What is a clinical trial?
A clinical trial is a research study in which participants evaluate therapeutic approaches.These may include medicines, gene or cell therapies, medical devices, surgical or radiological procedures, behavioral interventions, or preventive strategies.
Although targeted to specific groups, clinical trials can involve subjects of all ages and backgrounds, including children. This diverse participation helps researchers understand how treatments work across different populations.
These studies can take different forms depending on their purpose, but they all address clear questions about safety, efficacy, or impact on daily life, to help inform decisions about these therapies’ clinical use.
In a clinical trial, participants are assigned according to a pre-defined therapeutic strategy or plan (protocol) to receive a health-related intervention.
The process is based on collaboration: Participants contribute their experiences and outcomes, while clinical and research teams make sure that strict protocols are followed and that participants receive appropriate care and are monitored throughout the trial.
Phases and regulation
Clinical trials are carried out in clearly defined phases, each with a specific purpose.
Before a clinical trial can begin, it must be carefully designed, reviewed and approved by ethics committees and regulatory authorities. Throughout the study, strict scientific, ethical and regulatory standards are consistently applied to protect participants and ensure that the results are reliable and the safety of the subjects is carefully protected.
Clinical trials are generally organised into four main phases, divided in:
- First line phaseswhich focus on safety, dosing, and early signs of benefit, often involving smaller groups of participants.
- Second line phaseswhich assess efficacy in larger groups and effectiveness more broadly, and compare new approaches with existing standards of care.
Phase I
Usually involve a small group of participants and are often the first time a new treatment is tested in humans. They focus on safety, side effects and identifying an appropriate dose.
Phase II
Include a larger group of participants and continue to monitor safety, while also scouting for signs of effectiveness.
Phase III
Involve large populations, often across multiple centres or countries. This phase provides more clarity on how well a treatment works, its side effects being monitored, and the main evidence needed for its regulatory approval is gathered and submitted.
Phase IV
Take place after a therapy has been approved and introduced into daily healthcare. These studies continue to monitor safety over longer periods and in broader, real‑world populations, helping researchers better understand the treatment’s long‑term risks, benefits in clinical practice (effectiveness) and optimal use.
Participant safety is a priority at every stage. Clinical trials are closely monitored, with clear rules for reporting adverse effects and reviewing emerging data, and with enough flexibility to halt and adapt a study if risks outweigh potential benefits.
This approach is particularly important in rare diseases, where children are often involved, and life‑threatening conditions are frequent.
The case of pathologies treated with mRNA, gene therapies and disease‑modifying therapies (DMTs) is particularly monitored over a longer period to ensure that no genetic effects appear in descendants.
Why clinical trials are key in rare diseases
Rare diseases are defined by the fact that each condition affects a small number of people.
However, when considered together, rare diseases affect more than 300 million people worldwide, including around 30 million people in Europe.
Despite this massive scope, most rare diseases still have no approved treatment.
Clinical trials play a central role in this context, as they are often the primary way to generate robust evidence about how a disease develops, how it affects patients, and which interventions may ultimately improve their living conditions.
Through clinical trials, researchers can evaluate potential treatments in a structured and regulated manner, ensuring that they are assessed for safety and effectiveness way before being introduced into standard clinical practice.
For rare diseases, this process is essential to move from limited, fragmented knowledge and care towards evidence‑based options that can inform diagnosis, treatment, and long‑term management, putting patients front and center. To them, although voluntary, taking part in clinical trials has substantial physiological and emotional implications.
Small and scattered patient population
Small sample sizes
It is often difficult to recruit enough patients, so studies typically include only a small number of participants. This makes it harder to draw strong and reliable conclusions.
Multinational recruitment
Patients are spread across countries, which means trials need to involve many centres. In consequence, it increases coordination efforts and adds complexity to the study.
Heterogeneity of patients
Patients may experience different symptoms or disease progression, making it more difficult to compare results and clearly identify treatment effects.
Limited knowledge about the disease
Lack of natural history data
When the course of the disease is not well understood, it becomes harder to tell whether changes are due to the treatment or the disease itself.
Lack of validated outcomes and registries
There are often no widely agreed measures or patient registries to guide trial design. This makes it harder to define what success looks like and how to measure it.
Challenges with trial design
Standard clinical trial designs do not always fit the reality of rare diseases. Alternative approaches are needed, but they are not always easy to implement or widely accepted.
Often led by academic teams with limited support
Limited institutional infrastructure
Many trials are led by academic teams because there is often limited commercial interest. However, these teams may not have the specialised legal, regulatory, and quality support needed to run complex studies.
Unclear sponsorship roles
Academic investigators often take on the role of sponsor, which brings important legal and financial responsibilities. Managing these responsibilities can be difficult, especially in studies that involve multiple countries.
Project management limitations
Academic-led trials are often smaller in scale and have fewer dedicated resources for coordination. This makes it harder to manage timelines, stakeholders, and other requirements in complex, international studies.
Do not fit standard funding models
Fragmented funding
Because rare diseases affect small populations, funding often comes from multiple national sources, making it harder to share resources across countries and limiting flexibility.
Budget inflexibility
Rare disease trials often require complex coordination across countries and systems. The true operational costs are not always fully anticipated, leading to gaps in key areas such as monitoring or data management.
Underestimation of costs
Academic-led trials are often smaller in scale and have fewer dedicated resources for coordination. This makes it harder to manage timelines, stakeholders, and other requirements in complex, international studies.
Require complex multinational collaboration
Non-harmonized site agreements
To recruit enough patients, trials need to involve multiple centres across countries. Each site may require different contracts, which can delay the start of the study.
Regulatory divergence and variable compliance requirements
Trials must comply with different national regulations and approval processes, as well as different requirements for aspects such as insurance or GCP training . This adds extra steps and can lead to delays, making coordination more difficult across countries.
Drug procurement and logistics
Rare disease trials often depend on specific or repurposed treatments. Differences in procurement rules and supply systems can slow down or limit access to these medicines.
Data management and monitoring differences
Data management and monitoring practices may also vary between countries. This adds another layer of complexity when running multinational trials.
ERDERA and clinical trials
ERDERA’s Clinical Trial Call will launch in June 2026. Have a look at here to find out more about it.
Key message:
For people living with a rare disease, clinical trials represent hope, a route towards faster diagnosis, treatment options, and ultimately, better living conditions.