What is a reference product?
A reference product is an innovator Marketing Authorisation (MA) that is periodically referred to when updating the safety information in a generic licence. The chosen reference product forms part of the basis for a generic licence to be granted by the competent authority.
Which products use a reference?
Many generic licences are granted on the condition that the information is kept up to date in line with the reference product, which is declared in the generic medicine’s MA application form.
Applicable generic licences include those with the following legal bases:
- Article 10(1) Generic,
- Article 10(3) Hybrid,
- Article 10(4) Biosimilar,
- Article 10(c) Informed Consent,
- Article 10(b) Fixed-dose combination: each active substance must be supported by a corresponding reference product if a reference product with active ingredients identical to the generic medicinal product does not exist.
Conversely, the following legal bases are exempt from utilising a reference product:
- Article 8(3) Full: these applications contain complete clinical and preclinical data, therefore not relying on a reference innovator,
- Article 10(a) Well Established Use: such medicines are based on published scientific literature and are not tied to a specific innovator,
- Article 14 Homeopathic registrations,
- Article 16a Traditional Herbal Registrations.
How is the product information compared?
The comparison itself is a simple process whereby the reference and generic SmPCs are read side-by-side and any discrepancies in sections 4 and 5 are evaluated. The key point is to know exactly which differences need addressing, which is where it can be useful to distinguish between meaningful and non-meaningful differences:
Note: the above table is not exhaustive.
Leaflets and labelling can be compared directly to the reference product to be considered in the same way, or they can be updated as a consequence of the comparison activity carried out on the SmPC.
Fusion top tip: it is very important to understand which parts of the text in an SmPC are specific to that product only and which parts are used as reference text. For instance, you don’t want to override any excipient warnings in section 4.4 of your product with irrelevant information from the reference product.
How often do these comparisons need to take place?
While the MHRA does not stipulate a minimum or maximum review period for this activity, it is a post-licensing obligation to keep any applicable products updated in line with its reference product over the product lifecycle. It may be best practice to arrange regular reviews (e.g. once every six months to a year) for each product. For larger portfolios, consider creating a fixed schedule of reviews throughout the year to ensure that all products have been captured.
When do updates need to be made to your licence?
If any meaningful differences have been identified, a variation is likely to follow. Non-meaningful differences can be made alongside meaningful updates if they are identified, or can be saved for the next regulatory opportunity if a variation is otherwise not required.
Alongside any regular review process you have in place, certain situations arise where you may need to perform an additional check on your product. These include (but are not limited to):
- Immediately after MA grant, your product information should be compared to your reference product, with any resultant variation to be submitted within six months of MA grant
- In response to an ad hoc request from the MHRA
- If you alter your regular review schedule, you may need to review your products twice in one cycle to ensure no products fall through the gaps.
Fusion top tip: discuss the need to submit reference comparison variations with the MHRA for your nationally authorised, non-marketed products. Some affiliates do not require these submissions in this scenario, and the MHRA have previously been open-minded to this cost-saving approach.
For detailed guidance regarding the submission of alignment variations, you can refer to our blog titled “UK Generics – Variations” or you can contact us for more bespoke advice.
Handling Reference Product Discontinuation
If the reference product is no longer available (i.e. has been discontinued or cancelled), performing comparison activities may not be feasible. We recommend asking the MHRA for advice. A suitable replacement reference product from the same global MAH may be proposed via a Type II variation.
Fusion top tip: when searching for a new reference product, the more individual aspects of a new prospective reference product that you can match to the reference being replaced, the greater the chance of acceptance from the MHRA. These include MAH, indications, authorisation route, strength, product form etc. Note: you cannot choose a generic licence as a reference product.
If you would like to discuss how Fusion Pharma can support you with reference product comparisons or processes surrounding this, please email us at hello@fusion-pharma-limited.com or phone us on +44 (0) 203 1379 799.
While the information in this article is considered to be true and correct at the date of publication, changes in guidance and/or experience may impact on the accuracy of the information. Please refer to the relevant guidance for the latest information.
