By Lily Borisov, Todd Johnson, and Lyn Agostinelli, Halloran Consulting Group, Inc.
Sponsor companies are starting to look beyond COVID-19 to the design and planning of resilient clinical trials that can withstand future pandemics and mitigate some of the key challenges experienced. Some of these challenges, including the inability to treat patients, lack of access to investigational products, missed patient visits, and limited data collection, were discussed during Halloran’s most recent COVID-19 Virtual Town Hall. The pandemic has forced our industry to critically examine and make decisions on what specific data we really need to assess the safety and efficacy of products. We must now rethink our design strategies and planning processes before starting studies to find the right fit-for-purpose virtual solutions and push the boundaries on our designs to ensure we are collecting what is truly important for research and our patients.
In previous town halls, sponsors have thoroughly discussed both reactive and proactive responses to the pandemic — whether it is switching to remote visits, investing in centralized monitoring platforms, investigating home healthcare options, or simply taking a more patient-centric approach to study design. But what has truly changed, in the short term, is that studies need to start because patients need to be treated and drug development cannot cease altogether. There is little doubt that the pandemic has significantly affected how studies are conducted, but are we seeing new studies now being designed and planned that are drastically different than those prior to the pandemic?
With 62 percent of attendees indicating that they have made changes to their documented processes (due to the pandemic), the town hall focused on understanding exactly what those changes are.
Considerations When Starting a New Trial
Flexibility is the driving force for developing new studies. From decreasing patient burden to diversifying sites to enforcing more rigorous risk management processes, sponsors have creatively enhanced their current processes versus completely reengineering standard operating procedures (SOPs) that would require significant resource investment. These nimble changes lay the groundwork for future and widespread process changes, when necessary. The following are three key topics to examine when you are seeking to increase study flexibility.
1. Site Selection
First, include a diverse selection of sites, both geographically and by center type. This pandemic has shown that countries and states within the U.S. are affected differently. Center types may be affected differently as well. For example, hospitals have been further taxed than non-hospital centers during the peak of the outbreak due to space and personnel being prioritized for patient treatment. When selecting sites, maintaining geographic and center type diversity allows you to maintain some level of enrollment. Not all sites will have strict restrictions; some sites were able to stay open during the pandemic due to having the appropriate amount of personal protective equipment (PPE) and safety measures in place to ensure patient safety. For sites that are still open, understanding when the site can continue to contribute in recruiting (will it be now or in the next six months?) will help to plan accordingly and meet recruitment deadlines.
Since not all visits can be done remotely, adding satellite sites in multiple geographic locations will help reduce travel for patients who require an in-person visit.
For new sites or sites that are reopening, conduct a site feasibility assessment, using a simple checklist. Due to COVID-19, some sites may have had to change their infrastructure to accommodate more ICU beds. The site feasibility assessment will be helpful in confirming if the site is still able to conduct the study.
2. Protocol Flexibility and Study Design
Build flexibility into protocols by adding language not only related to a pandemic but any other issues, such as weather-related concerns, that may hinder a patient’s ability to attend a visit and to allow more home healthcare and telemedicine options. Implement a protocol review committee that will deconstruct your protocol and justify each inclusion criteria, endpoint, assessment, and objective. This will help refine and reduce the number of endpoints you collect, as well as number of visits patients are responsible for attending.
Combining visits as much as possible and limiting non-critical activities are effective ways to simplify study design, while mapping out the patient journey will allow you to proactively identify events to execute in parallel and elements to eliminate in order to reduce enrollment time and reduce the number of protocol deviations.
It is increasingly important to get the patient’s perspective early on when developing the protocol, as the industry is seeing competition for patients across studies and therapeutic areas. Ensuring a patient-centric protocol will help with subject recruitment and retainment. One way to do this is to adopt methods from the Oncology Care Model that allow patients to visit different physicians in closer proximity to their homes. These physicians can be included in the study and work with the principal investigator for patients that choose this option.
A risk-based monitoring program can help ensure that key data can be reviewed to meet the study completion deliverables.
3. Plan Development and Process Changes
Consider risks like future pandemics, natural disasters, and geopolitical issues when developing plans. Cross-functional risk assessment activities are now more important than ever before. Create a business continuity plan that considers all the potential risks, and ensure the plan includes a guiding principle on maintaining investigational product supply to patients. Next, build a contingency plan that describes each country’s and site’s regulations regarding on-site visits and restrictive expiration dates. You should also perform a study risk assessment to identify and discuss all the risks, mitigations, and controls, with special focus on these new processes and virtual solutions that have not been used before.
Make sure you are aware of new guidance. The best way to stay on top of evolving guidelines is to develop a spreadsheet or other means to keep track of them. At the same time, continually assess SOPs for changes necessary from an inspection readiness perspective. Thorough SOPs should allow you to continue operations in the current state, while minimizing disruption. There is a possibility that the FDA may want COVID-19-related deviations in the annual report. Ensure you are updating any applicable SOPs/plans regarding protocol deviations.
