COVID-19 Regulatory Developments Impacting Technology Use in Clinical Trials
Note: This post has been updated on October 20, 2020 to incorporate updated guidance provided by FDA in v9 of their COVID-19 Guidance.
This post is guest-authored by Ari Feldman, Vice President, Global Compliance & Strategy, Philip Coran, Principal, Global Compliance & Strategy, and Fiona Maini, Principal, Global Compliance & Strategy, Medidata.
In light of the recent disruptions and challenges posed by COVID-19, there has been numerous expedited regulatory guidance(s) issued on managing trials during the pandemic. As a technology enabler, a number of the recommendations entail capabilities that our platform may facilitate. Highlights are listed below and we have focused on the G20 nations and will update this list periodically as more guidances are issued and updated.
Now is as good of a time as any to have a conversation with our clients. Global Compliance and Strategy (GCS) is leading an effort within Medidata to create a customer facing statement related to these recent regulatory developments and how Medidata may be able to assist. Please reach out to Philip Coran (firstname.lastname@example.org) or Ari Feldman (email@example.com) if you have questions or would like to contribute.
FDA (US): The US FDA issued emergency guidance (FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic) on March 18 followed by an amended guidance on March 27 (with a FAQ) and April 2, April 16, May 11, June 3, and July 2nd to address the current challenges to trial processes. Among many points the FDA calls for, using alternate methods to study conduct are highlighted:
Since trial participants may not be able to come to the investigational site for protocol specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants. Sponsors should determine if in-person visits are necessary to fully assure the safety of trial participants (for example to carry out procedures necessary to assess safety or the safe use of the investigational product appropriately)...
- Technology Diligence [when deciding to suspend or continue a trial]: “Assessing the continued availability of, and support for, information technology systems and any other technological tools that are needed to support the trial. Are current contingency plans adequate for the types of disruptions that might be anticipated? What other plans can be put in place to minimize any potential disruptions?” Note that many other proceed/suspend considerations are outlined in Question 1.
- Trial Virtualization (Question 5) Assessments and Approval Management: “changes in protocol conduct necessary to immediately assure patient safety, such as conducting telephone or video contact visits for safety monitoring rather than on-site visits, can be immediately implemented with subsequent review by the IRB and notification to FDA…”
- Telemedicine (Question 20 (July 2 version)) are discussed in detail. The FDA does not endorse any telemedicine best practices and equates them with live-in person sessions. The FDA provides the following considerations for video conferencing enabled visits:
- The investigator or study personnel who will conduct remote visits should be trained on how to conduct real-time video conferencing visits (e.g., training on the use of telemedicine for remote clinical trial visits).
- Procedures should be put in place to maintain a trial participant’s privacy, as would be done for a clinical visit.
- Both the investigator and the trial participant should confirm their respective identities with one another before engaging in a real-time video conference visit according to an identity verification plan developed by the sponsor.
- The date of a real-time video conference visit should be documented in the trial records—and if specified in the protocol, the time of the visit. Investigators should consider asking for the trial participant’s location during a video conference visit in case a medical emergency arises during the visit.
- FDA considers real-time video interactions, including telemedicine, as a live exchange of information between the trial personnel and trial participants. These interactions are not considered electronic records and therefore are not subject to 21 CFR part 11.
- Informed Consent including and Electronic Informed Consent for patients in isolation.
- Question 10: “If the technology is available, electronic methods of obtaining informed consent should be considered...” Workarounds including documentation, legally authorized representatives, and witnesses are discussed.
- Question 11 discusses consent where electronic consent is not an option.
- Question 12 addresses how informed consent “can be obtained and documented from a prospective trial participant (or legally authorized representative) when they cannot print and sign a paper copy of the consent form provided electronically by the investigator/designee, they cannot electronically sign the informed consent form, and providing a paper copy of the consent form via mail/courier is not feasible within the time frame for enrolment into the clinical trial?”
- Central and Remote Monitoring Programs for ongoing trials “If planned on-site monitoring visits are no longer possible, sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites.” See Question 9.
