10 May 2021
Chairs: Kelly Robinson (Health Canada) and Xavier Kurz (European Medicines Agency - EMA)
1. Welcome and introduction
Emer Cooke (EMA Executive Director and Chair of ICMRA) welcomed participants to the 6th ICMRA meeting on COVID-19 Real-World Evidence and Observational studies. She praised ICMRA members for all the work achieved so far to fight against COVID-19 infection in such a short period of time. Six vaccines have now been developed and authorised worldwide with more to come, and millions of doses have already been administered. Far from being a simple group of Medicines Regulatory Authorities exchanging good intentions, ICMRA is a very dynamic network of Regulators working together. The group provides an effective platform to share valuable information on medicinal products and expertise. It facilitates successful collaboration on important studies to evaluate the effects and risks linked to the virus, its treatments and vaccines, as we have recently seen with the management of rare thromboembolic events occurring following vaccination.
Intensive work will continue in 2021, with a continuous exchange of data on vaccines and methods to achieve a common understanding on the monitoring of their effectiveness and safety profiles. Pregnant women have so far not (or very little) been included in clinical trials on vaccines, making it difficult to ascertain their impact on this vulnerable population. Observational research applied consistently worldwide through sharing and implementation of protocols across countries/regions/centres will play a key role to generate valuable evidence and inform on public health policies that should be applied to these women. Finally, the initiative on building international cohorts has already proven very constructive with the studies on natural history of coagulopathy in COVID-19 and on steroids utilisation for the treatment of COVID-19 that are being performed in several countries thanks to common protocols, and which will already deliver some results in the next few months. Doors are wide open for any Regulatory Authorities to join the different technical working groups at any point in time.
Mrs Cooke finished by thanking all the members for their commitment to actively engage in the various projects on top of their regular activities. Covid-19 has been a game changer in the way regulators collaborate. The level of interactions through the various established networks should continue to be leveraged beyond the current pandemic, as unity builds strength to protect and promote public health.
2. ICMRA members initiatives on observational studies
Xavier Kurz (EMA) introduced the topic by presenting the challenges and uncertainties of using RWE for COVID-19 vaccine monitoring as well as possible solutions. Reference was made to the recent EMA work that aimed at contextualising the potential benefits and harms of Astra-Zeneca COVID-19 vaccine stratified by age group in the EU/EEA in the frame of a referral procedure under Article 5(3) of Regulation (EC) No 726/2004 (Webpage and LINK to assessment report). A question was raised as to how EMA had assessed the quality of evidence on the benefits aspect. X. Kurz clarified that several assumptions were tested through different sensitivity analyses to see if and how each of these assumptions would likely change results.
Regulators were invited to provide their feedback on whether they use RWE to support decision making in the context of COVID-19, and if yes, which challenges they have experienced and what options may address those. Participants were also asked if they exchange data with and/or use data from other regulators.
These questions led to an interesting discussion with interventions from different countries:
Kelly Robinson (Health Canada) highlighted that RWE was already used in Canada before the COVID-19 outbreak while acknowledging the well-known limitations and constraints. Health Canada works closely with the Drug Safety and Effectiveness Network (DSEN) to answer questions on the safety and effectiveness of pharmaceuticals when used by diverse patient populations outside the controlled experimental environment of clinical trials. The DSEN is currently involved in several COVID-19 ICMRA related projects including the ICMRA technical working groups on building international cohorts (natural history of coagulopathy in COVID-19 and steroids utilisation for the treatment of COVID-19 studies) and on pregnancy.
The main challenges encountered are linked to the quality, breadth and timely access to the data.
These can however be addressed thanks to a tight collaboration between regulators worldwide that allows sharing data, knowledge and tools under confidentiality agreements, which appear very useful as vaccines are rolled out in Canada.
Jesper Kjaer (DKMA) indicated that RWE is often used in Denmark thanks to well established registries that are playing an important role in following up individuals after their first and second doses of vaccine, and to assess if any label changes are necessary. DKMA regularly shares data with other European Nordic countries like Sweden and Norway. However, the main challenge remains the sharing of data across these borders.
