Executive Summary
The coronavirus pandemic could be a turning point for master protocol and platform trial designs, but clear guidance and coordination are still needed.
Two former US Food and Drug Administration commissioners – Mark McClellan and Scott Gottlieb – are among the most recent regulatory experts to join the international chorus calling for master protocols and platform trials to streamline evaluation of the vast but chaotic pipeline of COVID-19 treatment and vaccine candidates. The ex-commissioners also note the need for “clear regulatory guidance” to leverage the potential of such trial designs.
Master protocols are a cornerstone of the “critical path” for COVID-19 therapeutics proposed in a 20 May paper from the Duke-Margolis Center for Health Policy, which outlines a “hyper-parallel path for promising therapeutics that replaces and augments the usual highly sequential development process.” McClellan and Gottlieb co-authored the paper with former National Security Council director of medical and biodefense preparedness Luciana Borio (now at In-Q-Tel), Friends of Cancer Research director Jeff Allen, and Clinical Trials Transformation Initiative executive director Pamela Tenaerts.
“The goal should be to pursue coordination around recognized master protocols that can be widely adopted across many different institutions to support well-powered studies that can be completed rapidly,” the Duke-Margolis paper states.
Fast, But Not Efficient
There is growing concern about the hurried pace of COVID-19 drug development. Many trials “do not randomize patients using widely-accepted and thus comparable treatment protocols, are too small to provide definitive answers about a product’s safety and effectiveness, or are planned using individual protocols that are hard to align with other studies underway,” McClellan, Gottlieb, et al. observed.
The federal clinicaltrials.gov database offers a hint of the scope of the problem: more than 1,000 interventional studies for SARS-CoV-2 infection are listed. The increasingly controversial anti-malarial drug hydroxychloroquine is included in 191 of those trials, further illustrating the need for coordination.
Hydroxychloroquine also is the most-studied drug in the major ongoing platform trials, suggesting that efforts to rationalize drug development can still run into problems of duplication and coordination.
European regulators sounded a similar alarm in a recent Clinical Pharmacology and Therapeutics article on the mushrooming of stand-alone COVID-19 trials and single-agent observational studies. (Also see “EU Regulators Concerned By Mushrooming Of Small COVID-19 Trials” – Pink Sheet, 19 May, 2020.)
“There is broad agreement among regulators that such large multi-centre, multi-arm clinical trials need to be prioritised because they are most likely to generate the robust evidence needed to enable rapid assessment and authorisation of COVID-19 therapeutics and vaccines,” the International Coalition of Medicines Regulatory Authorities (ICMRA) noted in a summary of 14 May virtual meeting moderated by FDA Center for Drug Evaluation and Research director Janet Woodcock. (Also see “Coronavirus Update: Big Trials, New Vaccine Platforms, And Fake Chloroquine In Africa” – Pink Sheet, 19 May, 2020.) Woodcock now leads the therapeutics efforts of the Trump Administration’s Operation Warp Speed. (Also see “COVID-19 Staff Shakeup: Woodcock Moves to Commissioner’s Office As Marks Drops Out Of ‘Warp'” – Pink Sheet, 22 May, 2020.)
As the SARS-CoV-2 pandemic took hold, Woodcock has been advocating for the use of advanced clinical trial designs – platform trials, master protocols, pragmatic and adaptive study elements – to test multiple treatments at the same time. CDER has received a “rather overwhelming” volume of proposals to test coronavirus therapies, she told a Clinical Trials Transformation Initiative webinar, and without efficient clinical evaluation the surge risks depleting the capacity of the clinical research apparatus. (Also see “Woodcock Warns Research Apparatus Could Be Overwhelmed If Coronavirus Trials Don’t Use Master Protocols” – Pink Sheet, 27 Apr, 2020.)
Woodcock’s plea is unsurprising; the CDER director is a long-time proponent of master protocols (Also see “Master Protocols Are Both Welcome And Inevitable – US FDA’s Woodcock” – Pink Sheet, 6 Jul, 2017.). The agency’s recent formal guidance on development of COVID-19 therapeutics and preventive agents, however, is slightly cautious about master protocols and adaptive trials. (Also see “US FDA Welcomes Variety Of Phase II/III Trial Designs For COVID-19 Therapies, But With Standards” – Pink Sheet, 13 May, 2020.)
