Regulation of Vaccines in Europe

National Procedure

A national procedure applies when the manufacturer of a medicinal product or vaccine submits a marketing authorization application in a single member state where it intends to market the medicinal product or vaccine. This procedure for authorization of the product is the sole responsibility of the member states, and is only possible if the concerned medicinal product does not fall within the mandatory scope of the centralized procedure and if the application is submitted in only one Member State.

Decentralized Procedures

A medicinal product may receive a marketing authorization that is valid in more than one member state in the European Union by one of two decentralized procedures. In one, a marketing authorization application is submitted to more than one member state in parallel (referred to as decentralized procedure ). In the other, a member state grants the first marketing authorization, which is then mutually recognized in the other concerned member states chosen by the manufacturer of the medicinal product or vaccine; this is the mutual recognition procedure. Such procedures are facilitated by the Co-ordination Group for Mutual Recognition and Decentralized Procedures—Human (CMDh), which meets at the EMA monthly. The marketing authorization application submitted via one of these procedures (decentralized or mutual recognition) must be identical in all member states where it is submitted, including in the member state that conducts the primary assessment, called the reference member state.

Centralized Procedure

European Union (EU) regulations define which medicinal products must go through the centralized procedure to receive a marketing authorization that is valid for the whole of the EU. Annex I of Regulation (EU) No. 726/2004 specifies which medicinal products must be authorized by the centralized procedure (mandatory scope) (e.g., therapeutics intended to treat acquired immune deficiency syndrome (AIDS), cancer, neurodegenerative disorders, diabetes, auto-immune diseases, other immune dysfunctions, and viral diseases; advanced therapy medicinal products as defined in Article 2 of Regulation (EC) No 1394/2007 and medicinal products that are designated as orphan medicinal products pursuant to Regulation (EC) No 141/2000). ^, Vaccines mostly fall under the first indent of Annex I, that is, the centralized procedure is required for medicines that are developed by the following biotechnological processes: (1) recombinant DNA technology (e.g., Vaxchora) and (2) controlled expression of genes coding for biologically active proteins in prokaryotes (e.g., Cervarix, made using a Baculovirus expression system, and Gardasil produced in yeast cells) and eukaryotes including transformed mammalian cells. Vaccines containing a new active substance outside any of the mandatory categories defined in Annex I of Regulation (EU) No. 726/2004 may follow either the centralized procedure (under the optional scope) or the decentralized procedure. Any vaccines may be submitted centrally under one of the optional scopes, which covers products (1) that contain new active substances for indications other than those stated above; (2) that are a significant therapeutic, scientific, or technical innovation; and (3) whose authorization would be in the interest of public or animal health at EU level. In the case of the optional scope, the choice whether to follow the decentralized or centralized procedure lies with the applicant; however, the centralized procedure has clear advantages in terms of availability of pooled European expertise for assessment, harmonization across Europe, and immediate EU/EEA-wide marketing authorization.

The EMA and its Committee for Human Medicinal Products (CHMP ) is responsible for evaluating the quality, safety, and efficacy of medicinal products submitted through this procedure. The CHMP consists of one member plus an alternate for each EU member state as well as for Iceland, Liechtenstein, and Norway (European Economic Area countries), and five co-opted members selected based on their expertise and experience in evaluating medicinal products. The CHMP is assisted by a wide network of experts from all over Europe. The regulation allows the CHMP to establish working parties, such as the Vaccines Working Party and the Biologics Working Party, to draft guidance and advise the CHMP on specific aspects of product evaluation and supervision.

The CHMP relies on the recommendation of the Pharmacovigilance Risk Assessment Committee (PRAC ) for the evaluation of the Risk Management Plan (RMP).

The CHMP may also consult the Vaccines Scientific Advisory Group (SAG Vaccines ), which includes experts on vaccines from outside of the regulatory network and additional ad hoc leading experts in a vaccine or discipline-specific field based on the content of the questions posed by the CHMP. Scientific advisory groups assist the CHMP on specific questions, especially in cases where there is a divergence of scientific opinions at the level of the Committee.

