Development and maintenance of the Criteria

• Development of first edition
• 2008 clarification process
• 2010–11 Criteria Review
• Assessment of evidence
• Condition proforma
• Replacement and immunomodulation therapy
• Dosing
• Research priorities
• Maintenance

The purpose of the Criteria is to assist clinicians and transfusion medicine professionals identify the conditions and circumstances for which the use of intravenous immunoglobulin (IVIg) is clinically appropriate and able to be accessed under the National Blood Arrangements.

Development of first edition

In response to concerns that the AHMAC 2000 guidelines were in need of review, consultation about the development of criteria for IVIg use began in May 2004.

After a workshop was conducted in 2004 to gather information about the changes in the use of IVIg, the following activities, which led to the first edition of the Criteria being approved by Australian Health Minister’s in December 2007, were undertaken:

• In 2004 and 2005, systematic literature reviews of the efficacy and risks of IVIg treatment were undertaken.
• In August 2005, a discussion paper about the development of the new guidelines was circulated for comment, which resulted in a report outlining proposed options for the development of criteria for use.
• Based on the evidence, a clinical proforma and exposure draft of the Criteria were developed and reviewed by sub-groups of clinical experts in the disciplines of neurology, haematology and immunology before being circulated to the clinical community for comment.
• In late 2006, a clinical workshop was conducted to seek input into the proposed proforma and content.
• Finally, the Criteria were revised based on the outcomes of workshop, additional information, and expert opinion for approval by health ministers in December 2007.

Further details of the arrangements and process for developing the first edition of the Criteria is provided at Appendix C.

2008 clarification process

As part of the process to implement the new Criteria, the National Blood Authority (NBA) established a clarification process in November 2008. A consultation group, comprising senior clinical advisers, IVIg Authorisers, clinical representatives from all jurisdictions and a Jurisdictional Blood Committee (JBC) representative, was consulted on specific queries that arose in relation to interpretation of the Criteria.

A Resolution Group, comprising the senior clinical advisers from the consultation group, and a JBC representative, was established to consider the input of the wider consultation group and to determine resolutions. The Criteria Resolution Group’s consideration of the queries and comments resulted in some amendments to specific indications in the Criteria. The revisions were published on the NBA’s website (www.nba.gov.au) in February 2009.

Where agreement could not be reached on how to address the clarification matters, they were forwarded to the next formal review process. Any indications that were judged new indications were not considered as part of the clarification process.

2010–11 Criteria Review

In accordance with government commitments, JBC initiated a review of the Criteria in 2010. The 2010–11 Criteria Review was based on the following principles:

• safe, effective and affordable alternative therapies are preferable to IVIg;
• the lowest dose of IVIg for the shortest period should be prescribed to achieve the desired clinical outcome; and
• measurable clinical outcomes must be achieved for IVIg therapy to continue.

The focus of the 2010–11 Criteria Review was limited to proposals for any of the following:

• chapter reassignment of existing conditions;
• modifications to existing conditions;
• removal of existing conditions; or
• inclusion of new conditions.

In addition to providing evidence to support a proposal submitted to the review, each proposal also had to demonstrate international parity.

A National IVIg Criteria Review Working Group (NICRWG) was established to oversee the 2010–11 Criteria Review process.

The NICRWG comprised of representatives from both clinical and government sectors and individual experts who were engaged in the initial review.

The 2010–11 Criteria Review was undertaken using a rigorous and comprehensive process consisting of the following steps:

• formal submission process;
• review of submissions;
• systematic review process;
• development of revised wording;
• consensus process;
• public consultation; and
• finalisation and approval.

Throughout this process, experts from other clinical speciality areas were consulted for advice as required. Where possible, these individuals were sourced through relevant societies and colleges. Further details of the arrangements and process for developing the second edition of the Criteria is provided at Appendix C.

Assessment of evidence

During the development of the first edition of the Criteria and the 2010–11 Criteria Review, an assessment of the level of evidence was conducted.

The reviews followed the methods described in the National Health and Medical Research Council (NHMRC) handbook, How to review the evidence: systematic review and assessment of the scientific literature (NHMRC 2000)⁸ and the Evidence-based practice workbook published by BMJ Books (Glasziou et al 2007)⁹. Reviews were restricted to studies published since 2004 (the date of the last major systematic literature review conducted on the indications for IVIg use), and aimed to:

• identify and critically appraise the scientific literature regarding the efficacy and risks of IVIg therapy;
• analyse scientific publications (including existing guidelines) that identify the key therapeutic issues in IVIg therapy; and
• include studies comparing IVIg with other treatments, including immunoglobulin administered by other routes, when such other treatments have been studied in comparison with intravenous administration.

Biotext Pty Ltd was engaged by the NBA to undertake the systematic review. Biotext Pty Ltd worked closely with the NICRWG to develop review questions based on the ‘PICO’ method (population, intervention, comparator and outcome) for each condition included in the review.

Where appropriate, an evidence statement was developed for each clinical question using the NHMRC Evidence Statement Form as described in Additional levels of evidence and grades for recommendations for guideline developers (NHMRC 2008).10

An evidence report was prepared for each systematic review undertaken. The evidence reports included specific details of the review methods and search terms used for that particular condition.

As this was a partial review of the Criteria, and to ensure consistency in any revised edition, each evidence report includes an assessment of the alignment of the literature against the categories previously used in the Criteria, outlined in Table 1. As many of the systematically reviewed conditions are rare and there is limited published clinical evidence, this approach also assisted in the consensus process.

