he incredibly fast development and rollout of the COVID-19 vaccines would not have been possible without the critical contributions of real-world data and real-world evidence (RWD/RWE). But the race to use, understand, and accept RWD/RWE throughout the drug development life cycle started a long time ago. While regulators such as the US FDA, EMA, and Taiwan FDA (TFDA) have taken a more pragmatic approach in developing guidelines, regulations, and frameworks, we must ensure that the international collaboration and regulatory standards are harmonized and use similar, if not the same, scientific values. Much needs to be done in terms of predictability, data gathering and interpretation, methodologies used, and acceptance by regulators, HTAs, and payers.

RWD/RWE Around the Globe: Notable Mentions

At the beginning of 2022, most efforts evolved around advancing the flexibilities demonstrated in the regulatory community during the pandemic without losing focus due to new challenges arising from the war in Ukraine. One of the most notable global signs toward harmonization and convergence in this space came from the ICMRA statement on international collaboration to enable real-world evidence (RWE) for regulatory decision-making, which identifies four areas for regulatory cooperation: harmonization of terminologies for real-world data and real-world evidence; regulatory convergence on RWD and RWE guidance and best practices; readiness to address public health challenges and emerging health threats; and transparency. The position paper came a year after ICMRA members released their opinion on COVID-19 Real-World Evidence and Observational studies triggered by the ongoing pandemic emergency at that time. Whether the harmonization and convergence activities will be translated into ICH technical approaches or will fall under ICMRA’s mandate remains to be more concretely defined.

RWD/RWE in the Americas: Advancing PDUFA VII Commitments in the US

It has been almost seven years since the 21st Century Cures Act of 2016 was signed into US law, which is also when the terms “RWD” and “RWE” were first concretely defined by FDA. Fast forward to 2023: FDA has issued a number of guidances and announced its Advancing Real-World Evidence Program, which, according to FDA’s official statement, aims to “improve the quality and acceptability of RWE-based approaches in support of new intended labeling claims, including approval of new indications of approved medical products or to satisfy post-approval study requirements. The Advancing RWE Program fulfills an FDA commitment under PDUFA VII, incorporated as part of the FDA User Fee Reauthorization Act of 2022.”

FDA seems to be taking a pragmatic approach when it comes to releasing direction on the use and acceptance of RWD/RWE. During the past three years, FDA issued a number of draft guidelines for public consultation focusing on specific areas such as:

• Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products Guidance for Industry
• Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products
• Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products
• Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry
• Data Standards for Drug and Biological Product Submissions Containing Real-World Data.

Health Canada joined forces with CADTH (Canadian Agency for Drugs and Technologies in Health) and other stakeholder groups to release its Real-World Evidence Reporting Guidance, with the purpose of standardizing RWE reporting and best practices for RWE submissions as well as methodological considerations for HTA submissions, for public consultation.

The use and acceptance of RWD/RWE in the Americas is becoming more widespread and is expected to play an increasingly important role in regulatory decision-making, clinical practice guidelines, and health policy.

RWD/RWE in Europe: Putting Theory into Practice

At the European Union level, many regulatory and policy efforts were directed at the use of RWD/RWE for safety and post-marketing surveillance throughout 2022. Considerable efforts were made by EMA, CHMP, and ENCePP to deliver a number of guidelines that frame methods, processes, and requirements that industry should consider when using RWD/RWE. One considerable step taken by the EU regulatory institutions is the Guideline on registry-based studies, a comprehensive overview of key regulatory recommendations and methodologies for marketing authorization applicants and holders to consider when planning registry-based studies.

One of the most significant guidelines resulting from the pandemic’s impact on evidence generation is the ENCePP Guide on Methodological Standards in Pharmacoepidemiology (revision 10), which illustrates good practices and methodological developments in pharmacoepidemiology and dedicates several specific articles to RWE. The release of the European Health Data Space Regulation in 2022 has the potential to enable the EU to unleash the full potential presented by a common, joint health data ecosystem. Still in the review phase, this new regulation is anticipated to come into force in 2025 and have ramifications in many areas: from being able to control your own electronic health data as a patient, to tapping into a safe and secure data source for research, innovation, policy making, and regulatory activities.

2022 was also a prolific year for new initiatives and draft guidances from the HMA/EMA Joint Big Data Steering Group to continue to deliver on the promise of its Big Data Workplan 2022-2025, from publishing a list of metadata for real-world data catalogues which describes real-world data sources and studies, followed by a Good Practice Guide for the use of the Metadata Catalogue of Real-World Data Sources, to calling for applications on a pilot using raw data in medicine evaluation.

Also in 2022, DARWIN EU, coordinated by EMA, onboarded its first set of data partners with access to RWD from hospitals, primary care, health insurance, registries and biobanks, and other sources. At present, DARWIN EU has initiated four studies and has ten (10) data partners.

