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Regulatory enforcement actions, policy updates, and new guidelines show that ensuring the reliability of clinical data is an ongoing priority.
Public confidence in the safety and efficacy of medical products-particularly innovative cellular and gene therapies-requires sponsors to provide complete and accurate information in all regulatory submissions. Evidence that Novartis manipulated certain preclinical data in developing its $2 million breakthrough therapy Zolgensma-and did not disclose the problem until after FDA approved the product-produced a strong, public rebuke from FDA and an outcry from policymakers. FDA officials said they may pursue civil or criminal charges, and Congressional leaders demanded that Novartis provide a full accounting of its actions.
In a harsh statement issued in early August, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), emphasized the importance of FDA having confidence in all tests and data submitted by sponsors, particularly to support the rapid development and approval of innovative therapies that benefit from accelerated pathways. Two decades ago, the death of young Jesse Gelsinger in a gene therapy clinical trial brought development of the field to a halt, and regulators and investigators fear that safety issues raised by faulty studies or incomplete submissions could stymie continued progress in advancing cutting-edge medicines. The law requires submission of “truthful, complete and accurate data” in order for FDA to be able to protect the public health, Marks asserted.1
In publicizing this situation, FDA aimed to send a clear warning to biopharma companies that data manipulation is a serious offense, and that data quality is critical for accelerated approvals, as well as more routine regulatory actions. Marks said that Zolgensma would remain on the market, as the questionable test results involved early animal studies and not results of clinical trials, and thus did not compromise safety or efficacy for this potentially life-saving treatment. Yet, he acknowledged that if reviewers had been aware of the erroneous test data at Novartis’ AveXis unit, CBER probably would have delayed approval.
Particularly troubling is that the company evidently knew of the data errors as early as last March but did not launch a formal investigation until May, and did not reveal these issues until June. But that was after the agency approved Zolgensma on May 24 based on evidence that it dramatically improved the health of infants suffering from the most severe form of the neurodegenerative disease spinal muscular atrophy (SMA). However, an FDA follow-up inspection in late July of AveXis’ San Diego control test lab found evidence that management failed to thoroughly review unexplained discrepancies in potency assays, had incomplete records, and failed to follow quality control and test procedures. These events also raised questions about the dismissal of AveXis scientists who Novartis blamed for the data manipulation.
Ensuring the reliability of clinical data is an ongoing priority for FDA, as seen in repeated citations in warning letters of inadequate and inaccurate records at clinical sites in violation of good clinical practices (GCPs). Regulators addressed these concerns and outlined appropriate responses at a workshop in October 2018 on “Data Integrity in Global Clinical Trials” sponsored by FDA and the Medicines and Healthcare products Regulatory Agency UK (MHRA).2
International standards for data integrity also are being examined as part of a project to update policies to ensure human subjection protection and reliability of trial results by the International Council for Harmonisation (ICH). A new guideline (ICH E8) is under development to revise requirements for assuring data quality, along with policies governing clinical trial design, data sources, and the protection of trial participants. Sponsors say they would like to see clearer guidance on what specific information they should provide regulators when they uncover discrepancies in preclinical and clinical reports during drug development. These issues will be discussed further at an FDA public meeting on October 31, 2019 to review the draft E8 proposal and gather comments from stakeholders.
FDA has similar concerns about ensuring data integrity in drug manufacturing, as well as product development. A warning letter sent in August 2019 to Chinese over-the-counter drug manufacturer, Ningbo Huize Commodity Co., cites egregious data integrity lapses.3FDA banned import of the company’s products following a plant inspection where local staffers provided FDA investigators with documents that were clearly falsified, including batch production and control records for multiple drugs.
In highlighting this enforcement action, FDA acting commissioner Ned Sharpless stated that efforts to “prevent, uncover and combat data integrity lapses” is a continuing commitment for the agency. FDA requires sponsors to submit complete and accurate information in applications and, in turn, is providing additional resources to address data integrity issues through increased global inspections, updated guidance, and additional staff training.