​The importance of patient advocacy
in the EMA ODD process

Introduction

Traditional clinical and epidemiological datasets often fall short of fully capturing the varied challenges faced by patients. These datasets, while essential for regulatory evaluations and ODD applications, typically focus on measurable biological outcomes and prevalence statistics – metrics that fail to convey the lived realities of those navigating complex, chronic and often debilitating conditions. 

For the estimated 30 million individuals in the EU affected by rare diseases,^[1] the nuances of daily life, from caregiver burdens to emotional strain, social isolation and the failure of existing therapies to meet real-world needs, can remain invisible in conventional scientific discourse. Addressing these unseen aspects is critical for developing truly impactful therapies and achieving regulatory success under the EMA’s orphan designation framework.

Increasingly, patient advocacy groups and rare disease communities are stepping into this void, using structured, patient-driven tools to translate subjective experiences into evidence. These tools, including patient-reported outcome measures (PROMs), community surveys and qualitative interviews, are not merely anecdotal supplements; they are rigorous, methodologically sound data sources that help regulators understand unmet needs from the patient’s perspective. 

In parallel, the EMA has been evolving its patient engagement framework to bring patient voices into the regulatory process earlier and make them more central to the process. 

The EMA has demonstrated increasing openness to patient-derived evidence since patients were first appointed as members of the Committee for Orphan Medicinal Products (COMP) in 2000, although the journey is far from linear. Mechanisms like Day 1 early-contact meetings have strengthened collaboration. However, cases of ODD applications being withdrawn reveal ongoing friction points, particularly when regulatory expectations diverge from patient group priorities. These complexities emphasise the importance of strategic planning, early engagement and flexible negotiation frameworks that can balance regulations with patient integrity.

This article explores how patient-driven tools are helping define unmet medical need, how the EMA’s evolving engagement framework is enabling this shift and what sponsors must do to navigate these interwoven dimensions effectively. 

Defining unmet need through patient-driven tools

Clinical and epidemiological data are indispensable for orphan designation, but they rarely capture the nuances of patients’ daily lives. Patient advocacy groups address this gap by turning subjective experiences and anecdotes into actionable evidence.

In nearly 1,500 scientific advice (SA) and protocol assistance procedures from 2008 to 2020, patient contributions addressed key CT elements, such as comparator treatments, endpoint selection, study feasibility and quality of life concerns. These inputs altered the EMA’s guidance in 20% of cases and prompted deeper discussion in over half of all procedures.^[2]

Patient input is formally incorporated at the protocol assistance stage, which is a SA process specific to ODD in the EU. During this stage, sponsors routinely invite advocacy groups into pre- and post-submission meetings.

First, PROMs are developed in collaboration with patients to quantify symptom severity, functional limitations and quality of life impacts. This evidence feeds directly into the ‘no satisfactory method of diagnosis, prevention or treatment of the condition exists’ criteria and, if such a method exists, the medicine must be of ‘significant benefit’ for an EMA orphan designation application. PROMs must be validated within the target rare disease population to ensure content and construct validity, a process that often requires bespoke instrument development and iterative feedback loops with patient experts. This rigorous co-creation process ensures PROMs reflect the priorities and language of the patient community while, at the same time, provide validated measurements, enhancing their acceptability to regulators.

Comprehensive community surveys can then leverage established patient registries and advocacy networks to gather cross-sectional data on disease burden, treatment gaps and economic impacts. These surveys often surface underreported challenges, such as caregiver strain, social isolation and direct medical costs, that strengthen significant-benefit arguments. For example, Duchenne muscular dystrophy (DMD) patient groups, including Action Duchenne and the World Duchenne Organization, have played a crucial role in challenging the limitations of steroid treatments by establishing and maintaining DMD registries, such as the TREAT-NMD global registry. This registry has been used to determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients.^[3]

Qualitative interviews also provide granular insights into patient and caregiver experiences, revealing emotional tolls, therapy administration difficulties and adaptive behaviours that may not emerge in quantitative measures. 

By combining narrative accounts with PROM scores and survey statistics, sponsors can present a holistic disease profile that resonates with both regulators and external stakeholders. The power of qualitative data lies in its ability to humanise a dossier, transforming abstract metrics into real-world insights that illustrate unmet needs and justify endpoint selection.

An example of these patient-driven tools in action can be seen in the case of atidarsagene autotemcel (Libmeldy®), a gene therapy that was granted ODD in 2007 for the treatment of metachromatic leukodystrophy (MLD),  a rare, inherited disorder that affects the nervous system.^[4] Advocacy efforts from organisations like the ArchAngel MLD Trust and the MPS Society played a significant role in demonstrating the severity of the condition and the potential benefits of this drug. During the development, protocol assistance was received on multiple occasions to obtain guidance on the quality aspects and the clinical study programme, including the demonstration of significant benefit.^[5]

The EMA then granted an EU marketing authorisation (MA) for the gene therapy in 2020. As part of its recommendation for MA, the committees requested that the sponsor use a registry of patients to learn more about the long-term efficacy and safety of the medicine. Despite initially not recommending the drug due to long-term uncertainty in 2021,^[6] the National Institute for Health and Care Excellence (NICE) later recommended Libmeldy as an option in 2022. NICE noted the role of the patient organisations in this achievement and commended their detailed survey feedback on the effect of the drug on quality of life.^[7]

Without these rigorous, patient-driven tools, ODD applications risk relying on clinical or epidemiological arguments alone and miss the strongest advocates for why the drug matters. By systematically collecting what matters most to patients, sponsors can tailor inclusion criteria, select patient-relevant endpoints and ensure that trials capture meaningful outcomes. This not only strengthens the scientific rationale in protocol assistance meetings but also boosts patient recruitment and retention. Without recruitment and retention, there is no data.  

The EMA’s evolving patient engagement framework

The EMA has progressively enhanced its patient engagement framework to ensure the perspectives of patients are integral to the regulatory processes governing medicines within the EU. Before 2022, patient involvement in the EMA’s orphan designation process was largely consultative. Patient groups could provide written submissions, participate in public hearings and, in some cases, serve as observers in COMP meetings, but structured, early dialogue was absent. 

In recognising the value of patient input in regulatory activities, the EMA instigated dialogue with patients in 1996. Patients were first appointed as members of the COMP in 2000, then of the Paediatric Committee (PDCO), the Committee for Advanced Therapies (CAT) and the Pharmacovigilance and Risk Assessment Committee (PRAC).^[8] In 2005, a formal framework for interaction with patients and their organisations was established.^[9] This framework has since undergone several updates, with significant revisions in 2022 to strengthen patient involvement further.

In response to mounting evidence that patient contributions improved trial design and regulatory decision-making, the EMA then initiated pilot programmes in 2021 and 2022.^[10] During these pilots, COMP and the Committee for Medicinal Products for Human Use (CHMP) invited patient and healthcare professional organisations to early-contact meetings at Day 1 of marketing authorisation application (MAA) evaluations, enabling sponsors and patient groups to present contextual disease burden data alongside EMA experts.^[11] The success of these pilots prompted a full rollout of Day 1 early-contact procedures to all new MAAs by late 2022. 

Simultaneously, the Agency enhanced other avenues for patient input. Patient and consumer representatives became full members of COMP, empowering them to participate directly in orphan designation deliberations. As a result, structured consultations within the SA and protocol assistance framework now systematically include patient insights on endpoint selection, trial feasibility and ethical considerations. Although public hearings and written consultations remain vital for broader stakeholder engagement, they are now complemented by dedicated patient engagement meetings. 

The 2022 updates to the engagement framework aim to:

• Engage patients and consumers in regulatory activities from early development stages through to post-marketing surveillance, in order to capture their insights on disease burden, unmet needs and treatment outcomes
• Promote the creation of methodologies and guidance, such as those from the International Council for Harmonisation (ICH), to effectively collect and use patient experience data in regulatory decision-making
• Ensure patients, consumers and their representative organisations are consulted and involved in the development of EMA policies and plans
• Establish training programmes to provide patients and consumers with a clear understanding of EMA activities, their context and the roles they can play
• Improve patients’ and consumers’ comprehension of the EMA’s mandate and its role within the EU Regulatory Network concerning the development, evaluation, monitoring and information dissemination of medicines
• Develop effective communication tools and strategies to facilitate the dissemination of information to patients and consumer organisations, supporting their role in the safe and rational use of medicines^[12]

This evolution reflects a commitment to incorporating real-world experiences and insights from patients throughout the lifecycle of medicinal products. Taken together, these measures constitute a patient engagement framework that encourages dialogue and collaboration between sponsors, patient groups and the EMA to make regulatory decisions more patient-centric and enhance the trust and transparency of the regulatory process.

However, the question remains as to whether more can be done.

Coming to a mutually agreeable decision in the ODD process

From 2000 to 2024, 4,586 ODD submissions were made to the EMA. Of those submissions, 3,012 were approved by the European Commission (EC), and only 39 were refused. However, 1,346 applications were withdrawn after submission, so it is important to question this statistic and examine why this could be.^[13]

There are likely to be many contributing factors here; for example, failure to meet the required timeline and documentation for ODD submission or an inability to demonstrate significant benefit over existing therapies. Demonstrating significant benefit from nonclinical data is particularly difficult when there is insufficient information on the disease (as is often the case with rare diseases).  

It is often small biotechs or academic spinoffs that develop orphan drugs, so it is valuable for them to obtain orphan designation at an early stage to aid fundraising and enable continued development. Failing to meet the EMA’s criteria for ODD may lead to the halting of development in the particular drug, meaning that its potential benefit to patients is never recognised.  

Despite the EMA’s evolving engagement framework, coming to a mutually agreeable conclusion between the patient group, the sponsor and regulatory authorities is another, often overlooked, challenge. 

The way the EMA evaluates orphan conditions and their prevalence differs from that of other regions. For example, the orphan condition may comprise a broader population than the population defined by the proposed therapeutic indication, and it is this population on which the prevalence is estimated.^[14] As such, it is not uncommon for the COMP to modify the orphan condition during the designation process. However, patients or advocacy groups do not always welcome broadening the indication. 

An example of this challenge occurred during an ODD application for a rare developmental and epileptic encephalopathy (DEE) condition: cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD). Affecting approximately one in 40,000 to 60,000 live births,^[15] CDD is caused by pathogenic mutations in the CDKL5 gene.^[16] The disease can manifest in a broad range of clinical symptoms and severity, including early-onset, intractable epilepsy and neurodevelopmental delay, impacting cognitive, motor, speech and visual function.^[17] 

Although the EMA’s COMP initially validated the ODD application for treatment for CDD, the COMP then asked that the indication be broadened to encompass other neurological and developmental conditions. Historically, CDD was included in the diagnosis of Rett Syndrome, and there is a substantial overlap in the mutations leading to CDD and Rett Syndrome; in many cases, only genetic testing helps to differentiate between the two conditions. The COMP considered that, despite advances in scientific discrimination between Rett-like syndromes, for regulatory purposes, their separation into distinct designations was premature. 

This led to a significant point of negotiation as the patient advocacy group felt that broadening the indication would dilute the importance of their patient population and give false hope to patients without CDD, as there were no plans to investigate outside the specific indication. The patient group had researched and campaigned to have CDD seen as a distinct disease and did not agree that CDD comes under the Rett Syndrome umbrella.  

Despite efforts to resolve the issue, including a face-to-face oral explanation meeting with the EMA, the COMP still insisted the indication be expanded. The sponsor had a history of working with the patient group, and a substantial proportion of the patient pool for a CT would come from this group. As a result, the sponsor decided to listen to the patient group and withdraw the application, demonstrating the influence of patient advocacy – if not on the COMP, then on the sponsors.  

These challenges are not uncommon when developing new treatments for rare diseases, and highlight the complexities of ODD for rare conditions and the importance of strategic regulatory guidance, ongoing dialogue and stakeholder collaboration in drug development. 

This case also raises the question of ethics. Should a sponsor continue with an ODD application, broadening the indication, even if they have no plans to develop the drug for this wider indication? Equally, how can we balance regulations with sponsor integrity and patient needs to create an environment for co-development and ensure patient voices are heard by regulators? 

Practical sponsor strategies for leveraging the engagement framework

To navigate the complexities of patient input and ensure advocacy efforts align with regulatory expectations while maintaining the integrity of submissions, sponsors should establish:

• Early and continuous dialogue with patient organisations
• Transparent communication of trial designs and endpoints
• A steadfast commitment to addressing the unmet needs articulated by the patient community

Initiating dialogue with patient organisations, such as EURORDIS and disease-specific non-governmental organisations, before drafting an ODD application ensures patient priorities shape study design and evidence collection. Co-creating PROMs and surveys with patient experts validates the relevance of these tools and demonstrates to regulators that patient contributions underpin every element of the dossier. Training sessions for patient representatives on EMA processes and dossier structure can then further elevate the quality of input, enabling advocates to articulate insights effectively within regulatory contexts.

Sponsors should also capitalise on the EMA’s Day 1 early-contact meetings and protocol assistance consultations to align on endpoint selection, indication scope and significant benefit arguments. By presenting patient-driven evidence alongside clinical data in these forums, sponsors can secure valuable feedback and pre-empt potential objections. Importantly, every dialogue should be meticulously documented, with summaries incorporated into dossier sections dedicated to significant-benefit and protocol justification.

