On August 6, 2019, the U.S. Food and Drug Administration (FDA) released a statement that Novartis AG withheld notifying FDA about falsified data found in preclinical animal studies until after their $2.1 million gene-therapy drug, Zolgensma, was approved. Zolgensma, approved in May of this year, is intended to treat children less than 2 years of age with the most severe form of spinal muscular atrophy (SMA) and is only the second gene therapy treatment to be approved by the FDA. About 400 babies each year are born with the disorder in the United States. Zolgensma is currently under review by regulators in Europe and Japan.
Isolated incident or cultural problem?
AveXis Inc., the Novartis AG subsidiary that manufactures Zolgensma, told the agency five weeks after the approval about a “data manipulation issue” that resulted in inaccurate information regarding testing in animals submitted in the Biological Licensing Application (BLA). The next day, in a previously unannounced phone call with financial analysts, Novartis CEO, Vas Narasimhan, defended his company’s decision to postpone notification to the FDA about the discovery saying the company “tried to do the right things” in their investigative process. The conference call was Mr. Narasimhan’s first public statement on the data falsification. Mr. Narasimhan went on to say that Novartis waited for results of their internal investigation before informing the FDA “so that we could provide the best information,” not because the company wanted to win approval for Zolgensma before disclosing the problem. Novartis is now in the process of “exiting” a small number of scientists from AveXis who were “involved in the data inaccuracies.” He continued to described the problem as “an isolated incident” that doesn’t reflect a cultural problem at AveXis.
Insights from the FDA Inspection Report
However, a review of an FDA Inspection Report of the AveXis facility in San Diego, CA from August 2nd of this year showed that AveXis personnel were aware of potential data manipulation or fraudulent practices dating back to January 2018, and multiple instances of potential “data manipulation” were observed by FDA Inspectors during the review of records. For example, review of non-conformance reports from January and August 2018 by FDA inspectors found “assay forms not completed at time of CoA generation and approval”, forms with different “Generated On” date/time stamps, and recorded mouse survival days that differed from actual values by as much as 19 days, all without additional investigation by AveXis personnel. In all, there were five observations listed on the FDA 483 related to a lack of documentation, lack of Quality Unit independence, lack of adherence to established procedures, and lack of real-time recording of data. To the informed observer, these observations point to a culture that failed to consistently implement quality controls, and not “an isolated incident”.
A complete assessment of the impact of the data manipulation will require additional investigation and discussions both internally within FDA and with AveXis. Submission of one or more BLA supplements for FDA review by AveXis over the next several months will also be required. The Novartis CEO stated that he is “committed to rebuild trust with society, deeply, for me personally all the way through the leadership team and the broader organization”. Regardless, since FDA became aware of the issue of the data manipulation that created inaccuracies in their Zolgensma BLA after the product was approved, acting FDA commissioner Ned Sharpless, M.D., tweeted on Tuesday that “in this case, the agency will use its full authorities to take action, if appropriate, which may include civil or criminal penalties.”
Impact on interpretation of clinical trial results
It is important to note that there is no evidence that any other data, particularly patient clinical data, were manipulated. The data that were manipulated involve the results of a murine model assay that was critical in characterizing the comparability between the Phase 1 and Phase 3 versions of the drug product. FDA does not believe at this time that the data manipulation impacted the interpretation of the results of the animal toxicology studies or the Phase 3 clinical trial used as the basis for the BLA approval in May. FDA remains confident that Phase 3 clinical trial results of Zolgensma continue to provide compelling evidence of the effectiveness of the drug in SMA. This data along with sufficient evidence of safety supports keeping Zolgensma on the market as a safe, pure, and effective treatment for the indicated population.
When an issue of potential data manipulation or fraud arises within an organization, it is important as Quality professionals to sound the alarm and perform full, robust investigations to determine, immediately mitigate, and potentially eliminate the root cause(s). Full accountability is only achieved with independence of the Quality Unit and a strong culture of compliance supported by management. It is the responsibility of any organization with a pending submission to raise such issues to the FDA immediately; do not wait until an internal investigation is complete or you have the “answer” to inform regulators of the problem. To not do so puts the entire organization at risk of additional scrutiny by regulators, investors, and the public. Furthermore, such an act may permanently erode trust in the organization, its leaders and employees.
The experienced Quality and Regulatory Advisors at Pearl Pathways can help your organization navigate communication with FDA and provide a pathway for earning trust even in difficult and sensitive situations.