Healthcare professionals and public health authorities will have a central role in discussing vaccination against COVID-19 with their patients.
Despite a large number of clinical trials and extensive global development underway, to date there are still few effective anti-viral medicines for the treatment of COVID-19 infection. This makes the role of vaccines for COVID-19 even more important.
The global impact of the COVID-19 pandemic has resulted in an unprecedented level of public interest in vaccines and their development and regulatory review. This has taken place mainly through mass and social media. The same channels have also led to a significant amount of misinformation and disinformation circulating about the pandemic. This may lead some to express concerns about getting vaccinated - or even be strongly opposed to vaccination. Another challenge in communicating the importance of COVID-19 vaccination is that so far, globally, younger adults are typically less clinically affected by COVID-19 infection and could see limited value in getting vaccinated, although they may have personal experience or come in contact with family members or friends affected by serious COVID-19 disease.
We appreciate that you, your colleagues and your patients may have a number of questions around the development, regulatory review and ongoing safety monitoring of COVID-19 vaccines.
The rapid development of COVID-19 vaccines, with many using new technologies, the comparatively short clinical trials and the proposed use of conditional, provisional or emergency use authorisation regulatory processes may leave healthcare providers and patients with questions and concerns. It is also likely that several different COVID-19 vaccines, based on different technologies, will become available over the coming year.
This statement explains the regulatory processes associated with the review of COVID-19 vaccines for safety, efficacy and quality. It also explains the arrangements put in place both nationally and globally for ongoing safety monitoring of different COVID-19 vaccines once they are on the market.
It is widely anticipated that vaccination against COVID-19 will be instrumental in ending the global pandemic and saving lives.
This International Coalition of Medicines Regulatory Authorities (ICMRA)[*] statement aims to inform and help healthcare professionals answer questions about the role of regulators in the oversight of COVID-19 vaccines. It explains how vaccines undergo robust scientific evaluation to determine their safety, efficacy and quality and how safety will continue to be closely monitored after approval.
People who are not vaccinated remain at risk of spreading the virus. Herd immunity through vaccination occurs when the majority of population has been vaccinated and can no longer give the virus to others, hence protecting themselves as well as those who cannot be vaccinated. Achieving ‘herd immunity’ and reducing the effective reproduction number of infection disease as much as possible is important. If ‘herd immunity’ is not achieved by enough people being vaccinated this could seriously affect vulnerable people, including immunocompromised people who cannot receive vaccines, or those who respond poorly to vaccination and therefore are more readily infected. Herd immunity requires a combination of high vaccination coverage with vaccines that are both effective and provide a reasonable duration of protection. Achieving ‘herd immunity’ will allow a return to normal societal functioning and re-opening of economies.
Regulators independently and rigorously evaluate scientific and clinical evidence provided by industry sponsors of vaccines, as well as other available evidence. Each vaccine is thoroughly assessed for safety, efficacy and pharmaceutical quality to determine whether it can be authorised, using available scientific evidence from animal data, human clinical trials, and manufacturing information to assess its benefits and risks.
Public health agencies develop and deliver vaccination programs. Often working with their expert immunisation technical advisory committees, this includes prioritising populations for vaccination, issuing additional recommendations and providing information about vaccines and immunization. They also collaborate with regulators to monitor vaccine safety after they are approved for use.
Safety evidence is an essential part of the regulatory submission for COVID-19 vaccines as they will be administered globally to help control the pandemic. Safety evidence is gathered during all phases of the vaccine development process.
Both common and infrequent side effects need to be examined and reported in the regulatory submission. Typically, regulators will require that participants in clinical trials have been followed for at least 1-2 months after receiving their final vaccine dose. Based on previous experience with vaccines the most serious (but very rare) adverse events appear within such timeframes. There will also be longer term (over 6 months) follow up of those who participated in the earlier phases of the clinical trials of each vaccine. Many trial participants will also be followed for at least 1 year to assess the duration of protection and longer-term safety of individual vaccines.
Apart from information on the types of immune responses induced by the vaccine, data in well-designed clinical trials must be submitted to regulators to demonstrate that the vaccine does in fact prevent COVID-19 in sufficient numbers of subjects (generally, at least 10,000 and usually about 30,000), representing a spread of age groups and subjects with co-morbidities. Given the disproportionate impact of COVID-19 on the elderly, most developers of COVID-19 vaccines have included significant numbers of elderly participants in clinical trials.
The safety and efficacy of each vaccine are also carefully evaluated independently on a product by product basis. Clinical trials should show that a candidate vaccine very significantly reduces COVID-19 in people who are vaccinated, compared to a control group of people who don’t receive the vaccine, through a reduction in numbers of laboratory confirmed SARS-CoV-2 infections. It is expected that candidate vaccines should also reduce the transmission of disease between individuals.
