registration of biological medicinal products in eu a
TRANSCRIPT
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Registration of biological Registration of biological medicinal products in EU
A regulatory perspective
Pavia 11th May 2012
An agency of the European Union
Carla MartinoQuality of Medicines (Biologicals) – European Medicines Agency
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars – principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars – principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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European Medicines Agency (EMA)
A decentralised body of the EU, founded in 1995, based in London, UK
Mission:Mission:to foster scientific excellence in the evaluation and supervision of medicines, for the benefit f bli d i l h lth i 500 of public and animal health, serving over 500
million users of medicinal productsresponsible for centralised procedure and co-p pordination of EU networkplays a role in stimulating innovation and research in the pharmaceutical sectorresearch in the pharmaceutical sector
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An interface of cooperation and coordination of EU Member States’ activitiesof EU Member States activities
• Single marketing authorisation applicationvalid throughout EU (centralised procedure)
• EU Network for scientific advice & expertise pconstitutes of– 27 EU Member states– > 40 national competent authorities
4 500 European experts– 4,500 European experts
• Referral or arbitration procedures for medicines approved via non-centralised ppauthorisation procedures
• Coordination of activities: – Inspection– Pharmacovigilance (new Regulation 2012)
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European Regulatory Network4 500 E t4,500 European experts
National Competent Authorities
Working
EMA secretariat
Working PartiesCommittees
5
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European Marketing Authorisation ProceduresKey Principles
-- Approval in Approval in n or all n or all MSs => EU Authorisation systemMSs => EU Authorisation system
3 EU procedures3 EU procedures: Centralised Procedure (CP)
Mutual Recognition Procedure (MRP)
Decentralised Procedure (DCP)
A l i 1 MS A l i 1 MS i l h i i d-- Approval in 1 MS => Approval in 1 MS => National Authorisation Procedure
Route? Choice? Depending on type of product
and authorisation history in EUand authorisation history in EU
+
Regulatory & marketing strategy
Company preferences etc …
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Mutual Recognition Procedure
1 Member State (e.g. Italy) performs assessment of application
1 National MA1 National MA
Subsequent application to n MSsOth M b St t t Other Member States to “mutually recognise”the Italian assessment(90 days) n National MAs
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Decentralised Procedure
Parallel submissions in n MSs:
‘Reference’ MS performs- Reference MS performsassessment (120 days)
- Peer review by other MSs:‘Concerned’ MSs (90 days):
* Assessment report* SmPC, leaflet and labelling, g
- n MSs grant national MA after agreement (in 30 days)
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Centralised Procedure
1 Scientific Opinion 1 Commission Decision valid throughout EU
1 Product Information translated into all official EU languagesofficial EU languages
Established since Nov 2005 with entry into force of Reg EC no. 726/2004
Not open to all medicinal products but dedicated to eligible productsNot open to all medicinal products, but dedicated to eligible productsas defined in the legislation (Annex to Regulation EC 726/2004)
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Centralised Procedure - 210 days
D.1 D.120 D.121 D.210
Pre-submissionPrimary
EvaluationClock Stop
SecondaryEvaluation
PostAuthorisationEvaluation Stop Evaluation Authorisation
LoQ AnswersLetter of
Rap/Co-RapDay 80
LoQ Answers
Response -PhVig-Variations
Intent
Rap/Co-Rap CHMP ARDay 80 Assessment
Reports
pAssessment
-Variations-Extensions-Renewal
Pre-submission
i
EPAR
meeting
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Mandatory scope
Art. 3(1) & Annex of Reg (EC) No 726/2004 Medicines derived from biotechnology and other high-tech
processes (e.g. recombinant DNA technology, controlled
( ) g ( ) /
expression of genes, hybridoma and monoclonal antibody methods), including biosimilars
