Office of Regulated Nonclinical Studies Connecting scientific research with regulatory requirements

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.