Clinical Pharmacology Modelling and Simulation, GSK, London, UK.
Clinical Pharmacology, Modelling and Simulation, Parexel International, Dublin, Ireland.
J Transl Med. 2023 Jan 11;21(1):17. doi: 10.1186/s12967-022-03849-y.
In drug development, few molecules from a large pool of early candidates become successful medicines after demonstrating a favourable benefit-risk ratio. Many decisions are made along the way to continue or stop the development of a molecule. The probability of pharmacological success, or PoPS, is a tool for informing early-stage decisions based on benefit and risk data available at the time.
The PoPS is the probability that most patients can achieve adequate pharmacology for the intended indication while minimising the number of subjects exposed to safety risk. This probability is usually a function of dose; hence its computation typically requires exposure-response models for pharmacology and safety. The levels of adequate pharmacology and acceptable risk must be specified. The uncertainties in these levels, in the exposure-response relationships, and in relevant translation all need to be identified. Several examples of different indications are used to illustrate how this approach can facilitate molecule progression decisions for preclinical and early clinical development. The examples show that PoPS assessment is an effective mechanism for integrating multi-source data, identifying knowledge gaps, and forcing transparency of assumptions. With its application, translational modelling becomes more meaningful and dose prediction more rigorous. Its successful implementation calls for early planning, sound understanding of the disease-drug system, and cross-discipline collaboration. Furthermore, the PoPS evolves as relevant knowledge grows.
The PoPS is a powerful evidence-based framework to formally capture multiple uncertainties into a single probability term for assessing benefit-risk ratio. In GSK, it is now expected for governance review at all early-phase decision gates.
在药物开发过程中，从大量早期候选药物中只有少数分子在展示出有利的获益-风险比后才能成为成功的药物。在开发过程中，有许多决策需要作出，以决定继续或停止药物的开发。药效成功率（PoPS）是一种工具，用于根据当时可用的获益和风险数据，为早期决策提供信息。
PoPS 是指大多数患者能够达到预期适应症所需的充分药效，同时使暴露于安全风险的受试者人数最小化的概率。这个概率通常是剂量的函数；因此，其计算通常需要药理学和安全性的暴露-反应模型。必须指定充分的药效和可接受的风险水平。这些水平的不确定性、暴露-反应关系中的不确定性以及相关的转化都需要确定。使用不同适应症的几个例子来说明如何使用这种方法来促进临床前和早期临床开发中的分子进展决策。这些例子表明，PoPS 评估是一种有效的机制，可以整合多源数据、识别知识差距，并强制假设的透明度。通过其应用，转化模型变得更有意义，剂量预测更严格。其成功实施需要早期规划、对疾病-药物系统的深刻理解和跨学科合作。此外，随着相关知识的增长，PoPS 也在不断发展。
PoPS 是一种强大的基于证据的框架，可将多种不确定性纳入单个概率术语中，以评估获益-风险比。在葛兰素史克，现在预计在所有早期决策关口都需要进行治理审查。
