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NICE or Nasty?
Clinical Oncology (2002) 14: 86–88 doi:10.1053/clon.2002.0069, available online at http://www.idealibrary.com on
Oncology Practice: Editorial NICE or Nasty? The National Institute of Clinical Excellence (NICE) was set up 3 years ago as a Special Health Authority to ‘provide patients, health professionals and the public with authoritative, robust and reliable guidance on current practice’. Although there are many important areas of prescribing practice with major health economic implications, NICE has been asked to appraise a range of treatments to which access is not consistently available across the country so that instances of ‘postcode prescribing’ can be identified and corrected with a minimum of political damage. In December 2001 the Department of Health issued statutory directions that Health Authorities and Primary Care Trusts would be required to make funding available to enable NICE’s guidance on health treatments to be implemented. Although the source of funding to respond to this directive has not been identified it nonetheless gives additional weight to guidance issued by NICE as a result of its Technology Appraisal Process. In these circumstances it would seem to be appropriate to examine the way in which NICE guidance is produced and to test whether it achieves its stated aims. The Department of Health and the National Assembly for Wales select ‘technologies’ (not just pharmaceuticals, but medical devices, diagnostic techniques and other medical interventions) for appraisal based on the likelihood that they will either ‘result in a significant health benefit’, ‘result in a significant impact on other health-related government policies’, ‘have a significant impact on NHS resources’ or that ‘NICE is likely to be able to add value by issuing national guidance’. The subsequent appraisal by NICE is therefore required to evaluate both the clinical effectiveness and cost effectiveness of the technology together with its wider implications for the NHS. As far as pharmaceutical products are concerned this process is necessarily applied to drugs which have already been licensed by the Medicine Controls Agency (MCA) in an exhaustive process which involves pre-marketing assessment of the medicine’s safety, quality and efficacy based on an examination of all the research and test results submitted by the manufacturer. The registration process controlled by the MCA defines a drug’s ‘licensed indication’ and this forms the sole clinical setting in which NICE will Correspondence and offprint requests to: Dr S. A. Johnson, Dept of Haematology, Taunton & Somerset Hospital, Musgrove Park, Taunton, TA1 5DA, U.K. E-mail: [email protected] 0936–6555/02/020086+03 $35.00/0
examine evidence even if clinical practice involves wider use. Oncology drugs appear to have attracted disproportionate attention from NICE. The cost of prescriptions in the treatment of malignant disease (£205 million in 1999) is only tenth is the list of expenditure by disease areas (first is cardiovascular system at £1391 million, second is central nervous system at £1031 million) but of the technology appraisals of drugs/drug groups completed or planned by NICE, fifteen out of forty relate to cytotoxic drugs. The scope for delivering substantial financial savings by demonstrating failings in cost effectiveness alone for cytotoxic drugs may therefore be very limited and the cost to the manufacturer of responding to the NICE technology appraisal process may represent a significant disincentive to the marketing of a drug which has only a limited clinical application. The Technology Appraisal process should start with a notification to the manufacturer or sponsor at least 9 months in advance that their technology is likely to be the subject of referral to NICE. The manufacturer will then prepare a submission to NICE covering the clinical background and efficacy together with health economic analyses and a projection of the proportion of eligible patients who might benefit from treatment. Other relevant professional organizations and patient groups may also be invited to submit evidence at this stage in the process. Meanwhile NICE will commission a systematic review of the technology from an Appraisals Team (usually situated in an academic department of Public Health) which will be asked to prepare an Evaluation Report for consideration by the NICE Appraisal Committee. It is the Institute’s Appraisal Committee, ‘composed of individuals who can take both a specific and a wider view of the evidence presented to them’ who will produce the guidance; the members are likely to be drawn from a pool consisting of non-clinical academics (9), clinicians, including general practitioners (8), health service administrators (5) and members of the pharmaceutical industry (1). The initial meeting of the Appraisal Committee will also probably be attended by one or two invited specialists from within the clinical area under consideration although these will not be invited to offer formal submissions. The advice of the Appraisal Committee is presented first as a Provisional Appraisal Determination (PAD) which is released in confidence to the manufacturer and those other groups which submitted evidence. At this stage there is an opportunity to send written comments and make representations which
