Accelerating COVID-19 Therapeutic Interventions and Vaccines(ACTIV): Designing Master Protocols for Evaluation of CandidateCOVID-19 Therapeutics

Working in an unprecedented time frame, the AcceleratingCOVID-19 Therapeutic Interventions and Vaccines (ACTIV)public–private partnership developed and launched 9 masterprotocols between 14 April 2020 and 31 May 2021 to allowfor the coordinated and efficient evaluation of multiple investi-gational therapeutic agents for COVID-19. The ACTIV masterprotocols were designed with a portfolio approach to servethe following patient populations with COVID-19: mild to mod-erately ill outpatients, moderately ill inpatients, and critically illinpatients. To facilitate the execution of these studies and mini-mize start-up time, ACTIV selected several existing networks tolaunch the master protocols. The master protocols were alsodesigned to test several agent classes prioritized by ACTIV thatcovered the spectrum of the disease pathophysiology. Each

protocol, either adaptive or pragmatic, was designed to effi-ciently select those treatments that provide benefit to patientswhile rapidly eliminating those that were either ineffective orunsafe. The ACTIV Therapeutics-Clinical Working Group mem-bers describe the process by which these master protocolswere designed, developed, and launched. Lessons learnedthat may be useful in meeting the challenges of a future pan-demic are also described.

Ann Intern Med. doi:10.7326/M21-1269 Annals.orgFor author, article, and disclosure information, see end of text.This article was published at Annals.org on 29 June 2021.* For members of the ACTIV Therapeutics-Clinical Working Group, see theAppendix (available at Annals.org).

Just 100 years after the devastating 1918 influenzapandemic, which left an estimated 50 million dead

worldwide, the SARS-CoV-2 pandemic has infectedmore than 163 million and killed more than 3.3 millionpeople globally in just over 16months. Advances in science,however, now enable implementation of biomedical inter-ventions—diagnostics, vaccines, and therapeutics—alongsidepublic health interventions to combat pandemics. In April2020, to harness the collective scientific power of both pub-lic and private sectors, the U.S. National Institutes of Health(NIH) established the public–private partnershipAccelerating COVID-19 Therapeutic Interventions andVaccines (ACTIV). ACTIV leverages the scientific innovation,knowledge, and biomedical resources of the U.S. govern-ment and the private sector to address a shared researchagenda. Its goal is to accelerate the development of vac-cines and therapeutics to mitigate COVID-19 morbidityand mortality and to hasten an end to the pandemic(Figure 1) (1). Bringing together biomedical resour-ces from 18 pharmaceutical companies, the NIH, theBiomedical Advanced Research and DevelopmentAuthority, the Centers for Disease Control and Prevention,other U.S. government agencies, and academics, the ACTIVpartnership was organized into the following 4 workinggroups: Preclinical, Therapeutics-Clinical, Vaccines, andClinical Trial Capacity.

The Therapeutics-Clinical Working Group (TX-ClinicalWG) had 2 charges: first, develop a systematic review pro-cess for identification and prioritization of therapeutic can-didates, and second, create master protocols for efficient,flexible, rigorous assessment of safety and efficacy ofselected candidates. The initial working group member-ship included 32 experts from 22 organizations. To tackleboth assigned tasks, the ACTIV TX-Clinical WG split into 2subgroups, one to develop a process for prioritizing agents(subject of a separate publication) and a second for masterprotocol development.

When the TX-Clinical WG launched, the clinicalresearch landscape reflected the lack of a harmonizedresearch agenda for COVID-19 therapeutics. Hundredsof trials were registered in ClinicalTrials.gov, but mostlacked essential design features, such as randomization,controls, and adequate sample sizes to generate action-able evidence (2). In the context of increasing casecounts, hospitals operating beyond surge capacity, grow-ing numbers of small or poorly designed clinical trials,trials competing for identical patient populations, andlimited understanding of disease pathogenesis, theTX-Clinical WG designed a series of rigorous masterprotocols aligned with the emerging stages of diseasepathogenesis and available candidate treatments. TheTX-Clinical WG also laid the groundwork for implement-ing the trials, which included interviewing and identifyingthe protocol leadership, regulatory sponsors, drugsuppliers, and clinical trial networks necessary to fully de-velop the protocols, infrastructure, and governance toconduct the trials. Execution of the trials leveraged allresources of ACTIV, and later of Operation Warp Speed,to make them operational.

RATIONALE FOR THE USE OF MASTER

PROTOCOLS IN A PANDEMIC

Per the definition from the U.S. Food and DrugAdministration, a master protocol uses a single trial infra-structure, trial design, and protocol to evaluate 1 or moredrugs in 1 or more diseases for efficient and accelerateddrug development (3). For ACTIV, master protocols werechosen as the primary vehicle for assessing selected ther-apeutics for several reasons. First, the ability to study mul-tiple agents under a single, overarching protocol wasessential, given the large number of agents anticipatedfor study. The Agent Prioritization subgroup of the TX-Clinical WG reviewed agents from multiple therapeutic

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classes targeting different aspects of disease pathogene-sis and natural history (such as antiviral agents, immunemodulators, and supportive therapies). Further, agentswere selected for study in different populations (forexample, hospitalized persons both in and out of the in-tensive care unit; infected but not yet hospitalized per-sons, both symptomatic and asymptomatic; and those atrisk but not yet infected [ACTIV population priorities areshown in Appendix Figure 1, available at Annals.org]).Designing individual protocols to evaluate every agent inevery relevant population was simply not feasible.

Second, the ability to incorporate innovative designelements into a master protocol was seen as a significantadvantage. The research objectives of screening numer-ous agents to identify the most promising candidatesbased on preliminary evidence and providing substantialevidence of safety and efficacy to support regulatory ap-proval called for innovative trial designs to provide effi-ciency, flexibility, and power.

Finally, speed was of the utmost importance. Masterprotocols require time and resources for upfront plan-ning exceeding those of a traditional, single-agent proto-col. This early investment, however, was anticipated torealize and retain trial efficiency, as more agents becameavailable for testing, by avoiding study start-up under anew protocol with additional agents.