The scientific review of a marketing authorization application is performed to the highest scientific standards, following a flexible timetable. The total duration to assess a marketing authorization application, draft and discuss reports, and adopt an opinion should not take more than 210 days. This duration can be shortened under certain conditions. Although the dossier submitted by the marketing authorization holder forms the basis for the evaluation of the benefits and risks of the vaccine, other sources of information, including the ECDC, national research institutions, academia, or the World Health Organization (WHO), might, in addition, be consulted during a scientific assessment. The result of the evaluation is a positive (favorable) or negative (unfavorable) CHMP opinion to recommend the European Commission on granting a marketing authorization for the medicinal product.

Three types of marketing authorizations can be recommended by the CHMP: standard marketing authorization, conditional marketing authorization, and marketing authorization under exceptional circumstances.

A standard marketing authorization is agreed on by the CHMP for a medicinal product for which a positive benefit-and-risk assessment has been concluded based on a comprehensive dataset in line with relevant scientific guidelines.

A conditional marketing authorization may be recommended by the CHMP for certain categories of medicinal products and in certain situations, when, in order to meet unmet medical needs and in the interests of public health, it may be necessary to accept data that at that stage are still less complete than in normal circumstances. Therefore such authorization is subject to specific obligations to provide the missing data by prespecified timelines. The products concerned cover also medicinal products to be used in emergency situations in response to public health threats duly recognized either by the WHO or by the EC. A conditional marketing authorization is valid for 1 year and is renewable until the specific obligations are fulfilled, after which it can be converted to a full marketing authorization.

The CHMP may recommend granting a marketing authorization under exceptional circumstances, subject to specific conditions, if the applicant can justify that comprehensive data on the efficacy and safety under normal conditions of use may never be provided for one of the following reasons :

• The indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence.

• In the present state of scientific knowledge, comprehensive information cannot be provided.

• It would be contrary to generally accepted principles of medical ethics to collect such information.

In all instances, the final opinion adopted by the CHMP is sent to the European Commission. If the EC standing committee’s opinion is favorable, the European Commission issues a formal decision that serves legally as the EU marketing authorization, which is valid in all member states throughout the EU/EEA. Following the Commission’s Decision, the EMA publishes the European Public Assessment Report after deleting commercially confidential information.

Efficacy

Ideally, protective efficacy studies are necessary for authorization of new vaccines. However, in some situations, efficacy studies are either not necessary or not feasible, and the use of immunogenicity endpoints to predict protection against disease can be justified as a surrogate of efficacy. Examples include cases such as:

• Efficacy trials are not needed if an immunological correlate of protection against a specific infectious disease (e.g., diphtheria, tetanus) has been established.

• Efficacy trials may not need to be conducted if estimation of protective efficacy is not feasible because the potentially preventable infectious disease does not occur (e.g., smallpox, anthrax, H5N1 influenza) or occurs at a rate too low (e.g., brucellosis, Q fever) or in unpredictable short-lived outbreaks (e.g., some viral haemorrhagic fevers) for a study to be performed in a reasonable timeframe. In such cases, unless an immune correlate of protection exists, the efficacy of a new vaccine may be estimated by comparing its immune responses with those seen in past studies of similar authorized vaccines with proven protective efficacy (e.g., acellular pertussis vaccines, pandemic influenza, or vaccines against HPV).

In the case when a protective efficacy study is not performed, the applicant needs to provide a sound justification for the lack of such data.

The protocols used for studies of protective efficacy should include a rationale for the choice of the study population and a detailed description of the methods used for diagnosing infection (e.g., clinically apparent or inapparent infections). In principle, validated methods should be used for diagnosis or for other evaluations (e.g., histology or RT-PCR methods).

Vaccines intended for prophylaxis against a newly emerging infectious agent, such as SARS-CoV-2, should preferentially demonstrate efficacy in preventing clinically apparent disease in a large phase 3 randomized double blind clinical trial. Ideally, prevention of symptomatic disease of any severity should be considered as a primary endpoint, in line with a potential indication, whereas prevention of severe outcomes (e.g., prevention of severe disease or hospitalization/death) or prevention of infection could be considered as secondary endpoints. However in other cases (e.g., ZIKA), design and feasibility of clinical efficacy trials might be challenging. Special trial designs are acceptable to streamline development such as ring vaccination as it was used for Ebola in 2016 or phase 1/2/3 adaptive design as for SARS-CoV-2.

