Why diagnostic readiness is becoming the next rare disease access barrier
For decades, rare disease screening has been shaped by a cautious principle: do not test for a condition unless there is something useful to offer the patient.
That principle was ethically understandable. A diagnosis without treatment can create anxiety, uncertainty and stigma. Screening programmes are not simply technical exercises; they are public-health interventions. They must consider benefit, harm, false positives, false negatives, confirmatory testing, counselling, consent, cost and system capacity.
But rare disease medicine is changing faster than the diagnostic infrastructure around it.
A growing number of diseases once described as untreatable now have plausible therapeutic routes: gene therapy, RNA therapy, enzyme replacement, haematopoietic stem cell approaches, metabolic correction, targeted small molecules, cell-based therapies and disease-modifying interventions. In several conditions, the most important treatment window is not late disease. It is before irreversible damage has occurred.
That changes the access question.
It is no longer enough to ask whether a treatment can be authorised.
The harder question is whether the health system can identify the right patients early enough for the treatment to matter.
In rare disease, diagnosis is no longer just a clinical pathway issue. It is becoming a determinant of therapeutic value, trial feasibility, HTA confidence and commercial adoption.
The diagnostic access gap
The central problem can be described as the diagnostic access gap.
The diagnostic access gap is the distance between the number of patients who could benefit from a therapy and the number who can realistically be identified, confirmed, referred and treated within the clinically meaningful window.
That gap matters because rare disease markets are not defined only by epidemiology. They are defined by diagnosis.
The prevalent population is not the same as the diagnosed population.
The diagnosed population is not the same as the eligible population.
The eligible population is not the same as the reachable, treatment-ready population.
A therapy can be authorised for a genetically defined disease, but the health system can only treat the patients it can find, confirm and refer in time.
That is why approval alone does not create access.
The diagnostic paradox
Rare disease development depends on patients being found.
Patients are needed to define prevalence, describe natural history, validate biomarkers, recruit trials, understand genotype-phenotype relationships, model disease progression, estimate budget impact and demonstrate the value of earlier intervention.
Yet many patients remain invisible because the testing infrastructure has historically excluded conditions where no approved treatment was available.
This creates a circular problem.
A condition is not screened because there is no treatment.
A treatment is harder to develop because patients are not found.
Prevalence remains uncertain because diagnosis is late or incomplete.
Natural history remains weak.
Trial recruitment is slower than expected.
Payers see uncertainty.
Investors hesitate.
And when a therapy finally arrives, the company may discover that authorisation has not created a market. The patients exist, but the system has not built a reliable way to find them.
This is not theoretical. It is already visible in rare disease policy, newborn screening, genomic medicine and health technology assessment.
MLD: the clearest warning
Metachromatic leukodystrophy, or MLD, is one of the clearest examples.
MLD is a severe inherited lysosomal storage disorder affecting the nervous system. For the most rapidly progressive forms, timing is central. Treatment is most valuable before major neurological decline. Once function is lost, it may not be recoverable.
This means early diagnosis is not just useful. It is structurally connected to the value of treatment.
The UK already has NICE guidance recommending atidarsagene autotemcel, marketed as Libmeldy, for defined children with MLD. NICE states that the therapy is for children with late infantile or early juvenile forms of the disease, including pre-symptomatic and early symptomatic populations.
NICE HST18:
https://www.nice.org.uk/guidance/hst18
The FDA has also approved Lenmeldy, another name for atidarsagene autotemcel, for children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile MLD.
FDA Lenmeldy product information:
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy
But screening policy has not moved at the same speed.
The UK National Screening Committee does not currently recommend newborn screening for MLD. Its current recommendation says screening is not recommended because it is not yet known whether the screening test is accurate, whether a suitable cut-off has been set, and whether early treatment as a result of screening improves long-term outcomes.
UK NSC MLD recommendation:
https://view-health-screening-recommendations.service.gov.uk/metachromatic-leukodystrophy/
This is the access paradox in its purest form.
The therapeutic case depends on early diagnosis.
The screening case requires evidence that early diagnosis improves outcomes.
But that evidence is difficult to generate if the system is not routinely finding patients early.
In the United States, the policy signal is different. In December 2025, the US Department of Health and Human Services approved the addition of Duchenne muscular dystrophy and MLD to the Recommended Uniform Screening Panel.
HHS announcement:
https://www.hhs.gov/press-room/secretary-kennedy-adds-duchenne-muscular-dystrophy-metachromatic-leukodystrophy-to-newborn-screenings.html
That is a major milestone. But it does not mean every newborn in the United States is immediately screened for MLD. Newborn screening is implemented at state level. A federal RUSP recommendation begins the process; it does not complete it.
For companies, this is the warning.
A therapy may be scientifically impressive, clinically rational and reimbursed in principle, but if the screening system is not ready, the product may struggle to reach patients at the point of greatest benefit.
Duchenne: recommendation is not implementation
Duchenne muscular dystrophy shows the same problem from another angle.
Duchenne has historically been diagnosed after symptoms become visible. By then, muscle damage is already underway. Earlier identification changes the possibility of intervention, surveillance, family planning, trial participation and access to new therapies.
The FDA expanded approval of Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy, in June 2024 for individuals aged four years and older with a confirmed mutation in the DMD gene.
FDA Elevidys announcement:
https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy
Yet the diagnostic pathway remains a problem. A 2025 study on diagnostic delay in Duchenne reported that, despite the availability of clinical laboratory tests and genetic testing, diagnostic delay remains a persistent issue.
Duchenne diagnostic delay paper:
https://pmc.ncbi.nlm.nih.gov/articles/PMC12803425/
A 2024 paper on newborn screening for Duchenne describes the case for earlier identification and the barriers to implementation.
Newborn screening for Duchenne:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10965484/
The important point is not simply that Duchenne should be diagnosed earlier. It is that ordinary clinical detection may no longer be good enough for an era of earlier intervention, trial readiness and disease-modifying treatment.
The addition of Duchenne to the US Recommended Uniform Screening Panel is therefore highly significant. But a federal recommendation is not the same as operational implementation. States require laboratory methods, funding, reporting systems, confirmatory testing pathways, neuromuscular referral capacity, counselling and governance.
That distinction matters commercially.
A launch forecast that assumes every eligible patient can be found is not a forecast. It is a hope.
SMA: treatment exists, but screening still has to be operationalised
Spinal muscular atrophy is perhaps the most practical UK example.
SMA is already treatable. Early diagnosis can substantially change the disease course. NICE has evaluated disease-modifying treatments for SMA, including nusinersen and risdiplam. NICE published technology appraisal guidance TA1162 on 4 June 2026.
NICE TA1162:
https://www.nice.org.uk/guidance/ta1162
Yet newborn screening for SMA is still not fully established across the UK.
In England, the in-service evaluation of newborn screening for SMA is due to begin from October 2026. The UK National Screening Committee describes the evaluation here:
UK NSC SMA in-service evaluation:
https://nationalscreening.blog.gov.uk/2026/05/12/ise-of-newborn-screening-for-sma-set-to-begin-in-england-from-october-2026/
The House of Commons Library briefing on SMA and newborn screening, published in June 2026, is also useful background:
House of Commons Library briefing:
https://commonslibrary.parliament.uk/research-briefings/cbp-10909/
The SMA example is not a failure of science. It is how screening policy works. Screening programmes have to meet a higher evidentiary and operational threshold than individual treatment decisions. They must consider test performance, false positives, false negatives, treatment availability, clinical utility, cost-effectiveness, implementation feasibility and the consequences of identifying disease before symptoms.
But for innovators, the implication is unavoidable.
The existence of a therapy does not automatically create the diagnostic system required to deliver it.
Not every rare disease needs newborn screening
This point is important.
Diagnostic readiness is not the same as population newborn screening.
Newborn screening is one route to earlier diagnosis. It is not the only route. Some conditions will meet the threshold for population screening. Others will not. Some may be better suited to targeted testing, cascade testing, reflex testing after sentinel symptoms, specialist laboratory triggers, genomic testing in defined clinical pathways, EHR-enabled case finding, registry development or systematic referral from paediatrics, neurology, metabolic medicine, cardiology, nephrology or primary care.
The strategic question is not only:
Should this disease be screened nationally?
The better question is:
What is the earliest responsible point at which the health system can identify a patient who may benefit?
That distinction matters because a rare disease company can still build diagnostic readiness even when national population screening is not appropriate, not yet accepted, or not yet funded.
Adult rare disease: the same problem appears later in the pathway
The same logic applies beyond newborn screening.
In adult rare diseases, the problem is often not population screening but case finding. Patients appear in ordinary clinical pathways with non-specific symptoms. The diagnosis is missed because the disease looks like something more common.
Transthyretin amyloid cardiomyopathy, or ATTR-CM, is a good example.
NICE recommends tafamidis for treating transthyretin amyloidosis with cardiomyopathy in adults, within its marketing authorisation and commercial arrangement.
NICE TA984:
https://www.nice.org.uk/guidance/ta984
But ATTR-CM has historically been under-recognised, partly because patients present through heart failure, hypertrophy, arrhythmia, carpal tunnel syndrome, spinal stenosis or incidental imaging findings. The diagnostic route matters. A European Journal of Heart Failure paper on diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy found different routes to diagnosis, including heart failure, incidental imaging and other clinical pathways, with later heart-failure pathways associated with worse clinical status.
Diagnostic pathways to wild-type ATTR cardiac amyloidosis:
https://academic.oup.com/eurjhf/article/25/6/845/8341792
A 2025 update on transthyretin amyloid cardiomyopathy also emphasises evolving diagnostic strategies and the need for early detection.
ATTR-CM 2025 update:
https://pmc.ncbi.nlm.nih.gov/articles/PMC12250813/
Fabry disease offers another adult and family-based example.
Fabry disease is treatable, but diagnosis is often delayed because symptoms are variable, multi-systemic and easily attributed to more common conditions. A 2023 review on newborn screening for Fabry disease notes that diagnosis is often delayed until organ damage is already severe, making specific treatments less effective.
Fabry newborn screening review:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10299185/
Cascade genetic screening in known families can identify affected relatives earlier. A Danish Fabry disease study describes systematic cascade screening as a simple and effective method for early diagnosis in known families.
Danish Fabry cascade screening study:
https://pmc.ncbi.nlm.nih.gov/articles/PMC9668118/
These examples show that the diagnostic access gap is not only a newborn screening issue.
It appears wherever the treatment window, referral pathway and diagnostic system are misaligned.
Genomic newborn screening is moving from theory to infrastructure
The wider scientific literature is moving in the same direction.
Genomic newborn screening is no longer only a theoretical debate. A 2026 European Journal of Human Genetics scoping review describes a rapidly expanding field, with growing empirical evidence and active implementation projects.
Genomic newborn screening scoping review:
https://www.nature.com/articles/s41431-026-02108-8
A 2026 European Journal of Human Genetics paper argues that the classic Wilson and Jungner screening principles, developed in 1968, are incomplete for genomic newborn screening and proposes a multi-dimensional framework for establishing and managing genomic screening programmes.
Multi-dimensional framework for genomic newborn screening:
https://www.nature.com/articles/s41431-026-02045-6
Genomics England’s Generation Study is another important example. It is sequencing the genomes of up to 100,000 newborn babies in partnership with the NHS to evaluate whether earlier genomic diagnosis can improve care for rare genetic conditions.
Genomics England Generation Study:
https://www.genomicsengland.co.uk/initiatives/newborns
The Generation Study conditions list includes more than 200 rare genetic conditions selected according to defined principles.
Generation Study conditions list:
https://www.genomicsengland.co.uk/initiatives/newborns/choosing-conditions/conditions-list-generation-study
This matters because it shows a shift in the centre of gravity.
Rare disease diagnosis is moving from a late-stage explanation of symptoms towards an early-stage infrastructure for intervention.
But genomic newborn screening also raises difficult questions about consent, data retention, uncertain findings, equity, psychological impact, clinical utility and long-term governance. A 2026 European Journal of Human Genetics paper on data retention in genomic newborn screening discusses some of these ethical and regulatory challenges.
Genomic newborn screening and data retention:
https://www.nature.com/articles/s41431-026-02120-y
That is why diagnostic readiness must be evidence-led. It cannot be a slogan.
The ethics cannot be an afterthought
The answer is not indiscriminate testing.
Earlier diagnosis has to be justified.
Screening can create harm if it identifies uncertain risk, exposes families to ambiguous findings, or diagnoses disease before the health system can offer counselling, confirmatory testing and timely treatment.
Genomic testing adds further complexity. A result may have implications for parents, siblings and future children. It may reveal carrier status, uncertain variants, adult-onset risks or information that families did not expect to receive. Data retention raises questions about consent, future use, research access and clinical reuse.
The commercial case for patient finding must therefore be built on the same foundation as the clinical case: analytical validity, clinical validity, clinical utility, proportionality, consent, counselling, equity and a credible pathway after the result.
This matters because patient finding without a pathway is not access.
It is risk.
Natural history is now an access asset
The same logic applies to natural history.
In rare disease, natural history is often treated as scientific background. That is too narrow. Natural history is one of the foundations of access.
It defines disease stages, progression rates, treatment windows, endpoint selection, external control options, trial feasibility, economic modelling and the cost of diagnostic delay.
FDA has explicitly recognised the importance of natural history studies in rare disease drug development.
FDA natural history guidance:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development
FDA rare disease drug development guidance resources:
https://www.fda.gov/drugs/guidances-drugs/guidance-documents-rare-disease-drug-development
A 2025 review on trial readiness in rare inherited metabolic diseases makes the same point from a development perspective: understanding natural history is central to trial readiness.
