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Jill Wechsler is BioPharm International's Washington Editor, firstname.lastname@example.org.
Falsified documents and manipulated test results prompt warnings and investigations.
Because federal investigators cannot inspect every drug test site or production facility, FDA relies on manufacturers to submit complete and accurate information in all submissions and market applications, especially for innovative cell and gene therapies. Evidence that Novartis submitted manipulated data from certain preclinical tests related to its production process for breakthrough therapy Zolgensma recently produced a strong, public warning from FDA, with implications that the agency may pursue civil or criminal charges.
also blasted Novartis and demanded a full accounting of its actions (1).
Another strongly worded warning letter from FDA to Chinese over-the-counter drug manufacturer, Ningbo Huize Commodity Co., similarly cited egregious data integrity lapses (2). In a statement issued on Aug. 20, 2019, FDA said it was banning the import of all the company’s products following a plant inspection where local staffers provided FDA investigators with documents that were clearly falsified, including cleaning validation reports and batch production and control records for multiple drugs (3).
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 current good manufacturing practices (CGMPs) (4), 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.
Data integrity issues involving manufacturing activities are cited regularly in warning letters related to manufacturing facility inspections at home and abroad. A letter dated July 9, 2019 warned Indoco Remedies Ltd. of Mumbai, India of GMP and data integrity violations at a facility in Goa (5). It cited problems with batch production and control records for products intended for the US market. And a June 13, 2019 warning letter to Akorn Inc. raised concerns about the firm’s failure to ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of its products (6). FDA cites a previous warning letter regarding inadequate quality controls at another Akorn production site and demands prompt correction of all cited violations or risk legal action and delays in product approvals.
In the Novartis case, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), sharply rebuked the company, emphasizing the importance of FDA having confidence in all tests and data provided by sponsors, particularly to support the rapid development and accelerated approval of innovative therapies. The submission of “truthful, complete, and accurate data” is critical for FDA to be able to protect the public health, and the law requires it, Marks asserted in a statement on Aug. 6, 2019 (7).
FDA’s pronouncements aim to provide clear warnings to manufacturers that data manipulation is a serious offense, and that data quality is critical for product approval and continued marketing. Marks said that Zolgensma would remain on the market, as the faulty information involved early animal studies related to developing the production process for Zolgensma and did not compromise product safety. But he acknowledged that if the agency had been aware of the data manipulation by Novartis’ AveXis unit, it probably would have delayed approval of the lifesaving $2-million drug.
Although Novartis claimed that it quickly investigated allegations of data manipulation when the issues first surfaced internally, the timing and disclosure of these problems raise questions. The company evidently knew of the data errors as early as March 2019 but did not launch a formal investigation until May and did not reveal its concerns until June. And that was after the May 24, 2019 approval of Zolgensma, based on limited, but convincing evidence that it dramatically improved the health of infants suffering from the most severe form of the neurodegenerative disease spinal muscular atrophy.
FDA compliance officers continue to investigate whether Novartis and AveXis staffers intentionally hid evidence of data manipulation until after approval. According to press reports, FDA inspectors raised questions about a mouse essay at an inspection of a Novartis manufacturing facility in Illinois earlier this year, but company staff said they had been corrected. However, FDA’s follow-up inspection in July 2019 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 (8).
Novartis dismissed the AveXis scientists linked to the data manipulation, but FDA holds corporate management responsible for ensuring adherence to rules at all levels. Although only a small portion of product test data in the market application appears to be manipulated, FDA says that a thorough assessment of all information will determine if further warnings or limits are warranted for this new therapy that has limited patient experience.
1. Senator Chuck Grassley,
, Aug. 9, 2019.
2. FDA, Warning Letter to NingBo Huize Commodity Co., Ltd., Aug. 2, 2019.
3. FDA, “FDA Warns Company for Putting Consumers at Risk with Drug Manufacturing Data Integrity Violations,” Press Release, Aug. 20, 2019.
4. FDA, Data Integrity and Compliance with Drug CGMP Questions and Answers, Guidance for Industry (CDER, 2018), www.fda.gov/media/119570/download.
5. FDA, Warning Letter to Indoco Remedies Limited, July 9, 2019.
6. FDA, Warning Letter to Akorn Inc., June 13, 2019.
7. Dr. Peter Marks, MD, Statement on Data Accuracy Issues with Recently Approved Gene Therapy, Press Release, August 6, 2019.
8. FDA, Form 483 to AveXis, Inc., August 2, 2019.
Vol. 32, No. 10
When referring to this article, please cite it as J. Wechsler, "Data Integrity Violations Draw Strong FDA Rebukes," BioPharm International 32 (10) 2019.