What do we know?

  • Ivacaftor efficacy in clinical trials is 9.9-10.6% improvement in FEV11. Effectiveness is around 6%2.
  • This efficacy-effectiveness gap is unlikely to be explained by patient characteristics between clinical trial and real-world studies.
  • Maintenance therapy continued in the clinical trials1 but there is real world evidence of declining inhaled therapies use following Ivacaftor initiation3,4.
  • Body mass index (BMI) continues to improve over the first five years of treatment with Ivacaftor while lung function declines back to baseline by year five, suggesting a lung target to optimise Ivacaftor outcomes5.
  • Results of Ivacaftor real-world evaluation were only available six years after the widespread introduction of Ivacaftor in the UK2.
  • In the four years since the efficacy-effectiveness gap was identified, the reasons, and therefore potential targets for intervention to close the gap, haven’t been systematically investigated or explained.
  • Traditional real-world evaluation of Kaftrio planned by NICE in co-operation with Pharma and the UK CF Registry is likely to take some time.

The importance

  • Drug cost which may exceed £100k per patient per year6,7.
  • Ivacaftor efficacy-effectiveness gap identified but mechanism still unknown.
  • Unlike Ivacaftor, Kaftrio is suitable for the majority of the UK CF population so the need to understand optimal use is greater. 
  • Kaftrio is highly efficacious; 14.3% between-group FEV1 difference over six months8 but likely that an efficacy-effectiveness gap will also exist and may be exacerbated by emphasis in the CF community around reducing treatment burden by dropping inhaled therapies following the initiation of modulators9,10.
  • 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 gaps. The CFHealthHub digital learning health system is well-configured to deliver this.
  • There are changes in treatment prescriptions and treatment-taking following modulator instigation and uncertainty for pwCf and clinicians about how to manage this.

The plan

A prospective, observational study using real-time data collected routinely via the CFHealthHub digital learning health system to take an initial look at the efficacy-effectiveness gap for Kaftrio, and the potential impact of adherence to inhaled therapies on the efficacy-effectiveness gap.

This approach also aims to have an intervention component that closes the efficacy-effectiveness gap in a real-world setting by generating new evidence through data analytics using data from a range of sources in real-time8.  Find more details here:


A first look within the first seven months of Kaftrio initiation at the:

  1. Real-world effectiveness of Kaftrio among adults with CF
  2. Efficacy-effectiveness gap for Kaftrio among adults with CF
  3. Change in adherence during inhaled therapies among adults with CF
  4. Potential impact of objective adherence to inhaled therapies on the efficacy-effectiveness gap
  5. Potential impact of medication possession ratio (MPR) to Kaftrio on the efficacy-effectiveness gap

Read more: Inhaled Therapy Adherence and Outcomes to Kaftrio in Cystic Fibrosis – Full Text View – ClinicalTrials.gov

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1.         Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. Nov 3 2011;365(18):1663-72. doi:10.1056/NEJMoa1105185

2.         Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. Aug 2018;73(8):731-740. doi:10.1136/thoraxjnl-2017-210394

3.         Hubert D, Dehillotte C, Munck A, et al. Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real-world setting. J Cyst Fibros. Jan 2018;17(1):89-95. doi:10.1016/j.jcf.2017.07.001

4.         Granger E, Davies G, Keogh RH. Treatment patterns in people with cystic fibrosis: have they changed since the introduction of ivacaftor? J Cyst Fibros. Sep 5 2021;doi:10.1016/j.jcf.2021.08.014

5.         Duckers J, Lesher B, Thorat T, et al. Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review. J Clin Med. Apr 6 2021;10(7)doi:10.3390/jcm10071527

6.         Bush A, Simmonds NJ. Hot off the breath: ‘I’ve a cost for’—the 64 million dollar question. Thorax. 2012;67(5):382-384. doi:10.1136/thoraxjnl-2012-201798

7.         Cohen D, Raftery J. Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding. Bmj. Feb 12 2014;348:g1445. doi:10.1136/bmj.g1445

8.         Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. Nov 7 2019;381(19):1809-1819. doi:10.1056/NEJMoa1908639

9.         Davies G, Rowbotham NJ, Smith S, et al. Characterising burden of treatment in cystic fibrosis to identify priority areas for clinical trials. J Cyst Fibros. May 2020;19(3):499-502. doi:10.1016/j.jcf.2019.10.025

10.       Gifford AH, Mayer-Hamblett N, Pearson K, Nichols DP. Answering the call to address cystic fibrosis treatment burden in the era of highly effective CFTR modulator therapy. Journal of Cystic Fibrosis. 2020;19(5):762-767. doi:10.1016/j.jcf.2019.11.007

11. https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-guidelines/how-we-develop-nice-guidelines/data-and-analytics-statement-of-intent

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