GLP vs non-GLP Studies: When to perform your toxicology studies and other IND-enabling studies GLP, and when are non-GLP studies the best choice?

GLP vs non-GLP Studies: When to perform your toxicology studies and other IND-enabling studies GLP, and when are non-GLP studies the best choice?

GLP-compliant toxicology studies are a necessary step in taking an experimental drug into clinical development and further onto the market. However, not every toxicology study needs to be GLP-compliant. Understanding which is appropriate can help streamline your drug development efforts.

By Mark Terry | December 11, 2023

Good Laboratory Practice (GLP) is a set of federal regulations that cover the planning, monitoring, performing, and reporting of non-clinical health and safety studies when developing drugs. GLP compliance is required for many aspects of preclinical studies, but not all. This article will provide an overview of the difference between GLP and non-GLP toxicology studies to help you make informed decisions when working with your Contract Research Organization (CRO).

GLP versus Non-GLP: How to select the best path?

The primary difference between GLP and non-GLP toxicology studies is evaluations of safety. Non-GLP toxicology studies aren’t as rigorous as GLP studies. Areas where GLP is required include, broadly, food and color additives, animal food additives, drugs for animals, human drugs and biologics, medical devices for humans, and electronic products. Non-clinical laboratory studies where FDA GLP compliance is required, include:

• Most nonclinical toxicology studies, including studies required for submission of an Investigational New Drug (IND) application.
• Toxicity profiles.
• Evaluating risks of clinical trials in humans or animals.
• When evaluating for adverse effects, including teratogenic and carcinogenic effects.
• To determine safe levels for use.

Areas in which GLP compliance is not required include discovery, basic research, screening, and in vitro studies where safety is not being evaluated. Areas where GLP compliance is not required include:

• In vitro drug metabolism and drug interaction studies.
• In vitro toxicology studies, genotoxicity, mutagenicity, and safety pharmacology.
• In some cases, if a sponsor company wants to evaluate preliminary drug safety by collecting data on a compound’s absorption, distribution, metabolism and elimination (ADME), non-GLP studies may be an option. This allows the sponsor to better understand the drug’s tolerability in different systems before running studies where GLP is required.

Which studies must be GLP and which can potentially be non-GLP are not cut-and-dried. Even though non-GLP studies don’t have to meet GLP requirements, they still need to generate high-quality, reviewed, reliable data. Technically, in the U.S. and in many other countries, in vitro drug interaction studies like CYP inhibition, induction or reaction phenotyping, transporter inhibition, or substrate potential fall under non-GLP studies. However, due to their importance, Bjornsson et al. noted that these studies must be “performed with high quality and consistency, particularly when the studies ultimately influence the design of clinical trials.”¹ The FDA also requires these studies be performed “in the spirit of GLP.”²

The FDA has also issued the S6 addendum³ and the S9 addendum, providing more nuance on the agency’s thinking on preclinical safety evaluation for biotechnology-derived pharmaceuticals and anticancer pharmaceuticals, respectively. The agency notes that companies can “use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.”

When is Non-GLP appropriate and when is it necessary?

Although the FDA and other regulators provide guidelines and overall regulations, determining exactly which studies are appropriate and when they should be performed can require careful planning that takes into consideration budgets and timelines. Conducting unnecessary GLP studies can waste time and money. Working early with an experienced CRO on which type of test or toxicology study is appropriate for your needs can save both time and money.

How to plan appropriately to meet deadlines and control costs.

The success of GLP toxicology studies is highly dependent upon comprehensive protocol design. Companies should identify the appropriate animal models, endpoints, dose ranges, and study duration. To maintain data quality, study protocols should be well-designed. Study protocols should also take into consideration species-specific characteristics of the animal to ensure the results are relevant to humans.

Noble Life Sciences works closely with its partners to identify appropriate animal models and carefully consider the client’s specific drug development objectives. Noble Life Sciences’ team has years of experience determining optimal dose ranges, study duration, and endpoints while prioritizing data quality via standard procedures and meticulous data collection techniques.

What are the bottlenecks to overcome to successfully complete your study?

GLP toxicology studies can be complex, and sponsor companies should be prepared to address common problems that arise during the studies. These can include problems with animal health or dosing, laboratory supply chain issues, or unexpected results. It is important to have a clear plan mapped out that includes contingency plans to address these common issues.

Noble Life Sciences’ teams are well-equipped to assist their clients in navigating any issues that may arise during the GLP toxicology studies, whether common or anomalies. 

Who should be on the project team to make an efficient study? 

Successful completion of a GLP study requires a major commitment of personnel, time and materials. A significant percentage of GLP is collecting full documentation and being able to recreate a study on paper for it to be legally defensible. Dedicated personnel are vital. They should be appropriately trained in GLP, be committed to the project, and be clear on how these studies are prioritized with their other duties.

There are five specific types of positions:

1. Sponsor/Testing Facility Management. There should be one individual who represents the organization with a level of responsibility for ensuring the work is completed in an appropriate and timely fashion.
2. Study Director (SD). This individual is responsible for the overall performance of a study and will act as the single main point of contact. As a result, that individual is the sole person who can make decisions about the study and changes to the protocol.
3. Field Investigator (FI). Although more than a single person can act as an FI within a study, only one should be assigned to a single field trial at any one time.
4. Laboratory Investigator (LI). This individual acts as the team leader, requiring strong management skills and a technical background.
5. Quality Assurance Officer (QA). There may be more than one QA officer, but one individual should take the leadership responsibilities. As such, this person is responsible for, and will sign, the protocol and final report.

Conclusion

GLP-compliant toxicity studies are sometimes considered to be “routine” compared to early investigative studies. However, even though U.S. and international regulators have outlined the parameters of GLP toxicology studies, results are not routine and can generate unexpected data. Any data can be a critical factor in identifying important issues for the viability of an experimental compound. Working with an experienced and high-quality CRO partner such as Noble Life Sciences can help drug developers streamline their preclinical toxicology studies and create efficiencies that can keep drug development on track. Reach out to a Noble Life Sciences representative today to discuss your GMP toxicology needs. 

Sources

1. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: A Pharmaceutical Research and Manufacturers of American (PhRMA) perspective. Drug Metab Dispos. 2003;31(7):815-32. https://pubmed.ncbi.nlm.nih.gov/12814957/

1. Tucker GT, Houston JB, Huang S-M. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential—towards a consensus. Br J Clin Pharmacol. 2001;52(1):107-117. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014497/

1. Guidance for Industry. S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. May 2012. U.S. Food and Drug Administration. https://www.fda.gov/files/drugs/published/S6-%28R1%29-Addendum–Preclinical-Safety-Evaluation-of-Biotechnology—Derived-Pharmaceuticals.pdf

1. Guidance Document. S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. March 2010. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s9-nonclinical-evaluation-anticancer-pharmaceuticals