Navigating the Convergence of Payer and Regulator Evidence Requirements Opportunities and Challenges

Transcription

1 Navigating the Convergence of Payer and Regulator Evidence Requirements Opportunities and Challenges Krista A. Payne Executive Director, Value Demonstration Principle Scientific Consultant Dr Janine Collins Senior Director EU Risk Management February 12, 2014

2 Topics Observations in Observational Studies Landscape trends and opportunities Convergence of evidence requirements Trends in Payer evidence needs Trends in Regulator evidence needs Evidence gathering over the product life-cycle Opportunities for cost and timeline efficiencies Summary of recommendations

3 Observations in Observational Studies

4 Observational Studies.. A study in which participants are not randomized or otherwise assigned to an exposure. The choice of treatments is up to patients and their physicians ISPOR Task Force, May 2011 Sometimes referred to as: Natural Experiments (Meyer, 1995; Rosenzweig & Wolpin, 2000) Quasi-experiments (Shadish, Cook & Campbell, 2002) Common Observational Study Approaches: Retrospective: Multi-national Chart Reviews Prospective Studies: HEOR/Disease/Product/Pregnancy Registries Outcomes of interest Population characteristics Treatment Patterns and Resource Utilization Lost productivity Quality of Life (QOL) Treatment satisfaction Persistence / compliance Clinical - Severity / Disease progression / Vital status / SAEs/Aes

5 Hybrid Observational Studies Observational study with diverse array of outcomes of interest e.g., Inclusion of health economic and HRQoL variables in safety registries Integration of more than one methodology in a common core study protocol e.g., Pairing of retrospective chart review with prospective clinical assessments of effectiveness, patient and/or caregiver interviews Disease Registry to Product Registry Big Data plus direct-to-patient surveys

6 Trending Market Forces and Opportunities Trend Medical Devices Drug Utilization Studies (DUS) Convergence of Payer and Regulator Requirements Benefit-risk Evaluations Comparative / Relative Effectiveness Research Patient Adherence and Evaluations of Effectiveness Formulation changes and Rx-to- OTC Switches Anticipated Impact (+) Increasing evidence/data requirements for devices resulting in increased need for Time and Motion studies (+) Enhanced surveillance of post-market treatment patterns and (in)appropriate medication use will increase need for multinational chart review studies (secondary sources of data frequently lacking in the EU) (+) Need for health economic and patient-centric outcomes data pre- and post market (e.g., EMA Roadmap to 2015) (+) Increased regulatory need for quantitative and systematic assessments of benefits and risks of drugs (+) Increased need for HEOR observational studies and pragmatic trials (+) Patient support programs by industry Increasing in frequency in number need to evaluate effectiveness (+) Increasingly common; evidence required to demonstrate value and understand associated risks

7 CER Context Adapted from Eichler et al, Nature Rev Drug Disc, 2010 Study Type Pros Cons Active-controlled superiorityshowing randomized controlled trial (RCT) Two-arm non-inferiorityshowing RCT Active-and placebo-controlled RCT Pragmatic clinical trial Observational Studies High internal validity May provide relevant relative efficacy (RE) information if comparator deemed appropriate May be the only alternative available for demonstration of efficacy if placebo-controlled RCT considered unethical Provides limited RE info Most informative trial design High internal validity High external validity Demonstrates high relative effectiveness May be conducted retrospectively or prospectively Less expensive and time-consuming than RCTs Large patient numbers can be observed Often requires large sample size Only one comparator can usually be studied May lack assay sensitivity and therefore internal validity Non achievable if placebo control considered unethical Often requires large sample size Lower signal-to-noise ration than conventional RCTs Requires larger sample size May mask small true differences between treatments Non-randomized information Subject to high risk of confounding variables Adapted from Eichler et al, Nature Rev Drug Disc,

8 Trending EMA Road Map to 2015 EMA/299/895/2009 XX XX XX

9 Convergence of Regulators & Payers (Eichler, 2010) 9

10 The Payer

11 Payors Require Value Demonstration. In addition to evidence of efficacy and safety, novel drugs, drug formulations and/or medical devices must also demonstrate value for money spent Payer/reimbursement evidence requirements (volume and rigor) increasing R&D dollars decreasing Cost and time efficient real-world, multi-national studies increasingly warranted Strategies underlying Value Demonstration evidence gathering include: Highlighting unmet need Describing burden of illness associated with standard of care Collecting health care resource utilization, and quality of life data in realworld patient populations Stand alone studies Data inputs to Health Economic models or other analyses 11

