Appraisal Consultation Document - Drotrecogin alfa (activated) for severe sepsis
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE
Appraisal Consultation Document
Drotrecogin alfa (activated) for severe sepsis
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The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of drotrecogin alfa (activated) and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of drotrecogin alfa (activated). This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. The process the Institute will follow after the consultation period is summarised below. For further details, see the Guide to the Technology Appraisal Process (this document is available on the Institute's website, www.nice.org.uk).
The key dates for this appraisal are: Details of membership of the Appraisal Committee are given in Appendix A and a list of the sources of evidence used in the preparation of this document is given in Appendix B. |
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Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Drotrecogin alfa (activated) is recommended for use in adult patients with severe sepsis and multiple organ failure who are also being provided with appropriate optimum intensive care support. |
| 1.2 | The use of drotrecogin alfa (activated) should be initiated and supervised by a specialist with intensive care skills. |
| 2 | Clinical need and practice |
| 2.1 | Sepsis is a clinical response to infection. This clinical response is referred to as the systemic inflammatory response syndrome. Sepsis is termed severe when it is associated with organ failure, tissue hypoperfusion or hypotension. It most commonly arises from bacterial infection but it can also be caused by a variety of other micro-organisms such as viruses and fungi. |
| 2.2 | The Intensive Care National Audit and Research Centre (ICNARC) carried out an observational cohort study comprising data from 91 adult general intensive care units (ICUs) in England, Wales and Northern Ireland between 1995 and 2000. It found that the prevalence of severe sepsis in the first 24 hours in intensive care in England, Wales and Northern Ireland was an estimated 27%. This is equivalent to a little over 21,000 cases per annum in England and Wales. Severe sepsis usually develops as a consequence of infection in general medical and surgical wards, but is usually managed for the most part after the patient has been transferred to an ICU. Despite advances in critical care, the mortality rate from severe sepsis is estimated to vary between 30% and 50%. |
| 2.3 | Several scoring systems have been developed to assess the severity of sepsis and to estimate the probability of certain outcomes (for example, death) for groups of patients. These include the APACHE (Acute Physiology, Age and Chronic Health Evaluation) II and the SOFA (Sequential Organ Failure Assessment) scoring systems. |
| 2.4 | Most studies examine the burden of disease in the context of hospital resource use. While patients with severe sepsis represent 27% of ICU admissions, they account for 46% of all ICU bed days and 33% of all hospital bed days consumed by patients admitted to the ICU. |
| 2.5 | The cost of treating patients with sepsis is relatively high, as a large proportion of patients require prolonged stays and aggressive treatment in an intensive care setting. A patient in an ICU is estimated to cost six times more per day than a patient in a general ward, and a patient in a high dependency unit is estimated to cost three times more than a patient on a general ward. The average cost per bed day in UK ICUs was £1232 in 2002. |
| 2.6 | Patients who survive an episode of severe sepsis may have permanent damage to organs or tissues, resulting in a significant, ongoing burden of ill-health. In the years following intensive care, many in this group of patients have a poor health-related quality of life and an increased risk of death compared with the general population. For example, a high level of disability is often seen among survivors of severe meningococcal septicaemia because of amputations and organ failure. There is, however, a scarcity of published information on the quality of life following recovery from severe sepsis. |
| 2.7 | Current management of severe sepsis involves both treatment of the underlying infection, primarily with antibiotics, and supportive treatments according to the signs and symptoms shown by the patient. The choice of antibiotic will depend on the results (where available) of positive microbiological culture results, the likely source of infection, and the likely tissue uptake of the antibiotic. |
