PDUFA VI: Innovative Trial Design Proposal Includes Modeling, Simulation

Executive Summary

FDA and industry appear interested in creating systems for testing simulation and modeling approaches to clinical trial design as part of PDUFA VI.

Both are among potential enhancements to the prescription drug user fee program renewal and could help sponsors deploy novel trial designs more easily as well as allow some more certainty that FDA will accept them.

“Model-informed drug development,” which FDA described as “pharmaco-statistical models derived from preclinical and clinical data sources,” could be among the new trial design ideas included in the new PDUFA commitments.

The approaches could help inform regulatory decisions, such as patient selection for clinical trials, individualized dosing in specific patient populations, and the need for post-marketing studies, the agency said during a Nov. 18 PDUFA VI Regulatory Decision Tools Subgroup meeting, according to minutes (PDF).

Both industry and FDA proposed holding public workshops on modeling and developing guidance along with Manual of Policies and Procedures (MaPP) or Standard Operating Policies and Procedures documents for agency staff during PDUFA VI.

FDA also proposed a pilot program with a “limited number” of INDs involved where sponsors could have dedicated meetings “to discuss the development and application of models and simulations,” such as for disease progression or concentration response, according to the minutes.

If added to the PDUFA VI commitment letter, the innovative trial designs language would continue efforts to earmark user fee revenue to support regulatory science and streamline drug development.

The PDUFA V commitment letter included goals to enhance meta-analyses methods and the use of biomarkers and pharmacogenomics, as well as the advancement of patient reported outcomes (“PDUFA V: Final Recommendations Fund Proposals In Two Of Three Tiers” — “The Pink Sheet,” May 2, 2011).

The agency has long been flexible with clinical trial designs, particularly when determining drug efficacy in the rare disease setting (“FDA Orphan Approval Flexibility Remains Steady As Pressure Increases” — “The Pink Sheet,” Oct. 27, 2014).

Simulation Approaches Considered

Discussions also covered PDUFA changes “intended to advance simulation approaches that can support innovation and regulatory evaluation of novel complex clinical trial designs.”

In addition, the proposal could “clarify for sponsors FDA expectations for simulations needed to adequately characterize the performance of these complex trials,” according to the minutes.

Just like with the modeling proposal, FDA and industry representatives suggested scheduling a public workshop and developing guidances and MaPPs for agency staff on simulation approaches.

Industry also said it wants “more explicit processes for FDA to review and discuss a sponsor’s use of innovative clinical trial designs,” according to the minutes.

FDA proposed a pilot program for “highly innovative trial designs” where simulations are needed to determine operating characteristics.

It would include a limited number of INDs and allow dedicated meetings with the sponsor to discuss agency expectations and its review of the simulations, according to the minutes.

Industry also wanted what appeared to be a more structured process for the innovative trial design discussions, but FDA said requiring a Type B meeting timeframe or a Special Protocol Assessment process likely would not be feasible (“PDUFA VI: Innovative Trial Design Talks Can’t Have Formal Meeting Goals, FDA Says” — “The Pink Sheet” DAILY, Nov. 30, 2015).

Staffing Will Be A Focus

For both clinical trial proposals, agency officials reminded industry representatives that it would need specialized staff and additional regulatory science and review capacity, according to the minutes.

Hiring is emerging as a major theme in the PDUFA renewal discussions.

FDA plans call for adding staff to address its workload demands during the next PDUFA cycle.

The PDUFA VI Reauthorization Steering Committee reviewed government hiring practices during a Nov. 10 meeting, along with FDA efforts to streamline and enhance its efforts to recruit and retain staff.

FDA said it already plans improvements to its position classification process and position management system, contractor capacity support to human resources, and “a new function dedicated to scientific staff recruitment and retention,” according to the Nov. 10 meeting minutes (PDF).

The Center for Drug Evaluation and Research has about 680 openings, including several executive positions, director Janet Woodcock said Dec. 14 during the FDA-CMS Summit.

But agency recruitment suffers from a lengthy hiring process and a pay scale that is limited compared to industry.

Richard Pazdur, director of the Office of Hematology and Oncology Drug Products within CDER’s Office of New Drugs, has suggested focusing on academic rather than industry candidates to fill openings (“FDA Talent Hunt: Is Recruiting From Academia Better Than Industry?” — “The Pink Sheet,” Nov. 30, 2015).

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