Protocol deviations

We acknowledge that the COVID-19 situation is likely to introduce more protocol deviations than normal. We expect that the sponsor escalates and manages such protocol deviations in accordance with their standard procedures. A proportionate approach will be taken by the GCP inspectors 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.

An increase in protocol deviations in relation to the COVID-19 situation will in itself not trigger the actions required by GCP 5.20. They will however need to be assessed and reported in the clinical study report, following ICH E3.

Changes to monitoring

Certain sponsor oversight responsibilities, such as monitoring and quality assurance activities need to be re-assessed and temporary, alternative proportionate mechanisms of oversight may be required. The extent of on-site monitoring, if it remains feasible, should take into account national and local restrictions, the urgency (e.g. source data verification can often be postponed) and the availability of site staff, and should only be performed as agreed with investigator sites. The burden of the introduction of any alternative measures for the site staff and facilities should also be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site.

Risk assessment

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

All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor (ICH GCP section 5.0). It is expected that the sponsor performs a risk assessment of each individual ongoing trial and the investigator of each individual participant and implements measures which prioritize subject safety and data validity. In case these two conflicts, subject safety always prevails. These risk assessments should be based on relevant parties’ input and should be documented on an ongoing basis. It is important that sponsors in their risk assessment consider prioritization of critical tasks in the clinical trial and how these are best maintained.

The sponsor should reassess risks as the situation develops. This reassessment should also be documented. It is possible that with the escalation of the pandemic, local circumstances lead to a local change in risk assessment, therefore the need to implement additional measures may arise, and an investigator-driven risk assessment might be necessary (and communicated to the sponsor).

Regarding participants enrolled in ongoing clinical trials that may be determined as being a risk group for COVID-19 or who are in trials involving therapies which may increase such risk, the potential impact of COVID-19 on these patient groups should be carefully considered when deciding to start or continue such trials.

Submitting paperwork for trials which have been halted

If your trial has been halted due to issues related to COVID-19, you will not normally need to inform us. The trial master file should include a note that the trial was halted and the reason. If a halt is due to either of the below scenarios however, you do need to inform us:

• A direct participant safety issue, especially if there is the potential to impact other trials; please inform us in the normal way
• A medicines supply issue, as we can escalate this to DHSC. Inform us of this directly by phone or email rather than an amendment form

Protocol deviations and serious breaches

Patients may be advised to stay away from hospitals and GP sites due to existing health problems that may put them at risk of infection, or they may be reluctant to travel to sites where there are high densities of people. They may also have been advised to self-isolate as a precaution or as a result of confirmed infection so are unable to undertake required clinical trial activities.

There will therefore be an increase in protocol deviations. Please ensure they are well documented, to enable appropriate evaluation for the trial. An increase in protocol deviations in relation to coronavirus will not constitute a serious breach, therefore there is no need to report this to us (unless of course patients are being put at risk).

Protocol waivers

Prospective protocol waivers remain unacceptable. We would not expect you to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests. Safety of patients remains a priority and they should not be included into a trial unless you can confirm they meet the inclusion and exclusion criteria.

Similarly, if the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed.

This may also extend to the whole trial in some cases, and a Sponsor and Investigator should remember they can use Urgent Safety Measures, or even temporarily halt a trial, or halt recruitment, if this is the best way forward.

• Changes in a protocol are typically not implemented before review and approval by the IRB/IEC, and in some cases, by FDA. Sponsors and clinical investigators are encouraged to engage with IRBs/IEC as early as possible when urgent or emergent changes to the protocol or informed consent are anticipated as a result of COVID-19. Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterwards.4 FDA encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants.
• The implementation of alternative processes should be consistent with the protocol to the extent possible, and sponsors and clinical investigators should document the reason for any contingency measures implemented. Sponsors and clinical investigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those changes and indicate which trial participants were impacted and how those trial participants were impacted.
• Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing information (e.g., for protocol-specified procedures). It will be important to capture specific information in the case report form that explains the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summarized in the clinical study report, will be helpful to the sponsor and FDA.
• If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative secure delivery methods. For other investigational products that are normally administered in a health care setting, consulting FDA review divisions on plans for alternative administration (e.g., home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain and should be addressed and documented.
• Sponsors, in consultation with clinical investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), may determine that the protection of a participant’s safety, welfare, and rights is best served by continuing a study participant in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial. Such decisions will depend on specific circumstances, including the nature of the investigational product, the ability to conduct appropriate safetymonitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial.

Contingency planning

• Institutions, individual principal investigators (PIs) and sponsors should be undertaking contingency planning to address the potential impact of COVID-19 and responses to the crisis on current, ongoing clinical trials. This planning should include:
  • Priority: assessment of the importance of and the risks associated with continuing the trial as designed or with necessary modifications. Responses could include continuing the trial in its present form, conducting the trial in a modified form, suspending the trial or closing the trial.
  • Participation: assessment of the ability of participants to participate in the trial in accordance with protocol requirements and consideration of alternative models for participation that would not compromise the integrity of the trial.
  • Capacity: assessment of the resources available for continuing the trial, including research staff, clinical support staff, pharmacy support, other support staff, space, equipment, supplies, etc. A component of a capacity assessment will be consideration of the need to re-allocate research staff to clinical care and other areas of patient support.
• Contingency planning will need to be an ongoing process.

Communications

• Decisions and actions in response to the crisis will be most effective if they are taken after appropriate consultation with the key stakeholders in a clinical trial: institutions, researchers, sponsors, regulators (if relevant) and, in some cases, participants. However, the need for rapid responses may require decisions and actions by one or more parties without prior consultation with the others. In such cases, all key stakeholders should be informed of the decisions and actions taken at the earliest opportunity.

Participants

• The safety and well-being of trial participants, other patients, family members, researchers and other clinical and support staff is paramount.
• In trials that proceed without modification, participants should explicitly be given the following options:
  • continuing to participate in the trial
  • suspending their participation, if this is viable, or
  • withdrawing from the trial.
• Participants who do not attend clinic visits or complete other trial activities may be reminded that these are required; however, if a patient declines or actively refuses to participate in trial activities, then their decision should be respected and they should be considered to have withdrawn from the trial. These participants should be informed that their decision will not affect their ongoing treatment or participation in future clinical trials.
• Participants who choose to move off the investigational product and onto standard care, and who do not wish to continue with site visits may be able to remain on trial for follow-up only.
• In trials that have been modified, participants should explicitly be given the following options:
  • Participating in the trial, as modified, inclusive of alternative mechanisms for engagement such as remote visits, data collection, monitoring, etc., as appropriate
  • Suspending their participation, if this is viable, or
  • Withdrawing from the trial.
• In a situation where a trial participant is unable to attend a visit or otherwise fulfill a condition of participation due to public health directives or government policy (such as restricted travel between states and territories), sponsors and researchers are encouraged to facilitate the participant being able to continue to participate in the trial at a site that is within the limits of any such restrictions. If available, such adjustments could be ‘pre-approved’ per the guidance provided below for amendments. Data collected could then be transmitted to the site that the participant would normally have attended.

Alternative models for conducting clinical trials

• Researchers and sponsors should educate themselves about novel approaches to the conduct of clinical trials, such as decentralized trials (i.e. teletrials) and hybrid models in which participants can be recruited and participate remotely and data can be captured remotely via available technology.
• HRECs should consider whether to actively encourage alternative models for conducting clinical trials, where possible and appropriate.