Extract from the first joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 26 August 2022

The framework and specifications for WHO Listed Authorities (WLAs) were developed in response to changes to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) structure in 2015 which had an impact on the definition of stringent regulatory authorities (SRAs). The definition of WLAs, which will replace SRAs, was adopted by the Expert Committee for Specifications for Pharmaceutical Products (ECSPP) in October 2020 (WHO TRS 1033) and corresponds to a national regulatory authority (NRA) or a regional regulatory system that complies with all the relevant indicators and requirements specified by WHO for the requested scope of listing, based on an established benchmarking and a performance evaluation process. The objectives are to build capacity consistent with good regulatory practices in Member States as well as to promote regulatory cooperation, convergence and transparency through networking, work sharing and reliance. A policy document describing the purpose, definitions and high level operating principles related to the evaluation and public listing of authorities was published in 2021^.1

The WLA was launched on 31 March 2022.² The voluntary process is initiated by a request for a performance evaluation from a Member State for a national or regional regulatory authority that must have a maturity level 3 to be eligible. To be publicly listed as a WLA the regulatory authority will undergo a performance evaluation process, which differs from benchmarking processes as it is more like an inspection and audit and is not intended to help build capacity. The approach is based on the established global benchmarking tool (GBT) and a performance evaluation framework (PEF), which is a series of new indicators and tools for performance evaluation. The PEF has 7 performance evaluation indicators (PEIs) and a vigilance field trip which are described in a specific manual that also has checklists. The PEF will be piloted in 2 to 4 countries and based on the results the PEF manual will be updated and the WLA operational guidance will be published by the end of 2022. The promotion of reliance by the WLA initiative was discussed. The benefits of the WLA process and recognition of regulatory decisions made by WLAs to manufactures and procurement agencies were highlighted. Overall WLA will contribute to facilitating access to good quality medicinal products and vaccines.

Full report the first joint meeting of WHO GACVS and WHO ACSoMP, published in the WHO Weekly Epidemiological Record of 26 August 2022

Coordination of trials, research and development and the “ACT Accelerator”

WHO is coordinating global research on diagnostic tests, therapeutics and vaccines against the SARS-CoV-2 virus responsible for COVID-19 disease. The Department of Regulation and Prequalification at WHO headquarters collaborates with regulators worldwide and provides regular updates on regulation and a platform for rapid exchange of information to align regulations and fast-track approval of clinical trials and marketing authorizations to ensure a swift response when a vaccine becomes available.

The WHO “ACT Accelerator”, launched in April 2020, is intended as an end-to-end process for coordinating research and development (R&D) through to equitable access to the resulting products. It consists of 4 pillars and workstreams addressing vaccines (led jointly by WHO, the Coalition for Epidemic Preparedness Innovations (CEPI) and Gavi, the Vaccine Alliance), therapeutics, diagnostics and a cross-cutting area provisionally called “health systems strengthening”.

The Global Research and Innovation Forum (Geneva, 11–12 February 2020) drew up a research plan and established 9 working groups in various areas of research, on which regulators are represented. In the area of vaccine development, the working groups comprise: reagents and immunoassays; animal models; vaccine R&D; target product profiles; and vaccine prioritization. The vaccine development community has responded rapidly with over 120 COVID-19 vaccine candidates (as at 27 May 2020) based on both traditional vaccine platforms and completely new ones, including DNA and mRNA.

WHO has designed a protocol for a randomized controlled clinical trial in several countries for testing many different candidate vaccines against a placebo control. The trial will include vaccine safety, to which GACVS could usefully contribute. Regulators are included in designing the trial. WHO will also issue guidance on the operational criteria for and ethics of human challenge studies with SARS-CoV-2.

