Interdependencies of Pharmacovigilance and Regulatory Affairs

Transcription

1 Lorenz userbridge 2013 Budapest, September 17th Interdependencies of Pharmacovigilance and Regulatory Affairs Dr. rer. nat. Markus Dehnhardt Deputy QPPV Biologist Toxicologist Medical advisor

2 Agenda 1. What is Pharmacovigilance (PV) 2. PV life cycle 3. PV interfaces with Regulatory Affairs (RA) 4. PV Legislation in EU 5. Conclusion 6. References

3 What is Pharmacovigilance Science and activities for surveillance of safety of medicinal products Activities for detection and defence of medicinal product hazards Assessment, understanding and prevention of Adverse Drug Reactions (ADR) Reporting sources are competent authorities, patients, pharmacists, physicians and pharmaceutical entrepreneurs Risk management Prevention of medication errors Communication of medicinal product information

4 Pharmacovigilance life cycle Phase I DSUR Phase II AE-/SUSAR-reporting Phase III Proof of safety & efficacy Audits/ authority inspections PV-System/PSMF RMP Phase IV QPPV proposed Marketing authorization application Regulatory effort/ administration: also increasing in life cycle PSUR authorized product information AE/ADR-reporting Product launch Marketing authorization with/without obligation Variations Additional monitoring Signalmanagement EVMPD reporting PRAC/CMDh: Art. 31/Art. 107 Referrals Postmarketing Renewal PASS/PAES Var.: Prod. Inform./PSMF USR/DDL

5 Pharmacovigilance life cycle Phase I DSUR Phase II AE-/SUSAR-reporting Phase III Proof of safety & efficacy Interface between PV and RA Audits/ authority inspections PV-System/PSMF 1 RMP 2 Phase IV QPPV proposed Marketing authorization application Regulatory effort/ administration: also increasing in life cycle PSUR 3 authorized product information 4 AE/ADR-reporting Product launch 5 Marketing authorization with/without obligation Variations 6 Additional monitoring Signalmanagement EVMPD reporting 7 PRAC/CMDh: Art. 31/Art. 107 Referrals Postmarketing Renewal 8 PASS/PAES Var.: Prod. Inform./PSMF 9 USR/DDL

6 Interdependencies of PV with RA 1. Pharmacovigilance System Master File (PSMF) 2. Risk Management Plan (RMP) 3. Proposed SmPC/proposed common SmPC submitted with application 4. Authorized product information (SmPC, PIL, Mockups) with MA granted 5. PSUR (PBRER, PA(D)ER) 6. Variations as part of routine RA 7. EVMPD 8. Renewal procedure 9. Variations following referral procedures

7 Interdependencies of PV with RA 1. Pharmacovigilance System Master File (PSMF) QPPV to be assigned with marketing authorization application by RA Submission of company specific summary description of PV system to submit by RA Overview of products (RA), audits/inspections (PV) Regularly update (PV) PSUR list, RMP updates and obligations tracking necessary Recommendation: Address responsibilities Keep highly variable parts as annexes Follow by tracking and versioning, database Consider involvement of Safety Data Exchange Agreements SDAE(s) and legal department

8 Interdependencies of PV with RA 2. Risk Management Plan (RMP) Product specific Tracking of variations by RA department May involve risk minimization measures Common sections with PSUR/addendum to CO Products under close monitoring and AEs under closer surveillance (PSUR) Recommendation: Address responsibilities (RA/PV department) Track variations Develop strategy for harmonization of regularly update with e.g. PSUR and/or annual review

9 Interdependencies of PV with RA 3. Proposed SmPC/PIL submitted with application Generation from own clinical trials (originator) Adaptation towards originator (generic products) Company Core Safety Information (CCSI)/ core SmPC/ common SmPCs Due with application for maketing authorization Recommendation: Address responsibilities (RA/PV department) Develop strategy for harmonization of worldwide marketed products as soon as MA granted Track submission content as well as submission status (database)

10 Interdependencies of PV with RA 4. Authorized product information (SmPC, PIL, Mockups) with MA Valid product information, may vary by country Local product information may need to be revised following national requirements Variations have to be reflected in RMP and PSUR MA- and Launch date availability to QPPV (information from RA to PV) Recommendation: Compile central/core safety information Develop strategy for worldwide harmonization of safety information Track implementation into national labels as well as submission status (database) Ensure availability and access of information for departments involved

11 Interdependencies of PV with RA 5. PSURs (PBRER considered equivalent) EU/EEA: Work sharing procedure until 2014, then central PRAC assessment EU/EEA: Interval following URD list or synchronization list Assessment of PSUR may result in a CSP, triggering an update of CCDS/national SmPCs Final Assessment Report (FAR): 4 months variation submission deadline EEA-ICH-region specific Originator/generic/other Recommendation: Track implementation as well as submission status Develop strategy for concerted implementation in various countries Develop company policy and processes to support the required information shape for three ICH regions