12 Current Context. Eichler H-G: Winning regulatory approval is of little use to industry or to patients when a drug is not reimbursed, as access to high-priced drugs will effectively be precluded to most patients. The decision-making power of payors has grown at the expense of individual physicians, as prescribing decisions are becoming more restricted by payors reimbursement decisions. Success in the marketplace of a new premium-priced drug is now less driven by conventional marketing and sales efforts, but by the ability to demonstrate added therapeutic value to the payors. 12

13 Payor Evidence Needs. Is there clinical benefit? Does thereapy/procedure work? Is this impact quantifiable? If so, what is the incremental benefit versus standard of care? Cost? Does cost outweigh the benefit? Are there cost savings to be accrued? Utilization? Who will receive the treatment? Who will benefit most? 13

14 Paradigm Shift (Prof. Mondher Toumi, MD, Lyon) Decision Point to Decision Window 14

15 Real-world Evidence Needs Addressed by Chart Reviews Patient Characteristics Patterns of Care/Resource Utilization Demographics, medical/disease/treatment history (e.g. diagnosis, date of onset, co-morbidities) Visits by type of health care provider, medications, diagnostics, procedures, ER visits, hospitalizations Drug Utilization On-/Off-label use, prescription patterns, dose intensity Effectiveness Clinical outcomes Unmet Need e.g. therapeutic inertia and turbulence Safety AEs, SAEs (previously reported/non-reported as per usual care) Personalized Medicine Dx, screening, clinical utility

16 Case Study: Multi-national Chart Reviews Example #1: Metastatic Colorectal Cancer (mcrc): Patterns of Care, Clinical Outcomes, Resource Utilisation and Costs Client need: To understand real-world patterns of care, resource utilisation and clinical characteristics of a cohort of mcrc patients, and to estimate costs of care Data used to: Characterise patient population, describe burden of illness Inform/populate health economic analyses 25 sites: Belgium, Germany, Italy, Portugal, Netherlands N=500 Target cohort identified from usual care medical charts of specialty oncology treatment centres (range: university hospitals to community hospitals) Clinical and resource use outcomes Focus on survival, complex medication regimens (on and off-label) Chart abstraction performed by site MD, study coordinator or research nurse and entered into secure study web site 16

17 Multi-national Chart Review / Drug Utilization Study Key Words: On-/Off-label use, prescription patterns, patient characteristics Client need: Evaluate physician adherence to label indication and instructions for use in usual care Data used to: Describe patterns of care Satisfy a REMS requirement Context: Cardiovascular 375 sites: US N=1,052 Target cohort identified from a random selection of the usual care medical charts in outpatient clinics Adherence Focus on patient management while on drug, off-label use Chart abstraction performed by site MD or nurse and entered into EDC 17

18 The Regulator

19 Pharmacovigilance legislation July 2012 Strengthened a proactive approach to patient safety Risk Assessment Risk Minimisation Assessment of effectiveness of risk minimisation activities Proactive post authorisation safety surveillance Spontaneous reporting system may not be sufficient Growing trend towards post authorisation safety studies Good Pharmacovigilance Practice Module V: Risk Management Systems Module VIII: Post Authorisation Safety Studies Module XVI: Risk Minimisation measures: selection of tools and effectiveness indicators Coming soon. Use of pharmacogenomic methodologies in pharmacovigilance evaluation 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 19

20 Risk Management Module V: Risk Management Identified Risks Potential Risks Missing Information Pharmacovigilance Plan Routine +/- Additional Pharmacovigilance Additional Efficacy Data Risk Minimisation activities Routine +/- Additional Risk Minimisation Assessment of effectiveness of risk minimisation Module XVI: Risk Minimisation measures: selection of tools and effectiveness indicators Outcome indicators Process indicators Was risk minimisation actually implemented Assessment of clinical knowledge Assessment of clinical actions (prescribing behaviour) Drug Utilisation Studies 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 20

21 Module VIII: Post-authorization Safety Study (PASS) Defined in Directive 2001/83/EC (DIR) Art 1(15) as any study relating to an authorized medicinal product conducted with the aim of identifying, characterizing, or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures Study is defined a PASS on the basis of study objectives not methodology employed PASS can answer any of the following : o Quantify potential or identified risks o Evaluate risks of drug in populations where safety information is limited or missing o Evaluate risks of drug after long-term use o Provide evidence of absence of risks o Assess patterns of drug use that add information related to drug safety o Measure effectiveness of a risk minimization activity 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 21

