In March, most European Union (‘EU’) countries ordered some form of lockdown and adopted many national measures to address or prevent issues raised by COVID-19. The health crisis pushed national authorities to focus on their respective populations and needs, but measures were also adopted at the European level. The European health regulators, i.e., the European Commission (‘EU Commission’), European Medicines Agency (‘EMA’) and Heads of Medicines Agencies (‘HMA’) (collectively ‘European Regulators’), worked together and tried to coordinate national actions.
This alert is threefold. After having identified the main measures adopted by the European Regulators with regard to medicinal products and medical devices (A), it discusses the Guidance on the Management of Clinical Trials During the COVID-19 Pandemic and, in particular, the direct supply of investigational medicinal products to trial subjects, an issue that is approached differently by the Member States (B). The alert then explains the Q&A on regulatory flexibility for medicinal products, insisting on the aspects that concern all medicinal products (C).
While those guidelines help companies adapting to the new environment, their implementation may prove challenging, especially in cases of divergent national measures. King & Spalding’s European regulatory lawyers assist sponsors in addressing conflicting issues (patient safety, trial integrity, ethics), drafting standard operating procedures and structuring appropriate documentation for their changes to ongoing clinical trials. They advise holders of marketing authorizations on regulatory issues arising out the pandemic and, more generally, companies on the manufacture and distribution of essential health products and help them navigating national divergences.
The European Regulators are working together in the fight against COVID-19 and the resolution of the health problems they create. Exhibit 1 below contains a list of the main EU guidelines adopted for medicinal products and medical devices since the beginning of the health crisis.
With regard to medicinal products, the EMA participates in the EU Executive Steering Group on shortages of medicines caused by the COVID-19 infection (‘EU Executive Steering Group’), and has set up a COVID-19 EMA Pandemic Task Force (‘COVID-ETF’) to assist Member States and the EU Commission in dealing with development, authorization and safety monitoring of therapeutics and vaccines intended for treatment or prevention of COVID-19. The EMA also participates in the International Coalition of Medicines Regulatory Authorities (‘ICMRA’), an international collaboration for the development of treatments against COVID-19.
Several guidelines have been adopted so far, including those discussed below on the management of clinical trials and regulatory flexibility and the Guidelines on the optimal and rational supply of medicines to avoid shortages during the COVID-19 outbreak (EU Commission, 8 April 2020). These last guidelines recommend measures to Member States and thus only indirectly impact companies. With regard to supply, the recommended actions are: increasing and reorganizing production; ensuring manufacturing continues at full capacity; implementing regulatory flexibility; monitoring available stocks at national level; ensuring necessary support to the wholesale sector; fully enforcing the green lanes; facilitating air freight and other forms of transport; and ensuring fair distribution.
The EU Commission also took measures in relation to medical devices, the most important of which probably is to propose postponing the application of the new Medical Devices Regulation by one year, from May 2020 to May 2021. No such postponement is proposed for the new In Vitro Devices Regulation. The EU Commission also adopted a general Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the COVID-19 context (EU Commission, 4 April 2020) that indicates the applicable rules that have been or may be adapted due to the COVID-19.
The European Data Protection Board (“EDPB”) is active as well. Recently, it announced a guideline on the processing of health data for research purposes in the context of the COVID-19 outbreak. Mid-March, it already published a Statement on the processing of personal data in the context of the COVID-19 outbreak, stressing that data controllers and processors must ensure the protection of personal data, even in these exceptional times. Emergency is a legal condition that may legitimize restrictions of freedoms but only if these restrictions are proportionate and limited to the emergency period.
ONGOING CLINICAL TRIALS
Ongoing clinical trials are significantly affected by the coronavirus that prevents trial subjects from going to investigating sites or meeting investigators, and forces healthcare professionals, health institutions and, more generally, the entire medical community to focus on treatments against COVID-19. In mid-March several national regulators provided guidance to help sponsors deciding on and handling the changes to be made to ongoing clinical trials due to COVID-19. The European Regulators then stepped in and adopted a guideline - Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic - on 20 March 2020 (‘EU CT Guidance’).
The EU CT Guidance was updated on 27 March (Update of Guidance on the management of clinical trials during the COVID-19 pandemic) and a new update is expected by the end of April. Moreover, on 25 March, the CHMP published a draft “Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials” for public consultation.
The EU CT Guidance, which primarily addresses sponsors, covers ongoing clinical trials and clinical trials for treatments of COVID-19. It is very similar to the FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic.
With regard to ongoing clinical trials, the EU CT Guidance requires sponsors to conduct a risk assessment of each trial and, on that basis, to decide the changes to be brought to the trial in order to secure, first and foremost, trial subjects’ safety and then trial integrity. Any change has to be thoroughly documented in view of future GCP inspections. The EU CT Guidance discusses specific changes such as remote monitoring and auditing and related issues such as informed re-consent and financial compensation. It also explains the formalities to be carried out – or not – to implement those changes.
While the EU CT Guidance tries to harmonize the national positions, it stresses that national measures may have been adopted that complement it or prevail over it. In doing so, the EU CT Guidance expressly references national law concerns such as remote source data verification and the supply of investigational medicinal products (IMP) to trial subjects.
