National Institute for Health and Care Excellence (NICE)
Full Text Guideline
Evidence Supporting the Recommendations
The type of evidence supporting the recommendations is not specifically stated for each recommendation.
The Appraisal Committee considered clinical and cost-effectiveness evidence submitted by the company that manufactures dabrafenib and a review of this submission by the Evidence Review Group (ERG). The main clinical effectiveness evidence came from an international, multi-centre, randomised, open-label, active-controlled trial. For cost-effectiveness, the Appraisal Committee considered an economic model submitted by the manufacturer.
Implementation of the Guideline
- Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, National Health Service (NHS) England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within 3 months of its date of publication.
- When NICE recommends a treatment 'as an option', the NHS must make sure it is available within the period set out in the paragraph above. This means that, if a patient has unresectable or metastatic BRAF V600 mutation-positive melanoma and the doctor responsible for their care thinks that dabrafenib is the right treatment, it should be available for use, in line with NICE's recommendations.
- The Department of Health and the company have agreed that dabrafenib will be available to the NHS with a patient access scheme that makes dabrafenib available with a discount. The size of the discount is commercial in confidence. It is the responsibility of the company to communicate details of the discount to the relevant NHS organisations. Any enquiries from NHS organisations about the patient access scheme should be directed to the manufacturer's customer contact centre on 0800 221 441.
- NICE has developed a costing statement explaining the resource impact of this guidance (see also the "Availability of Companion Documents" field).
Benefits/Harms of Implementing the Guideline Recommendations
Appropriate use of dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma
- The summary of product characteristics lists the following very common adverse reactions for dabrafenib: papilloma, decreased appetite, headache, cough, nausea, vomiting, diarrhoea, hyperkeratosis, alopecia, rash, palmar-plantar erythrodysaesthesia syndrome, arthralgia, myalgia, pain in extremity, pyrexia, fatigue, chills and asthenia.
- The data from the December 2012 analysis of the BREAK-3 trial showed that the most commonly reported grade 3 adverse events with dabrafenib were pyrexia, back pain, squamous cell carcinoma and hyperglycaemia; whereas neutropenia, decreased appetite and leukopenia had a higher incidence in the dacarbazine arm.
For full details of adverse reactions and contraindications, see the summary of product characteristics.
Rating Scheme for the Strength of the Recommendations
- This guidance represents the views of the National Institute for Health and Care Excellence (NICE) and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
- Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the Liverpool Reviews and Implementation Group (LRiG) (see the "Availability of Companion Documents" field).
Critique of Methods of Review(s)
Bibliographic databases including MEDLINE (1980 onwards and In process and other non-indexed citations), EMBASE (1980 onwards) and the Cochrane Library (1980 onwards) were searched on 22 October 2012. These searches were updated in October 2013 to identify additional published studies of relevance to the submission. No strategies for identifying ongoing studies are provided in the manufacturer's submission (MS). For all databases, a combination of free text and index terms were appropriately used.
The inclusion and exclusion criteria used in the original systematic review (October 2012) are presented in detail in the MS (Table 3). The criteria for the updated review are summarised in the table below. In addition to the interventions and comparators specified by NICE, it is noted that trametinib, ipilimumab and fotemustine were also included. It is stated that these interventions were identified from clinical practice or from ongoing clinical trials for the treatment of metastatic melanoma. The ERG notes that as of October 2013, both dabrafenib monotherapy and dabrafenib + trametinib (dual therapy) were included in the NICE appraisal process.
Table. Eligibility Criteria Used for Manufacturer's Updated Systematic Review (October 2013)
|Population||Adults with advanced or metastatic melanoma|| |
|Interventions||Dabrafenib; trametinib; vemurafenib; dacarbazine||Other interventions|
|Comparators||Vemurafenib; dacarbazine||Other comparators|
|Outcomes||Efficacy: OS; PFS; ORR: CR + PR; proportion of patients with stable disease and progressive disease; TTR, DoR; HRQoL |
Safety: Incidence and severity of all AEs; incidence and severity of specific AEs; withdrawals due to AEs; withdrawals due to death; SAEs
|Study design||RCTs||All other types of studies, reviews, letters and commentaries|
AE, adverse event; CR, complete response; DoR, duration of response; HRQoL, health-related quality of life; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial remission; RCT, randomised controlled trial; SAE, serious adverse event; TTR, time to treatment response
Summary of the ERG's Critique of Submitted Clinical Effectiveness Evidence
The ERG is satisfied with the search strategy employed by the manufacturer to identify clinical effectiveness studies. It does not believe there are additional studies relevant to the decision problem which have not been identified by the manufacturer.
