Select Committee on Health Minutes of Evidence

Paper 1




  1.  The Institute rejects allegations that its guidance is "flawed". The processes adopted by the NICE involve:

    —  an independent, peer reviewed systematic review of the totality of the available knowledge is commissioned from one of the NHS R&D's Health Technology Assessment groups and then quality-controlled by the National Centre for Health Technology Assessment;

    —  consideration of written evidence from relevant professional groups and patient/carer organisations;

    —  consideration of evidence from patient and clinical experts invited to the relevant meetings of the Appraisal Committee;

    —  detailed consideration, on two separate occasions, by its independent Appraisal Committee of all the evidence submitted to the Institute; and

    —  the opportunity for the consultees to request an appeal before a panel whose members have not been involved with the appraisal.

  These arrangements are more public, thorough and inclusive than any other form of scrutiny (nationally or internationally) of which we are aware.

  2.  The Institute considers the evidence not just from the perspective of doctors, or even a wider definition of health professionals, but in a way that takes account of the views of those with the condition and those who speak for them. This means more than simply asking for their views on draft documents. It involves actively seeking evidence from them and providing them with the opportunity to talk directly to the Appraisal Committee, as the evidence is being interpreted.

  3.  The Institute rejects the suggestion that it has contradicted the Summary of Product Characteristics for any pharmaceutical. Whilst at some date in the future it may be appropriate to do so, this would be confined to established technologies which have been in use for many years, and where there is good evidence for their clinical and cost effectiveness. There are no circumstances where the Institute would promote a new, or recently licensed technology outside its authorised indications.

  4.  The Institute rejects criticisms that its guidance should incorporate a complete account of the use of a particular technology. For pharmaceuticals these are fully described in the Summary of Product Characteristics which is subject to the approval of either the Medicines Control Agency or the European Medicines Evaluation Agency (depending on the grantee of marketing authorisation). It should be noted that neither the Drug and Therapeutics Bulletin, nor the British National Formulary, provide the full prescribing details that are to be found in manufacturers' Summaries of Product Characteristics.

  5.  The Institute provides two forms of guidance for health professionals—appraisals of the use of individual (or groups of related) health technologies, and clinical guidelines on the management of particular conditions. Each represent important forms of guidance, and clinicians welcome both. The guidance on individual health technologies is based on clinical and cost effectiveness and provides clinicians with an indication as to when they are most appropriately deployed in the management of a particular condition. Clinical guidelines, also based on clinical and cost effectiveness, cover a wider area of clinical practice and are much more lengthy in the time needed for their construction. Where appraisals are undertaken, on a related area of clinical practice, in advance of a guideline, the result of the appraisal is incorporated by the guideline developers.

  6.  No appeal was made by any group representing health care professionals against any of the appraisals criticised by the Drugs and Therapeutics Bulletin.


  In considering the criticisms of the Drugs and Therapeutics Committee, it is worth noting some of the characteristics of the Institute's approach which might lead to differences in the way in which evidence is interpreted by the two organisations:

    —  before the independent advisory Appraisal Committee begins its deliberations, evidence is actively sought from patients and their carers, health professionals and manufacturers or sponsors, in the case of a clinical or diagnostic procedure;

    —  the Appraisal Committee considers evidence of both clinical and cost effectiveness and views from the perspective of clinicians and patients;

    —  patient/carers and health professionals themselves nominate representatives to attend and inform the Appraisal Committee and all consultees are provided with the opportunity to comment, both on the evidence and on provisional conclusions;

    —  consultees have the right of appeal against the final proposed guidance to the NHS before it is issued.


  DTB criticism:

    —  Limitations of the trials included in the pooled analysis, making the subsequent interpretation "highly questionable".

    —  Link between complications requiring antibiotics and subsequent hospitalisation and death. Antibiotic therapy is often used for minor infections. The observed reduction of 6 per cent did not reach statistical significance.

    —  If a day's reduction is not a compelling reason for otherwise healthy adults, it is "questionable" that it could be so regarded for those in the at risk population.