CRITICAL DESIGN DECISIONS IN DEVELOPING

ACTIV MASTER PROTOCOLS

With the decision that master protocols would be thevehicle for agent evaluation, the next step was to agreeon critical trial design features to ensure rapid initiation ofand consistency across various protocols developed, be-ginning with the research objectives (Figure 2). Someselected agents would be approved for another indica-tion with a well-characterized safety profile in the indi-cated population. The evaluation of repurposed agentscould begin with a phase 3 investigation designed to pro-vide evidence of efficacy and safety for expanded

approval as a SARS-CoV-2 treatment. Other agents wouldbe early in development with minimal clinical data avail-able, requiring an exploratory trial design to evaluate tol-erability and pharmacologic activity. Seamless phase 2/3trial designs (4) would be ideal to screen these agents forgraduation to a more rigorous investigation within thesame protocol, where graduation rules could be basedon the likelihood that the agent would prove successful ina phase 3 trial of reasonable size (5). For either exploratoryor confirmatory research objectives, adaptive platformtrial designs (6) can provide flexibility and speed of deci-sion making—both essential during a pandemic. With anadaptive platform design, the trial infrastructure is estab-lished, master protocol developed, and study launchedwhen at least 1 agent and appropriate comparator areavailable for study. Other agents are added to the plat-form as they become available, through amendments tothe master protocol. Interim analyses of accumulatingdata are done throughout the study to determine if anyagents demonstrate futility and should be discontinued,preserving resources for more promising agents, or if anyagents demonstrate early evidence of efficacy, safety, andtolerability and could graduate for further study or pro-ceed to regulatory submissions. Theoretically, once anadaptive platform design is established, the master proto-col can run in perpetuity. Not knowing agent availability,criticality of timing for treatment in disease pathogenesis,or pandemic duration, ACTIV deemed the adaptive plat-form design the ideal choice.

The framework for evaluating each agent was a sec-ond key decision in developing the ACTIV master proto-cols. Without proven SARS-CoV-2 therapies, our primaryobjective was to generate evidence that 1 or moreselected agents was safe and effective. Comparison ofagents or determination of best agent in class was, there-fore, not a focus in designing the master protocols; eachagent would be compared with a suitable control. Thegoal was to generate evidence to support regulatory ap-proval of each agent independently of other agents.Focusing on this evaluation framework provided flexibility

Figure 1.Organization of the ACTIV partner leadership and working groups.

Preclinical Therapeutic Clinical Clinical Trial Capacity Vaccines

Leadership Group

Executive CommitteeCochairsFrancis Collins, NIHPaul Stoffels, Johnson &Johnson

MembersMikael Dolsten, PfizerAnthony Fauci, NIHGary Gibbons, NIHWilliam Pao, RocheJanet Woodcock, FDA

Working Groups

Increase access to animal modelsIdentify informative assays

Prioritize and test potential therapeutic agentsDevelop master protocol for clinical trials

Develop survey instrumentsDevelop inventory of clinical trial networksGuide development of innovative solutions

Accelerate evaluation of vaccine candidatesIdentify biomarkers to speed approvalProvide evidence to address safety concerns

ACTIV= Accelerating COVID-19 Therapeutic Interventions and Vaccines; FDA= Food and Drug Administration; NIH= National Institutes of Health.(Reproduced fromCollins and Stoffels [1] with permission of the Journal of the AmericanMedical Association.).

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in starting and stopping the study of individual agentswhile the master protocol continued.

Understanding that standard of care would evolvethroughout the pandemic and new treatment informationand supportive care interventions would be obtained,agents would necessarily be evaluated in ACTIV as add-ontherapies to current standard of care and could thereforeenter the platform without stopping the trial. If matchingplacebos were available, the comparison control would bematching placebo plus standard of care, enabling double-blind implementation of the master protocols. This feature,combined with randomization, was considered importantfor primary end points requiring subjective assessment (forexample, time to recovery as opposed tomortality).

Randomization was considered essential to generat-ing reliable evidence from ACTIV master protocols, andnonrandomized studies were never a real consideration.ACTIV anticipated that some novel agents would beselected for evaluation, and ACTIV's ability to providehigh-quality, comparative data on safety, tolerability, andpharmacologic activity of those agents, consistent withearly-stage drug development, was critical.

Because each protocol was designed to evaluate mul-tiple agents, it was decided during planning that wheneverpossible, a 2-step randomization procedure would beimplemented, with agent assignment at stage 1 and activeversus placebo assignment (for each agent with matchingplacebo available) at stage 2. Equal allocation would beused at the first step, with the possibility to adapt this ratioif needed. For example, 1 agent in a protocol might havemore stringent safety exclusion criteria than other agents.

Weighting the first step of randomization in its favor wouldfacilitate recruitment for that agent. As agents entered andleft the platform, this 2-step allocation algorithm could beeasily adapted to the number of active interventions.

Given the desire to efficiently evaluate agents, a deci-sion was made to share control participants amongagents within a master protocol, thereby minimizing par-ticipants receiving placebo and reducing the overall sam-ple size required for adequate power. Ability to sharecontrol participants is a key design innovation available inmaster protocols. The absence of a precision medicineobjective, where patients are targeted for an interventionon the basis of their phenotype or genotype, allowed forbroad sharing of control participants, in contrast to othermaster protocols (7). For implementation, allocationratios at step 2 of randomization would reflect this sharing(for example, 3:1 for active vs. placebo with 3 agents).

Although early agreement was reached to share con-trol participants among concurrently tested agents, evenwhen method of administration differed (for example,injection vs. oral), concerns emerged about sharing con-trol participants across time. Data from control partici-pants generated before an agent entered the study mightnot be comparable to data from concurrent control partic-ipants given possible evolution of the disease or concur-rent supportive care, and if so, potential for bias would beintroduced into the primary analyses if nonconcurrentcontrols were used. Whether borrowing of control dataacross time would be allowed, and if so, how distant intime data could be, was determined for each protocol.Another limitation on control sharing resulted from some

Figure 2.Design decisions for ACTIV master protocols.

