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【分享】具有全新降低血糖机制的新药被fda专家小组否定 [精华]

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这个帖子发布于9年零275天前，其中的信息可能已发生改变或有所发展。

FDA Panel Votes Against Diabetes Pill，Matthew Perrone，Drug Discovery & Development - July 20, 2011

fda15人专家小组昨天9对6票否定治疗糖尿病新药的决定，其理由是对此药可能引发癌症的数据不足。这不是fda官方最后决定，但是可以看成是官方决定。

此药具有全新机制的控制血糖功能，通过清除尿中葡萄糖量而降低血中糖量，此作用机理和传统降血糖机理完全不一样，是一类全新降糖药物，也是这类作用机理中第一个药物。

由于是全新机制的降血糖药物，审评者对这些数据的评估也没有很多经验，有一个参入评审者说在要在做出最后决定之前的10秒钟他的主意改变了4次，当然这是和夸张的说法，但是可以看出对新机制药物要做出正确的决定很艰难，哪怕你有很多可靠的数据。

此药的有效性方面没有多少疑问。主要关注在是否引发癌症、肝脏毒性和感染方面，数据显示和对照组比较很难让人放心，例如在超过5000个病人中用药组膀胱癌发现有9例而非用药组没有一个，这样的数据很明显表面膀胱癌发病率和用药的关系，特别是在这么大的样本中。

本人的看法是此药如果再做癌症安全方面的实验，很难通过，因为现有的数据已经比较清楚说明了膀胱癌和药物的关系。个再做同样实验，结果很难被推翻。

从这样的临床实验看，具有全新机制的药物研发风险很大，而且不可控。严重不良反应真的很难预测和控制。但是这样的实验给后来者奠定了很好的基础，也许会少犯同样的错误。

其实在任何一个临床试验数据里都可以找到很多问题，只要不是核心的就好。在这个实验中，有人说老年人和非美籍病例数太少。如果有了这些数据，一定有人会说亚裔病人太少。问题是在一个临床试验中不可能包涵所有情况。

大家猜猜公司还会继续补充安全性方面的数据啊？我想会的，理由是这2个公司都很有实力，钱不是最大问题，对于这样全新机制的新药有效性没有问题，现在放弃很可惜。

下面是全文：
WASHINGTON (AP) - The majority of advisers on a federal health panel say a first-of-a-kind diabetes drug that uses a new method to reduce blood sugar shouldn't be approved for U.S. patients after higher rates of bladder and breast cancer were reported among patients in company trials.A Food and Drug Administration panel voted 9-6 against the experimental diabetes pill from Bristol-Myers Squibb and AstraZeneca, while expressing hope that the drug might ultimately be approved if safety questions are resolved. The vote is only a recommendation for FDA, which will make a final decision on the drug before the end of October.

Dapagliflozin is a once-a-day pill designed to help diabetics eliminate excess sugar in their urine. That differs from older drugs that decrease the amount of sugar absorbed from food and stored in the liver. The companies have touted it as the first in a new class of drugs to address the nation's growing diabetes epidemic, which affects more than 25 million people.

Nearly all the panelists praised the drug's innovative approach to lowering blood glucose, but a majority said they wanted more information on a host of safety concerns, including cancer, infections and possible liver toxicity.

"It was the closest of calls, I changed my mind about four times in the last 10 seconds," said Dr. Erica Brittain, a biostatistician with the National Institutes of Health, who voted against the drug. "The level of evidence about the cancer is fairly weak, but it's just that the uncertainty is still there."
The companies reported nine bladder cancers among over 5,000 people taking the drug in company studies, compared with none among those taking a dummy pill. There were nine cases of breast cancer among 2,100 women taking the drug, compared with one in the control group. While the company studies were not designed to measure cancer risk, panelists noted that the incidence of cancers was four to five times higher than expected in the population.

Panelists said they would like more data on cancer rates in patients, but acknowledged that a definitive study of the risk probably would not be feasible, since it would mean enrolling more than 30,000 patients for several years.

"There are some things we can't learn from clinical trials," said Dr. Ed Hendricks of the Center for Weight Management in Sacramento, Calif., who voted to approve the drug. "Sometimes to introduce new, innovative medical therapies we have to make decisions with a certain amount of uncertainty."

The drug was also associated with bladder and urinary tract infections, due to increased sugar eliminated in patients' urine, and the companies suggested this factor may have led to higher detection of bladder cancers. That rationale did not explain why bladder cancers reported were limited to men, since urinary tract infections are more common in women. Panelists also complained about the small number of elderly and African-American patients enrolled in company studies. People in those groups are more predisposed to have diabetes.

People with type 2 diabetes are unable to properly break down carbohydrates, either because their bodies do not produce enough insulin or have become resistant to the hormone, which controls blood sugar levels. These patients are at higher risk for heart attacks, kidney problems, blindness and other serious complications. Diabetics often require multiple drugs with different mechanisms of action to control their blood sugar levels.
New York-based Bristol-Myers Squibb Co. and London-based AstraZeneca PLC already co-market the diabetes drug Onglyza, which increases insulin production while reducing glucose production.

Date: July 19, 2011
Source: Associated Press

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2011-07-21 17:00 浏览 : 100170 回复 : 144

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yuuyake

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可能先回顾一下数据吧，先仔细review每个具体的case，还有临床前的安全性、包括遗传毒性和动物致癌性研究等，看有无解释；还需要结合流行病学数据进行统计和分析，初步评估药物是否导致癌症的发生率增加。然后再来判定下一步该如何。

2011-07-21 17:24

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• 基层诊室的故事【我的故事侧重于记述生命中的一种状况（患病）以及来访者对它的态度】

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严重打击，尤其对AZ。

一个解释是有于增加泌尿感染所以泌尿科检查次数增加，所以增加膀胱癌发现几率，但没有数据这显然不能说服任何人。

2011-07-21 18:53

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• 新冠疫苗的奥秘——如何选择疫苗抗原？（转载）

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依我看公司现阶段可以做的最重要事情是全部跟踪这9个患膀胱癌症病人和他们的家属的所有临床和用药历史资料，对他们做更多实验室检查。这样做目的是看看这些病人是否由于其他原因导致膀胱癌，而不是此药引起的。现在比较难以解释的是9个膀胱癌患者都是男性，女性中没有发现，男性好像对此药更敏感。是否和雄性激素水平有关？如果此推理成立，也许可以让此药只用于女性患者。

另外仔细分析药物剂量和癌症起始时间关系也很重要，这样对下面的工作具有很好的指导价值。对这些病人和癌症有关的基因和biomarkers做细致的工作，从中找到有用的信息。

当然相关的动物实验也可以做，特别是在猴子或具有同样疾病的模型中。但是这些数据仅仅具有比较好的发表价值了。

2011-07-21 19:06

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blueskychina 编辑于 2011-07-22 14:59

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