15_7_20_MSAC CA 1592 _PID_updated_tracked



Review of Immunoglobulin (Ig) for Primary Immunodeficiency Diseases (PID)with Antibody DeficiencyJuly 2020MSAC application no. 1592Contracted Assessment? Commonwealth of Australia 2019ISSN (Online) 1443-7139Internet site work is copyright. You may download, display, print and reproduce this material in unaltered form only (retaining this notice) for your personal, non-commercial use or use within your organisation. Apart from any use as permitted under the Copyright Act 1968, all other rights are reserved. Requests and inquiries concerning reproduction and rights should be addressed to Commonwealth Copyright Administration, Attorney-General's Department, Robert Garran Offices, National Circuit, Barton ACT 2600 or posted at copies of the report can be obtained from the Medical Service Advisory Committee’s Internet site at about the content of the report should be emailed to hta@.au.The technical information in this document is used by the Medical Services Advisory Committee (MSAC) to inform its deliberations. MSAC is an independent committee which has been established to provide advice to the Minister for Health on the strength of evidence available on new and existing medical technologies and procedures in terms of their safety, effectiveness and cost-effectiveness. This advice will help to inform government decisions about which medical services should attract funding under Medicare.MSAC’s advice does not necessarily reflect the views of all individuals who participated in the MSAC evaluation.This report was prepared by ASERNIP-S of the Royal Australasian College of Surgeons. Clinical advice was provided by the Immunoglobulin Review Reference Group. The report was commissioned by the Australian Government Department of Health. The suggested citation for this document is:Duncan, J., Forel, D., Gaget, V., Vandepeer, M., Tivey, D. Wendy, B. (2020). Immunoglobulin (Ig) for Primary Immunodeficiency Diseases (PID). MSAC Application 1592, Assessment Report. Commonwealth of Australia, Canberra, ACT. Contents TOC \o "1-3" \h \z \u Contents PAGEREF _Toc48222396 \h iiiTables PAGEREF _Toc48222397 \h viBoxes PAGEREF _Toc48222398 \h viiiFigures PAGEREF _Toc48222399 \h viiiExecutive Summary PAGEREF _Toc48222400 \h 9Alignment with agreed PICO Confirmation PAGEREF _Toc48222401 \h 10Proposed Medical Service PAGEREF _Toc48222402 \h 10Proposal for Public Funding PAGEREF _Toc48222403 \h 11Population PAGEREF _Toc48222404 \h 11Comparator Details PAGEREF _Toc48222405 \h 12Clinical management algorithm(s) PAGEREF _Toc48222406 \h 12Key Differences in the Delivery of the Proposed Medical Service and the Main Comparator PAGEREF _Toc48222407 \h 13Clinical Claim PAGEREF _Toc48222408 \h 13Approach Taken to the Evidence Assessment PAGEREF _Toc48222409 \h 13Characteristics of the Evidence Base PAGEREF _Toc48222410 \h 14Results PAGEREF _Toc48222411 \h 14Translation Issues PAGEREF _Toc48222412 \h 16Economic Evaluation PAGEREF _Toc48222413 \h 16Estimated Extent of Use and Financial Implications PAGEREF _Toc48222414 \h 17Consumer impact summary PAGEREF _Toc48222415 \h 18Other Relevant Considerations PAGEREF _Toc48222416 \h 18Acronyms and Abbreviations PAGEREF _Toc48222417 \h 20Section AContext PAGEREF _Toc48222418 \h 22A.1.Items in the agreed PICO Confirmation PAGEREF _Toc48222419 \h 22A.2.Medical Service PAGEREF _Toc48222420 \h 23Marketing status of technology PAGEREF _Toc48222421 \h 25Other Indications PAGEREF _Toc48222422 \h 27Current funding arrangements PAGEREF _Toc48222423 \h 28A.3.Proposal for Public Funding PAGEREF _Toc48222424 \h 28A.4.Population PAGEREF _Toc48222425 \h 28A.parator Details PAGEREF _Toc48222426 \h 33A.6.Clinical management Algorithms PAGEREF _Toc48222427 \h 33A.7.Key Differences in the Delivery of the Proposed Medical Service and the Main Comparator PAGEREF _Toc48222428 \h 35A.8.Clinical Claim PAGEREF _Toc48222429 \h 35A.9.Summary of the PICO PAGEREF _Toc48222430 \h 35A.10.Consumer impact statement PAGEREF _Toc48222431 \h 36Section BClinical Evaluation PAGEREF _Toc48222432 \h 38B.1.Literature Sources and Search Strategies PAGEREF _Toc48222433 \h 38B.2.Results of Literature Search PAGEREF _Toc48222434 \h 38Study selection PAGEREF _Toc48222435 \h 40Clinical trials search PAGEREF _Toc48222436 \h 41Appraisal of the evidence PAGEREF _Toc48222437 \h 41B.3.Risk of Bias Assessment PAGEREF _Toc48222438 \h 41B.4.Characteristics of the Evidence Base PAGEREF _Toc48222439 \h 42B.5.Outcome Measures and Analysis PAGEREF _Toc48222440 \h 55B.6.Results of the Systematic Literature review PAGEREF _Toc48222441 \h 57Is it safe? PAGEREF _Toc48222442 \h 57Is it effective? PAGEREF _Toc48222443 \h 62Comparative effectiveness PAGEREF _Toc48222444 \h 62Case series pre/post effectiveness data PAGEREF _Toc48222445 \h 65Supplementary evidence: Studies comparing IVIg to IMIg or SCIg PAGEREF _Toc48222446 \h 70Supplementary evidence: What do existing systematic reviews say? PAGEREF _Toc48222447 \h 72B.7.Extended Assessment of Harms PAGEREF _Toc48222448 \h 77B.8.Interpretation of the Clinical Evidence PAGEREF _Toc48222449 \h 78Section CTranslation Issues PAGEREF _Toc48222450 \h 81Section DReview of Economic Evaluations PAGEREF _Toc48222451 \h 82D.1.Overview PAGEREF _Toc48222452 \h 82D.2.Existing evidence PAGEREF _Toc48222453 \h 82Literature search and selection PAGEREF _Toc48222454 \h 82Key characteristics of the costing studies included PAGEREF _Toc48222455 \h 84Applicability to the Australian clinical context PAGEREF _Toc48222456 \h 89Feasibility of conducting model-based economic evaluation PAGEREF _Toc48222457 \h 90D.3.Variables used in the cost consequence analysis PAGEREF _Toc48222458 \h 91The cost of Ig and its administration PAGEREF _Toc48222459 \h 91The cost of Management of PID Related conditions PAGEREF _Toc48222460 \h 94D.4.Results of the cost consequence analysis PAGEREF _Toc48222461 \h 97Cost consequence analysis PAGEREF _Toc48222462 \h 97Sensitivity analyses on the cost consequence analysis PAGEREF _Toc48222463 \h 97Section EFinancial Implications PAGEREF _Toc48222464 \h 100E.1 Justification of the Selection of Sources of Data PAGEREF _Toc48222465 \h 100E.2 Use and cost of Ig for PID PAGEREF _Toc48222466 \h 101E.2.1 Number of patients with the medical condition PAGEREF _Toc48222467 \h 101E.2.2 Costs of Ig delivery PAGEREF _Toc48222468 \h 106E.3 Sensitivity analyses PAGEREF _Toc48222469 \h 108Section FOther relevant considerations PAGEREF _Toc48222470 \h 110Appendix AClinical Experts and Assessment Group PAGEREF _Toc48222471 \h 111Assessment group PAGEREF _Toc48222472 \h 111Appendix BSearch strategies PAGEREF _Toc48222473 \h 112Bibliographic databases PAGEREF _Toc48222474 \h 112Additional sources of literature PAGEREF _Toc48222475 \h 112Search Terms Used in Economic Review PAGEREF _Toc48222476 \h 113Appendix CStudies included in the Systematic Review PAGEREF _Toc48222477 \h 115Appendix DEvidence Profile Tables PAGEREF _Toc48222478 \h 125Appendix EExcluded Studies PAGEREF _Toc48222479 \h 126Cohort studies not reporting Ig outcomes (n = 10) PAGEREF _Toc48222480 \h 126Non-randomised studies comparing Ig to Ig (n = 73) PAGEREF _Toc48222481 \h 127Single arm studies on PID other than CVID (n = 164) PAGEREF _Toc48222482 \h 134Appendix F Clinical Trials Searches PAGEREF _Toc48222483 \h 154References PAGEREF _Toc48222484 \h 195Tables TOC \h \z \c "Table" Table 1 Ig usage, patient and episode numbers for PID with antibody deficiency in 2018-19 (NBA, 2019) PAGEREF _Toc45800566 \h 12Table 2 Balance of clinical benefits and harms of intervention, relative to comparator, and as measured by the critical patient-relevant outcomes in the key studies PAGEREF _Toc45800567 \h 15Table 3Total Ig costs including delivery PAGEREF _Toc45800568 \h 17Table 4 Sensitivity analyses considering only Ig costs (not delivery) PAGEREF _Toc45800569 \h 17Table 5 Approved Ig dosage for replacement therapy in patients with PID with antibody deficiency (per indication) according to the Criteria Version 3 (NBA, 2018) PAGEREF _Toc45800570 \h 24Table 6Ig products indicated for PID listed on the ARTG according to the Referral Form (Table 1; page 6) PAGEREF _Toc45800571 \h 26Table 7 Top 10 medical conditions for which Ig was issued in 2017-18(NBA, 2017-18) PAGEREF _Toc45800572 \h 27Table 8 Ig usage, patient and episode numbers for PID with antibody deficiency in 2018-19 (NBA, 2019) PAGEREF _Toc45800573 \h 32Table 9Search terms used for the PubMed and Embase searches PAGEREF _Toc45800574 \h 38Table 10Additional study selection criteria PAGEREF _Toc45800575 \h 39Table 11Potential applicability issues identified PAGEREF _Toc45800576 \h 44Table 12Diagnostic criteria used in the studies PAGEREF _Toc45800577 \h 46Table 13Characteristics of the comparative studies PAGEREF _Toc45800578 \h 48Table 14Characteristics of the single-arm studies of patients with CVID PAGEREF _Toc45800579 \h 49Table 15Summary of safety data PAGEREF _Toc45800580 \h 59Table 16 Number of infections, hospital admissions, bronchiectasis, missed days from school or work and deaths in Ig-treated and untreated CVID patients PAGEREF _Toc45800581 \h 63Table 17 Infectious and non-infectious complications among Ig-treated (early diagnosis) and untreated (delayed diagnosis) CVID patients PAGEREF _Toc45800582 \h 63Table 18Summary of effectiveness results PAGEREF _Toc45800583 \h 66Table 19Characteristics of the systematic reviews PAGEREF _Toc45800584 \h 73Table 20Balance of clinical benefits and harms of intervention, relative to comparator, and as measured by the critical patient-relevant outcomes in the key studies PAGEREF _Toc45800585 \h 79Table 21Selection criteria for literature review PAGEREF _Toc45800586 \h 83Table 22The key characteristics and evidence profile presented in the included model-based studies PAGEREF _Toc45800587 \h 84Table 23Key study characteristics for budgetary analysis for PID patients PAGEREF _Toc45800588 \h 86Table 24PID population projected via different methods PAGEREF _Toc45800589 \h 103Table 25Ig usage split for PID patients PAGEREF _Toc45800590 \h 104Table 26Average dosage per person of Ig by sources and types PAGEREF _Toc45800591 \h 104Table 27Unit cost of Ig by sources and types PAGEREF _Toc45800592 \h 105Table 28Cost projection of IVIg for PID from 2021 to 2025 PAGEREF _Toc45800593 \h 105Table 29Cost projection of SCIg for PID from 2021 to 2025 PAGEREF _Toc45800594 \h 106Table 30Total Ig cost projection from 2021 to 2025 PAGEREF _Toc45800595 \h 106Table 31Costs associated with Ig delivery via the intravenous route (IVIg) PAGEREF _Toc45800596 \h 107Table 32Total Ig costs including delivery PAGEREF _Toc45800597 \h 108Table 33Sensitivity analyses considering only Ig costs (not delivery) PAGEREF _Toc45800598 \h 109Table 34Profiles of comparative studies on Ig replacement therapy in patients with PID included in the systematic literature review PAGEREF _Toc45800599 \h 115Table 35Profiles of single arm cohort studies assessing the safety and effectiveness of Ig replacement therapy for patients diagnosed with CVID PAGEREF _Toc45800600 \h 117Table 36Risk of bias of the comparative study Aghamohammadi et al. (2009) using the ROBINS-1 tool (Sterne et al., 2016): PAGEREF _Toc45800601 \h 121Table 37Quality appraisal of the selected case series studies using the IHE assessment tool. PAGEREF _Toc45800602 \h 122Table 38Evidence profile table example 1 for Ig compared to no treatment for patients with CVID PAGEREF _Toc45800603 \h 125Table 39Search terms used for and ANZCTR searches PAGEREF _Toc45800604 \h 154Table 40Identified trials in patients with PID. PAGEREF _Toc45800605 \h 154Boxes TOC \h \z \c "Box" Box 1Criteria for identifying and selecting studies to determine the safety of Ig in patients with PID with antibody deficiency PAGEREF _Toc48222485 \h 36Box 2Criteria for identifying and selecting studies to determine the effectiveness of Ig in patients with PID with antibody deficiency PAGEREF _Toc48222486 \h 36Figures TOC \h \z \c "Figure" Figure 1Clinical management algorithm for initial access to Ig for patients with PID with antibody deficiency. PAGEREF _Toc48222487 \h 34Figure 2Clinical management algorithm for continued access to Ig for patients with PID with antibody deficiency. PAGEREF _Toc48222488 \h 34Figure 3Clinical management for patients with PID with antibody deficiency in the absence (or failure) of Ig. PAGEREF _Toc48222489 \h 35Figure 4 Summary of the process used to identify and select studies for the assessment PAGEREF _Toc48222490 \h 40Figure 5PID patient numbers projected by specific PID subtypes PAGEREF _Toc48222491 \h 102Figure 6Total PID patient projection via different methods PAGEREF _Toc48222492 \h 103Executive SummaryMain issues for MSAC considerationIg was generally associated with mild adverse events. Severe events are rare and mostly resolved by treatment cessation. Ig was associated with lowered infection rates, (including upper and lower respiratory tract infections, pneumonia, otitis media, sinusitis and diarrhoea) lower hospitalisation rates and higher IgG levels.Data on the safety and effectiveness of Ig in patients with PID is limited, at high risk of bias and rated as low-very low quality for effectiveness outcomes.Despite the significant limitations associated with the evidence base, it is unlikely that higher quality studies addressing these issues will be forthcoming. The Assessment group has identified potential areas for future research for patients with PID in Australia: From a clinical effectiveness point of view, research into the impact of co-interventions on outcomes would be helpful to resolve the confounding issues identified in the evidence base. It may be useful to establish a registry or database for PID patients and document the treatment(s) they are receiving. This would be helpful to understand Ig therapy coverage and true population prevalence in Australia.It would be beneficial to have more granular information on how Ig is used for PID in Australia. Ideally, future research would focus on each PID subgroup separately and be aimed to answer the questions such as; usage patterns for children compared to adults, how disease severity may impact Ig usage, patterns of Ig usage, trial periods off Ig and which patients successfully stop or reduce their Ig usage. Immunoglobulin (Ig) for Primary Immunodeficiency Diseases (PID) with Antibody Deficiency This Assessment of immunoglobulin (Ig) for the treatment of primary immunodeficiency diseases (PID) with antibody deficiency is intended for the Medical Services Advisory Committee (MSAC). Immunoglobulin replacement therapy for this indication is presently funded by the National Blood Authority (NBA) under the national blood supply arrangements, but the cost-effectiveness of this use has not previously been established. The target population is people with PID currently eligible for Ig treatment under the Criteria for Clinical Use of Immunoglobulin in Australia (herein described as ‘the Criteria Version 3’)Alignment with agreed PICO ConfirmationThis Assessment of Ig for the treatment of PID with antibody deficiency addresses most of the PICO elements that were pre-specified in the PICO Confirmation that was ratified by the Immunoglobulin Review Reference Group. Insufficient comparative evidence in patients with PID was identified; therefore, the Assessment also includes single arm studies. These were limited to patients with common variable immune deficiency (CVID) in accordance with the PICO Confirmation.Proposed Medical ServiceThe intervention under review is Ig for immunoreplacement therapy in people with PID with antibody deficiency. Ig replacement therapy is a blood-based treatment whereby Ig is administered into the bloodstream of a person with PID in order to provide them with the antibodies needed to adequately fight infections.In Australia, Version 3.1 of the Criteria Version 3 outlines which patients are eligible for Government funded Ig treatment. The Criteria Version 3 provides a list of medical conditions and specific circumstances around entitlement for publicly funded Ig treatment, as well as an outline of the approved Ig dosage and recommended duration of use. REF _Ref27399792 \h \* MERGEFORMAT Table 5 (Section A.2.) summarises the approved dosage and medical review conditions described in the Criteria Version 3 for patients with PID with antibody deficiency. Ig can be delivered in one of two ways; intravenously (IVIg) or via subcutaneous injection (SCIg), both of these administration methods are used for publicly funded Ig in Australia. The main difference between the two delivery methods is that IVIg requires venous access, can deliver larger volumes (therefore fewer doses) and is carried out by skilled healthcare professionals in a hospital setting. SCIg, which delivers smaller volumes, may be self-administered at home (following appropriate training by a registered nurse or technician).Ig products used for replacement therapy in PID are funded under the National Blood Authority (NBA). The NBA has contracts with suppliers to source products both domestically (from plasma collected by the Australian Red Cross Blood Service) and through a range of international suppliers. The sixteen Ig items on the ARTG that are relevant to this application are shown in REF _Ref364240778 \h \* MERGEFORMAT Table 6 (Section A.2.).Proposal for Public FundingThere are no proposed MBS items relevant to this Assessment. PopulationPID refers to a large heterogeneous group of disorders where one or more components of the immune system is compromised, leading to absent or impaired immune function. The specific conditions (as diagnosed by an Immunologist) described in the Criteria Version 3 for patients with PID with antibody deficiency to be eligible for publicly funded Ig treatment in Australia are:Severe combined immunodeficiency (SCID)Combined immunodeficiency (e.g. thymoma)Combined immunodeficiency with associated or syndromal featuresCommon variable immunodeficiency (CVID)Possible CVID – below normal serum IgG but normal serum IgASevere reduction in all Ig isotypes with decreased or absent B-cellsSevere reduction in at least two Ig isotypes with low/normal B-cells (e.g. CVID)Severe reduction in serum IgG and IgA with normal/elevated IgMTransient hypogammaglobulinaemia of infancyLymphoproliferative syndromesPeople with immunodeficiency disorders are prone to infection (increased frequency and severity), abnormal inflammation, cancer and autoimmune diseases. PID are considered rare disorders; however, their true incidence and prevalence (individually or collectively) is unknown. The Australasian Society of Clinical Immunology and Allergy PID Register conducted a cumulative, cross-sectional survey of PID patients in Australia and New Zealand and identified 1,209 patients across 88 centres and 56 PID syndromes ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>14</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007b)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578269087">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, P.</author><author>Riminton, S.</author></authors></contributors><auth-address>Department of Immunology, Concord Hospital, Sydney, Australia.