FDA由于经费问题停止工作后FDA局长首次公开发声！展示了未来关注的领域！

美国食品和药物管理局正在目睹一系列细胞和基因治疗产品进入早期发展阶段，研究新药（IND）应用数量大幅增加就是证明。基于此项活动，我们预计未来几年细胞和基因治疗产品的批准数量将会增加，这反映了这些新创新的重大科学进步和临床前景。
我们预计，到2020年，我们每年将接收超过200个IND，这是基于目前已向FDA提交的800多个基于活性细胞或直接施用的基因治疗IND的总数。到2025年，我们预测FDA将根据对当前管道的评估和这些产品的临床成功率，每年批准10到20种细胞和基因治疗产品。在没有FY19拨款给FDA的这段时间里，我们一直专注于确保在法律允许的范围内继续我们工作的关键方面。目前，对于用户收费计划所涵盖的产品，包括细胞和基因治疗产品，我们对现有医疗产品应用和相关政策制定的审查由有限的结转用户费余额提供资金。我们将继续向公众介绍我们如何接近我们的工作。
我们正在努力扩展我们的评估小组，致力于评估这些应用程序，以跟上新产品开发的快速扩展。我们的最终目标是向负责监督这些产品的临床调查，开发和审查的小组增加约50名临床评审员。
该活动反映了这些技术的发展及其对人类健康的应用的转折点。它类似于20世纪90年代后期抗体药物开发加速的时期，以及单克隆抗体作为现代治疗方案主干的主流化。
就抗体而言，它是一种产品创新，在这些产品的推进中引发了一个转折点，之后抗体药物成为医疗保健的支柱。具体而言，广泛采用安全有效的抗体人源化平台，并最终开发出完全不受机体先天免疫系统排斥的人单克隆抗体。
在基因治疗的情况下，它同样是一种产品创新，已经标志着这些疗法发展的一个转折点，以及新产品活动的激增。在这种情况下，它是用于递送基因治疗产品的安全有效载体的出现，例如采用腺相关病毒（AAV）载体。
产品创新是推动这些产品开发成有效疗法的关键因素，这一事实凸显了围绕这些产品相关问题推进与创新相关的合理政策的重要性。
基因治疗产品现在有可能治愈难治性疾病，并从根本上改变许多其他烦恼疾病的轨迹。为了推动这些机会，FDA计划在2019年在我们的药物开发框架中引入额外的新政策指导和其他进展。今天，我们希望借此机会预览该政策议程，并就我们的政策重点提供一些观点。来年，因为它涉及这些技术。
首先，我们将与赞助商合作，最大限度地利用我们的快速计划，包括再生医学高级治疗（RMAT）指定和加速批准。我们相信，对于针对严重或危及生命的疾病或病症的可用疗法提供有意义的治疗优势的基因疗法产品，加速的批准途径提供了一些独特的机会。一方面，加速审批途径可能为批准新疗法提供更快的途径，包括在重大的，未满足的医疗需求中的潜在疗效。但该途径还为FDA提供了额外的权限，要求进行上市后的后续研究。由于与基因治疗产品相关的许多风险涉及产品耐久性和罕见脱靶效应可能性的问题，因此在任何合理规模的研究中进行能够解决所有这些理论风险的上市前试验可能是不可行的。 。强大的上市后工具，例如在加速审批途径下向FDA提供的工具，特别是对于获得RMAT认可的产品，可以帮助实现开发更大数据集以及时解决这些理论风险的目标。
其次，我们正在计划一系列与活跃产品开发的不同领域相关的临床指导文件。我们打算推进的临床指导文件包括用于遗传性血液病，如血友病等基因治疗产品开发的指导文件。
我们还打算制定一份指导文件，为与某些神经退行性疾病的基因治疗产品的开发相关的产品开发问题提供建议。加速审批途径可能仅适用于某些情况。
例如，我们打算提出指导，以解决当基因治疗产品的目标是潜在的单基因变化时如何使用加速批准途径，该单基因变化导至可用治疗无法解决的严重疾病。在这些情况下，基因疗法可以改变或治愈导至疾病并导至疾病进展的潜在遗传缺陷。
我们的指导还将提出如果基因疗法产生旨在治疗神经退行性疾病症状的基因改变，或者通过改变相信的蛋白质或酶的表达来改变其过程，更传统的药物开发方法可能更合适。在疾病的进展中发挥作用。在这些情况下，基因治疗不是为了治愈潜在的病症，而是影响其病程或症状。我们打算解释说，证明这种方法的安全性和益处通常需要更传统的临床研究，并建议实现这一目标的方法。