Screening trial (phase 2) to identify promising agents vs.confirmatory trial (phase 3) to generate evidence that couldsupport product approval

Research objectives

Adequate power to detect moderately sized treatment effects withrespect to primary end points

Power

Bayesian analyses to refine these rules during the study on thebasis of accumulating information about the ability of earlyassessments to predict later clinical end points

Graduation rules(for seamless 2/3 designs)

Moderately aggressive futility boundaries considered essential tomake room for more promising agents

Early stopping rules(for futility)

Two steps, with treatment assignment at the first step followed byactive vs. matching placebo assignment at the second

Randomization

Blinded sample size review and adjustment considered optional foreach protocol

Design adaptations

Comparative analyses to evaluate each agent vs. control ratherthan analyses comparing agents with each other

Evaluation framework

Alignment of end points to existing trials was imperative instreamlining efforts and promoting comparative analyses acrosstrials

End point alignment

Control participants pooled across agents and mode ofadministration, but caution advised in pooling across time

Shared controls

Each decision made for the master protocols was critical for tailoring them to the specific needs of the patients and the portfolio of studies that ACTIVwas seeking to create to best address the therapeutic testing needs for the pandemic. ACTIV= Accelerating COVID-19 Therapeutic Interventions andVaccines.

Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics SPECIAL ARTICLE

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agents havingmore restrictive safety exclusions than otheragents in a master protocol. Comparative analyses ofsuch an agent would be limited to control data from par-ticipants who would be eligible to receive the agent.Careful monitoring would be required to ensure that anyrestrictions were not substantially affecting the power ofthe planned analyses.

The next critical design decision concerned thepower available for statistical analyses of each agent andthe potential effect on power of interim analyses or otherdesign adaptations. Consistent with the urgency for iden-tifying safe, effective treatments, agreement was reachedfor the first master protocols to provide adequate powerto detect moderate treatment effects with respect toprimary end points. At the same time, fairly aggressivefutility stopping ruleswould be used to optimize resourcesfor the most promising agents. Some later protocolsfocused on agents hypothesized to have very largeeffects. Statisticians from all stakeholders (pharmaceutical,government, and academic statisticians) worked togetherto conduct extensive simulations for each protocol andpresent benefits and risks of various analysis proposals tothe ACTIV team. Decisions made for frequency of interimdata reviews and stopping rules for both futility and effi-cacy reflected ACTIV's overarching goals, namely, todetermine agent efficacy and safety most efficiently whileensuring a meaningful clinical effect of successful agents.Additional adaptations, such as blinded sample size re-estimation during a study, were proposed for some proto-cols with similar considerations.

For master protocols with research objectives span-ning both exploratory and confirmatory phases (forexample, seamless phase 2/3 designs), decisions aboutgraduation rules from 1 phase to the other were needed.These rules typically depend on early phase assessments(such as symptoms or viral load for outpatients) that arebelieved, but not yet proven, to predict end points at alater phase (such as hospitalization and sustained recov-ery). For SARS-CoV-2, little was known about relation-ships between early and late phase end points for anypatient populations, making a priori specification of grad-uation rules difficult. The master protocol design team ofthe TX-Clinical WG agreed that, where possible, Bayesianstatistical methods would be used to pool accumulatingdata across agents in a master protocol to assess theserelationships and adjust graduation rules accordingly.

The final design consideration that generated lengthydiscussion was alignment of end points across ACTIV mas-ter protocols. The TX-Clinical WG agreed that end pointscould differ by patient population (for example, outpatientvs. inpatient) but believed that it was important to harmo-nize end points with existing (non-ACTIV) trials of thesame population and to select simple, established meas-ures that resonate with regulators, clinicians, and patientsto streamline efforts and promote comparability across tri-als. Because ACTIV protocols were intended to generateevidence to support regulatory approval, input from regu-latory partners was instrumental in guiding end pointdetermination. Early ACTIV studies would rely on clinicalend points for efficacy evaluation because surrogate endpoints (for example, virologic) were not yet established.

The COVID-19 ordinal scale was identified as a reliableand meaningful clinical end point to support product ap-proval (8, 9), and early ACTIV protocols incorporated var-iations of that scale as primary end points.

PROCESSES TO DEVELOP AND LAUNCH THE

ACTIV MASTER PROTOCOLS

Having agreed on the critical design elements ofeach master protocol, the TX-Clinical WG next needed todetermine how many master protocols should be devel-oped and how they should be differentiated. In theory,designing 1 large, complex master protocol encompass-ing all agents, regardless of drug class or patient popula-tion, was possible; however, given the need for quickstart-up and ease of interpretability of trial results tofacilitate their translation to clinical practice, the groupdecided to simultaneously launch multiple master proto-cols by leveraging existing infrastructure where possible.Protocols would be differentiated by patient populationand drug class. Developing separate master protocols forinpatient and outpatient populations would enable exist-ing networks with experience in different populations tobe used for ACTIV trials. Aligning master protocols todrug classes allowed trial designs to be tailored to therequirements of each class regarding safety data collec-tion, definition and timing of end points for capturing pre-dicted drug effects, and other considerations.

Protocols of existing COVID-19 trials (such asACTT [Adaptive COVID-19 Treatment Trial], REMAP-CAP [Randomised, Embedded, Multi-factorial, AdaptivePlatform Trial for Community-Acquired Pneumonia], andI-SPY COVID-19 TRIAL [An Adaptive Platform Trial forCritically Ill Patients]) were collected and reviewed by theworking group to determine whether the networks forthese protocols could be engaged to develop and launchan ACTIV master protocol. The ACTT-1 and ACTT-2 proto-cols were selected as the basis for a master protocol forimmune modulators in hospitalized patients (ACTIV-1).Repurposing the ACTT protocols for ACTIV-1 meant thatthe team started with a well-designed, field-tested trialfound to be successful in identifying an effective interven-tion, remdesivir. This made drafting the protocol more effi-cient and helped harmonize data collection and end pointswith existing trials. The team adapted the ACTT protocol toreflect critical ACTIV design decisions (Figure 2) and knowl-edge gained about the pandemic. Before the protocol wasfinalized, remdesivir gained emergency use authorization(10) and was incorporated as standard of care. ACTIV-1was designed quickly to evaluate the first agents priori-tized, but finding a network to house the protocol after thefact slowed the implementation process.

