COVID-19 Regulatory Developments Impacting Technology Use in Clinical Trials
Note: This post has been updated on April 3, 2020 to reflect additional guidance provided by MHRA, HSA, and PMDA.
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 an increase in activity in promoting the use of technology in clinical trials. Below is a link to the statement from the FDA (US Regulator), MHRA Inspectorate (UK Regulator), various Institutional Review Boards (IRBs), and ACRO (Association of Clinical Research Organizations). Links to these statements are also included in this post for reference.
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 (email@example.com) or Ari Feldman (firstname.lastname@example.org) if you have questions or would like to contribute.
FDA: 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) 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?”
- Please note that Medidata has been receiving COVID readiness inquiries from numerous clients for some time now.
- 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…”
- 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.
- 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.
- 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….”
MHRA: The UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued guidance on March 19, Managing clinical trials during Coronavirus (COVID-19), in addition to its blog the week prior suggesting alternate methods to visits, monitoring, and other pragmatic approaches to trial disruption.
Update April 3, 2020: The MHRA has published updated guidance for industry on flexible approaches to regulation. 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
EMA: 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.)
Update March 26, 2020: The EMA has issued a new guidance document: Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials. 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. "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."
- Monitoring challenges are discussed but unlike the FDA, MHRA, and HSA (Singapore), the EMA is reluctant to suggest remote Source Data Verification (SDV) as an option.
- Protocol amendments (informal translation: “When plans and procedures of clinical trials have changed by COVID-19, these changes should be properly documented and reported/discussed with the sponsor. The special contact has been set up for sponsors to consult with PMDA for this issue”)
- informed consent,
- protocol deviation handling,
- remote monitoring,
- investigational product provisioning including direct to patient
*Note that the link to this document was unavailable on April 3 2020 at the prior publication link: https://www.pmda.go.jp/files/000234651.pdf possibly because of an outage or an update in process.
HSA (Singapore) Health Sciences Authority: the HSA issued guidance on March 27 2020 speaks of remote visits, direct investigational product provisioning, remote monitoring options including remote SDV as well as other topics.
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.
Similarly, Addvarra calls for alternate methods as a matter of patient safety.
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.
Finally, ACRO has helpful perspective as this challenge is worldwide in its reach. Per ACRO:
Over the past several weeks, ACRO 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/