The coronavirus has had an enormous impact on European regulatory activity. To ease the strain and maintain vital supplies, the European Commission, European Medicines Agency, and Heads of Medicines Agencies published updated guidance in April, including new flexibility and simplified and accelerated authorisation procedures. Here, Monia Nica, senior regulatory affairs manager at Arriello, summarises the new allowances.
Masks
Potential threats to essential product supply due to Covid-19, and challenges managing the usual regulatory administration processes, have caused agencies across Europe to joined forces to determine how best to maintain continuity of drug availability. The result is a new set of guidelines for the exceptional circumstances triggered by the pandemic, published in April and last updated in July by the European Commission (EC), in collaboration with the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh), and the European Medicines Agency (EMA).
It is important that marketing authorisation holders (MAHs) are aware of all the amended requirements, so that they do not leave themselves open to gaps or delays in supply. So what’s changed?
Expedited approvals for Covid-linked products.
With so much research going on into potential treatments, aids and vaccines for Covid-19, speed to market is of the essence. The European authorities have agreed to a ‘zero-day’ mutual recognition/repeat use procedure so that applications for access to new/additional markets are not delayed by the usual rounds of administrative preparations. So if a drug is seen to help Covid-19 patients, it can be authorised and rolled out to other EU member states at an accelerated pace. Similar provisions have been made for helpful drugs identified in regions beyond the EU, to expedite their availability in Europe.
Relaxed renewals & sunset clause requirements.
Requirements around renewals’ dossier submissions have been relaxed so that if the request is justified, dossiers could be submitted after the usual deadline.
Additional flexibility has been extended around sunset clauses, too. Ordinarily these dictate that the marketing authorisation of a medicine ceases to be valid if the medicine is not placed on the market within three years of the authorisation being granted, or if the medicine is removed from the market for three consecutive years. As the pandemic continues to play out, extensions can be requested without the need for further justification if this is due to the pandemic.
Accelerated change management in the supply chain for critical Covid-19 medicines.
A new exceptional change management process (ECMP), applicable to critical Covid-19 medicines, allows for the swift implementation of changes in the manufacturing process or supply chain, to mitigate potential supply shortages. If an MAH needs to call upon active substances from suppliers that are not registered in the original dossier, for example, the procedure for logging that variation is now much simpler. Although as part of the commitment to safety and quality MAHs still need to notify the authorities about any changes within two days of implementation, they now have up to six months to submit the formal variation documentation. But crucially they don’t have to wait for approval before implementing the changes.
GMP/GDP certification & inspections.
Usually, Good Manufacturing and Distribution Practice (GMP/GDP) certificates are valid for five years and inevitably many expired during the global pandemic lockdown. To avoid gaps in product supply, authorities in Europe have extended current certificates until the end of 2021, without the need for any remedial action. This applies both to manufacturers and to importers of active substances and of finished medicinal products. Inspections, which cannot be conducted on site currently, may still be carried out through other channels – for instance, remotely.
Labelling flexibility.
To prevent updated labelling becoming a barrier to continuous product supply, requirements have been relaxed. For example, during the pandemic information may not have to be translated into the relevant official language if there are severe problems of availability of that medicinal product in a given EU member state.
Pharmacovigilance.
Guidance around pharmacovigilance (PV) inspections was added in July 2020. If on-site inspections of companies’ PV practices are not currently possible, evaluations could be conducted using alternative channels including conference calls and online document sharing. Where remote inspections and system audits are permitted, it is important that these continue. Submitting individual case safety reports (ICSRs) in a timely fashion and updating labelling continues to be a critical activity, and the latest guidance is available here: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/detailed-guidance-icsrs-context-covid-19-validity-coding-icsrs_en.pdf.
Actions by Qualified Persons.
Although attention to detail cannot slide whatever the circumstances, there is some leeway in how checks by responsible persons are carried out. This includes auditing active substance manufacturers and certifying their products for batch release, which can now be done remotely. Where on-site audits of contract acceptors are not possible, the Qualified Person can fall back on paper-based audits and take into account the results of inspections or audits performed by EEA authorities. Remote audits should provide confidence that the contracted party is fit for purpose and will not negatively affect the wholesale distribution process.
Other exceptions
Although the agencies have published details of all the latest guidelines, including Frequently-Asked Questions which they continue to update, there will always be situations that are not addressed directly by the published advice. If a medicinal product is discovered to help Covid-19 patients, for example, but is not mentioned officially by the World Health Organization, it could fall into a grey area - potentially leading to supply issues if manufacturing capacity is restricted.
Addressing additional capacity might require specialist help too, if issues arise around serialisation for instance, when drawing on an alternative, short-term arrangement for packing and distribution.
Navigating exceptional circumstances has become a full-time job for those advising and helping MAHs as they strive to maintain market availability of critical products. The individual agencies each have their own advice, too.
To keep abreast of the latest developments, MAHs should check the agency web sites periodically, or consult an external regulatory advisor.