Artículo

Rare diseases and orphan drugs: Assessing the PV implications

Susanne Becker
Srikanth Jata, MBBS
Stephen Sun, MD, MPH

Rare diseases and orphan drugs present unique challenges and opportunities for pharmacovigilance operations. Their impact spans from adverse event reporting to aggregate safety analyses, health system interactions, and regulatory oversight. Grasping these implications and the often-complex nuances of orphan drugs is essential for drug safety professionals responsible for ensuring the safe use of therapies designed for small patient populations.

Defining rare diseases and orphan drugs

The United States Food and Drug Administration (FDA) defines a rare disease as one affecting fewer than 200,000 people in the country. The European Medicines Agency (EMA) uses a prevalence threshold of less than 5 in 10,000 people within the European Union.

To encourage the development of therapies for these under-treated and often life-threatening conditions, 92 countries worldwide implemented orphan drug policies.¹ For example, the FDA grants orphan status to drugs developed for conditions meeting its rare disease definition, offering incentives such as market exclusivity and tax credits. The EMA likewise provides orphan designation for drugs targeting rare conditions, with benefits including protocol assistance and fee reductions. While all orphan drugs target rare diseases, not all rare diseases have orphan drugs available.

The size of population, complexity and heterogeneity of rare diseases, and often sparse data to determine safety risks makes the job of adverse event reporting more challenging for pharmacovigilance (PV) professionals. This article charts the top eight challenges drug safety professionals face when dealing with rare diseases.

Challenges with validating safety in orphan drugs

1. Low case volumes and limited data

Small patient populations result in very few spontaneous adverse event (AE) reports, reducing statistical power and requiring emphasis on single cases.² Companies are therefore often obliged to perform systematic follow-up, for example through registries and/or post-market approval.

2. Challenges in signal detection using standard methods

Traditional quantitative signal detection methods (e.g., disproportionality analyses) are less effective with small datasets, requiring greater reliance on qualitative review and expert judgment.³

3. Incomplete or poorly detailed AE reports

Reports often have limited information, complicating causality assessments and necessitating follow up or supplemental data sources.⁴ While the rare disease community, including patients and healthcare professionals, often can provide more detailed data, particularly if the drug is new, the limited data set remains a challenge.

4. Different treatment standards and standards of care

Different treatment standards and standards of care (including non-drug interventions, dietary recommendations, vaccination schedules, follow up, etc.), yet with the same effect, pose a challenge. These factors need to be considered when planning further studies.

5. Lack of robust baseline disease information

Baseline rates of symptoms and complications are often unknown and inadequate natural history data makes it difficult to interpret clinical outcomes. This makes it difficult to distinguish drug related adverse events from the disease manifestations.^5,6 Differentiating drug induced effects from disease progression is particularly difficult in heterogeneous, rapidly evolving rare conditions and may require case by case experienced medical reviewers in consultation with specialists to help adjudicate the case.

6. Restricted access and high treatment costs

Orphan drugs are often costly and prescribed commonly in specialist centers or by sub-specialists, limiting patient exposure and further constraining the volume of safety data. As a result, specialist centers may allow safety issues to be more closely and effectively managed, reflecting a trade off whereby lower overall safety case volumes are balanced by richer, more comprehensive medical histories within individual cases.

7. Heightened regulatory expectations for enhanced surveillance

Regulators may require tailored risk management plans, frequent narrative safety updates, mandatory registries, and post authorization safety studies despite limited available data. Both FDA and EMA expect robust post-marketing surveillance, such as enhanced risk management plans (RMPs) tailored to the rare disease context⁷ and risk evaluation and mitigation strategies;⁸ frequent and detailed safety updates; and patient registries to supplement spontaneous reporting.⁹ Regulators may require additional post-authorization safety studies (PASS) and expect sponsors to proactively address gaps in safety information.¹⁰

8. Voice and verification of patient inputs

Patient organizations increasingly amplify the collective voice of patients and caregivers, bringing visibility to symptom burden, treatment impact, and disease progression that may be underrepresented in traditional clinical and safety data. While this amplified real world feedback can help contextualize adverse events and address gaps in baseline disease understanding, it is also important to have careful validation and structured interpretation to account for variability, reporting bias, and the absence of standardized clinical assessment.

