Quick Read: FDA's New Draft Guidance On Data Integrity For In Vivo BA/BE Studies

By Susan Shockey, Clarkston Consulting

The U.S. FDA has long been concerned with integrity of data related to GMP processes and documentation, including data submitted as part of applications for approvals. This focus has recently been extended to specifically address integrity of the data for bioavailability (BA) and bioequivalence (BE) studies submitted as part of applications for approvals in new drug applications and biologic license applications.

As a result of this increased focus, the FDA released a draft guidance on Data Integrity for In Vivo Bioavailability and Bioequivalence Studies on April 24, 2024.¹

The FDA stated in the federal register announcement² and in the guidance that they have “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. Data integrity concerns can impact application acceptance for filing, assessment, regulatory actions, and approval as well as post-approval actions, such as therapeutic equivalence ratings.”

Draft Guidance Explained

The purpose of the new draft guidance is to provide recommendations on achieving and maintaining data integrity for the clinical, nonclinical, and bioanalytical portions of BA and BE studies. The FDA also encourages consideration of these recommendations when conducting other studies, including in vitro, pharmacology, and toxicology studies.

The guidance provides recommendations to achieve and maintain data integrity³ with respect to (1) applicants, (2) testing site management, and (3) quality management system implementation and management.

Key points include the following.

1. Recommendations For Applicants
   1. Applicants should ensure the integrity and confidentiality of data and implement an appropriate system to manage data quality throughout all stages of the BA and BE study. They should have a quality management system that includes the design and implementation of efficient protocols for study conduct to support the reliability of study results and participants’ rights, safety, and well-being.
   2. When applicants contract with testing sites to conduct all or part of the BA and BE studies, they should ensure the testing sites are in compliance with all applicable statutes and regulations. It’s recommended that applicants have a robust site selection process to ensure they use qualified testing sites, develop a monitoring plan to verify the testing sites continuing compliance, and conduct periodic audits to verify the testing site’s compliance with their responsibilities.
2. Recommendations For Testing Site Management
   1. Testing site management is responsible for the organization and functioning of the sites where BA and BE studies are conducted or analyzed. The FDA recommends that sites ensure they have an adequate organizational structure, employ qualified and trained personnel, develop data integrity policies and objectives, create and encourage a quality culture, and implement and maintain a quality management system.⁴
   2. In a quality culture, people understand that data integrity is an organizational core value, and management demonstrates a commitment to quality. Employee engagement and empowerment are promoted by setting the expectation that data quality and integrity are the responsibilities of everyone in the organization, providing data integrity training to all appropriate personnel, and encouraging open and transparent communication between all levels of the organization, especially for reporting data integrity concerns.
3. Recommendations For The Quality Management System
   1. Use of an effective quality management system⁵ to help ensure data integrity is critical for both applicants doing their own testing as well as for contracted testing sites. Applicants and testing sites should identify and implement the most effective and efficient risk-based controls based on their processes and procedures. Key elements to be included in the quality management system include the following:
      1. Data Governance: Data governance refers to the sum total of the arrangements to ensure data integrity throughout the data life cycle and should address the roles, responsibilities, and accountability for all phases in the collection of data.
      2. Records Management: Data should be retained in such a manner that they are protected, enduring, readily retrievable, and remain readable throughout the records retention period, including collection and documentation, analysis, storage, backup, archive, and retrieval.
      3. Training: All personnel should be trained on practices, procedures, and regulatory requirements of data integrity, on measures to prevent and detect data integrity issues, and on how to report data integrity errors or concerns.
      4. Access and Privileges: The FDA recommends that the quality management system has documentation that defines the access and privileges of all users and system administrators and uses access controls to ensure that personnel only have access to the functionality that is appropriate for their respective role and that personnel have unique log-in credentials.
      5. Audit Trails: An audit trail is a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. Audit trails should capture when, by whom, and the reasons for all changes that were made to the electronic record.
      6. Quality Assurance and Quality Control: A quality assurance program should ensure the proper functioning of the processes, controls, equipment, and personnel that are part of the quality management system. The quality control program should manage risks associated with each element of the quality management system by identifying and correcting data integrity weaknesses and issues in processes and controls, training, and knowledge deficiencies. The quality control program should also include processes for recognizing and addressing compromised data.

Request For Public Comments By June 3, 2024

Because these new recommendations may have a substantial impact on applicants and testing sites, the FDA has issued this as a draft guidance, with a request for comments from the public. The FDA has requested that comments be submitted by June 3, 2024, in order to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance. Comments may be submitted at any time with reference to Docket No. FDA-2024-D-1245 at https://www.regulations.gov/docket/FDA-2024-D-1245/document.

References

1. U.S. Food & Drug Administration. (2024, April 24). Data Integrity for In Vivo Bioavailability and Bioequivalence Studies. U.S. Food & Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-in-vivo-bioavailability-and-bioequivalence-studies
2. Department of Health and Human Services. (2024, April). Data Integrity for In Vivo Bioavailability and Bioequivalence Studies; Draft Guidance for Industry; Availability. U.S. Food & Drug Administration. https://public-inspection.federalregister.gov/2024-07080.pdf
3. Jones, L.L. (2024, May 2). Integrating Data Integrity into Your Quality System. Clarkston Consulting. https://clarkstonconsulting.com/insights/integrating-data-integrity-into-your-quality-system/
4. Jones, L.L. (2020, March 23). Why Invest in a Quality Management System (QMS)? Clarkston Consulting. https://clarkstonconsulting.com/insights/why-invest-in-a-quality-management-system-qms/
5. Shah, A. & Shockey, S. (2022, August 2). Considerations for Selecting a Quality Management System (QMS) Software. Clarkston Consulting. https://clarkstonconsulting.com/insights/quality-management-system-qms-software/

About The Author:

Susan Shockey is a director with Clarkston Consulting and has wide-ranging experience in quality and regulatory compliance. She has 18 years in the life sciences area, focusing on quality systems, quality process improvement, and inspection preparation and remediation. Prior to that, she spent 15 years in quality assurance engineering supporting manufacturing, testing, and validation of NASA space flight and military hardware.

Editor’s Note: The article above serves as a great concise summary of the draft guidance. If you happen to be looking for a more detailed summary, check out this article we published.