Optimizing Access With Real-World Evidence

James Harnett, PharmD, MS

Sr. Director, Analytical Science Lead Real World Data & Analytics CoE, Patient & Health Impact

Pfizer Inc.

September 20, 2017

The speaker is an employee of Pfizer Inc. Views expressed are the speaker’s own and do not necessarily represent those of Pfizer.

These slides are not intended for wider distribution outside the intended purpose without speaker’s approval.

Disclaimer

Overview

• Demonstrating how RWE informed R&D better addresses multiple stakeholder needs for access

• Using RWE to identify rare disease populations and rare safety outcomes – avoiding labour and resource intensive patient registries

• Analyzing RWE potential for comparative effectiveness studies, precision medicine and future label enhancements

What are we trying to achieve?

Improve Patient Outcomes by Getting the Right Treatment to the Right Patient at the

Right Time

New Treatment Options

Access to Innovative Treatments

Optimize Patient Outcomes

• Only 5% of candidate medicines prove to be safe and effective (1)

• 6% of RCTs completed on time across industry (2)

• Payers looking for evidence on their populations with different comparators and different outcomes vs. RCTs

• 59% NICE reviews result in recommendations (3) • 80%+ generic dispensing rates (4)

• Gaps in wellness visits • Gaps in information collection outside visits • Data trapped in unstructured parts of electronic medical

records • Fragmented systems, data, capabilities

1. Pharmaceutical Research and Manufacturers of America, Drug Discovery and Development: Understanding the R&D Process, www.innovation.org.

2. Available at: http://www.decisionviewsoftware.com/news/press-release/decisionview-launches-quarterly-report-clinical-trial-enrollment-benchmarks 3. https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technology-appraisal-guidance/summary-of-decisions 4. Available at: http://www.managedhealthcareconnect.com/articles/trends-generic-drug-pricing-and-utilization

How will we achieve this?

Electronic Medical/

Health Record

Wearables Patient Reported

Genomic, Registries,

RCTs, other

Claims

1. Promote EHR as the RWD Hub

Key to promoting a Rapid Learning Health System

R&D Payer CER Precision Rx Regulators

3. Share how to leverage

Systems

Payers

Patients

Researchers

2. Patient-Centered collaboration

Industry Heading to RWD/E Driven R&D – EHR is Changing the Model

http://www.optum.ca/content/dam/optum/resources/produ

ctSheets/OptumInsight_Clinformatics_SampleData.pdf

1. Identify

Targets

3. Data Driven Study

Criteria Identification

and Simulation 4. Study Cohort Enriched

Investigator Identification Impact of marketed

product MOA on

new disease

Genome

_+ EHR

2. Validate

Targets

5. Study

Enrollment/

Conduct Ex, eMERGE

Industry Heading to RWD/E Driven R&D – EHR is Changing the Model

http://www.optum.ca/content/dam/optum/resources/produ

ctSheets/OptumInsight_Clinformatics_SampleData.pdf

1. Identify

Targets

3. Data Driven Study

Criteria Identification

and Simulation 4. Study Cohort Enriched

Investigator Identification Impact of marketed

product MOA on

new disease

Genome

_+ EHR

2. Validate

Targets

5. Study

Enrollment/

Conduct Ex, eMERGE

Expecting Bigger Investments in RWD/E Partnerships

RWD for US Payers moving from nice-to-have to requirement

Current Model in US

RCTs RWE

• Smaller population (3-5% potential)

• SOC/PBO comparators

• Compliant medication use

• Short-term clinical efficacy

Approval

• Larger, broader populations • More comparators • Real-world medication use • Broader, longer-term outcomes

Access Uptake

?

RCTs RWE Approval Access Uptake

• Coverage with evidence development

• Indication/ Value-based pricing

• Outcome-based contracting

Emerging Models in US (mandatory)

A brief look at Outcomes-based Contracting

OBA= performance in a defined patient population is tracked over a specified period of time in a defined population or at the individual patient level, and the amount or level of reimbursement is determined based on the outcomes achieved (1,2)

• Most examples in Europe over past decade but emerging in US

• Rely on a measurable outcomes of interest – Outcomes are typically objective (vs. subjective) and ideally have both

clinical and financial impact (ex, hospitalizations)

– Measurable

• Claims – visits, refills

• Laboratory data – HbA1C, LDL, etc.

• Clinical

– Registries – richer clinical information in smaller populations, may not capture all patients under agreements (ex, Italy)

– Electronic medical records – larger populations, but much of the clinical information is in unstructured (ie, notes) components of records

1. Carlson JJ, et al.. Health Policy. 2010 Aug;96(3):179-90. 2. Garrison LP, et al. Value Health. 2013 Jul-Aug;16:703-19.

