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Dr. Christa SchröderPaul-Ehrlich-Institut, LangenUnit „European Procedures“
schch@pei.de
Definition and Goals of Drug Regulatory Affairsand Good Regulatory Practice
ZAFES – CurriculumRegulatory Affairs (Module 11)
Dr. Christa Schröder, Paul-Ehrlich-Institut2
Content
§ Information on DRA§ Legislation§ Marketing Authorisation§ Centralised procedure§ Mutual recognition procedure§ Decentralised procedure
§ Variations§ Good Regulatory Practices
2
Dr. Christa Schröder, Paul-Ehrlich-Institut3
Information on DRA
§ Legislation§ Guidelines§ Decisions / statements of key regulators§ Comments / interpretations§ Discussions at trade association meetings
will be found in§ journals (Official Journal of the European Community (EU),
Bundesanzeiger (DE) , Regulatory Affairs Journal)§ databases and§ internet homepages, and is presented at§ meetings
Dr. Christa Schröder, Paul-Ehrlich-Institut4
Regulatory Information published by authorities (1)
§ Official Journal of the EuropeanUnion
The Official Journal is comprisedof two series:
The L series contains EUlegislation includingregulations, directives,decisions, recommendationsand opinions.
The C series contains reports andannouncements including thejudgments of the EuropeanCourt of Justice and the Courtof First Instance.
There is also a supplementary Sseries containing invitations totender.
3
Dr. Christa Schröder, Paul-Ehrlich-Institut5
Regulatory Information published by authorities (2)§ Bundesanzeiger
§ Der Bundesanzeiger ist neben demBundesgesetzblatt ein weiteresVerkündungs- undBekanntmachungsorgan der deutschenBundesbehörden. Es wird vomBundesministerium der Justizherausgegeben. Zusätzlich ist derBundesanzeigerPflichtveröffentlichungsblatt fürgerichtliche und sonstigeBekanntmachungen, für alleHandelsregistereintragungen sowie fürgesetzlich vorgeschriebeneVeröffentlichungen vonJahresabschlüssen undHinterlegungsbekanntmachungen derUnternehmen. In den letzten Jahren wirddie herkömmliche Ausgabe auf Papiermehr und mehr durch den im Internetveröffentlichten elektronischenBundesanzeiger ersetzt. Dabei erfolgenVeröffentlichungen üblicherweise nichtparallel in beiden Formen.
Dr. Christa Schröder, Paul-Ehrlich-Institut6
Regulatory Information published by commercial editors
§ Websites of differentassociations e.g.§ EFPIA - Europ. Fed. Of Pharm.
Industries & associationshttp://www.efpia.org
§ VFA – Verband ForschenderArzneimittelhersteller
http://www.vfa.de
§ BPI - Bundesverband derPharmazeutischen Industrie
http://www.bpi.de
4
Dr. Christa Schröder, Paul-Ehrlich-Institut7
Regulatory Information published by commercial editors
§ Commecial databases e.g.
