Real-World Evidence (RWE) As an Indispensable Source for the Ongoing Assessment of Cardiovascular Treatments

Getting to the Heart of the Matter: Real-World Evidence (RWE) as an Indispensable Source for the Ongoing Assessment of Cardiovascular Treatments

ISPOR 20th Annual European Congress

Avalere Health | An Inovalon Company November 7, 2017 14:00–15:00

Getting to the Heart of the Matter: Real-World Evidence (RWE) as an Indispensable Source for the Ongoing Assessment of Cardiovascular Treatments

INTRODUCTION

1 Speakers

Name Title Affiliation

Vice President Kathleen Avalere Health Hughes Washington, DC [email protected]

Chair, British Society of Cardiovascular Research Colin Berry, MD Chair of Cardiology and Imaging Glasgow, Scotland [email protected]

Associate Director, Research and Development National Institute for Health and Páll Jónsson Care Excellence Manchester, United Kingdom [email protected]

Director, Global Health Economics Amgen Yi Qian Thousand Oaks, CA [email protected]

Evidence is in Demand

“If we want more evidence-based practice, we need more practice-based evidence”

Dr. Lawrence W. Green, DrPH, MPH Professor Emeritus School UCSF School of Medicine

2 Real World Evidence in Cardiology 1 2

Longitudinal Tracking Outcomes in Unfiltered Population

• Analysis of the impact of risk factor • Patients in the real world are often modification on prevention of older and have more comorbid cardiac adverse events is conditions than those included in enhanced by long term tracking a clinical trial cohort • Example - evaluation of impact of hypertension on adverse cardiac events

Focus of RWE in Cardiology – Broad Themes

Cholesterol Novel Oral Post-MI Risk factors lowering Anticoagulants Care for CVD agents

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3 Real World Evidence – Influence on Guidelines

Incorporation of real world evidence into practice guidelines has lagged behind the push for its collection, but utilization seems to be gaining increasing traction.

A study published in the BMC Identified 25 guidance documents Journal of Health Services referencing studies rooted in data Research in 2016 examined from the Clinical Practice all national guidelines Research Datalink (CPRD), all published since 2000 published after 2007

Found that just 11% of A similar study published in the recommendations cited data US in 2009 examined guidelines from multiple sources, beyond published by the ACC and AHA expert opinion or evidence from a single RCT

Oyinlola JO, Campbell J, Kousoulis AA. Is real world evidence influencing practice? A systematic review of CPRD research in NICE guidances. BMC Health Services Research. 2016;16:299. doi:10.1186/s12913-016-1562-8. Tricoci P, Allen JM, Kramer JM, et al. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009;301:831–41 7 Copyright 2017. Avalere Health LLC. All Rights Reserved.

Getting to the Heart of the Matter: Real-World Evidence as an Indispensable Source for the Ongoing Assessment of Cardiovascular Treatments Colin Berry FRCP PhD

ISPOR, ISPOR 20th Annual European Congress 7 November 2017

4 Disclosures Institutional research agreements – CB & University of Glasgow hold consultancy and research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, Menarini, Novartis, Philips, and Siemens Healthcare.

Advances in CV medicine

1.Body textTherapy – Sacubitril valsartan in heart failure 2. Diagnostics – Cardiac CT 3. Conclusions

5 Innovation ?

Clinical problem Idea Body text Peer, patient / staff discussion Grant application Ethics NHS Management approval Placebo-controlled trial (efficacy) Effectiveness / clinical experience

New treatments for heart disease

Body text

6 Sacubitril/Valsartan in chronic heart failure

PARADIGM-HF trial: 8442 patients, HF, LVEF<40%, • Sacubitril/Valsartan vs. enalapril • BodyCV textdeath or heart failure, HR (95%CI) 0.80, 0.73, 0.87 • Death  HR 0.84 (0.76, 0.93) Novartis to NICE • Cost - 200 mg, 56 pack: £91.56, twice daily, £21978p.a. • ICER for sacubitril valsartan vs. ACE inhibitors was £17,939 per QALY gained (incremental - costs of £7514, QALYs of 0.42). • The probabilities of sacubitril valsartan being cost-effective at thresholds of £20,000 and £30,000 = 64% and 93%, respectively. • NICE Expert Review Group queried ‘how representative are the trial population to UK?’