  Zanamivir is licensed for the treatment of influenza Type A & B in adults when influenza is circulating in the community. The Institute has appraised it twice: in November 1999, following a rapid review, and in October 2000 following a formal appraisal.

  In the first (rapid) appraisal, the trial data revealed that there was a reduction in duration of the symptoms of influenza in the pooled intention to treat population of about a day. The rapid review committee was interested to understand the effect of zanamivir on patients with pre-existing conditions (such as cardiovascular, renal and respiratory diseases) and in the elderly, where it is known that influenza can cause complications and death. Although such patients were included in the studies referred to above, they were not sufficiently numerous to enable any conclusions to be reached. The committee was also concerned to understand the likely impact of widespread prescribing of zanamivir on the ability of general practitioners and primary care professionals in general, to maintain a balanced range of services. There was relatively little information available to enable this impact to be accurately estimated.

  The committee concluded that the benefit for otherwise healthy adults of a day's reduction in the symptoms of influenza, whilst important for some individuals, did not constitute an efficient use of NHS resources. In particular, the committee was concerned about the possibility that widespread prescribing in the adult population during an epidemic would have a detrimental impact on the ability of primary care to maintain a full service. The committee called for further information on this and on the effectiveness of zanamivir in the "at risk" groups. This was communicated to the manufacturer and the Institute agreed to review any further relevant data in 2000.

  A second appraisal was undertaken in 2000, as part of the Institute's formal appraisal programme, and as recommended in the original (rapid) guidance. An assessment report was commissioned from the West Midlands Development and Evaluation Service at the University of Birmingham, through the NHS Research and Development Programme. Following a review of this report, the Appraisal Committee concluded that no new material evidence had emerged to suggest a change to the existing guidance and proceeded to consult on this basis. During the consultation period, the manufacturer, Glaxo Wellcome, presented the results of a further clinical trial. This was the first trial specifically recruiting an at risk population to be reported. The West Midlands team were asked to produce a supplementary assessment report taking account of this trial.

  The West Midlands team, in their original assessment report, used data from a meta-analysis produced by Glaxo-Wellcome to report antibiotic usage—this showed a 6 per cent reduction in antibiotic use for respiratory complications. The new trial showed similar reductions (5 per cent) which did not reach statistical significance. In their submission Glaxo Wellcome presented an integrated analysis that gave an estimate of a 6 per cent reduction in complications requiring antibiotic use in the at risk population (95 per cent CI 0 per cent to 11 per cent). The West Midlands team did a meta-analysis using virtually the same data set . Using a fixed effects model this gave a similar estimate of a 6 per cent (95 per cent CI 0 per cent to 11 per cent) reduction in complications requiring antibiotics, which is on the borderline of statistical significance. The West Midlands team concluded, however, that it was in their view a true effect. The Appraisal Committee considered that this "pooled analysis" was scientifically appropriate and in accordance with the practice adopted both nationally and internationally. It considered that reductions in complications requiring antibiotics was a reasonable intermediate end point. It therefore concurred with the conclusion of the assessment report authors that by reducing complications requiring antibiotics, it is probable that hospitalisation is also reduced and that deaths are avoided. The Appraisal Committee therefore advised that zanamivir should be offered to patients in the at risk population.

  This new trial was not available to the regulatory body at the time zanamivir was licensed and could not, therefore have influenced the references to the effect of zanamivir in at risk groups in the Summary of Product Characteristics. Because the Institute is required to take account of all the best available evidence, it was appropriate for it to use the new trial to inform its revised conclusions. Nevertheless, the Institute's advice is within the product's authorised indications.

