Source : 'The Pink Sheet'
Experience during the COVID-19 pandemic should help to guide companies and regulators towards new ways of approaching clinical trials, with more use of novel study design, remote site monitoring, and wider use of digital technology, industry speakers said during a webinar this week organized by the European pharma industry body EFPIA.
Representatives of pharmaceutical companies and the European Commission said experience during the pandemic might also help to spur greater harmonization in the way that clinical trials are managed in the EU member states.
The 19 May webinar, entitled “Clinical Trials at the time of COVID-19 And Beyond,” looked at the impact of the coronavirus on trials that were already under way when the pandemic broke as well as those that have been initiated to study potential treatments and vaccines for the disease.
In the case of ongoing trials, “we had to look initially at how those trials were impacted, how enrolled patients were affected, where they were in their follow-up, and whether we had the safety and efficacy data,” said Chrissie Fletcher, vice-president, development biostatistics, at GlaxoSmithKline.
“Many of us in the industry are looking at doing risk assessments of studies to understand the full impact, and the regulators are asking us to do that as well,” Fletcher said. “We need to understand the implications for proposed studies, and the assumptions we used and whether they are still relevant. We are looking at adjusting planned analyses to accommodate the impact of the pandemic so we might need to do some additional subgroup analyses and explore some of the sensitivities of the data we have collected.”
Nick Sykes, senior director of global regulatory policy and intelligence at Pfizer, elaborated on some of the specific trial challenges presented by the pandemic, such problems traveling to the trial site, managing interactions between investigator and participant, supply chain interruptions and so on. One way of dealing with this was to stop enrolment for a while, particularly at the start of the pandemic, but “I think we are now moving beyond that and starting to re-enrol in some of these trials,” Sykes said.
“As the crisis continued and we started trials of COVID treatments and vaccines, we have been working with the authorities to get these trials started as quickly as we possibly can, looking at fast regulatory approval times… and ensure that these kinds of COVID treatments are prioritized as well and looking at ways we can collaborate and share infrastructure around these trials.”
Looking at the lessons to be learned from the crisis for future approaches to clinical trials, Sykes noted that the need for innovative trial designs that could get new treatments to patients more quickly was one of the pillars of EFPIA’s “Regulatory road to innovation” – a set of proposals on how the EU regulatory framework needed to evolve to benefit from advances in science and digital technology.
“During the crisis we have been trying to use this this pillar to encourage innovative ways of thinking to evaluate new medicinal products,” he said, such as by using decentralized trial designs, “or doing some activities remotely that we would normally do on site.” These activities included remote source data verification, so that “we don’t have to go to the site to verify the source data.”
He said industry believed that through a collaborative effort among sponsors, regulators, patients, investigators and others involved “we should be able to develop and coordinate an efficient clinical trial framework that is tailored to this outbreak, that uses novel approaches for designing clinical trials, such as master protocol trials and further remote monitoring suitable for use in a public health emergency.”
While progress had been made on novel trial designs, they “take a lot of modeling and simulation,” said Fletcher. “When we design a more complex study we need to understand the operating characteristics and the assumptions we are going to be making. We are trying to accelerate but also generate high-quality data,” she said.
Such trials can be difficult to put into operation so what is needed is “cutting edge design to give the right evidence in a timely fashion, but there are challenges,” she said. “Do you have the data you need to make the decisions you need in real time, and how do you use digital technology to collect data?” One effect of the pandemic is that it has led to greater use of digital technology, she added.
The European Commission was quick to produce new guidance documents on the management of clinical trials during the pandemic, first in March then an updated version in April, looking, among other things, at that measures sponsors could take to mitigate trial disruptions without compromising data quality and patient safety. ("EU Allows More Flexibility In Managing Trials During COVID19" "Pink Sheet" )
Kristof Bonnarens, policy officer for pharmaceuticals at the commission's health directorate (DG SANTE), said the commission recognized early on that there was a need for more “hands-on” guidance on what to do about ongoing trials in Europe amid the coronavirus outbreak. While the EU member states have competence for clinical trials, he noted, “of course there is an EU framework to take into account.”
