• National Institute for Health and Clinical Excellence (NICE). Pemetrexed for the treatment of non-small-cell lung cancer. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Aug. 20 p. (Technology appraisal guidance; no. 124).

This is the current release of the guideline.

Non-small-cell lung cancer

Assessment of Therapeutic Effectiveness
Treatment

Family Practice
Internal Medicine
Oncology

Advanced Practice Nurses
Nurses
Physician Assistants
Physicians

To evaluate the clinical effectiveness and cost-effectiveness of pemetrexed for the treatment of non-small-cell lung cancer

Patients with non-small-cell lung cancer

Pemetrexed for the treatment of non-small-cell lung cancer (considered but not recommended)

• Clinical effectiveness
  • Overall survival
  • Time to documented progression of disease
  • Progression-free survival
  • Duration of tumour response
  • Quality of life
  • The incidence of adverse events
• Cost-effectiveness

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Searches of Unpublished Data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 Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review 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, University of Liverpool (see the "Availability of Companion Documents" field).

Clinical Effectiveness

Search Strategy

The literature searches in the manufacturer's submission were clearly reported with details of the search strategies and terms included. Three electronic databases were searched (Medline, Embase and the Cochrane Library) covering the period 1966 to May 2006.

In addition, one set of conference proceedings, American Society of Clinical Oncology (ASCO 2006), and Eli Lilly's unpublished data were searched.

Other relevant databases and conference sites which were not searched include Web of Science, Institute for Scientific Information (ISI) Proceedings and the European Society for Medical Oncology (ESMO) proceedings.

Search terms for electronic databases appropriately included a combination of free-text and index terms (non-small cell lung cancer) combined with drug names (pemetrexed, docetaxel or erlotinib) used as free-text terms.

Although the intervention under appraisal is pemetrexed for relapsed non-small-cell lung cancer (NSCLC), the search strategies used in the submission were appropriately expanded to include comparative studies of docetaxel, erlotinib and best supportive care (BSC) for further supporting evidence.

Inclusion and Exclusion Criteria

Details of inclusion and exclusion criteria are provided in Table 3-2 of the Evidence Review Group (ERG) Report (see the "Availability of Companion Documents" field) and are considered appropriate and complete.

A flow diagram and a table of included trials in the submission indicates that, of the 976 (non-duplicated) publications to which the inclusion criteria were applied, a total of nine trials was considered for inclusion in the review. This included one head to head trial that forms the basis of the direct comparison (JMEI), with an additional eight trials to inform indirect comparisons.

The searching exercise and application of inclusion criteria conducted by the ERG confirms the finding of only one relevant trial used in the direct comparison and an additional eight trials used in the indirect comparison.

Cost-Effectiveness

Identification and Description of Studies

The submission provided details of the electronic search strategy, including the search strings used for each database utilised. However, they did not include a record of the number of hits achieved by each search, nor the number of studies included and excluded at each stage, making replication of the search strategy impossible.

Studies were included in the economic review if they:

• Included a full or partial economic analysis
• Included patients with NSCLC receiving second-line treatment
• Were original and had not been reported elsewhere

Studies were excluded from the economic review if they:

• Were population based economic models
• Included NSCLC patients receiving first-line treatment
• Included small cell lung cancer patients
• Were editorials, letters or review articles describing data that had been reported elsewhere
• Were not English language papers

Using these inclusion and exclusion criteria, the company identified three full economic evaluations (none of which included pemetrexed as a comparator), eight studies evaluating costs and resources (two of which included pemetrexed), and 12 studies focusing on patient quality of life.

Studies identified under the heading 'resource use and cost' and 'quality of life' include papers on first-line therapies; whether this is a violation of the inclusion criteria is unclear. If it is not, other relevant studies could have been listed in the search results. Also, the company submission acknowledges that their review of quality of life studies needs to be updated.

Clinical Effectiveness

One direct comparison trial (JMEI) and 8 indirect comparison trials were identified.

Cost-Effectiveness

A total of 23 studies were identified: three full economic evaluations, eight studies evaluating costs and resources, and 12 studies focusing on patient quality of life.

Expert Consensus

Not applicable

Systematic Review with Evidence Tables

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review 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, University of Liverpool (see the "Availability of Companion Documents" field).

Clinical Effectiveness

Critique of Systematic Clinical Review

Key aspects of the methodological quality of the company's review of the clinical literature were assessed based on an accepted quality assessment checklist item and the results are summarised in Table 3-1 of the ERG Report (see the "Availability of Companion Documents" field).

Quality Assessment

The company included a quality assessment of the nine included trials in the appendices of the submission. These tables include details of randomisation, adequacy of follow up, blinding of outcome assessment, whether the trials were parallel groups or crossover and whether the trial was conducted in the UK. Unfortunately the keys used in these tables are incomplete and it is therefore not possible to interpret the results. The submission does not report how the data quality assessment was conducted (e.g. independently or by more than one reviewer).