  The Institute recommended the supply of zanamivir through the use of patient group directions after discussions with the Department of Health. In doing so, we were mindful of the need to offer advice which would have the effect of minimising the additional workload in primary care (but particularly on general practitioners) whilst offering qualifying patients rapid access to the medicine. Any medicine which might be the subject of a patient group direction will have contra-indications. Prescribers and those who supply medicines through patient group directions will wish to be aware of the safety profile of any drug they offer to patients. "Black triangle" medicines are not excluded from patient group directions and clearly, had the Department of Health considered that what we were suggesting was an inappropriate use of patient group directions (because of concerns over antibiotic resistance), they would not have agreed to it. As far as the safety concerns which were noted, the Institute's position is that prescribers should be aware of the contra-indications and warnings referred to in the Summary of Product Characteristics, and any additional safety information published by the manufacturer or the Committee on Safety of Medicines.


  DTB criticism:

    —  NICE guidance recommends use "in ways not recommended by the manufacturer". Specifically, by suggesting that patients whose blood glucose remains high despite an adequate trial of metformin plus sulphonylurea combination should be offered either glitazone in combination with metformin or sulphonylurea as an alternative to starting insulin.

    —  There is "no evidence" to support these unlicensed indications and therefore the guidance "lacks credibility".

  NICE response:

  The thiazolidinediones are clinically effective as second line agents for glucose lowering in people with Type 2 diabetes. The review of studies showed this was also the case for these agents in first-line therapy. However, the Institute's guidance does not recommend the use of thiazolidinedione monotherapy, either first or second-line because it is not a licensed indication.

  The guidance recommends the use of combination therapy when monotherapy alone does not achieve optimal glucose control. The guidance also recommends that the first option for combination therapy should be metformin and sulphonylurea, unless there are contraindications to, or problems with their tolerability. The thiazolidinediones are clinically effective for glucose lowering as add-on agents in people with Type 2 diabetes. Currently there is no evidence of improved clinical outcomes using combination therapy with thiazolidinediones compared with sulphonylurea/metformin combinations. However, evidence suggests that combination therapy with thiazolidinedione and either metformin or sulphonylurea could be offered if patients are unable to take metformin/sulphonylurea combination or if blood glucose remains high, despite an adequate trial of the latter. In this context, improved control of blood sugar is considered both nationally and internationally to be a reasonable intermediate outcome.

  The decision whether to continue with oral therapy or to commence insulin therapy when for example glycaemic control is considered inadequate must be based on expert clinical judgment coupled with individual patient choice. The Institute emphasizes that its guidance was not discordant with the licensed indications.


  DTB criticism;

    —  NICE guidance is "of limited value" because it makes no attempt to advise on use of the other licensed—dexamfetamine. As a result, healthcare professionals "have no way of knowing whether NICE intends that dexamfetamine should be used as an alternative to methylphenidates reserved only for certain (undefined) groups of children or not used at all".

    —  There "is little difference in effectiveness between dexamfetamine and the methylphenidates" and the former is much cheaper than the latter.

    —  The guidance "fails to answer key questions or to provide comprehensive and complete advice on whether, when and how drug therapy should be used in the NHS to manage children with ADHD".

  NICE response:

  The Institute was not asked to undertake an appraisal of dexamfetamine. The request that it received from the Department of Health and the National Assembly for Wales was clearly limited to the methylphenidates. The underlying reason was the controversy, at the time, over the use of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD). The fact that the Institute did not offer advice on the use of dexamfetamine does not, in any way detracts from its value. In addition, we received no suggestion from any of the clinical experts or professional groups we consulted that, for the appraisal to be of value it was necessary for it to include dexamfetamine.

  The guidance concludes that "methylphenidate is recommended for use as part of a comprehensive treatment programme for children with a diagnosis of severe Attention Deficit/Hyperactivity Disorder (ADHD)". The guidance goes on to describe the arrangements which should be put in place to enable accurate diagnosis and the health professionals which should be responsible both for diagnosis and for initiating treatment:

    —  Diagnosis should be based on a timely, comprehensive assessment conducted by a child/adolescent psychiatrist or a paediatrician with expertise in ADHD. It should also involve children, parents and carers and the child's school, and take into account cultural factors in the child's environment. Multidisciplinary assessment, which may include educational or clinical psychologists and social workers, is advisable for children who present with indications of significant co morbidity.