Regardless of how large a phase 3 pivotal efficacy and safety trial could be, demonstration of reduced pathogen transmission may not be expected, and may only be established by means of observational studies conducted post-authorization during mass vaccination campaigns. Similar considerations apply to the possibility of identifying potential rare and very rare adverse events during clinical development. Therefore, post-authorization safety surveillance and effectiveness studies are critical, especially in an emergency context where millions of people are expected to be vaccinated in a short time frame. Plans to evaluate vaccine safety and effectiveness in real life settings should be included in the RMP and assessed by EMA prior to authorization.

Other Approaches for Estimating Vaccine Efficacy

Special considerations apply to clinical development of vaccines when (1) protective efficacy studies are not feasible, (2) there is no possibility of comparing immune responses between a candidate vaccine and a licensed vaccine for which there is documented efficacy or effectiveness, and (3) when there is no established immunological correlate of protection. This is the case, for example, of vaccines intended to prevent rare infectious diseases or pathogens that cause unpredictable outbreaks or epidemics and that carry considerable morbidity and mortality, including widespread disruption to the human population after deliberate release or after spillover to humans. In this case a potential approach to authorization should be discussed with the Agency.

As an alternative route to efficacy or comparative immunobridging trials for authorization, it may be possible to obtain an estimate of vaccine efficacy from a human challenge study, provided a suitable challenge strain can be identified and an effective treatment is available if needed. Limitations to this approach, beside the ethical aspects and availability of rescue therapy, include the need to use a specific inoculum or an attenuated strain, which may hamper interpretation of results. Therefore, the use of this approach for regulatory purposes will have to be considered on a case-by-case basis.

In some cases, the only option may be the use of data on protective efficacy from challenge studies in animal models and then infer protection in humans based on comparison of key immune markers. For example, for the authorization of some Ebola vaccines, vaccine-induced antibodies in clinical trials participants were of similar magnitude to antibodies with a protective effect against a rapidly progressing lethal Ebola virus infection in nonhuman primates. If possible, immunogenicity studies should focus on measuring functional immune responses. Taking the results of these and any other relevant investigations together (e.g., passive immunization studies using animal or human sera), a risk-to-benefit relationship could be derived that might support authorization.

In these contexts, it becomes very important that studies to estimate vaccine efficacy or effectiveness are conducted post-authorization whenever possible. It is also likely that reliable data could be obtained only from national surveillance programs operated by public health authorities or those coordinated by the ECDC. Applicants are encouraged to work with public health authorities to develop plans that would allow collection of data on safety and efficacy if the opportunity arises (e.g., a significant outbreak or major epidemic).

Immunogenicity

Immunogenicity data to characterize the immune response to the vaccine and to support the development of a specific posology need to be collected under all circumstances.

With special emphasis for novel vaccines, or vaccines against a newly emerging health threat, a thorough characterization of the immune responses induced by the vaccine is expected to be conducted in early clinical trials and, before that, in adequate animal models for the disease to be prevented. A well-justified dose-finding investigation should be put in place, especially when adjuvants are intended to be included in the vaccine formulation for inducing broader immune responses or for antigen sparing.

Safety

Safety data should usually be collected after each dose of the vaccine. Because most adverse reactions to vaccines occur within the first few days after each dose, it is generally accepted to focus the collection of information on solicited adverse events that occur within 5–7 days after vaccination (longer for live vaccines), and to collect all other unsolicited adverse events at trial visits or remotely for the duration of the trial. As already mentioned, in most cases it is not reasonable to expect that the pre-authorization safety database is sufficiently large to identify rare adverse events. As a minimum, the total data from pre-authorization studies should be sufficient to reliably determine the frequency of uncommon local and systemic adverse events that have an incidence of between 1 per 100 and 1 per 1000 vaccinated persons. Unless otherwise justified depending on for example, existing knowledge on a specific vaccine platform, the recommended minimum sample size should be at least 3000 subjects for new vaccines, provided no unexpected safety issues are identified during development that may require a larger safety dataset preapproval. Certain vaccines, such as those containing novel adjuvants, may have to provide additional evidence of their safe use.

