Periodic Benefit Risk Evaluation Report (PBRER) PIPA Conference Nov 7, 2014 Joerg Seebeck, MD

Periodic Benefit Risk Evaluation Report (PBRER) PIPA Conference Nov 7, 2014 Joerg Seebeck, MD

Aims of this presentation Concept of PBRER Content and form (selected topics)

REGULATORY BACKGROUND Based on ICH-E2C (R2), step 4 Nov 2012 Implementation in Europe via GVP module VII (revision 1, 9 Dec 2013) PBRER are referred to as PSUR EU relevant legislation Directive 2001/83 & 2010/84/EU Regulation 726 / 2004 & 520 / 2012

MAIN PURPOSE OF PSURs B R B R B R TIME B/R assessment at pre-defined intervals throughout the product life-cycle (or upon request)

MODULAR APPROACH MA Approval DSUR DSUR DSUR DMP RMP RMP RMP PSUR PSUR PSUR Common content: - See next slide

COMMON SECTION BETWEEN PSUR & RMP

PSUR A tool to report signals? Y Report via P-PV-emerging-safetyissue@ema.europa.eu Validated Signal ESI N Manage differently (Report in PSUR) PSUR not a tool for initial reporting of signals fulfilling ESI criteria PSUR is a tool to provide an update about the signalling status of a product (signals closed, ongoing) Also, the production of a PSUR can lead to the identification of signals (to be reported as ESI, if fulfilling ESI-criteria)

Severity of risk (a) B/R evaluation principles include Safety, efficacy, effectiveness data Missing data* (e.g. special populations) Consider all uses (authorized & non-authorized) Consider data back to the DIBD Risk Characteristics *Certainty / Uncertainty (about a & b) Frequency (b) (probability)

Principles for the preparation of PSURs 1 active substance per 1 PSUR (all pharmaceutical forms; exceptions possible) Where required, use summaries of case narratives (not the CIOMS I text) Include interval and cumulative data

Reference Information (Reference Product Information) Content: Core safety information + authorised indications in ICH countries (corresponds to important baseline efficacy and effectiveness information 17.1) Format CCDS CCSI When no CCSI or CCDS exists, an alternative RPI has to be specified: e.g. local SmPC

Reference Information Management 1. Perform SD (including review of labels) Common problems: RPI too narrow (core CCSI), Low number of listed events False positive signals 4. Use adjusted RPI for next review cycle 2. Update RPI RPI too wide (e.g. local SmPC) high number of listed events False negative signals* 3. Adjust local labels to RPI *E.g. disharmony of USPI vs EU-SmPC due to different document structures and implementation policies

Format and contents of the PSUR

Overview Part I: Title page including signature Part II: Executive Summary Part III: Table of contents 1. Introduction 2. Worldwide marketing authorisation status 3. Actions taken in the reporting interval for safety reasons 4. Changes to the reference safety information 5. Estimated exposure and use patterns 6. Data in summary tabulations 7. Summaries of significant findings from clinical trials during the reporting interval 8. Finding from non-interventional studies 9. Information from other clinical trials and sources 10. Non-clinical data 11. Literature 12. Other periodic reports 13. Lack of efficacy in controlled clinical trials 14. Late breaking information 15. Overview of signals (new, ongoing, closed) 16. Signal and risk evaluation 17. Benefit evaluation 18. Integrated benefit-risk analysis for authorised indications 19. Conclusions and actions 20. Appendices to the PSUR

Data in summary tabulations Spontaneous data Use event-level for seriousness Represent PT level and SOC Present cumulative and interval Include all sources (HCP, nhcp, lit, solicited) Note: listedness is not required but causality

Summary tabulations; Clinical Trial data (B.5.6.2); principles Discuss only (own) MA sponsored trials MA explain any omission of data Represent data cumulatively (separate presentation of interval data not required (but discuss emerging issues; see B.5.7) Tabulate investigational drug & comparator Option to organise data by trial, or program, or indication, or route of administration, or other criteria Show serious events not reactions; i.e. causality not required (do not show non-serious events) No unblinding of data required Add appendix listing all sponsored postauthorisation interventional trials

B.5.7 Subsection - Clinical Trial data (discuss for emerging issues) B.5.7.1 Completed clinical trials B.5.7.2 Ongoing clinical trials B.5.7.3 Long term follow-up (especially advanced therapy products) B.5.7.4 Other therapeutic use of medicinal product; based on protocols with solicited reporting as per ICH E2D e.g Expanded access programmes Compassionate use programmes Particular patient use Other organised data collections interventional

B.5.8 Findings from noninterventional studies Observational studies Epidemiological studies Registries Active surveillance programmes Drug utilisation studies ( RMP) Appendix: list all MA-sponsored noninterventional studies Noninterventional

B.5.9 Information from other clinical trials and sources 5.9.1 Other Clinical trials ; MAH has access to data but is not the sponsor E.g. meta-analysis of RCT Co-development partner Investigator initiated trials

B.5.11 Literature Lit ICSR Lit non-icsr Pregnancy outcomes (including termination) with no adverse outcomes Use in paediatric populations Compassionate supply, named patient use Lack of efficacy (see also section 5.13) Etc.

