PfSPZ Vaccines: Quality Systems, Manufacturing, Regulatory, and Clinical Quality and Data Management Support for Product Commercialization

摘要 Sanaria的恶性疟原虫（Pf）子孢子（SPZ）疫苗开发计划正在接受 全球支持。Sanaria的两种主要PfSPZ疫苗的11项试验，其中包括约1，500 受试者，于2015年底启动（坦桑尼亚，美国）或将于2016年初开始（肯尼亚、加纳、赤道几内亚 几内亚（EG）、布基纳法索、德国和美国）。这些试验将评估1至3个剂量方案， 在德国进行的一项试验显示，9周内对控制的人类疟疾感染（CHMI）具有100%的保护效力 在3剂、8周方案的最后一剂后。对CHMI的保护效力持续至少一年， 并在马里进行至少6个月的强烈自然传播。这一成功导致了 与国际PfSPZ联盟合作开发4阶段临床开发计划。 已完成的试验（第1阶段）和上述新试验（第2阶段）旨在优化免疫接种 为支持生物制品许可证申请的关键III期临床试验（第3阶段）做准备的方案 (BLA)FDA和商业化（发布）。第4阶段（许可后）包括大规模疫苗 管理（MVA）运动，以阻止Pf的传播，并消除> 250，000的寄生虫 比奥科岛的人口，例如。通过SBIR赠款和美国军事合同，Sanaria正在扩大规模 生产和改进其疫苗生产设施，以满足第3阶段和上市合规性要求。 然而，我们的质量保证（QA）和质量控制中有一些至关重要的、没有资金支持的组成部分， (QC)，制造，监管和临床质量和数据管理计划，必须升级 并最终确定。该CRPP项目将解决其中几个关键组成部分。总体目标是 增加Sanaria目前的努力，以实现商业化的准备和优化的机会， 成功的第3阶段计划、BLA、产品发布以及发布后的第4阶段测试和维护。我们会的 1)建立并实施符合统一监管标准的QA和QC计划， 适当的组织和系统基础设施; 2）正式评估制造过程，包括 无菌生产的失效模式和效应分析（FMEA）风险评估和确认 流程; 3）过渡到电子通用技术文件（eCTD）格式的监管申报， 建立托管监管文件管理平台，为FDA制定战略框架 提交和互动，并制定和实施BLA提交和监管SOP的计划 完成;和4）开发符合第3阶段的临床质量体系，包括临床SOP，建立 符合CDISC标准的临床数据管理平台，导入临床试验数据，生成临床研究 为所有缺乏CSR的临床试验提供CSR，并对试验主文件进行质量审查稽查。 该提案的资金将大大缩短产品许可和发布的时间，这将导致 销售和收入至少提前一年，否则可能，并将挽救许多生命。

ABSTRACT Sanaria’s Plasmodium falciparum (Pf) sporozoite (SPZ) vaccines development program is receiving overwhelming global support. Eleven trials of Sanaria’s two primary PfSPZ vaccines which include ~1,500 subjects, were initiated in late 2015 (Tanzania, U.S.) or will start in early 2016 (Kenya, Ghana, Equatorial Guinea (EG), Burkina Faso, Germany, and the U.S.). These trials will assess 1 to 3 dose regimens based on a trial in Germany showing 100% protective efficacy against controlled human malaria infection (CHMI) 9 weeks after the last dose of a 3-dose, 8-week regimen. Protective efficacy is durable against CHMI for at least a year, and against intense natural transmission in Mali for at least 6 months. This success has led to the development, in collaboration with the International PfSPZ Consortium, of a 4-stage clinical development plan. The completed trials (stage 1) and above-mentioned new trials (stage 2) are intended to optimize immunization regimens in preparation for pivotal phase 3 clinical trials (stage 3) to support a Biologics License Application (BLA) to the FDA and commercialization (launch). Stage 4 (post licensure) includes a mass vaccine administration (MVA) campaign to halt transmission of Pf and eliminate the parasite from the >250,000 population of Bioko Island, EG. Through SBIR grants and U.S. military contracts, Sanaria is scaling up manufacturing and improving its vaccine manufacturing facility to meet phase 3 and launch compliance. However there are critically important, unfunded components of our quality assurance (QA), quality control (QC), manufacturing, regulatory, and clinical quality and data management programs, which must be upgraded and finalized. This CRPP project will address several of these key components. The overarching goal is to augment Sanaria’s current efforts to achieve commercialization readiness and optimize chances of a successful phase 3 program, BLA, product launch, and post launch phase 4 testing and maintenance. We will, 1) Establish and implement a QA and QC program that meets harmonized regulatory standards with appropriate organizational and systems infrastructure; 2) Formally assess manufacturing processes, including Failure Modes and Effects Analysis (FMEA) risk assessment and validation of the aseptic manufacturing processes; 3) Transition to regulatory submissions in electronic common technical document (eCTD) format, establish a platform for hosted regulatory document management, develop a strategic framework for FDA submissions and interactions, and develop and implement plans for BLA submission and regulatory SOP completion; and 4) Develop phase 3 compliant clinical quality systems, including clinical SOPs, establish a CDISC compliant clinical data management platform, import data from clinical trials, generate Clinical Study Reports (CSRs) for all clinical trials lacking CSRs, and conduct a quality review audit of trial master files. Funding of this proposal will significantly shorten the time until product licensure and launch, which will lead to sales and income at least a year earlier than otherwise possible, and will save many lives.