Updated: FDA Reviewing Data Manipulation in Application for Novartis Gene Therapy Zolgensma

Regulatory NewsRegulatory News | 06 August 2019 |  By 

In a statement issued Tuesday, Peter Marks, director of the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER), said the agency is investigating data manipulation submitted in the biologics license application (BLA) for Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec-xioi).
Zolgensma was developed by AveXis, Inc., which was acquired by Novartis in an $8.7 billion deal in April 2018 and was approved last May to treat children ages two and younger with a rare, severe form of spinal muscular atrophy (SMA) caused by a mutation in the survival motor neuron 1 (SMN1) gene.
The gene therapy is considered to be the world’s most expensive drug at $2.1 million, or five annual installments of $425,000. AveXis was also awarded a rare pediatric disease priority review voucher alongside the approval.
According to Marks, FDA was informed by AveXis on 28 June that some of the nonclinical data included in the BLA for Zolgensma was manipulated.
“FDA is carefully assessing this situation and remains confident that Zolgensma should remain on the market. Out of the large amount of submitted information reviewed by the agency, our concerns at this time are limited to only a small portion of the product testing data that was contained in the marketing application,” Marks said.
Marks also said that AveXis was aware of the data manipulation “before the FDA approved the product, yet did not inform the FDA until after the product was approved,” and warned that the company could be subject to civil or criminal penalties.

A Novartis representative referred Focus to a statement released by the company Tuesday evening that emphasized that Novartis is “fully confident in the safety, quality and efficacy of Zolgensma.”
According to a memorandum from Wilson Bryan, director of the Office of Tissues and Advanced Therapies, AveXis was aware of the data manipulation as early as 14 March 2019, more than two months before the BLA was approved. While Bryan states that he believes the BLA would have ultimately been approved, he notes that its approval would have been delayed beyond the Prescription Drug User Fee Act (PDUFA) goal date of 31 May 2019 had the agency been aware of the data manipulation sooner.

In a call with investors on Wednesday, Novartis CEO Vasant Narasimhan said the company launched an internal investigation into the data manipulations as soon as it learned of them in mid-March before launching a “full technical quality investigation” in May. At the conclusion of that investigation, Narasimhan said the company “proactively” notified FDA, as well as European and Japanese regulators of the data manipulation.

Narasimhan also stressed that the company did not delay notifying regulators due to the timing of the BLA.
In the memorandum, Bryan describes the manipulated data as stemming from an in vivo murine potency assay. Bryan writes that this data “was critical in characterizing the comparability between” the versions of the gene therapy administered in the Phase I and Phase III clinical trials.
“The data that were manipulated involve the results of an assay (SOP-285) that was critical in characterizing the comparability between the two versions of the product. The data manipulation seems likely to impact the interpretation of the Phase I clinical trial results, as well as the interpretation of some, but not all, of the nonclinical studies in the original BLA,” Bryan writes.
Bryan notes that he has “no reason to believe” that any other data submitted in the BLA were manipulated and that there is “no evidence that patient clinical data were manipulated.”
After learning of the data manipulation, FDA inspected AveXis’ San Diego, CA facility from 24 July-2 August, handing the firm an inspection report with five observations for issues including failing to thoroughly review unexplained data discrepancies, incomplete laboratory records and failure to follow laboratory test procedures.


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