In Europe as in the U.S., biopharma organizations, regulators, and health technology assessment (HTA) bodies are increasingly leaning on real-world evidence (RWE) as a complement to randomized controlled trials (RCTs) to inform decision-making. Despite some similarities, the roles RWE plays to assess safety in the post-approval space varies between and within the regions, and safety teams within European biopharma organizations face unique challenges to using and accessing real-world data (RWD).
To better understand how RWE can support the safety landscape in Europe, we spoke with Pierre Engel, Pharm.D., Ph.D., Aetion’s Senior Director of European Business Development. Dr. Engel has worked at the leading edge of regulatory safety developments for most of his career, and is an expert in the conduct of Post‐Authorization Safety Studies (PASS).
Dr. Engel joined Aetion from IQVIA, where he most recently co-led the Global Enriched Study Team and worked with biopharma and the EMA to drive RWE adoption and advance innovative safety and epidemiology research projects. Throughout his tenure, he helped teams navigate the European Medicines Agency’s (EMA’s) guideline on good pharmacovigilance practices (GVP) module VIII, which focused on PASS, as well as the Pharmacovigilance Risk Assessment Committee’s (PRAC’s) reviews. He was elected as a steering group member for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) until 2016, where he witnessed the evolving landscape for EMA-required safety studies.
Read on to hear Dr. Engel’s perspective on how innovative safety teams in Europe are executing RWE programs and safety studies to meet the needs of regulators, HTAs, and other stakeholders.
Responses have been edited for clarity and length.
Q: What does the current landscape of RWE for safety in Europe look like?
A: In the post-approval space, the role of RWE differs at the regulatory and HTA levels. RWE adoption also varies across Europe; policy makers and HTAs in some European countries only accept “locally” collected data, while others don’t accept RWE in any instance.
While RWE has the potential to serve as a complementary source of evidence on the safety and effectiveness of drugs, methodological and operational challenges can hinder its uptake. One major challenge to the use of RWE in Europe lies in facilitating the collection of consistent RWE across European Union (EU) Member States, while ensuring that RWE responds to specific regulatory requirements. It’s important to achieve interoperability between national data infrastructures, and to establish RWE analytic standards and systems to address these issues.
Currently, the safety field benefits most from harmonized guidance across Europe, thanks especially to the measures the EMA has put forth to monitor pharmacovigilance in the EU. Since 2012, Market Authorisation Holders have needed to follow specific, centralized requirements laid out in the EMA’s GVP, as well as the strong guidances set forth by ENCePP.
Q: What are the more progressive safety teams doing to advance their RWE strategies?
A: From my perspective, the most progressive safety teams working with RWE have made a significant investment in hiring data scientists and epidemiologists, accessing the right data, and, importantly, choosing the right analytic tools to conduct rapid, scientifically valid RWE projects.
These teams also meet proactively with regulatory bodies to discuss the acceptability of innovative safety study designs, such as the use of external comparators, enriched studies using both primary and secondary data collection techniques, or pragmatic clinical trials. Many also partner on numerous strategic initiatives to advance RWE globally and in Europe, such as the Innovative Medicines Initiative.
Q: What are the key challenges safety teams face in generating and working with RWE? How would they solve these challenges?
A: While many safety teams agree that RWD hold promise to support evidence generation and complement RCTs in evidence packages, they often experience methodological problems and high demands regarding the quality control infrastructure for RWD collection. They also face a heterogeneity of perspectives from internal stakeholders and differences in outcome measures for RWE generation. Finally, a lot of safety teams lack practical experience with regulatory bodies’ requirements for RWE to support safety.
These teams are eager to learn more about data sources that collect robust RWD for safety assessments, how to access them, how robust and validated they are, and how they can be used in regulatory submissions. Due to the mosaic of RWD sources available across Europe—electronic medical records, claims, national registries, and others—safety teams need the right partners with the appropriate expertise, credentials, and analytic tools to meet their research needs.