NICE and Sacubitril/Valsartan in chronic heart failure

Body text

NICE to Novartis Technology appraisal led to adoption in the NHS Prescribed by specialists in heart failure https://www.nice.org.uk/guidance/ta388/documents/appraisal-consultation-document

7 New tests for heart disease Invasive Non-invasive Pressure wire MRI Body text

AOCT B CT

CT coronary angiography

1. High negative predictive accuracy 2. BodyModerately text high positive predictive accuracy Limited accuracy and precision for stenosis severity 3. Incidental findings 4. Non-diagnostic images in 5 – 10% all-comers 5. Heart rate ~ 60 / min

8 Current imaging trials > 30,000 randomised subjects

Diagnosis of angina Revasc. vs OMT CMR CEMARC-2 Body text SPECT / ECHO / CMR CTA SCOT-HEART, PROMISE ISCHEMIA SPECT / CTA CARE-CCTA ECHO REVIVED FFR-CT FORECAST CMR vs. Invasive Anatomy vs. function MR-INFORM SPECT vs. CTA CTA vs. Invasive RESCUE, PROMISE DISCHARGE SPECT vs. Advanced imaging AIMI-HF

SCOT-HEART CT coronary angiography

Body text

Lancet, March 2015

Disclosure: Colin Berry – TSC member, Local PI

9 SCOT-HEART

• Design Diagnostic trial • Setting Chest pain clinic Body text Standard care vs. Intervention Stress test + 0 Stress test + CTCA • Enrolment after the clinic assessment • Aim: to assess the effect of CTCA on diagnosis, management and outcome • Open label – unblinded, potential for confounding

Scottish COmputed Tomography of the HEART (SCOT-HEART) Trial Trial Population Randomization 1:1 11% of all Patients N = 4,146 Excluded From the Trial

47% of Eligible Body text Standard of Care Standard of Care + Patients CT Coronary Angiogram Recruited Into the Trial N = 2,073 N = 2,073

CT Coronary Angiogram 100% Data for the n=1,778 Computed Tomography Primary End-point Coronary Angiogram Non-completion 295 Ill-health/death 6 N = 3 Intention-to-Treat Patient default 245 Analysis Technical 10 Other 34

Data for Primary Data for Primary Endpoint Endpoint N = 2,073 N = 2,073

10 CT Coronary Angiography: Diagnosis Baseline Compared to 6 Weeks

Overall Changes in Diagnosis: 25% versus 1%, P<0.001 Attending Clinician: Diagnosis of Coronary Heart Disease

BodyCertainty text 2.56 [2.33-2.79] Frequency 1.09 [1.02-1.17]

Attending Clinician: Diagnosis of Angina due to CHD (Primary End-point)

Certainty 1.79 [1.62-1.96] Frequency 0.93 [0.85-1.02]

0.0 1.0 2.0 3.0 4.0 Relative Risk [95% Confidence Intervals] SCOT-HEART Investigators, Lancet 2015

NHS – CTCA guidelines

• NICE-95: Chest pain of recent onset

NovemberBody text 2016 update Offer 64-slice (or above) CT coronary angiography if clinical assessment indicates typical or atypical angina • Health economic analysis (by protocol) not published • Quality of life improves in both groups but less in the CT group vs. standard care. Williams M et al Heart 2017 • CEMARC-2, JAMA 2016 CT  unnecessary angiography NICE  Major implications for the NHS: ? availability of CT & Radiologists, waiting lists for CT ++, etc.

