Outsourcing-Pharma recently had a conversation with LaRee Tracy (LT), director of biostatistics with contract research organization (CRO) Phastar, about real-world evidence (RWE), real-world data (RWD), and what regulations like the 21st Century Cures Act might mean for sites and sponsors.
OSP: Could you please tell me how RWE compares to RWD?
LT: Real-world evidence is the clinical evidence on the risks and benefits of a medical product that is derived from the evaluation of real-world data (RWD). Compared to data derived from randomized clinical trials, data routinely obtained in the real world setting better reflects the actual clinical setting. The idea behind use of RWD is to move outside of the restricted, stand-alone, clinical trial/research environment into a more general, real-world environment.
OSP: What are the key differences between RWD and RWE that trial teams should understand?
LT: RWD are data relating to patient health status and the delivery of healthcare that are routinely collected through a myriad of sources including patient electronic health records, disease registries, billing and claims-managed healthcare systems, patient-generated health data such as wearables and mobile devices, safety surveillance systems and observational studies. The information gained through a systematic, planned analyses of RWD constitutes real-word evidence.
OSP: How does use of RWE help accelerate discovery of therapies?
LT: Presently, it is unclear how RWE will accelerate discovery of new therapies. The 21st Century Cures Act, which was signed into law on December 13, 2016, included language around the use of RWE to help support approval of a new indication for an already approved drug product under 505(c) of the Food Drug and Cosmetic Act, or to support or satisfy a post-approval study requirement. As such, RWE can be used to expand current labeling and fulfill regulatory post-approval study requirements.
Outside of this legislation, RWD has often been used in the evaluation of products for rare diseases for which traditional RCTs are not feasible. For example, evidence supporting the approval of Brineur (cerliponase alfa) for the treatment of neuronal ceroid lipofuscinosis type 2 disease, a rare neurodegenerative disorder in children due to a lysosomal enzyme deficiency, was based on data from a single arm study and an indirect comparison against a historical control derived from a natural history disease registry.
A second example where a natural history control group was used in the evaluation of treatment response was for Myozyme to treat Pompe disease.
OSP: Electronic health records (EHR) can create some problems and challenges. Could you please highlight some of the key problems, and how these might create problems for researchers?
LT: The large appeal in considering EHR data as RWD is the copious nature of these data given advances in electronic data capture in the past decade or more. However, use of these data in RWE generation has several challenges, with the primary one being that these data are generally collected for purposes of healthcare quality management and optimization and for billing purposes rather than for clinical research; consequently, there is a lack of data covering the patient experience and outcome.
In addition, there is considerable variability within and across EHR systems in level of detail and quality of the health-related data. Within the same system and across systems, there can be a lack of interoperability. For example, inpatient and clinic encounter data residing on separate systems, creating challenges when attempting to assess patient medical history.
EHRs have shown to be useful, however, in identifying patients as potential participants in prospective research as well as capturing coded, validated events, e.g. mortality, stroke, myocardial infarction.
OSP: How does the framework for FDA’s RWE program help—what existing challenges and questions does the guidance help users steer clear of?
LT: This document, released in 2018, provides a framework which is multi-faceted including: efforts to streamline internal processes and understanding of RWD/RWE, the goal to develop guidance for industry on RWE, plans to engage stakeholders and to establish demonstration projects to assess data relevancy, common data models, digital tech tools, and RWE study designs.
The general framework has three main components, which are: the need to assess RWD as fit for use, determine if study designs used to generate RWE are adequate to inform regulatory decisions and if study conduct meets regulatory standards such as data monitoring and collection. What the framework does not include are required standards or methodologies for RWD collection and analyses or specific examples where RWE could be included in evaluation of evidence.
The FDA has already issued a guidance on submitting documents using RWE and RWD as well as guidance on use of electronic records and signatures in clinical investigation. Still pending -but due by 2021- is draft guidance on how the FDA will rely on RWE to support approval of a new indication for an existing product and to help satisfy post-marketing study requirements.
The remaining challenges include the methodological considerations including prospective study designs that may fulfill regulatory standards and approaches for using and validating retrospective data.
OSP: Where does this document (and other regulatory bodies) fall short in terms of RWE guidance?
LT: Greater transparency is needed to understand the regulatory process and consideration of RWD during a product application review. For example, when are historical data considered primary evidence and when are they considered supportive only?
OSP: What do we mean by “pragmatic trials”?
LT: These are randomized clinical trials using enrollment criteria considered to be less restrictive than those built into traditional clinical trials, often study multiple medical products/interventions simultaneously, are parsimonious in data collection and patient encounters/visits and often screen and enroll participants virtually or part-virtually, e.g. web-based participant screening.
OSP: How might the COVID-19 pandemic be impacting use and understanding of RWE?
LT: To reduce or avoid potential infection, data collection for purposes of clinical research and routine healthcare required a shift toward more virtual collection methods. This shift will likely lead to new or improved data collection platforms and collaborative efforts that will support future work with RWD.