Dr. Christa Schröder, Paul-Ehrlich-Institut8
Information on DRA
§ Links to Key European Institutions
§ European Commission, Enterprise DG
http://ec.europa.eu/enterprise/pharmaceuticals/index en.htm
§ European Medicines Evaluation Agency EMEA
http://emea.europa.eu/
§ (National) Medicines Authorities in the European Union
http://heads.medagencies.org/
5
Dr. Christa Schröder, Paul-Ehrlich-Institut9
Information on DRA – Mutual Recognition Product Index ofmedicinal products approved through the MRP /DCP procedure
Dr. Christa Schröder, Paul-Ehrlich-Institut10
Website der HMA
6
Dr. Christa Schröder, Paul-Ehrlich-Institut11
Information on DRA - European Public Assessment Report
Dr. Christa Schröder, Paul-Ehrlich-Institut12
Information on DRA – National lists of approved products
§ E.g. Rote Liste (Germany)
7
Dr. Christa Schröder, Paul-Ehrlich-Institut13
Hierachy of the Community texts
Pharmaceutical Law1. Binding Legislation
Regulations (Verordnung) (e.g. 726/2004/EC)directly binding
Directives (Richtlinie)national law (e.g. 2001/83/EC 14. AMG Novelle)
2. Soft law – not legally bindingRecommendations (Council, Parl.)Guidelines (EU Commission, EMEA, CHMP, ICH, WHO)Notice to Apllicants
Dr. Christa Schröder, Paul-Ehrlich-Institut14
Rules Govering Medicinal Products in the EU (Eudralex)
§ Volume 1 – Community legislation§ Volume 2 – The Notice to Applicants (NtA)§ Volume 2A – Procedures for Marketing Authorisation§ Volume 2B – Presentation and content of the application dossier
§ Volume2C – Regulatory Guidelines§ Volume 3 - Guidelines – Quality, safety, efficacy§ Volume 4 - guide to Good Manufacturing Practice for
Medicinal products§ Volume 5-8 – Veterinary issues§ Volume 9 – Pharmacovigilance§ Volume 10 – Good Clinical Practice
8
Dr. Christa Schröder, Paul-Ehrlich-Institut15
Basic Classification of Medicines
§ Medicinal products / Medicinal devices for human orveterinary use
§ New active substances / Generic medicinal Products§ Biological Products / Biotechnology Products§ Immunological Medicinal Products§ Prescription / non-prescription§ Herbal Medicinal Products / Traditional Herbal Medicinal
Products§ Radiopharmaceuticals
Dr. Christa Schröder, Paul-Ehrlich-Institut16
Basic Classification of Medicines
§ Directive 2001/83/EC, Article 1 (2) Medicinal Product§ Any substance or combination of substances presented for treating
or preventing disease in human beings§ Any substance or combination of substances which may be
administered to human beings with a view to making medicaldiagnosis or to restoring, correcting or modifying physiologicalfunctions in human beings
§ Article 2(2) In cases of doubt, where, taking into account all istcharacteristics, a product may fall within the definition of a„medicinal product“ and within the definition of a product coveredby other Community legislation the provisions of this Directive shallapply
9
Dr. Christa Schröder, Paul-Ehrlich-Institut17
Basic Classification of Medicines
Acc. To Directive 2001/83/ECBiological Product§ A biological medicinal product is a product, the active substance of
which is a biological substance§ Produced by or extracted from a biological source§ That needs for its characterization and the determination of ist quality a
combination of physiochemical-biological testing, together with theproduction process and ist control
§ The following shall be considered as biological medicinal products:§ Medicinal products derived from human blood and human plasma as
defined, respectively in paragraphs (4) and (10) of Article 1§ Medicinal products falling within the scope of Part A of the Annex to
Regulation (EEC) No 2309/93§ Advanced therapy medicinal products as defined in Part IV of this Annex
Dr. Christa Schröder, Paul-Ehrlich-Institut18
Basic Classification of MedcinesBiotechnology Product (Annex to Regulation 726/2004/EC)
10
Dr. Christa Schröder, Paul-Ehrlich-Institut19
Marketing Authorisation
Options§ Centralised Procedure
§ Mutual Recognition Procedure
§ Decentralised Procedure
§ National Procedure
NationalDecentralised
CentralisedMutual Recogntion
CENTRALISED PROCEDURE FOR MARKETINGAUTHORISATION APPLICATIONS EVALUATION
11
Dr. Christa Schröder, Paul-Ehrlich-Institut21
§ Article 3(1): “mandatory” scope
§ Article 3(2): “optional” scope
§ (a) new active substance not authorised; or
§ (b) significant therapeutic, scientific or technical innovation or
interests of patients at Community level.
