By Hannah Yee and Todd Johnson, Halloran Consulting Group, Inc.
As the COVID-19 pandemic continues to evolve, conversations around reopening strategies and business continuity have become increasingly important. Sponsors and sites have been executing contingency plans to minimize delays, protect data integrity, limit attrition, and ease site burden; yet, the challenge continues to be reacting quickly enough to keep up with a situation that changes by the hour. It’s becoming clear that we need proactive, collaborative planning and execution to mitigate the impact we’ll absorb when the pandemic loosens its grip on our industry, along with a significant effort to advance our virtual capabilities forward.
Halloran’s latest COVID-19 Virtual Town Hall focused on proactively planning different scenarios for our new “normal.” Topics included, but were not limited to:
- How best to address statistical implications from missed patient visits, tests, and increased protocol deviations
- Communications and planning from a quality perspective
- Assessing near-term needs from sites to mitigate the impact, and outlining long-term needs for future support
The open forum gave both sponsors and sites a voice in the conversation, allowing them an opportunity to communicate their needs, learnings, and challenges to an audience eager to learn from their perspectives and contribute themselves. (Links to previous COVID-19 Town Halls recaps can be found at the end of this article.)
Prepare For Missing Data
As we transition out of this pandemic, it’s important to seek input from biostatisticians on the coronavirus’s impact. For example, failing to capture data from patients in clinical trials has become a common occurrence due to COVID-related mandates that limit patient access to sites. Statisticians, clinical teams, vendors, and sites need to collaborate to assess the magnitude of impact on the patient level while continuously prioritizing patient safety.
Additionally, stakeholders must build mitigations and rationale around any missing data and at-risk endpoints. When thinking about your statistics strategy for missing data, remember to 1) collect what you can, 2) document what happened, and 3) analyze.
1. Collect what you can.
Thanks to technology, there are a variety of alternative ways to collect data, such as phoning patients, facilitating telemedicine visits, and arranging local lab/clinic visits. The emphasis should be on data collection and limiting the barriers for patients to provide required study data. Flexibility is critical — whether clinical trial material is shipped directly to patient homes or a study visit is completed via phone or video. From a statistical perspective, having some data to include in the analysis is better than no data, especially from a safety standpoint. Sponsors can proactively assess their current (and future) protocols to identify visit conversion opportunities and incorporate input directly from patients and sites along the way.
Identify flexible analysis windows and conduct evaluations at the most opportune time, even if they fall outside the normal protocol parameters. Based on the guidance issued by the FDA and other regulatory agencies around COVID-19, there is an understanding that missing data will be inevitable; however, there is still a requirement to document the rationale accompanying patient-level data omissions. Experts at the recent town hall shared some strategies for documenting data on missed visits or deviations due to remote, virtual, or off-schedule windows:
- Capture deviations in a queryable format to be extracted in a report in the future.
- Write an overarching protocol addendum to capture changes to procedures.
- Maintain a separate log list to track all deviations related to COVID-19, including all email, phone, and video correspondence between sites, sponsors, and physicians.
2. Document what happened.
These adjustments may require revised language in statistical analysis plans (SAPs), data processes, and data management plans to loosen operational directives and allow a maximum number of patients to be included in the analyses.
Sponsors should require statisticians to run additional analyses around sensitivity, safety, and treatment effects pre/post/during COVID19. For time-based comparison analyses, statisticians are relying upon site-level data when defining the start and finish of the pandemic, as conditions are highly dependent on locality. In other words, pandemic analyses should begin at the site level, not the study level.
Create A Quality Checklist
Sponsors and sites should be proactively running through a quality checklist tailored to specific COVID-impacted areas. The checklist should include a post-COVID quality plan, or modifications to an existing quality plan, addressing actions taken during COVID-19 and continued risks that will need to be considered and mitigated.
It should also include a communications strategy covering internal leadership/teams, external partners/vendors, sites, study participants, and regulatory agencies. The strategy should include timing, frequency, and messaging content.
