FDA“创新行动计划”促进药品研发与审评

来 源

CDE网站;凡默谷

译 者

CDE统计与临床药理学部

徐毛迪 彭京亚 译
杨进波 王亚宁 谢海棠 审校

导 读

如何提高药品的审评质量和效率，一直是业内和审评机构共同追求的目标。

FDA新任局长Scott Gottlieb 博士于2017年7月7日在FDA的官方博客-FDA Voice上发表了题为“ How FDA Plans to Help Consumers Capitalize on Advances in Science”的文章，旨在推行“创新行动计划”，使公众尽快获益于安全有效的新药和新的医疗技术。

其中，重点提出了用建模和模拟的方法推动药物和器械的审评审批。本文全文登录了该篇文章并随文附录中文译文，以飨各位业内同仁，以期共同探讨如何采用先进科学技术手段在保证药品质量的前提下，提高我国药品审评的效率。

FDA 计划如何帮助消费者利用科学进步

科学发展到现今阶段，新的医疗技术有望为越来越多的医学难题提供更好的治疗方案。在过去的几十年中，科学进步使我们对人类疾病基于基因和蛋白水平的理解有了根本性进步，这些科学进步也在逐渐被转化为新药。而在更多情况之下，这些治疗是针对引起不同疾病的潜在机制。这些发展有望控制甚至治愈更多的疾病。

以此为契机，FDA 将很快公布一项全面的“创新行动计划”，该项计划旨在确保FDA的管理流程现代高效，使患者能及时获益于安全有效的新技术。我们需要确保监管原则的高效率和与时俱进。

我们并不希望在监管方面给新的医疗创新设置门槛，这不仅增加了新技术面世的时间、成本和不确定性，也于理解产品的安全和功能无益。

新医药创新的最终定价需要衡量技术开发所需的资本成本。不仅在研究和开发的直接成本方面如此，成本还需计算努力的时间和不确定性。

因为FDA促进公共卫生发展的使命，该计划势在必行。这还包括在FDA批准创新后，我们有义务在现有职责范围内确保正在采取的措施也有助于获取创新。医疗市场的科技准入对公共卫生的发展至关重要。新技术的价格也影响到人们获取这些新药的能力。因此，我们需要注意监管流程成本，需要意识到这些成本也会影响创新的可及性以及其最终定价的方式。

由此，作为FDA公共卫生使命的一部分，我们需要确保一切行动采取基于风险的方法。《21 世纪治愈法案》（以下简称“法案”）给予 FDA 许多新的权力和资源来完成这项使命。法案为 FDA 提供了旨在使监管方案现代化的工具。这一切努力皆为确保我们正全力以赴加快安全有效的新产品的面世。

计算机临床试验使用计算机模型和模拟来开发和评估器械和药品。建模和模拟在组织各种数据集和探索备选研究设计方面发挥关键作用。

安全和有效的新药借助此可通过临床试验的不同阶段取得更高效的发展。

FDA 通过与提供额外专业知识和基础设施的外部各方的多次合作，在建模和模拟方面做出努力，以推动这些最先进技术的发展。

今天，我们公布了为执行法案不同方面而正采取的措施的详细工作计划。在此，我想突出其中的一项措施，一项FDA正在投资并将作为更广泛的“创新行动计划”的一部分继续扩大投资的措施，即在临床试验中使用计算机工具来改进药物研发和改革监管流程。

FDA 药品审评与研究中心（CDER）目前正在使用建模和模拟来预测临床结果，指导临床试验设计，支持有效性证据，优化给药方案，预测药物安全性，以及评估潜在的不良事件发生机制。

