What’s New?

• Yesterday, Friends of Cancer Research (FOCR) hosted its 2023 annual meeting. The agenda featured three substantive sessions on topics FDA has been focused on for the past year including dose selection in early clinical studies, evaluating the use of oncology products in real-life versus in a controlled research setting, and how real-world data can be leveraged for regulatory decision-making.
• The first session of the meeting was organized as a fireside chat with FDA Commissioner ROBERT CALIFF and new NIH Director MONICA BERTAGNOLLI, moderated by the President and CEO of Friends, JEFF ALLEN. This discussion was highly anticipated given Bertagnolli’s very recent transition to the role of NIH Director, an appointment that was confirmed by the U.S. Senate just last Tuesday. Later sessions during the meeting elaborated on several of the topics touched on by Bertagnolli and Califf. [Read AgencyIQ’s recap of the discussion here.]

Designing studies to assess the performance of cancer treatments in the “real world”

• One of the panel sessions focused on the use of “pragmatic trial elements” during drug development. For context, while conventional clinical trials seek to assess the safety and efficacy of an investigational product within a tightly controlled research setting, pragmatic trials seek to evaluate the product’s performance in the “real world.” This ties into one of the biggest issues discussed by researchers, sponsors, regulators and patients in recent years: The need for better alignment between treatment regimens used in clinical trials and those used in practice.
• This year, FOCR published a white paper on strategies which could enable clinical trials to more accurately reflect treatment delivery in practice. The paper offers strategies like broadening eligibility criteria, selecting routine clinical practice sites, offering flexibility in monitoring treatment, and streamlining data collection. Such approaches would not only offer better insight on the performance of an investigational product but would also lower the burden for participants, likely making it easier for a wider range of patients to participate in clinical trials.
• The white paper also reviews the considerations that must be made when determining the appropriateness of a pragmatic trial design. For example, the paper notes that these studies may be used to support regulatory submission in only certain situations, including fulfilling post-marketing commitments, supporting label updates or supporting a supplemental approval or expanded indication. Along these same lines, a table included in the paper cites the existence of “previous supporting data – safety and efficacy” and the use of agents with FDA approval for the targeted condition as important components for trials with pragmatic designs. That being said, clinical trials as a whole can and should incorporate elements of pragmatic design whenever possible.
• The panel was comprised of a subset of the contributors to the white paper. Among them was ERIN LARKINS, supervisory associate director for the Division of Oncology 2 at FDA, who described the sequence of events that sparked the agency’s interest in this topic. According to Larkins, it started with a small, randomized trial which assessed the performance of two existing products to treat lung cancer when used as a combination. While the trial was too small to support a regulatory approval, the combination showed a modest overall survival benefit when compared to the two drugs used alone, which led to an internal discussion on how the FDA could support these types of studies.
• The outcome of these discussions: Project Pragmatica. This program, managed by the FDA’s Oncology Center of Excellence (OCE), seeks to determine how trials can be designed in a way that more accurately reflects clinical care. Larkins explained that such approaches would provide significant benefit to clinicians by answering practical questions that directly inform treatment decisions but have traditionally resided outside the scope of conventional trials (e.g., whether using two currently approved products together might be a better option than either product alone). One outcome of Project Pragmatica was a joint study conducted by the National Cancer Institute (NCI) and FDA called the Pragmatica-Lung trial. Larkins explained that this trial represents the “far end of the spectrum,” as it is “about as pared down as you can get a study, and a large part of that has to do with the amount of data we have.” However, OCE doesn’t want the trial to be a “one-off” study or for stakeholders to think this the only pragmatic approach the agency endorses. “The key is to look at pragmatic design elements,” she explained, “and every trial can be looked at to see if you can incorporate pragmatic design elements.”