在开发安全有效的基于细胞的基因疗法（如CAR-T细胞）时也会出现其他关键挑战，包括以安全，可靠和具有成本效益的方式制造这些产品的复杂性，以及允许的方式。在诊所有效使用这些产品。我们的新指南将为创新者如何引入制造方面的进展提供参数，以促进CAR-T疗法的更有效开发和应用，而无需进行昂贵的新临床研究。我们打算通过现有技术和检查提出有助于确保最终产品安全性和有效性的方法，以及在批准变更之前可能需要进行有限的临床桥接研究，随后可能会提交真实提供的其他临床信息。引入变更后的世界数据。
我们打算开发的这类指导文件将有助于推进与CAR-T和其他细胞治疗产品的有效开发相关的科学原理。我们打算发布的指南将促进更好地理解关键质量属性和与产品制造相关的其他因素。我们的目标之一是允许开发更清晰的参数，以便何时可以进行微小的制造变更，而不需要额外的桥接研究。我们还将与利益相关方合作，并打算在未来几个月召开公开会议，讨论如何在制造过程中引入不仅仅是微小的变化时加快必要的临床桥接研究，但这些变化并不代表向根本不同的产品。我们打算引入各种主题，例如遗传构建体的改进和更有效的细胞培养方法的引入。
我们还打算制定新的指南，以继续促进安全有效的细胞再生医学产品的有效开发。
虽然我们对这一领域的科学和临床发展的进步感到非常鼓舞，但我们仍然关注FDA，在这个领域工作的许多人正在开发受到上市前批准的产品，但这些人在外面经营监管合规性，在某些情况下，这些产品正在创造潜在的重要意义。虽然我们对这一领域的科学和临床发展的进步感到非常鼓舞，但我们仍然关注FDA，在这个领域工作的许多人正在开发受到上市前批准的产品，但这些人在外面经营在某些情况下，基于我们如何相信细胞疗法正在制造并交付给患者，这些产品正在为患者带来潜在的重大安全问题。在这些情况下，制造商未能回应FDA要求与该机构就如何遵守法规进行对话的要求。我们计划在2019年采取额外的执法行动，以解决对患者构成潜在危害的重大风险的产品。
与此同时，我们致力于继续开发有效途径，使赞助商在遵守法规要求的同时，为其产品批准新的生物制剂许可证申请（BLA）。为了实现这一目标，我们打算在今年发布的一份指南将概述一种拟议的创新试验设计，通过该设计，个体研究人员可以按照共同的制造协议汇集其临床数据，从而开发出更强大的数据集，以获得BLA。
这里的想法是帮助小型赞助商，包括学术研究人员，他们可能没有足够的规模自行进行临床试验，与其他同样位置的人一起工作。然后，这些赞助商可以汇集临床数据，以证明使用通用制造协议和产品质量规格制造的产品的安全性和有效性，并用于共同的临床目的，但不同的研究人员和机构在当地提供治疗。我们已经有学术研究人员联盟，他们正在与FDA就这一拟议的新方法进行积极讨论。我们打算发布的指导文件将更清楚地概述推行这种新方法的建议程序。
总之，这些指导文件以及我们计划在2019年发布的其他政策旨在帮助推进细胞和基因治疗领域。
我们相信这些基于细胞的基因治疗技术为解决一些最难治的疾病带来了巨大的希望。但是，由于它们的新颖性，也带来了新的不确定性和一些独特的理论风险。我们的努力旨在帮助创新者积极应对这些潜在风险，同时我们为这些创新的持续发展勾勒出现代而有效的途径。

The FDA is witnessing a surge of cell and gene therapy products entering early development, evidenced by a large upswing in the number of investigational new drug (IND) applications. Based on this activity, we anticipate that the number of product approvals for cell and gene therapies will grow in the coming years, reflecting significant scientific advancement and the clinical promise of these new innovations.

