NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
SPECIFICATION FOR MANUFACTURER/SPONSOR SUBMISSION FOR SINGLE TECHNOLOGY APPRAISAL (STA)
DRAFT FOR CONSULTATION
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| Instructions for sponsors | ||||||||||||||||||||||||||||||||||||||||||
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This specification for NICE single technology appraisal (STA) submission is designed to indicate to manufacturers/sponsors the information required by NICE. The specification should be adhered to wherever possible and should be completed with reference to NICE's Guide to the methods of technology Appraisal, particularly with regard to the ‘Reference Case'. Sections that are not considered to be relevant should be marked ‘N/A' and a justification given for this response. If a submission is based on preliminary regulatory recommendations, the sponsor must advise NICE immediately of any variation between the preliminary and final approval. A submission should be as succinct and informative as possible and should be sent to NICE electronically in a form that can be modified, that is, in Word or compatible format and not as a PDF file, to enable easy removal of confidential information. A list of all references must be provided, together with paper or electronic copies. For model-based economic evaluations, a fully executable electronic copy of the model should be submitted. The Evidence Review Group should have full access to the programming code, and running of the model should be unhindered. C are should be taken to ensure that the submitted versions of the model program and the content of the submission match. If the model is not constructed using Excel or DATA / TreeAge software, the Institute should be informed in advance of submission. The submission is a stand-alone document. An appendix may be used for information that exceeds the level of detail requested but which is considered to be relevant to the submission. The appendix should not be used to present core information. For example, it is not acceptable to attach a key study as an appendix and to complete the efficacy section with 'see Appendix X.' Clinical trial reports and protocols should not be submitted but must made available on request. Trials should be identified by the first author or trial ID rather than relying on numerical referencing alone (for example, ‘Trial XYZ/Jones et al. 126 found ABC' rather than ‘One trial 126 found ABC'). Manufacturers and sponsors must ensure that all relevant material pertinent to the STA has been disclosed to the Institute at the time of submission. There will be no subsequent opportunity to submit information within a STA unless further information is requested by the Institute. When making a submission, manufacturers and sponsors should check that:
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| Disclosure of information | ||||||||||||||||||||||||||||||||||||||||||
To ensure that the appraisal process is as transparent as possible, the Institute considers it highly desirable that evidence pivotal to the Appraisal Committee's decisions should be publicly available. Ideally, all the evidence seen by the Committee should be available to all consultees and commentators on request. Under exceptional circumstances, unpublished evidence is accepted under agreement of confidentiality. Such evidence includes ‘commercial in confidence' information and data that are awaiting publication (‘academic in confidence'). As a minimum, a structured abstract will need to be made available for public disclosure, using a recognised format such as the CONSORT statement (www.consort-statement.org). The Institute will ask you to reconsider restrictions on the release of data either when there appears to be no obvious reason for the restrictions, or when such restrictions would make it difficult or impossible for us to show the evidential basis for our guidance. Information that has been put into the public domain, anywhere in the world, cannot be marked as confidential. Where data are commercial or academic in confidence it is the sponsor's responsibility to clearly highlight them, and to provide reasons why they are confidential and the timescale within which they will remain confidential. The NICE checklist of confidential information should be completed. Information that is confidential will be removed from documents that are made available to the public. If a checklist of confidential information has not been provided, NICE will assume that there is no confidential information in your submission. It is the responsibility of the sponsor to ensure that the confidential information checklist is kept up to date. Confidential information submitted will be made available for review by the Evidence Review Group and the Appraisal Committee. Confidential information may be distributed to consultees with your permission. NICE will at all times seek to protect the confidentiality of the information you submit but nothing will restrict the disclosure of information by the Institute that is required by law (including in particular but without limitation the Freedom of Information Act 2000). The Freedom of Information Act 2000, which came into force on 1 January 2005, enables any person to obtain information from public authorities like NICE. The Act obliges the Institute to respond to requests about the recorded information it holds and it gives people a right of access to that information. This obligation extends to submissions made to NICE. Information that is designated as commercial in confidence may be exempt under the Act. On receipt of a request for information, the NICE secretariat will make every effort to contact your designated company representative to confirm the status of any information previously deemed as commercial in confidence before making any decision on disclosure. For further information please see the NICE website (www.nice.org.uk). |
