November 27, 2020

expert comments on vaccine safety and monitoring

With a lot of recent focus on vaccines, here are some general comments from Dr Craig Hartford and Dr Penny Ward on how the safety of vaccines is assessed.

Dr Craig Hartford, Committee Member of the Faculty of Pharmaceutical Medicine’s Policy and Communications Group, said:

“Vaccines approved by the MHRA are safe and effective for use.

“Establishing the safety of a vaccine starts way back in the early research programs in which the vaccine is tested in vitro and in vivo to determine its safety profile before even beginning to test the vaccine in human volunteer clinical studies. This “pre-clinical” testing provides extensive information about the predicted safety of the vaccine in humans, and is conducted by scientists with advanced subject matter expertise in assessing and minimizing the potential toxic effects of a vaccine.

“Once the vaccine fulfills pre-clinical safety criteria that allow for its preliminary safe testing in humans, then only does the testing of the vaccine in humans start.

In “Phase 1” studies in humans the safety and tolerability of the vaccine is specifically focused on, yielding information about the early responses of our human bodies to the vaccine.  This allows the clinical investigators and the manufacturer to assess both common side effects as well to glean information about how the vaccine is acting inside our body, not only in terms of an immune response to the vaccine but also how all other systems in the body are responding to the vaccine. It also allows the vaccine study team to begin to assess what the right dose of the vaccine is likely to be so that any potential side effects are minimized.

“Only once this early testing in humans is completed, and the vaccine is shown to be well tolerated and safe in a small number of subjects, is the vaccine then allowed by the Regulator and manufacturer to be administered to a much bigger and broader population through what are known as Phase 2 and Phase 3 clinical studies. Here a broader spectrum of subjects participate in the studies. In these studies the vaccine safety is monitored not only by the manufacturer and by the clinical investigators but also by an independent data safety monitoring board, oversight by an independent ethics committee and indeed by regulators themselves. Vaccine manufacturers have dedicated safety professionals, i.e. people whose only role is to monitor the safety of the vaccines, assigned to the vaccine development team and they are specifically continuously monitoring the safety of the product during development. They also have safety teams who make decisions about the safety of the vaccine’s safety internally.

“Following the demonstration of safe use in Phase 3 clinical trials, the safety experts at the manufacturer produce a full clinical summary of safety and benefit-risk assessment and present that document to the regulator for review during the regulatory approval stage. This information along with all other sources of information about the vaccine are fully reviewed and considered by the regulator in arriving at a decision as to whether the vaccine is safe and effective to be administered to the public, i.e. in arriving at the decision that the vaccine has a positive benefit-risk profile.

“Furthermore, the close scrutiny of the safety of the product, continues well beyond the approval for use stage. Once the vaccine is made available to the public, reports from health care professionals and from patients about side effects are monitored daily. Each safety or side effect report is reviewed individually as well as cumulatively with all other side effect reports, also employing advanced computer methods to identify safety signals for a product.  If a safety signal is identified, that signal will be further evaluated in great detail by both the manufacturer as well as by the regulator to determine if the safety signal may be a potential risk to the public. If a potential risk is identified, and that risk is considered to be important, then that risk is minimized using a Risk Management Plan which is formally generated and implemented to carefully manage that risk. This includes additional safety monitoring  activities, such as actively exploring safety events that are considered to be of interest and conducting special Post-Approval Safety Studies.

“In addition, the manufacturer produces for the regulator a Periodic Benefit-Risk Evaluation Report about all aspects of the safety and efficacy of the vaccine, for regular scrutiny by the regulator. Vaccines safety is not only monitored in the UK but globally e.g., by WHO, and all that information where relevant is reported to the MHRA by the manufacturer for continuous safety assessment.

“Regarding monitoring the Safety of the Vaccine in the UK, it is worth mentioning here in particular the MHRA’s Yellow Card Scheme**:  The Yellow Card Scheme will be very important to helping monitor the safety of the Covid-19 vaccines, along with other safety monitoring systems and safety monitoring plans implemented by e.g. companies, the regulators, the WHO and other coordinating bodies. The MHRA have published a specific Coronavirus Yellow Card reporting site, reflecting the importance of this area and the importance of the reporting of vaccine side effects by both the public and HCPs.

“In summary, all medicines and vaccines can have some side effects, but these side effects are unusual, they are typically mild, transient and not serious, and serious side effects are rare. The benefits of the vaccine outweigh the risks and the safety of vaccines is very closely monitored and assessed. The COVID-19 Vaccine when approved for use in the UK by the MHRA is safe and effective for use in the public.

**The MHRA yellow card scheme is useful for collecting and monitoring information on suspected safety concerns or incidents involving medicines and medical devices. Per MHRA, the purpose of the scheme is to provide an early warning that the safety of a product may require further investigation. Reports can be made for all medicines including vaccines, blood factors and immunoglobulins, herbal medicines and homeopathic remedies, and all medical devices available on the UK market, as well as e-cigarrettes, so it covers reporting for the vast majority of products for which a side effect/incident may be experienced by a patient. There are several prominent examples of the safety issues which Yellow Card reports have contributed to in the assessment of or helped to identify. The MHRA’s yellow card scheme is viewed globally as a high standard Regulatory adverse event reporting system. The more information a HCP or Patient provides, the more useful the report is towards assessing a product’s safety – some individual reports lacking comprehensive information can be of limited value. It is important to note that the yellow card scheme is one important tool for monitoring the safety of products, there are other methods for collecting safety information in general that may additionally be in operation in parallel, and information from sources outside of the UK are also considered by companies and regulators when in assessing the safety of a product.

