Off-label use refers to the application of an approved medicinal product outside the indications, dosages, patient groups, or routes of administration specified in its marketing authorization (Summary of Product Characteristics, SmPC). The term is derived from the English expression “off-label” and literally means “outside the product labeling.” Off-label use is legally permissible in most European countries but falls under the sole responsibility of the prescribing physician and is not covered by regulatory approval. In medical practice, off-label use is encountered daily: physicians in clinics and practices regularly use medications outside their approved indications when scientific evidence supports it and no better alternative is available. Estimates suggest that in certain specialties, a significant proportion of all medicinal product prescriptions are for off-label use. Despite this prevalence, systematic clinical data demonstrating safety and efficacy outside the approved indication are often lacking.
Legal Framework in Germany and the EU
In Germany, off-label use is generally permitted but is subject to specific requirements. According to the principles of the German Medicines Act (Arzneimittelgesetz, AMG) and the professional code of conduct for physicians, the physician must inform the patient about the off-label nature of the prescription and conduct an individual benefit-risk assessment. In such cases, liability for adverse effects shifts from the manufacturer to the prescribing physician. The patient must be informed, and this information must be documented, allowing the patient sufficient time to make a decision.
At the EU level, there is no uniform regulation. The EMA has highlighted the need to record and report off-label applications in various guidelines, particularly within the framework of pharmacovigilance. According to EU Pharmacovigilance Directive 2010/84/EU, suspected adverse reactions from off-label use must also be reported. Manufacturers are not obliged to actively promote off-label uses or generate clinical data for them, but they may respond to scientific inquiries.
Common Areas of Application
Off-label use is widespread in clinical practice, particularly in pediatrics, oncology, and psychiatry. In pediatrics, many medicinal products lack clinical studies involving children, as they were historically excluded from clinical trials. The EU Paediatric Regulation (EC No. 1901/2006) has partially addressed this issue by obliging manufacturers to submit pediatric investigation plans. Nevertheless, off-label use remains common in this area.
In oncology, cytostatics and immunotherapeutics are regularly used for tumor entities for which no marketing authorization exists, but scientific evidence from clinical studies or case series is available. In Germany, the Federal Joint Committee (G-BA) has established regulations for reimbursement by statutory health insurance funds when off-label applications meet specific evidence requirements. In psychiatry, off-label use of antipsychotics and antidepressants is particularly common, as marketing authorizations often cover only individual diagnoses, but the active substances are used more broadly clinically.
Distinction from Compassionate Use and Unlicensed Use
Off-label use must be distinguished from related concepts. Compassionate use involves the application of a medicinal product not yet authorized, within the framework of a government-approved program for severely ill patients. Off-label use, however, always concerns an already authorized product used outside its approved indications.
“Unlicensed Use” refers to the application of unauthorized medicinal products, such as magistral preparations produced in-house or imported products without national authorization. The regulatory and liability consequences are significantly more far-reaching than with off-label use. In clinical practice, these terms are sometimes used synonymously, although they describe legally distinct situations.
Pharmacovigilance and Reporting Obligations
Adverse drug reactions (ADRs) from off-label use are subject to the same reporting obligations as those within the approved indications. Physicians are obliged to report suspected side effects to the competent authority (in Germany: BfArM or Paul-Ehrlich-Institut). Manufacturers must include off-label reports that come to their attention in their Periodic Safety Update Reports (PSURs) and Risk Management Plans (RMPs) and consider them in the benefit-risk assessment.
In clinical research, off-label use can, under certain conditions, be the subject of a non-interventional study to systematically collect safety and efficacy data. Full-service CROs like mediconomics support pharmaceutical companies with regulatory classification, study planning, and pharmacovigilance related to off-label issues. Such studies provide important insights for potential label extensions and supplement the safety profile in the Risk Management Plan.
The distinction between off-label use and a regular marketing authorization status is not always clear. In some cases, medicinal products are authorized in one country but not in another – the use of the product is then off-label in the second country, even though a regular authorization exists in a different jurisdiction. This constellation is particularly relevant in rare diseases, where international evidence is often used as a basis for treatment. Physicians and hospital pharmacists must carefully examine which legal and liability requirements apply in their jurisdiction in such situations. Close cooperation with the Regulatory Affairs team and medical department is essential in these constellations.
Frequently Asked Questions (FAQ)
May a manufacturer actively promote off-label use?
No. The promotion of a medicinal product outside its approved indication is prohibited in the EU under Directive 2001/83/EC. However, manufacturers may provide information on data concerning off-label uses at scientific congresses and in specialist publications, and respond to specific medical inquiries from physicians.
Do health insurance companies cover the costs of off-label applications?
In Germany, reimbursement by statutory health insurance funds is generally possible if the off-label use is justified by a serious illness, no approved alternative is available, and sufficient evidence of benefit exists. The G-BA evaluates corresponding active substances and publishes a list of reimbursable off-label uses.