gd deposition in the body background of ema recommandation · pharmacovigilance • european...
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Gd deposition in the body
Background of EMA recommandation
Olivier Clément
Hôpital Européen Georges Pompidou
Paris
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European Authorities in
Pharmacovigilance
• European Commission (Brussels)
Executive body of EU, proposing legislation, implementing
decisions… For registration, driving & adoption of the decision
(EU license)
• National Competent Authorities
Health Authorities of each member state
• EMA (CHMP, PRAC.. And scientific advisory committees)
Helps, protect and promote health in Europe by
evaluating medicines for human and veterinary use
Good Pharmacovigilance Practices, EMA, Accessed Dec-2014
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp
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EMA
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Science and activities relating to the detection,
assessment, understanding and prevention of adverse
reaction or any other drug-related problem1,
Based on spontaneous reporting, and post-authorisation
studies,
National/Regional Networks and Marketing Authorization
Holder (MAH) PV system2.
Pharmacovigilance (PV)
1. WHO report 2006_http://www.who.int/medicines/areas/quality_safety/safety_efficacy/Pharmacovigilance_B.pdf last access Dec 2015
2. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:0074:0099:EN:PDF last access Dec 2015
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Pharmacovigilance Actions
• When new information warrants action, regulators have
several tools available:
• Update patient information/Summary of Product
Characteristics (SmPC),
• Inform patients and/or healthcare professionals (DHPC,
educational material),
• Review of benefit-risk profile of medicine (referral),
• Restrict access to medicine,
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• A referral is a procedure used to resolve issues of either
quality, safety or efficacy, including disagreements and
address concerns at EU level; it can be started by the EU,
any member state or the company
• The EMA is asked to conduct scientific assessment of a
particular medicine or class of products
• Safety related referrals are assessed by PRAC, and CHMP
or CMDh
Safety Referral procedures – Article 31 (1)
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• Decisions varies from maintaining the marketing
authorization, to its suspension; to modify information
about the product (SmPC, package leaflet); to conduct a
drug utilization study..
• Adoption of the PRAC decision by consensus or majority
vote;
• The PRAC decision may be re-examined on MA holder’s
request;
• Finally, the European Commission issues a decision to all
States;
• Member States have to implement decision in 30 days.
Safety Referral procedures (2)
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• Retinoïds
• Injectable anti allergic drugs containing bovine lactose
• Valproate in pregnancy
• Gadolinium containing agents
Ongoing Referrals procedures
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Nephrogenic Systemic Fibrosis
Brain Hypersignals
• Procedures « Referral under article 31 of Directive
2001/83/EC »
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NSF : EUROPE SAG meeting dec 2007
• Different Gd contrast agent classes
• Harmonisation necessary : breast feeding, pregnancy, child, elderly, hepatic transplant
• Responses of the different companies
• New SAG meeting in october 2009
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EUROPE documents
• 20th Nov 2009 :
– Press release
– Questions and answers
• 1st July 2010 :
– COMMISSION DECISION
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Commission Decision 1/7/10
• Classes of Gd chelates
• Low risk (macrocycles)
• Medium risk (substituted linear)
• High risk (linear)
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/referral_search.jsp&mid=WC0b01ac05805c516f&source
=homeMedSearch&category=human&keyword=gadolinium&status=final&isNewQuery=true
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Brain Hypersignals : EMA
• Pharmacovigilance Risk Assessment Committee
(PRAC) 4-7 May 2015 discussion
• MHRA (UK agency) sent a letter in June 2015
to Companies with a list of questions
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Brain Hypersignals
• On March 2016, the European commission triggered a
procedure under article 31 of Directive 2001/83/EC:
• the Pharmacovigilance Risk Assessment Committee
(PRAC) must:
Assess the impact of the new findings on the
benefice/risk balance of all Gadolinium-containing
contrast agents,
Issue recommendation concerning the Marketing
Authorisations (MA)
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Brain Hypersignals : EMA
• Start of the Referral procedure March 2016 PRAC• http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/g
adolinium_contrast_agents_31/Procedure_started/WC500203485.pdf
• List of questions
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EMA : Questions to the companies
Question 1
•Concerning your Gadolinium-containing contrast agent :
•a) Figures on sales and patient exposure
•b) Information in the summary of product characteristics
(SmPC) and package leaflet (PL)
•c) An overview of the approved indication(s) of your
Gadolinium-containing contrast agent outside the EU
•Question 2
•Provide complete product information
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EMA : Questions to the companies
Question 3
•Please provide all available safety data relevant to
evaluate the risk of accumulation of gadolinium in the brain
with your Gadolinium-containing contrast agent • Locations
• Cumulative dose
• Patient characteristics, renal function
• Comparison with other products
• Disease that could influence deposition
•The MAH should discuss the mechanism of transfer of
gadolinium into the brain and the chemical form in which it
is deposited.
