The race to find a vaccine for the Sars-CoV-2 virus has encountered the first issue, as the development of the so-called Oxford vaccine (AZD1222) by AstraZeneca has now restarted after the short stop occured at the beginning of September following the observation of an unexplained possible severe adverse event occurred in the UK Phase 3 trial (see here AZ’s press release). Even if no further medical information will be disclosed, the sponsor communicated that trial investigators and participants will be updated with the relevant information to be disclosed also on global clinical registries, according to the clinical trial and regulatory standards. The decision to resume the trial was assumed on the basis of the considerations made by the independent committee called to review the data related to this event in order to establish if there is a cause relation with the vaccination. The AZD1222 vaccine is based on a replication-deficient chimpanzee viral vector using a weakened version of a common cold virus (adenovirus) containing the genetic material of the Sars-CoV-2 virus spike protein. The vaccination induces the production of the surface spike protein, which primes the immune system to attack the wild virus when it infects the body.

The EU Commission strategy for vaccines

The European strategy to accelerate the development, manufacturing and use of vaccines against Covid-19 was presented in mid-June by the European Commission. “Nothing is certain, but I am confident that we can mobilise the resources to find a vaccine to beat this virus once and for all. This vaccine will be a breakthrough in the fight against the coronavirus, and a testament to what partners can achieve when we put our minds, research and resources together”, said the European Commission president Ursula von der Leyen. The Commission’s expected timeframe for the availability of the new vaccine was between 12 and 18 months (thus up to end 2021). 

Quality, safety and efficacy is one of the main targets of the strategy, as for every new medicine under development. This shall parallel the swift and equitable access to vaccines for all EU’s Member States while taking also into account the solidarity needed at the global level.

Sufficient supplies to Member States shall be pursued by mean of Advance Purchase Agreements (APAs) closed with vaccine producers through the Emergency Support Instrument. APAs are to be signed directly with the single biopharmaceutical companies by the EU Commission on behalf of the Member States, and are based on the payment of part of the upfront costs of vaccines’ development in return for the right for governments to buy a specified number of doses in a given timeframe. To fund of this action the Commission is using part of the €2.7 billion Emergency Support Instrument, and a possibility to access loans from the European Investment Bank is also available.

Green light to GMO vaccines

In mid-June the EU Commission also proposed a new regulationon the conduct of clinical trials with and supply of medicinal products for human use containing or consisting of genetically modified organisms intended to treat or prevent coronavirus disease”, which is part of the European vaccine strategy. The proposal was adopted by both the European Parliament and the European Council one month later, in mid-July (see here the final text).

The initiative is aimed to solve issues posed by the GMO legislation with respect to the possible use of vaccines against the Sars-CoV-2 virus and which may fall within the definition of GMO (as for example the above mentioned Oxford vaccine), as they are based on genetically modified viruses. The Commission aims to adapt the regulatory framework to ensure a rapid clinical development of Covid-19 vaccines while safeguarding safety and efficacy for the volunteers participating to the trials and for the entire European population. 

The Coronavirus outbreak has created an unprecedented public health emergency. The development of vaccines and therapies against the virus is of major public interest and we are collectively called to make safe and efficacious medicinal products available to our citizens as soon as possible”, states the document. According to the regulation, Member States can authorise the supply and administration of medicinal products for human use (including those containing GMOs) even in the absence of a marketing authorisation in case of “urgent need to address the specific needs of a patient, for compassionate use, or in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation that could cause harm”. The protection of public health becomes in these instances the first priority, according to the Commission, and it must prevail over all other considerations.In the situation of public health emergency created by the Covid-19 pandemic, there is an overriding interest in protecting human health”, states the document. 

The approved text allows to derogate the need of prior environmental risk assessment or consent (a normal request for GMO products) for most operations related to the conduct of Covid-related clinical trials. The regulation is in any case limited in time: it will apply up to when the WHO will declare finished the pandemic, or upon the validity into force of an implementing act by the Commission recognising a situation of public health emergency due to Covid-19 (see also RAPS Regulatory Focus).