In contrast, the outpatient and inpatient master proto-cols to investigate neutralizing antibodies and other anti-viral agents, ACTIV-2 and ACTIV-3, were developed afterfirst identifying existing, NIH-funded clinical trial networksfor implementation. INSIGHT (International Network forStrategic Initiatives in Global HIV Trials) (hospitalizedpatients), CTSN (Cardiothoracic Surgical Trials Network)and the PETAL (Prevention and Early Treatment of AcuteLung Injury) Network (critically ill patients), and ACTG

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Figure 3. Summary of ACTIV master protocols along disease progression and their current status.

Seve

rity

of

illne

ss

No illness

Noinfection

Death

Convalescence

After illness

ACTIV-1

ACTIV-2

Trial launched on 3 August 2020Initial agents for testing: nMABs (Lilly and Brii Bio)Agents in the pipeline: nMABs, nPABs, IFN-β, and oral antivirals

ACTIV-3

Trial launched on 4 August 2020Initial agents for testing: nMABs (Lilly, Brii Bio, GSK-Vir)Agents in the pipeline: nMABs, antiviralsPublished report on first nMABs in NEJM on 22 December

ACTIV-3B

Trial launched on 21 April 2021Initial agent for testing: aviptadilAgents in the pipeline: immune modulators for ARDS

ACTIV-4A

Trial launched on 17 September 2020Initial agents for testing: LMWH and UFHAgents in the pipeline: P2Y12 inhibitors (antiplatelet agents)

ACTIV-4B

Trial launched on 17 September 2020Initial agents for testing: low-dose aspirin, prophylactic-dose apixaban, therapeutic-dose apixaban

ACTIV-4C

Trial launched on 9 February 2021Initial agent for testing: apixaban

ACTIV-5

Trial launched on 9 October 2020Initial agents for testing: risankizumab and lenzilumab

ACTIV-6

Trial to be launchedInitial agent for testing: ivermectin

Stage 1(Early infection; outpatient;

~80% patients)

Stage 2(Pulmonary phase; inpatient;

~15% patients)

Stage 3(Hyperinflammation phase;

inpatient ICU; ~5% patients)

Viral responsephase

Host inflammatoryresponse phase

Clinical signsand symptoms

Infected; not hospitalized(with or without limitations)

Hospitalized;(no active medical problems �

receiving O2)

Hospitalized;(high-flow O2 �

mechanical ventilation)

Potentialmaster

protocolACTIV-4cACTIV-2, ACTIV-4b, ACTIV-6 ACTIV-1, ACTIV-3, ACTIV-3b ACTIV-4a, ACTIV-5

Master Protocol Protocol Description Current Trial Status

Inpatient, randomized, double-blind, phase 3 master protocolHost-targeted immune modulatorsNCATS TIN + DCRI + TRI + CROTarget sample size (patients per group): 540

Outpatient, randomized, double-blind, phase 2/3 master protocolnMABs and oral antiviralsNIAID ACTG + CROTarget sample size (patients per group): 421 (IV agents); to be determined (others)

Inpatient, randomized, double-blind, phase 3 master protocolnMABsNIAID INSIGHT + NHLBI PETAL + NHLBI CTSN + VA + CROTarget sample size (patients per group): 500

Inpatient, randomized, double-blind, phase 3 master protocolHost-targeted immune modulatorsNIAID INSIGHT + NHLBI PETAL + NHLBI CTSN + VA + CROTarget sample size (patients per group): 310

Inpatient, pragmatic, randomized, open-label, phase 3 master protocolAnticoagulants, antiplatelet agents, other antithromboticsNHLBI CONNECTS NetworkTarget sample size (patients per group): 1000

Outpatient, randomized, double-blind, phase 3 master protocolAnticoagulants, antiplatelet agents, other antithromboticsNHLBI CONNECTS NetworkTarget sample size (patients per group): 1750

Outpatient, convalescent, randomized, double-blind, phase 3 master protocol Anticoagulants, antiplatelet agents, other antithromboticsNHLBI CONNECTS NetworkTarget sample size (patients per group): 2660

Inpatient, randomized, double-blind, phase 2 master protocolProof-of-concept study to identify promising treatmentsNIAID + CROTarget sample size (patients per group): 500

Outpatient, randomized, double-blind, phase 3 master protocolExisting prescription and over-the-counter medicationsNCATS + DCRI + PCORnet + SignalPath + CROTarget sample size (patients per group): 300

Trial launched on 16 October 2020Initial agents for testing: abatacept, cenicriviroc, infliximab