</auth-address><titles><title>Primary immunodeficiency diseases in Australia and New Zealand</title><secondary-title>J Clin Immunol</secondary-title><alt-title>Journal of clinical immunology</alt-title></titles><alt-periodical><full-title>Journal of Clinical Immunology</full-title></alt-periodical><pages>517-24</pages><volume>27</volume><number>5</number><edition>2007/06/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Australia/epidemiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/therapeutic use</keyword><keyword>Immunologic Deficiency Syndromes/drug therapy/*epidemiology/immunology</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>New Zealand/epidemiology</keyword><keyword>Prevalence</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0271-9142 (Print)&#xD;0271-9142</isbn><accession-num>17588141</accession-num><urls></urls><electronic-resource-num>10.1007/s10875-007-9105-z</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kirkpatrick and Riminton, 2007b). Based on these data the estimated prevalence of PID was 5.6 cases per 100,000 population for Australia. However, using 2018-19 data on Ig use for PID provided by the NBA, the prevalence of PID is calculated as being approximately 9.09 per 100,000 population. The differences between these prevalence estimates over the past 20 years may be due to one or more reasons such as: increasing diagnostic capabilities; changes in disease definitions; or improved access to treatments. It is also important to note that PID patients (diagnosed or undiagnosed) who are not on Ig therapy are not included in the Ig usage data from the NBA. Consequently, the NBA data might underestimate the total (potentially eligible) population in Australia with PID. REF _Ref34208916 \h \* MERGEFORMAT Table 1 describes the number of patients in 2018/19 accessing Ig therapy funded by the NBA. The total number of patients treated for that period was 2,292.Table SEQ Table \* ARABIC 1 Ig usage, patient and episode numbers for PID with antibody deficiency in 2018-19 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019)Specific condition nameIg usage (grams)Patient countTreatment episodesTotal Private Public SCID10,4964255086464CID1,094852151Wiskott-Aldrich syndromeA 8455521339CVID639,1091,84726,5905,74020,850Possible CVID7,8015531971248Severe reduction in all Ig isotypes with decreased or absent B-cells826533-33X-linked agammaglobulinaemiaB40,2211181,7252111,514Severe reduction in at least two Ig isotypes with low/normal B-cells 9,5606750468436Severe reduction in serum IgG and IgA with normal/elevated IgM 308216511Transient hypogammaglobulinaemia of infancy3323301317Lymphoproliferative syndromes 348115-15Other PID35,3771391,7412671,474TOTAL746,3162,29231,6276,47525,152Source: Personal Communication from National Blood Authority: Phase 2 HTA conditions, received January 2020. ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019) Abbreviations: CID: combined immunodeficiency; CVID: Common variable immunodeficiency; Ig: immunoglobulin; Ig A: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; SCID: severe combined immunodeficiency.Notes: A = Wiskott-Aldrich syndrome is one example of CID with syndromal features. B = X-linked agammaglobulinaemia is one example of a PID where all Ig isotypes are reduced, and B-cells are decreased/absent. Comparator Details The comparator for Ig replacement therapy for the treatment of PID with antibody deficiency in this Assessment is no Ig (no active treatment). This may or may not include supportive care including antibiotic treatment, prophylactic antibiotics and antimicrobials. The Immunoglobulin Review Reference Group, when advising on the Referral Form, agreed that given the heterogeneous patient group comprising PID with antibody deficiency, ‘no Ig’ is the most appropriate comparator for this condition (PICO Confirmation page 18). The Immunoglobulin Review Reference Group also confirmed that there are no active comparators to IVIg for the treatment of PIDs available in Australia (PICO Confirmation page 18).Clinical management algorithm(s) REF _Ref27380868 \h \* MERGEFORMAT Figure 1 and REF _Ref29991544 \h \* MERGEFORMAT Figure 2 (Section A.6.) describe the current management of patients with PID with antibody deficiency using IVIg, funded by the National Blood Authority (for initial access to Ig and continued access to Ig, respectively). For eligible patients, Ig therapy is funded for 6 months, at which point a review by an immunologist is required. REF _Ref29991575 \h \* MERGEFORMAT Figure 3 (section A.6.) describes the current management of patients with PID with antibody deficiency, where IVIg is not a treatment option. This is either due to contraindications or ineligibility according to the Criteria Version 3 (including patients who were previously eligible for treatment under the Criteria Version 3 but are no longer, for example, due to treatment failure). For these patients, best supportive care is the only treatment available. Key Differences in the Delivery of the Proposed Medical Service and the Main Comparator The main comparator for Ig therapy, for the purposes of this Assessment, is no Ig. The way in which Ig therapy is delivered has been described above. For the comparator (no Ig) standard of care may or may not include supportive treatment including antibiotics and antimicrobials. Clinical ClaimThe following clinical claims have been made regarding Ig use for the treatment of PID with antibody deficiency:Ig has superior effectiveness and inferior safety compared to no Ig.Approach Taken to the Evidence AssessmentA systematic review of published literature was undertaken on 20/11/2019 (PubMed) and 25/11/2019 (Embase) to identify relevant published studies and systematic reviews. Searches were conducted of the databases and sources described in Appendix B. Search terms are described in Section B.1.A PRISMA flowchart (Figure 2, Section B.2.) provides a graphic depiction of the results of the literature search and the application of the study selection criteria. Comparative studies on the safety and effectiveness of Ig in patients with PID were included. Single arm studies on patients with CVID were also included in accordance with the PICO Confirmation. The searches identified four comparative studies, seventeen single arm studies providing pre- and post-Ig treatment data and/or Ig safety data.A profile of each included study is given in REF _Ref364237249 \h \* MERGEFORMAT Appendix C and summarised in Section B.4. Supplementary evidence is presented at the end of Section B.6. This evidence does not directly inform on the comparative safety and effectiveness of Ig compared to no treatment in patients with PID; however, it is evidence that the Assessment Group felt provided additional context on the use of Ig to treat PID which may be of interest to the Immunoglobulin Review Reference Group, MSAC and the NBA. Risk of bias was assessed using the Cochrane ROBINS-1 tool for the comparative studies and the Institute of Health Economics quality appraisal tool for the case series studies. GRADE methodology was used to appraise the overall quality of the evidence base for each outcome.Characteristics of the Evidence BaseFour non-randomised comparative studies and seventeen case series studies were identified for inclusion in this Assessment. The characteristics of the evidence base are detailed in Section B.4. All the included studies were at high risk of bias and several potential applicability issues were identified:The evidence only included patients with CVIDThe age of patients was markedly lower than the average age of CVID patients receiving Ig funded by the NBAThe included studies used a different diagnostic criterion to those listed in The Criteria Version 3The included studies only reported results for IVIg; SCIg is also used for PID in AustraliaCo-interventions and other confounding factors were rarely reported or adequately assessed. ResultsSafety No comparative safety data was identified. Given the comparator is ‘no treatment’ there are not expected to be any safety issues relevant to the comparator.Ig use was associated with mostly mild adverse events (chills, flushing, fever, nausea, headache, muscle ache, mild anxiety, pharyngolaryngeal pain, fatigue and hypotension) occurring in 14% to 67% of patients and 2% to 22% of infusions.Moderate events (rash, severe headache, abdominal pain, joint pain, chest tightness, vomiting, wheezing and mild dyspnoea) occurred in 6.7% to 24% of patients and 0.2% to 1.5% of infusions and were resolved by slowing or stopping the infusions.Severe events (severe chest pain, severe wheezing/breathlessness, severe headache, severe dizziness, tightness of the throat pressure in the chest sensation, collapse and moderate events that were persistent and could not be prevented by pre-infusion treatment with steroids and antihistamines) were rare occurring in 0% to 5% of patients and 0% to 0.2% of infusions. These events required adrenaline, hospitalisation, withdrawal of treatment, or changing to SCIg administration.Effectiveness One comparative study was identified which retrospectively compared a group of patients on Ig treatment to a group of patients not on Ig treatment due to delayed diagnosis. IVIg treatment was associated with improved patient outcomes (including lower infection rates, hospital admissions, bronchiectasis and mortality). This study was assessed as being at high risk of bias.Data from single arm studies of patients with CVID comparing pre- and post-treatment outcomes reported consistent findings. The post-Ig outcomes (infection rates, IgG levels and hospitalisation rates) were improved compared to those measured pre-Ig treatment.Data from three studies reporting a mean age similar to that of Australian patients receiving NBA-funded Ig were consistent with the overall results of the Assessment. All three studies reported that Ig use was associated with reductions in infection rate compared to pre-treatment rates.Supplementary evidence from one RCT and five systematic reviews of observational studies found SCIg was at least non-inferior to IVIg. Therefore, it was considered reasonable to extrapolate the results of this review to patients on SCIg therapy for CVID. SCIg may be associated with high rates of minor local adverse events at the infusion site but lower rates of systemic adverse events.Key issues with the evidence base were identified which may have a substantial effect on effectiveness results. Confounding factors and co-interventions were generally not reported and not investigated; therefore, it is not clear how these influence results. Unadjusted co-intervention use may bias results in favour of Ig. Most studies were retrospective; it was not clear that all patient information was captured consistently and comprehensively. Further, it was not clear if any eligible patients were excluded from analysis. The impact these issues may have on results is uncertain. Despite the significant limitations associated with the evidence base, it is unlikely that higher quality studies will be forthcoming to investigate the comparative effectiveness of Ig therapy in patients with PID. No relevant upcoming clinical trials were identified, and due to the low incidence of PID, recruiting enough patients for a large prospective trial may not be feasible and/or ethical. The summary of findings is shown in REF _Ref421184437 \h \* MERGEFORMAT Table 2.Table SEQ Table \* ARABIC 2Balance of clinical benefits and harms of intervention, relative to comparator, and as measured by the critical patient-relevant outcomes in the key studies Outcome(units, follow-up)No. of studies and study designRisk of biasEffect Ig Effect no treatment QualityImportanceAdverse eventsfollow up: range 1 years to 12 years (count)8 observational studiesSerious184/434 (42.4%)NA????Moderate qualityCriticalSerious adverse events (count)5 observational studiesSerious20/519 (3.9%)NA????Moderate qualityCriticalLower respiratory infection rates (per patient per year)8 observational studiesVery seriousRange of means0.16-0.34Range of means0.28-2.04????Very low qualityCriticalIgG trough levels (mg/dl)7 observational studiesSeriousRange of means455-891Range of means195-416????Low qualityCriticalHospitalisations (per patient per year)4 observational studiesVery seriousRange of means0.13-0.7Range of means1.35-3.4????Very low qualityCriticalAbbreviations: Ig: immunoglobulin, IgG: immunoglobulin G, NA: not applicable. Source: GRADE Working Group grades of evidence (Guyatt et al., 2013)???? High quality: We are very confident that the true effect lies close to that of the estimate of effect. ???? Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ???? Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. ???? Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.On the basis of the benefits and harms reported in the evidence base (summarised above), it is suggested that, relative to no treatment, Ig has inferior safety and may have superior effectiveness noting that there is only low- to very low-quality evidence available to support these conclusions.Translation IssuesTranslation of the clinical evidence was not undertaken.Economic EvaluationTo understand the cost-effectiveness profile of Ig replacement therapy for PID patients, a review of literature on published economic evaluations were conducted. Results of the literature review were used to inform feasibility of performing a model-based economic evaluation. The literature searches and selection identified 15 relevant studies where six were model-based economic evaluations, six were cost analyses on disease burden and budgetary impact, and the remaining three were reviews of economic studies. None of the identified studies compared Ig use to non-Ig standard care for PID patients. Comparative studies were all focused on how IVIg and SCIg is compared in terms of clinical and economic outcomes. Despite the diversity in modelling approaches and evaluation results, there was a consistent finding across all studies: SCIg is likely to be substantially more cost-effective compared to IVIg. Given the limitations with the available evidence , it was determined in consultation with the Immunoglobulin Review Reference Group that conducting a modelled economic evaluation comparing Ig and non-Ig standard of care would not be feasible or meaningful for decision-making. Furthermore, as Ig use for patients with PID is considered to be the standard clinical management strategy (particularly for patients with common subtypes of PID including common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA)) further evidence for ‘no Ig’ use (required to populate an economic model) is unlikely to be forthcoming. A simplified cost-consequence (CCA) analysis was conducted to estimate the economic impact of Ig for PID patients. The CCA was limited to a one-year time horizon and considered the cost differences between Ig and no Ig in terms of Ig itself, Ig administration costs, and the incremental costs of treating serious infections and managing bronchiectasis. The overall incremental cost was estimated at $18,281.01 per year per patient, driven largely by the direct cost of Ig (with some cost offsets associated with avoidance of hospitalisations due to serious infections). More detailed results are provided in Section D.4 together with sensitivity analyses around uncertainties in the cost estimates for managing serious infections and bronchiectasis.Estimated Extent of Use and Financial ImplicationsFinancial estimates are primarily based on the Ig usage figures from the past two financial years (2017 to 2019) provided by the NBA, as well as externally sourced epidemiological studies conducted in Australia. The base case relies on the population prevalence for PID of 9.09 per 100,000 Australians, projected over five years assuming annual population growth of 1.5%. The total Ig costs, including delivery costs, are summarised in REF _Ref395200110 \h \* MERGEFORMAT Table 3.Table SEQ Table \* ARABIC 3Total Ig costs including deliveryFY20212022202320242025SourceCalculation referenceIVIg number18051832186018881916 REF _Ref41572303 \h Table 25ASCIg number570579587596605 REF _Ref41572303 \h Table 25BTotal cost of Ig delivery$6,879,371$6,982,561$7,087,300$7,193,609$7,301,513CalculatedC Ig product costs $43,566,409$44,219,905$44,883,204$45,556,452$46,239,799 REF _Ref41572655 \h Table 30DGrand total of Ig for PID patients$50,445,780$51,202,467$51,970,504$52,750,061$53,541,312Calculated E = C + D% of delivery from the total 13.64%13.64%13.64%13.64%13.64%Calculated F = C ÷ EAbbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearSensitivity analyses were conducted to test assumptions in patient number estimates, the price of Ig and Ig dosage. These are summarised in the table below.Table SEQ Table \* ARABIC 4Sensitivity analyses considering only Ig costs (not delivery)Year20212022202320242025Base caseIg cost alone$43,566,409$44,219,905$44,883,204$45,556,452$46,239,799Ig cost aloneSensitivity analysisPID patients via Method 2Uncertainty range by Method 1 and Method 3$41,896,385($40.5m, $47.9m)$41,849,003($40.0m, $49.9m)$41,801,621($39.5m, $51.9m) $41,754,239($39.1m, $53.8m)$41,706,857($38.5m, $55.8m)Price of Ig at lowest cost ($44.94)$32,409,774$32,895,920$33,389,359$33,890,200$34,398,553Price of Ig at highest ($140.18)$101,094,839$102,611,262$104,150,431$105,712,687$107,298,378Price of Ig at weighted average ($94.51)$68,158,605$69,180,984$70,218,699$71,271,980$72,341,05910% increase in dosage$47,923,050$48,641,896$49,371,524$50,112,097$50,863,77910% decrease in dosage$39,209,768$39,797,915$40,394,884$41,000,807$41,615,819Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearConsumer impact summaryThe draft Referral Form was released for Targeted Consultation in August 2019 and the PICO Confirmation was released to Sponsor companies in December 2019. Four submissions were received; three from industry and one from a consumer group. Overall, both industry and the consumer group were supportive of the use of Ig to treat PID as set out by the Criteria Version 3 and depicted in the Referral Form. Industry discouraged further limitation to access of Ig in Australia and expressed concerns about the feasibility of conducting clinical comparisons across a highly heterogeneous population and the Assessment’s ability to draw meaningful conclusions. One sponsor provided feedback on the approach outlined in the PICO Confirmation and was supportive of the approach noting that allogenic transplantations may be a relevant comparator to Ig and there were 26 such transplants performed in Australia in 2016. The consumer representative was highly supportive of Ig therapy for PID; and provided personal examples of significant improvements in quality of life. Noted disadvantages included adverse events, regular attendance to hospital for Ig infusions, and time spent travelling and waiting due to delays in day units. However, consumers considered that the advantages of Ig therapy outweigh any potential disadvantages.Other Relevant ConsiderationsThe Assessment group has identified the following areas for future research on PID in Australia:Currently, most evidence considers all forms of PID together; having studies that report data separately for each subtype would be informative. This may be difficult due to the rare nature of these conditions. From a clinical effectiveness point of view, research into the impact of co-interventions on outcomes would be helpful to resolve the confounding issues identified in the evidence base. More broadly, it may be useful to establish a registry or database for PID patients and document the treatment(s) they are receiving. This would be helpful to understand Ig therapy coverage and true population prevalence in Australia.It would be beneficial to have more granular information on how Ig is used for PID in Australia. Ideally, future research would focus on each PID subgroup separately and be aimed to answer the questions such as:Is there any difference is usage patterns for children compared to adults? Does severity of disease impact Ig usage? Which patients are trialling periods off Ig and which of these patients are able to successful stop or reduce Ig usage? Is the pattern of Ig usage consistent over time for each PID subtype?Acronyms and Abbreviations Acronym/abbreviationMeaningAIHWARAGAustralian Institute of Health and Welfareautosomal recessive agammaglobulinemiaARTGAustralian Register of Therapeutic GoodsCD40LCD40 ligandCIconfidence intervalCIDcombined immunodeficiency CVIDcommon variable immunodeficiencyHESPHealth Expert Standing PanelHRQoLHealth-Related Quality of LifeHTAHealth Technology AssessmentICERIncremental Cost-Effectiveness RatioIgimmunoglobulin IgAimmunoglobulin AIgEimmunoglobulin EIgGimmunoglobulin GIgMimmunoglobulin MIMIgintramuscular immunoglobulin IVIgintravenous immunoglobulinLPSlymphoproliferative syndromesMAmeta-analysisMBSMedicare Benefits ScheduleMDmean differenceMSACMedical Services Advisory CommitteeNHMRCNational Health and Medical Research CouncilNKnatural killerPASCPICO Confirmation Advisory Sub-Committee of the MSACPIDprimary immunodeficiency diseasesQALYQoLQuality Adjusted Life YearQuality of lifeRCTrandomised controlled trialsSBIserious bacterial infectionSCIDsevere combined immunodeficiency SCIgsubcutaneous immunoglobulinTGATherapeutic Goods AdministrationTHItransient hypogammaglobulinaemia of infancy WASWiskott-Aldrich Syndrome XLAX-linked agammaglobulinaemia Section AContextThis Assessment of immunoglobulin (Ig) for the treatment of primary immunodeficiency diseases (PID) with antibody deficiency is intended for the Medical Services Advisory Committee (MSAC). MSAC evaluates new and existing health technologies and procedures in terms of their safety, effectiveness and cost-effectiveness, while taking into account other issues such as access and equity. MSAC adopts an evidence-based approach to its assessments, based on reviews of the scientific literature and other information sources, including clinical expertise.Immunoglobulin replacement therapy for this indication is presently funded by the National Blood Authority (NBA) under the national blood supply arrangements, but the cost-effectiveness of this use has not previously been established. As of 2017, the National Blood Agreement provides for MSAC to undertake evidence-based evaluation of blood products funded under the national blood supply arrangements at the request of the Jurisdictional Blood Committee (JBC). All Australian Governments, through the JBC, have agreed to conduct robust Health Technology Assessments of immunoglobulin use (Ig Reviews) funded under the National Blood Agreement. The Australian Government Department of Health has convened an Immunoglobulin Review Reference Group to provide advice to the Ig Reviews. The Population, Intervention, Comparator, Outcome (PICO) Confirmations for these products have been considered by the Immunoglobulin Review Reference Group instead of the PICO Advisory Sub-committee (PASC). Otherwise, the MSAC evaluation process remains the same as for applications for funding of new items on the Medical Benefits Schedule (MBS).ASERNIP-S, of the Royal Australasian College of Surgeons, has been commissioned by the Department of Health to conduct a systematic literature review of Ig replacement therapy for the treatment of PID with antibody deficiency. This Assessment has been undertaken to inform MSAC’s advice to the JBC regarding the clinical safety, effectiveness and cost-effectiveness of Ig replacement therapy for this indication. This contracted assessment complements the NBA Immunoglobulin Governance Program, which aims to strengthen clinical governance and authorisation of government-funded Ig in Australia.The criteria for evaluation of Ig replacement as it is currently funded for this indication in Australia were outlined in a PICO Confirmation that was discussed at the Immunoglobulin Review Reference Group meeting on 13 November 2019 and ratified on 11 December 2019.Appendix A provides a list of the people involved in the development of this Assessment report. Items in the agreed PICO ConfirmationThis Assessment of Ig for the treatment of PID with antibody deficiency addresses most of the PICO elements that were pre-specified in the PICO Confirmation that was ratified by the Immunoglobulin Review Reference Group. Insufficient comparative evidence in patients with PID was identified; therefore, the Assessment also includes single arm studies. These were limited to patients with common variable immune deficiency (CVID) in accordance with the PICO Confirmation.Medical ServiceThe intervention under review is Ig for immuno-replacement therapy in people with PID with antibody deficiency. Ig replacement therapy is a blood-based treatment whereby Ig is administered into the bloodstream of a person with PID in order to provide them with the antibodies needed to adequately fight infections. Immunoglobulin G (IgG) is one kind of antibody found in blood plasma that is necessary to fight infection; people with PID have poor IgG levels and/or function ADDIN EN.CITE <EndNote><Cite><Author>AAAAI</Author><Year>2019</Year><RecNum>5</RecNum><DisplayText>(AAAAI, 2019)</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576455435">5</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>AAAAI, </author></authors></contributors><titles><title>Immunoglobulin (IgG) replacement therapy</title></titles><volume>2019</volume><number>December 16</number><dates><year>2019</year></dates><publisher>American Acedemy of Allergy, Asthma and Immunology</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">(igg)-replacement-therapy</style></url></related-urls></urls></record></Cite></EndNote>(AAAAI, 2019). Serum IgG levels (the measure of IgG in the bloodstream) in healthy people range from approximately 4g/L in early infancy to 11g/L in adulthood ADDIN EN.CITE <EndNote><Cite><Author>Stiehm</Author><Year>1966</Year><RecNum>12</RecNum><DisplayText>(Stiehm and Fudenberg, 1966)</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578265949">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stiehm, E. R.</author><author>Fudenberg, H. H.</author></authors></contributors><titles><title>Serum levels of immune globulins in health and disease: a survey</title><secondary-title>Pediatrics</secondary-title><alt-title>Pediatrics</alt-title></titles><periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></periodical><alt-periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></alt-periodical><pages>715-27</pages><volume>37</volume><number>5</number><edition>1966/05/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>*Agammaglobulinemia</keyword><keyword>Agranulocytosis/*immunology</keyword><keyword>Anemia, Aplastic/*immunology</keyword><keyword>Asian Continental Ancestry Group</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Chromosome Aberrations/*immunology</keyword><keyword>Chromosome Disorders</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunodiffusion</keyword><keyword>Immunoelectrophoresis</keyword><keyword>Infant</keyword><keyword>Leukemia, Myeloid/*immunology</keyword><keyword>Male</keyword><keyword>Turner Syndrome/*immunology</keyword><keyword>Wiskott-Aldrich Syndrome/*immunology</keyword></keywords><dates><year>1966</year><pub-dates><date>May</date></pub-dates></dates><isbn>0031-4005 (Print)&#xD;0031-4005</isbn><accession-num>4956666</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Stiehm and Fudenberg, 1966). Serum IgG concentrations of equal to or greater than 5g/L following Ig therapy has been recommended as adequate protection from serious infections in people with PID with antibody deficiency ADDIN EN.CITE <EndNote><Cite><Author>Shrestha</Author><Year>2019</Year><RecNum>9</RecNum><DisplayText>(Shrestha et al., 2019a)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576639896">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shrestha, Pragya</author><author>Karmacharya, Paras</author><author>Wang, Zhen</author><author>Donato, Anthony</author><author>Joshi, Avni Y.</author></authors></contributors><titles><title>Impact of IVIG vs. SCIG on IgG trough level and infection incidence in primary immunodeficiency diseases: A systematic review and meta-analysis of clinical studies</title><secondary-title>The World Allergy Organization journal</secondary-title><alt-title>World Allergy Organ J</alt-title></titles><periodical><full-title>The World Allergy Organization journal</full-title><abbr-1>World Allergy Organ J</abbr-1></periodical><alt-periodical><full-title>The World Allergy Organization journal</full-title><abbr-1>World Allergy Organ J</abbr-1></alt-periodical><pages>100068-100068</pages><volume>12</volume><number>10</number><keywords><keyword>IVIG</keyword><keyword>IgG trough</keyword><keyword>PIDD</keyword><keyword>Primary immunodeficiency disease</keyword><keyword>SCIG</keyword></keywords><dates><year>2019</year></dates><publisher>World Allergy Organization</publisher><isbn>1939-4551</isbn><accession-num>31641401</accession-num><urls><related-urls><url>;(Shrestha et al., 2019a). Serum IgG trough levels (the concentration of IgG in the bloodstream immediately preceding the next dose of Ig) are an important guide to Ig treatment success ADDIN EN.CITE <EndNote><Cite><Author>Shrestha</Author><Year>2019</Year><RecNum>9</RecNum><DisplayText>(Shrestha et al., 2019a)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576639896">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shrestha, Pragya</author><author>Karmacharya, Paras</author><author>Wang, Zhen</author><author>Donato, Anthony</author><author>Joshi, Avni Y.</author></authors></contributors><titles><title>Impact of IVIG vs. SCIG on IgG trough level and infection incidence in primary immunodeficiency diseases: A systematic review and meta-analysis of clinical studies</title><secondary-title>The World Allergy Organization journal</secondary-title><alt-title>World Allergy Organ J</alt-title></titles><periodical><full-title>The World Allergy Organization journal</full-title><abbr-1>World Allergy Organ J</abbr-1></periodical><alt-periodical><full-title>The World Allergy Organization journal</full-title><abbr-1>World Allergy Organ J</abbr-1></alt-periodical><pages>100068-100068</pages><volume>12</volume><number>10</number><keywords><keyword>IVIG</keyword><keyword>IgG trough</keyword><keyword>PIDD</keyword><keyword>Primary immunodeficiency disease</keyword><keyword>SCIG</keyword></keywords><dates><year>2019</year></dates><publisher>World Allergy Organization</publisher><isbn>1939-4551</isbn><accession-num>31641401</accession-num><urls><related-urls><url>;(Shrestha et al., 2019a). Ig therapy does not cure antibody deficiencies or reverse the long-term complications associated with chronic infections; however, it may help treat and prevent new infections, thus reducing the risk of (further) long-term complications ADDIN EN.CITE <EndNote><Cite><Author>ASCIA</Author><Year>2019</Year><RecNum>6</RecNum><DisplayText>(ASCIA, 2019c)</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576455811">6</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>ASCIA,</author></authors></contributors><titles><title>Immunoglobulin Replacement Therapy in Primary Immunodeficiencies</title></titles><volume>2019</volume><number>1st October</number><dates><year>2019</year></dates><pub-location>Australia</pub-location><publisher>Australasian Society of Clinical Immunology and Allergy</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(ASCIA, 2019c). Ig preparations were first used in the 1950s as replacement therapy for a range of PID ADDIN EN.CITE <EndNote><Cite><Author>Palabrica</Author><Year>2013</Year><RecNum>3</RecNum><DisplayText>(Palabrica et al., 2013)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575948947">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palabrica, Frances Rose R.</author><author>Kwong, Shirley L.</author><author>Padua, Florecita R.</author></authors></contributors><titles><title>Adverse events of intravenous immunoglobulin infusions: a ten-year retrospective study</title><secondary-title>Asia Pacific allergy</secondary-title><alt-title>Asia Pac Allergy</alt-title></titles><periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></periodical><alt-periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></alt-periodical><pages>249-256</pages><volume>3</volume><number>4</number><edition>2013/10/31</edition><keywords><keyword>Intravenous immunoglobulins</keyword><keyword>Retrospective study</keyword><keyword>Side effects</keyword></keywords><dates><year>2013</year></dates><publisher>Asia Pacific Association of Allergy, Asthma and Clinical Immunology</publisher><isbn>2233-8276&#xD;2233-8268</isbn><accession-num>24260730</accession-num><urls><related-urls><url>;(Palabrica et al., 2013). Ig was initially administered intramuscularly until the 1980s where highly purified monomeric suspensions of IgG became available for intravenous or subcutaneous use ADDIN EN.CITE <EndNote><Cite><Author>Palabrica</Author><Year>2013</Year><RecNum>3</RecNum><DisplayText>(Palabrica et al., 2013)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575948947">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palabrica, Frances Rose R.</author><author>Kwong, Shirley L.</author><author>Padua, Florecita R.</author></authors></contributors><titles><title>Adverse events of intravenous immunoglobulin infusions: a ten-year retrospective study</title><secondary-title>Asia Pacific allergy</secondary-title><alt-title>Asia Pac Allergy</alt-title></titles><periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></periodical><alt-periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></alt-periodical><pages>249-256</pages><volume>3</volume><number>4</number><edition>2013/10/31</edition><keywords><keyword>Intravenous immunoglobulins</keyword><keyword>Retrospective study</keyword><keyword>Side effects</keyword></keywords><dates><year>2013</year></dates><publisher>Asia Pacific Association of Allergy, Asthma and Clinical Immunology</publisher><isbn>2233-8276&#xD;2233-8268</isbn><accession-num>24260730</accession-num><urls><related-urls><url>;(Palabrica et al., 2013). Ig products are manufactured from the plasma of healthy donors. Plasma pools are derived from, on average, approximately 15,000 donors and purified via ethanol fractionation with additional steps to remove Ig aggregates PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZXNzPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Ness, 2019, Palabrica et al., 2013). The preparation is then stabilised using agents such as human albumin, glycine, polyethylene glycol or sugars (such as sucrose, maltose or glucose) ADDIN EN.CITE <EndNote><Cite><Author>Palabrica</Author><Year>2013</Year><RecNum>3</RecNum><DisplayText>(Palabrica et al., 2013)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575948947">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palabrica, Frances Rose R.</author><author>Kwong, Shirley L.</author><author>Padua, Florecita R.</author></authors></contributors><titles><title>Adverse events of intravenous immunoglobulin infusions: a ten-year retrospective study</title><secondary-title>Asia Pacific allergy</secondary-title><alt-title>Asia Pac Allergy</alt-title></titles><periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></periodical><alt-periodical><full-title>Asia Pacific allergy</full-title><abbr-1>Asia Pac Allergy</abbr-1></alt-periodical><pages>249-256</pages><volume>3</volume><number>4</number><edition>2013/10/31</edition><keywords><keyword>Intravenous immunoglobulins</keyword><keyword>Retrospective study</keyword><keyword>Side effects</keyword></keywords><dates><year>2013</year></dates><publisher>Asia Pacific Association of Allergy, Asthma and Clinical Immunology</publisher><isbn>2233-8276&#xD;2233-8268</isbn><accession-num>24260730</accession-num><urls><related-urls><url>;(Palabrica et al., 2013). The primary active ingredient of Ig preparations is IgG; however, preparations may vary in IgG monomer, dimer, aggregate concentrations, immunoglobulin A (IgA) and immunoglobulin M (IgM) content, the stabilisers and additives used, as well as the level of impurities present ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019).Dosage and clinical reviewIn Australia, Version 3.1 of the Criteria for Clinical Use of Immunoglobulin in Australia (herein described as ‘the Criteria Version 3’) outlines which patients are eligible for Ig treatment ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2018</Year><RecNum>2</RecNum><DisplayText>(NBA, 2018)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575946014">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA, </author></authors></contributors><titles><title>Criteria for the clinical use of immunoglobulin in Australi (the Criteria)</title></titles><volume>2019</volume><number>December 10</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2018). The Criteria Version 3 provides a list of medical conditions and specific circumstances around entitlement for publicly funded Ig treatment, as well as an outline of the approved Ig dosage and recommended duration of use. REF _Ref27399792 \h \* MERGEFORMAT Table 5 summarises the approved dosage and medical review conditions described in the Criteria Version 3 for patients with PID with antibody deficiency. As Ig is a finite high cost resource, the aim is to deliver the lowest dose possible of Ig that achieves the appropriate clinical outcome for each patient. Dosages outside of those parameters stipulated by the Criteria Version 3 must be authorised following a review of the rationale of the treating doctor. Table SEQ Table \* ARABIC 5Approved Ig dosage for replacement therapy in patients with PID with antibody deficiency (per indication) according to the Criteria Version 3 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2018</Year><RecNum>2</RecNum><DisplayText>(NBA, 2018)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575946014">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA, </author></authors></contributors><titles><title>Criteria for the clinical use of immunoglobulin in Australi (the Criteria)</title></titles><volume>2019</volume><number>December 10</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2018)Loading Dose Maintenance Dose Review by an ImmunologistCommon variable immunodeficiency (CVID) – European Society for Immunodeficiencies diagnostic criteria metOne dose of 0.4g/kg in the first month of therapy (in addition to the maintenance dose) is permitted if the serum IgG level is < 4g/L. 0.4 to 0.6g/kg every four weeks (intravenous Ig [IVIg]) or 0.1 to 0.15g/kg every week (subcutaneous Ig [SCIg]), or more frequently, to achieve IgG trough level of at least the lower limit of the age-specific serum immunoglobulin G (IgG) reference range. More frequent dosing to achieve IgG trough level of up to 9g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age-specific serum IgG reference range. A total dose of up to 1g/kg may be given over any four-week period.6 months, annually thereafter.Cessation of treatment should be considered at 12 months.Possible CVIDOne dose of 0.4g/kg in the first month of therapy (in addition to the maintenance dose) is permitted if the serum IgG level is < 4g/L. 0.4 to 0.6g/kg every four weeks (IVIg) or 0.1 to 0.15g/kg every week (SCIg), or more frequently, to achieve IgG trough level of at least the lower limit of the age-specific serum IgG reference range. More frequent dosing to achieve IgG trough level of up to 9g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age-specific serum IgG reference range. A total dose of up to 1g/kg may be given over any four-week period. 6 months, annually thereafter.Cessation of treatment should be considered at 12 months.Transient hypogammaglobulinaemia of infancy (children aged less than 4 years)One dose of 0.4g/kg in the first month of therapy (in addition to the maintenance dose) is permitted if the serum IgG level is < 4g/L. 0.4 to 0.6g/kg every four weeks (IVIg) or 0.1 to 0.15g/kg every week (SCIg), or more frequently, to achieve IgG trough level of at least the lower limit of the age-specific serum IgG reference range. More frequent dosing to achieve IgG trough level of up to 9g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age-specific serum IgG reference range. A total dose of up to 1g/kg may be given over any four-week period.6 months, annually thereafter.Cessation of treatment should be considered at 24 months.Primary immunodeficiency diseases for which immunoglobulin replacement is universally indicatedOne dose of 0.4g/kg in the first month of therapy (in addition to the maintenance dose) is permitted if the serum IgG level is < 4g/L. 0.4g/kg every four weeks (IVIg) or 0.1 to 0.15g/kg every week (SCIg), or more frequently, to achieve IgG trough level of at least the lower limit of the age-specific serum IgG reference range. More frequent dosing to achieve IgG trough level of up to 9g/L is permitted if chronic suppurative lung disease is not adequately controlled at an IgG trough level at the lower limit of the age-specific serum IgG reference range. A total dose of up to 1g/kg may be given over any four-week period. 6 months, annually thereafter*Abbreviations: CVID: Common variable immunodeficiency; IgG: immunoglobulin G; IVIg: intravenous immunoglobulin G; SCIg: subcutaneous immunoglobulin G. Note: Refer to the current product information sheet for further information on dose, administration and contraindications. *Patients generally require more than one authorisation for Ig therapy; however, the average duration of therapy is unknown given the vast number, and clinical variability, of conditions that comprise PID. An additional dose of 2g/kg is permitted at any stage to manage an enterovirus infection. As well as this, one dose of 0.4g/kg is permitted at any stage if the serum IgG level is less than 4g/L.Delivery methodsIg can be delivered in one of two ways; intravenously (IVIg) or via subcutaneous injection (SCIg). The main difference between the two delivery methods is that IVIg requires venous access, can deliver larger volumes (therefore fewer doses) and is carried out by skilled healthcare professionals in a hospital setting ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019). SCIg, which delivers smaller volumes, may be self-administered at home (following appropriate training by a registered nurse or technician) ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019). 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ADDIN EN.CITE.DATA (Ness, 2019, Palabrica et al., 2013). Because IVIg is administered under medical supervision its adverse events can usually be treated quickly and effectively ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019). SCIg requires more frequent dosages (due to smaller infusion volumes) via multiple injection sites around the body PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZXNzPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Ness, 2019, Palabrica et al., 2013). Adverse events for SCIg are typically localised to the injection site and smaller infusion volumes allow for steady absorption of Ig ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019). Serious adverse events of Ig therapy overall are rare and may include antibiotic allergy, anaphylaxis, veno-occlusive events and acute renal failure ADDIN EN.CITE <EndNote><Cite><Author>Ness</Author><Year>2019</Year><RecNum>4</RecNum><DisplayText>(Ness, 2019)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575949607">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ness, S.</author></authors></contributors><auth-address>Senior Director, Specialty Clinical Services, Managed Health Care Associates, Inc, Florham Park, NJ; President, Immune Globulin National Society. Email: sness@.</auth-address><titles><title>Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin</title><secondary-title>Am J Manag Care</secondary-title><alt-title>The American journal of managed care</alt-title></titles><periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></periodical><alt-periodical><full-title>Am J Manag Care</full-title><abbr-1>The American journal of managed care</abbr-1></alt-periodical><pages>S98-s104</pages><volume>25</volume><number>6 Suppl</number><edition>2019/07/19</edition><dates><year>2019</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1088-0224</isbn><accession-num>31318515</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Ness, 2019). Marketing status of technologyAll therapeutic products marketed in Australia require listing on the Australian Register of Therapeutic Goods (ARTG). MSAC will not consider a therapeutic product for reimbursement if it is not listed on the ARTG. Ig products used for replacement therapy in PID are funded under the National Blood Authority. The NBA has contracts with suppliers to source products both domestically (from plasma collected by the Australian Red Cross Blood Service) and through a range of international suppliers. The sixteen Ig items on the ARTG that are relevant to this application are shown in REF _Ref364240778 \h \* MERGEFORMAT Table 6; those currently funded by the National Blood Authority (7 products) are highlighted in grey. It is important to note that the funded Ig products may change over time, dependent on agreements with suppliers.Table SEQ Table \* ARABIC 6Ig products indicated for PID listed on the ARTG according to the Referral Form (Table 1; page 6)ARTG no.Product nameProduct descriptionSponsorIVIg143803 (20g/400ml); 143802 (10g/200ml); 143801 (5g/100ml); 143800 (2.5g/50ml); 140602 (0.5g/10ml)Flebogamma 5%5% DIF Human normal immunoglobulin intravenous use injection vialGrifols Australia Pty Ltd182359 (20g/200ml); 182358 (10g/100ml); 184353 (5g/50ml)Flebogamma 10%10% DIF Human normal immunoglobulin intravenous use injection vialGrifols Australia Pty Ltd162489 (20g/200ml); 162488 (10g/100ml); 162487 (5g/50ml); 162486 (2.5g/25ml)Intragam 10%Normal immunoglobulin (human) solution for injection vialCSL Behring Australia Pty Ltd164549 (10g/200ml); 164551 (5g/100ml); 164548 (2.5g/50ml); 164550 (1g/20ml)Intratect 5%5% human normal immunoglobulin solution for intravenous infusion vialPfizer Australia Pty Ltd232085 (20g/200ml); 232084 (10g/100ml); 232078 (5g/50ml); 232077 (1g/10ml)Intratect 10%10% human normal immunoglobulin solution for intravenous infusion vialPfizer Australia Pty Ltd113928 (10g/200ml); 113927 (5g/100ml); 113926 (2.5g/50ml); 113925 (1g/20ml)Octagam 5%Normal immunoglobulin (human) injection bottleOctapharma Australia Pty Ltd155604 (20g/200ml); 155603 (10g/100ml); 155602 (5g/50ml); 155601 (2g/20ml)Octagam 10%Normal immunoglobulin (human) injection vialOctapharma Australia Pty Ltd291644 (30g/300ml); 291646 (20g/200ml); 291648 (10g/100ml); 291647 (5g/50ml); 291740 (1g/10ml); 291645 (2.5g/25ml); Panzyga 10%Human normal immunoglobulin solution for intravenous infusion vialOctapharma Australia Pty Ltd219160 (40g/400ml); 143368 (20g/200ml); 143337 (10g/100ml); 143273 (5g/50ml) PriviIgen 10%Normal immunoglobulin (human) (100g/L, 10%) solution for intravenous infusionCSL Behring Australia Pty LtdSCIg282579Cuvitru 20%Normal immunoglobulin (human) infusion 20% for subcutaneous use in glass vialShire Australia Pty LtdAU 173315 (0.8g/5ml); 173323 (1.6g/10ml); 173324 (3.2g/20ml)NZ 204954 (0.8g/5ml); 204955 (1.6g/10ml); 204956 (3.2g/20ml) Evogam 16%Normal immunoglobulin (human) 16% w/v, injection solution vial for subcutaneous useCSL Behring Australia Pty Ltd128703 (1.65g/10ml); 128705 (3.3g/20ml)Gammanorm 16.5%Normal immunoglobulin (human) solution for intramuscular injection or subcutaneous infusion vialOctapharma Australia Pty Ltd285344 (5ml syringe); 285345 (10ml syringe); 207386 (5ml vial); 207385 (10ml vial); 207383 (20ml vial); 207384 (50ml vial)Hizentra 20%Human Normal Immunoglobulin 20% Solution for Subcutaneous Injection 5-10ml pre-filled syringe OR 5-50ml vialCSL Behring Australia Pty Ltd235178Hyqvia 10%Normal Immunoglobulin Infusion 10% (Human) with Vorhyaluronidase alfa, Injection solution for subcutaneous useShire Australia Pty LtdIVIg and SCIg116689 (1g/10ml); 117237 (2.5g/25ml); 117238 (5g/50ml); 117239 (10g/100ml); 117240 (20g/200ml)Gamunex 10%*Normal immunoglobulin (Human) intravenous solution vialGrifols Australia Pty Ltd198488 (30g/300ml); 131973 (20g/200ml); 131969 (10g/100ml); 131968 (5g/50ml); 131966 (2.5g/25ml); 131953 (1g/10ml)Kiovig 10%Normal immunoglobulin (human) solution for injection vialShire Australia Pty LtdSource: Therapeutic Goods Administration, accessed 16 December 2019Abbreviations: ARTG: Australian Register of Therapeutic Goods; IVIg: intravenous immunoglobulin; DIF: dual inactivation and filtration; IV: intravenous; SCIg: subcutaneous immunoglobulin; AU: Australia; NZ: New Zealand; SC: subcutaneous. Note: All products were registered medicines. Those products highlighted in grey are currently funded by the National Blood Authority. It is important to note these may change over time depending on supplier agreements. *Gamunex 10% is funded by the National Blood Authority for IVIg only. Other IndicationsIg is currently used in the treatment and management of a range of clinical conditions in Australia. The top 10 medical conditions for which Ig was issued, according to the National Blood Authority’s 2017-18 National Report on the Issue and Use of Immunoglobulin (Ig) are reported in REF _Ref27561539 \h \* MERGEFORMAT Table 7 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2017-18</Year><RecNum>8</RecNum><DisplayText>(NBA, 2017-18)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576630261">8</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig)</title></titles><volume>2019</volume><number>December 18</number><dates><year>2017-18</year></dates><publisher>National Blood Authority Australia,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2017-18).Table SEQ Table \* ARABIC 7Top 10 medical conditions for which Ig was issued in 2017-18 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2017-18</Year><RecNum>8</RecNum><DisplayText>(NBA, 2017-18)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576630261">8</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig)</title></titles><volume>2019</volume><number>December 18</number><dates><year>2017-18</year></dates><publisher>National Blood Authority Australia,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2017-18)ConditionImmunoglobulin issued (grams)Percentage change 2016-17 to 2017-18Acquired hypogammaglobulinaemia1,401,78914.1Chronic inflammatory demyelinating polyneuropathy1,290,61210.2Primary immunodeficiency diseases725,3263.4Myasthenia gravis514,01712.6Inflammatory myopathies377,47914.7Multifocal motor neuropathy354,4347.0Secondary hypogammaglobulinaemia222,13622.8Immune thrombocytopenic purpuria (in adults)218,1823.0Kidney transplantation126,5872.9Guillain-Barré syndrome 122,1397.0These 10 conditions accounted for approximately 88 per cent of all Ig issued in Australia ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2017-18</Year><RecNum>8</RecNum><DisplayText>(NBA, 2017-18)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576630261">8</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig)</title></titles><volume>2019</volume><number>December 18</number><dates><year>2017-18</year></dates><publisher>National Blood Authority Australia,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2017-18). In particular, PID with antibody deficiency accounted for approximately 12 per cent of total Ig use; this represents a 3.4 per cent increase in Ig use for this indication from 2016-17 to 2017-18 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2017-18</Year><RecNum>8</RecNum><DisplayText>(NBA, 2017-18)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576630261">8</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig)</title></titles><volume>2019</volume><number>December 18</number><dates><year>2017-18</year></dates><publisher>National Blood Authority Australia,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2017-18). Current funding arrangementsIn Australia, the Criteria Version 3 describes for which conditions Ig is publicly funded under the National Blood Authority. For PID these include: Severe combined immunodeficiency (SCID)Combined immunodeficiency (e.g. thymoma)Combined immunodeficiency with associated or syndromal featuresCommon variable immunodeficiency (CVID)Possible CVID – below normal serum IgG but normal serum IgASevere reduction in all Ig isotypes with decreased or absent B-cellsSevere reduction in at least two Ig isotypes with low/normal B-cells (e.g. CVID)Severe reduction in serum IgG and IgA with normal/elevated IgMTransient hypogammaglobulinaemia of infancyLymphoproliferative syndromesAdditional details for these conditions are reported in the ‘Population’ section of this Assessment. Ig therapy may be delivered in an inpatient or outpatient setting, as a private or public patient, as well as in the patient’s own home in some cases (for SCIg only, following appropriate training by a qualified nurse or technician). Access to Ig for patients who are not eligible under the National Blood Authority is possible though direct order arrangements. This may take place when the decision to prescribe Ig has been made by a hospital drug committee or similar. In this case, imported Ig products can be purchased directly from the supplier (for the same price negotiated by the National Blood Authority); however, full payment is required (from the patient or health service).Proposal for Public FundingThere are no proposed MBS items relevant to this Assessment. PopulationImmunodeficiency disorders are characterised by an immune system defect that prevents a person’s body from fighting infections and diseases ADDIN EN.CITE <EndNote><Cite><Author>Healtline</Author><Year>2019</Year><RecNum>1</RecNum><DisplayText>(Healtline, 2019)</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575944732">1</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Healtline, </author></authors></contributors><titles><title>Immunodeficiency Disorders</title></titles><volume>2019</volume><number>December 10</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Healtline, 2019). 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ADDIN EN.CITE.DATA (Immunodeficiency Australia, 2019, McCusker et al., 2018). There are two groups of immunodeficiency disorders; primary immunodeficiency diseases (PID) and secondary immunodeficiency diseases. PID are caused by inherited gene defects, often, but not always, present at birth or developed in the first few years of life ADDIN EN.CITE <EndNote><Cite><Author>Immunodeficiency Australia</Author><Year>2019</Year><RecNum>10</RecNum><DisplayText>(Immunodeficiency Australia, 2019)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576643954">10</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Immunodeficiency Australia, </author></authors></contributors><titles><title>Types of immunodeficiency disease</title></titles><volume>2019</volume><number>December 18</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Immunodeficiency Australia, 2019). Secondary immunodeficiency diseases are mostly caused by another disease, illness, injury or medication ADDIN EN.CITE <EndNote><Cite><Author>Immunodeficiency Australia</Author><Year>2019</Year><RecNum>10</RecNum><DisplayText>(Immunodeficiency Australia, 2019)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576643954">10</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Immunodeficiency Australia, </author></authors></contributors><titles><title>Types of immunodeficiency disease</title></titles><volume>2019</volume><number>December 18</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Immunodeficiency Australia, 2019). Secondary antibody deficiencies are covered by the categories of acquired and secondary hypogammaglobulinaemia in the Criteria Version 3 and have been reviewed separately (refer to MSAC Reviews 1565 and 1591).PID refers to a large heterogeneous group of disorders where one or more components of the immune system is compromised, leading to absent or impaired immune function ADDIN EN.CITE <EndNote><Cite><Author>McCusker</Author><Year>2018</Year><RecNum>11</RecNum><DisplayText>(McCusker et al., 2018)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576644423">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCusker, Christine</author><author>Upton, Julia</author><author>Warrington, Richard</author></authors></contributors><titles><title>Primary immunodeficiency</title><secondary-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</secondary-title><alt-title>Allergy Asthma Clin Immunol</alt-title></titles><periodical><full-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</full-title><abbr-1>Allergy Asthma Clin Immunol</abbr-1></periodical><alt-periodical><full-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</full-title><abbr-1>Allergy Asthma Clin Immunol</abbr-1></alt-periodical><pages>61-61</pages><volume>14</volume><number>Suppl 2</number><dates><year>2018</year></dates><publisher>BioMed Central</publisher><isbn>1710-1484&#xD;1710-1492</isbn><accession-num>30275850</accession-num><urls><related-urls><url>;(McCusker et al., 2018). PID are broadly separated as disorders of adaptive immunity or innate immunity. The focus of this Assessment is PID with antibody deficiency which are considered disorders of adaptive immunity. Specifically, defects relating to B-cell development and/or maturation result in B-cell disorders, or antibody deficiencies ADDIN EN.CITE <EndNote><Cite><Author>McCusker</Author><Year>2018</Year><RecNum>11</RecNum><DisplayText>(McCusker et al., 2018)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576644423">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCusker, Christine</author><author>Upton, Julia</author><author>Warrington, Richard</author></authors></contributors><titles><title>Primary immunodeficiency</title><secondary-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</secondary-title><alt-title>Allergy Asthma Clin Immunol</alt-title></titles><periodical><full-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</full-title><abbr-1>Allergy Asthma Clin Immunol</abbr-1></periodical><alt-periodical><full-title>Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology</full-title><abbr-1>Allergy Asthma Clin Immunol</abbr-1></alt-periodical><pages>61-61</pages><volume>14</volume><number>Suppl 2</number><dates><year>2018</year></dates><publisher>BioMed Central</publisher><isbn>1710-1484&#xD;1710-1492</isbn><accession-num>30275850</accession-num><urls><related-urls><url>;(McCusker et al., 2018). Over 350 different PID disorders are recognised by the World Health Organization (WHO), with new ones continually being discovered ADDIN EN.CITE <EndNote><Cite><Author>IDF</Author><Year>2020</Year><RecNum>35</RecNum><DisplayText>(IDF, 2020a)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579061128">35</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>IDF,</author></authors></contributors><titles><title>Specific Disease Types</title></titles><volume>2020</volume><number>January 20</number><dates><year>2020</year></dates><publisher>Immune Deficiency Foundation</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(IDF, 2020a). As such, the presentation of PID is highly variable. 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ADDIN EN.CITE.DATA (Joshi et al., 2009). Estimates of PID incidence and prevalence have been made based on registry data worldwide. The Australasian Society of Clinical Immunology and Allergy PID Register conducted a cumulative, cross-sectional survey of PID patients in Australia and New Zealand ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>14</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007b)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578269087">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, P.</author><author>Riminton, S.</author></authors></contributors><auth-address>Department of Immunology, Concord Hospital, Sydney, Australia.</auth-address><titles><title>Primary immunodeficiency diseases in Australia and New Zealand</title><secondary-title>J Clin Immunol</secondary-title><alt-title>Journal of clinical immunology</alt-title></titles><alt-periodical><full-title>Journal of Clinical Immunology</full-title></alt-periodical><pages>517-24</pages><volume>27</volume><number>5</number><edition>2007/06/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Australia/epidemiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/therapeutic use</keyword><keyword>Immunologic Deficiency Syndromes/drug therapy/*epidemiology/immunology</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>New Zealand/epidemiology</keyword><keyword>Prevalence</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0271-9142 (Print)&#xD;0271-9142</isbn><accession-num>17588141</accession-num><urls></urls><electronic-resource-num>10.1007/s10875-007-9105-z</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kirkpatrick and Riminton, 2007b). A total of 1,209 patients across 88 centres and 56 PID syndromes responded to the voluntary questionnaire ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>14</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007b)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578269087">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, P.</author><author>Riminton, S.</author></authors></contributors><auth-address>Department of Immunology, Concord Hospital, Sydney, Australia.</auth-address><titles><title>Primary immunodeficiency diseases in Australia and New Zealand</title><secondary-title>J Clin Immunol</secondary-title><alt-title>Journal of clinical immunology</alt-title></titles><alt-periodical><full-title>Journal of Clinical Immunology</full-title></alt-periodical><pages>517-24</pages><volume>27</volume><number>5</number><edition>2007/06/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Australia/epidemiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/therapeutic use</keyword><keyword>Immunologic Deficiency Syndromes/drug therapy/*epidemiology/immunology</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>New Zealand/epidemiology</keyword><keyword>Prevalence</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0271-9142 (Print)&#xD;0271-9142</isbn><accession-num>17588141</accession-num><urls></urls><electronic-resource-num>10.1007/s10875-007-9105-z</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kirkpatrick and Riminton, 2007b). Prevalence (cases per 100,000 population) was 5.6 for Australia and 4.9 for Australia and New Zealand combined. PID with antibody deficiency accounted for 77 per cent of patients ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>14</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007b)</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578269087">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, P.</author><author>Riminton, S.</author></authors></contributors><auth-address>Department of Immunology, Concord Hospital, Sydney, Australia.</auth-address><titles><title>Primary immunodeficiency diseases in Australia and New Zealand</title><secondary-title>J Clin Immunol</secondary-title><alt-title>Journal of clinical immunology</alt-title></titles><alt-periodical><full-title>Journal of Clinical Immunology</full-title></alt-periodical><pages>517-24</pages><volume>27</volume><number>5</number><edition>2007/06/26</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Australia/epidemiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/therapeutic use</keyword><keyword>Immunologic Deficiency Syndromes/drug therapy/*epidemiology/immunology</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>New Zealand/epidemiology</keyword><keyword>Prevalence</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0271-9142 (Print)&#xD;0271-9142</isbn><accession-num>17588141</accession-num><urls></urls><electronic-resource-num>10.1007/s10875-007-9105-z</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Kirkpatrick and Riminton, 2007b). The population described in the PICO Confirmation is patients with PID with antibody deficiency who are eligible for Ig treatment in Australia according to version 3.1 of the Criteria Version 3 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2018</Year><RecNum>2</RecNum><DisplayText>(NBA, 2018)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575946014">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA, </author></authors></contributors><titles><title>Criteria for the clinical use of immunoglobulin in Australi (the Criteria)</title></titles><volume>2019</volume><number>December 10</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2018). As previously mentioned, the Criteria Version 3 is a framework where the medical conditions and specific circumstances eligible for publicly funded Ig treatment in Australia are outlined ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2018</Year><RecNum>2</RecNum><DisplayText>(NBA, 2018)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575946014">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA, </author></authors></contributors><titles><title>Criteria for the clinical use of immunoglobulin in Australi (the Criteria)</title></titles><volume>2019</volume><number>December 10</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2018).The specific conditions (as diagnosed by an immunologist) described in the Criteria Version 3 for patients with PID with antibody deficiency to be eligible for publicly funded Ig treatment in Australia are listed and briefly explained below:Severe combined immunodeficiencySevere combined immunodeficiency (SCID) is generally considered the most serious of all PID as it is potentially fatal. There are at least 13 known genetic defects responsible for SCID which is characterised by the combined absence of both T- and B-lymphocyte function ADDIN EN.CITE <EndNote><Cite><Author>IDF</Author><Year>2019</Year><RecNum>15</RecNum><DisplayText>(IDF, 2019)</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578270594">15</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>IDF, </author></authors></contributors><titles><title>Severe combined immune deficiency and combined immune deficiency</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>Immune Deficiency Foundation,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(IDF, 2019). Despite this, 15 per cent of all infants with SCID have a gene defect of unknown origin ADDIN EN.CITE <EndNote><Cite><Author>NIAID</Author><Year>2019</Year><RecNum>16</RecNum><DisplayText>(NIAID, 2019)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578272952">16</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NIAID,</author></authors></contributors><titles><title>Severe combined immunodeficiency (SCID)</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>National Institute of Allergy and Infectious Diseases, </publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NIAID, 2019). SCID is generally inherited in an autosomal recessive pattern, with more than 80 per cent of cases having no family history of the disease ADDIN EN.CITE <EndNote><Cite><Author>NIAID</Author><Year>2019</Year><RecNum>16</RecNum><DisplayText>(NIAID, 2019)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578272952">16</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NIAID,</author></authors></contributors><titles><title>Severe combined immunodeficiency (SCID)</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>National Institute of Allergy and Infectious Diseases, </publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NIAID, 2019). The most common form of SCID is X-linked SCID (primarily affecting males) where white blood cells develop abnormally resulting in low T-cell and natural killer (NK) cell counts and B-cells that do not function ADDIN EN.CITE <EndNote><Cite><Author>NIAID</Author><Year>2019</Year><RecNum>16</RecNum><DisplayText>(NIAID, 2019)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578272952">16</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NIAID,</author></authors></contributors><titles><title>Severe combined immunodeficiency (SCID)</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>National Institute of Allergy and Infectious Diseases, </publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NIAID, 2019). Combined immunodeficiencyCombined immunodeficiency (CID) is generally less profound than SCID due to hypomorphic (partial) gene mutations ADDIN EN.CITE <EndNote><Cite><Author>Helen C Su</Author><Year>2014</Year><RecNum>18</RecNum><DisplayText>(Su, 2014)</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578279115">18</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Helen C Su</author></authors></contributors><titles><title>Combined immune deficiencies</title></titles><volume>2020</volume><number>January 6</number><dates><year>2014</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Su, 2014). As such, the two conditions differ in that SCID is characterised by no T-cell function and CID is characterised by low T-cell function. CID may be associated with thymoma, which is cancer of the thymus gland. The thymus is made up of lymphocytes and epithelial cells and plays a critical role in the production of immune cells in children ADDIN EN.CITE <EndNote><Cite><Author>Melissa Conrad-Stoppler</Author><Year>2018</Year><RecNum>17</RecNum><DisplayText>(Conrad-Stoppler, 2018)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578278328">17</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Melissa Conrad-Stoppler</author></authors></contributors><titles><title>Thymoma</title></titles><volume>2020</volume><number>January 6</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Conrad-Stoppler, 2018). Combined immunodeficiency with associated or syndromal featuresTwo examples of CID with associated or syndromal features include Wiskott-Aldrich syndrome (WAS) and ataxia telangiectasia. WAS is a rare X-linked recessive disease characterised by eczema, thrombocytopenia (reduced number and size of platelets), immune deficiency and bloody diarrhoea (as a result of thrombocytopenia) ADDIN EN.CITE <EndNote><Cite><Author>Fernandez</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(Fernandez, 2019)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578280170">19</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>James Fernandez</author></authors></contributors><titles><title>Wiskott-Aldrich Syndrome</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Fernandez, 2019). WAS is caused by mutations in the gene which codes for the WAS protein which is a cytoplasmic protein essential for B- and T-cell signalling ADDIN EN.CITE <EndNote><Cite><Author>Fernandez</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(Fernandez, 2019)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578280170">19</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>James Fernandez</author></authors></contributors><titles><title>Wiskott-Aldrich Syndrome</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Fernandez, 2019). Typically, in people with WAS, IgM levels are reduced, IgA and Immunoglobulin E (IgE) levels are elevated and IgG levels can be normal, reduced or elevated ADDIN EN.CITE <EndNote><Cite><Author>Fernandez</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(Fernandez, 2019)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578280170">19</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>James Fernandez</author></authors></contributors><titles><title>Wiskott-Aldrich Syndrome</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Fernandez, 2019). Ataxia telangiectasia, also known as Louis-Bar syndrome, is a rare disorder affecting the nervous system, immune system and other body systems; characterised by difficulty with control of movements ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>20</RecNum><DisplayText>(NLM, 2019a)</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281014">20</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Ataxia-telangiectasia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019a). Ataxia telangiectasia is caused by mutations in the ATM gene, which assists in normal cell division and DNA repair ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>20</RecNum><DisplayText>(NLM, 2019a)</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281014">20</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Ataxia-telangiectasia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019a). These mutations result in impaired or eliminated function of the ATM protein which causes cells to become unstable and die ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>20</RecNum><DisplayText>(NLM, 2019a)</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281014">20</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Ataxia-telangiectasia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine,</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019a). Approximately half of all people with ataxia telangiectasia are immunodeficient PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFwbGVzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA (Staples et al., 2008). When immunodeficiency is present, it typically presents as low IgG and IgA levels, as well as defective polysaccharide antibody responses and lymphopenia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFwbGVzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFwbGVzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA (Staples et al., 2008). T-cell function is generally normal; therefore, opportunistic infections are rare PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFwbGVzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA (Staples et al., 2008). Common variable immunodeficiencyCommon variable immunodeficiency (CVID) is one of the most common PID; traditionally characterised by decreased IgG and IgA levels, with or without decreased IgM ADDIN EN.CITE <EndNote><Cite><Author>ASCIA</Author><Year>2019</Year><RecNum>30</RecNum><DisplayText>(ASCIA, 2019a)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578374972">30</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>ASCIA,</author></authors></contributors><titles><title>Common variable immunodeficiency (CVID)</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><publisher>Australasian Society of Clinical Immunology and Allergy</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(ASCIA, 2019a), as well as T-cell defects, namely reduced proliferative capacity ADDIN EN.CITE <EndNote><Cite><Author>Strober</Author><Year>2000</Year><RecNum>32</RecNum><DisplayText>(Strober and Chua, 2000)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579046977">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Strober, W.</author><author>Chua, K.</author></authors></contributors><auth-address>National Institutes of Health, Bethesda, MD 20892-1890, USA.</auth-address><titles><title>Common variable immunodeficiency</title><secondary-title>Clin Rev Allergy Immunol</secondary-title><alt-title>Clinical reviews in allergy &amp; immunology</alt-title></titles><periodical><full-title>Clin Rev Allergy Immunol</full-title><abbr-1>Clinical reviews in allergy &amp; immunology</abbr-1></periodical><alt-periodical><full-title>Clin Rev Allergy Immunol</full-title><abbr-1>Clinical reviews in allergy &amp; immunology</abbr-1></alt-periodical><pages>157-81</pages><volume>19</volume><number>2</number><edition>2000/01/11</edition><keywords><keyword>*Common Variable Immunodeficiency</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword></keywords><dates><year>2000</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1080-0549 (Print)&#xD;1080-0549</isbn><accession-num>11107500</accession-num><urls></urls><electronic-resource-num>10.1385/criai:19:2:157</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Strober and Chua, 2000). Most people with CVID have normal B-cell levels that either do not mature correctly to produce effective antibodies or do not have the assistance of T-cells to carry out normal antibody responses ADDIN EN.CITE <EndNote><Cite><Author>ASCIA</Author><Year>2019</Year><RecNum>22</RecNum><DisplayText>(ASCIA, 2019b)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578284858">22</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>ASCIA,</author></authors></contributors><titles><title>Common variable immunodeficiency (CVID)</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>Australasian Society of Clinical Immunology and Allergy, </publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(ASCIA, 2019b). Unlike other PID, CVID may be diagnosed in adults; however, symptoms may start to appear in childhood ADDIN EN.CITE <EndNote><Cite><Author>ASCIA</Author><Year>2019</Year><RecNum>22</RecNum><DisplayText>(ASCIA, 2019b)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578284858">22</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>ASCIA,</author></authors></contributors><titles><title>Common variable immunodeficiency (CVID)</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>Australasian Society of Clinical Immunology and Allergy, </publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(ASCIA, 2019b). Approximately 10 per cent of cases of CVID have a known genetic cause ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2020</Year><RecNum>33</RecNum><DisplayText>(NLM, 2020)</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579047363">33</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Common variable immune deficiency</title></titles><volume>2020</volume><number>January 15</number><dates><year>2020</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2020). The main symptoms of CVID are hypogammaglobinemia and recurrent infections (particularly in the lungs, sinuses and ears) ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2020</Year><RecNum>33</RecNum><DisplayText>(NLM, 2020)</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579047363">33</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Common variable immune deficiency</title></titles><volume>2020</volume><number>January 15</number><dates><year>2020</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2020). Pneumonia is common in people with CVID, as well as infection or inflammation of the gastrointestinal tract, enlarged lymph nodes and spleen ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2020</Year><RecNum>33</RecNum><DisplayText>(NLM, 2020)</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579047363">33</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>Common variable immune deficiency</title></titles><volume>2020</volume><number>January 15</number><dates><year>2020</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2020). Possible CVID describes below normal serum IgG but normal serum IgA. Severe reduction in all Ig isotypes with decreased or absent B-cellsX-linked agammaglobulinaemia (XLA) is characterised by low or completely absent Ig in the bloodstream ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>21</RecNum><DisplayText>(NLM, 2019b)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281757">21</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>X-linked agammaglobulinemia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019b). XLA is present at birth, although symptoms generally do not develop until one to two months