Advanced-therapy medicines Advanced-therapy medicines Medicines intended for the treatment of HIV/AIDS, cancer,
diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases
Designated orphan medicines intended for the treatment of rare diseases. a d a
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A 3(2) f R l i (EC) N 726/2004
Optional Scope
Art. 3(2)(a) Art. 3(2)(b)
Art. 3(2) of Regulation (EC) No 726/2004
Significant Innovation
Art. 3(2)(a) Art. 3(2)(b)
New Active Substances
Innovation
Therapeutic &/
Interest of Patients atCommunity &/or
Scientific&/or
Community LevelOR
Technical
“known” AS
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Committee for Medicinal Products for Human UseHuman Use
SAG CVS
SafetyPhVig
Working Parties
SAG diagnostics
CVS
SAG
CHMP ScientificAdvice
Biologics
diagnostics Neurology
Patients and
Advice
Quality
SAG Diabetes
SAG and Consumers
Quality
SAG HIV / AntiviralSAG
Oncology
+ Ad hoc working partiese.g. Biosimilar Medicinal Products Working Party
Anti-Infectives
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EMA Committees on Human MedicinesEMA Committees on Human Medicines
CHMPCHMP(Committee for Human Medicinal Products)
Members: 1 per Member State + 1 alternate + 5 co-opted MembersNon voting members: ICE/NO
COMP(C i f O h M di i l P d )(Committee for Orphan Medicinal Products)
Members: 1 per Member State + 3 additional Members + 3 Patient OrganisationsNon voting Members: ICE/NO
HMPC (Committee for Herbal Medicinal Products)( )
Members: 1 per Member State + 1 alternate + 5 Co-Opted MembersNon-voting members: ICE/NO
PDCO(Paediatric Committee)
Members: 5 CHMP + 1 per other Member States + 3 HCP + 3 Patient Organisations + 1 alternateMembers: 5 CHMP + 1 per other Member States + 3 HCP + 3 Patient Organisations + 1 alternate per member; Non voting members: ICE/NO
CAT(Committee for Advanced Therapies)
Members: 5 CHMP + 1 per other Member States + 2 Clinicians and 2 Patient Organisations appointed by EC + 1 alternate per member; Non voting members: ICE/NO
PRAC(Pharmacovigilance Risk Assessment Committee ) chick-off July 2012
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Working partiesR l t f bi l i l di i l d t
Biologics working party Biosimilar WP
Relevant for biological medicinal products:
Biologics working party
• Initially established in 1986• Face-to-face meetings 11 times per
year
Biosimilar WP
Blood Products WPyear
• Quality aspects relating to biological and biotechnological medicinal products (including biosimilars)
WP
Vaccine WPbiosimilars)
Working parties’ tasks include:
• Preparation and revision of guidelines• Preparation and revision of guidelines• Provide scientific input to the CHMP and other Committees (e.g. CAT)• Contributing to international co-operation with other regulatory authorities• Liaising with interested parties (e.g. briefing meetings with industry)g p ( g g g y)• Organisation of workshops and trainings (e.g. biosimilar mAbs workshop, immunogenicity
workshop, assessor trainings)
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EMA is not responsible for:p
Assessment of all medicines in EU
Control and advertisement of medicines
R&D f di i
Regulation EC No. 726/2004 – Article 1
“The provisions of this Regulation shall not affect the powers of MS authorities as regards setting the prices of medicinal R&D of medicines
Clinical trial approval
regards setting the prices of medicinal products or their inclusion in the scope of the national health system or social securityschemes on the basis of health, economic and social conditions
Medical devices
P ice and eimb sement
a d soc a co d t o s
In particular, Member States shall be free to choose from the particulars shown in the marketing authorisation those therapeutic i di ti d k i hi h ill b Price and reimbursement
European health policies Price & reimbursement are responsibility of
indications and pack sizes which will be covered by their social security bodies.“
UE member states
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars – principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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Definition of biological medicinal productDirective 2011/83/EC - Annex IDirective 2011/83/EC - Annex I
“(…) A biological medicinal product is a product, the active substance of which is a biological substance.A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control.”