| 2.8 | Supportive treatment may include fluids, steroids, vasopressors and ventilatory support. Respiratory failure is very common during sepsis, with up to 85% of patients receiving ventilatory support during their illness. Up to 50% of these ventilated patients may develop adult (acute) respiratory distress syndrome, which is linked to a high mortality rate. Adequate fluid resuscitation with or without vasopressor support is also used to treat haemodynamic instability. |
| 3 | The technologies |
| 3.1 | Drotrecogin alfa (activated) (Xigris?, Eli Lilly), or recombinant human activated protein C, is a new treatment for patients with severe sepsis. It is licensed in the European Union for the treatment of adult patients with severe sepsis with multiple organ failure, when added to best standard care. |
| 3.2 | Activated protein C is an endogenous protein that promotes fibrinolysis and inhibits thrombosis; it also has anti-inflammatory actions. Drotrecogin alfa (activated) is understood to exert its action by modulating the coagulation cascade and inflammatory responses associated with severe sepsis. In patients with sepsis, levels of protein C are depleted and the ability to produce endogenous activated protein C is impaired, shifting the balance towards greater systemic inflammation, intra-vascular coagulation and organ failure. |
| 3.3 | Drotrecogin alfa (activated) may increase bleeding, and consequently it is contraindicated in certain patients such as those with active internal bleeding, chronic severe hepatic disease or intracranial pathology. For full details of side effects and contraindications, see the Summary of Product Characteristics. |
| 3.4 | The recommended standard treatment regimen for drotrecogin alfa (activated) is to infuse 24 µg of drug per kg body weight per hour for a period of 96 hours. The cost of a 5 mg vial of drotrecogin alfa (activated) is £152.05 (Monthly Index of Medical Specialties [MIMS, March 2004]). Therefore, the total acquisition cost for a 70-kg patient, for a full 96-hour course, is estimated to be £4905 excluding VAT. Costs may vary in different settings because of negotiated procurement discounts. Administration of the drug can be undertaken by qualified nursing staff using standard delivery equipment. Drotrecogin alfa (activated) must be delivered through a dedicated lumen of a multilumen central venous catheter or a dedicated intravenous catheter. The Assessment Report (see Appendix B) states that patients treated in this way require no special follow-up beyond the normal ongoing care offered to intensive care patients. |
| 4 | Evidence and interpretation |
| The Appraisal Committee considered evidence from a number of sources (see Appendix B). | |
| 4.1 | Clinical effectiveness |
| 4.1.1 | The Assessment Group (Southampton Health Technology Assessments Centre) considered evidence only from randomised controlled trials (RCTs) for its assessment of the technology's effectiveness. However, it considered a wider set of studies on the clinical use of drotrecogin alfa (activated) in its assessment of adverse effects. The generalisability of the available trial results to the UK context were estimated by comparing the participants and care used in the available RCTs to that in the UK. |
| 4.1.2 | Non-RCT data considered included the open-label ENHANCE study, two compassionate-use studies (EVAS and EVBC) and the unpublished, retrospective MERCURY study comprising analyses related to timing of drug administration. |
| 4.1.3 | Two RCTs were identified: EVAA (phase II) and the large phase III study, PROWESS. The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis has come primarily from PROWESS. The Assessment Group considered that, overall, this study had high internal validity and that the protocol changes that occurred during the course of the study did not appear to have biased the study's results in any way. The joint submission from the Intensive Care Society, the Scottish Intensive Care Society and others noted that it is generally believed that the protocol changes actually improved the study's power. |
| 4.1.4 | PROWESS randomised 1728 patients at centres across the world (1690 patients actually received the drug or placebo), although none were from the UK. The trial was designed to recruit 2280 patients, but enrolment was suspended after the second interim analysis when a statistically significant reduction in 28-day mortality was found. The suspension fulfilled pre-determined stopping rules. |
| 4.1.5 | The proportion of patients with hypertension at baseline was slightly lower in the placebo arm than the treatment group (35.0% versus 38.2%), but the proportions of those with previous myocardial infarction, congestive cardiomyopathy or diabetes were slightly higher in the placebo group. Higher proportions of patients in the placebo group also had septic shock (as defined by the sponsor), were being treated with vasopressors and were receiving mechanical ventilation. The US Food and Drug Administration concluded that these differences could slightly favour the drotrecogin alfa (activated)-treated group. |