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The purpose of the background section is to summarise and contextualise the decision problem. It should contain the following information. |
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1.1 Summary of decision problem [maximum 600 words] The purpose of this section is to summarise the decision problem and state the key factors that are addressed in the submission: 1. intervention [Response] 2. population, including subgroups [Response] 3. relevant comparator(s) [Response] 4. outcomes [Response] 5. key issues. [Response] |
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1.2 Description of technology under assessment 6. Give the brand name, approved name and where appropriate, therapeutic class. [Response] 7. Does the technology have a UK marketing authorisation/CE marking for the indications detailed in this submission? If yes, please give the date it received it. If no, please state current UK regulatory status, with relevant dates (for example, date of application and/or expected approval dates). [Response] 8. Does the technology have regulatory approval outside of the UK? [Response] 9. If the technology has not been launched, please supply the anticipated launch date for the UK. [Response] 10. Is the technology subject to any other form of Health Technology Assessment either in the UK or elsewhere? If so, what is the timescale for completion? [Response] 11. What is the principal mechanism of action of the technology? [Response] 12. For pharmaceuticals, what formulation(s) (for example, ampoule, vial, sustained release tablet), strength(s) and pack size(s) will be available? [Response] 13. What is the acquisition cost of the technology (minus VAT)? If the unit cost of the technology is not yet known, please provide details of the anticipated unit cost, including the range of possible unit costs. For devices, provide the list price and average selling price. [Response] 14. What are the (proposed) main indication(s)? [Response] 15. What is the proposed course of treatment? For pharmaceuticals, list the dose, dosing frequency, length of course and anticipated frequency of repeat courses of treatment. [Response] 16. What other therapies, if any, are likely to be prescribed as part of a course of treatment? [Response] 17. For patients being treated with this technology, are there any other aspects that need to be taken into account? For example, are there additional tests or investigations needed for selection, or particular administration requirements, or is there a need for monitoring of patients over and above usual clinical practice for this condition? If yes, provide details. [ Response – maximum 300 words] 18. For pharmaceuticals, please provide a Summary of Product Characteristics (SPC) or draft SPC as an appendix to the submission. 19. For devices, please provide the (anticipated) CE marking, including the indication for use, (draft) technical manual and details of any different versions of the same device, as an appendix to the submission. [Appendix details] 20. What is the current usage of the technology in the NHS? Include details of use in ongoing clinical trials. [ Response – maximum 300 words] |
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21. Please provide a brief overview of the disease and current treatment options. [Response] 22. What was the rationale for the development of the new technology? [ Response – maximum 200 words] 23. What is the suggested place in therapy for this technology with respect to treatments currently available? [ Response – maximum 200 words] 24. Describe any current variation in services and/or uncertainty about best practice, including cost effectiveness. [ Response – maximum 100 words] 25. Provide details of any relevant guidelines or protocols. [Response] |
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26. Describe the relevant comparator(s) and provide a justification for your selection. In some cases, comparisons with more than one comparator or combination-therapy comparators will be necessary. The Institute considers the most relevant comparators to be those that the new technology is attempting to displace from UK practice. [Response] 27. What are the main differences in the indications, contraindications, cautions, warnings and adverse effects between the proposed technology and the main comparator(s)? (100 word maximum) [Response] |
