1. FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS Federal Agency for Medicines and Health Products (FAMHP) Compassionate Use and Medical Need Program Pharma.be-BeApp, Brussels 16 November 2007 Greet MUSCH Head of R&D FAMHP/GM/16/11/2007 1

2. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 2 Overview 1 : Legal Framework 2 : Review of applications received until now 3 : Points of concern

3. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 3 1 :Legal Framework 1.1 : Regulation ( EC ) 726/2004 Art. 83 : Compassionate Use « making a medicinal product available for CU reasons to a group of patients with a chronically or seriously delibilating disease or whose disease is considered to be life threatening and who cannot be treated satisfactorily by an authorised medicinal product. » -> The medicinal product must be subject of a MA application or must be ondergoing a Clinical Trial

4. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 4 1 :Legal Framework 1.2 : CHMP Guideline on CU of medicinal products pursuant to (EC) 726/ 2004 Article 83 ( adopted 19 July 2007 ) - Compassionate use implementation remains a MS’s competence Art.83 is complementary to national legislations and provide an option to MS who wish to receive a CHMP opinion - The medicinal product is either the subject of an application for a centralised marketing autorisation or is undergoing clinical trials in the EU and/or elsewhere - Patients should always be considered for inclusion in clinical trials before being offered compassionate use programs

5. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 5 1.2 : CHMP Guideline on CU of medicinal products pursuant to (EC) 726/ 2004 Article 83 - In this guideline compassionate use does not refer to the use of an authorised medicinal product for an indication different from the one mentioned in the SPC - Other Principles and definitions - Initiation and request of CHMP opinion - CHMP opinion itself : grounds for assessing a request ; documentation to be supplied ; Pharmacovigilance - Link with MA

6. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 6 1.3 : National Law on medicinal products : 1 May 2006 Compassionate Use : For medicinal products without a MA Medical Need Program : For medicinal products with a MA for a certain indication

7. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 7 3 : National Law on medicinal products : 1 May 2006 Compassionate Use : Art.6 quater point 2 Articles 106 and 107 in the RD executive measures of the Law 1 May 2006 Medical Need Program : Art.6 quater point 3 Articles 108 and 109 in the RD executive measures of the Law 1 May 2006

8. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 8 3 : National Law on medicinal products : 1 May 2006 Medical Need Program : Art.6 quater point 3 : Application for MA for the indication envisaged is ongoing or MA for the indication envisaged has been granted but is not yet available on the market for the indication envisaged or Clinical trials are still running or clinical trials have been performed prooving the feasability of the MP for the indication envisaged

9. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 9 1.4: RD executive measures (Law 01.05.06) Compassionate Use : Art. 106 : Establishing a general program : - Positive advice of the EC mandatory - Inclusion criteria for acceptance of patients - Indication - Timespan in which the program will be running - Distribution ( modalities, costs, accountability ) - Informed Consent - data as required by the EU NfG

10. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 10 1.4: RD executive measures (Law 01.05.06) Compassionate Use : Art. 106 : Establishing a general program : - Application to the CA ( DGMP : Department R&D ) - same documentation including the positive advice of EC - data and formulars according to EU NfG - CA evaluates whether a CHMP opinion is to be requested or not  If yes : CHMP advice to be followed  If not : tacit approval after 2 weeks period - Archiving : copy of documents for a 10 years period

11. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 11 1.4: RD executive measures (Law 01.05.06) Compassionate Use : Art. 106 : Establishing a general program : In case of emergency :  Application to CA and EC justifying the urgency of the case

12. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 12 1.4: RD executive measures (Law 01.05.06) Compassionate Use : Art. 107 : Acceptance of Patiënts - Treating physician sends a request per patiënt, declaring that : - he takes the responsability for the use of this MP ( not yet authorised - chronic, life threatening disease, no alternative MP available on the Belgian market to treat the disease ; he describes the disease - he will inform the patiënt completely of all the modalities of the program - he will asap ask the patiënt for informed consent

13. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 13 1.4: RD executive measures (Law 01.05.06) Compassionate Use : Art. 107 : Acceptance of Patiënts - The company verifies the conformity to the program for each request and informs the applicant asap. - negative outcome : rationale is explained - positive outcome : the MP is provided to the treating physician according the established modalities and he labels the MP « compassionate use / not for sale ) - documents prooving that the treating physician has respected his duties are to be archived for 10 years.

14. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 14 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art.108 : Establishing a general program : - Notification to EC : - Inclusion criteria for acceptance of patients - Indication - Timespan in which the program will be running - Distribution ( modalities, costs, accountability ) - Informed Consent

15. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 15 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art.108 : Establishing a general program : - Notification to CA ( FAMHP: Department R&D ) : including the name of the EC concerned - Tacit approval aswell for EC as CA after a period of time of 2 weeks

16. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 16 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art.108 : Establishing a general program : - MAH informs the treating physician of the existence of the Medical Need Program and its conditions for application - Copy of documents to be archived by MAH to proove conformity to the Law/RD for a period of 10 years

17. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 17 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art.108 : Establishing a general program : In case of emergency :  Application to CA and EC justifying the urgency of the case

18. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 18 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art. 109 : Acceptance of Patiënts -Treating physician sends a request per patiënt, declaring that: - he takes the responsability for the use of this MP ( not yet authorised ) - chronic, life threatening disease, no alternative MP available on the Belgian market to treat the disease ; he describes the disease - he will inform the patiënt completely of all the modalities of the program - he will asap ask the patiënt for informed consent

19. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 19 1.4: RD executive measures (Law 01.05.06) Medical Need Program : Art. 109 : Acceptance of Patiënts - The company verifies the conformity to the program for each request and informs the applicant asap. - negative outcome : rationale is explained - positive outcome : the MP is provided to the treating physician according the established modalities and he labels the MP « compassionate use / not for sale ) - documents prooving that the treating physician has respected his duties are to be archived for 10 years.

20. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 20 2: Applications received until now 2.1 :Compassionate use : * Number of applications received :only 8  urgent cases ( one patient )  one program with positive advice of EC ( orphan drug ) * Questions raised :  one patient programs  CU programs requested for registered drugs ( incorrect comprehension of the definition ; is improving with time … but still a concern )

21. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 21 2: Applications received until now 2.2 : Medical Need Program : * Number of applications received : 17  Only 7 out of 17 with notified EC approval  Data obtained from the “ Literature “ : considered as “invalid“ Questions raised :  patients included in the original clinical trial but not fulfilling the re-imbursement criteria of RIZIV/INAMI

22. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 22 2: Applications received until now 2.2 : Medical Need Program :  legal framework too limitative ( data from the literature not retained as “ 4th criterium for MNP “ current position FAMHP : stimulate application for MA orphan drug / off-label use to be rediscussed with new government ?

23. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 23 3 : Other points of concern * Need for information / communication towards EC’s and health care professionals * Request to EC’s to notify the FAMHP for outcome decision related to approval CU-MNP via ct.ec@fagg-afmps.bect.ec@fagg-afmps.be * Enhanced scientific interaction between EC-CA about the justification of existing alternative therapies for instance or in case of negative opinion of EMEA * Notification to CHMP and role of CHMP ( need for harmonisation for CU programs in patients view perspective ) * Publication of register of approved CU ? * Follow-up of inclusion of patients in a CU/MNP program? * Amendments of CU/MNP programs ? * Safety reporting

24. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 24 4: Measures for improvement..? * Suggestions :  All applications / advices introduced via EC to be reported to CA via ct.ec@fagg.bect.ec@fagg.be  Inventory of practical cases by EC’s  Specific attention for 3th criterium for MNP: feasability of enrigestered drug to be prooved by CT in the new indication envisaged …  Template for CU/MNP to be provided by sponsors ? ( Informed Consent ; MNP ; Commitment of the treating physician )  Prospectives..?  Inventory of problems as experienced by sponsors …

25. FAMHP/GM 16/11/2007 FEDERAL AGENCY FOR MEDICINES AND HEALTH PRODUCTS 25 Many thanks for your attention