07/05/2024

At the beginning of April 2024, the US Food and Drug Administration (FDA) released a draft guidance for industry titled: Data Integrity for In Vivo Bioavailability and Bioequivalence Studies. Bioavailability (BA) is the rate and extent to which the active ingredient of a drug becomes available at the site of drug action. Bioequivalence (BE), when comparing drugs with the same active ingredient, is an absence of a significant difference in rate and extent the active ingredient becomes available at the site of drug action. BA and BE studies can be either clinical or analytical; however, as they are conducted in vivo, maintaining data integrity is critical for protecting the safety of the research participants. Maintaining data integrity is a shared value across all GxP fields; therefore, the recommended practices this guidance outlines may be applicable to more than BA and BE studies.

The draft guidance explains the difference between data quality and data integrity. While both are necessary to maintain in a clinical study in order to obtain reputable data, they each have important differences. Data quality is data that is obtained in compliance with applicable standards and determines if the data can be used for its intended purpose in the clinical research. If data is obtained with a disregard for the applicable standards (FDA rules, regulations, and guidelines and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines) the data would be considered low quality and may not be considered in regulatory decision making. Data integrity on the other hand is often defined by the ALCOA-C principles, meaning the source data/documents are:

Attributable: it should be clear who created, modified, or deleted the source data.
Legible: the source data should be easy to read so that there is no misunderstanding of the information.
Contemporaneous: all results from a study or changes made should be recorded in real time, signed, and dated.
Original: to ensure that the data was not modified the first item that a data point is recorded on is considered the original and is what is expected to be submitted during an FDA inspection unless there is a certified copy.
Accurate: source data should be a consistent and real representation the study facts and results.
Complete: all documents should be completely filled in including all the dates, names, locations applicable.

The draft guidance provides recommendations on how to maintain data integrity and quality within a site starting with the applicant (which in most cases is the sponsor or sponsor-investigator) as they have the ultimate responsibility of the initiation, management, and conduct of the study. These recommendations include:

Testing site selection: often times applicants will contract testing sites to complete specified portions of a study such as clinical, analytical, or general study-related activities. During the selection process, applicants should consider if the site has been qualified to complete the given task, if the site has had any findings in past FDA inspection and if these findings were remedied, and if the site’s personnel are educated, trained, and have experience with the given task.
Monitoring and Oversight: while the applicant may not be involved in conducting every section of the study, they should routinely be checking in on them to ensure that the contracted entities and staff are all working in compliance with applicable FDA and ICH guideline as well as the study protocol. This monitoring and oversight should involve:
- Monitoring Plan: testing sites should be assessing, controlling, communicating, and reviewing risks to data quality and integrity on a regular basis through a monitoring plan. The extent of the monitoring should be relative to the risk that the study data may be compromised.
- Audits: in tandem with the monitoring plan, testing sites are also recommended to conduct audits ahead of any FDA inspections and document and communicate any findings the audit may reveal. Routine audits will expose and gaps or shortcoming in the sites conduct and give them a chance to put corrective actions plans into place to remedy any potential issues that would come up during an FDA inspection.

The draft guidance also explains the importance of maintaining the core workplace value of “quality culture”, an environment where the study personnel know the significance of maintaining data quality and integrity and feel comfortable reporting any issues without fear of repercussions. At the same time, testing sites should also establish a well documented “Quality Management System” (QMS) which is comprised of, but not limited to:

Data governance and Data Lifecycle: this is the roles, responsibilities, and accountability of the personnel handling the data throughout the data lifecycle.
Record management: this includes, but is not limited to:
- Computer or Related Systems
- Collection and Documentation
- Sample Analysis
- Data Storage
- Data Backup
- Archival and Retrieval
Training: all site personnel should be trained and practiced on maintaining data integrity.
Access and Privilege: systems should be set up so that only the necessary personnel have access to the data input or manipulation.
Audit Trails: all creation, modification, and deletion of data should be properly dated and attributable to the personnel involved so auditors can reconstruct the full history of data without any unexplained gaps.
Quality Assurance and Quality Control: the QMS should have measures practices in place that assure data integrity is upheld as well as procedures in place to correct any data integrity weaknesses or issues.

The full draft guidance can be found here, the docket is open to comments until July 3rd, 2024, those who wish to comment can do so here. For more further assistance on preparing your site for upcoming inspections or to improve your existing QMS, Clinical Pathways offers a wide variety of inspection readiness, GxP auditing, quality systems, quality risk management, and monitoring services. Details about these services can be found at our website here.

-The Clinical Pathways Team

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