The top illustration outlines the disease progression and how each ACTIV master protocol targets the individual patient population. Our understandingof viral and immunomodulatory responses throughout the disease progression continues to evolve as we learn from available clinical data. ACTIV-1 is aphase 3 master protocol that tests promising immune modulators. ACTIV-2 is designed as a phase 2 trial that can expand seamlessly to phase 3 to eval-uate the efficacy and safety of various investigational agents, including monoclonal antibodies and antiviral agents. ACTIV-3 primarily aims to assesssafety and efficacy of investigational agents to reduce time to sustained recovery. The sister protocol, ACTIV-3B, aims to evaluate the safety and efficacyof investigational agents at improving outcomes for hospitalized patients with acute respiratory distress syndrome related to COVID-19. ACTIV-4 masterprotocols evaluate the safety and efficacy of various antithrombotic agents that aim to prevent, treat, and address COVID-19–associated coagulopathy(CAC), or clotting, as well as help understand the effects of CAC across 3 patient populations: inpatient, outpatient, and convalescent. ACTIV-5 isdesigned as a proof-of-concept phase 2 study to rapidly evaluate proposed treatments and advance them to phase 3 trials if efficacy is demonstrated.Finally, ACTIV-6 tests existing prescription and over-the-counter medications for people to self-administer (orally or with an inhaler), with the aim of pro-viding evidence-based treatment options for most adult patients with COVID-19 and mild to moderate symptoms. ACTG= AIDS Clinical Trials Group;ACTIV= Accelerating COVID-19 Therapeutic Interventions and Vaccines; ARDS= acute respiratory distress syndrome; CONNECTS= CollaboratingNetwork of Networks for Evaluating COVID-19 and Therapeutic Strategies; CRO= contract research organization; CTSN= Cardiothoracic Surgical TrialsNetwork; DCRI= Duke Clinical Research Institute; ICU= intensive care unit; IFN= interferon; IV= intravenous; INSIGHT= International Network forStrategic Initiatives in Global HIV Trials; LMWH= low-molecular-weight heparin; NCATS= National Center for Advancing Translational Sciences;NEJM= New England Journal of Medicine; NHLBI= National Heart, Lung, and Blood Institute; NIAID= National Institute of Allergy and InfectiousDiseases; nMAB= neutralizing monoclonal antibody; nPAB= neutralizing polyclonal antibody; PCORnet= National Patient-Centered Clinical ResearchNetwork; PETAL= Prevention and Early Treatment of Acute Lung Injury; TIN= Trial Innovation Network; TRI = Technical Resources International; UFH=unfractionated heparin; VA= Department of Veterans Affairs.

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(AIDS Clinical Trials Group) (outpatients) were engaged,taking advantage of existing clinical trial infrastructureand NIH support contracts. Advance network selectionincreased acceptance by network investigators, whohelped accelerate overall protocol initiation. This has-tened launch was critical for ACTIV-2 and ACTIV-3because of the need to test SARS-CoV-2 neutralizing anti-bodies and other antiviral agents for which the protocolswere designed. Another added advantage of selectingthe networks before designing the protocol was the com-bined expertise (for example, infectious disease and criti-cal care) available during protocol design from networksthat had not previously collaborated (Figure 3).

With ACTIV-4, ACTIV-5, and ACTIV-6, ACTIV similarlyaligned with existing networks and investigators to lever-age ongoing efforts and infrastructure. The suite of ACTIV-4 protocols was launched by the National Heart, Lung, andBlood Institute's CONNECTS (Collaborating Networkof Networks for Evaluating COVID-19 and TherapeuticStrategies) to test antithrombotic agents in all patient pop-ulations to address the rampant clotting conditions inpatients with COVID-19. ACTIV-5 was launched to allowquick screening of agents that are ready only for phase 2to determine if they should advance into one of the largerphase 3 master protocols. ACTIV-6, a light touch study,evaluates the efficacy of repurposed agents with solidsafety records in COVID-19 outpatients. The need forACTIV-6 arose from public and physician belief that agents(specifically ivermectin) had clinical benefit but that clinicalstudy data were insufficient to inform clinical guidelines.

In all cases, factors considered in selecting a networkincluded the need for global reach necessary for contin-ued enrollment given geographic epidemiologic variabil-ity of the pandemic, clinical network capacity with sitenumbers to meet enrollment targets, network experienceenrolling similar patient populations, determination ofwhether multiple networks should collaborate, institu-tional review board and data and safety monitoringboard challenges from networks, and contracting mecha-nisms for each network affecting the ability to rapidlyonboard and activate sites and vendors.

KEY ASPECTS OF SUCCESS AND CONSIDERATIONS

FOR FUTURE RESEARCH ABOUT PANDEMIC

RESPONSE

The need for high-quality clinical trials to evaluatecandidate therapeutics for safety and efficacy in COVID-19 has been an urgent priority since the start of the pan-demic. As of May 2021, ACTIV has launched 9 masterprotocols to create a portfolio of treatment trials toaddress the spectrum of COVID-19 disease (Figure 3); allwere developed with input from all ACTIV stakeholders,including the Food and Drug Administration. In theseefforts, ACTIV succeeded in bringing together expertsfrom government, industry, and academia and experi-enced clinical trial networks to urgently address thisneed. The following 9 themes, which could inform futurepreparedness and response efforts, were interwoven intothe project's success and ability to overcome challenges.

Singular goal. This teamof experts representing govern-ment, industry, and academia were highly motivated by acommon goal of quickly designing rigorous, controlled trialsto produce clinically actionable data, and scores of ACTIVmembers volunteered countless hours to this endeavor. Thismodel allowed input from diverse experts without concernabout receiving “credit” for success. Further, there were nosecondary agendas beyond accelerating evidence acquisi-tion for safe, effective therapies. The parallel process for iden-tifying agents for study through the Agent Prioritizationsubgroup also helped expedite the overall process. Groupsoutside the TX-Clinical WG were responsible for other tasks,such as advancedproduct commitments, supply chains, iden-tification of sites, and contract support for the studies. Beingpart of a functional U.S. government system enabled thegroup to have a laser focus on their piece of the larger effort.

Broad spectrum of expertise. The TX-Clinical WGmembers collectively reflected expertise across multiplekey areas, including regulatory processes, preclinical andclinical drug development, pharmacokinetics and phar-macodynamics, and biostatistics, enabling reliance onthe group to accelerate the common goal.

Leadership. The ACTIV executive committee, whichincluded senior leadership from the NIH, the Food andDrug Administration, Operation Warp Speed, industry,and others, was responsive to and supportive of theneeds of the TX-Clinical WG when challenges were ele-vated. The TX-Clinical WG leadership, co-led by repre-sentatives from the NIH and industry, escalated needsand barriers to the ACTIV executive committee. Overtime, ACTIV executive committee support solved chal-lenges that might have otherwise hindered success.Administrative and organizational leadership from theFoundation for the National Institutes of Health wasessential to the working group's success.