Modelling of COVID-19

The COVID-19 Multi-model Comparison Consortium compares forecasts from a number of modelling groups to advise policy-makers on interpretation of the models and their strengths and weaknesses. WHO and United Nations organizations are also harmonizing modelling to determine the impact of the COVID-19 epidemic and control measures on other public health programmes. Preliminary mapping of collaborations among large modelling groups and countries with less modelling capacity is under way. As part of the “Solidarity III Trials” within the WHO R&D Blueprint, WHO partners are establishing a global open-source database of public health and social measures, currently covering 189 countries.

Modelling tools such as the COVID-19 Scenario Analysis Tool developed by Imperial College London, United Kingdom, allow countries to make long-term projections of new cases, the numbers of patients who require hospitalization and/or critical care and the potential effects of different levels and durations of social intervention. Modelling is useful for understanding the impacts of social distancing, testing, contact tracing and household quarantine during a second wave of the COVID-19 pandemic and understanding which interventions are most effective in reducing the reproduction (R) number. How the pandemic evolves will depend on population immunity, for which studies of seroprevalence should be conducted, and the potential role of seasonality.

WHO provides a global platform for COVID-19 serology on 3 fronts. The Organization is working with a global network of laboratories and the Foundation for Innovative new Diagnostics (FIND) developing, evaluating and validating standardized serological assays for the SARS-CoV-2 virus. Within the Solidarity II global collaboration, it is accelerating the development and dissemination of well-characterized panels of sera, and it has adapted early epidemiological investigation protocols for COVID-19. Over 90 serological studies are under way. Preliminary, non-peer-reviewed results suggest that less than 10% of the populations studied have evidence of antibodies to the virus.

Many questions remain about the role of asymptomatic transmission of COVID-19. Models suggest that asymptomatic and presymptomatic transmission of the virus may be much higher than indicated empirically. Detailed contact tracing, epidemiological and seroepidemiological studies would provide further insight.

Evolution of the pandemic will depend on the longevity of immunity to COVID-19, the potential seasonality of the virus and cross-immunity with other human coronaviruses. Kissler et al.² modelled plausible transmission scenarios, varying duration of immunity after infection with the virus, seasonality of transmission and application of social measures (social distancing). The authors concluded that continuous surveillance and longitudinal serological studies will be necessary. In general, modelling is based on assumptions, and its accuracy depends on the quality of the available data. Models and assumptions are adapted as new information becomes available, and the conclusions must be communicated with care.

GACVS members observed that modelling should take into account the population density in study areas, population mobility, the socioeconomic and sociocultural context of the country, the impact of isolating patients in health-care facilities rather than in their homes and the potential that infection with other coronaviruses could increase the severity of COVID-19 disease instead of conferring cross-immunity.

² Kissler SM, et al. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 2020;368(6493):860–8.

Safety Platform for Emergency Vaccines

The Safety Platform for Emergency vACcines (SPEAC) is funded by CEPI through the Brighton Collaboration with the objective of harmonizing safety assessments from clinical trials (monitoring, investigation and analysis) with standard case definitions, tools and information aids. SPEAC is preparing lists of potential adverse events of special interest (AESI) in relation to COVID-19 and the case definitions. The list of AESI currently includes events known to be associated with either immunization or previously licensed vaccine platforms; it does not yet include the newer platforms or a systematic assessment of events related to adjuvants. The current SPEAC findings are based on clinical experience with COVID-19 in China in February 2020 and on a literature review of COVID-19 disease dating from mid-February to mid-May 2020.

Several body systems may be affected by COVID-19, leading to neurological, dermatological, cardiac or haematological problems, acute kidney or liver injury or multisystem inflammatory syndrome in children. No consensus was reached on inclusion of Kawasaki disease, as multisystem inflammatory syndrome in children appeared to be the most relevant AESI at this stage; other symptoms in children, including severe abdominal pain, were considered too general for inclusion.

