Adalimumab-ATTO(Amgen)

一、生物类似药：被 “刁难” 的平等化神器 生物类似药本是医疗平等化的得力工具，可如今想把它推向市场，那难度简直堪比登天。这背后，是品牌生物制剂制造商为保住自家重磅药物收入，疯狂游说的结果，导致生物类似药的监管复杂得像一团乱麻。2008 年 12 月 26 日，奥巴马当选总统但还没正式就职呢，我就迫不及待给他发了封邮件。没想到，两天后我们就在芝加哥他临时办公室碰面了。我一股脑儿倒出我的 “苦水”：我和伙伴们研发出能大幅降低昂贵生物制剂药物成本的救命生物类似药，可当时根本没有能让它们走向市场的监管途径。国会倒是有几项法案想给这事开条路，可都因为大型制药公司强烈反对生物类似药，最终没能通过。我和奥巴马见面时，相关立法的最新版本正僵在那儿呢。奥巴马听得可认真了，最后还撂下一句话：“这事能成！” 当时我心里还犯嘀咕，不太确定他啥意思，结果没过多久，在那厚达 11000 页的《平价医疗法案》（ACA）里，《生物制品价格竞争与创新法案》（BPCIA）就这么 “诞生” 了。随后，美国食品药品监督管理局（FDA）也出台了一系列生物类似药指南。 二、BPCIA：妥协下的 “难产” 可惜啊，这 BPCIA 满是妥协的痕迹。那些严格要求，简直把生物类似药当全新生物制剂来对待了。又是广泛的分析测试，又是动物毒理学和临床疗效测试，好多都是没必要的，纯粹是在瞎折腾、夸大难度。这么一来，开发一种生物类似药，成本得高达 1 亿到 3 亿美元，审批时间更是长达六到九年。你瞧，美国批准的第一种生物类似药 —— 山德士的 Zarxio（安进 Neupogen 的生物类似药，能刺激癌症患者白细胞生成），2015 年才上市，距离 BPCIA 出台都过去六年了。FDA 之前没批准过参考产品本身都有批次差异的产品，所以一直小心翼翼，不敢轻易冒险。直到现在，监管的动力还是不足。而且，围绕生物类似药的安全性和疗效，各种误解满天飞，这背后大多是大型制药公司在 “搅和”，就跟当初仿制药刚推出时一个样。 虽说让生物类似药变得可负担，不只是科学难题，但现状着实让人着急。如今，300 多种生物制剂获批了，可被批准为生物类似药的生物分子只有 66 种。不过，也不是毫无进展。2024 年，FDA 对可互换性指南做了重要又实用的修改。我满心期待，2025 年能解决生物类似药可负担性的最后一个大难题 —— 临床疗效测试要求，这一项几乎占了生物类似药开发成本的 70% 到 80% 呢。 我这辈子就想打破医疗障碍，让全球都能用上生物制剂。可大型制药公司一直反对生物类似药，像块大石头一样挡在我面前。但我相信，我多年的努力马上就能看到成果了。除了奥巴马，我还和好多政治家交流过，在国会作证，写了几十本书和大量期刊文章，提交了好多公民请愿书，就盼着能把 FDA 往正确方向 “推一推”。因为像生物类似药委员会这些机构对我的提议不感兴趣，我都打算独自对美国专利局提起集体诉讼了。 三、可互换性：没啥用的 “区分” 我参与推动的生物类似药监管流程变更里，有一项是最近取消可互换性的测试要求。2022 年，我发表了一篇论文，跟国会和 FDA 提议，不该把生物类似药分成两类 —— 一类是所谓的可互换生物类似药，不用医生干预就能替代参考产品，还有一年市场独占期；另一类就得医生签字同意，还没市场保护。我还就这事儿给 FDA 提交了公民请愿书，2023 年 9 月，FDA 为此开了公开会议讨论。会上大家似乎都觉得我说得对，两类生物类似药的存在不太合理。可会议刚结束，果不其然，大型制药公司就跳出来反对了。安进公司的 Leah Christl 就是个例子，她以前是 FDA 生物类似药的高级监管者，在《终点新闻》的文章里，就表达了公司对取消可互换性的反对意见。当时安进公司正给自家生物类似药 Amjevita（针对修美乐的生物类似药）申请可互换性认定呢。 我又给 FDA 提交了一份公民请愿书，强调 FDA 有权决定要不要重复测试来授予可互换性地位。2024 年 6 月，FDA 更新了可互换性政策，允许不做额外测试就能获得可互换性地位。这一指南虽说实际上取消了可互换性区别，可还保留了相关地位和复杂规定，比如确定独占性。我还挺荣幸，帮美国参议院起草了这项法案，虽说现在压力小了点，但我感觉更大的变化马上就会来。这些 FDA 生物类似药指南的变更，已经让开发成本大幅降低了，不过，还有最后一步要走。 四、平衡生物类似药与仿制药的 “赛场” 到目前为止，要是分子能在健康受试者的比较药代动力学研究里，展示出可比较的药效学标志物，FDA 和其他机构已经允许豁免临床疗效测试了。可监管机构还没松口，不让制药商跳过比较临床疗效测试，这一步其实没必要，却几乎让生物类似药开发成本增加了 70%。最近，英国药品和保健品管理局（MHRA）在生物类似药开发指南里建议，临床疗效测试可能不是必需的，欧洲药品管理局（EMA）也在起草概念文件，打算提类似建议。我在发表的文章里，多次建议 FDA 考虑，甚至有时别要求做这类测试。FDA 也计划做类似变更，可就是还没行动。 这一变化会以 FDA 指南的形式出现，就像最近关于生物类似药可互换性的文件那样。FDA 提议，药物开发商得申请豁免，才能不做额外测试就获得可互换生物类似药地位。要是 FDA 接受我的提议，让美国药典（USP）通过表征品牌参考产品来创建产品放行规格，那还能省下一大笔成本。这样一来，生物类似药开发商就能用这些规格认证自家药物，不用测试多个批次的品牌参考产品了。2018 年，FDA 阻止 USP 创建基于标准配方而非品牌产品的经典描述或 “药典”，理由是生物制剂结构独特、变化多，这种药典对生物类似药开发商来说，不是能接受的比较对象。我的提议通过让 USP 测试商业产品来创建规格，解决了这个难题。FDA 回应说要多点时间评估。要是我成功了，这一变化加上取消临床疗效测试，生物类似药的总开发成本就不会超过化学仿制药的开发成本了。 即便如此，还有个 “紧箍咒” 得解开：美国那不太道德的双重专利法，可能会大大推迟生物类似药上市。美国专利和商标局（USPTO）也意识到了，还向国会提交法案想取消这一法案，可就在准备投票的时候，USPTO 又撤回了法案。作为专利法从业者，我发表了详细论文，说明了为啥这一变化等同于利益冲突。我还让生物类似药委员会把这问题告上法庭，结果没看到任何行动，我就决定对 USPTO 提起集体诉讼。我邀请其他利益相关者加入，不用他们掏钱，诉讼费我来出。 一旦生物类似药开发成本降下来，就像我期待的那样，几十家仿制药公司肯定会涌入这个领域。100 多种等着进入市场的分子，都会以生物类似药的形式上市，到时候全世界的患者都能从这些神奇的救命疗法里受益。 参考资料： https://www.biospace.com/drug-development/opinion-biosimilars-shouldnt-be-this-hard-to-bring-to-market 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

iStock, wildpixel Biosimilars are essential healthcare equalizers, but their regulation is overly complicated due to lobbying by makers of branded biologics looking to maintain blockbuster revenue. On Dec. 26, 2008, after former President Barack Obama was elected but before he took office, I wrote him an email. Two days later, we met briefly in his interim office in Chicago. I elaborated on my plight: I and others had developed lifesaving biosimilars that could significantly reduce the cost of expensive biologics drugs. However, there was no regulatory pathway to bring them to market. Several bills had been introduced to Congress to provide this pathway, but none had passed, in part due to lobbying against biosimilars from Big Pharma. When I met with Obama, the latest variation of the legislation remained in limbo. The president-elect listened attentively and at the end of our meeting he said, “It will be done.” I wasn’t quite sure what he meant by that, but soon after, buried in the 