Guidance on the Management of Clinical Trials during COVID-19 

This guidance was updated on 28 May 2020 (version 6.0).

The HPRA acknowledges the potential impact of COVID-19 on the health system and broader society, and the impact it may have on clinical trials and subjects. The HPRA appreciates 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 subjects. The below guidance is intended to provide further clarity for all parties involved in clinical trials during this time.

  • The safety of the subject is of primary importance, and risks of involvement in the trial, in particular with added challenges due to COVID-19, should be weighed up against anticipated benefit for the subject and society (ref: principle 2.2 of ICH GCP). 

  • We have alerted the Department of Health, who are the responsible body for ethics committees, and HSE to the possibility of amendments relating to e.g. changes to a trial and/or sites, introduction of alternative site locations, and the possible need to suspend trials. 

  • We will give priority review to any new clinical trial applications relating to COVID-19, and/or amendments to existing clinical trials necessary as a result of COVID-19, priority reviews can be expedited where necessary. 

  • Substantial amendments should be submitted to the HPRA as required via standard reporting procedures (CESP or to submissions@hpra.ie). Urgent safety measures can be used, where appropriate; urgent safety measures, notifications and general CT queries can be emailed to clinicaltrials@hpra.ie. All submissions/notifications should be marked as “COVID-19 relevant”. This will ensure appropriate prioritisation of assessment. 

A. Investigator and site staff considerations

Various challenges exist which may result in restrictions of visits to healthcare facilities, increased demands on the health service and changes to trial staff availability. Subjects may also be required to self-isolate, which introduces difficulties for Investigators to maintain their medical oversight. These challenges could have an impact on the conduct of trials, such as the completion of study assessments, completion of study visits and the provision of IMP. The following guidance is provided:

  1. The impact of COVID-19 on the commencement of new trials, ongoing recruitment and continued subject participation needs to be considered. The ability to confirm eligibility, and to conduct key safety assessments and study evaluations, is of particular importance. Where required, recruitment should be temporarily halted, or suspended and subjects discontinued. Such decisions should be proportionate and based on benefit-risk considerations and impact on the health and safety of the subject. Where a subject is unable to attend the site, other measures, such as contact via phone or home nursing visit may be required to identify adverse events and ensure continuous medical care and oversight. However, the limitations of such methods should be taken into account, including the ability for investigator oversight. The addition of a new location to an existing trial site or the use of another trial site for subject visits may also be considered. Addition of a new trial site to the clinical trial would require amendment to the clinical trial application form and approval from the recognised ethics committee, notwithstanding the potential to use an urgent safety measure where appropriate.

  2. Subjects enrolled in certain clinical trials may be determined as at risk groups. In particular subjects who are immunosuppressed, over 60 years of age or have long term medical conditions (this list is not considered exhaustive, and medical judgement is required). Trials involving immunosuppressant therapies may also increase the risk of COVID-19 to subjects. The impact of COVID-19 on these patient groups should be carefully considered when deciding to start or continue such trials.

  3. An increase in protocol deviations may arise during this time. It is important that such deviations are clearly documented (ref: ICH GCP E6 4.5.3). A proportionate approach will be taken by the HPRA when such deviations are reviewed during inspections, in particular where the best interest of the subject is maintained, and the subject is not put at undue risk. This does not allow for the use of prospective “protocol waivers”.

  4. The impact of IMP provision to subjects should be considered, including what changes to existing practice may be required, should the need arise.

      1. Alternatives may include delivering the IMP directly from the investigator site to the subject’s home. Such measures raise various practical considerations, including whether the IMP is appropriate for home administration and general storage in the home, how stability of product will be maintained during transit (especially for cold chain product), how safe custody of product will be ensured and how IMP accountability will be managed. Such measures should be coupled with infection control considerations as the situation develops.

      2. Whilst specific guidance on this topic is limited, guidance from the Pharmaceutical Society of Ireland on the home delivery of medicines may be considered during decision making (version 1, July 2014, available here) and Joint HSE and PSI guidance on home delivery of medicines (dated 30 March 2020, available here). It should be noted that the guidance applies to retail pharmacy businesses and is specific to authorised products, and does not encompass all aspects relevant to the delivery of IMP, however, the principles may be of benefit in decision making. The HPRA Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances should also be considered (IA-G0011-2, dated 17 June 2017, available here).

      3. Changes to existing practice should be proportionate and based on benefit-risk principles, and the provision of IMP to patient directly in a healthcare facility is generally regarded as best practice, notwithstanding the potential impact of COVID-19.

B. Sponsor and contract research organisation (CRO) considerations

  1. The HPRA is aware that there may be an impact on the ability to accommodate on-site sponsor activities, such as monitoring visits or audits. Therefore, the necessity of on-site activities and/or appropriate alternatives may need to be considered.

  2. Centralised monitoring may be suitable alternatives in the interim, and their focus should be on core aspects of trial conduct.

