Clinical trials and early access programmes in rare disease

Research into rare conditions often involves using adapted clinical trial designs and accessing investigational medicines through alternative routes. This is due to the small number of patients affected by each rare disease and the fact that expertise is concentrated in specialist centres. Understanding how these processes work enables clinicians to better support patients and families who may wish to take part in research.

Clinical trials are research studies designed to evaluate whether a new intervention – like a drug, biologic medication or medical device – is safe, effective and suitable for use in humans. Before a new therapy can be tested in people, researchers carry out ‘pre-clinical’ work, which involves finding a promising drug, studying it in the laboratory and testing it in animals to check whether it is likely to be safe and effective.

Clinical trials typically progress through four phases:

• phase I assesses safety, tolerability and how the body processes the drug, often in small groups;
• phase II explores early signs of efficacy and refines dosage;
• phase III compares the treatment with standard care or a placebo on a larger scale, generating the evidence required for licensing; and
• phase IV is post-licensing monitoring to evaluate long-term safety and real-world effectiveness.

Rare diseases affect small, geographically dispersed populations, meaning that traditional large-scale trials are often not feasible. As a result, trial phases may be combined and adaptive designs may be used to make the best use of limited participant numbers.

Patients with rare diseases are usually cared for in specialist centres, with trials typically taking place in those settings. This can mean patients and families travelling long distances and attending extra appointments, creating practical and emotional burdens.

Healthy volunteer studies are often not possible, as key biomarkers or disease activity are only present in people with a particular condition. In addition, ethical considerations in progressive or life-limiting diseases mean that patients themselves are typically included, even in early phases.

Selecting endpoints that offer direct clinical benefit to patients is another challenge. Many rare diseases lack well-described natural history data or validated outcome measures. Endpoints must balance scientific rigour with outcomes that reflect meaningful improvements to patients’ lives.

Regulatory authorities, such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the US Food and Drug Administration (FDA), ensure that medicines, devices and biologics meet strict standards of safety, quality and efficacy. Several regulators offer expedited pathways for therapies targeting serious or unmet needs, including many rare diseases.

Following successful clinical trials, a therapy may receive marketing authorisation, meaning that it is licensed for use. In the UK, the National Institute for Health and Care Excellence (NICE) then assesses whether the treatment should be funded by the NHS.

For patients who have exhausted existing treatment options and cannot take part in a clinical trial, early access programmes (EAPs), sometimes called compassionate or expanded access, may allow them to receive an investigational therapy. Although the main purpose is treatment, these programmes might also provide valuable real-world data on how a therapy performs outside controlled trial settings.

As most rare diseases lack licensed treatments and many patients are unable to join trials, EAPs can offer a vital route to therapy and a source of hope.

Clinicians play a key role in raising awareness of research opportunities. Understanding local specialist centres, national trial registries and patient organisations can help with signposting patients towards relevant studies.

It is helpful to discuss clinical trials early, acknowledging the potential benefits and also the practical challenges. Support might include exploring travel needs, co-ordinating hospital appointments and helping patients understand eligibility criteria.

Patients often value the opportunity to contribute to research, even when the personal benefit to them is uncertain. Helping families understand the purpose, process and limitations of clinical trials and early access can strengthen their trust and empower them to make informed decisions.

• Most rare diseases have no licensed treatments, making clinical trials an important route to accessing emerging therapies.
• Trial design often needs to be adapted for rare disease due to small, geographically dispersed patient populations.
• Early access programmes may offer investigational medicines to eligible patients who cannot join clinical trials.
• Clinicians can support patients by signposting research opportunities and discussing the practical and emotional considerations of taking part in trials.
• Meaningful involvement in research can empower patients and contribute valuable real-world data to improve future care.

For clinicians

• Eurodis: Early access to promising medicines – compassionate use
• Medics for Rare Disease: Clinical Trials & Early Access Programmes e-learning
• Orphanet
• Rare Disease Research Network

For patients

• Beacon for Rare Diseases resources hub: Navigating access: A guide to early/managed access programs
• Eurodis: Early access to promising medicines – compassionate use
• NIHR: Be part of research
• Rare Disease Research Network