Phase 1 clinical trials: safety testing in healthy volunteers

What is a phase 1 clinical trial?

A Phase 1 trial is typically the first study of a medicine in humans, often called a "first-in-human" trial. Before it starts, the medicine has already been tested extensively in laboratory and animal studies, known as non-clinical or pre-clinical testing^[1].

Phase 1 studies seek to answer specific questions: is the medicine safe in humans, and at what levels is it tolerated; what does the body do to the medicine (pharmacokinetics, PK); what does the medicine do to the body (pharmacodynamics, PD); and what interactions occur with food, drink or other medicines^[1]. Phase 1 is not designed to prove that a medicine works — that question is addressed in later phases^[2].

Why are healthy volunteers used instead of patients?

Phase 1 trials are usually conducted in healthy volunteers because the objectives of the study are generally non-therapeutic — participants are not expected to benefit medically from taking part. A minority of Phase 1 trials are conducted in patients instead, because some investigational medicines — such as anti-cancer treatments — are too toxic to give to people without the disease^[1].

This distinction matters ethically. In a healthy-volunteer study there is no possible clinical benefit to weigh against the risk, so the concept of therapeutic equipoise used to justify risk in patient trials does not apply. This is one reason healthy participants in Phase 1 studies are often paid for their time and inconvenience, whereas payment is not typically offered to patients participating in later-phase trials of a disease-specific treatment^[2].

A typical Phase 1 study enrols around 20 to 80 people with no underlying health conditions, and researchers spend several months observing how their bodies react to the medicine^[3].

How is the first dose given to a person decided?

Before any dose is given to a healthy volunteer, non-clinical data — including animal pharmacology, toxicology and pharmacokinetics — are used to define a starting dose intended to be safe, guided by European Medicines Agency (EMA) recommendations on strategies to identify and mitigate risk in first-in-human trials. This EMA guideline, adopted by the Committee for Medicinal Products for Human Use (CHMP) on 20 July 2017 and in effect from 1 February 2018, sets out separate considerations for selecting a starting dose in healthy volunteers and in patients^[4].

Key factors considered when planning the risk profile of a first-in-human trial include the study population, the trial site, the first dose, the route and rate of administration, and the number of participants per dose group (cohort). Other factors include the sequence and interval between dosing participants within the same cohort, dose-escalation increments, the criteria for moving to the next dose cohort, stopping rules, and the maximum tolerated dose (MTD)^[1].

Even after extensive non-clinical testing, the side effects a medicine may cause in a person cannot be fully known before the first dose is given to a human. This uncertainty is why Phase 1 studies can carry significant risk, and why potential risk is estimated from animal models, prior human exposure to medicines with a related mechanism, and the biological nature of the target^[1].

What do single ascending dose (SAD) and multiple ascending dose (MAD) mean?

Many Phase 1 protocols combine several parts, commonly a single ascending dose (SAD) stage followed by a multiple ascending dose (MAD) stage, sometimes together with a food-interaction assessment^[5].

• Single ascending dose (SAD) — each participant receives one dose, either the investigational medicine or placebo, and successive groups (cohorts) receive progressively higher doses only after the previous cohort's safety data has been reviewed^[5];
• Multiple ascending dose (MAD) — participants receive repeated doses over several days, allowing researchers to observe how the medicine behaves with repeated exposure rather than a single administration^[6];
• Randomisation and blinding — within each dose group, participants are typically assigned at random to receive the active medicine or a placebo, and neither participants nor immediate study staff know who received which, a design known as double-blind^[6].

An example documented in a peer-reviewed protocol illustrates the scale involved: a first-in-human dose-escalation study divided participants into three sequential dose groups of eight people each (24 in total), with an internal safety review committee assessing emerging safety and blood-concentration data before allowing the study to move to the next, higher dose group^[6].

How does dose escalation actually proceed between cohorts?

A documented French Phase 1 trial of a chemical medicine given orally to healthy volunteers aged 18 to 55 shows how ascending-dose cohorts are typically staged over time. In that trial, eight ascending doses were planned, each tested in a cohort of eight volunteers, for 64 subjects in total in the single ascending dose part^[5].

Cohort	Dose	Timing relative to previous cohort
Cohort 1	0.25 mg	First administration in the trial
Cohort 2	1.25 mg	31 days after cohort 1
Cohort 3	2.5 mg	8 days after cohort 2
Cohort 4	5 mg	7 days after cohort 3
Cohort 5	10 mg	8 days after cohort 4
Cohort 6	20 mg	13 days after cohort 5

Within the first cohort, two volunteers received the first dose, and only after 24 hours of observation did the remaining six volunteers in that same cohort receive it — a staggered approach used to catch an unexpected reaction before exposing more people^[5].

Where do phase 1 trials take place, and what monitoring can you expect?

Phase 1 studies are often conducted at dedicated in-patient clinics, where participants are observed by experienced, full-time staff. First-in-human trials are preferably conducted at a single site with all possible safety provisions in place in case of an unexpected serious adverse reaction, including immediate access to emergency equipment, staff and, where necessary, intensive care unit facilities^[1].

In Germany, for example, each clinical trial for vaccines or biomedicines must receive a positive opinion from the responsible ethics committee and a positive evaluation and approval from the Paul-Ehrlich-Institut before it can begin. Across the European Union, quality-assurance measures aligned with Good Clinical Practice (GCP) are intended to ensure both the ethical conduct of the trial and the reliability of its results^[7].

