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2015InternationalGoodSubmissionPracticeWorkshoponPharmaceuticals
GoodSubmissionsforMarketingAuthorizationofGenericsinEU‐ ExpectationsfromtheEU
17.‐ 18.September2015GISNTUConventionCenter,Taipei,Taiwan
Peter Bachmann
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Contents
I. The EU – Territory and Rules
II. The EU – Definition of a Generic
III. The EU – Information and Advice
IV. The EU – an Electronic World
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I.The EU
‐ Territory and Rules ‐
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“United in Diversity“
EU / EEAPolitical Union of 28 States
506 Mio inhabitants
24 official languages
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Applicant / Marketing Authorisation Holder
The Applicant / Marketing Authorisation Holder (MAH) has to be a legal body (company) located inside theterritory of
• the EU for a central marketing authorisation• an EEA‐Member State for a national marketingauthorisation
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… European Pharmaceutical Legislation
• Directive 2001/83/EC, as amended (human)• Directive 2001/82/EC, as amended (veterinary)to be transposed into national legislation
therefore• harmonised data requirements and assessment for a marketing authorisation are in force in the EU/EEA
but• prescription status (Rx / OTC)• reimbursement by health insuranceare within the competence of the national states
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… basic principles• no approval „light“ for known active substances, but thesame basic principles are applicable as for a medicinalproduct with a new active substance.
• each application for a marketing authorisation isassessed in line with the principles of
efficacy safety quality
and approved if the benefit‐risk‐ratio is positive
• but the amount of data within the application for a marketing authorisation may differ
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Legal Basis for MAs in the EU/EEA
Article 8 full dossier
Article 10 (1) GenericArticle 10 (3) „Hybrid“
(‚Generic‘ with additional data)Article 10 (4) Biosimilar
Article 10a well established use applicationArticle 10b combination of known constituentsArticle 10c informed consent
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Generic Medicinal Product
• an application according to Article 10 is a deviation from the normal requirements (Article 8(3))
• therefore ‐ and from a legal point of view ‐ an application for a generic marketing authorisation is not a right in its own
• it is an option if all requirements of the legislations as stated in Article 10(1), 10(3) or 10(4) are fulfilled, respectively
• each subarticle of Article 10 is selfstanding – no combinations are possible
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II.The EU
‐ Definition of a Generic ‐
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Generic Medicinal Product ‐ (1)Article 10 (1), first subparagraph
“1. …the applicant shall not be required to provide the results of preclinical tests or clinical trials ...
therefore:• the generic applicant has to provide it’s own pharmaceutical dossier to prove the quality of the (generic) medicinal product
• independent evaluation; no assessment in comparison to the pharmaceutical quality of the reference medicinal product
• no relaxation of any quality requirements
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Active Substance: Quality Dossier
• CompleteModule 3.2. S– AS manufacturer = finished product manufacturer = applicant
– no protection of know‐how necessary/requested
• ASMF– for NCE or known chemical substances,
– not for biological medicinal products
• Certificate of Suitability of the European Directorate for theQuality of Medicines EDQM (CEP)– only for substances with a monograph in the European
Pharmacopoeia & not for biological active substances
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Substances with a monograph in the Ph.Eur. ‐ASMF vs. CEP
Identical requirements for the documentation to besupplied, i.e.
– Demonstration that pharmacopoeial monographis able to detect and determine all impurities
Assessment: Licensing authority ASMFEDQM CEP
… but in fact assessors from the NCAs are doing theassessment in both cases
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CEP (= Certificate of Suitability)
• for an active substance with a Ph. Eur.Monography• show the suitability of the monograph• can replace CTD‐Module 3S• no commercial confidential information is provided to the applicant of the finished medicinal product
• evaluation of the submitted dossier of the active substance– at the EDQM– by assessors of the NCA
• unic CEP numbering system allows traceability
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ASMF ‐ CTD
• The "open" part of the ASMF ‐ included in section 3.2.S ofCTD Module 3
• It is the responsibility of the applicant for a MA for a MP toensure that the complete ASMF
– applicant's ("open") part and
– the active substance manufacturer's restricted("closed") part
is supplied to the authorities directly by the ASM in the CTD format, synchronised to arrive at around the same time asthe MA application.
