Using Real-World Evidence to Transform Drug Development: Opportunities and Challenges

Harry Yang


In recent years there has been a growing interest in using real-world evidence (RWE) to support drug development, regulatory review, and healthcare decision-making. RWE, gleaned from real-world data (RWD), provides useful insights into disease prevalence, innovative trial design, comparative effectiveness and safety of treatment, and health economic value. Coupled with evidence from randomized controlled trials (RCTs), RWE enables drug developers, regulators, and healthcare providers to make more informed decisions. RWE has been at the forefront of pharmaceutical innovations, disrupting the way evidence is generated in the value chain of drug R&D and commercialization. The use of RWE is further powered by the new governmental policies and laws such as the 21st Century Cures Act in the United States and Conditional Approval (Martinalbo et al. 2016) and Adaptive Pathways in Europe (EMA 2016a,b). Leveraging RWE in regulatory decision is a key priority for many regulatory agencies. In the recently released U.S. Food and Drug Administration (FDA) guidance (FDA 2018a), it is stated that under the right conditions, data derived from real-world sources can be used to support regulatory decisions. When extracted from well-designed studies and appropriate analysis, RWE may constitute valid scientific evidence to support the early approval of a drug product, label change, or expansion. In this chapter we present the unprecedented opportunities and challenges of applying RWD and RWE in drug development and evaluation.

Traditional Drug Development Paradigm

Drug Development Progress

Drug development is a complex, lengthy, and resource-intensive process. Figure 1.1 presents a diagram of drug development.

The process commences with drug discovery. Scientists utilize many technologies such as synthetic chemistry and genomic sequencing to uncover targets that are causes of diseases. When a lead new molecular entity (NME) is identified, it is advanced to a pre-clinical development stage where the NME is tested both in vitro in cells and in vivo in various animal species to determine its safety and efficacy. This is followed by the clinical phase of product development, which typically follows a well-established paradigm, with the primary aim of generating evidence of drug safety and efficacy in support of marketing approval by regulatory authorities. It consists of three phases, Phase I, II, and III trials, with a focus on clinical pharmacology and early safety, efficacy evaluation in targeted patient populations, and confirmation of drug's safety and efficacy, respectively. Potentially, Phase IV studies, often termed post-approval trials, may be required after marketing approval. It is aimed at gaining better understanding of either potential long-term adverse effects or rare adverse events associated with the product. This post-marketing evaluation again draws insights from clinical studies in controlled settings. Clinical trials are often carried out utilizing a mechanism in which


Drug development process. Adopted from FDA website.

subjects in treatment group(s) or a control group are randomly assigned, and usually referred to as RCTs. Randomization is used to rule out the effects of potential confounding factors and ensure comparable patients across the groups (Barton 2000). Patients in the studies are closely followed to ensure treatment adherence. Additionally, individuals including the medical monitors from sponsors, patients, and investigators are blinded about the patient treatment, and the way data are analyzed is pre-specified. Together, these measures ensure internal validity of the study design and conclusions.

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