Optional Scope - Regulation (EC) No 726/2004
Dr. Christa Schröder, Paul-Ehrlich-Institut22
Compulsory scope of Centralised procedure/Therapeutic areas
Regulation 2004/726/EC: Medicinal products to be authorised by theCommunity include medicinal products for human use containing a newactive substance which, on the date of entry into force of this Regulation,was not authorised in the Community, for which the therapeuticindication is the treatment of any of the following diseases:
-acquired immune deficiency syndrome-cancer-neurodegenerative disorder-diabetes
and with effect from 20 May 2008:-auto-immune diseases and other immune dysfunctions-viral diseases
12
Dr. Christa Schröder, Paul-Ehrlich-Institut23
Overview of the Centralised ProcedureOverview of the Centralised Procedure
Day 121Day 121 -- 210210
CLOCKSTOP
Pre-submission
Primaryevaluation
Day 0Day 0 -- 120120
Secondary Opinion/Decisionevaluation
Post authorisationActivities
LAUNCH
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut24
CHMPCHMP
Landscape
COMP
Othergroups
13 WPs
Committee for Medicinal Products for Human Use
Committee forOrphan Medicinal Products
Working Parties
7 ScientificAdvisory Groups
Quelle: EMEA
13
Dr. Christa Schröder, Paul-Ehrlich-Institut25
Quality Review of DocumentsQuality Review of Documents
ScientificScientific AdvisoryAdvisoryGroups (Groups (SAGsSAGs))- HIV/ViralHIV/Viral DiseasesDiseases-- AntiAnti--InfectivesInfectives ((notnot HIV)HIV)-- CardiovascularCardiovascular-- CentralCentral NervousNervous SystemSystem-- DiabetesDiabetes && EndocrinologyEndocrinology-- DiagnosticsDiagnostics-- OncologyOncology
+ specific ad+ specific ad--hoc working groups orhoc working groups orsubgroup meetings when neededsubgroup meetings when needed
CHMP Working PartiesCHMP Working Parties
CHMP
Biological WPBiological WP
Safety WPSafety WP
BloodBlood ProductsProducts WPWP
Quality WPQuality WP
EfficacyEfficacy WPWP
PharmacovigilancePharmacovigilanceWPWP
Scientific Advice WPScientific Advice WP
Gene Therapy WPGene Therapy WP-- CellCellbased therapy WPbased therapy WP
Vaccine WPVaccine WP
(Pre(Pre--)clinical WP on comparability)clinical WP on comparability
Paediatric WPPaediatric WP
PharmacogeneticsPharmacogenetics WPWP
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut26
Dossier AssessmentBased on Assessment by Rapp/Co-Rapp
Peer ReviewPrecise and operational format
Reports to CHMPScientificAdvice MAA
•Initial MAA•List of Questions•Prior to Opinion•Possible Oral explanation•Variations•Line Extensions•Referrals
PMFVAMF
Pandemic fluMAA
(future)
MAPost AuthorisationPharmacovigalance
SAWPPossible oralexplanations
+BWPVWPSWPQWP
BWPVEGSAG
•Anti-infectives (not HIV)•Diagnostics•central Nervous System•Cardiovascular•Diabetes / Endocrinology
SWPQWP
BWP VWP PhVWPBWPVWPSWP
Dossier Assessment
Quelle: EMEA
14
Dr. Christa Schröder, Paul-Ehrlich-Institut27
Where to find Information about EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut28
Where to find WP and SAGs information
15
Dr. Christa Schröder, Paul-Ehrlich-Institut29Scientific Advice
- 12 to -36m
Filing strategy/ Confirmation EligibilityInvented name review
- 18m/-12m
-7/-6 mAppointment Rapporteurs +Pre- submission meetings
Orphan Drugdesignation
PrePre--submissionsubmission
PrePre--Submission phaseSubmission phase
-1 mRequest foraccelerated procedure
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut30
SubmissionApplication
Modules 1-5
Acceptabilityof application
D 1D 1Start ofStart of
procedureprocedure
PTL (with relevant PTMs): checkAdministrative partTechnical part (compliance with legal/regulatoryrequirements)Possible interaction with (Co-) rapporteurs todiscuss questions on admissibility
10 workingdays
Submission / Validation PhaseSubmission / Validation Phase
No scientific evaluation at this stageNo scientific evaluation at this stageQuelle: EMEA
16
Dr. Christa Schröder, Paul-Ehrlich-Institut31
Common Technical Document (CTD)Common Technical Document (CTD)
1Regional
AdministrativeInformation
Clinical DataStudy Reports
Quality DataStudy Reports
Nonclinical DataStudy Reports
Raw Data
Modul
e 2Mod
ule 1
NonclinicalOverview
Clinical
Over-view
Qualit
y
Overa
ll Sum
mar
y
NonclinicalSummaries
ClinicalSummary
Not part of CTDe.g Environmentalrisk assessmentOrphanExclusivity, RiskManagementSystem
CTD
2
3 54
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut32
Primary Evaluation PhasePrimary Evaluation Phase
D 112D 112Peer review
Tele-conference
D 1D 1 D 120D 120CHMP consolidated
List of QuestionsApprovability/non-
approvability
StopClock
Applicant
D 80D 80Rapp./Co-rapp AR
CHMPEMEA Applicant
D 100D 100CHMP
comments+ peer
reviewer
Quelle: EMEA
17
Dr. Christa Schröder, Paul-Ehrlich-Institut33
Secondary Evaluation PhaseSecondary Evaluation Phase
OpinionOpinion
D 180D 180Hearing?