Regulators may seek additional independent expert advice from independent scientific advisory committees to help inform their decision on whether to approve a vaccine. These committees are made up of experts in science, medicine (including infectious diseases) and public health and often include consumer representatives.
Any COVID-19 vaccine that receives regulatory approval must be manufactured according to internationally agreed stringent regulatory standards of good manufacturing practices (GMP). Regulators will review data to confirm that the manufacturing process at each production site is well controlled and consistent. This will include data on the identity and purity of the vaccine components and its potency, as well as data on every step of manufacturing and on the controls used to ensure that each batch of vaccine is consistently of a high quality. Data on vaccine stability must also be provided before a vaccine can be approved. Batches may also undergo evaluation by individual national regulatory authorities to ensure they meet international requirements, before they can be supplied.
After a vaccine is authorised, sponsors will be required to conduct robust safety and effectiveness monitoring (pharmacovigilance) and risk minimisation activities. They will need to continuously monitor vaccine safety to ensure that the benefits of the vaccine continue to outweigh the risks. To this end, regulators require vaccine sponsors to have risk management plans describing how they will undertake to monitor and minimise risks associated with their vaccines. Vaccine companies will also be required to continue safety surveillance from the ongoing clinical trials of their products, typically using a number of approaches:
It is very important that healthcare professionals not only diligently report adverse events that they see in their patients, but to also encourage people who are vaccinated to immediately report them to their healthcare professionals.
Regulators will develop lists of “Adverse Events of Special Interest” following vaccination. Some have been rarely associated with immunization and others are often reported but have not been found to have a causal association. Having background rates of these events will help ensure that any increases detected can be quickly verified. If a significantly increased frequency of certain serious adverse events is detected in vaccinated groups, then this will lead rapidly to regulatory actions.
The widespread use of COVID-19 vaccines, including in the elderly, will unfortunately mean that there will be many purely coincidental deaths and serious illnesses, unrelated to vaccinations. The job of each regulator is to establish causality – in other words, whether the vaccination is likely to have led to the serious outcome. There will also be a special focus on monitoring safety in pregnant women, persons with severe pre-existing illness, the elderly and children and interaction with other vaccines.
Regulators, in collaboration with public health authorities, are able to take decisive action if and when a safety issue is identified. These actions might include issuing safety communications for patients, healthcare professionals and the community; updating the product information or consumer information for the vaccine; preventing the release of a particular batch of vaccine; and, taking other regulatory actions as necessary.
Globally, the public can have confidence in the rigour of the process used to scientifically evaluate the safety, efficacy and quality of vaccines before they are approved for use in the wider population.
A: The speed of development of COVID-19 vaccines has been unprecedented for several reasons
ICMRA brings together the heads of 30 medicines regulatory authorities from every region in the world, with the WHO as an observer. Medicines regulators recognise their important role in facilitating the provision of access to safe and effective high-quality medicinal products that are essential to human health and well-being. This includes ensuring that the benefits of vaccines outweigh their risks.
 ICMRA is an international executive-level coalition of key regulators from every region in the world. It provides a global strategic focus for medicines regulators and gives strategic leadership on shared regulatory issues and challenges. Priorities include coordinated response to crisis situations. Members of the ICMRA include: Therapeutic Goods Administration (TGA), Australia; National Health Surveillance (ANVISA), Brazil; Health Products and Food Branch, Health Canada (HPFB-HC), Canada; China National Medical Products Administration (NMPA), China; European Medicines Agency (EMA) and European Commission - Directorate General for Health and Food Safety (DG - SANTE), European Union; French National Agency for Medicines and Health Products Safety (ANSM), France; Paul-Ehrlich-Institute (PEI), Germany; Health Product Regulatory Authority (HPRA), Ireland; Italian Medicines Agency (AIFA), Italy; Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA), Japan; Ministry of Food and Drug Safety (MFDS), Korea; Federal Commission for the Protection against Sanitary Risks (COFEPRIS), Mexico; Medicines Evaluation Board (MEB), Netherlands; Medsafe, Clinical Leadership, Protection & Regulation, Ministry of Health, New Zealand; National Agency for Food Drug Administration and Control (NAFDAC), Nigeria; Health Sciences Authority (HSA), Saudi Arabia Food and Drug Administration (SFDA); Singapore; Medicines Control Council (MCC), South Africa; Medical Products Agency, Sweden; Swissmedic, Switzerland; Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom; Food and Drug Administration (FDA), United States and the World Health Organization as an observer. Associate members include Austrian Medicines and Medical Devices Agency (AGES), Danish Medicines Agency, Israel Office of MedicalTechnology, Health Information and Research (MTHIR), Poland Office of Registration of Medicinal Products and Biocidal Products (URPLWMiPB), Russia Roszdravnadzor and Spain Agencia Española de Medicametos y Productos Sanitarios (AEMPS).