Description of themed issue

In this supplemental issue, the ACTIV Therapeutics-Clinical Working Groups (WGs) and Clinical Trial Teams document valuable lessons believed to benefit future healthcare leaders and researchers faced with preparing for and responding to global PHEs. Here, we present brief summaries from manuscripts that describe aspects of the design and implementation of master protocols; inpatient/outpatient site-specific challenges; statistical considerations for innovative, adaptive master protocols; and important approaches to community engagement. These findings inform lessons that pinpoint the importance of incentivizing collaboration through centralized resources, community outreach for efficient and equitable enrollment of populations most affected by PHEs, and global clinical trial collaboration. Implementation of these lessons, listed in Figure 2, will enhance global preparedness for the next PHE.

Figure 2.

Key lessons learned themes discussed in each of the ACTIV manuscripts. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; DCR = Department of Clinical Research; DSMB = Data and Safety Monitoring Board; GGP-EP = good participatory practice guidelines.

Acting as primers for readers to fully understand lessons shared in other articles, Draghia-Akli et al. describe ACTIV PPP efforts to identify effective treatments for SARS-CoV-2 and COVID-19 symptoms. Providing an executive view on ACTIV’s therapeutic efforts, Adam et al. describe the WGs’ efforts to assess over 800 potential therapeutic agents [Reference Bugin and Woodcock3], selecting 37 drug formulations for deployment across 11 platform trials designed by the WGs and trial teams [Reference Bugin and Woodcock4]. With 620 sites globally, over 26,000 patients were enrolled in these 11 master protocols.

Elaborating on ACTIV trial master protocol design, Jahromi et al. detail cross-protocol themes, including the sample size and power calculation, need for flexible eligibility criteria, selection of outcome measures and optimal endpoints, value of industry partnership, trial governance and network assembly, and criticality of early regulatory interactions. In a separate manuscript, Jahromi et al. present lessons for master protocol implementation, highlighting the importance of international regulatory body cross-communication; diverse patient engagement; universal outcomes platforms assembly; central data and biospecimen repositories; central resources for startup, training, and study monitoring; and the designation of resources for drug manufacturing/delivery to support interventions. Additionally, the team calls for the establishment of a US clinical research agenda that includes the maintenance of readily deployable clinical trial infrastructure.

Site-specific challenges in trial performance in inpatient and outpatient settings are presented by O’Halloran et al. and Oh et al., respectively. Universally, initial trial execution was challenged by infection control measures and limited availability of personal protective equipment (PPE). In response, many sites implemented electronic patient education and consent procedures, as well as remote patient monitoring. Both trial types dealt with clinically stretched resources and provider fatigue. However, unique to the outpatient cohort, limited infrastructure and trained personnel shortages impacted patient recruitment, enrollment, and follow-up. Inpatient sites adapted quickly to the evolving interface between clinical care and research: medication administration and laboratory draws timed to available clinical resources, and tools were developed to stratify enrollments across coinciding clinical trials.

Statistical considerations in platform trial development are outlined by Lindsell et al. for the ACTIV Cross-Trial Statistics Group. The PPP facilitated rapid response, protocol development, and adaptive design components. Across protocols, strict interim analyses and Bayesian algorithms informed early discontinuation of ineffective therapeutics in favor of new agents. Flexibility and trial adaptations were implemented to address temporal changes in disease severity, prevalence, population immunity, and evolving standards of care.

The importance of patient/community engagement is emphasized by Wohl et al. Authors highlight limitations to engagement including infection control requirements, community perceptions, political divisions, and variable penetrance of media/social media efforts across age, race, ethnic, and geographic demographics. The authors endorse activities such as comprehensive public messaging, interfacing with patients at hospitals and outpatient centers, and collaboration with teams harboring pre-established community relationships. While Wohl et al. focus mainly on outpatient recruitment, Marines-Price et al. provide an exemplar with the ACTIV-3 trial on Good Participatory Practice for inpatient studies during a PHE and peacetime. They detail standard and novel tools for study conduct, patient recruitment, and informed consent among others.

Time capsule: messages to the future

In this special issue, the ACTIV PPP highlighted the strengths of coordinated research strategies, flexible master protocol frameworks, and collaborative governance structures involving all relevant stakeholders. Further, ACTIV trial teams demonstrated exemplary clinical trial performance under extreme PHE conditions, which stretched the healthcare ecosystem to and beyond its breaking point. The ACTIV PPP garnered many successes; however, it also revealed, and failed to fully address, shortcomings in the healthcare ecosystem that must be rectified prior to the next PHE for an improved global response.

As noted in this issue, pandemic response efforts revealed the US clinical trial system places too much focus on large healthcare centers, retains uncoordinated efforts across sites and networks, lacks reach and ability to scale quickly into underserved population communities, and poorly incentivizes investigator collaboration. These shortcomings prevent the system from pivoting quickly during PHEs and cause trials to run inefficiently in peacetime. To improve future PHE response trajectories, we highlight a few critical challenges remaining in the clinical trial ecosystem below.