Guideline:
Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia
Bibliographic Source(s)
- National Institute for Health and Clinical Excellence (NICE). Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 24 p. (Technology appraisal guidance; no. 119).
Guideline Status
This is the current release of the guideline.
Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Intended Users
Advanced Practice Nurses
Nurses
Physician Assistants
Physicians
Guideline Objective(s)
To evaluate the clinical effectiveness and cost-effectiveness of fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukemia
Target Population
Patients with chronic lymphocytic leukemia (CLL)
Interventions and Practices Considered
Fludarabine (Fludara) monotherapy for the first-line treatment of chronic lymphocytic leukemia was considered but not recommended
Major Outcomes Considered
- Clinical effectiveness
- Progression-free survival
- Health-related quality of life
- Treatment response rates
- Incidence of adverse events
- Overall survival
- Cost-effectiveness
Methods Used to Collect/Select Evidence
Searches of Electronic Databases
Description of Methods used to Collect/Select the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical 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 Centre for Health Economics University of York and National Health Service (NHS) Northern and Yorkshire Regional Drug and Therapeutics Centre (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Search Strategy
A systematic literature search was undertaken by the ERG to verify the completeness of the methodology used by the manufacturer to retrieve relevant clinical studies presented in the submission.
Inclusion Criteria
Participants: Chronic Lymphocytic Leukaemia
Interventions: Fludarabine
Comparator: Any
Outcomes: No restrictions applied (outcomes included: overall survival progression-free survival overall response complete response partial response adverse drug reactions and quality of life)
Design: Randomised controlled trial (RCT)
Exclusion Criteria
Participants: Previously treated patients
Intervention: None
Refer to Appendix 2 of the ERG Report (see the "Availability of Companion Documents" field) for information on study selection databases and terms searched.
Relevant Ongoing Studies
The following databases were searched for current research: Current Controlled Trials register (searched across multiple registers including ISRCTN MRC NHS and the National Institutes of Health registers) IFPMA proceedings of the American Society for Clinical Oncology National Research Register and the National Cancer Institute British Society for Haematology Leukaemia Research Fund Scirus and a general web search using Google.
Other than more complete and fully published results of the studies included in the manufacturer's submission (principally CLL4 & CLL5) two studies were identified as relevant ongoing trials that are likely to provide significant additional evidence within the next 6 to 12 months.
Number of Source Documents
Clinical Effectiveness
Manufacturer submitted 7 studies.
Two ongoing studies were identified by the Evidence Review Group (ERG).
Cost-Effectiveness
Two papers were identified in both the manufacturer's submission and the ERG searches which reported on the cost-effectiveness of fludarabine monotherapy in comparison to chlorambucil in the management of chronic lymphocytic leukaemia (CLL) in previously untreated patients.
Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Rating Scheme for the Strength of the Evidence
Not applicable
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical 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 Centre for Health Economics University of York and National Health Service (NHS) Northern and Yorkshire Regional Drug and Therapeutics Centre (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Submission Trial Analysis
All studies included in the clinical evidence section of the Schering Health Care Ltd (SHC) submission were subjected to a detailed critical appraisal. The resultant appraisals were then compared to the data presented in the submission.
Refer to Section 4.2 of the ERG Report (see the "Availability of Companion Documents" field) for detailed discussion of the included trials.
Meta-Analyses
Of the seven studies included in the submission only two were fully published and the remaining five studies were available in abstract form only (Refer to Table 4.1 in the ERG Report [see the "Availability of Companion Documents" field]). These abstracts are unlikely to have been subject to peer-review and there are insufficient data in terms of the methods and results presented to allow for their inclusion in a robust meta-analysis. Of the two fully published studies one compares fludarabine (F) with fludarabine plus cyclophosphamide (FC) whilst the other compares F with chlorambucil (Chl). Therefore pooling of data would not add further insight to the decision problem.
Economic Evaluation
Sensitivity Analyses
The manufacturer's submission includes simple one-way deterministic survival analysis probabilistic sensitivity analysis and scenario analyses.
Model Validation
The submission reports that the structure and key assumptions in the model have been validated by two experts in the treatment of chronic lymphocytic leukaemia (CLL). They also report that numeric values in the model have been checked by an experienced modeller not involved in the construction of the model or the subsequent analyses.
