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8/10/2019 EWU PHRM 410 Lecture Slide 1.pdf
1/20
HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 1
Safeguarding public health
Drug regulation andlicensing
Mohammad Kawsar Sharif Siam
Lecturer, DOP, EWU
Slide 2
Overview
What makes a Medicinal Product
How a medicine is licensed in the
EU
Lifecycle of a Medicine
After the presentation you should be
able to:
Describe the key types of regulatory
involvement for a new medicinal
product
Describe the type of informationrequired to obtain a Marketing
Authorisation
Discuss the ways in which a product
may be developed after a Marketing
Authorisation is granted
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
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Slide 3
Medicinal ProductActive substance (API)
Excipients
Dosage form
Packaging
Product Information
Product name Label/PIL SPC or SmPC
What is a Medicinal product?
Brand vs Generic
Brand = innovator product,
eg Panadol tablets (GSK)
Generic = copy of active
substance and dosage formof Brand product,
eg Paracetamol tablets(Boots, Tesco, Asda)
Slide 4
Types of Regulation
Quality
Safety
Efficacy
Value for money
Compliance
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 3
Slide 5
Value for money
Is the medicine cost effective ?
Cost vs Benefit
Health Technology assessments
National Institute for Health and Clinical Excellence
(NICE)
Scottish Medicines Consortium
Pricing authorities
Slide 6
Quality, safety & efficacy
is the medicine well made?is the medicine safe for intended use?does the medicine work for intended use?
Risk vs benefit
Medicines Regulatory Agencies - Assessors
is the organisation complying with the relevant rules?
Medicines Regulatory Agencies - Inspectors
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 4
Slide 7
Major Regulatory Agencies
USA Food and Drug Administration (FDA)Japan Ministry of Health and Welfare
Canada Health Products & Food BranchAustralia Therapeutic Goods AdministrationChina SFDA
EU European Medicines Agency (EMA)
National Competent Authorities (NCA)
MHRA (UK)Afssaps (FR)
BfArM (DE)
Slide 8
MEDICINES CONTROL IN EU
Human Medicines: vaccines, toxins or serum blood
products, radio pharmaceuticals, herbals, homeopathic
Medicinal Devices
Veterinary Medicines
Feed Additives
8/10/2019 EWU PHRM 410 Lecture Slide 1.pdf
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 5
Slide 9
Current EU pharmaceutical legislation
Comprises:
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March2004 laying down Community procedures for the authorisation and supervision ofmedicinal products for human and veterinary use and establishing a European MedicinesAgency.
Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004amending Directive 2001/83/EC on the Community code relating to medicinal products forhuman use.
Directive 2004/24/EC of the European Parliament and the Council of 31 March 2004amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on theCommunity code relating to medicinal products for human use.
The consolidated Directive 2001/83/EC of the European Parliament and of the Council of6 November 2001 on the Community code relating to medicinal products for human use asamended by Directive 2002/98/EC, Directive 2004/24/EC and Directive 2004/27/EC
Regulation (EC) No 1234/2008 of the European Parliament and of the Council of 24November 2008 concerning the examination of variations to the terms of marketing
authorisations of medicinal products for human and veterinary use (the variations regulation)
Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15December 2010 amending, as regards pharmacovigilance procedures for theauthorisation and supervision of medicinal products for human and veterinary use (the newpharmacovigilance regulation - entry into force July 2012)
Slide 10
Developing a new medicine
Pre-clinical Phase 1 Phase 2 Phase 3Life cycle
management
Discovery:
Identification of
target
active
Development:
Chemistry
Toxicology
Animal models
Early human
exposure:
Safety in
humanvolunteers
PK
Pharmaceutical development
Clinical trials
Proof of concept
Dose finding
Proof of efficacy
Common side
effects
MA Approval
MA
application
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 6
Slide 11
Life cyclemanagement
Developing a new medicine Regulatory
involvement
MAapplication
Pre-clinical Phase 1 Phase 2 Phase 3
Pharmaceutical development
Clinical trials
Rationale
Dosing regimen
Safety Investigations
Manufacture
Scientific advice
InspectionsGLP GCP GMP GPV
MA Approval
Clinical Trial ApplicationProduct Licence
Product Information
Dosage form
Packaging
Manufacture & Supply
Pharmacovigilance
Slide 12
Clinical Trial Applications
Governed by Clinical Trial Directive (Directive 2001/20/EC)- Published April 2001; Implemented by May 2004
Need authorisation for commencing or conducting a clinical trial,- authorised by the NCA- has a favourable opinion by an ethics committee.
Assessment by NCAs:- Is the existing safety knowledge of a new drug sufficient to proceed
with a new trial- is the trial designed so that it will capture new safety signals/adverse
events/side effects- Is the drug manufactured appropriately
Risks (of trial) vs benefit (of new knowledge)
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
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Pre-clinical Phase 1 Phase 2 Phase 3
Discovery:
Identification of
target
active
Development:
Chemistry
Toxicology
Animal models
Early human
exposure:
Safety in
human
volunteers
PK
Clinical trials
Proof of concept
Dose finding
Proof of efficacy
Common side
effects
MAapplication
Obtaining a Marketing Authorisation -
what is assessed?
