Preclinical development refers to the phase of drug development that takes place before a substance is first used in humans. During this phase, the efficacy, safety, and pharmacological properties of a new active substance are investigated in laboratory and animal studies. The results of preclinical studies form the scientific basis for the first clinical trial in humans and are a prerequisite for submitting a clinical trial application (CTA or Investigational New Drug Application, IND in the USA). Without sufficient preclinical data, regulatory authorities will not approve a clinical Phase I study. The results from the preclinical phase also significantly influence dose finding, patient selection, and safety monitoring in the first clinical trial.
Objectives and Content of Preclinical Development
Preclinical development pursues several parallel objectives. First, demonstration of pharmacological efficacy: Does the substance act on the intended mechanism in the animal model? Second, toxicological characterization: Which adverse effects occur at which dose, and which organ systems are affected? Third, safety pharmacology testing: Does the substance affect the cardiovascular system, the central nervous system, or respiration? These safety pharmacology studies are regulated by ICH guidelines S7A and S7B.
In parallel, basic pharmacokinetic data are collected: How is the substance absorbed, distributed, metabolized, and excreted? Which metabolites are formed? How does the substance behave in different species? These data are critical for selecting the appropriate animal species for toxicity studies and for planning the first human dose.
Toxicity Studies and GLP Requirements
Toxicity studies are the cornerstone of preclinical development. They include single-dose studies (acute toxicity), repeat-dose studies (subacute and chronic toxicity), genotoxicity studies, reproductive toxicity studies, and carcinogenicity studies. Which studies must be completed before study initiation depends on the planned duration and patient population of the clinical trial and is regulated in ICH guidelines M3(R2) and S1–S9.
All regulatory-relevant preclinical studies intended to serve as the basis for a clinical trial or marketing authorization application must be conducted under Good Laboratory Practice (GLP) conditions. GLP is a quality system that ensures preclinical studies are planned, conducted, documented, and reported according to defined standards. Compliance with GLP is inspected by national authorities. Studies without GLP compliance are not recognized by EMA and FDA for marketing authorization procedures.
From Active Substance to Clinical Trial
The path from discovery of an active substance to the first clinical trial typically takes four to six years. Initially, a large number of substances are tested for biological activity in high-throughput screening procedures. Promising candidates are chemically modified during lead optimization to improve efficacy, selectivity, and stability. The optimized drug candidate then undergoes the complete preclinical safety program.
Once all required preclinical data are available, the Investigational Medicinal Product Dossier (IMPD) is prepared, which summarizes all preclinical and quality-related data. This dossier is submitted to the competent authority and the ethics committee together with the study protocol. Only after regulatory approval may the first clinical trial (Phase I) in humans begin.
Translation Problems and Limitations of Animal Models
A central challenge of preclinical development is the so-called translational gap: Many active substances show good efficacy in animal models but fail in clinical development in humans. Causes include differences in pharmacology between species, unsuitable animal models for complex diseases such as cancer or neurodegenerative diseases, and differences in the immune system. This discrepancy is one of the main reasons for the high failure rate in clinical drug development.
To improve the predictive power of preclinical studies, human cell models, organoids, and in silico methods are increasingly being used. These modern approaches cannot completely replace animal testing, but they meaningfully complement the preclinical program and can identify critical safety signals early. Furthermore, they contribute to reducing the number of laboratory animals used, which is ethically imperative and increasingly required by regulators. Full-service CROs such as mediconomics advise sponsors on planning the preclinical development program, selecting appropriate study designs, and regulatory submission of CTA documentation.
Preclinical development is also of particular importance for dose finding in the first clinical trial. The starting dose in humans is derived from the No-Observed-Adverse-Effect-Level dose (NOAEL) from the most sensitive animal model and is provided with a safety factor that reduces the risk for healthy subjects to an acceptable minimum. ICH guideline M3(R2) and the FDA guidance on dose escalation in Phase I studies provide detailed instructions for this calculation. An overly conservative starting dose unnecessarily prolongs the Phase I study, while an excessively high starting dose creates unacceptable risks for study participants. Correct derivation of the safe starting dose for humans from animal data requires deep pharmacological expertise, knowledge of species differences, and solid experience with the regulatory requirements of EMA and FDA.
Frequently Asked Questions (FAQ)
Which Preclinical Studies Are Mandatory Before a Phase I Study?
At minimum, the following must be available: acute and repeat-dose studies (duration corresponding to the planned clinical phase), safety pharmacology (cardiovascular, central nervous system, respiration), initial genotoxicity data, and basic pharmacokinetic data. The exact requirements are regulated in ICH M3(R2) and depend on indication, target population, and treatment duration.
What Does GLP Mean in Practice?
GLP prescribes how preclinical studies are planned, conducted, and documented: study director, quality assurance unit, archiving, equipment validation, and test substance characterization must comply with precisely defined standards. Non-GLP studies are permissible for exploratory purposes but are not usable for regulatory submission.