The world of orphan drugs is both fascinating and challenging. These medicines are developed to treat rare diseases – conditions that affect only a small fraction of the population. Yet their rarity is precisely what makes their safety monitoring so complex.

Only a few patients have ever used orphan drugs before they reach the market. This means limited exposure and a lack of comprehensive safety data. Without enough patients, detecting rare or long-term adverse effects is hard.

That’s why post-marketing surveillance is a cornerstone of pharmacovigilance for orphan medicines. Continuous monitoring helps regulators, healthcare professionals, and patients make informed decisions about their use.

What Counts as a “Rare” Disease?

Interestingly, there’s still no global consensus on the definition of a rare disease.

In the United States, a rare disease affects fewer than 200,000 people (or fewer than 650 per million). In the European Union, fewer than 5 in 10,000 individuals (or fewer than 500 per million).

According to the European Medicines Agency (EMA), around 36 million people in the EU live with a rare disease.

How a Drug Qualifies for Orphan Designation

To earn orphan status in the EU, a medicine must meet several criteria:

• It treats, prevents, or diagnoses a life-threatening or chronically debilitating disease.

• The condition affects no more than 5 in 10,000 people, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development.

• There’s no satisfactory existing treatment, or the new drug offers a significant benefit over available options.

Since 2000, more than 3,000 medicines have received orphan designation, and over 260 have been authorised in the EU.

The Knowledge Gap in Rare Diseases

Scientific knowledge about rare diseases remains limited. Although around five new rare diseases are described in medical literature every week, fewer than 1,000 have been studied in depth.

This lack of data makes it extremely difficult to define orphan drugs’ efficacy and safety profiles – especially those targeting ultrarare diseases or pediatric populations.

The Challenge of Limited Safety Data for Orphan Drugs

Clinical trials for orphan drugs often include only a few dozen or a few hundred patients. As a result, only the most common adverse reactions can be detected before approval.

For example, according to the “Rule of 3’s,” if a trial includes 300 patients, it can only rule out with 95% confidence that an adverse reaction affects more than 1 in 100 patients. Anything rarer might remain invisible until after launch.

That’s why case reports – even a single, well-documented one – are vital in this field. Each report helps uncover unknown adverse drug reactions and adds a piece to the safety puzzle.

When the Disease Itself Blurs the Picture

In some cases, the underlying disease makes it difficult to determine whether an adverse event is caused by the drug or the illness itself. For example, medicines for inborn metabolic disorders or storage diseases are often given to critically ill children, where side effects may mimic disease symptoms.

Furthermore, treatments that extend survival in previously fatal conditions create new patient populations with unknown long-term outcomes. A “new” adverse event in such patients might reflect disease progression rather than a drug reaction.

Why Traditional Signal Detection Doesn’t Work

Traditional statistical signal detection is often ineffective for orphan drugs because of the small number of patients, low report volumes, and confounding conditions.

Instead, qualitative approaches – such as proactive post-marketing safety studies – play a more meaningful role. These methods help define safety profiles and assess the benefit-risk balance of orphan medicines.

The SFDA Experience: A Case Study in Orphan Drug Safety

DrugCard’s pharmacovigilance specialists recently reviewed an insightful article in Uppsala Reports titled “Safety Monitoring of Orphan Drugs: The SFDA Experience.”

The Saudi Food and Drug Authority (SFDA) examined 35 orphan drugs approved between 2016 and 2023. Researchers analysed data from the AdisInsight database, reviewing over 1,400 reported adverse events.

Their findings led to:

• 14 updates to local product information,

• 20 comprehensive safety reviews,

• and 24 potential safety signals under evaluation.

These efforts resulted in requests for additional safety data for six signals, monitoring for thirteen, and discontinuation for five others.

This project shows how systematic literature monitoring and global-local collaboration can enhance orphan drug safety.

Why Local Monitoring Matters Too for Orphan Drugs Safety

Orphan diseases often have unique geographic patterns. For example, a rare condition prevalent in an Eastern country may present differently than in a European population. Local literature monitoring ensures that regional safety data aren’t overlooked – a crucial step in protecting patients worldwide.

Local journals, hospital bulletins, and national conference proceedings frequently publish case reports and clinical observations that never reach international databases. Such publications can reveal early signs of unexpected adverse reactions, unique drug-disease interactions, or even ethnic-specific safety concerns that global monitoring may overlook.

Moreover, some orphan drugs are used off-label or under special access programs in specific regions before receiving broader approval. Monitoring local scientific publications helps capture safety signals emerging from these real-world settings.

Building a Better Post-Marketing Safety Network

Data on orphan drugs is inevitably limited at the time of marketing approval. Every available source – clinical trials, scientific literature, spontaneous reports, and even real-world monitoring technologies – should be integrated into risk management plans.

As more data emerge, safety and effectiveness profiles must be continuously updated, and healthcare professionals promptly informed. This ongoing process ensures that the benefit-risk balance of orphan drugs remains transparent and favourable for patients.

Conclusion

Pharmacovigilance for orphan drugs is not just about monitoring – it’s about connecting every data point, no matter how small, to protect some of the most vulnerable patients.

For pharmacovigilance professionals, including local literature in routine surveillance ensures a more complete and context-sensitive safety assessment. Regulatory authorities and pharmaceutical companies can make better-informed decisions about labelling updates, risk management strategies, and communication with healthcare providers by integrating local findings with global data.

As science evolves, so must our vigilance. After all, every rare disease patient deserves hope and safety.