Consent
Informed consent is a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is usually documented by means of a written, dual signed (patient and person taking informed consent) and dated informed consent form. In an infectious disease setting, the patient may have capacity to consent but there are practical limitations to the provision of the written evidence of this. For example, a hard copy of the patient information sheet and consent form can enter the ward, but cannot leave the ward once signed, due to the risk of infection transmission on paper documents. Various solutions have been considered and incorporated in trials investigating treatments for COVID-19 as discussed in Table 1. There are well-used options of entering adults lacking capacity to consent (8) and minors (9)onto a clinical trial without consent.
Table 1
Examples of different ways of taking consent used in COVID-19 trials
Type of consent | Comment | Pros | Cons |
How consent is taken |
E-consent face-to-face | There is validated software, often linked to data management capture tools, available that can be downloaded onto a tablet for patients to provide electronic consent. Generic electronic signature products can also be used. | Informed consent can be enhanced with various features e.g. video information, call out boxes, pictures, consent flags (dependent on the software solution). A central record can be maintained by those who require it e.g. sponsor or CTU. Sites have access to electronic record of the informed consent form (ICF). Sites can clean electronic devices between use. Solves the problem of moving paper within infectious areas (red zones). The approach is supported by the MHRA and HRA (17). Some evidence that eConsent improves recruitment (18). | The software has cost implications for sponsors. The availability of electronic devices in hospitals is limited or incurs a cost for sites or sponsor to purchase. Storage and charging need to be arranged. The local team may not be familiar with the software. Those monitoring will also need to be trained on this method/software. |
E-consent conducted by video call | Interested participants are directed to a trial website, which outlines the study and provides the PIS. The interested participant goes through simple screening questions and those that pass are asked to provide contact details. The CTU receives the details and liaises with a clinician to call the patient. If eligible, a video call is set up with the clinician, where the PIS is discussed in full, eligibility is taken and consent is provided by the patient and clinician. On verification of consent, an email is sent to the participant which holds a link to their consent form. The clinician and CTU can access the consent form via the secure website. | Trial consent can be taken anywhere and the patient does not need to be co-located with the clinician. Site staff burden is reduced as the trial has a central group of clinicians to liaise with patients and take consent. Patients are not required to leave their homes during a pandemic so virus transmission risk reduced. Copies of the consent form are provided by email link to patients, as a record of patient consent. Evidence of consent is available to sponsor/CTU by electronic means via a secure website. | Patients may not be familiar or comfortable with sending contact details via the trial website. Patients may not be familiar with video calls. Where patients do not have access to the required technology, back up measures should be considered so that they are not excluded from the research for this reason. Additional training requirements to conventional consent. Physical examinations are not possible. High risk trials are likely to be unsuitable, due to the virtual nature of the trial or additional steps to confirm eligibility via patient records need to be implemented. Need a process in place to verify the participant is who they say they are – photo ID for example |
Photo of written consent | Patients are provided with paper copies of the written informed consent documents on the ward. Patients/Investigators sign and date consent and a photo or scan is taken of signed documents. | There are minimal cost implications, unless hospital equipment needs to be purchased. Provision of consent is in line with usual process which local team are familiar with. Solves the problem of moving paper within infectious areas as the paper version can be processed or destroyed (and documented) in accordance with local policies. | Data Protection considerations must be considered. E.g. : • Sites need to be compliant with their data protection policies/GDPR/SOPs, which does include photography. Emailing identifiable images to central office may need advance consideration of data protection issues, secure transfer and site training. Sites need access to devices to be able to take photographs. Risk that signatures are not legible/visible in photos/scans, there is a risk that the photo is lost or deleted in error resulting in a loss of evidence of consent. |
Who takes the consent |