Speed, efficiency, and rigor as driving principles in mas-ter protocol design. The desire for speed, efficiency, andrigor led to an early decision to use adaptive platform trialsdone under overarching master protocols for the simultane-ous testing of multiple agents and to allow interventions tobe added as new data emerged and more was learnedabout COVID-19 disease pathogenesis. Various statisticalapproaches to trial design, adaptation, and analysiswere adopted, including both frequentist and Bayesianapproaches, taking into account theparticular researchobjec-tives of each protocol. It was also agreed that scientific rigorand ability to assess both safety and efficacy should not besacrificed for speed; therefore, the master protocols wereappropriately powered to see clinically meaningful, definitiveresults. Although this requires larger sample sizes, the impor-tant benefits will be ease of interpretation and confidence inresults. Another speed-enhancing decision wasmade to ena-ble ACTIV trial teams towork with pharmaceutical companiesduring their phase 1 studies, enabling rapid onboarding ofagents into themaster protocols if phase 1 resultswereprom-ising. Over time, commitment to speed, efficiency, and rigorultimately resulted in a process and protocols in which phar-maceutical companies trusted that the trials would producedata that would support their clinical development plans.

Global clinical trials research capacity. Given antici-pated and actual variability of the COVID-19 pandemic,

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the decision to create several clinical research networkswith global research capacity has enabled global enroll-ment despite country shifts in COVID-19 incidence.Global sites are anticipated to contribute informationaround potential potency differences based on emer-gence of SARS-CoV-2 variants andmutations of concern.

Tradeoffs and challenges. Enrollment rates and siteactivation were initially slow despite rapid protocol devel-opment. ACTIV was launched in April 2020, more than 3months into the pandemic, and clinical research capaci-ties at the major research institutions were alreadyengaged in investigator-initiated protocols or industry tri-als. Early outreach letters to sites by Francis Collins, theNIH director, conveyed that the ACTIV protocols were apriority of the U.S. government research agenda. In addi-tion to trial competition, commitment to rigor enablingassessment of both safety and efficacy led to longer pro-tocol initiation times at clinical trial sites due to regulatoryand operational requirements. Sites worked throughlogistic hurdles and grappled with handling the addi-tional burden of implementing a clinical trial on top ofdelivering clinical care. However, once the master proto-cols were implemented at clinical trial sites, the teamsbecame efficient at adding and eliminating therapeuticcandidates with no interruption to the trials. It would takefar more time and resources to design and implement in-dependent phase 2 and 3 trials for each individualcandidate. Furthermore, multiple individual trials createcompetition for resources, as well as for participants, ateach site. Differences in approaches within and acrossregulatory agencies also created challenges for country-level approvals. In some countries, regulators prioritizedspecific country trials, resulting in delays. Likewise, with dif-ferent regulatory approaches to a given master protocol

(such as inclusion of pregnant women), the master proto-cols are implemented differently in different countries.

Future research response agenda prioritized by theU.S. government for health emergencies. The ACTIV TX-Clinical WG initiated 9 master protocols within 13 months(with the ACTIV-2 and ACTIV-3 initiation within months;Figure 4 presents a timeline, and additional ACTIV trialtimelines are shown in Appendix Figures 2 and 3 [avail-able at Annals.org]). On the basis of this success, theteam recommends that when the next pandemic strikes,a public–private partnership similar to ACTIV be quicklyestablished, ensuring assembly of relevant expertise andresources to accelerate a prioritized research agenda thatincludes rigorous clinical trials. Repurposing existing,field-tested protocols; early involvement of federallyfunded investigators and clinical trial networks; and align-ment with ongoing efforts can bring critically needed effi-ciency to identify safe, effective therapeutics to mitigatemorbidity and mortality from a novel deadly pathogen(Figure 5). In addition, the ACTIV team would recom-mend that the U.S. government and the infectious dis-ease community keep global clinical trial networks activeand “trial-ready” for the next pandemic. Even more effec-tive would be to bring together all clinical trial sites capa-ble of performing trials in a pandemic, to unify thenational research response in order to prioritize masterprotocols and eliminate competition from smaller, lessclinically relevant clinical trials—similar to efforts by theU.K. National Institute for Health Research (11) inresponse to COVID-19. A final lesson that the ACTIV TX-Clinical WG would emphasize to any team desiring todesign and execute master protocols in a future pan-demic is not to wait for the perfect scenario or protocoldesign to emerge, because that can waste valuable time;

Figure 4. Timeline for ACTIV-2 and ACTIV-3 master protocol development.

Protocol Development and Approval

Trial Setup and Operation

Trial LaunchActivities

Ongoing

Ongoing

Ongoing

• Draft and refine protocol

• FDA pre-IND review

• Revise protocol

• FDA IND review

• Protocol amendments

• Assemble required resources

• Select CRO

• Trial stand-up

• Trial execution

• Additional site activation

June 2020 July 2020 August 2020 September 2020 October 2020

The time to design, obtain approval, and launch is shown here. Overall, trial initiation completed in about 2.5 mo. Having a dedicated network and prin-cipal investigator champion during the trial design and setup resulted in rapid trial activation. ACTIV= Accelerating COVID-19 TherapeuticInterventions and Vaccines; CRO= contract research organization; FDA= Food and Drug Administration; IND= investigational new drug.

Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics SPECIAL ARTICLE

Annals.org Annals of Internal Medicine 7

move forward with the best strategy that can be executedunder urgent timelines.

Lisa LaVange, PhDUniversity of North Carolina, Chapel Hill, North Carolina

Stacey J. Adam, PhDFoundation for the National Institutes of Health, NorthBethesda, Maryland

Judith S. Currier, MD, MScUniversity of California, Los Angeles, Los Angeles, California

Elizabeth S. Higgs, MD, MIA, DTMHSarahW. Read, MD; for theACTIV Therapeutics-Clinical Working Group*National Institute of Allergy and Infectious Diseases, NationalInstitutes of Health, Bethesda, Maryland

Lora A. Reineck, MD, MSNational Heart, Lung, and Blood Institute, National Institutes ofHealth, Bethesda, Maryland

Eric A. Hughes, MD, PhDNovartis Pharma, Basel, Switzerland

Acknowledgment: The ACTIV TX-Clinical WG thanks all of themembers of their team, the ACTIV leadership, and all who arehelping to conduct the ACTIV master protocols. In addition,the team acknowledges all of the support received from theOperation Warp Speed Therapeutic Team (now known as the

Federal COVID-19 Response Countermeasures AccelerationGroup).

