7/22/2019 Benefit Risk Analysis
1/53
7/22/2019 Benefit Risk Analysis
2/53
Webcast Notes
Interact with speaker by typing your questions in the Submit
Question box located below the video window
You can enlarge the slide window at anytime by clicking onthe Enlarge Slides button, located below the presentation
window. The slides will advance automatically throughout the
event
If you are experiencing technical problems with viewing or
hearing this webcast, please click on the Help button below
the video window
7/22/2019 Benefit Risk Analysis
3/53
Mapi 2013, All rights reserved 3
EU PV Changes to PSURs &Strategies for Benefit-Risk Analysis
Hemendra Misra MD, MPH, MSc, Senior Director, ProductRisk Management
William C. Maier MPH, PHD, Chief Scientific Officer
29 May 2013
7/22/2019 Benefit Risk Analysis
4/53
Mapi 2013, All rights reserved 4
Hemendra Misra MD, MPH, MSc
Senior Director, Product Risk Management
GERMANY
Pharmacovigilance Physician with seventeen years of international work experience
Nine years of Industry experience (Pharma & CRO) - Medical Monitor, Drug SafetyPhysician, Safety Expert, Risk Management Expert
Took a lead scientific, commercial and organizational role in the development of safetyand risk management services for both new and existing pharmaceutical companyclients
Medical practice includes positions in hospitals in India and with Medecines SansFrontieres (Doctors Without Borders)
Public health experience:
Consultant for a WHO Anti-Malaria program in India
Member of the STB SARS Containment Team in Singapore
Medical Officer for the Health Promotion Board in Singapore
2
7/22/2019 Benefit Risk Analysis
5/53
Mapi 2013, All rights reserved 5
William C. Maier, PhD
Chief Scientific OfficerUK
Over 20 years experience in biopharmaceuticalindustry with specialty in the design, analysis,and interpretation for epidemiology &observational studiesEditor PharmacoEPI and Risk ManagementNewsletter www.prmnewsletter.orgFrequent international speaker on Epidemiology,Health Technology Assessment, Drug Safety and RiskManagementPreviously Senior Director of Epidemiology at GSK and Elan
PharmaceuticalsEMEA Working Group MemberNetwork of Pharmacoepidemiology Centres in EU EnCEPP Project
Specialties Respiratory, Endocrinology, Gastrointestinal,Autoimmune, Vaccines, Oncology
7/22/2019 Benefit Risk Analysis
6/53
Mapi 2013, All rights reserved 6
Agenda
Topic Presenter
The new PSUR and itsrequirements
Hemendra Misra
Challenges in preparing the PSUR Hemendra Misra
Strategies for presenting thebenefit-risk analysis
Will Maier
Summary Hemendra Misra
Questions Hemendra Misra & Will Maier
7/22/2019 Benefit Risk Analysis
7/53 Mapi 2013, All rights reserved 7
Section 1The new PSUR and its
requirements
7/22/2019 Benefit Risk Analysis
8/53 Mapi 2013, All rights reserved 8
The new PSUR - Definition
Periodic safety update reports (PSURs) arepharmacovigilance documents intended to providean evaluation of the risk-benefit balance of amedicinal product. They shall be submitted bymarketing authorisation holders at defined timepoints during the post-authorisation phase.