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Heterogeneity – Examples
Extracts from a biological source
Medicinal products developed by biotechnological processes (e.g. recombinant proteins, monoclonal antibodies)antibodies)
Immunological medicinal product (e.g. vaccines, toxins, allergen products)allergen products)
Human blood and plasma-derived (e.g. albumin, coagulating factors, immunoglobulins)g g , g )
Advanced Therapy (ATMP)
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Different level of complexity
Gene Therapy
Simple Chemicals
Proteins, Antibodies
Peptides to 20-30 AA
Vaccines Blood/plasma derived
Cell Therapy
Tissue Eng.
SyntheticSyntheticrDNArDNA
NaturalNatural
Viable Viable llll
Aspirin
NaturalNaturalSourceSource
cellscellsInsulin
Immunoglobulin
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fi i i fDefinition of ATMPReg 1347/2007 and Part IV of Annex I Dir 2001/83/EC
Gene therapymedicinal products
Somatic cell therapymedicinal products
Tissue engineeringproducts
adenovirus mammalian cell cornea transplant
Combined ATMP + Medical Device artificial skin
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Bridging the gapLegislation
Medicinal Products Regulation EC
(No) 1394/2007
MedicalDevices
Legislation
Dir 2001/83/EC(No) 1394/2007
Dir 93/42/EEC
Advanced TherapiesScience
Biologicals
Medical Devices
Pharmaceuticals(e.g. aspirin)
Biotech(e.g. insulin)
Gene Therapy Cell Therapy Tissue Engineering
Expertise
CHMP CAT
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PRODUCTION PROCESS FOR A PRODUCTION PROCESS FOR A BIOTECHNOLOGY PRODUCT
Host CellHost Cell Cell BanksCell Banks FermentationFermentation ReagentsReagents
Genetic MaterialGenetic Material
HarvestingHarvesting ReagentsReagents
Drown StreamProcessing
Drown StreamProcessing ReagentsReagents
Drug Substance
Drug Substance
StorageStorageSubstanceSubstance
Finished Finished StorageStorage ExcipientsExcipientsProductProduct
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The process defines the product
“One process – one product” paradigm
The process defines the product
One process – one product paradigm
Biotechnological medicinal products are ’individuals’
Biotechnological medicinal products are more than the drug substanceBiotechnological medicinal products are more than the drug substance
Small changes can have a high impact- changes in the manufacturig process (e.g. expression system)
- fluctuations in the manufacturing process (e.g. pH, temperature, culture media)
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ProductControl of raw and starting materials Product
Control of i di
Control of intermediatesprocess
parameters
QUALITYQUALITYControl of drug
substance and drug Process
QUALITYQUALITY
Pproductvalidation
& evaluationGood Process manufacturing
Practice
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Ability to Characterise
Simple Ch i l
Proteins, Antibodies
Peptides to 20 30 AA
Vaccines Blood/plasma derived
Cell Therapy
Tissue Eng
Gene Therapy
Chemicals Antibodiesto 20-30 AA derived Tissue Eng.
