NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE GUIDANCE EXECUTIVE (GE)
Review of TA241; Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia (CML) (part review of NICE technology appraisal guidance 70), and dasatinib and nilotinib for people with CML for whom treatment with imatinib has failed because of intolerance
This guidance was issued in January 2012
The review date for this guidance is September 2014
1. Recommendation TA241 should be moved to the static guidance list. That we consult on this proposal.
2. Original remits To appraise the clinical and cost effectiveness of dasatinib, high dose imatinib and nilotinib within their licensed indications for the treatment of people with chronic myeloid leukaemia who are resistant to standard dose imatinib.
3. Current guidance 1.1 Nilotinib is recommended for the treatment of chronic or accelerated phase Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) in adults:
whose CML is resistant to treatment with standard-dose imatinib or
who have imatinib intolerance and
if the manufacturer makes nilotinib available with the discount agreed as part of the patient access scheme
1.2 Dasatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase CML in adults with imatinib intolerance or whose CML is resistant to treatment with standard-dose imatinib.
1.3 High-dose imatinib is not recommended for the treatment of chronic, accelerated or blast-crisis phase Philadelphia-chromosome-positive CML that is resistant to standard-dose imatinib
Confidential information has been removed. 1 of 19 1.4 People who are currently receiving dasatinib or high-dose imatinib for the treatment of CML should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
4. Rationale1 No new evidence has been found that would justify a review and no there is no indication that there are any ongoing studies whose results might change the guidance.
5. Implications for other guidance producing programmes There is no proposed or ongoing guidance development that overlaps with this review proposal.
6. New evidence The search strategy from the original assessment report was re-run on the Cochrane Library, Medline, Medline In-Process and Embase. References from January 2011 were reviewed for the imatinib-resistant population and references from June 2009 onwards were reviewed for the imatinib-intolerant population. Additional searches of clinical trials registries and other sources were also carried out. The results of the literature search are discussed in the ‘Summary of evidence and implications for review’ section below. See Appendix 2 for further details of ongoing and unpublished studies.
7. Summary of evidence and implications for review The marketing authorisation for dasatinib at the time of developing technology appraisal 241 was ‘for the treatment of 'adult patients with newly diagnosed Philadelphia-chromosome-positive chronic myelogenous leukaemia in the chronic phase' and 'adult patients with chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate'. ************************************************************************************************ ************************************************************************************************ ************************************************************************************************ ******************************************************.
The marketing authorisation for imatinib at the time of developing technology appraisal 241 was for ‘the treatment of adult and paediatric patients with newly diagnosed Philadelphia-chromosome- (BCR-ABL) positive CML for whom bone marrow transplantation is not considered as the first line of treatment’ and for 'adult and paediatric patients with Philadelphia chromosome-positive CML in chronic phase after failure of interferon alfa therapy (recommended dose 400 mg once daily) or in accelerated phase or blast crisis (recommended dose 600 mg once daily)'. The manufacturer has indicated that there is no current intention to apply for an extension of the licence. However, imatinib received a license extension in May 2013 for ‘the
1 A list of the options for consideration, and the consequences of each option is provided in Appendix 1 at the end of this paper
Confidential information has been removed. 2 of 19 treatment of paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy’.
The marketing authorisation for nilotinib at the time of developing technology appraisal 241 was for the treatment of 'adult patients with newly diagnosed Philadelphia-chromosome-positive chronic myelogenous leukaemia (CML) in the chronic phase' and 'adult patients with chronic phase and accelerated phase Philadelphia-chromosome-positive CML with resistance or intolerance to prior therapy including imatinib'. The manufacturer has indicated that there is no current intension to apply for any extensions to the license. The European Medicines Agency website states that in May 2014 Novartis (the manufacturer of nilotinib) withdrew a request for a license extension ‘to treat patients with Philadelphia- chromosome-positive chronic myelogenous leukaemia (CML) in whom treatment with another cancer medicine, imatinib, has not led to a ‘complete molecular response’.