- Question 14 goes into greater detail on remote monitoring and source data verification. FDA suggests the possibility of remote SDV of critical study documentation and source data. Remote monitoring should be focused on "trial activities that are essential to the safety of trial participants and/or data reliability". The Question then suggests two possible methods of enabling remote access including a secure portal by the site OR site uploading certified copies to a sponsor controlled electronic system or other cloud based repository... However, the investigator would retain originals and control of the source documents. The nature of storage would be temporary and would be discarded after remote review has concluded.
- Home Delivery of Investigational Product (Question 7): “...If the protocol indicates pharmacy dispensing for self-administration at home, and this is changed to direct-to-patient shipments, then a protocol amendment would be required to permit home delivery of investigational product….”
- ClinRO (clinical outcome assessments) and PerfO (Performance Outcome assessments) through remote methods is discussed in Question 13.
- Question 25 addresses continuing electronic records/signatures expectations by the Agency from 21 CFR Part 11. As Medidata offerings continue to be Part 11 ready, there is no major change with this new guidance. However, the agency reiterates its narrowing interpretation of the applicability of Part 11 in general and refers to the prior draft guidance from June 2017 as well as the 2003 guidance.
EMA (European Union): The European Medicines Agency (EMA) has issued multiple guidances which may be found here. Among its recommendations, the EMA suggests converting physical site visits to remote visits when possible (in the March 20 guidance.) Based on our read of the document, there are a few points noted by the EMA that underscore the important role of technology in the execution of clinical trials:
- EMA is advocating for the continuance of ongoing clinical trials. "It is an ethical mandate to proceed with a trial that has been started as long as there is an opportunity that the efforts taken by patients and physicians can benefit drug development and patient care."
- Data collection should continue despite the absence of in-person interactions. 'Data collection should preferably not stop and should continue as long as possible.'
- A risk-based approach to ensuring continuity. "A 'Risk-assessment of the impact of: i) COVID-19 potentially affecting trial participants directly and (ii) COVID-19 related measures affecting clinical trial conduct on trial integrity and interpretability is recommended.'
EMA version 3 release of 28 April 2020 expands on the prior two versions of GUIDANCE ON THE MANAGEMENT OF CLINICAL TRIALS DURING THE COVID-19 (CORONAVIRUS) PANDEMIC). The key changes from version 2 to version 3 are around the guidance duration, communication with authorities, distributor to trial participant IMP shipment, monitoring remote source data verification and auditing.
- EMA Guidance Duration - The guidance highlights in bold that the simplification measures that come with the guidance ‘…will only last during the current public health crisis until the revocation of this guidance, when there is a consensus that the period of the COVID-19 outbreak in the EU/EEA, has passed.'
- Distribution and Handling of IMP - Updates are made within the section ‘Changes distribution of investigational medicinal products’ regarding:
- further education and training of the trial participant around the receipt and handling and self administration of the IMP.
- The delivery process from site to trial participant, logistical and financial assistance provided by the sponsor for example selection of the appropriate courier.
- If the site is unable to provide the distribution of IMP then alternative methods via distributors can be leveraged and with the appropriate contracts in place between the sponsor and the distributor.
- IMP shipment can be only be dispatched to the trial participant after agreement with the investigator and the investigator should explain the process and gain consent.
- The courier needs to be informed of and commit to shipment conditions and appropriate procedures in place
- Monitoring challenges (Section 11 and Annex) are discussed including remote and centralized monitoring.
- Centralised monitoring of data acquired by electronic data capture systems (e.g. eCRFs, central laboratory or ECG / imaging data, ePROs etc.) that are in place or could be put in place provides additional monitoring capabilities that can supplement and temporarily replace on-site monitoring through a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner.
- Remote source data verification (SDV) will currently only be considered necessary for very few trials when in line with national law (or temporary national emergency measures) . 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. It should focus on the quality control of critical data such as primary efficacy data and important safety data. Important secondary efficacy data may be monitored simultaneously, provided this does not result in a need to access additional documents and therefore in an increased burden for trial site staff... [in these very limited circumstances] principal investigators should make their own determination as to whether or not the situation at their clinical site allows any of the following options for remote SDV:
- Sharing pseudonymised copies of trial related source documents with the monitor; this may be done electronically where manageable by the site staff;
- Direct, suitably controlled remote access to trial participants’ electronic medical records;
- Video review of medical records with clinical site team support, without sending any copy to the monitor and without the monitor recording images during the review.
