Off-label prescribing—the use of a licensed medicinal product for an indication, dosage, route of administration, or patient population not covered by its marketing authorisation—is a widespread and essential clinical practice. However, it represents one of the most significant blind spots in pharmacovigilance. Unlike on-label use, off-label prescribing occurs without the safety net of rigorous pre-marketing clinical trials, leaving patients exposed to unknown risks and pharmacovigilance systems struggling to detect and characterise adverse events.
This article provides a comprehensive medical and regulatory analysis of off-label use as a pharmacovigilance blind spot. We explore the definition and scope of off-label prescribing, its public health implications, the regulatory framework governing adverse event reporting for off-label use (including EMA and FDA guidance), and the data showing that off-label use is associated with a significantly higher risk of serious adverse drug reactions. We then examine advanced detection methods—including real-world data linkage, natural language processing, social media monitoring, and artificial intelligence—that can help identify off-label ADRs. Finally, we provide practical strategies for healthcare professionals, pharmaceutical companies, and regulators to close this critical safety gap.
1. Introduction: The Scale and Significance of Off-Label Prescribing
Off-label prescribing is a common practice across virtually all medical specialties. A systematic analysis of the WHO Essential Medicines List (EML) found that off-label prevalence among these essential medicines was 60.0%, with the most frequent off-label use observed in infectious diseases (30.5%) and oncology (25.2%). Alarmingly, only 11% of these off-label uses were backed by Level A evidence (high-quality randomised controlled trials), while 32% were supported by Level C evidence (expert opinion or case reports) . The reliance on low-quality evidence for off-label prescribing underscores the urgent need for robust pharmacovigilance surveillance.
In paediatric populations, the problem is particularly acute. Children are often given medicines that have only been tested in adults and are not officially approved for paediatric use—this is known as “off-label use.” The World Health Organization has highlighted the unacceptable state of monitoring medicine-related problems in children worldwide, noting that less than 10% of all serious adverse reactions to medicines are reported globally. The risk of adverse drug reactions (ADRs) is 3.4 times higher with off-label prescriptions compared to on-label ones (odds ratio 3.4; 95% CI 1.47–7.89), as demonstrated in a prospective study of paediatric haematology-oncology patients. Furthermore, a 14-year analysis of VigiBase reports from Serbia found that although off-label and unlicensed drugs accounted for a minority of paediatric reports, they were associated with a higher proportion of serious reported ADRs, particularly in the neonatal period.
2. Defining Off-Label Use: A Regulatory Perspective
2.1 The EMA Definition
The European Medicines Agency (EMA) defines off-label use under its Good Pharmacovigilance Practices (GVP) guidelines as use outside the terms of the marketing authorisation. The EMA explicitly includes off-label use in the category of “use outside the marketing authorisation,” which also encompasses overdose, misuse, abuse, and medication errors.
The EMA further clarifies that reports of overdose, abuse, off-label use, misuse, or medication error with no associated adverse reaction should not be reported or submitted as individual case safety reports (ICSRs) . However, when a suspected adverse reaction is associated with off-label use, it is subject to standard pharmacovigilance reporting requirements . Importantly, the EMA’s GVP Module VI states that reports associated with off-label use should be routinely followed up to ensure that information is as complete as possible regarding symptoms, treatments, suspected medicinal products, outcomes, and the context of occurrence (e.g., unauthorised indication or population).
The EMA also explicitly includes off-label use in its list of pharmacovigilance-relevant events, alongside overdose, misuse, abuse, medication errors, and quality defects. Off-label use in paediatric populations is specifically addressed, with EMA guidance stating that pharmacovigilance applies to off-label and unlicensed as well as licensed use in children.
2.2 The FDA Position
The U.S. Food and Drug Administration (FDA) has similar requirements. An adverse experience associated with the use of a product for an unapproved indication should be reported to the FDA as is required for any other spontaneously reported adverse experience occurring in the United States (e.g., a 15-day report for a serious, unexpected adverse experience). However, a lack of effect report for an unapproved indication should not be reported on an FDA Form 3500A; instead, such information should be included in the narrative summary section of a periodic report.