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28. Describe the strategies used to retrieve relevant clinical data both from the published literature and from unpublished data held by the company. The methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced, and the rationale for any inclusion and exclusion criteria used should be provided. Specify: 29. the specific databases searched and service provider used (for example, Dialog, DataStar, OVID, Silver Platter), including at least:
[Response] 30. the date the search was conducted [Response] 31. the date span of the search [Response] 32. the complete search strategies used, including all the search terms: Textwords (free text), Subject Index Headings (e.g. MeSH) and the relationship between the search terms (e.g. Boolean) [Response] 33. details of any additional searches, for example searches of company databases (include a description of each database) [Response] 34. the inclusion and exclusion criteria [Response] 35. the data abstraction strategy. [Response] |
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2.2.1 Complete RCT list 36. Provide a list of all RCTs that compare the intervention with other therapies, including placebo. The list must be complete and will be validated by searches conducted by the Evidence Review Group. Where data from a single study have been drawn from more than one source (e.g. a poster and a published report) and/or where trials are linked (e.g. an open-label extension to an RCT), this should be made clear. [List] 2.2.2 Relevant RCT list 37. List all randomised trials that compare the technology directly with the main comparator(s). If there are none, state this. Where data from a single study have been drawn from more than one source (e.g. a poster and a published report) and/or where trials are linked (e.g. an open-label extension to an RCT), this should be made clear. [List] 38. Please provide details of relevant ongoing studies from which additional evidence is likely to be available in the next 6–12 months. [Details] 39. A flow diagram of numbers of number of studies included and excluded at each stage should be provided as per the QUORUM statement. [Flow diagram] |
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40. As a minimum, the summary should include information on the following aspects of the study but the list is not exhaustive. Where there is more than one RCT please tabulate the information. 2.3.1 Methods 41. Describe the trial design (e.g. degree and method of blinding and randomisation) and interventions. [Response] 2.3.2 Population 42. Provide details of the inclusion and exclusion criteria and describe the patient characteristics at baseline. Highlight any differences between study groups. [Response] 2.3.3 Patient numbers 43. Provide details of the numbers of patients eligible to enter the trial, randomised, and allocated to each treatment. Provide details of patients who crossed over treatment groups and dropped out from the trial. This information should be presented as a CONSORT flow chart. [Flow chart] 2.3.4 Outcomes 44. Provide details of the outcomes investigated and the measures used to investigate those outcomes. This may include therapeutic outcomes and patient-related outcomes such as assessment of quality of life, social outcomes etc. and any arrangements to measure concordance. Where appropriate, also provide details of the principal outcome measure(s) including details of length of follow-up, timing of assessments, scoring methods, evidence of validity and current status of the measure (e.g. approval by professional bodies, licensing authority, etc.). [Response] 2.3.5 Statistical analysis and definition of study groups 45. State the primary hypothesis or hypotheses under consideration and statistical analysis used in testing hypotheses. Also provide details of the power of the study and a description of sample size calculation including assumptions. Provide details of how the analysis took account of patients who withdrew (e.g. a description of the intention-to treat analysis including censoring methods; whether a per-protocol analysis was undertaken). Provide details of any subgroup analyses that were undertaken. [Response] |
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For each of the following methodological topics, choose the description that best fits each trial. If there is more than one trial, tabulate the responses, highlighting any ‘commercial in confidence' data. Your results will be validated by the assessor. 2.4.1 Randomisation 46. Which of the following best describes the randomisation? A) No details of randomisation are available, or the method used was inadequate (e.g. randomisation according to the day of the week, even/odd medical record numbers). B) An insecure randomisation method was used, where clinical staff could possibly learn of the treatment assignment (e.g. randomisation sequence kept in the clinical area and open/unblinded trial; treatment assignment kept in consecutive ‘sealed' envelopes and open/unblinded trial). C) A secure randomisation method was used, where the randomisation sequence was kept away from the clinical area and administered by staff not directly involved in patient care. 2.4.2 Adequacy of follow-up 47. Which of the following best describes the adequacy of follow-up? A) There were significant numbers of drop-outs with no assessment of trial outcome(s) in the subjects who dropped out, and drop-out rates differed between treated and control groups. B) There were some drop-outs with no assessment of trial outcome(s) in the subjects who dropped out, and drop-out rates were (approximately) equivalent in treated and control groups. C) Trial outcome(s) were assessed in all treated and control subjects. 