關(guān)于百健(BIIB.US)治療AD新藥aducanumab獲批，F(xiàn)DA這樣回復(fù)

FDA加速批準(zhǔn)Biogen(BIIB.US)阿爾茨海默病藥物aducanumab的消息被業(yè)界廣泛關(guān)注。歡呼者表示這是自2003年以來(lái)FDA批準(zhǔn)的首個(gè)治療AD的新藥，F(xiàn)DA力排眾議可喜可賀；也有觀點(diǎn)認(rèn)為FDA此舉批準(zhǔn)實(shí)為“飲鴆止渴”，不顧外部專家組的反對(duì)而做出了錯(cuò)誤選擇，以至于多名參與審評(píng)的專家直接辭職；同時(shí)也有觀點(diǎn)認(rèn)為“希望比療效更重要”，藥品承載的不僅僅是科學(xué)屬性，它還承載著為患者極其家屬傳遞希望的使命。

對(duì)此事件，醫(yī)藥魔方在第一時(shí)間收集業(yè)內(nèi)反饋，并在FDA駐華辦公室的協(xié)助下，書面采訪了FDA。很快，F(xiàn)DA藥物評(píng)價(jià)與研究中心（CDER）新聞發(fā)言人Kohler Charles也給出了書面回復(fù)，供大家參考。以下是對(duì)FDA回復(fù)內(nèi)容的翻譯稿。

醫(yī)藥魔方：您好！產(chǎn)業(yè)界普遍認(rèn)為FDA此次批準(zhǔn)Aducanumab對(duì)患者疾病特征（Aβ水平、疾病嚴(yán)重程度、ApoE水平等）沒(méi)有限制、包括沒(méi)有腦水腫的注意事項(xiàng)或者黑框警告，有些讓人費(fèi)解。是否會(huì)有進(jìn)一步的方法控制藥物使用風(fēng)險(xiǎn)？

FDA：Aduhelm的處方信息包括淀粉樣蛋白相關(guān)成像異常 (ARIA) 的警告，最常見的是大腦區(qū)域的暫時(shí)腫脹，通常會(huì)隨著時(shí)間的推移而消退并且不會(huì)引起癥狀，盡管有些人可能會(huì)出現(xiàn)頭痛等癥狀 、意識(shí)模糊、頭暈、視力改變或惡心。Aduhelm 的另一個(gè)警告是過(guò)敏反應(yīng)的風(fēng)險(xiǎn)，包括血管性水腫和蕁麻疹。Aduhelm 最常見的副作用是淀粉樣蛋白相關(guān)成像異常 (ARIA)、頭痛、跌倒、腹瀉和意識(shí)模糊、譫妄、精神狀態(tài)改變、定向障礙。

根據(jù)加速批準(zhǔn)條款，該條款為患有該疾病的患者提供更早的治療機(jī)會(huì)，F(xiàn)DA 要求Biogen進(jìn)行一項(xiàng)新的隨機(jī)、對(duì)照臨床試驗(yàn)，以驗(yàn)證該藥物的臨床益處。如果試驗(yàn)未能驗(yàn)證臨床獲益，F(xiàn)DA 可能會(huì)啟動(dòng)程序以撤回對(duì)該藥物的批準(zhǔn)。

醫(yī)藥魔方：根據(jù)公開資料，F(xiàn)DA去年年底招募的顧問(wèn)專家組會(huì)議反對(duì)臨床研究結(jié)果支持患者獲益。如今該藥物被批準(zhǔn)，能否請(qǐng)您進(jìn)一步分享一些FDA的考慮？審評(píng)人員是否認(rèn)為某些研究或文獻(xiàn)發(fā)表是關(guān)鍵性的證據(jù)，可以支持Aβ斑塊減少與臨床獲益之間的聯(lián)系？

FDA：我們考慮了委員會(huì)的意見，權(quán)衡了申請(qǐng)中的整體證據(jù)，并考慮了幾乎沒(méi)有治療選擇的AD患者的可怕情況?；诖耍現(xiàn)DA得出結(jié)論，加速批準(zhǔn)是合適的。加速批準(zhǔn)是批準(zhǔn)用于解決需求未滿足的嚴(yán)重疾病的藥物的途徑。

我們認(rèn)為，有大量證據(jù)表明 Aduhelm 減少了大腦中的淀粉樣蛋白斑塊，并進(jìn)一步得出結(jié)論，淀粉樣蛋白斑塊的減少有理由預(yù)測(cè)臨床獲益，滿足加速批準(zhǔn)的要求。

加速批準(zhǔn)途徑使 FDA 能夠更早地接觸患者，同時(shí)認(rèn)識(shí)到替代終點(diǎn)是否能準(zhǔn)確預(yù)測(cè)臨床益處仍存在一些不確定性。獲得加速批準(zhǔn)的藥物必須符合與獲得傳統(tǒng)批準(zhǔn)的藥物相同的安全性和有效性法定標(biāo)準(zhǔn)。在加速批準(zhǔn)下，F(xiàn)DA 可以依賴特定類型的證據(jù)，例如藥物對(duì)替代終點(diǎn)的影響，作為批準(zhǔn)的基礎(chǔ)。

另外，Biogen公司必須進(jìn)行旨在驗(yàn)證臨床效益的批準(zhǔn)后臨床試驗(yàn)。

醫(yī)藥魔方：我們從一些渠道獲悉，這款藥物獲批，主要是與定量藥理學(xué)這塊的知識(shí)相關(guān)，的確如此嗎？

FDA：在數(shù)據(jù)不明確的情況下做出監(jiān)管決策時(shí)，我們遵循了我們一貫的行動(dòng)方針。其中包括：1）仔細(xì)核查所有臨床試驗(yàn)結(jié)果；2）征求外部中樞神經(jīng)系統(tǒng)藥物咨詢委員會(huì)的意見；3）聽取了患者社區(qū)的意見；4）審查所有相關(guān)數(shù)據(jù)。

我們最終決定使用加速批準(zhǔn)途徑——該途徑旨在為患有嚴(yán)重疾病的患者提供早期潛在有價(jià)值的療法，使這些患者未得到的需求被滿足。通常，盡管藥物的益處存在一些不確定性，但使患者臨床獲益的可能性比較大。

在確定該申請(qǐng)符合加速批準(zhǔn)的要求時(shí)，F(xiàn)DA才得出結(jié)論，批準(zhǔn)Aduhelm對(duì)阿爾茨海默病患者的益處超過(guò)了該療法帶來(lái)的風(fēng)險(xiǎn)。

醫(yī)藥魔方：面對(duì)阿爾茲海默癥的這樣發(fā)病機(jī)制不明確的疾病，站在評(píng)審機(jī)構(gòu)的角度是否會(huì)對(duì)藥物的評(píng)價(jià)更加寬容？FDA會(huì)如何兼顧滿足患者需求和科學(xué)證據(jù)兩方面的要素？

FDA：我們認(rèn)識(shí)到需要為 AD 患者提供額外的安全有效的治療方法。 我們致力于與公司和患者社區(qū)合作，以促進(jìn)開發(fā)安全有效的阿爾茨海默病治療方法。

以下為英文原文：

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.

本文編選自微信公眾號(hào)“醫(yī)藥魔方”，作者：醫(yī)藥魔方；智通財(cái)經(jīng)編輯：陳詩(shī)燁