Q: How do safety needs differ between European and U.S. biopharma organizations?
A: The U.S. Food and Drug Administration (FDA) and the EMA are generally aligned in terms of using RWE for safety, and both already accept RWE in the form of post-authorization drug safety surveillance studies—known as PASS in Europe and Post-Marketing Requirements (PMRs) in the U.S. Generally, they ask for three major post-approval study types to help meet safety requirements: (1) drug utilization studies to characterize drug use and patient profiles, (2) mid- or long-term prospective cohort studies to monitor safety longitudinally, and (3) risk minimization effectiveness studies to assess compliance to the label, educational materials, or awareness of patient alerts to report adverse events.
The FDA and the EMA are also at roughly the same stages of considering RWD alongside RCT evidence when evaluating new therapies, devices, or indications. Numerous guidance documents or policies from the FDA and EMA—especially GVP and the 21st Century Cures Act—have accelerated the adoption and use of RWE in regulatory decision-making.
Nevertheless, I would say the “what” and “how” of collecting and using RWD for safety may differ between the two sides of the Atlantic. For example, the RWD landscape in Europe is far more fragmented than it is in the U.S., and data access is often a key challenge to overcome in order to obtain good quality data. Therefore, in Europe we see more local safety studies conducted with a limited sample size. To address sample size challenges in some rare diseases or niche oncology indications, both the FDA and EMA are embracing innovative study designs, such as RCTs with an external comparator arm built from RWD, or comparative safety cohort studies using an historical comparator drawn from secondary data sources.
In addition, though the same safety event or a drug adverse reaction could be experienced by a U.S. citizen and by someone in Europe, its characterization in datasets may vary due to inconsistent coding, data structure, or reporting from one data source to another. Off-label use may also vary.
To address some of these issues, regulators are also encouraging discussions with Marketing Authorization Holders through multiple open channels—for instance, the Duke-Margolis Center for Health Policy in the U.S. and ENCePP in Europe—to exchange scientific advice.
Q: What makes Aetion a strong partner for EU safety teams?
A: The EMA, like the FDA, is building knowledge about when RWE can support its decisions (and when RWE is not appropriate), and it has made significant investments already, as reflected in the work accomplished by the EMA and Heads of Medicines Agencies’ joint Big Data Task Force. One of the EMA’s top priorities for the next few years is to invest in analytic capabilities.
Combined with Aetion’s scientific expertise, I believe that Aetion Evidence Platform® (AEP) is uniquely positioned to support EU safety teams. The FDA has already selected Aetion to help advance modern approaches to drug approval and safety processes, and Aetion is now established in Europe as an ENCePP member and contributor to the EMA’s Working Group 4 on multidatabase studies. We look forward to continuing to set standards for the use of RWE in safety by contributing to additional regulator-led safety initiatives.
Q: What does the future look like for safety teams in the EU?
A: Historically, safety and pharmacovigilance teams haven’t always worked closely with pharmacoepidemiology groups, so trial design and post-marketing efforts were often disjointed. This has drastically changed during the last decade, as RWE specialists have become better integrated across the product lifecycle. Regulators and groups like the International Society for Pharmacoepidemiology have also pushed for increased use of RWE by enforcing guidance documents that favor the use of RWE in decision-making.
Nowadays, epidemiologists are more frequently embedded in safety groups, and safety physicians are trained in RWE, allowing them to sit in the “driver’s seat” to design and execute safety studies.
RWE can support approvals for new indications for drugs already on the market, and this role will grow more robust over time. RWE will also continue to highlight potential safety issues in approved drugs, and may complement clinical trials to strengthen evidence packages. The EMA—like the FDA—is increasingly open to innovative study designs in the field of safety, such as building external comparator arms for RCTs. Over time, more safety groups and physicians will strengthen their epidemiology expertise, and may be likely to conduct even more RWE analyses. By using the appropriate, scientifically validated tools, this work will definitely strengthen research in the safety field.