7/22/2019 Benefit Risk Analysis
9/53 Mapi 2013, All rights reserved 9
Legal basis for the PSUR
Regulation (EU) No 1235/2010Directive 2010/84/EU
Commission Implementing Regulation (EU) No520/2012
Guidance on scope, objectives, format andcontent of the PSUR
European Medicines Agency (EMA) Guideline on goodpharmacovigilance practices (GVP) Module VII
Periodic safety update report
based on those for the Periodic Benefit Risk EvaluationReport (PBRER) described in the ICH-E2C(R2) guideline
7/22/2019 Benefit Risk Analysis
10/53 Mapi 2013, All rights reserved 10
Structure of the PSURPart 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 reference safety information
5. Estimated exposure and use patterns
5.1. Cumulative subject exposure in clinical trials
5.2. Cumulative and interval patient exposure from marketing experience
6. Data in summary tabulations
6.1. Reference information
6.2. Cumulative summary tabulations of serious adverse events from clinical trials
6.3. Cumulative and interval summary tabulations from post-marketing data sources
7. Summaries of significant findings from clinical trials during the reporting interval
7.1. Completed clinical trials
7.2. Ongoing clinical trials
7.3. Long-term follow-up
7.4. Other therapeutic use of medicinal product
7.5. New safety data related to fixed combination therapies
8. Findings from non-interventional studies
9. Information from other clinical trials and sources
9.1. Other clinical trials
9.2. Medication errors
10. Non-clinical Data
7/22/2019 Benefit Risk Analysis
11/53 Mapi 2013, All rights reserved 11
Structure of the PSUR (2)11. Literature
12. Other periodic reports
13. Lack of efficacy in controlled clinical trials
14. Late-breaking information
15. Overview of signals: new, ongoing or closed
16. Signal and risk evaluation
16.1. Summaries of safety concerns
16.2. Signal evaluation
16.3. Evaluation of risks and new information
16.4. Characterisation of risks
16.5. Effectiveness of risk minimisation (if applicable)
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
18. Integrated benefit-risk analysis for authorised indications
18.1. Benefit-risk context Medical need and important alternatives
18.2. Benefit-risk analysis evaluation
19. Conclusions and actions
20. Appendices to the PSUR
7/22/2019 Benefit Risk Analysis
12/53 Mapi 2013, All rights reserved 12
Key Changes to the PSUR
Objective, format, content, timelines
New section on Benefit-risk evaluation
New section on Safety Signals
No routine line-listings required
No PSURs required for certain category of productsgeneric medicinal products
well-established use medicinal products
homeopathic medicinal products
traditional herbal medicinal products
Operational aspects
7/22/2019 Benefit Risk Analysis
13/53 Mapi 2013, All rights reserved 13
Potential sources of information for the PSUR(efficacy, effectiveness, safety information)
non-clinical studies
spontaneous reports (e.g. on the marketing authorisation holders safetydatabase)
active surveillance systems (e.g. sentinel sites)
investigations of product quality
product usage data and drug utilisation information
clinical trials, including research in unauthorised indications or populations
observational studies, including registries
patient support programs
systematic reviews and meta-analysis
marketing authorisation holders sponsored websites
published scientific literature or reports from abstracts, including information
presented at scientific meetingsunpublished manuscripts
licensing partners, other sponsors or academic institutions and researchnetworks
competent authorities (worldwide)
7/22/2019 Benefit Risk Analysis
14/53 Mapi 2013, All rights reserved 14
Overview of Signals
7/22/2019 Benefit Risk Analysis
15/53 Mapi 2013, All rights reserved 15
Safety Signal Evaluation
source or trigger of the signal
background relevant to the evaluation
method(s) of evaluation, including data sources, search criteria (whereapplicable, the specific MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) orStandardised MedDRA Queries (SMQs) that were reviewed), and analytical
approaches
results - a summary and critical analysis of the data considered inthe signal evaluation; where integral to the assessment, this may include adescription of a case series or an individual case (e.g. an index case of welldocumented agranulocytosis or Stevens Johnson Syndrome)
discussion
conclusion
7/22/2019 Benefit Risk Analysis
16/53 Mapi 2013, All rights reserved 16
The EU single assessment
In order to increase the shared use of resources between
competent authorities in Member States, a single assessmentof PSURs shall be performed in the EU
A single EU PSUR assessment provides a mechanism forevaluating the totality of available data on the benefits
and risks of an active substance or combination of activesubstances.
The EU single assessment is the assessment of PSURs formedicinal products
subject to different marketing authorisations
containing the same active substance or the same combination of activesubstances
whether or not held by the same marketing authorisation holder
and for which the frequency and dates of submission of PSUR have beenharmonised in the list of EU reference dates
7/22/2019 Benefit Risk Analysis
17/53 Mapi 2013, All rights reserved 17
European Union reference date (EURD)
This corresponds to the date of the first or the earliestknown date of the marketing authorisation in the Unionof a medicinal product containing the active substance orcombination of active substances
EU reference dates list - a list of active substances and
combinations of active substances sorted in alphabeticalorder, for which PSURs shall be submitted in accordance withthe EU reference dates and frequencies determined by theCommittee for Medicinal Products for Human Use (CHMP) andthe Coordination Group for Mutual Recognition andDecentralised Procedures - Human (CMDh) following
consultation with the Pharmacovigilance and Risk AssessmentCommittee (PRAC)
The EURD list is available on the web portal of EMA
7/22/2019 Benefit Risk Analysis
18/53 Mapi 2013, All rights reserved 18
Frequency of the PSUR
The MAH is required to submit PSURs once a medicinal
product is authorised in the EU, even if it is not marketed
If the active substance contained in the medicinal product isnot listed on the EURD list, the MAH should continue tosubmit PSUR according to the condition in the MA if any,
otherwise according to the standard submission cycle:Immediately upon request
At least 6 monthly after authorisation and until the placing on themarket
At least 6 monthly for the first two years after being placed on themarket
Annually for the subsequent two yearsThereafter at three-yearly intervals
The EURD list is binding from DLPs as of1st April 2013
7/22/2019 Benefit Risk Analysis
19/53 Mapi 2013, All rights reserved 19
Timelines for submission
Marketing authorisation holders should submit to theAgency PSURs within 70 or 90 days from the datalock point:
within 70 calendar days of the data lock point (day 0) for PSURscovering intervals up to 12 months (including intervals of exactly12 months); and
within 90 calendar days of the data lock point (day 0) for PSURscovering intervals in excess of 12 months;
the timeline for the submission of ad hoc PSURs requested bycompetent authorities will be normally specified in the request,otherwise the ad hoc PSURs should be submitted within 90 daysof the data lock point.
