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Lapse spotlights wider actions to ensure data accuracy.
Key to maintaining public confidence in the safety and efficacy of medical products-particularly innovative cellular and gene therapies-is for 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 strongly worded, public rebuke from the agency 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
Although Marks said that Zolgensma would remain on the market, as the faulty information involved early animal studies and did not compromise safety or efficacy for this potentially life-saving treatment, 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.
Meanwhile, 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 called spinal muscular atrophy (SMA). AveXis benefited from fast track and breakthrough therapy status, as well as FDA priority review and orphan drug designation. FDA also awarded the company a rare pediatric disease priority review
voucher, a highly valuable option for Novartis.
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 common regulatory actions. Although Novartis claimed that it quickly investigated allegations of data manipulation when concerns first surfaced internally, the timing and disclosure of its problems raise questions that warrant full examination by FDA and others. An FDA follow-up inspection in late July of AveXis’ San Diego control test lab reported that management failed to thoroughly review unexplained discrepancies in potency assays, had incomplete records, and did not follow quality control and test procedures. The criticism raises questions about whether the dismissal of AveXis scientists by Novartis fully addressed the serious lapses in quality controls at the company.
Ensuring the reliability of all clinical and manufacturing data is an ongoing priority for FDA, as seen in frequent citations in warning letters of inadequate and inaccurate records at clinical sites in violation of good clinical practices (GCPs), and at production facilities that find violations of good manufacturing practices (cGMPs).
Another strongly worded warning letter in August from FDA to Chinese over-the-counter drug manufacturer, Ningbo Huize Commodity Co., similarly cited egregious data errors. In a statement issued Aug. 20, FDA said it was banning the import of all the company’s products following a plant inspection where local staffers provided agency investigators with documents that were clearly falsified, including batch production and control records for multiple drugs.2
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 of the agency and involves increased global inspections, updated guidance, and additional staff training. FDA published final guidance in December 2018 for ensuring data integrity in compliance with cGMPs, which emphasizes the importance of company top management establishing a “quality culture” that acknowledges the importance and value of data integrity in all aspects of drug development and production.3
More advice on FDA requirements and recommendations for ensuring data accuracy were offered 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). The regulators highlighted the frequency of citing sponsors and clinical investigators in inspection reports for inadequate and inaccurate records and strategies for avoiding such warnings.4
The issue also is being addressed in a project to update standards from the International Council for Harmonization (ICH) to ensure human subject protection and reliability of trial results. 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 need clearer guidance on what specific information they should provide regulators when they uncover discrepancies in preclinical and clinical reports during drug development. That and other issues will be addressed at an FDA public meeting on Oct. 31 to review the draft E8 proposal and gather comments from all stakeholders.
Jill Wechsler is Pharmaceutical Executive’s Washington Correspondent. She can be reached at firstname.lastname@example.org