Fully Fully Characterised Characterised ((e.g. HPLC, ID e.g. HPLC, ID Assay/Purity)Assay/Purity)
Characterisation:Characterisation:many methods, many methods,
includingincluding BioassayBioassay
Physicochemical Physicochemical Characterisation Characterisation
may not be may not be possiblepossibleAssay/Purity)Assay/Purity)
Defined by Defined by S ifi tiS ifi ti
DefinedDefinedDefined byDefined by
SpecificationsSpecifications
possiblepossible
SpecificationsSpecifications by by ProcessProcessSpecificationsSpecificationsand Processand Process
Increasing requirements for Increasing requirements for nonnon--clinical clinical and and clinical dataclinical data
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Potency Assay
Physicochemical tests alone usually insufficient to permit f fprediction of the biological activities Need of appropriate bioassay
or potency assay
Potency:- quantitative measure of the biological activity of the product,
based on the attribute of the product and relevant for its efficacy and safety profile in the patients (ICHQ6B)
- it is a measure of the product activity expressed in terms of the amount required to produce an effect of given intensity
- It is linked to the relevant biological properties of the product- The assay demonstrating the biological activity should be based on the
intended biological effect which should ideally be related to the clinical g yresponse (i.e. predictive of product’s clinical performance)
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28
PURITY PROFILEPURITY PROFILE
desired
PURITY PROFILEPURITY PROFILE
PRODUCTdesired product
PRODUCT RELATED
SUBSTANCES
Peptide Post-translational PROFILEPROFILE 3D-
variants variantsPROFILEPROFILE
degradation PROCESS
structure
PRODUCT degradation PROCESSRELATED
IMPURITIES
PRODUCT RELATED
IMPURITIES
IMPURITY PROFILEIMPURITY PROFILE
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Sources of product variability
Variants: Variants: MOLECULAR MOLECULAR
HETEROGENEITYHETEROGENEITYconformational / clipped / glycosylation / substitutionconformational / clipped / glycosylation / substitutionRelated substances:Related substances:disulfide bond / oxidation / deamidation / aggregationdisulfide bond / oxidation / deamidation / aggregation
Drug substance:Drug substance:
PROCESS PROCESS
Drug substance:Drug substance:host cells and vectors, fermentation conditions, down stream host cells and vectors, fermentation conditions, down stream purification, process Impurities (proteins / DNA), reagents / purification, process Impurities (proteins / DNA), reagents / column leachables, analytical techniques, IPCcolumn leachables, analytical techniques, IPC
VARIABLESVARIABLES Drug products:Drug products:changes to manufacturing Process, excipients, changes to manufacturing Process, excipients, pharmaceutical form, route of administration, analyticalpharmaceutical form, route of administration, analyticalpharmaceutical form, route of administration, analytical pharmaceutical form, route of administration, analytical techniques and IPCtechniques and IPC
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What we know andWhat we know andWhat we don’t know
Information provided in the dossier for review
Information and Information and knowledge within the Company some parts accessible at inspections
30
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars - principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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What is a biosimilar?
Legislation: Article 10(4) of Directive 2001/83/EC as amended
‘Biogenerics’? ‘Biogenerics’? BiosimilarsBiosimilars2001/83/EC, as amended
• Where there are differences, particularly relating to raw materials or manufacturing processes of biosimilar and reference product, then results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided
• The type and quantity of supplementary datato be provided must comply with the relevant criteria stated in Annex I and relevant guidelines
• The results of other tests and trials from the reference medicinal product’s dossier shall not be provided
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Biosimilar Process versus originator
Usually identical
Similar ordifferent
cellspExpression
Usually different
Cloning the gene of interest into an expression vector
Transfer into host cellexpression vector
Different cell growth and
fermentation di i
Usually similar or
conditions
Diff t
same formulation
i
Formulation and filling
Different purification
process
FermentationPurification
Source: Niklas Ekman (fimea)
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Comparability exerciseComparability exercise
• Stepwise head-to-head comparison at the levels of quality, p p q y,safety and efficacy to demonstrate that the biosimilar and the reference medicinal product have similar profiles in terms of quality, safety and efficacy q y y y
• Depending on the similarity on the quality profile, the extent of the non-clinical and clinical testing may be reducedcompared to a stand-alone development
• Any differences in the quality attributes require a i f j ifi i f h i l i li i i h satisfactory justification of the potential implications with
regard to the safety and efficacy of the product
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Dossier requirements for BiosimilarsDossier requirements for Biosimilars
CTD Module Originator Biosimilar
3 Q lit3
Cross reference4
Quality
Non-ClinicalCross reference
5Cross reference
Clinical
Cross reference –class specific
Safety and Efficacy
Integrated Comparability Exercise –product specific
Quality, Safety and Efficacy
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Evolution of Biosimilars in the EUEvolution of Biosimilars in the EULegislation GuidanceOverarching guideline
Directive 2001/83/EC
Directive 2004/27/EC
Quality guidelineNon-clinical/Clinical guideline
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Product-class specific guidelines
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
First biosimilars First biosimilars authorised –
Omnitrope and Valtropin
(somatropin)
First biosimilar epoetinsauthorised
First biosimilar filgrastims authorised
Product evaluation
36
(somatropin)
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Biosimilar MAA Proceduresstatus March 2012
1 Omnitrope (somatropin) Sandoz Authorised
2 Valtropin (somatropin) Biopartners Authorised
3 Alpheon (interferon alfa) Biopartners Negative
4 Binocrit (epoetin alfa) Sandoz Authorised
5 Epoetin alfa Hexal (epoetin alfa) Hexal Authorised
6 Abseamed (epoetin alfa) Medice Authorised
7 Silapo (epoetin zeta) Stada Authorised7 Silapo (epoetin zeta) Stada Authorised
8 Retacrit (epoetin zeta) Hospira Authorised
9 Insulin Marvel Short (human insulin) Marvel Life Sciences Withdrawn
10 Insulin Marvel Intermediate (human insulin) Marvel Life Sciences Withdrawn( )
11 Insulin Marvel Long (human insulin) Marvel Life Sciences Withdrawn
12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorised/Withdrawn p.a.
