New Variations Regulations 1084/2003 and 1085/2003

The new Variations Regulations (Commission Regulation) EC No 1084/2003 (4) for the Mutual Recognition Procedure and EC No 1085/2003 (5) for the centralised procedure are in force since 01 October 2003 for notifications and applications submitted on or after this date.

The new Variations Regulations list two different Type I variations (Type IA and Type IB according to Annex I of CR 1084/2003) and line extensions (according to Annex II of CR 1084/2003). Type IA and IB variations follow the notification procedure, Type II variations need approval.

The new variation categories are summarized below:

Type IA variations are a new category of variations that have been redefined as 'minor' changes which only have to be notified to the competent authorities. The notification procedure is also called the 'Tell , wait, thenand do'-procedure and was set out to provide for rapid processing of variations. Type IA changes that are listed in Annex I of CR 1084/2003 are defined as administrative changes and/or simple changes with no possible impact on the safety of the medicinal product. All possible variations that are not listed in Annex I are classified as Type II variations.

Validation of Type IA variations areis done by the Reference Member State (RMS) in case of the decentralised Mutual Recognition Pprocedures and areis done by EMEA in case of the centralised procedure. In case of the Mutual Recognition Pdecentralised procedure the RMS will inform the other national competent authorities concerned and the marketing authorisation holder in the RMS accordingly.

Type IB (Notification)

The Type IB Variations are the 'minor' changes that implicit approval within a 30-day waiting period. The evaluation and approval of the procedure is done by the RMS who will inform the other national competent authorities concerned and the marketing authorisation holder in the RMS accordingly.

For acceptance of a Type IA and IB notification, documentation in support of the notified changes must be submitted. In order to clarify what documentation should be submitted with these notifications, the Guideline on Dossier requirements for Type IA and Type IB Notifications (July 2003) (6) has been prepared
(http://dg3.eudra.org/F2/eudralex/vol-2/C/GdVarTypIAB_rev0_200307.pdf). In order to submit the notifications, the New application form for variation to a marketing authorisation for medicinal products (human and veterinary) to be used in the mutual recognition and the centralised procedure (7) has to be filled in
(http://dg3.eudra.org/F2/eudralex/vol-6/newdoc/newvarform_%20250703.doc).

Type II (Approval)

The Type IIB Variations are the 'major' changes that need approval that. An approval has to be waited for (timeframe: 960 days with an option for changes to indications to extend to 1290 days). All possible changes that are not listed in Annex I are defined as Type II variations. All those changes that are neither covered by Annex I of CR 1084/2003 (Type IA/IB variations) nor are MR-Variations at all (in case the change has to be done according to national law, if the change is a line extension according to Annex II of CR 1084/2003 or if the change is a new marketing application) are Type II variations. With regard to the approval procedure for major variations type II, the marketing authorisation holder has to submit an application accompanied by different documents summarized in CR 1084/2003 (MR procedure) and CR 1085/2003 (centralised procedure) respectively. Validation of Type II variations are done by the Reference Member State (RMS) in case of the Mutual Recognition Procedures and are done by EMEA in case of the centralised procedure.

New is the fourth category for line extensions that have been legally defined for the first time in the European Union. 'Extension' applies to products with the same legal name, but where defined changes have been made, e.g. replacement of the active substance(s) by a different salt/ester complex or derivative, where the efficacy/safety remains the same, changes to strenght, pharmaceutical form and route of administration, etc.

For the topic of Regulatory Affairs we are organising the education course CTD, CEP and DMF in Basle, Switzerland, on 5-6 April 2004.

1. Commission Regulation (EC) No 541/95 of 10 March 1995 (as amended in 1998), concerning the examination of variations to the terms of a marketing authorization granted by a competent authority of a Member State
2. Commission Regulation (EC) No 542/95 of 10 March 1995 (as amended in 1998), concerning the examination of variations to the terms of a marketing authorization falling within scope of Council Regulation (EEC) No 2309/93
3. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use
   http://dg3.eudra.org/F2/pharmacos/docs/Doc2001/nov/Codifications/
   HumanCode2001-83/2001-83EN.pdf
4. Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State
   http://dg3.eudra.org/F2/eudralex/vol-1/new_v1/reg_comm_1084_2003_en.pdf
5. Commission Regulation (EC) No 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products falling within the scope of Council Regulation (EEC) No 2309/93
   http://dg3.eudra.org/F2/eudralex/vol-1/new_v1/reg_comm_1085_2003%20_en.pdf
6. Guideline on Dossier requirements for Type IA and Type IB Notifications (July 2003)
   http://dg3.eudra.org/F2/eudralex/vol-2/C/GdVarTypIAB_rev0_200307.pdf
7. New application form for variation to a marketing authorisation for medicinal products (human and veterinary) to be used in the mutual recognition and the centralised procedure
   http://dg3.eudra.org/F2/eudralex/vol-6/newdoc/newvarform_%20250703.doc

Author:
Dr Barbara Jentges
CONCEPT HEIDELBERG