Overview

The development of this guideline was based upon methods outlined in the ‘NICE guidelines manual’ (NICE 2009, 2012) A team of health professionals, lay representatives and technical experts known as the Guideline Development Group (GDG) (Appendix E.1), with support from the NCC-C staff, undertook the development of this clinical guideline. The basic steps in the process of developing a guideline are listed and discussed below:

• using the remit, define the scope which sets the inclusion/exclusion criteria of the guideline
• forming the GDG
• developing clinical questions
• identifying the health economic priorities
• developing the review protocol
• systematically searching for the evidence
• critically appraising the evidence
• incorporating health economic evidence
• distilling and synthesising the evidence and writing recommendations
• agreeing the recommendations
• structuring and writing the guideline
• updating the guideline.

The Scope

The remit was translated into a scope document by the Guideline Development Group (GDG) Chair and Lead Clinician and staff at the NCC-C in accordance with processes established by NICE (NICE 2009). The purpose of the scope was to:

• set the boundaries of the development work and provide a clear framework to enable work to stay within the priorities agreed by NICE and the NCC-C and the remit set by the DH
• inform professionals and the public about the expected content of the guideline.
• provide an overview of the population and healthcare settings the guideline would include and exclude
• specify the key clinical issues that will be covered by the guideline
• inform the development of the clinical questions and search strategy

Before the guideline development process started, the draft scope was presented and discussed at a stakeholder workshop. The list of key clinical issues were discussed and revised before the formal consultation process. Further details of the discussion at the stakeholder workshop can be found on the NICE website (www.nice.org.uk).

The scope was subject to a four week stakeholder consultation in accordance with processes established by NICE in the ‘NICE guidelines manual’ (NICE 2009). The full scope is shown in Appendix D. During the consultation period, the scope was posted on the NICE website (www.nice.org.uk). Comments were invited from registered stakeholder organisations, NICE staff and the NICE Guideline Review Panel (GRP)⁸. Further information about the GRP can also be found on the NICE website. The NCC-C and NICE reviewed the scope in light of comments received, and the revised scope was reviewed by the GRP, signed off by NICE and posted on the NICE website.

The Guideline Development Group (GDG)

The neutropenic sepsis GDG was recruited in line with the ‘NICE guidelines manual’ (NICE 2009). The first step was to appoint a Chair and a Lead Clinician. Advertisements were placed for both posts and candidates were interviewed before being offered the role. The NCC-C Director, GDG Chair and Lead Clinician identified a list of specialties that needed to be represented on the GDG. Details of the adverts were sent to the main stakeholder organisations, cancer networks and patient organisations/charities (Appendix E.2). Individual GDG members were selected by the NCC-C Director, GDG Chair and Lead Clinician, based on their application forms. The guideline development process was supported by staff from the NCC-C, who undertook the clinical and health economics literature searches, reviewed and presented the evidence to the GDG, managed the process and contributed to drafting the guideline. At the start of the guideline development process all GDG members' interests were recorded on a standard declaration form that covered consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG meetings, members declared new, arising conflicts of interest which were always recorded (Appendix E.1).

Guideline Development Group Meetings

Eleven GDG meetings were held between 21^st September 2010 and 18^th May 2012. During each GDG meeting (held over either one or two days) clinical questions and clinical and economic evidence were reviewed, assessed and recommendations formulated. At each meeting patient/carer and service-user concerns were routinely discussed as part of a standing agenda item.

NCC-C project managers divided the GDG workload by allocating specific clinical questions, relevant to their area of clinical practice, to small sub-groups of the GDG in order to simplify and speed up the guideline development process. These groups considered the evidence, as reviewed by the researcher, and synthesised it into draft recommendations before presenting it to the GDG as a whole. Each clinical question was led by a GDG member with expert knowledge of the clinical area (usually one of the healthcare professionals). The GDG subgroups often helped refine the clinical questions and the clinical definitions of treatments. They also assisted the NCC-C team in drafting the section of the guideline relevant to their specific topic.

Patient/Carer Members

Individuals with direct experience of neutropenic sepsis gave an important user focus to the GDG and the guideline development process. The GDG included three patient/carer members. They contributed as full GDG members to writing the clinical questions, helping to ensure that the evidence addressed their views and preferences, highlighting sensitive issues and terminology relevant to the guideline and bringing service-user research to the attention of the GDG.