B.5.15 Overview of Signals: new, ongoing or closed Provide high level overview of signals Do not include not evaluated statistical signals New signal = signal identified during reporting interval Closed signal = signal evaluated not refuted, not ongoing; or refuted Ongoing signal = under evaluation during end of reporting interval

B.5.15 Overview of Signals: new, ongoing or closed Describe signal in tabular format (here or in appendix) Provide detailed assessment of closed signals under section 16.2 signal evaluation

B.5.15 Signal Summary Tabulation

B.5.16 Signal and risk evaluation Summary about what is known about important identified and potential risks and missing information ( RMP); 5.16.1 Old status Evaluation of all signals closed during the reporting interval; 5.16.2 Evaluation of new information with respect to known identified and potential risks; 5.16.3 Updated characterisation of important risks (where applicable); 5.16.4 Summary of effectiveness of risk minimisation activities New status

B.5.16.1 Summary of Safety Describe important and potential risks and missing information (use safety specification) If no safety specification is available, consider: Important adverse reactions Interaction (drug-drug, drug-food) medication errors Occupational exposure Class effects Concerns

B.5.16.2 Signal evaluation Summarise evaluation of all safety signals that were closed during the reporting interval (whether or not classified as important) Categories Closed and refuted signals Closed (= important identified risk) Closed (= important potential risk) Closed (= potential risk but not important) Closed (= identified risk but not important) Inclusion in RMP Relevant for B/R Practical consequence? (see next slide)

Mapping signals and risks to PSUR sections ICHE2E = Safety Specification

B.5.17 Benefit Evaluation 17.1 Important baseline efficacy and effectiveness information 17.2 Newly identified information on efficacy and effectiveness 17.3 Characterisation of benefits baseline Integrates 17.1 &17.2 and supports B/R evaluation

B.5.17.3 characterisation of benefits If required, consider (selection): new information that challenges validity surrogate endpoint Clinical relevance of the effect size Generalisibility of treatment response across indicated patient population Duration of effect Comparative efficacy

B.5.18 Integrated benefit-risk analysis for authorized indications Critical analysis and integration of subsections Characterisation of risks 16.4 Vs Characterisation of benefits 17.3

B.5.18.1 Medical need and important alternatives Alternatives (medical, surgical, no treatment) Tip: consider guidelines from expert organisations (NICE, American Heart Association etc)

B.5.18.2 B/R analysis evaluation B/R specific to indication and population Multiple indications multiple B/Rs Potentially differentiate by population (e.g. paediatric vs adult)

B.5.18.2 B/R analysis evaluation (cont.) Present B and R in a way that facilitates comparison Focus on important B and R Context of use (prevention, severity of illness) Key benefits: effect size and duration, clinical importance, generalisibility, efficacy in non-responders to other therapies Risk: clinical importance (frequency, seriousness, predicatability, preventability, reversibility, off label use, misuse) Explain methodology Do not consider economic arguments

B.5.19. Conclusions & actions B/R status changed / unchanged RSI change (Describe here proposed changes to SmPC) RMP update required? Additional Risk Minimisation activities required?

Appendices RSI Cumulative summary tabulations Summary Safety Signals Listings All MAH-sponsored interventional trials All MAH-sponsored non-interventional trials List of sources of information used to prepare the PSUR Regional appendix

Regional appendix RSI Cumulative summary tabulations Summary Safety Signals Listings All MAH-sponsored interventional trials All MAH-sponsored non-interventional trials List of sources of information used to prepare the PSUR Regional appendix

Thank you for you attention. Questions?

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Regional appendix C.5.1 Proposed product information SmPC / PIL, list ongoing variations C.5.2 Proposed additional PV and Risk Minimisation activities Statement of intention to submit RMP, or Updated RMP Summary of safety concerns (from RMP available at beginning of PSUR) Final study report (PASS) Risk minimisation: (useful) other region material

Administrative aspects Submit PSUR 70 days after DLP (12 month PSUR) Submit PSUR 90 days after DLP (> 12 month PSUR)

Administrative aspects PSUR submission requirements waived for: Routine generic medicinal products (authorised under Art 10(1) of DIR 2001/83 Well-established use medicinal products (Art 10a) Homeopathic medicinal products (Art 14) Traditional herbal medicinal products (Art 16a), 107 b (3) a + b