Date published: 15 July, 2025
Date last updated: 15 July, 2025
Specialised commissioning

NHS England commissioning statement: Arrangements for access to cystic fibrosis transmembrane conductance regulator (CFTR) modulators for licensed and off-label use in patients with cystic fibrosis

Version 4.0, July 2025.

Commissioning position

NHS England has confirmed that vanzacaftor–tezacaftor–deutivacaftor will be made available as a treatment option for people with cystic fibrosis (CF) who have 1 of an expanded range of CF transmembrane conductance regulator (CFTR) mutations within the criteria set out in this commissioning statement. NHS England has confirmed that it will be expanding the availability of ivacaftor–tezacaftor–elexacaftor as a treatment option for people with CF who have 1 of an expanded range of CFTR mutations within the criteria set out in this commissioning statement.

Ivacaftor monotherapy will remain available as a treatment option in line with its licensed indications within the criteria consistent with the August 2024 commissioning statement.

NHS England will continue to provide ivacaftor monotherapy and tezacaftor–ivacaftor as a treatment option for people with CF who have 1 of an expanded range of CFTR mutations within the criteria consistent with the August 2024 commissioning statement. Ivacaftor monotherapy and tezacaftor–ivacaftor will continue to be available to patients with named mutations approved by the US Food and Drug Administration (FDA) for which the use of the medications would be off-label in England.

Vanzacaftor–tezacaftor–deutivacaftor and ivacaftor–tezacaftor–elexacaftor will be available to patients who have at least 1 non-Class I mutation in the CFTR gene as outlined by the European Medicines Agency (EMA) for which the use of the medications would be off-label in England. Vanzacaftor–tezacaftor–deutivacaftor will also be available as a treatment option in line with its licensed indication within the criteria set out in this commissioning statement.

The treatments in this policy will be available through the access agreement in place between NHS England and Vertex pharmaceuticals.

Licensed indications for ivacaftor–tezacaftor–elexacaftor plus ivacaftor alone, tezacaftor–ivacaftor plus ivacaftor alone, and lumacaftor–ivacaftor respectively, are covered by National Institute for Health and Care Excellence (NICE) TA988 and are outside the scope of this commissioning statement. Use in the population covered by the NICE guidance for vanzacaftor–tezacaftor–deutivacaftor [NICE ID6372] is outside the scope of this commissioning statement.

The Condition

CF is the most common, life-limiting, recessively inherited disease in the UK, affecting approximately 11,300 people (9,300 in England). A defect in the CFTR protein results in a reduction in quantity of the CFTR channels and/or a reduction in function of the CFTR channels resulting in a reduction in the passage of chloride ions through the open channel pore. This affects the balance of salt ions and fluids inside and outside of the cell (see reference 1). This imbalance leads to thick, sticky mucus in the lungs, pancreas, and other organs.

Complications of CF include increased susceptibility to serious infections, reduced lung function, pancreatic insufficiency and CF related diabetes, liver cirrhosis, osteoporosis and osteopenia. There is no cure for CF. In severe cases of CF, when the lungs stop working properly and all medical treatments have failed to help, a lung transplant may be recommended. Therapeutic treatments for CF include antibiotics to prevent and treat chest infection and medicines to reduce the levels of mucus in the body. The latter includes the CFTR modulator therapies ivacaftor, lumacaftor–ivacaftor, tezacaftor–ivacaftor, ivacaftor–tezacaftor–elexacaftor and vanzacaftor–tezacaftor–deutivacaftor.  

Ivacaftor (monotherapy) licensed use

This commissioning statement remains consistent with the licensed indications of the previous relevant clinical commissioning statement: ‘Ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor for licensed and off-label use in patients with cystic fibrosis who have named mutations [210508P]’. Under this updated commissioning statement NHS England continues to commission ivacaftor (monotherapy) within its licensed indications:

  • as monotherapy for the treatment of infants aged at least 1 month, toddlers and children weighing 3 kg to less than 25 kg with CF who have an R117H CFTR mutation or 1 of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R
  • as monotherapy for the treatment of adults, adolescents, and children aged 6 years and older and weighing 25 kg or more with CF who have an R117H CFTR mutation or 1 of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

The look-up table of licensed mutations from the manufacturer can be found on the CF Source website.