2.4.3 Blinding of outcomes assessment 48. Which of the following best describes the blinding of the outcomes assessment? A) There was an inadequate attempt (or no attempt) to blind observer(s), and the measurement technique was subject to observer bias (e.g. blood pressure measurement with standard sphygmomanometer; measurement of vertebral height on an X-ray). B) The observer(s) were kept fully blinded to treatment assignment, or the measurement technique was not subject to observer bias (e.g. measurement of bone mineral density or survival). 2.4.4 Other 49. Was the design parallel-group or cross-over? Indicate for each cross-over trial whether a carry-over effect is likely. [Response] 50. Was the trial conducted in the UK (or were one or more centres of the multinational trial located in the UK)? If not, where was the trial conducted and is clinical practice likely to differ from UK practice? [Response] 51. How do the subjects included in the trial compare with patients who are likely to receive the drug in the UK? Consider factors known to affect outcomes in the main indication such as demographics, epidemiology, disease severity, setting. [Response] 52. For pharmaceuticals, what dosage regimens were used in the trial? Are they within those detailed in the Summary of Product Characteristics? [Response] 53. What was the median (and range) duration of follow-up in the trial? [Response] |
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2.5 Results of the comparative randomised trials 54. Provide the results for all relevant outcome measure(s). If there is more than one trial, tabulate the responses, highlighting any ‘commercial in confidence' data. The information may be presented graphically to supplement text and tabulated data. Data from intention-to-treat analyses should be presented wherever possible. For each outcome:
[Results table/graph] 55. Where interim trial data are quoted this should be clearly stated along with the point at which data were taken and the time remaining until completion of that trial. Analytical adjustments should be described to cater for the interim nature of the data. 56. If the trial measures a number of outcomes, discuss whether and how an adjustment was made for multiple comparisons in the analysis. 57. Other relevant data that may assist in interpretation of the results may be included, such as adherence to medication and/or study protocol. |
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58. Where more than one study is available consideration should be given to undertaking a meta-analysis. The following steps should be used as a minimum.
[Meta-analysis results table/graph] |
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2.7 Indirect/mixed treatment comparisons 59. In circumstances where there are no RCTs that directly compare the technology with the comparator(s) of interest consideration should be given to using indirect/mixed treatment comparisons. Give a full description of the methodology used and provide a justification for the approach. [Response] |
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60. Give a brief overview of the safety of the technology compared to the comparator(s). Give incidence rates if appropriate. Evidence from comparative trials and regulatory summaries is preferred; however, findings from non-comparative trials may sometimes be relevant. For example, they may demonstrate a relative lack of adverse effects commonly associated with the comparator or the occurrence of adverse effects not significantly associated with other treatments. If any of the main trials are primarily designed to assess a safety outcome (for example, they are powered to detect significant differences between treatments with respect to incidence of an adverse effect) these should be reported here in the same detail as described previously (section 3) for efficacy trials. [ Response – maximum 2000 words] |
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2.9 Interpretation of clinical evidence (400 word maximum) 61. Provide a brief statement of the relevance of the evidence base to the decision problem. Include a discussion of the relevance of the outcomes assessed in clinical trials to the clinical benefits experienced by patients in practice. [Response] 62. Identify any factors that may influence the applicability of study results to patients in routine clinical practice; for example, issues relating to conduct of the trial versus clinical practice or the choice of eligible patients. State any criteria that would be used in clinical practice to select suitable patients based on the evidence submitted. What proportion of the evidence base is for the dose(s) given in the SPC? [Response] |
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3.1 Published cost-effectiveness estimates 3.1.1 Identification and description of studies 63. Describe the strategies used to retrieve relevant cost-effectiveness studies from the published literature and from unpublished data held by the company. The methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced and the rationale for any inclusion and exclusion criteria used should be provided. Specify: 64. the specific databases searched and service provider used (for example, Dialog, DataStar, OVID, Silver Platter), including at least:
