Q:What is the “must-have” and “good-to-have” CMC information for a gene therapy product going into phase 3 IND studies or late-phase studies that intend to support a marketing approval?
对于一个进入三期IND研究或打算支持上市许可后期研究的基因治疗产品，“必须有”和“最好有”的CMC信息是什么?
A:Thanks. That’s a good question, especially as I think we can all agree we’re in an exciting time in the gene therapy field, where there’s a number of products that are entering late-stage development. In addition to safety, which is our main concern during early-phase studies, late-phase studies should reflect the planned commercial setting so that you can support interpretation of the clinical study data in order to assess the product’s efficacy.
谢谢。这是一个很好的问题，特别是我认为我们都同意我们在基因治疗领域处于一个激动人心的时期，有许多产品进入了后期开发阶段。除了我们在早期研究中主要关注的安全性问题，后期研究应反映计划的商业环境，以便你可以支持临床研究数据的解释，以评估产品的疗效。
The gene therapy CMC guidance does provide some insight into these phase-specific expectations. But I’m going to highlight what you might consider some must-haves and good-to-haves here.
基因治疗CMC指南确实对这些特定阶段的期望提供了一些见解。但我将在这里强调一些你可能考虑必须有和最好有的内容。
First and foremost, you must have qualified assays, including a potency assay, in place prior to initiating studies that are intended to provide the primary efficacy data for licensure. And so we do assess that based on the clinical study design, as Denise said. As many times, our products don’t have what would be called a formal phase 3 study. And so for these late-stage studies, you should also have appropriate CGMPs in place in order to support the product quality and facility control.
首先也是最重要的，在开始旨在为许可提供主要疗效数据的研究之前，你们必须有合格的分析，包括效价分析。所以就像Denise说的我们根据临床研究设计进行评估。很多时候，我们的产品没有所谓的正式第三阶段研究。所以对于这些后期研究，你们也应该有适当的cGMPs来支持产品质量和设施控制。
Our general advice is that you should determine where the variability and risk are possible in your process. And then, through that risk assessment, you should ensure that you have the controls in place in order to reduce the variability of your product. And this is going to be assessed on a product-by-product basis. For instance, for a fresh cell-based gene therapy, shipping validation should be conducted in order to support that the product quality is not affected from the time of release to the time of delivery and administration at the clinical site. For an AAV vector, the product should be formulated using a nominal titer so that you can gain experience with the commercial dosing strategy. And that can be part of the interpretation of the efficacy assessment.
我们的一般建议是，你应该确定工艺中哪些地方可能存在可变性和风险点。然后，通过风险评估，你应该确保你有适当的控制以降低产品的可变性。这将基于产品进行评估。例如，对于一种基于新鲜细胞的基因疗法，应进行运输验证，以支持产品质量从放行时间到交付时间和临床给药时间不受影响。对于AAV载体，产品应使用名义滴度配制，以便您可以获得商业给药策略的经验。这可以作为疗效评估解释的一部分。
Overall, we recommend that you move to the expected commercial configuration prior to conducting this pivotal study. And this will reduce the risk in your developmental process. This includes using the intended commercial manufacturing process at the intended manufacturing facility and using the expected lot release testing strategy. And this will position you to have the maximal data at your disposal to use for your license application. And it’s also going to reduce the complications related to comparability assessments that may occur during the BLA review.
总的来说，我们建议你在进行这项关键研究之前转移到预期的商业配置。这将降低你开发过程中的风险。这包括在预期的生产工厂使用预期的商业生产工艺和使用预期的批放行检测策略。这将使你拥有最大的数据，用于你的许可证申请。这也将减少在BLA审查期间的与可比性评估相关的关联审查。