FDA Had Questions About Novartis’ Data Practices During Mayzent MS Approval

Novartis logo on side of tall building

On March 27, the U.S. Food and Drug Administration (FDA) approved Novartis’ Mayzent (isiponimod) for adults with relapsing types of multiple sclerosis, including secondary progressive multiple sclerosis (SPMS) with active disease, relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS).

Now, Regulatory Focus reports that the FDA had questions about Novartis’ data practices found during a clinical inspection. In one study, the FDA stated that blinding “was not adequately maintained as specified in the protocol throughout the course of the trial at 62 (21%) of 294 sites. Study personnel were given inappropriate access to the first dose and main databases affecting 285 (17%) out of 1651 total study subjects.”

The FDA said that its ability to track user activities in two databases was limited because the system lacked access to audit trails. “Novartis did not have sufficient procedures outlined in their monitoring plan for granting and revoking access as well as detecting inappropriate access to databases that contained study information that could be potentially unblinding. Novartis CARs [clinical research associates] did not properly grant study personnel (e.g., study coordinators, investigators, and EDSS raters) access to the databases used in the trial. In addition, the CRAs failed to identify cases where inappropriate database access was granted to site personnel.”

There is no indication on the part of the agency on whether this inappropriate access led to any bias. It did say it couldn’t rule it out, especially for 163 of the 285 patients whose study assessments were performed by main database users and Expanded Disability Status Scale (EDSS) raters, in other words, blinded study personnel, who were given inappropriate access to the first dose database and the main databases.

Regulatory Focus writes, “In an email last December, FDA called on Novartis to conduct a sensitivity analysis, excluding in the per-protocol analysis subjects who may have been impacted, including 62 subjects who were potentially affected by the 11 EDSS raters who had inappropriate access to the first dose or main databases and 101 subjects who were potentially affected by the 32 users of the main database who had inappropriate access to the first dose database.”

On March 26, the FDA announced its approval of the drug, noting Mayzent proved efficacy in a clinical trial of 1,651 patients comparing the drug to placebo in SPMS patients. The primary endpoint was time to three-month confirmed progression in disability. “The fraction of patients with confirmed progression of disability was statistically significantly lower in the Mayzent group than in the placebo group. Mayzent also decreased the number of relapsed experienced by these patients. In the subgroup of patients with non-active SPMS, the results were not statistically significant.”

If there were any questions about the validity of the trial or the drug’s efficacy and safety based on the inspection, there is no mention of it in the announcement. There is no indication whether Novartis conducted the sensitivity analysis and if the results of it were taken into consideration when approving the drug, although that seems likely.

In the Phase III EXPAND trial, which was the basis of the approval, Mayzent was found to significantly decrease the risk of three- month confirmed disability progression, with a 21% reduction compared to placebo; and a 33% reduction compared to placebo in patients with relapse activity in the two years before screening. Mayzent also meaningfully delayed the risk of six-month CDP by 26% compared to placebo and decreased the annualized relapse rate (ARR) by 55%. It also showed significant favorable outcomes in other measures of MS disease activity, including cognition, MRI disease activity and brain shrinkage.

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