Two key points that had been raised by stakeholders and were be addressed in the guidance, Bonnarens said, related to the distribution of the investigational medicinal product (for example, how to prevent avoidable site visits and ensure participants get their medicines) and remote source data verification (again without having to visit the trial site).
Sykes said he wanted to make two “provocative” points about the guidance and the way clinical trials are run in the EU.
He said the speed with which the guidance was produced during the pandemic was “remarkable” but that there were still many areas where things were not harmonized. For example, the guidance says that remote source data verification is allowed but “some member states say on their websites still that you can’t. So we do have an issue there.”
The other big challenge, Sykes continued, was “explaining to my US colleagues, who have one regulatory system through the FDA [Food and Drug Administration], that the EMA [European Medicines Agency] doesn’t really have much to do with clinical trials in Europe, that it is all run at member state level, and that is why we have different outcomes and approaches” in the EU. “That has been a big challenge for them, so the more harmonization we can get across Europe in clinical trials, the better.”
“I don’t feel provoked at all,” Bonnarens declared in response. EU lawmakers made a “deliberate choice” to go for a system where trials are still governed at national level, "so the consequence is that there can be differences. At present with the current legal framework this is the best we could do,” he observed.
Bonnarens also discussed the issue of revoking the COVID-19 clinical trial guidance once the pandemic was over. The commission had been “clear that this guidance had a beginning and an end. So as soon as pandemic is over, the guidance will end,” he observed. However, it is not entirely clear how we will know when that moment has come.
The matter of how and when the guidance should be revoked had been discussed at another recent webinar, “where this was the most asked question,” Bonnarens said. It would be “quite a difficult task to acknowledge that the situation is better,” he noted.
“I don’t want to put a close date on this, I don’t want to have it country by country – what we want is a long transition into the non-pandemic period to ensure that everyone can take the proper action in their own member state and can have some margin of manoeuvre. So let’s just say that there will be a discussion, and it will not come overnight.”
Asked about the lessons the guidance might have for the future, Bonnarens said that during the pandemic “we will see a lot of things… that we have not seen before, new approaches, new ways of thinking on clinical trials that will give us quite a lot of information on how we can improve, both towards patients… and also towards better collection of data. It would be strange in my view if we didn’t use that lesson learned to develop a system that has a better chance of developing new innovative drugs and getting them to patients sooner.”
Cesar Hernandez Garcia, head of department at the Spanish medicines agency (AEMPS), said that there had already been much discussion about speeding up trial processes and using new technology, dealing with pragmatic trials, and so on, but “maybe the crisis will accelerate the discussion” and present “different perspectives.”
“I think that new ways of analyzing clinical trials, taking data from patients, monitoring, all that can be discussed,” he said.
The discussion turned to whether the experience with COVID-19 showed that there was a need for greater harmonization in the way that clinical trials are managed in Europe.
Bonnarens noted that 27 May would see the “sixth birthday” of the new EU Clinical Trial Regulation (CTR), which he described as “a key element” of harmonization in Europe. A central component of the new rules is the proposed Clinical Trial Information System (CTIS), which must be certified as fully functional before the provisions of the legislation can take effect.
This has fallen well behind schedule, though, and the audit of the CTIS is now not due to begin until the end of this year, meaning that the CTR might not take effect until the beginning of 2022. ("Yet More Delay For EU Clinical Trial Regulation" "Pink Sheet" )
“Personally I think it is long overdue that this piece of legislation enters into force, because it triggers harmonization at the dossier level, and also within and among the member states on clinical trial approaches,” Bonnarens said.
“At the moment we need a strong legal push for harmonization in Europe. That doesn’t mean that in the current state of things we are not harmonizing more – the guidance we just brought out is a good example of that – but there are other examples of harmonization work happening, driven with the help of people from the European Commission and the [EU] Heads of Medicines Agencies in collaboration with industry and academia, and even in some cases with patients and investigators.”
By Ian Schofield