22 Retrospective PASS/PMR: Drug Utilization Study (DUS) Drug Utilization Studies (DUS) mandated by healthcare regulators such as the EMA are increasing by common Accepted as valid PASS methodology Retrospective design minimizes impact of Hawthorne Effect (knowledge of prospective study could impact prescribing behaviour) Can be implemented using databases or de novo data collection (e.g., chart review) To minimize response bias, well suited for evaluations, behavioral in nature, such as: On/off-label use Dosing Adherence to RMP requirements Databases may not suffice and chart review studies may be warranted if: Data sources lacking in country/region of interest ICD-9/10 (or other) code lacking specificity Indicators of prescriber adherence to RMP or reasons for off-label use not in database 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 22

23 Example: Drug A Application for an Orphan Indication Clinical trial experience N=150 6 months duration Risk Management Plan Identified Risks Hepatotoxicity Interaction between drug A and drugs XYZ Potential Risks Medication error (complex dose regime; dose reductions in certain populations) Off label use (different indications; different patient population) Consider Prospective PASS Disease or Product Registry Drug Utilisation Study What other information does the company need? Efficacy? Patient Reported Outcomes? Patterns of use? Duration of treatment? Missing Information Long term use 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 23

24 Multi-faceted Disease and Product Registry Registry = An organized system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition or exposure Can be used as a data source within which studies can be performed Enrollment usually on the basis of a diagnosis (disease registry), or drug prescription (exposure registry) Both before and after the introduction of the new product Observe disease, including heterogeneity Understand current care patterns, outcomes and identify unmet needs Understand relationship between treatments and outcomes Contribute to design of future trials & increase efficiency of program Establish Sponsor as a credible player in this therapeutic area Build and maintain relationships with key practitioners After the introduction of the new product Meet regulatory requirements and understand value of new product Understand facilitators/barriers to initial use and appropriate adherence Monitor off label uses and other unknown usage issues Provide continuous source of data for benefit-risk & value dissemination with publications and presentations

25 Disease/Product Registry Integration Enroll in Disease Registry 24 Months Novel Rx? Novel Rx? Novel Rx Launch No Yes Continue Disease Registry Enroll in Disease/Product Registry 24 Months Complete Product CRF

26 Case Study 26

27 Case Study Primary Objective Assessment of safety of ADVATE treatment by measuring the incidence of serious adverse effects caused by ADVATE treatment and non serious adverse effects which were at least possibly related to ADVATE in subjects receiving ADVATE. Secondary Objective Assessment of HRQOL in this patient population. 573 patients enrolled in PASS study 205 patients were evaluated for HRQOL

28 Case Study Conclusion Physical but not mental HRQOL is diminished in haemophilia patients. The presence of target joint development was negatively associated with physical HRQOL, with a greater association in older than younger patients. These data may be of significant interest to political or medical decision makers who have the ability to make broad policy changes that can affect haemophilia patients in their community. (Page 419)

29 PASS - Expanding Objectives Beyond Safety! Meet post-market regulatory and payer requirements Understand value of new product Observe disease, including heterogeneity Understand current care patterns, outcomes and identify unmet needs in routine medical care Understand relationship between treatments and outcomes Understand facilitators/barriers to initial use and appropriate adherence Monitor off label uses and other unknown usage issues Provide continuous source of data for benefit-risk & value dissemination with publications and presentations Establish Sponsor as a credible player in this therapeutic area Build and maintain relationships with key practitioners 29

30 PASS - Expanding Outcomes Beyond Safety! Population characteristics o Real-world versus RCT / external versus internal validity Treatment Patterns and Resource Utilization o Medications Duration of treatment; Line of therapy o Physican consultations (Specialist versus GP / In-patient versus Out-patient o ER visits and hospitalizations o Procedures and diagnostics o Medications: Rx & OTC Lost productivity / opportunity costs Quality of Life (QOL) / PROs o Health status: Generic / Disease specific; Utilities Treatment satisfaction Persistence / compliance 30

