Skip to content

Pink Sheet – Pandemic Accelerates US FDA’s Use Of Real-World Data From Clinical Trial Design To Supply Chain

Pink Sheet – Pandemic Accelerates US FDA’s Use Of Real-World Data From Clinical Trial Design To Supply Chain

Executive Summary

FDA’s Amy Abernethy describes how agency’s use of real-world data has evolved in response to COVID-19 and the ‘a-ha’ moment of leveraging different data sources to understand the coronavirus. Takeda R&D President Andrew Plump notes difficulties with platform trials and limitations on data sharing.

The US Food and Drug Administration has advanced the use of real-world data to tackle the COVID-19 pandemic, using it to understand the disease, plan clinical trials, and manage the medical product supply chain to prevent shortages.

Amy Abernethy, FDA’s principal deputy commissioner, described the evolution of the agency’s use of real-world data during the pandemic at the FDA/CMS Summit in December. She noted that it began when FDA partnered with the Reagan-Udall Foundation and the Friends of Cancer Research to form the COVID-19 Evidence Accelerator. (Also see “US FDA Looking To Real-World Evidence To Fill in Gaps On COVID-19 Vaccines” – Pink Sheet, 11 Jun, 2020.)

The initiative brought together experts in health data aggregation and analytics to figure out how to use real-world data to answer questions FDA had about COVID-19. It now has more than 600 participants.

The agency sought to find out the natural history of the disease and clinical epidemiology and outcomes, such as the mortality rate and the number of people hospitalized and admitted to intensive care units. Participants also looked at how real-world data can be used to help plan and prioritize clinical trials and evaluate the real-world performance of COVID-19 diagnostic tests.

“One of the things that I’ve watched happen in the context of COVID-19 that’s quite different is the use of data to solve problems now.” –FDA’s Amy Abernethy

“What did we learn during this book of work for real-world data in the context of COVID-19 and how does that inform our regulatory thinking?” Abernethy asked. One of the things that has become apparent is that it is really important “how we define how patients are doing right now, and then thinking about the appropriate design of clinical trials within this context.”

She said the evidence accelerator also identified the need to develop real-world data science and the importance of transparency. It also showed the importance of having agency staff at the table, Abernathy said, as this “helps us at FDA build the muscle of how to think about these datasets, both the opportunities as well as potential pitfalls.”

Assessing Supply Chain Vulnerabilities

Asked how the use of real-world data has changed inside the agency, she cited FDA’s use of the data to solve problems.

“Historically at the agency, outside of purchased datasets that often were unwieldly and only certain people had access to, we generally don’t do primary analyses as a way of quickly understanding how to better manage a problem sitting in front of us,” Abernethy stated. “One of the things that I’ve watched happen in the context of COVID-19 that’s quite different is the use of data to solve problems now.”

For example, she said the agency has started using real-world data to understand the vulnerabilities of the medical product supply chain to better manage it and prevent shortages. In addition, she said the agency is looking at datasets to learn what information they provide about the risk of a particular problem with a medical product, such as coagulopathy, and how to put it in context.

‘Fair Amount Of Hubris’ Going Into Pandemic

Abernethy also spoke about the current use of real-world data at the Milken Institute’s Future of Health Summit in December. She noted that the ability to leverage different data sources to describe what is going on with the coronavirus “has been one of the big a-ha’s in the real-world data space for COVID-19.”

“I think going into the pandemic there was a fair amount of hubris,” Abernethy said. We felt that this was observational research that we know how to do well “and in fact, what we’ve seen in spades, both at FDA and really across this entire space, is the incredible need to develop the science.”

“So this is not only about understanding the datasets, but it’s about developing the science, making sure we can confidently identify the perfect person with COVID, being able to figure out. . . mortality in a particular dataset, being able to figure out what are the appropriate methods by data source or data type and align that in real time.”

She said real-world data is usually generated outside a traditional clinical trial and consists of information “that helps us tell a story that sometimes can be analyzed in a way that provides compelling clinical evidence but many times really helps us understand directionality.”

The agency is now asking questions about the outcomes of people with post-syndromic symptoms, the long haulers. FDA is also looking at the ability of real-world data to take the place of clinical trials in some instances, such as in understanding effectiveness or efficacy. “But I see that is really a downstream task of real world data, not really upstream,” Abernethy said.

What Will Persist

Abernethy was asked what approaches to real-word data will continue after the COVID-19 pandemic subsides.

“I think that first of all, there is now a language around real world data that I think will persist way past the pandemic,” she replied. “I think that there is the development of regulatory familiarity at FDA that will persist. I think that we will also see that worldwide.”

She noted that FDA has had conversations with regulators around the world about this. “I think that there is more humility in this space about what can and cannot be done and I think we will see that continue. And I think we’ll also start to see some of these learnings built into guidances that are part of our 21st Century Cures commitment going forward,” she said.

FDA is thinking about using the evidence accelerator model to address the opioid crisis and develop solutions within the context of healthcare delivery, Abernethy said. The agency is also talking about applying an evidence accelerator model for digital health solutions.

