COVID-19 pandemic and regulatory guidelines on clinical trial conduct; similarities and differences between regions
Introduction
Multiple global regulatory authorities have issued guidances and blogs to assist sponsors in managing and planning for the impact of the COVID-19 pandemic specifically on ongoing clinical trials.
The most detailed guidances have come from the FDA and also from the EMA multiple EU national competent authorities and Brazil. In addition, the UK has issued guidance on managing clinical trials during COVID-19. China has already approved clinical trials for COVID-19 and while Japan (PMDA), Canada and some South American authorities have not issued specific guidelines in relation to clinical trial impact, they are expected to take positions that are largely in line with other major regulators.
Health Authority guidances are expected to be updated regularly. Some of the differences in emphasis between the EMA and FDA reflect the higher numbers affected by the COVID-19 outbreak in Europe compared with the US.
Guidances similarities
The main challenges that face ongoing trials include national and local government advice to the population on actions necessary to minimize infection and spread during this pandemic. This advice varies between regions in terms of the stringency of travel restrictions; requirements for social distancing, lockdown and quarantine as well as testing and contact tracing.
Governments’ advice will impact trial subjects and staff. In the population, the higher the number affected by COVID-19 the higher the burden on the healthcare system and staff. In high density COVID-19 disease burden areas, these factors will significantly reduce the availability of staff to conduct visits, notify serious adverse events and comply with trial protocols. The reduction in supply of medicines exported from some regions, supply chain delays, the need for IMP (Investigational Medicinal Product) delivery to the trial subjects to minimize the risk of infection to subjects and staff all combine to make alternative strategies necessary. The vulnerability of trial subjects to harm will vary with the underlying condition, age, comorbidities and the nature of the IMP.
The potential impact from the pandemic and government advice range from stopping trials, slowing recruitment, postponing new site activation, delaying the trial duration, delaying endpoint measurement, amending how patient assessments are conducted, monitoring and reporting adverse events, home delivery of the IMP or delivery to a local healthcare facility closer to the patient where possible and the ability of staff to comply with protocol procedures.
All guidances issued from regulatory authorities in relation to ongoing clinical trials focus on three main areas; assuring subject safety, maintaining compliance with GCP and minimizing the risk to data integrity.
All regulatory authorities who have issued guidelines highlight the priority of ensuring trial participants’ safety. Risk assessments for any changes to the trial need to be done by the sponsor to justify what was changed, why it was done and how patients’ safety was maintained.
For urgent safety amendments, these can be implemented first (if necessary after agreement from the IRB) and then communicated to the regulatory authority later in order to avoid immediate delays while ensuring the communication of important changes.
Additional challenges include maintaining GCP compliance and minimizing the risk to data integrity when sites visits and data collection cannot be performed as per the protocol. For this, alternative temporary approaches including centralized monitoring have been advised, followed up later by more intense monitoring and in-person data verification.
All regulatory authorities understand that there will be more protocol deviations in view of COVID-19, and they will expedite assessment of amendments to the protocol. On completion of the trial full documentation of how each subject was affected by such changes will need to be provided in the CSR (Clinical Study Report).
Guidances differences
An additional consideration specifically from the harmonized European Union (EU) / European Economic Area (EAA)-level guidance jointly issued by the European Medicines Agency (EMA), Good Clinical Practice (GCP) Inspectors Working Group, the Clinical Trials Facilitation and Coordination Group (CTFG, a working group of the Heads of Medicines Agency (HMA)), the Clinical Trials Expert Group (CTEG, a working group of the European Commission representing Ethics Committees and National Competent Authorities) and the European Commission (EC) ) was that, (in exceptional and unavoidable situations based on the personal risk-benefit ratio for the individual trial participants), transfer of participants to investigational sites away from risk zones, or to sites closer to their home, or to sites already participating in the trial, or to new sites could occur; this could be implemented as an urgent safety measure initially, followed by a substantial amendment application in due course. This additional advice from the harmonized EU/EEA-level guidance reflects the growing severity of the COVID-19 pandemic in Europe. However, this guidance only aims to serve as a set of recommendations, which will not be accepted in every Member State in the EU. The Italian Agency (AIFA) guideline has stated that a site not authorized to participate in the specific clinical trial is “not considered as suitable as back-up, since it is not active, it does not know the trial and could not ensure a proper therapeutic continuity for the patient”.
Because of government lockdowns, some agencies will be closed or working with a skeleton staff, which will impact amendments to trials in countries such as Malaysia and the Philippines.
The Czech Republic regulatory Authority (SÚKL) has strongly advised sponsors not to initiate newly authorized clinical trials and not to enroll new patients in ongoing clinical trials during this critical period.
In addition, for ongoing trials SÚKL advises that subjects should be contacted by telephone to check whether the subject is quarantined as a result of visiting identified risk areas, if the subject has confirmed coronavirus infection, if subject resides in a household with an individual who is quarantined and whether the subject agrees with any proposed procedures as a result of the current epidemiological situation.
The National Agency for Medicines and Medical Devices in Romania (ANMDMR) specifically requires companies conducting clinical trials in Romania to identify the potential impact of general protection measures against the COVID-19 pandemic on the current activities carried out in each clinical trial and to notify the ANMDMR of the necessary plan of specific measures. These can be considered, on a case by case basis, as urgent safety measures with immediate implementation. In addition, ANMAT in Argentina also requested all sponsors to submit risk mitigation plans within 15 days. While no other agencies have specifically requested the sponsors of ongoing clinical trials to communicate with them about the specific planned changes, it is advisable to plan these as soon as possible for all ongoing trials in any region.
Conclusions
The proactive guidelines released from regulatory authorities help sponsors to focus on areas of particular concern during the COVID-19 pandemic. The guidances issued are highly similar with the message that all decisions and changes made to trials should be proportionate and based on benefit-risk considerations and impact on the health and safety of the subject. There currently are local regulatory nuances on how specific types of mitigation measures should be documented and communicated to regulatory authorities, and so local regulatory expert input will be helpful to maintain regulatory compliance. While some regulatory agencies who have not been put on lockdown have already issued guidance for fast track approval procedures for clinical trials investigating treatments for Covid-1., they are also expediting evaluation of substantial amendments resulting from COVID-19.
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