13 Ratiograstim (filgrastim) Ratiopharm Authorised
14 Biograstim (filgrastim) CT Arzneimittel Authorised
15 Tevagrastim (filgrastim) Teva Authorised
16 Filgrastim Hexal (filgrastim) Hexal Authorised
17 Zarzio (filgrastim) Sandoz Authorised17 Zarzio (filgrastim) Sandoz Authorised
18 Nivestim (filgrastim) Hospira Authorised
19 Epostim (epoetin alfa) Reliance Genemedix Withdrawn
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Challenges for biosimilarsBiosimilars currently licensed are “small biologicals”I i i l th t f bi i il di i l d t li t
Challenges for biosimilars
In principle, the concept of biosimilar medicinal products applies to any biological
Can more complex biologicals (e.g. mAb) be biosimilars?H f ?
How much do we need to know?How far can we go?
How much „similarity“ do we need?
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars – principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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Where to start?
Marketing Authorisation Marketing Authorisation Application Post-authorisation procedures
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1. EMA Scientific guidelineshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cb
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ICH id li ICH guidelines http://www.ich.org
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2. SME Status• Legal basis - Reg (EC) No 2049/2005, Commission Recommendation 2003/361/EC
• Applicants to be designated as ‘SME’ must:pp g- be established in the EU Community- employ less than 250 employees, and- have an annual turnover of not more than €50 million or
an annual balance sheet total of not more than €43 million- an annual balance sheet total of not more than €43 million
• Incentives offered to ‘SME’ companies:- Administrative and procedural assistance from the SME Office at EMAAdministrative and procedural assistance from the SME Office at EMA- Fee reductions for scientific advice, inspections- Deferral of the fee payable for an application for MA or related inspection- Assistance with translations of the product information submitted in MAA
• SME Office at EMA: [email protected]– Facilitate communication between SMEs and EMA
Offers assistance and advise to SMEs – Offers assistance and advise to SMEs – Organise workshops and training sessions
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3. Innovation Task Force Briefing Meeting g g
• EMA multidisciplinary group since 2001
• “Soft landing zone” to establish early dialogue (Briefing Meetings) with sponsors of Emerging Therapies and Technologies (e g advanced therapies)Technologies (e.g. advanced therapies)
• Involvement of Committees and/or Working parties
• Early dialogue with EMA and experts to present the product and get an understanding on EMA proceduresg g p
• Where to find information on EMA website:http://www ema europa eu/ema/index jsp?curl=pages/regulation/general/general content 000334 jsphttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000334.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800ba1d9
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4. Orphan designation
• Legal basis - Reg (EC) No 141/2000 • Committees for Orphan Medicinal Products (COMP) • Orphan designation can be obtained at any stage of
development before Marketing Authorisation no fees – 90 development before Marketing Authorisation no fees – 90 days procedure
• Criteria: – Indication: life threatening or debilitating condition– Epidemiological: prevalence < 5/10.000 in EU
No satisfactory methods exist or significant benefit over – No satisfactory methods exist or significant benefit over authorized products/methods OREconomical: unlikely to generate sufficient return on investment– Economical: unlikely to generate sufficient return on investment