Designing real-world (academic) studies with regulatory submission in mind

• Another panel session focused on how academic-led studies can contribute to the knowledge base used for regulatory decision making. This is another topic for which FOCR facilitated the development of a white paper this year. The paper explains that academic-led research—in contrast to industry-sponsored studies—often seeks to address questions that are important in clinical practice but are different from those addressed in clinical trials to support drug development and product approval. For example, these studies may assess the product’s performance in “rare cancers, underrepresented patient groups, or patients excluded in the pivotal trial (e.g., older adults or those with organ dysfunction).” Furthermore, they may seek to evaluate the use of different doses, treatment regimens, or combinations of products to treat patients.
• While this information may be of significant interest to sponsors and/or regulators, lack of coordination between the investigator, regulators, and sponsors can result in the generation of data that isn’t suitable for regulatory use. Thus, FOCR convened a multidisciplinary group of stakeholders to identify the barriers and opportunities to improve collaboration between these sectors. During the panel session, the FDA’s perspective on the takeaways gleaned during the paper’s development was offered by CHRISTY OSGOOD, a cross-discipline team leader within the Division of Oncology 1. First and foremost, Osgood stated that regulators—FDA and other health authorities—need data that can be used to make a risk-benefit assessment.
• While the FDA “completely understands” that researchers in academia usually have different goals in mind when they first initiate such studies, by thoughtfully designing studies to meet regulatory submission standards at their outset, investigators can ensure the eventual results can be used in a way that is truly impactful. “I would say if we’re hearing about it at the very end, sometimes what we find is that the trial wasn’t actually adequately designed for registration purpose,” she explained. For example, Osgood noted that common issues include: the use of an endpoint that isn’t appropriate for the particular disease being studied, the level of statistical significance used doesn’t allow for robust interpretation of results, and/or the sample size used for the study is too small to be adequately powered.
• Osgood added that another common issue for academic investigators is that they may not provide information that is sufficient for FDA use for a risk determination. While the amount of data required is context specific, she encouraged investigators to contact FDA as early as possible to ensure studies are adequately designed to enable regulatory use. She also noted that the FDA doesn’t have “hundreds of statisticians to dig through data or hundreds of medical officers” to review submissions. The higher the quality of data that is submitted to the agency, the easier it is for reviewers to use it in making a risk-benefit decision. On this note, she suggested that even aligning on how the data that is submitted is cleaned and formatted could be an easy topic for stakeholders to collaborate on, which would have a meaningful impact, “As I was preparing for this, I wondered why aren’t I suggesting this? Why don’t we sit down with our stats and data management colleagues … and talk about ‘How are you going to clean the data at the end?’ And if we knew that, even without the data, we could implement those same checks now which ultimately will help get that data cleaner, faster.”
• These are challenges that the NCI is all too familiar with as well. Another contributor to the white paper, MARGARET (MEG) MOONEY from NCI’s Cancer Therapy Evaluation Program, shared how the NCI is working with investigators to ensure the data generated in government-sponsored trials is fit for regulatory purposes as well. While NIH’s systems are set up to support registrational data collection for every trial, any time an investigator is considering a trial with possible registrational intent, Mooney said that NCI immediately brings in the sponsor to ensure the groups are aligned. While she indicated this can be a bit of an onerous process, it’s nothing compared to the process investigators must go through if they decide at the end of the study that it merits regulatory review. In these cases, investigators may have to go back and gather all the information that would have been collected throughout the study if it had been designed with registrational intent from the beginning.

