Q:What are the major CMC considerations between first in human studies in late phase studies that are intended to support the marketing approval? Are OTAT expectations more strit than other FDA divisions?
在最初的人体研究和旨在支持上市批准的后期研究之间，CMC的主要考虑因素是什么?OTAT的要求是否比其他部门更严格？
A:Welcome, everyone. The main concern for phase 1 studies is to ensure the safety of participants. Phase-appropriate CMC expectations were published and outlined in a 2020 gene therapy CMC guidance. This guidance references many FDA and ICH guidance documents. Hopefully, we’re consistent with that. For first-in-human studies, the materials used to make the product should be qualified as suitable for clinical use.
欢迎各位，第一阶段研究的主要关注点是确保参与者的安全。FDA在2020年发布的基因治疗CMC指南中（Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)）指南中发表并概述了相适应的CMC预期。希望我们是一致的。对于首次人体研究，用于制造产品的材料应被认证为适合临床使用。
We also want to make sure that the clinical material is comparable to the preclinical material so that we can ensure that the preclinical safety data is applicable. The product and the process should be sufficiently described in your IND and supported with data so that we can assess product safety. And as clinical development progresses, the expectation is that product characterization and controls need to increase at the same pace.
我们也希望确保临床材料与临床前材料具有可比性，这样就可以确保临床前安全数据适用。产品和工艺应在你的IND中有充分的描述，并有数据支持，以便我们评估产品安全性。随着临床开发的进展，预期产品表征和控制需要以同样的速度增加。
Regarding CMC expectations and whether we’re stricter than other agencies, CMC expectations for INDs and BLAs are broadly applied across all CBER review divisions. I don’t think, in general, our expectations are stricter. However, our consideration of risk-benefit is often complex. About 50% of our products are for rare disease indications with currently no available treatment. Some of the things we consider in our risk-benefitanalysis include the fact that many of these products are often administered [at] one time at very high doses intended to have a long-term or lifetime expression. Since you only get one shot at administration, it’s important that you don’t have a low quality, which will limit your successful development. Some products also have well-documented toxicities, so we need to consider this also in our risk-benefit analysis.
关于CMC的期望以及我们是否比其他机构更严格，IND和BLA的CMC期望广泛适用于CBER的所有审查部门。总的来说，我不认为我们的期望更严格了。然而，我们对风险-收益的考虑往往是复杂的。我们约50%的产品用于目前没有治疗方法的罕见疾病。我们在风险效益分析中考虑的一些因素包括，许多此类产品通常一次性给予非常高的剂量，目的是具有长期或终生的表达。因为你只有一次管理机会，所以你的质量不能低，这将限制你的成功开发。有些产品也有充分证明的毒性，所以我们也需要在我们的风险-收益分析中考虑这一点。
Many gene therapy studies often include pediatric subjects. When pediatric subjects are included, you need to have a prospect of benefit. Product quality needs to be controlled to ensure that all participants receive a similar product of defined quality.
许多基因治疗研究通常包括儿科受试者。当儿科受试者被包括在内时，你需要有一个有益的前景。产品质量需要控制，以确保所有参与者都能收到相同质量的产品。
Another thing that we consider is that recent clinical successes have resulted in gene therapy products being developed at an increasingly accelerated pace with many trials not designed as typical phase 1 studies. Therefore, we really consider the CMC information in the context of a clinical trial design. For instance, if a clinical protocol is listed as a randomized, placebo-controlled, double-blind study for a rare disease in 50 subjects, we’re pretty much going to assess the CMC information a little bit more stringently than if it’s a typical 3+3 dose escalation study.
我们考虑的另一件事是，最近的临床成功导致基因治疗产品的开发速度越来越快，许多试验并不是作为典型的1期研究设计的。因此，我们真正考虑CMC信息是在临床试验设计的背景下。例如，如果一项临床方案被列为针对50名受试者的罕见疾病的随机、安慰剂对照、双盲研究，我们很可能会比典型的3+3剂量递增研究更严格地评估CMC信息。
There’ll be another question on later-phase studies, and Kim will go into that. One of the main things we want for you to keep in mind is that product development should keep pace with clinical development. Thank you. Back to you, Steven.
还有一个关于后期研究的问题，Kim会讲到。我们希望你们记住的一件主要事情是产品开发应该跟上临床开发的步伐。谢谢你！到你了，Steven。