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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 efÂficacy of medical products-particularly innovative cellular and gene therapies-requires sponsors to provide complete and accurate information in all regulatory submissions. Evidence that Novartis maÂnipulated certain preclinical data in develÂoping its $2 million breakthrough therapy Zolgensma-and did not disclose the probÂlem 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 crimiÂnal charges, and Congressional leaders demanded that Novartis provide a full acÂcounting of its actions.
In a harsh statement issued in early August, Peter Marks, director of the CenÂter for Biologics Evaluation and Research (CBER), emphasized the importance of FDA having confidence in all tests and data submitted by sponsors, particularly to supÂport 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 submisÂsion of “truthful, complete and accurate data” in order for FDA to be able to protect the public health, Marks asserted.
In publicizing this situation, FDA aimed to send a clear warning to biopharma comÂpanies 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 reÂviewers 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 neurodeÂgenerative disease spinal muscular atrophy (SMA). However, an FDA follow-up inspecÂtion in late July of AveXis’ San Diego control test lab found evidence that management failed to thoroughly review unexplained disÂcrepancies in potency assays, had incomÂplete records, and failed to follow quality control and test procedures. These events led to the dismissal of AveXis scientists and Novartis restructuring its relationship with AveXis to increase oversight.
Reliability of results
Ensuring the reliability of clinical data is an ongoing priority for FDA, as seen in reÂpeated citations in warning letters of inadÂequate and inaccurate records at clinical sites in violation of good clinical practices (GCPs). Regulators addressed these conÂcerns and outlined appropriate responses at a workshop in October 2018 on “Data Integrity in Global Clinical Trials” sponÂsored by FDA and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
International standards for data integÂrity also are being examined as part of a project to update policies to ensure huÂman subjection protection and reliability of trial results by the International Council for Harmonization (ICH). A new guideline (ICH E8) is under development to revise reÂquirements 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 informaÂtion they should provide regulators when they uncover discrepancies in preclinical and clinical reports during drug developÂment. These issues will be discussed furÂther at an FDA public meeting on Oct. 31 to review the draft E8 proposal and gather comments from stakeholders.
FDA has similar concerns about ensurÂing data integrity in drug manufacturing, as well as product development. A warning letter sent in August to Chinese over-the-counter drug manufacturer, Ningbo Huize Commodity Co., cites egregious data inÂtegrity lapses. FDA banned import of the company’s products following a plant inÂspection 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 conÂtinuing 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 guidÂance, and additional staff training.
Jill Wechsler is the Washington Correspondent for Applied Clinical Trials.