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
the Appraisal Committee will consider before submitting its Determination to the Appraisal Executive of NICE who will be responsible for issuing the Final Appraisal Determination (FAD). If the manufacturer or sponsor requests an opportunity to make further representations concerning the contents of the FAD these are directed to an appeals panel which is separate and distinct from the Appraisal Committee and if these representations are upheld modifications will be made to the FAD. At the end of the process, guidance is released by the Board of NICE to the NHS and may be accompanied by management guidance from the NHS Executive. The process described above is apparently fair and even reasonably expedient since the entire sequence may well take less than a year to complete. Needless to say, the course of Appraisal Determination does not necessarily run smoothly and I would like to examine the process as applied to three agents used in the treatment of haematological malignancies in order to highlight some of the problems encountered on the way. Fludarabine has been licensed since 1994 for second line use in the treatment of Chronic Lymphocytic Leukaemia (CLL). The same external group which had been asked to prepare the systematic review of Fludarabine was also asked to provide the Evaluation Report for the use of Rituximab in the treatment of Follicular NonHodgkin’s Lymphoma. One of the problems of methodologies dependent on the conduct of a Systematic Review is that those responsible for performing the work have expertise in looking things up but not in the specific subject under review. The suggestion (in the context of a Cochrane Review) that the sifting of such clinical evidence should be within the competence even of ‘capable patients or their lawyers’ [1] has been strongly challenged by a re-analysis of the conclusions of the review conducted by an expert in the clinical field under evaluation [2]. Despite extensive consultation with external clinical experts, the Evaluation Report submitted to the Appraisals Team continued to present an interpretation of the data in relation to Fludarabine with which clinicians would not have been in full agreement. Separate submissions were of course made by the manufacturer of Fludarabine and a number of other organizations including the British Committee for Standards in Haematology (on behalf of the British Society for Haematology) and the Royal College of Pathologists; these submissions were prepared by clinical experts within the field. There appeared to be considerable difficulty in explaining the nature of CLL and the expectation of multiple relapses over several years requiring a sequence of therapeutic options (in contrast for instance to the clear evidence of an increase in median survival of 1.2 months achieved by treating pancreatic cancer with gemcitabine or 2 months achieved for second-line treatment of advanced breast cancer with paclitaxel). Since a clear-cut survival advantage did not represent an appropriate end-point alternative approaches were needed. When the PAD was issued
87
it came to a conclusion which was completely at odds with the professional view and a further detailed submission was prepared by (among others) the BCSH to refute its conclusions. A FAD was issued by NICE which ignored rather than challenged the submissions and an appeal was lodged. Before the appeal was heard, a second FAD was issued which coincided with the widely held professional view that Fludarabine has a major role in the treatment of relapsed CLL and should be approved for its licensed indication. Further evidence appeared to have been reviewed and a sensible decision was taken to examine a broader view of the activity of Fludarabine including information concerning its activity in first-line treatment of CLL. It may also be relevant that in their conclusions concerning ‘implications for the NHS’, NICE were able to state that ‘this guidance is not expected to result in a net increase in NHS expenditure in England and Wales because Fludarabine is already in common use’. Rituximab has had a much rockier ride through the system. Licensed since 1999 for treatment of patients with stage III/IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy, the conduct of the systematic review and production of the Evaluation Report again caused considerable problems. It seemed to take some time to get across the fact that ‘at second relapse’ is not the same as ‘second-line’ and that ‘chemoresistant’ is a state in which studies involving comparisons with chemotherapy cannot be undertaken. The same problems in understanding the clinical course of a disease involving multiple relapses and several therapeutic interventions were apparent as those encountered with the CLL submission and there was again difficulty in discounting overall survival as a suitable end-point. In common with the Technology Appraisal of Fludarabine for CLL it became apparent that the choice of clinical experts was limited and it was inevitable that some of the same individuals would be asked to provide advice to the manufacturer, the team conducting the systematic review, one or other of the professional organizations and possibly even to one of the patient groups. Despite this uniformity of clinical advice the initial PAD produced by NICE was full of errors and mistaken assumptions and also proposed that further studies which were impracticable or unethical be performed. Replies from the manufacturer and professional groups were submitted and (at least as far as the submission by the BCSH was concerned) the evidence was ignored in the FAD. At the formal appeals process attended by the manufacturer and professional and patient groups suggestions were made from the Appraisals Committee that clinicians present were acting as part of a campaign orchestrated by the pharmaceutical industry and the Appeals chairman was obliged to intervene to have the remarks withdrawn. Following the appeal a new PAD was issued acknowledging the activity of Rituximab in chemoresistant disease and asking for a non-comparative registrybased study to acquire additional evidence of efficacy,