11 Real-world evidence PLATFORM observational study

Body text

Real-world evidence in absence of Phase 3 RCT

Body text

12 Conclusions

1. Quality of evidence in therapeutic

Body textRCTs with placebo is higher (but imperfections exist) 2. Imaging trials – open label (bias), multiple emerging trials 3. Diagnostics endorsed without RCT, but real-world evidence

Thank you for your attention

13 Getting to the heart of the matter An HTA perspective Getting to the heart of the matter An HTA perspective Páll Jónsson

PAssociateáll Jónsson Director, Research and Development Associate Director, Research and Development

27 1

HTA has a problem! Increasingly limited data

RCTs do not Increasing answer all decision HTA uncertainty questions

Real-world evidence (RWE) has a role, but issues with data quality, robustness results and limited/varied acceptance by different HTA bodies

14 HTA has a problem!

Increasingly limited HTA has a problem! Incdatareasingly limited data

RCTs do not Increasing answer all decision RCTs do not HTA questions uncertaintyIncreasing answer all decision HTA uncertainty questions

Real-world evidence (RWE) has a role, but issues with data quality, Rrobustnesseal-world eresultsviden cande (R limited/variedWE) has a role acceptance, but issues by w idifferentth data q HTAual ibodiesty, robustness results and limited/varied acceptance by different HTA bodies

Acceptability of RWE varies across Europe

Some disadvantages of RWD in HTA

• Limited availability of RWD at time of assessment • Potential for bias (e.g. selection, information, confounding bias) • Poor quality (e.g. incomplete or missing data) • Data sources not established for research purposes (e.g. EHR, claims databases)

Gill, J. et al. 2016. ”The use of Real World Evidence in the European Makady A, Goettsch W. 2015 ”Review of Policies And context”. DOI: 10.21953/LSE.68442 Perspectives on Real-World Data for Drug Development and Assessment” IMI GetReal Deliverable. Available at www.imi- getreal.eu.

15 Science Policy and Research at NICE

HTA has a problem! Increasingly limited data

RCTs do not Increasing answer all decision HTA uncertainty questions

Real-world evidence (RWE) has a role, but issues with data quality, robustness results and limited/varied acceptance by different HTA bodies

NICE´s European partnerships in real-world evidence

16 IMI GetReal: Some learnings on RWE

Further case studies needed where evidence gaps are examined and the suitability of RWE is tested

HRWETA should has complement a problratherem! than replaceInc rerandomisedasingly trials limited data A role in confirming where real-world effectiveness differs from efficacy in RCTs

Stakeholder’s limited acceptanceRCT ofs RWE do not primarily due to Increasing concerns around robustness of adatansw ander aevidencell synthesis decision HTA uncertainty Methods and analytical techniquesque needstions developing Advancing Evidence Generation for New Drugs: IMI GetReal’s Recommendations on Further work is required to understand limitations of RWE in Real-World Evidence (www.imi-getreal.eu) decision making Real-world evidence (RWE) has a role, but issues with data quality, robustness results and limited/varied acceptance by different HTA bodies

What does our methods guide* say on RWE?

* NICE Technology Appraisals

17 RCTs vs non-RCTs: A HTA perspective

RCTs remain gold standard in HTA

Alternative evidence generation could be explored when: - Efficacy differs from effectiveness HT-AIssues has with a pr population:oblem! Increasingly • Insufficient patient numbers limited data • Inaccessible (e.g. vulnerable) patients • Patients of interest excluded, e.g. age, co-morbidities, concurrent medications • High unmet need, smaller population and therefore not commercially viable • Too broad RCTs do not Increasing answer all - Comparators: may not represent standard ofde carecision HTA - Outcomes: may report intermediate outcomesunc eratherrtaint ythan outcomes of interest - Timing: may be too shortque ins tdurationions - Setting: may not represent typical practice

ReNotal-w justor lRWE:d evi dmoreence pragmatic (RWE) ha trialss a r ocouldle, b uhelpt iss resolveues wi tsomeh da tofa qtheseualit issues!y, robustness results and limited/varied acceptance by different HTA bodies

RWE in appraisal of cardiovascular treatments Potential uses

(Relative) Evaluation of To help Understanding effectiveness risk of long establish persistence to in patients term adverse baseline risk treatment with events comorbidities

In NMAs To support To evaluate CV where H2H To support Cost and extrapolation events after data on effectiveness disutility of CV of outcomes time-limited comparators where events beyond trial treatment not available(?)

