Centralised Procedure and Scientific Advice: an Overview

Transcription

1 Centralised Procedure and Scientific Advice: an Overview Andrea Laslop Head of Scientific Office AGES Medizinmarktaufsicht AGES Vienna 30/01/2018 Austrian Federal Office for Safety in Health Care

2 Centralised Procedure 1 Application (at EMA) 1 Review process with 2 independent primary reviewers (via CHMP = Committee for Human Medicinal Products) Single scientific opinion 1 common Product Information 1 EU-wide license (via European Commission) in all 28 member states of the EU EEA countries (Iceland, Norway and Liechtenstein) also adopt the EC decision Introduction basic aspects 2

3 Centralised Procedure Mandatory scope of CP Biotechnology products including advanced therapies Orphan designated medicinal products New active substances with the following therapeutic indications: Acquired immuno-deficiency syndrome (AIDS) Cancer Diabetes Neurodegenerative disorders Viral diseases Autoimmune diseases and other immune dysfunctions Optional scope of CP New active substances Generics of centrally authorised products Eligibility defined by CHMP for Significant therapeutic, scientific or technical innovations: Complete new alternative for treatment, diagnosis or prevention Based on significant new scientific knowledge New technological application Interest of patients at the community level 3

4 CHMP and Working Parties Biosimilar Medicines Working Party Biostatistics Working Party Blood Products Working Party Chair (28 + 2) x 2 MS delegates + NO and IS CHMP delivers MA opinion to EC Scientific Advice Working Party Safety Working Party Quality Working Party Biologics Working Party Patients and Consumers Working Party 5 co-opted members Vaccines Working Party Scientific Advisory Groups Efficacy Therapeutic Subgroups Working Parties Healthcare Professionals Working Party AT member & alternate: Andrea Laslop & Milena Stain (both SCIO) 4

5 Centralised Procedure Appointment of (Co-)Rapporteur CHMP Rapporteur for each assessment CHMP Co-Rapporteur for new applications in most cases (but rarely for generics), for all referrals, only for major variations within life-cycle CHMP Peer Reviewer only for new applications (rarely for generics, not for referrals) PRAC Rapporteur pre: RMP, post: all safety issues Criteria/Responsibilities: CHMP member or alternate plus national assessment team Bidding process with selection according to expertise More often now also appointment of multinational teams Rapporteur in charge of all assessment reports during procedure Co-Rapporteur provides separate independent AR in first phase 5

6 Centralised Procedure Rapporteurships after Brexit Transition period in work from Q to Q Replacement of UK as Rapporteur or Co-Rapporteur CHMP Co-Rapporteur will become the Rapporteur, CHMP Peer Reviewer will become the Co-Rapporteur these procedures will have a ceiling Once the ceiling is reached, further procedures will be transferred in INN clusters, ATC-codes, as generics or hybrids 3 step allocation process to be implemented now 1 st with criteria and ceiling 2 nd with criteria and no ceiling 3 rd open bidding 6

7 Centralised Procedure Standard timetable until marketing authorisation in centralised procedure SUBMISSION Day 1 Start of procedure D80 2 ARs Primary Evaluation D120 CHMP LoQ Clock Stop Clock Start D121 Responses to LoQ D150 Joint AR D180 List of Outstanding issues Secondary Evaluation Clock Stop Clock Start D181 Responses (Oral Explanation) D210 CHMP opinion EC DECISION 2 or 3 (or 6) months 1 or 1+ 1 (OE) or clock stop 2+1 (OE) months clock stop D120 LoQs: major objections (MOs) or other concerns (OCs) OE: presentation by Company questions discussion within committee (trend) vote 7

8 Centralised Procedure Day 210: CHMP-Meeting CHMP Opinion On the basis of recommendation by Rapporteur and Co-Rapporteur, taking into account all comments by other members and discussion within the committee Decision by consensus or majority Absolute majority of votes (= half of all members entitled to vote + 1 = currently 17 votes out of 33) for positive opinion, otherwise negative outcome Vote of Norway and Iceland does not count for majority decision Quorum of 22 members necessary for valid voting process Divergent positions of members in minority are recorded, written statements are signed and appended to CHMP AR 8

9 Centralised Procedure European Public Assessment Report Publication on EMA s website after commission decision ( Find Medicine Human Medicines EPARs) Publication contains Assessment history together with discussion of the benefit/risk leading to the (positive) outcome and potential divergent positions Commercially confidential content is removed Product information and conditions of use Summary for the public in lay language In case of refusal of the MAA a Refusal EPAR is published, together with a short Q&A document (these products must not be marketed anywhere in the EU/EEA) 9

10 Centralised Procedure Re-examination after negative opinion Deadline of 15 days to apply for re-examination Within 60 days the applicant needs to make his case with detailed arguments against the grounds for refusal CHMP appoints new Rapporteur and Co-Rapporteur (if possible with divergent views) Only those parts are re-discussed and assessed that led to the negative opinion No submission of new scientific data (but new analyses) allowed Often a SAG or adhoc expert group meeting is convened Usually also another OE takes place, but no clock-stop New CHMP opinion within 60 days of the procedure 10

11 EMA Annual Report Innovations advancing public health, 7 Orphan medicines, 7 Accelerated assessments, 8 Conditional marketing authorisations 11

12 Centralised MA applications CHMP (Co-)Rapporteur/Peer review ( ) AT appointment in centralised MAA Role AT Rapporteur Co-Rapporteur Sum Peer Reviewer Sum Type MAA Full application Biosimilar Generic/Hybrid