Critique of Manufacturer's Economic Model
The ERG has considered the methods applied in the manufacturer's economic evaluation in the context of the critical appraisal questions listed in Table 5.2 of the ERG Report (see the "Availability of Companion Documents" field) which are drawn from common checklists for economic evaluation methods.
Additional Sensitivity Analyses Undertaken by the ERG
A key assumption made in the manufacturer's submission was that the re-treatment response rate for FC was the same as the initial treatment response rate. This assumption was made on the basis that no other evidence was identified to inform this parameter estimate. While such an approach may be considered justifiable (in the absence of contradictory evidence from the literature) it does appear a strong assumption given that the evidence for the re-treatment response rates for F and Chl reported in the literature are both lower than the estimates used for first-line treatment. The ERG was also concerned that the choice of values used in the sensitivity analysis undertaken in the submission for FC was not sufficiently rigorous to test the robustness of the model results since it was based on the 95% confidence interval from the bootstrap of the initial treatment rate. The ERG has varied the potential probability of response to re-treatment with FC from 0.1 to 0.9 to determine how sensitive the cost-effectiveness results are to this parameter. The results are provided in Table 6.1 of the Assessment Report (see the "Availability of Companion Documents" field).
The results of the additional sensitivity analysis demonstrate that the re-treatment response rate would have to be significantly lower than that assumed for first-line treatment before this might result in a change to the decision related to the cost-effectiveness of FC. Indeed the results suggest that the re-treatment response rate would have to fall to somewhere between 0.3 and 0.4 before FC no longer appears cost-effective in comparison to Chl.
Refer to Sections 4 5 and 6 of the ERG Report (see the "Availability of Companion Documents" field) for additional information on methods used to analyze the evidence.
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
Considerations
Technology appraisal recommendations are based on a review of clinical and economic evidence.
Technology Appraisal Process
The National Institute for Health and Clinical 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 website. 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.
Rating Scheme for the Strength of the Recommendations
Not applicable
Cost Analysis
The manufacturer's submission contained an economic analysis comparing fludarabine monotherapy fludarabine plus cyclophosphamide and chlorambucil. Only the economic evidence for fludarabine monotherapy compared with chlorambucil is presented in the original guideline document. The economic analyses were based on a Markov state transition model with a 20-year time horizon. The economic model used patient-level data from the CLL4 trial to inform first-line treatment with data for second-line and salvage treatments taken from a variety of published sources. The manufacturer submitted revised base-case economic analyses following clarifications requested by the Evidence Review Group (ERG). These showed an incremental cost-effectiveness ratio (ICER) of 26105 pounds sterling per quality-adjusted life year (QALY) for fludarabine monotherapy compared with chlorambucil.
The ERG assessed the manufacturer's economic model and noted that the main drivers of the ICERs presented were time horizon and rates of response to retreatment with the same chemotherapeutic agent as that used in first-line treatment.
The ICER for fludarabine monotherapy compared with chlorambucil for a 15-year time horizon was 28178 pounds sterling per QALY. For 10-year and 5-year time horizons the ICERs were 42516 pounds sterling per QALY and 310663 pounds sterling per QALY respectively. The ERG stated that the extrapolation of model data is likely to be central to the validity of the ICERs presented. The ERG also noted that an assumption of constant transition probabilities over time was used within the manufacturer's model. Because patient-level data from the CLL4 trial were available the ERG stated that this assumption should have been validated using formal survival analysis. It therefore performed a survival analysis using patient-level data from the CLL4 trial the results of which showed that the assumption of constant transition probabilities is not supported. However incorporating the results of the ERG's survival analysis into the economic model would have required a substantial restructuring of the model. Correcting this assumption was expected to increase the ICER for fludarabine monotherapy compared with chlorambucil.
The ERG report noted the way in which retreatment response rates for fludarabine monotherapy and chlorambucil were modelled. For fludarabine monotherapy the first-line treatment response rate (77%) was taken from the CLL4 study and the retreatment response rate (74%) was taken from the existing literature as presented in the manufacturer's submission. For chlorambucil the first-line treatment response rate (69%) was taken from the CLL4 study and the retreatment response rate (35%) was taken from the existing literature as presented in the manufacturer's submission. This led to a base-case ICER of 26105 pounds sterling per QALY for fludarabine monotherapy compared with chlorambucil. Because no retreatment response rates were available from the CLL4 study and because of the limited evidence available in existing literature the manufacturer's submission presented a one-way sensitivity analysis in which retreatment response rates were assumed to be the same as first-line treatment response rates for all the treatment arms in the economic model. This resulted in an ICER of 86770 pounds sterling per QALY for fludarabine monotherapy compared with chlorambucil.