What happened during the 2016 BIA 10-2474 trial, and why is it discussed today?

A well-documented serious incident occurred during a Phase 1 trial of the medicine BIA 10-2474, sponsored by BIAL laboratories and conducted by BIOTRIAL in Rennes, France, registered as EudraCT no. 2015-001799-24. The trial was a double-blind, randomised, placebo-controlled study combining single and multiple ascending doses with a food-interaction assessment in healthy volunteers. It was authorised by the French national medicines agency (ANSM) on 26 June 2015 after protocol changes had been requested during review^[5].

The trial site, BIOTRIAL, had previously undergone inspections by ANSM, including one in October 2014 to assess compliance with Good Clinical Practice and one in December 2014 to assess compliance with Good Laboratory Practice for pre-clinical work related to other products^[5]. This incident is one of the reference cases behind the EMA's updated guideline on identifying and mitigating risk in first-in-human and early clinical trials, revised and adopted in 2017^[4].

What rights and protections does a phase 1 participant have?

Before joining a trial, a prospective participant must receive an informed consent document describing the study, and must sign it before any study procedure begins. Any compensation offered to healthy volunteers must comply with local law, must never be linked to the level of risk involved, and the amount must be reviewed by an ethics committee and stated in the informed consent document the participant signs^[1].

All clinical trials conducted in the European Union or European Economic Area whose data are intended to support a marketing authorisation must comply with EU clinical trial legislation, and must adhere to Good Clinical Practice and the principles of the Declaration of Helsinki^[7]. A study protocol example states this explicitly: the trial is performed in accordance with ethical principles consistent with the Declaration of Helsinki, the ICH Guideline for Good Clinical Practice E6(R2), and applicable EU and local regulatory requirements^[6].

Information on registered clinical trials in the EU, including their status and design, is published in publicly accessible databases — the EudraCT database, which covers primarily past trials, and the Clinical Trials Information System (CTIS)^[7]. A participant or prospective participant can use these registries to check a trial's approval status and its registration number, such as the EudraCT or NCT number quoted in the study protocol^[6].

What should you report during the trial, and who reviews it?

If you notice any new symptom, discomfort or change in how you feel after receiving a dose, tell the study staff immediately — this is the mechanism by which unexpected reactions are caught before more participants are exposed to a higher dose^[5]. In the example study design described earlier, an internal safety review committee monitors emerging safety and plasma concentration data for each dose group and must give a favourable recommendation before the study can move to the next, higher dose^[6].

Because Phase 1 trials are usually observation-intensive, participants can expect frequent blood draws, vital sign checks and structured symptom questioning throughout their stay at the study site, particularly during the hours immediately following each dose^[1].

When should you seek independent medical or ethical advice before joining?

Because Phase 1 trials are generally non-therapeutic for healthy volunteers, there is no expected medical benefit to weigh against the risk of participating. It is therefore reasonable to ask the study team directly what is known and not known about the medicine's safety before you consent^[2]. Ask specifically what non-clinical (animal) data exist, what the starting dose is based on, what stopping rules apply, and what emergency provisions are in place at the trial site^[4]. If you are a patient rather than a healthy volunteer being asked to join a Phase 1 study — for example for a cancer treatment — ask what happens if the treatment helps you but the trial ends, since access to the same medicine before marketing authorisation is not guaranteed^[2].

Summary

Phase 1 trials exist to answer a narrow but essential question — is this new medicine safe enough in people, and at what dose — before any claim about effectiveness is tested in later phases. The process relies on staged dose escalation, close monitoring, an independent ethics committee and a national regulator, and a documented informed consent process that a volunteer can walk away from at any time.

Understanding the structure of single and multiple ascending dose designs, knowing what a stopping rule and a safety review committee are for, and knowing where to check a trial's registration can help a prospective participant or their carer ask better questions before signing up.

1. [1] Phase I Trials - EUPATI Toolbox (accessed 2 June 2026) — https://toolbox.eupati.eu/resources/phase-i-trials/
2. [2] Hanauer SB. The Ethics of Phase I Trials of Biologic Agents. Nat Clin Pract Gastroenterol Hepatol. 2008;5(10):533 — https://www.medscape.com/viewarticle/582224
3. [3] Seladi-Schulman J. Clinical Trial Phases: What Happens in Phase 0, I, II, III, and IV. Healthline. Updated 22 June 2019 — https://www.healthline.com/health/clinical-trial-phases
4. [4] Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products, EMEA/CHMP/SWP/28367/07 Rev. 1 (accessed 2 June 2026) — https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-and-mitigate-risks-first-human-and-early-clinical-trials-investigational-medicinal-products-revision-1_en.pdf
5. [5] Chronology of the evaluation and performance of the clinical trial sponsored by BIAL laboratories and conducted by BIOTRIAL in Rennes (accessed 2 June 2026) — https://archive.ansm.sante.fr/content/download/85117/1074133/version/2/file/Chrono+point+dinfo+27.01.16_EN_1.pdf
6. [6] https://bmjopen.bmj.com/content/13/2/e064866
7. [7] Clinical Trials - Paul-Ehrlich-Institut (accessed 2 June 2026) — https://www.pei.de/EN/regulation/clinical-trials/clinical-trials-content.html