Data Extraction

The submission reports that data (from all nine trials) were extracted using a structured form. Further details of the data extraction process (e.g. number of reviewers and whether data were extracted independently) were not provided in the submission. Study data tables are extensive but somewhat confusing.

Combination of Studies

A meta-analysis was not undertaken by the company as there is only one trial included in the review of direct comparisons. However, the submission pools evidence from a range of studies and carries out indirect comparisons, the results of which are used in the economic analysis.

Refer to Section 3 of the ERG Report (see the "Availability of Companion Documents" field) for more information.

Cost-Effectiveness

Data Extraction

The company extracted data from the 23 papers included in the review. The three full economic evaluations, together with the two relevant costing studies were extracted into structured tables collecting data on title, aims, methods, results, and relevance to decision-making in England and Wales. Data were extracted on title, aims and methods from the remaining 18 papers. Both forms of data extraction are simplistic and do not provide sufficient detail for a comprehensive comparison of studies. The limited commentary accompanying the data extraction tables makes it difficult to interpret the overall results of the studies.

The 23 studies from which data have been extracted are heterogeneous in terms of type of evaluation (full economic evaluations and partial economic evaluations) and type of study (empirical cost-effectiveness study, review of cost-effectiveness studies). Only two of the included papers appear to be full economic evaluations which are relevant to the UK National Health Service (NHS). Both of these studies assess the cost-effectiveness of docetaxel versus best supportive care (BSC).

As none of the papers compared pemetrexed with docetaxel, BSC, or erlotinib, these studies are not directly comparable with the economic evaluation presented in the company submission.

Quality Assessment

No formal quality assessment of the included papers is reported.

Summary and Conclusions

The economic literature review did not identify any full economic evaluations which compared the use of pemetrexed with docetaxel, erlotinib or BSC for the second-line treatment of non-small-cell lung cancer (NSCLC). A total of three full economic evaluations and 20 partial analyses were identified; however, as discussed above, several resource and costs studies may have been missed. The data extraction of the economic literature undertaken by the company is lacking in depth, and no quality assessment of the included studies is provided.

Refer to Section 4 of the ERG Report (see the "Availability of Companion Documents" field) for more information.

Expert Consensus

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.

Not applicable

The manufacturer's submission presented an economic analysis based on a Markov model with a 3-year time horizon. The estimates of efficacy used in the economic model were based on an unadjusted indirect comparison of absolute overall survival in which weighted estimates of absolute survival were pooled from single arms of different trials in published literature. The median absolute overall survival was estimated to be 8.3 months for pemetrexed based on the results of the JMEI trial, 7.0 months for docetaxel based on the pooled results of seven trials, and 4.9 months for BSC based on the pooled results of three trials. When these absolute overall survival parameters were put into the economic model, the predicted mean life years gained were estimated to be 11.0 months for pemetrexed, 8.8 months for docetaxel and 7.2 months for best supportive care (BSC). The manufacturer's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of 18,672 pounds sterling per additional quality-adjusted life year (QALY) gained for pemetrexed compared with docetaxel and an ICER of 16,458 pounds sterling per additional QALY gained for pemetrexed compared with BSC.

An adjusted indirect comparison, conducted as a sensitivity analysis, pooled median overall survival from single arms of the trials to estimate hazard rates for each treatment group. The adjusted indirect comparison estimated the life years gained to be 14.4 months for pemetrexed and 12.4 months for docetaxel. This analysis found that the mean ICER of pemetrexed compared with docetaxel was 31,612 pounds sterling per additional QALY gained and the mean ICER of pemetrexed compared with BSC was 10,298 pounds sterling per additional QALY gained.

The Evidence Review Group (ERG) considered the effect on the ICER of assuming equivalent overall survival for pemetrexed and docetaxel, in place of the manufacturer's assumption of greater survival. In this situation, the ERG estimated that the ICER for pemetrexed versus docetaxel would increase to approximately 458,000 pounds sterling per additional QALY gained. It also noted that if the revised estimates of drug acquisition/administration costs, costs of treating adverse events, and non-treatment-related and palliative care costs were included in the analysis, the ICER for pemetrexed versus docetaxel could be up to 1.8 million pounds sterling per additional QALY gained.

The ERG evaluated the manufacturer's economic analysis of pemetrexed versus BSC. Based on the manufacturer's estimates of survival and QALYs for the BSC group, but using a survival effect of pemetrexed equivalent to docetaxel, and revised cost estimates, the ERG estimated an ICER of approximately 60,000 pounds sterling per additional QALY gained.