12 Interdependencies of PV with RA 6. Variations as part of routine RA Valid product information, may vary with countries Local SmPCs may need to be revised following national requirements (e.g. CA) Variations have to be reflected in RMP and PSUR MA- and Launch date availability to QPPV (information from RA to PV) Global requirements versus national labels and national requirements for global labels Recommendation: Compile a central/core safety information Develop strategy for worldwide harmonization of safety information Track submission status as well as implementation into national labelling Ensure availability and access of information for departments involved

13 Interdependencies of PV with RA 7. Renewal process Complex requirement for PV and RA Redundancy for information (PSUR/addendum to CO/RMP/PSMF) High complexity to coordinate dependent processes, information flow and responsibilities Recommendation: Define cross departmental renewal process including responsibilities o Information sharing o Roles and responsibilities o Meeting structures o Approval procedures

14 Interdependencies of PV with RA 8. EVMPD Accountability often in RA department and responsibility in PV (QPPV) High effort, especially with products in various strengths Relevant updates cannot be reported electronically to EMA, datasets must be nullified and submitted new Recommendation: Specific synchronization between RA and PV necessary Track status of submissions as MA specific (not API-specific, database) Ensure ressources availability for high volume of updates (new submissions)

15 Interdependencies of PV with RA 9. Referral procedures and subsequent variations Different referral procedures (Art. 31/Art. 107) with different time lines may result in request for o Post Authorization Safety Study (PASS) o Post Authorization Efficacy Study (PAES) o Product information update Urgent Safety Restrictions (USR), Dear Doctor Letter (DDL) may trigger referral Accountability and responsibility between RA and PV often unclear Recommendation: Define cross departmental renewal process including responsibilities o update of local labels Consider class effects as well as single API effects

16 Triggers for CCDS/CCSI update + different ICH-regions do not yet acknowledge RA documents of one another (e.g. CSP PSUR-WSP) definition of a company position for multi-ich-region companies on handling/ weighting of ICHspecific documents, e.g. SOP + local CA acknowledgements/approvals may vary in schedule Good tracking and proper justification of data + buffer for delayed/postponed elements/processes + when the complete process is triggered by EU-URD-List, and the requirement of a PSUR is updated, the whole process would have to be updated. suggestion: rely on EU-WSP CSP final assessment report. + concertation of many different departments, avoidance of endless circuits with request for delivery of data necessary transparent available information to all departments on central position

17 PV: EU Legislation Regulation EC/726/2004 Directive 2001/83/EG Commission Implementing Regulation amended by Reg EC/1235/2010 amended by Dir 2010/84/EC (EU) No. 520/2012 Good Pharmacovigilance (PV)- Practices (GVP) Module Regulation EC/1234/2008 as 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 Art. 17 Data archive PSUR 25a Delegated Acts 87 b Urgent safety procedures 26, 27 C.I.4 63e EudraVigilance-Database 5, , 10 Medicinal literature 27 C.I.4 Adverse drug reactions 5, , 107a 13 Chapter V VI 63c Pharmacovigilance system 17 10, 17 1, 101, 104 Art. 8 I 62, 63b PRAC 8 61a PSMF 22, 25 16(4), 7, 35 23(4), 104(3)(b) 3, 4 Chapter I II C.I.8 22 (2), 63b (2) 1(28e) PSUR , b, c 14 Chapter VII, Annex II VII C.I.3, C.I.10 63d (1) PV-Inspections 111(1) Art. III 15(1)(f);10(3),14(2) RMP 21, 26, 8 1, 22c, 104a, 15 Chapter VI, Annex I V C.I.11 62, 63b 28a 106c Signal management 11 Chapter III IX C.I.4 Safety/ Post authorization 16 10a, 28b 9, 24, 25 1(15), 22a, 16 Chapter VIII, Annex VIII 63f-g safety study 107m-q III Efficacy/ Post authorization 16 10a 9 22a efficacy study EVMPD 57(2) Variations C.I. 29 MA application (QPPV) I 63 a; 21, MA 2.4.4

18 Conclusion Focus on harmonization of information content in order to minimize efforts creating multiple shapes of similar content Interdependencies between RA and PV are complex, therefore cross-functional design of processes is a necessity for the future Cross-functional RA and PV processes shall be enabled by one central data repository, one IT business process platform to support workflow

19 Grazie! Tack så mycket! Bedankt! Vielen Dank! Ευχαριστώ πολύ! Děkuji moc!

20 References Legislative texts 520/2012 (EU Commission implementation regulation of 19 th June 2012 relating to Regulation 726/2004 and Directive DIR 2001/83/EG PV activities; Directive 2001/83/EG Directive 2010/84 Regulation EC/726/2004 amended by Reg EC/1235/2010 Regulation EC/1234/2008 as amended by EC 712/2012 Germany: Zweites Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften. Bundesgesetzblatt Jahrgang 2012 Teil I (50), ; pp Regulatory important documents/guidelines/websites etc. Guideline on good pharmacovigilance practices (GVP) Module IX EMA/827661/2011 Signal management _library/scientific_guideline/2012/06/wc pdf Guideline on the use of statistical signal detection methods in the Eudravigilance database EMA 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; Disclaimer: This material is the property of Kohne Pharma GmbH. The information is to be used only in connection with matters authorized 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.