| 4.1.6 | The primary efficacy end point in PROWESS was death from any cause and was assessed 28 days after the initiation of the infusion. PROWESS demonstrated a statistically significant absolute risk reduction (ARR) in 28-day mortality of 6.5% (95% confidence interval [CI], 2.2 to 10.7; intention-to-treat result), which is equivalent to a relative risk of death of 0.79 (95% CI 0.68 to 0.92). (Mortality in the placebo and treatment groups was 31.3% and 24.8%, respectively.) Longer-term follow-up of PROWESS patients (the EVBI study) showed that the survival benefit was maintained at 90 days (p = 0.048), although over the entire duration of follow-up (30-month data), the trend towards increased median survival was non-significant (log rank p = 0.097). However, the survival curves did not meet. (Long-term follow-up indicated an increase of about 9 months in median survival, from 846 days in the placebo group to 1113 days in the drotrecogin alfa [activated] group.) |
| 4.1.7 | Health-related quality of life was not assessed in either RCT. |
| Subgroup analyses | |
| 4.1.8 | The PROWESS trial data has been further analysed by means of pre-specified and retrospective subgroup analyses. The results show that certain patient groups may benefit more from the administration of drotrecogin alfa (activated) than others. |
| 4.1.9 | Subgroup analyses planned a priori suggested that there may be a progressive reduction in the relative risk of death (at 28 days) in patients treated with drotrecogin alfa (activated) who had increasing numbers of organ failures at baseline: the relative risk decreased from 0.92 (95% CI 0.63 to 1.35) in patients with one organ failure at baseline to 0.60 (95% CI 0.33 to 1.11) in those with five organ failures. Results for the individual subgroups did not show a statistically significant effect of drotrecogin alfa (activated) on the relative risk of death; however, when the subgroups containing two or more organ failures were combined, the relative risk of death was statistically significantly lower in those treated with drotrecogin alfa (activated) compared with placebo (0.78, 95% CI 0.66 to 0.93). (Mortality in these combined placebo and treatment groups was 33.9% and 26.5%, respectively.) The corresponding results for a longer follow-up were marked academic in confidence. |
| 4.1.10 | Patients in the PROWESS trial were stratified at baseline according to the severity of disease as reflected by the score on the APACHE II. Prospectively defined subgroup analyses found that a statistically significant mortality reduction was limited to patients with an APACHE II score of 25 or more at baseline. The relative risk of death in this subgroup was found to be 0.71 (95% CI 0.59 to 0.85). (Mortality in the placebo and treatment groups was 44.7% and 30.9%, respectively.) |
| 4.1.11 | In a retrospective subgroup analysis, patients were stratified at baseline according to the SOFA scoring system. On the basis of the score obtained, patients were divided into SOFA quartiles. Patients in all subgroups experienced a survival benefit from drotrecogin alfa (activated), though the relative benefit was greatest for those in the first and fourth quartiles (the relative risk of death was 0.74 and 0.75, respectively). (The raw data required to calculate the confidence intervals for the relative risks according to SOFA quartile were not available to the Assessment Group.) |
| Adverse effects | |
| 4.1.12 | There were no statistically significant differences in the incidences of serious adverse events between drotrecogin alfa (activated) and placebo in either RCT. The incidence of bleeding events was statistically significantly higher in the intervention arm of the PROWESS study compared with the placebo group (24.9% and 17.7%, respectively, p < 0.001). In this study the incidences of serious bleeding events were 3.5% and 2.0% for the intervention and placebo groups, respectively (p < 0.10 for all serious bleeding events). |
| 4.1.13 | The incidence of serious bleeding events was higher in the open-label ENHANCE study (n = 2378; 3.8% during infusion) when compared with the RCTs. (This study used eligibility criteria similar to those used in PROWESS.) The incidence of intracranial haemorrhage was also higher in ENHANCE than in PROWESS (0.6% versus 0.2%), although the incidences of fatal intracranial haemorrhages were the same in these two studies (0.2%). |
| 4.2 | Cost effectiveness |
