Clinical Evaluation of vaccines

By Prof. Guido RASI, Director Executif of EMA

Vaccines are arguably among the most cost-effective and successful interventions in public health. Regulatory authorities are responsible for evaluating vaccines prior to marketing authorisation and continually monitor vaccines that are placed on the market to ensure requirements for quality, safety and effectiveness are met.

Robust and established criteria for evidence to be generated during vaccine development are in place and illustrated in dedicated up to date guidance documents issued by EMA.

EMA also offers the possibility of scientific advice to discuss elements related to a specific vaccine, that cannot be addressed by guidelines.

Several new vaccines are currently under development. These cover pathogens for which a vaccine is not yet available or pathogens for which current options may provide further improvements. In order to efficiently advance the development of these vaccines, it has been advocated for a more conducive environment to foster vaccines research and development in the EU and retain the current vaccines expertise and infrastructure.

Innovative technologies such as nucleic acids and viral vectored vaccines, including heterologous prime-boost strategies, or alter- native routes of administration such as needle free mucosal administration, are emerging approaches requiring where an understanding of the underlining science is needed to establish regulatory requirements.

In early clinical studies, the aim is usually to determine safety and immunogenicity of the vaccine in a limited number of vaccinees, according to different doses and schedules, so to define the posology to be progressed into later clinical studies.

Research geared towards gaining more insight into the immune response that confers protection after vaccination or natural exposure would help in streamlining the development of new vaccines. In addition, new generation assays for both humoral and cell mediated immune responses could facilitate antigen(s) and regimen selection, and support definition of correlates of protection with major impact on the development process.

In case there is no immune marker that can be accepted as surrogate endpoint for protection, and whenever possible, studies to determine the efficacy of the vaccine in preventing the disease in the target population is required. Depending on the incidence of the infectious disease to be prevented, often these randomised studies require large sample sizes, in the order of the thousands, to meet the study objectives.

For several diseases and pathogens, the conduct of field efficacy trials is hampered by the relative rarity of cases that can be recruited in a reasonable timeframe. In such instances, provided feasible and scientifically adequate, approaches such as human challenge studies, or inferring protection from animal models of disease, have been proposed. More in-depth understanding of these models and their surrogacy is needed to help regulators in determining their value across the different development phases.

Late stage clinical trials usually provide major contribution to the safety database of the vaccine.

Besides standard requirement for the safety evaluation of medicinal products, adverse events of special interest following immunisation are proactively collected in the clinical trials. The actual size of the safety database at time of approval may vary for each vaccine depending on the identified potential risks. However, in principle the database should be sufficiently large to estimate the frequency of uncommon adverse events (occurring in- between 1/100 and 1/1000 vaccinated persons). Depending on the vaccine and the target population, there is a need to consider the number of subjects in the target population within a certain age range or belonging to any special population, e.g. immunodeficient subjects or pregnant women, to be included in the safety database.

After approval, there is a need to make sure that, vaccines are continuously monitored so that emerging information on their benefit risk balance is rapidly evaluated.

To facilitate this, risk management plans are put in place at time of approval summarising, among other aspects, the activities needed to gather additional information on the safety of the vaccine. Effectiveness studies, that reflect real-world efficacy in terms of both the direct and indirect effect of the vaccine, are in certain cases required as post-approval commitments. The existence of networks that can rapidly conduct safety and effectiveness studies in the post-authorisation phase would be instrumental for a timely and efficient collection of these data. Collaboration with public health authorities is often necessary to allow the conduct of these studies, which calls for a structured and transparent collaboration among the different stakeholders.

A platform that would enable the conduct of these studies across the EU would be of major public health relevance as it would support more rapid and better-informed public health policy decisions on vaccination in Europe through knowledge sharing and utilisation of common methodologies.

At the same time, it would also facilitate rapid and robust regulatory decisions on individual vaccines. Overall, provision of greater assurance on the robust evaluation of vaccine safety and vaccine effectiveness, would improve public confidence in vaccines and vaccination monitoring programmes.

Indeed, the growing phenomenon of vaccines hesitancy is negatively affecting vaccination campaigns in many countries in the EU and elsewhere in the world, with detrimental consequences on the ability to protect citizens and save lives due to the spread of vaccine preventable diseases. Regulators have a major role to play in improving transparency and providing easily accessible way information on vaccine product ingredients and the assessment of quality, safety and efficacy, including safeguarding their scientific integrity.

The collaboration with ECDC, health care professionals and other authorities around the world, to raise awareness on safety and effectiveness of vaccines, and the creation of an EU vaccination portal to proactively share information on vaccines and vaccination in the EU, are important steps forward in that regard.