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Pink Sheet – Pediatric Drug Development A Priority For US FDA’s New Oncology Center Of Excellence

Pink Sheet – Pediatric Drug Development A Priority For US FDA’s New Oncology Center Of Excellence

Executive Summary

Existing regulatory authorities could be optimized to speed development of promising pediatric cancer therapeutics, particularly those that don’t work in adult cancers.


Accelerating the development of pediatric cancer therapeutics and diagnostics will be a key focus for the US FDA’s new Oncology Center of Excellence (OCE).


“As part of the newly formed Oncology Center of Excellence, one of our top priorities is to do what we can to help move pediatric oncology drug development forward,” Division of Oncology Products 2 Acting Associate Director Martha Donoghue said Feb. 21 at a Friends of Cancer Research meeting on pediatric drug development.


“We have at last count now about 17 or 18 pediatric hematologists/oncologists on staff” with varying areas of expertise, and “we are all committed to doing our part as regulators and as resources to the pediatric oncology community … to move things forward.”

“We do not want to be barriers” to the pediatric drug development process, FDA’s Donoghue said.

Donoghue’s comments suggest an early focus for the OCE, a new center that will leverage the regulatory and review expertise across FDA’s medical product centers. OCE is aimed at expediting the development of oncology and malignant hematology-related medical products and supporting an integrated approach in the clinical evaluation of drugs, biologics and devices for cancer.


OCE’s creation was announced in June as part of the federal Cancer Moonshot Initiative. At that time, FDA Office of Hematology and Oncology Products (OHOP) Director Richard Pazdur was named as acting director. (Also see “FDA’s Pazdur Jumps Over To New ‘Moonshot’ Role” – Pink Sheet, 29 Jun, 2016.)


FDA has since removed the “acting” from Pazdur’s title. On Jan. 19, then-FDA Commissioner Robert Califf announced OCE’s formal launch and Pazdur’s appointment as the center’s permanent director. The announcement came on Califf’s last full day as commissioner and was part of a rush of FDA operational and regulatory news ahead of the Jan. 20 inauguration of President Donald Trump. (Also see “FDA’s Document Dump: Guidance Release Skyrockets Ahead Of Trump’s Arrival” – Pink Sheet, 22 Jan, 2017.)


Pazdur is expected to retain his duties as OHOP director. (Also see “FDA’s Pazdur To Retain Drug Approval Duties In Oncology Center Of Excellence” – Pink Sheet, 7 Nov, 2016.)

Center Organization Still A Work In Progress

Despite the official launch announcement, FDA has publicly shared few details about the new center’s operating framework and structure. “FDA is taking important steps to formalize the structure and implementation of the OCE as part of its overarching effort to better address the needs of cancer patients, through reorganization within the FDA’s Office of Medical Products and Tobacco,” Califf’s Jan. 19 announcement states.


It seems that even those on the inside aren’t yet exactly sure what the new center will look like. “That structure of the OCE isn’t made public yet and, frankly, I don’t know a lot of the information myself,” Donoghue said. “But I do know that one thing that we’re prioritizing is trying to increase the efficiency of working between centers.”


For example, she noted that pediatric devices and in vitro diagnostics is “a huge area of unmet medical need” and will be a focus for greater intra-agency collaboration and coordination under OCE. “I do think that what will come out of this new system is more streamlined and more open and unified communication from the agency on these issues, because we recognize that development plans really require … coordination with all of those aspects, and that’s something we’re giving priority to.”

Optimizing Existing Regulatory Authority …

The Friends of Cancer Research meeting served as a forum for discussion on use of master trial protocols as a way to overcome challenges inherent in pediatric cancer drug development.


Among FDA speakers at the meeting, a common refrain was the agency’s desire to maximize its regulatory authority in a way that serves not as a roadblock but, rather, helps move development of new pediatric cancer therapeutics forward more quickly.


The agency staffers’ comments to a generally friendly audience may be viewed as a counterpoint to President Donald Trump’s view that FDA is not doing enough to accelerate drug approvals and his announced, but still unspecified, plans to streamline the agency and lift some of industry’s regulatory burdens. (Also see “Trump Promises Changes To ‘A Lot Of Rules’ At US FDA” – Pink Sheet, 31 Jan, 2017.)


“We’re cognizant of the fact that we do not want to be barriers” to the pediatric drug development process “and we want to do what we can to help promote the process,” Donoghue said. “Part of that is leveraging our existing regulations which are primarily incentive programs and we are working on doing that to the best of our ability.”


FDA has been “very proactive in promoting a collaborative approach to timely pediatric drug development,” said Gregory Reaman, OHOP associate director for oncology sciences.

Written requests can be used to spur and reward innovative trial designs and development strategies.

“We can only do what we are authorized to do by legislation. We have no other mechanism by which to operate,” Reaman said. “But we can optimize as best we can that regulatory authority, so we have been proactively attempting to identify new, promising products, engage with industry and academia early, as well as advocacy groups to study these promising products and hopefully harnessing regulatory science.”


