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2021 Virtual GPF Slides

Published by Health Technology Assessment International (HTAi), 2021-02-26 19:11:06

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18th HTAi Global Policy Forum Considering and Communicating Uncertainty in HTA 22, 24, and 26 February 2021 Virtual

Welcome and Introductions Monday, February 22

Welcome/Introductions • New GPF members: BC Cancer, AQuAS, IETS, Boehringer Ingelheim, W.L. Gore & Associates • Patient representatives: – Ann Single – Ivett Jakab – Aline Silveira Silva – Elisabeth Oehrlein – Anne-Pierre Pickaert • Invited speakers, HTAi Board members

Welcome/Introductions • With ~100 attendees (!), no time for individual introductions • Please use your full name and affiliation as your “Zoom name” to save time • Rename either from your image window or the “participant pane” - >

Ground rules/housekeeping • Chatham House Rule: −Participants are free to use the information received, but neither the identity nor the affiliation of the speaker(s), nor that of any other participant, may be publicly revealed −This includes social media! −Presentations, Zoom recordings, etc. can be shared within member organizations

Ground rules/housekeeping • Meeting participation will work best if you change your view setting to “Speaker View”

Ground rules/housekeeping • HTAi organizers will mute all microphones and we ask you turn off all cameras while each speaker is presenting • Speakers will receive a 2-minute “warning” in the Chat window; I will come on at ~1 minute over time to move us along • Brief time allotted after each talk for clarifying questions only (plenary/breakout for broader discussion)

Ground rules/housekeeping • Participants may raise their virtual “hands” to ask questions or participate in discussion – You will be called on in the order in which you raised your hand • You may also ask questions or share your thoughts via the Chat window – We will regularly pull questions and themes from Chat into the discussion

Ground rules/housekeeping • If you need help or technical assistance, please email Bryce Doherty at [email protected]

Sli.do During the meeting you will be prompted on when to open sli.do Visit sli.do or www.slido.com Enter the event code #2021GPF

2021 Global Policy Forum Considering & Communicating Uncertainty in HTA

Until Next Year, den Hague…

Participation Guidance • Structure: “ITO” framework • Focus: Key considerations for HTA management of uncertainty and conveyance of the role uncertainty plays in decisions and recommendations • Useful sections of program −Key questions and background (pp. 8-10) −Annex 2: HTA examples (pp. 35-46)

Why Focus on This Now? • Have we had greater uncertainty in our lifetimes?

Agenda: Day 1 • Background paper summary: Rebecca Trowman • Keynote recap and Q&A with Tim Caulfield • Coffee Break • Plenary talks – Rosanne Janssens, KU Leuven – Tina Wang, CIRS – Alexander Natz, EUCOPE • Coffee Break • Plenary discussion: the future of uncertainty and impact for HTA • GROUP PHOTO!

Topic Introduction and Background HTAi 2021 Global Policy Forum

Development of Background Paper: • Expert interviews • Literature and website reviews • HTA Agency survey • GPF member consultation • Annex 1: Examples of Evidence Rating Mechanisms • Annex 2: Examples of HTA Agency Methods Regarding Uncertainty • Annex 3: Case Studies

Johari Window “There are TO OTHERS “Known Knowns” known knowns, known unknowns “Known Unknowns” and unknown unknow ns” D .R u m s f e l d “Unknown Knowns” “Unknown Unknowns” TO SELF

INPUT MechanismsTHROUGHPUT OUTPUT for additional Collect evidence, inputCritically examine Communicate the information and Mechanisms forevidence and weigh theoutcome, the level of perspectives; explore the presence and impact additionaluncertainty and itsuncertainty and its of uncertainty deliberationimpact impact Stakeholder Involvement Stakeholder Involvement Stakeholder Involvement • Scoping discussions • Attendance/participation • Review and feedback on • Input via templated in evidence presentation draft recommendations submission forms and deliberation • Discussion with • Testimony for committee committee members • Feedback from HTA staff

Jigsaw Puzzles- An Analogy Input Throughput Output

Input Uncertainty Type Common Issues Exploration/Quantification Methods Clinical Small studies; single arm studies; -Quality measures (e.g. GRADE) short follow-up; non-generalizable -Surrogates (calibrated/tested) Economic trial populations and comparators Model (parameter and Parameter: -Calibration structural) Point estimates; sample sizes -Sensitivity analyses (deterministic/scenario/ Affordability (impacted by generalizability as above) threshold/probabilistic) Structural: Too many/not enough health states; -VoI analyses discounting; time horizon -TRUST -TRUST4RD Size of population; real world costs Sensitivity/scenario analysis Budget impact analysis