Overview of Manufacturer's Cost-effectiveness Literature Review
Objective of the Manufacturer's Cost-effectiveness Literature Review
The manufacturer's search was designed to capture economic literature which focussed on treatments for metastatic melanoma. The initial searches were conducted on 10 April 2012 and were updated on the 24 and 25 October 2013. The databases were searched from start of database (1960) to 24/25 October 2013.
The following data sources were used to retrieve economic and quality of life evidence:
- Medline (Embase.com; http://www.embase.com/)
- EMBASE (Embase.com; http://www.embase.com/)
- MEDLINE In-process (PubMed [in-process citations]; http://www.ncbi.nlm.nih.gov/sites/entrez)
- Cochrane (National Health Service Economic Evaluation Database [NHS EED]) (Cochrane library; http://mrw.interscience.wiley.com/cochrane/cochrane_search_fs.html)
- Cochrane (CENTRAL and Method Studies) (Cochrane library; http://mrw.interscience.wiley.com/cochrane/cochrane_search_fs.html)
- EconLIT (AEAweb.org interface)
The manufacturer states that a search of the Centre for Reviews and Dissemination (CRD) database was also undertaken to identify relevant technology appraisals.
Inclusion and Exclusion Criteria Used in Study Selection
Table. Economic Evaluation Search Inclusion and Exclusion Criteria
|Population||Adults (males and females) of any age or race with unresectable advanced or metastatic or malignant melanoma (Stage IIIc or IV)|
|Study type and design||Cost studies/surveys/analyses; database studies collecting cost data; resource surveys; cost effectiveness analyses; cost utility analyses; cost benefit analyses; cost minimisation analyses; budget impact models; cost consequences studies|
|Intervention||All pharmacological treatments; all treatments including adjuvant therapy; surgery, radiotherapy or isolated limb perfusion; any other treatment|
|Language restriction||English only|
|Publication timeframe||No date restriction for database searches; Year 2009 to 2011 for conference proceedings|
|Subgroup analyses||Subgroup data for the disease of interest, adult population, disease stage|
|Language||Languages other than English|
Summary of the ERG's Critique of Cost-effectiveness Evidence Submitted
The ERG is satisfied with the search strategy employed by the manufacturer to identify cost effectiveness studies, and is reasonably confident that no other relevant published articles exist. In addition, the ERG agrees with the manufacturer's view that there is insufficient evidence to facilitate the development of an economic case for previously treated (second-line) patients.
One study (BREAK-3) was the only identified trial that examined the effects of dabrafenib; therefore, it was considered to be the key trial of interest. Supporting evidence was also provided from four other studies, none of which were used in quantitative analyses. Figure 3 in the manufacturer's submission (MS) shows a flow diagram of the numbers of studies included and excluded at each stage of the review process (see the "Availability of Companion Documents" field).
- Nine cost-effectiveness studies met the inclusion criteria for the systematic review but only one was deemed relevant by the manufacturer for discussion. In addition, the manufacturer identified one relevant National Institute for Health and Care Excellence (NICE) single technology appraisal, "Vemurafenib for the treatment of locally advanced or metastatic BRAF v600 mutation-positive malignant melanoma (NICE technology appraisal 269)."
- The manufacturer submitted an economic model.
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by Liverpool Reviews and Implementation Group (LRiG) (see the "Availability of Companion Documents" field).
Critique of the Methods of Review(s)
Details of the data extraction strategy are reported in the manufacturer's submission (MS) (see the "Availability of Companion Documents" field). Data from the included studies were appropriately extracted in parallel by two independent reviewers with any differences considered and reconciled by a third reviewer. Where more than one identified publication described a single trial, data were appropriately compiled into a single entry in the data extraction table to avoid the double counting of patients. The types of data extracted appear to be comprehensive.
A descriptive critical appraisal of all the included studies was conducted using comprehensive assessment criteria based on the recommendations in the NICE Single Technology Assessment (STA) guidelines.
