Why the FDA Dropped the Hammer on Novartis Data Manipulation Scandal

为什么 FDA 放弃了关于诺华(Novartis)公司数据操纵扫描的锤子

2019-08-21 22:11:41 BioSpace


In early August, the U.S. Food and Drug Administration (FDA) announced that the data involved in the preclinical approval process of Novartis’ gene therapy Zolgensma for spinal muscular atrophy (SMA) was manipulated. The therapy, which was developed by AveXis, a Novartis subsidiary, was approved by the agency in May. Some have wondered why the agency has hit back at Novartis so hard when the data in question didn’t have any effect on the eventual outcomes of the product’s effectiveness and safety. In the original announcement, the FDA said AveXis informed the agency “about a data manipulation issue that impacts the accuracy of certain data from product testing performed in animals submitted in the biologics license application.” The data was used by the company to support the development of its production process, and the data does not seem to change the agency’s positive assessment of the information from the human clinical trials. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research,wrote the original FDA memo that started the crisis and told STAT that any time data is mishandled and leads to a patient being harmed, it sets the entire field back and undermines the public trust in the agency and the pharmaceutical industry. Although as far as is known, nobody has been harmed anywhere along the way in the Novartis Zolgensma development and approval process, Marks cited Jesse Gelsinger, who died in September 1999 during a gene therapy clinical trial. hbspt.cta.load(4413123, '404ba7a7-73a5-4877-8e77-f29b5ce4a0f2', {}); That clinical trial was run by the University of Pennsylvania and was a gene therapy for ornithine transcarbalmylase deficiency, which includes an inability to metabolize ammonia. Gelsinger had a massive immune response to the gene therapy that led to multiple organ failure and brain death. “We just so happened to be lucky in this case that when we look at everything, at the end of the day, there’s no concern about this particular product,” Marks told STAT. “But we don’t want anyone to think that it isn’t important to do the right thing and to make sure that the information that we get is correct.” The data manipulation in the Novartis’ Zolgensma case didn’t undermine the benefits of the therapy. The issues revolved around efforts AveXis researchers took to evaluate the potency of the viruses used in Zolgensma to carry the new genetic material. It was used to compare earlier and later versions of the therapeutic used in clinical trials. Part of what has made the story so big is simply timing—because of the presidential election cycle, drug pricing is a hot-button issue. The U.S. Senate has weighed in on the issue. Specifically, U.S. Senate Finance Committee Chairman Chuck Grassley (R-IA) has requested details about the data manipulation. Five senators, including presidential candidates Elizabeth Warren (D-MA) and Bernie Sanders (I-VT), wrote a letter to the FDA urging it to take forceful action. Reportedly the FDA has referred the matter to its Office of Criminal Investigations to launch a preliminary inquiry. Submitting false data to the FDA as part of a New Drug Application (NDA) could be a crime if the investigation finds the actions were intentional. So far Novartis has ousted five of the scientists involved in the scandal and appointed a new chief scientific officer for AveXis. AveXis has also parted ways with its scientific founder and chief scientific officer. Brian Kaspar, chief scientific officer, and Allan Kaspar, the company’s head of research and development, are no longer with the company and, according to AveXis, have not been involved in AveXis operations since May. Brian Kaspar has denied any wrongdoing. Page Bouchard, who has been with Novartis for 10 years, is taking over their roles. Marks notes that gene therapy products are being evaluated for more than 800 different uses, developed by big pharma companies and small biotechs. “They all need to understand that the information that the agency gets needs to be accurate, truthful, and complete,” he told STAT. “And that means that it may take a little more time to get there.”
8月初,美国食品药品监督管理局( FDA )宣布,诺华(Novartis)基因治疗佐尔甘斯瘤用于脊柱肌肉萎缩症( SMA )的临床前审批过程中涉及的数据被篡改。该疗法是由诺华(Novartis)的子公司 AveXis 开发的,于5月份获得了该机构的批准。 有些人想知道,当相关数据对产品的有效性和安全性的最终结果没有任何影响时,该机构为何如此严厉地打击了诺华(Novartis)。 FDA 在最初的声明中表示, AveXis 公司向 FDA 通报了“一个数据操纵问题,这会影响生物制剂许可申请中提交的动物产品测试的某些数据的准确性”。该数据被公司用于支持其生产工艺的开发,该数据似乎没有改变该机构对人体临床试验信息的积极评估。 FDA 生物逻辑评估和研究中心主任彼得·马克斯( Peter Marks )撰写了 FDA 的原始备忘录,该备忘录引发了这场危机,并告诉 STAT ,一旦数据处理不当,导致患者受到伤害,就会让整个领域倒退,损害公众对 FDA 和制药业的信任。尽管就目前所知,在诺华(Novartis)佐尔甘马研发和批准过程中,没有人在任何地方受到伤害, Marks 引用 Jesse Gelsinger 的话说,他于1999年9月在基因治疗临床试验中去世。 。cta 。负载(443123,'4044a7a7-73a5-4877-8e77-f29b5ce4a0f2',{}); 该临床试验由宾夕法尼亚大学进行,是一种基因治疗鸟氨酸转氨酶缺乏,其中包括无法代谢氨。Gelsinger 对导致多器官衰竭和脑死亡的基因治疗有巨大的免疫反应。 “在这种情况下,我们碰巧是幸运的,当我们看完所有的东西时,在一天结束的时候,对这个特定的产品没有任何担忧,” Marks 告诉 STAT 。“但我们不希望任何人认为做正确的事情并确保我们得到的信息是正确的并不重要。” 诺华( Novartis )的佐尔甘斯曼( Zolgensma )病例的数据操纵并未损害该疗法的益处。这些问题围绕着 AveXis 研究人员为评估 Zolgensma 病毒携带新遗传物质的效力所做的努力。它被用来比较早期和后期版本的治疗用于临床试验。 这件事之所以如此重要,部分原因在于时机选择——因为总统选举周期,药品定价是一个热门话题。美国参议院对这个问题进行了权衡。具体而言,美国参议院财政委员会主席查克·格拉斯利( R-IA )要求提供有关数据操纵的细节。五位参议员,包括总统候选人伊丽莎白·沃伦( ElizabethWarren )和伯尼·桑德斯( BernieSanders , I-VT )写了一封信,敦促 FDA 采取有力行动。 据报道, FDA 已将此事提交其刑事调查办公室展开初步调查。如果调查发现这些行为是故意的,向 FDA 提交虚假数据作为新药申请( NDA )的一部分可能是犯罪。 到目前为止,诺华(Novartis)已经解雇了5名卷入这起丑闻的科学家,并任命了一名新的首席科学家为艾维斯。AveXis 也与其科学创始人和首席科学家分道扬镳。首席科学官布赖恩·卡斯帕( Brian Kaspar )和该公司研发主管艾伦·卡斯帕( Allan Kaspar )已不再与该公司合作,根据 AveXis 的说法,自5月份以来,一直未参与 AveXi 的运营。布赖恩·卡斯帕( Brian Kaspar )否认存在任何不当行为。佩奇·布查德已经在诺华(Novartis)公司工作了10年,他正在接手他们的工作。 Marks 指出,由大型制药公司和小型生物技术公司开发的基因治疗产品正在进行800多种不同用途的评估。“他们都需要明白,机构获得的信息必须准确、真实和完整,”他对 STAT 表示。“这意味着可能需要更多时间才能到达那里。”