  3. In relation to remote source data verification (SDV), the following guidance is provided. The reader should also refer to guidance published on the European Commission website (see reference section below).:

      1. Remote SDV may be considered only during the public health crisis for trials involving COVID-19 treatment or prevention or in the final data cleaning steps before database lock in pivotal trials investigating serious or life-threatening conditions with no satisfactory treatment option.

      2. Remote access to electronic health records have various considerations, including, whether access may be restricted to subject’s files enrolled in the clinical trials only. Further guidance is also available on the GCP special topics section of the website here.

      3. Ethical aspects should be addressed. It should be ensured that the REC agree to such alternatives, and that subjects have been appropriately consented (the wording on the informed consent forms should be reviewed to ensure it covers such remote activities, or if not, re-consenting may be required accordingly).

      4. The sponsor should consider data protection considerations, and the impact this could have on the sharing of data. For example, the security of such systems and whether monitors viewing such information will be working in sufficiently secure and private workspaces.

  4. The burden of the introduction of such measures on the site staff and facilities should also be considered, and a proportionate approach should be taken, balancing appropriate oversight with the capacity of the site. For example, where paper based medical records are kept, the requirement to scan and share pseudonymised information may place a disproportionate burden on investigator site staff.

  5. Other on-site activities, such as sponsor support in the maintenance of essential documents at the site (the investigator site file), needs to be considered, and alternatives may be appropriate during this period.

  6. Such activities form an important aspect of sponsor oversight and support, and any deviations from current practices should be proportionate, justifiable and clearly documented (ref: ICH GCP 5.0.4).

  7. The impact of IMP supply to sites and IMP management should be considered, including any restrictions and challenges on manufacturing, transport/delivery to sites and/or to subjects.

  8. The supply of IMP from sponsor contracted distributor directly to subjects is not currently considered acceptable. The allocation of IMP is the responsibility of the investigator (ref: ICH GCP E6 4.6). As outlined under the investigator and site staff considerations section of this guidance (point A.4), the supply of IMP from the investigator site to the subject’s home via a delivery service may be considered, and the sponsor may provide assistance and advice to the investigator in relation to this.

  9. Amendments to register alternative sources of comparator or background therapies/ non-IMPs will be expedited.

  10. Sponsor and CRO staff may have an increased requirement to work from home, having travel restrictions imposed, or may be unavailable due to illness. The impact of this on sponsor activities and the requirement for contingency measures should be considered.

  11. Sponsors are reminded of SUSAR reporting requirements, as outlined in ‘CT-3’ and Directive 2001/20/EC. Whilst measures should be taken to avoid late reporting, should instances occur, they should be documented as deviations and appropriate CAPAs implemented accordingly.

The HPRA is committed to providing all necessary support during this time, and will provide further guidance as required.

Notes

The European Commission, the European Medicines Agency (EMA) and the national Head of Medicines Agencies (HMA) have published new recommendations for sponsors on how to manage the conduct of clinical trials in the context of the coronavirus disease (COVID-19) pandemic. Guidance is available at the following link under the heading “Guidance on the management of clinical trials during COVID-19 pandemic”: https://ec.europa.eu/health/documents/eudralex/vol-10_en

The EMA’s Biostatistics Working Party (BSWP) have published the following guidance on implications of COVID-19 for methodological aspects of ongoing clinical trials:
https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-aspects-ongoing-clinical-trials

History of changes

Initial version (version 1.0), dated 13 March 2020

Version 2.0, dated 16 March 2020

  1. Included a statement reminding the sponsor they may submit a substantial amendment to the HPRA as required and they should mark this as Covid for prioritisation of assessment.

  2. Added clarification to the potential for investigators to use alternative locations / new trial sites for CT activities and the requirement to make submissions to the REC when new trial sites are added.

  3. Reference to remote monitoring has been removed and the term centralised monitoring is used only in line with terminology in ICH GCP E6.

  4. Added a reference to the HPRA guide for the transport of medicinal products, as this may also apply to home delivery of IMP.

Version 3.0, dated 23 March 2020

  1. Link to EMA/HMA guidance

  2. Added versioning to the document.

Version 4.0, dated 26 March 2020

  1. Addition of contact details for submission of substantial amendments.

  2. Addition of statement reminding readers of SUSAR reporting requirements.

Version 5.0, dated 02 April 2020

  1. Addition of clarification indicating that remote source data verification is generally not acceptable.

  2. Addition of clarification that sponsor to subject IMP supply is not acceptable.

  3. Addition of joint PSI/HSE guidance relating to medicines delivery during Covid-19 outbreak.

  4. Addition of link to EMA’s Biostatistics Working Party (BSWP) guidance. 

Version 6,0, dated 28 May 2020

  1. Inclusion of further guidance on remote SDV and considerations (point B.3). In particular, that remote SDV is generally not acceptable, however, it may be an option during the pandemic, and various aspects (ethical, data protection, electronic health record functionalities, and burden on the investigator site) the sponsor must consider.

  2. Additional wording to add clarity relating to direct supply of IMP from a sponsor contracted distributor directly to a subject (point B.7).

  3. Introduction of numbering of points in the guidance.

  4. Inclusion of a history of changes section of the webpage.