Background

Clinical guidelines should be aimed at improving clinical practice and should avoid ending up as ‘evidence-based textbooks’ or making recommendations on topics where there is already agreed clinical practice. Therefore the list of key clinical issues listed in the scope were developed in areas that were known to be controversial or uncertain, where there was identifiable practice variation, or where NICE guidelines were likely to have most impact.

Method

From each of the key clinical issues identified in the scope the GDG formulated a clinical question. For clinical questions about interventions, the PICO framework was used. This structured approach divides each question into four components: P - the population (the population under study, I -, the interventions (what is being done), C - the comparisons (other main treatment options), O - the outcomes (the measures of how effective the interventions have been). Where appropriate, the clinical questions were refined once the evidence had been searched and, where necessary, sub-questions were generated.

The final list of clinical questions can be found in the scope (Appendix E).

Review of Clinical Literature

Developing the review protocol

For each clinical question, the information specialist and researcher (with input from other technical team and GDG members) prepared a review protocol. This protocol explains how the review was to be carried out (Table A) in order to develop a plan of how to review the evidence, limit the introduction of bias and for the purposes of reproducibility. All review protocols can be found in the full full evidence review.

Table A

Components of the review protocol.

GRADE (Grading of Recommendations, Assessment, Development and Evaluation)

For interventional questions, studies which matched the inclusion criteria were evaluated and presented using a modification of GRADE (NICE 2009; http://gradeworkinggroup.org/). Where possible this included meta-analysis and synthesis of data into a GRADE ‘evidence profile’. The evidence profile shows, for each outcome, an overall assessment of both the quality of the evidence as a whole (low, moderate or high) as well as an estimate of the size of effect. A narrative summary (evidence statement) was also prepared.

Each topic outcome was examined for the quality elements defined in Table B and subsequently graded using the quality levels listed in Table C. The reasons for downgrading or upgrading specific outcomes were explained in footnotes.

Table B

Descriptions of quality elements of GRADE.

Table C

Overall quality of outcome evidence in GRADE.

All procedures were fully compliant with NICE methodology as detailed in the ‘NICE guidelines manual’ (NICE 2009). In general, no formal contact was made with authors; however, there were ad hoc occasions when this was required in order to clarify specific details.

For non-interventional questions, for example the questions regarding diagnostic test accuracy, a narrative summary of the quality of the evidence was given.

Needs Assessment

As part of the guideline development process the NCC-C invited a specialist registrar, with the support of the GDG, to undertake a needs assessment (Appendix E.3). The needs assessment aims to describe the burden of disease and current service provision for patients with neutropenic sepsis in England and Wales, which informed the development of the guideline.

Assessment of the effectiveness of interventions is not included in the needs assessment, and was undertaken separately by researchers in the NCC-C as part of the guideline development process.

The information included in the needs assessment document was presented to the GDG. Most of the information was presented in the early stages of guideline development, and other information was included to meet the evolving information needs of the GDG during the course of guideline development.

Incorporating Health Economics Evidence

The aim of providing economic input into the development of the guideline was to inform the GDG of potential economic issues relating to the prevention and management of neutropenic sepsis. Health economics is about improving the health of the population through the efficient use of resources. In addition to assessing clinical effectiveness, it is important to investigate whether health services are being used in a cost effective manner in order to maximise health gain from available resources.

Methods for reviewing and appraising economic evidence

The aim of reviewing and appraising the existing economic literature is to identify relevant economic evaluations that compare both costs and health consequences of alternative interventions and that are applicable to NHS practice. Thus studies that only report costs, non-comparative studies or ‘cost of illness’ studies are generally excluded from the reviews (NICE, 2009).

Economic studies identified through a systematic search of the literature are appraised using a methodology checklist designed for economic evaluations (NICE, 2009, Appendix H). This checklist is not intended to judge the quality of a study per se, but to determine whether an existing economic evaluation is useful to inform the decision-making of the GDG for a specific topic within the Guideline. There are two parts to the appraisal process; the first step is to assess applicability (i.e. the relevance of the study to the specific guideline topic and the NICE reference case) (Table D).

Table D

Applicability criteria.

In the second step, only those studies deemed directly or partially applicable are further assessed for limitations (i.e. the methodological quality, Table E).

Table E

Methodological quality.

Where relevant, a summary of the main findings from the systematic search, review and appraisal of economic evidence is presented in an economic evidence profile alongside the GRADE table for clinical evidence.

