NVS Novartis AG

Drugmaker blames former researchers for drawn-out disclosure of data manipulation

By Denise Roland 

This article is being republished as part of our daily reproduction of WSJ.com articles that also appeared in the U.S. print edition of The Wall Street Journal (September 25, 2019).

Novartis AG said that an internal probe of data manipulation at one of its drug-development units was hindered by two brothers, both senior researchers whom it later fired.

The Swiss drug giant said in a newly disclosed letter to the U.S. Food and Drug Administration that its months-long investigation into the issue was "significantly drawn out" due to a "lack of cooperation and categorical denial of the allegations" by the brothers.

Novartis and the FDA disclosed in August they had identified data manipulation in testing of a gene-therapy treatment that was conducted by AveXis, a Chicago-based company Novartis bought in 2018 for $8.7 billion. The treatment, developed by AveXis and later dubbed Zolgensma, is now the world's most expensive drug

The FDA is probing why Novartis didn't disclose the manipulation when it first became aware of it earlier this year. The agency has allowed Novartis to continue selling the drug, finding the data manipulation didn't affect its efficacy or safety. Zolgensma treats a devastating infant muscle-wasting disease.

Novartis's letter to the FDA, dated Aug. 23 but only made public Tuesday, detailed a whistleblower's allegation that Brian and Allan Kaspar directly altered or instructed others to alter data. Brian Kaspar was an early senior researcher on the team that developed Zolgensma and held the title "scientific founder" at AveXis. His brother Allan was head of research and development.

The Wall Street Journal previously reported the company struggled to manage a fast ramp-up of its research and manufacturing operations, citing former employees. They described a race to develop the drug that, at times, yielded mistakes, including misstated dosing figures from early-stage trials of the drug.

The brothers were put on administrative leave in early May and terminated with cause in August, Novartis said. Brian Kaspar's lawyer, John Hueston, said in a statement that his client cooperated with the company investigation and continues to categorically deny wrongdoing. Mr. Hueston described Novartis's account in the letter to the FDA as a "shameless attempt" to blame others for AveXis management's own disclosure decisions. Allan Kaspar also wasn't immediately available to comment. He hasn't previously commented on the matter.

The data manipulation involves experiments run on mice in 2017 and part of 2018 that were designed to compare the strength of Zolgensma made at a manufacturing plant in Libertyville, Ill., near Chicago, with an earlier version made at Nationwide Children's Hospital in Columbus, Ohio. Novartis has acknowledged that the data manipulation took place and, in the August 23 letter, said the Kaspar brothers "could not offer a credible explanation for revisions to and inconsistencies in the data."

Novartis has come under fire for taking so long to disclose the data manipulation issue to the FDA. The allegation was first made at AveXis in mid-March and was shared with the wider Novartis organization on March 28, the letter said. By early May, Novartis had concluded that the allegations were credible. But Novartis notified the FDA of the issue on June 28, a full month after Zolgensma was approved by the agency and went on sale.

In the letter, Novartis laid out in detail the steps it and the AveXis unit took to investigate the allegations. It said that a lack of cooperation from the Kaspar brothers prolonged the initial investigation into whether the allegations could be substantiated. It said that, as a result, investigators had to review thousands of handwritten and electronic records on the experimental mice, a task it estimated took 2,000 hours collectively. That part of the investigation was completed by early May.

To explain why it didn't then flag the issue to the FDA for another two months, Novartis said it went on to conduct a preliminary investigation into the root cause of the data manipulation before notifying the agency. It said that it was following standard industry practice in doing so, given there was no evidence that the discrepancies affected the safety or effectiveness of Zolgensma.

The company acknowledged that, given the novelty of gene therapy, it should have notified the agency earlier. Zolgensma is only the second such treatment to go on sale in the U.S. Earlier this month, Novartis pledged to alert the FDA in the future to any data-integrity concerns within five working days of any "credible allegation" about its drug testing.

Novartis also outlined steps it was taking to strengthen its oversight of data integrity at AveXis, such as fully integrating AveXis's quality-control organization with that of Novartis. The company has also hired an outside manufacturing expert to conduct a sweeping investigation of the data generated by AveXis to ensure that data manipulation hasn't taken place elsewhere.

Write to Denise Roland at Denise.Roland@wsj.com

(END) Dow Jones Newswires

September 25, 2019 02:47 ET (06:47 GMT)

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