11,000 pages of the Affordable Healthcare Act (ACA) was a revised version of the legislation dubbed the Biologics Price Competition and Innovation Act (BPCIA). A host of FDA guidances for biosimilars followed. Unfortunately, the BPCIA contained many compromises—strict requirements that essentially treated biosimilars as new biological drugs. These included extensive analytical, animal toxicology and clinical efficacy testing, most redundant and blown out of proportion. Ultimately, these requirements pushed the costs of developing a biosimilar to $100–300 million , with approval timelines of six to nine years. Indeed, the first biosimilar approved in the U.S.—Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen used to stimulate white blood cell production in cancer patients—didn’t hit the market until 2015, six years after the BPCIA paved the way. The FDA had no experience approving a product where even the reference product varies from batch to batch—and had no reason to take a risk. Still today, there is a lack of regulatory motivation. Moreover, many misconceptions swirled about the safety and efficacy of biosimilars— many broadly fanned by Big Pharma —just as when generic drugs were introduced. Making biosimilars affordable is more than a scientific challenge. Today, only 66 biological molecules are approved as biosimilars despite more than 300 approved biologics . But progress has been made. In 2024, the FDA made important and beneficial changes to its interchangeability guidelines. And I’m hopeful that the only remaining hurdle to affordable biosimilars, a clinical efficacy testing requirement that adds almost 70–80% of the development cost, will be resolved in 2025. My life’s mission has been to break down healthcare barriers to ensure global access to biological drugs. Big Pharma’s long opposition to the emergence of biosimilars has always been a stumbling block. Now, I believe I’m on the cusp of seeing my life’s work pay off. Besides Obama, I have met with numerous politicians, testified in front of Congress, authored dozens of books and scores of journal articles and filed multiple Citizen Petitions to push the FDA in the right direction. I will soon class action lawsuit against the U.S. Patent Office, on my own, since the biosimilar agencies such as Biosimilar Council have not shown any interest in my proposal to do so . I am determined to see this through. Not only do these issues remain a professional challenge for me as CTO of the biosimilars company ABYOLO, but more importantly, the world needs better regulatory requirements for biosimilars to incentivize their development. If made widely available, these generic versions of biologic drugs can make a massive difference in the global population’s health. Interchangeability: A Pointless Distinction Among the changes I helped initiate to the regulatory process for biosimilars is the recent removal of testing requirements for interchangeability . In 2022, I published a paper suggesting to Congress and the FDA that there should not be two classes of biosimilars —the so-called interchangeable ones, which are permitted to be given in place of the reference product without prescriber intervention and are provided with one year of market exclusivity, and the rest, which do require a doctor to sign off and are given no market protections. I also filed a Citizen Petition on this issue, and the FDA held an open meeting to discuss it in September 2023. Everyone at the meeting seemed to agree with my arguments that the two classes of biosimilars are illogical. However, soon after the meeting came —predictably—a deluge of opposition from Big Pharma. One example was Amgen’s Leah Christl, a former top FDA regulator of biosimilars, who, in an Endpoints News article, voiced her company’s opposition to the push to do away with interchangeability. At the time, Amgen sought the interchangeability designation for a biosimilar to Humira called Amjevita. I filed