We anticipate that by 2020 we will be receiving more than 200 INDs per year, building upon our total of more than 800 active cell-based or directly administered gene therapy INDs currently on file with the FDA. And by 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products. During this period without a FY19 appropriation for FDA, we’ve been focused on making sure that we continue critical aspects of our work, to the extent permitted by law. At this time, for products covered by a user fee program, including cell and gene therapy products, our review of existing medical product applications and associated policy development is funded by limited carryover user fee balances. We’ll continue to update the public on how we’re approaching our work.

We’re working to expand our review group dedicated to the evaluation of these applications to keep pace with the rapid expansion in new product development. Our eventual goal is to add about 50 additional clinical reviewers to the group charged with overseeing the clinical investigation, development, and review of these products.

The activity reflects a turning point in the development of these technologies and their application to human health. It’s similar to the period marking an acceleration in the development of antibody drugs in the late 1990s, and the mainstreaming of monoclonal antibodies as the backbone of modern treatment regimens.

In the case of antibodies, it was a product innovation that sparked an inflection point in the advance of those products, after which antibody drugs became a mainstay of medical care. Specifically, it was the widespread adoption of safe and effective platforms for humanizing antibodies and, eventually, developing fully human monoclonal antibodies that weren’t rejected by the body’s innate immune system.

In the case of gene therapy, it’s similarly a product innovation that has marked an inflection point in the development of these therapies, and a surge in new product activity. In this case, it was the advent of safe and effective vectors for the delivery of gene therapy products, such as the adoption of adeno-associated virus (AAV) vectors.

The fact that product innovations are a key enabling advance in promoting the development of these products into effective therapies underscores the importance of advancing sound policy related to innovation around these product-related issues.

Gene therapy products now have the potential to cure intractable diseases, and fundamentally alter the trajectory of many other vexing illnesses. To advance these opportunities, the FDA plans to introduce additional new policy guidance and other advances in our drug development framework in 2019. Today, we want to take an opportunity to preview that policy agenda and offer some perspective on the focus of our policies over the coming year as it relates to these technologies.

First, we will work with sponsors to make maximum use of our expedited programs including regenerative medicine advanced therapy (RMAT) designation and accelerated approval. We believe that for gene therapy products that are offering meaningful therapeutic advantage over available therapies for a serious or life-threatening disease or condition, the accelerated approval pathway offers some unique opportunities.

For one thing, the accelerated approval pathway may offer a faster route to approval for new treatments, including potentially curative benefits in significant, unmet medical needs. But the pathway also offers additional authorities for FDA to require postmarket follow-up studies. Since many of the risks associated with gene therapy products relate to questions about the product’s durability and potential for rare instances of off-target effects, it may not be feasible to conduct pre-market trials that address all these theoretical risks in any reasonably sized study. Robust postmarket tools, such as those afforded to the FDA under the accelerated approval pathway, particularly for products granted RMAT designation, can help achieve the goal of developing a larger data set to address these theoretical risks in a timely fashion.

Second, we’re planning a series of clinical guidance documents related to different areas of active product development. Among the clinical guidance documents that we intend to advance include guidance documents for the development of gene therapy products for inherited blood disorders such as hemophilia, among others.

We also intend to develop a guidance document for providing recommendations on product development issues related to the development of gene therapy products for certain neurodegenerative diseases. Here the accelerated approval pathway may only be applicable in certain circumstances.

For example, we intend to propose guidance to address how the accelerated approval pathway may be used when the target of the gene therapy product is an underlying monogenetic change that causes a serious disorder not addressed by available therapy. In these cases, the gene therapy could offer the potential to alter or cure the underlying genetic defect that gives rise to, and causes the advance of, a disease.

