REAL WORLD DATA

Amr Makady, MScAssistent Project Manager (IMI-GetReal)Zorginstituut NederlandPhD Candidate at Utrecht University

Jong-NVTAG MasterclassRotterdam 26.11.2015

Rachel Kalf, MScAssistent Research Officer (IMI-GetReal)Zorginstituut Nederland

Content

� Context sketching

� IMI-GetReal Project

� What is RWD?

� Example of RWD use in HTA:� Conditional Reimbursement� Pompe’s Disease

� Social Media: A source for RWD?

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Zorginstituut Nederland

□ Independent, non-departmental, governmental institution

□ Involved in two Dutch statutory healthcare insurance schemes:

■ The Health Insurance Act (Zorgverzekeringswet)■ The Exceptional Medical Expenses Act (Algemene Wet

Bijzondere Ziektekosten, AWBZ)

Zorginstituut Nederland (cont.)

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Efficacy vs Relative Effectiveness

� Efficacy: The extent to which a healthcare intervention produces a therapeutic effect as compared to a placebo intervention under ideal conditions (i.e. highly-controlled conditions). (Adapted from High Level Pharmaceutical Forum, 2008 & Strom, 2006)

� Relative Effectiveness: The extent to which an intervention does more good than harm, when compared to one or more intervention alternatives for achieving the desired results and when providedunder the routine setting of health care practice. (Adapted from High Level Pharmaceutical Forum, 2008)

Is there an efficacy-effectiveness gap?

The observed discrepancy between effects of a health intervention in routine clinical practice as compared with the effects demonstrated in randomisedcontrolled clinical trials. (Adapted from Eichler et al., 2011)

Clinical Studies in Product Lifecycle

� High internal validity

� Causal inference

� Control of known and unknown confounders

� BUT: Limited external validity

� Lower internal validity� Higher external

validity (clinical population)

� Questionable control of known and unknown confounders

� E.g.: PCT, Large simple trials, OS

RCT Alternative Study Designs

Why is this an issue?

Results from RCT’s used to:� Extrapolate long-term safety

and efficacy� Model effectiveness� Assess and decide on

relative effectiveness

IMI-GetReal

� Project Duration: 3 years

� Project Aim:� Incorporate real-world data

(RWD) in drug development & assessment.

� Multiple stakeholderinvolvement

� Project Outline: 5 Work Packages

� www.imi-getreal.eu

Overview of Work Packages

� WP1: Developing a framework for the assessment of development strategies that provide evidence of relative effectiveness

� WP2: Understanding how different pre-authorisation studies can inform the assessment of relative effectiveness

� WP3: Addressing operational and practical issues of conducting relative effectiveness research earlier in the drug development

� WP4: Promoting best practice in evidence synthesis and predictive modelling of relative effectiveness

� WP5: Managing the GetReal consortium by providing scientific, governance, and management direction to the project

WP1 Case Study

� Role: ZIN as co-lead

� Topic: Metastatic Melanoma

� Research Themes:� Combining RWD with RCT data

– better effectiveness estimates using registries? NL/ITA/FR

� The use of social media sources to inform effectiveness estimates?

What is Real-World Data?

“So, we usually base our definition on the ISPOR criteria. So, basically in simple terms we are look ing at data that are collected outside of the conventio nal randomized clinical trial...” – Pharmaceutical Industry B

Differing Ideas and Definitions

“Ehm to me the term RWD is about the scientific process. So I think of it as a step that isn’t done in a RCT. So it is a definition by exclusion. - HTA Agency B

“It is not a term that I am very familiar with at all .” –Initiative A

Q1: What is RWD?

Think about:

� Not an RCT� Observational nature� HRQoL� Long-term effects

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RWD: Een lastig begrip?

Source: Makady et al. (2015). What is RWD?: a review of definitions. (Article in progress)

Defining Real-World Data

Source: Adapted from Makady et al., 2015

RWD is defined as an umbrella term for data regarding the effects of health interventions (e.g.

benefit, risk, resource use, etc) that are not collected in the context of conventional randomised

controlled trials. Instead, RWD is collected both prospectively and retrospectively from observations

of routine clinical practice.

Data collected include, but are not limited to, clinical and economic outcomes, patient-reported outcomes

(PRO) and health-related quality of life (HRQoL).

Q2: Is RWD Relevant for HTA?

Think About:

� Treatment effects: 1º & 2º� Medical Costs: direct & indirect� Quality of Life (QoL)� Pharmacoeconomic Models (Markov

states, Decision Trees)

Is RWD Relevant for HTA?

� Large simple trials/ Pragmatic clinical trials:� Sufficient numbers to capture outcomes such as hospitalisations

(direct medical costs)� Resource use and costs measured better reflect community-based

setting (direct & indirect medical costs)

� Patient registries:� Understanding natural history of disease (transition probabilities for

economic model)� Measuring long-term health outcomes and side-effects (effectiveness

component of economic model)� Examining treatment history to better calculate resource use (direct &

indirect medical costs)

� Health Surveys:� Descriptions of health status (QALY calculations)

Contexts for RWD Use

Conditional Reimbursement & Pompe’sDisease

Example of RWD Use in HTA

Conditional Reimbursement (CR)

� Medicines must be effective, and preferably cost-effective, to be included in reimbursement schemes

� If uncertainties exists (E/CE), CR is implemented:� T=0: medicine allowed on market with promise for

further data collection� T=4: re-assessment of E/CE based on collected data

� Eventual full reimbursement denied or granted

Pompe’s Disease

� Orphan disease� Patients suffer a deficiency in alglucosidase-alpha

(GAA) enzyme levels� Classic/ juvenile form:

� Symptoms present in first months of life� Progressive muscle weakness and heart wall enlargement

� Non-classic/ latent form:� Manifests either in juveniles or adults� Patients have basal GAA activity; less acute symptoms with

slower disease progression; mobility, disability, breathing

Myozyme® (alglucosidase alpha)

� Indication: Chronic enzyme-replacement therapy (ERT) for patients diagnosed with Pompe’sdisease

� Registered Dose: 20 mg/kg per 2 weeks� Mechanism of Action: Substitute for lysosomal

hydrolase (alglucosidase-alpha) deficient patients

� Why Conditional Reimbursement?� At T=0: uncertainties on effectiveness for non-classic

form� At T=4: re-assessment of E/CE

Observational Studies at T=4Author & Year

Study Design Patient Population

Intervention Follow-up Time

Outcome measures

Kishnani(2009)

Open-label extension of RCT

Classic form (n=16)

Myozyme 20 or 40mg/kg per 2 weeks

Up to 3 years Survival; Use of breathing apparatus at 24 & 36 months of age

Nicolino(2009)

Multicenter, open-label

Classic form, 6-36 months of age (n=21)

Myozyme 20 or 40mg/kg per 2 weeks

52-120 weeks Survival; Survival without breathing apparatus; motor symptoms

Chakrapani(2010)

Retrospective Classic form (n=20)

Myozyme 20 mg/kg per week

Median 31 months (1-102 months)

Survival; Age at diagnosis; Feeding; Motor abilities

Kishani(2006)

Retrospective dossiers study

Classic form, 0-1 years old (n=168)

None N/A Kaplan-Meier Analysis

NL Prospective Cohort at T=4Author & Year

Study Design

Patient Population

Intervention Follow-up Time

Outcome measures

ZonMw Prospective, open-label

Classic & Non-classic forms, 10-79 years old (n=99)

Myozyme Median 6 years

Survival; Cardiac hypertrophy; Muscle function; Degree of disability; Lung function; QoL

Kanters Prospective study, open-label

Non-classic form (n=145)

Untreated = 72; Myozyme = 73

3 years QoL

IPA/ Erasmus PomeSurvey

Partially retrospective and prospective

Non-classic form (n= 271 + 412)

Untreated = 75, Myozyme = 196

9 years (2002-2011)

Survival; Use of wheelchair; Use of breathing apparatus

Q3: How would you use these RWD sources as inputs for PE analysis?

� Aim: cost-effectiveness of Myozyme use within classic form in the setting of Dutch clinical practice

� Think about:� Which study(s) to chose for the following

aspects?� Choice of model type: CEA, CUA, CBA � Outcome measures� Costs (direct, indirect)� Input parameters (e.g. transitions)

Cost-Utility Analysis at T=4

� Aim: cost-effectiveness of alglucosidase alpha in Dutch clinical practice for classic form

� Perspective: societal (direct med/non-med, indirect)

� Comparator: best supportive care� Outcome measures:

� QoL� Survival

� Time Horizon: 15 years� Model: Micro-simulation model, 0.5yr cycle (classic)

1yr cycle (non-classic)

Selected Study Population

� Classic patients (n=8)�Total of 16 patients in NL prospective cohort

� Source: ZonMw prospective cohort

Outcome Measures

� QoL (utility):� Calculated from EQ-5D data of adult, non-classic patients� Source: ZonMw prospective cohort

� Survival:� Classic form (treated): Kishnani et al. (2006)� Classic form (untreated): Kishnani et al. (2009)

Costs

� Direct medical costs:� Within and outside hospital setting� Including infusion costs

� Indirect medical costs:� Productivity loss

� Costs were specified per item in total number of users, as well as the average use per patient.

� Sources: ZonMw; Oostenbrink et al., NZa

Calculating the ICER

Incremental Cost-Effectiveness Ratio:

Calculating the ICER

Q4: Your Thoughts & Remarks

� Is the use of RWD in this way acceptable?� Do you trust the quality of evidence?� How would you have done it differently?

A source for RWD?

Social Media

What is Social Media?

Social media are defined as ‘a group of Internet-based applications that allow the creation and exchange of user generated content’.

Source: Kaplan, et al. Business Horizons (2010)

Types of Social Media

1. Collaborative projects

2. Blogs

3. Content communities

4. Social networking sites

5. Virtual worlds

Sources: Kaplan, et al. Business Horizons 2010Grajales, et al. JMIR 2014; 16(2)

What is, and isn’t Social Media?

Social Media = Big Data

Big Data ≈ Social Media

Social Media ≈ Patient Powered Research Networks

≈ Health Apps (e.g. Apple ResearchKit)

GetReal: Social Media as RWE?

Aim: Explore the potential for health data collected via social media to supplement evidence on effectiveness, or how it could be developed to meet such a goal.

Research questions:� How has social media been used to collect health data? � What health data is generated via online patient

networks? � What are the policy concerns and acceptability of social

media generated health data?� Can social media play a role in early drug development?

Review: Collecting Social Media Data

� Aim: To assess if and how health data generated fromsocial media could contribute in the assessment of relativeeffectiveness.

� Focus: Oncology

� Scientific and grey literature search:

� 794 hits

� Included:

� 5 scientific papers

Q5: How and what type of SMD?

Think About: � Which information patients share� Which information patients search for� What type of social media patients use to

share or search

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Review Results: Study Characteristics

Study Analysis type

Study design Study period

Posts analyzed (# of respondents)

Type of social media used to collect health data

Type of health data collected

Beusterien2013

Qualitative Retrospective 52 days 1522 posts (264)

2 forums AE’s, physical & emotional impacts

Freifeld2014

Quantitative and qualitative

Retrospective 7 months

6,900,000 posts (N/A)

Twitter AE’s

Mao2013

Quantitative and qualitative

Retrospective 8 years 1,235,400 posts (N/A)

12 forums AE’s and adherence

Pages2014

Qualitative Retrospective 1 year 111 posts (66) 5 forums AE’s

Zaid2014

Quantitative Prospective 30 days N/A (57) Survey on support group’s Facebooknews feed

Socio-demographic factors, disease specific characteristics, and QoL

Q6: What are the strengths & limitations of SMD?

Think About: � The added value compared to traditional data

collection� The type of data that is collected� Possible biases

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Review Results: Strengths & Limitations of SMDStrengths Limitations

■ Patient perspective

■ Collection PROMS efficient and comprehensive

■ Complementary

■ Rapid information on AEs

■ Access to patients over wide geographic areas

■ Access to patients with rare diseases

■ Identify AEs that resonate most to patients

■ Identify new/unlabelled AEs

■ Short time period

■ Highly motivated patient population

■ Validating authenticity

■ Selection bias■ Information bias

■ Incomplete data

■ Volume of posts

■ Noisy data■ Frequency data is no indication of

prevalence AEs

Review Results: Acceptability

Study Acceptability of SMD

Beusterien2013

Patient views accepted in PRO research in understanding disease and treatment impact.

Freifeld2014

Importance patients views recognized by regulatory authorities.Not used in routine surveillance yet.

Mao2013

Observed frequency key AEs reflected those reported in traditional studies.

Pages2014

Pharmaceutical companies use social media to inform on AEs.

Zaid2014

N/A

Online Patient Networks

Online patient network

Members Conditions Treatments Data sources Scientific publications

CureTogether 25.000+ 637 N/A Members Unclear

Mediguard 2.690.000 40 ~6400 Members Unclear

PatientsLikeMe

350.000 2500+ ~6000 Members Yes

Treato N/A 14.748 26.616 Mining the web

No

Patient Perspectives on HRQoL

Disease: Melanoma (stage I – IV)

Problem: Current HRQoL questionnaires insufficiently reflect patients’

needs

Research questions:1. Is it feasible to use a European patient network to distribute a survey

via social media?2. How do closed and open social media compare?3. How do patients on social media compare to the general melanoma

patient population?

Example: Coosto

Q7: Social Media in HTA?

Q7: Social Media in HTA?

� Social media may be a potential source to collect RWD on relative effectiveness

� Main potential for social media lies in collecting data on AEs, adherence, quality of life, switching behaviours

� Debate amongst stakeholders regardingacceptability and possibilities important

Any questions?

amakady@zinl.nl

Work: +31 20 797 8482

rkalf@zinl.nl

Work: +31 20 797 8188

Thank you for your attention!