Financial Support: Support for this effort was provided throughthe ACTIV partnership.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-1269.

Corresponding Author: Stacey Adam, PhD, Cancer ResearchPartnerships, Foundation for the National Institutes of Health,11400 Rockville Pike #600, North Bethesda, MD 20852; e-mail,sadam@fnih.org.

Current author addresses and author contributions are avail-able at Annals.org.

References1. Collins FS, Stoffels P.AcceleratingCOVID-19 therapeutic interventionsand vaccines (ACTIV): an unprecedented partnership for unprecedentedtimes. JAMA. 2020;323:2455-2457. [PMID: 32421150] doi:10.1001/jama.2020.89202. Bugin K, Woodcock J. Trends in COVID-19 therapeutic clinicaltrials. Nat Rev Drug Discov. 2021;20:254-255. [PMID: 33633370]doi:10.1038/d41573-021-00037-33. Woodcock J, LaVange LM.Master protocols to study multiple thera-pies, multiple diseases, or both. N Engl J Med. 2017;377:62-70. [PMID:28679092] doi:10.1056/NEJMra15100624. Geiger MJ, Skrivanek Z, Gaydos B, et al. An adaptive, dose-find-ing, seamless phase 2/3 study of a long-acting glucagon-like pep-tide-1 analog (dulaglutide): trial design and baseline characteristics. JDiabetes Sci Technol. 2012;6:1319-27. [PMID: 23294776]5. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plusneoadjuvant chemotherapy on pathologic complete response in

Figure 5. Strategic decisions and considerations for the ACTIV master protocols.

Tria

l Set

upSt

udy

Des

ign

Division of patient populations (i.e., inpatient vs. outpatient) can expedite initiation

Platform master protocol designs allow for sharing of placebo controls for concurrently runagents, thus optimizing the number of patients that receive investigational products in the trial

Powering sufficiently for both EUA and full FDA approval is essential in a pandemic situation

Bayesian trial design can provide flexibility for graduation of agents from early to late stage

Selection of aggressive efficacy and futility rules can allow for quick evaluation of agents

Using resources from both the public/government sector and the private sector allows foroptimal construction of trial teams and networks

Selecting an existing network and trial PIs at the start of trial design results in quickerinitiation and greater clinical site buy-in

Sufficient funding and site staff support are critical for trial initiation

Transparent, clear, and frequent communication with all involved parties is essential

ACTIV= Accelerating COVID-19 Therapeutic Interventions and Vaccines; EUA= emergency use authorization; FDA= Food and Drug Administration;PI= principal investigator.

SPECIAL ARTICLE Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics

8 Annals of Internal Medicine Annals.org

women with early-stage breast cancer: an analysis of the ongoingphase 2 adaptively randomized I-SPY2 trial. JAMA Oncol.2020;6:676-684. [PMID: 32053137] doi:10.1001/jamaoncol.2019.66506. Saville BR, Berry SM. Efficiencies of platform clinical trials: a vision ofthe future. Clin Trials. 2016;13:358-66. [PMID: 26908536] doi:10.1177/17407745156263627. Redman MW, Papadimitrakopoulou VA, Minichiello K, et al. Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer(Lung-MAP SWOG S1400): a biomarker-driven master protocol. LancetOncol. 2020;21:1589-1601. [PMID: 33125909] doi:10.1016/S1470-2045(20)30475-7

8. WHO Working Group on the Clinical Characterisation andManagement of COVID-19 infection. A minimal common outcomemeasure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20:e192-e197. [PMID: 32539990] doi:10.1016/S1473-3099(20)30483-79. Adaptive COVID-19 Treatment Trial (ACTT) [clinical trial]. Accessedat https://clinicaltrials.gov/ct2/show/NCT04280705 on 15 April 2021.10. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study GroupMembers. Remdesivir for the treatment of Covid-19 — final report. NEngl J Med. 2020;383:1813-1826. [PMID: 32445440] doi:10.1056/NEJMoa200776411. RECOVERY Trial. Nuffield Department of Population Health. 2021.Accessed at www.recoverytrial.net on 15 April 2021.

Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics SPECIAL ARTICLE

Annals.org Annals of Internal Medicine 9

Current Author Addresses: Dr. LaVange: 135 Dauer Drive,Campus Box #7420, UNC-CH, Chapel Hill, NC 27599-7420.Dr. Adam: 11400 Rockville Pike #600, North Bethesda, MD20852.Dr. Currier: 911 Broxton Avenue, Suite 200, Los Angeles, CA90024.Dr. Higgs: 10 Center Drive, Bethesda, MD 20814.Dr. Reineck: 6705 Rockledge Drive, Room 407-L, Bethesda, MD20892.Dr. Hughes: 28 Berry Lane, Lakeville, PA 18438.Dr. Read: 5601 Fishers Lane, Room 8D25, Rockville, MD 20852.

Author Contributions: Conception and design: L. LaVange, S.J.Adam, J.S. Currier, E.S. Higgs, L.A. Reineck, E.A. Hughes, S.W.Read.Analysis and interpretation of the data: S.J. Adam, E.S. Higgs,E.A. Hughes.Drafting of the article: L. LaVange, S.J. Adam, J.S. Currier, E.S.Higgs, L.A. Reineck, E.A. Hughes, S.W. Read.Critical revision of the article for important intellectual content:L. LaVange, J.S. Currier, E.S. Higgs, L.A. Reineck.Final approval of the article: L. LaVange, S.J. Adam, J.S. Currier,E.S. Higgs, L.A. Reineck, E.A. Hughes, S.W. Read.Statistical expertise: L. LaVange.Administrative, technical, or logistic support: S.J. Adam.Collection and assembly of data: S.J. Adam, E.S. Higgs, E.A.Hughes.

