Implementing Benefit-Risk Management More Effectively

Transcription

1 Implementing Benefit-Risk Management More Effectively Steve Mayall, Principal Consultant June 2017 Pope Woodhead & Associates Ltd. The Old Grammar School, 1 Ramsey Road, St. Ives, Cambridgeshire, PE27 5BZ, UK Tel: +44 (0)

2 Having a robust, structured benefit-risk (B-R) assessment process has recently become a much higher priority Challenges Raised expectations for demonstrating B-R Past decade of B-R initiatives established approaches More global alignment on B-R requirements Recent ICH M4E(R2) guideline introduces structured B-R information into the CTD High influence of health technology assessments (HTAs) Diversity of national, regional, and local needs for product B-R value Increased transparency of B-R data EMA public access to clinical CTD submission package information Needed throughout the product life cycle From first-in-man clinical studies through to post launch Structured B-R assessment process 2

3 Benefit-risk evaluations perform a critical role throughout the product life cycle Challenges What B-R assessment approach should we use? What evidence is already available? Where are the gaps? How does the B-R profile compare to the TPP? Phases I - II Phase III How do we express B-R: to regulators in the CTD submission? to payers in pricing and reimbursement documents? to HCPs and patients/carers in comms materials? How do further safety and outcomes data impact B-R? What is the B-R balance for new indications? How do we report B-R in the PBRER/PSUR, RMP updates, etc? Filing Approval Post launch 3

4 Each benefit-risk assessment impacts a variety of downstream deliverables for multiple stakeholders Challenges Audience Ph1 Ph2 Ph3 Submissions/ Filing Approval/ Launch Post launch Agree B-R ownership Internal Produce TPP Refine and test TPP Perform B-R assessments at appropriate intervals Develop and update DRMP Prepare DSUR Update DSUR Update DSUR Produce/update PBRER Regulators Prepare drug label Prepare MAA, CTD B-R section Develop EU-RMP, REMS, etc. Agree & develop Risk Minimization Strategy & Measures (RMMs) EU-RMP & RMM updates RMM effectiveness eval. Clinical study approvals Add l evidence gen. strategy (PV plan) RWE for regulators/payers Implement studies/registry Qual pricing research Quant pricing research Payers Early value proposition Early economic model GVD; BI/CE models Payer education/ engagement tools Develop scientific communication plan MEA (finance /outcome-based) strategy HCPs/ Investigators Patients/ Caregivers Develop & update Investigator s Brochure Informed consent form User test RMMs KOL engagement plan User test RMMs Implement HCP RMMs Design and use other external communication materials Implement Patient RMMs Deliverable finalization 4

5 The ICH M4E(R2) guideline provides a new structure for benefit-risk information in the CTD Clinical Overview, driving change Challenges Global approach for presenting product B-R information in filings for approval M4E(R2) revised guideline adopted by ICH in June 2016 Section Benefits and Risks Conclusions Therapeutic Context Describe medical need Disease or Condition Current Therapies Benefits Risks Benefit-Risk Assessment Appendix Describe key benefits (major efficacy endpoints; may also include combination endpoints, important characteristics) Describe key risks (subset of important risks ) and how they will be managed Summary and explanation of B-R conclusions, interpreting data from the previous subsections. May include tables and graphical displays Presentation of more detailed B-R methodology 5

6 Objectives Approach At a fundamental level, an assessment approach centres on three phases to plan, assess, and communicate audience-centric benefit-risk results 1 Framework 2 3 identification and methodology Benefit-risk assessment alignment Communicate and integrate B-R findings Define overarching framework to support systematic decision-making Identify potential individual techniques/methodologies Perform B-R assessment according to the agreed framework and relevant methodologies Communicate findings to specific stakeholder audiences via tailored visualisations Incorporate assessment findings into product development Select Implement 6

7 Benefit-risk assessment frameworks offer a structured approach to the decision-making process Approach Framework choice PrOACT-URL Output EMA Effects Table Produces Benefit-Risk Action Team (BRAT)? Multi-Criteria Decision Analysis (MCDA) FDA Benefit-Risk Framework Table? CTD Clinical Overview Benefits and Risks Conclusions Adapted from Phillips et al., 2011; Coplan et al., 2011; Hughes et al., 2013; Thokala et al.,

