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After wrangling all day over semantics and a potential precedent-setting dataset, an FDA advisory committee voted to recommend approval of eflornithine (difluoromethylornithine; DFMO) maintenance for high-risk pediatric neuroblastoma in complete remission after standard therapy.

By a 14-6 vote, the Oncologic Drugs Advisory Committee (ODAC) decided that the totality of evidence presented was sufficient to show that DFMO maintenance improved 2-year event-free survival (EFS). The evidence included a single-arm prospective clinical trial with an external control group, supplemented by several smaller clinical studies and persuasive preclinical data.

"I think the general consensus is that there's a tremendous amount of difficulty interpreting this kind of data in a rare disease and sincere appreciation of the panel for all the work that went into this incredibly robust analysis," said ODAC chair Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora. "There is general agreement that the totality of the data appear to support the assertion that DFMO does improve event-free survival, or at least that the results were more likely than not to be something more than just the result of chance."

"There are clear areas of disagreement within the panel," Lieu added. "That is whether this type of data should really ever be used, given the concern regarding confounders and biases that are just inherent to these external controls. Certainly, there's a lot of concern from the group about what the future holds for drug development and what level of evidence the FDA will require in similar situations in the future.... There is also some disagreement in this group about whether a randomized, controlled trial is potentially feasible and whether it can be done in a timely fashion."

Primary clinical support for the application came from a single-arm trial that included about 100 patients who were in complete remission following standard treatment, which could have included chemotherapy, surgery, radiotherapy, and immunotherapy. The core analysis, a propensity-matched comparison, involved 90 patients from the DFMO trial and 270 patients selected from a large randomized trial of immunotherapy in high-risk pediatric neuroblastoma.

Patients in the two comparative groups received identical treatment with the exception of DFMO. The primary endpoint was 2-year EFS, and data analysis yielded an EFS hazard ratio of 0.48 in favor of DFMO, based on an estimated 70% 2-year EFS derived from the propensity-matched control group. An analysis of overall survival (a secondary endpoint) produced a survival hazard of 0.32 in favor of DFMO.

"I believe the data for event-free survival is compelling, but I don't believe that the efficacy is as high as what's been reported because of the lack of randomization and what I honestly believe is just an inherent bias in an external control, that likely overestimates the benefit of DFMO," said Lieu. "I believe the FDA's additional analyses to deal with these confounding variables were compelling and that they were generally consistent with the primary analysis."

Considering the relatively favorable toxicity profile of DFMO, "I believe that the expected benefits outweigh the risks of treatment here," he added.

The FDA staff prepared for ODAC noted that a randomized trial is the gold standard for clinical trials assessing time to events. However, a well-designed external control is acceptable under certain circumstances. Additionally, a confirmatory prospective clinical trial is the accepted standard for a new drug approval application. Again, as circumstances dictate, other sources of data, including preclinical data, can be used in support of an application.

Several members of the panel expressed concern that acceptance of the data will set a precedent that will lead to future applicants to seek approval without the usual evidentiary requirements. Others speculated that a randomized trial in this disease might be unethical, once the favorable results from the DFMO trial become widely available. Planned and ongoing trials in high-risk pediatric neuroblastoma might not be finished until sometime in the next decade.

Panelist Shahab Asgharzadeh, MD, of Children's Hospital Los Angeles, said the circumstances surrounding the disease calls for flexibility.

"Given that these studies are not like a typical adult study, where you're looking for a 6 months' increase in survival to get FDA approval, these are changes that will affect the child for the rest of their life," he said. "I appreciate that the ideal way to do this would be a randomized clinical trial. [But] the guidelines also suggest that we could use the external control for this purpose. There's flexibility and this should be addressed in this rare population of patients."

The panel also struggled with language of the question posed to them: Whether the applicant (US WorldMeds) provided "sufficient evidence" that DFMO improves EFS. The FDA's Nicole Drezner, MD, said the charge to the panel was to consider the "totality of evidence." The FDA ultimately will determine whether the evidence meets regulatory standards, she added.

The FDA is not bound by advisory committee decisions but usually follows their recommendations.

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