Both quality personnel and the FDA have predicted some of the issues with pandemic operations, but much is still unknown on the impact these rapidly implemented pandemic processes.
While many biopharmaceutical companies have adapted to operating amidst the COVID-19 pandemic, the sudden shift in processes and clinical trial operating models has raised concerns amongst quality professionals in the industry. Both quality personnel and the FDA have predicted some of the issues with pandemic operations, but much is still unknown on the impact these rapidly implemented pandemic processes are having on clinical trial quality and good clinical practice (GCP) compliance. There was much discussion on risk mitigation and shifting quality assurance perspectives in this new operating environment at Fierce Life Science Events’ 2020 GCP Webcast Series.
Duncan Hall, CEO of TRI Trials, discussed how biopharmaceutical sponsors could better manage lockdowns, optimize risk, and future-proof clinical trials to build resilience against future disruptions. To efficiently navigate the impact, decisions, and compliance of lockdown management, Hall discussed site and patient perspectives regarding safety, throughput, duration, and restrictions. Specifically, site considerations include implemented measures and social distancing to protect patients and personnel from COVID infection, and the impact these measures will have on patient throughput, research staff availability, visit costs, and scheduling. Additionally, site safety measures could impact visit durations, restricting the site from conducting specific procedures, patient communication, and procedural conduct. Patient considerations include the impact of additional site safety procedures, such as requiring personal protective equipment and sanitization procedures. Throughput and duration impacts include how the safety procedures and site resources may impact study visit duration, how the patient experiences study visits, and whether the safety procedures may restrict procedural conduct. Some recommendations include initially contacting the patients, preparing them for study site visits, informing the patients about the changes in procedures, and how that will impact them, and document decisions through new consents that delineate these changes. Hall also recommended reviewing study risks by conducting a new risk assessment, conducting an interim analysis to diagnose the study data, and determining whether the study is safe to continue or whether extensions or amendments need to be implemented.
Hall suggested that it would be wise for sponsors to evaluate critical variables, such as protocol review (i.e., reevaluate the primary and secondary study endpoints), and review how the protocol can be more streamlined in this new environment. Checking the schedule of assessments, methods of evaluations, and creating an integrated strategic monitoring plan can optimize clinical operations. To future-proof studies, Hall recommended simplifying and focusing on what is essential in the protocol and eliminating unnecessary data and processes, reducing on-site monitoring visits whenever possible, and supplement with remote monitoring (it is also crucial to evaluate on-site vs. centralized monitoring task and review overlap), and assessing how new processes and technologies can be implemented to reduce the unnecessary human to human contact. Hall emphasized that common mistakes include not utilizing risk assessments, stopping rather than challenging, addressing the symptoms and not the root-causes, assuming that the pandemic will be over in the next few months, and reverting to traditional clinical operational models.
Despite all the challenges, Hall was positive about the responses he’d seen from Sponsors and CROs. Many saw this as an opportunity to implement long overdue change and embrace a risk based methodology. Once companies started to realize it is possible not only to continue, but to improve clinical research with a reduced site visit and site monitoring approach to move to central monitoring and data driven decision making makes much more sense.
Celeste Gonzalez, Principal Specialist of Clinical QA at Boston Scientific, discussed how small companies could leverage resources to conduct remote monitoring during and post-COVID. Gonzalez referenced FDA’s Guidance On Conduct of Clinical Trials of Medical Product during COVID-19 Public Health Emergency. This guidance document goes into some of the typical clinical trial issues that sponsors should expect during the COVID-19 pandemic. For instance, the FDA indicated that sponsors should find alternative means to monitor study sites, such as remote and centralized monitoring, to review study procedures, trial participants’ status, and study progress. The guidance document specifies that sponsors should be particularly aware of documenting delayed identification of protocol deviations and GCP non-compliance that may have been missed during remote monitoring visits but were later identified in-person. This documentation should specify that the delays were because of postponed monitoring visits. Additionally, if eConsent is not available, study sites can email, fax, or mail a consent form to the patient, but the patient will need to sign and return the consent form. Gonzalez also offered pointers on leveraging eSource to collect data by referencing FDA’s guidance on Computerized Systems Used in Clinical Investigations, and Part 11, Electronic Records; Electronic Signatures -Scope and Application.
Clinical quality audits are changing and are moving in a different direction, according to Sharon Reinhard, VP of R&D QA at CSL Behring. Clinical quality is changing to prevention rather than correction, critical thinking vs. editing, root cause analysis vs. symptom identification, systemic vs. isolated errors, partnering vs. policing, and applying solutions vs. fixing individual issues. Reinhard emphasized a change in regulators’ approaches, as regulators focus on quality by design rather than symptomology. Reinhard explains that humans will be humans, and mistakes will happen; quality makes the most significant difference in a well-designed system. For example, a poorly designed clinical operational system will lead operators within that system (i.e., site staff and clinical operations personnel) to increase their likelihood of making mistakes. Addressing root causes that focus on the system rather than the individuals who made the mistakes makes a much more significant impact on overall quality. Reinhard emphasized that almost all failures can be attributed to management system failures, and proper management system design can set humans up for success and that no matter how well-designed the system is, there will always be instances (typically less than 5%) that the organization cannot do anything to prevent human errors from occurring. These management systems can include procedures, processes, indications, training, and human factors engineering.
Reinhard explained that while site audits make up most annual audits conducted by sponsors, these audits focus on the individual/site performance. Auditing is beneficial as it reveals symptoms; however, with proper root cause analysis, systemic issues can be identified and addressed, and the entire system will benefit (i.e., people are less prone to making errors) from this refined process. Reinhard recommended that sponsors should consider evolving their quality programs from auditing to addressing systemic issues; specifically, collaborating with stakeholders to identify highest risk areas, adding value earlier in the development process by evaluating protocols and methods to identify design flaws and weaknesses, and performing audits to identify root causes and modify bigger processes.
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.