centralised procedure and scientific advice: an overview · vote + 1 = currently 17 votes out of...

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

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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


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)


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



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



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



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



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)



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



EMA Annual Report 2016

• 6 Innovations advancing public health, 7 Orphan medicines, • 7 Accelerated assessments, 8 Conditional marketing authorisations


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


31 Full applications (2012 – 2017)


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



Neutropenia

Rheumatology/immunology

Neutropenia

Oncology


Prophylaxis of VTE

Osteoporosis

Neutropenia


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


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


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


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



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


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



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 !



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



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!



63 70

80 83 96

77

99 102 106 114

127

164

AT SAWP Co-ordinatorships (2006-2017) N

umbe

r

(per number appointed)


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



www.basg.gv.at 25


Ranking of SAWP Co-ordinatorships 2016

1 AT 127

1 UK 127

3 DE 126

4 NL 115

4 BE 115


www.basg.gv.at 26


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


33%

22%

45%

Quality Preclinical Clinical

centralised procedure and scientific advice: an overview · vote + 1 = currently 17 votes out of...

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