FiercePharma 2018-6-21文章（全文翻译）

翻译：张晋杰

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.

当日本武田公司的治疗痛风药物非布司他（Uloric）被FDA批准上市时，被要求进行上市后研究以进一步评估其安全性。现在，一个非营利性消费者游说组织表示，鉴于今年3月新英格兰医学杂志发布研究报告显示非布司他具有明显的致死性心脏风险后，FDA应该把非布司他（Uloric）从美国撤市。

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.

在该组织向FDA发出的公民请愿书中指出，大量的证据表明非布司他（Uloric)的严重心血管损害已经超过了已有的临床获益，而将该药留在市场只会导致患者产生更多本来可预防的伤害！

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.

日本制药公司1月份按照FDA要求提交了非布司他上市后心血管安全研究的结果，该公司正在“与FDA合作对该数据进行全面审查”，武田制药发言人告诉FiercePharma。

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

FDA发言人告诉FiercePharma，FDA将审查公民公民信函，并将直接回复武田公司。

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）于2009年被FDA批准用于治疗痛风患者的高尿酸血症，而不是直接减少痛风发作。但是之前武田制药公司于2005和2006年两次尝试均告失败。

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.

由于担心临床试验中观察到的心血管风险增加，FDA拒绝了非布司他的上市。在第二次NDA提交时，FDA审查员注意到非布司他（Uloric）治疗时12名受试者中有9人死于心血管原因，而发现没有严重的心血管不良事件与对照药别嘌呤醇或安慰剂有关。

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.

为了回应FDA的担忧，武田进行了另一项试验并最终没有找到相同的心血管安全性证据。但是，将所有三项三期研究和两项长期性延期研究的数据放在一起分析后，FDA审查人员无法确定性得出非布司他（Uloric）是否会带来更大的风险。所以，当FDA批准该药物上市时，要求在药物的标签上打了一个警告，并要求武田公司做一项大型的上市后研究，以进一步检测非布司他（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发布了一项药物安全性通讯，提醒公众注意非布司他增加心血管事件（与别嘌醇比较）。当时FDA表示将“进一步进行全面审查，一旦有任何新信息将及时公布于众”。

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月新英格兰医学杂志发表该项6,190例痛风患者的研究结果。指出在该研究中，研究人员发现平均治疗32个月后，非布司他和别嘌醇治疗组总体的不良心血管事件相似，但是非布司他组的全因死亡率和心血管死亡率高于别嘌呤醇组（注：非布司他组患者心血管死亡风险增加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，心脏性猝死最常见-非布司他组83例（2.7%），别嘌醇组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.

在上述研究发布后，武田公司在一份声明中表示，该研究中心血管死亡失衡的原因尚未确定。

“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.”

公共公民健康研究机构负责人医学博士Michael Carome指出，FDA应该要求在批准非布司他上市前而不是上市后设计适当的临床试验以评估非布司他的心血管风险。在该机构一项申明中提出，如果这个上市后临床研究数据在最初提交相关资料时就提供，几乎可以肯定FDA会拒绝批准非布司他上市!

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.

除了非布司他会增加心血管事件风险，FDA同时指出非布司他没有足够的证据显示对于痛风发作的预防作用比别嘌醇更有效。除此之外，非布司他还可以在降尿酸治疗过程中诱发急性痛风发作。

（转化医学网360zhyx.com）