Given the possibility of divergent stakeholder perspectives – exemplified by the CDD case –sponsors must also develop contingency plans. Preparing narrower or alternate indication proposals, as well as supplementary data packages, allows for adaptive responses to COMP requests without compromising patient-centred objectives. Engaging in facilitated mediation sessions, potentially with EMA support, can also help reconcile differences around scope and evidence requirements before formal submission.

Finally, sponsors must remain abreast of evolving EMA guidance on patient engagement, attending workshops and incorporating lessons from published COMP advice meetings into their regulatory strategy.

Conclusion

While necessary, clinical and epidemiological data are not always sufficient on their own to capture the full burden of rare diseases. When developed and validated in collaboration with advocacy groups, patient-driven tools like PROMs and community surveys help fill this gap by translating subjective insights into structured, actionable evidence. These contributions support regulatory criteria, such as demonstrating the absence of satisfactory treatments or establishing significant benefit over existing therapies, making them essential components of a successful ODD application. 

Although the EMA has progressively evolved its patient engagement framework to embed patient perspectives more deeply into the regulatory process, challenges remain. Differences in regulatory interpretation and patient community priorities can complicate the ODD process, particularly when regulators seek to broaden indications in ways that may dilute disease-specific patient advocacy efforts. These tensions highlight the need for clear communication, strategic preparation and flexibility on all sides.

References

^[1] Eurordis Rare Disease Europe (2025) ‘What is a rare disease?’. (Accessed: 27 May 2025). 

^[2] Murphy A, Bere N, Vamvakas S and Mavris M. (2022) ‘The Added Value of Patient Engagement in Early Dialogue at EMA: Scientific Advice as a Case Study’. Front Med. Volume 8:811855. doi: 10.3389/fmed.2021.811855

^[3] Koeks Z, Bladen CL, Salgado D, van Zwet E, Pogoryelova O, et al. (2017) ‘Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database’. J Neuromuscul Dis. 4(4):293-306. doi: 10.3233/JND-170280

^[4] European Medicines Agency (EMA) (2020) ‘Libmeldy’. (Accessed: 17 June 2025).

^[5] European Medicines Agency (EMA) (2020) ‘New gene therapy to treat rare genetic disorder metachromatic leukodystrophy’. (Accessed: 17 June 2025).

^[6] MPS Society (2021) ‘NICE unfortunately leans towards a no for the treatment of Metachromatic Leukodystrophy (MLD)’. (Accessed: 17 June 2025).

^[7] MLD Support Association UK (2022) ‘NICE final guidance approves life-changing gene therapy for treating Metachromatic Leukodystrophy (MLD)’. (Accessed: 17 June 2025).

^[8] Eurordis Rare Disease Europe (2025) ‘Patient organisations warn against EU rollback on patient involvement in medicines regulation’. (Accessed: 27 May 2025).

^[9] European Medicines Agency (EMA) (2025) ‘Patients and consumers – Key milestones of EMA interaction with patients and consumers’. (Accessed: 27 May 2025).

^[10] European Medicines Agency (EMA) (2022) ‘Pilot on early dialogue with patient organisations for orphan marketing authorisation applications: Outcome Report’. (Accessed: 27 May 2025).

^[11] European Medicines Agency (EMA) (2021) ‘Pilot phase for CHMP early contact with patient/consumer organisations’. (Accessed: 27 May 2025).

^[12] European Medicines Agency (EMA) (2022) ‘Engagement framework: EMA and patients, consumers and their organisations’. (Accessed: 27 May 2025).

^[13] European Medicines Agency (EMA) (2024) ‘Orphan Medicinal Product Designation: Overview 2000-2024’. (Accessed: 27 May 2025).

^[14] European Commission (2022) ‘Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another’. (Accessed: 27 May 2025).

^[15] Jakimiec M, Paprocka J and Śmigiel R (2020) ‘CDKL5 Deficiency Disorder-A Complex Epileptic Encephalopathy’. Brain Sci. 10(2):107. doi: 10.3390/brainsci10020107 

^[16] Hector RD, Kalscheuer VM, Hennig F, Leonard H, et al. (2017) ‘CDKL5 variants: Improving our understanding of a rare neurologic disorder’. Neurol Genet. 3(6):e200. doi: 10.1212/NXG.0000000000000200

^[17] International Foundation for CDKL5 Research (IFCR) (2025) ‘About CDKL5’. (Accessed: 27 May 2025).