Clinical Trial Conduct During COVID-19: Developing a Proactive Strategy Under Reactive Circumstances

Lessons Learned from a Virtual Town Hall held on April 24, 2020

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 6th 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.

Stats and data

As we transition out of this pandemic and into our new “normal”, 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 the hindrance caused by 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

• Visit conversion: 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 U.S. Food and Drug Administration (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, 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.

3) Analyze

• 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 vs. study-level.

A quality expert’s advice to sponsors when planning for a post-COVID19 world

• 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.
  • Communications strategy covering internal leadership/teams, external partners/vendors, sites, study participants, and regulatory agencies. The strategy should include timing, frequency, and messaging content.
  • An action plan or execution plan including:
    • 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 (and 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)
      • 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.

What sites need from sponsors

• Communication and updates around status, decisions, rationale, prioritization, and planning. While there is a preference for 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.
• Trust that sites are still able to meet sponsor needs, that sites will understand if sponsors need to delay milestones/timelines, and that sites are making patient-centric decisions around virtual phone/video patient visits, bulk procedures, visit windows, and general timing to minimize patient time onsite.
• An understanding that sites must take measures to protect their staff from exposure and burnout.
• Acknowledgment of 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) spend
  • Time spent triaging questions over email and the phone
• Alternatives such as adding protocol addenda to address COVID-related changes – this may accelerate or even eliminate IRB reviews as compared to protocol amendments.
• Cooperation creating 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
• Awareness that when onsite visits resume, some facilities (e.g. specialized labs) will be navigating significant activity backlogs and will require alternative solutions.
• Openness to adjusting the study budget and contract to account for COVID-related activities that sites have taken on.

What sponsors need from sites

• Communication around equipment gaps that the sponsor could help to close, such as PPE supply, IV bags, transfusion tubing, etc. Sponsors do not know if additional budget or PPE supplies are required unless sites openly communicate this.
• Awareness of which on-site activities are still occurring, the level of patient anxiety around virtual visits, and any activities burdening the site or the patient.
• Collaboration around visit conversion capabilities, alternatives, and technologies that are available to support business continuity.
• Participation in reopening planning including the prioritization of on-site visits/tests/data collection, ability to accommodate new study startups and/or lab access, and forecasts for an influx that may prevent the resumption of activities.

What patients need to feel comfortable participating in trials

• More time to review consent before enrolling.
• More options for study procedure locations:
  • Onsite
  • Local clinic/lab
  • At home via home-visit from a professional
  • 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.

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 norms that will equip us with the agility necessary to deliver therapies to patients effectively and efficiently even under circumstances that are outside the norm.

Please reach out to us if we can help in any way or would like to be included in any of our upcoming town halls.