Variations to licences: Experience to date

Background
The new Variations Regulation (EC/1234/2008) (external link) took effect on 1 January 2010. This immediately applied to variations to marketing authorisations covered by European procedures. However, the MHRA has also applied it to purely national variation applications since then.

Type IA notifications now follow a 'Do and tell' procedure. The changes should be implemented before submission and this allows marketing authorisation holders the requested flexibility in terms of when they wish to introduce these changes. In addition, Type IA notifications are not formally assessed, but simply checked by a Type IA team that is dedicated to the processing of Type IA notifications.

The undertakings provided by marketing authorisation holders with any Type IA notification(s) form a key part of the process and it should be noted that the 30-day regulatory procedure on submission does not include the possibility to clock off. There is therefore no opportunity to address any identified deficiencies in submissions.

Consequently, marketing authorisation holders have a key new responsibility in the management of these minor changes within their own organisation and must ensure that each submission is correct.

As far as the new system is concerned, a classification guideline (external link) has been developed that categorises different types of changes.

As far as changes that can be managed as Type IA notifications (minor in nature) are concerned, each identified change has specific conditions that must be met and the documentation requirements are also clearly stated in the classification guideline. Submissions that do not meet the relevant conditions or contain the required documents will be refused.

Where appropriate, Type IA changes that require immediate notification, as opposed to those that require notification within 12 months of implementation, have also been identified in the classification guideline. A single Type IA notification can include any number of independent Type IA changes, provided all the required conditions and documentation requirements are fully met.

Experience to date
The system has now been in operation for six months (as at August 2010). It is acknowledged that the system is still relatively new for some companies and that, depending upon how many Type IA variations a company may have had to manage during this period, experience is still being gained.

However, based on our experience to date, a significant number of Type IA notifications have been refused during this period (on average approximately 30%).

These refusals have been reviewed and the most common reasons for rejection were as follows:

• application form incorrectly completed, including absence of a clear 'present and proposed' section
• wrong change code specified and therefore wrong check list provided
• required check list not supplied or completed incorrectly
• missing supporting documents, including (where appropriate) updated product information
• implementation date not specified or before 1 January 2010 (when old system applied) or in the future
• collections for mixed procedure type (National and European)
• Qualified Person declaration not supplied or, depending on the nature of the change, does not cover all the required companies involved (active substance manufacturer, finished product manufacturer, batch release site) reference is made to published guidance relating to Qualified Person declarations 
• some change-specific issues where the application had been incorrectly submitted as a Type IA variation eg for batch size changes (active substance or finished product), if previous batch size change had been processed as a Type IA notification then the next change should be submitted as a Type IB variation.

The deficiencies are generally of an administrative nature and therefore could be readily avoided and are easily resolvable in a resubmission.

Since Type IA changes have already been implemented prior to submission, if they are refused, in accordance with the legislation, they should immediately cease to be applied. Therefore depending upon the nature of the deficiency, the implications of this could be significant. However, refusals should be completely avoidable, if appropriate care is taken during preparation and suitable checks are made prior to submission.

Advice for marketing authorisation holders
In order to avoid refusual of Type IA notifications, marketing authorisation holders need to acknowledge their responsibility in the overall process, applying care and suitable checks in the preparation of submissions, and are strongly advised to specifically consider the following points:

General

Please:

• note that there is no restriction on the number of Type IA changes that can be grouped in a single Type IA notification and that it can contain changes that require immediate notification as well as those that require notification within 12 months of implementation
• ensure that there is a suitable change management system in place which can effectively handle Type IA changes that should be implemented before formal notification
• ensure that staff are suitably qualified and appropriately trained and are familiar with the latest published guidance
• put in place appropriate quality control checks relating to the content of Type IA notifications before they are submitted.

Specific

• ensure that the application form is suitably completed, in accordance with the relevant guidance
• ensure that the correct change code(s) are specified, the check lists are completed correctly and that the relevant conditions and documentation requirements are fully met. In the event that any documentation requirement is not applicable, please use ‘NA’ instead of a tick and give a suitable explanation as to its non-applicability
• if a notification contains a number of different changes under the same general change code (high level), please ensure that separate check lists are supplied for each specific change code. Please note that in the event that a number of different changes fall under the same specific change code, it is acceptable to supply a single check list, provided that this is made clear in the submission and that all the conditions and documentation requirements apply, otherwise a separate check list should be provided for any change where there is a possible exception
• where the UK is Reference Member State (RMS) for Type IA notifications, since the receipt date and consequently the start of the procedure is dependent upon the submission of the notification along with the list of despatch dates, please ensure that the list of despatch dates is sent as soon as possible and that it confirms that submissions have been made to all involved Member States and that, where appropriate, any required fees have been paid
• if a Type IA change is totally dependent on another Type IB or Type II variation and cannot therefore be independently implemented before submission, it should always be grouped with the related variation and not held back until the related variation is approved, because it may impact the assessment of the related variation.

For further information on variations, please contact our Variations Section, 5.Y, 1151 Buckingham Palace Road, London, SW1W 9SZ , telephone 020 3080 7400, variationqueries@mhra.gsi.gov.uk