- Auditing Changes (Section 12) "on-site audits should, in general, be avoided or postponed. Audits should only be conducted if permitted under national, local and/or organisational social distancing restrictions. For critical trials, on-site audits as well as remote audits can be considered, after agreement with the investigator and if the audits are assessed as essential, e.g. triggered audits with the purpose of investigating serious deviations from the trial protocol or from the applicable legislation." Note that some authorities including Denmark have announced that onsite inspections are resuming in certain circumstances (See Sundhedsstyrelsen).
MHRA: The UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued initial guidance on March 19,2020 Managing clinical trials during Coronavirus (COVID-19) (with subsequent updates in April and May) on flexible approaches to regulation. Additionally, the MHRA updated its blog the week prior suggesting alternate methods to visits, monitoring, and other pragmatic approaches to trial disruption.
Following is a summary of matters impacting clinical trials/GCP:
- No need to inform the MHRA of a temporary halt of a clinical trial if related to COVID-19 and no need to inform the MHRA when it starts again
- Guidance on posting of IMP to trial subjects, consent can be done verbally and it will not need a substantial amendment
- Remote monitoring, allowance of remote access to medical records if appropriate security is in place
- Reduction of subject monitoring visits will not require a substantial amendment
- Understanding that safety reporting timelines will not always be met
- No requirement to report an increase in protocol deviations as serious breaches
In addition, the UK NIHR (National Institute for Health Research) issued guidance (May 21, 2020) on restarting paused NIHR research activities.
BfarM (Germany): the German Federal Institute for Drugs and Medical Devices has issued several guidances on clinical trials conduct during the Covid-19 Pandemic. In particular the Supplemental Recommendations speak to similar topics as other authorities including remote monitoring and remote SDV as a temporary option subject to strict controls:
...it is strongly recommended that remote monitoring in form of telephone and/or video visits will be limited to essential core data and processes to avoid an unnecessary burden on the investigator and the trial team. This usually includes data required for the continuous benefit-risk assessment, such as verification of compliance with inclusion and exclusion criteria, the doses and dose regimens of IMP(s) used and the complete recording of (serious) adverse events (pharmacovigilance) and key outcome parameters...
However, the essential requirements of data protection must be guaranteed. Documents or recordings containing personal data of trial subjects must not leave the trial site, not even as copies; thus, such data must not be permanently stored outside the trial site. Transmission of data and/or documents of any kind that goes beyond the mere transmission of a camera image content as well as the use of cloud solutions remain fundamentally inadmissible. The same applies to the transfer of such camera image content to third countries. The information and communication technology must be designed to ensure DSGVO (German name for General Data Protection Regulation)-compliant transmission. As a general rule, the established messenger services are not suitable for this purpose.
The Supplementary recommendations of BfArM and PEI to the European Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, version 3 (issued the week of May 17) provides further guidance on remote source data verification (rSDV) and outlines narrow circumstances and the related application/approval processes by the applicable federal authority and ethics committee(s). "In justified exceptional cases, the guideline provides [three options] for source data reconciliation without the monitor being physically present at the trial site."
Other topics include direct shipment to patients, protocol deviations, safety monitoring, etc.
ANSM (France): issued updated guidance on August 10, 2020. The guidance continues to reference multiple topics including, direct shipment of study drug under certain circumstances, tele-consultation as an option, centralized monitoring is permitted however (per informal translation) "Centralized monitoring is still possible with promoter / center contact subject to the availability of investigative teams in situations of tension. Sending copies of medical records, even pseudonymised, is not allowed." As with other authorities, these measures are only permitted during the emergency period.
PMDA (Japan): The Japanese Pharmaceuticals and Medical Devices Agency issued several statements and guidances in late March 2020 on COVID-19. Among the guidances is a Q&A that has been updated multiple times including April 3 and most recently on May 26, 2020. Excerpts below (based on unofficial translation):
- Question 1 & 2 - discusses shipment of investigational product between sites and direct to patients (allowable in some circumstances)
- Question 3- discusses monitoring challenges and centralized monitoring as a supplemental activity.
