Cystic fibrosis (CF) is a multi-system long-term genetic condition with median age at death of around 31 years . The gene mutation responsible for CF results in dysfunctional CF transmembrane conductance regulator (CFTR) protein, which is a chloride channel. Impaired chloride secretion leads to sticky and thick secretions for a range of epithelial tissues such as the airways and pancreatic duct; culminating in malabsorption of nutrient, recurrent respiratory infections, progressive lung damage and respiratory failure . Inhaled therapies e.g. antibiotics and mucolytics are important to prevent exacerbations and maintain lung health among people with CF [3-5]. With the advent of highly efficacious CFTR modulators, which are small molecules that bind to CFTR proteins to improve function, there is now the opportunity to address the basic defect of CFTR dysfunction and to modify the disease.
The first approved highly efficacious CFTR modulator is ivacaftor, which works for those with Class III and some of the Class IV mutations (which are found in around 8-10% of the UK CF population). The landmark randomised controlled trial (RCT) evaluating the efficacy of ivacaftor among adults with G551D mutation found a 10.6% between-group FEV1 difference over 12 months . The between-group FEV1 difference was 9.9% even among those ≥18 years in the RCT. However, real world data from the UK CF registry found a between-group FEV1 difference of only around 6% over 12 months . This efficacy-effectiveness gap is unlikely to be fully explained by differences in patient characteristics compared to the RCT because ivacaftor was only licensed in the UK for people with G551D mutation during the period of evaluation (from 2012 to 2013). It is important to note that preventative inhaled therapies were continued during the RCT  whereas there is real world evidence of declining inhaled therapies use following ivacaftor initiation . This may explain in part why the real world effectiveness of ivacaftor was only around 60% of the efficacy observed in the RCT where participants are likely to have maintained high level of adherence to inhaled therapies.
Closing the efficacy-effectiveness gap for highly efficacious modulators is particularly important given the drug cost which exceeds £100k per patient per year [9,10]. Although the real world evaluation of ivacaftor identified an important efficacy-effectiveness gap, it was unable to provide a mechanistic explanation for that gap. The results of the evaluation was only available six years after the widespread introduction of ivacaftor in the UK and did not really influence clinical practice. The National Institute of Health and Care Excellence (NICE) is planning a traditional real world evaluation of another highly efficacious CFTR modulator by working with Vertex and the UK CF registry. It is currently unclear how quickly the “traditional evaluation” will report, but given that registry data are not available until around seven months after the annual data collection process is completed, it is unlikely that the analysis will be available before 20 months after the roll-out of any highly efficacious CFTR modulators. However, the data analytic teams at NICE have sign-posted the intention to use digital learning health systems to deliver a real time rapid health technology assessment with the aim of identifying efficacy-effectiveness gap  and there is a recognition that the CFHealthHub digital learning health systems are well-configured to deliver such programmes. This approach also aims to have an intervention component that closes the efficacy-effectiveness gap in real world setting by generating new evidence through data analytics using data from a range of sources in real time . There is now an imperative to improve on the real world evaluation of CFTR modulators because Kaftrio, a triple combination of elexacaftor-tezacaftor-ivacaftor which works for around 80% of the UK CF population [12,13], will soon be widely available for adults with CF in the UK.
Though Kaftrio is highly efficacious (RCT showed found a 14.3% between-group FEV1 difference over 6 months ), it is likely that an efficacy-effectiveness gap will also exist. The gap may be exacerbated by the current emphasis in the CF community around the wish to reduce treatment burden by dropping inhaled therapies following the initiation of highly efficacious CFTR modulators [14,15]. We therefore propose a prospective observational study by leveraging real time data that are collected routinely via the CFHealthHub digital leaning health system (ISRCTN14464661) for an initial look at the efficacy-effectiveness gap for Kaftrio and the potential impact of adherence to inhaled therapies on the efficacy-effectiveness gap.
A first look within the first seven months of Kaftrio initiation at the
- Real-world effectiveness of Kaftrio among adults with CF
- Efficacy-effectiveness gap for Kaftrio among adults with CF
- Change in adherence during inhaled therapies among adults with CF
- Potential impact of objective adherence to inhaled therapies on the efficacy-effectiveness gap
- Potential impact of medication possession ratio (MPR) to Kaftrio on the efficacy-effectiveness gap
We anticipate that the study would produce initial results that will generate hypotheses for further testing with on-going data collection and linkage with data from the UK CF registry. The initial results would also guide real time plan-do-study-act (PDSA) cycles to narrow the efficacy-effectiveness gap for Kaftrio.
This study will start following ethics amendment approval. Routine data collection is on-going as per previous regulatory approval from London-Brent NHS Research Ethics Committee (reference number: 17/LO/0032).
Data analysis is planned to start in August 2021 for 3 months.