88
tolerance and impact on Quality of Life. This would appear to be a reasonable position which is likely to be acceptable to patients, clinicians and the manufacturer providing that the process is not made so complicated that a full-blown ’trial’ with the need for ethical approval is required. NICE have however felt able to issue advice recommending that Rituximab is not used for third-line or subsequent-line treatment of patients with recurrent or refractory stage III or IV follicular lymphoma despite the fact that it has been licensed for this indication by the MCA. The last agent which I would like to review is Imatinib mesylate, (Glivec) a new rationally designed agent for the treatment of chronic myeloid leukaemia (CML) licensed by the EMEA (European Agency for the Evaluation of Medicinal Products acting in the role of the MCA here) in November 2001. The licensed indication for Imatinib is in the treatment of patients with CML who are resistant to or intolerant of alpha interferon. NICE has called for submissions of evidence and presumably commissioned an Evaluation Report and has announced a date for the first appraisal meeting in April 2002. The cost of treatment with Imatinib will be high (approximately £18,000 per patient per year) but CML is a rare disease; the incidence in the U.K. is approximately 1:100,000 (estimated 500–800 new patients per year, estimated prevalence 3,000 to 4,000 patients). The only known ‘curative’ therapy for CML is allogeneic bone marrow transplantation although alpha Interferon has been shown to prolong survival compared with hydroxyurea or busulphan. Political concerns that criticism would arise if patients were denied treatment after the manufacturer’s provision of free drugs through its Extended Access Programme resulted in the Department of Health announcing in a letter to Regional Directors and Regional Cancer Co-ordinators that ‘there is no question of treatment being withdrawn from patients on funding grounds . . . treatment should only cease on clinical grounds’. The letter further informed Health Authorities that ‘delaying a decision until NICE has issued its advice is a refusal to fund treatment and would be regarded as a negative judgement’. Under these circumstances it seems entirely appropriate that an editorial in The Lancet should ask ‘where does this stance leave drug licensing and NICE appraisals? NICE’s process is so slow and its appraisal of imatinib now seems
completely superfluous’ [3] and that the authors should describe the delays introduced by the review as ‘NICEblight’. Meanwhile, a large trial to be conducted by an international collaboration of leukaemia trials groups is being undertaken to establish the role of Imatinib in the initial therapy of CML and in the U.K. efforts will be made to recruit all eligible patients and also to enrol the co-operation of all National Cancer Network leads; this approach will further limit the need for decisions concerning the use of Imatinib to be taken by external bodies using economic criteria. The examples which have been quoted above suggest that although NICE may have a role in providing ’authoritative, robust and reliable guidance’ its efforts to achieve this through methods based on economic analysis (especially of drugs) may be very unsatisfactory. The use of economic analysis to compare the costs and consequences of alternative treatments conceals value judgements behind a methodology which appears to provide a scientific rationale for allocating resources and containing costs. When this process is also operated in a setting where the advice of clinical experts is not properly considered, further flaws in the final decisions are inevitable. Instead of blanket decisions based on imperfect approaches, authorities should encourage clinicians to take the cost-effectiveness of treatment into account when they are making decisions at the individual patient level. S. A. JOHNSON
Taunton & Somerset Hospital, Taunton, Somerset, U.K.
REFERENCES Much of the information referred to in the text has been retrieved from web-based sources: National Institute of Clinical Excellence http://www.nice.org.uk/ Medicines Control Agency http://www.mca.gov.uk/ Association of the British Pharmaceutical Industry http:// www.abpi.org.uk/ British Committee for Standards in Haematology http:// www.bcshguidelines.com/ 1 McClelland B. Albumin: don’t confuse us with the facts. Brit Med J 1998;317:829–830. 2 Horsey P. Albumin and hypovolaemia: is the Cochrane evidence to be trusted? Lancet 2002;359:70–72. 3 Barbour V. Imatinib for chronic myeloid leukaemia: a NICE mess. Lancet 2001;358:1478.
Oncology Practice: Editorial NICE or Nasty? The National Institute of Clinical Excellence (NICE) was set up 3 years ago as a Special Health Authority to ‘provide patients, health professionals and the public with authoritative, robust and reliable guidance on current practice’. Although there are many important areas of prescribing practice with major health economic implications, NICE has been asked to appraise a range of treatments to which access is not consistently available across the country so that instances of ‘postcode prescribing’ can be identified and corrected with a minimum of political damage. In December 2001 the Department of Health issued statutory directions that Health Authorities and Primary Care Trusts would be required to make funding available to enable NICE’s guidance on health treatments to be implemented. Although the source of funding to respond to this directive has not been identified it nonetheless gives additional weight to guidance issued by NICE as a result of its Technology Appraisal Process. In these circumstances it would seem to be appropriate to examine the way in which NICE guidance is produced and to test whether it achieves its stated aims. The Department of Health and the National Assembly for Wales select ‘technologies’ (not just pharmaceuticals, but medical devices, diagnostic techniques and other medical interventions) for appraisal based on the likelihood that they will either ‘result in a significant health benefit’, ‘result in a significant impact on other health-related government policies’, ‘have a significant impact on NHS resources’ or that ‘NICE is likely to be able to add value by issuing national guidance’. The subsequent appraisal by NICE is therefore required to evaluate both the clinical effectiveness and cost effectiveness of the technology together with its wider implications for the NHS. As far as pharmaceutical products are concerned this process is necessarily applied to drugs which have already been licensed by the Medicine Controls Agency (MCA) in an exhaustive process which involves pre-marketing assessment of the medicine’s safety, quality and efficacy based on an examination of all the research and test results submitted by the manufacturer. The registration process controlled by the MCA defines a drug’s ‘licensed indication’ and this forms the sole clinical setting in which NICE will Correspondence and offprint requests to: Dr S. A. Johnson, Dept of Haematology, Taunton & Somerset Hospital, Musgrove Park, Taunton, TA1 5DA, U.K. E-mail: [email protected] 0936–6555/02/020086+03 $35.00/0
examine evidence even if clinical practice involves wider use. Oncology drugs appear to have attracted disproportionate attention from NICE. The cost of prescriptions in the treatment of malignant disease (£205 million in 1999) is only tenth is the list of expenditure by disease areas (first is cardiovascular system at £1391 million, second is central nervous system at £1031 million) but of the technology appraisals of drugs/drug groups completed or planned by NICE, fifteen out of forty relate to cytotoxic drugs. The scope for delivering substantial financial savings by demonstrating failings in cost effectiveness alone for cytotoxic drugs may therefore be very limited and the cost to the manufacturer of responding to the NICE technology appraisal process may represent a significant disincentive to the marketing of a drug which has only a limited clinical application. The Technology Appraisal process should start with a notification to the manufacturer or sponsor at least 9 months in advance that their technology is likely to be the subject of referral to NICE. The manufacturer will then prepare a submission to NICE covering the clinical background and efficacy together with health economic analyses and a projection of the proportion of eligible patients who might benefit from treatment. Other relevant professional organizations and patient groups may also be invited to submit evidence at this stage in the process. Meanwhile NICE will commission a systematic review of the technology from an Appraisals Team (usually situated in an academic department of Public Health) which will be asked to prepare an Evaluation Report for consideration by the NICE Appraisal Committee. It is the Institute’s Appraisal Committee, ‘composed of individuals who can take both a specific and a wider view of the evidence presented to them’ who will produce the guidance; the members are likely to be drawn from a pool consisting of non-clinical academics (9), clinicians, including general practitioners (8), health service administrators (5) and members of the pharmaceutical industry (1). The initial meeting of the Appraisal Committee will also probably be attended by one or two invited specialists from within the clinical area under consideration although these will not be invited to offer formal submissions. The advice of the Appraisal Committee is presented first as a Provisional Appraisal Determination (PAD) which is released in confidence to the manufacturer and those other groups which submitted evidence. At this stage there is an opportunity to send written comments and make representations which
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
the Appraisal Committee will consider before submitting its Determination to the Appraisal Executive of NICE who will be responsible for issuing the Final Appraisal Determination (FAD). If the manufacturer or sponsor requests an opportunity to make further representations concerning the contents of the FAD these are directed to an appeals panel which is separate and distinct from the Appraisal Committee and if these representations are upheld modifications will be made to the FAD. At the end of the process, guidance is released by the Board of NICE to the NHS and may be accompanied by management guidance from the NHS Executive. The process described above is apparently fair and even reasonably expedient since the entire sequence may well take less than a year to complete. Needless to say, the course of Appraisal Determination does not necessarily run smoothly and I would like to examine the process as applied to three agents used in the treatment of haematological malignancies in order to highlight some of the problems encountered on the way. Fludarabine has been licensed since 1994 for second line use in the treatment of Chronic Lymphocytic Leukaemia (CLL). The same external group which had been asked to prepare the systematic review of Fludarabine was also asked to provide the Evaluation Report for the use of Rituximab in the treatment of Follicular NonHodgkin’s Lymphoma. One of the problems of methodologies dependent on the conduct of a Systematic Review is that those responsible for performing the work have expertise in looking things up but not in the specific subject under review. The suggestion (in the context of a Cochrane Review) that the sifting of such clinical evidence should be within the competence even of ‘capable patients or their lawyers’ [1] has been strongly challenged by a re-analysis of the conclusions of the review conducted by an expert in the clinical field under evaluation [2]. Despite extensive consultation with external clinical experts, the Evaluation Report submitted to the Appraisals Team continued to present an interpretation of the data in relation to Fludarabine with which clinicians would not have been in full agreement. Separate submissions were of course made by the manufacturer of Fludarabine and a number of other organizations including the British Committee for Standards in Haematology (on behalf of the British Society for Haematology) and the Royal College of Pathologists; these submissions were prepared by clinical experts within the field. There appeared to be considerable difficulty in explaining the nature of CLL and the expectation of multiple relapses over several years requiring a sequence of therapeutic options (in contrast for instance to the clear evidence of an increase in median survival of 1.2 months achieved by treating pancreatic cancer with gemcitabine or 2 months achieved for second-line treatment of advanced breast cancer with paclitaxel). Since a clear-cut survival advantage did not represent an appropriate end-point alternative approaches were needed. When the PAD was issued
87
it came to a conclusion which was completely at odds with the professional view and a further detailed submission was prepared by (among others) the BCSH to refute its conclusions. A FAD was issued by NICE which ignored rather than challenged the submissions and an appeal was lodged. Before the appeal was heard, a second FAD was issued which coincided with the widely held professional view that Fludarabine has a major role in the treatment of relapsed CLL and should be approved for its licensed indication. Further evidence appeared to have been reviewed and a sensible decision was taken to examine a broader view of the activity of Fludarabine including information concerning its activity in first-line treatment of CLL. It may also be relevant that in their conclusions concerning ‘implications for the NHS’, NICE were able to state that ‘this guidance is not expected to result in a net increase in NHS expenditure in England and Wales because Fludarabine is already in common use’. Rituximab has had a much rockier ride through the system. Licensed since 1999 for treatment of patients with stage III/IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy, the conduct of the systematic review and production of the Evaluation Report again caused considerable problems. It seemed to take some time to get across the fact that ‘at second relapse’ is not the same as ‘second-line’ and that ‘chemoresistant’ is a state in which studies involving comparisons with chemotherapy cannot be undertaken. The same problems in understanding the clinical course of a disease involving multiple relapses and several therapeutic interventions were apparent as those encountered with the CLL submission and there was again difficulty in discounting overall survival as a suitable end-point. In common with the Technology Appraisal of Fludarabine for CLL it became apparent that the choice of clinical experts was limited and it was inevitable that some of the same individuals would be asked to provide advice to the manufacturer, the team conducting the systematic review, one or other of the professional organizations and possibly even to one of the patient groups. Despite this uniformity of clinical advice the initial PAD produced by NICE was full of errors and mistaken assumptions and also proposed that further studies which were impracticable or unethical be performed. Replies from the manufacturer and professional groups were submitted and (at least as far as the submission by the BCSH was concerned) the evidence was ignored in the FAD. At the formal appeals process attended by the manufacturer and professional and patient groups suggestions were made from the Appraisals Committee that clinicians present were acting as part of a campaign orchestrated by the pharmaceutical industry and the Appeals chairman was obliged to intervene to have the remarks withdrawn. Following the appeal a new PAD was issued acknowledging the activity of Rituximab in chemoresistant disease and asking for a non-comparative registrybased study to acquire additional evidence of efficacy,
