- Procedure started
- Under evaluation
- CHMP opinion
- European Commission final decision
Gadovist/Gadograf 1.0 mmol/ml contains gadobutrol, a neutral macrocyclic gadolinium (Gd) complex with contrast-enhancing properties, which is used for magnetic resonance imaging (MRI). MRI is a widely used technique for the evaluation and detection of diffuse liver disease as well as for further characterisation of focal liver disease. Gd-based contrast agents are frequently administered prior to contrast-enhanced dynamic liver MRI and may improve both detection and classification of focal liver lesions.
Gadovist/Gadograf was approved for "Contrast enhancement in cranial and spinal magnetic resonance imaging" in Germany in January 2000 and subsequently in June 2000 in the EU and Norway via the mutual recognition procedure (MRP). A label extension to the indication "Contrast-enhanced Magnetic resonance angiography" (CE-MRA) followed in November 2003.
In June 2005, a MR procedure started for a type II variation to add the indication of "Contrast enhanced MRI of other body regions: liver, kidneys" and the following posology and method of administration/dosage: "CE-MRI of other body regions: The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0 M solution". After finalisation of the procedure the Spanish Agency for Medicines and Health Products initiated a referral for arbitration to the CHMP under article 36.1 of Directive 2001/83/EC.
Having considered the grounds for the referral triggered by Spain, the CHMP, during its May 2006 plenary meeting, adopted a List of Questions and a TT for a referral procedure under Article 36. The CHMP appointed Dr. Broich (DE) as Rapporteur and Dr. Prieto (ES) as Co- Rapporteur.
The questions identified pertained to insufficient data on the evaluation of disseminated liver disease that could justify an extrapolation to the general population undergoing examinations of liver and kidney. Concerns were further raised with regards to the Paediatric Indication and the use of the comparator Magnevist. Magnevist is not approved "to classify focal lesions [of liver or kidney] as benign or malignant" throughout the EU and it was questioned whether it would support the granting of an indication for which Magnevist has not been approved. The Applicant was asked to justify the choice of this comparator and the clinical utility of Gadovist/Gadograf with respect to diagnostic thinking, therapeutic management and clinical outcome. A Request for Supplementary Information was adopted on 16 November 2006. The company responded to these points on 30 November 2006. In its response the Applicant addressed the issue of clinical utility by comparing Gadovist-enhanced with Magnevistenhanced MRI and underlined the diagnostic efficacy of Gadovist/Gadograf. The Applicant further agreed to the proposed wording by the CHMP as follows:
Section 4.1 (Indication):
"Contrast enhanced MRI of liver or kidneys in patients with high suspicion or evidence of having focal lesions to classify these lesions as benign or malignant". Section 4.2 (Posology):
Gadograf is not recommended for use in population below age 18 due to a lack of data on efficacy and safety."
The CHMP opinion was converted into a Decision by the European Commission on 13 April 2007.
The list of product names concerned is given in Annex I. The scientific conclusions are provided in Annex II and the amended Summary of Product Characteristics in Annex III.
|International non-proprietary name (INN) or common name||
Article 36 referrals (prior to July 2012)
This type of referral applied for a marketing authorisation that were granted via the mutual-recognition or decentralised procedure. It was triggered when a Member State considered that action (variation, suspension or withdrawal) was needed on the grounds of the need to protect public health. This referral has been replaced by Articles 107i and 31.
European Commission final decision
|EC decision date||
Opinion following an Article 36(1) referral Gadograf/Gadovist International Non-Proprietary Name (INN): Gadobutrol: Background information (PDF/30.6 KB)Adopted
First published: 13/04/2007
Last updated: 13/04/2007
Gadograf - Article 36 referral - Annex I, II, III, IV (PDF/169.23 KB)Adopted
First published: 09/11/2007
Last updated: 09/11/2007
Gadovist - Article 36 referral - Annex I, II, III, IV (PDF/182.65 KB)Adopted
First published: 09/11/2007
Last updated: 09/11/2007
- 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