[Response] 65. the date the search was conducted [Response] 66. the date span of the search [Response] 67. the complete search strategies used, including all the search terms: Textwords (free text), Subject Index Headings (e.g. MeSH) and the relationship between the search terms (e.g. Boolean) [Response] 68. details of any additional searches, for example searches of company databases. Include a description of each database [Response] 69. the inclusion and exclusion criteria [Response] 70. the data abstraction strategy. [Response] 3.1.2 Description of identified studies 71. Please provide a brief overview of each study, stating the aims, methods, results and relevance to decision-making in England and Wales. [Response] |
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3.2 De novo economic evaluation(s) 72. In the absence of a relevant published economic evaluation, manufacturers should submit their own economic evaluation. 3.2.1 A note on the Reference Case 73. When estimating cost effectiveness, particular emphasis should be given to adhering to the ‘Reference Case' (see NICE ‘Guide to the Methods of Technology Appraisal'). Reasons for deviating from it should be clearly explained. Particularly important features of the reference case include:
3.2.2 Technology (300 word maximum) 74. How is the technology (assumed to be) used within the economic evaluation? For example, give indications, and list concomitant treatments, doses, frequency and duration of use. The description should also include assumptions about continuation and cessation of the technology. [Response] 3.2.3 Evaluation design and structure 3.2.3.1 Patients 75. What group(s) of patients is /are included in the economic evaluation? Do they reflect the licensed indication? If not, how and why are there differences? What are the implications of this for the relevance of the evidence base to the decision problem; in other words, specify the data-gap. [Response] 76. Was the analysis carried out for any subgroups of patients? If so, how was this subgroup identified, what clinical information is there to support the biological plausibility and how was the statistical analysis undertaken? [Response] 77. Were any obvious subgroups not considered? If so, which ones, and why were they not considered? [Response] 78. At what points do patients ‘enter' and ‘exit' the evaluation? Do these points differ between treatment regimens? If so, how and why? [Response] 3.2.4 Comparator technology 79. What comparator(s) was/were used and why was it/were they chosen? The choice of comparator should be consistent with the information provided in Section X of your submission. [Response] 3.2.5 Study perspective 80. Did the perspective reflect NICE's Reference Case? If not, how and why did it differ? [Response] 81. What time horizon was used in the analysis and what was the justification for this choice? [Response] 3.2.6 Framework 3.2.6.1 Model-based evaluations 82. Please provide the following.
[Response] 83. Why was this particular type of model used? [Response] 84. What was the justification for the chosen structure/how was disease progression represented? [Response] 85. Is this consistent with a coherent and currently accepted theory of disease progression? [Response] 86. What were the sources of information used to develop and inform the structure of the model? [Response] 87. What other structures/measures of disease progression could have been used to inform the structure of the model? Why were they rejected? [Response] 88. Does the model structure reflect all essential features of the condition that are relevant to the decision problem? If not, why not? [Response] 89. For discrete time models, what was the model's cycle length, and why was this length chosen? Does this length reflect a minimum time over which the pathology or symptoms of a disease could differ? If not, why not? [Response] 90. If appropriate, was a half-cycle correction used in the model? If not, why not? [Response] 91. Are costs and clinical outcomes extrapolated beyond the trial follow-up period(s)? If so, what are the assumptions that underpin this extrapolation and why are they justified? In particular what assumption was used about the longer-term difference in effectiveness between the technology and its comparator? [Response] 3.2.6.2 Non-model-based economic evaluations
