Incorporating pragmatic and decentralized elements into postapproval studies poses less data collection and reliability risk than the premarket setting and can help the sponsor learn more about a drug’s effect in clinical practice, even if the trial is not aimed at expanding the approved indication.
Experts from the US Food and Drug Administration, academia, industry and patient advocacy discussed the benefits and risks of incorporating pragmatic and decentralized elements into postmarketing trials at the Friends of Cancer Research’s recent annual meeting.
Pragmatic elements can include expanding eligibility criteria and conducting assessments as part of routine care. It can also include electronic consent or telehealth visits, as well as using local labs for testing rather than centralized facilities.
“Generally speaking, we recognize that there are many potential benefits to introducing pragmatism into our clinical trials in terms of making them more accessible, making them easier on sites, incorporating a more generalizable patient population, generating data that is more broadly applicable to the intent-to-treat population,” said session moderator Richard Schilsky, professor emeritus at the University of Chicago.
However, incorporating pragmatic elements includes risks, such as uncertainty about the consistency and quality of data collected and interpretability of trial results.
“One way potentially of mitigating some of those risks is to at least initially focus on introducing more pragmatic elements in the postmarket setting,” Schilsky said.
FDA Commissioner Robert Califf, who was the keynote speaker prior to the panel’s discussion, strongly supported the idea.
While premarketing trials could be made more efficient, “I think the big deal is doing very efficient, streamlined, pragmatic clinical trials postmarket to answer these questions that have a huge effect on clinical practice and patients,” Califf said.
Better evidence generation in the postmarket setting has been a priority for Califf in his second stint as FDA commissioner.
“What you get in that postmarket phase is so dependent just on marketing, not on high-quality evidence,” he said.
Not An ‘All Or Nothing’ Approach
The FDA and particularly its Oncology Center of Excellence have encouraged sponsors to include more pragmatic and decentralized elements in clinical trials. In September, the agency issued draft guidance on integrating randomized clinical trials into routine clinical practice and final guidance on conducting trials with decentralized elements.
In May, OCE debuted Project 5 in 5, a crowdsourcing initiative aimed at identifying five clinically relevant questions that can be answered in pragmatic clinical trials using FDA-approved cancer treatments over the next five years.
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FDA speakers at the FOCR meeting dispelled the notion that it is “all or nothing” when using pragmatic and decentralized elements. They said almost any type of trial could contain the approaches.
“There’s no such thing as a pragmatic trial or a nonpragmatic trial, a decentralized trial or a nondecentralized trial,” OCE Deputy Director Paul Kluetz said. “There are elements of both that should be considered and can be integrated in most trials.”
“There are multiple trials going on in the same indication with very similar drugs, and I would think a patient would want to go on a trial, things being equal, that was less burdensome for them to participate in.”
FDA’s Paul Kluetz
“All trials, even the most complicated and early trials, can look to expand eligibility and can look to decentralize some of the conduct,” Kluetz said. “The appropriate degree of how pragmatic or how decentralized is obviously going to be context dependent and based on what’s known about the drug.”
Kluetz gave several reasons for sponsors to consider incorporating pragmatic and decentralized elements into their trials, adding that not all questions can be answered in a “highly explanatory randomized clinical trial”
“Certainly, patients will benefit from less burdensome trials,” he said. “I think investigators and study staff who are really overburdened right now will benefit from more simple, less complex trials, more consistent with routine care.”
“I think decision-makers like FDA and health technology assessment agencies will benefit from more generalizable evidence that will look more like the US population in those who elected to take the drug in the postmarketing setting,” Kluetz added. “And I do think sponsors have incentives. They will benefit from more patient-centric trials with faster enrollment and less attrition.”
Kluetz also suggested competitive reasons for adopting a more pragmatic or decentralized approach to trials.
“There are multiple trials going on in the same indication with very similar drugs, and I would think a patient would want to go on a trial, things being equal, that was less burdensome for them to participate in,” he said.
But Kluetz also said understanding sponsor concerns about the uncertainty, costs and risk of including pragmatic elements is important.
“Anytime you do something different you’re putting a lot on the line, and I don’t think we should look the other way to that,” he said. “I do think that the uncertainty, the costs and the risks will decrease with experience.”
The postmarket setting offers a lower-risk opportunity for incorporating pragmatic or decentralized elements into a study, said Donna Rivera, OCE’s associate director of pharmacoepidemiology and head of the oncology real-world evidence program.
“In the postmarket setting, you have a situation where there’s a well understood safety profile, and safety is paramount,” Rivera said. “You have well understood and available efficacy data, and that means there’s an evidentiary foundation to think about how we might introduce pragmatic elements.”
Rivera added that the FDA thinks about pragmatic elements as a continuum.
“Most trials can introduce some level of pragmatism in the conduct, in the measurement or in the eligibility,” she said. “For example, it’s not collecting no safety data or all safety data, but maybe selective safety data reporting.”
