This agreement relates to:
- Tezacaftor and ivacaftor (Symkevi®) in combination with ivacaftor (kalydeco) for treating cystic fibrosis patients who are homozygous for the F508del mutation or who are heterozygous F508del mutation.
- Lumacaftor and ivacaftor (Orkambi®) for treating cystic fibrosis homozygous for the F508del mutation.
- Ivacaftor (Kalydeco) for treating cystic fibrosis with specified gating mutations or R117H mutation.
Parties to this agreement
- NHS England, whose legal name is the NHS Commissioning Board and whose principal office is at Quarry House, Quarry Hill, Leeds, LS2 7UE ("NHSE");
- The National Institute for Health and Care Excellence, a non-departmental public body established under primary legislation and based at 10 Spring Gardens, London SW1A 2BU (“NICE”);
- UK Cystic Fibrosis Trust, a charity dedicated to the interests of people living with cystic fibrosis, whose office is at 1 Aldgate, London EC3N 1RE (“CF Trust”), and the manager of the UK Cystic Fibrosis Registry;
- Vertex Pharmaceuticals (Europe) Limited, a company incorporated in England having its principal place of business at Level 9, Paddington Central, 2 Kingdom Street, London W2 6BD, United Kingdom (“Vertex”), and licensed seller of lumacaftor-ivacaftor (Orkambi), tezacaftor-ivacaftor (Symkevi) and ivacaftor (Kalydeco) respectively;
Each a "Party" and together the "Parties".
In consideration of the promises, rights and obligations contained in:
- this Agreement; and
- the access agreement put in place between NHS England and Vertex in respect of the above-mentioned drugs,
the sufficiency of which is acknowledged by each of the Parties, it is agreed as follows:
1. Purpose of this agreement
1.1 NHS England and Vertex have concluded an access agreement to enable eligible patients in England access to treatment with ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor via the NHS.
1.2 The purpose of this agreement is to describe the arrangements intended to capture the data that may address uncertainties identified by NICE’s technology appraisal committee.
2. Commencement and period of agreement
2.1 This agreement will commence on the date of publication of this agreement on the NICE website, following execution of this agreement by all parties.
2.2 This agreement will expire upon the earlier of either 2.2.1 or 2.2.2.
2.2.1 Publication of NICE's recommendation following a guidance review of the new evidence collected during the initial term of this interim access agreement.
2.2.2 Termination of the access agreement between NHS England and Vertex.
3. Areas of clinical uncertainty with respect to lumacaftor/ivacaftor and tezacaftor/ivacaftor
3.1 At the time of the original appraisal of lumacaftor/ivacaftor (TA398) the NICE committee indentified the following key uncertainties:
- Long-term treatment effects on ppFEV1
- The impact of treatment on lung function decline
- Treatment discontinuation rates and reasons for discontinuation
- Treatment compliance rates
- Comparative outcomes for different disease severities
- The impact of treatment on caregivers
- Comparative treatment pathway costs.
4. Sources of data
4.1 Data will be collected from patients who start or receive treatment with ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor during the term of this agreement. Patients who stop treatment during this term will also continue to be monitored for disease deterioration and supported with other clinical measures.
4.2 The data that will be collected are summarised in table 1.
4.3 Sources of data that could resolve the key uncertainties include:
- Primarily, real world data collected by the UK Cystic Fibrosis (CF) Registry
- Pharmacy home delivery data to inform compliance rates
- Potentially other Vertex studies that will require prospective primary data collection.
4.4 The protocol, governance and data protection clauses for 4.3 (ii) and (iii) will be defined by Vertex and are outside of the remit of this agreement.
Table 1: Outline of data to be collected from the UK CF Registry
- The Parties agree that the recommended frequency and upload of the listed assessments is beyond the standard of care and routine upload frequency in current practice, however where possible assessments are encouraged to be conducted and uploaded using the UK CF Registry ‘encounter’ form, as per the recommended frequency in table 1.
- At a minimum, assessments should be conducted and uploaded annually (using the UK CF Registry ‘annual’ form).
- Further agreements will be established between Vertex and the CF Trust as per 8.1 and 8.2 which may redefine the data collection requirements in table 1.
- Quality of Life (QoL) data collections further to those listed in table 1 will be explored by the Parties.
Key data items
It is expected that the following data items will be collected as part of routine clinical practice; upon feasibility of these data being captured by clinicians in the registry, where available these data will be part of the dataset.