The agency wants industry sponsors to start conducting pediatric studies earlier in a drug’s development. Ideally, pediatric studies should be initiated immediately following adult Phase I studies if a scientific rationale for pediatric use exists, Reaman said. “We’re not quite there yet,” but we’re “getting closer.”


Toward this end, FDA has been issuing written requests for studies under the Best Pharmaceuticals for Children Act (BPCA) earlier in the development process. Sponsors who complete studies in response to a BPCA written request are eligible for six months of marketing exclusivity for an approved drug.


In the past, written requests often were not issued until after drug approval. “We’re now trying to issue written requests before new drug applications come in,” Reaman said.

Written requests also can be used to spur and reward innovative trial designs and development strategies.

“We’ve actually issued a written request to a sponsor for embedding a pediatric trial in an adult study that will probably only accrue a handful of patients, so I think this is really pretty novel,” Reaman said.

… While Eyeing An Expansion Of PREA

Reaman bemoaned the lack of impact that the Pediatric Research Equity Act (PREA) has had on pediatric cancer drug development. Under PREA, FDA can require studies in pediatric populations specific to the adult indication for which the drug is under review.


“The unfortunate thing is it applies only to indications included in the submission,” Reaman said. In addition, “drugs with orphan designation are exempted from PREA. Forty percent of new oncology products in the last three years have received orphan designation.”


“Essentially PREA has no relevance to pediatric cancer,” Reaman said, although the agency would like to see this dynamic change.


“Expanding the authority of PREA is clearly something that we’ve talked about,” Reaman said. “Requiring studies based on molecular mechanism of action could certainly increase the number of pediatric studies under PREA.”


Legislation introduced in the House and Senate in 2016 would do just that; the RACE for Children Act would require pediatric studies based upon a drug’s molecular target and eliminate the pediatric study exemption for drugs approved in rare adult cancers. (Also see “Pediatric Study Requirements For Cancer Have FDA Support, But Pose Industry Challenges” – Pink Sheet, 3 Aug, 2016.)


Although the companion bills never made it out of their respective committees in the House and Senate, they are expected to be reintroduced soon and could find their way into legislation reauthorizing the prescription and generic drug, biosimilar and device user fee programs that must be enacted before the existing programs expire Sept. 30.

Drugs Without An Adult Indication

Most pediatric cancer drug development is inextricably tied to use in adults, but there currently is no “legislative fix” for investigational agents whose usefulness is limited to the pediatric setting, Reaman said.


While there are “very meaningful and early incentives to industry,” such as the pediatric rare disease priority review voucher program, these “require more evaluation,” Reaman said.


FDA is not a fan of the pediatric rare disease and tropical disease priority review voucher programs, saying that they have adversely impacted its ability to set public health priorities and effectively manage its workload. (Also see “Review Voucher Program For Rare Pediatric Diseases Should Not Be Reauthorized, FDA Says” – Pink Sheet, 2 Mar, 2016.) Although FDA did not support reauthorization of the pediatric rare disease voucher program, Congress renewed it until 2020 as part of the 21st Century Cures Act and also established a new voucher program for medical countermeasures. (Also see “The Evolution Of 21st Century Cures Legislation” – Pink Sheet, 29 Nov, 2016.)

The Orphan Drug Act’s incentives are “not adequately taken advantage of in pediatric cancer.” – FDA’s Reaman

Sarepta Therapeutics Inc.’s recent sale of a voucher for $125m suggests the growing number of vouchers awarded by the agency could be depressing their value on the open market. (Also see “Gilead Buys Its Third Priority Review Voucher, But Is The Mania Over?” – Pink Sheet, 21 Feb, 2017.)


A better option for incentivizing novel pediatric drug development may be found in optimizing the Orphan Drug Act, “which in my opinion is not adequately taken advantage of in pediatric cancer,” Reaman said. The Orphan Drug Act provides a host of financial incentives, seven years of marketing exclusivity and more regulatory flexibility, he noted.


“I think this is something that really could benefit pediatric drug development particularly since nearly 40% of all oncology products are designated orphan drugs, and what could be a bigger orphan than children?”


Donoghue urged sponsors to talk to FDA early about the designing the most efficient drug development program possible, particularly in cases where an adult indication is not being pursued.


“We want to be resources to help small companies [and] big companies that may have a first-in-pediatric drug that may not work for any adult cancer figure out a feasible way to move their drug development forward in a way that that can be accomplished,” Donoghue said.


“And that doesn’t necessarily mean a clinical trial of 100 patients,” she continued. “If we have a drug that we think will work and has a big signal and it’s for a rare cancer, it may not and should not require studying 100 patients or more. It really just depends. And I think early communication with us, helping us partner with you in designing the most efficient drug development program possible, is a top priority for us.”…