Gd deposition in the body

Background of EMA recommandation

Olivier Clément

Hôpital Européen Georges Pompidou

Paris

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

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,

• 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)

• 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)

• Retinoïds

• Injectable anti allergic drugs containing bovine lactose

• Valproate in pregnancy

• Gadolinium containing agents

Ongoing Referrals procedures

Nephrogenic Systemic Fibrosis

Brain Hypersignals

• Procedures « Referral under article 31 of Directive

2001/83/EC »

10

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

12

Commission Decision 1/7/10

• Classes of Gd chelates

• Low risk (macrocycles)

• Medium risk (substituted linear)

• High risk (linear)

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

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

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)

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

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

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.

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

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)

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

Brain Hypersignals : Referral

• Rapporteur / co-rapporteur assesment reports circulated

to PRAC and CHMP May 2016

• Meeting in London in Sept 2016

– Experts

– Companies

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.

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.

Brain Hypersignals : Referral

• Report PRAC march 2017 :

– Re-examination requested by Bracco and GE

– New expertise, rapporteurs,

– New SAG group June

– Nouvel avis Ju2017

PRAC decision 6 july 2017

• Suspension MA for linears

– Magnevist (except articular)

– Omniscan

• Maintain Primovist Multihance

– Liver imaging

• Macrocyclics maintained

• (Dotarem, Gadovist, Prohance)

CHMP validation

20/7/17

European

Commission

>

Standing Committee

14/11/17

FDA pannel

8 sept 2017

Hypersignals : summary

• GBCA mandatory for diagnostic imaging

• Good Risk / Benefit balance

• Major indications for macrocyclics

• Withdrawal of linears: pending

Standing Committee

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

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.

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.