88
tolerance and impact on Quality of Life. This would appear to be a reasonable position which is likely to be acceptable to patients, clinicians and the manufacturer providing that the process is not made so complicated that a full-blown ’trial’ with the need for ethical approval is required. NICE have however felt able to issue advice recommending that Rituximab is not used for third-line or subsequent-line treatment of patients with recurrent or refractory stage III or IV follicular lymphoma despite the fact that it has been licensed for this indication by the MCA. The last agent which I would like to review is Imatinib mesylate, (Glivec) a new rationally designed agent for the treatment of chronic myeloid leukaemia (CML) licensed by the EMEA (European Agency for the Evaluation of Medicinal Products acting in the role of the MCA here) in November 2001. The licensed indication for Imatinib is in the treatment of patients with CML who are resistant to or intolerant of alpha interferon. NICE has called for submissions of evidence and presumably commissioned an Evaluation Report and has announced a date for the first appraisal meeting in April 2002. The cost of treatment with Imatinib will be high (approximately £18,000 per patient per year) but CML is a rare disease; the incidence in the U.K. is approximately 1:100,000 (estimated 500–800 new patients per year, estimated prevalence 3,000 to 4,000 patients). The only known ‘curative’ therapy for CML is allogeneic bone marrow transplantation although alpha Interferon has been shown to prolong survival compared with hydroxyurea or busulphan. Political concerns that criticism would arise if patients were denied treatment after the manufacturer’s provision of free drugs through its Extended Access Programme resulted in the Department of Health announcing in a letter to Regional Directors and Regional Cancer Co-ordinators that ‘there is no question of treatment being withdrawn from patients on funding grounds . . . treatment should only cease on clinical grounds’. The letter further informed Health Authorities that ‘delaying a decision until NICE has issued its advice is a refusal to fund treatment and would be regarded as a negative judgement’. Under these circumstances it seems entirely appropriate that an editorial in The Lancet should ask ‘where does this stance leave drug licensing and NICE appraisals? NICE’s process is so slow and its appraisal of imatinib now seems
completely superfluous’ [3] and that the authors should describe the delays introduced by the review as ‘NICEblight’. Meanwhile, a large trial to be conducted by an international collaboration of leukaemia trials groups is being undertaken to establish the role of Imatinib in the initial therapy of CML and in the U.K. efforts will be made to recruit all eligible patients and also to enrol the co-operation of all National Cancer Network leads; this approach will further limit the need for decisions concerning the use of Imatinib to be taken by external bodies using economic criteria. The examples which have been quoted above suggest that although NICE may have a role in providing ’authoritative, robust and reliable guidance’ its efforts to achieve this through methods based on economic analysis (especially of drugs) may be very unsatisfactory. The use of economic analysis to compare the costs and consequences of alternative treatments conceals value judgements behind a methodology which appears to provide a scientific rationale for allocating resources and containing costs. When this process is also operated in a setting where the advice of clinical experts is not properly considered, further flaws in the final decisions are inevitable. Instead of blanket decisions based on imperfect approaches, authorities should encourage clinicians to take the cost-effectiveness of treatment into account when they are making decisions at the individual patient level. S. A. JOHNSON
Taunton & Somerset Hospital, Taunton, Somerset, U.K.
REFERENCES Much of the information referred to in the text has been retrieved from web-based sources: National Institute of Clinical Excellence http://www.nice.org.uk/ Medicines Control Agency http://www.mca.gov.uk/ Association of the British Pharmaceutical Industry http:// www.abpi.org.uk/ British Committee for Standards in Haematology http:// www.bcshguidelines.com/ 1 McClelland B. Albumin: don’t confuse us with the facts. Brit Med J 1998;317:829–830. 2 Horsey P. Albumin and hypovolaemia: is the Cochrane evidence to be trusted? Lancet 2002;359:70–72. 3 Barbour V. Imatinib for chronic myeloid leukaemia: a NICE mess. Lancet 2001;358:1478.