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Current status:
European Commission final decision


MultiHance is a paramagnetic contrast agent for use in diagnostic magnetic resonance imaging (MRI), containing the active substance gadobenic acid 334 mg/ml, as the dimeglumine salt. The indication when first authorised in a number of Member States related to imaging of the liver, for the detection of focal liver lesions in patients with known or suspected primary liver cancer (e.g. hepatocellular carcinoma) or metastatic disease.

In November 1998, Bracco s.p.a. submitted applications for a Type II variation in the Mutual Recognition procedure, with the United Kingdom as Reference Member State, for MultiHance. The scope of the variation was to extend the indication to include MRI imaging of the CNS, in addition to the liver. The Mutual Recognition Variation procedure started on 8 December 1998. The Concerned Member States were Austria, Belgium, Denmark, Germany, Finland, Greece, France, Ireland, Italy, Luxembourg, The Netherlands and Sweden. The Concerned Member State, France, not agreeing to the conclusions and proposals in the Reference Member State's final variation assessment report referred the reasons for disagreement to the EMEA on 5 October 1999, with a request to initiate an arbitration procedure in order to clarify the matter.

The objections raised by France related to the main Phase III trials designed to show non-inferiority of MultiHance to an authorised comparator product. In summary, the referral notification stated that it was not possible to conclude non-inferiority of MultiHance to the comparator product in the main Phase III trials, mainly due to a major problem of external validity of the comparator, and to methodological biases. The CPMP prepared a list of questions for the Marketing Authorisation Holder, including the above issues, and the arbitration procedure started on 21 October 1999. The Applicant's response to this list of questions was received in February 2000 and the CPMP started the clock on 18 February 2000.

The CPMP having considered the written responses provided by the Applicant, the joint Rapporteur/Co- Rapporteur's assessment report, an oral explanation by the Marketing Authorisation Holder and the comments from CPMP members was of the opinion that the objections raised by France should not prevent the approval of the variation applied for.

The CPMP therefore adopted a positive opinion on 25 May 2000 CPMP recommending the granting of the variation of the Marketing Authorisation for MultiHance, and the amendment of the Summary of Product Characteristics.

An overall summary of the scientific evaluation is provided, together with the amended SPC.

A Decision was issued by the European Commission on 15 September 2000.

Key facts

Approved name
International non-proprietary name (INN) or common name
gadobenic acid
Reference number
Article 6(12) referrals (prior to January 2010)

This type of referral was triggered for a medicine that had been authorised by mutual recognition or via the decentralised procedure when there was disagreement between Member States on a variation (type II). This referral has been replaced by Article 13 referrals.

European Commission final decision
Opinion date
EC decision date

All documents

Document description

  • Questions and answers (Q&A) - easy-to-understand summary of key issues and Committee conclusions
  • Summary of Opinion - contains the CHMP opinion of the referred medicine(s)
  • List of the medicines affected by the referral (Annex I)
  • Scientific conclusions of the Committee (Annex II)

The following two documents are sometimes available:

  • Changes to the summary of product characteristics, labeling or package leaflet (also known as Annex III) - available when changes havebeen recommended by the Committee
  • Conditions of the marketing authorisation (also known as Annex IV) - available when the Committee recommends measures to be takenfor the marketing authorisation(s) such as safety measures or extra studies

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