The surge in real-world data presents opportunities for greater understanding of patients and conditions, but it needs standardising and harmonising to liberate its full potential
Bold photographic images provoke lasting impressions and command attention; they are moments when form and substance combine perfectly, and they also create a telling parallel for clinical trials.
The deeper you look and the more you magnify, the richer the details that emerge. Generate more pixels and you get a cleaner, sharper view, yet in standard clinical trials (CTs) the image stops at a regulation magnification and any further intelligence can be lost in the background.
Real-world evidence (RWE) – generated from the host of data sources that constitute real-world data (RWD) – is the focus-puller of drug development. It realises the capability for a clinical director to drive into an expression or reaction, or zoom out for a more complete view of how the action impacts other players on the periphery; the actors of the original scene yet to have their own exposure.
RWE has not quite had its Hollywood moment but the rave reviews are growing as its value is being demonstrated across drug development, trial diversity and understanding of the impact of healthcare systems, policies, economics and social determinants on patient care.
Its potential to deliver insights at speed, compared to the years required by randomised controlled trials (RCTs), and reveal unchartered intelligence on underrepresented groups cannot be ignored, but realising the benefits in full is some distance away.
“I would say that this is a movement, not a moment, and we are well into it,” says Christina Mack, Chief Scientific Officer, Real-World Solutions at IQVIA. “Regulatory bodies across the globe are accepting RWE to support submissions, as evidenced by emerging RWE Guidelines released by almost all regulatory bodies across the globe, as well as subsequent decisions using real-world data as important evidence.
“We need to have a clear understanding of what types of RWE are appropriate for use within given research questions. We work closely with our partners across the industry to help define and inform best practices here. Fit-for-purpose is key.”
Christina describes how evidence generated from real-world data has already been used successfully to support regulatory decision-making, including in a label expansion of Pfizer’s targeted therapy Ibrance to include treatment of male patients with breast cancer.
“Breast cancer in males is rare, making inclusion of this population in RCTs a challenge. Using real-world data pharmacy and medical claims, the safety profile for this treatment in males was shown to be consistent with that in females, increasing access to treatments for a wider population of patients who can benefit,” she added.
‘Stakeholders must continue working through challenges associated with point-of-care trials and implement solutions moving forward for a more sustainable and equitable clinical trials enterprise’
New insights
Aneta Tyszkiewicz, Associate Director, Digital & Data, EFPIA, which represents the biopharmaceutical industry operating in Europe, underscores that RWE and RWD have multi-ple potential benefits, including the ability to address questions not covered by clinical trials and allow for more flexible, iterative approaches to evidence generations.
“RWE provides insights that inform all aspects of drug development from discovery to outcomes research. Feedback loops from clinical care to research and development allow for better, faster decision-making through product development to delivery of healthcare,” she said. “The main advantage over data and evidence from clinical trials is that RWD and the resulting RWE reflect real clinical practice. RWD can enable a better view of the actual effectiveness and characteristics of a medical product or technology, and create new insights to improve health outcomes for patients and efficiency of healthcare systems.”
EFPIA, whose membership includes 37 national bodies and 38 leading pharmaceutical companies, is encouraging collaboration among stakeholders and is compiling an expanding body of evidence of where RWE and RWD has been instrumental in supporting regulatory filings and delivering therapies to patients.
But Aneta echoes the need for standardisation as RWE’s influence and deployment grows at different rates, driven by nuanced methodologies, across geographies. She added: “The variety in research objectives, study designs, data and methods presents a challenge for standardisation. Regulators and other decision-makers across the globe evaluating RWE hold different expectations regarding their use and fitness for purpose. This diversity within and across regions persists, including across and within stakeholder groups, although efforts are underway to improve convergence where possible.
“A reliable data ecosystem is essential to accomplish a basic level of quality, relevance and interoperability amongst health data with the ability to link different sources. In this context, a European Health Data Space (EHDS) is one of the main priorities of the European Commission.
“Several barriers to the use of RWE in the EU require close consideration, including concerns with regard to data privacy and access issues, as well as to relevance, fragmentation, depth and quality of data sources, and familiarity with analytical methods. The variety of sources, inconsistencies in the application of the GDPR in the EU, and lack of interoperability between data sources are some factors preventing the harmonised collection of data and its use for research purposes.”
