Product- and population-specific pharmacovigilance guidance
The general good pharmacovigilance practices apply to every medicine, but some products and populations carry further guidance of their own. Biological medicines and children each have a considerations chapter, vaccines have guidance that changes what a periodic report contains and how its data are analysed, and COVID-19 vaccines carried monitoring on top of the practices that apply to all medicines.
Biological medicines
On 15 August 2016 the European Medicines Agency adopted a new chapter of its good pharmacovigilance practices, entitled "Product- or population-specific considerations II: Biological medicinal products". The chapter provides guidance on how to better monitor and manage the safety of biological medicines in order to optimise their safe and effective use in Europe. It highlights issues and challenges specific to the pharmacovigilance of biological medicines, such as variability of the active substance or traceability of products, recommends how to address them, and outlines the roles and responsibilities of the various actors.
The chapter applies to biological medicines, to biosimilars, and to medicines that contain the same or a closely related active substance but are not authorised as biosimilars. It does not apply to vaccines or advanced therapy medicinal products, because separate guidance already exists for these.
The paediatric population
On 30 November 2018 the European Medicines Agency published good pharmacovigilance practice chapter IV, on specific considerations for the paediatric population. The chapter offers a holistic view of paediatric pharmacovigilance and provides guidance on how to make best use of existing tools and processes to address the specific needs and challenges of monitoring the safety of medicines used in children. It also advises on how to adapt regulatory requirements to the paediatric population in the European Union. The chapter was finalised after careful consideration of the extensive feedback received during a public consultation, and it replaces the 2007 guideline of the agency's human medicines committee on the conduct of pharmacovigilance for medicines used by the paediatric population.
The chapter covers approved medicines with a paediatric indication or with an ongoing paediatric development, and also medicines approved only for adults when they are used off-label to treat children, that is, for a medical purpose not in accordance with the terms of the marketing authorisation. A dedicated approach to pharmacovigilance in children is especially important because paediatric clinical trials are often limited in size and duration, and adverse reactions in children may differ substantially from those in adults in frequency, nature, severity and presentation.
The guidance focuses on aspects of pharmacovigilance of particular relevance to the use of medicines in children, such as off-label use and medication errors, and contains paediatric-specific guidance on all major pharmacovigilance tools and processes, including risk management plans, periodic safety update reports, post-authorisation safety studies, signal management and safety communication. It highlights the need to include comprehensive information in adverse drug reaction reports, such as the child's age, weight and height and the indication or intention of use of the medicine, including its strength, dose and pharmaceutical form. Such information is important for all actors involved in safety reporting of medicines in children, including pharmaceutical companies, sponsors of clinical studies and regulatory authorities, but also parents and carers, healthcare professionals, patient and healthcare professional organisations, and organisations of national healthcare systems.
Vaccines
A CIOMS and WHO working group defined the pharmacovigilance of vaccines as the "science and activities related to the detection, assessment, understanding and communication of adverse events following immunisation and other vaccine- or immunisation-related issues, and to the prevention of untoward effects of the vaccine or immunisation". Like that of all medicinal products, the use of vaccines is not without safety concerns and requires stringent processes to ensure continuous surveillance of quality, efficacy and safety. Although pharmacovigilance processes for vaccines are similar to those applied to other medicinal products, there are vaccine-specific aspects that the pharmacovigilance medical writer should consider when preparing safety documents such as the periodic benefit-risk evaluation report.
The European good pharmacovigilance practices that govern other medicinal products also apply to vaccines. In addition, there is specific good pharmacovigilance practice guidance for vaccines, including advice on the analysis of safety data for periodic benefit-risk evaluation reports and risk management plans, to help marketing authorisation holders appreciate the vaccine-specific aspects of pharmacovigilance that arise from the unique challenges of these products.
Vaccines are complex biological products that may include multiple antigens, live organisms, adjuvants and preservatives, components that all have potential implications for safety and require specific manufacturing processes underpinned by constantly evolving technology. Consequently, vaccines require specific pharmacovigilance systems and present many challenges that have implications for the analysis of safety data in periodic reports. During mass vaccination programmes, a high volume of suspected adverse reactions can be reported to the marketing authorisation holder in a short period, and they need to be handled and assessed efficiently. Mass vaccination programmes also need real-time signal assessment so that potential new risks are identified in time. This is of specific importance for prophylactic vaccines against infectious diseases, because they are administered to an otherwise healthy population and the acceptable level of risk is therefore lower than for other medicinal products.