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Orphan Drugs BenefitsOrphan Drugs - Benefits
• 10 years exclusivity from the date of marketing
authorisation
• Free Protocol assistance from the EMA
• Direct access to Centralised Procedure
Fee reductions for MA applications and EMA • Fee reductions for MA applications and EMA
procedures
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5. ATMP specific procedures5. ATMP specific procedures
1. ATMP CLASSIFICATION:- Legal basis: Art 17 of Reg EC No 1394/2007
- Scope: to determine whether a product based on genes, cells or tissues meets the scientific criteria which define ATMPsmeets the scientific criteria which define ATMPs- Optional, 60 days procedure - No fee- Only involves CAT (Committee of Advances Therapy)- Publication of summaries of recommendation on ATMP classification as:
h di i l d– Gene therapy medicinal product – Somatic cell therapy medicinal product – Tissue engineering products– Combined ATMP
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2. CERTIFICATION OF Q and NC data for ATMP by SME
− Legal basis: Art 18 Reg EC no 1394/2007 and Reg EC No 668/2009
− Eligibility: SMEs developing ATMPs
− What is the aim of certification?
- scientific evaluation of early quality and non-clinical data generated with y q y gthe product (Module 3 and 4 only)
- “snapshot” in time of the applicant data with respect to the review standards of an MAAstandards of an MAA
- no advice for further development of the product (not a scientific advice!)
an incentives to SMEs who wish to license out their technology or could be - an incentives to SMEs who wish to license out their technology or could be used to attract venture capital allowing the SME to further develop their product
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6. Scientific Advice /Protocol AssistanceProtocol Assistance
• Legal basis – Art 57.1 Reg (EC) No 726/2004
O i l/ l d bi di f EMA & C b • Optional/voluntary procedure, not binding for EMA & Company, but strong commitment from the CHMP is achieved
• Scope: prospective, no data pre-assessment, generally product specific advice
• SAWP – multidisciplinary expert group:– 28 members appointed by expertise not by Member State, selected based on
complementary scientific competence (pre-clinical, pharmacokinetics, different therapeutic area, statistics)p , )
– 3 COMP, 1 CAT, 1 PDCO
• BWP also involved for the quality part of the advice
• 40/70 days procedure: written procedure/discussion meeting
• Fee incentives:– fee waiver (SMEs) or reduction for orphan products Protocol Assistance
f f d l– fee waiver for paediatric-only– fee reduction SMEs (10 % full fee)
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S i tifi Ad i dScientific Advice procedure
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FAQs SA: Quality, Non-clinical & Clinical
Does the CHMP agree with…
1. Quality/CMC- Proposed potency testing and specificationsfor characterization and release?- Overall approach to show comparability?- Proposed stability protocol?
Biologics WP
Proposed stability protocol?
2. Non-clinical and Clinical- Relevance of the proposed animal models for a product with human specific
( i l d l i i ki h h di )targets (animal models mimicking the human disease)- Carcinogenicity and reprotoxicity study waivers, etc.- Design key features exploratory/pivotal clinical trial?
-endpointsendpoints-definition of patient population (inclusion and exclusion criteria)-comparator-placebo-controlled study design acceptable in this indication?
i l i t l t d b i f l?-single pivotal study as basis for approval?-size of safety database at the time of MAA?