| 4.2.1 | The literature search undertaken by the Assessment Group identified three published cost-effectiveness analyses that were performed from a North American perspective. The Assessment Group also identified six published abstracts and two further unpublished abstracts. The manufacturer provided two economic evaluations (one based on PROWESS day 28 data and one on available follow-up information) and a model as part of its submission. In addition, the Assessment Group developed a model to assess the cost-effectiveness of drotrecogin alfa (activated) plus conventional care versus conventional care alone in a UK cohort of adult patients with severe sepsis. |
| 4.2.2 | The published cost-effectiveness studies have applied a range of methods to the estimation of benefits. The cost-effectiveness abstracts did not provide very much detail on the methods used. (One abstract that examined the cost effectiveness of drotrecogin alfa [activated] in a German setting has now been published in full but was unavailable when the Assessment Report was produced.) Of the eight abstracts identified, seven applied analyses on European populations. All reported economic evaluations used the PROWESS trial data from those patients actually treated to estimate the benefits associated with drotrecogin alfa (activated). |
| 4.2.3 | The published US and Canadian papers estimated an incremental gain per treated patient of between 0.38 and 0.68 life years (for patients with severe sepsis). The additional costs associated with drotrecogin alfa (activated) in patients with severe sepsis considered by these studies included the acquisition cost of the drug, an additional cost associated with an increased risk of severe bleeding events, hospitalisation costs associated with additional survivors of severe sepsis, and the long-term healthcare costs associated with additional survivors of severe sepsis. |
| 4.2.4 | The three published North American studies estimated the incremental costs to be between around $10,000 and $16,000 per patient treated. Estimates of cost per life year and cost per quality-adjusted life year (QALY) ranged from $15,801 to $33,000 and from $20,047 to $48,800, respectively. These estimates were for all the patients eligible for inclusion in the PROWESS study. For patients regarded as at an increased risk of death, as indicated by an APACHE II score of 25 or more, the cost-effectiveness profile was more favourable (costs per life year and per QALY are lower). However, for patients with an APACHE II score of less than 25, the studies reported that treatment with drotrecogin alfa (activated) was associated with a very unfavourable cost-effectiveness profile (the technology was either dominated by conventional care or associated with an incremental cost per QALY of greater than $400,000). |
| 4.2.5 | The terms of the licence dictate that the relevant patient group for any European analysis comprises patients with severe sepsis and multiple organ failure. The European studies have largely focused on this licence indication. As in the case of patients stratified by APACHE II score, the effectiveness of treatment was greater in the multiple organ failure group compared with the general 'all patients' group reported in PROWESS. Hence the cost-effectiveness profile in this subgroup was reported to be more favourable than the 'all patients' analysis. |
| 4.2.6 | The published European analysis examined the cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis in Germany. For the base-case analysis it was assumed that the ARR at final patient discharge was the same as the ARR reported at 28 days (that is, 7.3% for patients with multiple organ failure). The long-term healthcare costs of survivors were not included in the analysis. The discounted incremental gain in life years was reported to be 0.69 for patients with multiple organ failure (discounted life expectancy per additional survivor was 9.5 years). The discounted incremental cost-effectiveness was reported to be ?12,880 per life year gained. |
| 4.2.7 | In a UK study, available only in abstract form, the reported cost per life year gained for the full PROWESS patient group was between £7037 and £9519, depending on the method used to estimate life expectancy (with the cost per QALY estimate for this group being between £10,199 and £13,796). Costs per life year and per QALY for the patient group with multiple organ failure were reported as £4716 and £6385, respectively. This analysis excluded long-term costs for those who survive severe sepsis. |
| 4.2.8 | In general, the various sensitivity analyses reported in the published studies show that the results were robust to variations in most assumptions. |
