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Pink Sheet – Project Pragmatica: US FDA’s OCE Initiative Aims To Encourage Simple Clinical Trials

Pink Sheet – Project Pragmatica: US FDA’s OCE Initiative Aims To Encourage Simple Clinical Trials

Richard Pazdur likely did not surprise anyone when he complained to Friends of Cancer Research Annual Meeting attendees that oncology clinical trials are too complicated. But the director of the US Food and Drug Administration’s Oncology Center of Excellence got a few laughs when he announced his solution.

“Well of course we have to launch another project,” Pazdur said.

Project Pragmatica, the latest of a growing number of OCE “projects,” will involve a clinical trial whose only endpoint will be overall survival in the hopes of encouraging more of the same going forward.

“We’ve made these trials just way too complicated. Just mind-boggling complicated,” Pazdur said during the 17 November FOCR event.

“I think we have to simplify trials,” he added. “This field is evolving so fast. We have to answer the questions relatively rapidly.”

The idea emerged from a proposal that was included in the Lung Cancer Master Protocol (Lung-MAP) trial, an ongoing study in advanced non-small cell lung cancer. Lung-MAP’s umbrella structure allows several drugs to be tested at the same time and in patients most likely to benefit.

Pazdur said a trial of ramucirumab and pembrolizumab versus standard of care won on overall survival, “however there were problems with the trial, the alpha allocation. It really wasn’t meant to be a registration trial.”

“I thought this would really be a great idea to kind of do a pragmatic trial,” he said. “Here again preserving randomization, but making it as simple as possible.”

“What we discussed with the [National Cancer Institute] is basically having really only one endpoint of the trial and that is overall survival,” Pazdur added. “Just give me the data of date of randomization to date of death.”

NCI also should deepen its relationship with oncology sponsors and consider handling US enrollment of clinical trials for novel products, Pazdur said during the meeting. (See sidebar.)

No Extensive Safety Reporting Necessary

The trial is testing the combination in stage IV or recurring non-small cell lung cancer, but will not require extensive safety reporting.

“I’m not interested in the safety of these drugs,” he said. “If we don’t know the safety of pembrolizumab at this time after being used, I think, on a million patients worldwide, we better fold up our shop here so to speak and likewise for the other drug.”

The design also will allow more patients to participate, Pazdur said.

“I don’t care about their BUN [blood urea nitrogen], I don’t care about their renal function, I don’t care about their platelet count, I don’t care about their hemoglobin,” he said. “So very minimal eligibility criteria and basically no safety reporting other than for hospitalizations or toxicities that are not described in the safety endpoint.”

NCI Director Monica Bertagnolli said the trial will not include “a lot of things that we kind of have a knee-jerk reaction and just put into our studies because often that’s what we’ve done.”

The Project Pragmatica trial design began in July. Bertagnolli said during the meeting that it would be going to the central institutional review board that day and will open in January 2023.

“That is amazing,” she said. “This is what we need.”

Many FDA officials regularly call for a streamlining of the clinical trial infrastructure, to eliminate bureaucracy and duplication and increase collaboration. (Also see “FDA’s Pazdur Believes ‘Advanced Research’ Project Could Address Trial ‘Wastefulness’” – Pink Sheet, 2 Aug, 2021.)

OCE Projects Target Many Areas Of Clinical Development

The list of OCE projects attacking various concerns with drug development in the field continue to grow.

Project Site Selector was launched earlier this year to determine why sponsors are increasingly using foreign clinical trial sites and potentially entice more enrollment of US patients.  (Also see “US FDA’s Project Site Selector Kicks Off With A Look At Why Cancer Trials Go Overseas” – Pink Sheet, 1 Aug, 2022.)

Project FrontRunner encourages sponsors to use randomized control trials and develop products outside the refractory setting.  (Also see “Cancer And Accelerated Approval: FDA To Crack Down On Single-Arm Trials, Refractory Disease Focus” – Pink Sheet, 10 Jun, 2022.)

Project Equity is intended to improve clinical diversity (Also see “US FDA Calls For Clinical Trial Diversity Plan ‘As Soon As Practicable’ In Product Development” – Pink Sheet, 18 Apr, 2022.), while Project Catalyst was launched to provide small companies help and educational resources to make cancer treatments available sooner.

Project Significant provides a forum for stakeholders to discuss the design and analysis of oncology clinical trials and Project Silver will help increase the representation of adults age 65 and older in clinical trials.

Project Protect will ensure sponsors receive consistent advice and review of oncology drug safety signals, while Project Optimus will help improve dose optimization and dose selection.  (Also see “US FDA Project Protect Oncology Safety Program In Broad Use After Quiet Launch” – Pink Sheet, 28 Mar, 2022.)

And Project Orbis is intended to increase oncology treatment availability by allowing other countries to review participating applications at the same time as US regulators.  (Also see “Project Orbis Nears 30 Approvals In Oncology; Could China Be Added?” – Pink Sheet, 8 Sep, 2021.)