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7. Paediatrics 7. Paediatrics
• Legal basis – Reg (EC) no. 1091/2006
• Improve the health of children:• Improve the health of children:– Avoid the off label use in children of medicines primarily
developed for adultsp
– Increase availability of authorised medicines for children
• Achieve the above: Achieve the above:– Without unnecessary studies in children
– Without delaying authorization for adultsWithout delaying authorization for adults
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Paediatric Investigation Plan (PIP)
• Basis for development and authorisation of a medicinal product for all paediatric medicinal product for all paediatric population subsets
• Includes details of the timing and the measures proposed, to demonstrate:– Quality– Safety
Marketing Authorisation Safety
– Efficacy
• To be agreed upon and/or amendedb th PDCO
Criteria
by the PDCO• Binding on company compliance check
at the time of validation of Marketing gAuthorisation Application (MAA)
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When is a PIP necessary?
RequiredRequired– when applying for a new marketing authorisation– in case of an already authorised and “patented” product, when applying for a new
indication / route / dosage form (but not for new strengths)
Not requiredNot required- Off-patent products already authorised in the EUp p y
- New medicinal products that belong to some specific groups:
- Herbal medicinal products, Homeopathic products, Generic products, Hybrid products biosimilar productsproducts, biosimilar products
- Class-waivers:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000036.jsp&mid=WC0b01ac05801177cd
− for all products in a condition (e g treatment of Alzheimer’s disease)− for all products in a condition (e.g. treatment of Alzheimer s disease)− for a class of products in a condition (e.g. ‘glitazones’ in the treatment of type II diabetes
mellitus)
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When should the PIP be requested?When should the PIP be requested?
MA
Non-clin Phase 1 Phase 2 Phase 3 Post approval
MA
Non-clin Phase 1 Phase 2 Phase 3 Post approval
Paediatric Compliance(PIP Amendments)
Investigation PlanCompliancecheck
Paediatric CommitteePaediatric Committee(PDCO)
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8. What about Clinical Trials?
Legal basis - Directive 2001/20/EC ‘Clinical Trial Directive’
Not under the responsibility of EMA
Responsibility at National level in competent authorities
Not under the responsibility of EMA
European level:
• European Clinical Trial Facilitation Group (Voluntary Harmonisation Procedure (VHP) for assessment of multinational Harmonisation Procedure (VHP) for assessment of multinational clinical trials)
• National experts at the level of Committes and Working Parties
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• Harmonization of scientific requirements at EU and international level (EMA/ICH guidelines)
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9. Marketing Authorisation Application
Common
Application
Module 1Regional
Information
Module 1Common Technical Document
Introduction 2.2
1.0Document
Module 2QualityOverall
Summary2.3
Non clinicalOverview
and Summary2 4 -2 6
ClinicalOverview
and Summary2 5-2 7
Module 2
2.4 -2.6 2.5 2.7
Module 3 Module 4
Non clinical
Module 5
ClinicalQuality
3.0
Non clinicalStudy Reports
4.0
ClinicalStudy Reports
5.058
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Assessment procedureDay 180 List of OutstandingDay 180 List of Outstanding
Issues (LoOI)*CHMP
AREPAR
Clock Stop*
Day 120 List of Questions (LoQ)
Pre-sub-mission Primary Evaluation Clock
Stop Secondary Evaluation
D
Day 1 Day 120 day 121 Day 180 Day 181 Day 210Answers
Scientific Advice
Rap/Co-Rap
Decision M
Proces
Validation
Day 150 Joint Assessment Report Rap/Co Rap aking
ss
Day 80 Assessment Reports from each Rapporteur
from Rapporteurs
*optional
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Product team
Co-RapporteurRapporteur
SA/ODInspection
GMP/GLP/GCP
Co Rapporteur
PTM
PTLPaediatric
PTMQuality or
Safety/Efficacy
PTMRegulatory
Affairs Administrative
Risk management
Affairs AdministrativeAssistant
APPLICANT
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EPAREPAREuropean Public Assessment Report
Summary all readers
PresentationsPackage Leaflet
S f
all readers
patients PRODUCT
Summary ofProduct Characteristics
Labelling pharmacists/patients
health professionals INFORMATION
Scientific discussion
Steps taken before authorisation