SPEAC has made an initial list of 18 AESI, some of which, including generalized convulsions, Guillain-Barré syndrome and anaphylaxis, already have a Brighton Collaboration case definition, while many COVID-19-related events do not have such a definition. The priority AESI that still lack a case definition include enhanced disease after immunization, multisystem inflammatory syndrome in children and acute respiratory distress syndrome. SPEAC plans to make its first COVID-19-related case definitions available in June 2020. SPEAC will also review published evidence to identify the background incidence rates in target populations and the causes, risk factors and differential diagnoses and map the AESI to the corresponding codes of the International Classification of Diseases (ICD) and the Medical Dictionary for Regulatory Activities (MedDRA). A number of tools will be developed, such as tabular presentation of AESI background rates, a data extraction form and a tabular checklist of diagnostic certainty.

Introduction of several different COVID-19 vaccines on a massive scale with new techniques, such as DNA or mRNA platforms, will create new challenges for public health. To ensure their safety, regulators should have systems for detecting and minimizing serious risks to patients, with full transparency. Additional data on effectiveness and safety must be collected quickly after new vaccines are approved; however, if millions or billions of people receive the new vaccines, regulatory authorities may be overwhelmed by the number of adverse events reported, emphasizing the importance of comprehensive advance preparation.

Regulatory processes already in place for emerging health threats can be adapted as necessary in order to grant marketing authorization for safe, effective, high-quality COVID-19 vaccines as soon as possible. For example, in Europe, building on experience during the 2009 pandemic of H1N1 influenza, a pandemic task force has been established for rapid approval of vaccines for which there is sound scientific evidence. This task force will rapidly provide the European Medicines Agency (EMA) with scientific advice on the design of clinical trials, agreement on paediatric investigation plans, 15-day rolling reviews of emerging data and accelerated assessment of applications for marketing authorization. The EMA is in contact with over 50 prospective vaccine manufacturers and laboratories seeking information about the criteria for and conduct of COVID-19 clinical trials.

The current guidance and format of the risk management plan in the European Union will be maintained. In addition to routine post-licensure surveillance, other studies and enhanced safety surveillance by vaccine manufacturers may be required, including active follow-up of vaccinated people, enhanced passive surveillance (through rapid estimation of vaccine usage and facilitation of passive reporting by patients and physicians, data mining and use of electronic health records) and formal phase IV (post-marketing) studies. Lists of AESI and age-specific background rates will be necessary and also standard definitions and MedDRA terms, which should be internationally agreed. At present, however, it will be difficult to prepare a core risk management plan in view of the uncertainty about the new vaccines and their safety profiles. Rapid publication of a summary of the risk management plans associated with vaccines approved by regulatory authorities will be helpful.

Pharmacovigilance will be tailored to emerging information and data from clinical trials. Signal management is particularly important given the expected sharp rise in reports of adverse events. This will include shortened reporting timelines and semi-automated signal detection methods. Rapid investigation of and response to safety issues and rapid communication of the results will be essential. Expedited summary safety reports from vaccine manufacturers to national and regional regulatory authorities such as EMA, with a simplified, standardized format, could focus on AESI and serious unlisted adverse drug reactions and track vaccine distribution by brand name, batch number and patient characteristics. National authorities may, however, be better placed than European authorities or vaccine manufacturers to track vaccine distribution by brand and batch number, for instance with the new 2-dimensional barcode system. Other national measures could include vaccination registers and traceability systems for vaccines. The Emerging Safety Issue notification system is being reinforced.

The aim of a vaccine monitoring project (vACcine Covid-19 monitoring readineSS – ACCESS), funded by EMA and launched in May 2020, is to generate background rates of AESI, write a series of protocols for prospective and retrospective monitoring of safety and effectiveness and identify a European network of data sources for continuous monitoring of the coverage, safety and effectiveness of COVID-19 vaccines. The International Coalition of Medicines Regulatory Agencies (ICMRA) will initiate a number of collaborations, including a study on the natural history of COVID-19 in pregnancy, pregnancy outcomes and neonates.