Additional timelines provided due to the increasedcomplexity of the PSUR
7/22/2019 Benefit Risk Analysis
20/53
Mapi 2013, All rights reserved 20
Interim Arrangements for submission of PSURs
Before the Agencys PSUR repository is in place
MAHs shall submit the PSURs to all competent authorities in MemberStates in which the medicinal products are authorised
For the substances or combination of active substances subject to asingle assessment or for which an EU reference date has beenestablished, the PSURs should be also sent to the Agency
The competent authorities in Member States requirements for thesubmission of PSURs during this transitional period are published in the
Agency web-site
From 12 months after the functionalities of the repository havebeen established and have been announced by the Agency, themarketing authorisation holders shall submit the PSURselectronically to the Agency
Once the structured electronic format ePSUR, based on contentagreed in the ICH-E2C(R2), becomes available, marketingauthorisation holders will have the possibility to submit PSURs andrelated documents automatically via an electronic gateway
7/22/2019 Benefit Risk Analysis
21/53
Mapi 2013, All rights reserved 21
Evaluation of the PSUR
Day Action
Day 0 Start of the procedure according to the published timetable
Day 60 PRAC Rapporteurs preliminary assessment report
Day 90 MAH and PRAC members comments
Day 105 PRAC Rapporteurs updated assessment report (if necessary)
Day 120 PRAC recommendation adoption with the final PRAC assessmentreport
Day 134 CHMP opinion / CMDh position
7/22/2019 Benefit Risk Analysis
22/53
Mapi 2013, All rights reserved 22
Transparency
Publication of PSUR-related documents on the European
medicines and national medicines web-portals
list of EU reference dates and frequency of submission of PSURs
final assessment conclusions of the adopted assessment reports
PRAC recommendations including relevant annexes
CMDh position including relevant annexes and where applicable, detailedexplanation on scientific grounds for any differences with the PRACrecommendations
CHMP opinion including relevant annexes and where applicable, detailed
explanation on scientific grounds for any differences with the PRACrecommendations
European Commission decision
7/22/2019 Benefit Risk Analysis
23/53
Mapi 2013, All rights reserved 23
Quality Management System at MAH
Specific quality system procedures and processes shall be in place in order
to ensure the update of product information
Responsibility of the marketing authorisation holder to check regularly the list ofEU reference dates and frequency of submission published in the Europeanmedicines web-portal to ensure compliance with the PSUR reportingrequirements for their medicinal products
Systems should be in place to schedule the production of PSURs as perregulatory requirements and ad hoc requests
For those medicinal products where the submission of an RMP is not required,the marketing authorisation holder should maintain on file a specification ofimportant identified risks, important potential risks and importantmissing information in order to support the preparation of the PSURs
The marketing authorisation holder should have procedures in place to followthe requirements established by the Agency for the submission of PSURs.
The QPPV shall be responsible for the establishment and maintenance ofthe pharmacovigilance system
7/22/2019 Benefit Risk Analysis
24/53
Mapi 2013, All rights reserved 24
Section 1Challenges in preparing the
PSUR
7/22/2019 Benefit Risk Analysis
25/53
Mapi 2013, All rights reserved 25
New document, new requirements
Creation of a new process for producing the reportbased on new and additional data required fromdifferent stakeholders
New templateModular structure
E-submissions
Training of resourcesIdentification of concerned Departments
Identification of relevant personnel
Internal/External training
Maintaining complianceDocumentation
Internal/external audits
7/22/2019 Benefit Risk Analysis
26/53
Mapi 2013, All rights reserved 26
Multi-functional involvement
Roles, responsibilities and timelines for gathering thedata required
Clear leadership
Early planning
Availability of personnel
Timely contributions by stakeholders
Peak workloads
Appropriate oversight if you consider outsourcing
Close collaboration
Commitment by different stakeholdersRegular communication
Agreement on conclusions
7/22/2019 Benefit Risk Analysis
27/53
Mapi 2013, All rights reserved 27
Signal Management Process
Signal Detection processDocumented, compliant process and system
Timely follow-up of signalsTime & Resource constraints
Training
Overview of signalsClear ownership
Up-to-date information
7/22/2019 Benefit Risk Analysis
28/53
Mapi 2013, All rights reserved 28
No globally accepted standards of benefit-riskmethodology
New requirement
Wide variation exists in the industry
Qualitative or Quantitative?