我们将会就如何进一步发掘计算机工具的各个方面的功能和如何将这些功能纳入药物研发的不同方面及时更新指南。

CDER 通过建模和模拟策略解决诸多药物研发、监管和治疗性问题。

CDER 的应用学部（OTS）在审评“研究性新药申请（INDs）”和“新药申请（NDAs）”时即采用了相同的策略。

仅就策略之益处举一例，随着我们进入个体化给药时代，结合药物代谢酶中个体生理学和遗传学方面的建模和模拟正被用于甄别需要剂量调整的患者亚组。

整合这些方法以评估在患者中药物相互作用、肾功能障碍和肝功能不全的综合影响，并酌情在药品标签中描述相应的临床管理策略。

建模和模拟还可以协助创建自然历史数据库以支持基于模型的药物研发，如通过使FDA 能够在临床试验中对安慰剂组的某些方面建模，而提高临床试验的有效率。

目前，FDA 正在与科学家合作开发在帕金森病、亨廷顿舞蹈病、阿尔茨海默病和肌营养不良症中的自然历史模型。

建模和模拟的一个重要目的是更好地评估在由于体量小而难以研究的罕见疾病群体中的新治疗的行为。

为推进这些机遇，我们需要继续在高性能计算上投入。计算能力正成为我们的审评人员操作大型数据集的能力的关键要求，后者正是现在药物申请的常见特征。

FDA 正努力提高高性能计算中的能力，并通过 FDA 科学计算委员会的工作努力探索建模方法、增强监管力度。

FDA 器械中心也是这项工作的重要组成部分。医疗器械与放射健康中心（CDRH）也正在建立用于产品设计和评估的计算机监管模型，包括开发模型数字图书馆和一组用于器械测试的“虚拟患者”。一致性是一个重要目标。我们需要确保在不同的医药产品中和 FDA 不同部门间采取的策略是一致的。

FDA 正在努力最大限度地发挥国会给予我们的授权和资源，以推进针对患者的医药创新。为确保整个机构协调和沟通的顺利进行，我们成立了一个机构内的法案指导委员会。

自从 2016 年 12 月 13 日近 1000 页的医药法案颁布后，该委员会详细分析法案条款，列出了所有与 FDA 相关的要求清单，并正在协助推动工作团队帮助FDA 利用法案提供的机会。今天，我们发布了法案可交付成果的初始清单，以期能为公众跟踪我们的进展提供工具。

从清单中可看出，我们已着手执行了几项重要的法案规定。法案 1002 条在 9 年内授权 5 亿美元经费，帮助 FDA 支付某些法律部分的实施费用。

依照要求，我们制定了一份工作计划草案，说明FDA 将如何根据每年的拨款使用这笔经费。我们在 5 月份的公开会议上已向 FDA 科学委员会提交了工作计划草案供其审议。今天，我们将发布于 6 月 9 日呈交国会的最终工作计划，其中包括来自 FDA 科学委员会的建议。

FDA依据法案正在推行的一些其它值得注意的举措有

1）生物制品审评与研究中心（CBER）正在实施再生医学高级疗法，或 RMAT 认定。

这一新流程提供了获取 FDA 现有加速计划的另一路径，可用于某些细胞治疗产品、治疗性组织工程产品和包含再生医学技术制品的联合产品。这些工作的目标是帮助促进这些新产品的开发和批准。

截至目前，我们已经收到了二十几份 RMAT 认定请求，其中四个已经通过了认证审批。为继续推进这些机会，FDA将于今年 9 月公布一项指导再生医学产品开发和FDA 正确监管的政策框架。

这项新的政策将包括一系列涵盖再生医学产品法规诸多方面的指南文件。作为FDA“创新行动计划”的一部分，它将阐释FDA对于再生医学产品进行适当和高效监管监督以证明这些产品的安全性和有效性的政策。