of age once the mother’s antibodies (acquired before birth) are depleted ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>21</RecNum><DisplayText>(NLM, 2019b)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281757">21</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>X-linked agammaglobulinemia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019b). People with XLA do not lack the genes required to produce Ig, rather the enzyme (Bruton’s agammaglobulinaemia tyrosine kinase) responsible for the maturation of B-cells. The lack, or insufficiency, of B-cells results in no, or low Ig levels in the bloodstream ADDIN EN.CITE <EndNote><Cite><Author>NLM</Author><Year>2019</Year><RecNum>21</RecNum><DisplayText>(NLM, 2019b)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578281757">21</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NLM,</author></authors></contributors><titles><title>X-linked agammaglobulinemia</title></titles><volume>2020</volume><number>January 6</number><dates><year>2019</year></dates><publisher>US National Library of Medicine</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(NLM, 2019b). Severe reduction in serum IgG and IgA with normal/elevated IgMThe above occurs in people with CD40 ligand (CD40L) deficiency. CD40L is a membrane bound protein which helps mediate the interaction between antigen presenting cells and lymphocytes. The absence of this protein results in defects in cellular and humoral immunity leading to recurrent infection PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXNodTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Bishu et al., 2009). The survival rate of people with CD40L deficiency at 25 years is 20 per cent (when Ig therapy and best supportive care is used) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXNodTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Bishu et al., 2009). Transient hypogammaglobulinaemia of infancyTransient hypogammaglobulinaemia of infancy (THI) is a relatively common PID in infants and young children characterised by reduced IgG with or without decreased IgA and IgM levels but with normal (or near-normal) antibody responses to protein immunisations ADDIN EN.CITE <EndNote><Cite><Author>Knutsen</Author><Year>2019</Year><RecNum>26</RecNum><DisplayText>(Knutsen, 2019)</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578356618">26</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Alan P Knutsen</author></authors></contributors><titles><title>Transient hypogammaglobulinemia of infancy</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Knutsen, 2019). Onset of THI generally occurs around 6 months of age, when the IgG acquired before birth are depleted. Symptoms may include recurrent infections of the upper and lower respiratory tract, allergic manifestations (such as asthma, eczema and food allergies) and gastrointestinal difficulties (such as chronic diarrhoea and persistent vomiting) ADDIN EN.CITE <EndNote><Cite><Author>IDF</Author><Year>2020</Year><RecNum>34</RecNum><DisplayText>(IDF, 2020b)</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1579047941">34</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>IDF</author></authors></contributors><titles><title>Transient Hypogammaglobulinemia of Infancy</title></titles><volume>2020</volume><number>January 15</number><dates><year>2020</year></dates><publisher>Immune Deficiency Foundation</publisher><urls><related-urls><url><style face="underline" font="default" size="100%">;(IDF, 2020b). In most children, Ig levels normalise by 2 years of age (with some children taking up to age 6) ADDIN EN.CITE <EndNote><Cite><Author>Knutsen</Author><Year>2019</Year><RecNum>26</RecNum><DisplayText>(Knutsen, 2019)</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578356618">26</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Alan P Knutsen</author></authors></contributors><titles><title>Transient hypogammaglobulinemia of infancy</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Knutsen, 2019). Lymphoproliferative syndromesLymphoproliferative syndromes (LPS) are a heterogeneous group of diseases characterised by the uncontrolled production of T- and B-cells. The result of this is immunodeficiency, a dysfunctional immune system and lymphocyte dysregulation ADDIN EN.CITE <EndNote><Cite><Author>Angel A Justiz-Vaillant and Christopher M Stang</Author><Year>2019</Year><RecNum>27</RecNum><DisplayText>(Angel A Justiz-Vaillant and Christopher M Stang, 2019)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578367085">27</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Angel A Justiz-Vaillant and Christopher M Stang, </author></authors></contributors><titles><title>Lymphoproliferative disorders</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Angel A Justiz-Vaillant and Christopher M Stang, 2019). X-linked LPS (type 1 and 2) is a mutation of the X chromosome which predisposes NK cell and T-cell LPS ADDIN EN.CITE <EndNote><Cite><Author>Angel A Justiz-Vaillant and Christopher M Stang</Author><Year>2019</Year><RecNum>27</RecNum><DisplayText>(Angel A Justiz-Vaillant and Christopher M Stang, 2019)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578367085">27</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Angel A Justiz-Vaillant and Christopher M Stang, </author></authors></contributors><titles><title>Lymphoproliferative disorders</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Angel A Justiz-Vaillant and Christopher M Stang, 2019). CD27 deficiency is an autosomal recessive immunodeficiency disorder associated with LPS. CD27 is a molecule that regulates T-, NK-, B- and plasma cell function, survival and differentiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gTW9udGZyYW5zPC9BdXRob3I+PFllYXI+MjAxMjwv

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ADDIN EN.CITE.DATA (van Montfrans et al., 2012). In its absence, symptoms vary from asymptomatic borderline to low hypogammaglobulinaemia to symptomatic inflammatory response with life threatening complications, including haemophagocytic lymphohistiocytosis, LPS and malignant lymphoma ADDIN EN.CITE <EndNote><Cite><Author>Salzer</Author><Year>2013</Year><RecNum>29</RecNum><DisplayText>(Salzer et al., 2013)</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578368325">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salzer, Elisabeth</author><author>Daschkey, Svenja</author><author>Choo, Sharon</author><author>Gombert, Michael</author><author>Santos-Valente, Elisangela</author><author>Ginzel, Sebastian</author><author>Schwendinger, Martina</author><author>Haas, Oskar A.</author><author>Fritsch, Gerhard</author><author>Pickl, Winfried F.</author><author>F?rster-Waldl, Elisabeth</author><author>Borkhardt, Arndt</author><author>Boztug, Kaan</author><author>Bienemann, Kirsten</author><author>Seidel, Markus G.</author></authors></contributors><titles><title>Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27</title><secondary-title>Haematologica</secondary-title></titles><periodical><full-title>Haematologica</full-title></periodical><pages>473-478</pages><volume>98</volume><number>3</number><dates><year>2013</year></dates><urls><related-urls><url>;(Salzer et al., 2013). People with SCID, WAS, ataxia telangiectasia and CVID are also prone to LPS ADDIN EN.CITE <EndNote><Cite><Author>Angel A Justiz-Vaillant and Christopher M Stang</Author><Year>2019</Year><RecNum>27</RecNum><DisplayText>(Angel A Justiz-Vaillant and Christopher M Stang, 2019)</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578367085">27</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Angel A Justiz-Vaillant and Christopher M Stang, </author></authors></contributors><titles><title>Lymphoproliferative disorders</title></titles><volume>2020</volume><number>January 7</number><dates><year>2019</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(Angel A Justiz-Vaillant and Christopher M Stang, 2019).Ig usage for PID conditionsIg therapy, funded by the NBA, in 2018-19 for the above conditions is described in REF _Ref29197504 \h \* MERGEFORMAT Table 8 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019). The total number of patients treated for that period was 2,292 (in 31,627 episodes), with the largest number of patients treated for CVID ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019). Table SEQ Table \* ARABIC 8 Ig usage, patient and episode numbers for PID with antibody deficiency in 2018-19 ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019)Specific condition nameIg usage (grams)Patient countTreatment episodesTotal Private Public SCID10,4964255086464CID1,094852151Wiskott-Aldrich syndromeA 8455521339CVID639,1091,84726,5905,74020,850Possible CVID7,8015531971248Severe reduction in all Ig isotypes with decreased or absent B-cells826533-33X-linked agammaglobulinaemiaB40,2211181,7252111,514Severe reduction in at least two Ig isotypes with low/normal B-cells 9,5606750468436Severe reduction in serum IgG and IgA with normal/elevated IgM 308216511Transient hypogammaglobulinaemia of infancy3323301317Lymphoproliferative syndromes 348115-15Other PID35,3771391,7412671,474TOTAL746,3162,29231,6276,47525,152Source: Personal Communication from National Blood Authority: Phase 2 HTA conditions, received January 2020. ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2019</Year><RecNum>24</RecNum><DisplayText>(NBA, 2019)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1578355361">24</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>NBA,</author></authors></contributors><titles><title>Phase 2 HTA conditions data</title></titles><dates><year>2019</year><pub-dates><date>23 Decemebr 2020</date></pub-dates></dates><publisher>National Blood Authority Australia, </publisher><urls></urls><access-date>7 January 2020</access-date></record></Cite></EndNote>(NBA, 2019) Abbreviations: CID: combined immunodeficiency; CVID: Common variable immunodeficiency; Ig: immunoglobulin; Ig A: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; SCID: severe combined immunodeficiency.Notes: A = Wiskott-Aldrich syndrome is one example of CID with syndromal features. B = X-linked agammaglobulinaemia is one example of a PID where all Ig isotypes are reduced, and B-cells are decreased/absent. Exclusion Criteria for Ig use in patients with PIDThe Criteria Version 3 outlines that PID patients with the following conditions are not eligible for Ig therapy under this indication (these may be eligible under other indications):Acquired hypogammaglobulinaemia secondary to haematological malignancy or post-haematopoietic stem cell transplantationSpecific antibody deficiencyIgG subclass deficiencySecondary hypogammaglobulinaemia (including iatrogenic immunodeficiency) ADDIN EN.CITE <EndNote><Cite><Author>NBA</Author><Year>2018</Year><RecNum>2</RecNum><DisplayText>(NBA, 2018)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1575946014">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NBA, </author></authors></contributors><titles><title>Criteria for the clinical use of immunoglobulin in Australi (the Criteria)</title></titles><volume>2019</volume><number>December 10</number><dates><year>2018</year></dates><urls><related-urls><url><style face="underline" font="default" size="100%">;(NBA, 2018).Other contraindications to Ig therapy may include allergies to human Ig or to a specific stabiliser or additive ingredient present in the Ig preparation (these vary from product to product).Comparator DetailsThe comparator for Ig replacement therapy for the treatment of PID with antibody deficiency in this Assessment is no Ig (no active treatment). This may or may not include supportive care including antibiotic treatment, prophylactic antibiotics and antimicrobials.Given the broad range of conditions that comprise PID and their clinical variations in presentation, there is no one standard of care treatment for PID ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>7</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007a)</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576628253">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, Philippa</author><author>Riminton, Sean</author></authors></contributors><titles><title>Primary Immunodeficiency Diseases in Australia and New Zealand</title><secondary-title>Journal of Clinical Immunology</secondary-title></titles><periodical><full-title>Journal of Clinical Immunology</full-title></periodical><pages>517-524</pages><volume>27</volume><number>5</number><dates><year>2007</year><pub-dates><date>2007/09/01</date></pub-dates></dates><isbn>1573-2592</isbn><urls><related-urls><url>;(Kirkpatrick and Riminton, 2007a). Standard therapies, other than Ig, may include haematopoietic stem cell transplant and/or gene therapy, splenectomy, thymectomy, chemotherapy, immunomodulation, antivirals, plasmapheresis, rituximab and cytokine inhibitors or supplements (Referral Form; page 22). This, together with the unlikely availability of comparative evidence for this patient population, supports the use of no Ig as an appropriate comparator for this Assessment. Clinical management Algorithms REF _Ref27380868 \h \* MERGEFORMAT Figure 1 and REF _Ref29991544 \h \* MERGEFORMAT Figure 2 describe the current management of patients with PID with antibody deficiency using IVIg, funded by the NBA (for initial access to Ig and continued access to Ig, respectively). It is important to note that these clinical management algorithms are a representation only as not all conditions are able to be captured in the flowchart. REF _Ref29991575 \h \* MERGEFORMAT Figure 3 describes the current management of patients with PID with antibody deficiency, where IVIg is not a treatment option. This is either due to contraindications or ineligibility according to the Criteria Version 3 (including patients who were previously eligible for treatment under the Criteria Version 3 but are no longer, for example, due to treatment failure). -74295033845500Figure SEQ Figure \* ARABIC 1Clinical management algorithm for initial access to Ig for patients with PID with antibody deficiency.Source: Reproduced from Figure 1, page 15 of the Referral Form. Abbreviations: CVID: Common variable immunodeficiency; ESID: European Society for Immunodeficiencies; Ig: Immunoglobulin; PID: Primary Immunodeficiency Diseases-7747029527500Figure SEQ Figure \* ARABIC 2Clinical management algorithm for continued access to Ig for patients with PID with antibody deficiency. Source: Reproduced from Figure 2, page 21 of the Referral Form. Abbreviations: CVID: Common variable immunodeficiency; ESID: European Society for Immunodeficiencies; Ig: Immunoglobulin; PID: Primary Immunodeficiency DiseasesFigure SEQ Figure \* ARABIC 3Clinical management for patients with PID with antibody deficiency in the absence (or failure) of Ig.Source: Reproduced from Figure 3, page 24 of the Referral Form. Abbreviations: Ig: Immunoglobulin; PID: Primary Immunodeficiency DiseasesKey Differences in the Delivery of the Proposed Medical Service and the Main Comparator The main comparator for Ig therapy, for the purposes of this Assessment, is no Ig. The way in which Ig therapy is delivered has been described above. For the comparator (no Ig) standard of care may or may not include supportive treatment including antibiotics and antimicrobials. Clinical ClaimThe following clinical claims have been made regarding Ig use for the treatment of PID with antibody deficiency:Ig has superior effectiveness and inferior safety compared to no Ig.Summary of the PICOThe guiding framework of a PICO Confirmation is recommended by MSAC for each Assessment. The PICO Confirmation describes current clinical practice and reflects the likely future practice with the proposed medical service. The Population, Intervention, Comparator and Outcomes (PICO) that were pre-specified to guide the systematic literature review are presented in Box 1 and REF _Ref395200521 \h \* MERGEFORMAT Box 2.Box SEQ Box \* ARABIC 1Criteria for identifying and selecting studies to determine the safety of Ig in patients with PID with antibody deficiencySelection criteriaDescriptionPopulationPatients with primary immunodeficiency diseases (PID) with antibody deficiency InterventionIntravenous and/or subcutaneous immunoglobulin (IVIg and/or SCIg)ComparatorNo IgOutcomesCritical for decision making: serious adverse events (e.g. antibiotic allergy, anaphylaxis, veno-occlusive events, acute renal failure/dysfunction), antibiotic resistance, blood-borne infections, thrombophlebitis. Important, but not critical for decision making: short-lived, systemic adverse events (e.g. fevers, headaches, allergic reactions, hives, chills, arthralgia, nausea, vomiting, low blood pressure, moderate low back pain).Systematic review questionWhat is the relative safety of Ig (IVIg and SCIg) for the treatment of PID with antibody deficiency? Abbreviations: Ig: immunoglobulin; IVIg: intravenous immunoglobulin; PID: primary immunodeficiency diseases; SCIg: subcutaneous immunoglobulin.Box SEQ Box \* ARABIC 2Criteria for identifying and selecting studies to determine the effectiveness of Ig in patients with PID with antibody deficiency Selection criteriaDescriptionPopulationPatients with primary immunodeficiency diseases (PID) with antibody deficiencyInterventionIntravenous and subcutaneous immunoglobulin (IVIg and SCIg)ComparatorNo IgOutcomesCritical for decision making: number of infections, number of antibiotic treatments, morbidity, quality of life, mortality, IgG trough levels, bronchiectasis.Systematic review questionWhat is the relative effectiveness of Ig (IVIg and SCIg) for the treatment of PID with antibody deficiency?Abbreviations: Ig: immunoglobulin; IgG: immunoglobulin G; IVIg: intravenous immunoglobulin; PID: primary immunodeficiency diseases; SCIg: subcutaneous immunoglobulin.Consumer impact statementThe draft Referral Form was released for Targeted Consultation in August 2019 and the PICO Confirmation was released to Sponsor companies in December 2019. Four submissions were received; three from industry and one from a consumer group. Overall, both industry and the consumer group were supportive of the use of Ig to treat PID as set out by the Criteria Version 3 and depicted in the Referral Form. Industry discouraged further limitation to access of Ig in Australia and expressed concerns about the feasibility of conducting clinical comparisons across a highly heterogeneous population and the Assessment’s ability to draw meaningful conclusions. One sponsor provided feedback on the approach outline in the PICO Confirmation and was supportive of the approach noting that allogenic transplantations may be a relevant comparator to Ig and there were 26 such transplants performed in Australia in 2016. The consumer representative was highly supportive of Ig therapy for PID; and provided personal examples of significant improvements in quality of life. Noted disadvantages included adverse events, regular attendance to hospital for Ig infusions, and time spent travelling and waiting due to delays in day units. However, consumers considered that the advantages of Ig therapy outweigh any potential disadvantages.Section BClinical Evaluation Literature Sources and Search StrategiesThe medical literature was searched on 20/11/2019 (PubMed) and 25/11/2019 (Embase) to identify relevant published studies and systematic reviews. Searches were conducted of the databases and sources described in Appendix B. Search terms are described in REF _Ref363722464 \h \* MERGEFORMAT Table 9. After reviewing the list of references within systematic reviews selected during the drafting of this Assessment, additional relevant references and studies were included. Table SEQ Table \* ARABIC 9Search terms used for the PubMed and Embase