Written by Dr Victoria Datsenko, Vice President of Clinical Services; Lucy Fulford-Smith, Head of Pharmacovigilance and Medical Services; and Marcelo Vaz, Vice President of Medical Services.
Originally published in Rare Revolution Magazine.
Patients with rare diseases often face a lengthy journey from first presentation to diagnosis.
Early symptoms can be intermittent, appear unrelated, non-specific or overlap with those seen in many common diseases. Consequently, patients may spend years moving between clinicians and institutions, undergoing repeat investigations and collecting provisional (incorrect) diagnoses before they reach the right specialist.
That journey is frequently described as the ‘diagnostic odyssey’, which can have significant consequences.
For patients, their quality of life may be reduced due to poor symptom management and progression; they may experience potentially preventable but irreversible organ system damage and, ultimately, suffer early clinical decline.
For sponsors and clinical study teams, this diagnostic journey is a critical, often underestimated determinant of clinical trial readiness. Diagnostic challenges mean it is harder to identify patients, fewer are eligible for trials once found and their clinical baselines and endpoint measures are harder to interpret. These complexities make safety oversight and efficacy assessments difficult to interpret and monitor throughout clinical development.
In this context, patient organisations often become the bridge between uncertainty and direction.
They help individuals understand likely pathways and advocate for patients within the healthcare system, helping to push for appropriate referrals, confirmatory testing, treatment access facilitation and recognition of condition-specific needs.
Why does misdiagnosis happen in rare diseases?
Misdiagnosis is often a multi-factorial problem, with ambiguous symptoms being amplified by clinicians’ unfamiliarity with the disease, inconsistent referral pathways and limited access to confirmatory testing. It can also be exacerbated by broader symptom-led labelling, where conditions are framed around a clinical cluster rather than a specific underlying cause.
For example, ambiguity often appears in inherited conditions such as alpha-1 antitrypsin deficiency (AATD)1, where early signs may emerge through respiratory, hepatic or general paediatric presentations rather than being recognised as part of one underlying disorder.
Structural factors matter as much as clinical ones here.
In the UK, the public structure of the National Health System (NHS) means the particularity of the individual is often blurred by the need to care for many.
Individuals must consult their general practitioner (GP) as a first point of contact, before specialist referral can be made. Physicians have limited time to evaluate the patient and many GPs may encounter a rare disease presentation only once, if at all, in their careers—potentially delaying appropriate testing or referral to specialist centres.
In other settings, private pathways can offer a faster route to diagnosis. For example, in Brazil, supplementary private plans sit alongside the unified health system and may be used to move more quickly through parts of the system. However, in the United States, private insurance is the main gateway to care for most people and varies markedly by state and insurer, strongly influencing access.
How do diagnostic delay, misdiagnosis and indication broadening impact clinical trial readiness?
Improving trial readiness by designing with the diagnostic odyssey in mind
Rare diseases often result in a varied range of comorbidities for patients and create a long diagnostic odyssey. Trial design needs to reflect that reality without weakening scientific rigour.
As such, trial readiness requires integrated, cross-functional input that is built long before the first site opens. Clinical development and operations, medical oversight and pharmacovigilance need a shared view of what is plausible for the disease stage being studied, how diagnostic certainty will be confirmed and how the standard of care will be applied consistently across countries, sites and over time.
That begins with designing the study around real-world diagnostic and treatment pathways, rather than retrofitting the protocol once recruitment slows.
Four actions consistently help:
- Define the right population, then clarify the diagnosis. Inclusion and exclusion criteria should reflect real-world presentation rather than an idealised archetype. Overly narrow definitions can fail operationally in underdiagnosed conditions; overly broad inclusion criteria can introduce avoidable heterogeneity.
- Align early with regulators on rigour, safety and feasibility. Agree on diagnostic evidence requirements across countries, acceptable standard of care variation and mitigations to protect interpretability.
- Engage patient organisations as partners, not just recruitment tools. When engaged with respect and transparency, these groups can meaningfully shape feasibility, protocol acceptability and communication plans, and help ensure research is aligned with patient priorities.
- Build routes to the right patients, not just the nearest sites. Sponsors need targeted awareness strategies that help clinicians and patient communities recognise when a trial may be relevant, including intentional referral pathways into specialist centres, clear pre-screening routes that support timely diagnostic confirmation and partnerships with registries where appropriate.
Ultimately, trial readiness depends on reducing ambiguity early—in diagnosis, in population definition and in how the indication is framed. The earlier sponsors align on who the trial is truly for, the less avoidable variability, screening failure rate and downstream risk they carry into execution.
References
[1] https://ecronicon.net/assets/ecprm/pdf/ECPRM-14-01118.pdf
[2] https://tmcpharma.com/wp-content/uploads/2025/03/CDKL5-Case-Study.pdf