Monia Nica outlines the temporary changes to European regulatory requirements spurred by the coronavirus pandemic

COVID-19 has had a huge impact on European regulatory activity. Peaks in demand for certain product groups, and disruption to production and to supply chains, have put pressure on international medicines companies. Regulatory authorities have had to respond to this, and to their own challenges in managing administrative processes when offices have been closed and the usual administration has come up against practical constraints and delays.

To ease the strain and maintain vital supplies, the European Commission, European Medicines Agency and Heads of Medicines Agencies published updated guidance in April, featuring some agreed measures to promote new flexibility and simplified and accelerated authorisation procedures. Here, Monia Nica, Senior Regulatory Affairs Manager at Arriello, summarises the main changes, many of which will stay in place until at least the end of this year.

Necessity is the mother of invention and, at the peak of the COVID-19 pandemic, due to potential threats to essential product supply and challenges managing the usual regulatory administration processes, agencies across Europe joined forces to determine how best to maintain continuity of drug availability.

Although high safety standards had to be upheld, the authorities needed to find a workable solution to keep pipelines moving. 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).

The measures have implications for marketing authorisation and regulatory procedures; manufacturing and importing; GMP and GDP (Good Manufacturing/ Distribution Practice) certificates and

inspections; critical change management; labelling and packaging management; and pharmacovigilance/adverse event reporting.

In many cases, the new guidelines offer a welcome aid to life sciences companies trying to maintain market availability of critical medicines. However 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, and what do MAHs need to know?

1. 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. For this reason, 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.

2. Relaxed renewals & sunset clause requirements.

In recognition of the exceptional circumstances currently, requirements around renewals’ dossier submissions have been relaxed so that postponement is acceptable if the request is justified: ie the dossier could be submitted after the usual deadline. Under normal circumstances, failure to file on time can lead to marketing authorisation invalidation with the potential for gaps in supply.

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.

3. 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 much simpler than it would have been. 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.

4. 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.

5. 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.

6. 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

7. 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.

Beyond the small print

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 Organisation, it could fall into a grey area – potentially leading to supply issues if manufacturing capacity is restricted. Addressing additional capacity might require specialist help, for instance, if issues arise around serialisation 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. For instance, EMA has issued its own specific guidance on accelerated review procedures for potential COVID-19 vaccines and other potential breakthrough products. This includes accessing rapid scientific advice – in support of evidence generation planning for treatments and vaccines for COVID-19 – a review process which must now happen within 20 days, in contrast to the standard 40-70 days.

It all adds up to a lot of information to digest, though many of the measures make good practical sense. To keep abreast of the latest developments, MAHs should check the agency websites periodically, or consult an external regulatory advisor.

Monia Nica is senior regulatory affairs manager at market access, regulatory affairs and pharmacovigilance solutions and services group Arriello