Slide 14
Modules
1
2
3
4
5
Dossier - CTD
MA internal database
Production/Control sites
Manufacturer/QC/batch release Distribution
Ownership
- responsibility (MAH/contractor)
Product Information
Product name Label/PIL SPC
Obtaining a Marketing Authorisation -
what else is assessed?
Medicinal ProductActive
Excipients
Dosage form
Packaging
8/10/2019 EWU PHRM 410 Lecture Slide 1.pdf
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 8
Slide 15
M4 - Non-clinical:are there any seriousunwanted effects in
animals of relevance
to humans?
M3 - Quality:Is the product well
made?
M5 - Clinical:
Pharmacology, safety,efficacy (statistical)
is the medicine safe for
intended use?
does the medicine work forintended use?
Slide 16
What is assessed (Quality, Efficacy, Safety):
Pharmaceutical (Module 3): How is the active substance and product made ? How long is it stable ? (shelf life) Does it need to be kept cold? (Storage conditions)
Non-clinical (Module 4): Does it have any serious unwanted effects in animals of relevance to humans?
Pharmacological (Module 5):
Where does the active act in the body? How long does it stay in the body? How is it removed from the body? Are there any relevant drug-drug interactions ?
Clinical (Module 5 Efficacy, Safety): Does it treat the condition it will be indicated for ? Has the right dose been chosen ? Does it have any serious unwanted effects ? (side effects) Have the right patients been studied? Is it likely to work in a wider group of patients ?
Statistical (all, particularly Module 5): Have they studied enough patients to draw these conclusions? Can the results be explained by chance or other reasons? How did they cope with missing data?
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awsar Sharif Siam, DOP, EWU
MKSS 9
Slide 17
Summary of Product Charactaristics (SmPC or
SPC)
Defines the licensed use of a product:
provides information for prescribers on how to use the medicinal product safelyand effectively- what the medicine is used for and by which patients (indications)- Dose & how often it should be taken (posology)- When not to use (contraindications)- Things to be aware of to maximise safe use of the product (warnings &
precautions, interactions, use during pregnancy etc)- Known side effects
Provides the information that should be included in the Patient InformationLeaflet- Lay translation- Rules on presentation (font size, readability etc)
Limits the advertising claims for a product
Slide 18
Summary of Product Charactaristics (SmPC)
8/10/2019 EWU PHRM 410 Lecture Slide 1.pdf
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HRM 410 Lecture 1: Mohammad
awsar Sharif Siam, DOP, EWU
MKSS 10
Slide 19
Other Regulatory requirements
Identifying and managing risk:
- Pharmacovigilance system
- Risk Management Plan
- (Risk minimisation measures)
Paediatric Investigation Plan
- Needs according to age bands
- Obligatory, deferral or waiver
Advertising / educational materials pre-vetting
Slide 20
Application assessment process
Assessment
Application
submitted
MAH
response
AR RFI
LOQ
consultation
Assessment
ARFinal Decision
consultation
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awsar Sharif Siam, DOP, EWU
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Slide 21
European licensing routes to obtain
Marketing Authorisation for humanmedicines
National
- Single Member State
- ie MA only valid in that MS
Mutual Recognition / Decentralised
- Selected Member States
- Can withdraw from individual MS
Centralised
- All Member States
- Compulsory route for certain product types and therapeutic areas
Slide 22
National MR / DCP Centralised
Submission NCA RMS + CMS EMA
Assessment NCA RMSon behalf of CMS
Rapporteur (NCA)
Co-Rapporteur(NCA)
ConsultationExternal
Expert(s)CMSs CHMP (MSs)
Communicationwith applicant
NCARMS
on behalf of CMSEMA
Licence issuer NCA RMS + CMS NCAsEU Commision
EMA
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awsar Sharif Siam, DOP, EWU
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Slide 23
UK External Advice
Commission on Human Medicines (CHM) Independent experts appointed by Ministers established 2005 (replaced Medicines Commission & CSM)
Expert Advisory Groups- Chemistry, Pharmacy & Standards EAG- Pharmacovigilance EAG- Clinical Trials EAG- Paediatric Medicines EAG- Patient & Public engagement EAG
- Therapeutic area EAGs:- Biologicals & Vaccines EAG
- Cardiovascular, Diabetes & Renal, Respiratory & Allergy- Gastroenterology, Rheumatology, Immunology & Dermatology- Medicines for Womens Health- Neurology, Pain & Psychiatry- Oncology & Haematology
Slide 24
Quality WorkingParty
European Expertise
Scientific AdviceWorking Party
European Experts List
CHMP COMP
PDCO
Temporary WPsSafety Working
Party
Efficacy
Working Party
Scientific
Advisory Group
Biologicals
Working Party
Source EMA
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awsar Sharif Siam, DOP, EWU
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Slide 25
Co-ordination group for Mutual Recognition and
Decentralised Procedures (CMDh)
Responsible for smooth functioning of MRP + DCP (scientific
and regulatory)
- any question related to MAs in more than one M/S
- Rules of Procedure
- Transparency
Avoid referrals to CHMP
Ensure consistency of standards
Good quality decisions for Public Health
Harmonisation of SPCs
Harmonised view on interpretation of legal framework
Regulatory memory
Variations grouping
Slide 26
Lifecycle management what happens after MA grant?