It is common for any spontaneous reporting system to potentially have relative “under-reporting” as a factor and this factor is always considered when assessing the safety of a product. Generically, the reasons for under-reporting are varied and likely multifactorial e.g. patients awareness of and access to a reporting system, whether the side effect is severe/frequent/persistent enough to stimulate the patient to make a report, patients may only report a suspected side effect when they consider that their HCP has not paid enough attention to their concerns, some patients see that the side effect is already listed in the patient leaflet and don’t think they should report it again, some patients report the issue to their Health Care Providers (HCPs)  and thus rely on the HCP to report the event, etc.

Under-reporting of side effects per se does not yield a reporting system to be of low value – the Trends in side effect/incidents reporting are important and useful, in addition to the absolute number of side effects reported. The phenomenon of “stimulated reporting” is a feature of all spontaneous safety reporting systems where e.g. patient/public awareness of a particular side effect for a product is increased (such as by a media coverage of it) that then leads to more patients reporting that side effect, which usually results in a “spike” in the frequency of those side effects being reported.

If you think a medicine, vaccine or herbal or complementary remedy has caused an unwanted side effect, you should report the problem on a Yellow Card. The MHRA state that it is especially useful to know about  a suspected side effect that is not mentioned in the patient information leaflet supplied with the medicine, a suspected side effect that causes problems bad enough to interfere with everyday activities, a suspected side effect that happens when you’re taking more than one medicine, and could be caused by interactions..

The increased availability of the Yellow Card Scheme’s App should help facilitate reporting. In addition you can report on a Yellow Card form, which you can find at pharmacies, GP surgeries or from the Yellow Card hotline by calling freephone 0808 100 3352 during business hours. The Yellow Card form can also be downloaded, to print and complete.

The Yellow Card scheme is run by the MHRA and relies on voluntary reporting of suspected ADRs by health professionals and patients. The MHRA’s yellow card scheme was one of the  world’s first spontaneous reporting schemes for the reporting of suspected side effects and is viewed by most as a relatively high standard (if not the gold standard) Regulatory adverse event reporting system. Many “higher income” countries now also have well developed spontaneous reporting systems.

Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:

“Before any medicine (including vaccines) can be approved for use the manufacturer has to submit all the data they have which documents the safety of the medicine. This includes results from animal toxicology studies and also all the results from human clinical trials including the early and later phase trials. The manufacturer and the regulator need to consider the benefit – risk balance of the medicine/vaccine based on the efficacy found (in the case of a vaccine protection against disease (milder forms as well as more severe disease leading to hospitalisation and death) and the side effects reported by the recipients compared to side effects reported by people in the control group during the study period. Some side effects are logical as these vaccines are injected into the arm, and include reactions at the injection site and often a mild flu like illness which is a result of stimulating the immune system. These usually wear off within days of the vaccine dose. So, if the vaccine is effective at reducing the frequency of disease, particularly severe disease, and the safety profile is mostly related to these relatively unimportant, transient and manageable side effects, the vaccine can be licensed. However, safety follow up doesn’t stop at this point.

“Because vaccines have been studied extensively for many decades, we do know that very very rarely more serious side effects might occur. This can include serious allergic reactions (hives, swelling of the face and tongue, wheezing) at the time of the injection or shortly afterwards and this is looked for and can be promptly managed at the time – serious allergic reactions occur in about 1:1 million vaccine injections.

“For influenza vaccine, a progressive neuromuscular weakness known as Guillaume Barre Syndrome has been observed but this is extremely rare (less than 1 in 1 million people) and is more common following naturally acquired influenza infection than after the vaccine.

“It would be unlikely that any of these serious reactions in a clinical trial including a few tens of thousands of subjects, because of their rarity. For this reason, we must carry on assessing the safety of the vaccine in clinical use; there will be a training program for vaccine administrators to help them to recognise any possible allergic reactions at the time of administration. All GPs will also be aware of the need to check up on any person not feeling well, or developing clumsiness or muscle weakness after having received a vaccine and usually this disease is treatable and most patients eventually recover. All side effects are reported in the UK using the Yellow Card Scheme (see Yellow Card Scheme – MHRA ) and there is also a downloadable App. Patients can also self report problems using this scheme.

“Lastly, proactive searching of the General Practice Research Database anonymized clinical data can be used to detect early signals of potential safety concerns and a consortium of safety organisations has been built to help with active monitoring of vaccine safety using this facility.”

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Dr Craig Hartford: “No relevant declarations of interest: I do not perceive any Conflicts of Interest; I am a Pfizer past employee, predating Pfizer’s coronavirus vaccine development; I own shares in pharmaceutical companies”

 Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development.  Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections.  Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases.  Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”