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Austrian Federal Office for Safety in Health Care www.basg.gv.at
Andrea Laslop Head of Scientific Office AGES Medizinmarktaufsicht AGES – Vienna – 30/01/2018
Centralised Procedure and Scientific Advice: an Overview
www.basg.gv.at 2 A. Laslop, AGES, Vienna, 30 January 2018
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
www.basg.gv.at 3 A. Laslop, AGES, Vienna, 30 January 2018
Centralised Procedure
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
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
www.basg.gv.at 4 A. Laslop, AGES, Vienna, 30 January 2018
CHMP and Working Parties
Biologics Working Party
Safety Working Party
Blood Products Working Party
Quality Working Party
Efficacy Therapeutic Subgroups Working
Parties
Scientific Advice Working Party
Vaccines Working Party
Biosimilar Medicines Working Party
(28 + 2) x 2 MS delegates +
NO and IS Chair
Scientific Advisory Groups
CHMP delivers MA
opinion to EC
Biostatistics Working Party
Patients’and Consumers’
Working Party
Healthcare Professionals’ Working Party
5 co-opted members
AT member & alternate: Andrea Laslop & Milena Stain (both SCIO)
www.basg.gv.at 5 A. Laslop, AGES, Vienna, 30 January 2018
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
Centralised Procedure
www.basg.gv.at 6 A. Laslop, AGES, Vienna, 30 January 2018
Rapporteurships after Brexit • Transition period in work from Q4 2018 to Q1 2019 • 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 1st with criteria and ceiling –
2nd with criteria and no ceiling –
3rd open bidding
Centralised Procedure
www.basg.gv.at 7 A. Laslop, AGES, Vienna, 30 January 2018
D120 LoQs: major objections (MOs) or other concerns (OCs) OE: presentation by Company – questions – discussion within committee – (trend) vote
Clock Stop
D120 CHMP LoQ
D121 Responses to LoQ
Day 1 Start of procedure
D80 2 ARs
D150 Joint AR
D180 List of Outstanding issues
D210 CHMP opinion
2 or 3 (or 6) months 1 or 1+ 1 (OE) or clock stop 2+1 (OE) months clock stop
Secondary Evaluation Clock Stop
E
C D
ECIS
ION
D181 Responses
SUB
MIS
SIO
N
Primary Evaluation Clock Start
Clock Start
(Oral Explanation)
Standard timetable until marketing authorisation in centralised procedure
Centralised Procedure
www.basg.gv.at 8 A. Laslop, AGES, Vienna, 30 January 2018
CHMP Opinion • Day 210: CHMP-Meeting
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
Centralised Procedure
www.basg.gv.at 9 A. Laslop, AGES, Vienna, 30 January 2018
European Public Assessment Report • Publication on EMA‘s website after commission decision
(www.ema.europa.eu – 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)
Centralised Procedure
www.basg.gv.at 10 A. Laslop, AGES, Vienna, 30 January 2018
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
Centralised Procedure
www.basg.gv.at 11 A. Laslop, AGES, Vienna, 30 January 2018
EMA Annual Report 2016
• 6 Innovations advancing public health, 7 Orphan medicines, • 7 Accelerated assessments, 8 Conditional marketing authorisations
www.basg.gv.at 12 A. Laslop, AGES, Vienna, 30 January 2018
Centralised MA applications
CHMP (Co-)Rapporteur/Peer review (2012-2017) AT – appointment in centralised MAA
2012 2013 2014 2015 2016 2017
Role AT Rapporteur 3 5 6 12 7 11 Co-Rapporteur 3 3 1 3 5 4 Sum 6 8 7 15 12 15
Peer Reviewer 1 6 3 2 5
Sum 6 9 13 18 14 20
Type MAA Full application 3 4 6 7 4 7 Biosimilar 2 1 6 6 12 Generic/Hybrid 3 3 6 5 4 1
www.basg.gv.at 13 A. Laslop, AGES, Vienna, 30 January 2018
31 Full applications (2012 – 2017)
