1. Respiratory Effectiveness Group: Steering Committee Meeting The Arch Hotel, London 15 February, 2013 (8.30–16.00, The Martini Library)

2. Meeting Objective Devise an action plan! o Ideas: What are we going to do? o Details: How are we going to do it? o Priorities: When are we going to do it? o Collaborations: Who’s going to do it? o Funding: How can we make sure we can afford it?

3. Morning Agenda: 8.30–11:40 8:30–9:00: Introductions & Updates (David / Alison) 9:00–10:20: Sharing Research interests o Jon: 9:00–9:20Comparative effectiveness Research: an overview from the US o Jerry: 9:20–9:40Analytic hierarchy to define priorities for effectiveness/implementation research o Richard: 9:40–10:00The RO1 NIH submission / COPD gene group – potential collaborations o Leif: 10:00–10:20: Real-life effectiveness of different treatment modalities of asthma or COPD in patients with significant co-morbidities 10:20–10:40BREAK o Andrew: 10:40–11:00e-Health in COPD and asthma: tracking exacerbations, guideline dissemination and physician education o Gary: 11:00–11:20The fallacy of asthma guidelines: Discrepancy between science and practice o Marc: 11:20–11:40The Respiratory Effectiveness Group in COPD 11:40–12:30LUNCH

4. Afternoon Agenda: 12.30–16.00 12.30–14.30: Brainstorming how to turn the ideas into reality 14:30–14:45BREAK 14.45–15.30Consolidating ideas and setting priorities 15.30–16.00Other business Future meetings Engaging the wider group Securing sponsorship 16:00MEETING CLOSE

5. Introductions Steering Committee o David Price o Jon Campbell o Richard Martin o Jerry Krishnan o Andrew McIvor o Leif Bjermer o Marc Miravitlles o Gary Wong Im plementation Manager: Alison Chisholm Absent Committee Members: Christian Virchow; Guy Brusselle; Nicolas Roche; Alberto Papi; Nikos Papadopoulos; Stephen Holgate, Elliot Israel

6. Welcome and update Evolving landscape: David Price What have we achieved so far: Alison Chisholm Studies underway already: David Price 8:30–9.00

7. Evolving landscape: timeline Brussels Declaration on Asthma: stated a need to include evidence from real world studies in treatment guidelines Michael Rawlins (NICE Chairman): RCTs should be complemented by a diversity of approaches that involve analysing the totality of the evidence base 2008 ATS/ERS Large, prospective studies in ʻ real- world ʼ settings (e.g., trials designed pragmatically to reflect everyday clinical practice) to ensure they provide content validity as well as reflect clinically meaningful outcomes 2009 ARIA / GA2LEN Proposed the use of composite measures when evaluating asthma control and called for the measurement properties to be validated in clinical trials 2010 NHLBI expert workshop Highlighted areas that need strengthening in order to optimize the potential of real- life/comparative effectiveness (CER) research in pulmonary diseases, sleep, and critical care. 2011 REG was founded! 2012

8. Drivers for change: EU perspective Clinical drivers: o On-going need to improve patient outcomes o Evidence-based decisions require representative data Budget pressures increasing the need to demonstrate: o Affordability of therapies o Value of therapies Pharma o Bringing products to market is only the first step –Licensing ≠ approved –Licensing ≠ reimbursement –Licensing ≠ usage o Increasing need to invest in demonstrating the value proposition for new and existing products

9. Population Reversibility Severity Age / sex mix Attitude to disease Smoke exposure Concomitant disease Individual variation in response “real-life” population of patients Efficacy x Effectivenes s Clinical drivers: representative data

10. Criteria for selecting asthma patients to a clinical trial: o Lung function 50–80% predicted o Bronchodilator reversibility o No co-morbidities o Non smokers or ex-smokers <10 pack years o Good treatment compliance o Symptomatic and regular relief medication use o Good inhaler technique Travers et al. Thorax 2007

11. Norwegian study of asthma patients to identify who would be eligible for standard clinical trials 1.2% Herland K, et al. Respir Med. 2005;99:11-9 Patient population

12. Does it matter if we exclude patients with: o Lesser reversibility than 20% o Active rhinitis o Smokers o Lower adherence o Poor inhaler technique AND o Design the study not like real-life? o Study only lasts 3 months? Clinical drivers: representative data

13. Real-life studies Clinical drivers: representative data

14. RCTsPragmatic Observational trials studies Experiment, observation, mathematics, individually and collectively, have a crucial role in providing the evidential basis for modern therapeutics. Arguments about the importance of each are an unnecessary distraction. Hierarchies of evidence should be replaced by accepting – indeed embracing – a diversity of approaches. Sir Michael Rawlins, Head of NICE, Lancet 2008 Contemporary View Evidence continuum – complementary study designs Evidence base: hierarchy—continuum Traditional View

15. Commercial drivers… Testing What We Think We Know. New York Times - August 19, 2012 “The truth is that for a large part of medical practice, we don’t know what works. But we pay for it anyway.” H. Gilbert Welch, MD,Geisel School of Medicine at Dartmouth

16. Commercial drivers… Drugs must be shown to: o Be safe o Be efficacious o Address an unmet clinical need But also to be: o Cost-effective o Affordable o …“value propositions”

17. Development of guidelines Interventional studies (RCT): Efficacy Safety Effectiveness Observational studies (pharmaco- epidemiology): Safety Cost- effectiveness Effectiveness

18. The future of drug research Multiple rich heterogeneous and intricately constructed ‘real world’ data sets of Electronic Medical Records and Transactional Claims databases o Surveillance approaches are now being innovatively applied to such data o Several international initiatives and partnerships doing essential foundational work in the field o Challenging how to determine how to best utilise this wealth of data, and how to best incorporate such analyses into overall safety strategies Analysis of real world data is only one potential component of an overall continual assessment of risk benefit

19. However… there are challenges ObstacleSolution? No standard methods or endpoints Carry out validation studies Set standards Enforce minimum planning by offering study registration Concerns around internal validity and confounding of results Match patients Explore different matching methods; set gold standard Cynicism around retrospective data mining Promote and facilitate a priori study registration Limited understanding of how to interpret the data Educate and raise awareness Limited penetration of the data: – to high impact journals – clinical guidelines Address the issues above, and the data will start to talk for itself…? Set up REG  an international, collaborative approach