8 Life cycle B-R A flexible benefit-risk approach is needed across the product life cycle Life cycle stage B-R assessments throughout the product life cycle Suitable level of assessment for different life cycle stages Product evidence base Potential for new data Audience and end-deliverable Adapt B-R assessment to quantity, quality and consistency of available product benefit and risk data Non-clinical, clinical, post-marketing, external data sources Influence of multiple indications and use of comparators Incorporate preferences of key stakeholders, e.g. patients B-R assessment helps identify gaps in the development programme and supports decision-making Target stakeholders may be regulators, payers, healthcare professionals and/or patients Visualisation outputs depend on where B-R assessment results will be presented 8

9 Organisation factors Given the quantity and timing of impacted activities, a benefit-risk assessment strategy should be developed at an early stage Benefit to product Reduces impact of post- Phase 3 time & resource requirements Identifies issues & potential solutions early, to minimise future delays/costs Allows for faster & more efficient decision-making across functions Supports ongoing & future discussions with regulators & payers Rationale Pre-filing period is already filled with many time-consuming activities B-R assessments typically require a significant degree of time and resource Producing a useful B-R assessment is an iterative process Complexity of differences (both regulatory & market access) across markets Permits efficient development planning and data generation needs to address gaps B-R approach can remain flexible/adaptable to Phase 3 results Summary of current data in structured format keeps decision-making process systematic Enables efficient addition of new data to the B-R assessment Common company view of B-R profile allows for consistent approach and helps reduce fragmentation between functional areas Demonstrating a systematic, justifiable B-R assessment approach increases likelihood of regulatory approval Presenting a concise, clear B-R profile aids interpretation Proactive approach reduces the likelihood of imposed commitments 9

10 Organisational factors are also important for the benefit-risk assessment approach taken Organisation factors Companies Regulators Big pharma company FDA Crossfunctional interactions Global-tolocal interactions EMA Varying organisational complexity Consistency of interactions MHLW/ PMDA Biotech Other Health Authorities 10

11 The chosen benefit-risk assessment approach needs embedding within an organisation to succeed Change management factors might be viewed as mundane but are critical! Organisation factors People Senior management should be visibly supportive and remain engaged All relevant functional areas engaged and teams with clearly defined roles Strong communication and training that maintain momentum Process Structured B-R approach customised to the needs and complexity of the organisation Successfully interacts with existing company procedures Pilot Careful selection of pilot projects Critical for demonstrating value to stakeholders and providing early, tangible evidence of success Adapt approach based on pilot before wider roll-out 11

12 The benefit-risk process interacts with and impacts the gated development process Life cycle process Ph1 Ph2 Ph3 Submissions/ Filing Approval/ Launch Post launch TPP TPP TPP CTD PBRER/ PSUR B-R evaluation B-R evaluation B-R evaluation and develop B-R materials Refine B-R profile and materials What is the role of B-R information currently in the gated development process? Variation through life cycle and for licencing Where are the current issues and what impacts are they having? Significant problems and risks What B-R information does a TPP currently contain? Are there testable B-R assumptions, how consistent? When are TPPs initially developed in the life cycle? What is the current ownership for B-R information and decisions during the life cycle? Interactions between product teams, SMT, other functions, etc. 12

13 From a wider benefit-risk management perspective, adaptation is required to evolving guidance EU-RMP Update to GVP Module V (Risk management systems) came into effect in March in EU Further explanation on the focus of EU-RMPs in relation to safety concerns (important identified or important potential risks and missing information) Justification required for whether or not risks are important and potential to reclassify risks Removal of duplicated information within GVP Module V and other guidance documents Requirements for different types of initial MAAs modified to ensure risk-proportionate RMPs Updated EU-RMP template released in parallel RMPs submitted for initial MAAs and Day 121 responses accepted in old format until end of September 13

14 Conclusions Conclusions A structured approach to B-R assessment is important from both a product life cycle and portfolio perspective B-R initiatives and guidance, including ICH M4E(R2), are driving a more structured approach Selection of the most appropriate B-R framework, underlying techniques and visualisations is key A successful assessment approach depends on addressing critical organisational factors 14

15 Thank you! Steve Mayall Principal Consultant Pope Woodhead 15