31 Opportunities for Efficient Evidence Generation

32 Evidence planning & strategy Evidence Gathering Across the Product Life-Cycle Phase I / II Phase III Filing/Launch Phase IIIb/IV Peri & Post Approval Research Clinical studies: Design, recruiting, execution & analysis Registries: Design, recruiting, execution & analysis (disease, patient, pregnancy) Post marketing studies End-point design and evaluation HE modeling & simulation Outcomes studies & analysis HEOR Lit reviews & meta-analysis Value dossiers Retrospective analyses, real world analyses Comparative effectiveness Payer, patient & HCP research Safety & Risk Management Safety analyses, studies & registries Risk mgmt / REMS Pharmacovigilance / Surveillance 32

33 Landscape Considerations Current environment presents formidable challenges: Likely that authorities will continue to tighten regulatory processes in relation to market access Evidentiary requirements increasing but research dollars decreasing Market is increasingly study design astute Peer review of studies extremely rigorous - publication in top tier journals difficult Critical review, organization, and prioritization of research questions are paramount An evidence generation strategy can inform data collection requirements

34 Strategic Evidence Generation Planning The right Evidence to the right Audience Identify unmet need Determine & align value Create implementation plan Evidence Generation Communication & Dissemination (payers, health authorities, regulatory, thought leaders, etc.) Optimal Product Positioning Product Life Cycle at the right Time

35 To Succeed in this Evolving Landscape Critical to optimize study designs and streamline evidence development efforts Novel study design approaches and methodologies will play a critical role in sponsors ability to adapt By the time products achieve post market status, significant investments have already been made Cost and timeline efficiencies can be achieved through re-purposing of study materials and operational observational study infrastructures implemented earlier in the product life-cycle Late Phase trends and evidence requirements can be anticipated

36 Strategic Designs Over the Life-cycle Studies in support of Product X are often implemented as stand-alone research projects Paradigm shift towards programs of studies Core design features may be very different across study types and methodologies Retrospective versus prospective RCT vs PCT vs registry vs chart review Studies offer different evidence to address different stakeholder needs and evidentiary requirements As stand alone studies, each data collection undertaking is associated with significant resources, time and costs Optimal product positioning and market uptake requires a thoughtful multiyear, multidimensional strategy that culminates in an evidence base which will facilitate product coverage, reimbursement and adoption

37 Evidence Generation Across the Product Life-cycle Launch T= -4 + years T= -2 years T=0 years T= 2 + years Retrospective Chart Review Hybrid Observational Product Safety Study Cohort Characterization Patterns of Care Resource Utilization PROs Safety New Product Hypothetical Safety integration of an observational, hybrid, single-protocol design including a multi-national chart review and peri- and post-approval study

38 Opportunities for Cost and Timeline Efficiencies Significant cost and timelines savings can be realized through re-purposing of: Study materials: study protocols and CRFs Database programming, data dictionaries Data capture infrastructure EDC platform / ecrf Sites and investigators / recruitment, contracting and enrollment Conservation of patients! Increasing return on investment over time Fixed costs invested up front Cost per patient decreases over time ROI increases over time Significant fixed cost savings Study materials: 22-35% reduction EDC infrastructure /ecrf: 60%-70% reduction

39 Barriers to Efficiency Lack of comprehensive and strategic, value-driven evidence generation plan Value message delineation through evidence delivery Too little.too late. Study designs not strategic or forward thinking enough Sponsor internal stakeholder silos HEOR teams Clinical development teams Safety and PV teams Poor documentation, tracking and filing of study deliverables and tools across stakeholder groups/disciplines and time Poor information and knowledge management User friendly infrastructures warranted

40 Lessons Learned Build a value strategy to help streamline and prioritize data collection initiatives Evidence requirements gap analysis is paramount to inform study planning Aim is to employ the right design(s) for the purpose Focused & streamlined - prioritization of study variables Scientific rigor important but practicality and operational feasibility must impact decision making Efficiency is important but one design may not fulfill all objectives Common infrastructure can support multiple studies Involvement of local sponsor affiliates and clinician KOLs early in design phase adds quality and validity Senior authorship will require early participation in design activities Advisory boards for program versus project oversight

41 Strategies and Recommendations Drive Event Model to Process Model - continued evidence development Look for opportunities to optimize research funding investments Need for Smart study designs Leadership in the creation, maintenance and analytics of real-world data repositories Tailored datasets; hypothesis generating Big data Keeping it simple but maximizing data return Those at the helm of study design activities must offer leadership with respect to: Scientific rigor for small or large scale studies Operational efficiencies and streamlining Transparency re: consequences of trade-offs between science and logistics Risk mitigation strategies Public forum discussion and debate!

42 Q&A 02/17/ Express Scripts Holding Company All Rights Reserved ubc.com 42