Our guidance will also propose how a more traditional approach to drug development may be more appropriate if the gene therapy creates a genetic alteration aimed at treating the symptoms of a neurodegenerative disease, or potentially altering its course by altering the expression of a protein or enzyme believed to play a role in the advance of a disease. In these cases, the gene therapy wouldn’t be intended to cure the underlying condition but instead, affect its course or symptoms. We intend to explain that demonstrating the safety and benefits of such an approach could typically require a more traditional clinical study and recommend ways this can be achieved.

Other critical challenges also arise in the development of safe and effective cell-based gene therapies such as CAR-T cells, including the complexities associated with manufacturing these products in a safe, reliable and cost-effective way, and in a manner that allows for the efficient use of these products in the clinic. Our new guidance will recommend parameters for how innovators can introduce advances in manufacturing that promote the more efficient development and application of CAR-T therapies without necessarily requiring costly new clinical investigations. We intend to propose ways to help ensure the safety and effectiveness of the resulting products through available technologies and examinations, and when limited clinical bridging studies may be needed prior to approval of a change, possibly followed by the submission of additional clinical information supplied by real-world data after the change is introduced.

This category of guidance documents that we intend to develop will help advance scientific principles related to the efficient development of CAR-T and other cellular therapy products. The guidance that we intend to issue will promote a better understanding of the critical quality attributes and other factors related to product manufacturing. One of our goals here is to allow for the development of clearer parameters for when minor manufacturing changes can be made that wouldn’t require additional bridging studies. We will also be working with stakeholders and intend to hold a public meeting in the coming months to discuss ways to expedite the necessary clinical bridging studies when more than minor changes are introduced in the manufacturing process, but such changes do not represent a transformation to a fundamentally different product. We intend to introduce various topics, such as the refinement of genetic constructs and the introduction of more efficient cell culture methods.

We also intend to develop new guidance to continue to promote the efficient development of safe and effective cell-based regenerative medicine products.

Though we are very encouraged by the advances in science and clinical development in this field, we remain concerned at the FDA that a number of individuals working in this space are developing products that are subject to pre-market approval, but these individuals are operating outside of regulatory compliance and, in some cases, these products are creating potential significant safety concerns to patients based on how we believe the cell therapies are being manufactured and delivered to patients. In these cases, the manufacturers have failed to respond to the FDA’s request to have a dialogue with the agency about how to come into regulatory compliance. We plan additional enforcement actions in 2019 to address products that pose a significant risk of potential harm to patients.

At the same time, we are committed to continue to develop efficient pathways by which sponsors can come into regulatory compliance while working toward approval of a new Biologics License Application (BLA) for their products. To advance this goal, one guidance that we intend to issue this year will outline a proposed innovative trial design by which individual researchers can pool their clinical data after following a common manufacturing protocol, and thereby develop a more robust data set for purposes of gaining a BLA.

The idea here is to assist small sponsors, including academic investigators, who may not be of sufficient scale to conduct a clinical trial on their own, to band together with others similarly situated. These sponsors can then pool clinical data to demonstrate the safety and effectiveness of a product that is manufactured with a common manufacturing protocol and product quality specifications, and used for a common clinical purpose, but where the therapies are being delivered locally by different investigators and institutions. We already have consortiums of academic investigators who are in active discussions with the FDA about this proposed new approach. The guidance document we intend to issue will outline more clearly the recommended procedures for pursuing this novel approach.

Taken together, these guidance documents, along with other policies that we plan to issue in 2019, are aimed at helping advance the field of cell and gene therapy.

We believe these cell-based and gene therapy technologies hold tremendous promise for addressing some of the most intractable diseases. But with their novelty, also comes new uncertainties and some unique, theoretical risks. Our efforts are aimed at helping innovators proactively address these potential risks, while we outline a modern and efficient pathway for the continued development of these innovations.

参考资料：

Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies