EU pharma package: orphan exclusivity and HTA evidence

The pharma package is the first major revision of EU pharmaceutical law since 2004, and it is close to final but not there yet. On 28 September 2026 the Council adopted its first-reading position on the new Regulation and Directive. The European Parliament still has to complete its second reading before the texts can be published. 

The standard orphan market exclusivity would fall from ten years to nine. A new category of breakthrough orphan medicinal products would receive eleven. The clock would also work differently. Today each orphan marketing authorisation carries its own exclusivity period. Under the new rules, all orphan authorisations for the same active substance would share one period, starting with the first orphan marketing authorisation in the Union.

Later indications could still extend that period. A new therapeutic indication in a different orphan condition would add twelve months, provided it is authorised at least two years before exclusivity expires. The extension can be granted twice, each time for a different orphan condition. Under the orphan rules alone, a standard orphan medicine could therefore reach eleven years and a breakthrough medicine thirteen. Orphan medicines authorised through the well-established-use route would receive four years, and the current review after six years would disappear.

Why this matters for HTA evidence teams

A medicine would qualify as breakthrough if two conditions are met. No medicinal product may yet be authorised in the Union for the orphan condition. And use of the medicine must result in a clinically relevant reduction in disease morbidity or mortality for the relevant patient population. The second condition puts patient outcomes into the exclusivity decision, and that is where it meets health technology assessment.

The overlap is real but partial, because three different questions are being asked. The breakthrough classification asks whether the condition is untreated and whether the medicine produces a clinically relevant reduction in morbidity or mortality. EU joint clinical assessment asks what the medicine's relative effects are against the comparators and outcomes in its PICO-based assessment scope. National HTA bodies then reach their own conclusions on clinical added value, uncertainty, cost effectiveness, affordability and place in therapy.

None of these answers settles the others. Breakthrough status would not guarantee a positive joint assessment or a favourable national decision. A medicine could also show clear relative benefit for HTA purposes and still miss breakthrough status, simply because another product is already authorised for the condition.

The timing brings the three together. From 13 January 2028, new orphan medicinal products fall within the scope of EU joint clinical assessment. The joint assessment reports relative clinical effects and makes no value or reimbursement judgement, which stays with Member States. Orphan programmes that file from 2028 onwards will face joint assessment, and those filing after the new rules apply will also face the breakthrough test.

Four evidence issues to plan for

The first is outcomes. Teams should check early whether their endpoints can support a claim about morbidity or mortality, and how function and quality of life are captured. Surrogate markers may support authorisation without speaking directly to the breakthrough criterion. How regulators will interpret "clinically relevant" in this context is not yet clear.

The second is comparators. Joint assessment scopes are built from Member States' PICO requests and can include several populations and comparators. Anticipating them early reduces the risk of evidence that answers the regulator's question but not the assessors'.

The third is external evidence. Where randomised comparative trials are difficult, natural history data, external controls, validated patient-relevant outcome measures, specialist-centre networks and patient input may be important in demonstrating a clinically meaningful effect. None of them is a statutory requirement. In very small populations, they often determine how convincing the evidence is.

The fourth is uncertainty. Regulators, joint assessors and national bodies handle uncertainty differently, and data cuts, estimands and length of follow-up may need to serve all three. We think the realistic goal is a common evidence backbone for regulatory, joint and national processes, built with those differences in mind, rather than one dataset that fits every audience.

A Batten disease example

Batten disease shows how the first breakthrough condition could play out. It is a group of inherited neuronal ceroid lipofuscinoses, each linked to a different gene. One form, CLN2 disease, already has an EU-authorised therapy, cerliponase alfa (Brineura). Other forms, including CLN3 disease, have no authorised treatment.

Current EMA practice gives a signal. In 2019 the agency granted orphan designation to a CLN3 gene therapy for the broader condition "neuronal ceroid lipofuscinosis". It noted that Brineura was already authorised for CLN2, so the sponsor had to show potential significant benefit. If that broad definition carries into the new breakthrough test, Brineura could affect a CLN3 programme's eligibility. Whether the criterion will be applied this way is uncertain. Developers in conditions with genetic subtypes should consider how their condition is defined well before filing.

Status and transition

Once Parliament has voted, the texts enter into force twenty days after publication, and most of the Regulation applies 24 months later. No vote date had been confirmed at the time of writing. If publication happens around the turn of the year, the new orphan rules would apply from early 2029.

Under the transitional provisions, an orphan marketing authorisation application submitted before the application date would keep the current ten-year period for that initial authorisation. Other applications for orphan products with the same active substance would fall under the new single-clock and extension rules, even if submitted before that date. What counts is when the application is submitted, not whether a programme or designation is already under way.

We will update this piece when the Parliament votes and the final text is published.

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