The literature searches identified 33 studies, since the development of NICE technology appraisal 241, of which 5 were relevant to the treatment of imatinib- resistant CML or for people with imatinib intolerance being treated with dasatinib, high-dose imatinib and nilotinib. The Committee for technology appraisal 241 noted a lack of comparative trials between nilotinib, dasatinib and imatinib and that the trials available at the time were of short duration. A prospective study (Choi et al., 2012: n=43; nilotinib n=22, high-dose imatinib n=21) and the RE-NICE study (Choi et al, 2013: n=52; nilotinib n=26, high-dose imatinib n=26) both compared the efficacy of switching patients from standard-dose imatinib to nilotinib or high-dose imatinib. Both studies had the primary endpoint to evaluate the cumulative major molecular response rates by 12 months. In the prospective study, the cumulative incidence of major molecular response, by 12 months, showed no significant difference between the nilotinib arm and the high-dose imatinib arm (37.8+11.9% compared with 34.8+10.6%, p=0.789). The RE-NICE study came to the same conclusion with the cumulative incidence of major molecular response by 12 months showing no significant difference (41.1% compared with 28.8%, p=0.334).
The Committee had also noted no evidence on the use of dasatinib or high-dose imatinib given as an adjuvant treatment with intensive chemotherapy for acute chemotherapy and a very limited evidence base for blast-crisis phase of the disease. The Committee commented that most of the clinical-effectiveness data came from trials which contained a mixed population of people with imatinib-resistant CML and people with imatinib intolerance. The studies identified during the literature searches for this review proposal paper did not provide evidence to fill any of these data gaps identified by the Committee in the original appraisal.
The current prices specified in the British National Formulary (BNF) edition 67 for dasatinib, imatinib, nilotinib and interferon alfa are the same as published in technology appraisal 241 and the price of hydroxycarbamide has reduced slightly. The tablet sizes available have changed for dasatinib (70mg, 60 pack no longer available and 80mg and 140mg, 30 pack now available) and capsule sizes for nilotinib (150mg capsule now also available), since technology appraisal 241 was published, however the prices for the different doses have remained the same. **************************************************************************. Since the development of technology appraisal 241, 4 generic versions of imatinib have been
Confidential information has been removed. 3 of 19 developed and received marketing authorisations, imatinib Accord, imatinib Actavis, imatinib Medac and imatinib Teva. There are currently no prices available for the generics in the BNF or MIMS. No further technology appraisal guidance for CML in adults with imatinib-resistant CML and people with imatinib intolerance has been published since January 2012, suggesting no new comparator therapies have entered the market.
The clinical effectiveness evidence identified from the literature searches, registered trials and current list prices of the technologies do not suggest the recommendations of technology appraisal 241 need reviewing.
Based on the above information, it is proposed that technology appraisal guidance 241 is transferred to the ‘static guidance list’.
8. Implementation A submission from Implementation is included in Appendix 3.
Data is available on the volume of dasatinib, imatinib and nilotinib prescribing in primary care and in hospital and dispensed in the community in England between April 2009 and March 2014. The ePACT data suggests that the use of dasatinib and imatinib decreased and use of nilotinib increased after the publication of NICE technology appraisal 232.
There is insufficient evidence to make any firm conclusions on the adherence to NICE technology appraisal guidance 241, or whether there is any regional variation in clinical practice in England and Wales.
9. Equality issues During the original appraisal the Committee noted the argument that if dasatinib, high-dose imatinib or nilotinib are not recommended for the treatment of imatinib- resistant CML then this could raise issues in relation to race, age (the elderly), and comorbidities. However, the Committee concluded that allowing for clinical decisions relating to a range of possible treatments based on individual assessment of risk and benefit does not limit access to the technology for any specific protected group compared with other people.
10. GE paper sign off: Janet Robertson, 12th August 2014
Contributors to this paper: Information Specialist: Tom Hudson
Technical Lead: Caroline Hall
Implementation Analyst: Liesl Millar
Project Manager: Andrew Kenyon
Confidential information has been removed. 4 of 19 Appendix 1 – explanation of options When considering whether to review one of its Technology Appraisals NICE must select one of the options in the table below:
Options Consequence Selected – ‘Yes/No’
A review of the guidance should A review of the appraisal will be planned No be planned into the appraisal into the NICE’s work programme. work programme. The review will be conducted through the MTA process.