The additional guidance on vaccines intended for prophylaxis against infectious diseases advises that vaccination failures be reported as lack of therapeutic efficacy within 15 days of the marketing authorisation holder becoming aware of them, because they represent potential signals of reduced immunogenicity in the patient population, declining immunity, or loss of coverage for the target antigens. The concept of a signal for vaccines is consistent with the definition applied to other medicinal products, but unlike for other products, data suggestive of reduced efficacy, vaccine failures and changes to product quality could also constitute a safety signal for a vaccine. For these reasons, vaccine pharmacovigilance requires extremely detailed post-marketing surveillance data, so that the specific vaccine batch administered to each patient is recorded in the case reports entered into the holder's safety database.
Adverse events following immunisation are reviewed against five possible designated categories: vaccine product-related, vaccine quality defect-related, immunisation error-related, immunisation anxiety-related, and coincidental event. In the review of safety data for a vaccine periodic report, these categories support the analysis of the root causes of the reported adverse events, which enables the holder to further refine the applicable risk minimisation measures.
Additional data elements in a vaccine periodic report
As for other authorised medicinal products, the content of a European periodic benefit-risk evaluation report for a vaccine is governed by GVP Module VII (Revision 1) and ICH E2C(R2). The complex multicomponent nature of vaccines makes it necessary to include additional data elements in a vaccine report, to allow assessment of their impact on the safety profile. The additional data elements, with the report sections that carry them, are:
- vaccination errors, in Section 9.2
- published safety data on similar vaccines, in Section 11
- published safety data on other vaccine constituents, such as preservatives and adjuvants, in Section 11
- vaccine failures and lack of efficacy or effectiveness, in Section 13
- vaccine anxiety-related reactions, in Sections 15 and 16
A vaccine report requires analysis of any data pertinent to vaccination errors in Section 9.2. These may include case reports describing inappropriate methods of administration, such as the wrong route of administration, insufficient doses or failure to use the authorised diluent, or failure to comply with the authorised vaccination schedule. The review of vaccination errors needs to include the cause of the error when it is available, such as confusion over the product labelling or multiple vaccination programmes leading to too many administrations, and an assessment of the associated clinical consequences, which may include the onset of specific adverse events or vaccination failure. Section 9.2 of a vaccine report should also assess any reports of improper handling or storage of the product, because such issues could lead to adverse effects from contamination of the vaccine with bacterial or other potentially infectious agents.
Section 11 of a vaccine report requires analysis of any new and significant safety information from the published literature, and the requirement extends to published data relevant to other products of the same class. A vaccine report goes a step further and requires review of published information about other vaccine constituents, such as preservatives, stabilisers and adjuvants, so the search and review criteria for the published literature need to be designed to account for this requirement.
Section 13 of a vaccine report requires analysis of any case reports describing vaccine failures, which are determined from clinical endpoints or from the immunological parameters used to monitor disease progression. The analysis needs to distinguish primary vaccine failure, such as lack of seroconversion or seroprotection, from secondary vaccine failure, such as declining immunity after an otherwise successful vaccination. The analysis should also determine whether the failure was an actual vaccine failure or a failure to vaccinate, such as administration errors leading to an inadequate dose or missing recommended booster vaccinations. A failure to vaccinate involves inappropriate administration of the vaccine, so its analysis should be cross-referenced to the analysis of vaccination errors in Section 9.2. The analysis of vaccine failures should further aim to determine whether the failure was vaccinee-related or vaccine-related. Vaccinee-related failures may be linked to the patient's health status, such as pre-existing infections, immunodeficiency, immunosuppression and age-related decline in immune responsiveness. Vaccine-related failures indicate lack of vaccine effectiveness against the target antigen, which may be associated with manufacturing issues or with insufficient or lost coverage against the organisms responsible for the target disease.
In the vaccine setting, the analysis in Sections 15 and 16 extends to vaccine or immunisation anxiety-related reactions, such as vasovagal syncope, hyperventilation-mediated reactions and stress-related psychiatric disorders. Consideration should also be given to the analysis of adverse events associated with co-administration of the vaccine with other vaccines, and the consequent implications for safety should be reviewed.