7/22/2019 Benefit Risk Analysis
29/53
Mapi 2013, All rights reserved 29
Strategies for presenting thebenefit-risk analysis
7/22/2019 Benefit Risk Analysis
30/53
Mapi 2013, All rights reserved 30
GVP Definition: Risk-benefit balance
An evaluation of the positive therapeutic effects ofthe medicinal product in relation to the risks [DIR2001/83/EC Art 1(28a)] (i.e. any risk relating to thequality, safety or efficacy of the medicinal product asregards patients health or public health [DIR2001/83/EC Art 1(28)]).
7/22/2019 Benefit Risk Analysis
31/53
Mapi 2013, All rights reserved 31
GVP Module Guidance - Provide a clearexplanation of the methodology and reasoning
used to develop the benefit-risk evaluation:
The assumptions, considerations, and judgement orweighting that support the conclusions of the benefit-risk evaluation should be clear.
If a formal quantitative or semi-quantitative assessmentof benefit-risk is provided, a summary of the methodsshould be included.
Economic considerations (e.g. cost-effectiveness)should not be considered in the benefit-risk evaluation.
7/22/2019 Benefit Risk Analysis
32/53
Mapi 2013, All rights reserved 32
ICH EC2 Benefit:Risk Assessment Method
Onlykey benefits and risks considered in the evaluationshould be specified
Context of use of the medicinal product
Benefit - consider its nature, clinical importance,
duration, and generalizability, as well as evidence ofefficacy in non-responders to other therapies andalternative treatments.
Risk - consider its clinical importance, e.g., nature oftoxicity, seriousness, frequency, predictability,
preventability, reversibility, impact on patients, andwhether it arose from off-label use, a new use, ormisuse.
7/22/2019 Benefit Risk Analysis
33/53
Mapi 2013, All rights reserved 33
ICH EC2 Benefit:Risk Assessment Method (2)
Strengths, weaknesses, and uncertainties of theevidence should be considered when formulating thebenefit-risk evaluation.
Explanation of the methodology and reasoning used todevelop the benefit-risk evaluation
Comment on the feasibility of expressing benefitsand risks in such a way as to facilitate theircomparison.
If a formal quantitative assessment of benefit-riskis provided, a summary of the methods should be
included.Economic considerations (e.g., cost-effectiveness)
should not be considered in the benefit-riskevaluation.
7/22/2019 Benefit Risk Analysis
34/53
Mapi 2013, All rights reserved 34
FTIHdecisionpoint
Ph 2bdecisionpoint
Commit toP3 decisionpoint
Filedecisionpoint
Development ActivitiesPost-Marketing Plan
Epidemiology disease info
Expected Actual use Target & actual use
pop.co-morbidities
Increased awareness in
target populationActual use population
Pre-clin data, Competitors,
Previous experience,
regulatory knowledge+ Phase I-II data
+ Phase II-III data + Post-marketing
experience
Pre-clin data, Competitors,
Previous experience,
regulatory knowledge
+ Phase I-II data,
Health
outcomes
+ Phase II-III data,
health economics
+ Post-
marketingexperience
Candidateselection
Disease specific
B:R profile (& model)B:R profile based on product facts
(reality profile)
D
isease
Risk
Be
nefit
P
rofile
Strategy
Systematic Benefit and Risk Assessment used to Build Development and Post-Marketing Strategy (2002)
7/22/2019 Benefit Risk Analysis
35/53
Mapi 2013, All rights reserved 35
Eichler (EMA) DIA Annual Meeting June 2009
7/22/2019 Benefit Risk Analysis
36/53
Mapi 2013, All rights reserved 36
Benefit-risk methodology project (2010)
7/22/2019 Benefit Risk Analysis
37/53
Mapi 2013, All rights reserved 37
Qualitative Approaches
A generic qualitative approach of eight steps fordecision making, PrOACT, is presented as it might applyto decision-making by regulators, followed bydescriptions of three approaches currently underdevelopment: PhRMA BRAT, CMR CASS study and FDA
BRF.