The decision to review the NICE will reconsider whether a review is No guidance should be deferred to a necessary at the specified date. specified date.
A review of the guidance should A review of the appraisal(s) will be No be combined with a review of a planned into NICE’s work programme as a related technology appraisal. The Multiple Technology Appraisal, alongside review will be conducted through the specified related technology. the MTA process.
A review of the guidance should A review of the appraisal(s) will be No be combined with a new planned into NICE’s work programme as a technology appraisal that has Multiple Technology Appraisal, alongside recently been referred to NICE. the newly referred technology. The review will be conducted through the MTA process.
The guidance should be The on-going guideline will include the No incorporated into an on-going recommendations of the technology clinical guideline. appraisal. The technology appraisal will remain extant alongside the guideline. Normally it will also be recommended that the technology appraisal guidance is moved to the static list until such time as the clinical guideline is considered for review. This option has the effect of preserving the funding direction associated with a positive recommendation in a NICE technology appraisal.
Confidential information has been removed. 5 of 19 Options Consequence Selected – ‘Yes/No’
The guidance should be updated Responsibility for the updating the No in an on-going clinical guideline. technology appraisal passes to the NICE Clinical Guidelines programme. Once the guideline is published the technology appraisal will be withdrawn. Note that this option does not preserve the funding direction associated with a positive recommendation in a NICE Technology Appraisal. However, if the recommendations are unchanged from the technology appraisal, the technology appraisal can be left in place (effectively the same as incorporation).
The guidance should be The guidance will remain in place, in its Yes transferred to the ‘static current form, unless NICE becomes aware guidance list’. of substantive information which would make it reconsider. Literature searches are carried out every 5 years to check whether any of the Appraisals on the static list should be flagged for review.
NICE would typically consider updating a technology appraisal in an ongoing guideline if the following criteria were met:
i. The technology falls within the scope of a clinical guideline (or public health guidance)
ii. There is no proposed change to an existing Patient Access Scheme or Flexible Pricing arrangement for the technology, or no new proposal(s) for such a scheme or arrangement
iii. There is no new evidence that is likely to lead to a significant change in the clinical and cost effectiveness of a treatment
iv. The treatment is well established and embedded in the NHS. Evidence that a treatment is not well established or embedded may include;
Spending on a treatment for the indication which was the subject of the appraisal continues to rise
There is evidence of unjustified variation across the country in access to a treatment
There is plausible and verifiable information to suggest that the availability of the treatment is likely to suffer if the funding direction were removed
Confidential information has been removed. 6 of 19 The treatment is excluded from the Payment by Results tariff
v. Stakeholder opinion, expressed in response to review consultation, is broadly supportive of the proposal.
Confidential information has been removed. 7 of 19 Appendix 2 – supporting information
Relevant Institute work
Published Bosutinib for previously treated chronic myeloid leukaemia. NICE Technology Appraisal TA299. Issued: November 2013. Review date: July 2016.
Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia (part review of technology appraisal guidance 70). NICE Technology Appraisal TA251. Issued: April 2012. Review date: currently under review.
Guidance on the use of imatinib for chronic myeloid leukaemia. NICE Technology Appraisal TA70. Issued: October 2013. Partially updated by TAs 241 and 251. Review date: currently under review.
Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE Technology Appraisal TA218. Issued: March 2011. Static guidance.
Confidential information has been removed. 8 of 19 Details of changes to the indications of the technology
Indication considered in original Proposed indication (for this appraisal appraisal)
Dasatinib: No change. Treatment of adult patients with chronic, *********************************************** accelerated or blast phase CML with *********************************************** resistance or intolerance to prior therapy *********************************************** including imatinib mesilate. *********************************************** *********************************************** *********************************************** *****************************
Imatinib: No change. Treatment of adult and paediatric patients with newly diagnosed Philadelphia-chromosome- (BCR-ABL) positive CML for whom bone marrow transplantation is not considered as the first line of treatment, and for adult and paediatric patients with Philadelphia- chromosome-positive CML in chronic phase after failure of interferon alfa therapy (standard recommended dose 400 mg once daily) or in accelerated phase or blast crisis (standard recommended dose 600 mg once daily). TA241 specifically considers “high dose” imatinib treatment, defined as doses of 600 mg or 800 mg/day in the chronic phase disease or 800 mg/day in the accelerated phase or blast crisis. The SPC states that increased doses may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response.
