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An FDA advisory committee will wade into a complicated comparison of a high unmet need in oncology versus uncertainty about whether a drug has "substantial evidence" of effectiveness.

At the center of the balancing act is an approval application for eflornithine (difluoromethylornithine; DFMO) for high-risk pediatric neuroblastoma. The Oncologic Drugs Advisory Committee (ODAC) will weigh in on whether a single, well-designed prospective study with an external control group -- plus nonclinical, exploratory, and expanded-access data -- constitutes sufficient evidence to recommend approval.

Randomized controlled trials are the gold standard for evaluating time-to-event endpoints, FDA staff members noted in their . However, data from the large prospective single-arm trial produced data suggesting "substantial improvement over a benchmark historic control."

"The use of an externally controlled trial to support a marketing application may be acceptable in the setting of a rare disease with a well-defined natural history and poor prognosis if the expected treatment effect is estimated to be large, particularly in a setting where conduct of an RCT [randomized controlled trial] may be infeasible," FDA staff wrote.

"There are inherent limitations in interpreting the estimated treatment effect of a single nonrandomized, externally controlled trial," they added. "These potential biases may impact the estimated treatment effect in ways that may not be directly quantifiable."

In 2019, the FDA issued for demonstrating "substantial evidence of effectiveness." The guidance stated that "in general, substantiation of a drug's effectiveness obtained with two trials, especially with complementary design, will provide more convincing evidence of effectiveness than would a single trial ... Under certain circumstances and consistent with FDAMA [the FDA Modernization Act of 1997], FDA can conclude that one adequate and well-controlled clinical investigation plus confirmatory evidence is sufficient to establish effectiveness."

"Given the reliance on a single externally controlled clinical trial, the additional nonclinical and clinical data submitted by the applicant are particularly important to support efficacy in this application," FDA staff noted in summarizing the issues surrounding the application. "FDA considers independently conducted nonclinical data as well as clinical data from early-phase studies and an expanded-access program provided by the applicant to be sources of potential confirmatory evidence."

The fact that DFMO is a cytostatic agent, as opposed to cytotoxic, further complicates evaluation of efficacy, staff added.

In its , applicant US WorldMeds emphasized the quality of the data submitted, adherence to FDA data criteria, the demonstration of a substantial improvement in event-free survival (EFS) with DFMO in the prospective clinical trial, and the lack of effective options to prevent neuroblastoma relapse, which has a poor prognosis.

"The relapse risk reduction and long-term survival benefits from DFMO maintenance therapy in patients with HRNB [high-risk neuroblastoma] who achieve remission greatly outweigh the risks" which can be managed or mitigated with dose modification or reduction, the company wrote. "There is substantial evidence that DFMO extends remission, reduces the risk of relapse, and increases durable long-term survival beyond what is possible with upfront SoC [standard of care] alone -- enabling more young patients with HRNB to survive into adulthood and live full lives."

Primary support for the application came from a of DFMO maintenance therapy for 105 patients in complete remission following upfront therapy (consisting of chemotherapy, surgery as indicated, consolidation as indicated, radiation therapy as indicated, or antiganglioside 2 antibody therapy). After completing 2 years of DFMO maintenance, patients were followed for an additional 5 years. The primary endpoint was EFS at 2 years.

External came from a large, multicenter, randomized trial comparing immunotherapy plus standard therapy versus standard therapy for patients with newly diagnosed high-risk neuroblastoma in at least partial remission after induction and consolidation therapy. On the basis of this trial, the benchmark EFS for the phase II trial of DFMO was 70%. The comparison included 270 patients with complete information from the multicenter randomized trial propensity matched with 90 participants in the DFMO study.

Comparison of the DFMO results with those of the randomized trial produced an EFS hazard ratio of 0.48 and an overall survival hazard ratio of 0.32 in favor of DFMO. In general, sensitivity and supportive analyses yielded similar results, according to FDA staff.

Notable adverse events associated with DFMO were changes in liver function tests, myelosuppression, and hearing loss.

ODAC will convene at 9:30 a.m. ET Wednesday, and the meeting can be .

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