Understanding GLP and Non-GLP Toxicology Studies in Drug Development

What are Good Laboratory Practices?

In 1972, New Zealand first legislated to require all laboratories conducting scientific experimental research to register, which is Good Laboratory Practice (GLP). In 1973, Denmark proposed a similar National Experimental Council Act. In 1978, FDA launched the Good Laboratory Practice for Nonclinical Laboratory Studies (GLP), which standardized the standards for toxicological testing, made toxicity test results more convincing, comparable, and evaluable, and included them in federal regulations. This marks the true birth of GLP regulations.

GLP refer to a set of principles and regulations designed to ensure the integrity, reproducibility, and reliability of non-clinical health and safety studies. Initially introduced by FDA in response to concerns about the scientific quality and reliability of data from nonclinical studies, GLP standards were aimed at improving the quality of toxicology studies, environmental safety assessments, and other preclinical research. The framework outlined by GLP emphasizes meticulous planning, organization, and monitoring of studies, as well as the rigorous documentation of procedures, results, and safety protocols.

Following FDA's initiative, the Organization for Economic Co-operation and Development (OECD) published the GLP principles in 1981 to harmonize regulatory standards globally. Today, GLP is recognized worldwide as the gold standard for conducting non-clinical studies, ensuring that data is universally acceptable to regulatory agencies across countries.

Toxicology studies in drug development

Drug toxicology is based on the physical and chemical properties of drugs, using the principles and methods of toxicology, to conduct a comprehensive and systematic safety evaluation of drugs and clarify their toxic mechanisms. Its main purpose is to guide clinical rational drug use, reduce adverse drug reactions and reduce the failure of new drug development due to drug toxicity. The key to successful drug toxicology studies is the effective combination of safety data with other specific molecular characteristics, such as absorption, distribution, metabolism, and excretion (ADME), as well as physicochemical properties, to address the inherent risks of potential targets and potential lead drugs. This involves a paradigm shift from the use of classical in vivo toxicological approaches to translational mechanically-based in vitro tests that can serve as a reliable predictive alternative to in vivo studies. In recent years, significant innovative advances have been made in areas such as induced pluripotent stem cells (IPscs), 3D tissue models, microphysical systems (MPS), and imaging techniques that have the potential to greatly improve the predictive value of toxicological research analyses.

Types of toxicology studies

Several types of toxicology studies are conducted during the preclinical phase of drug development:

Acute toxicity studies: These studies assess the immediate toxic effects of a drug after a single dose or short-term exposure.

Chronic toxicity studies: These studies evaluate the long-term effects of repeated exposure to a drug, often over a period of months or years.

Genetic Toxicology: These studies investigate whether a drug causes genetic damage, which could result in cancer or heritable genetic mutations.

Carcinogenicity studies: These studies are designed to identify whether a drug has the potential to cause cancer after long-term exposure.

Safety pharmacology studies: These studies examine the effects of a drug on key physiological functions such as heart rate, blood pressure, and respiration.

GLP toxicology studies

GLP toxicology studies adhere to a strict set of regulatory guidelines and requirements that ensure the study data is reliable, reproducible, and scientifically sound. These studies are conducted under highly controlled conditions, with careful documentation of all procedures, results, and adverse events.

Key components of GLP toxicology studies

GLP toxicology studies emphasize standardization of laboratory environmental management. To ensure the reliability and reproducibility of data, laboratories must comply with GLP regulations in terms of facilities, personnel, equipment and operating procedures. Laboratory personnel need to receive prescribed training to ensure that they are proficient in operating procedures and can perform experiments correctly.

GLP studies should be conducted under the guidance of a detailed test plan, which should include information such as the purpose of the test, materials used, experimental design, methods and evaluation criteria. In addition, all data and observations must be recorded during the experiment, and any deviations from the plan need to be recorded and explained. These records should be kept to ensure the reproducibility and traceability of the study.

Implement strict quality control procedures, including data collection, processing, analysis and reporting, to ensure data integrity and accuracy. Measuring instruments need to be calibrated and maintained regularly to ensure that they work properly and provide reliable data.

Research reports should be clear, accurate and provide all necessary raw data and analytical results to allow independent review and verification. The reviewers must have no direct connection with the experimenter to objectively and impartially assess the scientificity and credibility of the study.

When is GLP required?

GLP is required for studies that support regulatory submissions, particularly those required for IND applications and approval. Regulatory authorities such as the FDA require that toxicology studies conducted for human risk assessment meet GLP standards. This ensures the reliability of the data and helps mitigate risks in clinical trial phases.

Toxicology studies at BOC Sciences

Non-GLP toxicology

Non-GLP toxicology studies refer to studies that do not adhere to the formal GLP standards. While non-GLP studies may not require the same level of documentation, quality control, and organizational oversight as GLP studies, they still produce scientifically valid and reliable data. These studies are typically used during the early stages of drug development when exploratory data is needed.

Characteristics of non-GLP studies

Flexibility: Non-GLP studies are more flexible in terms of study design, duration, and sample size.

Cost-Effective: Non-GLP studies are generally less expensive than GLP studies because they do not require extensive documentation, validation, or regulatory oversight.

Faster turnaround: The reduced regulatory burden allows for quicker execution and reporting of results, which can be advantageous for early-phase decision-making.

When can non-GLP testing be considered?

Non-GLP testing is most commonly used in the early stages of drug development, such as exploratory research, drug metabolism studies, and screening for potential drug candidates. Non-GLP studies are particularly useful for generating preliminary safety data, such as ADME properties, that can inform further development decisions.

Non-GLP studies are also appropriate when the primary goal is to gather data for internal decision-making rather than regulatory submission. These studies help identify compounds with promising pharmacokinetic profiles or potential safety issues, allowing researchers to prioritize candidates for further investigation.

GLP vs non-GLP toxicology studies

The primary differences between GLP and non-GLP toxicology studies lie in their regulatory requirements, reporting standards, and the level of oversight involved:

Regulatory requirements: GLP studies are required for regulatory submissions, while non-GLP studies are typically used for internal decision-making or early-phase research.

Documentation: GLP studies require comprehensive study reports, including detailed protocols, results, and deviations. Non-GLP studies may only require data summaries.

Sample size and duration: GLP studies often involve larger sample sizes and longer durations to meet regulatory standards, whereas non-GLP studies can be more streamlined and focused on specific objectives.

Advantages of GLP studies: The main advantage of GLP studies is that they generate data that can be used to support regulatory submissions. This is crucial for obtaining IND approval and advancing to clinical trials. GLP studies also provide a high level of assurance regarding data integrity and reproducibility.

Advantages of non-GLP studies: Non-GLP studies are advantageous in the early stages of drug development because they are more flexible, cost-effective, and faster to conduct. They are ideal for exploratory research and preliminary safety assessments.