placebo
group, resulted in a similar HR of 2.83 (95%CI: 1.02–7.85, p = 0.040).[2]
Ghostwriting
Internal documents show that many of the firm's employees were involved in
ghostwriting and that this was considered as a recognized method to ensure
“timely progress” of the firm's publications. The firm's director of the US Medical
and Scientific Affairs acknowledged that ghostwritten documents were sent to
the FDA and to the US medical community and that some of these documents
concerned the question of bladder cancer associated with pioglitazone.
Furthermore, it has been shown that, in 2003, the firm's causation trial expert
sent a “white paper” regarding bladder cancer to the FDA that was partly written
by the firm's employees before the expert even began consulting with the
firm.[4]
Conclusions
In September 2014, the US District Court for the Western District of Louisiana
condemned Takeda and Eli Lilly for “wanton and reckless” conduct failing to
adequately warn about the potential risk of bladder cancer with pioglitazone,
which they knew about.[9] The firm was ordered to pay more than $9 billion in
punitive damage to the plaintiffs, but this amount was later reduced to a total of
$36.8 million. In April 2015, Takeda agreed to pay $2.37 billion to settle
thousands of bladder cancer lawsuits involving its drug. That makes, with Merck
paying $4.85 billion for heart attacks cases related to Vioxx® in 2007, one of
the largest pharmaceutical company payouts in history.
The examples presented here prompt us to be aware that every level of data
production by the firms (basic pharmacology, animal studies, and
epidemiological research) could be subject to misconduct such as hiding and
manipulating data that eventually results in delay or lack of crucial safety
information for the regulators, the healthcare professionals, and their patients.
Key Points
 In September 2014, the manufacturers of pioglitazone
were condemned by an US court for not having
warned about the potential risk of bladder cancer,
which they knew about.
 Misconducts such as hiding and manipulating data
can occur at every step of safety information
production by the pharmaceutical industries.
 These examples illustrate the crucial need for more
transparency to improve drug safety assessment and
management.
Message
$2.37 billion （$2,370,000,000 23.7億ドル）
日本円で 2844億円(120円として)
和解金を支払うことになった経緯は興味深い！
また、トヨタの場合は韓国だが、今回はフラン
ス人が大きな役割をしている。ある意味戦争？
とは言っても、科学的には？？？であるが。
しかもpioglitazoneは使われ続けられているし