A wide variety of initiatives have been implemented at various level of the European institutions in order to fight against the diffusion of the Sars-Cov-2 virus. Among these are the institution of the EMA pandemic Task Force Covid-ETF and the Q&A document providing guidance to stakeholders on adaptations to the regulatory framework to address the new challenges, jointly published by the EU Commission, EMA and the European medicines regulatory network. These three actors also agreed on measures to face the impact of the epidemic on the due schedule of inspections of manufacturing facilities or other sites relevant for medicinal products in the European Union.

The Covid-ETF Task Force

The European Medicines Agency announced at the end of March 2020 the composition and objectives of its new pandemic Task Force, Covid-ETF. The task force has been set up in accordance with EMA’s Health Threat Plan and it is acting in support to the European Commission and Member States to cope with the spread of the epidemic, namely on aspects related to the development, authorisation and safety monitoring of therapeutics and vaccines intended for the treatment or prevention of Covid-19. The complexity of the new disease required EMA to revise the composition and line of action of its ETF so to face new challenges in terms of identification of the potential or repurposed medicinal products which may prove useful for prophylaxis or treatment, and the coordination of clinical trials across Europe.

The Covid-ETF is run under the supervision of EMA’s CHMP Committee and is chaired by the Agency’s scientific lead for the Covid-19 pandemic. Members include the heads of the CHMP, Paediatric (PDCO) and Pharmacovigilance Risk Assessment (PRAC) Committees and those of several EMA’s working groups (SAWP, VWP, IDWP, BWP, QWP, SWP, BPWP, CMDh), plus two additional representatives from the Co-ordination group for Mutual recognition and Decentralised procedures – human (CMDh) of the Heads of Medicines Agencies, two members from the Clinical Trial Facilitation Group (CTFG), and the CHMP Rapporteur and Co-rapporteur for products intended for treatment or prevention of Covid- 19, as well as three CHMP peer reviewers across all products. Specific experts from the rapporteurs’/peer reviewers’ teams may also be appointed, as well as a representative from Reference Member State (RMS) for products in the context of mutual recognition/decentralised procedures. Meeting of the Covid-ETF Task Force can be attended also by EMA’s Executive Director and representatives from the European Commission. Experts from other working groups (GCP IWG, PhV IWG, GMDP IWG) and observers from the WHO, the European Centre for Disease Prevention and Control or the EDQM (or other regulatory authorities) can be invited whenever appropriate. 

The mandate assigned to the Task Force includes the reviewing of all scientific data on Covid-19 medicinal products, including those requested to pharmaceutical companies. Preliminary discussion may also start with the interested parties, and comments on development plans is possible when formal rapid scientific advice is not feasible. The Task Force also provides support to run clinical trials in the European Union, and contributes to product-related assessment acting as peer reviewer and as forum for discussion on the rolling data assessment. The PRAC Committee’s activities also benefit from the work of the Covid-ETF, which is in charge of providing scientific input to committees and working parties and to draft scientific positions and input to public communications. 

The guideline on medicines to treat Covid-19

A Notice to Guidance on expectations for medicinal products for human use during the Covid-19 pandemic has been released on April 10th in the form of a Q&A document. The guideline, jointly developed by the EU Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group and EMA, describes how the traditional regulatory framework has been adapted to face the challenge to rapidly and safely identify useful treatments and vaccines against the virus.

The document specifies the procedures to rapidly obtain a marketing authorisation (MA) in other European countries for an already approved medicinal product, or how to activate compassionate use for not yet approved ones. MA holders unable to fulfil the deadlines for authorisation renewal due to the pandemic are advised to contact the relevant authorities. MAHs can also request an exemption to the sunset clause in view of exceptional circumstances and on public health grounds, should the launch of new products had to be postponed due to the health emergency. 

A very hot issue during last months was represented by the difficulties to guarantee a steady flow of APIs and intermediates from China and India for the manufacturing of medicines in Europe. Question 2.1 addresses how to rapidly add a new manufacturing site for part or all of the manufacturing process, in order to reduce the risk of shortages or disruption of supply. The chosen tool is an Exceptional Change Management Process (ECMP), that MAHs can activate for crucial medicines for treatment of Covid-19 patients. ECMP allows MAHs to source starting materials, reagents, intermediates or active substances from suppliers not specifically mentioned in the marketing authorisation “if that is necessary to prevent/mitigate shortages of supplies in the EU”. The same applies to using manufacturing sites or sites responsible for quality control that are not specifically mentioned in the dossier.

Question 2.2 describes how to handle possible issues with GMP certificates, as international inspections have been blocked with the global lockdown. For manufacturing sites located within the European Economic Area (EEA), the validity of GMP certificates should be extended until the end of 2021 without need for further action. The same applies to extra-EEA sites, unless the issuing/supervisory authority takes any action that affects the validity of the certificate. Should an inspection be required, and in case of no operational mutual recognition agreement (MRA) or scope not covered by the MRA, a distant assessment by an EEA supervisory authority may be conducted. In this case, the certificate will indicate that it has been granted on the basis of a distant assessment. The guideline also indicates that the pre-approval or routine on-site inspections will resume as soon as restrictions are lifted, according to a risk-based planning taking into account the date of the last inspection. 

GDP certificates should also maintain validity up to the end of 2021 (Q 2.3), in this case too due to the current difficulties to run inspections of distributors and wholesalers. 

According to Question 2.4, QPs can run remote batch certification, provided they have access to all information necessary. This provision is valid for all EU countries, also those which normally do not allow this type of remote procedure. QPs can also run paper-based audits of site supplying the active substance should the on-site audits not possible due to travel restrictions. 

QPs are responsible for the verification batches of investigational medicinal products imported from third countries are compliant with the terms of the clinical trial authorisation and manufactured in accordance with quality standards at least equivalent to GMP requirements applied in the EEA.

Regulatory authorities should be contacted by MAHs experiencing difficulties with the approved quality controls, so to present an adapted control scheme based on a risk-based approach (Q 3.1).

The guideline also provides indication of the priorities and timing to communicate adverse events for drugs used to treat Covid-19, including those used off-label (Q 4.1). Question 5.1 discusses issues related to labelling and packaging of products to be exported in other EU countries, establishing the possibility to avoid translation into the relevant official language if there are severe problems of availability of that medicinal product in the Member State. 

A fast-track route for the approval of Covid’s medicines and vaccines

The wide diffusion of the Covid-19 infection at the global level asks for accelerated regulatory procedures in order to rapidly make available new therapeutic options to patients. Together with our scientific committees and working parties, we have adapted our procedures in order to significantly shorten our own regulatory timelines for the review of new medicines and vaccines against Covid-19,” said EMA’s Executive Director Guido Rasi. “However, the rapid approval of therapeutics and vaccines will only be possible if applications are supported by robust and sound scientific evidence that allows EMA to conclude on a positive benefit-risk balance for these products.

The Agency’s emerging health threats plan represents the basis of EMA’s planning to make available accelerated procedures, which are managed for review by the above mentioned Covid-ETF Task Force. Rapid scientific advice is the central measure for new products under development, waiving the respective fees and with a length for the procedure reduced to 20 days. Rapid agreement of paediatric investigation plans (PIPs) and rapid compliance check are other options available, all requiring submission of a “well-prepared dossier” to EMA. Procedures of authorisation and post-authorisation are expected to require less than the standard 210 days maximum. Rolling review, in particular, can be used in a public health emergency to assess data for a promising medicine as they become available, while accelerated assessment can reduce the review time to less than 150 days.