武田 痛風藥Uloric 下市風險: serious cardiovascular harms

美國FDA被要求把非布司他（Uloric）從美國撤市 張晉傑 藥時代FiercePharma 2018-6-21文章（全文翻譯） 翻譯：張晉傑

When Takeda's gout drug Uloric (febuxostat) was approved by the FDA, it was with a requirement for postmarketing studies to further assess its safety. Now a nonprofit consumer advocacy group says the FDA should remove the drug from the U.S. market after findings released this March show significant deadly heart risks.

當日本武田公司的治療痛風藥物非布司他（Uloric）被FDA批准上市時，被要求進行上市後研究以進一步評估其安全性。現在，一個非營利性消費者遊說組織表示，鑒於今年3月新英格蘭醫學雜誌發佈研究報告顯示非布司他具有明顯的致死性心臟風險後，FDA應該把非布司他（Uloric）從美國撤市。

In a petition (PDF) sent to the FDA on Thursday, Public Citizen stated there is "overwhelming evidence that the serious cardiovascular harms of [Uloric] outweigh any purported clinical benefit," and that leaving it on the market would only cause "further preventable harm" to patients.

在該組織向FDA發出的公民請願書中指出，大量的證據表明非布司他（Uloric)的嚴重心血管損害已經超過了已有的臨床獲益，而將該藥留在市場只會導致患者產生更多本來可預防的傷害！

The Japanese pharma submitted results from a postmarketing cardiovascular safety study previously required by the FDA in January, and it is "working with the agency to conduct a comprehensive review of this data," a Takeda spokeswoman told FiercePharma.

日本製藥公司1月份按照FDA要求提交了非布司他上市後心血管安全研究的結果，該公司正在"與FDA合作對該資料進行全面審查"，武田製藥發言人告訴FiercePharma。

A spokesman for the FDA told FiercePharma the agency will review Public Citizen's letter and will respond directly to the organization.

FDA發言人告訴FiercePharma，FDA將審查公民公民信函，並將直接回復武田公司。

The 2009 approval allowed Uloric to be used as a treatment of hyperuricemia—instead of for the direct reduction in gout flares—in gout patients. But it followed two failed attempts in 2005 and 2006 under TAP Pharmaceutical.

非布司他（Uloric）於2009年被FDA批准用於治療痛風患者的高尿酸血症，而不是直接減少痛風發作。但是之前武田製藥公司於2005和2006年兩次嘗試均告失敗。

The FDA had rejected the medication out of concerns for increased cardiovascular risks observed in clinical trials. At the time of the second NDA submission, FDA reviewers noted 9 of the total 12 deaths among subjects on Uloric were attributable to CV causes, whereas no serious adverse CV events were linked to comparator allopurinol or placebo.

由於擔心臨床試驗中觀察到的心血管風險增加，FDA拒絕了非布司他的上市。在第二次NDA提交時，FDA審查員注意到非布司他（Uloric）治療時12名受試者中有9人死於心血管原因，而發現沒有嚴重的心血管不良事件與對照藥別嘌呤醇或安慰劑有關。

In response to the FDA's concern, Takeda conducted another trial that ultimately didn't find the same CV safety signal. But after putting data from all three phase 3 studies and two long-term extension studies together, the FDA reviewers couldn't determine "with much confidence" whether Uloric poses greater risk. So, when they did approve the drug, they slapped a warning on the drug's label and asked Takeda to run a large, postmakreting study to further examine Uloric's CV safety profile.

為了回應FDA的擔憂，武田進行了另一項試驗並最終沒有找到相同的心血管安全性證據。但是，將所有三項三期研究和兩項長期性延期研究的資料放在一起分析後，FDA審查人員無法確定性得出非布司他（Uloric）是否會帶來更大的風險。所以，當FDA批准該藥物上市時，要求在藥物的標籤上打了一個警告，並要求武田公司做一項大型的上市後研究，以進一步檢測非布司他（Uloric）的心血管安全性。

Concerns flared up on Nov. 15, 2017, when the FDA issued a drug safety communication alerting the public of increased cardiovascular events with Uloric, compared to allopurinol. The agency at that time said it will "conduct a comprehensive review and will update the public with any new information," once it has the full final result

2017年11月15日，FDA發佈了一項藥物安全性通訊，提醒公眾注意非布司他增加心血管事件（與別嘌醇比較）。當時FDA表示將"進一步進行全面審查，一旦有任何新資訊將及時公佈於眾"。

Findings from the 6,190-subject study were then published this March in The New England Journal of Medicine. In that study, researchers noted that after 32 months, overall adverse CV events were similar in both arms, but "[a]ll-cause mortality and cardiovascular mortality were higher with [Uloric] than with allopurinol."

今年3月新英格蘭醫學雜誌發表該項6,190例痛風患者的研究結果。指出在該研究中，研究人員發現平均治療32個月後，非布司他和別嘌醇治療組總體的不良心血管事件相似，但是非布司他組的全因死亡率和心血管死亡率高於別嘌呤醇組（注：非布司他組患者心血管死亡風險增加34%（HR 1.34，95% CI，1.03-1.73），全因死亡率增加22%（HR 1.22，95% CI，1.01-1.47）。其中，心臟性猝死最常見-非布司他組83例（2.7%），別嘌醇組56例（1.8%））。

Following the release of the study, Takeda said in a statement that the reason for the imbalance in cardiovascular deaths has not been identified.

在上述研究發佈後，武田公司在一份聲明中表示，該研究中心血管死亡失衡的原因尚未確定。

"The agency should have demanded that an appropriately designed clinical trial to assess febuxostat's cardiovascular risks be conducted before, not after approval," said Michael Carome, M.D., director of Public Citizen's Health Research Group, in a statement. "The FDA almost certainly would have denied approval of febuxostat if data from this post-market trial had been available at the time of the initial submission."

公共公民健康研究機構負責人醫學博士Michael Carome指出，FDA應該要求在批准非布司他上市前而不是上市後設計適當的臨床試驗以評估非布司他的心血管風險。在該機構一項申明中提出，如果這個上市後臨床研究資料在最初提交相關資料時就提供，幾乎可以肯定FDA會拒絕批准非布司他上市!

Besides higher risks of cardiovascular risks, the organization also argued there's not enough data showing Uloric is more effective in the actual prevention of gout flares, other than that it's able to lower serum uric acid levels, which can cause acute painful gout episodes.

除了非布司他會增加心血管事件風險，FDA同時指出非布司他沒有足夠的證據顯示對於痛風發作的預防作用比別嘌醇更有效。除此之外，非布司他還可以在降尿酸治療過程中誘發急性痛風發作。