Centralised MA applications
Wound healing
Hair loss
Weight loss
Oncology
Coagulopathy
Metabolic disease in haemodialysis
Osteoporosis
Coagulopathy/thrombocytopenia
Atopic dermatitis
Non-infectious uveitis
Respiratory disease in neonates
Coagulopathy/haemoglobinopathy
Peer
Rev
iew
erCo
-Ra
ppor
teur
Rapp
orte
ur
9
4
1
1
1
2
1
3
6 1
1
1 12x
10x
9x
AT – appointment in centralised MAA
www.basg.gv.at 14 A. Laslop, AGES, Vienna, 30 January 2018
Centralised MA applications
Neutropenia
Rheumatology/immunology
Neutropenia
Oncology
Rheumatology/immunology
Prophylaxis of VTE
Osteoporosis
Neutropenia
Rheumatology/immunology
Peer
Revi
ewer
Co-R
appo
rteu
rRa
ppor
teur
27 Biosimilar applications (2012 – 2017) AT – appointment in centralised MAA
5
6
3
5
2
2
2
1
1
15x
6x
6x
www.basg.gv.at 15 A. Laslop, AGES, Vienna, 30 January 2018
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
EMA Scientific Advice
www.basg.gv.at 16 A. Laslop, AGES, Vienna, 30 January 2018
EMA Guidance for applicants seeking scientific advice and protocol assistance http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004089.pdf
EMA SA & PA: Flowchart of Procedure
EMA Scientific Advice
www.basg.gv.at 17
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
A. Laslop, AGES, Vienna, 30 January 2018
EMA Scientific Advice
www.basg.gv.at 18 A. Laslop, AGES, Vienna, 30 January 2018
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
EMA Scientific Advice
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
www.basg.gv.at 19 A. Laslop, AGES, Vienna, 30 January 2018
Benefits of Scientific Advice
X X X X X X X X X X X X X X
• Common position on scientific and regulatory aspects
• Consistency of recommendations
• Increased chances of successful development see e.g. Marketing authorisation of
orphan medicines in Europe from 2000 to 2013. Hofer et al., Drug Discovery Today, November 2017
EMA Scientific Advice
www.basg.gv.at 20 A. Laslop, AGES, Vienna, 30 January 2018
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 !
EMA Scientific Advice
www.basg.gv.at 21 A. Laslop, AGES, Vienna, 30 January 2018
What are Less Useful Questions • Size of the safety data package – usually no pre-
assessment 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
EMA Scientific Advice
www.basg.gv.at 22 A. Laslop, AGES, Vienna, 30 January 2018
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!
EMA Scientific Advice
www.basg.gv.at 23 A. Laslop, AGES, Vienna, 30 January 2018
63 70
80 83 96
77
99 102 106 114
127
164
AT SAWP Co-ordinatorships (2006-2017) N
umbe
r
(per number appointed)
EMA Scientific Advice
420 473
549 510
582
EMA: in total
www.basg.gv.at
98
49
38 30
22
20
19 17
16 14 12 9 7
AT SAWP Co-ordinatorships (2011 – 2016) BiosimilarsMiscellaneousBloodEndocrinologyOphthalmologyCNSOncologyImmunologyCVSVaccinesOsteoporosis/-arthritisGenericsInfectious Diseases
14%
28%
11% 8%
6%
6%
5%
5% 5%
4%
per product or disease type
Total number: 351 without AT COMP Member in SAWP
3% 3% 2%
24
EMA Scientific Advice
A. Laslop, AGES, Vienna, 30 January 2018
www.basg.gv.at 25
EMA Scientific Advice
Ranking of SAWP Co-ordinatorships 2016
1 AT 127
1 UK 127
3 DE 126
4 NL 115
4 BE 115
A. Laslop, AGES, Vienna, 30 January 2018
www.basg.gv.at 26
EMA Scientific Advice
63 16 41 5 3 2 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 2
130
AT SAWP Co-ordinatorships 2017 concluded, per type of procedure
without AT COMP Member in SAWP
A. Laslop, AGES, Vienna, 30 January 2018
33%
22%
45%
Quality Preclinical Clinical
www.basg.gv.at 27 A. Laslop, AGES, Vienna, 30 January 2018