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3.2.7 Evidence 3.2.7.1 Clinical evidence Where relevant, answers to the following questions should be derived from and consistent with, the clinical evidence section of the submission. Cross references should be provided. If alternative sources of evidence have been used, the method of identification, selection and synthesis should be provided and a justification for the approach provided. 92. How was the baseline risk of disease progression estimated (also state which treatment strategy represents the baseline)? [Response] 93. How were the relative risks of disease progression estimated? [Response] 94. Were intermediate outcome measures linked to final outcomes (such as patient survival and quality-adjusted life years [QALYs])? If so, how was this relationship estimated, what sources of evidence were used and what other evidence is there to support it? [Response] 95. Were the health effects of adverse events associated with the technology included in the economic evaluation? If not, would their inclusion increase or decrease the estimated cost effectiveness of this technology? [Response] 96. Was expert opinion used to estimate any clinical parameters? If so, how were the experts identified, to which variables did this apply, and what was the method of elicitation used? [Response] 97. What remaining assumptions regarding clinical evidence were made? Why are they considered to be reasonable? [Response] 3.2.7.2 Measurement and valuation of health 98. Which health benefits were measured and how was this undertaken? [Response] 99. Which health benefits were valued? How and why were these values selected? What other values could have been used instead? [Response] 100. Were health benefits measured and valued in a manner that was consistent with NICE's Reference Case? If not, which approach was used? [Response] 101. Which possible (dis)health benefits were excluded from the evaluation (for example, adverse events of treatment)? [Response] 102. If health benefits were not expressed using QALYs, what health outcome measure was used and what was the justification for this approach? [Response] 3.2.8 Resource identification, measurement and valuation 103. What resources were included in the evaluation (the list should be comprehensive and as disaggregated as possible)? [Response] 104. How were the resources measured? [Response] 105. Were the resources measured using the same source(s) of evidence as the baseline and relative risks of disease progression? [Response] 106. What source(s) of information were used to value the resources? [Response] 107. What is the (anticipated) acquisition cost excluding VAT of the intervention(s)? [Response] 108. Were the resources measured and valued in a manner consistent with the Reference Case? If not, how and why do the approaches differ? [Response] 109. Were resource values indexed to the current price year? [Response] 110. Provide details and a justification for any assumptions that were made in the estimation of resource measurement and valuation. [Response] |
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3.3.1 Time preferences 111. Were costs and health benefits discounted at the rates specified in NICE's Reference Case? [Response] 3.3.2 Non-linearity 112. Was probabilistic sensitivity analysis (PSA) undertaken? If not, why not? If it was, the distributions and their sources should be clearly stated; including the derivation and value of ‘priors'. [Response] 3.3.3 Statistical analysis 113. How were rates or probabilities based on intervals transformed into (transition) probabilities? [Response] 114. Is there evidence that (transition) probabilities should vary over time for the condition at hand? If so, has this been included in the evaluation? If there is evidence that this is the case, but it has not been included, provide an explanation of why it has been excluded. [Response] 3.3.4 Validity 115. Describe the measures that have been taken to validate and check the model. [Response]
3.4.1 Base-case result and PSA 116. What was the base-case result (e.g. costs, QALYs and incremental cost per QALY) and was it based on PSA? [Response] 117. Please provide cost-effectiveness acceptability curves and scatterplots on cost-effectiveness quadrants. [Response] 118. Were results reported for different subgroups of patients? If so, what were the results for them? [Response] 3.4.2 One-way/multiway sensitivity analysis Sensitivity analysis should be conducted over a plausible range of prices for technologies whose final price/acquisition cost has not been confirmed. 119. Which variables were subject to sensitivity analysis? [Response] 120. What were the main findings of the sensitivity analysis? [Response] 121. Has the uncertainty associated with structural uncertainty been investigated? To what extent could/does this type of uncertainty change the results? [Response] 3.4.3 Interpretation of economic evidence (300 word maximum) 122. Are the results from this economic evaluation consistent with the published economic literature? If not, why do the results from this evaluation differ and why should the results in the submission be given more credence than those in the published literature? [Response] 123. Is the economic evaluation relevant to all groups of patients who could potentially use the technology? [Response] 124. What are the main strengths and weaknesses of the evaluation? How should these affect the interpretation of the results? [Response] 125. What further analyses could be undertaken to enhance the robustness/completeness of the results? [Response] |
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Please use the Vancouver style (i.e. consecutive numbering throughout the main text with up to six authors quoted in full followed by et al. in the reference list). There should not be any references in the summary. For example:
[References] |
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[Details of appendices] |
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