Differences in the safety profile might be observed between certain subpopulations (e.g., children or older adults vs adults, or frail vs healthy individuals) and also with consecutive doses during the immunization schedule. In these cases, it may be necessary to obtain sufficient data to detect at least uncommon adverse events in various subsets before a marketing authorization could be granted.

The duration of the safety follow-up in the pivotal clinical trial(s) can be variable and should consider specific uncertainties (e.g., 3 years for dengue due to potential risks of enhanced disease following natural infection of vaccinated individuals).

An adequate characterization of the risks should be available from relevant animal studies (including GLP-compliant studies where applicable) prior to start of first in human trials. This was the case for the theoretical risk of vaccine-associated enhanced disease (VAED) with SARS-CoV-2 vaccines.

Considerations for Data Requirements During Public Health Emergencies

In accordance with Article 14-a of Regulation (EC) No 726/2004, a positive opinion for a Conditional Marketing Authorization (CMA) can be recommended by the CHMP prior to the availability of comprehensive efficacy or safety data if a full dataset can likely be obtained post-authorization. A CMA is an important tool to allow for a medicine or a vaccine to become available sooner to address an unmet medical need *

* As defined according to art 14-a comma 2 of Reg 726/2004.

against a seriously debilitating or life-threatening disease including during emergency situations, such as the COVID-19 pandemic. In emergency situations, a marketing authorization for such medicinal products may be granted also where comprehensive nonclinical or pharmaceutical data have not been supplied.

The submission within prespecified timelines of a full dataset shall be legally imposed on the manufacturer by means of so-called specific obligations to the marketing authorization. Other essential requisites for a CMA to be applicable include: (1) the available data, albeit not comprehensive, are in any case sufficient to conclude on a positive benefit/risk balance for the medicine/vaccine, and (2) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required. A CMA can be converted into a standard MA once the CHMP considers that comprehensive data is available and confirm positive benefit-risk balance.

For conditional approval during an emergency situation, efficacy data from the primary analysis of an adequately powered trial are expected to be available at the time of opinion. In certain cases, and depending on the perceived emergency of the situation, data from a prespecified successful interim analysis could be accepted to support an early decision, if compelling. Safety and tolerability data should as a minimum cover the timeframe in which most adverse events are known to occur (i.e., 4–6 weeks after the last dose of the primary vaccination series). Trials are expected to continue in a blinded fashion until study end in order to allow for collection of long term safety and efficacy data, even if the primary objective was met or the vaccine was approved. Submission of these data and of full clinical trial reports shall be imposed as specific obligations in the context of the CMA.

This was the case for several SARS-CoV-2 vaccines that were authorized with unprecedented speed during the COVID-19 pandemic.

As previously mentioned, a CMA is applicable also in cases where pharmaceutical data are incomplete at the time of opinion. For example, this was the case for Ervebo, for which data on certain manufacturing process details, including the confirmation of the validated status of the active substance and finished product manufacturing process, comprehensive comparability data to confirm the representativeness of the material used in the clinical trials, additional process validation/process performance qualification data were submitted postapproval within a year from opinion.

During an emergency, the acceptability of specific risks associated with vaccination has to be contextualized with the benefits associated with vaccination at a personal and population level and with the specificities of the emergency and the public health needs in the EU. This is the case for example for very rare adverse events such as thrombosis with thrombocytopenia syndrome (TTS) or myocarditis which have been associated with some SARS-COV-2 vaccines. In the context of the morbidity and mortality associated with the disease and the high expected benefits of the vaccines against severe outcomes and death, the benefit/risk is considered positive.

Risk contextualization is normally performed by Public Health Authorities and National Immunization Technical Advisory Groups (NITAGs ), which at the level of the EU Member States have to decide on the most appropriate vaccination strategies for the specific local situation.