the european regulatory network benefit/risk evaluation of
TRANSCRIPT
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The European Regulatory
Network
Benefit/risk evaluation of
medicines during their life
cycle
Tamás L. Paál Professor emeritus
retired Head of the Hungarian medicines regulatory agency
CEMDC PharmaTrain Module 1a
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Apology
• This is an introductory lecture outlining
the importance of regulatory affairs and
its professionals in medicine research
and development as well as in their life-
cycle management
• Its all important parts will be dealt with
by other lecturers in detail
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Acronyms used in this lecture
• ADR adverse drug reaction
• AR assessment report
• BE bioequivalence
• CAT committee of advanced therapy medicinal products
• CHMP committee on human medicinal products
• COMP committee of orphan medicinal products
• CVMP committee of veterinary medicinal products
• CMDh coordination group (human medicines)
• CMDv coordination group (veterinary medicines)
CMS concerned member state
CP centralised procedure
CT clinical trial
CTD common technical document
DE data exclusivity
DHPC „Dear Health-care
professional communication”
DP decentralised procedure
EEA European Economic Area
EC European Commission
EMA European Medicines Agency
EU European Union
GCP good clinical practice
GLP good laboratory practice
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Acronyms used in this lecture
• HMA Heads of medicines agencies
• HMPC committee of herbal medicinal products
• MA marketing authorisation
• MP medicinal product
• MRP mutual recognition procedure
• NCA national competent authority
• NP non-prescription medicine
• PAES post-approval efficacy study
• PASS post-approval safety study
• PDCO paediatric committee
• Ph. Eur. European pharmacopoeia
• PIL patient information (package) leaflet
• POM presription-only medicine
• PRAC pharmacovigilance risk assessment committee
• PSUR periodic safety update report
• PV pharmacovigilance
• PVMF pharmacovigilance master file
• QPPV pharmacovigilance qualified person
• RAP regulatory affairs professional
• R&D research and development
• RMS reference member state
• RMP risk-management plan
• SmPC Summary of Product Characteristics
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Topics
• Medicine R&D and regulatory affairs
• Classical authorisation – pre-authorisation
– submission • EU authorisation procedures
– assessment and scientific advice • the EU Drug Regulatory Authority system, EMA
• The future: adaptive licensing
• Post-marketing regulatory supervision – quality defects
– pharmacovigilance
– regulatory control of info provided by industry
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The aim of medicine R&D 1/2
• The obvious answer: new medicines to treat
patients to answer unmet medical needs!
• But it may only be valid for teams in the
Pharma industry!
• Partly! What about
– generic medicines
– new presentations of well-established medicines
(Ascorbic acid, Vitamin C)
– new dosage-forms (transdermal patches)
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The aim of medicine R&D 2/2
• The obvious answer: „new medicines to treat patients to answer unmet medical needs!”
• But even less obvious for academic research: chemists, pharmacists or pharmacologists or clinicians working more-or-less in isolation…
• only part of the R&D with different actual (foreseen) aim: dissertation, publication – „biologically active substances are those that,
when administered to experimental animals, result in a publication…”
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Medicine authorisation and
academic R&D
• Actual aim: completing a study and writing report/publication versus authorised medicinal product as soon as possible
• Rules, issues taken into account: the Art of the science versus minimum set of tests/studies, their sequence and timing, compilation of data (=regulatory affairs)
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What are regulatory affairs?
I have so much data! How
to present them for
medicine authorisation?
regulatory
affairs
professional
I
know!
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What are regulatory affairs?
I have so much data! How
to present them for
medicine authorisation?
regulatory
affairs
professional
I
know!
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What are regulatory affairs?
I have so much data! How
to present them for
medicine authorisation?
regulatory
affairs
professional
I
know!
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Regulatory affairs
• It is not true that more and more data generated with a biological active substance and its potential dosage-forms „will automatically be compiled” to permit its marketing authorisation
• The opposite is true: selecting the more appropriate marketing authorisation route determines the set, sequence and timing of data to be generated!
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„Classical” medicine
authorisation
• i.e. all the data incl. clinical trials
needed for the (planned) claimed
indications accomplished
• The role of the Firm’s regulatory affairs
professionals:
– during generation of the data
– when the dossier for marketing
authorisation is compiled
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During generation of data
(Firm’s regulatory affairs professionals RAPs
are ideally involved in)
• development strategy according to the
prospective MA legal base and MA route
• conduct of the research (only what is
needed, according to the relevant guidelines,
sequence and timing)
• interim evaluation (from the point of view of
the prospective MA dossier)
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Development strategy: selecting the
legal basis referring to the Community code
2001/83/EC
•full application (Art. 8(3), own results exclusively)
•bibliographic application (Art. 10a, well-established use, 10+
years, min. 1 good CT)
•mixed application (Annex 1, 7. mixture of the former two
•generic application (Art. 10(1), DE expired, Patent? BE needed…
•hybrid application (Art. 10(3), non-generic with or without BE
•fixed combination (Art. 10b, new, „not hitherto used”
•Variation of an existing MA (Commission Regulation 1234/2008/EC)
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Development strategy: selecting
MA route
Where are the expected markets?
