How soon will digital endpoints become a cornerstone for future drug development?

Highlights

• Late stage failures are decreasing productivity in Pharma R&D.

• Endpoints, non-reflective of patient needs, are not met causing late stage failure.

• The FDA encourages the use of digital technology to asses patients’ needs.

• A consortium aims to get regulatory acceptance for real world walking speed.

• This collaborative approach will ensure patient centric innovation & endpoints.

Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic–industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems.

Introduction

Pharmaceutical innovation needs to become more patient centric, and digital applications are set to revolutionize clinical research, delivering a wealth of individual patient data. This is at least the way recent industry and consultancy publications frame it [1]. In a similar recent statement, the FDA commissioner sees a role of wearables to better understand a patient’s well-being and needs [2]. Typically, endpoints accepted by the FDA include how a patient feels or functions and/or if they live longer. In selected cases, surrogate endpoints [e.g., validated biomarkers, such as blood pressure or low-density lipoprotein (LDL) cholesterol concentration] can replace relevant clinical endpoints, such as mortality [3]. The approvals granted based on surrogate medical evidence are often subject to post-approval Phase 4 studies to confirm and/or strengthen the evidence. Furthermore, health technology assessment (HTA) agencies want to evaluate evidence regarding clinical and cost effectiveness, safety, and overall patient benefit of the pharmaceutical intervention. Currently, the pharmaceutical industry is challenged by declining research and development (R&D) productivity, with the return on investment (ROI) in the industry at an all-time low of 3.7% in 2016 [4]. Scannell and co-workers named this phenomenon ‘Eroom’s law’, in reverse to the widely known Moore’s law on computational processor power, in that pharmaceutical R&D becomes slower and more expensive over time, despite advances in biomedical sciences [5]. One distinct problem that can be identified is the increasing number of so-called ‘late-stage failures’. These are mostly Phase 3 studies in which primary efficacy endpoints were not met or safety signals emerged. Hwang and co-workers, using public sources, showed that, between 1998 and 2015, out of 640 novel therapeutics, 57% failed because of inadequate efficacy and not meeting the studied endpoints [6]. A recent publication from MIT, using two large data sets, showed a success rate of only 40% for Phase 3 studies [7]. Of course, at the time point at which these late-stage failures occur, large investments have already been made. This translates into a diminishing pipeline and portfolio value and reduced ROI of the overall pharma R&D activities. A question that needs to be asked is whether preclinical scenarios are disconnected from real clinical outcomes If yes, no new endpoint could help to reduce the number of late-stage failures. If no, the reason for Eroom’s law could be a failure to translate meaningful changes in disease state in currently used endpoints.