The drug development process involves the conduct of both clinical and nonclinical studies. Nonclinical studies include experiments on animal models, and depending on the intended use, they may follow GLP regulations. Preclinical studies are early experiments such as pharmacokinetic studies, ADME studies, and toxicology studies (tox study) in drug development. These preliminary tests generally are not GLP compliant. However, other studies such as genotoxicity, safety pharmacology, and repeated dose toxicity studies should be GLP compliant and must be completed before submitting IND applications.
After IND approval, other GLP studies such as carcinogenicity, chronic toxicity, and reproductive toxicity studies are conducted, together with the completion of nonclinical toxicology studies. However, sponsors may face challenges while performing in vivo toxicology studies, and adequate measures will be needed to overcome these challenges.
How to overcome GLP toxicology challenges?
In preclinical toxicology testing, dose-range finding studies are the first in-vivo toxicology studies that need GLP compliance. It is common to perform toxicity tests in rodents before moving on to non-rodent species. Non-rodent species provide enough data that can be utilized to design subsequent toxicological studies. The dose selection is generally performed through the Maximum Tolerated Dose test (MTD). MTD test identifies the dose levels at which organ toxicity is observed.
Post preliminary toxicity tests, GLP toxicity studies are performed in two animal species. The design of these studies is based on data from exploratory toxicity studies. Such early insights help determine doses, duration and analyze side effects in subsequent toxicity studies. It is recommended to perform dose selection, repeated dose toxicity, and genotoxicity studies before first-in-human trials. These study series complemented with other nonclinical data may help receive clearance to conduct tests in human subjects. However, it is crucial that the test formulation used in GLP toxicology studies must be in its final formulation and preferably follow the same route of administration that is intended for human treatment.
Determining repeated dose toxicity study duration is crucial for the planning and design of nonclinical studies. Generally, the study duration of toxicity analysis in two mammalian species should be similar or may even go longer than human studies, but must not exceed the time recommended by FDA guidelines.
Toxicokinetic studies are another batch of GLP toxicology tests performed during nonclinical studies. Toxicokinetic studies are similar to pharmacokinetic studies but are performed at toxic doses. Data generated from these studies combined with other toxicity data helps interpret and compare clinical data and help recommend doses for subsequent clinical trials. Hence, taking adequate measures while performing toxicokinetic analysis may help accelerate the drug development process.
The road ahead
Several preclinical toxicology studies can be performed in parallel to make early go/no-go decisions. Initial non-GLP tox studies combined with GLP standard safety studies prove decisive in the success of biologics and small molecule drug products. Clinical and preclinical toxicology studies performed with excellent scientific protocol and adequate GLP compliance are critical in supporting IND/NDA application and the successful approval of small and large molecule drug products.