U.K. sets the bar for COVID-19 master protocols
The world needs to prioritize master protocols for COVID-19 and the U.K. is leading the charge
Master protocol trials have emerged as the fastest path to definitive answers on candidate therapies and vaccines for COVID-19, but in most regions these trials are not getting prioritized over individual clinical studies. The rest of the world can learn from the U.K.’s example of how to coordinate and promote master protocols.
The U.K. government is doing much more than funding adaptive master protocols trials for COVID-19. It has designated a trio of such trials a national priority, and has stepped in to ensure the trials cover different stages of the disease and have the all resources they need to be successful, funneling patients, therapies and trial sites into setting them up for success.
This week, the government added another layer to its centralized strategy, unveiling a master protocol trial dubbed ACCORD aimed at establishing initial clinical validation of therapies before moving them into the three later-stage trials (see “U.K.’s ACCORD Platform Trial”).
This is one of several ways the U.K. is implementing its co-ordinated systems to defeat the pandemic, according to a commentary today in BioCentury by SV Health Investors Managing Partner Kate Bingham (see “How the U.K. Healthcare Sector is Leveraging Its Strengths to Beat COVID-19”).
Master protocol trials enable multiple treatments to be evaluated in parallel using the same endpoints, data analysis methods and other protocol parameters. The trial arms share resources, such as a single control arm, and the structure’s adaptive design employs Bayesian statistics to get an early read on which treatments are working (see “Master Protocols Emerge as a Critical Clinical Tool Against COVID-19”).
The U.K. has been quick to recognize their importance in COVID-19, where an abundance of smaller trials creates redundancy and will slow progress on countermeasures. The danger is that there will be “an inconclusive trial, because we’re competing for patients or we’re making a bold set of assumptions,” said Ben Saville, a senior statistical scientist at Berry Consultants LLC, which specializes in adaptive trials.
“What the U.K. has done is really the gold standard for COVID-19.”
At a webinar hosted by the Clinical Trials Transformation Initiative (CTTI) last week, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), called out the overwhelming number of inquiries and proposals about COVID-19 that FDA has received.
“Although we may not run out of patients, unfortunately, we may run out of research personnel and time available to do that in this way, having separate development programs,” Woodcock said. “We think there is urgent need for master protocols.”
Master protocols are gathering steam -- outside of the U.K.’s four trials, at least five multicenter master protocol trials are under way for COVID-19 around the globe, with two launched in the last month (see “COVID-19 Master Protocols”).
But other regions have not had the high-level co-ordination to ensure master protocols are prioritized over the individual studies investigators plan to launch.
“What the U.K. has done is really the gold standard for COVID-19. They were able to say ‘these are the three trials we’re focusing on, and various chief medical officers have made comment that they want citizens to enroll in these trials,” said Saville.
How the U.K. is getting it right
The U.K.’s unified healthcare system gives it an edge when it comes to centralizing clinical trial infrastructure.
“The U.K. was able to do this because they have a centralized healthcare system, a relatively small geographic area, and all of the trials have the same funding source,” said Saville. “Other trials that want to get government funding will not be able to if they’re trying to enroll these populations. Academics trying to do clinical trials will have to look at different populations.”
The CMOs for each U.K. country, plus the NHS’ National Medical Director, issued a letter on April 1 to hospitals urging them to enroll patient in the three trials.
“If you think of how the healthcare system is organized, the only way to access patients is through those programs.”
The U.K. trials cover patient populations across three disease stages -- not hospitalized, moderately ill hospitalized, and severely ill -- and the government is squeezing out most of the smaller studies that would otherwise enroll these patients.
Richard Godfrey, CEO of BerGenBio ASA (OSE:BGBIO), which is developing the first therapy selected for the ACCORD trial, said that although the company didn’t look into running an independent trial, he expects it wouldn’t have been possible. “If you think of how the healthcare system is organized, the only way to access patients is through those programs.”
In contrast, in the U.S., which has become the epicenter of the pandemic with almost one third of the confirmed cases worldwide, adoption of master protocols has lagged.
That could be fixed with coordination across industry and government.
“In the U.S., historically we have a strong tradition of volunteerism and, at our best, a strong tradition of collaboration between the public and private sectors that can work quite well. If we can combine the resources and operational expertise of the private sector with the scientific knowledge of the NIH, I think we could have a very effective platform for development of an adaptive trial structure,” said Elliott Levy, SVP of global development at Amgen Inc. (NASDAQ:AMGN).
“It would be ideal,” he added, “if we could promote the creation of a suite of large platform trials that would cover the disease spectrum and discourage the creation of studies that evaluate only a single agent at a time.”
