European Union: European Medicines Agency (EMA) Issues Updated Rules For Clinical Development Of Vaccines

EMA launches public consultation on revised guideline on clinical evaluation of vaccines

On April 26, 2018, the European Medicines Agency (EMA) released a revised guideline on the clinical evaluation of vaccines23 for a six-month public consultation. This guideline addresses the clinical evaluation of vaccines intended for the prevention of infectious diseases. It includes considerations for trials intended to document the safety, immunogenicity and efficacy of new candidate vaccines and to support changes in the prescribing information of licensed vaccines. It also considers the need for and use of vaccine effectiveness studies.

Since the adoption of EMEA/CHMP/VWP/164653/2005, many new vaccines have been approved in the EU or have received a positive opinion under Article 58 of Regulation (EC) No 726/2004, including several vaccines intended to prevent infectious diseases for which there was previously no vaccine available. Some of these vaccines include antigenic substances from multiple pathogens or from multiple subtypes of a single pathogen. These applications have raised several issues for vaccine clinical development programmes that were not addressed in the previous guideline. Furthermore, there have been requests for scientific advice on vaccine clinical development programmes which point to the need to provide updated or additional guidance on some issues like considerations for conducting vaccine efficacy trials, identification of immune correlates of protection, vaccines intended to be used in heterologous prime-boost regimens and vaccines to be administered to pregnant women to protect their infants during the first months of life.

Vaccines undergo a rigorous scientific review to ensure that they are safe and effective. The updated guideline introduces additional safeguards for European Union citizens and ensures that the evaluation is in line with the most up-to-date scientific knowledge and technological developments.

In response to recurring issues arising in scientific advice and in application dossiers, this revised guidance includes a discussion of factors to consider when planning and interpreting the results of comparative immunogenicity trials. For example, the importance of considering the severity, mortality and/or risk of permanent sequel ae of the infectious disease to be prevented as well as the robustness of the assays to determine the immune response when selecting non-inferiority margins and assessing the clinical impact of failing to meet pre- defined criteria. In trials that compare candidate and licensed vaccines containing antigens from different numbers of subtypes of the same organism consideration is given to interpretation of immune responses to non- shared subtypes.

The revised version of the guideline also adds considerations to priming and boosting strategies, including the option of heterologous prime-boost, which entails administration of one type of vaccine first followed by a different type of vaccine for the same pathogen later. The need to develop vaccine for pathogens that may cause future epidemics and for which conducting clinical trials outside of outbreaks might be problematic, is also addressed.

EMA's draft guideline includes specific considerations for clinical trials with vaccines in special populations such as:

1. Pregnant women: Vaccination during pregnancy may have one or more of the following aims: i) to protect the pregnant subject; ii) to protect the fetus from intra-uterine infection; iii) to protect the infant for as long as protective levels of maternal antibody persist in the post-natal period.

  • If the candidate vaccine is not approved for use in non-pregnant adults, safety and immunogenicity data should be obtained from non-pregnant female subjects of childbearing age before proceeding to trials in pregnant subjects. Safety and immunogenicity trials to support selection of dose regimens should enroll subjects at a stage of pregnancy appropriate to the primary objective, i.e. as early as possible in pregnancy to protect the mother and/or fetus and later in pregnancy to maximize maternal antibody levels in the neonate.
  • If the primary aim of vaccination during pregnancy is to protect the infant in the first months of life, the dose-finding trials should include measurement of antibody levels in cord blood samples taken at delivery. The data should be sufficient to provide an estimate of inter-individual variability and to assess the effect of time interval between vaccination and delivery on maternal antibody levels in infants. The persistence of detectable maternal antibody in infants against the target organism should be evaluated as part of the dose-finding process. If the overall strategy involves vaccinating pregnant subjects followed by active vaccination of their infants against the same antigen(s), the antibody decay curve in infants may provide a preliminary indication of the timing of the first infant dose.
  • If an ICP is established for the infectious disease to be prevented and depending on the primary objective and the safety profile, the maternal vaccination regimen should maximise the proportions of pregnant women or cord blood samples with antibody that exceeds the ICP. If there is no ICP and there is no licensed vaccine of known efficacy to which the candidate vaccine could be compared (i.e. using immunobridging to infer efficacy), a vaccine efficacy trial would usually be necessary. In all trials conducted in pregnant subjects, adequate mechanisms should be in place to document the outcome of the pregnancy. For example, information should be collected on the duration of gestation, the condition of the infant at birth and any congenital conditions.

2. Elderlysubjects: For most vaccines, elderly subjects have lower responses to vaccination compared to younger subjects, which may reflect immunosenescence and/or the prevalence of specific underlying diseases or medications that have a negative impact on the immune system. On occasion, immune responses may be higher in the elderly if they are more likely, than younger adults, to have been primed by natural exposure or prior vaccination. Therefore, it is important that adequate dose-finding studies are conducted for vaccines proposed for use in the elderly and that all age subgroups are investigated (e.g. 65-74 years, 75-84 years and 85 years or more) to determine whether different doses and/or regimens are needed as age increases.

If efficacy trials are to be conducted in elderly subjects, it is recommended that there be stratification by age sub- groups. Furthermore, the impact of any underlying conditions or medications known or likely to affect immune responses should be investigated during the clinical trials. The safety of vaccines in the elderly should be documented in subsets with certain underlying conditions and levels of frailty to determine whether the safety profile is broadly acceptable.

3. Immunodeficient subjects: Due to the wide range of types of immunodeficiency that may result from congenital or acquired conditions or from iatrogenic intervention, only some of which may impact on the immune response to a specific type of vaccine, trials that assess safety, immunogenicity or efficacy in a broad immunodeficient population are not recommended.

Trials intended to support dose recommendations for immunodeficient subjects should plan to enroll well- defined sub-populations of subjects with immune deficiencies that have been selected based on those most likely to affect the immune response to a specific vaccine. Unless there is a well-established ICP that can be applied to the data, the usual aim of such trials will be to identify a posology that achieves comparable immune responses to those observed in immunocompetent subjects.

It is not expected to be feasible to study all immunodeficient sub-populations. The extent to which any one posology may be recommended beyond the exact population in which it was studied must be decided based on what is known about the relative importance of different immunological parameters for protection.

Footnotes

23 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/04/WC500248095.pdf

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