Our first CQAF Quarterly Meeting for Y2020 is indeed a unique event to remember as for the first time we break our tradition of meeting face to face in Beijing and Shanghai; and go with an all-virtual meeting to maintain social distancing and do our part to reduce/prevent the spread of Coronavirus (COVID-19) outbreak in the community.
Framing the unprecedented moment of our very first all-virtual meeting during the COVID-19 outbreak:
Our CQAF Q1 2020 meeting was held in the afternoon of 20th March and we are pleased to have Ms Liping Zhou as the host of our meeting; and joining virtually are 147 CQAF members from approximately 60 organizations, comprising of pharmaceutical companies, clinical trial institutions and contract research organizations.
It is not a surprise that we have chosen ‘Business continuity in the time of Coronavirus’ as the theme of our meeting since this is the talk of the town globally.
We want to thank our distinguished guests, Jiang Min (Director, GCP Office, Beijing Cancer Hospital) and Fannie Lai (Marken), Zhang Tong (Sanofi), who accepted our invitation to introduce their novel approach on remote SDV and direct-to-patient supply respectively. We also wish to extend our appreciation to our core members who brought their expertise to the table and addressed questions from the floor.
Let’s dive into the summary of our discussion:
The coronavirus outbreak is a good opportunity to put existing Business Continuity Plan into action and test. If our BCP does not cover disruption to clinical trial conduct, it is also the best time to update our BCP. As time is key to manage coronavirus crisis at a moment’s notice, it is critical to stay calm and exercise agility. In absence of internal procedures and external regulations, one should fall back to our fundamental GCP and ethical principles to guide our decisions and actions to protect the health and safety of our employees, healthcare professionals, patients and minimize community spread.
1. What should we consider when developing and communicating a BCP?
Stakeholders involvement:
Ensure all affected internal functions (e.g. clinical operations, medical, data management, statistics, pharmacovigilance and quality assurance etc) participate in the BCP development.
Engage all relevant external parties working in the clinical trial, e.g. investigators, vendors, to obtain alignment on the mitigations/action plans.
Impact analysis and risk assessment on key components of patient safety and data integrity to be collected in advance of may include but not limited to:
Trial status: e.g. subject enrollment, subjects on treatment, location, clinical supplies, data capture and site monitoring, EC application and approval
Scenarios/action plan: impact on stopping current treatment, missing data, subject safety monitoring and continuous treatment e.g. follow-up visits, delivering IP to patients, lab tests
Placing patient safety, including data integrity, in the heart of our mitigations plans:
The mitigation plan should be specific for each study, trial procedures, participating site and subjects.
In the event the alternative solution is to continue a subject’s safety assessment/treatment outside of the investigator site, e.g. at local hospital, the following should be ensured/assessed:
EC notification and approval
Subject’s informed consent to the alternative solution (verbal consent, if applicable)
PI/investigator’s oversight on the activities, including but not limited to:
* ensuring the qualification of local hospital staff and proper delegation
provision of all relevant source documentation/medical records from the local hospital/patients to the study investigators to timely assess subjects’ medical conditions and continuous study treatment, etc.
Information to be collected to facilitate regular monitoring and review on suitability, adequacy and effectiveness of the BCP; in particular to minimize the impact of the disruptions on trial conduct; patient safety, well-being and data integrity, including but not limited to:
Number of subjects at each site, location of each subject and COVID-19 status at the located city (no patient identifiable information should be collected)
Accessible medical care /qualified local hospital resources available to each subject, trial status of each subject, next study visit date
Follow up procedures and mitigations for each subject
IP: inventory at each site, storage condition, risk of stopping treatment/short of supply
Internal and external communication plan:
Besides on what, why, when, how, who to communicate internally, the communication with investigators, IRB and regulatory authority should in place to enable timely interaction and discussion for BCP implementation and modification.
It is also important to include communication by the investigators to the subjects to ensure all subjects are well-informed of changes to the study procedures as well as how their rights, personal information and well-being are protected.
Documentation and archiving of BCP related information, procedures and activities:
As all relevant communications, decisions, roles & responsibilities, procedures, training and/or activities are subjected for future reference, audits &/or inspections, the BCP should also describe the type and extend of documentation on communication, procedures and/or activities to be archived; examples including but not limited to impact/risk assessment results, action plans, trackers.
* providing relevant trainings to the local hospital staff as needed
* ensuring the availability of relevant equipment/facility and corresponding supporting document as needed (e.g. certifications, lab normal range, etc).
2. What do we need to pay attention to enable the implementation of remote source data monitoring and direct-to-patient?
Remote source data Monitoring
During the COVID-19 pandemic, CRA may not be able to perform on-site monitoring as planned. As such, remote monitoring can help with early detection of trial non-compliance and/or issue of data integrity. Some key aspects should be considered:
Determine the remote/central monitoring continuity plan based on risk assessment and implement a mitigation plan. Document the remote/central monitoring activities in the corresponding record (e.g. remote monitoring visit report, contact report).
Note: Assess the need to update the Monitoring Plan or as addendum to the Monitoring Plan for the implementation of central/remote monitoring in order to support the investigators/monitors to implement the BCP.
Encourage the use of alternative means of oversight (e.g. teleconferences / videoconferences) to communicate or provide instruction to the site and focus on key areas (e.g. subject visit/treatment/retention, drug compliance, study drug continuous supply, source document meeting ALCOA principle) to ensure data integrity, safety reporting, protocol/GCP compliance, informed consent, EC communication etc.