The year closed out with the release of the first-of-its-kind Data Quality Framework for EU medicines regulation, which addresses general considerations on data quality that are relevant for regulatory decision-making. Furthermore, EU member states such as Denmark, France, and Germany have launched national initiatives to promote the use of RWD/RWE in healthcare policy and decision-making.

In 2022, Swissmedic clarified their position on the use of real-world evidence, making it clear that it actively follows international developments related to use of RWD/RWE and that it is in continuous dialogue with its Access partners and other authorities to further evaluate and establish the value of RWD/RWE in regulatory decision-making.

In the United Kingdom, MHRA published the final guidance on The Target Development Profile Toolkit, an Adaptive Inspections tool designed to support the overarching Innovative Licensing and Access Pathway and “support the non-clinical, clinical and manufacturing design and development pathway to ensure protection of patients and reliability of results.”

There is an increasing (although fragmented) recognition of the potential of RWD/RWE to enhance regulatory decision-making throughout Europe, and EMA together with the national healthcare authorities are actively working to promote the use of RWD/RWE while ensuring its reliability and validity.

RWD/RWE in Asia: Regional Focus

In Asia Pacific, many regulatory authorities such as the China National Medical Products Administration (NMPA), Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), South Korea’s Ministry of Food and Drug Safety (MFDS), and Australia’s Therapeutic Goods Administration (TGA) have recognized the potential value of RWE in their regulatory decision-making processes.

In China, for example, the NMPA has established a “conditional approval” pathway for drugs that show promise based on RWD/RWE, allowing them to enter the market earlier while continuing to collect data to support their full approval. In 2021, the Center for Drug Evaluation (CDE) of NMPA issued Guidance for Real-World Data used to Generate Real-World Evidence covering a wide range of topics such as origin and actual situation, data adaptability evaluation, RWD handling, compliance, security and quality management systems, and communication with surveillance organizations.

Japan’s PMDA has also established a framework for using RWD/RWE in regulatory decision-making, with a focus on post-marketing surveillance and safety monitoring. The first guidelines issued by the Japanese authority focus on Basic Principles on Utilization of Registry for Applications and Points to Consider for Ensuring the Reliability in Utilization of Registry Data for Applications.

The MFDS in South Korea recently issued guidelines on the use of RWE in regulatory decision-making, with a focus on the use of RWD to support clinical trial design and post-market surveillance:

• Guideline on Risk Management Plan for Medicines to allow post-marketing safety study based on database study using RWD (in Korean)
• Guideline for Medical Information Database Research (in Korean)
• Guide on the Procedures for Providing a Post-Market Database of COVID-19 Vaccines (in Korean).

Medical information databases are a new data source for post-market research, and the need for specific guidelines for research practices using them is now emerging.

RWD/RWE use and acceptance is also gaining importance in Australia. TGA has established a framework for the use of RWD/RWE in regulatory decision-making, which includes the use of data from electronic health records, disease registries, and administrative data. Australia has also launched pilots to check the feasibility and reliability of RWD/RWE in specific regulatory contexts.

Overall, the use of RWD/RWE in regulatory decision-making is still relatively new in Asia, but its potential benefits in terms of accelerating drug approvals and improving patient outcomes are becoming increasingly recognized by regulatory authorities and interest in producing regulatory frameworks around it is increasing.

In other regions, RWD/RWE use and acceptance is still in the early stages, but recognition of the potential of RWD/RWE to inform regulatory decisions, support clinical practice, and inform healthcare policy is increasing.

Priorities in 2023

In 2023, all eyes are on the ICH Assembly scheduled for June 2023, which will analyze the Reflection Paper drafted by FDA, EMA, and Health Canada, focusing on “international harmonisation of real-world evidence terminology, and convergence of general principles regarding planning and reporting of studies using real-world data, with a focus on effectiveness of medicines.”

Although RWD/RWE will not be the answer to all research questions, it has the potential to reduce the burden of conducting clinical trials and advance the way we develop drugs. We live in a crucial moment in time when RWD/RWE could play a pivotal role in how we design clinical trials.

If FDA will focus on releasing guidance for externally controlled trials, non-interventional studies, and using clinical practice data in randomized controlled trials, EMA will continue advancing work through DARWIN EU and aim to conduct 150 studies by 2025 on the other side of the Atlantic.

There is need for increased awareness, education, and pilots to advance the use of RWD/RWE beyond safety studies or identifying new patient populations. Rather than just complement clinical trial data, RWE studies must generate their own reliable effectiveness, safety, and related data.

Conclusion

RWD and RWE are beginning to meaningfully impact nearly every phase of the drug or therapeutic lifecycle. They can generate faster approvals and access to medicines, and bridge the gaps for unmet medical needs, more economically and quickly than traditional randomized clinical trials. But as drug development becomes more personalized and the pace of innovation accelerates (especially in cell and gene therapies), this raises significant challenges for regulators who must make decisions based on existing regulatory frameworks. Building trust and confidence in RWD/RWE requires open dialogue and collaboration to ensure we all walk the same path toward a future-ready regulatory framework.