The primary goal of nonclinical studies is to identify potential drug compounds with the highest probability of success in terms of safe and effective drug molecules. Thus nonclinical studies lay the foundation for successive clinical trials in humans. Besides, nonclinical studies are complex and regulated by several guidelines.
As safety is of utmost importance, toxicology studies in drug development precede all scientific analysis. After a successful outcome of toxicology studies in animal models, the FDA authorizes the drug for in-human clinical trials. Thus, toxicological studies are crucial for the approval of IND applications and subsequent use in clinical development. Here we outline a step-by-step approach to nonclinical toxicology studies.
Nonclinical toxicology bioanalysis
The ultimate objective of toxicology (tox) studies is to estimate the potential toxicity of a drug compound. Researchers assess nonclinical toxicology through a series of studies, including
- Single-dose studies
- Repeated-dose studies
- Genotoxicity studies
- Carcinogenicity studies
- Development and reproductive studies
- Toxicokinetic studies.
Single-dose and dose-range finding studies
These studies are first conducted in rodents, followed by studies in animal species such as dogs. The main objectives are:
- Determine the No-observed adverse effect level (NOAEL) and identify the maximum tolerated dose
- Identify toxicity in organs
- Establish doses for in-human studies.
With repeated-dose studies, the objective is:
- Identify which target organs have toxicity
- Understand reversibility of toxic effects
- Establish doses for future clinical trials
- 7, 14, 28 days, and 3 months for subchronic studies
- 6, 9, and 12 months for chronic studies.
The primary aim is to identify potential damage to the chromosomes or DNA that may induce gene mutations and chromosomal damage.
This study assesses the carcinogenicity effects of the drug product. The study includes:
- 26-week transgenic mouse or 2-year mouse
- 2-year rat bioassay
Development and reproductive toxicology studies
These studies include:
- Fertility studies, typically in rat
- Teratology studies
- Peri and post-natal studies
Toxicokinetic (TK) analyses are generally performed during toxicological assessments. It evaluates systemic drug exposure and links the dose administered to the time course of the drug product. However, PK TK analysis conducted over multiple doses provides the best insights for toxicological studies.
Estimating the first dose in human trials
Determining the first doses for human trials are of utmost importance for the safety of study participants. Researchers use all relevant nonclinical data; however, the NOAEL is the primary factor for first-in-human doses. However, the study dose can be estimated through different nonclinical data, for exploratory studies in human subjects.
Nonclinical data affecting the approval of a drug product
Nonclinical toxicological studies provide crucial safety and efficacy data. Sponsors can use this data to halt the development of a drug candidate or assess possible toxic effects in humans. Conditions in which nonclinical data can stop the development of new drugs, include:
- Organ toxicity. For example, suppose a drug compound is toxic to the kidneys in animal models, In that case, sponsors can verify the nonclinical study and then may reconsider stopping the development of that specific drug candidate.
- Poor PK properties. Poor PK properties are red flags. If the drug does not perform its intended role, sponsors generally halt the further development of the drug product.