another Citizen Petition with the FDA, emphasizing that the agency can determine if repeated testing is necessary to award interchangeable status. In June 2024, the FDA updated its interchangeability status policy , allowing this status without conducting additional testing. This FDA guideline essentially removed an interchangeability distinction yet maintained its status and complications, such as determining exclusivity. I had the privilege of assisting the U.S. Senate in writing this bill, and while there is less pressure now, I anticipate this will come soon. These and other changes in the FDA biosimilar guidelines have substantially reduced the development cost. However, we still have one last step. Evening the Biosimilar-Generic Playing Field So far, the FDA and other agencies have waived clinical efficacy testing if these molecules demonstrate pharmacodynamic markers that can be compared within the comparative pharmacokinetic studies in healthy subjects. Regulators have not yet allowed for drugmakers to skip comparative clinical efficacy testing, however—a step that is unnecessary and adds almost 70% to the development cost of biosimilars . Recently, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) suggested in its biosimilars development guidelines that clinical efficacy testing may not be necessary, and the European Medicines Agency (EMA) is working on a concept paper for a similar recommendation. I have repeatedly advised the FDA in my publications to make such testing open for consideration—and sometimes not required. The FDA is planning a similar change but has yet to act. The change will come in the form of FDA guidance, such as recent documents from the agency on biosimilar interchangeability . The FDA has suggested that drug developers will have to request a waiver to secure interchangeable biosimilar status without conducting additional testing. Another significant cost saving will come if the FDA accepts my proposal to let the U.S. Pharmacopeia (USP) create product release specifications by characterizing branded reference products. These product release specifications could then be used by developers of biosimilars to qualify their drugs without the need to test multiple lots of the branded reference product. In 2018, the FDA blocked the USP from creating classical descriptions, or “monographs,” of pharmaceutical products that are based on standard formulations instead of branded products, saying that due to the variability in structure that is unique to biologics, such monographs would not be acceptable comparisons for biosimilar developers. My proposal overcomes this by having USP create specifications by testing commercial products. The FDA has responded to me asking for more time to evaluate my request. Should I succeed, the combination of this change and the removal of clinical efficacy testing will bring the total development cost of biosimilars to no more than the development of chemical generic drugs. Even then, there will still be one more constraint to be removed: the unethical double-patenting laws in the U.S. that can significantly delay the entry of biosimilars. The U.S. Patent and Tradmark Office (USPTO) recognized this and presented a bill to Congress to remove it; however, just when it was ready to go to vote, the USPTO withdrew it. As a patent law practitioner, I published a detailed paper showing why this change is tantamount to a conflict of interest. I also asked the Biosimilar Council to take this issue to court. Still, seeing no move, I have decided to class action lawsuit against the USPTO. I am inviting other stakeholders to join without any financial obligation as I fund this lawsuit. Once the cost of biosimilar development drops, as I anticipate it will, dozens of generic companies will enter the field. More than 100 molecules awaiting entry will arrive as biosimilars, and the world’s patients will benefit from these remarkable lifesaving treatments.