Trial readiness and natural history in rare inherited metabolic diseases:
https://pmc.ncbi.nlm.nih.gov/articles/PMC12550222/
This is why patient finding cannot be reduced to recruitment.
Patient finding is the mechanism by which prevalence, progression, phenotype, treatment timing, trial design and payer uncertainty become measurable.
A company that cannot describe how patients are found may struggle to defend how many patients exist, when they should be treated, what outcomes should be expected, and what value earlier intervention creates.
HTA bodies will see the diagnostic gap
Rare disease companies often spend years preparing the regulatory dossier, the clinical evidence package and the payer submission. Diagnostic readiness is sometimes treated as a later medical affairs or launch issue.
That sequence is increasingly unsafe.
For HTA bodies and payers, diagnostic delay creates modelling uncertainty.
The trial population may be earlier-stage than the real-world diagnosed population.
The eligible population may be genetically defined, while the diagnosed population is pathway-defined.
The economic model may assume early treatment, while the health system mostly finds late disease.
Screening costs may sit in a different budget from the therapy.
Long-term benefits may accrue to health, social care, education and families, while the acquisition cost sits immediately with the payer.
The payer may ask a simple question:
Who pays to find the patient?
This is not a technical detail. It determines whether the value proposition is believable.
The MLD, SMA and ATTR-CM examples show this clearly.
NICE can recommend a therapy, as it has done for MLD and SMA, while the screening or diagnostic system still requires separate evidence, infrastructure and implementation. NICE can recommend tafamidis for ATTR-CM, while clinical systems still need diagnostic pathways that identify patients earlier and more consistently.
HTA approval validates the treatment under defined conditions.
It does not automatically validate the diagnostic pathway required to find every patient who might benefit.
That is the new access problem.
The commercial problem: authorisation does not create the market
For many rare diseases, diagnosis is part of the product’s value proposition. It determines who can benefit, when they can benefit, and whether the health system can act before disease progression changes the treatment opportunity.
If diagnostic infrastructure is weak, several things follow.
Prevalence estimates become unreliable.
The addressable population is overstated or understated.
Trial recruitment is slower than expected.
Natural history data remain incomplete.
Treatment centres see patients too late.
Payers question budget impact assumptions.
HTA bodies see uncertainty in the link between early diagnosis and long-term outcomes.
Families experience delay despite the existence of treatment.
The company then faces an uncomfortable reality: the product may be approved, but the market has not been built.
What companies should do now
The opportunity is to move earlier.
A rare disease company should not wait until approval to ask whether patients can be found. It should begin mapping the diagnostic pathway during clinical development, ideally before pivotal evidence generation is complete.
A diagnostic readiness plan should answer ten practical questions:
- Who is missed?
- Where are they missed?
- How could they be found earlier?
- What test is required?
- What confirmatory pathway is needed?
- What evidence would a screening or genomic-testing body require?
- How many patients are likely to be treatable in time?
- Which centres can manage them?
- How does earlier diagnosis change outcomes?
- How should those changes be represented in the HTA and payer case?
The first task is to separate four populations that are often confused:
the prevalent population;
the diagnosed population;
the eligible population;
and the reachable, treatment-ready population.
Each is different. The difference between them is the diagnostic access gap.
The second task is to build a diagnostic pathway map. Where do patients first appear? Primary care? Paediatrics? Neurology? Emergency care? Developmental delay clinics? Genetics? Metabolic medicine? Cardiology? Nephrology? What symptoms trigger testing? Which tests are used? Where do patients disappear?
The third task is to build natural history and patient-finding together. Natural history is not only academic. It defines progression, timing, endpoints, external controls and the cost of diagnostic delay.
The fourth task is to prepare a screening evidence dossier. This should include analytical validity, clinical validity, clinical utility, cut-offs, false positives, false negatives, confirmatory testing, counselling burden, laboratory capacity, acceptability, feasibility and health-economic impact.
The fifth task is to engage upstream organisations early: screening committees, genomic medicine services, national laboratories, rare disease networks, clinical societies, patient organisations and centres of excellence.
The sixth task is to model the value of time. For many rare diseases, the economic case is not simply treatment versus no treatment. It is early treatment versus late treatment.
That is where access strategy becomes scientific rather than promotional.
The strategic lesson
Rare disease access is moving upstream.
The old sequence was simple: develop the drug, gain approval, negotiate reimbursement, then find patients.
For many rare diseases, that sequence is now too slow.
The new sequence is different: understand the diagnostic gap, generate natural history evidence, build patient-finding infrastructure, support screening readiness, define the treatable population, and then launch into a system that can actually identify eligible patients.
