When the start of a clinical trial is announced, the news is often summarized in just a few words: “a new treatment enters Phase I.” Behind that moment, however, are years of research, regulatory evaluation, and a carefully designed sequence of steps intended to ensure that the process is both safe and scientifically sound.
In diseases such as amyotrophic lateral sclerosis (ALS), where medical needs remain urgent, understanding how clinical development works also helps explain why advancing new therapies requires time, evidence, and progressive validation.
Before the clinical trial: everything starts in the laboratory
Before a treatment can be tested in humans, it must go through several preliminary stages. The first step is to determine whether the molecule actually works from a biological perspective. At this initial stage, researchers study its mechanism of action and evaluate its efficacy in the laboratory using cellular models and, in some cases, animal models, depending on the disease and the availability of suitable experimental systems to reproduce it.
If the results are promising, development moves into the regulatory preclinical phase. At this stage, the active compound, known as the API (Active Pharmaceutical Ingredient)—must be produced under standardized quality conditions in order to carry out all the safety studies required before administration in humans.
From there, preclinical studies are conducted in different animal species, including both rodents and non-rodents, with the goal of analyzing the treatment’s safety at multiple levels. In the case of AP-2, for example, these studies were carried out in rodent and mini-pig models.
In addition to the experimental work, this phase also involves extensive regulatory preparation. To request authorization for a clinical trial, specific documentation must be submitted to regulatory agencies. One of the most important documents is the clinical protocol, developed together with the clinical trial unit responsible for the study, which defines how the trial will be conducted and how participant safety will be monitored.
Alongside this, the so-called CMC document (Chemistry, Manufacturing and Controls) is submitted, containing all information related to the compound’s composition, structure, manufacturing, and quality control, ensuring it meets the required standards for administration in humans. This is complemented by the Investigator’s Brochure (IB), a document that compiles all preclinical results obtained up to that point and serves to demonstrate the treatment’s safety profile before entering the clinical phase.
In Europe, this process takes place within the regulatory framework coordinated by the European Medicines Agency (EMA). Subsequently, national bodies such as the Spanish Agency of Medicines and Medical Devices (AEMPS) evaluate the scientific and regulatory documentation required to authorize the start of the clinical trial.
Only once all these evaluations are favorable can the study in humans begin.
Phase I: the first step in humans
Phase I marks the first step of a new treatment in humans. In most cases, this stage is initially conducted in healthy volunteers and has one very specific objective: evaluating the safety of the treatment.
In addition to detecting potential adverse effects, researchers study how the compound behaves inside the body, that is, how it is absorbed, distributed, metabolized, and eliminated. This is known as pharmacokinetics.
At this stage, highly controlled strategies are often used to minimize risk. One of them is the use of sentinel participants.
What are sentinel participants?
In first-in-human studies, especially when a treatment is administered for the first time, researchers do not begin by treating all participants simultaneously.
The first individuals to receive the compound are known as sentinel participants. These are usually one or two people within a specific cohort who are intensively monitored during the first hours or days.
The logic behind this approach is simple: to confirm that no unexpected problems arise before continuing with the rest of the participants.
If everything progresses as expected, the study moves forward gradually with additional participants and, in some cases, different treatment doses.
What happens next: Phases Ib, II, and III
Once Phase I has been completed, clinical development continues progressively.
In diseases such as ALS, it is common for a Phase Ib study to already include diagnosed patients in order to continue evaluating the compound’s safety within the real context of the disease.
Subsequently, Phase II aims to obtain the first signs of efficacy, in other words, to determine whether the treatment produces a clinically meaningful benefit. Larger groups of patients participate at this stage, and researchers begin defining which doses or strategies may be most appropriate.
Finally, Phase III involves larger studies, often international in scope, intended to confirm the treatment’s efficacy and safety in a broader patient population. In these phases, and sometimes in earlier stages depending on the study design, results may be compared against placebo or the existing standard treatment in order to objectively evaluate the impact of the new compound. The evidence generated in these studies is what later supports an application for marketing authorization.
International regulation and clinical development
Although there may be regulatory differences between regions, the overall structure of clinical phases is very similar worldwide.
Both Europe and the United States follow shared scientific and ethical standards, largely coordinated through international organizations such as the ICH (International Council for Harmonisation), which establishes common guidelines for drug development.
The main differences generally lie in regulatory aspects, evaluation timelines, or administrative procedures between agencies such as the EMA in Europe and the FDA in the United States.
In recent years, both Europe and the U.S. have also promoted accelerated pathways for rare diseases or conditions with high unmet medical needs, aiming to facilitate the advancement of innovative therapies while maintaining safety standards.
A long but necessary process
From the outside, clinical development may appear slow. But each phase exists to answer different questions and reduce uncertainty before a treatment reaches patients.
In complex diseases such as ALS, where many questions remain unanswered, every clinical trial also contributes new knowledge about the disease itself.
At Molefy Pharma, this process is part of the work we carry out to translate years of biomedical research into the clinical setting. Our therapeutic candidate AP-2 is currently in Phase Ia clinical development following AEMPS authorization to begin the study in healthy volunteers at Hospital Universitario de La Princesa (Madrid). This initial phase focuses on evaluating the safety and behavior of the compound within the body—an essential step before advancing to studies in ALS patients.
Beyond clinical development itself, every advance also represents an opportunity to deepen our understanding of the disease and bring new therapeutic possibilities closer to patients and their families.