The Growing Interdependencies Between Pharmacovigilance ...productlifegroup.com/wp-content/uploads/2015/01/Presentation_RMPV... · The Growing Interdependencies Between Pharmacovigilance

Commercial and in Confidence www.productlifegroup.com 1

The Growing

Interdependencies Between

Pharmacovigilance and

Regulatory Affairs

25th Sep 2014

http://www.productlifegroup.com/

Commercial and in Confidence www.productlifegroup.com 2 Commercial and in Confidence www.productlifegroup.com 2

Kohne Pharma profile

Founded: 1974, 100% ProductLife S.A.

Office: Haan, Germany

Employees: 17 highly qualified consultants

Overview: • Consultancy services provided for more than 350

customers

across Europe

• Regulatory affairs, electronic Common Technical

Document/ Common European Submission Platform

• Pharmacovigilance

• Quality assurance

• Sales and brokerage of marketing authorisations (MAs),

ongoing registrations, and dossiers

Submission platform:

LORENZ docuBridge, eValidator, drugTrack

Business partners:

Cipla, Tecnimede, medac, Haupt Pharma, Genepharm, LESVI,

Vipharm

MAs completed with 14 regulatory authorities in Europe



http://www.kohne-pharma.com/kohnenew/cms/front_content.php


Agenda

1. Overview of European pharmacovigilance

(PV) requirements

2. Legislation

3. Interdependencies of various

PV tasks in a regulatory affairs environment

4. New European Medicines Agency initiatives

on risk management and things to come in

PV in brief during the next year

5. Challenges and recommendations

6. References



Overview on European PV-requirements


Pharmacovigilance life cycle: European Union/

European Economic Area (EU/EEA)

DSUR

QPPV

PSUR

RMP PV system/PSMF

Authorised product information

AE-/SUSAR-reporting AE/ADR-reporting

Marketing authorisation with/without obligation

Safety signal management

Additional monitoring

PRAC/CMDh: Art. 31/Art. 107 Referrals

PASS/PAES

USR/DDL

Var.: Prod. Inform./PSMF

Renewal

Proof of safety and efficacy

Product launch

Proposed

EVMPD reporting

Marketing authorisation application

Postmarketing Phase IV Phase I Phase III Phase II

Variations

Regulatory effort/administration: Also increasing in life cycle

Audits/authority inspections




Pharmacovigilance life cycle: European Union/

European Economic Area (EU/EEA)

DSUR

QPPV

PSUR

RMP PV system/PSMF

Authorised product information

AE-/SUSAR-reporting AE/ADR-reporting

Marketing authorisation with/without obligation

Safety signal management

Additional monitoring

PRAC/CMDh: Art. 31/Art. 107 Referrals

PASS/PAES

USR/DDL

Var.: Prod. Inform./PSMF

Renewal

Proof of safety and efficacy

Product launch

Proposed

EVMPD reporting

Marketing authorisation application

Postmarketing Phase IV Phase I Phase III Phase II

Variations

Regulatory effort/administration: Also increasing in life cycle

Audits/authority inspections

1 2

3 4

5

6

7

9

8

Interface between pharmacovigilance

and regulatory affairs




Overview on European PV-requirements

• Legislation is usually specific to a certain economic area,

such as the EEA, the USA, or Asia Pacific

• Requirements of pharmaceutical companies are usually

not specific to those single areas but, rather, to various

areas

• Companies have to interpret legal requirements for their

individual company structure

• They also have to harmonise the international laws and

requirements of different regions with their portfolio or

company international setup



Legislation


Legislation

• Regulation (EC) No 726/2004, amended by Regulation (EC) No 1235/2010

• Directive 2001/83/EG, amended by Directive 2010/84/EC

• Commission Implementing Regulation (EU) No 520/2012

• Good Pharmacovigilance Practice (GVP) Modules

• Regulation (EC) No 1234/2008, as amended by EC 712/2012

• Delegated Act on Post-Authorisation Efficacy Studies (Article 10b of

Regulation (EC) No 726/2004 and Article 22b of Directive 2001/83/EC)

• Pharmacovigilance fee Regulation (Regulation [EU] No 658/2014 of the

European parliament and of the council of 15 May 2014) and

• For Germany: Zweites Gesetz zur Änderung arzneimittelrechtlicher

(German act on drug law, AMG)

Framework for PV obligations in the European Economic Area, defined by:




Legislation

Regulation EC/726/2004

amended by Reg

EC/1235/2010

Directive 2001/83/EG

amended by Dir 2010/84/EC

Commission Implementing

Regulation

(EU) No. 520/2012

Good Pharmaco-

vigilance (PV)-

Practices (GVP)

Module

Regulation

EC/1234/2008as

amended by EC

712/2012

German act on drug

law (AMG)