For all these CFTR products where the UK licence is amended in the future, eligible patients will automatically have access under those terms. The manufacturer will be responsible for supplying an age-appropriate product within the UK.

Ivacaftor (monotherapy) off-label use

Where the UK medicines regulator may not consider the evidence for some named CFTR mutations, NHS England will continue to reimburse the off-label use of ivacaftor in line with the approach to in vitro data taken by the US FDA, and the approved list of named mutations as outlined in this commissioning statement.

A clinician considering prescribing a medication outside the terms of the licence (‘off-label’) should do so in accordance with the Medicines and Healthcare products Regulatory Agency (MHRA) and General Medical Council (GMC) guidance which apply throughout England and the UK. The GMC guidance states prescribing unlicensed medicines may be necessary where ‘there is no suitably licensed medicine that will meet the patient’s need’. Should clinicians consider this appropriate for their patients, and they have followed local medicines governance arrangements for off-label use, then NHS England will meet these costs as follows:

  • ivacaftor: people with CF aged 1 month and older who are heterozygous in the CFTR gene for any one of the FDA-approved mutations outside the UK licence

Access for prescribers and pharmacists to the look up table for establishing patient eligibility for off-licence indications can be sought by contacting england.npoc-internalmedicine@nhs.net

Combination therapy licensed use

Under this updated commissioning statement NHS England will commission vanzacaftor–tezacaftor–deutivacaftor for those patients not covered by the NICE guidance within its licensed indications:

  • for people with CF aged 6 years and older who have a non-F508del responsive mutation in the CFTR gene

The look-up table of licensed mutations from the manufacturer can be found on the CF Source website.

Licensed indications for ivacaftor–tezacaftor–elexacaftor plus ivacaftor alone are covered by NICE TA988 and are outside the scope of this commissioning statement.

For all these CFTR products where the UK licence is amended in the future, eligible patients will automatically have access under those terms. The manufacturer will be responsible for supplying an age-appropriate product within the UK.

Combination therapy off-label use

Where the UK medicines regulator may not consider the evidence for some named CFTR mutations, NHS England will continue to reimburse the off-label use of tezacaftor–ivacaftor in line with the approach to in vitro data taken by the US FDA, and the approved list of named mutations as outlined in this commissioning statement.

Where the UK medicines regulator may not consider the evidence for some CFTR mutations, NHS England will reimburse the off-label use of ivacaftor–tezacaftor–elexacaftor and vanzacaftor–tezacaftor–deutivacaftor in line with the approach taken by the EMA, as outlined in this commissioning statement. 

A clinician considering prescribing a medication outside the terms of the licence (‘off-label’) should do so in accordance with MHRA and GMC guidance which apply throughout England and the UK. The GMC guidance states prescribing unlicensed medicines may be necessary where ‘there is no suitably licensed medicine that will meet the patient’s need’. Should clinicians consider this appropriate for their patients and they have followed local medicines governance arrangements for off-label use, then NHS England will reimburse the off-label use of tezacaftor-ivacaftor, ivacaftor–tezacaftor–elexacaftor and vanzacaftor–tezacaftor–deutivacaftor as outlined below:

Named CFTR mutations that have not been considered by the UK regulator  

Where the UK medicines regulator has not considered the evidence for some named CFTR mutations, NHS England will reimburse the off-label use of tezacaftor–ivacaftor in line with the approach to in vitro data taken by the US FDA and the approved list of named mutations as follows:

  • tezacaftor-ivacaftor: people with CF aged 6 years and older who have any one of the FDA-approved named mutations outside the UK licence. In addition, 14 mutations licensed by the UK regulator for people with CF who have the F508del mutation are included for off -label prescribing when combined with any mutation other than F508del

In reaching this decision, NHS England has considered the FDA approach using a cell-based in vitro system/study* to validate the efficacy of tezacaftor–ivacaftor for an expanded range of mutations (clinical data were not available or readily feasible due to the rarity of the mutations under consideration).

