At the Nov. 12 Friends of Cancer Research (FOCR) annual meeting, regulators, clinical trialists and industry convened to address ways to boost efficiency in oncology clinical trials and make regulatory processes more efficient. The day was organized around three foundational white papers published by FOCR; AgencyIQ has highlights and takeaways here.
The Friends of Cancer Research (FOCR) 17th Annual Meeting featured both top regulators and a detailed oncology development roadmap
- The Nov. 12 meeting was organized as a series of panels, each with a distinct focus. FOCR issued whitepapers prior to the meeting with more detailed information, which AgencyIQ has linked and summarized below. A common thread between the topics: innovative strategies to increase the speed of development while maintaining data quality and patient safety.
- The panelists featured a high-profile roster of regulators, funders, industry executives, and academics. Between the three sessions, FDA Commissioner ROBERT CALIFF And National Cancer Institute (NCI) Director KIMRYN RATHMELL provided high-level remarks. Both Califf and Rathmell are presidential appointees and are set to exit their posts in the coming months, with the upcoming transition to a second presidency for DONALD TRUMP. [ See AgencyIQ’s curated collection related to the election and transition here.]
- The meeting offered oncology sponsors detailed frameworks and resources across the development spectrum. Simultaneously, the working groups highlighted specific areas that would benefit from additional clarification or investment from the agency. AgencyIQ has highlights below.
Session 1: Interim overall survival evaluations and implications for trial designs and analysis plans
- Background: Overall survival (OS) is a clinically meaningful measure of both efficacy and safety, and is considered the gold standard for verifying clinical benefit of cancer products. It is defined as the time from trial randomization until death from any cause in the intent-to-treat population. Accurate evaluation of OS often requires lengthy follow-up periods, which has led to the use of surrogate and intermediate endpoints like as progression-free survival (PFS) and objective response rate (ORR) as the basis of approval for many initial regulatory decisions. However, interim OS data is assessed at this point for safety, an approach that comes with challenges because the data are often immature.
- Regulatory context: Since 2022, OCE’s Project Endpoint has sought to foster consistency and advancement in endpoint development. The group, led by NICOLE GORMLEY, Director of FDA’s Division of Hematologic Malignancies 2, has focused extensively on OS assessment and interpretation. Through this effort, FDA partnered with the American Association for Cancer Research (AACR) and the American Statistical Association (ASA) to host a July 2023 workshop on the challenges of measuring OS [ Read AgencyIQ’s in-depth analysis of the workshop here.]. A session at the 2024 AACR annual meeting built on the workshop’s discussions, highlighting issues related to how unequal randomization and crossover affect OS measurement [ Read AgencyIQ analysis here.]. Most recently, a group of regulators (including Gormley) authored a perspective article in the September 2024 edition of Clinical Cancer Research that “shares best practices, proposes novel statistical methodologies, and provides detailed recommendations to improve the rigor of using OS data to inform benefit–risk assessments.”
- The FOCR white paper: Based on the work described above, the white paper laid out best practices for trial designs and analysis plans, emphasizing the importance of prospective planning for how OS data will be handled. The paper described how a “streamlined” quantitative framework can be applied to more straightforward trials, while a “comprehensive” framework should be applied to trials with greater complexity (i.e., crossover between treatment groups). The paper offered specific strategy considerations from design to analysis to interpretation. Finally, the FOCR paper mapped out future work to conduct simulations that “enhance the accuracy and reliability of interim OS data interpretation.” These simulations could be carried out by a multistakeholder consortium.
- Eli Lilly’s VP of Clinical Development, GEOFF OXNARD, summarized the issue faced by industry and regulators when early OS data provides hazard ratios with broad confidence intervals: “To some extent the question becomes, do we as a community want to act urgently when you first see the difference in a surrogate endpoint, or do we feel less urgency and want 50 more months to go by—or more—before we should have confidence in the risk-benefit from that data?”
- Gormley emphasized that OS data should be planned and robust. In her experience, a major discussion thread with sponsors relates to the volume and fraction of overall survival information that is expected at timepoints throughout the trial. The agency asks for expectations on availability at the readout of the intermediate endpoint, along with the timeframe for a complete OS assessment. Gormley also stressed that OS is assessed “in the context of all of the data that we have available to us at that time.” However, she said that the requisite supportive data should be considered on a disease-specific, case-by-case basis and encouraged sponsors to engage with the agency on the matter.