    —  Treatment with methylphenidate should only be initiated by child and adolescent psychiatrists or paediatricians with expertise in ADHD, but continued prescribing and monitoring may be performed by general practitioners, under shared care arrangements with specialists.

    —  Careful titration is required to determine the optimal dose level and timing for methylphenidate. The drug should be discontinued if improvement of symptoms is not observed after appropriate dose adjustment.

    —  A comprehensive treatment programme should involve advice and support to parents and teachers, and could, but does not need to, include specific psychological treatment (such as behavioural therapy). While this wider service is desirable, any shortfall in its provision should not be used as a reason for delaying the appropriate use of medication.

    —  Children on methylphenidate therapy should receive regular monitoring. When improvement has occurred and the child's condition is stable, treatment can be discontinued at intervals, under careful specialist supervision, in order to assess both the child's progress and the need for continuation of therapy.

  The guidance does not suggest that methylphenidate is more effective than dexamfetamine. Nor does it, explicitly or implicitly, recommend that it should be used in preference to dexamfetamine. It offers clear advice that methylphenidate is both clinically and cost effective when used as part of a properly organised treatment programme. It is a matter for parents, children (where appropriate) and prescribers to decide which is preferred, in individual cases.


  DTB criticism:

    —  Trials assessed the effects of these drugs on patients' cognitive functions and "global measures". There is "considerable doubt" about the relevance of these indicators for patients.

    —  The guidance offers "no (other) convincing rationale for recommending the use of (these three drugs) in the NHS".

  NICE response:

  The Institute recognised the difficulties associated with diagnosing Alzheimer's Disease. Our guidance notes that there is no measure of quality of life for use in patients with cognitive impairment that is universally satisfactory. However, the RCT evidence reviewed by the Appraisal Committee showed that all three drugs produce significant improvement in cognitive function.

  Patient groups encouraged the Institute in the view that any intervention for Alzheimer's disease needs to be evaluated in terms of the significance which patients and carers place on its benefits. In its evidence to the Institute, the Alzheimer's Society submitted the results of a survey which considered the views of almost 1000 people with Alzheimer's who had been prescribed donepezil. From this survey, the Society concluded that ". . . it is the changes in behaviour and mood that appear to be most frequently reported by people affected and their carers." This survey result was supported by the oral evidence given by those who spoke for patients during the appraisal and by the clinical experts consulted by the Appraisal Committee. This encouraged the Appraisal Committee to take the view that there is a relationship between the measures of disease progression used in the clinical trials and the global effects reported by patients.

  In addition, the guidance carefully contextualises the use of these medicines, by describing the arrangements which should be in place for assessing patients, prior to commencement of therapy. It advises that only those patients with mild to moderate disease, with an MMSE score of 12 or above, should be considered for therapy with these medicines.

  It concludes by recommending that patients who continue on the drug should be reviewed by MMSE score and global, functional and behavioural assessment every six months. The drug should normally only be continued while their MMSE score remains above 12 points, and their global, functional and behavioural condition remains at a level where the drug is considered to be having a worthwhile effect. When the MMSE score falls below 12 points, patients should not normally be prescribed any of these three drugs. Any review involving MMSE assessment should be undertaken by an appropriate specialist team, unless there are locally-agreed protocols for shared care.

  The guidance is therefore both appropriately cautious and adequately targeted to provide sufficient advice to clinicians, as they exercise appropriate judgement in individual cases.


  DTB criticism:

    —  A suggestion that the Institute failed to take due note of the assessment report's observations that "There is limited evidence of a modest benefit in tracheostomy-free survival for patients taking riluzole." and "Even under the most optimistic assumptions, riluzole at best only postpones death for a few months".

    —  Guidance wrongly quotes the Assessment Report's calculation of the relative reduction in hazard ratio (17 per cent at 18 months as opposed to 12 per cent at 18 months). Claims that there is "considerable statistical uncertainty" about this effect.

    —  The guidance should therefore have been "clearer" in explaining that the evidence about the effect of the drug extending tracheostomy free life is "equivocal".

