Local Review Requirements/Procedures
The clinical trials were impacted by varying VAMC review requirements and approval processes. Although VA policy defines standard requirements, the timing and procedures are left to the individual facility to determine any local factors to accommodate and/or resource availability. While such an approach is well understood within the VA, external sponsors were not as familiar and assumed a more uniform approach across all sites. In response, some VAMCs established ad hoc research and development committee review procedures, allowing study teams to obtain the necessary reviews in a timely fashion. However, not all VAMCs had the infrastructure (especially when clinical personnel had been redeployed to other priorities) to respond with such agility. One critical role of the VA Central Office coordinating entities was to communicate and manage external sponsor and group expectations surrounding individual site review time lines. However, establishing policies and procedures that focus on streamlining local review processes helped to broadly mitigate the COVID-19 trial challenges.
Study Design Demands
The design of COVID-19 studies combined with the uncertainty of the pandemic required rapid protocol changes and adaptations that were often difficult to deliver. The multinetwork trials that the VA collaborated on were platform or master protocol designs. These designs emphasized overall goals (eg, treating patients requiring intensive care unit care). However, because this trial strategy also introduces complexities that may impact review and execution among those unfamiliar with it, there is a need for increased discussion and understanding of this methodology.8 For example, there can be shared control groups, reliance on specific criteria for halting because of safety or futility concerns, or continuation and expansion applied through an external review board. Delays may arise when changes to study protocols occur rapidly or frequently and necessitate new regulatory reviews, negotiation of new agreements, modifications to contracts, changes to entry criteria, etc.
While the VA has adopted a quality by design framework, VA investigators noted many missed opportunities related to looking at outcomes with new diagnostics, studies of serology, outcomes related to vaccinations, and understanding the natural history of disease in these trials.9 The limited opportunities for investigator input suggested that the advantages offered by platform designs were not maximized during pandemic-focused urgencies. It was unclear whether this barrier was created by a general lack of awareness by sponsors or a lack of opportunities. At the very least, quality by design approaches may help avoid redundancies in documentation or study processes at the central and site levels.
Contracting and Budgeting
Given external sponsorship of COVID-19 trials, efficient contracting and budgeting were critical for a rapid start up. The variability of processes associated with these trials created several challenges that were compounded by issues, such as site sub-agreements and budget documents that did not always go to the correct groups and individuals. Furthermore, the VA’s ability to use contracted resources (eg, tents, trailers, personnel) that external sponsors had built into their contracts was more difficult for VA as a federal agency governed by other statues and policies. This also put VAMCs at a disadvantage from a timing perspective, as the VA often required additional time to find equivalent solutions that met federal regulations.
Although the VA was able to establish contract solutions to some issues, time was still lost while working to secure initial funding. Additionally, for needs such as home phlebotomy—commended for convenience to veterans and research staff—and engaging a specialized research team in the Office of General Counsel, early awareness of protocol needs and sponsor solutions could allow VA to pursue alternatives sooner.
Central-Level Systems and Processes
Not all challenges were at the VAMC level. As the ORD explored solutions, it learned that various tools and study platforms were available but not considered. Applications, such as eConsent, and file-sharing platforms that met existing information security and privacy requirements were needed but had to comply with the Privacy Act of 1974, Federal Information Security Modernization Act, and other requirements. Using sponsor-provided devices, such as drug temperature monitoring equipment, required additional review to ensure that they met system requirements for a national health care system. In addition, the VA uses a clinical trials management review system; however, its implementation was new at the time these trials began. Furthermore, the system engaged with some commercial IRBs but not all. This resulted in additional delays as VAMCs and central resources worked to familiarize themselves with the system and procedures.
The ability to work collaboratively across the VA includes having a framework in which key startup processes are standardized. This allows for efficiency and minimizes variability. Also, all stakeholders should understand the importance of holding discussions to identify appropriate solutions, guidance, and instruction. Finally, the VA must strive to be more nimble when adapting technological, regulatory, and financial processes.