Throughput Uncertainty • Understanding Uncertainty Stakeholder inputs Consistency of terminology • Managing Uncertainty Deliberating on Uncertainty • Context of Uncertainty Financial Risk Mitigation Generate Additional Evidence Consistency and Predictability

WHO? Output Uncertainty communicates: WHAT? TO WHOM ? HOW? WHAT EFFECT ? Patients (citizens), Manufacturers, Health System Stakeholders

Case Study Examples Case Study Considerations Recommendations CAR T Therapy (Kymriah) Small trial population; single arm studies Recommended in most jurisdictions after (historical controls); short follow-up, up to re-submissions with MEA in place Spinal Muscular Atrophy $475k USD (Spinraza and Zolgensma) Small trial populations (imbalanced), short Various subgroups for spinraza Transvaginal Mesh follow-up, multiple subtypes, $750k + recommended, all with MEA in place. $375k USD p.a. (spinraza) and $2.125m USD (zolgensma) Zolgensma not yet widely assessed (ICER suggest the ‘one-shot’ is cost effective) Approved for use with limited evidence Variable recommendations (in use -> base, limited credentialling and caution->banned) assessment of the surgical procedure Patient counselling and education key

Thank You 1-780-448-4881 | [email protected]| | htai.org Follow us on Twitter, Facebook, Linked In @HTAiorg

Disclaimer • The views and opinions are those of the individual presenter and should not be attributed to any organisation with which the presenter is employed or affiliated. • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws. Used by permission. All rights reserved. 26

Uncertainty: what’s in a name? “A feeling that blocks or Several definitions… delays decisions1” “The inability to act “A general term referring to all types deterministically owing to lack of of limitations in available knowledge cause-effect understanding4” that affect the range and probability of possible answers to an assessment question2“ “A situation in which one has no “The difference in the amount of “Lack of precise knowledge about which of the information required to perform a knowledge about the several states of nature has occurred task and the amount of information likelihood of events6” or will occur3” already possessed by the organisation5” 27 1Lipshitz and Strauss, 1997; 2EFSA Scientific Committee, 2018; 3Anderson et al. (1981); 4Thompson (1967) ); 5Galbraith (1973) ); 6Hogarth (1987)

Uncertainty: what’s in a name? “A feeling that blocks or Several definitions…with related concepts delays decisions1” “The inability to act “A general term referring to all types of limitations in available deterministically owing to lack of knowledge that affect the range and cause-effect understanding4” probability of possible answers to an assessment question2“ “A situation in which one has no “The difference in the amount of “Lack of precise knowledge about which of the information required to perform a several states of nature has occurred task and the amount of information knowledge about the or will occur3” already possessed by the likelihood of events6” organisation5” 28 1Lipshitz and Strauss, 1997; 2EFSA Scientific Committee, 2018; 3Anderson et al. (1981); 4Thompson (1967) ); 5Galbraith (1973) ); 6Hogarth (1987)

Regulatory benefit-risk assessment • Balancing the desired effects or 'benefits' of a medicine against its undesired effects or 'risks’ • Regulators recommend marketing authorisation Benefits if they judge benefits > risks • In contrast, a medicine whose risks > benefits is Risks not recommended for authorisation • Complex because of uncertainties around the data (benefits and risks) that is available at a given point in time 29

Uncertainties in regulatory benefit-risk assessment Where do they stem from? Industry Regulators HTA/payers Physicians Patients Generation of data Assessment of data Assessment of common data HTA: Health Technology Assessment  knowledge gaps  common knowledge gaps  uncertainties  common uncertainties 30

What kind of uncertainties do regulators assess? EPAR, SmPC, RMP of How do regulators manage uncertainties? oncology products Analysis of uncertainties and coping strategies from: • European Assessment Reports (EPARs) • Summary of the Risk Management Plan (RMP) • Summary of Product Characteristics (SmPC) 31 Janssens et al., ISPOR conference, 2019

Characterising uncertainties and coping strategies: an example - TYPE of UNCERTAINTY: what caused the uncertainty? - ISSUE of UNCERTAINTY: what was the uncertainty about? - COPING STRATEGY: how was the uncertainty addressed? 32