• Decentralised Procedure (RMS? CMSs? – consensus possible)
• National in 1 MS than Mutual Recog-nition Procedure (CMSs? – risk of referral)
• Centralised Procedure (EEA-wide MA but higher cost, SmPC-PIL-label in all languages…)
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Note: marketing authorisation
routes in the EU
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Marketing authorisation
procedures in the EU
• Involving one single member
state: national NP
• Community
– Involving all member states:
Centralised CP
– Involving two/several member
states:
• Mutual recognition MRP
• Decentralised DP
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National application
• When the Firm wants to market a
product in one member state
exclusively
• Line-extensions of former national
applications
• Can always be turned to an MRP!
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Centralised MA procedure
• Mandatory: products of biotech
substances, HIV/AIDS, cancer, diabetes,
neurodegenerative diseases, orphan
drugs (5:100,000), advanced therapy
(gene, somatic cell- and tissue therapy)
products
• Possible:
new active substances
“high-tech products”
new, “important” indication
blood products
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Centralised procedure
• One single application to EMA, London
• Committee assessment (2 rapporteurs from MSs
then vote)
• 210 days dead-line, then EMA issues Accompanying
Sheets (SmPC, PIL) and Assessment Report AR in all
languages
• MSs: 15-day possibility for „serious risk to public
health” appeal (Standing Committee procedure)
• Then signature by the EC in Brussels: MA valid for
the whole EU
• If negative: banned for the whole EU!
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Mutual recognition
• (When the product has already been
authorised for marketing in at least one
MS)
• The Firm requests an AR (in English) from
that NCA (it is the RMS then)
• It, together with the full documentation
submitted to CMSs asking a „recognition”
of the AR (time-frames!)
• Opposing opinions: appeal (see CP, the
decision is binding)
• Any variations: similar procedure
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Decentralised procedure
• New product with no existing MA in the
EEA
• Possible: any product for which CP is
not mandatory
• “Referens MS (DRA)”, RMS where the
NCA makes the first assessment
(chosen by the Applicant) and
• Concerned MS (DRA) CMS
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Decentralised procedure
• Application dossiers sent to RMS and CMSs, validation
• RMS: preliminary MA issued (time-frame!), SmPC, PIL, label and AR (in English)
• Discussion with to CMSs = final MA = harmonised national MAs in RMS and all CMSs
• Opposing opinions: appeal (see CP)
• Any variations: similar procedure
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Back to the conduct of R&D: the
role of Firm’s RAPs
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Conduct of research
Explain direct and indirect „hard law” plus „soft law” („researchers tend to follow the more recent literature…)
• direct hard law: you must do that (e.g. GLP, GCP, Ph. Eur.)
• indirect hard law: do what you like but you must submit your (MA) request in the following structured way (if something missing it needs a good expla-nation) (e.g. CTD, content of a MA dossier Annex 1)
• soft law: official guidelines: „quasi-mandatory”: do not ignore them without a good reason and explanation…
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Hierarchy of official (scientific)
guidelines („soft law”)
– EMA CHMP
• Quality 61 (+ 28 Q/A)
• Non-Clinical 55 (+ 3 Q/A)
• Clinical 169 (+ numerous Core SmPCs + many
Concept Papers)
• Multidisciplinary 8 (+ many Q/A)
– ICH
– Other consensus materials
– The scientific literature…
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Regulation of R&D
Law, direct
Soft law, direct
Indirect by law
API, chem.-
pharm.
Synthesis
Manuf.
Quality
Stability
API, animal
Pharmacology
Toxicology
Medicinal product
Dosage-form
Manuf.
