Dalantercept

近日，美国两名临床研究人员因伪造临床试验数据被法院分别判处46个月和30个月的监禁，并处以213.45万美元（约1383万元）的罚款。 FDA刑事调查部门表示，发现任何人伪造试验数据都将进行起诉。   本次案件中，52岁的Eduardo Navarro和50岁的Nayade Varona均是Tellus临床研究（Tellus Clinical Research）机构的工作人员。Navarro是一名护士，也是Tellus的副研究员；Varona是Tellus的助理研究协调员。   根据法庭文件，她们承认与他人共同伪造了两项临床试验的数据，通过伪造医疗记录，让文件看起来像是受试者参加了临床试验，但实际上受试者并没有参加。   01  “惯犯” Tellus Tellus是一家临床研究机构，曾与辉瑞、吉利德、武田、勃林格殷格翰和礼来等知名制药公司合作过。 近几年，Tellus所做的临床试验中有一些试验也受到了质疑，包括Braeburn 制药的阿片类药物依赖有关的试验和吉利德的糖尿病药物研究试验。   同时，这次的临床试验数据造假问题并不是Tellus第一次被指控。今年3月， Tellus的老板Fidalgis Font、主要调查员Martin Valdes医生和两位高管Julio Lopez、Duniel Tejeda被指控串谋进行邮件和电汇欺诈，Valdes 和Font 被指控洗钱，Valdes 还进一步被指控向FDA检查员作虚假陈述。   起诉书显示，至少从 2014年2月到2016年7月，4位被告在Tellus 临床研究机构工作期间捏造临床试验数据以牟利。被告在明知受试者不符合参加临床试验标准的情况下仍然招募受试者，并伪造受试者实验室检查结果、医疗记录，虚假陈述受试者正在服用该临床试验研究的药物，但实际上受试者并未服用。目前，此案还在审理中。   FDA刑事调查助理专员Catherine A. Hermsen 说：“临床试验可靠和准确的数据是FDA评估新药的基础。受损的临床试验数据可能会影响FDA对所审查药物安全性和有效性的决定。我们将继续监控、调查那些行为可能破坏FDA批准程序并危害公众健康的人，并将其绳之以法。”   美国司法部民事司代理助理检察长Brian M. Boynton说：“必须保障临床试验数据的准确性和真实性，这对于确保FDA所批药物的安全性至关重要。被告却伪造试验数据，让患者处于危险之中。司法部将追查和起诉那些将个人利益置于公共健康之上的人。”   “伪造临床数据是辜负公众信任，危及消费者安全的行为。”美国检察官Ariana Fajardo Orshan说：“借虚假临床数据危害公众健康并牟利的人，将受到起诉并严惩。起诉这些案件也将继续是我们办公室的首要任务。”   在Navarro和Varona临床试验数据造假的案件中，FDA刑事调查办公室负责调查这起案件；民事法庭消费者保护分部的审判律师劳伦·埃尔夫纳和约书亚·罗斯曼负责对此案进行起诉；美国佛罗里达州南区检察官办公室提供关键援助。   02 愈发严格的FDA   近几年，FDA对于临床试验数据的管理愈发严格。   过去十年，英国和欧洲常常出现制药公司推迟或隐瞒试验数据的情况，引发公众对批准药品安全性的担忧。2019 年 11 月，一项发表在《新英格兰医学杂志》上研究显示，制药公司和学术研究中心在报告人体研究结果方面略有进展，更多的试验结果被公开，但试验数据质量成为大问题。   在数据被推迟公开或被隐藏，甚至提交虚假数据“成风”时，去年7月，FDA发布有关对违反《FDA 修订法案》（FDAAA）第801节条款的定稿指南： 对未注册研究，不向 ClinicalTrial.gov报告结果或提交虚假信息的试验申办者进行处罚，单个程序中裁定的所有违法行为，最高罚款不超过1万美元。如果申办者在收到此类违法行为通知后的30天内仍未纠正违法行为，则在违规行为发生后的每一天加收不超过1万美元的罚款，直至纠正违规行为为止。   定稿指南发布后，依旧有部分申报者未遵守指南要求。根据Trials Tracker数据，近 9900 项临床试验中约有28% 的结果尚未报告给 ClinicalTrials.gov，FDA也未收到任何罚款。   在当大多数人认为这又是一次“雷声大，雨点小”的规定时，终于在今年4月FDA开始行动了。   4月28日，FDA向未能向联邦注册机构提交临床试验必要信息的申办人 Acceleron Pharma 发布不合规通知，并警示可能面临罚款。这是FDA发布定稿指南以来首次发出不合规通知，也被认为是首次采取罚款措施来回应大众对提高临床研究透明度的要求。 FDA表示，早在去年7月就已经因未提交关于Dalantercept药物治疗晚期肾细胞癌的II期试验结果而向Acceleron发出警告信，但Acceleron一直未做出纠正。FDA 指出，Acceleron必须在5月27日之前公布数据，否则将面临每天最高 1 万美元的民事罚款或其它监管行动，包括禁制令或刑事诉讼。   收到通知后，Acceleron 公司表示在试验结果未达到预期后，公司已经于2017年停止了该药物的研发。不过还是会遵守FDA的要求，在规定的30天补救期内，将临床试验结果发布在ClinicalTrials.gov上。   紧接着，今年7月，FDA发出了第二张不合规通知。FDA称，制药公司Accuitis在使用ACU-D1治疗玫瑰痤疮的临床试验中未能按照联邦法规的要求在联邦注册机构提交临床试验结果，已经在去年10月份就该问题致信Accuitis，并要求 “立即提交所有要求的结果信息”。但很显然Accuitis没有遵守FDA的要求。   FDA在不合规通知中指出，Accuitis 必须在30 天之内公布数据，否则将面临每天最高1万美元的民事罚款或其它监管行动。   FDA中心的监管顾问Jan Hewett说：“FDA虽然希望申报者自愿遵守规定，但更多的是希望受监管者了解合规的重要性和不合规时对药物研究和评价带来的潜在不良影响。”   对于临床试验数据的监管，我国药监局也曾采取过雷霆手段。   2015年7月22日，国家食品药品监督管理总局发布《关于开展药物临床试验数据自查核查工作的公告（2015年第117号）》，按“最严谨的标准、最严格的监管、最严厉的处罚、最严肃的问责，确保广大人民群众饮食用药安全”要求，对1622个已申报生产或进口的待审药品注册申请开展药物临床试验数据核查，如有问题主动撤回。对于在规定时间没有提交报告或撤回的申请，总局将进行飞行检查。一旦查出问题，企业将面临“3年内不受理其申请”、“吊销药物临床试验机构的资格”、“列入黑名单”等严格处罚。   彼时，800多家药企面临着“撤，还是不撤”的考验。在感受到此次公告内容并不是说说而已之后，一大批企业纷纷撤回注册申请。这一事件也被医药界称为“722惨案”。   当时中国的临床试验数据质量如何？看到未撤回申请的企业几乎是外企时，便有了答案。“722惨案”的严格监管也为之后的临床试验数据质量奠定了重要基础。   药品作为治病救人的产品，其安全性无疑是最重要的。而药品的安全性需要监管者的严格执法，但最根本上靠的还是药企的自我严格要求和诚实守信。  

