Guidance on the management of clinical trials during COVID-19 

This guidance was updated on 07 April 2021 (version 8.0).

The HPRA acknowledges the 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 the length of the period of disruption remains uncertain. 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.

2. 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 in exceptional circumstances. The decision to add a new trial site should be risk-assessed and the decision to commence at a new site should be taken on the basis that the safety of the subject can be assured and the trial may be conducted in compliant manner. 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.

3. 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.

4. An increase in protocol deviations may arise during this time, in particular for studies which commenced prior to the pandemic. 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”.

5. The impact on the provision of IMP 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.

   See also point B. 11 & 12 below. 

B. Sponsor and contract research organisation (CRO) considerations

Monitoring 

1. The HPRA is aware that there may be an impact on the ability to accommodate on-site sponsor activities, such as site initiation visits, monitoring visits and audits. Therefore, the necessity of on-site activities and/or appropriate alternatives may need to be considered. The sponsor/CRO should update monitoring plans/associated documentation to take account of alternative measures.

2. If it is considered appropriate to initiate a site during the pandemic, the sponsor/CRO may need to consider what aspects could be conducted remotely. The sponsor may also take previous experience with the site into consideration, which may aid in targeting areas of focus and reduce the requirement for on-site activities.

3. Centralised monitoring may have increased importance and use for the purposes of monitoring  and its focus should be on core aspects of trial conduct.

4. Remote monitoring of sites, such as via telephone, video conferencing and emails, may be of increased use. These activities enable the monitor to discuss the trial with the investigator and site staff. These activities could be used to gather information on the clinical trial progress, to exchange information on the resolution of problems, review of procedures, trial participant status as well as to facilitate remote site selection and investigator training for critical trials.

5. 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. Its introduction may be considered for trials: 

   • involving COVID-19 treatment or prevention;

   • investigating serious or life-threatening conditions;

   • where the absence of SDV for critical data may likely pose unacceptable risks to participants’ safety or the reliability/integrity of trial results;

   • involving particularly vulnerable participants such as children or those temporarily (e.g. trials in emergency situations) or permanently (e.g. trials in patients with advanced dementia) incapable of giving their informed consent or

   • in pivotal trials.

   2. Options which would be considered acceptable for remote SDV include:

      • Redaction of copies of source records which are sent to the monitor remotely. In such instances, it is important that information which may identify subjects is redacted, and personnel completing this activity should consider a QC check to assure all relevant information has been redacted.

      • Live video monitoring of source records. The video link should be secure, and no recordings made (included care to delete any temporary or cached files). Screenshots must not be taken.

      • Remote access to electronic health records (if available). It should be ensured that the monitor’s access is  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. The monitor should ensure that they are working in a sufficiently secure and private workspace while undertaking this activity.

   4. The sending of unredacted copies of medical notes off site for monitoring purposes is not acceptable.

   5. Ethical aspects should be addressed. For any trials which commenced prior to the pandemic, the wording of the informed consent forms should be reviewed to ensure it is sufficiently broad to allow for such activities, and if not, re-consenting may be required. For trials commenced after restrictions caused by the pandemic were evident, where remote SDV is proposed, the sponsor should ensure appropriate wording is including in the informed consent form to outline circumstances in which the subject’s medical notes may be accessed remotely.

   6. The sponsor should consider data protection requirements, 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.

6. The burden of the introduction of alternative 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. It is important that this is considered within the context of the importance of monitoring to ensure the safety of subjects, integrity of data and compliance with the protocol and GCP.  

7. 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.

8. 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).

9. The sponsor are not required to submit a substantial amendment to the HPRA for the introduction of such alternative measures, unless the protocol states that monitoring activities would take place on site. 

Supply and allocation of IMP

10. 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.

11. 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.

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

Other considerations 

13. 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.

14. 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.

Version 7.0, dated 04 December 2020

1. Acknowledgement that the length of the period of disruption caused by the pandemic on the conduct of clinical trials remains uncertain.

2. Addition of headers to section B to group information provided under specific topics.

3. Further information provided on the conduct of remote activities during the pandemic, such as site initiation visits and monitoring visits (point B.2). Circumstances where remote SDV may be appropriate broadened for pivotal trials investigating serious or life-threatening conditions trials to include the treatments under investigation may lead to significant benefit for the subject. Examples of types of remote SDV considered appropriate included (section 5).

4. Amended wording included to ensure alternative measures do not place a disproportionate burden on investigator sites, whilst also acknowledging this in the context of the importance of monitoring (point B.6).

5. Clarification that a substantial amendment is not required to be submitted to the HPRA to introduce alternative monitoring measures unless the protocol states that monitoring would take place on site.

6. Re-numbering and insertion of points as follows:

   • re-numbering of points B.2 to B.3, B.3 to B.5, B.4 to B.6, B.5 to B.7, B.6 to B.8, B.7 to B.10, B.8 to B.11, B.9 to B.12, B.10 to B.13 and B.11 to B.14,

   • Insertion of points B.2, B.4 and B.9.

Version 8.0, dated 07 April 2021

1. Updated point B. 5. a to expand situations where rSDV may be used during the pandemic, in line with updates to the updated joint European Commission, EMA and HMA guidance, v4, dated 04 February 2021.

2. Clarified wording in point B. 5. b. e on consent required to conduct rSDV.

3. Corrected typographical errors.