Abstract. This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

Our study suggests that the Society for Fetal Urology grading system has good intrarater but modest interrater reliability. Individual rater interpretations of the grading system may explain the modest interrater agreement. Proposed modifications to the Society for Fetal Urology classification system, such as distinguishing between diffuse and segmental cortical thinning, may improve reliability.

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic.

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Drug regulators around the world make decisions about drug approvability based on qualitative benefit–risk analysis. In this work, a quantitative benefit–risk analysis approach captures regulatory decision‐making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression‐free survival (PFS), and objective response rate (ORR) which are different than benefit–risk analysis based on overall survival (OS). Twenty‐three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit–risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit–risk framework.

The analysis of benefit and risk is an important aspect of decision-making throughout the drug lifecycle. In this work, the use of a benefit-risk analysis approach to support decision-making was explored. The proposed approach builds on the qualitative US Food and Drug Administration (FDA) approach to include a more explicit analysis based on international standards and guidance that enables aggregation and comparison of benefit and risk on a common basis and a lifecycle focus. The approach is demonstrated on six decisions over the lifecycle (e.g., accelerated approval, withdrawal, and traditional approval) using two case studies: natalizumab for multiple sclerosis (MS) and bedaquiline for multidrug-resistant tuberculosis (MDR-TB).

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