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EMA : Questions to the companies
Question 4
•What are the possible clinical implications of
accumulation
Question 5
•Please specify if there are groups of patients (e.g.
diseases, age groups, demographics) or specific
circumstances where use of your product has particular
clinical advantages, relative to other products in the class
of gadolinium in the brain
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EMA : Questions to the companies
Question 6
•Provide a full benefit/risk assessment of your
Gadolinium-containing contrast agent in the currently
approved indication(s) in the EU.
•This should include an assessment on the impact of
occurrence of accumulation of gadolinium in the brain and
other tissues (including liver, kidney, muscle, skin and
bone)
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EMA : Questions to the companies
Question 7
•Please provide proposals and justifications for any risk
minimisation measures (including changes to the
SmPC/PL)
Question 8
•Summarise the previous, planned and ongoing studies
into this area for your product, and make proposals for
additional non-clinical, mechanistic and clinical research
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Brain Hypersignals : Referral
• Rapporteur / co-rapporteur assesment reports circulated
to PRAC and CHMP May 2016
• Meeting in London in Sept 2016
– Experts
– Companies
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Brain Hypersignals : Referral
• Report PRAC march 2017 :
– Stop linears
– Except Primovist for liver
imaging and Magnevist intra
articular
– Keep macrocyclics
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
An agency of the European Union
Telephone +44 (0)20 3660 6000 Facsim ile +44 (0)20 3660 5555
Send a quest ion v ia our w ebsite www.ema.europa.eu/contact
© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.
10 March 2017
EMA/157486/2017 Media and Public Relations
PRAC concludes assessment of gadolinium agents used in
body scans and recommends regulatory actions, including
suspension for some marketing authorisations Review finds evidence of gadolinium deposits in the brain after MRI body
scans but no signs of harm
EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of
the marketing authorisations for four linear gadolinium contrast agents because of evidence that small
amounts of the gadolinium they contain are deposited in the brain.
The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid
and gadoversetamide, which are given to patients to enhance images from magnetic resonance
imaging (MRI) body scans.
The PRAC’s review of gadolinium agents found convincing evidence of accumulation of gadolinium in
the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal
intensity seen on MRI scan images many months after the last injection of a gadolinium contrast
agent.
The companies concerned by this review have the right to request the PRAC to re-examine its
recommendations.
The PRAC’s final recommendations will be sent to the Committee for Medicinal Products for Human Use
(CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.
Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC
took a precautionary approach, noting that data on the long-term effects in the brain are limited.
Deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin
plaques and nephrogenic systemic fibrosis,1 a scarring condition in patients with kidney impairment.
Furthermore, non-clinical laboratory studies have shown that gadolinium can be harmful to tissues.
The four agents recommended for suspension are referred to as linear agents. Linear agents have a
structure more likely to release gadolinium, which can build up in body tissues. Other agents, known
as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The
1 See EMA review of gadolinium contrast agents in 2010.
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30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
An agency of the European Union
Telephone +44 (0)20 3660 6000 Facsim ile +44 (0)20 3660 5555
Send a quest ion v ia our w ebsite www.ema.europa.eu/contact
© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.