COVID-19 impedes trial subjects’ visits to sites and investigators, and therefore the supply of IMPs to trial subjects. The EU CT Guidance indicates changes that can be made to provide trial subjects with the IMP and non-IMP as needed according to the trial protocol. Those changes have to be reflected in the protocol and communicated to the competent regulatory authorities.
- The following measures can be considered as long as that they do not create shortages of marketed medicinal products:
- Larger amounts of trial medications than normally foreseen can be provided to the trial subject in order to sustain him for a longer period and thereby avoid non-critical visits to the investigator site. This option however requires that the continuation of treatment is under adequate supervision of the responsible investigator.
- An appropriate stock of trial medications should be maintained to ensure treatment in case of distribution failure.
- In case of urgent shortage of IMP at some sites and a direct distribution of the IMP to a site by the usual distributor is not possible, the IMP may be re-distributed between sites in accordance with GMP Annex 13 (section 47). The same applies in case of transfer of trial subjects from one site to another site.
- Following the reduction of physical site visits, a delivery of the IMP directly to trial subjects is generally accepted but from investigating sites. Direct IMP delivery from sponsor to trial subjects is only accepted in a few Member States and strictly during this emergency situation; hence, the EU CT Guidance advises sponsors to check national guidelines. Exhibit 2 below reproduces national guidelines on the management of IMPs.
What about medical devices? No EU guidance on management of clinical investigations during COVID-19 has been adopted. However, certain national guidelines on clinical trials specify that they cover both medicinal products and medical devices (for example, Portugal), and in practice, national competent authorities and ethics committees apply the same principles as for clinical trials.
On 10 April, the European Regulators published a Q&A on Regulatory Expectations for Medicinal Products for Human Use during COVID-19 Pandemic (EU Regulatory Q&A) that provides guidance to holders of marketing authorizations (‘MAH’) on regulatory expectations and flexibility during the COVID-19 pandemic. The Q&A is divided in four sections - MA, manufacturing, quality and product information. It only includes six questions but will be regularly updated; additional questions on Good Manufacturing Practice are expected very soon.
Some questions concern products that are crucial for treating patients with COVID-19:
- Can medicinal products intended for use in COVID-19 patients be marketed without MA?
- How can changes in the manufacturing/supply chain be implemented swiftly to ensure continuity of supplies to the EU of crucial medicines for treatment of COVID-19 patients?
- Can quality requirements be waived/adapted for medicines intended to be used for the treatment of COVID-19 patients?
The EU Regulatory Q&A however neither defines nor lists those crucial products. We note that companies should identify any regulatory action relating to COVID-19 by “CONCERNS COVID-19” in order to secure a quicker treatment of their applications/requests.
Other questions apply to all medicinal products:
- Can a renewal application be postponed? MAHs facing difficulties in submitting renewal applications, including for conditional MA, within the regulatory deadline (at least 9 months before expiration) due to exceptional circumstances arising from the COVID pandemic, should contact the competent health regulator and file a justified request to postpone the submission.
- Does the 'sunset clause' apply? MAHs are reminded of the possibility of requesting an exemption in view of exceptional circumstances and on public health grounds. During the pandemic, the EU Commission may accept sunset clause requests that are based on the pandemic, without the need for any further justification.
- Is there any flexibility in the labelling and packaging requirements to facilitate the movement of medicinal products within the EU? It is necessary to facilitate the movement of medicinal products within the EU so that they can be made available in the Member States where they are needed the most. During the COVID-19 pandemic, Member States may accept that: the product information is not translated into the relevant official language; national specific information does not appear in the packaging/labelling; and the presentation differs from the authorized presentations. The CMDh has agreed to apply the labelling and packaging flexibilities to crucial medicines for use in COVID-19 patients, and further guidance on specific national requirements/procedures will be developed by CMDh.
What about medical devices? Like for medicinal products, the EU guidelines permit derogations from the applicable rules but primarily for the devices that are essential in relation to COVID-19. The EU Commission’s Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the COVID-19 context, for example, indicates that Member States may authorize the marketing of individual medical devices for which the required conformity assessment procedure has not been conducted. The Guidance lists the factors to be taken into consideration by the Member States when deciding on requests for derogation, which should be temporary (the device becomes compliant, suitable substitutes become available, the health crisis disappears).
The European Regulators have adopted guidelines to help companies adapting to the new environment created by COVID-19. The implementation of those guidelines however may be challenging. On the one hand, the guidelines set out general principles to be applied on a case by case basis. On another hand, the EU guidelines are based on national measures, which they try to coordinate, and national divergences remain.
More generally, the steps taken in the EU illustrate future legal and regulatory needs. There is a pressing need to permit, encourage and organize more ‘remote’ activities, in particular for clinical trials, and the following months will show whether remote activities are valid alternatives for clinical research. There also is a pressing need to regulate supplies at the European level rather than at the national level to avoid shortages in and ensure equitable supplies to all EU countries.
King & Spalding’s experienced European regulatory lawyers assist sponsors in addressing conflicting issues (patient safety, trial integrity, ethics), drafting standard operating procedures and structuring appropriate documentation for their changes to ongoing clinical. Risk-assessments should be conducted in the framework of a written policy and procedure, with documentation of the decision-making, and decision-making may require rapid revision of study documentation, review/revision of existing contractual arrangements, personnel training, and thoughtful recordkeeping. Furthermore, our lawyers advise MAH on regulatory issues arising out the pandemic and help companies distributing essential health products and navigating national recommendations.