| 4.2.9 | In the analyses provided by the manufacturer (Eli Lilly), the discounted incremental life years gained were reported to be 1.1 (PROWESS day 28 analysis) and 0.71 (analysis based on follow-up data) life years per treated patient, in patients with severe sepsis and multiple organ failure (that is, the European licence indication). The additional mean costs per patient treated were estimated at £5106 based on 28-day effectiveness data and at £5331 based on longer-term follow-up data. This corresponded to incremental cost-effectiveness ratios of £6637 per QALY and £10,937 per QALY, respectively, based on a single utility estimate of 0.69. Notably, lifetime healthcare costs were not included in the analyses. |
| 4.2.10 | In its cost-effectiveness model, the Assessment Group used data on a baseline cohort of UK patients (from ICNARC), defined according to the criteria used in the PROWESS study, applying the same inclusion criteria as PROWESS, but not the same exclusion criteria. The Assessment Group did not apply the same exclusion criteria as were used in PROWESS because it was thought that a different set of eligibility criteria would be applied in clinical practice. The 28-day mortality for patients in the baseline cohort with severe sepsis was 41.5% (95% CI 40.8% to 42.3%). This was much higher than the mortality rate reported in the placebo arm of the PROWESS study (31.3%). Among the subgroup of patients with multiple organ failure, the baseline 28-day mortality was 46.2% (95% CI 45.3% to 47.1%). (The mortality of this subgroup in the placebo arm of the PROWESS trial was 33.9%.) Long-term NHS costs were included in the base-case analysis. (The published US and Canadian studies also included lifetime healthcare costs for survivors.) |
| 4.2.11 | The Assessment Group estimated a discounted incremental gain of 1.35 (SD, 0.43) life years per treated patient, in patients with severe sepsis and multiple organ failure. In terms of the incremental cost-effectiveness ratio, the Assessment Group estimated a base-case cost per QALY of £8228 in patients with severe sepsis and multiple organ failure (based on 28-day survival data and a single utility estimate of 0.6). Excluding long-term NHS costs the incremental cost per QALY reduces to £6691. |
| 4.2.12 | The results of probabilistic sensitivity analysis undertaken by the Assessment Group showed that if the NHS was willing to pay £20,000 per QALY, drotrecogin alfa (activated) would be a cost-effective use of resources in 98.7% of simulations (in patients with severe sepsis and multiple organ failure). |
| 4.2.13 | In a sensitivity analysis, the Assessment Group examined the impact of varying the effectiveness of drotrecogin alfa (activated). The relative risk for the intervention was varied between 0.7 and 0.95 (the standard error was assumed to be the same as in the base-case model). The corresponding cost per QALY in the severe sepsis and multiple organ failure group was found to range from £6778 to £28,868. |
| 4.2.14 | In summary, the UK analyses indicate a cost per QALY of less than £11,000 for patients with severe sepsis and multiple organ failure treated with drotrecogin alfa (activated). If all patients are considered, the cost per QALY profile becomes less favourable. Other available studies are broadly consistent with these findings, although North American estimates of cost per QALY are higher. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Committee reviewed the evidence available on the clinical and cost effectiveness of drotrecogin alfa (activated), having considered evidence on the nature of the condition and the views of patients who had developed severe sepsis, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. |
| 4.3.2 | The Committee was mindful of the current licensed indication for the use of drotrecogin alfa (activated), which was based on a subgroup analysis of a single RCT. Patients were recruited to this trial in centres across the world but not in the UK. The Committee therefore considered carefully the generalisability of the study findings to an English and Welsh setting. |
| 4.3.3 | There is some evidence that the results of PROWESS are generalisable to a UK population. Submissions from professional organisations and experts for this appraisal stated that datasets from ICNARC and the Scottish Intensive Care Society Audit Group indicate that the characteristics of patients in the UK with severe sepsis are similar to those seen in the PROWESS trial, if the full eligibility criteria of that trial are applied. Additionally, the mortality rates observed in these surrogate UK populations are similar to those of the PROWESS control group. (Results from the ICNARC audit, for example, indicate a 28-day mortality of 32.7%.) |
| 4.3.4 | The results from the open-label ENHANCE study, which included UK centres, also lend some support to the generalisability of the PROWESS findings. (Mortality at 28 days was found to be 25.3%.) The Committee was therefore persuaded by the current evidence and by that presented by experts for this appraisal that the survival advantages seen in the PROWESS study are likely to be generalisable to a UK population. |
