Are you planning to amend your product dossier and wondering how you should do this? Note that any changes to the terms of a marketing authorisation (MA) for medicinal products authorised pursuant to EU legislation should be notified to relevant Authority (or Authorities) as a variation.
Provisions concerning the examination of variations to the terms of all marketing authorisations for both medicinal products for human use and veterinary medicinal products (granted in accordance with Comission Regulation (EC) No 726/2004, Directive 2001/83/EC, Directive 2001/82/EC, and Council Directive 87/22/EEC) are laid down in Regulation (EC) No 1234/2008 of November 2008 (hereafter: Variations Regulation). This Regulation also determines different types of variations. Special kind of these variations are type IA/IAIN variations, which are notified by the MAH following prior implementation.
Let’s find out what types of variations should be considered by the MAH and why implementation date is so crucial when introducing minor type IA/IAIN variations to your dossier.
Types of variations – how are they classified?
Variations can be classified in different types, depending on the level of risk to public or animal health and the impact on the quality, safety and efficacy of the medicinal product concerned. In general, there are four types of variations, defined by Variations Regulation:
- Minor variation of Type IA – a variation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned;
- Minor variation of Type IB – means a variation which is neither a minor variation of type IA nor a major variation of type II nor an extension;
- Major variation of Type II – means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned;
- Extensions – means variations which are listed in Annex I to Variations Regulation and fulfils the required conditions, for example change or addition of a new pharmaceutical form, addition of a new strength.
In order to bring further predictability, guidelines on the details of the various types of variations (available on EUR-Lex website) are established and regularly updated in the light of scientific and technical progress, with the aim of developing international harmonisation. These guidelines are intended to facilitate the interpretation of the Variations Regulation. They provide details on the application of the relevant procedures, including a description of all the corresponding steps from the submission of an application for a variation to the final outcome of the procedure.
Moreover, the Annex to these guidelines provides details of the classification of variations into the abovementioned types (IA, IB and II). This Annex also presents further information, where appropriate, on the documentation to be submitted for specific variations and conditions that should be met, if applicable. Therefore, in case you were not sure what documents you should prepare for planned variation submission – all information gathered in the mentioned Annex should help you.
Taking above into consideration, you may be still wondering what is so special about type IA variations. So, now let’s turn to key information about this type of variations and discuss main differences compared to other types.
‘Do and Tell’ procedure – a key definition of type IA variations
Type IA variations are intended to provide a simple, rapid and efficient procedure for minor changes. What is important and worth highlighting is the fact that such variations do not require prior approval but can be implemented prior to notification to the relevant authorities. That is why it is said that firstly you ‘do’ – simply you make the change, and then you ‘tell’ – what means that you submit proper application to authority.
In general, type IA variations must be submitted by the MAH within 12 months following implementation of introduced changes. Nevertheless, certain minor variations of type IA require immediate notification after implementation. Therefore, type IA variations are divided into the following two subcategories, which impact their submission:
- Type IA variations requiring immediate notification (IAIN) – variations that must be submitted immediately to the national competent authorities or EMA following implementation, in order to ensure the continuous supervision of the medicinal product.
- Type-IA variations not requiring immediate notification (IA) – variations that do not require immediate notification and may be submitted by the MAH within 12 months after implementation. Naturally, these variations can be submitted earlier, when MAH wishes to facilitate dossier lifecycle maintenance or keep the Product Information up-to-date.
What’s interesting, the 12-month deadline to submit type IA variations allows for an annual reporting. So called “annual report” is not a specific procedure but it just means a submission of several minor variations of type IA that have been implemented during the previous 12 months. It is up to the applicant if and when to submit an annual report. The submission of type IA notifications in the form of an annual report is not mandatory, but it may be useful. MAHs may quite easily group type IA/IAIN variations under a single notification to the same relevant authority, or to group them with other types of variation. Grouping is also allowed for several MAs under a single notification provided that the variations are the same for all MAs concerned and they are notified at the same time to the same relevant authority. However, it is vital to remember that the notification of these variations in a single submission is only possible where the conditions for grouping set out in Variations Regulation apply.
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What does implementation date actually mean?
Since term “implementation date” is mentioned very often when we speak of type IA variations, let’s clarify the meaning of it.
Implementation date should be considered taking into account the scope of changes introduced in your medicinal product dossier, and therefore:
- For changes influencing Product Information, it is when the company internally approves the revised Product Information (PI). The revised PI will then be used in the next packaging run.
- For quality changes, it is when the company makes the change in its own quality system.
- For changes to the pharmacovigilance system, it is when the company makes the change in its pharmacovigilance system (i.e. when it internally approves the summary of pharmacovigilance system incorporating the changes).
Implementation date should be stated in the application form for notified variation or in case of grouping – for each variation included in the application.
Moreover, for type IA/IAIN variations concerning PI: the “Date of revision of the text” for Summary of Product Characteristics and Package Leaflet will correspond to the implementation date.
When planning the submission of type IA variation, MAH has to be sure that all conditions and documentation requirements listed in variation classification guidelines are met. Where applicable, reference to a classification recommendation published in accordance with Article 5 of the Variations Regulation used for the relevant application can be made. The relevant authority will check the correctness of the application form, the presence of the required documentation and compliance with the required conditions, in accordance with the classification guidelines. There is no request by the RMS for clarification, information or documentation from the MAH and there is no clock-stop or suspension of the process. If all the documentation has not been provided, the type IA variation notification will be deemed unacceptable and the MAH should immediately cease to apply the concerned variation(s). MAH may also decide to submit a new variation, which will require a new, separate submission.
Requirements on implementation date in Poland
The President of Office for Registration of Medicinal Products, Medical Devices and Biocidal Products issued a Communication of 22nd July, 2011 in connection with the implementation and bringing into force variations submitted pursuant to Variations Regulation.
In overall, implementation date is defined as per European legislations. But, this particular Communication specifies that type IA variations should be brought into force within 6 months from the date of implementation. It means that after 6 months from the implementation of type IA variation, MAH is obliged to release batches of medicinal product based on the updated dossier – including changes resulting from relevant type IA variation(s). Therefore, implementation of changes should be planned carefully, taking into account also manufacturing schedules – especially when type IA variations influences PI and printing of updated packaging materials has to be considered.
Summary
There are many things that have to be considered by the MAHs when introducing changes to the dossier of their medicinal products. Depending on the level of risk to public or animal health and the impact on the quality, safety and efficacy of your medicinal product, different type and classification of variations should be chosen. When you are planning only minor changes with a minimal impact on your dossier in overall, you may be able to choose ‘Do and Tell’ procedure – simply submit type IA/IAIN variation. Therefore, it is crucial to understand the meaning of the implementation date and how it relates to your product’s lifecycle maintenance and manufacturing plans. Also, there is a list of conditions that has to be fulfilled and required documentation to be submitted if you wish your type IA variation application to be accepted by the relevant authorities.
MAHs must in all cases comply with the requirements of Community legislation and due to this fact, good understanding of Variations Regulation and related guidelines is vital.
If you have any questions about Variations Regulation and implementation guidelines for type IA variations or any other Regulatory Affairs topics, please contact us.