Quality
Stability
Clinical
trials
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Possible tasks of RAPs
during R&D
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The „regulatory rules”
Main rule:
• steps of the MP R&D have a defined
sequence (the next starts when the formers
are ready) to avoid unnecessary repetitions
• Moreover, some steps may only be planned
based on the results of former ones
Sub-rule: sometimes „iterative approach”
possible/needed giving rise to some
simplifications then repetitions
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Consecutive phases of MP R&DA
(simplified) „molecule
research”
API quality
„fixed” experimental
toxicology
experimental
pharmacology
dosage-form
development API
manufacture
ready, fixed
dosage-form
manufacture fixed
human clinical
trials
MA submission
time scale
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RAPs to advise reasearchers on
timing and sequence… 1/2
• Identify „critical steps” of synthesis
still at laboratory level (IPC needed
later)
• Reactant quality – think about
carryover of their impurities to finished
API
• Impurity profiling may be finished only
when maximal daily doses are known
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RAPs to advise reasearchers on
timing and sequence… 2/2
• Selection of dosage-form and strengths correlation with the dosage regimen – even „titration” should be executed – bisecting or breaking line on tablets?
• Carcinogenecity needed if – 6 months chronic/intermittant treatment
– strong tissue binding
• Lentgh of planned human CT phase determines the length and kind of toxicity studies completed before
• …
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Connection of Firms’ R&D and
RAP units
Two organisational extremes
• RAP member of specific R&D teams to guide them (good, advising acc. to
previous slides possible)
• RD accomplished than data given to RAP unit „to compile the dossier for MA” (bad, inconsistencies during R&D
should be „remedied” /hidden?/ later)
…and anything between the two
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RAPs’ task: compliation of
the MA dossier
CTD and submission
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M3
Quality
M4
Non-clinical
study reports
M5
Clinical study
reports
Quality
overall
summary
Non-clinical
overview
Clinical
overview
Non-clinical
summary
Clinical
summary
Regional
administrative
information M1
M2
Not part
of CTD
CTD
Common
Technical
Document
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After submission…
• The Firm’s RAPs’ task temporarily finished (except deficiencies found)
• The Medicines Regulatory Authorities have – coordinating RAPs (coordinating Community MA
procedures)
– assessor RAPs (same R&D experts as at Firms, but „at the other side of the table”)
• their task is the execution of the quality and therapeutic benefit/risk assessment and the consecutive issuance/rejection of the MA as well as scientific advice for Firms during R&D
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Before going into details…
…in order to have a structured view,
discussion of
• the regulatory authority structure in the
EU
in a nutshell!
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Competent authorities in the EU
• European Medicines Agency EMA
(London)
• National competent authorities NCA in
MSs
• The Network of NCAs (Heads of
Medicines Agencies, HMA)
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EMA
Established in 1995
Task:
• CP and arbitrations
• EU-wide Databases (EudraVigilance, EudraCT…)
• Decisions on CPs (e.g. parallel trade)
• EU-wide coordination
Structure:
• „The Secretariate”
• Management Board
• Scientific Committees
• Working Parties
(one member per member state)
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EMA Committees
• C’ttee of Human Medicinal Products CHMP
• C’ttee of Veterinary Medicinal Products
CVMP
• C’ttee of Orphan Medicinal Products
COMP
• Herbal Medicinal Products C’ttee HMPC
• Pediatric Committee PDCO
• C’ttee of Advanced Therapy Medicinal
Products CAT
• Pharmacovigilance Risk Assessment
Committee PRAC
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HMA
• 4 meetings annually (human/vet + joint)
• Harmonised approaches, policies
• In case of crisis: harmonised decisions
• Rapid Alerts
• Sending members to the Coordination groups CMDh and CMDv (MRPs and DPs!) as well as to the EC’s Working Parties
It is more than the sum total of NCAs!
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NCAs
• National competent authorities
– NPs,
– all kinds of inspections „on behalf of the
Community”,
– decision on non-CP-authorised products
(quality defects, recalls),
– national pharmacovigilance,
– regulatory control of information provided
by the Pharma industry
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Scientific advice
EMA
• prospective centralised applications
• advanced therapy MPs (even cerifying
research units)
NCAs
• any issue, submission
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The future: adaptive licensing
Present:
• CT after CT involving more and more subsets of patients (e.g. treatment-naive - single sickness – polymorbid – impaired liver and kidney – elderly – children…): the product is not available
• licensing (MA): the MP is available off-label even to patient subsets not subjected to CT
Future (adaptive licensing):
• after the first positive CT MA issued, MP indicated to the subsets of patients subjected to the CT exclusively
• CTs going on, indication in MA widened gradually
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Regulatory control of MPs during
their life cycle
It is not finished with the MA = life cycle regulatory control
• Quality: quality defect monitoring system and decision making
• Benefit/risk:
– Post-approval Efficacy Studies PAES
– Pharmacovigilance PV including Post-Approval Safety Studies PASS, Risk-Management Plans RMPs, Periodic Safety Update Reports PSURs
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Quality defect monitoring
system
• Both EMA (for CP-autorised MPs) and
national competent authorities
• Various forms
– spontaneous reports of suspected quality defects
(MAHs, wholesalers, pharmacists)
– sample-taking from the market and analysis (e.g.
