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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
2
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
4
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
5
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
6
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
9
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
12
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
13
New role for personal health devices and social media?
14
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
15
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
16
Problem: HTA/reimbursement is fragmented
INAHTA Members
Regulators are centralized
59 members from 23 countriesMyriad of regional reimbursement and insurance organisms
17
RWE for HTA: 1) IQWIG (DE) criteria
18
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
19
(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:
20
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)
21
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
22
A flurry of related initiatives
Built on scientific advice, central compassionate use, conditional MA,
registries & RMP
RWE
23
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
24
Adaptive licensing projects
Better wordings:
Facilitated (incremental) regulatory pathways
MAPPs (Medicines AdaptedPathways to Patients) < EFPIA
25
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
26
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)
27
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
28
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
29
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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