The ERG noted that the manufacturer's submission stated that improved progression-free survival with fludarabine monotherapy was linked to improvements in quality of life in the CLL4 trial. However the impact of the adverse effects of fludarabine specifically the potential additional costs related to increased hospitalisations due to infections was not explored in the manufacturer's economic model. Although the manufacturer's model included sensitivity analysis to assess potential decreases in utilities and quality of life as a result of adverse events the ERG considered that the omission of the treatment costs of adverse events was likely to have resulted in an underestimation of the ICERs for fludarabine monotherapy compared with chlorambucil.
Method of Guideline Validation
External Peer Review
Description of Method of Guideline Validation
Consultee organizations 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.
- Manufacturer/sponsors
- 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.
Major Recommendations
This technology appraisal considers the clinical and cost effectiveness of fludarabine monotherapy only. No recommendations have been made with respect to fludarabine plus cyclophosphamide combination therapy because the current marketing authorisation does not specifically provide a recommendation that fludarabine should be used concurrently with other drugs for the treatment of chronic lymphocytic leukaemia.
Clarification was sought with the Medicines and Healthcare Regulatory Authority (MHRA) on the issue of the inclusion of the combination of fludarabine and cyclophosphamide in the marketing authorisation of fludarabine. In all correspondence received from the MHRA including that shared with National Institute for Health and Clinical Excellence (NICE) by Schering Health Care Limited it has been made clear that "the MHRA does not consider that the current marketing authorisations for oral and intravenous (i/v) Fludara (PL/0053/0239 and /0290) specifically provide a recommendation that fludarabine should be used concurrently with other drugs for the treatment of chronic lymphocytic leukaemia."
The MHRA has further clarified that in general it would expect a manufacturer or sponsor to request a variation in the marketing authorisation when:
- The summary of product characteristics (SPC) in general and specifically the "therapeutic indications" section does not contain references to the combination therapy and the company wishes to promote the use of combination therapy
- The use of the combination has implications for the dosage specifications in the "posology and method of administration" section of the SPC
In the case of fludarabine the SPCs do not contain references to the combination therapy. With reference to the second point the dosage of fludarabine (i/v 25 mg/m2 for 3 days and oral 24 mg/m2 for 5 days) in the evidence base for the combination therapy that was submitted by the manufacturer (the CLL4 trial) is different from the fludarabine dosage specified in its SPCs (i/v 25 mg/m2 for 5 days and oral 40 mg/m2 for 5 days).
Fludarabine monotherapy within its licensed indication is not recommended for the first-line treatment of chronic lymphocytic leukaemia.
Clinical Algorithm(s)
None provided
Type of Evidence supporting the Recommendations
The type of evidence supporting the recommendations is not specifically stated.
Potential Benefits
Appropriate use of fludarabine for the treatment of chronic lymphocytic leukemia
Potential Harms
The most common adverse events associated with fludarabine treatment include anaemia thrombocytopenia neutropenia and infections (for example pneumonia and herpes virus infections).
For full details of side effects and contraindications see the summary of product characteristics (SPC) available at http://emc.medicines.org.uk/.
Qualifying Statements
This guidance represents the view of the Institute which was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not however override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient in consultation with the patient and/or guardian or carer.
Description of Implementation Strategy
- The Healthcare Commission assesses the performance of National Health Service (NHS) organisations in meeting core and developmental standards set by the Department of Health in "'Standards for better health" issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by National Institute for Health and Clinical Excellence (NICE) technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
- "Healthcare Standards for Wales"' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance normally within 3 months.
- NICE has developed tools to help organisations implement this guidance (listed below). These are available on NICE website (http://guidance.nice.org.uk/TA119) (see also the "Availability of Companion Documents" field).
- A costing statement explaining the resource impact of this guidance.
- Audit criteria to monitor local practice.
Implementation Tools
Audit Criteria/Indicators
Patient Resources
Quick Reference Guides/Physician Guides
Resources
For information about availability see the "Availability of Companion Documents" and "Patient Resources" fields below.
IOM Care Need
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness
Bibliographic Source(s)
- National Institute for Health and Clinical Excellence (NICE). Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 24 p. (Technology appraisal guidance; no. 119).
