WOW! What a buzz around Real Word Evidence (RWE)! I don’t think I have ever heard so much enthusiasm and expression of need for RWE and collaboration between European (EU) agencies. It was coming from all directions at ISPOR Europe 2022.
The interest and commitment to RWE by health technology assessment (HTA) and regulatory authorities is clear. Dalia Dawoud, Associate Director at The National Institute of Clinical Excellence (NICE) organization, United Kingdom (UK) suggested over 80% of NICE’s HTAs included some form of RWE, averaging 40% across other HTA agencies in 2021. This compares to 40% of European Medicines Agency (EMA) marketing authorization applications including RWE , however, use of RWE is set to increase.
RWE comes in many forms from epidemiological studies of disease incidence and prevalence to patient reported outcomes and experiences outside of a randomized controlled trial (RCT). Throughout the conference we heard much about the EMA and EU HTA bodies plans for the use of RWE in decision-making. The two key initiatives prominent throughout the conference were: DARWIN EU® (Data Analysis and Real-World Interrogation Network) and the EU Joint Clinical Assessments for HTA.
Peter Arlett (Head of Data Analytics and Methods Task Force, EMA) gave a great summary of DARWIN EU® in Monday’s breakout session. Artlett explained the federated network of real world health care data, with data that remain local. DARWIN EU® will provide scientific expertise in formulating and conducting real-world health care studies. By 2025 it is projected that DARWIN EU® will deliver 150 RWE studies annually. The intention is to provide RWE study results on the use, safety and effectiveness of medicines in a timely manner and increase the consistency of study results. It is also hoped that HTA bodies will also benefit from DARWIN EU® as a source of real world data (RWD). Arlett was proud to let attendees know that since its conception, nearly three years ago, DARWIN EU® already has 10 data partners and the first pilot studies have been launched. The intention is to add 10 new partners each year. DARWIN EU® is expected to be fully operational in 2024, answering questions to support EMA scientific committees and those of medicines authorities within an EU member state . Arlett emphasized it was about ‘enabling use and establishing value’ .
In addition, Artlett told us the EMA has an agreed list of metadata with a catalogue of RWD sources and studies. We heard that a good practice guide for the use of real-world metadata from the EMA is imminent.
Joint Clinical Assessment
At Tuesday’s Educational Symposia, Tommy Bramley (Senior Vice President of Global Consulting at AmerisourceBergen) gave a very clear summary of the EU Joint Clinical Assessments. Joint Clinical Assessments (JCAs) is at the heart of EU joint regulation for HTA, which was enacted earlier this year on the 12th January, 2022. The other elements of the EU joint HTA are joint scientific consultations, identification of emerging health technologies and methodological and procedural guidance. The joint technical work for these elements will be conducted by subgroups of national representatives overseen by the Coordination Group. The regulation replaces the current voluntary network of national authorities (HTA Network), and EUnetHTA (European Network for Health Technology Assessment). The latter will be disbanded in September 2023 
Bramely provided a schema showing how the JCA is initiated with a ‘letter of intent’ from the drug developer parallel to filing with the EMA. The JCA subgroup will request information from the drug developer following the ‘PICO’ scheme of Patient population, Intervention, Comparator and Outcomes. The drug developer then has to submit their dossier 45 days prior to positive opinion by the CHMP (Committee for Medicinal Products for Human Use) and the assessment report is to be provided 30 days after the EU Commission decision regarding market authorization approval.
The JCA is currently within the pilot phase, but it is not long before 12 January 2025 when JCA will be mandatory for oncology drugs and advanced therapy medicinal products (ATMPs). On the 13th January 2028, JCA will be mandatory for orphan drugs, and by the 13th January 2030 it will be mandatory for all drugs registered with the EMA.
JCAs are not legally binding but it is expected that they are given ‘due consideration’. Final appraisal is at the national level as are decisions on pricing and reimbursement. Data submitted for a JCA must not be resubmitted to a national HTA body by a drug company, since it is already available via the JCA system.
The main intent of the JCA is to reduce the access gaps to medicines across Europe. Time to HTA recommendations after regulatory approval differs hugely across Europe. Patients in Northern and Western Europe access new products 100-200 days after market authorization compared to 600-1000 days after market authorization in Southern and Eastern Europe . Other intentions of JCAs include standardizing HTA, minimizing repetition of country dossiers and providing HTA at the EU level for those countries without a national HTA body.
Expectations and Challenges
Regulatory authorities are interested in risk-benefit and the safety of medicines whereas HTA bodies are interested in the long-term effectiveness, quality of life and value of health technologies (including medicines). Although their interests differ, there are similarities in their cause: for patients to have timely access to beneficial medicines by considering the available evidence. These similarities and differences open up both opportunities and challenges.