D 121D 121 DD 150150Joint Rapp./Co-rapp. AR
D 210D 210Opinion
CHMPEMEA Applicant
D 170D 170Comments
CHMP
Day 181Day 181Hearing
Consensus?Vote?
Benefit
Risk
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut34
Different type of MADifferent type of MAMA under Exceptional CircumstancesMA under Exceptional Circumstances
§ Comprehensive data cannot beprovided (specific situationsforeseen in the legislation)
§ Reviewed annually to reassessthe risk-benefit balance
§ Will not (normally) lead tocompletion of the dossier andbecome a “normal” marketauthorisation
Conditional MAConditional MA
§ positive benefit-risk balance§ comprehensive data likely to be provided§ unmet medical fulfilled§ benefit to public health of immediate
availability outweighs risk inherent –additional data is required
§ Authorisation valid for one year, on arenewable basis
§ Once the pending studies are provided, itcan become a “normal” marketingauthorisation
18
Dr. Christa Schröder, Paul-Ehrlich-Institut35
Accelerated procedureAccelerated procedure
ØØ Scientific opinion in 150 daysScientific opinion in 150 days (instead of 210)(instead of 210)
§ 1st phase similar§ Day 120 Opinion or List of outstanding issues
§ Day 121-150 Oral explanation if applicable + Opinion
Dr. Christa Schröder, Paul-Ehrlich-Institut36
Overview
Medicinal Products for the Community
Scientific AdviceProcedure
Scientific Advice by SAWP
CP: Standard Evaluation orAccelerated Procedure
CHMPOpinion
EC DecisionMA
Conditional ApprovalExceptional Circumstances“Normal” Circumstances
CompassionateUse Procedure
CompassionateUse Procedure
CompassionateUse Procedure
CompassionateUse Procedure
Orphan Medicinal ProductsOrphan Designation
By COMP/ECOrphan Designation
Procedure
Orphan Designationmandatory access to CP
Protocol assistanceby SAWP
Protocol assistanceprocedure
CP
CHMPOpinion
EC DecisionMA
Medicinal Products for outside the community in collaboration with WHOWHO
eligibility Scientific Advice Procedure
ScientificAdvice
by SAWP
WHOeligibility
CP CHMPOpinion
19
Dr. Christa Schröder, Paul-Ehrlich-Institut37
Compassionate Use (Reg 726/2004/EC Art. 14 and Dir2001/83/EC)
§ Supply of an unlicensed medicinal product to patients for
whom no standard alternative therapies are available
§ Usually reserved for the treatment of serious diseases
§ Takes place before or during the assessment procedure for
the granting of a MA and ends with the result of the
procedure
§ Enables innovative drugs to be made available to patients
during the development programme
Dr. Christa Schröder, Paul-Ehrlich-Institut38
Getting a MA for a new medicinal productGetting a MA for a new medicinal product
CHMPOpinion(s) Translation to all other
19 official EuropeanEnglish languages + Bulgarian & Version
Romanian(as signed offby the TransmissionTransmissionCHMPChairman)
day 0day 0 day 27day 27Commission M.S. Applicant(s)
Quelle: EMEA
20
Dr. Christa Schröder, Paul-Ehrlich-Institut39
Summary
authorisedpresentations
Labelling
AuthorisationScientific Basis
Steps taken for the assessmentof the product
Steps taken after grantingthe Marketing Authorisation
Summary of ProductCharacteristics
All readers
All readers
Health professionals
Scientific communityHealth professionals
Pharmacists/patients
Anyone interested
Anyone interested
available in English
available in allEU languages
Package LeafletPatients
== CHMP Assessment Report after deletion of information ofCHMP Assessment Report after deletion of information ofcommercially confidential naturecommercially confidential nature
EPAREPAR -- European Public Assessment ReportEuropean Public Assessment Report
Quelle: EMEA
Dr. Christa Schröder, Paul-Ehrlich-Institut40
European Public Assessment Report
21
Mutual Recognition Procedure
Decentralised procedure