Sreemanee Dorajoo (HSA Singapore) confirms that RWE is currently used to estimate some of the baseline incidence of adverse events seen after vaccination. Regulators have access to patients’ level data of the entire country through medical/electronic health records (nationwide – 80% of 5M people). The difficulty lays in the quality of the data collected which requires thorough cleaning and validation assessment to ensure the information can be trusted. At this moment, Singapore has not shared with or used data from another Regulatory Authority.
Moji Adeyeye (National Agency for Food & Drug Administration and Control in Africa - NAFDAC) explained about the issues encountered in some African countries due to the lack of awareness of healthcare workers on the importance of collecting information on health status of individuals before vaccinations, as this step may prevent adverse events/adverse drug reactions from occurring. This is now being addressed through extensive training as well as sensitisation of the population through regular media messages. M. Adeyeye mentioned that MHRA is helping NAFDAC in training healthcare workers and establishing processes for the collection of data in a standardised way thanks to the Med-safety application, for the reporting to competent authorities, and for the analysis of safety data. NAFDAC is also planning to launch a prospective cohort monitoring for 3 years looking at genomics impact on COVID-19 infection.
David Wood (WHO) informed the participants that WHO was to host a global research forum on 13-14 May where challenges on RWE usage would be discussed and to which colleagues could register (LINK).
John Concato (FDA) said that RWE is used on a case by case basis, but the challenge is often linked to the reliability of the data.
Feedback received in writing:
ANVISA: The use of RWE has not yet been regulated to support decisions in the context of Covid-19. The expectation is the presentation of confirmatory data obtained through clinical studies with adequate design. The main challenges seen are linked to the quality of data as well as the need to ensure representativeness of the Brazilian population to obtain external validity, given the vast size of Brazil, its cultural and socioeconomic diversity, and the uneven access to technology and health resources. RWD and RWE also has limitations in supporting efficacy claims for drugs. Confounding factors and biases arising from non-randomized evidence may present challenges for statistical evaluation due to uncertainties and limitations for assessment and interpretation of causal inferences.
In cases where the use of RWD and RWE has previously been agreed upon with other Regulatory Agencies, it is common for applicants to submit the same documentation containing RWE and RWD, even though Anvisa does not have specific guidelines for this type of evidence.
In the majority of cases, RWE and RWD are generated from international databases to meet the regulatory requirements of other countries, which makes the interpretation of results in the Brazilian context more complex. This situation is not completely new, because there are cases where data from clinical trials conducted exclusively in other countries to prove the efficacy and safety of drugs is accepted by Anvisa for review. However, in those cases, the Agency has a guideline for reviewers that provides general considerations for extrapolation of foreign data.
We understand that there is still a long way to go to increase the confidence in and the credibility of these sources of information. For these goals to be met, we will need to interact with stakeholders to share knowledge and define the best use of RWD in regulatory assessments; develop specific guidelines regarding the use of RWD, following the steps of good regulatory practices; update internal regulations and procedures in the different areas of the Agency that assess clinical evidence; interact with several national stakeholders to build the interoperability of databases; and to qualify existing ones, in order to improve the quality of data collected to ensure a better regulatory decision-making process. ANVISA exchanges data with other regulators through Confidentiality Agreements and participation International forums. We use the guidance of the nº 70/2019 and nº 85/2018 service guidelines (OS) for use of assessment reports from other regulatory agencies.
Junko Sato (PMDA): During the assessment of medicinal products, we look at published scientific articles as references. We have not used RWE in post-approval so far, but we have imposed observational studies under clinical practice to MAHs. The main challenges is the reliability of the data, which we address by judging this limitation by taking data characteristics into consideration. Except for safety information, we are sharing latest information to other Regulatory Authorities once available. We refer to ICSR, O/E analysis, and pharmacoepidemiologic data, if they are categorized as RWE.
Nouf Alfadel (Saudi Food and Drug Authority - SFDA): At SFDA, we rely on pharmacovigilance data. The challenge is the insufficient information in the pharmacovigilance data such as demographics, medical history, concomitant medications, procedures, laboratory results, vital signs, etc. We do collaborate with the Ministry of Health, using standardized data extraction tool, extraction of data from electronic medical record systems of the hospitals. We exchange the pharmacovigilance data with WHO. We search the publicly available pharmacovigilance databases such as EudraVigilance and FDA’s Vaccine Adverse Event Reporting System (VAERS).
