The US Food and Drug Administration (FDA) has issued a statement addressing product-testing data used to support the production process in the biologics license application (BLA) for Novartis’ Zolgensma (onasemnogone abeparvovec-xioi), a gene therapy. The treatment was approved by the FDA earlier this year for treating spinal muscular therapy (SMA), a rare neuromuscular disorder, in children less than two years old. The agency’s concerns relate only to the product-testing data used to support the production process for the product and not the agency’s clinical assessment of the product.

In May 2019, the FDA approved Zolgensma, a gene-therapy product intended to treat children less than two years of age with SMA with bi-allelic mutations in the survival motor neuron 1 gene. In June 2019, AveXis, a Novartis company and the product’s manufacturer, voluntarily self-disclosed to the FDA and to other health authorities about a data-manipulation issue that impacts the accuracy of certain data from product testing performed in animals submitted in the BLA and reviewed by the FDA.

“The FDA is carefully assessing this situation and remains confident that Zolgensma should remain on the market,” said the FDA in an August 6, 2019 statement. “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. This product testing data was used by the manufacturer to support the development of its production process for the product. These data do not change the agency’s positive assessment of the information from the human clinical trials that were conducted as part of the development program. The totality of the evidence demonstrating the product’s effectiveness and its safety profile continues to provide compelling evidence supporting an overall favorable benefit-risk profile. However, the integrity of the product testing data used in the development of the product’s manufacturing process is still a matter that we are continuing to evaluate and take very seriously.”

The FDA continued to say: “We are carefully assessing the issue of the manipulation of the product testing data used in the production process and are conducting a thorough assessment of the information from a recently completed inspection.  In part, this will allow us to determine the implications for the FDA’s scientific review of the information in the BLA and will allow us to amend our publicly posted BLA reviews, as appropriate.”

The agency said that it is also aware that AveXis became aware of the issue of the data manipulation that created inaccuracies in its BLA before the FDA approved the product, yet did not inform the FDA until after the product was approved. “The agency will use its full authorities to take action, if appropriate, which may include civil or criminal penalties,” said the FDA in its statement.

In response, Novartis issued a statement on August 6, 2019 to say that “Avexis had become aware of allegations of data manipulation in a specific animal testing procedure used in the development of the product. The assays in question were used for initial product testing and are not currently used for commercial product release. An investigation was immediately initiated to rapidly understand any implications and address the situation. Once we had interim conclusions from our investigations, we shared our findings with the FDA. As noted by the FDA, the data in question were a small portion of our overall submission and are limited to an older process no longer in use.”

In its statement, Novartis emphasized that “[a]t no time during the investigation did the findings indicate issues with product safety, efficacy or quality. We remain fully capable of releasing high-quality, fully compliant Zolgensma to patients in need,” said the company in its statement. “We have and will continue to work in close cooperation with the FDA to appropriately update our submission and address any quality gaps identified.”

Novartis says that it does not expect the issue to impact the timing of its ongoing Zolgensma regulatory filings and development programs.

Source: Novartis, FDA