7/22/2019 Benefit Risk Analysis
38/53
Mapi 2013, All rights reserved 38
PrOACT
PROBLEM. Determine the nature of the problem and its context(approve/disapprove, restrict);
OBJECTIVES. Identify objectives that indicate the overall purposes tobe achieved (e.g., maximise favourable effects, minimiseunfavourable effects), and develop criteria against which thealternatives can be evaluated
ALTERNATIVES. Identify the options (actions about a medicinalproduct or the products themselves) to be evaluated
CONSEQUENCES. describe how the alternative would perform on thecriteria
TRADE-OFFS. Assess the balance between favourable andunfavourable effects.
UNCERTAINTY. Consider how the balance between favourable andunfavourable effects would change by taking account of the
uncertainty associated with the consequences.RISK. Judge the relative importance of the Agencys risk attitude forthis medicinal product and how risk would be
LINKED DECISIONS. Consider the consistency of this decision withsimilar past decisions, and assess whether taking this decision couldimpact future decisions
7/22/2019 Benefit Risk Analysis
39/53
Mapi 2013, All rights reserved 39
A sub-discipline of operations researchthat explicitly considers multi-criteria indecision-making environments.7 steps that form a conceptual framework.
Establish the decision context.
Identify the options to be appraised.
Identification of the benefit and risk criteria & organization into a value tree.
Assessment of expected performance of each option against criteria.
Assign weights for each criterion to reflect relative importance.
Calculation of weighted scores at each level in hierarchy and overall.
Examination of results and sensitivity analysis.
Quantitative B-R Methods
MULTI-CRITERIA DECISION ANALYIS (MCDA)
7/22/2019 Benefit Risk Analysis
40/53
Mapi 2013, All rights reserved 40
7/22/2019 Benefit Risk Analysis
41/53
Mapi 2013, All rights reserved 41
7/22/2019 Benefit Risk Analysis
42/53
Mapi 2013, All rights reserved 42
7/22/2019 Benefit Risk Analysis
43/53
Mapi 2013, All rights reserved 43
7/22/2019 Benefit Risk Analysis
44/53
Mapi 2013, All rights reserved 44
7/22/2019 Benefit Risk Analysis
45/53
Mapi 2013, All rights reserved 45
7/22/2019 Benefit Risk Analysis
46/53
Mapi 2013, All rights reserved 46
7/22/2019 Benefit Risk Analysis
47/53
Mapi 2013, All rights reserved 47
7/22/2019 Benefit Risk Analysis
48/53
Mapi 2013, All rights reserved 48
Current Scenario:
Systematic Structured Benefit:Risk Assessment isbecoming part of regulatory requirements in EU, USA,Japan
Qualitative approaches generally similar
Quantitative approaches - limited by ability to comparedissimilar health benefits and risks
MCDA provides modelling technique to comparedifferent benefits and risks, provides tools for sensitivityanalysis
EMA and other EU regulatory agencies working tounderstand decision making context
7/22/2019 Benefit Risk Analysis
49/53
Mapi 2013, All rights reserved 49
Summary
7/22/2019 Benefit Risk Analysis
50/53
Mapi 2013, All rights reserved 50
Summary
There has been a paradigm shift in the new format andcontent of the PSUR, legally required in the EU from Jan 2013and accepted in the other ICH regions - US and Japan
The sections on signal detection and benefit-risk analysispresent new challenges for the preparation of the PSUR
If a formal quantitative or semi-quantitative assessment ofbenefit-risk is provided, a summary of the methods should beincluded
The assumptions, considerations, and judgement or weightingthat support the conclusions of the benefit-risk evaluationshould be clear
7/22/2019 Benefit Risk Analysis
51/53
Mapi 2013, All rights reserved 51
Questions
7/22/2019 Benefit Risk Analysis
52/53
Mapi 2013, All rights reserved 52
Thank you for attending!
Hemendra Misra: [email protected]
Will Maier: [email protected]
7/22/2019 Benefit Risk Analysis
53/53
Global Head Office: 27 rue de la Villette | 69003 Lyon | France | Tel: +33 (0) 4 72 13 66 93
US Head Office: 2343 Alexandria Drive | Suite 100 | Lexington | KY 40504 | USA | Tel +1 859 223 4334
[email protected] | www.mapigroup.com