Recommendations for navigating PV challenges

The safety assessment challenges that orphan drugs present require companies to adopt early planning for their data follow-up strategies after approval. This includes clarifying how additional data will be collected and from what sources, for example disease registries, literature searches, and direct patient and HCP outreach.

To ensure the issues relating to small patient numbers and lack of baseline disease information are properly planned for and enable access to comprehensive safety data, companies should work with all key stakeholders -- including specialist centers, other healthcare professionals, patient advocacy groups, and caregivers and patients.

Companies should also take advantage of scientific advice procedures with the regulatory authorities to ensure health authority expectations are met, and to ensure they have the flexibility to adapt to these requirements.

Additionally, companies should work with experts in the field who help them to address these challenges and offer key support, such as carrying out advanced literature searches supported by artificial intelligence-led analysis.

Conclusion

Rare diseases and orphan drugs require specialized and adaptable approaches in pharmacovigilance operations. While FDA and EMA both recognize the challenges rare disease present, safety remains the foremost priority for regulators and both have laid out clear regulatory expectations, including enhanced surveillance and methodological flexibility.

Challenges in adverse event reporting, aggregate analyses, and signal detection must be addressed through tailored strategies, cross-disciplinary collaboration, and proactive engagement with healthcare systems. By understanding and adapting to these implications, drug safety professionals can ensure the continued protection of patients affected by rare diseases.

*Fuentes que continúan a continuación

About the authors:

Susanne Becker is Service Line Lead, QPPV Solutions, at Cencora. She is an experienced pharmacovigilance professional including experiences as a QPPV in the EU/EEA.

Srikanth Jata, MBBS, is Service Line Lead, Signaling, Benefit-Risk Management, at Cencora. He has extensive experience in pharmacovigilance, signal and project management, and aggregate safety reporting.

Stephen Sun, MD, MPH, is Head of Pharmacovigilance and the Practice Area Lead for Benefit-Risk Management for Cencora. He has worked in generics, branded, and OTC products as a sponsor overseeing clinical, medical affairs, and drug safety. He has also served as a medical officer in risk management and controlled substances at the US FDA.

Descargo de responsabilidad:
La información proporcionada en este artículo no constituye asesoramiento legal. Cencora, Inc. recomienda encarecidamente a los lectores que revisen la información disponible relacionada con los temas tratados y que confíen en su propia experiencia y conocimientos para tomar decisiones al respecto.

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Sources

^1.Chan A, Chan V, Olsson S, et al. Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis. Value in Health, 2020; 23, 1580-1591. Accessed 6 May 2026. https://www.valueinhealthjournal.com/article/S1098-3015(20)34413-2/fulltext#:~:text=Of%20the%20200%20countries%20or,of%20patients%20with%20rare%20diseases
^2.Price J. What Can Big Data Offer the Pharmacovigilance of Orphan Drugs? Clinical Therapeutics, Volume 38, Issue 12, December 2016. Accessed 6 May 2026. https://www.sciencedirect.com/science/article/abs/pii/S0149291816308475
^3.Sardella M, Lungu C. Evaluation of quantitative signal detection in EudraVigilance for orphan drugs: possible risk of false negatives. Ther Adv Drug Saf., Oct 2019. Accessed 6 May 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC6804351/
^4.Jonker CJ, de Vries ST, van den Berg HM, et al. Capturing Data in Rare Disease Registries to Support Regulatory Decision Making: A Survey Study Among Industry and Other Stakeholders. Drug Saf., Aug 2021. Accessed 6 May 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC8279983/
^5.Sardella M, Belcher G. Pharmacovigilance of medicines for rare and ultrarare diseases. Ther Adv Drug Saf., Aug 2018. Accessed 6 May 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC6243425/
^6.Rare Diseases: Natural History Studies for Drug Development, FDA, March 2019. Accessed 6 May 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development
^7.Risk management plans (RMP) in post-authorisation phase: questions and answers, EMA. Accessed 6 May 2026. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/risk-management-plans-rmp-post-authorisation-phase-questions-answers
^8.REMS Compliance Program, FDA. Accessed 6 May 2026. https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/rems-compliance-program
^9.Patient registries, EMA. Accessed 6 May 2026. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/patient-registries
^10.Bilton D, Caine N, Cunningham S et al., Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry, The Lancet Respiratory Medicine, July 2018. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30192-9/fulltext

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