Look behind the lecture: the relevance of registry and real-world data throughout a product’s lifecycle
Michael Fronstin (Kantar Health, PA, USA) discusses his presentation from the Patient Registries, Real-World Evidence and HEOR meeting (27–28 January 2020; Miami, FL, USA) on how the validity and rigor of registry data are perceived by industry stakeholders and what can be done to enhance these.
Please could you introduce yourself?
I am the Global Head of the Innovations Team, Real-World Evidence (RWE), within the Health division of Kantar (Kantar Health; PA, USA). I have been with Kantar for approximately 15 years, during which time I have led the North American RWE team, in addition to other departments.
The Health division of Kantar is a leading data analytics and research company servicing the life sciences industry. We conduct research across the globe to uncover RWE and commercial insights. By combining the deep expertise of our people, our data and our innovative analytics, we help our clients develop and commercialize innovative products that improve the lives of patients around the world.
What is the importance and relevance of registry and real-world data (RWD) in regulatory safety studies?
Registry and RWD are critically important to regulatory authorities as they represent the best way to confirm the safety profile of an investigational compound in real-world settings, outside of the confines of randomized clinical trials (RCTs). RWD from registries can help identify latent or serious adverse events in the approved studied population for a product, as well as among subpopulations not included in an RCT.
The importance of registry and RWD to regulatory authorities extends beyond safety and pharmacovigilance requirements. Over the last decade, EMA and US FDA guidance documents have emphasized the value of registries and RWD sources for enhancing understanding of the natural history of diseases.
“Registry and RWD are critically important to regulatory authorities as they represent the best way to confirm the safety profile of an investigational compound in real-world settings…”
Two recent examples include the EMA’s November 2018 discussion paper titled ‘Use of patient disease registries for regulatory purposes — methodological and operational considerations’, and the FDA’s March 2019 draft guidance ‘Rare diseases: natural history studies for drug development’.
Marketing authorization holders of new and existing compounds will turn to registries and RWD throughout a product’s lifecycle to identify potential patient populations and meaningful clinical and patient-related endpoints as part of their clinical development programs. Patient registries provide a view into the natural history of a disease and, later in the development cycle of a product, have increasingly been accepted as an external control arm data source in single-arm RCTs. In later phases of the lifecycle, the marketing authorization holder may even leverage the same registries for safety purposes to fulfil regulatory mandated requirements.
“The importance of registry and RWD to regulatory authorities extends beyond safety and pharmacovigilance requirements.”
Further, patient registries — or dual-source, patient—physician registries — can help uncover safety signals that may have been initially overlooked by physicians during routine clinical practice. To avoid overreporting or misreporting by patients, patient-reported events can be substantiated and validated via medical documentation or by treating physicians.
What are some of the challenges associated with employing these data and how may these be overcome?
There are plenty of challenges associated with using existing registries or when developing a prospective registry. One must consider many factors including: data ownership and governance, proper patient consent, how to identify and measure meaningful outcomes, representation and other potential biases, and compliance with Good Clinical Practices, Good Epidemiological Practices and GDPR.
To overcome these challenges, industry stakeholders must align on who owns the underlying data and how they can be used. Informed patient consent must take into consideration short- and long-term utilization and reporting of the data. Having a comprehensive understanding of the protocol and content, as well as identifying a core dataset when multiple sets are being aggregated, can all help ensure harmonization, which is particularly important for safety reporting.
“Designing a global registry to be scientifically rigorous and of high quality can be a complex and expensive endeavor.”
However, unique challenges exist while working in rare diseases, including oncology. RCTs and registries attempt to include or compete for the same patient participants. In order to enroll an acceptable number of patients, registries in rare disease indications are likely to be global and must consider the various regulatory and cultural differences within each country. Designing a global registry to be scientifically rigorous and of high quality can be a complex and expensive endeavor.
None of these considerations that I have mentioned are new; what is new is creating scientific, high-quality hybrid registries that combine secondary and primary data sources. This brings its own set of challenges, including those associated with aligning data sources, compliance with the Health Insurance Portability and Accountability Act (HIPAA), other privacy compliance issues and difficulties associated with engaging stakeholders who are not necessarily used to viewing electronic health record data as a potential source for hybrid studies.
“None of these considerations that I have mentioned are new; what is new is creating scientific, high-quality hybrid registries that combine secondary and primary data sources.”
So called ‘secondary data’ bring their own challenges — electronic health records and administrative claims datasets weren’t designed for research purposes and, often, the value is hidden in the physician notes.
Having a comprehensive understanding of each data source — what they include, their strengths and limitations — can help ensure data are fit for purpose and of regulatory-grade quality.
What do you perceive to be the current industry perspective on the use of registries as a methodology and source for regulatory safety studies?
Increasingly, stakeholders have been initiating their safety evaluations by turning to secondary databases — including electronic health records and/or claims data. Although valuable, these databases were originally established for administrative purposes, not for research, let alone post-marketing commitments.
“Having a comprehensive understanding of each data source — what they include, their strengths and limitations — can help ensure data are fit for purpose and of regulatory-grade quality.”
As these databases continue to be leveraged, industry stakeholders recognize the value of registries as the ideal method and source for safety studies; the number of registries being registered with the National Institutes of Health (MD, USA) at clinicaltrial.gov and with the EMA, continue to rise.
Marketing authorization holders are increasingly turning to RWD as they attempt to identify predetermined cohorts from which to measure and report safety. This includes aggregating and linking existing registries, primary research and administrative claims, and electronic health record data.
What steps need to be taken to increase the perception of scientific registries as validated data sources?
As an industry, we can continue to increase the perception of scientific registries as validated data sources by being transparent: publishing protocols, populations and endpoints in peer-reviewed journals is a great start.
As an industry, we can continue to increase the perception of scientific registries as validated data sources by being transparent…”
Transparency related to data sources and cohort definitions is a must and registering ongoing work on publicly available portals — such as clinicaltrials.gov or the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance — will help. Further, understanding the difference between a research-grade registry and a regulatory-grade registry prior to protocol development is critical.
How do you see the perception and use of these data changing in the future?
The acceptance of registries and RWD for regulatory purposes is already strong and will continue in a positive direction with the addition of new applications, including label expansions and external control arms for RCTs.
One relatively recent example is the label expansion for Pfizer’s (NY, USA) breast cancer compound Ibranz®, to also include men. A second, multifaceted, example concerns Zolgensma®, the gene therapy for spinal muscular atrophy introduced by AveXis (a Novartis company; IL, USA) in 2019. The ongoing, single-arm, Phase III clinical trial of Zolgensma utilized available RWD as a control.
Further, post-marketing pharmacovigilance requirements for Zolgensma include a prospective, observational registry, which will assess treatment effectiveness, long-term safety and overall survival. AveXis will be required to include at least 500 patients for a minimum of 15 years or until time of death.
“…understanding the difference between a research-grade registry and a regulatory-grade registry prior to protocol development is critical.”
Thought leaders within the industry are already designing the next wave of registries that are compliant with Good Clinical Practices and Good Epidemiological Practices and are, therefore, able to produce reliable and scientifically robust results. In addition to new hybrid registries, the advent and importance of clinical outcome assessments — including passively collected patient data via mHealth and connected devices — and identifying latent safety signals via social media and social listening, is well underway.
As these results continue to become available, the positive perception of these data and their ability to leverage safety results will ensure registries remain at the forefront of RWD delivery.
Disclosures:
Fronstin does not hold any financial positions in companies discussed in this article.
The opinions expressed in this feature are those of the interviewee/author and do not necessarily reflect the views of The Evidence Base® or Future Science Group.