Continuing Development of PPCM Vaginal Contraceptive Microbicide

描述（由申请人提供）：该项目的目标是继续开发一种含有PPCM的新型双指征阴道避孕抗疱疹杀菌剂产品。我们将执行生成IND提交所需的药理学/毒理学和化学制造与控制（CMC）信息所需的所有任务，并向FDA概述早期临床研究设计。开发将是批准或不批准的决定和里程碑，以有效地（资源、成本和时间）在生物相关模型中评估药物的活性和安全性，满足FDA和ICH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其消费者可接受性、安全性和有效性，解决最近在艾滋病毒杀微生物剂试验中遇到的合规问题；然后选择较优的产品形式进行最后的临床前研究。在获得批准的十个月内，三种不同阴道制剂（水凝胶、胚珠和薄膜）的原型制剂将使用工业配方进行快速制备，并在四种非GLP模型中进行分析测试和评估：10天兔阴道刺激（RVI）、最先进的体外安全性模型、小鼠hsv预防模型和兔避孕模型（由NICHD资助），为我们选择一种产品形式进行进一步开发提供数据。利用Regis Chemical在第一阶段SBIR中生产的1kg PPCM，将选择一种剂型，结合使用车辆控制产品的消费者反馈，由商业合同制造商通过全面开发产品配方、工艺和包装来推进。CMO将生产用于IND的产品，使GLP毒理学和产品稳定性研究成为可能。合理的报价是从该领域最负盛名的首席营销官那里获得的。从第二期SBIR拨款批准开始，将编制和发布一份ind会议前的简报文件。该文件将与向FDA提交的IND开发问题一起提交。这些问题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1kg GMP批次原料药（PPCM）的生产和质量控制测试做准备。第一项是执行质量协议（双方承诺满足质量和监管要求）；制造控制;以及适用于早期临床试验的GMP批次原料药的放行和稳定性监测所需的合格/验证的分析试验方法。

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.