它还将建立一个可访问的协作框架，使医疗服务提供者更容易地证明在当地医疗机构中推进的再生产品的这些原则。我们希望助力这些有望治疗甚至治愈疾病的科学进步。

为实现这些目标，我们需要确保执行现代化的监管体系，可以让创新者达到法规要求，证明新产品的安全性和有效性。

2）新成立的卓越肿瘤中心（Oncology Center of Excellence）是 FDA 首个专注于特定疾病领域而不是产品类型的跨中心机构。

该机构旨在通过协调 FDA 药品、器械和生物制品中心的临床审评达成的协同效应，使肿瘤和血液学医药产品的研发更具效率。

这个新机构将允许我们的审评专家共同合作，采取药品生命周期管理策略开发药物，并针对新的癌症治疗方案进行上市后监管。

 3）依据法案的规定，CDRH 豁免了 70多 种 I 类器械类型的 510(k) 申报要求。

CDRH 还提议豁免另外 1000 多种 II 类器械类型 510(k) 申报，基于初步判定上市前审评并不完全能保证提供合理的安全性和有效性证明。这一举措将减少器械企业的监管负担，消除企业成本和支出。

 4）为进一步使我们的监管要求与法案规定一致，CDRH 还修订了现行法规，允许更多的器械符合对小型患者群体的人道主义器械豁免资格。

我们将允许研究人员通过中央机构伦理审查委员会而不是强制使用地方伦理审查委员会寻求对器械临床试验的批准。

依据法案规定，CDRH 还发布了 FDA 将在 510(k)[2]申请表中要求经验证的使用说明和有关清洁、消毒和灭菌的验证数据的可重复使用器械清单。这些新要求于 2017 年 8 月 8 日生效。

 5）最后，上个月，CDER 与 CBER 合作公布了一份以患者为中心的药物研发指南的制定和发布计划。研讨会和新指南将公布FDA采取更系统的方法从患者角度来指导监管决策的计划。

我们正处于科学和医学技术变革时代的起始阶段。通过新法案的实施，以及我们构建新的“创新行动计划”来执行法案的努力，希望能帮助消费者从发展中获益。FDA在追求法案所提供的机遇方面取得的进展说明了FDA对法律条文和法律精神的热忱和承诺。

请收藏法案网页和我们的服务器，以便通过我们坚持不懈推进这些共同目标的工作跟踪我们的进展。

[1] 译自2017年7月7日FDA Voice “How FDA Plans to Help Consumers Capitalize on Advances in Science”，作者Scott Gottlieb 博士，现FDA 局长。
[2]  510(k)文件是向FDA递交的上市前申请文件，目的是证明申请上市的器械与不受上市前批准(PMA)影响的合法上市器械同样安全有效，即为等价器械(substantially equivalent)。

因其对应《联邦食品、药品和化妆品法》第510条（k）款，故通常称为510（k）文件。

How FDA Plans to Help Consumers Capitalize on Advances in Science

We’re at a point in science where new medical technologies hold out the promise of better treatments for a widening number of vexing conditions. Over the last few decades, science has enabled fundamental advances in our understanding of the genetic and protein bases of human disease. These developments are already being translated into new medicines. In more cases, these treatments target the underlying mechanisms that drive different diseases. These advances hold out the promise of arresting and even curing a growing number of diseases.

To build upon such opportunities, FDA will soon unveil a comprehensive Innovation Initiative. It will be aimed at making sure our regulatory processes are modern and efficient, so that safe and effective new technologies can reach patients in a timely fashion. We need to make sure that our regulatory principles are efficient and informed by the most up to date science. We don’t want to present regulatory barriers to beneficial new medical innovations that add to the time, cost, and uncertainty of bringing these technologies forward if they don’t add to our understanding of the product’s safety and benefits.

This imperative is driven by our mandate to promote the public health. It includes a responsibility to make sure that we’re taking steps, within the scope of our existing responsibilities, to also help facilitate access to new innovations once FDA approves them. Access to advances in medical care is a critical component of public health. And the price of new technology affects the ability of people to access these new treatments. We therefore need to be mindful of the costs of our regulatory processes, to the degree that these costs also affect the availability of new innovations, and the way that they are ultimately priced.