Performing remote SDR/SDV (Source Data Review/Source Data Verification):
In general, remote SDR/SDV is not recommended during COVID-19 pandemic
Remote SDR/SDV on (pseudo)anonymized data would only be recommended in exceptional circumstances, e.g. studies with critical timeline (data cleaning), but a risk assessment at study level is needed to justify the scope and extent of remote review/verification (e.g. primary study endpoints, critical safety data, etc.).
Remote SDR/SDV against certified copies of medical records (hard copy or via validated e-system) should be in line with the investigator site’s policy and local regulations.
Assess the feasibility of remote SDR/SDV in consideration of site resource, security of document transfer (e.g. e-mail encryption), remote access approach and access control. In the event the site can grant a (pseudo)anonymized electronic health record to the site monitors for remote data review, the reliability of the remote platform need to be assessed.
Train the monitor to ensure he/she follow the requirement of remote SDR/SDV. The monitor is required to check and validate the completeness of the source document provided for remote SDR/SDV upon the next on-site visit.
Direct to patient (DTP)
DTP is an effective ancillary solution for all parties under the situation of COVID-19 pandemic. With DTP, while the risk of COVID-19 infection could be minimized, there are also other benefits, such as:
Subjects may experience convenience and flexibility of door-to-door delivery enabling them to receive new therapies faster;
Investigators may recruit subjects from a wider geographical area and population structure; DTP may also enable patients to continue the study;
Sponsor may achieve the last lap of supply chain security to ensure better consistency, achieve study time and enable study to continue.
Apply the fundamental principles to comply with trial protocol and to protect trial subject. Implement DTP when it is within the protocol requirements. Otherwise, before selecting DTP as a solution, one need to assess the risk of IP withdrawal. If the risk of IP withdrawal overweigh the risk of COVID-19, we should take relevant actions to protect the patient. Agreement/consent from the investigator, EC , patient on DTP shall be obtained in advance prior to implementation.
The vendor and its staff should have the relevant certification in place to provide the service.
The vendor staff should be trained for the particular requirement from the study, sponsor, regulators and/or site (e.g. temperature control, data protection, etc) prior to the conduct of the activities.
Having said this, there are some aspects for consideration while implementation of Investigational Product (IP) delivery from direct to patient (depot to patient) or the hospital to patient:
What factors should be considered during the qualification of DTP vendor and its staff?
In the event there is a need to transfer patients to another site or send patients to a local hospital for safety monitoring, please refer to The European Medicines Agency’s ‘Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) pandemic Version 1 (20/03/2020)’ for further guidance.
3. What are the considerations for a remote audit at an investigator’s site during COVID-19?
During COVID-19, one should evaluate the feasibility as well as business priority before instituting a remote audit to enable continuous quality oversight. Based on the feasibility outcome; one should review the need to redefine the audit objective and scope based on the feasibility.
In determining whether a remote investigator site audit need to be implemented, the following should be considered:
Business criticality and the purpose of the audit to be conducted during COVID-19;
Other alternative approaches to ensure the sponsor quality oversight
Other possible mitigations to address the risks of cancelling the audit during COVID-19
Feasibility check with all stakeholders before implementing the remote auditing, e.g. site acceptance, possibility of remote access to document.
It is important to bear in mind the following:
Completeness and reliability of documents provided for the remote auditing may affect a full assessment of investigator site’s compliance in line with the protocol, GCP and applicable regulation.
Securing the assurance of the protection of patients’ confidentiality and study information during the conduct of the remote auditing.
4. What should we do after BCP set up?
BCP set up is key step to enable continuous operations before and during execution of COVID-19 pandemic recovery.
Thus, after the BCP is established, the immediate step is to implement the plan to continue and recover prioritized activities within the identified timeframes and agreed capacity.
If during the regular cross-functional team review it came to light the risk of continuing a trial during COVID-19 pandemic outweigh the potential benefits, suspension of the clinical trial should be considered, and the rationale and decision of suspension shall be communicated with all involved partied according to regulatory requirements.
As BCP is a living document, it is important to stay updated on changes on the coronavirus situation and apply PDCA (Plan, Do, Check, Act) to adjust and critically review existing BCP to mitigate (potentially) new disruptions to clinical trial activities timely and thereby continuously improve our BCP during the outbreak.
Due to the limited time, we are not able to cover the various topics on how to manage clinical trials during the COVID-19 pandemic comprehensively at the panel discussion. As such, do refer to the following publications by the European Medicines Agency and FDA for further guidance:
1) EMA Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) pandemic Version 1 (20/03/2020)
2) FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic; Guidance for Industry, Investigators, and Institutional Review Boards March 2020
3) MHRA Advice for Management of Clinical Trials in relation to Coronavirus – 12 March 2020
Everyone of us working directly or indirectly in clinical trial management plays a material role in upholding the safety of our patients and integrity of clinical trial data and we hope the above information is helpful for you. Feel free to continue to share your experience, lessons learnt and best practice in the CQAF Wechat group. Meanwhile, stay safe, healthy and positive in this unprecedented time!
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Acknowledgement: Min Jiang, Fanny Lai, Tong Zhang, and CQAF Core Team
Author: Hannah Chen, Cathy Liu, Ellyne Setiawan, Guiqin Yu, Liping Zhou
Editor: Fengsong Wang, Lanjing Zhang
Upcoming CQAF Events
CQAF 10’year anniversary / 2020 Annual Meeting --- Sep 2020
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