Novartis submitted manipulated data in its application to the Food and Drug Administration for the gene therapy Zolgensma, the agency revealed Tuesday, stating the drugmaker knew of the problem but failed to tell regulators before the treatment's approval.
The FDA affirmed that Zolgensma should remain on the market and reiterated its confidence in the therapy's clinical results. But an agency memo noted that had the regulator been informed of the data issues prior to its approval, it would have delayed its decision in order to further investigate the manipulation and its effects.
Zolgensma's OK, granted May 24 for infants with a deadly inherited disease called spinal muscular atrophy, was a major milestone for both Novartis and the gene therapy field. At a price of $2.1 million, Zolgensma is also the most expensive treatment ever brought to market, giving it an even higher profile than its billing as a potential cure.
"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," said Peter Marks, head of the FDA's Center for Biologics Evaluation and Research, in an August 6 statement.
Yet the FDA still took the rare step of noting it would use its "full authorities" to take action against AveXis, the Novartis unit which developed Zolgensma, if warranted by an ongoing assessment. Such action could include civil or criminal penalties, the agency said.
"We maintain that the totality of the evidence demonstrating the product's effectiveness and its safety profile continue to provide compelling evidence supporting an overall favorable benefit-risk profile," said Novartis in a statement.
At issue is an assay used to compare a version of Zolgensma used in Phase 1 testing with a later version administered in ongoing Phase 3 trials. In between, Novartis changed how it made Zolgensma and needed to prove to the FDA the two versions had similar therapeutic activity.
According to the FDA's memo, AveXis manipulated results from that test, an intervention that "seems likely to impact the interpretation of the Phase 1 clinical trial results" as well as those from some nonclinical studies included in Novartis' application.
The assay was used in mice to assess the potency of Zolgensma. It's not currently used to release product lots of the current version of Zolgensma, the FDA said.
Still, the Phase 1 data Novartis submitted to win clearance of Zolgensma were a particularly crucial part of its application. In the study, called START, 15 infants with the most severe form of SMA were treated with Zolgensma. All remained alive and off permanent ventilation at two years, a milestone almost never achieved in untreated patients.
In the memo, Wilson Bryan, head of the FDA's Office of Tissues and Advanced Therapies, noted that both the Phase 1 and Phase 3 versions of Zolgensma use the same vector and therapeutic gene, giving him confidence the clinical results from Phase 1 confirm the effectiveness of the Phase 3 product.
AveXis first learned of the data manipulation as soon as mid-March, the FDA said, but did not inform the FDA of the issues until June 28, more than a month after Zolgensma's OK.
In July, the FDA conducted an inspection of an AveXis facility in Irvine, California, detailing in a report the biotech's failure to review unexplained discrepancies in mouse data. Notably, FDA inspectors found no documentation explaining why AveXis waited until May 15 to open a non-conformance report, two months after an initial allegation of data mismanagement was made to the company's chief quality officer.
"We rely on truthful scientific data to make regulatory decisions, and we take the issue of data integrity very seriously," acting FDA Commissioner Ned Sharpless wrote on Twitter.
The FDA intends to further investigate the issue and could require AveXis submit "one or more" supplemental applications, a process that could take several months.
In its statement, Novartis said it does not expect the data issues to impacting the timing of its ongoing Zolgensma regulatory submissions or development.
Novartis bought AveXis last year for $8.7 billion, in large part due to promising data for the then experimental Zolgensma. The acquisition is the most notable piece of CEO Vas Narasimhan's strategy to invest in complex medicines like cell and gene therapy.
U.S.-listed shares in Novartis slid by nearly 3% Tuesday, while Biogen, which makes a competing drug for SMA, rose by 2%.