Regulatory Operations  Institutional Office of Regulated Nonclinical Studies (ORNcS)

Policy 11.02.01 Institutional Office of Regulated Nonclinical Studies

“The Institutional Office of Regulated Nonclinical Studies (ORNcS) is granted authority to assess/evaluate funding applications that include regulatory compliance with the Good Laboratory Practice (GLP) Regulations. The subsequent planning, management and regulatory oversight of GLP compliant studies is managed through the ORNcS via partnership with the Principal Investigator. ORNcS is required to be involved in all studies regarding any material or mention of GLP standards…”

Read the full policy. When in doubt, or for more information, please contact Dr. David Beasley or Ms. Melissa Eitzen or send a general email to ORNcS@utmb.edu.

In 2002, the United States Department of Health and Human Services Food and Drug Administration (FDA) published the final rule for New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible. The regulations, which allow the equivalent of human phase III clinical trials to be performed in animal studies when human studies are not ethical or feasible, are commonly referred to as the Animal Rule (21 CFR Parts 314 and 601, 2002).

In the introduction to the supplementary information of the Animal Rule is this statement: “All studies subject to this rule must be conducted in accordance with preexisting requirements under the good laboratory practices (21 CFR part 58) regulations and the Animal Welfare Act (7 U.S.C. 2131 et. seq.).” Because of the increased safety risk and highly infectious nature of the agents that fall under the purview of the Animal Rule, these studies are often performed in high or maximum (BSL-3 or BSL-4) biocontainment laboratories. The logistics of assuring accurate and reliable data are collected and transferred from a BSL-4 (i.e., maximum biocontainment) laboratory, conducting the study under regulatory oversight, maintaining animal records equating to clinical case files, characterizing the disease-causing agent, and designing the appropriate study to satisfy the regulatory reviewers that study data are equivalent to the outcome in humans are challenging and complex. The FDA Guidance for Industry: Product Development Under the Animal Rule provides the current thinking of expectations, including complying with the GLP regulations “to the extent practicable.”

According to the FDA Compliance Program Inspection of Nonclinical Laboratories Conducting Animal Rule-Specific Studies, “The Good Laboratory Practice (GLP) regulations (21 CFR part 58) were developed as a quality system for nonclinical safety studies, and thus, do not address the Animal Rule-specific studies. FDA, however, considers the GLP regulations to be a well-established and relevant framework (e.g., definitions, procedures, roles and responsibilities, and controls) for ensuring data quality and integrity in Animal Rule-specific studies.”

Use of the Animal Rule pathway to seek a regulatory decision is determined by the Agency through sponsor interaction. The FDA strongly encourages sponsors of medical countermeasures to establish early and ongoing communication with the FDA. Animal Rule studies performed at UTMB must involve the ORNcS, to include critical phase inspections performed by the Quality Assurance Unit (QAU).

The Animal Rule, associated Guidance Documents and the Compliance Program are all available on fda.gov and are listed individually under ORNcS Education and Resources.

Compliance is not a standalone element of a grant or contract; compliance is integrated in the design, conduct, and oversight of a regulated nonclinical study (or series of studies). If the funding agency requires GLP compliance (or mentions GLP as a reference standard) and/or if the study satisfies the scope of the GLP regulations, or Animal Rule, and the sponsor intends to submit the data to the Agency for a regulatory decision, contact ORNcS for review prior to submission. Regulated studies require a combination of scientific expertise and independent regulatory oversight. A significant increase in personnel, time, and effort is required to assure compliance.

Additionally, sponsors may require elements of GLP to assure data quality and integrity and to enhance efficiency by more rapidly progressing products through the regulatory pipeline. Some sponsors may view the requirement as a risk-based business decision whereas others may include elements to enhance the rigor and reproducibility of the study(ies). Sponsors may also have received feedback from the FDA and prospectively included the requirement. ORNcS can assist UTMB investigators during preliminary discussions with prospective sponsors to determine the necessity for, and appropriateness of, GLP quality system elements for their planned scope of work.

Per UTMB IHOP Policy 11.02.01 Institutional Office of Regulated Nonclinical Studies, “ORNcS is required to be involved in all studies regarding any material or mention of GLP standards…”

Contact Dr. David Beasley, Ms. Melissa Eitzen, or send a general email inquiry to ORNcS@utmb.edu for more information or to request a review.

