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FDA Investigating Data Manipulation in Gene Therapy Approval

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(Gerd Altmann, Pixabay)

7 Aug. 2019. The Food and Drug Administration is investigating manipulation of preclinical tests submitted for its approval of a gene therapy to treat a rare disease. The FDA’s is looking into data submitted by drug maker Novartis for review of Zolgensma, the company’s gene therapy for spinal muscular atrophy, approved by FDA on 24 May 2019.

Spinal muscular atrophy or SMA is an inherited condition in infants where specialized motor nerve cells in the spinal cord and brain stem are missing, leading to wasting away of muscles for crawling, walking, sitting up, and head movements. In severe cases, muscles for breathing and swallowing can also be affected. The disease is caused by a mutation in survival motor neuron 1 or SMN1 gene that encodes for a protein needed for healthy functioning of motor neurons or nerve cells.

Zolgensma uses a benign virus, called an adeno-associated virus, given as a single infusion to deliver a healthy SMN1 gene copy into targeted motor neurons that produces the functioning proteins needed by children with spinal muscular atrophy. FDA approved Zolgensma in part on results from clinical trials in the U.S. and Europe showing children less than 2 years in age receiving the healthy gene showing more improvement in meeting motor function milestones than children with spinal muscular atrophy typically demonstrate, such as controlling head movements or sitting up on their own.

An incident report by Wilson Bryan, director of FDA’s Office of Tissues and Advanced Therapies noted evidence of data manipulation in tests of Zolgensma’s potency on lab mice conducted by AveXis, a biotechnology company that originally developed the gene therapy. As reported by Science & Enterprise, Novartis acquired AveXis for $8.7 billion in April 2018.

Bryan’s report, dated 26 July, says the potency tests in question measure therapeutic activity of the treatment, but because of evidence of manipulation, results of those tests are not reliable. However, says the report, other potency tests done by AveXis do not indicate manipulation. Data from early- and late-stage clinical trials also do not show evidence of manipulation, and continue to support the agency’s original conclusions that Zolgensma is safe and effective for its intended patients.

Nonetheless, the incident report indicates AveXis was aware of the preclinical data manipulation in March 2019, but waited until June 2019 to tell FDA. Bryan says a more timely notice of the manipulated data could have delayed the FDA’s approval of Zolgensma, while the agency investigated the irregularities.

In an FDA statement yesterday, Peter Marks, director of the agency’s Center for Biologics Evaluation and Research, says, “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.” Marks adds, “The agency will use its full authorities to take action, if appropriate, which may include civil or criminal penalties.”

In a company statement, Novartis notes that “FDA supports the continued marketing and use of Zolgensma for patients with spinal muscular atrophy (SMA) less than 2 years of age. 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.”

Zolgensma generated controversy over its pricing when FDA approved the treatment. AveXis set a list price of $2,125,000, which prompted an immediate push-back from Institute for Clinical and Economic Review, or ICER, an independent group that analyzes drug effectiveness and value, calling them “above commonly accepted cost-effectiveness thresholds.” ICER later acknowledged new clinical trial data show longer-lasting effects of Zolgensma treatments, and as a result, enable the treatments to fall within its value-based benchmark range.

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