Keynote Session: Showcasing OCE’s efforts

• The meeting also featured a keynote moderated by OCE Director RICHARD PAZDUR, where FDA staff ran through a list of projects currently underway within OCE. Throughout the session, Pazdur shared the sentiments of previous speakers regarding the need to work closely with clinicians, investigators, small biotech companies and larger industry sponsors to appropriately navigate the regulatory process.
• R ANGELO de CLARO, associate director for Global Clinical Sciences at OCE, provided a look into the progress of Project Orbis. This program, which launched in 2019, provides a framework for the concurrent submission and review of oncology applications to multiple regulators. The program now includes the U.S., Canada, Australia, Singapore, Switzerland, Brazil, Israel and the U.K. Claro announced at the meeting that Japan has reached an agreement with the FDA and will be collaborating as an observer. The FDA has also had interest from the European Medicines Agency this year. Per Claro, about 400 marketing applications have been submitted across the eight regulatory agencies, which has led to about 350 regulatory actions. The median submission gap across all applications is just one month and the action gap is about six months. “These numbers are very remarkable considering that previously some of these other agencies were not even getting the drugs or were dealing with lags of about 12 to 24 months,” he added.
• Project Confirm, which is focused on confirmation of benefit for oncology accelerated approvals, has a big day planned this week. GAUTAM MEHTA from the Division of Clinical Oncology 2 stated that November 16 is a very important day for Project Confirm, since it’s the day the Oncologic Drugs Advisory Committee (ODAC) is slated to discuss long-delayed confirmatory trials after accelerated approval of two cancer products. “This is part of the broader scope of Project Confirm, where we are really trying to analyze our outcomes, which is the accelerated approval program in oncology, and on Thursday we want to specifically focus on this topic – the delay of verification of benefit after accelerated approval is granted,” said Mehta, the lead FDA staffer for Project Confirm. During the meeting, FDA presenters will discuss the risks involved with delayed confirmation and some strategies to mitigate those risks. AgencyIQ will be providing an in-depth analysis of that meeting later this week.
• According to Pazdur, the FDA is now taking a firm stance with accelerated approvals – requiring that confirmatory trials are ongoing at the time of approval. He clarified that ongoing does not mean “one patient enrolled,” it means true progressive enrollment. Pazdur encouraged sponsors to speak with the agency “before you begin any patient on any trial” to establish both the initial and confirmatory trials and the timelines for completion. “The days of doing a single-arm trial of 100 patients with X response rate and saying, ‘Well, we’ll get to the confirmatory trial someday’ – those days are over. OK, I want to make sure that people understand this. This is going to be a period, perhaps if you want to test the FDA on this, this is going to be a period, I will quote myself, of tough love, OK?” He also clarified that, considering the issues with accelerated approval have all stemmed from cases where confirmatory studies have not been initiated at time of approval, he has the support of the FDA leadership on this approach.
• Mehta reinforced the importance of these new timelines, citing the FDA’s internal research showing that there is almost a four-year advantage in confirming clinical benefit if the confirmatory study is already ongoing at the time of accelerated approval. Pushing for this timeline for confirmatory trials will help to ensure that the FDA “minimize[s] the risks of accelerated approval while still leveraging its benefits,” he confirmed.
• A relatively lesser-known program that OCE chose to highlight during the keynote – Project Catalyst. This program is designed to help small companies and academic accelerators to develop novel oncology therapies. JEFF SUMMERS, associate director of translational sciences, described his four years working with this program as the most fun he’s had at the agency during his 20-year tenure. He spoke with passion about the difference that the program can make, referring to it as “kind of like the democratization of anticancer development.” From the perspective of the FDA, assisting original investigators in taking a newly discovered therapy all the way through to regulatory approval likely results in a shorter time to market. As Summers stated, “a novel anticancer therapy is a lamentable thing to have languish or sit on a shelf.”
• Project Catalyst is focused on fostering informal scientific discussions where people can get non-binding information or guidance on their drug development programs. Importantly, these discussions all occur prior to the submission of an Investigational New Drug application (IND). According to Summers, in the context of scientific advances that have led to faster translation from bench to bedside, this faster translation “comes [with] a lot less experience with the enterprise of drug development, and as you all know, that enterprise can be relatively complicated.” In addition to assisting researchers in creating an appropriate drug development program, Summers feels that it also allows them to learn that the “FDA isn’t a black box and not something to be fearful of.” Pazdur reinforced the importance of this program and his desire to highlight it at this meeting, saying that he feels most of the meeting attendees may be unfamiliar with it.
• What’s next for OCE? When this question was posed to the panel as a whole, Pazdur joked, “I have to think about that because usually these projects come to me spontaneously.” He clarified that, typically, the ideas for OCE initiatives come from problems that the agency sees in their day-to-day operations. In fact, Project Confirm came to fruition due to the number of calls the agency was receiving from the press looking for data on accelerated approvals. This led them to realize that they needed a website providing this information, and then the concept for the project expanded from there. One upcoming project that Summers plugged at the end of the panel – a public-private partnership between the NIH, NCI, and FDA’s OCE that will focus on the development of treatments for ultra-rare tumors.

https://fda.agencyiq.com/article/0000018b-d605-d7d5-a1db-f7376ce30000