ACTIV trials: cross-trial lessons learned for master protocol implementation

Maryam Keshtkar-Jahromi¹, Stacey J Adam², Indira Brar³, Lucy K Chung⁴, Judith S Currier⁵, Eric S Daar⁶, Victoria J Davey⁷, Eileen T Denning⁸, Annetine C Gelijns⁹, Elizabeth S Higgs¹⁰, Prasanna Jagannathan¹¹, Arzhang Cyrus Javan¹², Tomas O Jensen¹³, Nikolaus Jilg¹⁴, Ioannis Kalomenidis¹⁵, Peter Kim¹², Seema U Nayak¹, Matthew Newell¹⁶, Babafemi O Taiwo¹⁷, Tammy Yokum¹, Yvette Delph¹⁸

Affiliations

¹ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
² Foundation for the National Institutes of Health, North Bethesda, MD, USA.
³ Henry Ford Health, Detroit, MI, USA.
⁴ CAMRIS International (under Contract No. 75N93019D00025) with National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesd, MD, USA.
⁵ JSC Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁶ Division of HIV Medicine, Lundquist Institute at Harbor- University of California Los Angeles Medical Center, Torrance, CA, USA.
⁷ Office of Research and Development, US Department of Veterans Affairs, Washington, DC, USA.
⁸ Division of Biostatistics & Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA.
⁹ Population Health Science and Policy, Mount Sinai, New York, NY, USA.
¹⁰ Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, National Institutes of Health, Rockville, MD, USA.
¹¹ Stanford University, Stanford, CA, USA.
¹² National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
¹³ Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark.
¹⁴ Division of Infectious Diseases, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens School of Medicine, Evangelismos Hospital, Athens, Greece.
¹⁶ Global Health & Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, CA, USA.
¹⁷ Northwestern University, Evanston, IL, USA.
¹⁸ Axle Informatics, North Bethesda, MD, USA.

PMID: 39540114
PMCID: PMC11557279
DOI: 10.1017/cts.2024.507

Review

ACTIV trials: cross-trial lessons learned for master protocol implementation

Maryam Keshtkar-Jahromi et al. J Clin Transl Sci. 2024.

. 2024 Oct 15;8(1):e152.

doi: 10.1017/cts.2024.507. eCollection 2024.

Authors

Affiliations

¹ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
² Foundation for the National Institutes of Health, North Bethesda, MD, USA.
³ Henry Ford Health, Detroit, MI, USA.
⁴ CAMRIS International (under Contract No. 75N93019D00025) with National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesd, MD, USA.
⁵ JSC Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁶ Division of HIV Medicine, Lundquist Institute at Harbor- University of California Los Angeles Medical Center, Torrance, CA, USA.
⁷ Office of Research and Development, US Department of Veterans Affairs, Washington, DC, USA.
⁸ Division of Biostatistics & Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA.
⁹ Population Health Science and Policy, Mount Sinai, New York, NY, USA.
¹⁰ Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, National Institutes of Health, Rockville, MD, USA.
¹¹ Stanford University, Stanford, CA, USA.
¹² National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
¹³ Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark.
¹⁴ Division of Infectious Diseases, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens School of Medicine, Evangelismos Hospital, Athens, Greece.
¹⁶ Global Health & Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, CA, USA.
¹⁷ Northwestern University, Evanston, IL, USA.
¹⁸ Axle Informatics, North Bethesda, MD, USA.

PMID: 39540114
PMCID: PMC11557279
DOI: 10.1017/cts.2024.507

Abstract

The United States Government (USG) public-private partnership "Accelerating COVID-19 Treatment Interventions and Vaccines" (ACTIV) was launched to identify safe, effective therapeutics to treat patients with Coronavirus Disease 2019 (COVID-19) and prevent hospitalization, progression of disease, and death. Eleven original master protocols were developed by ACTIV, and thirty-seven therapeutic agents entered evaluation for treatment benefit. Challenges encountered during trial implementation led to innovations enabling initiation and enrollment of over 26,000 participants in the trials. While only two ACTIV trials continue to enroll, the recommendations here reflect information from all the trials as of May 2023. We review clinical trial implementation challenges and corresponding lessons learned to inform future therapeutic clinical trials implemented in response to a public health emergency and the conduct of complex clinical trials during "peacetime," as well.

Keywords: Accelerating COVID-19 Treatment Interventions and Vaccines; COVID-19; clinical trial implementation; master protocol; preparedness; trial platform.

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Conflict of interest statement

None.

Figures

**Figure 1.**
COVID-19 cases and deaths in the US (2020–2022). Permissions received to use the data from Johns Hopkins University Coronavirus Resource Center. https://coronavirus.jhu.edu/region/united-states. ACTIV = Accelerating COVID-19 Treatment Interventions and Vaccines.

**Figure 2.**
ACTIV master protocol implementation lessons learned: the high-level takeaway lessons learned from the trial implementation of the ACTIV master protocols and potential solutions that may be utilized in future pandemics. ACTIV = Accelerating COVID-19 Treatment Interventions and Vaccines; IDIQ = indefinite delivery indefinite quantity; OTA = other transactional authority; QA = quality assessment; TMF = Trial Master File; IDS = Investigational Drug Services; IP = investigational products; SOC = standard of care; DSMB = Data and Safety Monitoring Board; GPP = good participatory practices.

See this image and copyright information in PMC

References

1. Buchman TG, Draghia-Akli R, Adam SJ, et al. Accelerating coronavirus Disease 2019 therapeutic interventions and vaccines-selecting compounds for clinical evaluation in coronavirus Disease 2019 clinical trials. Crit Care Med. 2021;1(11):1963–1973. doi: 10.1097/CCM.0000000000005295. - DOI - PMC - PubMed
1. National Center for Advancing Translational Sciences. Master Protocol. NCATS Toolkit. (https://toolkit.ncats.nih.gov/glossary/master-protocol/) Accessed July 2, 2023.
1. LaVange L, Adam SJ, Currier JS, et al. Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV): designing master protocols for evaluation of candidate COVID-19 therapeutics. Ann Intern Med. 2021;174(9):1293–1300. doi: 10.7326/M21-1269. - DOI - PMC - PubMed
1. Clinical & Translational Science Awards Program. CTSA. 2023. (https://ncats.nih.gov/research/research-activities/ctsa#:~:text=We%20sup...) Accessed March 2, 2023.
1. AIDS Clinical Trial Group. 2023. (https://actgnetwork.org/) Accessed March 2, 2023.

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ACTIV trials: cross-trial lessons learned for master protocol implementation

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ACTIV trials: cross-trial lessons learned for master protocol implementation

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Grants and funding

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