Rationale Article Rationale Article Rationale Reference

Additional monitoring 23(1), 23(2) 106

Audits/inspections 104 Article 17

Data archive Periodic

Safety Update Report 25a

Delegated acts 87 b

Urgent safety procedures 26, 27 C.I.4 § 63e

EudraVigilance database 5, 6 24 9, 10

Medicinal literature 27 C.I.4

Adverse drug reactions 5, 19 107, 107(3) Recital 13 Chapter V VI § 63c

Pharmacovigilance system 17 10, 17 1, 101, 104 Article 8 I § 62, 63b

Pharmacovigilance Risk

Assessment Committee 8 61a

Pharmacovigilance system

master file 22, 25 16(4), 1(28d,e) 7, 35 23(4), 104(3)(b) 3, 4 Chapter I II C.I.8 § 22 (2), § 63b (2)

Periodic Safety Update

Report 21 25a, 28 22, 23 107b, c, d, e, g 14 Chapter VII, Annex II VII C.I.3, C.I.10 § 63d (1)

PV inspections 111(1) Article

15(1)(f);10(3),14(2) III

Risk management plan 21, 26, 28a 8 1, 22c, 104a, 106c 15 Chapter VI, Annex I V C.I.11 § 62, 63b

Signal management 11 Chapter III IX C.I.4

Safety/postauthorisation

safety study 16 10a, 28b 9, 24, 25 1(15), 22a, 107m-q 16 Chapter VIII, Annex III VIII § 63f-g

Efficacy/postauthorisation

efficacy study 16 10a 9 22a

XEVMPD 23(1), 57(2) VII

Variations 8(3), 10 (a,b), 11,

32 (5), 23, 55

C.I., Chapter II, IIa,

III and IV § 29

MA application (qualified

person for

pharmacovigilance [QPPV])

5 23 9 103 I § 63 a; § 21, MA 2.4.4



Interdependencies of various PV tasks in a regulatory affairs environment


Interdependencies of PV with RA





• QPPV to be assigned with marketing authorisation application by RA

• Company-specific summary description of PV system to be submitted by RA

• For every MA, a type 1A variation according to C.I.9 has to be submitted €410.-/MA

• Overview on products (RA), audits/inspections (PV)

• Regularly update (PV)

• PSUR list, RMP updates, and obligations tracking necessary

• Legal basis: Dir 2001/83/EC Art. 1(28d) and Commission Implementing Regulation, (EU)

No 520/2012; Directive 2010/84/EC in art. 23(4) and 104(3 b), respectively

• Address responsibilities

• Keep highly variable parts as annexes

• Follow by tracking and versioning, database

• Consider involvement of safety data exchange agreements and legal department




• Product specific

• Tracking of variations by RA department

• May involve risk minimisation measures

• Common sections with PSUR/addendum to clinical overview (CO)

• Products under close monitoring and adverse events under closer surveillance (PSUR)

• Legal basis: Commission Implementing Regulation (EU) No. 520/2012 § 15, chapter VI

(art. 30 to 33), and annex I; Reg EC/726/2004 amended by Reg EC/1235/2010 art. 21,

26, and 28a; Dir 2001/83/EG amended by Dir 2010/84/EC paragraph 8, art. 1 (28b and c),

8 (3), 22c, 104a, and 106c; module V GVP modules, in regulation EC/1234/2008 as

amended by EC 712/2012, section C.I.11 and German act on drug law § 62 and § 63b.

• Address responsibilities (RA/PV department)

• Track variations

• Develop strategy for harmonisation of regular update with, for instance, PSUR

and/or annual review




• Generation from own clinical trials (originator)

• Adaptation towards originator (generic products)

• Company core safety information/core SmPC/common SmPCs

• Due with application for maketing authorisation

• Legal basis: Reg EC/726/2004 amended by Reg EC/1235/2010; chapter 3, art. 48;

EVMPD: art. 57(2); Dir 2001/83/EG; paragraph 9; art. 104 (1, 2, and 3); GVP module I,

section CI, section I.C.1.1, I.C.1.2, and I.C.1.3; German act on drug law; § 22, § 29, and §

63; guidelines on details of the various categories of variations and on operation of the

procedures laid down in chapters II, IIa, III, and IV of Commission Implementing Regulation

(EC) No 1234/2008, section CI, permit adaptation of the SmPC to the innovator

• Address responsibilities (RA/PV department)

• Develop strategy for harmonisation of worldwide marketed products as soon as MA granted

• Track proposed information implementation into local labels as well as submission status

(database)




• Valid product information may vary with different countries

• Local SmPCs may need to be revised to meet national requirements

• Variations have to be reflected in RMP and PSUR

• Launch date not identical with MA (information from RA to PV)

