Off-Label Drug Use and Pharmacovigilance: EMA Outlines What MAHs Need to Collect and Report

Posted 23 May 2016 By Zachary Brennan


Pharmaceutical companies operating in the EU will need to collect and report information on the off-label use of their medicines under new obligations making their way from draft to final form at the European Medicines Agency (EMA) this summer.

In late April, EMA offered a reflection paper, open for comment through 29 July, which offers the agency’s proposal for the collection and reporting of information on off-label use for marketing authorization holders (MAHs), in relation to their pharmacovigilance obligations provided in Title IX of Directive 2001/83/EC.


In line with EMA’s pharmacovigilance directive, off-label use “relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the authorised product information. The focus is on the intention of the healthcare professional to use a product outside the authorised conditions of use.”

EMA also makes clear that medication errors should be clearly distinguished from patient misuse of a drug, where “misuse relates to situations where the medicinal product is intentionally and inappropriately used not in accordance with the authorised product information ... For cases where a patient has misunderstood the instructions for how to use the medicine correctly, this should be considered an error and appropriate MedDRA terms selected to represent the event, e.g. LLT Tablet crushed incorrectly.”

The release of the 10-page reflection paper follows questions raised by the industry group, the European Federation of Pharmaceutical Industries and Associations (EFPIA), on the management of individual reports of off-label use not associated with harm to a patient.

And this latest EMA proposal “distinguishes the situations where the off-label use of a medicinal product results in the occurrence of a suspected adverse reaction and those where it does not” and incorporates feedback from the Pharmacovigilance Risk Assessment Committee (PRAC) addressing the member states that already have implemented specific national guidance regarding the notification by MAHs of practices of off-label use, though EMA notes that the draft “should not be interpreted as preventing the fulfilment by MAHs of national obligations.”


In a presentation on the plan, EMA officials made clear of the distinctions between the off-label use of a medicine that results in harm to a patient and such off-label use that does not result in harm.

The obligations of MAHs in relation to the collection and reporting of information related to the off-label use of drugs resulting in harm (i.e. associated with the occurrence of suspected adverse events), includes:

  • Reporting of individual cases of off-label use associated with suspected adverse reactions;
  • Periodic reporting of the clinical importance of risks related to the off-label use of a medicinal product; and
  • Risk management planning based on the quantification of off-label use in the context of particular risks and concerns.  

And where there’s potential for off-label use, and such use is considered to raise a safety concern, a risk management plan “should be used to clarify the obligations for the MAH: In terms of collection and follow-up of cases of off-label use (including cases not associated with suspected adverse reactions); [and] In terms of additional structured investigations (drug utilisation studies, searches in databases).”

For products without a risk management plan, MAHs and competent authorities should consider, according to EMA, whether off-label use constitutes a safety concern, and if it does, whether a risk management plan or a Post Authorisation Safety Study is necessary.

Draft reflection paper on collecting and reporting information on off-label use in pharmacovigilance

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Tags: off-label drug use, off label, EU pharmacovigilance

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