Witness (11) | A witness could be present at the time the patient gives oral consent. The witness then provides written proof of the witnessing of oral consent in a non-infected area. | There are no cost implications, a paper copy of the written informed consent document is maintained and available for monitoring purposes. | Reliant on the availability of a witness at the time of consent. |
Personal Legal Representative (PerLR) | The use of personal legal representatives is a well established method of consent for use in certain situations. Some COVID-19 trials have made use of this due to patients requiring mechanical ventilation. A relative or close friend is approached, either in person or via telephone, provided with the relevant information sheets and asked if they feel the participant would consent to being included in the research. If they feel the participant would be happy to take part then a personal legal representative consent form is completed. In the context of COVID-19, these conversations should take place outside the infection area (red zone). If the participant regains capacity to consent at a later date they are provided with the relevant information sheets and are asked to complete the consent forms indicating that they are happy for data to be used/to continue in the trial. | No cost implications. Paper copies of written informed consent are available for monitoring purposes. Preferential even when the relative or close friend was on the phone and the clinician documents their consent and the clinician signs the consent form. 1 | May be restricted to use only with patients who lack capacity to consent due to the severity of their illness. Family may be unsure of what the participant’s wishes would be and may be reluctant to provide consent on their behalf. |
Professional Legal Representative (ProfLR) | For patients who are critically ill and are unable to provide consent and there is either no-one suitable by virtue of their relationship to the patient or a suitable person does not wish to or is unavailable to act as the legal representative, a professional legal representative (ProfLR) may be approached. This is a medical professional caring for the patient who is unconnected to the trial. If they have no medical or ethical objections to the participant taking part then a ProfLR consent form is completed. Again in the context of COVID-19 research, all paperwork should be completed and stored outside the infection area (red zone). If the patient regains capacity to consent, they will be asked to complete consent to continue as detailed above. | No cost implications. Paper copies of written informed consent are available for monitoring purposes. | Restricted to use only with patients who lack capacity to consent due to the severity of their illness. |
1 In Scotland the ‘guardian or welfare attorney’ is first preference, prior to nearest relative. |
Legend: ’electronic methods for seeking informed consent’ and ‘eConsent’ refer to the use of any electronic media to convey information and to see and/ or document consent via an electronic device |
Please could Table 1 go hereDuring the development of COVID-19 trials, several CTUs utilised early and ongoing communication with the HRA to ensure planning of the consent process was optimal and realistic (due to limited resource at sites and various challenges associated with COVID-19 ‘red zones’, conscious / unconscious patients, restricted (no) face to face contact with relatives).
Some COVID-19 trial designs (platform trials including more than one primary aim) were innovative in that they required consideration of several options for taking consent (Table 1). This was discussed with the HRA.
Monitoring without on-site visit option
In the setting of a global pandemic access to trial sites for non-essential staff is likely to be restricted and therefore on-site visits need to be mitigated. In the UK COVID-19 pandemic, the HRA advised trials to consider what monitoring was required immediately as opposed to what could be delayed. As long as it did not add to a site’s burden, the HRA allowed alternative monitoring arrangements to be made without a protocol amendment (if site level schedules were specified in the protocol). The risk assessment and/or monitoring plan may need to be adapted with the acceptance of some risks which would under usual circumstances be mitigated by on-site monitoring review. Critical data points should be risk assessed for likelihood of error and if errors occur whether they could be detected via a centralised monitoring method or accepted. Errors may also be picked up without the need to see the source data and can be checked by real-time review of data entered into the eCRF by CTU staff and where obvious errors are noted, or missing critical data are identified, this can be clarified directly with the trial site. Where these risks cannot be accepted or mitigated in this way a remote monitoring method is necessary which may include remote SDV or SDR. Remote monitoring can be achieved a number of ways but relies heavily on site input and is, therefore, limited by site capacity. Table 2 summarises remote monitoring methods and the authors’ experience of these.