| 4.3.5 | The Committee noted that the cost-effectiveness analyses reviewed by the Assessment Group showed some variability in terms of the estimated incremental cost per QALY. In addition, the Committee noted that the Assessment Group's estimate of the incremental life years gained was generally higher than the estimates reported in the literature. |
| 4.3.6 | The Committee further noted that the trial analysis did not take account of any possible bias introduced by stopping early. The effect of any such bias would be to overestimate the absolute risk reduction in death. The Assessment Group undertook a sensitivity analysis examining the variation in the incremental cost per QALY by relative risk, which showed that the magnitude of any bias would have to be extreme to overturn the conclusion that drotrecogin alfa (activated) is cost effective in patients with severe sepsis and multiple organ failure. The Committee was therefore persuaded that overall, the intervention was a cost-effective option for patients with severe sepsis who were at an increased risk of death because of multiple organ failure. |
| 4.3.7 | The Committee also discussed who should supervise the use of drotrecogin alfa (activated) and the appropriate setting for its administration. It was strongly argued by the clinical experts that the administration of drotrecogin alfa (activated) should be confined to an ICU setting, but the Committee recognised that patients with severe sepsis are not always managed in an ICU setting. Nevertheless, the Committee considered that it was most important that any patient considered for treatment with drotrecogin alfa (activated) should also be provided with appropriate optimum intensive care support. |
| 4.3.8 | The Committee considered that only appropriately skilled staff should be able to prescribe drotrecogin alfa (activated). It was persuaded, therefore, that the administration of drotrecogin alfa (activated) should take place under the supervision of a specialist with intensive care skills. The Committee was persuaded that in defining the appropriate specialist in this regard, appropriate competencies rather than a particular specialty were crucial in determining who should have responsibility for supervising the use of drotrecogin alfa (activated). |
| 4.3.9 | The Committee discussed the importance of taking into account several factors (for example, co-morbidities) when considering patients likely to receive this treatment. In particular, the Committee considered that because of the potential side effects of drotrecogin alfa (activated) (such as increased bleeding), patient selection was crucial in order to optimise the risk-benefit ratio for each patient. |
| 4.3.10 | The Committee also discussed the usefulness of the available scoring systems in selecting the patients most likely to benefit from treatment with drotrecogin alfa (activated). Both the experts for the appraisal and the Assessment Group advised against the use of the APACHE II or SOFA scoring systems. For example, it was argued that the APACHE II scoring system gives a high weighting to factors such as increased age and chronic ill health, and was not designed for individual prognostic use. In addition, it was noted that this tool was validated for use within the first 24 hours of admission into the ICU, although in the PROWESS trial, the APACHE II score was determined at the point of study entry. The Committee was also advised that the SOFA scoring system was not developed to predict patient outcome. The Committee accepted that such tools would therefore not be suitable aids in selecting patients for treatment with drotrecogin alfa (activated). |
| 5 | Proposed recommendations for further research |
| 5.1 | Research is currently being undertaken by the manufacturer into the clinical effectiveness of drotrecogin alfa (activated) in a paediatric population. The manufacturer is also conducting research into the use of heparin prophylaxis during treatment with drotrecogin alfa (activated) in patients with severe sepsis at high risk of death. It is also in the process of setting up an extended dosing study in Europe. |
| 5.2 | Further research is required on the longer-term impact of drotrecogin alfa (activated) on mortality, morbidity, health-related quality of life and resource use among UK patients with severe sepsis and multiple organ failure. Survivors of severe sepsis generally have a low health-related quality of life and are at increased risk of death, at least in the initial few years following the septic episode. The potential of drotrecogin alfa (activated) to offset this burden of illness has yet to be adequately defined. In addition, little is known about the long-term costs incurred when patients survive sepsis. The longer-term impact of drotrecogin alfa (activated) could be assessed by means of case-control studies, observational research and clinical audit using high-quality databases. |