  Institute response:

  The guidance did indeed contain the misprint referred to above. This has been acknowledged by the Institute.

  The DTB criticism refers to the apparent differences between the Institute's guidance and the assessment report. Assessment reports are commissioned by the National Coordinating Centre for Health Technology Assessment, on the Institute's behalf. Their purpose is to assemble the available evidence of clinical and cost effectiveness. Their authors are not asked to interpret this evidence, although they do, importantly, comment on its appropriateness and its robustness. It is for the Appraisal Committee alone to draw conclusions from the evidence and formulate the guidance.

  The Appraisal Committee took careful account of the assessment report. It considered its findings both with the report's authors and with the patients groups and clinical experts who attended its meetings. The Committee considered the statistical analysis which had been undertaken on the clinical trial data in the assessment report. The Appraisal Committee took the view that, in the light of comments from the Motor Neurone Disease Association, a three month extension to life without a tracheostomy could not be considered as "modest". Having considered the economic analysis, the Appraisal Committee concluded that those patients should have the opportunity to receive this therapy.


  DTB criticism:

    —  NICE has issued guidance on two drugs for obesity, but had given "no advice on how the two drugs should be used in relation to each other. It is unclear as to whether NICE regards them as interchangeable or whether they might be suitable for particular groups of patients.

    —  The guidance fails to offer "clear, integrated advice on the use of these two treatments in the overall management of patients who are obese".

    —  "As a result, it is possible that individual healthcare professionals and service providers will have to formulate their own policies on selecting between and using the two treatments: this could lead to marked variation in practice throughout the NHS (which would be) counter to NICE's remit to end confusion by providing a single national focus".

    —  The guidance fails to mention "some of the practical limitations" on the use of sibutramine which "limit its value". The DTB noted that it had recommended against the use of the drug for a variety of reasons, including "the stringent requirements for monitoring during treatment".

  Institute response:

  These medicines were originally part of the same appraisal. They had to be considered separately because sibutramine received its licence later than anticipated and after orlistat. The Institute will only issue guidance on pharmaceuticals once the licensed indications have been approved. The aim of the appraisal was to assess the role of both medicines in the management of obesity. The Institute was not asked to develop a clinical guideline on the management of this condition. Clinical guidelines are separately requested and commissioned by the Institute though a different process.

  While the guidance was not expected to be in a clinical guideline format, in both guidance documents there is an emphasis on considering these drugs in the context of an overall approach to the management of obesity. The first recommendation in the Sibutramine guidance states "

    —  sibutramine should be prescribed only as part of an overall treatment plan".

  The third recommendation states that "

    —  when treatment with sibutramine is offered, arrangements should be made for appropriate health professionals to offer concomitant advice, support, and counselling on diet, physical activity and behavioural strategies". It goes on to state "that sibutramine should not be prescribed unless adequate arrangements for monitoring both weight loss and adverse effects can be made available".

  It was not appropriate for the guidance to go into the details of these plans or arrangements. Nevertheless, it does state that " there is no evidence to support co-prescribing with other pharmacotherapy aimed at weight reduction". In the implementation section the guidance again emphasises that "to facilitate the appropriate use of pharmacological management of obesity, training and resourcing of a sufficient number of primary care staff (practice nurse, nurse practitioners and health visitors) supported by community dieticians will be necessary so that they can carry out initial patient assessments and provide continuing advice and support for patients before, during and after treatment". In the related guidance section, the reader's attention is drawn to the Institute's other guidance in this field including the current appraisal on the role of surgery in the treatment of obesity.

  In addition, the guidance clearly refers to the principal contra-indications of sibutramine and how practitioners should monitor patients to assess these side effects to avoid or minimise potential harm.


  In its written submission to the Select Committee, the BNF stated that:

    On rare occasions, the Joint Formulary Committee has agreed to omit mention of NICE guidelines because of concerns about the quality of the advice. The BNF has identified a number of difficulties with NICE appraisals."