Table 2
Remote monitoring methods for SDV and other checks
Remote Monitoring Method | Experience |
Direct Access to Site Electronic Medical Record provided to the monitor | Direct access to patients EHR (Electronic Health Record) away from the site creates issues around confidentiality and is only feasible where the HER was set-up with such access in mind. Consideration needs to be given on where access takes place, for example will monitors be accessing records in an open plan office, public space or other location where others who are not authorised could view sensitive information. Host organisations and sponsors (with input from their Caldicott Guardian if applicable) need to provide explicit instructions on what can be accessed where, and an agreement from the monitors that this will be complied with. Access from home can be acceptable, provided that there is somewhere private that this can be done, away from family etc. The device through which this is accessed must have adequate security, such as adequate firewalls, secure log-in and passwords etc, and must not be left unattended and accessible. The instructions should not allow printing, emailing or downloading of any records, or this should be disabled within the system. See MHRA guidance (10). Our recent experience is that this has been possible for one UK NHS Trust. This method is highly effective and does not cause a high burden for trial sites as monitors can access the data and perform review without site staff input, other than IT providing access and for addressing critical issues at the end of the review. |
Provision of pseudonymised source documents | Only provided for a very small amount of data and trials. High burden for sites to redact source data and open to errors in redaction and copying. EMA guidance states that documents monitored in this way need to be rechecked on-site.(11) |
Videoconferencing, site staff use a secure conferencing platform and screen share the view of the health record with the monitor. | No experience to date but some trial sites are considering this where it is not possible to provide the monitor with direct access to the electronic health record. As site staff will need to access the record and share their screen during the whole review this is a high burden to sites. There is also anecdotal experience that some sites do not allow use of videoconferencing due to data protection concerns and NHS local policies on video conferencing; there is site variation on which systems may be permitted (if any). |
Monitoring by phone* | Phone conversations using a monitoring checklist can be useful but are reliant on sites having capacity. Source documentation is not specifically being reviewed, but the discussion can provide the opportunity to identify concerns and support the site. |
Questionnaires, site quality control checklists and essential documents sent by the site to the monitor | Limited, due to site capacity for completing checklists and scanning and emailing documents. Found to be useful for IMP accountability and acceptable to sites where pharmacy resource was not redeployed. |
* SDV not possible by this method |
Consideration also needs to be given to the process of triggering on-site monitoring visits. Where these visits will not be possible, alternative actions will need be taken such as telephone contact with site staff to assess compliance / issues and other remote monitoring activities (Table 2).
Table 3 gives more detail on phone and videoconference remote monitoring
Table 3
Working example of monitoring using phone and video conferencing
Action item | Aim | Monitor’s Actions | Comments |
1 | Decrease the requirement for site level monitoring; by implementing alternative monitoring mitigations | TC or email site staff (PI team) to ask if/when they are available for a TC or VC in place of an on-site monitoring visit AND what data could be shared with the monitor ahead of this virtual meeting. | Use video conferencing if the site has the IT access. If not, then a TC. Ensure monitors have the flexibility to meet with site staff when it is convenient for the sites. |
2 | Prioritise patient safety, outstanding site actions and data integrity of the study primary end-point for remote monitoring | Develop a template tracker to ensure the minimum safety & primary end-point data are discussed in the TC/VC. | Put the questions in priority order for the TC/VC. |
3 | Give the site as much time as possible to prepare* *Note that for COVID-19 studies; sites should be informed of and agree to the minimum data they will be asked to supply for remote monitoring, where employed. | Request appropriate documents ahead of the meeting – keep this to a critical minimum. | This could include investigator site files (ISFs); delegation logs; primary end-point pseudonymised source data. |
4 | Conduct a successful site TC/VC. | Review appropriate documents ahead of meeting. | In line with preparation for all monitoring visit types |
5 | Prioritise the discussion with site in case the call is cut short by technical problems or a local emergency. | Use the template tracker completed with all actions required of site & prioritise the TC/VC discussion accordingly. | Discuss the timing of next remote visit |
6 | Manage any resulting issues | Escalate any unreported SAEs, missing visits, major deviations impact on patient safety/data integrity of missing visits. | Quality, CI, PI, stats and sponsor may need to be consulted. Update study risk assessment with site-specific issues and/or availability during COVID-19 outbreak. Consider what appropriate actions, if necessary should be undertaken |
7 | Complete the monitoring visit report (MVR) and site f/up letter. | As normal. | No comments. |
TC: teleconference; VC video conference; CI Chief Investigator; PI Principle Investigator |
It may also be possible that sites, particularly those experienced in early phase work, may be able to perform SDV within their usual process and experience. We have experience of sites, for COVID-19 trials, taking on the SDV task in this way, utilising independent staff and a robust process. |
For trials in set-up where remote monitoring is planned upfront, this should be reflected in the protocol, risk assessment and informed consent. |
Monitoring without on-site or remote monitoring option
In the setting of a global pandemic, the use of remote monitoring methods may be limited or even impossible due to lack of research staff time. In this situation focused risk-based monitoring may be considered. With this method of monitoring the sponsor should identify the key risks involved with the trial and develop a centralised method of reviewing these risks. Primarily the focus should be on patient safety, primary outcome measure data and any other data considered critical. An example from one CTU was to focus on data relating to patient safety. Data relating to adverse events and protocol deviations were collated and reviewed at monthly Trial Management Group (TMG) meetings where the frequency and type of events as well as the quality of the data submitted was considered. Anything which raised concern with the TMG triggered a telephone call with the site principal investigator, and further investigation was carried out if necessary. A Data Monitoring Committee (DMC) was also convened monthly with the aim of independently reviewing safety data. This method requires timely submission of data from the site so emerging triggers can be quickly identified.