| 5.3 | Further research is also needed on the effect of the timing of treatment with drotrecogin alfa (activated) on outcomes in severe sepsis. There is some evidence to indicate that the prompt initiation of appropriate therapies leads to improved outcomes. However, further research is needed to characterise more fully the importance of timing on the benefits associated with using drotrecogin alfa (activated). |
| 5.4 | There is some evidence that the benefit of drotrecogin alfa (activated) varies according to the infecting agent and also the site of infection. Further research is needed - by means of a national intensive care audit, for example - to clarify the benefit profile of drotrecogin alfa (activated) in these particular subgroups of patients. |
| 6 |
Preliminary views on the resource impact for the NHS |
| 6.1 | This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible. |
| 6.2 | There are marked variations in the cited incidences of severe sepsis in the literature. Data from ICNARC estimate the prevalence of severe sepsis (in the first 24 hours) at 27% of ICU admissions, with 84% of these patients having multiple organ failure. The experts for this appraisal stated that far fewer patients would actually be eligible for treatment, once contraindications and individual patient characteristics were taken into account. They estimated that approximately 3-5% of patients admitted to ICUs in the UK could be eligible to receive drotrecogin alfa (activated). Assuming that there are approximately 78,000 adult patients admitted to ICUs in England and Wales per annum, this corresponds to an estimated annual drug acquisition cost of between £11 million and £19 million excluding VAT (£13 million to £22 million including VAT). Using the Assessment Group's estimate of the incremental cost of treating patients with drotrecogin alfa (activated) (that is, approximately £6700), the overall cost of treatment is expected to lie between £16 million and £26 million excluding VAT (£18 million and £31 million including VAT). |
| 7 | Proposals for implementation and audit |
| This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1. | |
| 7.1 | Clinicians who care for adults with severe sepsis and multiple organ failure should review their current practice and policies to take account of the guidance set out in Section 1. |
| 7.2 | Local guidelines or care pathways for people who have severe sepsis and multiple organ failure should incorporate the guidance. |
| 7.3 | To measure compliance locally with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in Appendix C. |
| 7.3.1 | Drotrecogin alfa (activated) is used in adults with severe sepsis and multiple organ failure who are also being provided with appropriate optimum intensive care support. |
| 7.3.2 | The use of drotrecogin alfa (activated) is initiated and supervised by a specialist with intensive care skills. |
| 8 | Related guidance |
| 8.1 | There is no related guidance for this technology. |
| 9 | Proposed date for review of guidance |
| 9.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review. |
| 9.2 | It is proposed that the guidance on this technology is reviewed in August 2007. |
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David Barnett |
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Chair, Appraisal Committee |
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March 2004 |
| Appendix A. Appraisal Committee members |
| NOTE The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into three branches, with the chair, vice-chair and a number of other members between them attending meetings of all branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches. |
| 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. |
| The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. |
| Dr Jane Adam Radiologist, St George's Hospital, London |
| Professor Ron Akehurst Dean of School of Health and Related Research, University of Sheffield |
| Dr Sunil Angris General Practitioner, Waterhouses Medical Practice, Staffordshire |
| Professor David Barnett (Chair) Professor of Clinical Pharmacology, University of Leicester |
| Professor Stirling Bryan Professor of Health Economics, Health Economics Facility, Health Services Management Centre, University of Birmingham |
| Professor John Cairns Professor of Health Economics, Health Economics Research Unit, University of Aberdeen |
| Professor David Chadwick Professor of Neurology, Department of Neurological Science, Walton Centre for Neurology & Neurosurgery, Liverpool |