CDER Office of Medical Policy director Jacqueline Corrigan-Curay reported increased interest in master protocols in the COVID-19 era during a recent interview with the Pink Sheet. Nonetheless, the FDA may be struggling to promote the fundamentals of conventional clinical trial design. “We still try hard to get people to have a control group,” CDER deputy director for clinical science Robert Temple said in the same interview. “Not everybody wants to have a control group.” (Also see “US FDA Pushing Coronavirus Trial Sponsors To Include Control Groups” – Pink Sheet, 21 May, 2020.)
The US National Institutes of Allergy and Infectious Diseases was fast out of the gate with a master protocol for COVID-19, the adaptive ACTT trial program. The Phase III ACTT-1 trial kicked off 21 February comparing Gilead’s antiviral remdesivir against placebo in hospitalized patients. The study stopped enrolling patients in mid-April, and positive early data has already been released, most recently in the New England Journal of Medicine on 22 May. (Also see “More Remdesivir Data, More Questions Linger” – Pink Sheet, 28 May, 2020.)
A second drug candidate, Eli Lilly & Co.’s Olumiant (baricitinib), debuted in the Phase III ACTT-2 trial, which started 8 May. ACTT-2 is comparing the combination of remdesivir and baricitinib against a control arm of remdesivir plus placebo.
The National Institutes of Health is leading a partnership of government agencies, industry and academia, known as Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), with ambitious aims to coordinate and prioritize COVID-19 R&D, including the use of master protocols. “The ACTIV public-private partnership and collaborative harmonized efficacy trials are enabling models to achieve our common goals,” concluded an 11 May commentary in Science co-authored by NIH Director Francis Collins, NIAID director Anthony Fauci, NIAID Vaccine Research Center director John Mascola and Lawrence Corey of the Fred Hutchinson Cancer Research Center in Seattle.
The therapeutics clinical working group presented its first list of repurposed already-approved drugs for inclusion in ACTIV’s master protocol for adaptive clinical trials on 6 May. The group recommended six agents, “including immunomodulators and supportive therapies,” winnowed down from 39 agents that saw final prioritization review, Collins and Johnson & Johnson exec Paul Stoffels reported in an 18 May Journal of the American Medical Association article on the partnership. ACTIV aims to test candidates simultaneously against a common control arm, with results anticipated in the summer. (Also see “NIH Partnership To Pick COVID-19 Therapeutics For Clinical Trials; Results Anticipated By Summer” – Pink Sheet, 19 Apr, 2020.)
The World Health Organization is also conducting a master protocol trial, dubbed “Solidarity,” to test COVID-19 treatments. The Solidarity trial, launched on 18 March, has enrolled 3,500 patients from 17 countries, according to the WHO. The trial has five arms: local standard of care, remdesevir, lopinavir plus ritonavir (AbbVie Inc.’s Kaletra), lopinavir/ritonavir plus interferon beta-1a, and hydroxychloroquine. Enrollment in the hydroxychloroquine arm was paused on 25 May while the organization addresses concerns about the drug’s safety and lack of efficacy.
ACTIV’s vaccines working group is working toward harmonized master protocols “to enable transparent evaluation of the relative effectiveness of each vaccine approach,” the NIH leaders said in Science. More than 120 candidates are in the works to prevent SARS-CoV-2 infection, according to the Pink Sheet’s COVID-19 pipeline, representing a variety of technologies including mRNA vaccines, DNA plasmids, peptide vaccines, inactivated vaccines, and multiple different vectors.
“This harmonization can best be achieved through public-private partnerships such as ACTIV, in which government-supported central laboratories and independent biostatisticians serve as key resources for efficacy trials, thereby providing a standardized way to assess the relative immune responses of different types of vaccines,” Collins, Fauci et al continued.
“Data should be shared among companies and be provided to independent statistical evaluation, allowing the early evaluation of a potential surrogate marker of protection, which would markedly speed licensure and distribution,” the said. “Such data can only be obtained from harmonization and collaboration early on, during the planning of efficacy trials.”