Barriers To Conducting Decentralized Trials
Sponsors have not seen significant barriers to utilizing decentralized methods and are taking advantage of the current circumstances as an opportunity to accelerate acceptance of decentralized/virtual trials. However, there are some obstacles preventing complete adoption, including the following:
- Utilizing telemedicine is challenging because many scales or patient reported outcomes (ePROs) are not validated to use virtually. However, some sponsors have continued using these tools virtually to help collect the critical data that is needed to keep studies moving forward and patients safe.
- Utilizing home healthcare is challenging in this current environment due to patients’ reluctance to welcome strangers in their home. Notably, this may be less of a problem when the pandemic is behind us.
- Decentralized trials encourage a new way of thinking, which can bring about internal challenges.
- Cross-functional alignment with this new way of thinking can be challenging. Specifically, when not performing 100 percent source data validation (SDV), more up-front planning is needed to identify what will need SDV, why, and how remote monitoring and risk-based monitoring will be executed. Getting input from biometrics early on may help with streamlining the planning.
- Internal stakeholders need to be aware of all changes and clearly lay out any potential risks and mitigations related to patient safety and data integrity. Conducting a risk assessment is mandatory for most studies.
- Up-front costs may be higher when implementing these technologies, but they will be recouped in the long term because it gives your trial flexibility, alleviates time spent retroactive study changes, reduces monitoring on-site, and accelerates end of study data analysis.
In addition, some sponsors have cited difficulty getting sites on board with conducting home healthcare visits. This varies on a case-by-case basis; using a site feasibility assessment when choosing sites will allow you to gauge each site’s willingness to perform home healthcare visits. Finally, due to GDPR requirements, telehealth can be more difficult to implement in European countries, so it is vitally important to perform feasibility assessments of specific solutions at each site before assuming they will work across the entire study.
Engaging In Multidisciplinary Teamwork
Increase site engagement by interacting directly with principal investigators. It is extremely important to get their support of decentralized trial models and change implementation thereby leading to greater acceptance by other site personnel. Reach out to study coordinators or internal medical science liaisons to get the latest information on what current and future site environments will look like before you set out to lock down your study design and plans. Holding web sessions and open office hours allows sites to call in and give sponsors feedback on current site activities and operations. This will facilitate open, real-time communication.
It is also important to reach out to vendors about anticipated risks. Sponsors have reported that some vendors can be helpful in proactively identifying risks and associated mitigations. Ask vendors about current technology solutions for decentralized models, as they may already have telehealth/home healthcare services in place that will require you to be conscientious of what they use, how it will work, and what controls are in place. In some instances, you may want to assess various options to find the best mix of vendors for your particular studies that will provide the best chance of success. Spending the extra time up front to plan the options and select the best vendors will certainly pay off in the end.
COVID-19 has presented challenges across our industry. We can take lessons learned from this difficult situation and use them to improve trial design and planning by adopting a risk-based approach and utilizing our available resources effectively. For years, FDA guidance has encouraged us take advantage of decentralized trials. COVID-19 has helped us to accelerate into the future, but remember, success in this new paradigm is only possible with the right up-front design and planning processes. So, take the time to do it right!
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About The Authors:
Lily Borisov, a consultant and project associate at Halloran Consulting Group, has clinical trial experience in diagnostic development and has developed skills in clinical trial design, quality, project management, literature reviews, EDC, database management, and data analysis using SAS. Her responsibilities include establishing project timelines, supporting subject matter experts on specific projects, identifying opportunities for project expansion, and assisting with devising support strategy. Previously, Borisov worked as a senior clinical research coordinator at a biotechnology start-up, where she was involved in both study start-up and conduct. In this role, she worked interdepartmentally and helped develop tools, systems, and workflows to drive optimal clinical trial execution.
Todd Johnson, principal consultant at Halloran, has more than 20 years of experience in pharmaceutical development and clinical systems — from beginning his career as a clinical site monitor to developing operational performance dashboards and KPI/data reporting strategies. Having successfully managed clinical programs and assets, Johnson is knowledgeable in ICH/GCP, has clinical operations experience across multiple therapeutic areas, and has assisted in several successful IND and NDA submissions. Before joining Halloran, he led the Clinical Information and Informatics groups at Astellas and PPD, with an emphasis on operational performance metric/KPI assessment, data quality, benchmarking, dashboard development and reporting.
Lyn Agostinelli, principal consultant at Halloran, has over 33 years’ experience in the life science industry and clinical practice as a registered nurse. She has extensive experience managing clinical programs in pharmaceutical and device companies in both industry and academic settings, as well as experience in the development and implementation of quality systems to align with best practices and applicable regulations. Agostinelli serves as an interim VP/director of clinical operations with numerous clients, working with and mentoring their personnel as they start-up and execute complex studies. She routinely works with clients on inspection readiness activities, including mock bioresearch monitoring (BIMO) audits and training on regulatory authority interaction during inspections.