13 Centralised MA applications 31 Full applications ( ) AT appointment in centralised MAA 12x 10x Co- Rapporteur Rapporteur Coagulopathy/haemoglobinopathy Respiratory disease in neonates Non-infectious uveitis Atopic dermatitis Coagulopathy/thrombocytopenia Osteoporosis Metabolic disease in haemodialysis x Peer Reviewer Coagulopathy Oncology Weight loss Hair loss Wound healing

14 Centralised MA applications 27 Biosimilar applications ( ) AT appointment in centralised MAA Rheumatology/immunology 5 15x 6x 6x Peer Reviewer Co-Rapporteur Rapporteur Neutropenia Osteoporosis Prophylaxis of VTE Rheumatology/immunology Oncology Neutropenia Rheumatology/immunology Neutropenia

15 EMA Scientific Advice Scientific Advice (SA) or Protocol Assistance (PA) (for Orphan products) All aspects of a development program Quality, non-clinical, clinical, biostatistics, Broad advice on general procedures, e.g. diagnostic interventions, patient-reported outcome questionnaires Qualification procedures and opinions, e.g. biomarkers Joint advice (with FDA, with HTA institutions) Procedure 40 or 70 days (with oral discussion meeting) Prepared by the SAWP (Scientific Advice Working Party) Formal adoption by the CHMP Recommendations, not legally binding 15

16 EMA Scientific Advice EMA SA & PA: Flowchart of Procedure EMA Guidance for applicants seeking scientific advice and protocol assistance eu/docs/en_gb/documen t_library/regulatory_and _procedural_guideline/20 09/10/WC pdf 16

17 EMA Scientific Advice AT team in Scientific Advice Working Party (SAWP) 2 members + alternates nominated by the CHMP Christian Gartner & Stephan Lehr (both BPSV) Andrea Laslop (SCIO) & Andreas Kirisits (CASE) 1 member + alternate nominated by the PDCO Karl-Heinz Huemer (SCIO) & Johanna Wernsperger (CASE) 1 member nominated by the COMP Univ. Prof. Dr. Brigitte Blöchl-Daum (Med. Univ. Vienna) Altogether 70 members / alternates in the SAWP SAWP chair: R. Hemmings (from MHRA, UK) 52 nominated by CHMP, 5 by COMP, 6 by PDCO, 4 by CAT, 2 by PRAC Not based on MSs representation, but on expertise 17

18 EMA Scientific Advice Advice on Orphan Issues PA for orphan drugs has low fees Questions of significant benefit Parallel involvement of COMP Advice on Paediatric Issues Paediatric advice is free of charge Addresses questions on PIPs (Paediatric Investigation Plan) Parallel involvement of PDCO Advice on Advanced Therapies Advice on any kind of therapies based on genes, tissues or manipulated cells, etc. Parallel involvement of CAT Advice on Post- Authorisation Issues Advice on PASS and PAES protocols (post-authorisation safety and efficacy studies) Parallel involvement of PRAC 18

19 EMA Scientific Advice X Common X position on scientific X and regulatory X aspects Consistency X of recommendations X X Increased chances X of successful X development X X X X X Benefits of Scientific Advice see e.g. Marketing authorisation of orphan medicines in Europe from 2000 to Hofer et al., Drug Discovery Today, November

20 EMA Scientific Advice What are Useful Questions The more focussed a question is on a distinct issue E.g. on acceptability of the proposed primary endpoint The more facts are available and described in a precise manner E.g. on sample size calculation for the primary endpoint The better the rationale is deduced for a certain proposal E.g. on clinical relevance of the proposed endpoint the clearer the answer! 20

21 EMA Scientific Advice What are Less Useful Questions Size of the safety data package usually no preassessment is done standard response Acceptance of one pivotal trial the usual caveats are mentioned, importance of final data Wording of the indication usually premature to discuss, again will depend on final data Vague questions like do you agree with the general outline of the development program can only be answered vaguely 21

22 EMA Scientific Advice What You Should Consider Come early but not without a clear proposal Not e.g. what development does SAWP recommend? Come before all studies are ongoing, rather come again later E.g. discussion of long-term effects after first results Proof-of-concept data to inform further design Do not only expect endorsement of proposals Safe-guarding approaches may hinder improvement Be prepared to justify and to convince Deviations from guidelines acceptable? Global approaches viewed differently by different experts? Be prepared for open discussion and change Key Opinion Leaders (KOLs) are only KOLs after all! Flexibility on both sides! 22

23 EMA Scientific Advice EMA: in total AT SAWP Co-ordinatorships ( ) (per number appointed) 164 Number

24 EMA Scientific Advice % 6% 22 AT SAWP Co-ordinatorships ( ) 5% 6% 16 5% per product or disease type % % 3% 3% 2% 38 11% Total number: 351 without AT COMP Member in SAWP 98 28% 49 14% Biosimilars Miscellaneous Blood Endocrinology Ophthalmology CNS Oncology Immunology CVS Vaccines Osteoporosis/-arthritis Generics Infectious Diseases 24

25 EMA Scientific Advice Ranking of SAWP Co-ordinatorships AT UK DE NL BE

26 EMA Scientific Advice AT SAWP Co-ordinatorships 2017 concluded, per type of procedure Procedure SA Scientific Advice 63 PA Protocol Assistance 16 FU Follow-up Procedure 41 QSA Qualification Advice 5 QSO Qualification Opinion 3 HTA Parallel Advice with HTA % 45% 22% Quality Preclinical Clinical without AT COMP Member in SAWP 26

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