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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 プラセボ:6例 アクトス:6例 プラセボ:3例 アクトス:2例 プラセボ: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 プラセボ:3例 アクトス:4例 プラセボ: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