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Pink Sheet – Pediatric Cancer Studies: US FDA Promises Flexible Approach On Requirements

Pink Sheet – Pediatric Cancer Studies: US FDA Promises Flexible Approach On Requirements

Executive Summary

FDA says it will not be ‘held hostage’ by its list of molecular targets, but patient advocates worry agency will be deterred from requiring assessments for targets not on the list, while industry worries about being surprised by demands for pediatric data.


The US FDA is promising to take a flexible, transparent approach to the development and implementation of new pediatric study requirements for certain cancer drugs under the FDA Reauthorization Act (FDARA).


The agency intends use a transparent process to generate a list of molecular targets potentially relevant to pediatric cancers and will use that list as guidepost in deciding whether sponsors of novel drugs and biologics must conduct studies under the Pediatric Research Equity Act (PREA), FDA staff said at a Feb. 20 meeting sponsored by the Friends of Cancer Research (FOCR).


However, agency officials emphasized that the molecular target list will not amount to the be-all/end-all for determining whether sponsors must conduct pediatric studies of cancer drugs, and they noted the agency has discretion to require studies that don’t involve a listed target.


FOCR convened the meeting to discuss approaches for developing, updating and applying the molecular target lists the agency is required to establish under FDARA.


Discussion at the meeting highlighted the tension between patient advocates and academic clinical researchers eager to speed the development of cancer agents for pediatric use, and pharmaceutical manufacturers leery about testing new compounds in children without adequate data or transparency into FDA’s decision-making process for requiring such assessments.


Several speakers at the FOCR meeting acknowledged the lack of stakeholder consensus on issues related to development of a molecular targets list and its application in pediatric drug development.


“This dirty word, the molecular target list or the relevant target list, was not the idea of the FDA,” said Gregory Reaman, acting associate director for pediatric oncology at FDA’s Oncology Center of Excellence. “This was given to us by our legislators, your legislators. Like many legislated mandates, we’re dealing with some consequences here.”

Molecular Target Lists

FDARA not only reauthorized the prescription and generic drug and biosimilar user fee programs, it included provisions aimed at expanding the reach of PREA to pediatric cancer.


PREA’s impact in pediatric oncology has been limited because adult cancers for which drugs are approved, such as prostate and breast, tend to occur in different organs than childhood cancers. Consequently, most cancer drugs are exempt from PREA study requirements. Drugs with orphan designation, such as those for rare cancers, also have been exempt from PREA.


FDARA required that applications for novel drugs and biologics submitted three years after enactment 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. FDARA also eliminated the PREA exemption for orphan-designated drugs that fall into this category. (Also see “Pediatric Cancer Study Requirements Added To FDA User Fee Bill” – Pink Sheet, 11 Jul, 2017.)


Within one year of enactment, FDA must establish a list of molecular targets “substantially relevant to the growth and progression of a pediatric cancer” and that may trigger study requirements under the provision. The agency also must publish a list of molecular targets for which pediatric cancer study requirements will be automatically waived.


The agency must consult with the National Cancer Institute (NCI), members of the agency’s internal pediatric committee, and the Oncologic Drug Advisory Committee’s (ODAC) pediatric subcommittee in developing the lists. FDA is planning meetings in April and June on development of the target lists. (See box.)

Frameworks For Development …

At the FOCR meeting, representatives from FDA, industry, academia and the patient advocacy community discussed a proposed a framework of factors and characteristics that may guide determination of whether molecular targets are substantially relevant to the growth or progression of pediatric cancer. The framework factors include:

  • Target class;
  • Function and mechanism;
  • Nonclinical evidence;
  • Adult clinical experience;
  • Predictive biomarkers;
  • Target location; and
  • Whether there are agents in development that address the target.

A second proposed framework that may guide the determination of whether molecular targets are not relevant to pediatric cancer takes into account biologic implausibility, nonclinical evidence and evidence of a lack of clinical activity in adults.


Much of the discussion at the meeting focused on the role of the target lists themselves and how FDA might use those lists in deciding whether to require pediatric studies. FDA representatives found themselves having to walk the  line between patient advocates concerned that the proposed framework would limit the agency’s discretion to require studies, and industry representatives worried that the agency would surprise them with requirements for new studies based on the list of relevant targets.


“This framework, while incredibly textured and nuanced and an excellent guidepost, may have the effect of limiting or deterring FDA from issuing assessments for molecular targets not on the list,” said Nancy Goodman, executive director and founder of Kids v Cancer. She noted it will be challenging to keep the list of molecular targets current with the evolving science.


Goodman worried that the framework could be interpreted as requiring an unnecessarily high level of evidence before testing is allow to proceed in children.

“There’s nothing in this statute which requires a target to be on the list. So we don’t interpret that this is a requirement for requiring a pediatric evaluation.” – FDA’s Reaman

“Assessments may be delayed in our pursuit of preclinical data, in particular in vitro which just stakes a long time to generate,” Goodman said. “I hope that when there are cases where the FDA feels that the best thing to do is give kids with unmet medical need access to novel and exciting agents that they’ll feel that skipping this step when appropriate is what they will do. The statute does permit the FDA to make decisions and require assessments whether or not a molecular target is on the list.”


