Medicinal Products Legislation

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Current and Future EU Marketing Authorisation Variations Legislation for Medicines

Medicines are regulated throughout their entire lifecycle. When a marketing authorisation has been granted, any subsequent changes affecting the quality, safety or efficacy must be authorised according to the Variations Regulations.

This article explains the current European requirements for variations to marketing authorisations, and outlines the new legislative changes soon to be adopted throughout Europe.

Regulating change is essential to ensure that medicines remain of good quality, safe and efficacious, but regulation should not hinder changes that are beneficial to patients or public health. The legislation on variations must strike the right balance, and has undergone a review process to consider this point.

In the UK a scheme has already been introduced in April 2008 which has simplified the framework for variations to nationally authorised products. This will be the subject of a separate article.

Future Variations Legislation in the EU

In June 2008 the Standing Committee on Medicinal Products for Human Use voted overwhelming in favour of the new Commission Regulation on variations. This will now become legislation. It is anticipated to become effective during 2009, with a transitional period to allow adaptation to the new legal framework.

To reduce the number of variation procedures so Health Authority resource can be focussed on variations with a real impact on quality, safety or efficacy, the alternative of an annual reporting system is proposed for certain minor variations; with no prior approval required, variations can be notified within twelve months of implementation.

Homeopathic and traditional herbal medicines will be excluded from the scope of the Regulation.

Variation categories are defined:

Minor variation type IA: variation which has only a minimal or no impact, on the quality, safety or efficacy of the product
Major variation type II:variation which is not a line extension, but may have a significant impact on the quality, safety or efficacy of the medicinal product
Extension of a marketing authorisation: a variation which is listed in Annex I and fulfils the conditions therein
Minor variation type IB:variation which is neither a minor type IA, nor a major type II nor an extension.

Four annexes providing further definitions:

Annex I: extensions of marketing authorisations
Annex II: classification of variations
Annex III: cases for grouping variations
Annex IV: elements to be submitted

Timescales for approval processing and implementation are outlined below for marketing authorisations granted in accordance with Directive 87/22/EEC, Chapter 4 of Directive 2001/83/EC. Centralised marketing authorisations follow a similar schedule with the EMEA:

- Minor variation Type IA

Simultaneous submission to all relevant authorities a notification containing the elements listed in Annex IV. This notification must be submitted within twelve months following implementation of the variation. The notification must be immediately submitted after the implementation of the variation in special cases where minor variations require immediate notification for the continuous supervision of the medicinal product concerned.

Within 30 days following receipt of the notification, the RMS will inform finally if the decision is accepted or rejected.

- Minor variations Type IB

Simultaneous submission to all relevant authorities a notification containing the elements listed in Annex IV. If the notification fulfils the requirements the RMS shall, after consulting the other Member States concerned (CMS), acknowledge receipt of a valid notification.

If within 30 days of acknowledgement, no unfavourable opinion is received, the notification is considered accepted. The RMS will inform finally if the decision is accepted or rejected.

- Major variations type II

Simultaneous submission to all relevant authorities an application containing the elements listed in Annex IV. If the application fulfils the requirements the RMS will acknowledge receipt of a valid application, the procedure will start from this acknowledgement date.

Within 60 days the RMS will prepare an assessment report and a decision on the application, which shall be communicated to the CMS. If urgent the period may be shortened, or extended to 90 days for variations listed in Part 1 of Annex V.

Within 30 days following receipt of the decision and the RMS assessment, the CMS will recognise the decision and inform RMS. No disagreement from the CMS will be considered as recognition of the decision. The RMS will inform finally if the decision is accepted or rejected.

Grouping of variations will be allowable in order to facilitate the review of the individual variations and reduce administration burden. Several marketing authorisations from the same holder will be allowed if the changes are identical.

Urgent safety restriction is defined as an interim change of the product information due to new information on safety. A corresponding variation must be submitted within 15 days following the initiation of the restriction.

It is planned to draw up guidelines on the details of the various categories of variations, required documentation and guidelines on the operation of the procedures.

Current Variations Legislation and Guidance in the EU

The legal basis for variation of a Marketing Authorisation is Commission Regulations No. 1084/2003 and 1085/2003 EC, which came into force on 1 October 2003.

All Mutual Recognition/Decentralised/Centralised variations fall under this legislation. National marketing authorisations do not, although many EU countries process them in the same manner.

The categories of variations are:

- Type IA

- Type IB

Minor changes that meet certain conditions and only require specified supporting documents are Type IA. These changes are processed within a 14-day timescale involving a scientific validation only.

Minor changes that are supported by specified data for assessment are Type IB and follow a 30-day assessment procedure.

Currently there are 46 changes that may be considered either Type IA or Type IB notifications; these are set out in Volume 2A Chapter 5, NTA with guidance together with conditions necessary for following either a Type IA or Type IB procedure.

- Type II variations

Any change not on the Type 1A or 1B list. These are more complex changes will require a scientific assessment and usually follow a 90 day timetable.

Conclusion

The future legislation proposed offers benefits to both the industry and the Health Authorities to reduce administration and to streamline the timelines for approvals. The minor variations that can be implemented without awaiting acknowledgement by the health authority as currently required, will have clear benefits to the industry in terms of operational planning.

A simpler, clearer and more flexible legal framework, while guaranteeing the same level of public health protection will benefit all.