Belinostat

凭借FDA“加速批准”政策上市的药物，在上市后研究未能达到预期标准的情况下，FDA并未撤回审批，“加速批准”政策是否已成为某些药品的免死金牌？01FDA为何无动于衷？大多数情况下，FDA面对这些无效的上市后研究之所以选择“引而不发”，在很大程度上是这些药物身上的“未满足领域唯一疗效”的标签所决定的。尽管这所谓的唯一疗法在上市后研究中没有表现出期待的疗效，但这些“尾大不掉”的上市药物还是令FDA有些投鼠忌器的感觉。一旦将这些药物从市场上撤下，那么已经开始使用这些药物的患者又将重回无药可用的状态。然而，继续让患者使用无法被证明有效的药物，虽然可能在心理上或许能够给患者一些安慰，但在病情的拖延和浪费的成本方面所造成的损失也是显而易见的。FDA在进退维谷的局面中感受到压力，但如果他们选择将一款没有通过临床终点的药物保留在市场上，至少应该向公众阐明他们这种选择的理由。FDA应该向公众坦诚，他们为什么会选择与开发商进行协商，设计并开展进一步的研究。同时也有义务解释，为什么其它某些药物在未能通过上市后研究的情况下被FDA撤回了加速批准。02FDA有无区别对待？从另一个角度看，FDA也在努力清除上市后研究无效的加速批准。例如他们从2021年开始整肃一组PD-1/L1抑制剂的加速批准，这些适应症的上市后试验已完成，但未能验证临床效益，包括针对10个适应症的4种药物，最终制药商撤回了4个适应症。FDA在解释对上市后研究失败药物的区别对待，即为什么有的公司可以获得继续上市后研究的机会，而有的公司的加速审批被撤销这一现象时，FDA认为公司的规模对上市后研究的行为起到了重要的影响。很多大公司在进行上市后的验证研究中设计了多项临床试验，因此当一项失败时，他们仍然有回旋的余地，FDA也有耐心等待其它研究结果的出炉。例如当年默沙东的Keytruda在针对肝癌获得加速批准之后，它的上市后三期临床研究Keynote-240失败，但FDA并没有立即取消它的加速批准，这主要是因为FDA之前已经批准了Keytruda针对肝癌的其它上市后临床研究Keynote-394，在这种情况下，FDA通常不会立即做出取消加速批准的决定，而是将等待其它研究结果的出炉。Keynote-394最终达到了临床终点，并最终得到了Keytruda针对肝癌的全面批准。与之形成对比的是很多小型制药公司，他们获得加速批准的那款药物可能就是公司唯一上市资产。他们并不情愿像BMS那样主动撤回申请，但又宣称没有资金进行多线验证性研究，从而造成一旦唯一的验证性试验失败就无以为继的局面。除此之外，大型制药公司在加速批准后准备上市后研究的过程中更愿意与FDA加强互动，并且在获得加速批准之前就开始着手准备上市后验证研究，这恰好也是新的FDORA法案（《食品和药品综合改革法案》）赋予FDA的权力，允许FDA要求申办者在获得加速审批之前就开始验证性研究。FDORA法案还赋予了FDA面对那些拒绝自愿撤回加速批准产品或者适应症的申办者时，可以启动快速撤回程序，但允许申办者进行上诉或者与FDA专员会面。03如何权衡？上市后验证性研究未能证实药效却未被撤回，是药物审批和监管领域中一个备受争议的问题。FDA在加速批准时通常要求制药公司进行后市场验证性研究，以确认药物的实际效果。然而，当这些研究未能证实预期的益处时，一些药物可能仍然保留在市场上，因为FDA可能认为尚有一些患者可能从中获益，或者因为缺乏其他治疗选择。监管机构通常需要权衡药物的安全性和效果。即使验证性研究未能证实药物的临床益处，如果药物被认为对某些患者仍有积极作用，监管机构可能不会立即撤回批准，以确保患者有继续治疗的选择。一些人认为，这种情况反映了对新药审批标准的降低，以便更快地推出新药。他们担心，这可能导致一些药物在上市后未能充分证实其益处，却仍然继续销售。这种情况强调了对信息透明度的需求，包括在药物上市后追踪其效果和安全性，并向医生和患者提供准确的信息，以便做出明智的治疗决策。解决FDA面临的上市后验证性研究未能证实药效但未被撤回的问题需要综合考虑多个因素，包括患者需求、药物安全性和有效性、科学证据以及公共健康。以下是一些建议：强化信息透明度：FDA可以加强对于药物上市后的监管和信息透明度，确保医生和患者能够获得最新的临床数据。这有助于更全面地了解药物的实际效果和安全性。明确后市场研究要求：FDA可以在药物获得加速批准时明确规定后市场验证性研究的要求，并确保这些研究有足够的样本量和持续时间，以充分评估药物的效果和安全性。灵活性与严谨性的平衡：在审批和监管过程中，FDA需要在灵活性和严谨性之间寻找平衡。这意味着在加速批准的情况下，仍要确保对新药的审查具有足够的科学依据，而后市场监管也要持续进行。加强专家咨询：FDA可以更积极地与医学专家、研究人员和患者群体进行合作，获取更全面的意见。这有助于更好地理解特定药物对患者的真实效果和需求。实施更严格的审查标准：鉴于加速批准可能涉及降低一些审查标准，FDA可以考虑加强对加速批准申请的审查，以确保科学证据的充分性。激励药企完成后市场研究：FDA可以采取激励措施，鼓励制药公司完成后市场验证性研究，确保及时获得更多的数据来支持药物的安全性和有效性。这些建议的实施需要平衡各方的利益，并考虑到公共健康的整体目标。FDA在决策中需要权衡各种因素，以确保患者能够获得安全、有效的治疗，并确保医学进步的同时不牺牲科学严谨性。Ref.1.Sutter,S.Amgen’s Lumakras:FDA Flags‘Marginal’Efficacy Results,Potential Systemic Bias In Lung Cancer Trial.Pink Sheet.03.10.2023.2.Sutter,S.Confirmatory Trial Plan For Acrotech’s Folotyn,Beleodaq Needs Rethinking,FDA Panel Says.Pink Sheet.05.10.2023.3.Sutter,S.US FDA In No Hurry To Withdraw Amgen’s Lumakras Despite Negative Adcomm Vote On Confirmatory Trial Results.Pink Sheet.05.10.2023.4.Bristol Myers Squibb Statement on Opdivo®(nivolumab)Monotherapy Post-Sorafenib Hepatocellular Carcinoma U.S.Indication.BMS Press Release.21.07.2021.5.Sutter,S.How Fast Is‘Expedited’?Pepaxto To Show Speed Of New Withdrawal Process For Accelerated Approval Drugs.Pink Sheet.28.08.2023.6.Sutter,S.Pazdur On Accelerated Approval:FDA Needs To Explain Why It Does Not Always Seek Withdrawal When Trials Fail.Pink Sheet.30.01.2024.声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 德清君转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是昨天最受欢迎的文章哦