Dr. Christa Schröder, Paul-Ehrlich-Institut42
Scope of MRP/DCP:National Marketing Authorisation - (1)
§ new active substances (if not mandatory for the centralisedprocedure)§ generic medicinal products to national (and centralised)
authorised reference medicinal products (if not abiotechnological medicinal product)§ informed consent§ bibliographic applications (well established use (WEU))
22
Dr. Christa Schröder, Paul-Ehrlich-Institut43
Scope of MRP/DCP:National Marketing Authorisation - (2)
cont.§ line extensions to national authorisations§ known substances in new combination§ homeopathics§ traditional herbal medicinal products
Dr. Christa Schröder, Paul-Ehrlich-Institut44
MRP and DCP
Two routes to receive a MA
1. Mutual recognition procedure (MRP)where the medicinal product has already received in a MS a MA atthe time of application
or
2. Decentralised procedure (DCP)where the medicinal product has not received in a MS a MA at thetime of application
23
Dr. Christa Schröder, Paul-Ehrlich-Institut45
MRP and DCP
Procedures
Dr. Christa Schröder, Paul-Ehrlich-Institut46
Co-Ordination Group for Mutual Recognition and DecentralisedProcedures (CMD)
24
Dr. Christa Schröder, Paul-Ehrlich-Institut47
Discussionbetween all MSs90 days
MARMS
MARMS
MACMS
MACMS
MACMS
MACMS
MARMS
MACMS
MACMS
MRP DCPRMS
CMSsRMSApplicantDossier Dossier
CMSsAR, SPC,PL, label
90 days
Final SPC,PL, label
Draft AR,SPC, PL
Final AR,SPC, PL
Updateof AR
Proposal forchanges (CMSs)
Dossier120 days
Dr. Christa Schröder, Paul-Ehrlich-Institut48
Marketing Authorisation EUMRP§ First application to the Reference
Member State and granting of anational Marketing Authorisation(MA) – Assessment Report (AR)
§ For products with an existingnational MA the RMS has to updatethe AR
§ Identical applications to selectedConcerned Memeber States (CMS)
§ If agreement is reached after 90days – subsequent nationalAuthorisations in the cMS(Authorisation dates different)
§ If no agreement is reached – further60 days negotiation phase in theCoordination Group (CMD)
§ 1 SPC, Package leaflet, labelling;different brand names possible
DCP§ Only possible, if a national MA has
not yet been granted§ Identical applications to be
submitted simultanously to RMSand CMS
§ RMS prepares preliminary draft AR –comments by the cMS
§ RMS distributes Draft AR§ If agreement is reached after 90
days – subsequent nationalAuthorisations in the RMS and CMS(Authorisation dates different)
§ If no agreement is reached – further60 days negotiation phase in theCoordination Group (CMD)
§ 1 SPC, Package leaflet, labelling;different brand names possible
25
Dr. Christa Schröder, Paul-Ehrlich-Institut49
Variations
§ Definition of a Variation
Any amendment to the documentation – which is the legalbasis for the Marketing Authorisátion of the medicinalproduct – archived at the competent authority
Dr. Christa Schröder, Paul-Ehrlich-Institut50
Classification of Variations
Acc to Reg‘s 1085/2003/EC and 1084/2003/EC Annexes
§ Urgent safety restrictions: immediate information of the
EMEA / competent authorities
§ Type IA and IB (minor variations): Notification – Decision by
RMS
§ Type II is an approval procedure e.g. additional therapeutic
indication
§ Extension Application – leads to a Marketing Authorisation
26
Dr. Christa Schröder, Paul-Ehrlich-Institut51
Good Regulatory Practices
Good Regulatory Practices (GRP) can be defined as:
M. Korteweg, EMEA:A quality system to ensure that the users of medicinal
products, the applicants, the regulators are satisfied with thescientific advice, opinions, the establishment of MaximumResidue Levels, inspection and assessment reports andrelated documents, taking into consideration legalrequirements and guidance in order to protect and promotehuman and animal health.