New medical innovations are ultimately priced to a measure of the cost of the capital it takes to develop these technologies. This is true not only when it comes to the direct costs of research and development. Cost is also a function of the time and uncertainty of these endeavors.

For these reasons, as part of our public health mandate, we need to make sure that we’re taking a risk-based approach in everything we do. The 21st Century Cures Act gave FDA many new authorities and resources to accomplish this mission. “Cures” provides FDA with tools aimed at modernizing our regulatory programs. The goal of many of these efforts is to make sure that we’re taking every appropriate step to facilitate access to safe and effective new innovation.

Today we announced our detailed work plan for the steps we’re taking to implement different aspects of Cures. I want to highlight one example of these steps, which we’re investing in, and will be expanding on, as part of our broader Innovation Initiative. It’s the use of in silico tools in clinical trials for improving drug development and making regulation more efficient.

In silico clinical trials use computer models and simulations to develop and evaluate devices and drugs. Modeling and simulation play a critical role in organizing diverse data sets and exploring alternate study designs. This enables safe and effective new therapeutics to advance more efficiently through the different stages of clinical trials. FDA’s efforts in modeling and simulation are enabled through multiple collaborations with external parties that provide additional expertise and infrastructure to advance the development of these state-of-the-art technologies.

FDA’s Center for Drug Evaluation and Research (CDER) is currently using modeling and simulation to predict clinical outcomes, inform clinical trial designs, support evidence of effectiveness, optimize dosing, predict product safety, and evaluate potential adverse event mechanisms. We’ll be putting out additional, updated guidance on how aspects of these in silico tools can be advanced and incorporated into different aspects of drug development.

A variety of drug development, regulatory, and therapeutic questions are addressed by CDER through modeling and simulation strategies. CDER’s Office of Translational Sciences (OTS) uses these same strategies in the review of Investigational New Drugs Applications (INDs) and New Drug Applications (NDAs). To take just one example of the benefits of these approaches, as we enter an era of drug individualization, modeling and simulation that incorporates aspects of individual physiology and genetics in drug metabolizing enzymes is being used to identify patient subgroups that need dose adjustments. These approaches are incorporated to assess the combined effect of drug interactions, renal impairment, and hepatic insufficiency in patients, with clinical management strategies described in drug labeling where appropriate.

Another example is the use of modeling and simulation to assist in the creation of natural history databases to support model-based drug development. This could make clinical trials more efficient—for example, by enabling FDA to model some aspects of the behavior of the placebo arm in clinical trials. Right now, FDA is collaborating with scientists to develop such natural history models in Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and muscular dystrophy. An important objective of modeling and simulation is to better evaluate the behavior of new treatments in rare disease populations that are inherently hard to study due to their small size.

To advance these opportunities, we need to continue to invest in high performance computing. These computing capabilities are becoming a key requirement to the ability of our review staff to manipulate the large data sets that are now a common feature of drug applications. FDA is actively working to expand the agency’s capabilities in high performance computing, and to explore modeling approaches and enhance their regulatory impact, through an effort enabled by the work of the agency’s Scientific Computing Board.

FDA’s device center is also an integral part of this work. The Center for Devices and Radiological Health (CDRH) is also building in silico regulatory models for product design and evaluation, including the development of a digital library of models and a family of “virtual patients” for device testing. An important goal is consistency. We need to make sure that the adoption of these strategies is consistent across different medical products and across the agency.
FDA is working hard to maximize the authorities and resources Congress granted us to advance medical innovation for patients. To ensure smooth coordination and communication across the agency, we established an intra-agency Cures Steering Committee. Since enactment of the nearly 1,000-page law on December 13, 2016, the team has conducted a detailed analysis of the law’s provisions, compiled a list of all of its FDA-related requirements, and is helping to advance the work teams that will enable FDA to deliver on the law’s opportunities. Today, we’re posting an initial list of our Cures deliverables. It will eventually become a tracking tool to help the public follow our progress.