*Illustrative examples

18 A forward look: Core outcome sets

A more systematic approach to Frequency of patient participants included in the COS incorporating outcomes development process (%) 100 HTA has a problem! 90 Increasingly Stakeholder consensus 80 limited data 70 Multiple stakeholders views, 60 including patients 50 RCTs do not 40 Increasing answer all 30 decision Outcome definitions HTA 20 uncertainty questi10ons Measurement tools 0 Up to 2013 2014 - 2015 Ongoing COS Real-world evidence (RWE) has a role, but issues with data quality, Credit: COMET Initiative robustness results and limited/varied acceptance by different HTA bodies

GETTING TO THE HEART OF THE MATTER - FROM MANUFACTURES PERSPECTIVE

Yi Qian, Ph.D. Director Global Health Economics Amgen Inc., Thousand Oaks, CA, United States

19 Disclosure

Dr. Qian is an employee of Amgen, which provided financial support for this presentation. Dr. Qian owns Amgen stock.

Outline

• Leverage RWE to augment RCT data in support of product value propositions – Regulatory setting – Reimbursement setting • Examples in cardiovascular disease

20 Overall Limited Use of RWE for Regulatory Purpose1

New Drug Approvals Label Expansion/ Revisions Post Market Commitment

Dosing Accelerated New Safety safety approval indication; Confirmatory monitoring First NME revisions/ based on a New studies and approval comparativ surrogate population surveillance endpoint e efficacy

Occasional Use of RWE Limited Use of RWE Routine Use

NME = New molecular entity 1. Duke Margolis Center for Health Policy. White paper: A framework for regulatory use of real-world evidence, 2017 41

Increasing Interest in Incorporating RWE in Regulatory Setting

Workshop on identifying opportunities for ‘big data’ in medicines development and regulatory science

Held by EMA on 14–15 November 2016

Public workshop: Developing a Framework for Regulatory Use of Real-World Evidence Convened by the Duke-Robert J. Margolis, MD, Center for Health Policy at Duke University and supported by a cooperative agreement with FDA September 13, 2017

21 Despite Strong Interest, Challenges Remain…

FAIR - Findable, Accessible, Data Collection and Integration Interoperable and Reusable

• Overcome data limitations Data Analysis and Interpretation • Quality standard/best practice

• Clarities on “how” Regulatory Process/Pathways • Pilot programs

Increasing Recognition for RWE from HTA Bodies

Value and Importance of RWE Across Countries (Payer RWE voice of the customer project 2015)

8 1. Gill et al. (2016) The use of Real World Evidence in the European context: An analysis of key expert opinion. London School of Economics, London, UK. Retrieved from http://eprints.lse.ac.uk/68442/

22 A Multi-stakeholder Approach to Leverage the Potential of RWE

Establish scientific Streamline the Increase investment partnership in data regulatory/HTA and capabilities in data design/analysis/interpreta environment tion collection and access

Various Channels to Use RWE to Support Access and Treatment Decisions

Collecting patient Understanding safety data on the use patient profiles of the new medicine in the disease area

Patient experience or Measuring healthcare patient-reported related resource use outcomes in real Real-World and burden of illness clinical practice Evidence

Collecting utility data Evaluating prescribing for economic patterns and adherence modelling to the new medicine

Evaluating clinical outcomes associated with the new medicine

Association of the British Pharmaceutical Industry (2011) The Vision for Real World Data - Harnessing the Opportunities in the UK. 9