Dr. Christa Schröder, Paul-Ehrlich-Institut52
Good Regulatory Practices in a growing network of authorities
§ 1988 ICH Conference in Japan: harmonisation of technicalrequirements for registration of pharmaceuticals in humanuse
§ Authorities worked more and more together (CTD, exchangeof information, etc) – EU enlargement
§ Implies a common understanding of technical /regulatoryrequirements and consistency in interpretation andapplication whether in the area of assessments, inspectionsor pharmacovigilance
§ Need to ensure quality, consistency in a growing EU –establishment of management systems
27
Dr. Christa Schröder, Paul-Ehrlich-Institut53
Tools
§ Paul-Ehrlich-Institut: Peer Review
§ Medicines Agencies‘ Network: Benchmarking
Dr. Christa Schröder, Paul-Ehrlich-Institut54
§ PEI Peer Review Group: Definition
The PRG is a PEI-internal scientific panel, which bydiscussion of assessment reports…
…widens the scientific basis of decisions made by internal and externalassessors,
…provides assistance in critical / controversial issues....provides access to „regulatory memory“
The Peer Review Group as a tool to drive Good RegulatoryPractice
Quelle: C. Schneider
28
Dr. Christa Schröder, Paul-Ehrlich-Institut55
Regulatory Peer Review – why?
§ Regulatory decisions should include the following principles:
§ Based on science
§ At least for biological and biotechnological medicinal products: Bridging quality –non-clinical – clinical part
§ Consistency with previous regulatory decisions§ …for similar active substances from the same class§ …for active substances based on a similar
mechanism of action§ …for similar clinical indications
§ Requirements for Applicants should be similar
Quelle: C. Schneider
Dr. Christa Schröder, Paul-Ehrlich-Institut56
PRG meeting mandatory if:
PEI is Scientific Advice/Protocol AssistanceCo-ordinator
PEI is (Co-) Rapporteur in centralised procedure
The Peer Review Group as a tool to drive Good RegulatoryPractice
Scope recently extended:
PEI is Reference Member state in a MRP/DC
Referrals if induced by PEI
National Procedures(except certain cases, e.g. not virus-inactivated bloodcomponents for transfusion, parallel imports, )
Quelle: C. Schneider
29
Dr. Christa Schröder, Paul-Ehrlich-Institut57
EU Medicines Network
What isBENCHMARKING
OfEUROPEAN MEDICINES AGENCIES
BEMA?
CompareTo enrich, to learn, to find best practices, which are
(cost)-effective, efficient, feasible
Dr. Christa Schröder, Paul-Ehrlich-Institut58
BEMA - Aim
§ Identify and share best practices across the network of EUand EEA medicines agencies
§ Comparing individual management systems or processeswith the aim of learning from one another
§ Carried out by colleagues from another competent authoritywho are fulfilling the same responsibilities under legislationin different and complementary ways learning fromone another
§ The purpose of BEMA is to enable mutual exchange ofinformation, with a view to introducing improvementmeasures within agencies
30
Dr. Christa Schröder, Paul-Ehrlich-Institut59
Thank you very much!
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