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
National Institute for Health and Clinical Excellence (NICE)
Guideline Committee
Appraisal Committee
Composition of Group that Authored the Guideline
Committee Members: Dr Jane Adam Radiologist St George's Hospital London; Professor A E Ades MRC Senior Scientist MRC Health Services Research Collaboration Department of Social Medicine University of Bristol; Dr Amanda Adler Consultant Physician Addenbrooke's Hospital Cambridge; Dr Tom Aslan General Practitioner Stockwell London; Professor David Barnett (Chair) Professor of Clinical Pharmacology University of Leicester; Mrs Elizabeth Brain Lay Member; Dr Karl Claxton Health Economist University of York; Dr Richard Cookson Senior Lecturer in Health Economics School of Medicine Health Policy and Practice University of East Anglia; Mrs Fiona Duncan Clinical Nurse Specialist Anaesthetic Department Blackpool Victoria Hospital Blackpool; Dr Paul Ewings Statistician Taunton and Somerset NHS Trust Taunton; Professor John Geddes Professor of Epidemiological Psychiatry University of Oxford; Mr John Goulston Director of Finance Barts and the London NHS Trust; Ms Linda Hands Consultant Surgeon John Radcliffe Hospital; Dr Rowan Hillson Consultant Physician Diabeticare The Hillingdon Hospital; Professor Philip Home (Vice Chair) Professor of Diabetes Medicine University of Newcastle upon Tyne; Dr Terry John General Practitioner The Firs London; Professor Richard Lilford Professor of Clinical Epidemiology Department of Public Health and Epidemiology University of Birmingham; Dr Simon Mitchell Consultant Neonatal Paediatrician St Mary's Hospital Manchester; Dr Alec Miners Lecturer in Health Economics London School of Hygiene and Tropical Medicine; Ms Judith Paget Chief Executive Caerphilly Local Health Board Wales; Dr Ann Richardson Lay Member; Dr Stephen Saltissi Consultant Cardiologist Royal Liverpool University Hospital; Mr Mike Spencer General Manager Clinical Support Services Cardiff and Vale NHS Trust; Mr Mike Spencer General Manager Clinical Support Services Cardiff and Vale NHS Trust; Dr Debbie Stephenson Head of HTA Strategy Eli Lilly and Company; Professor Andrew Stevens Professor of Public Health University of Birmingham; Dr Cathryn Thomas General Practitioner & Associate Professor Department of Primary Care & General Practice University of Birmingham; Simon Thomas Consultant Physician General Medicine and Clinical Pharmacology Newcastle Hospitals NHS Trust; Mr David Thomson Lay Member; Dr Norman Vetter Reader Department of Epidemiology Statistics and Public Health College of Medicine University of Wales Cardiff; Professor Mary Watkins Professor of Nursing University of Plymouth; Dr Paul Watson Director of Commissioning East England Strategic Health Authority
Financial Disclosures/Conflicts of Interest
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.
Guideline Status
This is the current release of the guideline.
Guideline Availability
Electronic copies: Available in Portable Document Format (PDF) format from the National Institute for Health and Clinical Excellence (NICE) Web site.
Availability of Companion Documents
The following are available:
- Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. Quick reference guide. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 2 p. (Technology appraisal 119). Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
- Costing statement: Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 1 p. (Technology appraisal 119). Available in Portable Document Format (PDF) from the NICE Web site.
- Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. Audit criteria. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 8 p. (Technology appraisal 119). Available in Portable Document Format (PDF) from the NICE Web site.
- Fludarabine phosphate for the first-line treatment of chronic lymphocytic leukaemia. Evidence Review Group Report. Centre for Health Economics University of York and NHS Northern and Yorkshire Regional Drug and Therapeutics Centre York UK. 2006 Oct 17. 118 p. Electronic copies: Available from the NICE Web site.
Print copies: Available from the National Health Service (NHS) Response Line 0870 1555 455. ref: N1203. 11 Strand London WC2N 5HR.
Patient Resources
The following is available:
- Fludarabine for chronic lymphocytic leukaemia. Understanding NICE guidance - Information for people who use NHS services. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Feb. 4 p. (Technology appraisal 119).
Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
Print copies: Available from the NHS Response Line 0870 1555 455. ref: N1204. 11 Strand London WC2N 5HR.
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.
NGC STATUS
This NGC summary was completed by ECRI Institute on August 6 2007.
The National Institute for Health and Clinical 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.
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