3. Update on the three technical working groups initiated at the 19 May 2020 ICMRA meeting
a) Vaccine surveillance and vigilance (MHRA + TGA)
Patrick Batty (MHRA) provided an update on behalf of the ICMRA COVID-19 Vaccine Pharmacovigilance Network (VPN). A simulation exercise was performed following the NOMA notification on fatal cases following vaccination. The objective was to evaluate how information was conveyed through the Network. The group also regularly shares experience and identify best practice for the methods to calculate background rates and perform observed/expected analysis. Other issues discussed include emerging safety profiles with similar unusual clinical complexities (e.g. reports of thromboembolic events), safety and communications updates (e.g. on thrombosis with thrombocytopenia syndrome (TTS) and AstraZeneca vaccine), case definition (e.g. Brighton Collaboration case definition for TTS) and vaccines confidence.
P. Batty clarified that the VPN composition has evolved over time to add new members. There is no restriction in non-ICMRA members taking part in the VPN.
b) Pregnancy observational research (EMA)
Corinne de Vries (EMA) presented preliminary findings from the CONSIGN study (Covid-19 infectiON and medicineS In pregnancy) on drugs utilisation during the 1st wave. These findings show that pregnant women infected with COVID-19 are much less likely to receive treatment than non-pregnant women. In addition, a review of vaccines marketing authorisation dossiers highlighted that, while non-preclinical results (when any) have not showed any evidence of increased risk, pregnant women have not been included in randomised clinical trials of COVID-19 treatments and vaccines, meaning this population has not been studies until now. This reinforces the importance of RWE observational studies going forward in order to study the impact of medications on pregnant women and their new-borns.
EMA is planning to extend the CONSIGN project to allow for a meta-analysis to scale-up and further increase study power. At the moment, US FDA and academia groups have confirmed their participation to the project. All ICMRA members are welcome to take part with data at their disposal until July 2022. The meta-analysis is planned to be finalised in December 2022.
CONSIGN protocols and code books are published on the ENCePP website (see news item dated 29 April 2021 “International collaboration to study the impact of Covid-19 and medicines on pregnancy, maternal and neonatal outcomes”).
c) Building international cohorts (HC)
Craig Simon (Health Canada) updated participants on the 3rd working group which is composed of 3 key collaborative projects in which Health Canada, EMA and US FDA have agreed to contribute from their respective jurisdictions. Research is in either the late planning phases or is already underway:
Steroids utilisation for the treatment of COVID-19: EMA has developed a study protocol to meet one primary and numerous secondary objectives (EUPAS38759). A final report is expected in July 2021. US FDA has developed a protocol and is conducting research aligned with the EMA protocol using the Sentinel CDM. Health Canada will be leveraging the DSEN to conduct research aligned with the study protocol with the exception of the secondary objective for case definitions as it will be addressed separately by Health Canada.
Natural history of coagulopathy in COVID-19: US FDA is leading the project in collaboration with the Sentinel Initiative, and has developed a study protocol and statistical analysis plan. EMA has also developed a protocol and is conducting research aligned with US FDA aims 1 and 2 using the OMOP CDM. Health Canada will be leveraging the DSEN to conduct research aligned with aims 1 and 2 of the study protocols.
Health Canada has engaged the DSEN Research teams to investigate the reliability of COVID-19 case definitions in administrative and clinical databases and to:
- Explore the commonality of COVID-19 case definitions in Canada
- Investigate the operating characteristics of the case definitions of both confirmed and suspected cases across individual sites
Additional information, including a protocol and anticipated timelines, will be shared with the FDA and EMA as this research involves.
4. Summary and next steps
Xavier Kurz (EMA) closed the meeting by emphasizing how important time factor is in the fight against COVID-19. Good quality “real world” data are needed to collect as much information as possible in a short period of time to inform public health policies on treatments management and vaccinations.
Collaboration is key to accumulate data and generate evidence that can then be used for decision making and to avoid duplication. Good examples have been demonstrated during the meeting, like the provision of trainings and tools from one Regulatory Authority to another one in need.
The three technical working groups have proven to deliver substantial results including study protocols that are publicly available and that can be adapted worldwide. ICMRA members are encouraged to take part in any of the technical working groups as they consider fit taking into account available resources.