On August 24, 2016, the Food and Drug Administration (FDA) published a proposed rule which would amend the decades-old regulations governing good laboratory practices (GLPs) for nonclinical laboratory studies (21 CFR Part 58) to require a complete quality systems approach, referred to as a “GLP Quality System.” (hereinafter the “Proposed Rule”).

A nonclinical laboratory study is an in vivo or in vitro experiment in which a test article is studied prospectively in a test system under laboratory conditions to determine its safety. FDA’s GLP regulations are intended to ensure the quality and integrity of nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by FDA. The regulations as currently framed set forth the basic requirements for study conduct, personnel, facilities, equipment, written protocols, operating procedures, study reports, and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated products. In submitting applications to FDA, applicants must include a statement that nonclinical studies have been conducted in compliance with Part 58, or if a study was not conducted in compliance with GLP regulations, a brief statement of the reason for the noncompliance (which may limit FDA’s ability to rely on the data).

Although many research laboratories have moved toward the GLP Quality System approach in light of developing best practices and global standards, the Proposed Rule would provide an updated U.S. framework that requires laboratories to implement a GLP Quality System for such studies. In doing so, the Proposed Rule addresses comments to an Advanced Notice of Proposed Rulemaking published on December 21, 2010 (December 2010 ANPRM), including requests from industry to modernize the GLP regulations. The Proposed Rule also takes into account documents from the Organisation for Economic Co-operation and Development (OECD) GLP working group. If finalized, the Proposed Rule would apply to all products for which nonclinical laboratory studies are currently conducted that are not explicitly addressed in the current regulations, specifically tobacco products. In addition, the Proposed Rule would introduce and modify definitions, terms, and organizational and personnel roles and responsibilities consistent with the implementation of the proposed GLP Quality System and the prevalence of multisite studies.

These proposed changes are consistent with FDA’s increased focus on quality and integrity of data essential to assess the safety and effectiveness of FDA-regulated products and moves to further harmonize FDA research and data quality principles with OECD principles. This advisory focuses on three areas in which the proposed changes may have a significant effect on industry research practices: laboratory study oversight, data quality and integrity, and recordkeeping.

Laboratory Study Oversight

FDA proposes to add a new section on sponsor responsibilities that provides explicit provisions for the presently implied sponsor responsibilities throughout Part 58 and adds new ones.

These responsibilities include:

  • ensuring the study protocol meets the specified requirements and signing off on protocol amendments before implementation;
  • contracting with accredited animal welfare persons for animal studies;
  • assuming ultimate responsibility in the event that the sponsor decides to transfer any or all obligations under the section;
  • using qualified contracted persons to conduct a phase of the study;
  • ensuring appropriate communication among all persons conducting any phase of the study;
  • documenting that test, control, and reference articles are prepared, characterized, and labeled in accordance with Part 58, Subpart F;
  • informing the study director of any known potential risks of the test article to human health or to the environment, and any measures necessary to protect study personnel;
  • documenting and updating, as necessary, the archive location of all raw data and records; and
  • preparing the study results, final study reports, and any amendments for FDA submissions.

Similar to the approach currently permitted for interventional clinical research under the Good Clinical Practices regulations, the Proposed Rule recognizes that sponsors may delegate the conduct of laboratory studies to third-party research organizations, so long as the sponsor retains effective control over the study conduct. FDA proposes to require documentation of any transfer of regulatory responsibilities to a “contracted person”, referring to any person a sponsor utilizes to provide a service for the study, echoing the Quality Agreement requirements industry is familiar with in drug and medical device human research and manufacturing quality programs.

With respect to testing facility management, FDA proposes to specify that upper management at a testing facility or a test site is ultimately responsible for compliance with GLPs. This requires, among other things, establishing and updating written GLP Quality System standard operating procedures (SOPs).

The Proposed Rule emphasizes that proper data management practices are essential for effective system oversight, and that FDA intends to focus on this in GLP Bioresearch Monitoring (BIMO) inspections moving forward. The expanded responsibilities of management are consistent with the medical device quality systems regulations in 21 CFR Part 820, reflecting a true quality systems approach, and evidence a greater focus on management oversight of laboratory activities. Further, FDA proposes to add study director requirements to update the regulations and to address the prevalence of multisite studies. Study directors would not be able to delegate overall responsibility for a study, even though they may delegate certain responsibilities to a principal investigator. Similar to sponsors, study directors would have specific oversight and recordkeeping requirements.