Outcomes-based contracts offer great promise in US Manufacturer & Payer

Product Condition Outcomes Risk

Novartis & Aetna, Cigna, Harvard Pilgrim

Entresto Heart failure Heart failure hospitalization

Novartis will reduce the price of Entresto to payers, if the rate of heart failure hospitalization of patients on Entresto exceed a pre-specified threshold

P&G/Sanofi-Aventis & Health Alliance

Actonel Osteoporosis Non-spinal fractures

Limited reimbursement of fractures for patients (average medical expenses for any non-spinal fractures)

EMD Serono & Cigna

Rebif MS Hospitalization/ER

Net price linked to hospitalization, ER visits for relapse avoided

Amgen& Harvard Pilgrim

Repatha Hypercholesterolemia

LDL CV events

• Additional discounts if LDL cholesterol reductions not in line with clinical trial; discount if usage surpasses a predetermined level

• Rebate for the cost of Repatha for an eligible patient who has a heart attack or stroke while on Repatha

Common Features: • Objective endpoints

• Measurable in payer data feeds (claims, labs)

• May require minimal medication adherence

• Short-term evaluations

http://www.nehi.net/writable/publication_files/file/rewarding_results_moving_forward_on_value_based_contracting_for_biopharmaceuticals_copy1.pdf https://invivo.pharmamedtechbi.com/IV004953/US-OutcomesBased-Contracts-Big-Uptick-In-Interest-But-Not-Execution https://www.slideshare.net/NickMerryfield/us-pharma-outcomes-based-innovative-contracting-tracker-may-2017

Outcomes-based contracts in US (Cont’d) Manufacturer & Payer

Product Condition Outcomes Risk

Merck & Cigna , Aetna

Januvia, Janumet

Diabetes HbA1C • Larger rebates if need to add therapy to reach HbA1C goal (Aetna)

• Discounts if patients adherent on drugs don’t improve HbA1C (Cigna)

Lilly & Harvard Pilgrim

Tulicity Diabetes HbA1C • Preferred drug formulary; Price rebates tied to how well Trulicity performs versus other GLP-1 agonists in % members HbA1c <8%

• and higher net price if patients taking Trulicity achieve lower HbAIc levels than patients taking competing drugs

Gilead & Cigna Harvoni Hep C Sustained virologic response (SVR)

Discount linked to outcomes for preferred formulary status.

AZ & ESI Iressa Lung cancer Refill Has agreed to rebate a set amount if Iressa is discontinued before the third fill for any reason, including patient non-response

Lilly & Harvard Pilgrim

Forteo Osteoperosis Persistence Price reduction if increase in medication persistence (more patients injecting medication as they should, daily).

Amgen & Harvard Pilgrim

Enbrel RA Claims algorithm

HPHC pays less if members score below thresholds on six measures (adherence, dose escalation, switch/add, steroids)

But, there are significant challenges to consider for executing innovative agreements

Available at: https://www.statnews.com/wp-content/uploads/2017/03/PhRMA_ValueBased_MemberService_R23.pdf

RWD For Safety - Uncovering Rare/Previously Undetected Events

EMERGING ESTABLISHED

• Administrative and claims • Electronic Medical/Health

Records • Registry

Finding Patient Hot-Spots: Rare Diseases

Condition/Symptom 3

Condition/Symptom 2

Condition/Symptom 1

Condition/Symptom 4

Condition/Symptom 5

Condition/Symptom 6

Condition/Symptom 7

Condition/Symptom8

Diagnosis

Promise of RWD to Optimize Patient Outcomes: Focus on Precision Medicine in Clinical Practice

Precision Medicine

Are we ready?

Analytical capability or data issue?

"The field of artificial intelligence, despite its progress, is in its infancy,"

-Dario Gil, vice president of AI and Q (for quantum) at IBM Research

Source: J.M. McGinnis et al., “The case for More Active Policy Attention to Health Promotion”, Health Affairs 21, no.2 (2002)

Exciting Developments in US Regulatory Landscape for RWE beyond Safety

FDA Focus on Guidance, Initiatives and Collaborations to Improve Data Sources

EMA Focus on Low Intervention Studies/ Adaptive Pathway Guidance and Pilots

Opportunities for FDA Consideration of RWE beyond Safety

• Confirmatory studies for drugs approved under BTD/AA/Conditional Approval programs

• Label revisions or expansions (ex, new dosing schedule, line of therapy, combinations)

• New indications/line extensions for authorized drugs

• Utilize RWE in cases where RCT is not feasible/ethical – Virtual control group

– Rare diseases

• Initial approval/labelling ???

http://www.fda.gov/downloads/ForIndustry/UserFees/Prescription

DrugUserFee/UCM511438.pdf

PDUFA VI a. By no later than the end of FY 2021,

considering available input, such as from activities noted above, FDA will publish draft guidance on how RWE can contribute to the assessment of safety and effectiveness in regulatory submissions, for example in the approval of new supplemental indications and for the fulfillment of postmarketing commitments and requirements. FDA will work toward the goal of publishing a revised draft or final guidance within 18 months after the close of the public comment period.

21ST CCA definition of RWE: “data regarding the usage, or potential benefits or risks, of a drug derived from sources other than randomized clinical trials”

What kind of evidence will the FDA look for?

• Recent thoughts from FDA, reiterated at Duke Margolis Meeting on 9/13/17

• Real-world evidence defined by data source + degree of pragmatism

– “Real-world evidence can be generated from any study design as long as the data source is from routine care and the design is highly pragmatic, meaning the trial design and conduct closely approximate the eventual use of the product in clinical practice.“ • RCTs performed within the health care system are considered a source of RWE;

some observational studies are not RWD (Framingham)

• EMR and claims are excellent sources of RWD; RWD can be used during the conduct of a trial to reduce duplication of data input (Hx, AE reporting, endpoints)

– Reiterates importance of randomization for causal inference • Exceptions for rare disease and the pathophysiology and natural history of the

disease are well established

– Reference TASTE trial: Prospective, open-label, randomized, controlled clinical trial that using population-based registry

http://jamanetwork.com/journals/jama/fullarticle/2644655 https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_fda_slide_deck_2017_09_13.pdf https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf

EMA already has framework for something similar to FDA RWE proposal

• The low-intervention clinical trial must meet all of the following three criteria: – The investigational medicinal products, excluding placebos, are

authorized.

– According to the trial protocol, the investigational medicinal products are used in accordance with the terms of the marketing authorization or the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned.

– The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any member state concerned

Role of Observational Research?

Duke Margolis Report funded by FDA (September 2017)

• Interventional studies for RWE development for drug’s approved labeling – new indication or population

• Observational approaches may eventually be suitable for label change that incorporates new information closely associated with the accepted clinical evidence in the label or makes revisions to that information (e.g., drug-drug interactions, dosing).

Available at: https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf

Study Design: Observational Studies vs. RCTs

• “On average, there is little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions.”

Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane

Database of Systematic Reviews 2014, Issue 4. Art. No.: MR000034. DOI: 10.1002/14651858.MR000034.pub2.

Taking Observational RWE to Next Level - ISPOR/ ISPE guidance

• Confirmatory Study – “Evaluates the presence or absence of a pre-specified treatment effect and/or its magnitude”

– Hypothesis evaluation treatment effectiveness

– To inform recommendations

• Transparency & Reproducibility

– Pre-registration

– Publish and attestation of analysis plan conformation/deviation

– Ability to replicate (RECORD checklists)

– Replicate with different datasets/methods

– Publish criticisms/responses

– Multi-stakeholder involvement (patients, HCPs, payers, etc.)

• Publications in Value in Health (Jul-Aug 2017)/Pharmacoepidemiology and Drug Safety (Sep 2017)

JOINT ISPOR–ISPE SPECIAL TASK FORCE ON REAL WORLD EXPERIENCE IN REGULATORY DECISION MAKING: WILL TRANSPARENCY IMPROVE ACCEPTABILITY? (ISPOR 2017)

Are we ready? • EHR source data

– Interoperability/Linkages

– Quality/unstructured data

– HCP incentives

– Regulatory audit ability

• Outcome measures (RCT vs. RW?)

• Study design considerations

• Practitioners as Investigators

• Efficiencies (not expecting significant cost/time savings initially with PRCTs)

• Other

Cancer: • PFS, Response Rate not readily

available in most EHR data • OS needs another datasource

(challenges with Social Security DMF)

RA: Disease activity scores <5% in EHR vs CV: significant body of work using claims data

Concluding Thoughts • RWD offers opportunity to optimize access to innovative medicines

and improve patient outcomes by: • Revolutionizing R&D to get medicines to regulatory review faster

• Addressing requirement of payers via outcomes-based contracting

• Enabling precision medicine in physician office to tailor treatments

• Need to focus on data collection infrastructure in clinical practice (electronic health record) as RWD hub • Requires collaboration between payers and practices/systems to address the

quality of RWD

• Regulatory consideration of RWD/E beyond safety is the next biggest step • Industry has a key role as lead generator of research to advance examples of

pragmatic trials and observational studies

• Need to improve rigor and transparency of observational RWE

• Need patience and openness to learn challenges/opportunities

THANK YOU!!!