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Novartis AG and subsidiary AveXis Inc. may face civil or criminal action after revelations by the US Food and Drug Administration that not only was data used for approval of the gene therapy Zolgensma manipulated, but also that the company knew about the problem before the product was approved and did not disclose it.

Center for Biologics Evaluation and Research Director Peter Marks said in a 6 August statement that the FDA is assessing the situation, but "remains confident that Zolgensma should remain on the market."

Marks said the manipulated data is "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," Marks said in the statement. "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."

Novartis maintained in a statement that the company was fully confident in the safety, quality and efficacy of Zolgensma and was committed to taking appropriate actions to prevent future incidents across its portfolio. The company also said that it remains "fully capable of releasing high-quality, fully compliant Zolgensma to patients in need."

Novartis received approval for Zolgensma (onasemnogene abeparvovec-xioi) on 24 May. The gene therapy is indicated for treatment of children age two and younger with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 gene.

The treatment was haled as a breakthrough for a rare disease, but also criticized for its price. Novartis said the product will cost $2m, or $425,000 annually for five years. (Also see "It's Official: Novartis SMA Gene Therapy Zolgensma Is World's Most Expensive Drug" - Scrip, 24 May, 2019.)

Novartis informed FDA on 28 June about the data manipulation problem, which involved an in vivo murine potency assay. But agency officials added in the statement that the company was aware of the issue before Zolgensma was approved, potentially as early as 14 March, and did not tell the agency until after approval.

Wilson Bryan, director of CBER's Office of Tissues and Advanced Therapies, wrote in a post-approval memo on Zolgensma that had the issue been disclosed when known, approval likely still would have been granted, although it may have been delayed.

"The delay would have been necessary in order for the FDA to investigate the data manipulation, determine the impact of the data manipulation on the [chemistry, manufacturing, controls], pharmacology/toxicology, and clinical trial results, and revise the relevant BLA reviews," Bryan wrote. "However, I believe that CBER would have ultimately approved the BLA based on all information currently available, including compelling evidence of effectiveness and a favorable benefit-risk profile."

Marks said "the agency will use its full authorities to take action, if appropriate, which may include civil or criminal penalties," to deal with the issue. The agency would not comment further.

The FDA also is reviewing the manipulated product testing data used in the production process and assessing information from a recently completed inspection "to determine the implications for the FDA's scientific review of the information in the BLA," and will amend the publicly released review documents as appropriate, Marks said.

Novartis also said that it did not expect the news to affect the timing of any ongoing Zolgensma regulatory filings and development programs. The European Medicines Agency recently revoked the product's initial accelerated assessment, instead deciding the product will receive a standard review. (Also see "Novartis’s Zolgensma Loses EU Accelerated Assessment" - Scrip, 26 Jul, 2019.)

Manipulated Data Affected Phase I, III Product Comparability

Bryan wrote in the memo that the manipulated data involves the results of an assay used to compare the versions of the product manufactured for Phase I and Phase III clinical trials and animal toxicology studies, since the processes were different. He said the manipulated data likely impact interpretation of the results of the Phase I clinical trial results, and some of the nonclinical studies in the original BLA, but did not appear to impact interpretation of animal toxicology or Phase III clinical trial.

Bryan said the Phase III results still offer compelling evidence of efficacy and sufficient evidence of safety to support a favorable benefit-risk profile. He added that while Phase I and Phase III product comparability is in question, they are closely related because both consist of the same vector and transgene.

"Therefore, my current assessment is that the Phase I trial results provide supportive (confirmatory) evidence of the effectiveness of the Phase III product," he wrote. "The BLA meets the regulatory requirement for substantial evidence of effectiveness, based on one adequate and well-controlled investigation (i.e., the results of the Phase III trial) plus supportive evidence (i.e., the results of the Phase I trial). Based on the information currently available, Zolgensma is safe, pure, and potent (effective) for the indicated population."

Bryan also said a complete assessment of the impact of the manipulated data will require more investigation, as well as discussions within CBER and with Novartis. The company also may have to submit additional supplements for FDA review, which "may take at least several months." However, for the time being the Zolgensma label is adequate, he said.

483 Observations Included Possible Data Manipulation

FDA inspectors visited an AveXis control testing lab for an inspection from 24 July through 2 August, where data manipulation was among the observations noted.

In the 483 report, the inspector wrote that a Non-conformance Report (NCR) was initiated on 15 May after the company's Chief Quality Officer alleged data from in vivo relative potency assay studies "may have been mismanaged or even potentially manipulated."

The inspector indicated in the report that there was no documentation that an audit of other potentially impacted data, studies or reports was conducted or is planned to determine whether the allegations were true or that no more investigation was needed. The inspector also wrote that there was no documentation "as to why the NCR was not opened until 15 May 2019 when the initial allegation is documented as having been reported on 14 March 2019."

Inspectors also noted other NCR issues, including documentation generation discrepancies. In addition, laboratory records did not include complete data derived from all tests, examinations and assays necessary to assure compliance with specifications, quality control procedures were not fully followed, complete records of lab reference standardization were missing, and established test procedures were not followed.

Another Addition To High-Profile Data Integrity Problems

Unfortunately for the gene therapy industry, the Zolgensma case is the second data integrity problem involving the products to emerge in recent months. The South Korea Ministry of Food and Drug Safety pulled its approval of Kolon Life Science Inc.'s cell and gene therapy Invossa (TG-C) after determining the company submitted false data at the time of approval. (Also see "Invossa Approval Revoked As Korea Confirms False Data Submission" - Pink Sheet, 28 May, 2019.)

The move resulted in calls for the South Korean government to review all of its approved cell therapies to ensure the problem was not more widespread. (Also see "Invossa Fallout: Call For Review Of All Korea-Approved Cell Therapies" - Pink Sheet, 31 May, 2019.)

Data integrity problems also are not new for the FDA. The agency has investigated numerous cases and improved its forensic capabilities. (Also see "FDA's Improved Forensics Uncovers More Manufacturing Data Integrity Issues" - Pink Sheet, 4 Apr, 2016.)

A data fraud and manufacturing violations case against Ranbaxy Laboratories Ltd. resulted in a $500m settlement in 2013. The company faced several Good Manufacturing Practice and data integrity problems at several facilities in India. (Also see "Ranbaxy’s $500 Million Settlement Includes Criminal Penalties" - Pink Sheet, 13 May, 2013.)

In 2016, the FDA told new and generic drug sponsors to repeat bioequivalence and bioavailability studies conducted by Semler Research Center Private Ltd. after an inspection found invalid study data had been submitted. The agency decided it would no longer accept data generated by the company as the basis to approve an application. (Also see "Indian CRO Inspection Fall-Out: Semler's Clients Have To Repeat Studies For US FDA" - Pink Sheet, 25 Apr, 2016.) 

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