The question that the FDA and sponsors must consider is what pragmatic elements can be included in a given trial to make it fit for purpose, Rivera said.
Registrational Intent Vs. Guideline Support
Allen Chen, AstraZeneca global clinical head of late development oncology, said a postmarketing study’s primary objective is the main consideration when sponsors are weighing whether to include pragmatic elements.
“If you’re trying to generate data that potentially could lead to a label expansion or some kind of label update, then it’s likely that you’ll need to have more rigorous data collection that would be sufficient to support regulatory decision-making.”
AstraZeneca’s Allen Chen
“If you’re trying to generate data that potentially could lead to a label expansion or some kind of label update, then it’s likely that you’ll need to have more rigorous data collection that would be sufficient to support regulatory decision-making,” he said, adding that having early discussions with regulators to understand the data that will be accessible would be important.
If the study is not intended to lead to a labeling update, but could support an update in clinical guidelines, introducing some pragmatic elements may be appropriate, Chen said.
The FDA also sees an opportunity for building pragmatic elements into trials that are not intended for registrational purposes.
Project 5 in 5 received more than 30 submissions across various cancer types, Rivera said.
“One important factor, I think, is that not all these questions had registrational intent,” she said. “Registrational intent is just one part of this picture. It’s bigger than that.”
OCE is evaluating the ideas from Project 5 in 5 and working to evaluate incorporating more pragmatic design elements into clinical trials, OCE told the Pink Sheet.
Pros And Cons
The panelists, who also were among the co-authors of an FOCR-led white paper, discussed the pros and cons of adding pragmatic or decentralized elements to postmarketing studies in three scenarios. One scenario involved a trial enrolling racially and ethnically underrepresented patients in proportion to their representation in the US patient population and in sufficient numbers to characterize safety and efficacy of the approved drug.
Pragmatic and decentralized measures could include less restrictive inclusion/exclusion criteria, expanding trials to community sites and more streamlined collection of safety and efficacy data.
“The diversity of sites may lead to increased regulatory risks such as non-compliance or trial failure due to difficulties in maintaining protocol adherence.”
Friends of Cancer Research white paper
Chen said broadening eligibility criteria creates the potential for more heterogeneity in the population.
“Potentially the treatment effect is diluted with a broader population, or perhaps the safety looks different because you’ve introduced patients maybe who are a bit less fit than what you have in the pivotal trial. So that’s sort of a risk that needs to be considered.”
Some community sites may lack the infrastructure to effectively conduct clinical trials, and there may be increased complexities of trial management for sponsors, the white paper states.
“The diversity of sites may lead to increased regulatory risks such as noncompliance or trial failure due to difficulties in maintaining protocol adherence,” the group wrote in the paper.
Reduced data collection also carries a risk of increased variability.
“There may be delayed identification of imaging progression and treatment change, due to non-standardized assessment schedules,” the white paper states. “For sponsors, there may be a risk that outcomes are not directly comparable to registration-directed clinical trials given the potential increase in heterogeneity.”
Reduced safety data collection also may limit assessments of treatment tolerance and chronicity of low-grade adverse events, although symptomatic toxicities may be characterized with electronic patient-reported outcomes data.
Consequently, reduced safety data collection may be best suited for mature products with a well-characterized safety profile, the paper states.
Overcoming The Resistance
Schilsky asked about incentives to move the field toward more pragmatism in trials.
“It’s been reported that despite the fact that a lot of people have been talking about this for a long time, the number of trials that actually include a lot of practical elements is still limited, so there’s certainly some concern or resistance about moving in that direction,” he said.
“This is not going to be a flip the switch, the world is going to change tomorrow. But nothing is going to move the needle like success.”
Flatiron Health’s Neal Meropol
For a sponsor, the best outcome would be a label update for a broader or different population. Barring a new indication, there is still benefit if more pragmatic studies can lead to guideline updates, which in turn can help with reimbursement, Chen said.
“If you’re able to generate data, even if it doesn’t meet the bar for the label update, there is potentially other criteria or other outcomes with guidelines updates that can be beneficial for sponsors,” Chen said.
Trixia Camacho, VP-head of clinical research collaborations and medical evidence generation at Bristol-Myers Squibb, said the ability to add novice trialists and trial sites should help motivate sponsors.
“I think we have a tendency to go to where we have experience and comfort and incredible trial performance, but we also want to make sure that that has the broader applicability, and so I think we have huge incentive there,” Camacho said.
Progress in adopting pragmatic and decentralized elements is likely to be incremental. Stakeholders seeking clinical trial innovations and ways to streamline trial conduct are operating in a heavily regulated, risk-averse environment, said Neal Meropol, VP of research oncology at Flatiron Health.
“This is not going to be a flip the switch, the world is going to change tomorrow,” Meropol said. “But nothing is going to move the needle like success.”
Meropol urged the FDA to publicize submissions that include studies with pragmatic elements.
“Let’s be transparent,” he said. “Let’s publicize successes as well as failures and learn from them.”
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