The dawn of RWE efficacy
The RWE Collaborative at the Margolis Centre for Health Policy at Duke University in the US is breaking important ground with its multistakeholder engagement initiative and mission to develop a framework and guidance for evaluating RWE in the context of regulating drug and biologics. The mission includes evaluating RWE’s potential to support approvals of new labelling indications for already approved drugs and boost post-market study or evidentiary requirements concerning product safety and efficacy in the real world.
“We are at the dawn of generating RWE to assess not just safety but also efficacy in real-world settings for drugs and biologics with well-established safety profiles,” says Research Director Rachele Hendricks-Sturrup.
“At Duke-Margolis, we and our RWE Collaborative members recognise that a significant amount of patient information is captured at the point-of-care or at the patient-level from sources that include, but are not limited to, electronic health records, payer claims, registries and wearables, all of which can be a source of relevant and reliable RWD. The ultimate goal for RWD assessments is to help inform and support patient needs and questions concerning their health and access to care and health systems that are engaged in the continuous learning that is needed to improve their operations and patient experiences.”
In 2021, Duke-Margolis engaged a workstream of stakeholders within its RWE Collaborative focused on describing the value and current feasibility of point-of-care trials, and operational approach to conducting pragmatic trials in usual care settings. The White Paper from the workstream states: ‘Point-of-care trials have the potential to advance evidence generation, support product registration, and close important research gaps by involving more research sites and patients, but they have not been well-defined in literature or practice.‘
It adds: ‘As the technology and regulatory landscape continues to shift, point-of-care trials may provide meaningful improvements over traditional models of clinical research in settings where the approach is most applicable. Stakeholders must continue working through challenges associated with point-of-care trials and implement solutions moving forward for a more sustainable and equitable clinical trials enterprise.’
A diversity generator
RWE offers differing degrees of promise depending on its area of application, but it has unrivalled scope to accelerate the cause to improve diversity in the clinical trials arena.
Rachele observed: “There are ample opportunities to generate RWE concerning product safety and effectiveness in minority groups that are or have been underrepresented in traditional randomised controlled trials. One mechanism is through point-of-care trial implementation.”
Aneta agrees: “RWE plays a critical role in rare diseases and addressing the needs of vulnerable populations where the standard approach to clinical trials is challenging – if not impossible – and collection of complementary evidence can support regulatory decisions for such diseases and accelerate patients’ access to medicines.”
Christina added that RWE presents an opportunity to improve minority group representation in trials and said: “This is a place where RWE is essential. Understanding how therapies work across all affected patients is a responsibility that starts early in development and continues through post-marketing, where RWE can complete the picture.
“Gathering RWD from patients in their daily lives outside the trial can also identify measures to lower the barriers of participation, in addition to giving us more information about how the dif-ferent groups are impacted by their disease prior to introducing a novel therapy.”
New discoveries
This is also true in rare diseases and under-treated conditions such mental health and dementia where understanding of patients, and therefore treatment options, is limited.
Akrivia Health, a spin-out from the NHS and Oxford University in the UK, has become a lead-ing force in RWD for mental health through its repository of structured and unstructured data in neuroscience, linked with an extensive clinico-genomic data set.
“The question is: ‘How do we know what has been happening with these patients throughout their healthcare journey that will enable us to deliver precision medicine to one of the world‘s most growing and unmet needs?’”
observed Tina Marshall, Head of Commercial at Akrivia Health.
“This is where RWD and subsequently RWE come in. Our RWD captures clinical contact throughout the patients’ lifetime, permitting the longitudinal analysis of signs and symptoms, their time on or off medication, adverse reactions and differential diagnosis before a coded diagnosis, essentially their outcomes data, which enables disease progression to be mapped over time.”
The use of AI-driven NLP data enrichment can reveal unprecedented depths of patient and dis-ease characterisation and burden, which can lead to the discovery of ‘hidden’ patient profiles, help reduce costs in the drug development cycle and limit screen failure rate, Tina added.
“These are big challenges for organisations, particularly in the development of disease-modifying therapies in mental health, and RWD and RWE offer opportunities to gain a deep understanding of the patient, the disease burden and its severity,” she observed.
RWE is gathering pace, strength and influence, but it will have to contend with issues from the unstructured nature of data proliferation and noise from AI developments to move into a more transformative phase.
Published in the Pharmaceutical Market Europe • November 2023 • 26-27
By Danny Buckland
