Bruno FLAMION, MD, PhDPast Chair, Scientific Advice Working Party (SAWP) of the CHMP (EMA), London Past Chair, National Committee for Reimbursement of Medicines (CRM) at the

National Institute of Health and Disability Insurance (NIHDI), BrusselsProfessor of Physiology & Pharmacology, University of Namur, Belgium

Real World Evidence (RWE)

Setting the scene

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The randomised clinical trial (RCT) is the gold standard of drug development

AND

Pharma companies are using false word data to achieve regulatory approval (at FDA, EMA)

real world data are added as an afterthought

False vs real world evidence

How can you reconcile this?

3

A clinical trial...

is a prospective study comparing the effect and value of an intervention against a control in human beings (i.e., does not include observational studies)

is the most definitive tool for evaluation of the applicability of clinical research; is the gold standard of clinical research

has the potential to improve the quality of health care and control costs through careful comparison of alternative treatments

Clinical trials

From the NIH inventory of clinical trials, 1979

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1962 (USA) The Federal FDC Act requires that, to obtain marketing approval, manufacturers demonstrate the effectiveness of their products through substantial evidence, i.e. the conduct of adequate and well-controlled studies (with an s at the end of studies ).

1998

FDA requirements

From the FDA site

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Regulatory approval

Multiple benefits

Market access

Relentless growth of post-launch activities

Further restrictions

Reimbursement Coverage

UncertaintyIncreasing costs

Demonstration of added valueHTA

RWE

PREVIOUSLY TODAY

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Evaluation of safety, effectiveness and outcomes in routine clinical practice

Data collected in actual practice for many purposes, e.g. prove or disprove the added value of a medicinal product

Pragmatic clinical trials

Observational data (= real-world data)

What is RWE ?

MEDLINE: Pragmatic OR naturalistic

Patsopoulos, 2011 7

Explanatory vs pragmatic trials

Adapted from: Schwartz & Lellouch, 1967; McPherson, 2004 8

Explanatory trial Pragmatic trial

Experimental setting (including practitioners skills)

Routine care setting

Homogeneous group of patients More heterogeneous group

Evaluate efficacy Compare effectiveness

Placebo-controlled (if possible) Active comparator

Patients blinded Patients unblinded

Aim to equalise non-specific effects Optimise non-specific effects

Usually short-term follow-up Long-term follow-up

May manage with small sample sizes Require large sample sizes

High internal validity, lower external High external validity, lower internal

Low relevance/impact on practice High relevance/impact on practice

MEDLINE: Real world data/evidence

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1990

1995

2000

2005

2010

2014

0

20

40

60

80

MEDLINE: RWD or RWE

Real world evidence ISPOR 2007

Lou Garrison et al., ISPOR RWD Task Force 2007 & A. Pleil, Pfizer, 2008 10

e.g., claims database

Electronic Health Records (EHRs)

Real world evidence

11Lou Garrison et al., ISPOR RWD Task Force 2007

e.g., propensity score matching (PSM)

NB. Lots of good registries already exist; access and inference are the critical issues

privacy & ownership issues

Additional questions for RWE - 1

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What is the appropriate role of industry in registries and observational studies? (including industry developing EHR

and data mining technologies)

How to incentivize physicians for improving the system?

Additional questions for RWE - 2

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New role for personal health devices and social media?

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Regulators strongly attached to interventional studies for MA

Pragmatic trials remain exceptional (higher variability, regulatory suspicion towards unblinded data)

RW data (especially registries, observational data) increasingly accepted for safety commitments (RMPs and PASS = post-approval safety studies) may become common for PAES & post-approval commitments

In the (near) future: adaptive licensing?

RWE at the CHMP (regulators) level

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Brings important information on the place of a new treatment (sequence & line of therapy, severity of disease, comparisons with existing treatments)

Allows greater segmentation (who benefits & who does not)

Generates regional/national pharmacoeconomic data

Pharma industry remains reluctant (tends to do the minimum to obtain a competitive advantage and achieve reimbursement)

RWE at the HTA/payer level

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Problem: HTA/reimbursement is fragmented

INAHTA Members

Regulators are centralized

59 members from 23 countriesMyriad of regional reimbursement and insurance organisms

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RWE for HTA: 1) IQWIG (DE) criteria

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AG

EN

ZIA

ITAL

IAN

A D

EL

FAR

MA

CO

Aifa Monitoring Registers

Uncertainty or scarcity of evidence

of the real useAifa Monitoring

Registers

On-line data filling

Useful information on real practice an d ap

p

r opr i atenes s.

Hospitals RegionsLocal Health UnitsPharmaceutical companies

Other institutional bodies

Useful data on the effectiveness of medicines to support decisions for conditional reimbursement schemes.

Risk / cost sharingPayment by results

Data collected by health professionals for eligible patients

AS - IS INPUT OUTPUTPaolo Siviero, AIFA

RWE for HTA: 2) AIFA (IT) risk sharing schemes

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(Conclusions)

1- Long-term trials required to demonstrate added value

2- Need for real world data (long-term pragmatic CTs

and prospective observational data in large numbers of

patients) on:

Long-term cardiovascular safetyUse in patients with congestive heart failure class IV, history of urinary tract infections

Use in paediatric patients, pregnancy, nursing mothers, very elderly patients ( 85 years), patients with severe

hepatic impairment & with severe renal impairment

RWE for HTA: 3) EUNetHTA REA

Example:

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Frequent question: incidence and costs of failures (in some countries only) performance-based risk-sharing arrangements (PBRSAs)

ISPOR Task Force on PBRSAs (2013)Conclusion: cost-effective PBRSAs are a challenge The most frequent requests in managed entry schemes are:

Limit/cap the target population and follow E/S in that population Real-world data collection through PASS, observational studies,

resource utilization data, claims data & registries preferably (or necessarily) in the country of reference

There is no EU-wide model or transnational agreements but a lot of case-by-case decisions

RWE requests by reimbursement agencies (on top of HTA)

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Claims data & other administrative data notoriously poor in manycountries ongoing improvements, especially on the use of EHRs& e-Health (although usually no data on payments for services)

No guideline telling which data to collect in a given situation/country Uncertain value of observational studies to determine relative

effectiveness

Other limitations and benefits of RWE in Europe

Limitations

For cost-effectiveness calculations many reimbursement agencies accept modeling based on results of RCT + pre-launch observational data in other regions

RWE can also be used to build EBM, scientific guidelines, clinical practice

Benefits

Started January 2014

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A flurry of related initiatives

Built on scientific advice, central compassionate use, conditional MA,

registries & RMP

RWE

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GSK, UK Amgen, BE AstraZeneca, SE Bayer, DE Boehringer Ingelheim, DE BMS, US Eli Lilly, UK Hoffman-La Roche, CH

Janssen Pharmaceutica, BE Merck KGaA, DE MSD, US Novartis Pharma, CH Novo Nordisk, DK Sanofi-Aventis, FR Takeda Europe, UK 5 universities, EORTC EMA, NICE, HAS, ZIN

Public-private partnerships

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Adaptive licensing projects

Better wordings:

Facilitated (incremental) regulatory pathways

MAPPs (Medicines AdaptedPathways to Patients) < EFPIA

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EMAs AL pilot project

Goal: maximise positive impact of new medicines on public health by allowing faster approval and reducing the efficacy-effectiveness gap

Launched 19 March 2014 7 applications selected among 28 submissions (end of

9/2014) Confidential Product must meet high unmet need; program should be

in Phase I or II NB. Pilot project does not replace Scientific Advice

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Typical plans for an EMAs AL pilot project

1. Prospectively designed development2. Early multi-stakeholder dialogue (e.g. including NICE,

HAS, ZIN, patients organisations)3. Planned initial approval in a well-defined restricted

population (possibly on surrogate endpoints e.g. obesity with BMI>40); MA may be full, conditional, or under exceptional circumstances

4. Post-MA control of prescription & risk minimisation procedures + strategic collection and use of RWD in agreement with demands from HTA bodies, payers, HCPs, patients organisations

5. Iterative changes to SmPC6. (Uncertainty: adaptive pricing & reimbursement)

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Willingness to change towards AL and use of RWD

1. Regulators2. Industry3. Progressive HTA bodies4. Patients5. HCPs6. Payers (? Adaptive pricing ?)7. Conservative HTA bodies

Tentative ranking

Based on discussions with the above stakeholders

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1. RWE is based non-RCT data for regulatory, HTA, payers, EBM purposes

2. RWD are increasingly used by HTA/payers, mostly as a tool to control and restrict use (enabling access and reimbursement to some groups), not so much as a measurement of added therapeutic value

3. Industry is increasingly planning pre- and post-launch RWD collection based on the identified gaps in RCTs (safety, efficiency, comparator, subgroups)

4. The quality of observational studies, registries, etc., is critical; the use of high-quality EHRs is expected to rise

Conclusions - 1

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5. The regulatory use of PASS and PAES is increasing in the new pharmacovigilance era

6. EMA has recently launched a move towards adaptive licensing (aka FRP, or MAPP) this will require multi-stakeholder agreement on RWD collection and analysis

7. Many countries already have early access schemes they should be used with caution

8. A key driver for the RCTRWE paradigm shift will be the level of EU-wide HTA coordination (as well as regulators-HTA interactions)

Conclusions - 2

Thank you !!

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