- Addressing the crossover conundrum: The interpretability of OS data can be confounded by high rates of patient crossover between treatment groups, which introduces bias. Oxnard argued that the issues should not lead to “maladaptive” trial designs that do not include an option for crossover to preserve the integrity of OS data. He explained that crossover should be employed when it is beneficial to patients. He elaborated, “…you could imagine a trial overenrolling and overpowering, hoping to have extra events for an interim OS, when really what’s meaningful is the primary endpoint…” LISA RODRIGUEZ, Deputy Director of FDA’s Division of Biometrics IX, described how additional data can bolster the interpretability of crossover studies. This includes data related to timing, she said, asking, “Are patients crossing over early? Are they crossing over at a certain point?” While the best approach is prospective planning and supplementary analyses, she said, “We’re certainly open to looking at a variety of post hoc analyses, but again, that’s to help the interpretation,” with the understanding that these would “not necessarily [be] the primary analysis, right?”
- Additional strategies to increase OS data quality and meaning: Oxnard discussed the importance of ensuring that developers continue to collect OS data after a patient has completed or stopped therapy. He described the situation that happens all too often: “When the patient says, ‘I don’t want that extra EKG post-progression, I’m out, I withdraw consent,’ the site says, ‘Okay, no more OS collection, I guess.’” He suggested refining consent processes to allow a patient to opt in to continued OS follow-up. TONY SABIN, head of immuno-oncology statistics at GSK, suggested incorporating tools like Bayesian predictive modeling to interpret OS data. Regarding readiness, he said, “I think there’s some work to do, probably to find the best way forward and help contextualize the use of some of these methodologies in this space.”
Session 2: Enhancing post-marketing studies with pragmatism
- Background: Incorporating “pragmatic elements” into clinical trials aims to reduce undue burden to patients, investigators, and sponsors. As stated on the webpage for OCE’s Project Pragmatica, “Pragmatic trial elements take advantage of functional efficiencies such as fewer and simpler eligibility criteria and flexibilities in trial delivery and outcome measurement. The degree of flexibility is tailored to the trial context, keeping the safety of patients and the integrity of trial data at the forefront.”
- Regulatory context: The push for more pragmatic trials has intensified in recent years and is a key priority of current FDA Commissioner Califf. Some relevant efforts in FDA’s portfolio include the abovementioned Project Pragmatica, launched in 2022, along with CDER’s new Center for Clinical Trial Innovation (C3TI), which is conducting research in this space [ Read AgencyIQ analysis here.].
- The FOCR white paper: The postmarket setting could be a feasible proving ground for introduction of pragmatic elements because “more is known about the safety of the product, and additional questions remain about its optimal use in practice,” the white paper explains. The analysis uses the pragmatic-explanatory continuum indicator summary (PRECIS)-2 framework to describe these elements in the context of three scenarios. First, the group considered a postmarket trial aiming to “enroll racially and ethnically underrepresented patients in proportion to their representation in the U.S. population of patients within the disease indication, in sufficient numbers to characterize the safety and efficacy of the approved drug in the patient population.” As AgencyIQ has previously discussed, this particular ask is relatively common in the oncology space, though the actual execution by sponsors is variable. Second, the group considered postmarket trials that characterize a cumulative toxicity risk and associated mitigation measures. Last, the group considered a postmarket trial to examine the safety and efficacy of a product in an expanded biomarker-selected population. In conclusion, the working group explained that appropriate pragmatic trial design involves a balance of burden reduction and data quality.
- At the meeting, multiple stakeholders emphasized the importance of looking at pragmatic approaches as a continuum rather than a binary. University of Chicago researcher RICHARD SCHILSKY said, “Any trial can have pragmatic elements incorporated in it, and we as a community of trialists need to look more closely at every element around that PRACIS-2 wheel to think about when we’re designing a trial, how can we make it more pragmatic?”
- The conversation focused on the risks and benefits of selective safety data collection. From the perspective of University of Pennsylvania oncologist PETER O’DWYER, reduced data collection could bring more community-based sites into the fold and “expand the footprint of clinical trials.” TRIXIA CAMACHO, VP of Worldwide Medical Affairs at Bristol Myers Squibb described a measured approach, saying “I do think again it goes back down to the identification of what is the specific [adverse event] of interest? Can we work with agencies to ensure that we are collecting that at the appropriate cadence?”
- NEAL MEROPOL, VP of Research Oncology at Flatiron Health, called for transparency around use cases to promote uptake of the pragmatic approach. “Nothing is going to move the needle like success, and so my plea is that we try collectively meet early and often with the agency to discuss potential application of pragmatic elements, and that we publicize and highlight successes,” he said. Meropol also suggested that FDA develop resources with examples of submissions that successfully implemented pragmatic elements.
Session 3: A Common Strategy for Using ctDNA as an Intermediate Endpoint in Prospectively Designed Trials
- Background: Circulating tumor deoxyribonucleic acid (ctDNA) is fragmented genetic material of cancer cells that are found in the bloodstream. As dying cancer cells degrade, their cell contents are released into the patient’s circulation, affording the possibility of detecting fragments of DNA that are unique to the cancer. The technology, less invasive than conventional biopsies, can be used as a biomarker to detect and predict the presence and stage of some cancers. In the development space, ctDNA is being assessed as a tool to understand treatment effectiveness, since it indicates the amount of tumor DNA found in the blood.
- Regulatory context: FOCR has led efforts to harmonize ctDNA methods, beginning in 2019 with the organization of a multi-stakeholder initiative called ctDNA for Monitoring Treatment Response (ctMoniTR). [ See AgencyIQ analysis for a detailed breakdown of ctMoniTR meetings and whitepapers.] The FDA issued draft guidance in May 2022 on the use of ctDNA as a biomarker in investigational new drug (IND) and marketing applications in the early-stage, solid tumor setting. In the guidance, FDA described four scenarios for use of ctDNA: selection of the patient population, patient enrichment using molecular residual disease (MRD), as a measure of response in early trials, or to support pathologic complete response information following neoadjuvant therapy and as an early endpoint for clinical trials. However, the guidance made it clear that FDA was not ready to recognize ctDNA as a validated surrogate endpoint.
- The FOCR white paper: Towards validation of ctDNA. The paper outlines an “aligned approach” for ctDNA measurement in non-small cell lung cancer (aNSCLC) treated with immunotherapy (IO). This context was selected “due to the robust data established to date and ongoing drug development in this space.” Using the standardized approach, FOCR intends to combine data into a trial-level meta-analysis. The approach involves baseline ctDNA measurement prior to treatment initiation, four on-treatment measurements, and a measurement at 6 months post treatment-initiation. These should align with standards for radiologic measurements, when feasible. The whitepaper gets granular, providing required and recommended data to collect in tabular format. The working group also lays out parameters for assays, which at minimum should be “sensitive enough to detect ctDNA in at least 70% of patients at baseline.”
- The discussion at the meeting walked through how the group arrived at the recommendations provided in the whitepaper. Regarding the timing, Genentech data scientist ZOE JUNE ASSAF explained that the group did not want to “pigeonhole sponsors into really specific times” since studies have variability in treatment. Instead, the on-treatment measurements are anchored to treatment cycles, apart from one at the six-month mark.
- The recommendations for measurement technology also intend to afford flexibility, according to DAVID FABRIZIO, VP of Translational Strategy at Foundation Medicine. He pointed out that ctDNA measurement technology and calculation methods are advancing. “We definitely don’t want to stymie that advancement. And so rather than rely on a specific technology, we relied on a set of attributes, which is the sharpest sword that we have to wield right to ensure consistency of data collection and application of the technology.” ANAND PATHAK, medical officer in FDA’s Division of Molecular Genetics and Pathology added, “I would like to say that and acknowledge that we currently do not have any FDA-authorized tests for detecting ctDNA changes for any purpose.” Therefore, CDER conders a variety of attributes when considering whether results from different technologies can be pooled.
- The agency perspective: “FDA is very encouraged by these results. We’re really interested in bringing effective therapies to patients faster. That being said, we still need more data, and to accomplish that, we oftentimes will look to things like meta-analyses,” said PAZ VELLANKI, a clinical reviewer for Thoracic, Head, & Neck Cancer in FDA’s Office of Oncologic Diseases (OOD).
- OCE Deputy Director PAUL KLEUTZ posed a foundational, technical question on ctDNA measurement to the panel during the Q&A. “One of the hugest benefits of objective response rate is that causality is not an issue in single arm cohorts, and it’s because we all assume that tumors inexorably grow, if not intervened upon,” he observed, continuing, “Is there data on CtDNA regarding…whether it waxes and wanes more than, say, tumor response with respect to differential shedding, or, if you may, you may get some reduction in ctDNA for reasons other than therapy?” While the paper did not address the dynamics of ctDNA levels in untreated patients, Vellanki mused that serial measurements in early timepoints of treatment could be informative.
Featuring previous research by Rachel Coe and Chelsey McIntyre.
To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).
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