| Ms Ailsa Claire Chief Executive, Barnsley Primary Care Trust, South Yorkshire |
| Dr Lorna Duggan Consultant Forensic Psychiatrist in Developmental Disabilities, St Andrew's Hospital, Northampton |
| Mrs Fiona Duncan Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool |
| Dr Paul Ewings Statistician, Taunton & Somerset NHS Trust, Taunton |
| Mr Sanjay Gupta Stroke Services Manager, Basildon & Thurrock University Hospitals NHS Trust |
| Professor Philip Home (Vice-Chair) Professor of Diabetes Medicine, Department of Medicine, University of Newcastle upon Tyne |
| Dr Peter Jackson Clinical Pharmacologist, Molecular & Clinical Pharmacology, University of Sheffield |
| Dr Mike Laker Medical Director, Newcastle Hospitals NHS Trust, Royal Victoria Infirmary, Newcastle-Upon-Tyne |
| Dr Simon Mitchell Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester |
| Dr Virginia Pearson Chief Executive, South Petherton Hospital, South Somerset PCT |
| Dr Christa Roberts Industry Representative, UK Manager Vascular Intervention, Guidant Ltd |
| Mr Mike Spencer General Manager, Clinical Support Services, Cardiff and Vale NHS Trust |
| Dr Rod Taylor Senior Lecturer, Department of Public Health & Epidemiology, University of Birmingham |
| Dr Norman Waugh Department of Public Health, University of Aberdeen |
| Mrs Miranda Wheatley-Price Lay Representative, Director of Service Development, Colon Cancer Concern, London |
| NICE Project Team |
| Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute. |
| Francis Ruiz |
| Technical Lead, NICE project team |
| Nina Pinwill |
| Project Manager, NICE project team |
| Appendix B. Sources of evidence considered by the Committee | ||
| A |
The Assessment Report for this appraisal was prepared by the Southampton Health Technology Assessments Centre (SHTAC), University of Southampton: | |
| The clinical and cost-effectiveness of drotrecogin alfa (activated) (XigrisTM) for the treatment of severe sepsis in adults: a systematic review and economic evaluation, December 2003 | ||
| B | The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and Assessment Report. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD. | |
|
I Manufacturer/sponsors:
II Professional/specialist and patient/carer groups:
III Commentator organisations (without the right of appeal):
| ||
| C | The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on drotrecogin alfa (activated) by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD. | |
| ||
| Appendix C. Detail on criteria for audit of the use of drotrecogin alfa (activated) for severe sepsis | |||
| Possible objectives for an audit | |||
| An audit could be carried out on the appropriateness of use of drotrecogin alfa (activated) for severe sepsis. | |||
| Possible patients to be included in the audit | |||
| An audit could be carried out on people with severe sepsis and multiple organ failure receiving intensive care support in a reasonable time period for audit, for example, 6 months. | |||
| Measures that could be used as a basis for an audit | |||
| The measures that could be used in an audit of drotrecogin alfa (activated) are as follows. |
|
Criterion |
Standard |
Exception |
Definition of Terms |
|
1. Drotrecogin alfa (activated) is used for adults with the following: |
100% of people with severe sepsis and multiple organ failure and who are receiving optimum intensive care support |
A. Drotrecogin alfa (activated) is contraindicated B. The individual's condition is not suitable for the use of drotrecogin alfa (activated) |
'Optimum intensive care support' means a level of supportive care that patients would receive in an ICU setting including supportive treatments in accordance with the individual's signs and symptoms. Such care would ordinarily include the correct and prompt choice of antibiotic, taking into account any positive microbiological culture results, the likely source of infection and likely tissue uptake of the antibiotic. Supportive treatment can also include the administration of fluids, steroids, vasopressors and ventilatory support. Contraindications include active internal bleeding, chronic severe hepatic disease or intracranial pathology. |
| 2. The administration of drotrecogin alfa (activated) is initiated and supervised by a specialist with intensive care skills | 100% of people who are prescribed drotrecogin alfa (activated) |
A. None | Clinicians will need to agree locally on the competencies needed to initiate and supervise, and what constitutes initiation and supervision of, the administration of drotrecogin alfa (activated), for audit purposes. |
| Calculation of compliance with the measure | ||
|
Compliance (%) with each measure described in the table above is calculated as follows. | ||
|
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