• Global requirements versus national labels and national requirements

for global labels

• Legal basis: Authorisation according to the German act on drug law is given with § 21;

GVP module V section VII.B.4 reference information, and regulation 726/2004, chapter 2,

art. 16 (3), and product information must be kept up-to-date

• Compile central/core safety information

• Develop strategy for harmonisation following various possible triggers for update

• Track implementation into national labels as well as submission status (database)

• Consider availability of information for different departments at any time




• EU/EEA: Work-sharing procedure until 2014, then central Pharmacovigilance Risk Assessment

Committee (PRAC) assessment

• EU/EEA: Interval following European Union reference date (EURD) list or synchronisation list

• Assessment of PSUR may result in a core safety profile, triggering an update of company core data

sheet (CCDS)/national SmPCs

• Final assessment report: 4 months for submission of variations

• EEA‒International Conference on Harmonisation (ICH)‒region specific

• Originator/generic/other

• Legal basis: Reg (EC) No 726/2004, Dir 2001/83/EC and IR (EU) No 520/2012; GVP Module VII, e.g.,

subsection VII.B; ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2); EURD list, VII.C of GVP module

VII single EU assessment VII.C.4; synchronisation list; Dir Art. 107 and 107c (4, 5, and 6); IR Art. 34 (4

and 6); Dir 2001/83/EG Art. 107b (2, 3), Art. 107c (2, 4) and 107e; GVP module VII, C.1.

• Track implementation as well as submission status

• Develop strategy for concerted implementation in various countries

• Avoid multiple formats in various countries (e.g., EEA vs. non-EEA), or consider availability of respective

information

• Develop company policy for different ICH regions




• Valid product information may vary with countries

• Local SmPCs may need to be revised to meet national requirements (e.g., CA)

• Variations have to be reflected in RMP and PSUR

• Launch date not identical with MA (RA to inform PV)

• Global requirements versus national labels and national requirements for global labels

• Legal basis: Variations guideline chapters II, IIa, III, and IV of Commission Implementing

Regulation (EC) No 1234/2008, section C.I, German act on drug law

§ 29; Dir 2001/83/EG, paragraph 55. Art. §23 and art. 8 subs. 3 letter d and h, art. 10, 10a,

10b, and 11 or art. 32, subsection 5 or annex I

• Compile a central/core safety information

• Develop strategy for harmonisation following various possible triggers for update

• Track submission status as well as implementation into national labelling

• Need of availability of information for different departments at any time




• Complex requirement for PV and RA

• Redundancy for information (PSUR/addendum to CO/RMP/PSMF)

• Many departments involved

• Availability of information

• Coincident availability of necessary documents

• Legal basis: Dir 2001/83/EG art. §24; Dir 2001/83/EG art. 24 (3), art. 104 (3);

Reg EC/726/2004 amended by Reg EC/1235/2010 art. 14 (3); art. § 21 of the

German act on drug law, § 63; Dir 2001/83/EG art. § 24

• Make sure transparent availability of information and requests (e.g., at central server)

• Install project lead coordination/working groups/work flow control

• Hold regular meetings for update status check and timelines

• Consider implementation of approval procedures for different responsibilities into

project planning and before documents can be submitted




• Usually located in RA department

• Changes cannot be reported to European Medicines Agency; SmPC content: Challenging task,

especially with many products and various strengths

• Responsibility of the QPPV

• Since 2 July 2012, altered information to be submitted within 15 calendar days. ISO Identification

of Medicinal Product standards are to be implemented in July 2016

• From 16 June 2014 until 31 December 2014 marketing authorisation holders are obliged to

update the information

• Legal basis: Reg EC/726/2004 amended by Reg EC/1235/2010 in art. § 57(2); Legal Notice on

the Implementation of art. 57(2) of Reg (EC) No. 726/2004 Jan 2014 EMA/505633/2011, effective

date 16 June 2014; art. 26(1) of Reg (EC) No 726/2004 updated [IR art. 4(4), Reg art. 57(2)(c)];

art. 8(3) Dir 2001/83/EC (and within the eXtended EudraVigilance Medicinal Product Dictionary

[XEVMPD])

• Track status of submissions as MA specific (not active pharmaceutical ingredient [API]

specific, database)

• As soon as updates can be reported, address resources




• Different referral procedures (art. 31/art. 107) with different time lines

• May result in request for:

– Postauthorisation safety study (PASS)

– Postauthorisation efficacy study (PAES)

– Product information update

– Urgent safety restrictions (USRs), dear-doctor letter (DDL) may trigger referral

• Correspondence usually by RA department

• Legal basis: USR/referral procedures Dir 2001/83/EG as amended, articles 31, 107, § 63 e

of the German act on drug law; art. § 107i to 107k of Dir 2001/83/EG; subsections 1, 2, art. 107j (2), art.

