FDA turns attention to data integrity lapses at testing sites in new guidance

The US Food and Drug Administration (FDA) has issued a draft guidance outlining how manufacturers can ensure the data integrity of bioavailability (BA) and bioequivalence (BE) studies to support investigational new drug application (INDs), new drug applications (NDAs), and abbreviated new drug applications (ANDAs), and certain biologic license applications (BLAs).

The guidance was developed by FDA’s Office of Generic Drugs (OGD), the Office of Study Integrity and Surveillance (OSIS) and the Office of Clinical Pharmacology (OCP) in the Office of Translational Sciences (OTS) in the Center for Drug Evaluation and Research (CDER). FDA defines data integrity as the “accuracy, completeness, and reliability of data.”

FDA issued this guidance as part of its Generic Drug User Fee Amendments (GDUFA II) commitments and as part of its Drug Competition Action Plan, which aims to improve the efficiency of generic drug development.

The guidance also stems from FDA investigators’ concerns in recent years about the integrity of the data supplied by testing sites. The agency noted in an announcement that “FDA has observed data integrity concerns during the inspection of testing sites, clinical testing sites, and analytical testing sites, and during the assessment of the BA and BE study data submitted in support of applications.”

These concerns “can impact application acceptance for filing, assessment, regulatory actions, and approval as well as post-approval actions, such as therapeutic equivalence ratings.”

In one example, FDA issued a notification to pharmaceutical companies in November 2021 warning them to stop using the clinical and bioanalytical studies conducted by India-based Panexcell Clinical Lab and Synchron Research Services.

An analysis of the data generated at these companies and submitted in several applications found “significant instances of misconduct and violations of federal regulations, which resulted in the submission of invalid study data to FDA.” FDA requested that these companies that relied on this data to repeat the BA/BE studies.

The guidance recommends strategies for applicants and testing site management in achieving and maintaining data integrity in testing labs. FDA points out that the guidance is not a comprehensive list of all best practices, and advises applicants to consult other more general guidance for question on data integrity, including the agency’s December 2018 guidance on data integrity and compliance for drug current good manufacturing practice.

The new draft guidance covers how to select testing sites, ensure that robust monitoring and oversight of sites are in place, and how to implement monitoring plans and audits. It also addresses how testing site management can institute a robust quality management system, including an effective sample analysis system to stem potential data integrity problems.

When selecting testing sites, manufacturers should ensure they are using only qualified testing sites, and should also take into consideration the education, training, and experience of the testing site’s personnel, and site’s history of inspectional findings by FDA.

Applicants should also develop monitoring plans to ensure that testing sites are adequately assessed and reviewed and periodically audit testing sites’ compliance with the monitoring plan.

Ensure sites have a strong quality culture

Site management should ensure that a strong quality culture and a quality management system is in place to ward off potential problems. The guidance defines a quality culture as “an environment where personnel understand how their actions impact data integrity whereas a quality management system is all of the measures (e.g., training, communication) used to help ensure data integrity.”

FDA officials observed at a meeting that firms with strong quality cultures tend to avoid data integrity lapses more than firms with a weak quality culture. (RELATED: FDA officials: Firms with strong quality culture more resilient to data integrity problems, Regulatory Focus 26 April 2022).

Management should also ensure that sites have a robust system for sample collection. The guidance states that “the quality of clinical studies, especially those conducted and submitted to FDA in support of application approval, depend to a large extent on the bioanalysis of participant samples from in vivo BA and BE studies.”

If a sample analysis is conducted at a site different from the clinical testing site, management should ensure that study protocols, test methods, established practices, and SOPs have been followed, and that samples are collected as close as possible to the times specified in the study.

Management should also ensure that instruments and equipment, including balances, pipettes, centrifuges, mass spectrometers, liquid chromatographs, refrigerators, and storage freezers haven been calibrated and serviced per their SOPs. Further, equipment failures should be documented and investigated to evaluate any impact on sample stability.

The deadline for submitting comments is 3 July 2024.

Guidance, Federal Register notice

FDA turns attention to data integrity lapses at testing sites in new guidance

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