As you can see from the list, we’ve already implemented several important Cures provisions. Section 1002 of Cures authorized $500 million in new funding over 9 years to help FDA cover the cost of implementing certain parts of the law. Consistent with the law’s requirements, we developed a draft work plan demonstrating how FDA would use that funding, subject to annual appropriations. We submitted the draft work plan to FDA’s Science Board for its consideration at a public meeting in May. Today we’re posting the final work plan that we delivered to Congress on June 9th. It includes the recommendations from FDA’s Science Board.

Among some of the other noteworthy actions that we’re pursuing under Cures:
1. Our Center for Biologics Evaluation and Research (CBER) is implementing the Regenerative Medicine Advanced Therapy, or RMAT designation. This new process provides another pathway to access FDA’s existing expedited programs, and is available for certain cell therapies, therapeutic tissue engineering products, and certain combination products. The goal of these efforts is to help foster the development and approval of these novel products. We’ve already received almost two dozen requests for RMAT designation and granted four such designations to date. To continue to advance these opportunities, we’ll be announcing this September a comprehensive framework for the development and proper FDA oversight of regenerative medicine. This new policy effort will comprise a series of new guidance documents covering many aspects of the regulation of regenerative medicine products. It will be announced as part of our Innovation Initiative. It will delineate our policies for appropriate and efficient regulatory oversight of regenerative medicine products, in order to demonstrate their safety and effectiveness. It will also create an accessible framework that will enable providers to more easily collaborate on proving these principles for regenerative products that are advanced within local medical institutions. We want to help facilitate these scientific advances, which hold out tremendous potential for treating and even curing diseases. To achieve these goals, we need to make sure that we have a modern regulatory framework in place that can allow innovators to meet the statutory requirements for demonstrating safety and effectiveness.

2. The newly established Oncology Center of Excellence is the first inter-center institute at FDA that focuses on a specific disease area rather than type of product. It’s designed to take advantage of the synergies that can be achieved by coordinating the clinical review of products across FDA’s drug, device, and biologic centers to make the development of oncology and hematology medical products more efficient. This new center will allow our expert review staff to work together and take a life-cycle approach to the development and post-market regulation of new cancer treatment options.

3. Under provisions of Cures, CDRH exempted more than 70 Class I device types from the requirement to submit to FDA a 510(k) submission. CDRH also proposed exempting another 1,000+ Class II device types from having to submit a 510(k) submission based on an initial determination that premarket review is not necessary to provide a reasonable assurance of safety and effectiveness. This action will decrease regulatory burdens on the device industry and eliminate private costs and expenditures.

4. To further align our regulatory requirements with the provisions of Cures, CDRH also amended its current regulations to allow more devices to qualify for a humanitarian device exemption for small patient populations. We’ll allow researchers to seek approval for device clinical trials through a central institutional review board rather than mandating the use of local review boards. Under the provisions of Cures, CDRH has also published the list of reusable device types for which FDA will require validated instructions for use and validation data regarding cleaning, disinfection, and sterilization in 510(k)s. These new requirements go into effect on August 8, 2017.

5. Finally, last month CDER, working with CBER, issued a plan for the development and issuance of patient-focused drug development guidances. The workshops and the new guidance will set forth our plan to facilitate a more systematic approach to gathering and using patient perspectives to inform FDA’s regulatory decision-making.

We’re at the beginning of a transformative era in science and medical technology. Through our implementation of Cures, and our efforts to build on its provisions through a new Innovation Initiative, we hope that our collective efforts will help consumers benefit from this new progress. FDA’s headway in pursuing the opportunities enabled by Cures illustrates the agency’s enthusiasm and commitment to the law—both its letter and its spirit. Please bookmark the Cures web page and our tracker to follow our progress as we work to vigorously advance these shared goals.