Novartis, which last week was publicly shamed by the FDA for manipulating data tied to the application of its gene therapy Zolgensma, has said that it launched an investigation in March, as soon as it learned of the issue.
But records from the lab where the manipulation arose suggest that the company’s investigation may not have been as deep or wide as the Swiss drugmaker has proclaimed.
Documents referenced in a Form 483 by the FDA, which inspected the lab a month after it learned of the falsified records, also suggest the data-fudging began at least in early 2018 and could have been uncovered by managers at AveXis during several steps in the clinical outcome assessment.
Novartis has claimed that the company launched an internal probe when a scientist raised the allegations in March, and by early May had determined that scientist was correct. It didn't inform the FDA about the allegations until June 28, more than a month after Zolgensma was approved. Novartis said it needed to complete its probe before telling the FDA.
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But the FDA inspection report says it found that Novartis’ gene unit AveXis didn't open a Nonconformance Report into the potentially manipulated assay tests “until 15 May 2019" even though the "initial allegation is documented as having been reported on 14 March 2019.”
The issues exploded on the scene last week when acting FDA chief Ned Sharpless, M.D., announced its investigation. The agency said it has determined that the falsification was limited to “a small portion of the product testing data that was contained in the marketing application,” and that the drug was safe and effective and should remain on the market.
But Sharpless also tweeted that the agency "will use its full authorities to take action, if appropriate, which may include civil or criminal penalties."
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In a call with investors, Novartis CEO Vas Narasimhan declared the drugmaker had not tried to mislead the FDA and didn’t want to inform the agency until it knew exactly what had happened and whether the falsification put patients at risk. He said the investigation found the mismanaged data involved a potency assay Novartis no longer used in testing Zolgensma during production. Narasimhan said the Novartis' team did the “best we could."
Perhaps, but the Form 483 shows that some reports had date discrepancies noted during a historical data review on January 31, 2018. A nonconformance report also showed that that an assay "was not completed at the time of (clinical outcome assessment) generation and approval" for one lot. But the FDA says no one investigated further.
There was also a nonconformance report opened on Aug. 23, 2018 when discrepancies were found in the “data that was used to calculate relative potency for AVXS-101 Drug Product.” Then on Oct.15, 2018, another NCR was filed after inconsistencies were found in previously reported mouse. A quality control employee was verbally informed about the issue but didn’t require it be documented in writing.
Other issues uncovered by inspectors included that vivarium employees who had responsibilities for manufacturing functions were reporting to an R&D scientist with no GMP experience.
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The FDA has said it is continuing to investigate. Five Senate Democrats are also urging the agency to hold AveXis accountable for its “malfeasance, including through all appropriate criminal, civil and regulatory actions against the company.”
On top of that, the lawmakers are demanding Sharpless explain why the FDA decided last October to withdraw a regulation that would have required drugmakers to promptly report suspected falsified data, and whether the FDA plans to reinstate it in the wake of the AveXis case.
诺华( Novartis )上周因操纵与其基因治疗佐尔甘斯曼( Zolgensma )应用相关的数据而被 FDA 公开羞辱。该公司表示，一旦获悉此事，就在3月份启动了一项调查。
FDA 在一份483表格中引用的文件，在得知伪造的记录一个月后对实验室进行了检查，同时也表明数据造假至少在2018年初开始，在临床结果评估的几个步骤中， AveXis 的管理者可能已经发现了这些数据。
诺华（Novartis）声称，当一位科学家在3月提出指控时，该公司启动了一项内部调查，到5月初，该公司已认定科学家是正确的。在 Zolgensma 获得批准一个多月后， FDA 直到6月28日才将这些指控通知 FDA 。诺华（Novartis）表示，在告知 FDA 之前，它需要完成调查。
相关信息：随着诺华（Novartis）公司披露了 Zolgensma 操纵数据， FDA 准备对此进行打击
但 FDA 的检查报告称，它发现诺华（Novartis）的基因单位 AveXis 在“2019年5月15日之前”没有在可能被操纵的检测中打开不符合报告，尽管“最初的指控被记录为2019年3月14日的报告”。这是一个很好的例子
上周，代理 FDA 首席执行官 NedSharpless 宣布对此进行调查时，问题在现场爆发。该机构表示，它已确定，伪造行为仅限于“市场营销申请中包含的产品检测数据的一小部分”，而且该药物是安全有效的，应留在市场上。
但 Sharpless 还在推特上表示，该机构“将利用其全部权力，酌情采取行动，其中可能包括民事或刑事处罚。”这是一个很好的例子
诺华（Novartis）首席执行长纳拉希姆( Vas Narasimhan )在一次与投资者的电话会议上宣布，这家制药商并未试图误导 FDA ，也不想通知 FDA ，除非它确切知道发生了什么，以及造假是否会让患者面临风险。他说，调查发现，管理不善的数据涉及一种效力分析诺华（Novartis）公司不再用于测试佐尔甘马生产。Narasimhan 说诺华（Novartis）的团队做了“我们能做的最好”。
或许，但表格483显示，一些报告在2018年1月31日的历史数据审查中发现了日期差异。一份不合格报告还显示，一批“在（临床结果评估）产生和批准的时候”还没有完成检测。但是 FDA 表示没有人进一步调查。
2018年8月23日，当发现“用于计算 AVXS-101药物产品相对效力的数据”中存在差异时，也有一份不符合规定的报告。然后在2018年10月15日，在之前报道的鼠标中发现不一致后，又提交了 NCR 。一名质量控制员工口头告知了这个问题，但并不要求书面记录。
检查人员发现的其他问题包括，负责生产职能的 vivarium 雇员向没有 GMP 经验的研发科学家报告。
相关报道：桑德斯，沃伦加入参议员团队，抨击诺华（Novartis）的 Zolgensma 数据平台
FDA 表示正在继续调查。五名民主党参议员还敦促该机构追究 AveXi 公司“渎职行为的责任，包括对公司采取一切适当的刑事、民事和监管行动。”
除此之外，立法者要求 Sharpless 解释为什么 FDA 去年10月决定撤销一项要求制药商立即报告可疑伪造数据的法规，以及 FDA 是否计划在 AveXis 案之后恢复该法规。