Executive Summary

Pilot program that gives agency early look at pivotal data has forced sponsors to change how they go about preparing supplemental applications; potential expansion to new molecular entities would bring new challenges, including need to align manufacturing and clinical site inspections with expedited review timeline.

The US FDA’s Real-Time Oncology Review (RTOR) pilot program has required participating sponsors to change how they prepare and submit supplemental applications, but these challenges have come with some big payoffs, including greater certainty about application acceptance and review times that can be counted in days and weeks, as opposed to months.

While RTOR currently is being piloted for only the most straightforward supplemental applications, future expansion to more complex supplements or to new molecular entities (NME) could bring a host of additional challenges for the agency and sponsors, including the need to rethink how early companies should share information with FDA.

During a panel discussion at the Friends of Cancer Research (FOCR) annual meeting Nov. 13, representatives from industry and FDA discussed their experience to date with the Oncology Center of Excellence’s (OCE) RTOR and Assessment Aid (AAid) pilot programs. (See sidebar for story.)

FDA Commissioner Scott Gottlieb announced the initiatives at the American Society of Clinical Oncology annual meeting in June. (Also see “Gottlieb Uses ASCO Platform To Unveil Two Pilot Programs To Speed Drug Review” – Pink Sheet, 3 Jun, 2018.) Both programs are aimed at improving review quality and efficiency and expediting drug approvals.

Why Use RTOR?

RTOR grew out of the recognition that early engagement with sponsors is key to ensuring fit-for-purpose marketing applications, while also enabling the agency to front-load some review activities, FDA officials said.

OCE Director Richard Pazdur, who also serves as acting director of the Office of Hematology and Oncology Products, described RTOR as a “logical extension” of application orientation meetings with sponsors that occur shortly after NDA/BLA submission, but in a way that allows FDA to get a jump on reviewing the key clinical data before the full application comes in the door.

“Why can’t we read the data while the company is spending laborious efforts at getting all of their reports together, having every vice president of the company sign off on them … before they submit it to the FDA,” Pazdur said, describing the thinking behind the program.

Speeding up the approval process is an inherent but secondary goal of the program, said Pazdur, who maintained the primary focus is really on whether the data package will be sufficient to support a forthcoming application.

“No company wants to have a refuse to file, that’s for sure,” Pazdur said. “By looking at this data before it’s even submitted, we can simply call up the company and [say], ‘Look, you got problems here with this data package. We cannot analyze it.’ Rather than submitting it and having arguments with us regarding whether this should be filed or not, let’s just have that discussion up front.”

He contrasted RTOR, which focuses on an early look at the clinical data, with the rolling submission process, under which nonclinical, manufacturing and other components of an application are usually submitted ahead of pivotal clinical data.

“No reviewer wants to spend months looking at a clinical pharmacology application and writing it up … only to find that the application will not be submitted because the clinical trials failed,” Pazdur said. “That was one of the rate-limiting steps behind rolling reviews … we have to wait for the clinical portion.”

What Is The RTOR Pilot?

• Explores a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while maintaining and improving review quality and balancing the review team’s workload through data and analysis standardization, and early iterative engagement with the applicant.
• Allows for submission of key efficacy and safety tables/figures and datasets, proposed labeling and other information, prior to complete dossier submission.
• Open to supplements for oncology drugs and biologics likely to demonstrate substantial improvements over available therapies (such as those with breakthrough therapy designation), that have straightforward study designs and endpoints that can be easily interpreted.
• Excludes applications for NMEs and supplements involving chemistry, manufacturing and controls formulation changes, real-world evidence, pharmacology/toxicology data or companion diagnostics.

Early Package Submission

Once the clinical trial database is locked and top-line data are available, an applicant can request participation in the RTOR pilot by sending a request to the relevant FDA review division, which will respond within two weeks, said Qi Liu, a team leader in the Office of Clinical Pharmacology and a member of the OCE team that developed the pilot program.

If FDA grants the applicant’s request, an initial RTOR meeting will take place in about two weeks, at which FDA and the company will discuss logistics and come up with a tentative submission plan.

An early package submission for RTOR occurs approximately seven to 10 weeks prior to NDA/BLA submission. (See box) Participation in the pilot program also involves standing conference calls between agency reviewers and the sponsor.

To date, supplemental applications for four products have been approved under the RTOR pilot, the most recent being FDA’s Nov. 16 approval of Seattle Genetics Inc.’s Adcetris (brentuximab) for first-line treatment of peripheral T-cell lymphoma. (Also see “Keeping Track Of Approvals: Cancer, Cancer, And A Two-Week Cancer Review” – Pink Sheet, 18 Nov, 2018.)  Two of the four RTOR approvals also went through the AAid program (See chart, below.)

All of the approvals in the RTOR pilot have come ahead of the applications’ user fee dates, with approval times ranging from 11 days to five months after submission. In the case of Novartis AG’s Kisqali (ribociclib), FDA approved the supplement the same day it accepted it for filing and priority review.

