Executive Summary
US FDA plans to release a second set of guidances to industry; sponsors caution that tradeoffs need to be clear from onset.
Food & Drug Administration-led efforts to encourage oncology drug sponsors to open up pivotal trials to a broader and more diverse patient population will include the release of a second set of guidance documents outlining ways to streamline eligibility criteria, FDA Office of Oncologic Diseases Acting Deputy Director Julia Beaver said.
The US FDA hopes to build on progress from the first guidance documents finalized last year. Those address ways to include oncology patients with previously excluded criteria:
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Brain metastases,
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HIV/hepatitis infection,
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Organ dysfunction, and
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Pediatric patients.
Since the release of those guidances as drafts in 2019, “there’s definitely been more robust conversations on this issue, more questions going back and forth from companies to FDA and encouragement of rational expansion of the criteria,” Beaver said during an ASCO/Friends of Cancer Research event on 9 April. (Also see “Cancer Trials: US FDA Guidances Aim To Expand Eligibility Criteria And Better Inform Labeling” – Pink Sheet, 14 Mar, 2019.)
The new recommendations have resulted in a “substantial difference in the trials that are coming in for FDA review from first-in-human through to the pivotal trials,” Beaver said. “These guidance documents detail ways that safety and efficacy risks can be mitigated, and we’re planning for further guidance documents” to look at other typical exclusion criteria.
“We’ve seen some of this cultural change begin, but eligibility should not be static within a given drug development program. It really needs to evolve throughout the drug development process as knowledge emerges,” she added.
Letting the process evolve “is a key point to really successful implementation and having all stakeholders adapt to that cultural change is important.” In addition to her position at the Office of Oncologic Diseases, Beaver also serves as chief of medical oncology in the Oncology Center of Excellence.
Sneak Peak On Guidance Topics
ASCO and Friends made their recommendations in a perspective piece published online in Clinical Cancer Research on 1 March and in several single-topic articles in February. Based on that work, the next set of guidance documents are likely to focus on:
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Washout periods,
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Concomitant medications;
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Prior therapies,
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Laboratory reference ranges and test intervals; and
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Performance status.
The groups followed a similar strategy in advocating for the first set of four guidance documents, with a series of publications in the Journal of Clinical Oncology in 2017, followed by the submission of proposed guidance language to FDA in October 2018. (Also see “Cancer Trials: Broader Eligibility Criteria Could Mean Novel Labeling Claims” – Pink Sheet, 5 Dec, 2016.)
The guidance work is part of a joint ASCO/Friends project that began in 2016 to “develop and advance specific strategies to change the exclusionary nature of cancer clinical trial eligibility.” Through their partnership, the groups have proposed a new clinical trial paradigm, which has been embraced by both FDA and NCI, in which:
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Patients are eligible for a trial by default and excluded only when there is scientific rationale and/or evidence demonstrating that enrollment would compromise the patient’s safety.
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In all cases, protocol development begins with informed consent as the only eligibility criteria. Any inclusion/exclusion criteria are tailored to the scientific objectives of the study, based on the investigational treatment and study population, and address only substantiated participant risks.
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Trial participants more closely resemble the population intended to receive the therapy and no group is excluded without scientific justification based on current evidence.
Broader Eligibility Creates More Diversity
Broadening eligibility criteria also goes hand-in-hand with another FDA objective: improving diversity in clinical trials. “FDA has efforts underway to discuss diversity plans with companies early on in drug development – and the key is the early part, so that prospective planning can be implemented to encourage, facilitate and support the enrollment of a diverse patient population throughout that drug development lifecycle,” Beaver said.
“We’re really committed to working with companies toward this goal, because ultimately, this is a situation where you need buy-in from all of the stakeholders,” she said.
Drug sponsors have been more cautious about accepting the changes that accompany broadening the eligibility criteria – or at least that is the view conveyed by government officials during the event. (Also see “NCI’s Clinical Trial Accrual Is ‘Better’ Than Pharma Industry’s, Director Sharpless Says” – Pink Sheet, 12 Apr, 2021.)
Mitigating Risk Of Expanded Eligibility
Acting FDA Commissioner Janet Woodcock, who also spoke at the event, agreed with Beaver’s assessment, adding: “We need to go a little bit further” by including separate clinical trial arms for patients with co-morbidities, like renal failure. While those arms “don’t have to count in the major efficacy endpoints,” they can contribute to the safety analyses and “tell us information about people that are treated in the real world.”
That kind of model, Beaver said, would help address a key concern from drug sponsors: that expanding eligibility criteria would negatively impact efficacy results. “One concern that we’ve heard is that enrollment of a heterogenous population of patients in clinical trials – a more representative group – may result in really different efficacy than would otherwise be expected.”
Beaver echoed Woodcock’s earlier suggestion: “To mitigate this risk, a trial could enroll broadly, but focus on that subset efficacy population in that more homogenous group.” That would have “an added benefit of potentially removing certain requirements in the post-marketing setting, for instance, related to organ impairment, as the broader group would have already been studied in the clinical trial.”
Another industry concern is that expanding clinical trial eligibility will compromise safety. Again, Beaver argued the risk can be addressed: “This concern can also be mitigated by a logical approach to defining eligibility, allowing for either detection of safety signals in early clinical trials and submitting modification of subsequent criteria through the drug development process, as knowledge emerges, or alternatively, depending on the exact situation, allowing for expansion of eligibility is not safety concerns are first noted.”
‘The Tradeoffs Need to Be Clear’
Overall, the new recommendations are likely to be adopted without much hesitation from industry, although implementation may be more rapid in some areas than others, Bristol Myers Squibb Company Senior Director of Early Clinical Development, Oncology Ray Perez said during the ASCO/Friends event. “On the whole, I don’t anticipate that there will be large obstacles to adoption. The recommendations are largely clinical common sense.”
The rate of acceptance in industry will “boil down to perceived benefits versus risks,” Perez said. “The likely benefits would be faster enrollment and real-world-relevant populations. I think that everybody in clinical trials is working to improve participant diversity. I know that’s been an explicit focus within our own company and within other companies with which we interact. I think that will all be for the good.”
Explaining the data will be a key consideration, Perez cautioned. While more heterogenous populations in clinical trials will not be difficult to work through from a scientific perspective, “those have tremendous ramifications for messaging – for how people view the results of a newer treatment versus an older one,” he continued. “We will need a lot of conversation across stakeholders, careful planning, and guidance from health authorities in terms of how we can and ought to both interpret the data – but also frame the new findings versus old.”
Finally, recommendations that encourage flexibility in trial design over the product’s lifestyle are “great,” Perez said, but “we need to recognize that real-world cohorts added at different points in the lifecycle may have ramifications.” Adding a patient cohort primarily to track safety increases the cost of the trial, which may be fine as long as that is offset by fewer post-marketing requirements: “The tradeoffs need to be clear.”
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