All trials identified by the systematic review had different interventions and comparators and therefore it was not possible to conduct a meta-analysis. Findings were appropriately presented narratively. In addition, to compare interventions to comparators specified in the NICE scope, the manufacturer undertook an indirect treatment comparison (ITC).
Refer to section 4 in the ERG report for additional information on clinical effectiveness.
Overview of Manufacturer's Economic Modelling
Description of Manufacturer's Economic Model
A schematic of the manufacturer's model is provided in the MS and reproduced in Figure 2 in the ERG report. It comprises three health states described as progression-free, post progression and death. All patients enter the model in the 'progression-free' health state and are at risk of disease progression or death over time. Patients who progress are assumed to discontinue therapy, move to the 'Post progression' health state and stay in that health state until death. The model has been developed in Microsoft Excel and employs a 1-week cycle length.
Perspective, Time Horizon and Discounting
The manufacturer states that the economic appraisal is undertaken from the perspective of the National Health Service (NHS). Outcomes are expressed in terms of quality adjusted life years (QALYs) and life-years gained. The time horizon is set at 30 years and, in line with the NICE Methods Guide to Technology Appraisal, both costs and outcomes are discounted at 3.5%.
Refer to sections 5 and 6 in the ERG report for more information on cost-effectiveness assessment.
Technology appraisal recommendations are based on a review of clinical and economic evidence.
Technology Appraisal Process
The National Institute for Health and Care Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.
Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.
NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.
An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE Web site. Further comments are invited from everyone taking part.
When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.
Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.
Who Is on the Appraisal Committee?
NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.
Summary of Appraisal Committee's Key Conclusions
Availability and Nature of Evidence
The Committee did not consider the cost-effectiveness of dabrafenib compared with dacarbazine, having noted that dacarbazine was not an appropriate comparator as it was no longer used in clinical practice. It restricted its cost-effectiveness discussion to the comparison with vemurafenib.
Uncertainties Around and Plausibility of Assumptions and Inputs in the Economic Model
The Committee noted the Evidence Review Group's (ERG's) concerns regarding the structure of the model; in particular, the way the company modelled the clinical effectiveness estimates using a 3-stage approach, resulting in survival curves that did not appear clinically plausible. The Committee also noted the ERG's concerns with the company's indirect comparison and noted that the ERG had not carried out exploratory analyses of the clinical or cost effectiveness of dabrafenib compared with vemurafenib.
Incorporation of Health-related Quality-of-Life Benefits and Utility Values. Have Any Potential Significant and Substantial Health-related Benefits Been Identified That Were Not Included in the Economic Model, and How Have They Been Considered?
Treatment-specific EuroQoL EQ-5D utility data for pre-progression and post-progression, derived directly from BREAK-3, were used in the model for dabrafenib and dacarbazine. In the absence of comparable EQ-5D utility data for vemurafenib, the company assumed that the vemurafenib utility values would be the same as those for dabrafenib.
Are There Specific Groups of People for Whom the Technology Is Particularly Cost Effective?
What Are the Key Drivers of Cost-effectiveness?
The company conducted a series of deterministic sensitivity analyses. For the comparison of dabrafenib with dacarbazine, overall survival was the key driver of the cost-effectiveness results.
The key driver of the cost-effectiveness result for the comparison of dabrafenib with vemurafenib was the progression-free survival assumption.
Most Likely Cost-effectiveness Estimate (Given as an Incremental Cost-effectiveness Ratio [ICER])
The Committee noted that the company's base case ICER was £11,000 per quality-adjusted life year (QALY) gained for dabrafenib compared with vemurafenib, but was much lower than this if a class effect was assumed for dabrafenib and vemurafenib. In the absence of any further numerical analysis by the ERG, the Committee could not give an estimate of the most plausible ICER for the comparison of dabrafenib with vemurafenib.
External Peer Review
Consultee organisations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.
- Professional/specialist and patient/carer groups
- Commentator organisations (without the right of appeal)
In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.
Identifying Information and Availability
National Institute for Health and Care Excellence (NICE). Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. London (UK): National Institute for Health and Care Excellence (NICE); 2014 Oct. 36 p. (Technology appraisal guidance; no. 321).
Not applicable: The guideline was not adapted from another source.