Jason Armond / Los Angeles Times via Getty Images The U.S. Food and Drug Administration (FDA) has historically tended to keep more contentious relationships with some companies private. But recently, the FDA appears to be publicly scolding some biopharma companies over issues of concern. Most recently, the FDA issued an untitled letter to Amgen over misbranding of Neulasta (pegfilgrastim) injection “resulting from a false or misleading promotional communication.” The company gives promotional materials that the FDA says make false or misleading claims about the benefit of Neulasta when dosed via the Onpro on-body injector compared to a prefilled syringe. Neulasta is the reference product for all biosimilar pegfilgrastim products approved by the FDA, and they’re only available as a prefilled syringe. The FDA stated, “Amgen’s promotional communication cites an observational study and makes claims and presentations based on that study that create a misleading impression about the benefit of Neulasta by stating that there is a statistically significant higher risk of febrile neutropenia when pegfilgrastim is administered through a prefilled syringe compared to an Onpro on-body injector. FDA determined the claims and presentations are not supported due to multiple limitations of the study’s design and analytic strategy.” In mid-May, a recent notable case was when the FDA published a “Statement on Leronlimab,” CytoDyn’s monoclonal antibody. The drug was initially being developed for HIV and cancer before the company started testing it for COVID-19. In a rare case of public reprimand, the FDA accused CytoDyn of misrepresenting its clinical trial data for leronlimab in COVID-19, particularly two clinical trials, CD10, in 86 mild-to-moderate COVID-19 patients, and CD12, which involved 394 patients, arrowing in on severe symptoms of respiratory symptoms in COVID-19. In March, the company’s Phase III trial failed to hit the primary endpoint of reducing symptoms and was unable to hit all secondary endpoints, including decreasing mortality for COVID-19. But CytoDyn instead focused on a subgroup of 62 patients on mechanical ventilation, arguing that the drug caused a 24% decrease in all-cause mortality and a six-day reduction in hospitalization. They also issued a second press release describing an “age adjustment” analysis that the drug decreased mortality in older patients. The FDA stated, “It has become clear that the data currently available do not support the clinical benefit of leronlimab for the treatment of COVID-19. None of these analyses met statistical significance when using established and reliable analytical methods that correct for multiple comparisons.” An in April, the FDA sent a notice of noncompliance to Acceleron Pharma, alleging the company had failed to publish a summary of study