Key steps in the preclinical development of a drug

The preclinical development phase corresponds to the initial stage of a drug’s life cycle. It precedes clinical trials in humans. Its main objective is to provide initial data on the behavior of the experimental molecule “in vitro” and then “in vivo,” in order to ensure its safety and support future use in humans.

During this phase, the mechanism of action of the drug candidate is validated, and its safety (toxicity) and activity in the body are evaluated. A preliminary pharmacokinetic and pharmacodynamic profile is then established. All of this data is then used as a basis for calculating, with safety margins, the initial dose and route of administration for the first clinical study in humans.

 

 

Definition and objectives of preclinical development

Preclinical studies mark the first stage in the life cycle of a drug. Conducted on non-human systems (cell models followed by animal models), these studies identify the drug’s efficacy, mechanism of action, adverse effects, toxic doses, and target organs. They therefore include the analysis of pharmacodynamics, pharmacokinetics (ADME), and toxicology, in accordance with GLP requirements and ICH guidelines. Preclinical development is essential for compiling the regulatory dossier for the clinical trial application (CTA) and the marketing authorization application.

Please note: this article does not detail the clinical phases that follow the preclinical phase. However, it is important to note that the design of the first study in humans, particularly the choice of dose, route, and frequency of administration, is determined by the preclinical results of toxicology and pharmacokinetics. Similarly, the toxicology program continues in parallel with clinical development to monitor long-term safety.

 

 

The main stages of preclinical development

The preclinical phase comprises a series of pharmacological and toxicological studies conducted in a progressive manner.

 

In vitro studies (pharmacology and screening)

Tests conducted on cells or biochemical models confirm the targeted mechanism of action. They then enable promising candidate molecules to be quickly identified. This phase therefore provides early pharmaceutical proof of concept before progressing to more complex trials.

 

In vivo studies (efficacy and toxicology)

The selected candidates are then tested on animals to assess both efficacy and systemic toxicity. These experiments provide a preliminary safety profile: acute toxicity (single dose), subchronic and chronic toxicity (repeated doses), and reproductive toxicity.

 

Pharmacokinetics (ADME)

The fate of the drug in the body is then studied (Absorption, Distribution, Metabolism, Excretion). This step measures blood concentration over time, identifies metabolites, and evaluates how the compound is eliminated. It therefore defines, in particular, the appropriate route of administration and frequency in humans.

 

Pharmacodynamics

During this phase, the dose-response relationship is quantified using dose-response curves and parameters such as the median effective dose (efficacy threshold) and median lethal dose (toxicity threshold). It then validates the activity of the active ingredient at the cellular and organic levels.

 

Toxicology and safety pharmacology

These specific tests detect any potential adverse effects on vital systems. “Safety pharmacology studies” evaluate, for example, the effects of the candidate at doses higher than therapeutic doses on heart rate, blood pressure, brain function, etc. They follow the principles of the ICH S7A “Core Battery” and must meet GLP (Good Laboratory Practice) standards.

 

Specificities according to molecule type

The preclinical study plan varies depending on the nature of the candidate: small chemical molecules, biological molecules, or cell therapy or gene therapy drugs. Biological drugs, for example, require immunogenicity and binding stability testing. Gene therapies involve biodistribution and targeted genotoxicity studies. Additional recommendations are provided depending on the type of therapeutic entity, according to specific regulatory guidelines (EMA for Europe, FDA for the United States).

 

 

Preparation of the regulatory dossier

All preclinical results must be compiled in the regulatory development dossier. As part of a clinical trial application, data from preclinical studies are included in the Investigational Medicinal Product Dossier (IMPD) and/or summarized in the investigator’s brochure for a clinical trial application dossier. These elements are then included in the Common Technical Document (CTD), particularly modules 2 (syntheses) and 4 (non-clinical reports) for the marketing authorization application (MAA).

These detailed preclinical data are required by all health authorities in Europe and the United States. This is required even before clinical trials begin. To this end, it must comply with international standards (ICH guidelines). It must also demonstrate that the drug candidate is reasonably safe for initial testing in humans. This same data will be included in the marketing authorization application (MAA).

 

 

Challenges and issues in preclinical development

Several challenges arise during preclinical development.

 

Long duration and high cost

Preclinical development involves complex studies (in vitro, in vivo, toxicology, pharmacokinetics) over several years. Conducting these studies in accordance with GLP requires significant technical and financial resources. These early investments, with no guarantee of success, further increase the overall cost of drug development.

See also: Reducing drug development time

 

Very high failure rate

More than 90% of drug candidates fail during development. According to a Forbes study cited by PharmAnalyses, the failure rate for candidates is as high as 95%.

 

Strict regulatory constraints

Studies must comply with numerous standards. To this end, they follow a testing program tailored to each therapeutic indication. The required reports, which must be comprehensive and traceable, significantly increase the regulatory burden.

 

Ethical constraints related to animal testing

Animal testing, which is essential for preclinical studies, raises major ethical issues. Regulations therefore impose strict protocols, governed by GLP. Alternative approaches (organoids, organs on chips) are being developed in parallel to limit the use of animals.

 

Prediction limitations and health risks

Certain adverse effects remain difficult to detect in the preclinical phase. This structural risk therefore often requires a margin of safety (safety doses) to be built in. It also requires the continued collection of safety data (pharmacovigilance) well after the preclinical phase, when the drug is used in clinical trials.

 

 

Conclusion

Despite these limitations, preclinical development remains essential for the creation of safe and effective drugs. It serves not only to rule out dangerous candidates as early as possible, but also to deepen understanding of the drug. This must be done before taking the risk of administering it to humans for the first time.

 

 

1. ICH (International Council for Harmonization) is an international organization that develops harmonized guidelines to ensure the quality, safety, and efficacy of drugs in the world’s major regulatory markets.
2. GLP (Good Laboratory Practice) refers to an international regulatory framework that guarantees the quality, traceability, and reliability of non-clinical studies submitted to health authorities.

 

Sources:

• Pharmacomedicale: “Drug development and monitoring”
• Interpharma: “Preclinical phase”
• Leem: “Preclinical development or initial evaluation”
• Inserm: “Drug development: from test tube to pharmacy”