GENEVA – WHO has issued a statement in collaboration with International Coalition of Medicines Regulatory Authorities (ICMRA) to healthcare professionals on how COVID-19 vaccines will be regulated for safety and effectiveness. Healthcare professionals and public health authorities have a central role in discussing vaccination against COVID-19 with their patients.
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.
Fueled by these occurrences, WHO has issued a statement explaining 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 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.
Vaccines and the regulatory process
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 authorized, using available scientific evidence from animal data, human clinical trials, and manufacturing information to assess its benefits and risks.
The safety and efficacy of each vaccine is 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.
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.
Monitoring safety and effectiveness after vaccine approval
After a vaccine is authorized, sponsors will be required to conduct robust safety and effectiveness monitoring (pharmacovigilance) and risk minimization 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 minimize risks associated with their vaccines. Vaccine companies will also be required to continue safety surveillance from the ongoing clinical trials of their products.
Regulators do this by:
- Reviewing and analyzing adverse events reported by healthcare professionals and consumers and requiring industry vaccine companies (sometimes called “sponsors”) to report to regulators on adverse events received both within the regulator’s home country and globally;
- Many regulators will implement enhanced passive surveillance systems. These include systems to rapidly compare numbers of suspected side effects reported with vaccines to the numbers of events expected to occur by chance, and include access to near real-time data on vaccine usage in different settings. Several regulators also implemented traceability systems for different vaccine brands and batches;
- Taking rapid action to mitigate risks, also considering the information about emerging safety issues shared among regulators and researchers through international collaboration;
- Reviewing medical literature and other sources of new safety information;
- Requiring vaccine manufacturers to continue safety surveillance from the ongoing clinical trials of their products; and
- Many regulators also require vaccine manufacturers to have risk management plans describing how they will monitor and minimize risks, including further epidemiological studies, associated with their vaccines.
It is very important that healthcare professionals not only diligently report any adverse events they see in their patients, but also encourage people who are vaccinated to immediately report adverse events to their healthcare professionals or to the medicines regulator in countries where direct reports from members of the public are accepted by the regulator. Reporting all relevant events helps regulators assess the possible role of the vaccine in causing the adverse event and assists in identifying safety issues relating to newly introduced vaccines.
As part of the safety monitoring and review of all suspected side effects reporting for vaccines, regulators have developed lists of “Adverse Events of Special Interest”. These lists include some events that have been associated with other vaccines (for example anaphylaxis). Others are included on these lists because they are serious events that are important to monitor extremely closely, even though there is no evidence that they are causally associated with specific vaccines. Having information on the background rates of these events that would be expected in people who have not received a vaccine will help ensure that any increased reporting of these events can be quickly detected and thoroughly investigated by regulators.
The widespread use of COVID-19 vaccines, including in the elderly and in patients with underlying health conditions, will unfortunately mean that there will be deaths and serious illnesses that are purely coincidental and unrelated to vaccinations. The job of each regulator, together with the relevant medical experts and vaccine manufacturers is to determine causality. There will be a special focus on monitoring safety in some groups of people, such as pregnant women, persons with severe pre-existing illness, older people, children, and in people also receiving vaccines for prevention of other diseases.
Regulators, often in collaboration with public health authorities, are able to take decisive action if 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 such as restriction of vaccine authorization to a particular subgroup of the community or revocation of authorization.
Commonly reported adverse events
The most commonly-reported events with COVID-19 vaccines are expected vaccine side effects, such as headache, fatigue, muscle and joint pain, fever and chills and pain at the site of injection. The occurrence of these adverse events is consistent with what is already known about the vaccines from clinical trials.
Adverse events of special interest
Regulators approve and maintain an approval of a vaccine only if they determine that the known and potential benefits of the vaccine outweigh its known and potential risks.
Anaphylaxis is a very rare side effect that may occur with any vaccine. There have been some other reported adverse events which include facial weakness, seizures, loss of sense of taste or small and cardiac events, but none are confirmed to be causally related to the vaccines.
The major adverse event of special interest reported for these vaccines, which include the Pfizer and Moderna vaccines is anaphylaxis. Regulators carefully review the reports of possible anaphylaxis to determine whether they are consistent with true anaphylaxis and whether they may have been caused by the vaccine. Anaphylaxis reports remains very rare (in the order of 10 cases per million vaccinated).
Guidance on the management of possible anaphylaxis is included in the Product Information/Label for these vaccines. Routine vaccination procedures include keeping people under observation for at least 15 minutes after vaccination and having appropriate medical treatment on hand so that anaphylaxis can be rapidly managed. These vaccines should not be given to people with a known history of a severe allergic reaction to any of the vaccine components. A second dose of mRNA vaccine should not be given to those who have experienced anaphylaxis to the first dose.
There have been some other reported adverse events, which include unusual bleeding and blood clotting disorders, facial weakness, seizures, loss of sense of taste or smell and cardiac events. Regulators monitor and carefully review if there is a causal relationship between the vaccines with those adverse events, and, if appropriate, they will be included in Product Information / Product Label of vaccines of concern.
Adenovirus vector vaccines
These include the AstraZeneca, Janssen, Gamaleya and CanSino Biologics vaccines. Internationally, the AstraZeneca and Janssen COVID-19 vaccines have been associated with a very rare and unusual clotting syndrome involving thromboembolic events (blood clots) with thrombocytopenia (low blood platelet count). This condition has been termed Thrombosis with Thrombocytopenia Syndrome (TTS). Medicines regulators are meeting regularly to share information about cases to better characterise this risk and understand this syndrome. Less information is available internationally about adverse events following the Gamaleya and CanSino Biologics vaccines.
The overall number of reports received of blood clots in the veins or arteries (including venous thrombosis or venous thromboembolism) occurring without thrombocytopenia is no higher than the expected background population rate for the more common type of blood clots in most countries.
The spontaneous reporting rates of thromboembolic events with thrombocytopenia vary by country and the precise incidences are difficult to estimate, but for the AstraZeneca vaccine, based on substantial use in Europe and the UK, the frequency of such events is very rare. Available estimates are of the order of 10-15 per million people vaccinated (note that for some countries this statistic is based on the numbers of reports of suspected cases of TTS rather than numbers of confirmed cases). Thromboembolic events with thrombocytopenia have also been reported in the United States for the Janssen vaccine, at a rate of about 2-3 per million doses administered. National regulators are continuing to monitor the issue closely and to publish up to date information on the numbers of cases reported and the latest estimates of the incidence.
The cases of thromboembolic events with thrombocytopenia after vaccination were mainly reported for younger rather than older individuals. This, together with the risk of serious illness or death associated with COVID-19 being much higher in middle-aged and older people, has led public health authorities in some countries to recommend that vaccination with the Astra Zeneca vaccine not be initiated in younger individuals.
Healthcare professionals should be alert to the signs and symptoms of thromboembolism and thrombocytopenia as well as coagulopathies after vaccination as TTS requires specific management. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms such as a severe or persistent headache, blurred vision, shortness of breath, chest pain, leg swelling, persistent abdominal pain or unusual skin bruising and/or petechiae (tiny purple, red, or brown spots on the skin) mostly occurring within around 4-20 days after vaccination, although some cases have been reported later than 20 days post vaccination. This information is in the Product Information / Product Label of the vaccines as approved by regulators.