If high-quality published economic evidence relevant to current NHS practice was identified through the search, the existing literature was reviewed and appraised as described above. However, it is often the case that published economic studies may not be directly relevant to the specific clinical question as defined in the guideline or may not be comprehensive or conclusive enough to inform UK practice. In such cases, for priority topics, consideration was given to undertaking a new economic analysis as part of this guideline.

Linking to NICE technology appraisals

There are no published technology appraisals (TA) relevant to this guideline.

Agreeing the Recommendations

For each clinical question the GDG were presented with a summary of the clinical evidence, and, where appropriate, economic evidence, derived from the studies reviewed and appraised. From this information the GDG were able to derive the guideline recommendations. The link between the evidence and the view of the GDG in making each recommendation is made explicit in the accompanying LETR statement.

LETR (Linking Evidence to Recommendations) statements

As clinical guidelines were previously formatted, there was limited scope for expressing how and why a GDG made a particular recommendation from the evidence of clinical and cost effectiveness. To make this process more transparent to the reader, NICE have introduced an explicit, easily understood and consistent way of expressing the reasons for making each recommendation. This is known as the ‘LETR statement’ and will usually cover the following key points:

• the relative value placed on the outcomes considered
• the strength of evidence about benefits and harms for the intervention being considered
• the costs and cost-effectiveness of an intervention
• the quality of the evidence (see GRADE)
• the degree of consensus within the GDG
• other considerations – for example equalities issues

Where evidence was weak or lacking the GDG agreed the final recommendations through informal consensus. Shortly before the consultation period, ten key priorities and five key research recommendations were selected by the GDG for implementation and the patient algorithms were agreed. To avoid giving the impression that higher grade recommendations are of higher priority for implementation, NICE no longer assigns grades to recommendations.

Consultation and Validation of the Guideline

The draft of the guideline was prepared by NCC-C staff in partnership with the GDG Chair and Lead Clinician. This was then discussed and agreed with the GDG and subsequently forwarded to NICE for consultation with stakeholders.

Registered stakeholders (Appendix E.2) had one opportunity to comment on the draft guideline which was posted on the NICE website between 16 February 2012 and 28 March 2012 in line with NICE methodology (NICE 2009).

The pre-publication process

An embargoed pre-publication of the guideline was released to registered stakeholders to allow them to see how their comments have contributed to the development of the guideline and to give them time to prepare for publication. (NICE 2012).

The final document was then submitted to NICE for publication on their website. The other versions of the guideline (see below) were also discussed and approved by the GDG and published at the same time.

Other Versions of the Guideline

This full version of the guideline is available to download free of charge from the NICE website (www.nice.org.uk) and the NCC-C website (www.wales.nhs.uk/nccc).

NICE also produces three other versions of the neutropenic sepsis guideline which are available from the NICE website:

• the NICE guideline, which is a shorter version of this guideline, containing the key priorities, key research recommendations and all other recommendations
• NICE Pathways, which is an online tool for health and social care professionals that brings together all related NICE guidance and associated products in a set of interactive topic-based diagrams.
• ‘Understanding NICE Guidance’ (‘UNG’), which describes the guideline using non-technical language. It is written chiefly for people having anticancer treatment but may also be useful for their families and carers.

Updating the Guideline

Literature searches were repeated for all of the clinical questions at the end of the GDG development process, allowing any relevant papers published before November 2011 to be considered. Future guideline updates will consider evidence published after this cut-off date.

Three years after publication of the guideline, NICE will commission a review to determine whether the evidence base has progressed significantly to alter the guideline recommendations and warrant an early update.

Funding

The National Collaborating Centre for Cancer was commissioned by NICE to develop this guideline. Additional health economic advice and support for this guideline was provided by the London School of Hygiene and Tropical Medicine and funded by the National Collaborating Centre for Cancer.

Disclaimer

The GDG assumes that healthcare professionals will use clinical judgment, knowledge and expertise when deciding whether it is appropriate to apply these guidelines. The recommendations cited here are a guide and may not be appropriate for use in all situations. The decision to adopt any of the recommendations cited here must be made by the practitioner in light of individual patient circumstances, the wishes of the patient and clinical expertise.

The NCC-C disclaims any responsibility for damages arising out of the use or non-use of these guidelines and the literature used in support of these guidelines.