An upcoming trial in patients with colorectal cancer will be the first to test an DNMT inhibitor and an EZH2 inhibitor together in any type of cancer. A pair of epigenetic cancer drugs packs a “one-two punch” against colorectal tumors to knock them out more effectively than either medication alone, a new study in cells suggests.  In a journal article published March 27 in Science Advances, a team of researchers led by scientists from the Van Andel Institute in Grand Rapids, Michigan showed that a low dose of the DNA methyltransferase (DNMT) inhibitor decitabine combined with Tithe EZH2 inhibitor tazemetostat successfully induced changes that would make cancer cells more vulnerable to destruction by the immune system. The chemotherapy decitabine is commercialized by Eisai as Inqovi; tazemetostat is commercialized by Ipsen as Tazverik. Neither company was involved in the study.  While agents in both classes of drugs are FDA approved to treat blood cancer, they haven't had much success in solid tumors such as colorectal cancer, Scott Rothbart, Ph.D., the study’s corresponding author, said in a press release. “Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact, with the DNMT inhibitor priming cancer cells in a way that makes the EZH2 inhibitor more effective.”  “Epigenetic” is a term that refers to typically reversible modifications made to genes that do not directly alter the genes themselves, but rather affect their expression. Cancer progression involves many epigenetic changes both to the cancer cells themselves and to the immune cells that would otherwise destroy them.  Scientists have attempted to destroy cancer by countering these changes pharmacologically and restoring the expression of anti-cancer genes. The most established means of doing so is with histone deacetylase inhibitors, or HDAC inhibitors, such as Merck’s Zolinza (vorinostat) for lymphoma and Acrotech Biopharma’s Beleodaq (belinostat) for myeloma. The only other FDA-approved DNMT inhibitor besides Inquovi is Celgene’s acute myeloid leukemia drug Vidaza (azacitidine). Tazverik is the sole EZH2 inhibitor with FDA approval.  Earlier work by Van Andel Institute researchers showed that DNMT inhibitors cause cancer cells to act as though they’ve been infected by a virus, making them more vulnerable to one’s immune system. For the new study, the researchers hypothesized that because DNMT inhibitors alter the cells in a way that could make EZH2 inhibitors more effective, they would work better together than separately.  To see whether this was the case, the researchers started by testing them against different types of colorectal cancer cells on their own, then looked at them in combination. The results backed up their rationale: EZH2 inhibitors compounded the changes initiated by the DNMT inhibitors, boosting the duo’s effectiveness.   The findings are the basis for an upcoming clinical trial that will evaluate the pair against colorectal cancer in patients. Combinations of DNMT inhibitors and HDAC inhibitors have been tested in clinical trials to mixed results, the study noted. The new trial will be the first to evaluate a DNMT inhibitor and an EZH2 inhibitor.  Future studies should evaluate the pair with immunotherapies, too, Rothbart noted in the release. There’s evidence in preclinical models that the viruslike changes the drugs make in the cells could lead to a better response to drugs that boost the immune system. “These data suggest future directions for testing whether DAC and TAZ treatments might improve tumor response to immunomodulating agents,” the researchers wrote in the study.