FDA加速批准Biogen(BIIB.US)阿尔茨海默病药物aducanumab的消息被业界广泛关注。欢呼者表示这是自2003年以来FDA批准的首个治疗AD的新药，FDA力排众议可喜可贺；也有观点认为FDA此举批准实为“饮鸩止渴”，不顾外部专家组的反对而做出了错误选择，以至于多名参与审评的专家直接辞职；同时也有观点认为“希望比疗效更重要”，药品承载的不仅仅是科学属性，它还承载着为患者极其家属传递希望的使命。
对此事件，医药魔方在第一时间收集业内反馈，并在FDA驻华办公室的协助下，书面采访了FDA。很快，FDA药物评价与研究中心（CDER）新闻发言人Kohler Charles也给出了书面回复，供大家参考。以下是对FDA回复内容的翻译稿。
医药魔方：您好！产业界普遍认为FDA此次批准Aducanumab对患者疾病特征（Aβ水平、疾病严重程度、ApoE水平等）没有限制、包括没有脑水肿的注意事项或者黑框警告，有些让人费解。是否会有进一步的方法控制药物使用风险？
FDA：Aduhelm的处方信息包括淀粉样蛋白相关成像异常 (ARIA) 的警告，最常见的是大脑区域的暂时肿胀，通常会随着时间的推移而消退并且不会引起症状，尽管有些人可能会出现头痛等症状 、意识模糊、头晕、视力改变或恶心。Aduhelm 的另一个警告是过敏反应的风险，包括血管性水肿和荨麻疹。Aduhelm 最常见的副作用是淀粉样蛋白相关成像异常 (ARIA)、头痛、跌倒、腹泻和意识模糊、谵妄、精神状态改变、定向障碍。
根据加速批准条款，该条款为患有该疾病的患者提供更早的治疗机会，FDA 要求Biogen进行一项新的随机、对照临床试验，以验证该药物的临床益处。如果试验未能验证临床获益，FDA 可能会启动程序以撤回对该药物的批准。
医药魔方：根据公开资料，FDA去年年底招募的顾问专家组会议反对临床研究结果支持患者获益。如今该药物被批准，能否请您进一步分享一些FDA的考虑？审评人员是否认为某些研究或文献发表是关键性的证据，可以支持Aβ斑块减少与临床获益之间的联系？
FDA：我们考虑了委员会的意见，权衡了申请中的整体证据，并考虑了几乎没有治疗选择的AD患者的可怕情况。基于此，FDA得出结论，加速批准是合适的。加速批准是批准用于解决需求未满足的严重疾病的药物的途径。
我们认为，有大量证据表明 Aduhelm 减少了大脑中的淀粉样蛋白斑块，并进一步得出结论，淀粉样蛋白斑块的减少有理由预测临床获益，满足加速批准的要求。
加速批准途径使 FDA 能够更早地接触患者，同时认识到替代终点是否能准确预测临床益处仍存在一些不确定性。获得加速批准的药物必须符合与获得传统批准的药物相同的安全性和有效性法定标准。在加速批准下，FDA 可以依赖特定类型的证据，例如药物对替代终点的影响，作为批准的基础。
另外，Biogen公司必须进行旨在验证临床效益的批准后临床试验。
医药魔方：我们从一些渠道获悉，这款药物获批，主要是与定量药理学这块的知识相关，的确如此吗？
FDA：在数据不明确的情况下做出监管决策时，我们遵循了我们一贯的行动方针。其中包括：1）仔细核查所有临床试验结果；2）征求外部中枢神经系统药物咨询委员会的意见；3）听取了患者社区的意见；4）审查所有相关数据。
我们最终决定使用加速批准途径——该途径旨在为患有严重疾病的患者提供早期潜在有价值的疗法，使这些患者未得到的需求被满足。通常，尽管药物的益处存在一些不确定性，但使患者临床获益的可能性比较大。
在确定该申请符合加速批准的要求时，FDA才得出结论，批准Aduhelm对阿尔茨海默病患者的益处超过了该疗法带来的风险。
医药魔方：面对阿尔兹海默症的这样发病机制不明确的疾病，站在评审机构的角度是否会对药物的评价更加宽容？FDA会如何兼顾满足患者需求和科学证据两方面的要素？
FDA：我们认识到需要为 AD 患者提供额外的安全有效的治疗方法。 我们致力于与公司和患者社区合作，以促进开发安全有效的阿尔茨海默病治疗方法。
以下为英文原文：
Pharmcube：We are aware of significant industry discussion on FDA’s granting of Accelerated Approval for aducanumab. It puzzles a number of industry professionals given that the current approval placing no restrictions on the patient's disease background characteristics (Aβ level, disease severity, ApoE level, etc.), or precautions / warnings of any kind on adverse events like cerebral edema. Will there be additional measures in the future for patient risk control with regard to the use of aducanumab?
FDA：The prescribing information for Aduhelm includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms, though some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. Another warning for Aduhelm is for a risk of hypersensitivity reactions, including angioedema and urticaria. The most common side effects of Aduhelm were amyloid-related imaging abnormalities (ARIA), headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.
Under the accelerated approval provisions, which provide patients suffering from the disease earlier access to the treatment, FDA is requiring Biogen to conduct a new randomized, controlled clinical trial to verify the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.
Pharmcube：It was made public earlier that the Peripheral and Central Nervous System Drugs Advisory Committee FDA convened last year did not agree that the evidence supports the approval of this product. Now that the drug is approved, could you share some further considerations？Is there any research / publications that serve as the key pieces of evidence that lead the reviewers to correlate Aβ plaque reduction with clinical benefit?
FDA：We considered the committee’s input, weighed the overall evidence in the application, and considered the dire situation of patients with AD who have few treatment options. Based upon this, the FDA concluded that an accelerated approval was appropriate.
Accelerated approval is a pathway for approval of drugs intended to address serious diseases where there are unmet needs.
The Agency concluded that there was substantial evidence that Aduhelm reduces amyloid beta plaques in the brain, and further concluded that the reduction in amyloid beta plaques was reasonably likely to predict clinical benefit, meeting the requirements for an accelerated approval.
The accelerated approval pathway allows the FDA to provide earlier access to patients, recognizing that there remains some uncertainty about whether the surrogate endpoint will accurately predict clinical benefit. Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval. Under accelerated approval, FDA can rely on a particular kind of evidence, such as a drug’s effect on a surrogate endpoint, as a basis for approval.
The company must conduct a post-approval clinical trial that is intended to verify clinical benefit.
Pharmcube：We learned that pharmacometrics played significant part in the review process of aducanumab. Can you confirm this? If true, can you briefly explain the role that pharmacometrics played specifically in the review of this drug?
FDA：We followed our usual course of action when making regulatory decisions in situations where the data are not straightforward. We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data.
We ultimately decided to use the accelerated approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for accelerated approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.
Pharmcube：Regarding diseases like Alzheimer’s Disease of which pathogenesis are poorly understood to date, will US FDA be more tolerant on the evidence used in drug application? How will the FDA balance between urgent patient needs and scientific rigor?
FDA：We recognize the need for additional safe and effective treatments for patients living with AD. We are committed to engaging with companies and the patient community to facilitate the development of safe and effective treatments for Alzheimer’s Disease.
本文编选自微信公众号“医药魔方”，作者：医药魔方；智通财经编辑：陈诗烨
