Lomash Richa Madan, Dehdashti Jean, Shchelochkov Oleg A, Chandler Randy J, Li Lina, Manoli Irini, Sloan Jennifer L, Terse Pramod, Xu Xin, Saade Dimah, Stan Rodica, Brooks Philip J, Lo Donald C, Bönnemann Carsten G, Venditti Charles P, Pariser Anne R, Ottinger Elizabeth A
Therapeutic Development Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, Maryland, USA.
Division of Rare Diseases Research and Innovation, NCATS, NIH, Rockville, Maryland, USA.
Hum Gene Ther. 2025 Mar;36(5-6):653-662. doi: 10.1089/hum.2024.230. Epub 2025 Feb 20.
Gene therapy development presents multiple challenges, and early planning is vital in the successful implementation of such programs. The Platform Vector Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative developing adeno-associated virus (AAV) gene therapies for four low-prevalence rare diseases. Utilizing the platform-based approach, the program aims to incorporate efficiencies throughout the preclinical and clinical development processes followed by public dissemination of scientific and regulatory learnings. Early in development, the establishment of a Target Product Profile (TPP) by the research team is a critical step to guide product development and align preclinical studies to clinical objectives. Based on the specific needs of the investigational product as defined in the TPP, an overall regulatory strategy can then be outlined to meet the regulatory requirements for the first-in-human clinical trials. During the preclinical phase of development, sponsors may request meetings with the Food and Drug Administration (FDA) to gather feedback on the planned studies and regulatory strategy. To pave the way for PaVe-GT's first investigational AAV gene therapy lead candidate, AAV9-hPCCA, we sought early feedback from the FDA utilizing an INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meeting. Here, we elaborate on the value of establishing a TPP and the FDA INTERACT meeting by including our initial AAV9-hPCCA TPP, detailing our INTERACT meeting experience, providing all corresponding regulatory documentation, and highlighting lessons learned. The regulatory documents along with templates developed by our program can also be found on the PaVe-GT website (https://pave-gt.ncats.nih.gov/). This communication aims to provide stakeholders with resources that can be applied to drug development programs in establishing a viable regulatory path to clinical trial initiation.
基因治疗的发展面临多重挑战，早期规划对于此类项目的成功实施至关重要。平台载体基因治疗（PaVe-GT）项目是美国国立卫生研究院（NIH）的一项倡议，旨在为四种低发病率的罕见疾病开发腺相关病毒（AAV）基因疗法。该项目采用基于平台的方法，旨在在临床前和临床开发过程中提高效率，随后公开传播科学和监管方面的经验教训。在开发早期，研究团队制定目标产品概况（TPP）是指导产品开发并使临床前研究与临床目标保持一致的关键步骤。根据TPP中定义的研究产品的特定需求，然后可以概述总体监管策略，以满足首次人体临床试验的监管要求。在临床前开发阶段，申办者可能会请求与美国食品药品监督管理局（FDA）会面，以收集有关计划研究和监管策略的反馈。为了为PaVe-GT的首个研究性AAV基因治疗先导候选产品AAV9-hPCCA铺平道路，我们利用针对CBER/CDER产品的监管建议的初始目标参与（INTERACT）会议，寻求FDA的早期反馈。在此，我们通过纳入我们最初的AAV9-hPCCA TPP、详细介绍我们的INTERACT会议经验、提供所有相应的监管文件并突出经验教训，阐述建立TPP和FDA INTERACT会议的价值。我们项目制定的监管文件以及模板也可在PaVe-GT网站（https://pave-gt.ncats.nih.gov/）上找到。本交流旨在为利益相关者提供资源，这些资源可应用于药物开发项目，以建立可行的临床试验启动监管路径。
