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by: mark arnold

Rmark-arnold-1ecently, proposed revisions to the U.S. Good Laboratory Practices (GLP) regulation were published in the Federal Register. As part of the updates, the Food and Drug Administration (FDA) has tried to improve alignment with the Organization for Economic Co-operation and Development (OECD) GLPs, particularly with multisite studies, which are more frequently the norm today. Included in the Federal Register publication are not only the proposed changes, but also the background and rationale for the changes and the potential cost of implementation. 

Of notable relevance to those overseeing GLP-compliant studies are the proposed updates to roles, responsible signatory approvals, and assignment of a lead Quality Assurance Unit (QAU), which I’ll take in turn in this short blog entry.

  1. While the FDA has maintained the roles of management, study director, and quality assurance within their draft GLP revision, other changes to support multisite studies may require tweaking to make them practical.

“Management is responsible for establishing and maintaining conditions and procedures necessary for the conduct of nonclinical laboratory studies compliant with GLPs; the study director, as the sole point of study control, is responsible for implementing those procedures in specific studies; and the QAU is responsible for inspecting and general oversight of studies, verifying that they are GLP compliant or recommending changes needed for bringing them into compliance.”

These changes are all part of the GLP Quality System that FDA is looking to include, and these roles are responsible for ensuring quality and compliance.

  1. In the past, it was possible that a principal investigator (PI) (even though they were not named that) would receive a final signed protocol without ever having seen a draft, much less being able to comment on it. The proposed GLP revision includes changes related to the protocol and mandatory signers that specifically requires PIs and independent contributing scientists to be named within the protocol and be signatories to it.

“We propose expanding this provision to indicate study protocol approval by the dated signature of the study sponsor, the study director, independent contributing scientists, principal investigators, and any other person conducting a phase of the nonclinical laboratory study, as applicable.”

This adds an improved level of communication between the study director, sponsor, independent contributing scientists, and the PIs, and it ensures that all parties are aligned on the execution of the study. When changes occur in multisite studies that may span the globe, the combination of naming PIs and key contributors in the protocol could have led to extensive signatory requirements that may not have been the most effective and efficient. However, FDA has placed limits on who has to sign amendments to only those affected named parties before the amendment can be implemented. This clearly prevents massive rounds of signing for each amendment.

  1. As part of the overarching implementation of a GLP Quality System, “management with executive responsibility” is required to name a lead QAU. This brings into play two new aspects: 1) what is “management with executive responsibility,” and 2) what are the responsibilities of the lead QAU. As defined, they are:

“Management with executive responsibility means those senior employees of a testing facility or test site who have the authority to establish or make changes to the quality policy and GLP Quality System at the testing facility and test site, respectively.”

Lead Quality Assurance Unit: We propose adding a definition for a lead quality assurance unit (lead QAU) meaning the QAU responsible for quality assurance (QA) in a multisite nonclinical laboratory study. We propose that testing facility management with executive responsibility selects the lead QAU. The location of the lead QAU may be at the testing facility, with another person conducting a phase of the study, or provided through a contractual relationship. This definition is consistent with the definition for lead QAU in the OECD consensus document…”

This gets interesting as each participating site must havemanagement with executive responsibility” who ensures compliance through standard operating procedures (SOPs) and fulfills the roles delineated throughout the regulation for the role.  Therefore, who defines the lead QUA—is it the study director’s, the in vivo site’s, or the sponsor’s “management with executive responsibility”?

In reading further in the actual language of the proposed regulation section, some details emerge in 58.35 Quality assurance unit (QAU) “(2) Location and identity. (ii) For multisite studies, a lead QAU must be designated by testing facility management with executive responsibility and must have responsibility for the QA of the entire study. The lead QAU can consist of personnel at the testing facility, be a QAU for another person conducting a phase of the study, or be a separately contracted unit.

This definition requires understanding what the testing facility is, which has not changed from the existing regulation (58.3 (g) and (h)): “Testing facility means a person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system”. Thus, for most preclinical studies in drug development, the testing facility “management with executive responsibility” falls to the site where the test article is administered to animals. If a sponsor has contracted that portion of the study, negotiations may be required to define an acceptable Lead QUA for the primary parties.

These are just three examples that highlight how the proposed changes to the U.S. GLPs will result in careful consideration by the pharmaceutical and biotech industry on appropriate SOPs and operational activities to achieve compliance. Since these are currently just proposed regulation changes, interested parties, such as AAPS, have been invited to provide input to FDA. Additionally, industry should recognize that making changes in advance of a final regulation may put in place practices that are not aligned with the final regulation.

I’d like to thank and acknowledge Stephen Lowes and Eric Fluhler for their thoughtful review and comments.

Mark E. Arnold, Ph.D., is Site Lead for Covance bioanalytical services, West Trenton, NJ.  He is currently Vice Chair of APQ and is an AAPS fellow.