Ideally data should be captured in the registry as per the below recommended frequency. At a minimum, assessments should be conducted and uploaded annually using the CF registry 'annual' form.
|Assessment||Rationale||Recommended frequency: Baseline/Pre-treatment||Recommended frequency: 3 monthly||Recommended frequency: 6 monthly||Recommended frequency: Annually||Data collection tool|
|Poly-T status (R117H patients only. Patients are not required to have genetic retesting if genotyping has already been performed.)||Baseline characteristics||Yes||No||No||No||UK CF Registry|
|ppFEV1||Assessment of lung function||Yes||Yes||No||No||UK CF Registry|
|BMI (for patients greater than or equal to 18 years)||Assessment of non-respiratory symptoms||Yes||Yes||No||No||UK CF Registry|
|Height and weight (for patients under 18 years)||Assessment of non-respiratory symptoms||Yes||Yes||No||No||UK CF Registry|
|Lung transplant events||Assessment of pulmonary exacerbation||No||No||Yes||No||UK CF Registry|
|Use of intravenous antibiotics - hospital and home||Proxy for assessment of pulmonary exacerbation||No||No||Yes||No||UK CF Registry|
|Microbiology||Assessment of treatment efficacy||No||No||Yes||No||UK CF Registry|
|IV and Non-IV hospital admissions||Proxy for assessment of hospital admissions||No||No||Yes||No||UK CF Registry|
|CF related diabetes status||Assessment of non-respiratory symptoms||No||No||Yes||No||UK CF Registry|
|Treatment discontinuation status and reasons for treatment discontinuation - all treatment not just CFTRm.||Assessment of treatment discontinuation rates||No||No||Yes||No||UK CF Registry|
|Mortality||Assessment of overall survival||No||No||Yes||No||UK CF Registry|
|Faecal elastase||Assessment of pancreatic insufficiency||No||No||No||Yes||UK CF Registry|
Additional data collections
Where possible and where the infrastructure of the UK CF Registry allows, the following data items are considered to be highly relevant to any future evidence submissions and should be uploaded to the CF registry if collected.
|Assessment||Rationale||Recommended frequency||Data collection tool|
|Quality of life (tool to be determined)
(upload of domain scores/total score)
|Assessment of carer quality of life||6 monthly||UK CF Registry|
|Quality of life (CFQR)
(upload of domain scores/total score)
|Assessment of patient quality of life||6 monthly||UK CF Registry|
|Sweat chloride||Assessment of sweat chloride||Annually||UK CF Registry|
5. Data collection responsibilities
5.1 NHSE shall seek to ensure, to the extent reasonably possible, that the treating clinician collects the assessment outcomes and uploads these to the UK CF Registry, for patients who have consented to provide data to the UK CF Registry as per the table 1 (at a minimum annually).
5.2 The UK CF Trust, via the UK CF Registry will be responsible for providing the following outputs (further detail on report content will be outlines in the analysis plan as per 8.2):
- An interim data report to NICE, NHS England and Vertex 6 months after the commencement of this agreement detailing the number of patients receiving these therapies who are providing data to the UK CF Registry and an overview of data completeness for these patients. These reports will be used to determine whether real-world data collection is proceeding as anticipated and will not form part of the NICE guidance review.
- An interim analysis data report to NICE, NHS England and Vertex in calendar Q4 2020 for the purpose of a NICE guidance review of lumacaftor/ivacaftor and tezacaftor/ivacaftor.
- A final analysis data report to NICE, NHS England and Vertex in calendar Q2 2021 for the purpose of a NICE guidance review of lumacaftor/ivacaftor and tezacaftor/ivacaftor.Vertex is responsible for ensuring that the data collected on the relevant patients are provided to NICE as part of the appraisal process for lumacaftor/ivacaftor and tezacaftor/ivacaftor during the second year of this agreement.
6. Patient eligibility
6.1 In order for patients to be considered as eligible to participate in this data collection exercise, such patients shall be:
- located in England
- within the license indications for ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor in place at the date of execution of this agreement;
- Ivacaftor license indication:
- Patients must be aged 1 year or older
- AND have a confirmed mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) of at least one copy of the G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R (also known as gating mutations).
- OR patient is aged 18 years or older with at least one copy of the R117H mutation in the CFTR gene.
- Lumacaftor/ivacaftor license indication:
- All patients aged 2 years or older and confirmed homozygous F508del mutation of the CFTR gene.
- Tezacaftor/ivacaftor license indication:
- All patients aged 12 years or older and confirmed homozygous F508del mutation of the CFTR gene or confirmed heterozygous F508 del mutation of the CFTR gene AND have one of the following CTFR gene mutations:
P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.
- eligible to receive treatment using either ivacaftor, lumacaftor/ivacaftor or tezacaftor/ivacaftor during the term of the interim access agreement; and
- receiving treatment with either ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor during the time period in which the data is collected pursuant to this agreement.
6.2 All patients located in England who received treatment pursuant to Vertex’s managed access programme (which provided free ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor for the most needy patients, prior to the access agreement being executed and implemented) will transfer to product supplied to them on the terms contained in the access agreement.