Confidential information has been removed. 9 of 19 Indication considered in original Proposed indication (for this appraisal appraisal)
Nilotinib: No change. Treatment of 'adult patients with newly diagnosed Philadelphia-chromosome- positive chronic myelogenous leukaemia (CML) in the chronic phase' and 'adult patients with chronic phase and accelerated phase Philadelphia- chromosome-positive CML with resistance or intolerance to prior therapy including imatinib
Details of new products
Drug (manufacturer) Details (phase of development, expected launch date, ) Ponatinib (Iclusig) Launched in the UK in August 2013. Licensed for the treatment of people with chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation Omacetaxine Launched in the US for the treatment of CML that has mepesuccinate progressed after treatment with at least two tyrosine (Teva) kinase inhibitors. European regulatory filings were previously planned (2011) but current plans are unknown. Imatinib Teva Licensed in the EU for the EU for the treatment of: (Teva) – imatinib children with newly diagnosed Philadelphia biosimilar chromosome (bcr-abl) positive CML for whom bone marrow transplantation is not considered as the first line of treatment children with Philadelphia chromosome positive CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis adults with Ph+ CML in blast crisis adults with Philadelphia chromosome positive CML in blast crisis
Confidential information has been removed. 10 of 19 Registered and unpublished trials
Trial name and registration number Details Efficacy of Nilotinib Versus Imatinib in Nilotinib vs. high dose imatinib Ph+ CML in Early CP Who Have a N = 100 Suboptimal Molecular Response to Imatinib Estimated completion date: June 2014. RE-NICE; NCT01400074; CAMN107AKR01T. Still open for recruitment.
Nilotinib Versus Standard Imatinib N = 207 (400/600 mg QD) Comparing the Completed ~July 2014. Kinetics of Complete Molecular Response for CML-CP Pts With Evidence of Persistent Leukemia by RQ-PCR ENESTcmr; NCT00760877; CAMN107A2405; 2009-012616-40. Randomized ph Lll Study of Imatinib Nilotinib vs. high dose imatinib Dose Optimization vs Nilotinib in CML N = 188 Patients With Suboptimal Response to Imatinib Estimated completion date: August 2014. LASOR; NCT00802841; CAMN107A2404, 2008-007054-35. Still open for recruitment.
References Choi S-Y, Lee S-E, Jang E-J et al. (2012) Nilotinib versus high-dose imatinib in early chronic phase CML patients who have suboptimal molecular responses to standard-dose imatinib: Updated data from re-nice study. Blood 120 (21).
Choi S-Y, Lee S-E, Oh YJ et al. (2013) Nilotinib or high-dose imatinib compared with standard-dose imatinib in early chronic phase CML patients who have suboptimal molecular responses to standard- dose imatinib: Including updated data from re-nice study. Blood 122 (21). Cortes JE, De Souza CA, Lopez JL et al. (2013) Switching to nilotinib in patients (pts) with chronic myeloid Leukemia in chronic phase (CML-CP) with suboptimal cytogenetic response (CyR) on imatinib: First results of the LASOR trial. Blood 122 (21). Leber B, Cervantes F, Spector N et al. (2013) Achievement and maintenance of deeper molecular response by switching to nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib: ENESTcmr 36-month follow-up. Blood 122 (21). Shah NP, Guilhot F, Cortes JE et al. (Apr. 2014) Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 123 (15): 2317-2324.
Confidential information has been removed. 11 of 19 Appendix 3 – Implementation submission
1. Routine healthcare activity data 1.1. ePACT data
This section presents electronic prescribing analysis and cost tool (ePACT) data on the net ingredient cost (NIC) and volume of dasatinib, imatinib and nilotinib prescribed and dispensed in hospitals in England between April 2009 and March 2014.