data for its cancer combination therapy dalantercept and axitinib in the ClinicalTrials.gov online database. The FDA also threatened the company with a $10,000 fine or criminal prosecution if it didn’t post the result on the website within 30 days. Federal law requires companies to post a summary of their trial results on the ClnicalTrials.gov website within one year of study completion. In August 2020, the agency described its approach and outlined how it identifies a company that failed to submit its trial registration and/or summary results to the databank. Since that mandate was implemented, the agency had sent over 40 pre-notices of noncompliance, primarily verbal warnings. In the case of the duo therapy, the combination failed clinical trials, and Acceleron abandoned the drug before the noncompliance letter. But because it had not issued the summary result, it was facing a fine or criminal proceedings. In the agency’s letter, it wrote, “The FDA takes its role in enforcing the ClinicalTrials.gov registration and results information submission requirements extremely seriously and we will continue to encourage voluntary compliance with these requirements. When necessary, the FDA will take appropriate actions to help ensure that required information is available on ClinicalTrials.gov as required by law and for the benefit of clinical trial participants and public health.” Although the agency may be upping its public criticism of biopharma companies, the FDA has also become the center of serious criticism and turmoil over its approval of Biogen’s Alzheimer’s drug Aduhelm. The agency approved it despite its own Peripheral and Central Nervous System Drugs Advisory Committee voting strongly against it, and shifting from a clinical benefit endpoint to a surrogate biomarker endpoint utilizing an accelerated approval process. This resulted in three of the adcom members resigning in protest. In addition, the agency’s acting commissioner, Janet Woodcock, has requested the independent Office of the Inspector General to investigate how the FDA and Biogen representatives interacted before the endorsement. Also, the House Committee on Oversight and Reform announced plans to investigate the approval and pricing of Aduhelm. There are concerns that with the $56,000 price tag, and most of the millions of potential patients for the drug on Medicare, it could bankrupt the program. Even if about a third of the three to six million potential patients in the U.S. were given the drug, it would require spending more on Aduhelm alone than on Medicare Part B drugs in a single year together. It also prompted Biogen to change the label on the drug to define a narrower patient population. The decision has recently prompted a series of publications in JAMA Internal Medicine and others by various parties, including the FDA, justifying the decision or outlining the potential pitfalls long-term over the decision.