Where the UK medicines regulator has not considered the evidence for some named CFTR mutations, NHS England will reimburse the off-label use of ivacaftor–tezacaftor–elexacaftor and vanzacaftor–tezacaftor–deutivacaftor in line with the approach taken by the EMA as follows: 

  • ivacaftor–tezacaftor–elexacaftor: for people with CF aged 2 years and older who have at least one non-Class I mutation in the CFTR gene
  • vanzacaftor–tezacaftor–deutivacaftor: for people with CF aged 6 years and older who have at least 1 non-class I mutation in the CFTR gene

In reaching this decision, NHS England has considered the EMA approach presented to them.

Access for prescribers and pharmacists to the look up table for establishing patient eligibility for off-licence indications can be sought by contacting england.npoc-internalmedicine@nhs.net

For further details on prescribing, dosage, monitoring and stopping criteria, please see appendix 1.

*The in vitro system allowed for the assessment of changes in CFTR mediated chloride transport in response to ivacaftor and tezacaftor/ivacaftor in Fischer rat thyroid (FRT) cells expressing mutant CFTR channels. A shift in “percentage normal” CFTR chloride transport of at least 10% above baseline was the designated threshold for determining mutant CFTR channel response to the medications.

Mechanism for funding

NHS England will fund these treatments through specialised commissioning teams.

Commissioning statement review date

This is an urgent commissioning statement, which means that a full independent evidence review has not been conducted and public consultation has not been undertaken. If a review is needed due to a new evidence base, then NHS England should be contacted at this email address: england.CET@nhs.net

NICE

Supersedes

  • Clinical commissioning urgent policy statement ‘Ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor for licensed and off-label use in patients with cystic fibrosis who have named mutations’: [210508P] published August 2024
  • Clinical commissioning urgent policy statement ‘Cystic fibrosis modulator therapies access agreement for licensed mutations’: [200810P] published November 2023
  • Clinical commissioning urgent policy statement ‘Cystic fibrosis modulator therapies access agreement for licensed mutations’: [200810P] published May 2023
  • Clinical commissioning urgent policy statement ‘Cystic fibrosis modulator therapies access agreement for licensed mutations: [200810P] published January 2022
  • Clinical commissioning urgent policy statement ‘Cystic fibrosis modulator therapies access agreement for licensed mutations: [200810P] published on 21 January 2021
  • Clinical commissioning urgent policy statement ‘Ivacaftor and tezacaftor/ivacaftor for cystic fibrosis: “off-label” use in patients with named rarer mutations: [200809P]’ published on 21 January 2021
  • Commissioning statement ‘Ivacaftor, tezacaftor/ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor for licensed and off-label use in patients with cystic fibrosis who have named mutations [210508P) published on 10 May 2021

Equality statement

Promoting equality and addressing health inequalities are at the heart of NHS England’s values. Throughout the development of the policies and processes cited in this document, we have:

  • given due regard to the need to eliminate discrimination, harassment and victimisation, to advance equality of opportunity, and to foster good relations between people who share a relevant protected characteristic (as cited under the Equality Act 2010) and those who do not share it
  • given regard to the need to reduce inequalities between patients in access to and outcomes from healthcare services and to ensure services are provided in an integrated way where this might reduce health inequalities

Definitions

CFTR gene: refers to the cystic fibrosis transmembrane conductance regulator (CFTR) gene which contains the instructions for making the CFTR protein.

In vitro system/study: this refers to a study performed or taking place in a test tube, culture dish, or elsewhere outside a living organism.

Mutation: in this context ‘mutation’ refers to the changing of the structure of a gene, resulting in a variant form that may be transmitted to subsequent generations.

Osteoporosis: a medical condition in which the bones become brittle and fragile, typically as a result of hormonal changes, or deficiency of calcium or vitamin D.

Osteopenia: a medical condition in which the protein and mineral content of bone tissue is reduced, but less severely than in osteoporosis.