10 March 2017
EMA/157486/2017 Media and Public Relations
PRAC concludes assessment of gadolinium agents used in
body scans and recommends regulatory actions, including
suspension for some marketing authorisations Review finds evidence of gadolinium deposits in the brain after MRI body
scans but no signs of harm
EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of
the marketing authorisations for four linear gadolinium contrast agents because of evidence that small
amounts of the gadolinium they contain are deposited in the brain.
The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid
and gadoversetamide, which are given to patients to enhance images from magnetic resonance
imaging (MRI) body scans.
The PRAC’s review of gadolinium agents found convincing evidence of accumulation of gadolinium in
the brain from studies directly measuring gadolinium in brain tissues and areas of increased signal
intensity seen on MRI scan images many months after the last injection of a gadolinium contrast
agent.
The companies concerned by this review have the right to request the PRAC to re-examine its
recommendations.
The PRAC’s final recommendations will be sent to the Committee for Medicinal Products for Human Use
(CHMP) for its opinion. Further details will be published at the time of the CHMP opinion.
Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC
took a precautionary approach, noting that data on the long-term effects in the brain are limited.
Deposition of gadolinium in other organs and tissues has been associated with rare side effects of skin
plaques and nephrogenic systemic fibrosis,1 a scarring condition in patients with kidney impairment.
Furthermore, non-clinical laboratory studies have shown that gadolinium can be harmful to tissues.
The four agents recommended for suspension are referred to as linear agents. Linear agents have a
structure more likely to release gadolinium, which can build up in body tissues. Other agents, known
as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The
1 See EMA review of gadolinium contrast agents in 2010.
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Brain Hypersignals : Referral
• Report PRAC march 2017 :
– Re-examination requested by Bracco and GE
– New expertise, rapporteurs,
– New SAG group June
– Nouvel avis Ju2017
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PRAC decision 6 july 2017
• Suspension MA for linears
– Magnevist (except articular)
– Omniscan
• Maintain Primovist Multihance
– Liver imaging
• Macrocyclics maintained
• (Dotarem, Gadovist, Prohance)
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CHMP validation
20/7/17
European
Commission
>
Standing Committee
14/11/17
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FDA pannel
8 sept 2017
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Hypersignals : summary
• GBCA mandatory for diagnostic imaging
• Good Risk / Benefit balance
• Major indications for macrocyclics
• Withdrawal of linears: pending
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Standing Committee
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Standing Committee
On 22 September 2017, Poland informed the
Commission that they did not agree with the
CHMP opinion recommending suspension of
certain gadolinium containing medicinal products
and the Czech Republic and Italy raised concerns
about the draft decision and requested the
Commission to convene a meeting of the Standing
Committee on Medicinal Products for Human Use
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Standing Committee
Some Member States raised concerns
regarding the impact of the Commission
decision on the availability of contrast agents
in their territory. To address these concerns
the draft Commission decision was amended
to allow Member States to defer for up to 12
months the suspension of critical products on
the basis of potential unmet medical need and
considering the availability of suitable
alternative medicinal products.
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Standing Committee
Draft Commission Implementing Decision of XXX
concerning, in the framework of Article 31 of Directive
2001/83/EC of the European Parliament and of the
Council, the marketing authorisation granted by
Decision C(2007)3627 for “Optimark -
Gadoversetamide”, medicinal product for human use
The Standing Committee gave its favourable opinion with
unanimity on the Draft Commission Implementing Decision
of XXX concerning, in the framework of Article 31 of Directive
2001/83/EC of the European Parliament and of the Council,
the marketing authorisation granted by Decision
C(2007)3627 for “Optimark - Gadoversetamide”, medicinal
product for human use.