6.3 If the patient's genotype is unknown, an accurate and validated genotyping method should be performed before starting treatment to confirm the presence of an indicated mutation in the CFTR gene. CF clinical teams will need to review existing patients prior to changing or initiating new medications.
6.4 Future therapeutic indications (for ivacaftor, lumacaftor/ivacaftor or tezacaftor/ivacaftor) that receive a marketing authrorization from the European Medicines Agency during the term of this interim access agreement will automatically be considered part of this agreement.
6.5 NHSE shall seek to ensure, to the extent reasonably possible, that treating clinicians encourage patients to attend a clinic appointment every 6 months after treatment initiation.
6.6 NHSE shall seek to ensure, to the extent reasonably possible, that treating clinicians follow the recommendations and precautions set out in the Summary of Product Characteristics for each drug/treatment.
6.7 The parties agree that patients who are eligible for NHS treatment in England but have been sourcing these products abroad or through private prescriptions in England can access treatment via this interim access agreement so long as they are eligible as per lumacaftor/ivacaftor and tezacaftor/ivacaftor full license indications and their treating centre confirms that they are eligible for NHS treatment in England. In all these cases, the parties agree that it is for the patient/family to ensure that there is an appropriate handover between the organisation currently treating the patient and the NHS treating centre in England.
6.8 Clinicians should be familiar with the Marketing Authorisation and where applicable cease treatment where patients are unable to benefit from the treatment.
7. Data protection
7.1 Patient data collected as part of this interim access agreement will be in accordance with all applicable data protection legislation, including but not limited to the European Union’s General Data Protection Regulation.
8. Data analysis plan
8.1 The Parties shall work together to ensure that relevant aggregated data required for the NICE reconsideration of guidance for lumacaftor/ivacaftor and tezacaftor/ivacaftor is available during the second year of this agreement. Specifically, Vertex shall be responsible for putting in place – in accordance with 8.2 and the timeline set out immediately above – an agreement with CF Trust to ensure that necessary data contained in the UK CF Registry is analysed for this purpose.
8.2 Vertex (in consultation with the CF Trust) shall create a data analysis plan within 3 months following the commencement of this agreement, for review by NICE and NHS England at the first Interim Access Oversight Committee meeting.
9. Ownership of the data
9.1 The data will be owned by patients and managed by UK CF Trust but shared in aggregate (and/or anonymised) form with NHS England, NICE, and Vertex for the purpose of assessing the benefit of lumacaftor/ivacaftor and tezacaftor/ivacaftor.
9.2 Data collected into the UK CF Registry and included in any output reports as part of this agreement will be subject to the retention and publication policies of the UK CF Registry.
10. Funding for data collection and analysis
10.1 Vertex will be expected to pay direct and associated costs as agreed between CF Trust and Vertex for:
- Database management including quality assurance.
- Data analysis.
- Costs associated with accessing, registry database amendments and linking data to other sources (if applicable).
- Any other costs identified that are relevant to data collection and analysis associated with the uncertainties identified by the NICE appraisal committee.
10.2 Vertex shall provide NICE and NHS England assurances that separate agreements concerning the resources required to operationalize data collection and analyses have been agreed with relevant third parties within 3 months of the publication of this data collection agreement.
10.3 The relevant terms of the agreements specified in 8.2 should be presented to the Interim Access Oversight Committee for review at its first meeting (i.e. no later than 6 months after the commencement of this agreement).
11. Monitoring arrangements
11.1 NICE will convene a Interim Access Oversight Committee with representation from all Parties and expert treatment centres located in England.
11.2 The Interim Access Oversight Committee exists to oversee the operation of all aspects of the data collection agreement and to address issues that may arise throughout the term of the data collection agreement. A detailed description of the Interim Access Oversight Committee function will be available in a Terms of Reference document produced by NICE.
11.3 The Interim Access Oversight Committee will meet at a minimum of 6-monthly intervals throughout the interim access agreement period.
12. Governing law
12.1 This agreement shall be governed by the laws of England and Wales, and subject to the exclusive jurisdiction of its courts.
13.1 This Agreement creates rights only for the Parties. It may not be enforced by any third party.
13.2 This Agreement may be executed in any number of counterparts, each of which when executed and delivered shall constitute a duplicate original, but all the counterparts together shall constitute one agreement. Transmission of the executed signature page of a counterpart of this Agreement by (a) fax or (b) email (in PDF, JPEG or other agreed format) shall take effect as delivery of an executed counterpart of this Agreement. If either method of delivery is adopted, without prejudice to the validity of the agreement thus made, each Party shall provide the other with the original of such counterpart as soon as reasonably possible thereafter. No counterpart shall be effective until each Party has executed and delivered at least one counterpart.