Table 1 Level of evidence categories

Level of evidence categories

Category	Studies	Evidence
1	High-quality randomised controlled trials (RCTs)	Clear evidence of benefit
2a	Some RCTs and/or case studies	Evidence of probable benefit – more research needed
2b	Some RCTs and/or case studies	Evidence of no probable benefit – more research needed
2c	High-quality RCTs with conflicting results	Conflicting evidence of benefit
3	High-quality RCTs	Clear evidence of no benefit
4a	Small case studies only	Insufficient data
4b	No included studies	-

Condition proforma

The clinical criteria are contained within condition proforma and have been set out to cover four major issues:

• Indication for IVIg use – this specifies the purpose for which IVIg treatment would be considered once the condition has been confirmed using the proposed diagnostic parameters. The indication generally refers to the prevention or management of a particular manifestation of disease.
• Qualifying criteria – these are the criteria that should be fulfilled if IVIg is to be used. The qualifying criteria generally refer to matters such as patient selection, particular disease characteristics, disease severity, and any requirement for other treatments to have been demonstrably unsuccessful before IVIg is considered. The qualifying criteria are additional to diagnostic criteria.
• Exclusion criteria – these define the circumstances in which IVIg should not be used in patients who have the specified indication.
• Review criteria – these are the major clinical factors that should be taken into account when reviewing the progress of a patient who is receiving IVIg. They comprise parameters that indicate the patient’s response to IVIg and may be used to decide whether to:
  - continue or cease IVIg therapy;
  - or alter the dose or frequency of administration.

To establish if the patient is eligible to access IVIg funded under the National Blood Arrangements, the above clinical criteria are to be used in conjunction with:

• the diagnostic criteria that may indicate consideration of a patient for the use of IVIg therapy; and
• the category of available evidence on the effectiveness of IVIg therapy for a diagnosed condition.

Replacement and immunomodulation therapy

Most conditions considered for IVIg therapy comprise either an immunoglobulin replacement or an immunomodulatory indication. A few conditions involve both inflammatory and immunodeficiency phenomena and both indications may co-exist, or arise at different times.

Replacement therapy

In general, replacement therapy is indicated for patients who have primary or secondary immunodeficiency diseases only if they have recurrent and/or severe infections and deficient or absent antibody production.

In rare cases, recurrent infection may be related to a functional failure of the immune system to mount protective antibody responses to antigenic challenge despite normal serum total IgG. This is most often demonstrated by a lack of antibody response to polysaccharide and/or protein vaccines (i.e. antigenic challenge). Infection risk in immunodeficiency may also be related to deficits in peripheral blood subpopulations of memory B-lymphocytes defined by flow cytometry. However, serum levels of individual subclasses of IgG1–4 are relatively poorly predictive of infection risk.

Isolated IgG subclass deficiency is not sufficient to warrant IVIg therapy (see Specific antibody deficiency).

With very rare exceptions, replacement therapy is not indicated for patients who have laboratory evidence of immunodeficiency in the absence of clinical infections (i.e. primary prevention of infection). This is for three reasons:

• the human immune system is characterised by the redundancy of host defence mechanisms;
• laboratory tests are imperfect in their prediction of immune function; and
• primary prevention strategies would impose an unnecessarily large burden on IVIg supply.

Exceptions to this rule include the severe combined primary immunodeficiencies of childhood.

Immunomodulation therapy

IVIg can interrupt the pathological immune responses that result in a wide range of human diseases, including various diseases of the immune system, the nervous system, the blood and blood- forming organs, and the skin. The immunomodulatory effects of IVIg are likely to be exerted by several mechanisms that appear to act in concert. These mechanisms, which are not fully understood, include the following:

• neutralisation of auto-antibodies;
• inhibition of complement binding and activation;
• effects mediated by Fc receptor binding;
• enhancing clearance of pathogenic auto-antibodies via saturation of the FcRn salvage pathway;
• suppression of pathogenic cytokines;
• neutralisation of super-antigens; and
• down-regulation of T or B cell function

In general, immunomodulatory doses of IVIg are higher than replacement doses and some of the immunomodulatory actions are dose-dependent.

For each immunomodulatory indication, qualifying criteria are described and review criteria are listed. The qualifying criteria should be applied in deciding whether and how to use IVIg. The review criteria are intended as a guide to clinicians who are assessing the effectiveness of IVIg therapy in individual patients and, in many instances, facing a decision to continue or cease IVIg therapy.

Dosing

The dosing of IVIg will vary, depending on whether IVIg is for replacement therapy or immunomodulation and the individual patient’s condition, clinical presentation, comorbidities, concurrent therapy and response. While there is some evidence for the use of dosing based on lean body weight, further research is required. The lowest dose for the shortest duration required to achieve the desired outcome should be chosen.

Research priorities

The systematic review of the available literature of treatment options for IVIg showed there was a paucity of high-quality studies. During the development of the Criteria and the 2010–11 Criteria Review, a number of gaps in knowledge and evidence were identified:

• The need to assess the efficacy of alternative approaches to determining IVIg dosing for specific conditions including lean body mass based dosing.
• The need for an improved database of agreed minimum data fields that include information on the treatment outcomes of IVIg.
• The need for a mechanism to review and analyse IVIg use for conditions with high use, high rate of growth and/or high variability in use.
• The role of subcutaneous immunoglobulin as an alternative to IVIg.

Maintenance

Governments recognise the need for the conditions identified for IVIg therapy and the clinical criteria for IVIg use to be reviewed regularly to take account of the evolving processes of disease diagnosis, treatment and outcome evaluation.