This is not only better for companies. It is better for patients.
A therapy delivered after irreversible disease progression is not the same intervention as one delivered at the right biological moment.
In rare disease, timing is part of efficacy.
And if timing is part of efficacy, diagnosis is part of access.
The Odelle view
The next rare disease launch failures may not come from weak science or poor regulatory execution.
They may come from a simpler problem: the medicine was approved before the system knew how to find the patients.
MLD, Duchenne and SMA show the issue clearly. Therapies are emerging. Screening policy is moving. Genomic newborn screening is developing. Natural history evidence is becoming central to trial readiness and payer confidence. But implementation remains uneven, and the diagnostic pathway is often behind the therapeutic promise.
ATTR-CM and Fabry disease show the same issue in adult and family-based pathways. The challenge is not always newborn screening. Sometimes it is red-flag recognition, cascade testing, specialist referral, imaging, genetic confirmation or systematic case finding in high-risk groups.
The discipline that rare disease companies now need is not only regulatory strategy, clinical development or pricing strategy. It is pre-authorisation diagnostic access strategy.
That means building the evidence, pathway and population logic before launch, so that approval does not arrive into a system that is clinically willing but operationally unprepared.
Approval can validate the medicine.
Reimbursement can validate the price.
But only diagnostic readiness can make the eligible population real.
The treatment may exist.
But unless the patient can be found in time, the market does not.
References and further reading
- UK National Screening Committee. Metachromatic leukodystrophy screening recommendation.
https://view-health-screening-recommendations.service.gov.uk/metachromatic-leukodystrophy/ - NICE. Atidarsagene autotemcel for treating metachromatic leukodystrophy. Highly specialised technologies guidance HST18.
https://www.nice.org.uk/guidance/hst18 - FDA. Lenmeldy product information.
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy - US Department of Health and Human Services. Secretary Kennedy Adds Duchenne Muscular Dystrophy, Metachromatic Leukodystrophy to Newborn Screenings. 16 December 2025.
https://www.hhs.gov/press-room/secretary-kennedy-adds-duchenne-muscular-dystrophy-metachromatic-leukodystrophy-to-newborn-screenings.html - FDA. FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy. 20 June 2024.
https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy - Duchenne diagnostic delay study.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12803425/ - Newborn screening for Duchenne muscular dystrophy.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10965484/ - NICE. Nusinersen and risdiplam for treating spinal muscular atrophy. Technology appraisal guidance TA1162.
https://www.nice.org.uk/guidance/ta1162 - UK National Screening Committee blog. In-service evaluation of newborn screening for SMA set to begin in England from October 2026.
https://nationalscreening.blog.gov.uk/2026/05/12/ise-of-newborn-screening-for-sma-set-to-begin-in-england-from-october-2026/ - House of Commons Library. Spinal muscular atrophy and newborn screening.
https://commonslibrary.parliament.uk/research-briefings/cbp-10909/ - Genomics England. Newborn Genomes Programme / Generation Study.
https://www.genomicsengland.co.uk/initiatives/newborns - Genomics England. Generation Study conditions list.
https://www.genomicsengland.co.uk/initiatives/newborns/choosing-conditions/conditions-list-generation-study - Brown GL, et al. Genomic newborn screening: a scoping review of the field. European Journal of Human Genetics, 2026.
https://www.nature.com/articles/s41431-026-02108-8 - Schnabel-Besson E, et al. A multi-dimensional framework for establishing and managing a genomic newborn screening program. European Journal of Human Genetics, 2026.
https://www.nature.com/articles/s41431-026-02045-6 - Lewis ACF, et al. Genomic newborn screening: data retention for research and clinical reuse. European Journal of Human Genetics, 2026.
https://www.nature.com/articles/s41431-026-02120-y - FDA. Rare Diseases: Natural History Studies for Drug Development.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development - FDA. Guidance Documents for Rare Disease Drug Development.
https://www.fda.gov/drugs/guidances-drugs/guidance-documents-rare-disease-drug-development - Opladen T, et al. Trial readiness and natural history in rare inherited metabolic diseases.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12550222/ - NICE. Tafamidis for treating transthyretin amyloidosis with cardiomyopathy. Technology appraisal guidance TA984.
https://www.nice.org.uk/guidance/ta984 - Tini G, et al. Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy. European Journal of Heart Failure.
https://academic.oup.com/eurjhf/article/25/6/845/8341792 - Transthyretin amyloid cardiomyopathy — 2025 update.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12250813/ - Newborn screening for Fabry disease: current status and perspectives.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10299185/ - Systematic cascade screening in the Danish Fabry Disease Centre.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9668118/