Use of Real World Evidence (RWE) for regulatory purposes

While randomized controlled trials (RTCs) are the gold standard for generating evidence for regulatory decision making in the product lifecycle of drugs , some of the limitations by RTCs may be addressed by the use of real world evidence (RWE). RWE is information derived from the analysis of real-world data (RWD). While internal validity is high in RCTs, external validity is compromised due to the differences to be expected between RCT and real world regarding selection of population, length of treatment, and adherence to treatment. Effectiveness and safety of drugs in routine care may differ from the results of the underlying RCT. The use of RWD can address these challenges.

The European Medicines Agency (EMA) defines RWD as routinely collected data relating to patient health status or the delivery of health care from a variety of sources other than traditional clinical trials, i.e., registry data, health insurance data, data from biobanks, electronic health records, even data from health apps and social media to name some examples.

Moreover, RWD can help reduce the burden of study participants and fasten the processes of drug development. Besides conducting studies with RWD only, RWD can supplement clinical studies, e.g., with external or historical control groups, or clinical trials can be nested within existing cohorts (TwiCs).

Current use

Currently, RWD is typically analysed in post marketing surveillance for monitoring and assessing safety and effectiveness of drugs already authorized for routine care. For instance, suspected adverse drug reactions are managed and analysed in the system EudraVigilance, operated by the European Medicines Agency (EMA). Another example are pharmacoepidemiological analyses of health insurance data, which can give information on the effectiveness of a drug, i.e. the effect in practice, as opposed to efficacy, which is the performance under the ideal and controlled circumstances of a clinical trial. The frequency of use of RWE in earlier stages of the product lifecycle of a drug was low and has only recently increased. A study by EMA on drug development of medicinal products centrally authorized in Europe in 2018-2019 found that RWE was included in the pre-authorization phase of new drug applications to a varying degree according to stage: from 35% in early development and 49% in full development up to 98% in discovery (disease epidemiology) and 100% in lifecycle management in pre-approval phase (Eskola et al. 2022). In another systematic analysis of all market authorisation applications (MAAs) and extensions of indications (EOIs) submitted to the EMA from 2018-2019, 40% of MAAs and 18% of EOIs contained RWE, with RWE sources mainly being registries and hospital data (Flynn et al. 2021).

Challenges

There has been a lack of RWE data sources in Europe suitable for regulatory decision making. Currently, the Big Data Steering Group is establishing a RWD infrastructure in Europe through different initiatives like the coordination centre “Data Analytics and Real World Interrogation Network” (DARWIN EU®) or the framework “European Health Data Space” (EHDS). Moreover, many regulators are still sceptical about using RWE in the pre-authorization phase. The RWE community votes for a holistic approach for the generation of evidence for regulatory decision-making and sees RWE as supplementing traditional approaches.

Sources:

Eskola SM, Leufkens HGM, Bate A, De Bruin ML, Gardarsdottir H. Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019. Clin Pharmacol Ther. 2022 Jan;111(1):310-320. doi: 10.1002/cpt.2462. Epub 2021 Nov 16. PMID: 34689334; PMCID: PMC9299055.

Flynn R, Plueschke K, Quinten C, Strassmann V, Duijnhoven RG, Gordillo-Marañon M, Rueckbeil M, Cohet C, Kurz X. Marketing Authorization Applications Made to the European Medicines Agency in 2018-2019: What was the Contribution of Real-World Evidence? Clin Pharmacol Ther. 2022 Jan;111(1):90-97. doi: 10.1002/cpt.2461. Epub 2021 Nov 13. PMID: 34689339; PMCID: PMC9299056.

Wicherski J, Schneider K, Zinserling J, Heß S, Haenisch B, & Broich K. Real-world-Daten in der Arzneimittelregulation–aktuelle Entwicklungen und Ausblick. Prävention und Gesundheitsförderung, 2023, 1-8.