Pemetrexed Compared with Docetaxel

The Committee considered the manufacturer's assessment of the cost effectiveness of pemetrexed compared with docetaxel. It discussed both the base-case analysis based on an unadjusted indirect comparison of pooled absolute survival estimates from several trials, and a sensitivity analysis based on an adjusted indirect comparison of pooled rates from several trials. It considered both indirect comparisons inappropriate given the inconsistency of the findings in relation to the direct randomised comparison between pemetrexed and docetaxel in the JMEI trial. The Committee noted that both the base-case analysis (which estimated a mean survival of 11.0 months for pemetrexed and 8.8 months for docetaxel) and the adjusted indirect comparison (mean survival of 14.4 months for pemetrexed and 12.4 months for docetaxel) contradicted the results of the randomised controlled trial (RCT), which showed that the mean survival was 8.56 months for pemetrexed and 8.74 months for docetaxel. The Committee concluded that the survival estimates included in the manufacturer's economic analysis were inappropriate.

Pemetrexed Compared with Best Supportive Care

The Committee heard that the RCT of pemetrexed did not include patients who could not receive docetaxel and it was therefore concerned that the clinical effectiveness of pemetrexed had not been established in this context. Nevertheless, the Committee considered the calculations on the cost effectiveness of pemetrexed compared with BSC. It noted that the manufacturer's analysis assumed that mean survival for patients receiving pemetrexed was 11.0 months but considered that the mean survival from the RCT of pemetrexed (8.56 months) was more credible.

The Committee also considered the appropriateness of the cost estimates of BSC or non-treatment-related costs required in the two treatment arms. It noted that the manufacturer's cost estimates assumed that those receiving pemetrexed would only require treatment for adverse effects of treatment and not for disease-related symptoms (supportive care). The ERG suggested that the costs of treating disease-related symptoms would be the same for both treatment arms. The Committee proposed that those treated with pemetrexed would receive some underlying supportive care, but that this was plausibly at a lower rate than for patients not receiving active treatment .The Committee considered that if the cost of underlying supportive care for people receiving active treatment was 50% of that for people who were not, and using the ERG's other cost and survival assumptions (including the manufacturer's pooled estimate of mean overall survival for BSC of 7.2 months), the incremental cost would be approximately 8,000 pounds sterling, resulting in an ICER of over 50,000 pounds sterling per additional QALY gained.

The Committee concluded that pemetrexed would not be a cost-effective use of National Health Service (NHS) resources when compared with either docetaxel or BSC.

Refer to Sections 3 and 4 of the original guideline document for more information.

External Peer Review

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.

Pemetrexed is not recommended for the treatment of locally advanced or metastatic non-small-cell lung cancer.

People currently receiving pemetrexed should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate recommendation regarding the use of pemetrexed for the treatment of non-small-cell lung cancer

Pemetrexed is associated with suppression of bone marrow function, nausea and vomiting, fatigue and a range of other side effects.

For full details of side effects and contraindications, see the summary of product characteristics (SPC).

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.

Living with Illness

Effectiveness
Patient-centeredness

• National Institute for Health and Clinical Excellence (NICE). Pemetrexed for the treatment of non-small-cell lung cancer. London (UK): National Institute for Health and Clinical Excellence (NICE); 2007 Aug. 20 p. (Technology appraisal guidance; no. 124).

Not applicable: The guideline was not adapted from another source.

2007 Aug

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Professor David Barnett, Professor of Clinical Pharmacology, University of Leicester; Dr David W Black, Director of Public Health, Chesterfield PCT; Mr Brian Buckley, Chairman, Incontact; Professor Mike Campbell, Professor of Medical Statistics, University of Sheffield; Dr Carol Campbell, Senior Lecturer, University of Teesside; Dr Peter Clark, Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Merseyside; Ms Jude Cohen, Manager of Resources & Administration, Council for Psychotherapy (UKCP); Dr Christine Davey, Senior Researcher, North Yorkshire Alliance R&D Unit; Dr Mike Davies, Consultant Physician, Manchester Royal Infirmary; Mr Richard Devereaux-Phillips, Public Affairs Manager, Medtronic Ltd; Dr Rachel A Elliott, Clinical Senior Lecturer, The University of Manchester; Mrs Eleanor Grey, Lay Member; Dr Dyfrig Hughes, Senior Research Fellow in Pharmacoeconomics, Centre for the Economics of Health and Policy in Health, University of Wales, Bangor; Dr Catherine Jackson, Clinical Lecturer in Primary Care Medicine, Alyth Health Centre; Dr Peter Jackson, Clinical Pharmacologist, the University of Sheffield; Professor Peter Jones, Professor of Statistics and Dean Faculty of Natural Sciences, Keele University; Ms Rachel Lewis Nurse Advisor to the Department of Health; Dr Damien Longson, Consultant in Liaison Psychiatry, North Manchester General Hospital; Professor Jonathan Michaels, Professor of Vascular Surgery, University of Sheffield; Dr Eugene Milne Deputy Medical Director, North East Strategic Health Authority; Dr Simon Mitchell; Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester; Dr Martin J Price Head of Outcomes Research, Janssen-Cilag Ltd; Mr Miles Scott Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust; Professor Mark Sculpher, Professor of Health Economics, University of York; Professor Andrew Stevens, Chair of Appraisal Committee C; Dr Cathryn Patricia Thomas, Senior Lecturer, Department of Primary Care & General Practice

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 NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.