  In giving oral evidence, Dinesh Mehta, Executive Editor of the BNF is recorded as saying, in response to a question about the quality of NICE guidance and the occasions on which the BNF omits mention of it:

    "That is very rare and so far the committee has agreed on omitting just the one guidance on the management of patients who have just had a heart attack".  

  The guidance referred to is the Institute's clinical guideline entitled: Prophylaxis for patients who have experienced a myocardial infarction.

  The criticism made by the BNF in their evidence to the Select Committee was:

    —  initiation of drug therapy following a myocardial infarction should take place prior to discharge. The BNF took issue with the suggestion, in the NICE guidance, that therapy could be initiated in primary care.

NICE response:

  The Institute's guideline clearly states that therapy with beta-blockers, antiplatelets drugs (aspirin) and ACE inhibitors should be initiated whilst patients are in hospital. The guidelines recommends that if this has not happened, then primary care clinicians should initiate them as soon as possible after discharge.

  This is a common sense approach which reflects the continuity that needs to exist between secondary and primary care and; the continuing responsibility of general practitioners for ensuring adequate care post discharge.

  Criticisms of the Campaign for Effective and Rational Treatment (CERT) and representatives of the pharmaceutical industry regarding the NICE appraisal of trastuzumab (Herceptin).


    —  women had died because NICE had delayed issuing its guidance;

    —  there were unexplained and inexplicable delays in the Institute's appraisal of trastuzumab;

    —  that the effectiveness of the drug had been established unequivocally;

    —  that the publication of guidance on the other drug being appraised (vinorelbine) for breast cancer was being delayed because of the changes to the timetable for trastuzumab.

  Institute response:

    —  Trastuzumab is not a cure for cancer. It is used to extend life for some women with breast cancer. It was referred to NICE because there was uncertainty about its value in clinical practice, which had resulted in postcode prescribing. To suggest that women have died because NICE has extended its timeline is both erroneous and offensive.

    —  It has been suggested that the evidence for the clinical benefit of trastuzumab is "incontrovertible". The appraisal process will establish whether or not this is the case. In addition, the process will establish the cost effectiveness of the drug. Cost effectiveness is not established by simply taking the annual value of the drug and multiplying by extension to life, as was suggested by witnesses.

    —  The Institute extended the timetable for this appraisal following the responses it received from consultees during the appraisal (see below). The reasons for doing so were communicated to consultees on 13 August 2001 (see attachment) and subsequently posted on the Institute's web site. NICE recognises the importance of this appraisal to women with breast cancer and their families and carers, and we regret the need to extend the timetable. However, we believe strongly that we should take account of all the available evidence and that we should allocate sufficient time to do so. The consequences of a wrong decision would, obviously, be considerable.

    —  The appraisal of trastuzumab had not reached the stage of an appeal, so it was wrong to suggest that appeals were delaying publication. In any event, the opportunity to appeal is an important part of the Institute's process.

    —  During the consultation period, consultees made it clear that they believed that there was evidence available which had not been presented to the Appraisal Committee and which should be taken into account. The Institute, on the advice of the Appraisal Committee, therefore allowed an extension to the appraisal in order to allow full consideration of this evidence.

    —  As there was more of this additional evidence for vinorelbine than for trastuzumab, the Institute separated the timetables for the two appraisals to allow the Appraisal Committee to consider the additional data as soon as it was available. Therefore both appraisals are underway and there is no completed document on vinorelbine ready for publication.

    —  The Appraisal Committee met in October 2001 to consider the new evidence for trastuzumab. Following this meeting a new provisional appraisal determination was produced and circulated to consultees. Our process allows consultees four weeks to consider the document. They received the document on 14 November and had until 14 December to submit comments.

    —  The Appraisal Committee considered the responses in January and produced a final appraisal determination against which the consultees may appeal.

    —  If no appeals are heard, the guidance will be issued. The earliest date for the issue of guidance on trastuzumab is in March.

  Attachment: Letter to consultees from the apprasial programme Director in the appraisals of trastuzumab and vinorelbine.

13 August 2001

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