Executive Summary
Initial draft list of molecular target candidates has industry, investigators and patient advocates asking how the agency intends to prioritize targets and same-in-class molecules for pediatric studies, and how frequently it will update the list; industry representatives divided as to whether ‘broader is better’ when it comes to the target list.
The US FDA’s initial draft list of oncology molecular targets for which pediatric studies might be required has industry, investigators and patient advocates not only weighing the breadth of the list, but also jumping ahead to questions about how pediatric research will be prioritized among multiple drugs in the same class and logistics for updating the list.
More clarity on these issues may be coming in the next few months. The agency’s Oncologic Drugs Advisory Committee’s (ODAC) pediatric subcommittee will meet June 20 to discuss the initial lists of relevant and non-relevant molecular targets, considerations for applications of the lists, and the process for prioritization.
“The purpose of successfully implementing the legislation is really not to increase the number of early-phase studies in the pediatric population but to actually accelerate the timeline for the initiation of those studies when it’s appropriate.” – FDA’s Reaman
Under the FDA Reauthorization Act (FDARA), applications for novel drugs and biologics submitted after August 18, 2020 must include reports on a “molecularly targeted pediatric cancer investigation” if the product is intended for treatment of an adult cancer and directed at a molecular target that FDA determines to be “substantially relevant” to a pediatric cancer. The provision effectively extended the Pediatric Research Equity Act’s reach to the cancer setting. (Also see “Pediatric Cancer Study Requirements Added To FDA User Fee Bill” – Pink Sheet, 11 Jul, 2017.)
“The purpose of successfully implementing the legislation is really not to increase the number of early-phase studies in the pediatric population but to actually accelerate the timeline for the initiation of those studies when it’s appropriate,” Gregory Reaman, acting associate director for pediatric oncology at FDA’s Oncology Center of Excellence said at an April 20 meeting.
FDA has promised a flexible and transparent approach to developing and implementing the FDARA pediatric study requirements, which include generating a list of molecular targets considered substantially relevant to the growth and progression of a pediatric cancer that may trigger study requirements under the provision.
The draft candidate molecular target list discussed at the April 20 meeting is divided into four primary target class categories: gene abnormality; cell lineage; tumor microenvironment and immunotherapy; and other targets. In total, more than 140 targets or groups of targets are listed as potential candidates.
The agency also compiled a far shorter list of targets considered to be “non-relevant” to pediatric cancer and for which studies would be automatically waived under FDARA. (See table.)
Easing Regulatory Uncertainty
At the meeting’s outset, Reaman sought to dispel concerns he’s heard from stakeholders about the concept of the target lists and “what they are, what they do, what they can do.”
“This is a statutory requirement that was intended, I think in large part, to address regulatory uncertainty for industry and to guide decision-making,” he said.
“A target being designated as relevant and on the relevant list is neither an absolute nor an exclusive requirement for decisions related to pediatric evaluation,” Reaman said. “An agent can affect a target that’s on the list, but there may be reasons to not evaluate it. And something may not be on the list, but an agent becomes available that addresses a relevant target [and] could still require a pediatric evaluation.”
The candidate molecular target list was generated independent of whether a compound was in development or available for a particular target or whether a biomarker was available. The list was compiled using peer reviewed literature, abstracts and public databases, and there was no prespecified minimum evidentiary basis for a target’s inclusion on the list, he said.
While stakeholders made some suggestions for specific additions to the list and the inclusion of molecular pathways as well as specific targets, Reaman pushed back against suggestions that a threshold level of evidence should be required to include a target on the list.
“I would really question the need for a specific level of evidence,” he said. “Granted if we have something on the list or even if something’s not on the list, having an appropriate evidence base to support the biologic rationale for designing a trial or for even considering doing a trial I think is important, but that’s really sort of step two or step three. What we’re really doing here is broadly creating a list and, therefore, I don’t feel that we need to talk in great lengths about level of evidence because I think that will come later.”
Is Broader Better?
Meeting participants said the molecular target list is expected to inform FDA’s regulatory priorities for pediatric research as well as industry’s decision-making around compound selection and clinical development. In addition, the list could be used by grant-funding agencies to fund scientific projects.
Academic researchers and patient advocates generally said the target list should be broadly inclusive to encourage sponsors to think about pediatric development early, a position echoed by Hubert Caron, senior medical director for pediatric oncology at Roche.
A company is much more likely to come into FDA early to discuss potential pediatric study plans if they see that the target of their investigational drug is on the list, Caron said. “So I argue from an effective implementation of the [statute] point of view, the longer the list [and] the potential molecules, the better.”
However, others in industry raised concerns that an overly broad list would be of little help in guiding sponsors on the need for pediatric studies.
