Novartis Admits to ‘Mistake’ After Partial Clinical Hold Placed on Zolgensma Trial

Regulatory NewsRegulatory News | 31 October 2019 |  By 

Novartis on Wednesday said that the US Food and Drug Administration (FDA) placed a partial hold on intrathecal clinical trials of its gene therapy Zolgensma (onasemnogene abeparvovec-xioi) for spinal muscular atrophy (SMA) patients based on findings in a small preclinical animal study.
On Thursday, a Novartis spokesperson told Focus that a draft report of the preclinical safety findings was presented to the AveXis safety management team last March and the company “determined at that time that the safety finding should be included in the annual update of the investigator brochure planned for September 2019. Unfortunately, a mistake was made, and this update was not implemented.”
The omission was later identified as part of a Novartis review related to the Form 483 response from August, and the spokesperson told Focus, “This omission was identified and the issue quickly assessed and managed pursuant to existing Novartis safety processes and we notified health authorities and clinical trial investigators.”
But the spokesperson also said that Novartis notified investigators and FDA at the end of last week on the findings and was notified about the partial clinical hold earlier this week.
The company also stressed that the partial hold does not impact the marketing of Zolgensma or some other clinical trials.
“This was a small, AveXis-initiated pre-clinical study in which animal findings showed dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss. The trial involved 12 non-human primates,” the Novartis spokesperson said.
The clinical significance of the DRG inflammation observed in this pre-clinical animal study is not known and was not seen in prior animal studies, the company added. “We will continue to closely monitor for any reports of related safety events in patients,” Novartis said. “We will work diligently with FDA to identify any additional actions necessary to resume dosing in the AVXS-101 intrathecal clinical trials.”
In August, Novartis ran into trouble with FDA when data manipulation was uncovered in the Zolgensma application, although the manipulation did not affect FDA’s assessment of the gene therapy’s safety or efficacy. Questions related to the timeline of the uncovering of the manipulation were also raised.


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