Pre-clinical Studies in New Drug Development

The Drug Discovery and Development process encompasses several phases, and pre-clinical studies are among the most relevant ones. Pre-clinical studies in Drug Development bridge the gap between in vitro and in silico models to the introduction to human clinical trials. This term refers to any research activity with a drug or treatment before being tested in human volunteers. Through this process, researchers narrow down the possibilities from a nearly infinite number of potential therapeutic compounds to lead compounds, usually one or a few candidates for clinical trials.

Pre-clinical studies are filled with challenges, ranging from the appropriate animal species selection to the generation of relevant data for the subsequent clinical phases. In this article, we’ll elucidate the importance of pre-clinical studies in new Drug Development, and what phases a new drug must go through to be approved for the market.

The Importance of Pre-clinical Studies in Drug Development

Drug Discovery and Development is an expensive, highly regulated, complex, and extremely high-risk process. One noted issue with early Drug Development is a disconnect with clinical trials, where the translation has a success rate of less than 10%. The major causes of attrition are poor clinical efficacy and safety, typically investigated during pre-clinical studies in new Drug Development, with pre-clinical toxicology and pharmacology studies, respectively.

For this reason, pre-clinical Drug Development is crucial in the process, as the assays are designed to identify one or few lead candidates from several hits. Regulatory agencies require robust pre-clinical data to allow the progression to human testing, ensuring that only the most promising and safe candidates move forward. This rigorous evaluation is essential for minimizing human risk and optimizing the use of economic resources, as well as the chances of clinical success.

Pre-clinical studies in Drug Development encompass both in vitro and in vivo studies, and choosing the most time and cost-effective models is a crucial step. In vitro studies utilize cell cultures or other models to assess a drug's interaction with the target molecule and its impact on cellular processes. Promising in vitro results pave the way for in vivo studies with animal models closely resembling the targeted human disease. However, in recent years, there has been a growing interest in the use of New Alternative Models (NAM) during this phase, like Zebrafish, to support the 3Rs Principle of Replacing, Refining, and Reducing animal testing. Interestingly enough, zebrafish is a NAM that is in between an in vitro and in vivo model. Since one of its main advantages is that their embryos are transparent and have a fast development and small size, all the tools implemented in an in vitro laboratory can be used at this stage but in a whole living organism.

Drug Development: From Discovery to Approval

The Drug Discovery and Development process is typically divided into three major steps: lead optimization, pre-clinical development, and clinical trials. The boundary between pre-clinical development and clinical trial is sharply defined by filing an Investigational New Drug (IND) application, which is required before initiating the clinical trial and protecting the substance with a patent, ensuring intellectual property over this.

1. Lead Optimization

The process begins with the identification of promising drug candidates. This phase leverages diverse techniques, including High-Throughput Screening (HTS) of vast chemical libraries, target-based drug design utilizing structural biology and computational modeling, and the repurposing of existing drugs for novel therapeutic applications. Candidate selection hinges on thoroughly understanding the disease pathophysiology and identifying a targetable molecular pathway crucial for the disease progression.

2. Pre-clinical Drug Development

Once one or more candidates are identified, a typical pre-clinical Drug Development program consists of six major efforts: manufacture of drug substance or active pharmaceutical ingredient (API); pre-formulation and formulation (dosage design); analytical and bioanalytical methods development and validation; metabolism and pharmacokinetics; toxicology, both safety and genetic toxicology and possibly safety pharmacology; and Good Manufacturing Practices (GMP) production and documentation of the drug product for its use in clinical trials.

3. Clinical Trials

If preclinical studies demonstrate a favorable risk-benefit profile, the drug candidate progresses to clinical trials involving human subjects. Government agencies must authorize these clinical trials. They can be typically stratified into three progressive phases, with each phase expanding the number of participants and refining the understanding of the drug's safety and efficacy.

Phase I: This phase involves a small group of healthy human volunteers, primarily to evaluate safety and tolerability and start to determine the optimal dosage of the drug candidate.
Phase II: This phase aims to evaluate the drug's efficacy in patients with the condition of interest and further refine the safety parameters. It involves a larger number of participants and should establish the dosing regimen.
Phase III: Conducted with a significantly larger and more diverse patient population, this phase is designed to confirm the drug's efficacy, monitor side effects, compare it to commonly used treatments, and collect any kind of information that will allow for safe approval of the treatment.

4. Regulatory Approval

Following successful clinical trials, the pharmaceutical company redacts a comprehensive dossier of data encompassing the entire discovery and development process, including pre-clinical and clinical studies reports. This dossier is submitted to the corresponding regulatory agency for rigorous review to ensure the drug's safety, efficacy, and quality, along with its manufacturing and proposed labeling. If the regulatory authority determines that the drug's effectiveness for its intended use justifies its introduction to the market, it can be legally approved.

5. Post-Marketing Surveillance (Phase IV Clinical Trials)

Post-marketing surveillance programs are established to continuously monitor the drug's safety and efficacy in its daily use by the general population. This practice enables the identification of any long-term adverse effects or unforeseen drug interactions that may not have been detected during pre-clinical or clinical development phases I to III. Open communication between healthcare professionals, regulatory agencies, and pharmaceutical companies allows for continuous evaluation of the drug's risk-benefit profile in the real environment of use. It ensures its safe and effective utilization in daily clinical practice.