Figure 1 Cost and volume of dasatinib prescribed in hospital and dispensed in the community in England between April 2009 and March 2014.
Confidential information has been removed. 12 of 19 Figure 2 Cost and volume of imatinib prescribed in hospital and dispensed in the community in England between April 2009 and March 2014.
Figure 3 Cost and volume of nilotinib prescribed in hospital and dispensed in the community in in England between April 2009 and March 2014.
Confidential information has been removed. 13 of 19 Figure 4 Cost and volume of dasatinib prescribed and dispensed in the community in England between April 2009 and March 2014.
Figure 5 Cost and volume of imatinib prescribed and dispensed in the community in England between April 2009 and March 2014.
Confidential information has been removed. 14 of 19
Figure 6 Cost and volume of nilotinib prescribed and dispensed in the community in England between April 2009 and March 2014.
Confidential information has been removed. 15 of 19 1.2 Hospital Pharmacy Audit Index data This section presents Hospital Pharmacy Audit Index (HPAI) data on the net ingredient cost (NIC) and volume of dasatinib, imatinib and nilotinib prescribed and dispensed in hospitals in England between January 2001 and December 2011.
Figure 7 Cost and volume of dasatinib prescribed in hospitals in England
Confidential information has been removed. 16 of 19 Figure 8 Cost and volume of imatinib prescribed in hospitals in England
Figure 9 Cost and volume of nilotinib prescribed in hospitals in England
Confidential information has been removed. 17 of 19 2. Implementation studies from published literature No uptake information was found on the uptake database website for TA 241.
3. Qualitative input from the field team The implementation field team have not recorded any feedback in relation to this guidance.
4. Implementation studies from shared learning A search of the shared learning website highlighted no examples of TA241 being implemented.
Confidential information has been removed. 18 of 19 Healthcare activity data definitions ePACT Prescribing analysis and cost tool system
This information comes from the electronic prescribing analysis and cost tool (ePACT) system, which covers prescriptions by GPs and non-medical prescribers in England and dispensed in the community in the UK. The Prescription Services Division of the NHS Business Services Authority maintains the system. PACT data are used widely in the NHS to monitor prescribing at a local and national level. Prescriptions dispensed in hospitals, mental health units and private prescriptions, are not included in PACT data.
Measures of prescribing Prescription Items: Prescriptions are written on a prescription form. Each single item written on the form is counted as a prescription item. The number of items is a measure of how many times the drug has been prescribed.
Cost: The net ingredient cost (NIC) is the basic price of a drug listed in the drug tariff, or if not in the drug tariff, the manufacturer's list price.
Data limitations (national prescriptions) PACT data do not link to demographic data or information on patient diagnosis. Therefore the data cannot be used to provide prescribing information by age and sex or prescribing for specific conditions where the same drug is licensed for more than one indication.
IMS HEALTH Hospital Pharmacy Audit Index IMS HEALTH collects information from pharmacies in hospital trusts in the UK. The section of this database relating to England is available for monitoring the overall usage in drugs appraised by NICE. The IMS HPAI database is based on issues of medicines recorded on hospital pharmacy systems. Issues refer to all medicines supplied from hospital pharmacies to: wards; departments; clinics; theatres; satellite sites and to patients in outpatient clinics and on discharge.
Measures of prescribing Volume: The HPAI database measures volume in packs and a drug may be available in different pack sizes and pack sizes can vary between medicines.
Cost: Estimated costs are also calculated by IMS using the drug tariff and other standard price lists. Many hospitals receive discounts from suppliers and this is not reflected in the estimated cost.
Costs based on the drug tariff provide a degree of standardization allowing comparisons of prescribing data from different sources to be made. The costs stated in this report do not represent the true price paid by the NHS on medicines. The estimated costs are used as a proxy for utilization and are not suitable for financial planning.
Data limitations IMS HPAI data do not link to demographic or to diagnosis information on patients. Therefore, it cannot be used to provide prescribing information on age and sex or for prescribing of specific conditions where the same drug is licensed for more than one indication.
Confidential information has been removed. 19 of 19