The Q&A session at the MHRA Pharmacovigilance symposium on 26th March highlighted a lot of uncertainty over off-label usage. There is even confusion over what “off-label” actually means. This article looks at the responses given by the MHRA and what they mean for European pharmacovigilance practice.
What is off-label use?
Good Pharmacovigilance Practice defines off-label use as, a situation where “a medicinal product is intentionally used for a medical purpose not in accordance with the authorised product information.” This includes use of a product at an unauthorised dosage – not just for an unlicensed indication.
By contrast, misuse is where “a product is intentionally and inappropriately used not in accordance with the authorised product information.” The key distinction being that one is for a medical use whilst the other is for an inappropriate, often non-treatment-related use.
It is also important to remember that what is considered off-label in one country may not be in another region. For instance, the term “off-label” does not automatically include use outside the EU in an indication authorised in that territory that is not authorised in the EU.
Whilst the driving force behind off-label usage may be positive, it can pose problems, especially concerning the collation and reporting of adverse event reports.
PSURs…
All pharmaceuticals registered in the EU need Periodic Safety Update Reports (PSURs), coving all indications and including a risk:benefit analysis of the product in question. Initially, these must be submitted to the relevant Competent Authority (CA) every six months, even if the product in question is not marketed. The frequency drops to three years as the product becomes more established.
RMPs…
Risk-management Plans (RMPs) have been required for all new products registered in the EU after July 2012. They are similar to PSURs in that they cover all available safety data relating to a product but instead of being an update, reflect the current state of knowledge about the risks inherent in using a particular product.
Literature reports relating to off-label use should be flagged at the time either PSURs or RMPs are being produced.
Adverse reactions relating to off-label use should be processed in the normal way regardless of whether or not a PSUR or an RMP is required. However, there is no need to review off-label use reports that are not associated with an adverse reaction.
Discussion is currently taking place about the extent that Marketing Authorisation Holders (MAHs) must follow up on reports of off-label use. The MHRA’s current expectation is:
· If an unconfirmed report suggesting a potential off-label use e.g. "can product x be used in an unlicensed indication or manner" is made to an MAH’s medical enquiry service, the MAH would not normally be expected to follow up with the enquirer to establish whether the product had actually been used if an off-label way.
· If a confirmed report of off-label use is made to an MAH's medical enquiry service, but no adverse reaction is reported, the reports would normally be flagged in the medical enquiry system, so that the reports may be easily collated, for instance during the production of a PSUR or RMP update.
Off-label uses clearly play a potentially important role in contributing to the overall safety profile of medical products. It is important to treat adverse events in the same way as those relating to authorised indications and to closely monitor the way products are being used in practice.
We appreciate your interest this blog and would really like to know your views. Is this entry bang on the nail or widely off topic? Do you believe that approved and off-label uses should be handled differently? Please leave any of your questions or comments below. We’ll review and comment regularly.
Blog Author: Dr. P.V. Practice
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