Coming soon · Free guide · For pharma & biotech teams

Innovative Trial Designs in Rare Diseases

In rare diseases, patients are a finite resource. Discover the adaptive and master protocol designs that make the most of them, and what FDA and EMA expect.

  • Five adaptive designs: dose, population, randomisation, sample size and endpoints
  • Basket, umbrella and platform master protocols compared
  • What FDA and EMA expect, including the upcoming ICH E20 guideline
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Peter Morgan

Written by Peter Morgan
Senior Medical Writer, Azur Health Science
Innovative Trial Designs in Rare Diseases – coming soon
Innovative Trial Designs in Rare Diseases – cover
250+
projects delivered
FDA & EMA
submissions & approvals
20
medical writing & regulatory experts
Since 2017
supporting life sciences teams

Few patients, scattered worldwide, one shot at the trial.
Without the right design, good drugs can fail.

Too few patients to power a trial

Small, often distributed populations make it hard to recruit and retain enough patients to test endpoints with sufficient statistical power.

A cost few can absorb twice

Traditional trials are prohibitively expensive, and a failed study can end a programme, especially for smaller companies that cannot afford a new one.

A finite pool of patients

An inefficient design can exhaust the available patients and still fail to deliver robust evidence, while complex designs must remain acceptable to health authorities.

The result: over 75% of orphan drug studies in non-oncology indications fail, and for a substantial proportion the cause is recruitment, retention and statistical power, not lack of efficacy (Summar & Woodcock, 2026).

What the guide will cover

Six parts, from the patient supply problem to what regulators expect.

  1. 1
    Why Rare Disease Trials Need Innovative Designs
    FDA and EMA definitions, the supply-and-demand balance of a finite patient pool, and why regulators encourage complex designs.
  2. 2
    Adaptive Protocols
    Five pre-planned adaptations: dose groups, patient population, randomisation, sample size and endpoints.
  3. 3
    Key Considerations for Adaptive Designs
    Type I error, bias, prespecified stopping rules and operational risks.
  1. 4
    Master Protocols
    The overarching framework and its sub-protocols, with basket, umbrella and platform designs compared.
  2. 5
    Benefits of Master Protocols
    Shared infrastructure and control groups, efficient recruitment and better feasibility in rare diseases.
  3. 6
    The Regulatory Perspective
    What EMA and FDA expect: integration in the programme, statistical robustness and operational integrity.

What changes for your team

Without the guide
With the guide
Design choice
✕
Defaulting to a traditional trial the population cannot support.
✓
A design chosen to fit your patients, statistical power and budget.
Recruitment & power
✕
Struggling to recruit enough patients to power the endpoints.
✓
Adaptive and master designs that make the most of every patient.
Resources
✕
Statistical and operational gaps discovered late.
✓
The resources and expertise you need identified early.
Regulatory view
✕
Uncertainty about how FDA and EMA will view a non-traditional design.
✓
A design aligned with FDA and EMA guidance, discussed early with the agencies.
Outcome
✕
A costly study that fails for reasons other than efficacy.
✓
More robust results, with a greater likelihood of acceptance by health authorities.
Design choice
✕ Defaulting to a traditional trial the population cannot support.
✓ A design chosen to fit your patients, statistical power and budget.
Recruitment & power
✕ Struggling to recruit enough patients to power the endpoints.
✓ Adaptive and master designs that make the most of every patient.
Resources
✕ Statistical and operational gaps discovered late.
✓ The resources and expertise you need identified early.
Regulatory view
✕ Uncertainty about how FDA and EMA will view a non-traditional design.
✓ A design aligned with FDA and EMA guidance, discussed early with the agencies.
Outcome
✕ A costly study that fails for reasons other than efficacy.
✓ More robust results, with a greater likelihood of acceptance by health authorities.

What you will be able to do

  • Recognise when a traditional trial won’t work for a rare population
  • Compare five adaptive designs and three types of master protocol
  • Choose the design that fits your patients, power and budget
  • Anticipate statistical risks such as Type I error and bias
  • Align your design with FDA, EMA and ICH E20 expectations
  • Prepare early discussions with the agencies

Built for the leaders who design rare disease trials

Heads of Regulatory Affairs

Build submission-ready trial strategies.

Medical Writing Managers

Draft protocols for complex designs.

CMOs & senior clinical leaders

Stay accountable for study feasibility and rigour.

Clinical development & biostatistics leads

Shape the design and its statistical power.

Peter Morgan

About the author

Peter Morgan

Senior Medical Writer, Azur Health Science

Peter is a senior medical writer with a PhD in neural stem cell research and two post-doctoral fellowships in cellular neurophysiology. He works across autoimmune disease, endocrinology, oncology and inflammation, and enjoys applying a deep scientific foundation to new therapeutic areas.

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Medical writing, regulatory affairs, clinical and biostatistics teams in pharma, biotech and CROs who design or contribute to rare disease trials.

Yes. It draws on FDA guidance on adaptive designs, master protocols and complex innovative designs, the EMA reflection paper on adaptive designs, the CTFG recommendation paper and the ICH E20 guideline.

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