Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia

Latest online version of the Criteria

web capture of the Ig Criteria home pageAn adaptation of the second edition of the Criteria is applicable in BloodSTAR from its launch in July 2016. The Criteria as they appear in BloodSTAR can be viewed here.

During the BloodSTAR transition period, the addition of ‘new’ Criteria ‘evidence items’ fields does not change the basis for approval of authorisation of Ig product. Authorisers will evaluate authorisation requests with the same approach that applies to authorisation based on the use of previous paper forms. 

The Criteria for the clinical use of intravenous immunoglobulin in Australia Second Edition (IVIg Criteria Second Edition), released on 10 August 2012 is still current in those states that have not yet transitioned to BloodSTAR.

Download the Criteria

The Criteria for the clinical use of intravenous immunoglobulin in Australia Second Edition (IVIg Criteria Second Edition), released on 10 August 2012, supersedes the Criteria (2007).

(HTML)  (pdf)

The information and recommendations represent informed opinion, based where possible upon systematic review of the evidence. In the absence of published evidence, recommendations are based on clinical advice provided to the parties involved in developing the IVIg Criteria Second Edition.

Quick Reference Guide

To download the Quick Reference Guide developed to accompany the IVIg Criteria Second Edition, click on the links below.

 (HTML)    (pdf)

About the Criteria

IVIg is a precious biological product, and as such, its use should be consistent with the evidence base and prescribed for the treatment of patients who are likely to benefit from immunoglobulin therapy, and for whom there are no safe and effective alternative treatments. The Criteria for the Clinical Use of Intravenous Immunoglobulin (IVIg) in Australia (the Criteria) was first published 2007 to assist clinicians and transfusion medicine professionals to identify the conditions and circumstances for which the use of intravenous immunoglobulin (IVIg) is appropriate and funded under the National Blood Agreement.

The published criteria are not intended to be clinical practice guidelines. The information contained in the Criteria for the clinical use of intravenous immunoglobulin in Australia (the Criteria) intends only to provide information about criteria for accessing intravenous immunoglobulin funded under the national blood arrangements. Any advice relating to other forms of treatment relevant to the conditions in the Criteria have not been subject to a systematic review and should not be relied upon to guide treatment.

Patients and doctors should not use this information as a substitute for expert medical guidance and advice. The relevance and appropriateness of this information depends, amongst other things, on an accurate diagnosis, the severity of the condition being properly ascertained, the individual response to diagnostic tests and therapies, and other relevant circumstances in each case.

Inclusion of indications in the Criteria is based where possible upon systematic review of the evidence. In the absence of published evidence, information and access criteria are based on clinical advice provided to the development group by clinical colleges, clinical societies and individual experts.

Each person involved in developing the Criteria, and their employer where they are involved as an employee, or the organisation they represent where they are involved in a representative capacity, expressly disclaims and accepts no responsibility for any consequences arising from relying upon the information or recommendations contained herein.

The use of IVIg and the Criteria should be in line with the National Policy: Access to Government-Funded Immunoglobulin Products in Australia (the Policy).

Funding of Immunoglobulin Products under the National Blood Agreement

Several intravenous immunoglobulin products are currently registered on Therapeutic Goods Administration (TGA) Australian Register of Therapeutic Goods (ARTG) and are available for use in Australia.

While all products are assessed by the TGA against the same criteria, each manufacturer’s IVIg preparation is a unique product carrying its own specific evidence-based indications and safety profile. Information on individual products should be obtained from the TGA or the manufacturer.

There is not an exact alignment between TGA registered indications and the indications listed in the Criteria. Where safe and effective alternative therapies are available, the alternative product should be used in preference to IVIg.

In addition, IVIg is used to treat a growing number of diseases where immunomodulation or immunoglobulin replacement therapy is of benefit but the treatment indication does not have regulatory approval. Some of these uses of IVIg have a foundation in the medical literature and others are supported by clinical consensus but have a less conclusive basis in evidence.

Guided by policy objectives and aims in the National Blood Agreement, and under the National Blood Arrangements, governments have agreed to fund Immunoglobulin products for the conditions and indications described in the Criteria in one of three categories (previously listed in chapters 5-7 of the second edition of the Criteria):

  1. Conditions for which IVIg has an established therapeutic role (Chapter 5)

For these conditions, its use is supported by reasonable- quality evidence and expert opinion. For a number of conditions IVIg is first-line therapy in selected patients and may be the only established treatment option: for example, as replacement therapy in primary immunodeficiency disease.

  1. Conditions for which IVIg has an emerging therapeutic role (Chapter 6)

For these conditions, there is clinical support for IVIg use in selected patients, although the quality of evidence supporting use is variable. For many conditions, IVIg is considered only as second or third-line therapy when standard therapies have been proven to be ineffective, become intolerable, or are contraindicated. Many of these conditions are rare and as a result, the evidence of benefit is often patchy and inconclusive. Other conditions are more prevalent, yet the evidence of benefit is either conflicting or uncertain, requiring more research, or the use of IVIg represents a relatively new direction in their management and evidence of benefit is still emerging. For these conditions, the collection of effectiveness data is of particular importance.

  1. Conditions for which IVIg use is in exceptional circumstances only (Chapter 7)

These conditions rarely, if ever, require IVIg use, either because there are safe and effective alternative therapies, or because the evidence of benefit does not justify use in most cases. IVIg is considered to have a therapeutic role only in exceptional circumstances, such as in urgent or life-threatening circumstances, or in circumstances in which significant morbidity would be expected and other clinically appropriate therapies have been exhausted or are contraindicated.

