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European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

The increasing ability and expertise to reuse electronic real-world data (RWD) from routine healthcare systems continues to open up opportunities for investigators to conduct non-interventional studies on the utilisation, safety and effectiveness of medicinal products, and stimulate the development or improvement of design strategies to mitigate bias and generate valid real-world evidence (RWE), especially when the study aims to conclude on causal effects.

In this 11th Revision of the ENCePP Guide, the table of contents has been restructured to better reflect the evidence generation flow and provide greater emphasis on important methodology such as the causal inference target trial emulation approach, which is recommended by ENCePP for non-interventional causal inference studies, to improve internal validity and increase transparency on design characteristics. Chapter 4.2.6 on this topic has been further updated and expanded, and this methodology is integrated, with new references, in Chapters 4 on Study design, 16.1 on Comparative Effectiveness Research, 16.2 on Vaccine safety and effectiveness, and 16.6 on RWE and pharmacoepidemiology.

The HARPER protocol template was published in early 2023 to guide the structure and content of RWE study protocols, and serve as a tool to promote transparency, reproducibility and harmonisation of non-interventional study protocols, and facilitate their assessment by regulators and other stakeholders. HARPER is compatible with the legal format and content of GVP Module VIII and is therefore recommended for the development of post-authorisation study protocols.

On 5 May 2023, the World Health Organisation (WHO) announced that COVID-19 is now an established and ongoing health issue, which no longer constitutes a public health emergency of international concern (PHEIC). Nevertheless, the COVID-19 pandemic still has an impact on the work performed by pharmacoepidemiologists, due to the continued need to evaluate the use, safety and effectiveness of COVID-19 vaccines and therapeutics, and appraise the published evidence. As in Revisions 9 and 10, this 11th Revision builds on lessons from COVID-19 that can be applied in routine pharmacoepidemiological/RWE practice, as well as considered for pandemic preparedness. Several challenges remain, such as the availability of adequate information on vaccine exposure or variant-specific epidemiological data, the widespread use of self-testing that is not recorded in healthcare data sources, the low frequency of data source updates, and the lag times to access recent data, all of which still affects the speed of safety and effectiveness evaluation or its feasibility. ENCePP will continue to evaluate the very rich methodological work done by researchers during the pandemic and support drawing and addressing lessons learned. This includes considering the impact on studies in other areas that include the pandemic in their study period, since profound and varying changes in healthcare utilisation are also reflected in the data sources available for secondary use.

A large amount of literature has started accumulating on post-acute COVID-19 syndrome, or long COVID, in parallel to heightened awareness of this new public health challenge. Its prevalence is estimated to be around 45% among people who have been infected with SARS-CoV-2; based on an estimate of around 760 million infections worldwide at the time of publication of this 11th Revision, this translates into more than 300 million individuals who may have had, or are currently experiencing long COVID. Valid studies are needed to evaluate the incidence and risk factors of long COVID, characterise the multiple components of this syndrome, and identify the possible effects of treatments of the initial infection as well as of post-acute symptoms. This 11th Revision therefore continues to provide examples of COVID-19 related studies illustrating good practice and methodological developments in pharmacoepidemiology.

Finally, some chapters have been revised to reflect a fast changing environment in the field of pharmacoepidemiology and RWE: Chapter 9 on Research networks for multi-database studies addresses the expansion and use of DARWIN EU®; Chapter 12 on Statistical analyses includes a recommendation to consider the estimand framework to inform study design and data analysis choices; and Chapters 16.5 on Artificial intelligence in pharmacoepidemiology and 16.6 on RWE and pharmacoepidemiology have been extensively updated. Another emphasis is placed, in Chapters 3 on Protocol development and 4.1 on Overview of study designs, on the importance of design diagrams to foster transparency, enhance understanding of the study design, and support the evaluation of study protocols and the interpretation of study results.

We hope that this 11th Revision of the ENCePP Guide will continue to support good practices in pharmacoepidemiology/RWE, in Europe and elsewhere.

Susana Perez-Gutthann

Catherine Cohet

Co-Chairs of the ENCePP Steering Group