• Letter of Access to the CA
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Generic Medicinal Product ‐ (1a)
Article 10 (1), first subparagraph
“1. …the applicant shall not be required to provide the results of preclinical tests or clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product …
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Reference Medicinal Product: Definition
Article 10 (2) (a)
“... shall mean a medicinal product authorised under Article 6, in accordance with the provisions of Article 8;”
Article 8 full dossier Article 10a well established use application Article 10b combination of known constituents Article 10c informed consent
EU / EEA
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Routes for a generic application
Generic
central national
central national
Reference Medicinal Product
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Generic Medicinal Product ‐ (1b)Article 10 (1), first subparagraph
“1. …the applicant shall not be required to provide the results of preclinical tests or clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community.”
8 years data exclusivity+ 2 years market exclusivity = 10 yearsbut we don’t care about patents
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Generic Medicinal Product ‐ (2)
Article 10 (2) b: “generic medicinal product”• same qualitative and quantitative composition in active substances
but– the different salts, esters, ethers, isomeres, mixture of isomeres, complexes or derivatives are the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy.
– in such cases additional information of the proof of safety and/or efficiacy of the different salt, … must be supplied by the applicant.
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Generic Medicinal Product ‐ (3)
cont.
– if the different salts, esters, ethers, isomeres, mixture of isomeres, complexes or derivatives are the same active substance differ significantly in properties with regard to safety and/or efficacy.
application according toArticle 10(3) orArticle 8
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Generic Medicinal Product ‐ (4)
Article 10 (2) b: “generic medicinal product”
same qualitative and quantitative composition in active substances
• same pharmaceutical form as the reference medicinal product ‐ but all immediate‐release oral pharmaceutical forms are the same
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… same pharmaceutical form ‐ (1)
Standard Terms (pharmaceutical forms) of the European Pharmcopoeia are applicable by law
– therefore exemption by legislation ‐ but all immediate‐release oral pharmaceutical forms are the same
– consequences for all non‐immediate‐release oral forms e.g. modified release, gastro‐resistant tablets, gastro‐resistant capsules
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Generic Medicinal Product ‐ (5)
Article 10 (2) b: “generic medicinal product”
same qualitative and quantitative composition in active substances
same pharmaceutical form as the reference medicinal product ‐ but all immediate‐release oral pharmaceutical forms are the same
• bioequivalence with the reference medicinal product or waiver of bioequivalence according to guidelines
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Bioequivalence ‐ (1)
• the way to show therapeutic equivalence between the generic and the reference medicinal product
• bioequivalence is the surrogate for efficacy• revised ‘Guideline on the Investigation of Bioequivalence’ in force since 01 August 2010– major shift from clinical to pharmaceutical relevance
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Reference Test
Pharmaceutical EquivalentProducts
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
Bioequivalence ‐ (2)
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Bioequivalence ‐ (3)
Scope of the Guideline• focuses on recommendations for bioequivalence studies for immediate release formulations with systemic action
• sets the relevant criteria under which bioavailability studies– need not be required– are waived for additional strength– are needed for specific formulations– BCS (Biopharmaceutics Classification System) based Biowaiver
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Bioequivalence ‐ (5)
cont. Scope of the Guideline
the limits• guidance on BE‐studies for modified releaseproducts, transdermal products and orally inhaled products are given in other guidelines
• scope is limited to chemical entities• the general principles outlined in this guideline are not applicable to herbal medicinal products
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… if BE can not be shown: ‘Hybrid‘
Article 10(3) of Directive 2001/83/EC“In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis‐à‐vis the reference medicinal product, the results of the appropriate pre‐clinical tests or clinical trials shall be provided.”
