The COVID-19 pandemic has shaken clinical operations to its core. Nonetheless, sponsors, CROs, and sites are rapidly adapting their operational models to maintain patient safety, data quality, and integrity. At Questex’s 11^th Clinical Quality Oversight Forum in October, there was much discussion around changing clinical quality implementation during the pandemic.

Preserving Phase I research during the pandemic

COVID-19 has caused many disruptions; however, Oren Cohen, M.D., Chief Medical Officer at Covance and an alumnus of Dr. Anthony Fauci’s laboratory at the National Institute of Allergy and Infectious Diseases described how the Covance Phase I units rapidly adapted their centers to continue clinical operations during the pandemic. Implementation challenges included reluctance of study volunteers to be housed in a research unit for days-to-weeks at a time; the possibility of confounding COVID- related adverse events, staffing shortages due to illness or fear; and uncertainty with regard to the health status of key visitors to the sites, such as clinical monitors. These challenges in turn created the risk of incomplete cohorts (resulting in higher data variability, timeline delays), data quality risks, and data integrity risks (i.e., from subject withdrawals).

Dr. Cohen described study site operations at Covance Phase I units that have allowed for safe continuity of operations during the pandemic. All study volunteers are required to complete a symptoms and contact history questionnaire, and temperature checks are performed upon arrival; volunteers who had fever, symptoms suggestive of COVID-19, and/or were in close contact with someone who contracted COVID are not allowed in the units. All nonessential visits were canceled, and all staff and volunteers are required to wash their hands upon arrival.

Appropriate social distancing measures were put in place. Site staff and volunteers are required to remain six feet apart from one another, except when performing study procedures. Clinics are running at reduced bed occupancy in order to accommodate social distancing and gathering of multiple volunteers in café or recreation areas is not permitted. Site staff are adequately equipped with personal protective equipment (PPE), such as fluid resistant surgical masks, gloves, face shields, and all personnel in the unit, including volunteers, are required to wear masks except for when in the bedroom, eating, drinking, taking medications or showering. Enhanced sanitization procedures include additional cleaning of surfaces, regular clinical equipment cleaning, and additional handwashing and sanitization procedures.

The most effective intervention, however, has been implementation of molecular diagnostic testing for SARS-CoV-2. Dr. Cohen described implementation of a point-of-care SARS-CoV-2 polymerase chain reaction (PCR) test with a 30-minute readout time in the three Covance U.S. research clinics. In the UK, a combination approach is being taken with point-of-care antigen testing as well as laboratory-based PCR testing. To date, over 20,000 tests have been performed on volunteers, staff and visitors (e.g. clinical monitors), with a positivity rate of approximately 0.4%. Specific protocols are placed for volunteers who test positive for COVID at screening, check-in, or follow-up visits. If a patient tests positive during residence at the unit, they will be sent home to self-isolate, and staff that test positive will also be sent home immediately for isolation. No secondary cases have occurred, and no studies have been suspended due to COVID-related issues. This video is shown to volunteers before coming into the clinic to explain the new guidelines.

Virtual vendor qualification audits

In the past several years, many sponsors have implemented processes to involve clinical QA during vendor feasibility, and the process has paid off with risk mitigation strategies, especially during the pandemic. Sean Storms, Senior Director of Trial and Quality Systems at CSL Behring, discussed how to conduct virtual vendor qualification audits, including understanding the scope of the audit, remote audit challenges and advantages, and procedural changes.

Storms emphasized that it is essential for QA personnel to understand the protocol, the vendor’s statement of work and communicate the audit’s full scope with the vendor. Typically, audit topics include SOP review, org charts, computer systems, disaster recovery, and business continuity plans, and interviews with key personnel. Storms recommended that auditors perform document and procedural review in advance of the audit to maximize the audit time. Additionally, from a procedural and operational standpoint, Storms indicated that auditors should prepare how the audit will be conducted, such as ensuring that remote tools (i.e., Zoom, WebEx, etc.) function properly for the audit, using document sharing portals with appropriate permissions for access, and specifying precisely the audit’s requirements including documentation, timing, and audit scope.

Remote audit challenges include reduced ability to visit and visualize the facility, equipment, and processes, ad hoc documentation requests may not be produced rapidly, it may be more time-consuming to review documentation, as it is presented electronically, and not in person, challenges with reading body language, and time zone issues. Advantages include no travel costs and downtime, more time with document access after the audit, and reduced health and safety concerns. To ensure that remote auditing follows proper QA guidelines, sponsors must establish procedural changes to allow remote auditing. These changes include generating remote auditing guidance documents and SOPs.

How the TMF can unveil clinical trial quality issues

Trial Master File (TMF) management and compliance appear to be an increasingly popular topic among clinical QA professionals. Donna Dorozinsky, CEO of Just in Time GCP, highlighted that the TMF is a tool to ensure trial integrity and generate quality signals, such as gaps in site training, site monitoring, and sponsor oversight activities. Dorozinsky indicated that the TMF provides a window into clinical trial quality, and the gaps in the TMF may signal broader quality issues. For example, a missing site initiation visit (SIV) log could signal a quality process issue; to elaborate, it is easy to locate a misplaced document. Not documenting SIV training could suggest a potential quality gap in proper documentation, which is a process-related issue.

Other common areas of concern involve the clinical monitoring plan and trial team training documentation. For instance, a clinical monitoring plan could be missing; is this because it was not filed or because it was never approved? A lack of CRA training on the clinical monitoring plan could result in study quality concerns, such as varying monitoring visit frequency, timeliness of issuing reports, and delays in reporting quality problems. Typical actions to identify clinical quality gaps in monitoring include reviewing monitoring frequency to ensure it aligns with the monitoring plan, timeliness of reporting and upload to the TMF, documenting CRA transitions, CRA training documentation, and proper updates and appropriate version control to clinical monitoring plans.

Understanding gaps in sponsor oversight is also essential to gauge clinical trial quality. Items to look for include plans for documenting sponsor oversight, plans for identifying quality gaps and documentation, and evaluating whether there is proper documentation/minutes from internal meetings at the sponsor. To address these issues, Dorozinsky recommends implementing a risk management program, defining plans and documenting oversight activities, and documenting corrective actions.

Summary

To summarize, clinical QA and quality procedures are rapidly adapting to manage clinical trials during the pandemic. CROs and study sites are implementing novel procedures to mitigate COVID transmission in the site and encourage patients to continue clinical trial visits. Sponsors are now creating new approaches to conduct vendor audits remotely, which comes with its challenges and benefits, and there is an increasing focus on TMF quality and leveraging the TMF to diagnose operational quality at sites and sponsors.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.