1. Union referral procedures
Kaoutar AKOUH
AREIPS 2016/2017

2. Definition of a referral
Types of safety referrals
Article 107i and assessment
Article 31 and assessment
Drugs assessed under
articles 31 and 107i

3. WHAT IS A REFERRAL ? It may concern : safety quality, efficacy
B/R balance
EMA :
scientific assessment
committees (PRAC, CHMP/CMDh)
Procedure :
used to resolve issues
of a medicine
or a class of medicine

4. WHAT ABOUT THE ASSESSMENT ?
All other referrals :
assessed only by CHMP
Safety-related referrals :
PRAC recommendation
then either by the CHMP (at least one centrally authorized product)
or by the CMDh (no centrally authorized products)
EC decision if applicable
50% of the referrals

5. SAFETY-RELATED REFERRALS
Directive 2001/83/CE :
Article 31 : Union interest referral
Article 107i : Urgent union procedure
Regulation EC No 726/2004 :
Article 20 : Union interest referral (for CAP)
Article 5(3) : scientific opinion

6. ARTICLE 107i : URGENT UNION PROCEDURE
In which cases ?
safety issue (result of evaluation of PhV data)
urgent action is needed
Procedure initiated before a decision is taken :
suspension or revocation of a MA
prohibition of supply of a medicine
deletion of indication, reduction of the recommended dose, new contraindication
MAH :
interruption the placing on the market of a medicinal product,
action to have a MA withdrawn
has not applied for the renewal of a MA for a safety reason

7. URGENT UNION PROCEDURE
ARTICLE 107i :
URGENT UNION PROCEDURE
Who can initiate this procedure ?
Competent authority of a member state
European commission
Notification : details on the safety issue, sent to the EMA, all MS and the EC by the initiator
Which products ?
all the medicines : with a valid MA
generics or not
a range of medicines
a therapeutic class
affected by urgent safety issue
the product has to be authorized in several MS

8. ARTICLE 107i : URGENT UNION PROCEDURE
Assessment by the PRAC : 60 days, without clock-stop
assessment based on data collected (anyone can submit data in relation to the issue via a dedicated mailbox during 20 days)
60 days maximum time limit to issue a recommendation
public hearing is possible (doctors, patients can present relevant data for the assessment, not mandatory).
temporary measures can be taken at any time to protect public health:
by the MS
by the EC when a centrally authorized product is involved
ex: suspension of the MA, prohibition of the product

9. ARTICLE 107i : URGENT UNION PROCEDURE
Outcome of the assessment by the PRAC :
no further action or evaluation is required at the union level
the MAH should :
conduct further evaluation of data
sponsor a post-authorisation safety study
the MS or the MAH should implement risk minimisation measures
the MA should be suspended, revoked or not renewed
the MA should be varied (SmPC, package leaflet)

10. ARTICLE 107i : URGENT UNION PROCEDURE
Assessment by the CHMP/CMDh : 30 days
CMDh (only nationally authorized products) :
agrees immediately with the PRAC recommendation or within 30 days
position by consensus : sent to the MS and the MAH
position by majority vote : sent to the EC for a decision
CHMP (at least one centrally authorized product) :
agrees immediately with the PRAC recommendation
disagree with the PRAC recommendation : a timeframe of 30 days begins
the opinion is sent to the EC for a final decision
the EMA, MAH, MS receive the final decision by the EC

11. ARTICLE 107i : PROCEDURAL STEPS
2 months

12. DRUGS ASSESSED UNDER ARTICLE 107i
Cyproterone and EE containing medicines 2013 :
initiated at the request of France
assessment of the B/R balance : serious thromboembolic events + extensive off-label use as a contraceptive only
PRAC recommendation : Diane 35 and its generics outweigh the risks
CMDh endorsed by majority the PRAC recommendation
the CMDh position was sent to the EC for a final decision : MA is maintained with risk minimisation measures
to minimise the risk of thromboembolism :
updating of the product information
providing educational material to prescribers and patients highlighting the risks of thromboembolism

13. ARTICLE 31 : UNION INTEREST REFERRAL
In which cases ?
safety issue
Interests of the Union = interest of public health
no urgent action is required (possible clock-stop)
before a decision is taken about a MA :
an application
a suspension
a revocation
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14. UNION INTEREST REFERRAL
ARTICLE 31 :
UNION INTEREST REFERRAL
Who can initiate this procedure ?
Member state
European Commission
MA holder => a MS or the commission has to confirm the union interests
Initiator refers the matter to the PRAC : notification (details on the safety concern, how the union interests are involved)
Which products ?
a specific medicinal product
a range of medicinal products (same active substance)
a therapeutic class of medicinal products
affected by a safety issue
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15. UNION INTEREST REFERRAL
ARTICLE 31 :
UNION INTEREST REFERRAL
Assessment by the PRAC : 60 days, possible clock-stop
can be extended to 120 days (to take into account the MAH views, in case of public hearing)
PRAC recommendation adopted by consensus or by majority
after PRAC recommendation, the MAH has 15 days to request a re-examination
after this 15 days, the PRAC recommendation considered final and is sent to the CMDh or CHMP
Outcome of the assessment by the PRAC :
the MA can be maintained under certain conditions :
MAH has to conduct a drug use study
and/or to implement other minimisation risk measures
the MA should be varied :
product information should be corrected
the MA should be suspended or revoked
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16. UNION INTEREST REFERRAL
ARTICLE 31 :
UNION INTEREST REFERRAL
Assessment by the CHMP/CMDh : 30 days
the final PRAC recommendation is forwarded to the CHMP or CMDh
if the MAH disagree with the CMDh position or the CHMP opinion : possible re-examination, 15 days after the decision or position.
CMDh position or CHMP opinion immediately or within 30 days
EC final decision if applicable
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17. ARTICLE 31 : PROCEDURAL STEPS
2 months
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18. DRUGS UNDER EVALUATION IN 2016 : ARTICLE 31
Paracetamol modified and prolonged release tablets :
initiated at the request of Sweden
assessment of the B/R balance : overdoses
how to minimise the risk of overdoses ? (the standard procedures of immediate-release paracetamol are not enough)
review will be carried out by the PRAC + CMDh
Factor VIII medicines :
initiated at the request of Paul Ehrlich Institute
assessment of the risk of developing inhibitor proteins in patients starting treatment for hemophilia A (publication of a study : risk FVIII made by DNA recombinant > risk FVIII derived from blood)
EMA : assessment of the data of this study, necessity of minimisation risk measures or modifications in the MAs
review will be carried out by the PRAC + CHMP

19. TO SUM UP

20. Thank you for your attention !