This blog summarises two common examples of safety variations performed on generic licences:
- Authority-driven safety updates (e.g. PRAC recommendations, MHRA requests), and
- Reference product updates.
Authority-driven safety updates requiring a variation
Scientific bodies such as the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Medicinal Products in Human use (CHMP) release new recommendations to update the safety particulars of medicinal products continuously. These are received by regulatory teams in both branded and generic companies and will lead to a variation requirement. The MHRA may also disseminate ad hoc requests for specific sections of a medicine’s product information to be varied.
How to choose an appropriate variation category
Many authority requests will stipulate the exact variation type and change code required for the requested variation submission. The below list summarises potential variation categories based on the nature of the updates taking place:
- Minor type IAIN: No other non-related updates should be made in this type of submission, unless grouping. Such variations are not assessed by the MHRA and do not incur a fee. Type IAIN variations are used to confirm that only the changes requested in the original notification were made.
- Minor type IB: This category is commonly used when other changes are being made at the same time (e.g. typo corrections, inclusion of previously identified opportunistic updates), are assessed by the MHRA and carry a base fee of £419.
- Article 61(3)/BROMI: for updates that affect artwork only, not the SmPC.
The change code for these variations will typically be C.I.3.a, C.I.3.z or C.I.z, unless otherwise specified.
How to submit a variation to the MHRA
Once the SmPC/PIL/mock-ups have been updated as appropriate, an eCTD compilation will be required before submitting the information to the MHRA. The following should be included in the sequence:
- A cover letter and an eCTD tracking table
- An electronic Application Form (eAF)
- The authority request attached as a form annex or attached to the cover letter document
- Your product’s PIL mock-up (if PIL text updated and product is marketed).
Note: SmPC and PIL tracked and clean text can be included in your MHRA submission package in the working documents folder i.e. not as part of the eCTD.
Once compiled, the variation is submitted via the online portal to the MHRA.
Variations to update your licence in line with its reference product
Any requirement to update the product information of a granted licence in line with its reference product must be addressed by submitting a variation to the MHRA and must be performed irrespective of authorisation route. If you are unsure about this process or are unclear how to compare your product to its reference, please refer to our blog titled “UK Generics – How to compare your product information to a reference product“.
How to prepare a variation application for reference product updates
Once a comparison has been performed and discrepancies identified, the first step is to determine the variation type. These variations can be submitted as a Type IB (C.I.2.a) or a Type II (C.I.2.b) variation, depending on the following considerations:
- Has the reference product been changed (and is this the first update in line with this new reference)? If so, a Type II is required.
- Have any updates been identified for SmPC sections 4.1 or 4.2? These changes can be more tricky to implement and the MHRA will sometimes invalidate Type IB submissions affecting these sections. You may wish to try a Type IB first, but be prepared to resubmit as a Type II.
- Are there additional updates to be made? These can complicate matters if relying on submitting literature references (Type II recommended), but if simply grouping with authority-driven updates (e.g. IB C.I.2.a + IAIN C.I.3.a to make a grouped IB submission), it is trivial.
If none of the above apply, submit a Type IB variation by default.
Fusion top tip: if the reference product includes a new indication, verify whether it is protected by a patent. If it is, you must not attempt to include it in your own product information until that patent expires. This includes any information outside SmPC section 4.1 relating to that indication!
All variations to update in line with a reference product (type IB and II) require an eCTD compilation with the same information as detailed in the above section for authority-driven updates, except the authority request email is replaced by the reference product SmPC (and PIL if applicable). Type II submissions will require a Clinical Expert Statement and CV in Module 2 of the eCTD sequence, detailing all changes, including justifications, as required.
A common reference product VCR
The MHRA can return an unexpected Validation Correction Request (VCR) if the reference product you have included does not match the one they have on file. This can be for a wide variety of reasons, one of the most common being that the reference has undergone a change of ownership since your licence was granted. Whatever the reason, the most effective responses include either:
- Your product’s original Marketing Authorisation Application (MAA) form, showing the correct reference product, if it matches the one that the MHRA are disputing,
- Email proof of the MHRA confirming the use of your chosen reference product if it differs from the one indicated at MAA, or
- A grant letter from a previous alignment variation using your chosen reference product (this is sometimes insufficient proof on its own, but can be tried as a last resort).
If you would like to discuss how Fusion Pharma can support you with reference comparison variations, please email us at hello@fusion-pharma-limited.com or phone us on +44 (0) 203 1379 79.
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.