gscientific community /health professionals
of the product
Steps taken after granting the Marketing Authorisation (if applicable)
anyone interested
= available in all EU languages
the Marketing Authorisation (if applicable)
= available in English
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CHMP AR / EPAR
• Overview of the CHMP discussion
• Concise document which provides the scientific rationale on which the CHMP has based its opinionp
• Substantiation of the statements made in the different sections in the SmPC so that consistency between these two ydocuments is reached
• Description of key issues identified during the review / p y g /authorisation (e.g. major objections)
• Deletion of confidential information: from the CHMP AR to the EPAR
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General information to the public
Name, INN, therapeutic area, MAH
SmPC, Labelling, Package leaflet, SmPC, Labelling, Package leaflet, Presentations, Manufacturers (MAH, AS),
Conditions to the MA
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Biologicals – authorised via CPupdate March 2011update March 2011
16 Insulins & analogues15 Hormones 15 Hormones
14 Growth factor /citokines8 IFNs
9 Coagulation factors/ fibrinolitics5 EPOs
8 Other enzymes
1995 – 20th March 2012: 168 biologic products approved 8 negative opinions
20 withdrawal in pre-authorisation28 withdrawals in post-authorisation
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10. Post Authorisation ProceduresL l b i V i ti R l ti EC N 1234/2008 Legal basis - Variation Regulation EC No. 1234/2008
Changes not requiring Changes requiringg q gany prior approval
g q gprior approval
Type IAIN Type IIType IB ExtensionType IA
VariationsDo and tell
RISK
Evaluation Procedure adapted to the level of risk t Q lit S f t d Effi
RISK
to Quality Safety and Efficacy
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Grouping and Worksharing
If different related variations are ff i h d (MA)affecting the same product (MA)
The changes may be combined in one application: one application:
GROUPING
The changes may be combined
If the same change is affecting several products (MAs) of the same MAH
The changes may be combined in one application:
WORKSHARING
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Main changes introduced in Variation Classification Guideline - BiologicalsClassification Guideline - Biologicals
Quality changes - BiologicalsQuality changes Biologicals
• Downgrade changes where possible (e.g. Type II to IB)
C bilit d t ff f d di d• Comparability used as a cut-off for downgrading procedures
• Changes to PMFs/ VAMFs included in the Guideline for the first itime
• New concepts (applicable both to CHE and BIO):
e.g. Post approval Change Management Protocols
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AgendaAgenda
Introduction to the European Regulatory NetworkIntroduction to the European Regulatory Network
Overview on biologicals – different level of complexityOverview on biologicals different level of complexity
Biosimilars – principles and challengesos a s p c p es a d c a e ges
Marketing Authorization for biologicals in EUg g
Conclusions
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Preclinical Clinical Development MAA P t
Drug Development Overview
Discovery ChemistryPreclinicalDevelopment
Clinical Development
Phase I Phase II Phase III
MAAevaluation
Post marketing
EMA guidelines
SME Status
Briefing Meeting ITF
EMA guidelines
Orphan Designation
Scientific Advice/Protocol Assistance
Briefing Meeting ITF
PIP Submission
Scientific Advice/Protocol Assistance
ATMP classification
MAA Submission
Clinical trialsCertification of Q / NC data for ATMP
Post-authorisation
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In conclusion
Development
Regulations
Research – Discoveries
New technologies
Long term follow-up on g psafety & efficacy
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Acknowledgments
P. Richardson - Head of Section Biologicals Quality of Medicines EMAP. Richardson Head of Section Biologicals, Quality of Medicines, EMA
K. Tiitso – Scientific Administrator, Quality of Medicines, EMA
A Ganan – Scientific Administrator Quality of Medicines EMAA. Ganan Scientific Administrator, Quality of Medicines, EMA
N. Gate - Scientific Administrator, Quality of Medicines, EMA
P Celis – Scientific Administrator CAT Secretariat EMAP. Celis Scientific Administrator, CAT Secretariat, EMA
V. Jekerle – Scientific Administrator, Quality of Medicines, EMA
P Tomasi – Head of Section Paediatrics EMAP. Tomasi Head of Section, Paediatrics, EMA