Feedback from review teams and companies involved in the pilot has identified early engagement as a key to success because applicants have had to change their preparation order for different parts of the application, Liu said. Clear communication has been another important factor, both internal to FDA regarding expectations and timelines, and with sponsors about the type of information needed and when, she said.

Industry Goes ‘All In’

Representatives from Merck & Co. Inc. and Novartis, two of the earliest participants in the RTOR program, also shared their experiences at the FOCR meeting.

When FDA invited Merck to participate with a supplemental application for Keytruda (pembrolizumab), “we were all in,” said Jonathan Cheng, vice president and oncology therapeutic area head.

The program resulted in more streamlining and improved efficiency on the company’s end, Cheng said, noting that the program requires sponsors to rethink their processes for submission and the speed with which they prepare the components of an application.

“There is a cost. … Asking a group to do things twice as fast is not a zero-sum game.” – Merck’s Cheng

When it came to having to provide SDTM datasets for the RTOR early package submission, “rather than do it in a few months like we normally do, we were asking our statistical group to do it in a few weeks,” Cheng said. “And so at first they say, ‘Excuse me?’ And then they say, ‘Yes, this is the opportunity.’”

Novartis also faced challenges when it came to adjusting its submission preparation processes.

“We went in wholeheartedly understanding that it was going to be difficult for our team to change the way that we set up our submission processes,” said Jiten Rana, Novartis’ global program regulatory director. “We had to come up with new ways to submit. We had to understand what the regulatory implications would be, even from an operations perspective.”

The effort put in by sponsors is not trivial, Merck’s Cheng emphasized.

“There is a cost,” he said. “We, like our friends at Novartis, had to invent to new processes, and asking a group to do things twice as fast is not a zero-sum game.”

Where To Next?

The complexities under RTOR are likely to build as FDA and industry eye a potential expansion of the program.

A multi-stakeholder white paper developed by representatives from FDA, industry and a patient advocate proposes expanding the pilot in a stepwise approach as the agency and sponsors gain more experience with the front-loaded application process.

The paper suggests the next phase of the pilot could encompass supplemental applications involving more complex clinical trial designs, more challenging endpoints and simple scenarios involving companion diagnostics. After the agency gains experience with complex supplemental applications, FDA could expand eligibility to simple breakthrough-designated NME applications, the paper proposes.

Expanding RTOR to NMEs would raise important new considerations, including the need to align manufacturing processes and inspections, clinical site inspections, and Office of Prescription Drug Promotion review activities.

However, expanding RTOR to NMEs would raise important new considerations, including the need to align manufacturing processes and inspections, clinical site inspections, and Office of Prescription Drug Promotion activities to ensure earlier submission and review of marketing materials for accelerated approval drugs.

The manufacturing and quality issues were of particular concern to industry and FDA representatives on the panel given the challenges that some sponsors of breakthrough-designated products have encountered in getting the quality side of their operations to keep pace with the accelerated clinical development. (Also see “Breakthrough Designation Is A Two-Way Street, FDA Cautions Sponsors” – Pink Sheet, 29 Jun, 2015.) (Also see “EMA, FDA To Address Quality Issues For PRIME/Breakthrough Designation Products” – Pink Sheet, 31 Jul, 2018.)

The manufacturing challenges that could come with an RTOR expansion may be more manageable for large companies with their own manufacturing facilities than for smaller companies that rely primarily on contract manufacturers, said Giuseppe Randazzo, acting director of the Office of New Drug Products within FDA’s Office of Pharmaceutical Quality.

Early and frequent communication with FDA about the status of a sponsor’s manufacturing operations and quality testing has been an important lesson from the breakthrough therapy experience, Randazzo said. In addition, the earlier FDA can get facility information, the earlier it can start lining up site inspections, he said.

Industry representatives suggested the need for a framework to guide sponsors on how to prioritize work on the product quality/CMC side under RTOR.

Karen Jones, vice president and global head of the product development faster filing office at Genentech Inc. and Roche, suggested sponsors may need to begin such planning on the quality side even before pivotal trial results are in hand.

Under the current RTOR timeline, a sponsor sees the clinical data then has a conversation with FDA to find out if it’s going to be accepted, with the idea being that the regulatory process will accelerate from that point, Jones said. “I think the reality is … you have to actually make decisions within the organization even before the data comes in if we’re going to try to make some of these timelines.”

“We need to be able to launch these molecules” at the time of approval, Jones said. “The last place you want to be is having an FDA approval and not being able to launch.”

Pazdur suggested that top-line pivotal efficacy results should be the trigger for interactions under RTOR.

“It may pay when you know the top-line results to contact us immediately because all of our interests are based on big effect size or unmet medical need,” he said. “If we know that from the very beginning, even before you have your data lock, before you even clean the data, generally these don’t disappear.”

Such a phone call could start the process for planning manufacturing and clinical site inspections, Pazdur said. “The manufacturing and the clinical discussion are something that have to be planned out. These are rate limiting steps” that would benefit from additional lead time for the agency.

“We need to consider what data would we share prospectively that we don’t already share today, that would actually help the FDA do their job” sooner, Jones said.

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