“I’ve been very appreciative of the entire evidence accelerator community and what people have brought to the table and how really it’s acted as a catalyst to have different data holders, research teams, industry, government, NGOs, all learn from each other very quickly,” Abernethy said.

The evidence accelerator has provided a “critical opportunity to have regulators in the conversation,” she added. “One of the things that we’ve seen within the context of the pandemic, even within the platform trial discussion, is that we have to have regulatory familiarity, we have to see how methods work and also where they break down, how to have confidence in results, and how to build it into regulatory decisions.”

Regulatory Framework For Platform Trials Is Less Permissive

Abernethy spoke on a panel at the Milken meeting that addressed how COVID-19 is accelerating biomedical R&D. Other panelists included Takeda Pharmaceutical Co. Ltd. President of Research and Development Andrew Plump and Martin Landray, professor of medicine and epidemiology at the University of Oxford and co-chief investigator of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial.

Plump discussed Takeda’s experience participating in platform trials, including those being conducted in the I-SPY network and the National Institutes of Health’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative. Takeda also launched the COMMUNITY (COVID-19 Multiple Agents and Modulators Unified Industry Members) trial with Amgen, Inc. and UCB in November. The trial is initially studying Amgen’s Otezla (apremilast), Takeda’s investigational drug lanadelumab and UCB’s investigational medicine zilucoplan.

“It’s actually been quite hard to generate the level of clinical trial data sharing that could have, I think, even accelerated these discoveries more quickly.” – Takeda’s Andrew Plump

“Everybody and his or her mother are trying to get a drug tested in COVID, each with their own independent control arms. It’s just not efficient,” Plump stated. He said Takeda realized early on that the answer was to conduct platform trials like the RECOVERY trial underway in the UK, the world’s largest randomized clinical trial of potential COVID-19 treatments. (Also see “RECOVERY Coronavirus Study ‘Will Attract Global Players To UK’” – Pink Sheet, 8 Apr, 2020.)

“Unfortunately, they’re not easy,” he said. “To be fair, the regulatory framework, which started out highly permissive, started to get a bit more difficult and it took longer to work through. Not inappropriately so, but it just took longer to start to stand these more complex trials.”

Plump said they learned it is necessary to have infrastructure around the globe like the UK had so they are not limited to hospitals in the UK to run these studies. In addition, he noted the need to understand how to set up these platform trials outside of oncology more rapidly so researchers don’t have to wait six months into the pandemic to get these kinds of trials going.

Landray noted the crucial aspects of the RECOVERY trial, citing the need to have consent, patient follow up, and focus on the outcomes that matter. In addition, “the work has to be be absolutely minimal for the frontline doctors and nurses,” he said. “The success of the trial depends on them wanting to enroll patients. Make their job as easy as you possibly can.”

Landray said the “the magic moment” in the trial was seeing the results that showed the efficacy of dexamethasone. “On the 16th of June, we announced at lunchtime that dexamethasone reduces the risk of dying for patients admitted to hospital by a third amongst the people on ventilators and by about a fifth for people requiring other forms of respiratory support. It was NHS [National Health Service] policy across the UK at tea time, it was saving lives by the weekend and it’s essentially adopted into policy all around the world,” he said.

Data Sharing Has Been Disappointing

Plump commented on the partnerships that have arisen in response to the pandemic. Takeda is partnering with Moderna, Inc. and Novavax, Inc. to manufacture and distribute their vaccines in Asia. Plump noted that Takeda also has a unique manufacturing facility that allows it to make concentrated hyperimmune plasma.

Takeda is now working with about eight companies to run trials of hyperimmune immunoglobulin therapy for serious complications of the virus. (Also see “Takeda, CSL, Other Blood Plasma Firms Team On Hyperimmune COVID-19 Therapy” – Scrip, 6 Apr, 2020.)

Takeda is also a member of a consortia of more than 20 pharmaceutical and biotech companies called COVID R&D. The COMMUNITY trial evolved from that collaboration.

“In March of 2020 we started to gather a number of R&D heads across the industry just to see how we could work together, how we could improve data sharing, information sharing,” Plump said. “It was the Wild West. It was chaos in March outside of the UK.”

He said everyone was impressed with what Landry and his colleagues were doing in the UK. As of December, more than 20,000 patients had been enrolled in the RECOVERY trial from 176 National Health Service hospitals.

“We have to figure out how some of the best practices that have emerged over the last year can continue into the future,” Plump stated. “One area that I was actually a little bit disappointed over the last year [was] around data sharing.”

“The infrastructure of data that we have access to helps to set up hypotheses, to set up trials, to accelerate trials. It is a major part of the answer to our future. And in a setting like this where I thought it would have been quite easy to navigate data sharing and where you had great intent across the entire ecosystem, including in proprietary companies like ours, it’s actually been quite hard to generate the level of clinical trial data sharing that could have, I think, even accelerated these discoveries more quickly,” Plump stated.…