APPENDIX: MEMBERS OF THE ACTIVTHERAPEUTICS-CLINICAL WORKING GROUP

MembershipMembers of the ACTIV Therapeutics-Clinical Working

Group who authored this work: Lisa LaVange (University ofNorth Carolina, Chapel Hill); Stacey J. Adam (Foundationfor the National Institutes of Health); Judith S. Currier(University of California, Los Angeles); Elizabeth S. Higgs,Lora A. Reineck, and Sarah W. Read (National Institutes ofHealth); and Eric A. Hughes (Novartis Pharma).

Members of the ACTIV Therapeutics-Clinical WorkingGroup who contributed to this work but did not author it: NeilAggarwal, John Beigel, Sam Bozzette, Christine Colvis,Michelle Culp, Josh Fessel, Ellen Gadbois, Keith W. Hoots,Andrei Kindzelski, Walter Koroshetz, Joanne Lumsden, HilaryMarston, Ashley Parker, Amy Patterson, Yves Rosenberg, andMichael Proschan (National Institutes of Health); Mark Eisner(Genentech); Timothy Buchman (U.S. Department of Healthand Human Services); Timothy Burgess (Uniformed ServicesUniversity of the Health Sciences); Joan Butterton (Merck &Co.); Sylva Collins, Angelo R. De Claro, Daniel Rubin, Yuan LiShen, and Peter Stein (U.S. Food and Drug Administration);RuxandraDraghia-Akli (Janssen Pharmaceutical Companies ofJohnson & Johnson); Carl Garner (Eli Lilly and Company);Keith Gottesdiener (PrimeMedicine); DavidM. Hone, Revell L.Phillips, and Ronald B. Reisler (Defense Threat ReductionAgency); Jacqueline Kirchner and Mike Poole (Bill andMelinda Gates Foundation); Elliot Levy (Amgen); John W.Mellors (University of Pittsburgh); Sandeep Menon (Pfizer);

Linda Mollica, Naimish Patel, and Peter Wung (Sanofi);Amanda Peppercorn (GlaxoSmithKline); Martha Petrovick(Massachusetts Institute of Technology); David Wholley(Foundation for the National Institutes of Health); John Young(Roche); and Helen Chen, Alex Cwalina, and Hana Nasr(DeloitteConsulting).

Participating COVID-19 ACTIVGroupsDomestic and International Agencies

Biomedical Advanced Research and DevelopmentAuthority

EuropeanMedicines AgencyNational Institutes of HealthNational Institutes of Health: National Cancer InstituteNational Institutes of Health: National Center for

Advancing Translational SciencesNational Institutes of Health: National Heart, Lung,

and Blood InstituteNational Institutes of Health: National Institute of

Allergy and Infectious DiseasesNational Institutes of Health: Office of the DirectorU.S. Army Medical Research and Development

CommandU.S. Centers for Disease Control and PreventionU.S. Department of Veterans AffairsU.S. Food and Drug AdministrationU.S. OperationWarp SpeedWhite House COVID Response Team

Industry PartnersAbbVieAmgenAstraZenecaBristol Myers SquibbDewpoint TherapeuticsEisai Co.Eli Lilly and CompanyEvotecGilead SciencesGlaxoSmithKlineJohnson & JohnsonKarunaKSQ TherapeuticsMerck & Co.ModernaNovartis InternationalNovavaxPfizerRhythm PharmaceuticalsRocheSanofiTakeda Pharmaceutical CompanyVir Biotechnology

Nonprofit OrganizationsBill & Melinda Gates FoundationFoundation for the National Institutes of HealthFred Hutchinson Cancer Research CenterRTI International

Annals of Internal Medicine Annals.org

Appendix Figure 1. Priority populations for ACTIV.

Clinical Population Categories

1 2 3

(decreasing disease severity)

Critically ill/ventilated (ICU)

Hospitalized/moderately ill

(non-ICU)

Outpatient/ambulatory ill

Prophylaxis/prevention

To appropriately prioritize agents for the master protocols, the desired target populations needed to be agreed on by the ACTIV Therapeutics-ClinicalWorking Group. After much deliberation, the group decided given the high hospitalization and death rate early in the pandemic that the COVID-19patient population would be prioritized in the following order for agent review: 1) hospitalized/moderately ill (non-ICU) and critically ill/ventilated (ICU),2) outpatient/ambulatory ill, and 3) prophylaxis. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; ICU = intensive care unit.

Annals.org Annals of Internal Medicine

Appendix Figure 2. Timelines for ACTIV master protocol development.

ACTIV-1

ACTIV-2

ACTIV-3

ACTIV-4a

ACTIV-4b

ACTIV-4c

ACTIV-5

2020 2021

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Ongoing operations

Protocol development and approval

Operational planning/setup

Trial launchActivities

April May June July August September October November December January

Each ACTIV master protocol undergoes 3 main development stages: 1) protocol development and approval, which consists of designing and draftingthe protocol, onboarding participating companies for the refinement of the protocol, submitting for Food and Drug Administration (FDA) pre–investigational new drug (IND) review, revising the protocol, and submitting for FDA IND review; 2) operational planning/setup, which consists ofassembling required resources (e.g., sponsors, networks, and contract research organizations) and initiating the study at the site level (e.g., site registra-tion and activation); and 3) ongoing operations, which consists of trial execution, protocol amendments, and additional site identification, registration,and activation. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.

Annals of Internal Medicine Annals.org

Appendix Figure 3. Timelines for ACTIV-3B and ACTIV-6 master protocol development.

ACTIV-3B

ACTIV-6

Protocol development and approval

Operational planning/setup

Trial launchActivities

2021

Protocol development and approval

Operational planning/setup

Ongoing operations

Projected trial launch

2020

September October November December January April May JuneFebruary March

ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.

Annals.org Annals of Internal Medicine