searchesElement of clinical questionSearch termsPopulationMeSH words (PubMed)Combined immunodeficiency, x linked combined immunodeficiency, severe common variable immunodeficiency, Wiskott Aldrich syndrome, DiGeorge syndrome, ataxia telangiectasia, hyper IgM syndrome, lymphoproliferative disorder, X linked agammaglobulinemia.Subject headings (Embase)Combined immunodeficiency, common variable immunodeficiency, Wiskott-Aldrich syndrome, Di George syndrome, Ataxia telangiectasia, hyper IgM syndrome, lymphoproliferative disease, transient hypogammaglobulinemia, X linked agammaglobulinemia.Text words (PubMed and Embase)Primary hypogammaglobulinemia, primary immunodeficiencies, primary immunodeficiency, primary immune deficiency, PID and immune, combined immunodeficiency, combined immune deficiency, CVID and immune, SCID and immune, common variable immunodeficiency, common variable immune deficiency, CVID and immune, lymphoproliferative disease, lymphoproliferative syndrome, XLP and immune, Wiskott Aldrich syndrome, DiGeorge syndrome, Ataxia telangiectasia, X linked agammaglobulinemia, Bruton agammaglobulinemia, XLA and immune, Hype IgM syndrome, transient hypogammaglobulinemia, THI and immune, Good syndrome.InterventionMeSH words (PubMed)Immunoglobulins.Subject headings (Embase)Immunoglobulin.Text words (PubMed and Embase)Immunoglobulin, Ig, IVIg, SCIg.LimitsNone usedAbbreviations: CVID: common variable immunodeficiency; IgM: immunoglobulin M; IVIg: intravenous immunoglobulin; MeSH: medical subject headings; PID: primary immunodeficiency; SCID: severe combined immunodeficiency; SCIg: subcutaneous immunoglobulin; THI: transient hypogammaglobulinaemia of infancy; XLA: X-linked agammaglobulinaemia; XLP: X-linked lymphoproliferative disease. Results of Literature SearchA PRISMA flowchart (Figure 4) provides a graphic depiction of the results of the literature search and the application of the study selection criteria (listed in Box 1 and Box 2) (Liberati et al., 2009). Additional pre-specified criteria for study selection are reported in REF _Ref30080881 \h \* MERGEFORMAT Table 10.Table SEQ Table \* ARABIC 10Additional study selection criteriaStudy characteristicIncludeExcludeStudy typeRCTsComparative studiesCase series studies (CVID only)ACase reports (fewer than 10 patients)EditorialsNarrative reviewsConference abstractsLanguageEnglish languageNon-English language studiesAbbreviations: CVID: common variable immune deficiency; RCT: randomised controlled trial.Notes: A: the decision to limit case series studies to only those on CVID was in accordance with the PICO confirmation.From a total of 16,238 references, duplicates and foreign languages records (n = 3,973) were excluded. The remaining 12,265 references were screened by title and abstract by one of three reviewers, with 11,212 of these excluded due to wrong study type, wrong population, wrong intervention or non-English language. Full text review of 1,053 citations was completed by two reviewers independently and disagreements regarding study selection were resolved with a third independent reviewer. Studies that did not meet the inclusion criteria, or that met the inclusion criteria but contained insufficient or inadequate data for inclusion, are listed as Excluded Studies in Appendix D. All other studies meeting the inclusion criteria are listed in Appendix C.Figure SEQ Figure \* ARABIC 4 Summary of the process used to identify and select studies for the assessment Abbreviations: CVID: common variable immunodeficiency; Ig: immunoglobulin; PID: primary immunodeficiency.Study selectionThe searches identified four comparative studies and 17 single arm studies providing pre- and post-Ig treatment data and/or Ig safety data.A profile of each included study is given in REF _Ref364237249 \h \* MERGEFORMAT Appendix C. This study profile describes the authors, study ID, publication year, study design, quality (level of evidence and risk of bias), study location, setting, length of follow-up of patients, study population characteristics, description of the intervention, description of the comparator and the relevant outcomes assessed. Study characteristics are also summarised in a shorter format in Section B.4. Supplementary evidence is presented at the end of Section B.6. This evidence does not directly inform on the comparative safety and effectiveness of Ig compared to no treatment in patients with PID; however, it is evidence considered by the Assessment Group to provide additional context on the use of Ig to treat PID and which may be of interest to the Immunoglobulin Review Reference Group and MSAC. The supplementary evidence has not been assessed for risk of bias, and outcomes are not included in the GRADE quality appraisal presented in B.8.Clinical trials searchA search was conducted of and the Australian and New Zealand Clinical Trials Registry to identify any upcoming evidence that may impact the results of this review. The details of the searches and identified trials are presented in Appendix F. While a large number of trials in patients with PID were identified; none of these trials is expected to provide comparative evidence relevant to this review.Appraisal of the evidenceAppraisal of the evidence was conducted in four stages:Stage 1: Appraisal of the risk of bias within individual studies (or systematic reviews) included in the review (Section B.3).Stage 2: Extraction of the pre-specified outcomes for this assessment, synthesising (meta-analysing or a narrative synthesis) to determine an estimate of effect per outcome and determining the assumed baseline risk. Stage 3: Rating the overall quality of the evidence per outcome across studies, based on the study limitations (risk of bias), imprecision, inconsistency of results, indirectness of evidence, and the likelihood of publication bias. This was done to provide an indication of the confidence in the estimate of effect in the context of Australian clinical practice (Evidence profile tables, REF _Ref421017583 \h \* MERGEFORMAT Appendix D). Stage 4: Integration of this evidence for conclusions about the net clinical benefit of the intervention in the context of Australian clinical practice. (Sections B.6-8)Risk of Bias AssessmentA summary of the risk of bias tables are reported in Appendix C. Comparative studiesAghamohammadi et al. (2009) was assessed for risk of bias using the Cochrane ROBINS-1 tool ADDIN EN.CITE <EndNote><Cite><Author>Sterne</Author><Year>2016</Year><RecNum>41</RecNum><DisplayText>(Sterne et al., 2016)</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1583189733">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sterne, Jonathan AC</author><author>Hernán, Miguel A</author><author>Reeves, Barnaby C</author><author>Savovi?, Jelena</author><author>Berkman, Nancy D</author><author>Viswanathan, Meera</author><author>Henry, David</author><author>Altman, Douglas G</author><author>Ansari, Mohammed T</author><author>Boutron, Isabelle</author><author>Carpenter, James R</author><author>Chan, An-Wen</author><author>Churchill, Rachel</author><author>Deeks, Jonathan J</author><author>Hróbjartsson, Asbj?rn</author><author>Kirkham, Jamie</author><author>Jüni, Peter</author><author>Loke, Yoon K</author><author>Pigott, Theresa D</author><author>Ramsay, Craig R</author><author>Regidor, Deborah</author><author>Rothstein, Hannah R</author><author>Sandhu, Lakhbir</author><author>Santaguida, Pasqualina L</author><author>Schünemann, Holger J</author><author>Shea, Beverly</author><author>Shrier, Ian</author><author>Tugwell, Peter</author><author>Turner, Lucy</author><author>Valentine, Jeffrey C</author><author>Waddington, Hugh</author><author>Waters, Elizabeth</author><author>Wells, George A</author><author>Whiting, Penny F</author><author>Higgins, Julian PT</author></authors></contributors><titles><title>ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions</title></titles><pages>i4919</pages><volume>355</volume><dates><year>2016</year></dates><urls><related-urls><url> %J BMJ</electronic-resource-num></record></Cite></EndNote>(Sterne et al., 2016). Overall, the study was judged to be at serious risk of bias. Key issues included the likely failure to adjust for all confounding issues, the potential that patients with a delayed diagnosis may have a different disease course than those diagnosed immediately, the selection of patients based on characteristics observed after starting the intervention, uncertainty into how many patients were eligible for the study but not enrolled, and uncertainty around how many patients had missing data or incomplete medical histories recorded.The risk of bias for the three studies investigating IMIg has not been assessed and they are included as supplementary evidence only. Case seriesBy nature, case series studies have an inherent risk of bias compared to randomised controlled trials (RCT). In the absence of comparative data, case series studies were used to inform the safety and effectiveness of Ig usage for CVID. The Institute of Health Economics (IHE) quality appraisal checklist tool was used to appraise the quality of the selected case series ( REF _Ref30399046 \h \* MERGEFORMAT Table 37, Appendix C) ADDIN EN.CITE <EndNote><Cite><Author>IHE</Author><Year>2012</Year><RecNum>42</RecNum><DisplayText>(IHE, 2012)</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1583190222">42</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>IHE,</author></authors></contributors><titles><title>Development of a quality appraisal tool for case series studies using a modified Delphi technique </title></titles><volume>2020</volume><number>3 March</number><dates><year>2012</year></dates><publisher>Institute of Health Economics</publisher><urls><related-urls><url>;(IHE, 2012). Overall, the studies selected for this review have a high risk of bias. Most studies described the treatment, population characteristics and inclusion criteria appropriately, drew sound conclusions from the results presented, used appropriate statistical methods for the analysis of the results and presented data on random variability. Limitations of the case series studies were that most studies were retrospective, unblinded, conducted in single centres with non-consecutive recruitment, and most also failed to report their source of funding and conflicts of interest. Most studies failed to describe and assess co-interventions and confounding factors appropriately. Despite these limitations, no studies were excluded from this review due to an acceptably high risk of bias.Characteristics of the Evidence BaseFour non-randomised comparative studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2hhbW9oYW1tYWRpPC9BdXRob3I+PFllYXI+MjAwOTwv

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b3RlPn==

ADDIN EN.CITE.DATA (Aghamohammadi et al., 2009b, Cunningham-Rundles, 1989, Gardulf et al., 1993, Waniewski et al., 1994) and seventeen case series studies were identified for inclusion in this Assessment dXNpdGlzL2RpYWdub3Npczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk0PC95

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ADDIN EN.CITE.DATA (Aghamohammadi et al., 2003, Aghamohammadi et al., 2008, Alkan et al., 2017, Baris et al., 2011, Bayrakci et al., 2005, Busse et al., 2002, de Gracia et al., 2004, Martinez Garcia et al., 2001, Pourpak et al., 2006, Quinti et al., 2008, Quinti et al., 2007, Salehzadeh et al., 2010, Singh et al., 1994, Aghamohammadi et al., 2004, Berger et al., 2007, Bichuetti-Silva et al., 2014, Dashti-Khavidaki et al., 2009). Details on the individual studies included in the evidence base are provided in Appendix C and discussed below.The characteristics of the comparative studies are summarised in Appendix C and REF _Ref33534175 \h \* MERGEFORMAT Table 13. Aghamohammadi et al. (2009) compared the effectiveness of IVIg to no treatment (due to delayed diagnosis) in patients with CVID. Three other studies were identified that included a very limited comparison between patients predominantly on IMIg before entering the study to patients who had not received treatment prior to study enrolment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdW5uaW5naGFtLVJ1bmRsZXM8L0F1dGhvcj48WWVhcj4x

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ADDIN EN.CITE.DATA (Cunningham-Rundles, 1989, Gardulf et al., 1993, Waniewski et al., 1994). In these three studies, this comparison was not the primary aim of the study and is based on data collected at the study baseline. The primary aim of these studies was to investigate the pre/post impact of SCIg treatment on patients. The characteristics of the 17 single arm studies reporting pre/post data on the effect of Ig in patients with CVID is reported in Appendix C and summarised in REF _Ref33424408 \h \* MERGEFORMAT Table 14 below. The studies included a total of 1,010 patients with CVID, with a slightly higher proportion of male patients overall (350 males, 312 females in studies reporting patient gender). Length of follow-up ranged from six months to eleven years with eleven studies reporting mean/medium follow-up of at least two years.CVID was diagnosed according to the Pan-American Group for Immunodeficiency and the European Society for Immunodeficiencies (PAGID/ESID) criteria in ten studies, the WHO criteria in five studies, and two studies did not report which diagnostic criteria were used. The Criteria Version 3 defines CVID as below normal serum IgG and IgA (with or without IgM decrease) and possible CVID as below normal serum IgG but normal serum IgA level. The included studies provide a definition most consistent with CVID, not possible CVID; therefore, the applicability of this evidence to patients with possible CVID as defined in the Criteria Version 3 is not known.The mean/median age of patients varied widely across studies and ranged from 1.8 to 45 years. Seven studies reported mean/median age range less than 18 years while five studies reported a mean/median age greater than 18 years. Only one study (Baris et al., 2011) restricted enrolment to paediatric patients. The mean/median diagnostic delay experienced by patients ranged from 3.25 to 8.9 years. Five studies did not report baseline demographics for CVID patients separately. IVIg was used to treat patients in 15 of the studies, with doses typically delivered every three to four weeks ranging from 200 mg/kg to 800 mg/kg. Most studies used doses in the range of 300-500 mg/kg every three to four weeks. One study (de Garcia et al., 2004) used an initial loading dose of 200-300 mg/kg weekly for three weeks then 300 mg/kg once every three weeks.Bayrakci et al. (2005) and Singh et al. (1994) reported that patients were treated with either IVIg or IMIg and did not report results for the two routes of administration separately. Co-interventions included prophylactic antibiotics, chest therapy, inhaled corticosteroids and/or bronchodilators. In studies reporting their use, these interventions were usually targeted to patients with recurrent infections or patients with chronic pulmonary conditions. However, use of co-interventions was poorly reported with only five of seventeen studies commenting on their use. Advice from the Immunoglobulin Review Reference Group is that in Australia, co-interventions would typically include antibiotics and other antimicrobial agents (prophylactic, acute, and as rescue treatments), nebulised therapy (for example hypertonic saline), physiotherapy, nutritional support, treatment for autoimmune manifestations including immunosuppressive medications, cessation of smoking interventions, and support and bone marrow transplantation. Several potential applicability issues were identified with the evidence base, which may limit the generalisability of the results to the Australian clinical context. These are summarised in REF _Ref34054825 \h \* MERGEFORMAT Table 11.Table SEQ Table \* ARABIC 11Potential applicability issues identifiedPotential applicability issueEvidence baseIg use in AustraliaHow has issue been addressed?PopulationEvidence only covers patients with CVIDThe Criteria Version 3 covers Ig use for other forms of PID. These conditions may have different outcomes than those reported for CVID.The approach for the Assessment is in line with the PICO Confirmation and CVID is the PID for which Ig is most commonly funded in Australia (86% of Ig usage for PID in 2018/19 based on NBA data)ATherefore, the evidence is applicable to most Ig use.The applicability of the results to other PID conditions should be noted as an uncertainty.Age of patientsMany studies weighted towards paediatric patients, with seven studies reporting average patient age <18 years. From NBA data the average age of patients with CVID was 53 yearsSubgroup of studies which report a mean/median patient age similar to the Australian data were investigated separately to see if any difference in trend was observed.Diagnostic criteria usedSee also REF _Ref34057550 \h \* MERGEFORMAT Table 12PAGID/ESID 1999WHO 1999The Criteria Version 3See REF _Ref34057550 \h \* MERGEFORMAT Table 12 for a breakdown of differences between the different diagnostic criteria. While there are differences in the diagnostic criteria used in the evidence base and that required by the Criteria Version 3, these are considered unlikely to present a substantial applicability issue; however, this is noted as an uncertainty.Ig dosagesRange 200-800 mg/kg 3-4 weekly, most studies 300-500 mg/kg 3-4 weeklyMaintenance Dose (IVIg) 400-600 mg/kg every 4 weeks or more frequently to achieve IgG trough levels at least at the lower limit of the age-specific IgG reference range.Total dose 1000 mg/kg may be given in any 4-week period.Loading dose: 400 mg/kg in first month (in addition to maintenance) if serum IgG < 4g/lMedian dose 340 mg/kg per episodeMost studies used IVIg doses which would be allowed under The Criteria Version 3. This is noted as an uncertainty but evidence likely to be generalisable to Australian Context.Ig administration methodEvidence in IVIgCriteria allows SCIg and IVIgSupplementary evidence included to investigate any differences in safety/effectiveness between IVIg and SCIg.IMIg used in some (older studies)Criteria does not allow IMIgSupplementary evidence included to investigate any differences in safety/effectiveness between IVIg and IMIg. Advice from the Immunoglobulin Review Reference Group is that IMIg is no longer used ; therefore while this information may provide some information as to the effectiveness of Ig, the level of Ig may be subtherapeutic with IM administration and the associated response sub-optimal.Impact of co-interventionsPoorly reported in most studiesAdvice from the Immunoglobulin Review Reference Group is that in Australia, co-interventions including: prophylactic antibiotics, physiotherapy, hypertonic saline, nutritional supplementation, treatment of asthma, allergic rhinitis, sinus and middle ear surgery are the standard of care when patients are indicated.This may represent a significant generalisability issue and may confound the results of the review.Studies that report co-interventions and their effect separately have been investigated separately to attempt to quantify any confounding effect.Advice from the Immunoglobulin Review Reference Group is that it is difficult to separate the effect of Ig and any co-interventions. Abbreviations: CVID: common variable immunodeficiency, IgG: immunoglobulin G, IMIg: intramuscular immunoglobulin, IVIg: intravenous immunoglobulin, NBA: National Blood Authority, PAGID/ESID: Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, PICO: population, intervention, comparator, outcomes, PID: primary immunodeficiency diseases, SCIg: subcutaneous immunoglobulin, WHO: World Health Organisation.Note A: The percentage ultilisation