Characterising uncertainties and coping strategies: an example - TYPE of UNCERTAINTY: what caused the uncertainty? = lack of data - ISSUE of UNCERTAINTY: what was the uncertainty about? = long term effect - COPING STRATEGY: how was the uncertainty addressed? = submit data 33

Classification of 276 uncertainties and coping strategies TYPES of UNCERTAINTY: uncertainty caused by COPING STRATEGIES: what was done to address the ISSUES of UNCERTAINTY: uncertainty about uncertainty Insufficient data (65%) Effect size or type: 47% Ask data: 66% Unreliable data Subpopulation: 31% (21%) Accept uncertainty: Long term effect: 66% Conflicting 11% data: 8% Manage impact Benefit-risk via SmPC or Lack of balance: 7% RMM: 22% understanding Relative Apply of the data: effect or RMP reasoning: 5% measure: 4% 12% RMP: Risk Management Plan; SmPC: Summary of Product Characteristics; RMM: Risk Minimisation Measure 34 Janssens et al., ISPOR conference, 2019

Classification of 276 uncertainties and coping strategies EPAR, SmPC, RMP of oncology products • Regulators accepted the majority of uncertainties with request for more data post approval • The number of uncertainties per product was significantly lower for products with a Randomised Controlled Trial (RCT) • Regulators asked data significantly more for products without RCT, for products with conditional or with an exceptional marketing authorisation 35 Janssens et al., ISPOR conference, 2019

Uncertainties in regulatory benefit-risk assessment Take-aways & future outlooks • Uncertainties can influence, block or delay regulatory approval • More uncertainties when less comprehensive data; products without RCTs, for accelerated, conditional and exceptional approvals • Uncertainties at time of approval are passed onto the healthcare system (payers, physicians, patients) • Regulators should therefore continue striving for systematically communicating uncertainties in a detailed manner, and applied coping strategies, to inform downstream decision-makers and decisions • High-quality post-marketing studies should resolve uncertainties raised during the initial authorisation • Systematic identification, management and description of uncertainties is key for strengthening the quality of regulatory and down-stream decision-making 36 RCT: Randomised Controlled Trial

Thank You Questions, comments, suggestions, research ideas? Contact: [email protected] 37

Developing a framework for HTA management of uncertainty Feedback from CIRS Multi-stakeholder workshops Tina Wang, Manager - HTA programme Centre for Innovation in Regulatory Science (CIRS)

Overview Identifying and articulating types of uncertainties during development of new medicine. How can this improve Regulatory and HTA decision making?  Background of the workshop  Articulate uncertainty  Identify uncertainty  IUMP: Integrated Uncertainty Management Plan  The way forward

CIRS operates as a non-for- Understanding of the limits of our knowledge and profit organization, we aim providing a lifecycle framework to manage uncertainty to provide a neutral, independent, international forum for Regulators, HTA, Industry and other healthcare stakeholders to meet, debate and develop strategic and policy-level thinking. Identifying and understanding regulatory and reimbursement uncertainty during development: How can this improve predictability of regulatory and HTA outcomes? CIRS multi-stakeholder workshop: 9 - 10 October 2019

Types of uncertainty  stochastic uncertainty: uncertainty resulting from unpredictable conditions  epistemic uncertainty: uncertainty resulting from lack of available information  decision uncertainty: uncertainty resulting from a decision making process Regulator HTAi 2021 GPF Background paper HTA Payer Patient Industry Source: Adapted from Stolk P, CIRS-Utrecht Univ Joint Forum, November 2018

Identify uncertainty during development To identify resolvable and unresolvable uncertainties during development to improve better evidence generation. Resolvable For example, meaningful endpoints, Early identification tools • Adequate sample size reduces appropriate comparators, place in mitigation strategy clinical practice, model structure and imprecision input • Scientific rigour reduces bias Unresolvable For example, long-term outcomes for Risk-management tools, • Random and systematic error earlier treatment of degenerative post-approval evidence • Long-term patient-relevant diseases: Alzheimer’s, Multiple Sclerosis generation health outcomes Source: 2015 HTAi Global Policy Forum Background paper 2019 CIRS multi-stakeholder workshop: Identifying and understanding regulatory and reimbursement uncertainty during development: How can this improve predictability of regulatory and HTA outcomes?