23 To Assess Product Value, Different Questions Can Be Raised

For which patients does the What is the value of a drug in drug provide good value in a clinical trial setting? clinical practice/real world use? • • Good internal validity Better external validity • • Used to inform Typically used by clinical appropriate patients groups and/or access decisions

In CV Disease, Two Key Value Drivers Are Efficacy and Baseline Event Rates1-4

Quality of Life Efficacy Direct Medical Costs

Treatment Duration Baseline Event Rates Indirect Costs

CV, cardiovascular. References: 1. Data on file, Amgen; [Cost-effectiveness Analysis; 2017]. 2. Data on file, Amgen; [PHE Analysis; 2017]. 3. Gaziano TA, et al. JAMA Cardiol. 2016;1(6):666- 13 672. 4. Toth PP, et al. J Med Econ. 2017. In Press.

24 Real-world CV Event Rates Are ~2-3x Incident Rates in LLT Clinical Trials1-3

CV Event Rates* Reported in Clinical Trials and Real-World† CV Event Rates1-3

10 years

- 8

6 12.3 8.8

Patient 4

Event Rate per per 100 Rate Event 2 4.5 4.8

0 CTTC1 IMPROVE-IT2 IMPROVE-IT2 Real-world3

Incident (Time-to-first) Event All Observed Events

*CV events evaluated in this comparison included MI, UA, IS, coronary revascularization (coronary artery bypass graft or percutaneous coronary intervention), or CV-related death.1-3 †Real-world event rates are based on an analysis of patients in the CPRD database between 2004 and 2011. Patients were included the analysis based on eligibility criteria for the Repatha® CV Outcomes Study.3 CPRD, Clinical Practice Research Datalink; CV, cardiovascular; MI, myocardial infarction; IS, ischemic stroke; UA, unstable angina.

14 1. CTTC, et al. Lancet. 2010;376:1670-1681. 2. Data on file, Amgen; [Repatha CV Outcomes Study Incident Event Rate; 2017]. 3. Toth PP, et al. J Med Econ. 2017. In Press.

Use of Baseline Event Rates from RCTs May Underestimate Real-world Treatment Value1-7

$400,000 Arrieta 2017 $350,000 Kazi 2016 $300,000 ICER Report 2015 $250,000 Data from RW studies $200,000 Data from RCT studies Jena 2016 $150,000 Gandra 2016 $100,000 Toth 2017

$50,000 Incremental Cost perQALY* Cost Incremental $- - 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 Baseline Event Rate per 100 Patient-years* *Event rates and incremental cost per QALY were cited from published studies when reported.1-6 Estimates were calculated from the published studies if not directly reported.7 †Incremental costs per QALY and baseline event rates were based on cost-effectiveness analyses of PCSK9 inhibitors in patients with ASCVD (LDL-C threshold varied slightly across the studies).1-7 ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; ICER, Institute for Clinical and Economic Research; PCSK9, proprotein convertase subtilisin/kexin type 9; QALY, quality-adjusted life-year; RCT, randomized controlled trial. References: 1. Kazi DS, et al. JAMA. 2016;316(7):743-753. 2. Arrieta A, et al. PLoS One. 2017;12(1):e0169761. 3. Jena AB, et al. Am J Manag Care. 2016;22(6):e199-e207. 4. Gandra SR, et al. Clin Cardiol. 2016;39(6):313-320. 5. Toth PP, et al. J Med Econ. 2017:1-10. 6. ICER. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks. 2015. Final Report. 7. Toth PP, et al. J Med Econ. 2017;20(7):749-751. 50

25 The Question is – What Is Relevant to Inform Reimbursement and Treatment Decisions

Observational study - CVD-REAL2 Event rates of hospitalization for heart failure were: Control arm: 6.7/ 1,000 P-Ys RCT - EMPA-REG1 Event rates of hospitalization for heart failure were: Control arm: 14.5/1,000 P-Ys

