Better bioassays via designs for robots analyses with improved model selection and similarity bounds that limit potency bias

项目摘要 生物测定（bioassays）提供了复杂生物药品活性的关键测量 （蛋白质、疫苗、细胞治疗和基因治疗产品），特别是在产品开发期间， 生产质量控制。这些测定使用活体系统进行测量，并具有特殊的设计， 分析，以适应大的变化和混杂因素。常见实验室生物测定 强加了复杂的统计结构，如果设计和分析不当， 评估效力和有限的能力来监测检测是否出现问题。这些问题 导致制造商的批次放行失败，并减缓或阻碍 为消费者提供生物制药产品。 Precision Bioassay为生物测定提供统计服务，帮助开发，使用， 执行、验证、监测和管理生物测定，使用现代方法获得更好的信息， 性能，最终提高质量并加速生物制药药物的发现 产品.拟议的研究将产生三种新的工具，这些工具将改善生物测定的设计、分析和 监测，每一个将成为一个新的产品（软件和咨询支持的组合）。新生物测定法 利用现代机器人能力的设计，结合良好的分析， 与当前设计和分析混淆的重要变化来源;这改善了 信息将加速生物测定的发展，并加强对生物测定的监测。的改进方法 选择生物测定分析模型中包含的变异来源（基于等效性的随机 影响模型选择）将改善对经常被忽略的重要变异来源的估计， 目前的分析方法;这将大大改善生物测定监测。效力的限制偏倚是 确保生物测定适合其预期用途：一种新的方法来设定 供试品与标准品相似性的等效性试验将限制与允许浓度相关的效价偏倚 与预先指定的水平不相似，确保大多数相似的样本将通过相似性，以及 估计实现此性能目标所需的检测试剂盒大小。 在第二阶段，我们将使用原型软件扩展本研究的概念验证结果， 处理实际案例。这项研究的产品将成为我们现有产品中的附加产品包。 软件和咨询服务，将加速生物制药产品的开发。

Project Summary Biological assays (bioassays) provide critical measurements of the activity of complex biological drug products (proteins, vaccines, cell therapy, and gene therapy products) particularly during product development and production quality control. These assays use living systems for measurement and have special designs and analyses to accommodate the large variation and confounding factors involved. Common lab bioassays impose complex statistical structures that, if not designed and analyzed properly, lead to poor precision for estimates of potency and limited capabilities to monitor assays for developing problems. These problems contribute to lot release failures for manufacturers and slow down or block the development of biopharmaceutical products for consumers. Precision Bioassay provides statistical services for bioassays, helping organizations that develop, use, perform, validate, monitor, and regulate bioassays use modern methods to get better information and performance, ultimately improving the quality and accelerating the discovery of biopharmaceutical drug products. The proposed research will lead to three new tools that will improve bioassay design, analyses and monitoring, each will become a new product (a combination of software and consulting support). New bioassay designs that exploit the capabilities of modern robots will, in combination with good analyses, separate important sources of variation that are confounded with current designs and analyses; this improved information will accelerate bioassay development and enhance monitoring of bioassays. Improved methods for selection of which sources of variation to include in bioassay analysis models (equivalence-based random effects model selection) will improve estimation of important sources of variation that are often ignored with current analysis methods; this will substantially improve bioassay monitoring. Limiting bias of potency is essential to ensuring that a bioassay is fit for its intended use: a new approach to setting bounds for equivalence tests of similarity of test samples to standards will limit bias of potency associated with allowed non-similarity to pre-specified levels, ensure that most samples that are similar will pass similarity, and estimate the assay size required to achieve this performance target. In Phase II we will extend the proof-of-concept results from this research using prototype software able to address practical cases. The products from this research will become additional packages in our existing software and consulting services that will accelerate the development of biopharmaceutical products.