Note that monitoring of all studies during the COVID-19 pandemic is likely to lead to deviations from and updates to the monitoring plan due to changing conditions. Notes to file, monitoring mitigations and SOP deviations need to be discussed with the CTU’s Quality Assurance (QA) team, and Monitoring Visit Reports (MVRs) must accurately state the reason why no/reduced/outside of agreed window of monitoring has occurred. Study risk assessments should be updated and discussed with QA teams, CIs & sponsors.
Minimising data
A number of COVID-19 trials have been developed and set-up with the knowledge that on-site monitoring will not be possible. Many of these are Clinical Trials of an Investigational Medicinal Product (CTIMP) intended to support marketing authorisations, which would usually require a high level of on-site monitoring. As this may not be possible for the foreseeable future, consideration of alternative methods for data review and verification will have been considered, as discussed above.
Due to the potential for placing an increased burden on participating sites that some remote monitoring methods may pose, coupled with the need to be confident in the completeness and accuracy of data, one important consideration is the quantity and complexity of the data requested.
The collection of non-essential data has long been known to increase the burden on both participating sites and sponsor teams, and this is now starting to be quantified. Recent data from Fougerou-Leurent et al (12) suggest that only 13% of the data collected are critical data items and Crowley (13) at al found 5% of items were for the primary outcome of the trial.
If the data collected can be reduced to that which is considered critical, this will reduce the burden on sites for CRF completion and sponsor teams for monitoring. The reduction in data collection also has wide-reaching benefits for the sponsor including simplified and more rapid CRF and database development, more efficient data management and statistical analysis and most pertinent to this review, fewer data points for which monitoring is required. RECOVERY-RS reduced the data collection to be as simple as possible, via agreement between the Trial Management Group (including the trial statistician), programming team and QA team.
If the COVID-19 pandemic can bring one benefit to clinical research in the long-term, minimising data collection would be a wide reaching, mutually beneficial process improvement.
Although the requirement for data minimisation is well established and embedded within the Data Protection Act, 2018, the pandemic situation has encouraged trial development teams to consider data minimisation far more than they may have done previously. This was largely due to the pandemic clinical impact, when site staff were excessively busy so minimising data as much as possible was essential.
The role of the sponsor (as data controller) in guiding through policy, training, provision of eCRF platforms, review, etc., is absolutely critical (including where this level of oversight is carefully delegated to, e.g. a CTU) not only to the efficient delivery of research, as described here, but also for the sponsor to meet its legal obligations.
Altered data collection and retention
Limiting paper contamination within COVID-19 areas, as well as clinical trial burden due to the reduced staff resource at participating sites, has required other adaptations in how trials are managed. Examples from COVID-19 trials have included the completion of validated Patient Reported Outcome Measures (PROM) tools via the phone rather than patients completing the forms directly. This could be done by research staff at sites, or by CTU staff if patients have given consent for this.
COVID-19 trials also presented additional consideration when discussing where and how patients were identified and confirmed as COVID-19 positive. This was partially due to the rapidly evolving national situation around screening; availability of screening and false negative rates, and also how patients were managed once eligibility was confirmed as patients not requiring clinical care were discouraged from attending hospital settings. These issues present challenges for monitoring.
At a sponsor or central level, Trial Master Files (TMF) are often paper based. With many CTU staff moving to a home based working arrangement, mitigations have needed to be made. In some instances this has involved consideration and implementation of electronic TMF.
Site set up changes
Although some CTUs have previously carried out site initiation visits (SIVs) using video conferencing facilities instead of on-site visits, during the COVID-19 pandemic this has become the only solution for site initiation. The basic structure is similar to face-to-face SIVs with a comprehensive slide set, live presentations by the clinical and trial management teams, and an opportunity for questions. The familiar structure enables a trial team to develop materials in an established way, but to then adapt the delivery to suit the current environment. Sites also benefit from the questions that another site thinks to ask.