“Super-Generics”
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III.The EU
‐ Information and Advice forGeneric ‐
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… for central marketing authorisations – (1)
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… for central marketing authorisations – (2)
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… for national marketing authorisations – (1)
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… for national marketing authorisations – (2)
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Validation of an Application
• Administrative procedure (!) – therefore novalidation of the content of the application
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• Application not received/modules are missing • Proposed MAH not established in the EEA • Missing/incorrect fee• Application form/cover letter not signed/not signed with original signature • The application form is incorrect (eg. information missing, incorrect type of procedure, legal
basis incorrect, incorrect reference medicinal product, reference to an European reference medicinal product although there is a nationally authorised medicinal product)
• Documents in accordance with NtA, vol. 2B are missing or absence not justified (eq. Braille, Consultation with Target Patient Groups, Pharmacovigilance System, Environmental RiskAssessment, Specific Requirements for Different Application Types, Paediatric Regulation(whereapplicable))
• Annexes to the application form are missing or absence not justified (eg Declaration from the QP, TSE certificates for excipients of animal origin)
• Manufacturing licenses, GMP certificates and/or import licenses have not been updated or are missing. Proposed batch releaser is situated outside the EEA
• The comparator for the bioequivalence study does not originate from the EEA • …
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IV.The EU
‐ An Electronic World ‐
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Portals• no problem if submission to one agency only
• pure national submission: single national portal• centralised procedure: eSubmission Gateway
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eSubmission Gateway
Submission Sequence:• Electronic submission of eCTDs via secure Gateway (ESTRI Gateway)• eValidation• technical valid submissions are loaded into the Central Repository
Pharmaceutical Industry
Internet
Secure Gateway
CentralRepository
Validation
European Medicines Agency
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National Portals – to be replaced by ‘CESP‘
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CESP – how it works
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eSubmission Roadmap (reflecting final adopted version 1.0 dated 141107)
2013 2014 2015 2016 2017 2018
Use of eAF in all procedures (human and vet)
Single Submission Portal with integration of eAF
for all submissions (human and vet)
Use of VNeeS in CP, DCP and MRP (vet)
All submissions in CP, DCP and MRP (human) in
eCTD
Ongoing/optionalMandatory
Use of eCTD v.4
CESP (human and vet)
eGateway (CP)(human and vet)
eGateway (CP, human)
NCA use of Common Repository for all CP submissions(human)
All submissions in CP, DCP and MRP (vet) in VNeeS
NCA use of Common Repository for CP submissions (human)
Single submission portal - combined CESP/Gatewayin all other procedures (human and vet)
Use of NeeS and eCTD in DCP and MRP (human)
in CP
New MAA in DCP (human) in eCTD
All submissions in MRP (human)
New MAA in DCP and MRP (human) in eCTD
All other in CP and all MRP submissions (vet)
New MAA in CP and DCP (vet) in VNeeS
All other MRP submissions (human)
eAF in all procedures (human and vet)
All submissions in CP (human) in eCTD
Use of PSUR Repository for all CAPs and NAPs(human)
Use of PSUR Repository for CAPs and NAPs (human)
draft eSub
Roadmap
NCA & industry survey
eSub RoadmapAdoption
Single submission portal - combined CESP/Gatewayin CP (human)
in all other procedures
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Electronic Application Form (eAF)
eCTD
3. Quality 5. Clinical1. Regional
EU Module 1 (version 1.4) Cover letter Comprehensive table of contents Application form Product information Information about experts Specific requirements for different types of application Environmental risk assessment Information relating to orphan market exclusivity– …….
eAF
4. Non-clinical
2. Summaries
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ContactFederal Institute for Drugs and Medical DevicesExecutive Department ‘European and International Affairs’Kurt‐Georg‐Kiesinger‐Allee 3D‐53175 Bonn
Contact personPeter [email protected]. +49 (0)228 99 307 4163Fax +49 (0)228 99 307 3452
Thankyouverymuchforyourattention!