The FDA GLP regulations are a Quality Standard for the conduct of regulated studies specifically delineated in the Scope (§58.1) of Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58). The FDA expects the GLP regulations to be followed to the extent practicable for Animal Rule studies, to include the model defining natural history studies. There are several partnering Guidance for Industry documents that provide FDA’s current thinking on best approaches and expectations for the conduct and oversight of regulated studies. The ORNcS (both the Regulatory Science and the Regulatory Operations branch) can help navigate compliance requirements for study design, conduct, and oversight.

Below is a summary table of the types of documents required to satisfy overarching requirements. Study records should be transparent and allow for reconstruction of all study-related activities.

Studies Conducted Under a Quality System Using GLP as a Reference Standard.

*Definitions (per GLP regulations):

• Protocol = Approved document that clearly indicates the objectives and all methods for the conduct of the study. [Subpart G, Section 58.120 (a)]
• Study Director = Individual responsible for the overall conduct of a nonclinical laboratory study. [Subpart A, Section 58.3 (m)]

Quality Agreement

ORNcS Regulatory Operations can help with the development of Quality Agreements for industry- or government-funded contracts that may not have a strict regulatory compliance requirement but require a formal quality system infrastructure. A Quality Agreement may be included as part of the Sponsored Research Agreement to ensure clear definition of deliverables related to study planning, record keeping, data handling, data review and/or verification, and reporting of findings.

§58.25(a) of the FDA GLP Regulations states:

“a testing facility shall have a quality assurance unit (QAU) which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. For any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of that study…”

At UTMB, the independent QAU resides within the Regulatory Operations branch of the Institutional Office of Regulated Nonclinical Studies and remains separate from study conduct. The level of QAU involvement is dependent on each study and where it falls on the regulatory pathway. For Animal Rule studies, QAU conducts in-life critical phase inspections as determined during study protocol development. For other studies, the level of QAU oversight is determined through interactions with the study sponsor and the Principal Investigator of the grant/contract. A Quality Agreement is typically negotiated, through ORNcS Regulatory Operations, for regulated studies when GLP is the reference standard for assuring data quality and integrity. This Agreement defines compliance expectations.

Sponsor monitoring visits are frequently a part of regulated studies and are hosted by QAU. The number and frequency of these visits is determined during grant/contract negotiations; therefore, involvement of ORNcS Leadership is required.

The Regulatory Operations Team is independent from study conduct and provides support and oversight of nonclinical regulated studies. Services are integrated into the planning and conduct of regulated studies and require pre-submission discussion for incorporation. Below is a general list of responsibilities:

• QAU critical phase inspections
• QAU facility audits
• QAU data verification reviews
• Host of Agency and Sponsor audits
• Host of Sponsor qualification audits
• QC of data and collection forms for GDP prior to QA review
• Secure SOP management and distribution via Electronic Document
• Management System (EDMS)
• Document retention and archival of regulated studies
• Development and negotiation of Quality Agreements
• Regulatory consulting
• Submission Proposal review (collectively with ORNcS Regulatory Science Branch)
• Education (please see Education and Resources Section)

Data Quality

The GLP regulations are a Quality System intended to assure the quality and integrity of the data; this includes data derived from Animal Rule studies. Sponsors may include GLP compliance (or components thereof) as contractual or funding requirements.

The ALCOA principles of Good Documentation Practices (GDP) provide the foundation for assuring data quality, where:

• A= Attributable (the individual who collected the data or made the original observation)
• L = Legible (readable, code available)
• C = Contemporaneous (information recorded/captured/documented in real time)
• O = Original (or exact copy thereof)
• A = Accurate (truthful)

Data integrity can be evaluated through the lens of documentation (study records) being complete, consistent, enduring, and readily available.

The World Health Organization’s Handbook on Quality Practices in Basic Biomedical Research states the following:

“Making a full record of all information is essential not only to permit appropriate scientific interpretation of the results but also to enable complete reconstruction of the study, should this be necessary. Documentation is the only way of demonstrating what actually went on at the time of the experiment. Without documentation the process is meaningless; essentially there has been no study.”