National Institute for Health and Care Excellence (NICE)
Appraisal Committee Members: Dr Jane Adam (Chair), Department of Diagnostic Radiology, St George's Hospital, London; Professor Iain Squire (Vice-Chair), Consultant Physician, University Hospitals of Leicester; Professor Thanos Athanasiou, Professor of Cardiovascular Sciences and Cardiac Surgery, Imperial College London, Consultant Cardiothoracic Surgeon, Imperial College Healthcare NHS Trust; Dr Graham Ash, Consultant in General Adult Psychiatry, Lancashire Care NHS Foundation Trust; Dr Gerardine Bryant, GP, Swadlincote, Derbyshire; Dr Simon Bond, Senior Statistician, Cambridge Clinical Trials Unit; Dr Andrew England, Senior Lecturer, Directorate of Radiography, University of Salford; Mr Adrian Griffin, Vice President, HTA & International Policy, Johnson & Johnson; Dr Peter Heywood, Consultant Neurologist, Frenchay Hospital, Bristol; Dr Sharon Saint Lamont, Head of Clinical Quality, NHS England (North); Dr Louise Longworth, Reader in Health Economics, HERG, Brunel University; Dr Anne McCune, Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust; Professor John McMurray, Professor of Medical Cardiology, University of Glasgow; Dr Mohit Misra, GP, Queen Elizabeth Hospital, London; Mrs Sarah Parry, CNS Paediatric Pain Management, Bristol Royal Hospital for Children; Mrs Pamela Rees, Lay Member; Dr Ann Richardson, Lay Member; Mr Stephen Sharp, Senior Statistician, University of Cambridge MRC Epidemiology Unit; Dr Brian Shine, Consultant Chemical Pathologist, John Radcliffe Hospital, Oxford; Dr Peter Sims, GP, Devon; Mr David Thomson, Lay Member; Professor Olivia Wu, Professor of Health Technology Assessment, University of Glasgow
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
This is the current release of the guideline.
This guideline meets NGC's 2013 (revised) inclusion criteria.
Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site.
The following are available:
- Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. Costing statement. London (UK): National Institute for Health and Care Excellence (NICE); 2014 Oct. 1 p. (Technology appraisal guidance; no. 321). Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site.
- Fleeman N, Bagust A, Beale S, Boland A, Dickson R, Dwan K, Richardson M, Dundar Y, Davis H, Banks L. Dabrafenib for the treatment of unresectable, advanced or metastatic BRAFv600 mutation-positive melanoma [ID605]: a single technology appraisal. Liverpool (UK): Liverpool Reviews and Implementation Group (LRiG); 2014. 97 p. Electronic copies: Available from the NICE Web site.
- Melanoma (unresectable/metastatic BRAFV600 mutation-positive) - dabrafenib. Single technology appraisal (STA). Manufacturer's submission. GlaxoSmithKline UK; 2014 Apr. 210 p. Electronic copies: Available from the NICE Web site.
The following is available:
- Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. Information for the public. London (UK): National Institute for Health and Care Excellence (NICE); 2014 Oct. 3 p. (Technology appraisal guidance; no. 321). Electronic copies: Available from the National Institute for Health and Care Excellence (NICE) Web site.
Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.
This NGC summary was completed by ECRI Institute on November 18, 2014.
The National Institute for Health and Care Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their Technology Appraisal guidance with the intention of disseminating and facilitating the implementation of that guidance. NICE has not verified this content to confirm that it accurately reflects the original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE technology appraisal guidance is prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.
This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.
Unresectable or metastatic BRAF V600 mutation-positive melanoma
Assessment of Therapeutic Effectiveness
Advanced Practice Nurses
To evaluate the clinical effectiveness and cost-effectiveness of dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma
Adults with unresectable or metastatic BRAF V600 mutation-positive melanoma
- Clinical effectiveness
- Progression-free survival
- Overall survival
- Overall response rate
- Duration of response
- Health-related quality of life
- Adverse effects of treatment
Dabrafenib is recommended, within its marketing authorisation, as an option for treating unresectable or metastatic BRAF V600 mutation-positive melanoma only if the company provides dabrafenib with the discount agreed in the patient access scheme.
For full details of adverse reactions and contraindications, see the summary of product characteristics.
Institute of Medicine (IOM) National Healthcare Quality Report Categories
End of Life Care
Living with Illness
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