Authors: Sam Bryant, Regulatory Affairs Manager and Wim Neckebroeck, Director Regulatory Affairs

At the World Orphan Drug Congress (WODC) USA 2025, held in Boston, our team engaged with industry innovators to explore the evolving landscape of orphan drug development.  This blog highlights the main insights from the event, examining strategies to navigate the unique challenges of orphan drug development—from identifying patient populations and optimising clinical trial designs to aligning with regulatory expectations to ensure commercial viability. As the field progresses, these considerations are crucial to accelerating access to life-changing therapies for patients with rare diseases. 

What does clinical trial readiness mean for orphan drug development? 

Inherent to drug development for rare diseases is the limited number of patients that can be enrolled in clinical trials. However, this does not mean that having a rare disease is uncommon. In the EU, approximately 36 million people have a rare disease. 

A crucial starting point for health technology developers is to understand who the patients with the rare disease are and where they are located. This may involve considering decentralised clinical trials, which can significantly improve accessibility for patients with rare diseases. 

Additionally, health technology developers need to ensure they have adequate manufacturing facilities to allow for upscaling when needed. Timely planning is essential, as it can drastically impact timelines, especially in areas with complex manufacturing processes such as Advanced Therapy Medicinal Products (ATMPs). 

Clinical trial readiness also involves early interactions with regulatory bodies to ensure the correct setup of the clinical trial, ensuring the development of the right data. This is crucial not only for regulatory bodies but also for Health Technology Assessment (HTA) bodies, to avoid ending up with a safe and effective treatment that cannot be marketed due to misalignment in cost-effectiveness. 

Lastly, having the right people on board is essential. A multidisciplinary team consisting of clinicians, researchers, lab technicians, regulatory experts, quality assurance professionals, and statisticians is necessary to perform multiple tasks in parallel. 

EU HTA for orphan drugs : a burden or an opportunity? 

The EU HTA requirements for medicinal products in oncology and ATMP began in January 2025. For Orphan drugs, these requirements will only apply starting in 2028. However, this does not mean that the new European process should be ignored for Orphan drugs at this moment. Health technology developers (HTDs) should plan activities like robust Population, Intervention, Comparator, Outcome (PICO) prediction well in advance. It is generally recommended that preparations for JCA (Joint Clinical Assessment) begin 18 to 24 months before submitting the marketing authorisation to EMA. 

Preparing the joint clinical assessment dossier is an additional step that requires significant time and resources, necessitating HTDs to adapt their current practices to meet the new requirements. The EU HTA and the creation of a joint clinical assessment report are expected to benefit harmonisation across European countries. Although the JCA is not legally binding for national HTA, these bodies must consider it in their local evaluations. Many national HTA bodies have been heavily involved in shaping the EU HTA process, which is hoped to lead to a more consistent approach across Europe. 

A review of the current legislation is expected by 2028, providing health technology developers the opportunity to influence the final EU HTA process. Specific guidelines and implementing acts are likely to change by 2028, hopefully facilitating the implementation of the process for Orphan drugs. The launch of this new European HTA process will come with challenges, such as limited reviewer capacity and a lack of JSC slots for early discussions. However, there is hope that within 10 years, we will have a streamlined and efficient process similar to the marketing authorisations submitted to EMA in Europe. In this way, the JCA could potentially position Europe as a reference for other markets, similar to the role of marketing authorisations (e.g., LATAM). 

Overcoming commercial challenges in rare disease 

Recent challenges in the rare disease space have added considerable uncertainty for health technology developers of orphan medicines. Policy changes in the US, including sunsetting of the Priority Review Voucher (PRV), reduced funding from the National Institutes of Health (NIH) and staffing cuts at the Food and Drug Administration (FDA) all have the potential to negatively impact orphan medicine development.  

On the commercialisation side, some HTDs have pulled back from the market due to difficulties in price negotiation with payers and patient adoption of the new therapies. In addition, there remains uncertainty of the impact of the Inflation Reduction Act (IRA) Drug Price Negotiation Program (DPNP) on orphan medicines. Under the current legislation an orphan medicine will lose the exemption from Medicare price negotiations  if the label is extended to a second orphan indication. There is significant advocacy work on-going by patient groups and industry to ensure that the IRA does not impact access of patients to treatments of their rare disease.  

Despite these headwinds, all attendees at WODC USA remained determined to continue working to find solutions for patients suffering with rare diseases and provided strategic advice on how to overcome some of these challenges: 

• Patients: Development of treatments for rare diseases starts and ends with the patients and HTDs should keep patients central to their strategy. Consider from early stages what would be the expected benefit to patients, if they do not align with patient community  expectations then there will not be a market for the product. Including patients in clinical trial design improves recruitment and retention, accelerating timelines and patient voices can enhance discussions with payers and regulators. In a powerful example one Biotech described the impact of a patient attendance in a meeting with the FDA; first-hand testimony of living with the disease convinced the regulator of the urgent need for treatments. Patients are much more than just data tables! 

• Payers: The gap between regulatory approval and market access and reimbursement remains one of the biggest hurdles in the development of orphan medicines. Many presentations emphasised that HTDs should engage with HTA bodies and payers from early phases of development to ensure that the right data is generated. Particularly in rare diseases with a limited patient population, HTDs should think globally from beginning of development, not US first, then rest of world. 

• Prioritise: Orphan medicines do not have to be groundbreaking to treat rare disease patients, often a small improvement in symptoms can be life-changing for patients. Some HTDs at WODC USA were prioritising treatments with a broader impact on the symptoms of rare disease. This could be through repurposing/ repositioning of candidates into the rare disease space, or through products that target the symptoms of multiple rare diseases rather than a single genetic defect. 

At WODC USA positive examples of successful orphan drug development were shared: Zolgensma, a gene therapy for treating spinal muscular atrophy is now available in 50 markets; Vyjuvek a topical gene therapy for treatment of a rare skin condition developed by a small Biotech; Duvyzat, a small molecule HDAC inhibitor approved by the EMA for treatment of Duchenne Muscular Dystrophy (DMD). 

With commitment and a strategic mindset there remain many opportunities for HTDs to bring their innovative products to the market and change the lives of rare disease patients.

At Kintiga, we simplify the complex journey to achieve successful patient access across Europe. By uniting deep local market access expertise, a global perspective, and innovative strategies, we partner with health technology developers to deliver impactful, tailored solutions, maximising both market potential and patient outcomes for orphan drug therapies and beyond. 

If you would like to discuss any of the above insights in more detail, or find out how Kintiga can support you with JSC application or next HTA project, please get in touch via enquiries@kintiga.com