107g, 33, 34, 107k; PASS section 16, §§ 10a, 28b Reg EC/726/2004; Dir 2001/83/EG §§ 9, 24, 25, §

1(15), § 22a, § 107m-q; Implementing Regulation (EU) No 520/2012 section 16, chapter VIII and Annex

III; GVP module VIII; German act on drug law § 63f to g; section 16; art. §10b Reg EC/726/2004; Dir

2001/83/EG section 9 and art. § 22a; Reg (EU) No 357/2014; Reg (EC) No 726/2004

• Define a core process for update of local labels

• Consider class effects as well as single API effects

• Consider possible consequences in advance


New EMA initiatives on risk management and things to come in PV in brief/during the next year.


New European Medicines Agency initiatives on risk

management and things to come in PV in brief

during the next year

Advance Notification of signals on the PRAC agenda

• New service is for all QPPVs of the marketing authorisation holders registered in the article 57 database.

European Medicines Agency initiative for future benefit-risk assessment

• Regulatory and methodological standards to improve benefit-risk evaluation

of medicines, dated 10 April 2014: EMA/141854/2014

• Recent EMA/Committee for Medicinal Products for Human Use benefit-risk project

• PCWP/HCPWP workshop, February 2014

• Establishment of methodological standards

• Current international benefit-risk initiatives

Pharmacovigilance programme update

• Issue 1 send to QPPVs in July 2014, intended to be sent quarterly

• Topics addressed:

– Preparing for business change

– Database of medicinal products (art. 57)

– Medical literature monitoring

– Adverse-drug-reaction reporting and signal management

– Public Web site of suspected adverse reactions

– PSUR repository

– Pharmacovigilance fees




Challenges and recommendations: Continuous Benefit-Risk Assessment (BRA)

Items to consider further for benefit-risk

assessment:

• PSURs

• RMPs

• Additional monitoring

Continuous Benefit-Risk Assessment

BfArM- Safety-DB

Literature Research

Signal Management Web-Page

Screening

Enquiries via Med-Sci- System Regular assessment


Challenges and

recommendations


Challenges and recommendations

Concerted Department Collaboration (PV and RA):

• Have information available to all departments on central position

(database)

SmPC approvals:

• Track CCDS implementation into local SmPCs and approvals by

national CAs

• Fully reference CCDS data

• Harmonise safety-relevant RA and PV processes

• Simplify different departments’ complex matrix interdependencies




Challenges and recommendations

EU-URD-List

• Check monthly, address resources, reschedule work flow if

necessary.

ICH-Regions:

• Define company strategy—for example, by standard operating

procedure—for regulatory documents of one ICH region in another

(e.g., CSP from P-WSP).

Submission platform:

• Implementation of a modular system for availability and exchange of

information is needed (e.g., LORENZ systems, such as LORENZ

userBridge).







References

Legislative texts: • 520/2012 (EU Commission implementation regulation of 19 June 2012 relating to Regulation 726/2004 and Directive DIR 2001/83/EG PV activities;

http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:159:0005:0025:DE:PDF

• Directive 2001/83/EG

• Directive 2010/84

• Regulation EC/726/2004, amended by Reg EC/1235/2010

• Regulation EC/1234/2008, amended by EC 712/2012

• Germany: Zweites Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften. Bundesgesetzblatt Jahrgang 2012 Teil I (50), 25.10.2012; pp 2192

Important regulatory documents/guidelines/Web sites etc. • Guideline on good pharmacovigilance practices (GVP) – Module IX EMA/827661/2011 – Signal management

http://www.emea.europa.eu/docs/en_GB/document _library/Scientific_guideline/2012/06/WC500129138.pdf

• Guideline on the use of statistical signal detection methods in the EudraVigilance database

• European Medicines Agency template for EU risk management plans, including the annex I: Interface between EU-RMP and EudraVigilance

• Detailed guidance on the collection, verification, and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (CT-3) June 2012

• Volume 9A of the Rules Governing Medicinal Products in the EU: PV for medicinal products for human use

• Council for International Organizations of Medical Sciences (CIOMS) , Practical aspects of signal detection in pharmacovigilance: Report of CIOMS working group VIII; http://www.cioms.ch/frame_WGVIIIblurbDRAFT.htm

Disclaimer: This material is the property of Kohne Pharma GmbH. The information is to be used only in connection with matters authorised by Kohne Pharma GmbH,

and no unpublished information presented in this document is to be disclosed to others without prior written permission from Kohne Pharma GmbH.










http://www.cioms.ch/frame_WGVIIIblurbDRAFT.htm

http://www.cioms.ch/frame_WGVIIIblurbDRAFT.htm


Key contact

Markus Dehnhardt, PhD [email protected]

+ 49 2129 5301583



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