The COVID-19 pandemic has had a dramatic impact on European health systems, whose priority first and foremost is the treatment of patients suffering from this disease both in the in-patient and out-patient sectors. At the same time, Europe's medical community is involved in clinical trials, both ongoing and scheduled, which are essential for the development of medicines, treatments and vaccines, including in the area of virology where a race is currently on to develop a pharmacological treatment for COVID-19. In light of the COVID-19 crisis, sponsors and investigators need to react to these circumstances and adjust how they manage their trials and the people who participate in them.
For clinical trials, practical questions include: What happens if trial participants need to be self-isolated or even quarantined? How is the study plan affected if access to public places, including hospitals, is limited due to the risk of spreading infections? What if healthcare professionals are reallocated to staff hospitals during the COVID-19 crisis or are quarantined themselves? And how to cope with possible shortages of medical products under investigation?
A new EU guidance now available harmonises these issues by helping sponsors and investigators manoeuvre during these uncertain times. On 20 March 2020, the European Commission, the European Medicines Agency (EMA) and the national Head of Medicines Agencies (HMA) published new recommendations on how to manage the conduct of clinical trials in the context of the coronavirus disease (COVID-19) pandemic.
New clinical trial guidance
The guidance provides concrete information on changes and protocol deviations, which may be needed in the conduct of clinical trials to deal with the fallout of the COVID-19 pandemic. According to the EMA, the guidance includes a harmonised set of recommendations to ensure the utmost safety of trial participants while guaranteeing the quality of the data generated during a trial. It also advises how these changes should be communicated to authorities.
By way of introduction, the guidance states that the situation is evolving and pragmatic actions may be required to deal with the challenges of conducting research and in ensuring the rights, safety and wellbeing of participants. According to the guidance, the impact of COVID-19 must be considered in the context of ongoing trials, the decision to open a new trial site in an existing trial, ongoing recruitment and the continued involvement of participants in the trial, or on decisions to start new trials. This guidance will almost certainly be updated, depending on further developments in the evolving situation.
As for scope, the guidance points out that clinical trials are often authorised and supervised at the EU member-state level, and as a result sponsors and investigators are advised to take into account any specific national legislation and directives that may be in place. These national regulations complement the guidance and may even take priority.
The core of the guidance is concrete recommendations regarding planned or ongoing clinical trials:
- New trials: the guidance recommends that the feasibility of starting a new clinical trial or including new trial participants in an ongoing trial should be critically assessed by sponsors.
- Ongoing trials: The guidance urges sponsors to consider in their risk assessment whether certain cautionary measures should be taken during the COVID-19 crisis, which include:
- Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only necessary visits are performed at sites;
- A temporary halt at some or all trial sites;
- Suspension or slowing down of recruitment of new trial participants;
- Extension of the duration of the trial;
- Postponement of trials or activation of sites that have not yet been initiated;
- Closing of sites; and
- Adopting additional measures to ensure patient safety.
- Risk assessment: The guidance reaffirms that all decisions to adjust clinical trials need to be based on a solid risk assessment by the sponsor, putting the safety of participants first, particularly in light of the added risks due to the COVID-19 pandemic.
- Communication with authorities: The guidance states that if a new event is likely to have a serious effect on the benefit-risk balance of the trial, immediate actions may be required by the sponsor and investigator to protect the subjects against hazards. If changes are likely to affect safety, but do not require immediate action, it should be possible to submit them as amendment applications. Sponsors are, however, encouraged to take into account the limited capacity of assessors, and submit only high-quality and complete applications containing only necessary changes. Over reporting should be avoided.
- Agreements and communication with sites: The guidance recommends modifying existing agreements with investigator sites to reflect, document and clearly communicate changes in how trials are being conducted. To support implementation at sites, changes and local implications must be made clear, including the marking of amended documents with track changes.
- Changes to informed consent: According to the guidance, sponsors should be mindful of the current pressures on the medical profession and should carefully assess the pertinence of adding new subjects to ongoing clinical trials. Absolute priority should be given to clinical trials on treatments for COVID-19 and COVID-19 related illnesses, or trials on serious diseases with no satisfactory treatment option. If re-consents are necessary for the implementation of new urgent changes in trial conduct (mainly for reasons related to COVID-19), a visit of investigator sites for the sole purpose of obtaining re-consent should be avoided. Instead, alternative ways of obtaining these re-consents should be considered during the pandemic (e.g. contacting trial participants via phone or video-calls and obtaining oral consents supplemented with email confirmation). Any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity when trial participants are back at the regular sites.
- Changes in the distribution of investigational medicinal products (IMP): The guidance states that changes in the distribution of IMPs may be necessary to remove avoidable visits to sites and provide the patients with needed treatments. Sponsors should assess the risks relating to the product and consider any alternative shipping and storage arrangements, including direct delivery of IMPs to trial subjects' homes.
- Changes in monitoring: According to the guidance, certain sponsor oversight responsibilities may need to be re-assessed and oversight mechanisms that are temporary, alternative and proportionate may be required, such as in relation to on-site monitoring.
- Protocol deviations: It is acknowledged that the COVID-19 situation is likely to introduce more protocol deviations than normal, and it is expected that sponsors escalate and manage such protocol deviations in accordance with their standard procedures. The guidance urges GCP inspectors to take an appropriate approach when such deviations are reviewed during inspections, in particular where the best interest of the participant is maintained, and the participant is not put at risk.
- Reimbursement of exceptional expenses: If the implementation of urgent measures for the protection of participants involved in a clinical trial causes additional expenses to study subjects, the sponsor should compensate these expenses through the investigator. If additional financial compensation is provided to sites or investigators (e.g. for IMP deliveries), these costs must be documented and reimbursed in accordance with national legislation or the guidance.
- Initiation of new trials aiming to test new treatments for COVID-19: EU member states support the submission of large multinational clinical trial protocols for the investigation of new treatments for COVID-19. The guidance notes that the EMA provides a full fee waiver and fast-track procedure for scientific advice for developers of medicines or vaccines against COVID-19.
This guidance sends an important signal to all sponsors and investigators involved in the planning or implementation of clinical trials in these challenging times. Stakeholders active in this field should clarify for themselves how to react and adjust the management of their clinical trials. It must be kept in mind though that national authorities and ethics committees also need to be included in the implementation of concrete measures.
For more information on this guidance and how to conduct medical research in Germany and the EU, contact your regular CMS advisor or local CMS experts: