Evidence from real life studies. Example from COPD.
-To do the thing right, or to do the right thing. That is the question…
Minutes from the meeting:
To do the thing right
Or do the right thing
Evidence from real life studies. Examples from COPD
DSKF hosted a meeting to discuss the role of effectiveness studies the 8th of November 2016.
Senior Director Clinical Development and Project Physician Leader Robert Chan from GSK presented data from the recently published study “Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice” (Vestbo et al, NEJM, September 2016).
The study is the first real world study conducted before licensing. The investigated product Fluticasone Furoate-Vilanterol (FFV) is a ICS/LABA with a long half-life and once-daily dosing. It is now marketed under the brand name Relvar® Ellipta®.
Dr Chan presented the study with energy and enthusiasm. The aim of the study was to investigate FFV in as normal conditions as possible, in a “real life setting”, in a broader heterogeneous population. The comparator was usual care. The interaction with the patients was kept to a minimum in order to avoid unnecessary intervention and data were mostly collected electronically from electronic medical records and pharmacies. Dr Chan emphasized how the study contrasts to the classic randomized controlled trial. In a usual RCT in COPD patients, less than 10 % of the COPD population are normally eligible for the study due to extensive exclusion criteria, and patients generally are “over-compliant”. In the presented study, patients with co-morbidities were allowed, including use of other drugs and alcohol. The patients otherwise received usual care with no supervised adherence and only few extra contacts with health care professionals. Where the usual RCT is designed to assess the EFFICACY of a new drug, Dr Chan claimed that a “real-life-study” as the presented would assess the EFFECTIVENESS of a drug.
But DID FFV then add a (clinical meaningful) benefit to these real life patients? Regardless of whether it is a better drug or a better device, or just easier for patients to stay compliant with a once-a–day dosing.
Of 3161 patients screened, 2799 patients were randomized and followed for 12 months. The primary endpoint was annual rate of exacerbations, and the difference between the patient groups was (just) significant with an annual rate of 1.74 in the FFV group and 1.90 in the usual care group (difference 8.4 %, 95 % CI 1.1 – 15.2, p=0.02). It is worth mentioning that the primary effectiveness analysis was done in a subpopulation who had had one or more exacerbation in the year before the trial and therefore represents the most sick patients. In the entire population the difference was also significant with 1.50 exacerbations annually in the FFV group and 1.64 in the usual care group (difference 8.4 %, 95 % CI 1.4-14.9, p=0.02). There was no difference in the secondary outcomes: time-to-event, rate of severe exacerbations, COPD-related contacts, or hospital contacts (secondary health care contacts). For safety outcomes, the incidence of serious adverse events were similar. Pneumonia was a concern due to the ICS component, but there was no difference with 7 % in the FFV population and 6 % in the usual care group. More troublesome is the 45 deaths in the FFV group compared to 30 in the comparator.
So were we convinced of the effectiveness of FFV following Dr Chan’s presentation? Yes, compared to usual care, FFV is as efficient and seems safe – but the difference in number of deaths needs further discussion.
Are we convinced that FFV is better than usual care and a rational choice in COPD? Not really. Without even mentioning price, QALYs and added value, clinical pharmacologists like absolute values, and the difference in the annual exacerbation rate in the primary effectiveness analysis population was 0.16 (1.90 – 1.74). The patient reported outcomes (PROs) are not very useful in an open label study.
However, the design is interesting and a discussion of how we use and interpret studies in a real-life-setting is warranted. We have regarded the randomized trial as the gold standard, but as described convincingly by dr Chang, the RCT has its caveats and knowledge of how the drug will do in real life patients in real-life settings is lacking.
DSKF had invited professor Robin Christensen to speak in the second half of the meeting: “How to assess the evidence from real life studies and put the evidence where it belongs”. The answer was actually very simple: break down the evidence pyramid, use GRADE and GRADE will help you. GRADE is well-known to most DSKF members. We use the methodology in the e.g. RADS and national clinical guideline working parties. This afternoon, Prof Christensen gave the audience an entertaining lecture in GRADE emphasizing the point that also observational can be of high quality, and that we still need BOGSAT (Bunch of Old Guys/Gals Sitting Around a Table). An important point was that in the GRADE methodology the quality of the evidence is assessed and the quality of the evidence will determine the usability when making recommendations. This also applies to real-life studies.
Prof Christensen has initially a question for Dr Chang: I smell a rat, why did you change your mind and changed the protocol and reported the efficacy outcome in a subpopulation? The old rules of good scientific practice still applies, - also in real life studies.
/Kirstine Moll Harboe
Time / Venue: Kl.16:15-18:00. Tuesday, November 8th 2016.
Bispebjerg Hospital Bispebjerg Bakke 23, 2400 København NV www.bispebjerghospital.dk
Room: Den nye Pejsestue = lokale 14 i uddannelsesafdelingen
Participants: Members of DSKF. Interested non-members are welcome.
Participation is free, but participants must register no later than October 17th by mailing to Maija Haastrup (email@example.com )
16:15 Welcome. Chocolates/fruit and coffee/tea.
16:25 Methods and results of the recently published study:”Effectiveness of Fluticasone Furoate– Vilanterol for COPD in Clinical Practice” (NEJM sept 2016), presented by Dr Robert Chan.
Dr Robert Chan is currently a Senior Director Clinical Development and Project Physician Leader for the Respiratory Therapeutic Area Unit GlaxoSmithKline. Prior to joining industry Robert was a physician in St James’s Hospital Dublin and a research fellow / lecturer in the Department of Pharmacology and Therapeutics Trinity College Dublin in Ireland. Dr Chan has worked in various roles as a pharmaceutical physician covering the spectrum of drug development from Phase 1 to Phase 4. Dr Chan is an Educational Supervisor in pharmaceutical medicine as well as a Fellow of the Faculty of Pharmaceutical Medicine in the UK and a Member of the Royal College of Physician Ireland.
17:05 How to assess the evidence from real life studies and put the evidence where it belongs, Presented by Prof. Clin Epi, adj. Robin Christensen.
Professor Robin Christensen is a senior researcher, biostatistician and head of the ‘Musculoskeletal Statistics Unit’ at the Parker Institute at Bispebjerg and Frederiksberg Hospital. He is a professor of clinical epidemiology at the Faculty of Health Science, at the University of Southern Denmark. Kl.
17:40 Questions and Discussion. How to GRADE?
18:00 Thank you all. --
18:30 DSKF members only: Dinner (at own discretion).
Disclaimer: The meeting is held by DSKF. Presenters are not compensated for travel expenses or otherwise.