Data Quality and Integrity

The Proposed Rule adds a new section to Part 58 governing data quality and integrity. Most notably, this new section borrows from an approach FDA has set forth in the Current Good Manufacturing Practices (cGMPs) quality area. In its April 2016 Draft Guidance on Data Integrity and Compliance with cGMP, FDA states that “data integrity refers to the completeness, consistency, and accuracy of data.”

In describing “complete, consistent, and accurate data,” FDA uses the well-known mnemonic “ALCOA”, which stands for “attributable, legible, contemporaneous, original, and accurate.” Although FDA has not explicitly defined these five key attributes in the cGMP context, they are at the core of FDA’s expectations for data quality, building on regulations at 21 CFR Parts 211 and 212. The Proposed Rule “codifies” these ALCOA principles, however, FDA does not offer specific definitions for each element in the GLP context either. This likely suggests that the conceptual framework set forth in Parts 211 and 212 and in the April Draft Guidance should be applied to the GLP quality system. Based on FDA’s guidance documents and an accompanying presentation, and Parts 211 and 212, if the Proposed Rule is finalized, we believe the following descriptions for each ALCOA element would likely apply in the GLP context:

  • attributable: the individual(s) who entered and/or subsequently modified the data can be identified;
  • legible: electronic data and metadata should be in human-readable form and modifications should not obscure prior entries;
  • contemporaneous: the time of the data entry electronically or by other means should be in close proximity to the time of obtaining results from the clinical activity (i.e., at the time of performance);
  • original (or a true copy): the earliest record of the data, where changes and/or corrections do not obscure prior entries;
  • accurate: quality control measures and processes are in place to ensure that no errors have occurred during data collection so as to provide a valid representation of the results, or if errors have occurred, that they have been fully investigated and resulting corrections have been documented.

In addition to setting forth these standards for data quality, FDA proposes to update the current section on equipment design (21 CFR 58.61) to include computerized systems and other modern equipment used for maintenance, archiving, and retrieval of data. This proposed change is consistent with the fact that most data are now stored data electronically for easy access and further examination.

Furthermore, the Proposed Rule modifies the test, control, and reference articles section to require characterization information to be provided as soon as available to interpret the study properly. Reports submitted to FDA must provide study information based on the characteristics of the test article studied. The lack of characterization information limits the important test result discussion in the final study report. For nonclinical studies conducted in support of initiating clinical “first-in-human” studies, the characterization information is particularly important for human subject protection.

Finally, with regard to electronic data capture and maintenance, FDA proposes that electronic record systems need to be compliant with applicable regulations (specifically, 21 CFR Part 11). The final study report must contain all data accrued in the study so that there is no bias. Study data must be maintained in a manner that allows for reconstruction of the study for the purpose of assessing the quality and integrity of the data in light of later findings.

This clear application of Part 11 may be a reflection of negative inspectional observations and a concern that as more early-stage research shifts outside the U.S., FDA will increasingly need to rely on an audit trail to have meaningful risk-based oversight of foreign study sites.

Recordkeeping

Beyond the data management requirements noted above, the Proposed Rule adds a requirement for retention of correspondence and other documents relating to interpretation and evaluation of data, other than those documents contained in the final study report.

FDA also specifies a two-week timeframe for archiving required study material and requires archiving SOPs to include procedures specific to removing study materials. FDA believes that the timeframe provides stakeholders flexibility without compromising the integrity of the study material. Moreover, the SOP requirement ensures that material is not lost or destroyed if removed.

FDA also seeks to add an additional required retention period from the date an application or submission is administratively closed by FDA. The expanded scope of the retention period addresses applications that might not result in an approval, clearance, or a premarket authorization. As such, “administratively closed” includes those applications and submissions closed administratively with or without a decision. Moreover, recognizing that a change of archive location may be due to reasons other than closure of the testing facility, FDA proposes to include a timeframe for reporting that accommodates such changes. The timeframe ensures that facilities inform FDA and the study sponsor of the location of study materials, especially if a GLP BIMO inspection is warranted.

Conclusion

The Proposed Rule represents a rethinking and harmonization of Part 58 during a time in which FDA and the public have increasingly scrutinized industry research practices and transparency regarding data quality issues. The application of the GLP Quality System approach as the means to address these concerns should not come as a surprise to those who have worked in the regulatory field over the past ten years, and a similar approach has been applied in other areas of FDA’s jurisdiction. The increased attention to oversight, data integrity, and recordkeeping requirements will mean regulated entities will need to invest resources to ensure compliance, particularly with regard to oversight of contract research organizations and certain ex-US research facilities that historically have not been as attuned to FDA standards. FDA seeks public comments on the Proposed Rule until November 22, 2016.