Overview of ACTIV trial-specific lessons learned

Abstract

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) was an extraordinary example of a public-private partnership (PPP) that brought together over thirty organizations and hundreds of individuals to address one of the most pressing global health needs in recent decades. In particular, ACTIV provided a key avenue for testing numerous therapeutics for their potential benefit in treating the SARS-CoV-2 virus or the resulting symptoms of acute COVID-19 infection. Given the speed and scale at which ACTIV designed and implemented master protocols across global networks that it was simultaneously working to create, the PPP can provide valuable lessons for best practices and avoiding pitfalls the next time the world is faced with a global pandemic of a novel pathogen. This report provides a general overview of the ACTIV partnership to set the stage and context for the subsequent articles in this issue that will relay these lessons learned.

Keywords: ACTIV; COVID-19; drug testing; master protocols; public-private partnership.

Figure 1.

ACTIV organization structure with focus on clinical therapeutics components. Reflected in the figure is an overview of the organizational governance for the ACTIV partnership with a focus on the original working groups that contributed to the launch of the clinical therapeutics testing portfolio, including the Therapeutics-Clinical, Preclinical, and Clinical Trial Capacity Working Groups. The primary outputs of these working groups were review and prioritization of over 800 agents with 37 agents entering the master protocols that were established out of the analysis of numerous NIH and private sector clinical trial networks (54 CRO/SMOs and 600+ sites). While the STRIVE platform is a part of ACTIV, it was set up after the original protocols to continue to respond to COVID-19 post-pandemic and allow for greater pandemic preparedness. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; CRO = contract research organization; SMO = site management organization; STRIVE = Strategies and Treatments for Respiratory Infections and Viral Emergencies.

Figure 2.

ACTIV therapeutics master protocols. During the COVID-19 pandemic, ACTIV designed and launched the original 11 master protocols that were approved by the FDA. The majority of the trials were double-blind, randomized control trials (RCT) testing novel agents from various patient populations and therapeutic classes. However, the ACTIV-4A protocol used a more pragmatic approach and even collaborated with other global platforms. Despite being a double-blind RCT, ACTIV-6 experimented with a fully-remote, decentralized trial design, which turned out to be quite successful. Finally, all of the lessons learned from the original ACTIV inpatient RCTs were parlayed into the launch of the new STRIVE protocol that is intended to create a global warm-based clinical trial network that can continue to evaluate therapies for COVID-19 patients, as well as create an infrastructure that can pivot to a new response in the event of another pandemic. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; ARDS = Acute Respiratory Distress Syndrome; RCT = randomized controlled study; STRIVE = Strategies and Treatments for Respiratory Infections and Viral Emergencies.

Figure 3.

Timeline of the rise and fall of variants and approval of when different agents within ACTIV were granted EUAs. Permissions received to use the variant chart sourced from Our World in Data. SARS-CoV-2 sequences by variant, Sep 11, 2023 (ourworldindata.org). Data from the ACTIV master protocols contributed to some of the key EUAs during the pandemic both in the US and other countries. However, with the evolution of the pandemic, the efficacy of some of these agents waned supporting the need for standing platforms and trials to test novel agents against SARS-CoV-2 and its resulting disease pathobiology. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; US = United States of America.

Figure 4.

ACTIV trial summary demographics as of May 2023. Several trials have continued to enroll since May of 2023, so the total ACTIV trial enrollment is now over 26,000 participants from 11 countries across the globe with 3 of the original ACTIV master protocols still in operation as of this report submission (ACTIV-2D, ACTIV-4HT, and ACTIV-6). As shown by the data, across the ACTIV trials the median age of the trial participants was 57 years old, in line with the fact that SARS-CoV-2 more greatly effected older populations. The split between enrollment of male and female participants was virtually equal, and the predominant race that was recruited was White/Caucasian (71.3%). ACTIV had reasonably strong recruitment of Black/African American participants across the trials (14.3%) but had smaller populations of other races. Improvement in the diversity of race recruitment will be a strong target for future efforts. One area where ACTIV saw strong diversity in recruitment was among the Hispanic/Latino ethnicity (30.72%). The tactics for this success are discussed in the Outreach, Recruitment, and Engagement manuscript. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.