EMA’s infrastructure to monitor real-world development

The rapid evolution of the many Covid-19 vaccines towards advanced clinical phases and the eventual administration of the approved ones to the general population needs a parallel deployment of resources from the regulatory point of view in order to carefully monitor their real-world efficacy and safety. The European Medicines Agency (EMA) has announced at the end of July the creation of a dedicated infrastructure to support the monitoring of the safety and efficacy of Covid-19 treatments and vaccines used in day-to-day clinical practice. The real-world phase of development will be monitored by some academic and private partners that signed with EMA three distinct contracts for observational research.

The Utrecht University and the University Medical Center Utrecht will act as the coordinators of the CONSIGN project (‘Covid-19 infectiOn aNd medicineS In preGNancy’), aimed to collect data on the impact of the disease in different trimesters of pregnancy and on neonates (see here more details). The ConcePTION consortium established under the IMI Initiative (and part of the COVI-PREG project and the International Network of Obstetric Survey Systems-INOSS network) will also participate to the project. A global regulatory workshop to discuss these themes was also organised at the end of July by EMA in collaboration with ICMRA.

The private company IQVIA will be responsible for the building of a framework for the conduct of multicentre cohort studies on the use of medicines in Covid-19 patients. Among the main goals are the identification of large national cohorts and appropriate comparator groups, the development of a protocol template for multinational studies and the establishment of a collaborative framework for researchers. The project will also see the participation of the IMI’s European Health Data & Evidence Network (EHDEN) consortium, led by the Erasmus Medical Centre (Rotterdam, NL) and under the research coordination by the University of Oxford.

The ACCESS project (‘vACcine Covid-19 monitoring readinESS’) is another EMA’s initiative aimed to run preparatory research into data sources and methods to monitor the safety, effectiveness and coverage of authorised Covid-19 vaccines in the clinical practice. The infrastructure established by the Utrecht University will provide EMA additional pharmacovigilance information from spontaneous reporting – on the basis of a Europe-wide network of data sources, including health insurance records, GP and hospital health records – to be used for the Pharmacovigilance Risk Assessment Committee (PRAC)’s post-authorisation evaluation of new vaccines. This shall also support the identification of possible adverse events of special interest needing extra consideration by PRAC.

The Agency is also working to optimise regulatory guidance to companies involved in vaccines and medicines development for Covid-19. Under its coordination, for example, the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) has published the 8th revision of the ENCePP Guide on methodological standards in pharmacoepidemiology, which provides important highlights to plan Covid observational studies. ENCePP has also set up a dedicated Covid-19 response group; the advice is to enhance transparency through the registration of pharmacoepidemiological studies in the European Union electronic register of post-authorisation studies (EU PAS Register) and make study protocols and reports public.

Finally, EMA is also collaborating at the international level with the International Coalition of Medicines Regulatory Authorities (ICMRA) to improve cooperation in the areas of pregnancy research, building international clinical cohorts of Covid-19 patients and preparing a strong infrastructure for monitoring the safety and effectiveness of vaccines.

EFPIA on Covid-19 vaccine’s safety

The Federation of the European Pharmaceutical Industry Associations published at the end of August a statement to reassure on the attention producers are paying towards the safety of Covid-19 vaccines under study. The need to rapidly achieve the final goal and make a vaccine available is reflected by the fact that “work that would normally happen sequentially over time is now being run in parallel but never at the expense of safety or quality”.

Post-approval safety monitoring is already planned also from the producers perspective, and the administration of millions of doses around the world would make reasonable and possible that “some people receiving a Covid-19 vaccine will experience medical events following immunisation”. According to EFPIA, such an occurrence would be similar to all other medicinal products (including vaccines), as a result of the specific reactions that might affect single individuals. 

EFPIA’s statement indicates the will of the pharmaceutical industry to collaborate with governments to develop a system of compensation for the people that may result impacted by vaccine’s side-effects “Any system should aim to get the right level of compensation to the right patient when they need it, avoiding endless delays through prohibitively expensive litigation with uncertain outcomes”, states EFPIA. Discussions are ongoing to define the system’s mode of operation, says the statement. 

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