From Preclinical Studies to Clinical Trials: Steps and Process

The Drug Discovery and Development process is divided into several phases, from the initial efficacy and safety assays performed in vitro and in animals or New Alternative Models -NAMs-) to Clinical Trials in humans. Therefore, new drugs have to overcome several treacherous steps to comply with what is required in every step of the New Drug commercialization process.

Before testing a Drug in Clinical Trials, Early Drug Discovery and Preclinical Assays are the first steps to be fulfilled, which involve the discovery and development of active principles with potential therapeutic effects and their safety assessment. Once Preclinical Assays are successful, the new active principles enter Clinical Trials to test their safety and efficacy in humans.

The transition from animal testing to Clinical Trials represents major progress in the Drug Discovery and Development cycle. This implies the compound is suitable for experimentation in humans even though the drug has undergone excruciating testing and vast information has been gathered due to animal testing and previous phases of research, but still, it is necessary to explore the effects of the active compounds in humans once it is suitable to do so.

Clinical Trials must include human volunteers, in the first phase, taking into account they have signed an Informed consent, as no person should be placed against their will in a clinical trial. Importantly, no drug should ever be tested on anyone who has not given their voluntary consent, after explaining the reasons for the trial and the potential outcome in detail to the patient. As an added need, as well as in animals, to oversee and tackle all ethical aspects of the trials there is always an Ethical Committee involved who would approve the trial design.

Phase I Clinical Trials with the participation of volunteers are the first step after animal trials and an essential part of understanding how the human body reacts to a potential new drug or treatment. The US Food & Drug Administration (FDA) has set specific guidelines for the design of Clinical Trials.

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What are Early Drug Discovery and the Preclinical Phase?

The Early Drug Discovery process involves the discovery of drugs with potential therapeutic effects using in silico and in vitro assays, biochemical assays, and animal models or NAMs. After the candidate selection in the Early Drug Discovery Process, the new drugs enter in Preclinical Phases where they are refined and optimized in the laboratory for further validation of their therapeutic action and safety.

Nowadays, with the implementation of the 3Rs Principles (Replacement, Reduction, and Refinement of animals), NAMs, which aim to reduce and even to be an alternative to animal models, are gaining attention and represent a truly attractive alternative not only taking into consideration animal welfare but also cost-effectiveness. These alternatives include the improvement of in silico and in vitro assays to obtain better and more reliable information, minimizing the gap with in vivo models. Nevertheless, these assays are not yet so developed, and the use of animals remains mandatory. Fortunately, there are other approaches such as the use of the zebrafish model, which are not considered animals until the 6 day post-fertilization, that can provide, in many cases, as much information as with the use of mammal animals.

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In this sense, zebrafish represent a rather interesting NAM because it is a cost-effective, ethical, and highly scalable model that replicates very well effects on mammal animal mod, with high genetic homology with humans (higher than 70%) . The most transcendent benefits that zebrafish have are:

  • High reproductivity.
  • High scalability to perform Hight Content Screening (HCS) assays.
  • Fast organogenesis, presenting functional organs at 5 days post-fertilization.
  • Transparency in the larval stage, allowing in vivo phenotypic studies, based on image analysis.

To have a solid cost-effective alternative model is of great importance reducing the cost of the Drug Discovery & Development process, which nowadays is stimulated in millions of dollars and, in this sense, the zebrafish model represents an outstanding NAM to improve it.

At Biobide we have developed a vast variety of Preclinical Assays using zebrafish larvae. Thus, we have HCS assays for testing general and organ-specific toxicity (cardiac toxicity, neurotoxicity, teratogenicity, hepatotoxicity, kidney toxicity, etc. ) as well as efficacy, for finding safer and most efficient drug candidates.

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What are Clinical Trials?

When a Drug candidate shows a solid potential benefit with enough safety, it can potentially enter Clinical Trials to demonstrate its benefits and safety in humans. Typically, Clinical Trials are divided into four phases (I, II, III, and IV), each of which represents a step beyond product commercialization.

In Phase I the safety and side effects of the tested drug are analyzed in a small group of individuals, not more than a hundred, to confirm preclinical data, usually in healthy individuals. In Phase II the effectiveness, tolerability, and dosage of the drug are examined in 100 to 500 adult patients to confirm the medical benefits of the drug and the right doses to obtain them. Next, in Phase III the potential successful results of Phase II are tried to be confirmed in thousands of patients, including patients taking other medicines, to include interactions that could arise during regular use of them. Both Phase II and III are controlled studies with blind control groups, not receiving the new drug and treated groups receiving the study drug. Finally, Phase IV is after the commercialization, monitoring how the drug is commercially given to patients, both medical benefits and side effects being monitored to finally confirm previous studies.

Moving from Preclinical to Clinical Trials will be held on the results from Preclinical Assays, and the design of them will take into account the conclusions from those, including selected doses been effective in animals, extrapolated to humans thanks to pharmacokinetics and pharmacodynamics, the frequency and way of dosing, the effects to look for, or the patience distribution and biomarkers to follow.


The journey a Drug must undergo to be approved as medical treatment is tremendously laborious and exorbitant money-wise due to all the controls, hits and misses, and risks involved especially in the early stages of the process. Besides, the efficacy and security of a new medicine have to be very carefully checked and confirmed by the regulatory agencies before getting the green light for its commercialization.

This is the reason why despite thousands of candidate compounds being investigated in Preclinical Phases, only a few of them pass to Clinical Trials and are finally commercialized, after years of research, an average of 10-12 nowadays. However, these control steps are eminently crucial to claim the safety and efficacy of new medicines.

In this context, developing High Content Screening (HCS) assay in zebrafish can contribute significantly to the fastening of the Drug Discovery & Development process, due to their capacity to bring highly reliable data, and decrease the use of animals cost-effectively and faster.

Thus, Biobide is bringing a set of HCS toxicity and efficacy assays in zebrafish larvae that are highly reproducible and cost-efficient to test the adverse effects of hundreds of compounds in a shorter time.

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