References

  1. How does CF affect the body – Cystic Fibrosis Trust
  2. Advice for clinicians on cataract related to CFTER modifying drug of cystic fibrosis – The Royal College of Opthalmologists 2019
  3. FDA-approved drugs – U.S. Food and Drug Administration. Drugs@FDA
  4. Costa, E. et al. (2022) ‘The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis’, Orphanet Journal of Rare Diseases, 17(1). doi:10.1186/s13023-022-02350-5

Appendix 1: prescribing guidance and monitoring

All CFTR therapies should only be used in people diagnosed with CF. A diagnosis of CF should be made based on supportive diagnostic criteria in addition to the presence of mutations. In this case, a definitive diagnosis usually requires a sweat chloride >60mmol, abnormal nasal potential difference or abnormal intestinal current measurement on rectal biopsy. The CFTR therapies must only be prescribed by physicians with experience in the treatment of CF working within NHS England commissioned CF services in line with this commissioning statement. For patients whose genotype is unknown, an accurate and validated genotyping method will be performed before starting treatment to confirm the presence of an indicated mutation in the CFTR gene (see below under ivacaftor and tezacaftor-ivacaftor).

Access for prescribers and pharmacists to the look up table for establishing patient eligibility for off-licence indications can be sought by contacting england.npoc-internalmedicine@nhs.net

Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with CF. Liver function tests will be performed in all patients prior to initiating ivacaftor monotherapy or in a combination regimen as tezacaftor–ivacaftor or as the triple therapy ivacaftor–tezacaftor–elexacaftor or vanzacaftor–tezacaftor–deutivacaftor.  

Ivacaftor tablets and granules, and ivacaftor-tezacaftor-elexacaftor granules contain lactose. These will therefore not be prescribed to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or congenital glucose-galactose malabsorption.

Dosing

Ivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for ivacaftor, linked below:

Tezacaftor–ivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for tezacaftor–ivacaftor, linked below:

Ivacaftor–tezacaftor–elexacaftor dosage: all information regarding dosage can be found in the respective SmPCs for ivacaftor–tezacaftor–elexacaftor, linked below:

Vanzacaftor–tezacaftor–deutivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for vanzacaftor–tezacaftor–deutivacaftor, linked below:

Monitoring criteria  

Liver function tests must be carried out at least every 3 months during the first year of treatment and annually thereafter for all patients starting either ivacaftor monotherapy, in a combination regimen with lumacaftor–ivacaftor, tezacaftor–ivacaftor or as the triple therapy ivacaftor–tezacaftor–elexacaftor or vanzacaftor–tezacaftor–deutivacaftor.

In line with guidance from the Royal College of Ophthalmologists (see reference 2) it is recommended that patients aged less than 18 years when starting , either ivacaftor monotherapy, in a combination regimen with lumacaftor-ivacaftor, tezacaftor–ivacaftor or as the triple therapy ivacaftor–tezacaftor–elexacaftor or vanzacaftor–tezacaftor–deutivacaftor, should be seen on a regular basis by their local optometrist to detect any significant visual difficulties which may prompt referral to hospital eye services for further assessment.

When changing from one CFTR modulator to another, initial monitoring should be repeated.

Stopping criteria

In the event of significant elevations of transaminases (for example, patients with ALT or AST > 5 x the upper limit of normal (ULN), or ALT or AST > 3 x ULN with bilirubin > 2 x ULN), dosing with ivacaftor, tezacaftor-ivacaftor, ivacaftor–tezacaftor–elexacaftor or vanzacaftor–tezacaftor–deutivacaftor will be interrupted and laboratory tests closely followed until the abnormalities resolve.

Consideration will be given to delaying or discontinuing therapy if hepatotoxicity or renal toxicity occurs.

During pregnancy it is preferable to avoid the use of ivacaftor, tezacaftor–ivacaftor, ivacaftor–tezacaftor–elexacaftor and vanzacaftor–tezacaftor–deutivacaftor. For women who are breast-feeding and taking these therapies, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from these therapies, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.

Effective from

The commissioning statement is effective from the date of publication.  

Recommendations for data collection

Hospital trusts should submit data on the numbers of patients treated with CFTR modulators to the national Cystic Fibrosis Registry which is hosted by the Cystic Fibrosis Trust.  

 

Date published: 15 July, 2025
Date last updated: 15 July, 2025