However, Martina Uttenreuther-Fischer, senior clinical program leader in oncology medicine at Boehringer Ingelheim GMBH, said industry needs guidance from FDA on the threshold level of evidence necessary before testing a drug in children.


“You cannot just say I would like to do a trial in pediatric patients and I am doing that trial in pediatric patients,” Uttenreuther-Fischer said. “You have to consider this is a vulnerable population, that you need to have some safety data in adults available, that you need to have some [pharmacokinetic] data in adults available, and that you need to make sure that the target that presumably is a valid target maybe for the adult population also has some validity in pediatrics.”


Seeking to address the concerns from both sides, FDA’s Reaman said the proposed framework should not be viewed as “a completed construction project.”


“Frameworks, to me, allow lots of discussion, negotiation and evaluation of the science that may actually bring this forward. I think having some framework is reasonable,” he said.


“I think the fear that the framework is going to limit the authority of the FDA is not particularly well founded,” he continued. “There’s nothing in this statute which requires a target to be on the list. So we don’t interpret that this is a requirement for requiring a pediatric evaluation, and I think it’s going to require the discussion among regulators, industry, investigators to come to some agreement as to should this be evaluated and how may it best be evaluated.”


Reaman also noted that the focus of FDARA is not on complete pediatric development plans but, rather, on early evaluation of potentially relevant, novel agents. “We’re not trying to make industry or investigators look 10 years or 15 years down the road about where an agent may be in the therapeutic armamentarium of a specific disease,” he said.

… And A Process For Making Changes

The FOCR discussion document also proposed several mechanisms for ensuring that the molecular target lists are updated with the most relevant evidence available. These are:

  • An annual public workshop convened by FDA to discuss potential changes to the molecular target lists;
  • A transparent nomination mechanism during or prior to meetings of the pediatric subcommittee of ODAC; and
  • Creation of a transparent process for clinical investigators or sponsors to request a meeting with FDA to discuss new scientific data related to a target which may warrant a change in its status.


“Continuous review of nominations for potential targets of relevance obtained through any of the opportunities listed may be accomplished by a transparent mechanism where members of the pediatric subcommittee of the ODAC review nominations on an ad hoc basis to inform the FDA as to a target’s potential relevance,” the discussion document states. “Changes made to the list after nomination review could be made immediately and not wait for the next meeting” of ODAC’s pediatric panel.


An industry representative raised several concerns related to how the lists might be updated.


Industry needs a public, fair and transparent process for updating the lists, said Albert Allen, senior medical fellow in the medicines development unit at Eli Lilly & Co. Companies “need to know where they stand on this type of question: Is it something where they’re going to have to do pediatric research? Are they going to have to do the same thing as other competitors are doing?”


“This needs to be workable,” Allen continued,  adding that keeping the lists continuously updated could overwhelm FDA and NCI. He suggested the lists be updated once a year.


However, Nita Seibel, head of pediatric solid tumor therapeutics at NCI, said annual revisions might be too infrequent. “We’re so anxious to move things along, once a year seems long. I would hate for it to be a barrier,” she said, urging support for a fast-tracked process through the pediatric subcommittee of ODAC.


“The law does give FDA the ability to require something that’s not on the list,” Allen responded. “If you’re talking about those studies that are on the cutting edge where you maybe haven’t had that evaluation process, I see that as really the case where FDA would use that authority.”


Allen also raised transparency concerns with the concept of ad hoc review by members of ODAC’s pediatric subcommittee. “If there’s continuous review with the pediatric ODAC, but we don’t know what those communications are and such, it’s not open, it’s not transparent to us and we’re not able to participate,” he said.

“We don’t intend to be held hostage to the list.”  – FDA’s Donoghue

“These are required studies we’re being asked to do. I think industry is willing to do those studies, but we feel like we ought to know why we’re being asked to do them. And if we don’t have access to some of those discussions … this doesn’t feel like it’s a transparent or fair discussion,” he said.


Martha Donoghue, clinical lead for the gastrointestinal cancers team at FDA’s Office of Hematology and Oncology Products, said the agency intends to use the lists as a guide.


“We don’t intend to be held hostage to the list,” she said. If there is a drug in early development that could affect a target, the agency will encourage discussions with the sponsor about pediatric development even if the target is not on the list, she said.


“We have to be flexible in terms of how we view that list as a tool, and I think it’s important to have a transparent process in terms of how” targets are added or removed from the list, Donoghue said. She conceded, however, it may be difficult to completely fulfill this transparency goal because much of the information FDA sees from sponsors is considered confidential.

“I look at this continual kind of dialogue and communication about potential targets as a mechanism to … put things provisionally on a list for discussion as part of the subcommittee of ODAC or other public meeting, because I do share your interest in having this be a discussion that involves all stakeholders before we make substantive changes to the list that may help inform pertinent decisions about where or when not to investigate things in pediatrics,” Donoghue said.


Development of a pediatric study plan should be a process that involves communication between FDA and a sponsor and “there shouldn’t be any surprises,” Donoghue said. “I don’t think we’re doing our job if we’re dropping … a requirement into somebody’s lap without any discussion and negotiation.”…