The FDA’s regulations (21 CFR 312.7) strictly forbid a manufacturer from promoting a drug for any use other than what is in its approved Prescribing Information; doing so constitutes “misbranding.” However, this does not prevent healthcare professionals from prescribing off-label, and it does not exempt manufacturers from reporting adverse events associated with off-label use.
3. The Pharmacovigilance Blind Spot: Why Off-Label ADRs Are Underreported
3.1 Knowledge Gaps at Market Approval
At the time of marketing authorisation, significant knowledge gaps exist regarding a drug’s safety profile. As illustrated in a presentation by the Swiss Agency for Therapeutic Products, rare and very rare ADRs (incidence <0.1%) are typically not detected before approval because clinical trials are too small to capture them. To detect an ADR with an incidence of 1 in 10,000, approximately 30,000 exposed participants are needed; for an incidence of 1 in 100,000, 300,000 participants are required.
Specific populations—including children, pregnant women, the elderly, and patients with multiple comorbidities—are often under-represented in pre-marketing trials. Drug interactions and off-label use also represent significant knowledge gaps that only become apparent in real-world clinical practice.
3.2 The Underreporting Problem
Globally, less than 10% of all serious adverse reactions to medicines are reported. This underreporting is even more pronounced for off-label use for several reasons:
- Lack of awareness: Healthcare professionals may not recognise that they are prescribing off-label, or they may not consider the ADR to be related to the off-label use.
- Uncertainty about reporting requirements: There is confusion about whether ADRs associated with off-label use should be reported. Both EMA and FDA guidance confirm that they should be, but this is not widely known .
- Time constraints: In busy clinical practice, reporting ADRs is often deprioritised.
- Fear of legal or regulatory consequences: Some clinicians may be reluctant to report off-label ADRs for fear of scrutiny.
- Lack of feedback: When reports are submitted, reporters rarely receive feedback on the outcome, which reduces motivation for future reporting.
3.3 Data Fragmentation
Off-label prescribing is poorly captured in trial and post-market data and is often underreported. Claims or prescribing records show patterns of off-label use but do not link directly to outcomes. As noted in a comprehensive Frontiers article, linking prescribing/claims with outcomes data reveals both use patterns and associated risks, supporting proactive monitoring and targeted education around off-label use. Without such linkage, off-label ADRs remain invisible to pharmacovigilance systems.
4. The Evidence: Off-Label Use and Increased ADR Risk
4.1 Higher Risk of Serious ADRs
A prospective study found that the risk of ADRs was 3.4 times higher with off-label prescriptions compared to on-label ones (OR 3.4; 95% CI 1.47–7.89). This study showed the importance of proactive pharmacovigilance to efficiently highlight ADRs.
In paediatric populations, a 14-year analysis of VigiBase reports from Serbia found that although off-label and unlicensed drugs accounted for a minority of paediatric reports, they were associated with a higher proportion of serious reported ADRs, particularly in the neonatal period. The authors emphasised that these findings should be interpreted as pharmacovigilance reporting patterns rather than incidence-based estimates or proof of causality.
4.2 Off-Label Use in Specific Therapeutic Areas
A systematic analysis of the WHO Essential Medicines List found that off-label use was most frequent in infectious diseases (30.5%) and oncology (25.2%). These are areas where off-label prescribing is often driven by a lack of approved alternatives, particularly for rare or treatment-resistant conditions.
A review of gabapentinoid pharmacovigilance in Africa noted that gabapentinoids are frequently prescribed off-label for chronic pain, but African pharmacovigilance systems lack the resources to systematically monitor gabapentinoid-related harms.
5. Detection Methods: How to Identify Off-Label ADRs
5.1 Traditional Spontaneous Reporting
Spontaneous reporting systems remain the cornerstone of pharmacovigilance for off-label use. Both the EMA and FDA require reporting of ADRs associated with off-label use. However, as discussed, underreporting is a significant limitation.
5.2 Real-World Data (RWD) and Data Linkage
The integration of real-world data from multiple sources is one of the most promising approaches to detecting off-label ADRs. Key data sources include:
- Electronic Health Records (EHRs)
- Medical and pharmacy claims databases
- Patient registries
- Prescription databases
The linking of prescribing/claims data with outcomes data reveals both use patterns and associated risks, supporting proactive monitoring and targeted education around off-label use. Privacy-preserving record linkage (PPRL) methods, such as tokenization, enable secure, patient-level linkage of health data across datasets without exposing personally identifiable information.