Stratification of the vaccine safety analysis
The analysis of safety data in a vaccine report is enhanced by stratification, to elucidate the potential impact of age, product batches and patient subpopulations on the safety profile. The additional considerations for data analysis in a vaccine report are:
- age-based differences in the vaccine safety profile
- subpopulation-based differences in the vaccine safety profile, such as in pregnant women and immunocompromised patients
- the impact of manufacturing process changes and batch-related safety issues
- local versus systemic adverse effects per authorised dose and vaccination schedule
Because immunological responses to vaccines evolve with age, the analysis of safety and efficacy data in a vaccine report should be stratified by patient age group, to support the identification of risks that may be more prevalent in a specific age group. Stratification by age can also permit enhanced assessment of causality, particularly for adverse events concerning children, because it can provide a rationale for excluding clusters of adverse events that may be coincidental, that is, unrelated to vaccine exposure, if they are known to occur at a specific time during childhood. To support the age-stratified safety analysis, it is worth also presenting an analysis of patient exposure data stratified by age, although such stratification requires high-quality post-marketing surveillance data.
As with age, the analysis of safety data in a vaccine report should be stratified by patient subpopulation, which can include pregnant women and immunosuppressed or immunocompromised patients.
Vaccines tend to be multi-component products prepared using complex biological systems that are constantly evolving through technological advances but are also subject to more variability between manufacturing sites than other medicinal products. These factors can affect the safety profile of a vaccine through batch variability, so batch analyses may need to be included in the safety reviews of a vaccine report.
The data in a vaccine report should also be reviewed to characterise the product's safety profile with respect to the potential for local versus systemic adverse reactions, which supports the holder's refinement of the selected risk minimisation measures.
Benefit-risk assessment for vaccines
Vaccine-specific factors bring more complexity to the integrated benefit-risk assessment in a vaccine report. Prophylactic vaccines for infectious diseases are usually administered to an otherwise healthy population, including very young children and vulnerable people, so the acceptable level of risk is very low compared with medicines intended for serious illnesses such as cancer. Rightly or wrongly, this low acceptance of risk is often driven by public perceptions. Even so, benefit-risk assessments in vaccine reports need to consider the clinical consequences of contracting the vaccine-preventable disease. Because of the low acceptable level of risk, rare and non-serious events that may not significantly affect the benefit-risk assessment of other medicinal products can have a profound impact in the vaccine setting, and they are therefore reviewed with greater scrutiny in vaccine reports.
In stark contrast to many other medicinal products, there is arguably no such thing as an established safety profile in the vaccine setting, because the safety profile is liable to change over time through vaccine product variability arising from the manufacturing process and through potential changes in the strains of the organisms behind the target disease, which may also be affected by seasonal or geographical differences. This has significant implications for the integrated benefit-risk assessment in a vaccine report, because the benefit-risk balance is more dynamic and changeable than for many other medicinal products.
COVID-19 vaccines
On 13 November 2020 the European Medicines Agency and the national competent authorities of the EU member states published a safety monitoring plan for COVID-19 vaccines. The plan outlines how relevant new information emerging after the authorisation and uptake of COVID-19 vaccines in the pandemic would be collected and promptly reviewed. The safety of COVID-19 vaccines would be monitored under the good pharmacovigilance practices that apply to all medicines, but in view of the extraordinary circumstances the authorities planned several activities that apply specifically to these vaccines. Through these activities, the European medicines regulatory network would assess safety data emerging from a range of sources, such as spontaneous reporting and observational studies, address any potential safety concerns with appropriate regulatory action, and communicate with the public in a transparent and timely manner. The plan comprises new reporting obligations for companies, which would have to submit monthly safety reporting summaries in addition to the regular updates the legislation foresees. It also details the scientific studies already in place to monitor the safety, effectiveness and coverage of COVID-19 vaccines after authorisation, the exceptional transparency measures set up by the agency, and how the agency plans to engage with a wide range of EU stakeholders.
The agency also published guidance to support companies' preparation of risk management plans for COVID-19 vaccines, complementing the existing guidelines on the risk management plan format in the EU and the good pharmacovigilance practices. Its additional specific considerations address, for example:
- further information on vaccine safety that might be generated after marketing authorisation in special populations, such as the elderly, children or patients with comorbidities
- core requirements for lists of adverse events of special interest, methods used for signal detection, and follow-up of any safety signals identified in clinical trials
- submission of monthly summary safety reports by marketing authorisation holders to the agency, in addition to the usual periodic safety update reports
- traceability tools that can help record who has received which vaccine and from which batch
All activities that companies include in the risk management plan for a COVID-19 vaccine should take into account the agency's infrastructure to support the monitoring of the efficacy and safety of COVID-19 treatments and vaccines in day-to-day clinical practice.