Operation Warp Speed set an ambitious goal of millions of available doses of a COVID-19 vaccine in the US by January 2021. President Trump said that 14 of the most promising vaccine candidates have been identified, and the list will be narrowed to about eight for testing in early stage clinical trials, with three to five progressing to large randomized trials. The Department of Health and Human Services said the protocols will be set and overseen by the federal government, as opposed to the traditional public-private partnership model where companies decide their own clinical protocols. (Also see “Trump’s ‘Warp Speed’ Initiative Could Fund 3 to 5 Large-Scale COVID Vaccine Trials” – Pink Sheet, 17 May, 2020.)
Europe’s National Platforms
The European Medicines Agency set out a rationale for platform trials in the 14 May Clinical Pharmacology and Therapeutics article. Large platform trials “afford an opportunity to agree on clear and consistent definitions and categorization of disease stages, viral infection and respiratory distress, clear consistent endpoints and standard approaches for the measurement of these,” EMA senior medical officer Hans-Georg Eichler and colleagues wrote.
Several COVID-19 platform trials have been launched in Europe, but are national in scope. Austria’s ACOVACT trial in severely ill patients is studying hydroxychloroquine, lopinavir/ritonavir, AstraZeneca PLC’s angiotensin II receptor blocker candesartan (Atacand), and J&J’s anticoagulant Xarelto (rivaroxaban). A Danish trial in moderate to severe COVID-19 will test, in addition to hydroxychloroquine, Lilly’s Janus kinase inhibitor baricitinib (Olumiant), Sanofi and Regeneron Pharmaceuticals Inc.’s interleukin-6 receptor blocker Kevzara (sarilumab), and convalescent anti-SARS-CoV-2 plasma.
The UK is home to several platform trials, including the Phase II/III RECOVERY trial, launched in early April as “the largest randomized controlled trial of potential COVID-19 treatments in the world.” The Duke Margolis Center paper reported that RECOVERY had enrolled 10,000 eligible hospitalized patients in the UK in only eight weeks, “providing strong early evidence that simple, effective protocols can drive widespread participation.”
RECOVERY is currently evaluating lopinavir/ritonavir, low-dose dexamethasone, Roche’s IL-6 blocker Actemra (tocilizumab), convalescent plasma, and hydroxychloroquine. On 26 May, the trial organizers at the University of Oxford announced that the hydroxychloroquine arm would continue unchanged after a review of recent concerns about the drug’s safety and efficacy.
Hospitalized COVID-19 patients in the UK may also enroll in the Phase II ACCORD 2 and CATALYST platform trials. ACCORD 2 is evaluating BerGenBio ASA’s AXL kinase inhibitor bemcentinib, AstraZeneca’s anti-interleukin 33 monoclonal antibody MEDI3506 and BTK kinase inhibitor Calquence (acalabrutinib), Ra Pharmaceuticals Inc.’s complement inhibitor zilucoplan, and Wockhardt Ltd.’s heparin. The CATALYST study has a different lineup:Pfizer Inc.’s anti-CD33 antibody-drug conjugate Mylotarg (gemtuzumab ozogamicin), Izana Bioscience’s GM-CSF-targeting antibody namilumab, and Celltrion Inc.’s infliximab biosimilar Remsima.
The University of Oxford’s PRINCIPLE trial, on the other hand, calls itself “the only national priority platform trial in primary care.” The trial started with hydroxychloroquine, testing it to prevent hospitalization in people with COVID-19 symptoms who are age 65 and older, or people age 50 and older who are at higher risk of complications due to compromised immune systems, heart disease, asthma or lung disease, diabetes (not treated with insulin), neurological problems, or mild hepatic impairment. (Also see “Coronavirus Update: More EU R&D Projects, A Potential New Vaccine & Making Sense Of The Data Deluge” – Pink Sheet, 12 May, 2020.)
In the US, the Gates Foundation is funding an adaptive platform trial in high-risk outpatients coordinated by the University of Washington. The Phase II/III study kicked off 16 April with a control arm of vitamin C and folic acid, initially compared with hydroxychloroquine alone or in combination with azithromycin.