5.3 Natural Language Processing (NLP)
Natural language processing can extract information about off-label use from unstructured clinical notes and social media. As noted in a recent DOAJ article, posts mentioning off-label sildenafil use (11.4% of the corpus) showed 1.8-fold higher adverse event reporting rates compared to posts about on-label use.
NLP can differentiate between off-label and on-label drug-use ADEs, enabling more targeted signal detection. AI tools such as SIGNAL, developed by the IMI WEB-RADR Consortium, and ADESSA, implemented by Spain’s national agency, utilise machine learning and NLP to support real-time signal detection and automate case evaluations.
5.4 Social Media Monitoring
Social media platforms offer a novel avenue for pharmacovigilance by providing real-time, patient-generated data on medication use and adverse events. Social media can be particularly valuable for detecting ADRs associated with off-label use, where patients may be more likely to share their experiences online than through formal reporting channels.
5.5 Active Surveillance and Prospective Studies
Active pharmacovigilance—proactively monitoring patients for ADRs—is essential for detecting off-label ADRs. A prospective study of paediatric haematology-oncology patients showed that active pharmacovigilance efficiently highlighted ADRs associated with off-label use. The MEAP project in Italy demonstrated that active post-marketing pharmacovigilance programmes are a valid strategy to increase awareness, reduce underreporting, and provide information on drug safety in paediatric populations.
6. Reporting Off-Label ADRs: A Practical Guide
6.1 When to Report
| Scenario | Action |
|---|---|
| Off-label use with suspected adverse reaction | Report as ICSR to national pharmacovigilance system |
| Off-label use with no adverse reaction | Do not report as ICSR (EMA); may be included in PSUR |
| Off-label use with serious adverse reaction | Expedited reporting (e.g., 15-day timeline) |
| Lack of efficacy with off-label use | Generally not reported; may be included in periodic reports |
6.2 What Information to Include
When reporting an ADR associated with off-label use, include:
- Clear documentation of the off-label nature of the use (indication, dosage, route, population)
- Rationale for the off-label use (if known)
- Temporal relationship between drug administration and ADR onset
- Outcome of the ADR
- Dechallenge and rechallenge information (if available)
- Concomitant medications and relevant medical history
6.3 Reporting Channels
| Region | Primary Reporting System |
|---|---|
| EU | EudraVigilance (via national competent authorities) |
| USA | FDA FAERS (FDA Form 3500A) |
| Global | VigiBase (via national pharmacovigilance centres) |
7. Strategies to Close the PV Blind Spot
7.1 For Healthcare Professionals
| Strategy | Action |
|---|---|
| Awareness | Recognise that off-label ADRs must be reported |
| Documentation | Clearly document off-label use in medical records and ADR reports |
| Education | Educate colleagues and trainees about off-label pharmacovigilance |
| Patient engagement | Encourage patients to report any unusual symptoms |
| Active surveillance | Proactively monitor patients receiving off-label therapies |
7.2 For Pharmaceutical Companies
| Strategy | Action |
|---|---|
| Compliance | Ensure all off-label ADRs are reported as required |
| Signal detection | Use advanced analytics to detect off-label safety signals |
| Risk management plans | Include off-label use considerations in RMPs |
| Post-authorisation studies | Conduct studies in off-label populations (e.g., paediatric, elderly) |
7.3 For Regulators
| Strategy | Action |
|---|---|
| Guidance | Provide clear guidance on off-label ADR reporting |
| Data linkage | Facilitate linkage of prescribing and outcomes data |
| Active surveillance | Implement active surveillance programmes for high-risk off-label uses |
| International collaboration | Share data on off-label safety signals across jurisdictions |
7.4 For Researchers
| Strategy | Action |
|---|---|
| RWD studies | Use real-world data to characterise off-label use patterns and associated risks |
| NLP development | Develop NLP tools to automatically detect off-label use and associated ADRs |
| Signal detection methods | Develop methods to detect off-label safety signals |
| Pharmacoepidemiology | Study the epidemiology of off-label use and ADRs |
8. Case Studies and Real-World Examples
8.1 Off-Label Sildenafil Use Detected via Social Media
A study using natural language processing to detect adverse events in social media found that posts mentioning off-label sildenafil use (11.4% of the corpus) showed 1.8-fold higher adverse event reporting rates compared to posts mentioning on-label use. This highlights the value of social media monitoring for detecting off-label ADRs that may not be captured through traditional spontaneous reporting.