Immunoglobulin funded under the National Blood Arrangements is not available to treat conditions identified in a further category (also previously described in the Second edition of the Criteria):

  1. Conditions for which IvIg is not supported (Chapter 8)

IVIg therapy for these conditions is not supported or funded at this time, either because there is evidence of no benefit, insufficient evidence of benefit, or some evidence of benefit but preferred alternative therapies are available.

For conditions not described in Categories I-III above, approved recipients may obtain IVIg via the Jurisdictional Direct Order component of the IVIg Standing Offer arrangement.

Development and key principles

The term ‘criteria for use’ was chosen specifically to indicate a more directive framework to describe the circumstances, based on evidence and clinical experience, under which the clinical use of IVIg is considered appropriate to be funded in Australia.

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:

  1. In 2004 and 2005, systematic literature reviews of the efficacy and risks of IVIg treatment were undertaken.
  2. 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.
  3. 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.
  4. In late 2006, a clinical workshop was conducted to seek input into the proposed proforma and content.
  5. Finally, the Criteria were revised based on the outcomes of workshop, additional information, and expert opinion for approval by health ministers in December 2007.

The development of the Criteria was based on the following key principles:

  • Where safe, effective and affordable alternative therapies exist, these are considered preferable to IVIg.
  • When IVIg is used, the lowest dose for the shortest duration required to achieve the desired outcome should be chosen.
  • For ongoing therapy, the achievement of measurable clinical outcomes is a requirement and IVIg should not be continued in patients with no demonstrable clinical benefit.

More information about the development and process for publication of the Criteria First Edition can be found in the document below.

Review of the Criteria

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

Another systematic review, of a limited number of indications, was undertaken in 2010-11 to update the Criteria to its second edition (or Version 2). This review resulted in the addition of a small number of indications, removal of a small number of indications and a rewording of a limited number of indications.

The NBA established a National IVIg Criteria Review Working Group (Working Group). The Working Group invited the clinical community to make submissions. The submissions were confined to suggestions for new indications, changes to existing indications or removal of indications. Each submission had to be supported by evidence. The Working Group reviewed the submissions. Some submissions required systematic review of published medical literature while others required only minor wording changes or the removal of indications. The NBA contracted an expert to conduct the systematic reviews of the medical literature. Other submissions required only minor wording changes.

Public consultation on the proposed revisions to the Criteria commenced on Saturday 25 June 2011 and closed on Friday 19 August 2011. Notification of the public consultation was advertised in The Weekend Australian on Saturday 25 August 2011 and on the National Blood Authority website. A direct email was also sent to all stakeholders involved in the review process, relevant colleges and societies and all individuals who registered their interest on the NBA website.

Following consideration of the submissions, the NICRWG presented their final proposed changes to Health Ministers in June 2012 via the Jurisdictional Blood Committee governance channels. Final approval was required by Health Ministers because the Criteria determines the indications for which IVIg is funded nationally by all Australian governments.

Further details of the arrangements and process for developing the second edition of the Criteria is provided below.

Adaptation of the Criteria for BloodSTAR

An adaptation of the second edition of the Criteria is applicable in BloodSTAR from its launch in July 2016. The Criteria as they appear in BloodSTAR can be viewed hereCurrently immunoglobulin requests are authorised against the second edition of the Criteria. The Criteria that has been uploaded into the new Blood System for Tracking Authorisations and Reviews (BloodSTAR) which is currently being rolled out to states and territories from June to December 2016 is based on an adaptation of the Criteria, Second Edition (or Version 2) and the current authorisation request forms.  The adaptation has been required because there were certain fields in the system that could not be populated directly from Version 2 either because they were absent or ambiguous, or only referred to indirectly.

During the BloodSTAR transition period, the addition of ‘new’ Criteria ‘evidence items’ fields does not change the basis for approval of authorisation of Ig product. Authorisers will evaluate authorisation requests with the same approach that applies to authorisation based on the use of previous paper forms.

Further details about the adaptation of the Criteria for BloodSTAR are provided below.

When will Version 3 of the Criteria be available? 

The Criteria is also currently undergoing a third review by Specialist Working Groups (SWGs) in Neurology, Haematology, Immunology and Transplantation. 
Public consultation on the proposed Chapter 5 and 6 changes to the Criteria closed at 5pm on Monday 27 July 2015. The SWGs reviewed all submissions and revised the Criteria as necessary before submission to the National Immunoglobulin Governance Advisory Committee (NIGAC) in November 2015. NIGAC endorsed the changes which were presented to the Jurisdictional Blood Committee for endorsement. The Jurisdictional Blood Committee approved these changes in 2015.

Following the full national rollout of BloodSTAR, Version 3 of the Criteria will be uploaded to BloodSTAR in 2017.  

The SWGs are currently addressing conditions in Chapters 7 and 8. The approach being undertaken includes:

  • A brief review of recent literature to confirm the status of evidence supporting the use of IVIg in  the condition
  • Draft the justification for evidence and diagnostic description sections
  • Develop qualifying and review criteria and define appropriate evidence items, parameters and authorisation values
  • Define the length of treatment and dosing types/ ranges to be used.

The Chapter 7 and 8 changes will be presented to the Jurisdictional Blood Committee for endorsement in September 2016, and be available for the release of the Criteria, third edition in BloodSTAR in 2017. 

Assessment of evidence

During the development of the first edition of the Criteria and the subsequent reviews, 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 first 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).

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.

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

Table 1 - Level of Evidence categories

 

Replacement and immunomodulation therapy and dosing

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.

For more information

You can get more information about the criteria and process from the Ig Governance Program team by phoning 13 000 IGGOV (13 000 44468) or by email: IgGovernance [at] blood.gov.au.