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.



The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on

Click to Login as an existing user or Register so you can print this article.

In association with
Related Topics
Related Articles
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Mondaq Sign Up
Gain free access to lawyers expertise from more than 250 countries.
Email Address
Company Name
Confirm Password
Mondaq Newsalert
Select Topics
Select Regions
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of

To Use you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions