Pazdur prepared to unveil one pilot program, and previews another:
- A new pilot project: Project Pragmatica. Several weeks ago, AgencyIQ had confirmed with industry and agency sources that the Oncology Center of Excellence was working to develop a new pilot program, known only as Project Pragmatica. At today’s meeting, we heard for the first time the general details about what FDA’s Oncology Center of Excellence (OCE) wants to do. Speaking at an opening session, Oncology Center of Excellence (OCE) Director Richard Pazdur said the genesis for the idea – “a lightning bolt,” he called it – came after he saw a small trial done under the LungMAP master protocol for lung cancer studies. This study, he said, left him wondering “one thing, and one thing only: Is there a survival advantage?” That question, in turn, left Pazdur wondering if it would be possible to run a sort of ultra-efficient, simplified trial – a pragmatic trial – to answer that one, key question. The trial, he said, would “preserve randomization,” but make the rest of the trial design “as simple as possible” with respect to eligibility (“whoever goes on the trial, as long as it’s second-line, nothing else matters”) and safety reporting (“aside from hospitalization and anything unknown.”)
- Project Pragmatica as a reaction to trial complexity: “We’ve made these trials way too complicated,” Pazdur explained. “When I look at informed consent forms that go on for 20 pages, no patient is going to read these.” Patients basically only have one question for their doctor, Pazdur argued: If your mother was in my chair, what would you recommend that she do?
- How Pragmatica will work: While the details are still being worked out – an OCE staff member told us that a webpage officially launching the project is still a few weeks away – the basic outlines of the project were clear from Pazdur’s remarks at the conference. Pragmatic, simplified trials are intended for use only for products (alone or in combination) with extensively characterized safety profiles known to the FDA. The trial would have to assess a critical endpoint (such as overall survival), and include randomization (i.e., no single-arm studies).
- Additional information on Project Pragmatica came from an unexpected source: The new Director of the National Cancer Institute (NCI), Monica Bertagnolli. During an interview with FOCR Chair Ellen Siegel, Bertagnolli reiterated many of the themes raised by Pazdur, but spoke to another benefit of the approach as well: the time savings. “It’s very streamlined. I’m very happy to tell you the best part. Because one of the things we need to do is get these answers for patients much faster,” she said, noting that she had been a “sort of a fly on the wall for some of this” as the LungMAP study design came together — which had piqued Pazdur’s interest. “I know the study was being designed in July . This was a collaboration with NCI and the National Clinical Trials Network, FNIH, FDA, LungMAP… that study is going to the central IRB today, and it will open in January. That is amazing.”
- How can industry do more pragmatic studies? For Bertagnolli, trial sponsors need to consider some key questions: What do patients and doctors need? Is the research design fit-for-purpose? Is the study going to answer questions that patients and doctors need? Is the drug’s safety well-characterized and known to regulators? Do we have the right stakeholders and collaborators involved, including regulators? Without the right answers to those questions, a pragmatic approach likely isn’t appropriate.
- But this wasn’t the only OCE pilot program previewed at the FOCR meeting. Pazdur also spoke of his frustration of FDA and industry’s traditional approach to drug approvals involving companion diagnostics – a “one-drug, one-test” approach. Pazdur argued that this approach doesn’t serve patients by limiting them to a single make-or-break test that will mean the difference between whether a patient receives an oncology drug or not. “One issue we’re discussing and will soon unveil in another pilot program has to do with minimal performance criteria for a test, and embedding that criteria into a trial,” he said, indicating a preference to broadening the types of tests available for use.
Other noteworthy points from Pazdur:
- On remote work at the FDA: In a session featuring FDA Commissioner Robert Califf interviewing Pazdur, both leaders spoke to the benefits that remote work has afforded the agency – and provided a glimpse at the agency’s forthcoming remote work policies. Pazdur quipped that there seem to be “more security guards than employees” at the agency’s headquarters in Silver Spring, Maryland some days, but that it’s unrealistic to simply expect everyone to come back into the office. “We need to come to the realization that there has been a seismic shift in the expectations of the workforce,” he said, noting that both FDA and industry have experienced this shift. Califf agreed, saying that no one at the agency is arguing that 100% of staff should be back in the office. Both Califf and Pazdur spoke in favor of a “hybrid” model in which employees come into the office on an as-needed basis. The purpose of returning should not be “just to make an administrator happy,” noted Pazdur. Califf added that remote work options functioned well in Silicon Valley – just “not the Elon Musk type,” he joked as an aside. FDA has previously told AgencyIQ that it intends to offer an announcement about FDA’s work-from-home flexibility in later November 2022.
- On global clinical trials: There has been a significant amount of industry interest in FDA’s stance toward global clinical trials, and in particular trials run in China after the agency issued a Complete Response Letter to Eli Lilly based on what the FDA perceived as the firm’s overreliance on solely Chinese data to support of an investigational cancer PD-1 cancer drug. But according to Pazdur, some interpretations of FDA’s actions missed the broader point that the agency wants to make. The agency wants multi-regional clinical trials “that represent the major ICH regions,” he said, referring to the International Council for Harmonization, a group that counts regulators from the U.S., Europe, Japan, Canada, China and elsewhere as members. “We’re not suggesting that all trials need to be done in the U.S., but need representation from all the ICH regions,” Pazdur said. The issue is drugs being developed in a single country, he continued. “We find that problematic” since it doesn’t represent the diversity of the U.S. population. Pazdur did note that there were instances in which he took issue not just with a lack of representation, but with potential lapses in clinical ethics. If a company chooses to conduct a trial in another country where only an inferior comparator is approved just to avoid a superior comparator in the U.S., that represents an ethical problem, Pazdur argued. “People in clinical trials should be getting the best therapies,” he noted.
- On removing drugs from the market: Pazdur expressed frustration at the time it takes to remove certain drugs from the market even after data show the drug to not be effective for a particular indication. “If a study has failed – a confirmatory study has clearly failed – then I think that companies need to step up and take the drug off the market as rapidly as possible,” he said, adding that most companies do work with the FDA. But in cases where a sponsor isn’t willing to cooperate, it takes the FDA enormous amounts of resources to withdraw an indication or the drug’s approval in its entirety.
- The time between accelerated approval and confirmation of benefit is itself a “risk.” Of late, Pazdur has been an ardent supporter of ensuring that companies are prepared to confirm the benefit of their drugs once granted accelerated approval. In one notable recent announcement, ADC Therapeutics said that the FDA had advised the firm it would require that a confirmatory study be “underway and fully enrolled at the time of any BLA filing” if its biologic was to be considered under accelerated approval. While not citing ADC’s drug, specifically, Pazdur made the case that such actions were warranted. A lack of confirmed benefit “puts the patient at risk,” he argued. “Remember, there is a period of vulnerability that we need to control – between the time of the accelerated approval and the confirmation or lack of confirmation in benefit. And we should try to reduce that period of vulnerability as much as possible.” Califf agreed, saying that the agency both “needs more teeth” to withdraw products, and also needs to ensure that “confirmatory studies start before the approval.”
Other notable observations from OCE team members:
- Lola Fashoyin-Aje, associate director of the Oncology Center of Excellence, spoke extensively about OCE’s Project Frontrunner, an effort to encourage drug sponsors to “first develop and seek approval of new cancer drugs for advanced or metastatic disease, in an earlier clinical setting” rather than in later-line treatments. Fashoyin-Aje said she hoped that the project could benefit patients in a material way. “I think we owe that to our patients – to not be satisfied with incremental improvements in therapy. We really need to generate evidence that provides a comparative assessment of the standard of care so that we are continually pushing and identifying those candidate therapies toward our ultimate goal, which is to cure cancer.” At the same time, this choice – to develop early-line treatments or later-line treatments – isn’t mutually exclusive, she said. They can be developed simultaneously – you just don’t want the development of one to lead to a delay for the other approach.
- Fashoyin-Aje on accelerated approvals: “There’s nothing about the accelerated approval pathway that requires that we only use single-arm trials. There are opportunities to be very selective about the appropriate use of that trial design to support an approval. We’re not saying that there is no role for single-arm trials…. But as more therapeutic options become available, it’s really going to be quite important to generate evidence that provides that comparative evidence within a trial, not relying on cross-trial comparisons. Sometimes it’s not possible to do that, especially as we are redefining diseases within oncology. […] Accelerated approval does not equal single-arm trials.”
- Fashoyin-Aje on confirmatory studies: “The traditional or historical way that sponsors have sought accelerated approval is to get approval based on a single-arm trial, and then to design a subsequent trial that is a randomized controlled trial to verify clinical benefit. And the timing of initiating that trial has been variable […] but when that trial is initiated after the approval is granted, the timing is unacceptably long. […] It is important that the trial be initiated nearly concurrently with the trial that is designed to support the accelerated approval. Alternatively […] sponsors could just continue that trial.”
- Timil Patel, medical oncologist at OCE, on the topic of decentralized trials: Patel noted that the FDA has approved some drugs already that made use of protocol deviations to allow for remote monitoring during the pandemic, and that the agency is now hoping to better leverage what it has learned. “The theme I’m hearing from our industry sponsors is ‘uncertainty’ going forward. So that’s why we internally have reviewed applications during the pandemic that leveraged remote monitoring out of necessity. But some of those trials actually led to FDA approval. We’re hoping that we can collect that information from sponsors by serving the ones who actually got an FDA approval during Covid and who actually deployed these technologies to turn it around and say, this is a proof of concept that you guys utilized some component of hybrid decentralized clinical trials and ultimately received an FDA approval, but there’s no data. We don’t know how many companies actually did X, Y or Z, but we have that data, so we’re going to survey them, collect it and present it anonymously. We’re hoping that by doing that, we can show that these technologies are useful, they’re leading to FDA approvals, so maybe it should be considered that you can do this prospectively.”
- Vishal Bhatnagar, associate director for patient outcomes at OCE, spoke about patient centricity and dose optimization. “Patient centricity shouldn’t begin at Phase 3,” said Bhatnagar. Rather, it should begin as soon as patients are receiving treatment, he argued, noting that dose tolerability is an essential part of the efficacy of a drug. “We want to see doses in a randomized way,” not just to assess effectiveness, but also tolerability, he added, referring to OCE’s Project Optimus.