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awsar Sharif Siam, DOP, EWU
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Slide 27
Medicinal ProductAPI
Excipients
Dosage form
Packaging
Modules1
2
3
4
5
Dossier - CTD
Product Information
Product name Label/PIL SPC
Production/Control sites
Manufacturer/QC/batch release Distribution
Ownership
- responsibility (MAH/contractor)
MA internal database
Marketing Authorisations - need for change
Slide 28
Types of Variation
Type IA Type II
Evaluation Procedure adapted to the level of risk
Changes not requiring
any prior approval
Changes requiring
prior approval
Type IB ExtensionDesignSpace
Variations
Do & tell Tell, wait & doNo submissionreqd if within
an approved
design space
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awsar Sharif Siam, DOP, EWU
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Slide 29
Lifecycle management
New uses
(Medical variations)New safety data
(Medical variations)
Changes in production(Pharmaceutical variations)
Pharmacy/GSL
availability
(legal status
reclassification) Periodic review
(PSURs & Renewals)
Article 61(3)
(Label & leaflet changes)
Slide 30
The Yellow Card SchemeThe Yellow Card Scheme Reports submitted in
confidence by:
- Any health professional
- Patients and their
representatives
Reports from pharmaceutical
companies legal obligations
~22,000 reports received
annually
More than 600,000 UK
reports received to date
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awsar Sharif Siam, DOP, EWU
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Black Triangle SchemeBlack Triangle Scheme Intensive monitoring scheme for new products where
knowledge of risk benefit profile is limited Report all reactions for medicine, including non-serious
Black triangle symbol printed next to product name in
BNF, SmPC, advertising material, etc.
assigned to:
New active substances
Established active substances if product:
Contains a new combination of active substances Is administered by a novel route or dug delivery
system
Is for significant new indication which may alter
the risk benefit profile of the substance
Slide 32
Reasons for adding a Black TriangleReasons for adding a Black Triangle
New Formulation e.g. Requip XL (ropinirole)
New Combination e.g. Competact (pioglitazone &metformin)
New Indication e.g. Viread (Tenofovir Disoproxil forChronic Hepatitis B)
New route of administration e.g. Hycamtin (oral topotecan)
New Delivery System e.g. NuvaRing (ethinylestradiol &etonogestrel)
Reformulation in view of the risk of medication error e.g.NovoSeven (recombinant factor VIIa)
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awsar Sharif Siam, DOP, EWU
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Slide 34
Meaning of scientific data
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awsar Sharif Siam, DOP, EWU
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Slide 35
Periodic Reviews
Focus on safety
PSURs (Periodic Safety Update Reports)
- Safety of New Products reviewed frequently
- Less frequent reviews as safety becomes known
Renewal
- after 5 yrs of grant of MA, then unlimited validity
Community referrals- Resolve differences between MAs for similar products
(different Member States)
- Review Serious public health issues
Slide 36
Pharmacy/GSL
availability
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awsar Sharif Siam, DOP, EWU
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Any questions?
Slide 38
Crown copyright 2011
The materials featured within this MHRA presentation are subject to Crowncopyright protection. Any other copy or use of Crown copyright materialsfeatured in this presentation, in any form or medium, is subject to priorapproval of the MHRA which has Delegated Authority from Her Majesty'sStationery Office (HMSO) to administer Crown copyright for MHRAoriginated material. Applications should be in writing, clearly stating the
proposed use/reuse of the information, and should be sent to the MHRA atthe following address: Conference and Education Function, MHRA, 151Buckingham Palace Road, Victoria, London SW1W 9SZ. or e-mailspeakers@mhra.gsi.gov.uk. You may not sell or resell any informationreproduced to any third party without prior agreement. The permission toreproduce Crown copyright protected material does not extend to anymaterial in this pack which is subject to a separate licence or is thecopyright of a third party. Authorisation to reproduce such material must beobtained from the copyright holders concerned.
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awsar Sharif Siam, DOP, EWU
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Useful links
EMEA: http://www.ema.europa.eu/emaEudraLex* - The Rules Governing Medicinal Products in the European Unionhttp://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
CMDh / Heads of Medicines Agencies http://www.hma.eu/
MHRA http://www.mhra.gov.uk/index.htm
FDA Legal framework:
http://www.fda.gov/
ICH: www.ich.org
eMC: http://www.medicines.org.uk/emc