CP-authorised products by EMA via EDQM)
• Decision-making (up to the withdrawal of
defective batches)
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Pharmacovigilance
• Reason: real-life therapeutic
risk/benefit may be different from
risk/benefit seen in clinical trials
(effectiveness versus efficacy)
• It is vital that data on real-life medicine
use are collected and assessed in a
structured way
• The new EU PV legislation
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Former PV rules
Sources of data on MP adverse drug
reactions ADRs:
• CTs (limited)
• reports of health-care professionals
(real-life but spontaneous) to DRAs
• MAHs data (from all over the World)
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New EU PV rules
PV includes not only ADRs originating from application of a MP outside of or according to its SmPC but also those of
• medication errors
• off-label use
• inappropriate use
• abuse
PV: not simply „ADR collection”: an activity to monitor benefit/risk of medicines, decreasing their risks and incresing their benefits
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New EU PV rules
• Risk Management System: sum total of PV activities to identify, characterise, prevent or minimise risks, including assessment of their effectivity
• PV Master File PVMF detailed description of the former (covering the MAHs of more-than- one / all medicines)
• Risk Management Plan RMP: description of the risk management system concretised to one MP
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PASS, PAES
• National competent authority NCA (one
single market) or PRAC-initiated
(marketed in more MSs) post-approval
safety study PASS (safety concern, new
info) or
• NCA / CHMP-Commission post-
approval efficacy study PAES (re-
analysis of former benefit/risk)
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MPs subject to additional
monitoring
• MPs where the picture of benefit/risk
seems to be incomplete: strict
monitoring (5 years, subject of renewal)
in SmPC and PIL
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MAH’s duties 1/2
• Every MAH must have PV system summarised in a PVMF (on request NCAs have access) for new products
• 1 Qualified person for PV QPPV (in the EEA) (plus national focal point)
• RMP for every new MP (old ones: risk-based approach)
• Periodic Safety Update Reports PSUR (new data, use incidence, re-assessed benefit/risk) for high-risk products only
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MAH’s duties 2/2
• Sending all ADRs (assessed) to EMA
electronically
• Sending PSURs to EMA electronically
• PSUR to NCA: only if requested
• If info on safety of MP launched: info to
EMA and NCAs beforehand
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NCA’s duties
• Own PV system
• Nationally reported ADRs (assessed) to EMA electronically
• If urgent safety restriction: suspension of MA with concomitant info to other NCAs, EC and EMA
– mandatory DHPC letters
• If no remedy: MA withdrawal (subject of Community decision)
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PRAC procedures
Single assessment of RMPs (signals)
(rapporteur) – if action to take PRAC
advises CMDh
• If unanimous decision in CMDh the
NCAs execute the restrictions
nationally
• If only majority vote:
PRACEMA(CHMP)EC (decision)
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EMA’s duties 1/2
• List of MPs subject to additional monitoring
• EdraVigilance
• NCAs, EC, EMA full access
• MAHs access to the extent they need for their PV
• Healthcare professionals appropriate level access
• Web-based structural forms of reporting
• Repository of PSURs, their Ars (fully accessible for PRAC, CHMP, CMD, NCAs, EC
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EMA’s duties 2/2
• Web portal info on
– RMP summaries
– EEA locations of PVMFs, QPPvs
– PASS protocols and abstracts
– EU reference dates („MP birthdays”)
• Monitoring selected medical literature
for ADRs
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Control of Pharma industry
information (advertising) to the
public and to health-care
professionals
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Basic EU rules
• Non-prescription MPs NP may be
advertised to the general public
• Prescription-only medicines POM may
only be advertised to health-care
professionals
– „Correct information to patients on POM
by the Industry” raised by the EC but
subject of heated discussion in the
Council (member states)
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Control of NP advertising
• Any media
• Permitted, no NCA pre-assessment
• Penalties if incorrect or unethical
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Control of POM advertising to
health-care professionals
Various forms of the promotion (mostly to Doctors but also to pharmacists)
• sending pamphlets with literature data
• sending Medical Representatives (visitors)
• sponsoring Conferences (requesting one Session for advertising purposes)
• sponsoring participation of health-care professionals in foreign conferences
• providing „medicinal samples”
• giving them gifts
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Conclusion
• There are numerous activities
connected with R&D and life-cycle
management of MPs
• All have their „regulatory side”
• Without professionals who understand
and manage these affairs neither the
R&D nor life-cycle management of MPs
could be successful
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