- Question 4- protocol deviation management
- Questions 5-8 address other challenges including site transfers, family members acting on behalf of patients to acquire investigational product, having nurses possibly visit the patients' homes.
HSA (Singapore) Health Sciences Authority: the HSA issued guidance on July 29, 2020 speaks of remote visits, direct investigational product provisioning, remote monitoring options including remote SDV as well as other topics.
Health Canada issued updated guidance on September 29, 2020 speaking to similar topics as other competent authorities including alternate methods of trial conduct & consent (including electronic consent), direct shipment of investigational product, centralized monitoring, managing protocol deviations, and other mitigations.
Australia: the Australian Government Department of Health has issued guidance on managing trials during the COVID-19 pandemic. Similar topics are covered including but not limited to tele-health, receptivity to electronic consent, investigational product direct shipment to patients under quarantine, and the possibility to remotely source data verification (SDV).
China: On July 14, 2020,the NMPA issued COVID related guidance for comments. "Guiding Principles of Drug Clinical Trial Management during the New Coronary Pneumonia Outbreak."
Institutional Review Boards/Ethics Committees: As quasi-regulatory third parties charged with ensuring patient rights and well-being for each clinical trial, numerous IRBs have issued pragmatic guidance on the changing risk landscape in the age of COVID-19. For example, WCG, a US commercial IRB, suggests:
- Decreasing the number of protocol-mandated in-person study visits to healthcare facilities
- Replacing protocol-mandated visits to healthcare facilities with home visits or telemedicine, allowing blood draws at remote or commercial laboratories
- Shipping investigational products directly to research participants
Over the past several weeks, ACRO (Association of Clinical Research Organizations) has received reports from a number of member companies regarding the impact of COVID-19 on the conduct of clinical trials, especially in relation to clinical trial monitoring.
- Attached is a statement on the monitoring and oversight of clinical trials during the current public health crisis. These “Considerations to Support Clinical Trial Monitoring Oversight During COVID-19” make recommendations for monitoring that ACRO intends to be helpful to sponsors and research sites. The recommendations are also posted on ACRO's website: https://www.acrohealth.org/COVID-19/
- On March 27, Medidata had the opportunity to meet with a delegation from the FDA together with the ACRO CRO Forum and RBQM Working Group members, to discuss the recent FDA guidance on the conduct of clinical trials during the COVID-19 pandemic. Brian Barnes, Director, Product Management, led the meeting with ACRO, providing thought leadership to the FDA. The key points of the meeting included:
- Increased Emphasis on Risk Assessment Activities
- Encourage risk assessments at a project-level. Considerations should be taken to include consultation with the investigator at an individual site-level and in some cases, at a subject-level.
- Continuity of Monitoring
- Limited access to performance of on-site monitoring activities is advancing the need for alternative ways to provide clinical trial oversight and placing an emphasis on the impact of the site.
- When monitoring activities can be resumed discouraging 100% source document review (SDR) and source data verification (SDV) of all subjects, visits and data.
- Emphasis on a risk-based approach to monitoring activities.
- Alternative Data Collection Strategies
- There is potential to decentralize some components or procedures as a risk-mitigation strategy with an emphasis around alternative data collection methods that are acceptable using available site-specific solutions versus when necessary to implement validated study-specific methods
- Increased flexibility across sites within a trial may encourage greater adoption.
- This way of working provides continuity of clinical trials in the future while protecting patients and minimizing the burden on clinicians and healthcare workers
- ACRO has a decentralised trial working party formally established in 2019, working on the end to end process and quality by design and risk based approach aspects of a decentralised trial with authorities. The ACRO team recommended to meet with the FDA on this topic specifically in expediting and accelerate the discussion in the light of COVID.
- Increased Emphasis on Risk Assessment Activities
During the meeting ACRO provided perspective regarding missed subject visits. The FDA is very interested in data Medidata can provide regarding impact to subject visits. In general the FDA highlighted there was a lot of synergies between the ACRO and FDA thinking.
As Medidata has been suggesting for years, a more risk-based view to clinical trial activities is necessary. We expect a cascade of similar statements from other IRBs and regulatory authorities as we navigate this pandemic. We will update this as other major regulators publish their positions.