Tools used by companies to identify uncertainty Company Horizon scanning for HTA can facilitate understanding of the diversity in value Horizon Scanning frameworks and potentially identify commonalities in evidentiary requirements Multi-stakeholder Evidence generation during development Early scientific advice Post licensing evidence generation plan (PLEG) National HTA + HTA HTA + Regulator + HTA Payer HTA Source Adapted from Granados A : CIRS multi-stakeholder workshop, October 2019

Areas where early scientific advice could inform company strategy – company perception Enables early changes required for the development ; eg, endpoints,… Validates internal thinking and endorses clinical trial design Evidence package for regulatory submission strategy Improves understanding of the divergences of HTA requirements Deciding on possible regulatory pathway or designation Supports internal management decisions Used by management in development go/no go decisions Evidence package for HTA submission Enables cross-functional communication within my company Development of the product’s target product profile What to consider for post-approval plans Increasingly discussed at the recent early advice meetings 0 2 4 6 8 10 12 Critical Maybe useful Source: 2018 CIRS Multi-stakeholder workshop survey

Integrated Uncertainty Management Plan Explore concept of an “Integrated Uncertainty Management Plan” (IUMP) • A framework that can be used over the ‘life cycle’ with clinical development focus. • A living plan that is being produced by a company and discussed in the context of regulatory and HTA advice, including relevant stakeholders. • Should include identification of uncertainties in relation to key aspects of medicines development towards market. • Should include proposals on how to mitigate these uncertainties, including perspectives and preferences from patients and prescribers. • Should have a mechanism for continuous reporting / updating as development progresses. Source: Adapted from Syndicate discussion: CIRS multi-stakeholder workshop, October 2019

Key questions to be addressed Can regulators, HTA bodies, payers and companies utilize the same framework? • How are current regulatory and HTA pathways and guidance frameworks linked to the issue of uncertainties? • How can we create the same baseline understanding of handling mitigation of (aligned) uncertainties? • Do we need to consider that uncertainties must likely be addressed at different time points (stop / go decision points)? Assess the current regulatory and HTA pathways and guidance frameworks are linked to the issue of uncertainties Possibility to develop a list of uncertainties that need mitigation? • How are stakeholders currently working with and addressing uncertainties? • Alignment on identification of uncertainties across stakeholders or per stakeholder? • Do we consider variation in needs across disease areas? Milestone approach as a starting point for listing uncertainties. Source: Adapted from Syndicate discussion: CIRS multi-stakeholder workshop, October 2019

IUMP - milestone approach Uncertainty Uncertainty (HTA) Uncertainty Uncertainty - Comparator? - Right population? - Budget impact - What drives uptake and final - Outcomes? - Real life setting? access? - Target population? - Crossover? - Prescriber behaviour - Patient ident? - Added value? - Healthcare inftrastructure - Price / RoI? Uncertainty (Reg) Payers Commercialisation Market TPP - B/R Mitigation - Long term E and S? - Decision on lim data? - Mapping needs - Dialogue with Regulatory HTA stakeholders - Validation PROs Mitigation (HTA) Mitigation Mitigation - Biomarkers - Patient input - Horizon scanning - Horizon scanning - Extrapolation - C/E - Clinician perspective - Indirect comparison - Price - Best practice implementation - Post-appr RWE - Companion diagnostics Mitigation (Reg) - Post approval req Source: Adapted from Syndicate discussion: CIRS multi-stakeholder workshop, October 2019

The way forward Short term Longer term Mapping exercise on current context: Discuss and refine IUMP scope and methodology: • Re-visit current interaction framework with • Map existing advice pathways to recommendation on potential need for understand timing and purpose in relation changes – including patient and prescriber to development and which type of perspectives. uncertainties in scope. • Recommend structured methodology for assessing and aligning on uncertainties and • Map different HTA systems for better mitigation activities. understanding of potential ‘global’ • Assess and address gaps in incentives for approach to IUMP. data collection (uncertainties mitigation) in relation to IUMP framework. • Map existing activities across stakeholders with view to understanding potential for Source optimizing use / combine in context of Adapted from Syndicate recommendation: CIRS multi-stakeholder workshop, October 2019 IUMP framework.

Thank You Tina Wang Manager - HTA programme CIRS - Centre for Innovation in Regulatory Science [email protected]

Industry needs and responsibility in dealing with uncertainty in HTA decisions Dr. Alexander Natz, Secretary General EUCOPE 50


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