Continuing Development of PPCM Vaginal Contraceptive Microbicide

描述(申请人提供)：该项目的目标是继续开发一种新的、双适应症的阴道避孕抗疱疹杀微生物剂产品，含有PPCM。我们将执行生成IND提交所需的药理学/毒理学和化学制造和控制(CMC)信息所需的所有任务，并与FDA一起概述早期临床研究设计。开发将是通过/不通过决策和里程碑驱动的，以有效地(资源、成本和时间)评估药物产品的活性和安全性，满足FDA和ICH的要求，并生产适合早期临床试验材料的药物和产品。我们将通过开发三种原型并评估它们的消费者可接受性、安全性和有效性来解决最近的艾滋病毒杀微生物剂试验中遇到的依从性问题，然后选择最好的产品形式进行最终的临床前研究。在拨款批准的十个月内，三种不同的阴道制剂(水凝胶、胚珠和薄膜)的原型配方将使用行业中的改进配方快速制备出来，并在四个非GLP模型中进行分析测试和评估：10天兔阴道刺激(RVI)、安全性的尖端体外模型、小鼠模型中的HSV预防和兔体内避孕(由NICHD资助)，为我们选择一种产品形式进行进一步开发提供了数据。利用雷吉斯化学公司在第一阶段SBIR中生产的1公斤PPCM，将选择一种剂型，纳入使用车辆控制产品的消费者反馈，由商业合同制造商通过彻底开发产品配方、工艺和包装来推进。CMO将生产用于IND的产品，以便进行GLP毒理学和产品稳定性研究。价格合理的报价从该领域最负盛名的CMO那里获得。从第二阶段SBIR赠款批准开始，将编制和发布IND会议前简报文件。该文件将与IND开发问题一起提交给FDA以供回应。这些问题将包括最终确定药理学/毒理学研究方案和I-II期临床研究设计的问题。与此同时，将为临床使用的1公斤GMP批次药品(PPCM)的制造和质量控制测试做准备。第一个项目将是执行《质量协议》(双方承诺满足质量和监管要求)；生产控制；以及释放和监测适用于早期临床试验的GMP批次药物的稳定性所需的合格/有效的分析测试方法。

DESCRIPTION (provided by applicant): The goal of this project is to continue development of a novel, dual indication vaginal contraceptive anti-herpes microbicide product containing PPCM. We will conduct all tasks required to generate the Pharmacology/Toxicology and Chemistry Manufacturing and Controls (CMC) information required for IND submission, and outline the early clinical study designs with FDA. Development will be Go/No Go Decision and milestone driven to efficiently (resource, cost and time) evaluate the drug product in biologically relevant models for activity and safety, meet FDA and ICH requirements and manufacture drug and product suitable for early clinical trial material. We will address compliance issues experienced in recent HIV microbicide trials by developing three prototypes and evaluating their consumer acceptability, safety and efficacy; then selecting the superior product form for final preclinical studies. Within ten months of grant approval, prototype formulations of three different vaginal formulations (aqueous gel, ovule and thin film) will be quickly prepared using modified recipes from industry, analytically tested and evaluated in four non GLP models: 10-day Rabbit Vaginal Irritation (RVI), cutting edge in vitro models for safety, HSV-prevention in the mouse model and contraception in the rabbit (funded by NICHD) providing us with data to select one product form for further development. Utilizing the 1kg of PPCM manufactured by Regis Chemical in the Phase I SBIR, one dosage form will be selected, incorporating consumer feedback using vehicle control products, to be taken forward by a commercial contract manufacturer through thorough development of the product formula, process and package. The CMO will produce product for use in IND enabling GLP toxicology and product stability studies. Reasonably priced quotes were obtained from the most reputable CMOs in the field. From the initiation of Phase II SBIR grant approval, a pre-IND meeting briefing document will be compiled and issued. The document will be accompanied with IND development questions addressed to FDA for response. These will include questions to finalize the Pharmacology/Toxicology study protocols and Phase I-II clinical study designs. In parallel to that, preparations will be made for manufacturing and quality control testing of a 1kg GMP batch of drug substance (PPCM) for clinical use. The first item will be to implement the Quality Agreement (commitments by both parties to satisfy quality and regulatory requirements); manufacturing controls; and qualified/validated analytical test methods required to release and monitor the stability of the GMP lot of drug substance suitable for early clinical trials.