Leveraging Existing Clinical Trial Networks
Already-established clinical trial networks offer an accelerated path for investigation of COVID-19 therapies and vaccines, so the ACTIV partnership established a Clinical Trial Capacity Working Group to assemble and coordinate existing networks. “This will include developing an inventory of clinical trial networks supported by NIH and other funders in the public and private sectors, including contract research organizations,” Collins and Stoffel explained in JAMA.
“For each network, the working group seeks to identify their specialization in different populations and disease stages to leverage infrastructure and expertise from across multiple networks, and establish a coordination mechanism across networks,” they said. The group has “already identified 44 networks, with access to adult populations and within domestic reach.” Two survey instruments have been developed “to assess the capabilities and capacities of those networks,” as well as “a matrix to guide deployment of innovative solutions throughout the trial life cycle.”
The venerable I-SPY network, known for its master protocol for breast cancer therapies, launched the first adaptive platform design trial in COVID-19 acute respiratory distress syndrome in late April. “The goal is to evaluate 10-20 agents in a year, depending on how long the virus persists and the associated rate of respiratory distress,” Quantum Leap Healthcare Collaborative, which manages I-SPY, said.
The I-SPY COVID trial will evaluate both repurposed and novel drugs for their ability to decrease the number of critically ill patients that require mechanical ventilation in the ICU or die. “Successful candidates will also be evaluated on the basis of the capacity of the pharmaceutical sponsor to rapidly produce sufficient drug for use on a global scale,” the group noted.
To start, I-SPY COVID uses remdesivir plus standard of care as the backbone. The trial will test the addition of Allergan PLC’s chemokine receptor 2 and 5 dual antagonist cenicriviroc and of Takeda Pharmaceutical Co. Ltd.’s bradykinin B2 antagonist icatibant (Firazyr). On 27 May, Aerpio Pharmaceuticals Inc. announced that its Tie 2 activating compound razuprotafib (AKB-9778) would be joining the platform trial.
The international REMAP-CAP initiative, an intensive care unit clinical trial network established after the 2009 H1N1 pandemic to study community-acquired pneumonia, added a substudy – REMAP-COVID – to its ongoing platform trial. The COVID-19 substudy is testing lopinavir/ritonavir, hydroxycholoroquine, interferon beta-1a (Faron Pharmaceuticals Oys IV Traumakine), and the anti-interleukin-6 antibodies sarilumab (Kevzara) and tocilizumab (Actemra). (Also see “COVID-19 Phase III Trial Design: Big Ambitions, Little Consistency” – Pink Sheet, 11 May, 2020.)
The patient-centered clinical research network PCORnet, in collaboration with the Duke University Clinical Research Network, is conducting a platform trial in healthcare workers exposed to SARS-CoV-2. The HERO trial is currently testing hydroxychloroquine.
A Tool, Not A Panacea
“We acknowledge the difficulties of running larger, coordinated multicentre trials in an extremely challenging environment, especially in the early days of the pandemic,” the EMA’s Eichler et al. wrote.
“Yet, even platform trials may not provide the sole answer because even very large platform trials will not be able to test every plausible permutation for mixed antiviral and anti-inflammatory interventions.”
“Platform trials come with their own weaknesses such as (frequently) a lack of blinding,” the article acknowledges. The pandemic situation poses difficulties as well. “Controls become historical as disease management improves, requiring more sophisticated analyses,” they observed.
Novel trial designs “take a lot of modeling and simulation,” GlaxoSmithKline PLC VP-development biostatistics Chrissie Fletcher cautioned during a 19 May webinar organized by the European pharma industry group EFPIA. “We are trying to accelerate, but also generate high-quality data.”
“When we design a more complex study we need to understand the operating characteristics and the assumptions we are going to be making,” Fletcher explained.
The Duke-Margolis paper pointed out that master protocols will likely be needed “for a range of study types in different clinical settings,” from hospitalized seriously ill patients to people with milder disease in outpatient settings to prophylaxis in people at high risk of infection.
“In each situation, we should accelerate use of a specific master protocol that would be focused on enrolling patients in this particular care setting and disease stage,” McClellan, Gottlieb and colleagues stated.
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