Darshan Wariabharaj, director and global regulatory lead for oncology at Janssen R&D LLC, urged the agency not to lose site of the original legislative intent behind the list: providing guidance to industry and other stakeholders in fulfilling legislative requirements for developing pediatric study plans within a certain timeframe. “The more complex we have the list … the more difficult it will be to maintain and update the list and the potential utility,” he said.
Lucy Vereshchagina, vice president at the Pharmaceutical Research and Manufacturers of America (PhRMA), said an all-inclusive list would actually provide less publicly available guidance for companies, which will have to seek regulatory predictability through one-on-one interactions with FDA.
Reaman said he would like to see the list serve more than just providing regulatory certainty and responding to a piece of legislation.
“We ought to look at this as being something that does assist industry. As we move forward and review it on a regular basis in a mechanism yet to be discussed and fully determined, I think we have the opportunity to add things as evidence accumulates and science evolves,” he said. “I want to keep it broad, but I don’t want to make it so broad that it’s of little use to anybody.”
Reaman also added that as experience with the lists grows, the list of non-relevant targets may get larger. “Then I think that might provide more regulatory certainty or predictability for industry and for the agency.”
Framework Needed For Multiple Drugs In Class
Discussion about the development of the lists and the target candidates often segued into issues beyond the list itself, including the prioritization of targets and compounds for pediatric study.
“We don’t have the number of [pediatric] patients to study all of the novel therapies, so we’re going to have to prioritize,” Reaman said. “Most importantly, we’re going to have to prioritize same-in-class products because there’s absolutely no way we can do multiple early-phase studies of drugs with the same mechanism of action.”
How to implement the pediatric study requirements when there are multiple agents in a target class “really is an elephant in the room in terms of how we’re going to move these agents into clinical testing.” – NCI’s Smith
The issue of how to implement the FDARA requirements when there are multiple agents in a target class “really is an elephant in the room in terms of how we’re going to move these agents into clinical testing,” said Malcolm Smith, associate branch chief for pediatrics at the National Cancer Institute’s clinical investigations branch. “When there are five, 10, 20 agents in class, we really need a strategy for how we’re going to pick the one or two that we can probably study in our rare pediatric populations, so a framework for doing that really needs to be developed.”
“We need to be smart about picking those agents being developed for adult cancers that have the greatest chance of benefitting children,” Smith said. “There’s the risk that we have so many agents to choose from we could bring a lot of the wrong agents into testing, and we could take up the clinical trial slots that we have for different patient populations with ineffective drugs.”
Patient advocate Donna Ludwinski, director of research programs at Solving Kids’ Cancer, said that while the nature of the list seems appropriately comprehensive, “there isn’t a sense of what’s highly prioritized as an unmet need” as opposed to an area where extensive research efforts already are underway.
Industry representatives questioned how FDA would go about advising sponsors on the need for pediatric studies when there are multiple agents in a class being developed against the same target.
“With the more extensive list of targets [comes] the increased importance of the discussion with FDA and reducing the amount of duplicate discussions that may take place,” Janssen’s Wariabharaj said. For example, he said that when there is a class of 10 different agents it would be desirable to avoid a situation in which FDA has 10 separate discussions on the same issue with the sponsors of those agents.
PhRMA’s Vereshchagina said it is essential that FDA provide clarity and predictability on its implementation of the FDARA provisions.
Companies are already planning and making decisions about applications that will be submitted after Aug. 18, 2020, when the FDARA provisions take effect, she said. “Predictability is very important for companies because obviously they’re trying to make those decisions as early as possible in the drug development process.”
Timing of Updates In Question
Stakeholders also questioned how, and how often, FDA would update the list – a matter that was also the focus of extensive discussion at a recent Friends of Cancer Research meeting on the pediatric cancer study provisions. (Also see “Pediatric Cancer Studies: US FDA Promises Flexible Approach On Requirements” – Pink Sheet, 22 Feb, 2018.)
However, FDA has not announced its plans for updating lists.
“This is definitely an internal discussion we’ve been having at FDA: How often do we update the list? How do we update the list? What sort of evidence do we need to be able to update the list,” said Christy Osgood, a medical officer in FDA’s Division of Oncology Products II. “I think it’s going to be a multifactorial process. I don’t think you can say we need to update the list every two months because that might not even be feasible.”
FDA already is using the product applications and investigational new drug applications (INDs) that it sees to inform its thinking about targets for inclusion on the list, Osgood said.
“One way we are updating the list is as new stuff comes in, pediatric reviewers here are actually saying, ‘Is this a target?’” said Osgood. “If you are bringing a new molecular entity to us, we can look at it and say do we think this is a target based on just one application, one IND. … And so, we are trying to update the lists in multiple different ways.”
https://pink.pharmaintelligence.informa.com/PS122982/US-FDAs-Pediatric-…