Levy is participating in COVID R&D, a precompetitive consortium of over a dozen pharmas unveiled last month by BioCentury that has prioritized master protocols as a path to push forward experimental therapies as quickly as possible (see “Pharmas Align Behind Crowdsourcing Solution”).
The consortium announced this week a partnership with Quantum Leap Healthcare Collaborative to launch the adaptive I-SPY COVID trial to treat COVID-19 patients with acute respiratory distress syndrome (see “COVID R&D Consortium Launches I-SPY”).
The challenges in the U.S. are securing trial sites, ensuring the large-scale trials have little overlap in terms of region and patient group, and coordinating funding.
“It is very difficult for us to identify the most promising therapies for study.”
Access to trial sites has been an especially big problem. There are currently no U.S. sites for the WHO’s SOLIDARITY master protocol trial, and the international REMAP-CAP study only recently started enrolling patients at the University of Pittsburgh Medical Center, its first U.S. site.
During a webinar hosted by Berry Consultants last week, co-founder and president Scott Berry, who is on the REMAP-CAP steering committee, said it took a long time to find a U.S. site, and added that “the University of Pittsburgh Medical Center has over 100 people coming to them saying they want to run trials. There is this incredibly competitive nature of these trials.”
Laura Esserman, PI on the I-SPY 2 and I-SPY COVID trials and a professor at the University of California San Francisco, told BioCentury that finding high-quality trial sites has become difficult during the pandemic.
“Right now people are desperate and they’re giving patients everything. That’s understandable when you’re in a war zone and people are dying all around you,” she said.
At present, the U.K. is home to the largest COVID-19 trial in the world. The RECOVERY trial, which is being sponsored by the University of Oxford, has enrolled over 8,000 patients that fall into the hospitalized moderate disease category.
The trial, which launched in March, is focusing first on repurposed therapies for COVID-19, which represent the fastest path to authorization.
A second Oxford study, the PRINCIPLE trial, is unique in its focus on the primary care setting. The trial is enrolling high-risk patients -- those over 65 or over 50 with comorbidities -- who haven’t been admitted to the hospital. The goals are to keep them out, and to keep them alive. It is initially evaluating hydroxychloroquine.
The study has a smaller target population of 3,000, and began randomizing patients in early April.
The third trial is REMAP-CAP, an international study that was implemented in 2016 as a pandemic preparedness measure and is now enrolling severely ill COVID-19 patients.
The trial, which enrolls patients with community acquired pneumonia between pandemics, has a sleeping strata -- which they define as a set of patient characteristics -- that’s activated into a protocol when a pandemic is declared.
REMAP-CAP isn’t randomizing patients to receive a single therapy, but is a multifactorial trial that’s randomizing patients to receive a combination of therapies in each of several therapeutic domains. A patient will receive an antiviral, an immune modulator, a steroid and a macrolide antibiotic, or standard of care in each domain. It’s also expanding to include an anticoagulant, convalescent plasma, vitamin C and an ACE inhibitor.
The newest study -- the ACCORD trial -- addresses one of the biggest challenges that trial sponsors are facing: selecting compounds to study.
According to BioCentury’s COVID-19 Resource Center, there are over 350 therapies and vaccines in clinical and preclinical development, with more added daily.
“It is very difficult for us to identify the most promising therapies for study because there’s a tremendous amount of basic biological research on the disease that remains to be done,” said Levy
ACCORD may serve as a pre-screening step to help select compounds for the later-stage master protocols.
It also may help provide clinical validation for therapies that haven’t yet been approved in other indications, broadening the pool of candidates for trials like RECOVERY that haven’t been designed to provide the additional clinical validation that unapproved compounds require.
ACCORD is a Phase II/III study set to enroll 120 patients to receive BerGenBio’s AXL inhibitor bemcentinib in the Phase II part. The path through Phase III has yet to be determined, according to Godfrey.
“It is very difficult for us to identify the most promising therapies for study.”
“If the endpoints are met, it would pass into Phase III, and the idea is that it might pass through to the RECOVERY platform or remain, but either way the path would provide facilitated access to NHS patients, sites and investigators, as well as regulatory preference,” he said.
Table: Master protocols for COVID-19
At least eight adaptive master protocol trials have been launched for COVID-19, three of which have been designated priority trials by the U.K. government.
The table includes multicenter trials with adaptive structures for therapeutics. There is also at least one master protocol trial for vaccines.
Source: Trial websites, ClinicalTrials.gov, ISRCTN Registry