1. Zinman et al. (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM. 373:2117-28. DOI: 10.1056/NEJMoa1504720 2. Kosiborod et al. (2017) Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.117.029190

Moving Forward…

Demonstrate value with integrated evidence that seamlessly brings together randomized controlled trials and RWE

Access Quality of Life Affordability Efficacy

Effectiveness Safety

RCTs RWE

26 Getting to the Heart of the Matter: Real-World Evidence (RWE) as an Indispensable Source for the Ongoing Assessment of Cardiovascular Treatments

BRIEF REPORT FROM THE US AND COMMON THEMES

Real World Evidence Collection in Cardiology

Long-Term Cardiovascular Cohort Study Framingham • Cohort study started in 1948; project of the National Heart, Lung, and Blood Heart Study Institute in collaboration with Boston University • Originally enrolled 5,209 residents of Framingham, Massachusetts, USA is now on its third generation of participants • Established many of our core understandings of the epidemiology of hypertensive and arteriosclerotic cardiovascular disease

Retrospective Analysis of Outcomes of MI Cooperative • Examined the records of all hospitalizations for Medicare pts with principal Cardiovascular Project diagnosis of AMI in US states of Alabama, Connecticut, Iowa, and Wisconsin • Found significant reduction in mortality in patients receiving beta-blockers

Collection of Registries Created to Examine Cardiovascular Care National Cardiovascular • NCDR created in 1997 Data Registry (NCDR) • Hospital registries for inpatient setting: ACTION registry, Afib Ablation Registry, CathPCI Registry, ICD Registry, IMPACT Registry, LAAO Registry, PVI Registry, STS/ACC TVT Registry • Outpatient registries (ambulatory care): Diabetes Collaborative Registry, PINNACLE Registry • Research to Practice (R2P) initiative identifies impactful DV research and analyzes implications for clinical practice

https://www.framinghamheartstudy.org/ Mahmood SS, Levy D, et al. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. 2014:383(9921):999-1008. http://www.acc.org/latest-in-cardiology/clinical-trials/2010/02/23/18/58/ccp 6 https://cvquality.acc.org/NCDR-Home Copyright 2017. Avalere Health LLC. All Rights Reserved.

27 Use of RWE by Regulatory Bodies

FDA EMA

● Published guideline – “Use of Real-World ● Published guideline – “Guidance for Evidence to Support Regulatory Decision-Making Companies Considering the Adaptive for Medical Devices” Pathways Approach” o Emphasize that RCTs are the gold standard; do o Focused on facilitating the development of not indicate that RWE will be required for device medicines for patient populations with unmet approval medical need o Outlines the ways in which RWE may be o Establish the ways in which RWE can be utilized: used to supplement clinical trial data: 1. Expanded indications 1. Single arm studies for rare diseases 2. Post-market surveillance 2. Open-label salvage studies in patients 3. Demonstration of validity of a biomarker with no remaining therapeutic options 4. Support of RCT data 3. Collection of efficacy and safety data from early access/compassionate use 5. Generation of hypotheses to be programs examined by RCT 4. Post-authorization registries for long-term ● FDA has not yet released guidelines surrounding outcomes RWE for pharmaceuticals, but has indicated a statement is forthcoming

https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196726.pdf 55 Copyright 2017. Avalere Health LLC. All Rights Reserved.

Use of RWE by HTA/Payment Bodies

NICE Private Sector Payers

● Guidelines consistently state a preference for use ● Medical Clinical Policy Bulletins (CPBs) detail of data from RCTs but also state that non- the services and procedures considered randomized evidence should be routinely medically necessary providing guidance for considered and included coverage decisions. CPBs are based on: ● Recommendations for use of RWE in clinical o Review of available peer-reviewed, guidelines published studies, evidence-based o RCTs should be used when available consensus statements, expert opinions of healthcare professionals, guidelines o RWE may be deemed sufficient in the absence published by nationally recognized of RCT in the following circumstances: healthcare organizations 1. Adverse outcome likely if the person is not treated 2. Treatment gives a benefit so dramatic that it is unlikely to be caused by bias Public Sector: CMS 3. Side effects of treatment are acceptable • Coverage with evidence development 4. There is no alternative treatment • FDA/CMS parallel review

Oyinlola JO, Campbell J, Kousoulis AA. Is real world evidence influencing practice? A systematic review of CPRD research in NICE guidances. BMC Health Services Research. 2016;16:299. doi:10.1186/s12913-016-1562-8. https://www.nice.org.uk/process/pmg9/chapter/foreword https://www.aetna.com/health-care-professionals/clinical-policy-bulletins/medical-clinical-policy-bulletins.html# 56 Copyright 2017. Avalere Health LLC. All Rights Reserved.

28 RWE in Action – TAVR Device Approval

Background: TAVR devices are an innovative class of devices that enable treatment of patients with aortic valve disease who are deemed too high risk for conventional valve replacement

Utilization of RWE: Given the potential for benefit in a vulnerable population, the American College of Cardiology and Society of Thoracic Surgeons worked with the FDA and CMS to create a new pathway for device approval based on real world evidence Data Collection: ACC and STS converged on common data formats and 1 collection methods and created a new TAVR registry, enhancing ability to conduct prospective, randomized, post-market trials Regulatory Use: Evidence generated by the registry resulted in the 2013 FDA 2 approval of expanded indications for the Sapien Transcatheter Heart Valve

Take-aways: This case illustrates the willingness of regulatory bodies to work with manufacturers and healthcare providers to develop innovative strategies to get therapies into the hands of patients. This case also highlights the importance of creation of large patient registries to support the development of robust real world data

Carroll JD, Vemulapalli S, et al. Procedural Experience for Transcatheter Aortic Valve Replacement and Relation to Outcomes. Journal of the American College of Cardiology. Jul 2017, 70 (1) 29-41. https://blogs.fda.gov/fdavoice/index.php/2017/06/how-creative-fda-regulation-led-to-first-in-the-world- 57 approval-of-a-cutting-edge-heart-valve/ Copyright 2017. Avalere Health LLC. All Rights Reserved.

Conclusions

Importance of collecting real world evidence in cardiology has been well established

Conclusions from large patient registries have been influencing our understanding of CVD for decades

Inclusion of studies based on real world evidence into clinical practice guidelines has lagged evidence production

Generally, real world evidence has been cited only to support evidence from randomized controlled trials

Payers are just beginning to use RWE in coverage policies and experimentally in outcomes based contracting

With increasing focus on measuring quality, the volume of real world evidence will continue to grow. Payers, providers, industry, and regulatory bodies need to work together to create robust sources of evidence through standardized registries and guide incorporation into clinical and payer practice.

29 Focus of RWE in Cardiology – Broad Themes

Cholesterol Novel Oral Post-MI Risk factors lowering Anticoagulants Care for CVD agents 1 2 3 4

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Live Content Slide When playing as a slideshow, this slide will display live content

Poll: 1: How important is it to use RWE to improve use of novel oral anticoagulants in clinical practice: rate on a scale of 1-4, with 4 being highly important and 1 being less important

30 Live Content Slide When playing as a slideshow, this slide will display live content

Poll: 2: How important is it to use RWE to improve cholesterol lowering agents in clinical practice? Rate on a scale of 1-4 with 4 being very important and 1 being least important

Live Content Slide When playing as a slideshow, this slide will display live content

Poll: 3: How important is it to use RWE to improve post MI care in clinical practice? Rate on a scale of 1-4, with 4 being very important and 1 being least important

31 Live Content Slide When playing as a slideshow, this slide will display live content

Poll: 4: How important is it to use RWE to supplement RCT data to uncover risk factors for CVD to improve treatments in clinical practice? Rate on a scale of 1-4, with 4 being very important and 1 being least important