8.2 Off-Label Gabapentinoid Use in Africa
A review of gabapentinoid pharmacovigilance in Africa noted that gabapentinoids are frequently prescribed off-label for chronic pain. Unlike the UK’s comprehensive ADR surveillance, African pharmacovigilance systems lack the resources to systematically monitor gabapentinoid-related harms. This underscores the global disparities in pharmacovigilance capacity and the need for international collaboration.
8.3 Off-Label Use in Paediatric Haematology-Oncology
A prospective study of paediatric haematology-oncology patients found that the risk of ADR was 3.4 times higher with off-label prescriptions compared to on-label ones. The study showed the importance of proactive pharmacovigilance to efficiently highlight ADRs in this vulnerable population.
8.4 Off-Label Use of Dapagliflozin
The EMA has conducted routine pharmacovigilance activities to assess compliance with the labelling of dapagliflozin, particularly regarding off-label use in specific populations (e.g., patients with renal impairment). Off-label use in patients with moderate to severe renal impairment (CrCl <60 mL/min or eGFR <60 mL/min/1.73 m²) is explicitly not recommended.
Conclusion: Closing the Gap
Off-label prescribing is a necessary and essential component of clinical practice, providing patients with access to therapies that may not otherwise be available. However, the pharmacovigilance blind spot surrounding off-label use poses a significant threat to patient safety.
The evidence is clear: off-label use is associated with a significantly higher risk of serious ADRs , and less than 10% of serious ADRs are reported globally. Healthcare professionals, pharmaceutical companies, regulators, and researchers all have a role to play in closing this gap.
Key takeaways for healthcare professionals:
- Always report ADRs associated with off-label use—it is a regulatory requirement and a patient safety imperative.
- Document off-label use clearly in medical records and ADR reports.
- Be proactive in monitoring patients receiving off-label therapies.
- Educate colleagues and patients about the importance of off-label pharmacovigilance.
Key takeaways for regulators and industry:
- Provide clear guidance on off-label ADR reporting.
- Invest in data linkage and RWD infrastructure to detect off-label safety signals.
- Conduct post-authorisation studies in off-label populations.
- Foster international collaboration to share data on off-label safety signals.
By working together, we can transform off-label use from a pharmacovigilance blind spot into a well-monitored aspect of clinical practice, ensuring that patients receive the benefits of innovative therapies without being exposed to unknown risks.
References
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- World Health Organization. Safety of medicines for children. 2007.
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- Joksimovic J, Spasic DM, Kukuric M, et al. Serious Adverse Drug Reactions Associated with Off-Label and Unlicensed Drug Use in Children: A 14-Year Analysis of VigiBase Reports from Serbia. Children. 2026;13.
- Improving Drug Safety in Pediatric and Young Adult Patients with Hemato-Oncological Diseases: A Prospective Study of Active Pharmacovigilance.
- European Medicines Agency. Draft Guideline on Good Pharmacovigilance Practices (GVP) – Module VI (Rev 2). EMA/873138/2011 Rev 2.
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- U.S. Food and Drug Administration. Postmarketing Adverse Event Reporting Compliance Program.
- Frontiers. Leveraging real-world data for safety signal detection and risk management in pre- and post-market settings. 2025.
- Natural Language Processing for Pharmacovigilance: Detecting Novel Sildenafil Adverse Events in Social Media. DOAJ. 2025.
- Pharmacovigilance: Some basics of drug safety and special aspects for oncologists/hematologists. Swissmedic. 2023.
- EMA. Guidance on conduct of pharmacovigilance for medicines used by the paediatric population.
- EMA. Off-label use of dapagliflozin in specific populations.
- AI tools for signal detection: SIGNAL (IMI WEB-RADR Consortium) and ADESSA.
- Privacy-preserving record linkage (PPRL) methods.
- MEAP project: active post-marketing pharmacovigilance in Italy.