Preference for Randomised Controlled Trial Data Remains
On both the regulatory and HTA side there still remains a preference for data from RCTs.We repeatedly heard throughout the conference that RWE is to be used to fill in the evidence gaps.
Lifecycle RWE Generation
Speakers at Monday’s plenary session including Carlos Martin (Health Economist, Ministry of Health, Spain) and others throughout the conference highlighted the importance of identifying data gaps early on in a medicine’s life cycle and having a plan to generate evidence.
Emer Cooke (Executive Director, EMA) highlighted the importance of a connected lifecycle approach between the EMA and HTA. RWE early on in the drug’s life cycle might focus on the prevalence of disease, particularly important for orphan status, and the feasibility of trial design. Around market authorization RWE can have a role to contextualize clinical trial data. Post market authorization, RWE is likely to focus on safety. For single arm studies, historical controls may also be helpful for decision making at the EU level.
Accessing Real World Data
One of the recognized barriers to RWE is access to the RWD, as acknowledged by Dalia Dawoud (NICE, UK) in Monday’s breakout session. In the past there have been a number of BIG Data IMI (Innovative Medicines Initiative) programs funded jointly by the European Union and EFPIA (European Federation of Pharmaceutical Industries and Associations) . It is not clear how successful these initiatives or others have been nor, from the discussions heard at ISPOR, whether the current EU regulatory and HTA initiatives will leverage previous initiatives. Having said that, with the backing of the EMA and EU HTA legislation, this is the best chance we have to develop sources of RWD, but it will require a massive collaborative effort across academia, the medicine developers, and the national agencies with direct access to national health data.
Differing Use of Clinical Evidence Between EU Member States
Professor Michael Drummond (University of York) highlighted the clinical element of HTA is the most transferable across member states, hence the focus of the EU HTA on JCA. Nonetheless, member states differ in their use of clinical evidence in their local HTA assessments. Current standards of care may also differ between member states. This has implications for the use of direct and indirect comparison studies, which may become unwieldy and with comparators irrelevant for some member states. Some HTA bodies are also more willing to accept indirect treatment comparisons, others preferring to focus on head to head comparisons from RCTs. HTA agencies also differ in how prepared they are to accept surrogate endpoints and their readiness to use RWE to estimate the long-term clinical effects, especially when only single arm trial data are available. These methodology and practical issues still need to be ironed out.
Limited Reimbursement Resources
Iga Lipska (Health Policy Institute, Poland and Medical University of Gdansk) shared her belief that the HTA regulation will reduce the access gap to health care across the EU member states, but she warned that HTA bodies in Central and Eastern Europe may be wary of the EU regulation because of their limited reimbursement resources and inability to fund some health care technologies.
Finite Resources with the Collaboration
Both DARWIN EU® and JCAs have finite resourcing. There will be a need to prioritize within the collaboration as to what RWD is most valuable. As pointed out by Emer Cooke (EMA), the agencies will need to work with others, for example, patients, academia and developers to align on evidence gaps. International collaboration on RWD is particularly important for orphan medicinal products and ATMPs, which affect small patient populations and where there can be disparity in accepted trial endpoints.
Although there is a lot of alignment between HTA and EMA, there are differences and data needs will be somewhat different. As Wim Goettsch (Utrecht Centre for Pharmaceutical Policy and Regulation, Netherlands) emphasized, this needs to be taken into account when designing studies collecting RWD.
To reiterate my ‘tweet’ at ISPOR, it is great to see such enthusiasm with the right intent. With the backing of the EMA and EU HTA legislation, this is the best chance we have and it should be embraced, but there is much still to be done before 2025 and there are many challenges ahead. In the quest for RWE we must not forget that the intent should be to fill the evidence gaps with good quality data and, thus, facilitate patients’ access to beneficial medicines in a timely manner.
- Flynn R, Plueschke K, Quinten C, Strassmann V, Duijnhoven RG, Gordillo-Marañon, 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: 111 (1), 90-97
- https://www.ema.europa.eu/en/about-us/how-we-work/big-data/data-analysis-real-world-interrogation-network-darwin-eu accessed 16 November 2022
- Arlett P, Kiaer J, Broich K, Cooke E. Real-world evidence in EU medicines regulation: enabling use and establishing value. Clin. Pharmacol. Ther. 2022: 111 (1): 21-23
- https://health.ec.europa.eu/health-technology-assessment/regulation-health-technology-assessment_en accessed 16 November 2022
- European Federation of Pharmaceutical Industries and Associations (EFPIA). The root cause of unavailability and delay to innovative medicines. June 2020
- https://www.imi.europa.eu/ accessed 17 November 2022