In the RECOVERY-RS trial a large site-set up team was established, and SIVs were conducted every weekday at three time slots per day. Time slots were advertised to sites with booking details. This was cost and time-efficient for the trial team and for site staff, and enabled multiple sites to receive a SIV simultaneously. It also enabled multiple site staff to attend different SIV slots, from numerous locations, fitting in with workload and availability. With clear guidance on the meeting conduct, a separate member of the team managing the video conferencing admin, and questions posted via the ‘chat’ function, meetings ran smoothly and replicated a face to face meeting as much as possible.
Risk proportionate approaches should always be used to ensure oversight of adequate experience and training of site staff, and the current situation can provide an opportunity to tailor the oversight more specifically to each individual trial. It may not always be necessary to collect CVs and GCP certificates for all (or any) site staff, if the PI or R&D department can confirm they are held on site. The PI is responsible for their research team being trained and experienced in their role. Equally, a hierarchy of study-specific training requirements may be implemented to request a core set of study training to be completed and signed off by the PI only, with PI oversight to confirm site staff have appropriate training to perform their role within the trial. Websites can be a useful tool to provide and record training and also act as a document repository, alongside a website’s traditional remit of trial promotion. Training materials can be available for sites to access electronically, with the ability to ‘sign off’ training modules online removing the need for paper copies, simultaneously providing central oversight of each site’s training status (and potentially removing the need for a separate delegation log). This facilitates local site set-up, enabling work to be done at individually convenient times, without the need for printing facilities or transfer of paperwork.
Speed of trial development
Many CTUs redirected resource to COVID-19 trial development and staff have worked at pace, contributing many hours in a short time, collaborating with many individuals and organisations (pharma, laboratories, clinicians, government) to pull together and fast track trial ideas into solid trial proposals, creating protocols in just a few weeks. Throughout the process the MHRA and HRA have been available for early discussion, prior to submission, to ensure approvals can be swift following submission. In most cases MHRA and HRA approvals have been issued in a matter of days including national holidays. There have also been additional steps that COVID-19 trials have needed to navigate, the primary one being Urgent Public Health (UPH) priority approval which ensured sites prioritised work on COVID-19 trials with high priority questions as deemed by the government. Due to the overwhelming demand for UPH approval, their review was sometimes conducted in parallel with MHRA and HRA review in order to maintain trial set-up momentum.
Due to the speed of set-up, trial teams, including monitors, have been required to fast track trial risk assessments and the subsequent trial monitoring plans, including considerations of mitigations due to site access restrictions and minimised site resource requirements. There was little precedence for this in the UK at the time, meaning many sponsors were ‘thinking on their feet’ to provide pragmatic solutions to emerging and evolving challenges.
Early phase trials have been required to review Safety Review Committee (SRC) processes, as usual practice is complete SDV of the data being discussed which inform dose escalations. Trial specific mitigations have been considered (e.g. site performing SDV as described previously).
Whilst there have been significant achievements with developing complex trials in an expedited manner, there are some less positive aspects of the process. Accelerated protocol development and trial set-up processes have required a substantial resource allocation, which in most cases has been delivered by experienced staff working evenings and weekends for prolonged periods. Similarly, once approved the trials have required frequent amendment to account for the changing pandemic landscape, emerging safety information and differing processes across healthcare settings. The impact of these on the risk assessment and monitoring plans make this challenging for sponsors, CTUs and sites to manage.
Impact on non COVID-19 portfolio
Many sponsors and sites suspended recruitment into open trials at the start of the pandemic, and sites participating in open trials decided if patients already recruited into trials were able to continue treatment and follow-up. A risk-based approach was implemented and protocol processes were reviewed. Examples include clinician/patient phone calls rather than hospital clinic visits; transfer of patient care to alternative healthcare providers; provision of IMP to patients at home and use of validated safe-boxes for the return of samples via post. These actions have required changes to central monitoring of data, for example a metric alarm threshold for deviations would need to be increased. Often, SDV of data has been stopped with monitoring defaulting to central and remote monitoring, but this is expected to recommence as conditions permit.
Lastly, as sponsors and CTUs plan for trial restart, they should consider COVID-19 impact trial viability assessments which address if/how the trial population, interventions, and outcomes have been impacted to inform if trials are able to re-open or not, and whether any changes are required. Early and open engagement with the trial site staff and the R&D office is important. Trial opening and change decisions may require trial risk assessments and the data monitoring plans to be updated. Sites need to commit to the necessary monitoring and if the site cannot, then consideration may need to be given to keeping the site on hold to recruitment; this capacity review will often form part of the site level risk assessment, which are likely to be required prior to re-opening(14).