1

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

2

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!

12

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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