Finally, the checklist should incorporate an action plan or execution plan that includes:
- The near-term plan focused on moving forward once travel restrictions are lifted
- Study-specific protocol for documenting actions taken during the COVID-19 period, including any impacts on data
- Changes to the study protocol and operations to emphasize proper social distancing and protection for patients and staff (in alignment with the state, local, and institutional mandates)
- Monitoring strategy with areas of focus for sponsors and sites as they resume activities, whether using alternative or conventional methods (e.g., critical data points, retraining returning site staff/training new staff, identifying emerging risks to patient safety or data integrity, etc.)
- Participant-by-participant impact summary
- The long-term plan focused on necessary changes to site/vendor audits, missing data plans, virtual trial capabilities, and potential scenario planning for future pandemics. This plan should be built from documented COVID-19 deviations and associated impacts.
Give Sites What They Need
Communication and updates with sites around status, decisions, rationale, prioritization, and planning is critical. While sites prefer communications to come directly from the sponsor, CROs or monitors can provide updates as well. As with data collection, some communication is better than no communication. This is especially important for sites that are still able to keep trials progressing before deciding to delay studies entirely.
An action plan detailing steps for resuming operations with contingency plans is also important.
Trust that sites are still able to meet your needs, that they will understand if you need to delay milestones/timelines, and that they are making patient-centric decisions around virtual phone/video patient visits, bulk procedures, visit windows, and general timing to minimize patient time onsite.
Understanding that sites must take measures to protect their staff from exposure and burnout, and acknowledge the increase in out-of-scope expenses and activities, such as:
- Extra planning to accommodate bulk procedures and minimal time on site
- Research around local labs and clinics that can accept patients who don’t want to come onsite
- Telemedicine/virtual visit technology and associated ramp-up time
- Personal protective equipment (PPE) costs
- Time spent triaging questions over email and the phone
Be open to adjusting the study budget and contract to account for COVID-related activities that sites have taken on.
Consider alternatives such as adding protocol addenda to address COVID-related changes — this may accelerate or even eliminate institutional review board (IRB) reviews as compared to protocol amendments.
Cooperate with sites to create a patient-centric approach that strikes a balance between quelling patient anxiety and moving the study forward. Sites would encourage sponsors to:
- Allow shipments of oral drugs directly to patients
- Allow protocol deviations that are in the patient’s best interest
- Be creative with visit conversion tactics such as telemedicine
- Recognize which critical data and testing is required to keep the study moving forward
- Be sympathetic with the very real fear that patients are facing (now and in the future) when deciding whether to travel to sites for visits
- Be aware that some patients may prefer virtual visits, as support and participation from caregivers, friends, and family is more realistic at home than onsite.
Be aware that when onsite visits resume, some facilities (e.g., specialized labs) will be navigating significant activity backlogs and will require alternative solutions.
Give Patients What They Need
You can help make patients feel more comfortable participating in trials by providing them with:
- More time to review consent before enrolling
- More options for study procedure locations — onsite, at a local clinic/lab, at home via home-visit from a professional, or at home via telemedicine/video/phone
- Financial support for transportation to/from the visit site
- Reassurance that the visit site is clean and safe
- Honest and realistic communication from study staff, physicians, and nurses.
Collaboration Is The Best Way Forward
To escape our current cycle of reactivity and set a new standard of proactivity, it’s critical to share information and knowledge beyond our industry silos. Increased collaboration and communication between sites and sponsors will only serve to bolster our collective ability to plan ahead, anticipate, and execute in a way that will reduce the impact on our patients.
Importantly, this is an opportunity for us to come together and establish new practices that will equip us with the agility to deliver therapies to patients effectively and efficiently even under circumstances that are outside the norm.
If you would like to be included in future Halloran Virtual Town Halls on COVID-19, please send an email request to firstname.lastname@example.org.
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About The Authors:
Hannah Yee, MPH, a consultant at Halloran Consulting Group, is experienced in clinical research, product management, and product design in health technology. Her focuses are in organizational change, process improvement and design, root cause analysis, human-centered design, and user/patient experience. She has recently worked with early- and commercial-stage companies on systems implementations, organizational redesign, and change management in both the pharma and medical device industries. Prior to joining Halloran, Yee worked as a human factors engineering consultant at Emergo by UL, where she supported usability evaluations of medical devices for regulatory compliance and design.
Todd Johnson, principal consultant at Halloran Consulting Group, 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.