of 86% of Ig usage for PID being attributable to patients with CVID is based data provided by the NBA for 2018-19 (summarised in Table 8, Section A.4. of this report) and only considers usage for CVID (not including possible CVID).Table SEQ Table \* ARABIC 12Diagnostic criteria used in the studiesCriteriaSerum IgWHO (1999)Decreased serum IgG and IgA (not necessarily IgM)Diagnosis based on inclusion of other known causes of humoral immune defectsPAGID/ESID 1999Marked decrease in IgG (at least 2 SD below mean for age) and a marked decrease in IgA or IgMOnset > 2 years of ageAbsent isohemagglutinins and/or poor response to vaccinesDefined causes of hypogammaglobulinemia have been excludedThe Criteria Version 3Onset > 4 yearsMarked decrease in IgG with marked decrease in IgA with or without low or IgMDocumented failure of serum antibody response after vaccination OR IgG < 2 g/L and delay providing Ig therapy would present a significant risk OR absent haemagglutinins (if blood group not AB) OR patient has low switched memory B-cells (< 70% age-related normal value)Patient has increased susceptibility to infection OR patient has autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation or an affected family member with antibody deficiencyInitial review by an immunologist is required at 6 months and annually thereafter. Documentation of clinical effectiveness is required for continuation of Ig therapy.Key differences Age of onset > 2 years in the criteria used by the studies vs > 4 years in The Criteria Version 3.The Criteria Version 3 requires marked decrease in IgG and IgA (with or without IgM decrease) whereas other criteria require marked decrease in IgG with decrease in either IgA or IgM or both. The Criteria Version 3 requires a review by an immunologist after 6 months and documented clinical effectiveness is necessary for continuation of Ig therapy. The studies did not report whether an equivalent review was conducted; therefore, it is not clear how many patients in the included studies were not responding to Ig therapy and would have had therapy discontinued if this was required. No data was found investigating how many patients fail to respond to Ig therapy. Inclusion of patients who are not responding to therapy is likely to underestimate the effectiveness of Ig.Advice from the Immunoglobulin Review Reference Group is that it is very unlikely a patient with CVID would cease Ig treatment and it is unlikely that any patients in the included studies would have remained on Ig treatment if they were not responding, therefore, this is unlikely to present a significant applicability issue.Abbreviations: IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, SD: standard deviation, WHO: World Health Organisation. Table SEQ Table \* ARABIC 13Characteristics of the comparative studiesAuthor (year)CountryStudy designRoBDuration of follow-upNumber of patientsPatient populationDiagnostic criteriaPatient baseline characteristicsInterventionComparatorKey outcome(s)Aghamohammadi et al. (2009)IranComp, RetroSCHighI: median 7 years (range 4-21) C: median 5 years (range 1–15) I: n = 23C: n = 24CVID patients aged > 2 years referred to a medical centre between 1984–2009.I: Patients diagnosed within 6 years of onset and received appropriate treatment for at least 5 yearsC: Patients with a diagnostic delay > 6 years matched for age and gender with the I groupCriteria: PAGID/ESIDI groupM = 10, F = 13Median age = 15.6 yrs (range 7-50)Onset age: NRDiagnostic delay: median 2.6 yrs (range 0.5-5)C groupM = 12, F = 12Median age = 14.6 yrs (range 8-42)Onset age: NRDiagnostic delay: median 8.4 yrs (range 6-32)IVIg (400-600 mg/kg, every 3-4 weeks).Prophylactic antibiotics, antibiotics at first sign of infection, regular outpatient visits. No Ig or prophylactic treatment due to delayed diagnosisInfections, hospital admissions, non-infectious complications, bronchiectasis, missed days from work or school, mortalityCunningham-Rundles (1989)USAComp, RetroSCNANRI: n = 46C: n = 57Consecutive CVID patients aged > 2 yearsCriteria: March of Dimes Birth Defects CriteriaI + C combinedM = 51, F = 52Age mean 29 yrs (range 3-71)Onset age: mean 25 yrsDiagnostic delay: mean 3 yrsIMIg (dose NR)No treatmentTrough IgG, IgA and IgM levelsGardulf et al. (1993)SwedenComp, RetroMCNANRI: n = 15C: n = 10Consecutive patients aged ≥ 18 years with CVID (n = 23), XLA (n = 1), thymoma with hypogammaglobulinemia (n = 1)Criteria: NRI + C combinedM = 12, F = 13Age mean 43 yrs (SD 16)Onset age: mean 25 yrsDiagnostic delay: median 10 yrs (range 1-56)IMIg (n = 13) or IVIg (n = 2) for mean of 78 months (dose NR)No treatmentFunctional status, Recreational activity, IgG trough levelsWaniewski et al. (1994)PolandComp, RetroSCNANRI: n = 17C: n = 6Patients with CVID and increased infection rate aged ≥ 18 yearsCriteria: WHOI + C combinedM = 9, F = 14Age, onset age and diagnostic delay NRIMIg (dose NR)No treatmentSerum IgG levelsAbbreviations: C: comparator group; Comp: comparative study; Criteria: refers to the diagnostic criteria used to identify patients; CVID: common variable immunodeficiency, F: female patients, I: intervention group; Ig: immunoglobulin; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; IMIg: intramuscular immunoglobulin; IVIg: intravenous immunoglobulin; M: male patients, MC: multicentre study, n: number of patients; NA: not assessed, NR: not reported; PAGID/ESID: Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, PID: Primary Immunodeficiency Disease; Retro: retrospective study; SC: single centre study, SCIg: subcutaneous immunoglobulin; SD: standard deviation,.XLA: X-linked agammaglobulinaemia.Table SEQ Table \* ARABIC 14Characteristics of the single-arm studies of patients with CVIDAuthor (year)CountryStudy designRoBDuration of follow-upNumber of patients CVIDTotal CVID patient populationPatients baseline characteristicsInterventionCo-interventionsKey outcome(s)Aghamohammadi et al. (2003)IranCS, Pros, SCHigh36 months2545CVID patients receiving IVIg at a single referral centre from 1997-2000 Criteria: WHOM = 13, F = 12Mean age = 15.8 yrs (SD 6.5)Onset age, diagnostic delay, both NRIVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRTrough IgG levelsAEsAghamohammadi et al. (2004)IranCS, Retro, SCHighNR data collected over 7 yrs3171CVID patients receiving IVIg at a single referral centre from 1995-2002 Criteria: WHOM = 51, F = 20Mean age: 13.8 yrs (SD 5.5)Onset age, diagnostic delay, both NRIVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRAEsAghamohammadi et al. (2008)IranCS, Retro, SCHighMedian 3 years (range 0.1-18)64109CVID patients diagnosed and treated at a single referral centre from1980-2004Criteria: PAGID/ESIDM = 33, F = 31Median age 12.5 yrs (range 2.3-56)Onset age: median 2 yrs (range 0.5-46)Diagnostic delay median 3.25 yrs (range 0.5-39)IVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRIgG serum levelInfection (otitis media and sinusitis)Alkan et al. (2018)TurkeyCS, Retro, SCHighNR, data collected over 11 yrs1212CVID patients diagnosed at a single centre from 2001-2012Criteria: PAGID/ESIDM = 7, F = 5Median age 11.6 (SD 3.7)Onset age: median 7.2 yrs (SD 4.1)Diagnostic delay: median 4.3 yrs (SD 2.6)IVIg 500 mg/kg every 3 weeksCo-interventions: NRInfection (upper respiratory, lower respiratory)Bronchiectasis (rates and prognosis)Baris et al. (2011)TurkeyCS, Retro, SCHighMean 5.6 yrs (SD 3.5, range 1.3-14)Pre-Ig mean follow-up 1.1 yrs (SD 1.5)2929Paediatric CVID patients diagnosed at a single centre and monitored for at least 12 months pre/post Ig treatment from 1994-2009Criteria: PAGID/ESIDM = 22, F = 7Mean age: 1.8 yrs (SD 6.1)Onset age: mean 21 mo (SD 26.4)Diagnostic delay: mean 3.9 yrs (SD 3.3)IVIg 500 mg/kg every 3 weeksCo-interventions: Antibacterial prophylaxis (patients with upper respiratory infections >1 per mo), daily chest therapy, inhaled corticosteroids, bronchodilators (patients with bronchiectasis)Serum IgG levelsInfections (respiratory, gastrointestinal) Bronchiectasis (rates and prognosis)Hospital stays (length and number)Antibiotic usageGrowthBayrakci et al. (2005)TurkeyACS, Retro, SCHighMedian 4.25 yrs (range 1.25-12.25)2046CVID patients treated at a single centre from 1984-2000Criteria: WHOM = 20, F = 30Median age: 13.8 yrs (range 7.8-22.3)Onset age: median 1.8 yrs (range 0.1-5)Diagnostic delay: median 4.5 yrs range 0.25-11.4)IIVIg orIMIg median dose 370 mg/kgCo-interventions: Antibacterial prophylaxis (patients with upper respiratory infections >1 per mo)Trough Ig levelsInfection and hospitalisation ratesAEsBerger et al. (2007)USA/CanadaCS, Pros, MCHigh0.5 yrs32 (ITT)42Patients treated with stable IVIg therapy for > 6 mo at 11 sites in USA and 2 sites in Canada from 2004-2005Criteria: PAGID/ESIDBaseline data for CVID patients NRIVIg 200-800 mg/kg every 3-4 weeksCo-interventions: NRAEsBichuetti-Silva et al. (2014)BrazilCS, Pros, SCHigh2 yrs50117All patients with CVID who had received at least one dose of IVIg from August 2011-August 2013.Criteria: PAGID/ESIDBaseline data for CVID patients NRIVIg median dose 600 mg/kg every 3-4 weeksCo-interventions: NRAEsBusse et al. (2002)USACS, Retro, SCHighMean 6.6 yrs on IVIgB5050Most recently referred patients with CVID Criteria: PAGID/ESIDM = 20, F = 30Mean age: 42.0 yrs (SD 16.3)Age at onset, diagnostic delay NRIVIg 300-400 m/kg every 3-4 weeksCo-interventions: NRInfection rates (pneumonia)Dashti-Khavidaki et al. (2009)IranCS, Retro, SCHighNR data collected over 13 years5499Patients with CVID on stable IVIg treatment who had received at least 4 infusionsCriteria: PAGID/ESIDBaseline data for CVID patients NRIVIg 300-600 mg/kg every 3-4 weeksCo-interventions: NRAEsDe Garcia et al. (2004)SpainCS, Retro, SCHigh2 yrs2424Consecutive adult patients with CIVD diagnosed 1994-2001Criteria: WHOM = 10, F = 14Mean age: 45 yrs (SD 18)Onset age: NRDiagnostic delay: NRIVIg 200-300 mg/kg weekly for 3 weeks then every 3 weeks. Additional IVIg given if trough Ig levels < 600 mg/kg or if bacterial infections persistedCo-interventions:Postural drainage, chest percussion, bronchodilators, inhaled steroids and antibiotics considered if CPD presentIgG levels, Infection (serious and mild)AEsMartinez Garcia et al. (2001)SpainCS, Retro, SCHighMean 7.5 yrs1919Patients diagnosed with CVID on Ig replacement therapyCriteria: NRM = 12, F = 7Mean age: 33 yrs (SD 17.1)Onset age: mean 14.7 yrsDiagnostic delay: mean 8.5 yrsIVIg 300-600 mg/kg every 3 weeksCo-interventions: NRInfection (upper respiratory, pneumonia, sinusitis, otitis media) chronic pulmonary conditions (bronchiectasis, COPD, tuberculosis, asthma)Pourpak et al. (2006)IranCS, Retro SCHighMean 3.5 yrs (SD 2.95)2626Patients diagnosed with CVID from 1999-2002 receiving IVIg who had been observed for at least 9 moCriteria: WHOM = 14, F = 12Mean age: 12.4 yrs (SD 5.6)Onset age: mean 2.5 yrs (SD 3)Diagnostic delay: mean 5.7 yrs (SD 3.9)IVIg 400 mg/kg every 3-4 weeksCo-interventions: NRInfection (pneumonia)Hospital admission IgG levelsQuinti et al. (2008)ItalyCS, Pros, MCHigh1982 patient years262262Patients diagnosed with CVID in the Italian Primary Immunodeficiency Network (26 centres) from 1999-2007Criteria: PAGID/ESIDNRIVIg 400 mg/kg 2-3 weeklyCo-interventions: antibiotic prophylaxis (11.6% of patients)AEsQuinti et al. (2007)ItalyCS, Pros, MCHighMean 11.5 yrs (range 3-34)224224Patients diagnosed with CVID in the Italian Primary Immunodeficiency Network (26 centres) from 1999-2007Criteria: PAGID/ESIDM = 111, F = 113Mean age: 26.6 yrs (range 2-73)Onset age: mean 16.9 yrs (range 2-66)Diagnostic delay: mean 8.9 yrsIVIg 400 mg/kg 2-3 weeklyCo-interventions: antibiotic prophylaxis (11.6% of patients)Serum IgG levelsInfection (prevalence)Salehzadeh et al. (2010)IranCS, Retro, SCHighMean 8 yrs (SD 4.6)2424Patients aged >= 2 yrs with CVID diagnosed Criteria: PAGID/ESIDM = 17, F = 7Mean age 19.5 yrs (SD 12.6)Onset age: NRDiagnostic delay: median 5.3 yrs (0.25-39.75)IVIg 300-600 mg/kg every 3-4 weeksCo-interventions: NRSerum IgG levelsInfection (prevalence)Hospital admission ratesSingh et al. (1994)IndiaCS, Retro, SCHighNR1414Patients with CVIDCriteria: NRM = 10, F = 4Age range 2-40 yrsOnset age: NRDiagnostic delay: NRIVIg 10 ml/kg or IMIg 100 mg/kg at an interval to prevent diarrhoea and chest infectionsCo-interventions: prophylactic antibiotics usedAEsAbbreviations: AEs: adverse events; CS: case series study; Consec: consecutive patients; COPD: chronic obstructive pulmonary disease; CPD: chronic pulmonary disease; CVID: common variable immunodeficiency; F: number of female patients; IgG: immunoglobulin G; IMIg: intramuscular immunoglobulin, IVIg: intravenous immunoglobulin; ITT: intention to treat population; M: number of male patients; MC: multicentre; Mo: months; NR: not reported, PAGID/ESID: Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, PP: per protocol population; Pros: prospective study design; Retro: retrospective study design; SC: single centre; SD: standard deviation), USA: United States of America, WHO: World Health Organisation, Yrs: years.Note: A = Bayrakci et al. (2005) data was reported in trimesters, one trimester calculated to be 3 months based on total length of follow-up of 2733 months equating to 911 trimesters); B = Busse et al. (2002) note 3 patients began treatment on IMIg then switched to IVIg. Outcome Measures and AnalysisSee Appendix C for details on the outcomes measured in the included studies, along with the statistical methods used to analyse the results.No minimum clinically important difference (MCID) was defined for any outcome in the included studies. A targeted literature search also failed to identify any MCID. Advice from the Immunoglobulin Review Reference Group is that it is difficult to define an MCID for these outcomes as many variables need to be considered (including severity of infections, risks from infection, availability of hospital beds, time off work and school).The following methods were used to measure each outcome:Adverse events were assessed:during infusions by an immunologist and/or nurse and recorded on an a priori questionnaire (3 studies)during infusion by an immunologist and/or nurse and followed-up with a phone call to the patient 2-4 days post-infusion (1 study)during the infusion as observed by a clinician and reported by the patient at follow-up (1 study)IgG levels were measured by nephrology. IgG levels are a surrogate outcome purported to be linked to patient-relevant outcomes (e.g. infection rate). The validity of IgG as a surrogate has been investigated for patients with CVID. Gathmann et al. (2014) analysed data on 2,212 CVID patients and found IgG levels were negatively associated with rate of pneumonia (p < 0.01). When patients were categorised into one of five trough IgG level groups (<4 g/l, 4-7 g/l, 7-10 g/l, 10-12 g/l and > 12 g/l) there was a significant inverse relationship between IgG level and serious infection. IgG was also inversely associated with days in hospital when comparing patients with IgG levels < 4 g/l to those with levels >4 g/l. No relationship for “days missed” or “infection episodes (any severity)” were observed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXRobWFubjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

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ADDIN EN.CITE.DATA (Gathmann et al., 2014). Orange et al. (2010) investigated the impact of trough IgG levels on pneumonia incidence and found that pneumonia incidence declined by 21% for each 100 mg/dl increase in IgG (incidence ratio for CVID patients 0.785, 95% CI = 0.697, 0.885). Results from these studies indicate that it is relevant to report IgG levels and that higher levels may correspond to improved patient outcomes. A relevant clinically important trough level of IgG may be at a cut off of 4 g/l PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmFuZ2U8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Orange et al., 2010). A recent review investigated the impact of increasing IgG trough levels on infection rates in patients with PID and found that titrating IgG trough levels up to 9.9 g/l was associated with reduced rates of infections; however, titrating IgG beyond this level was not associated with increased benefit. The optimum IgG trough level for patients with PID is still unclear PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Lee et al., 2020). Advice from the Immunoglobulin Review Reference Group is that it is difficult to define a single value of IgG level that would represent a clinically meaningful response. The advice is that the aim of treatment is to normalise and reduce infection rather than achieve any one target IgG level.Infection was measured:from patient record review; only those requiring treatment were included (2 studies)from a review of patient records (4 studies)from a medical history and physical exam (1 study)via 6 monthly patient-reported via questionnaire (1 study)via 12-monthly structured physician-completed questionnaire (2 studies)Chart reviews and patient histories were supplemented by routine blood work (e.g. white cell counts), cultures and imaging. Due to the retrospective nature of many of the studies it is possible that infections, particularly those that did not require hospitalisation and/or treatment, may have been under-reported. However, patients with a diagnosis of PID are closely monitored and are likely to have had more accurate reporting of outcomes. Any under-reported infections are more likely to have occurred before diagnosis and this may underestimate the effectiveness of Ig treatment.Bronchiectasis was defined by the presence of:Chronic productive cough combined with characteristic CT findings (1 study)Reduced pulmonary function combined with high resolution CT findings reviewed by two independent chest radiologistsFindings on high resolution CT following blinded independent review by a radiologist and a pulmonologistDue to the low quality of the evidence base and lack of comparative studies it was not deemed appropriate to pool any results. Therefore, the results in Section B.6 are described narratively. Results of the Systematic Literature reviewIs it safe? Summary – What is the safety of Ig in patients with PID?No comparative safety data was identified. Given the comparator is ‘no treatment’ there are not expected to be any safety issues relevant to the comparator.Ig use was associated with mostly mild adverse events (chills, flushing, fever, nausea, headache, muscle ache, mild anxiety, pharyngolaryngeal pain, fatigue and hypotension) occurring in 14% to 67% of patients and 2% to 22% of infusions.Moderate events (rash, severe headache abdominal pain, joint pain, chest tightness, vomiting, wheezing and mild dyspnoea) occurred in 6.7% to 24% of patients and 0.2% to 1.5% of infusions, and were resolved by slowing or stopping the infusions.Severe events (severe chest pain, severe wheezing/breathlessness, severe headache, severe dizziness, tightness of the throat, sensation of pressure in the chest, collapse and moderate events that were persistent and could not be prevented by pre-infusion treatment with steroids and antihistamines) were rare, occurring in 0% to 5% of patients and 0% to 0.2% of infusions. These events required adrenaline, hospitalisation, withdrawal of treatment or changing to subcutaneous Ig administration.No study assessed the comparative safety of Ig and no treatment (including placebo trials). In this section, the safety of Ig in this section was informed from single arm studies investigating the safety of Ig in patients with CVID. REF _Ref34202331 \h \* MERGEFORMAT Table 15 summarises adverse events from the ten single-arm studies reporting data on the safety of Ig therapy. Most studies reported adverse events across the entire PID population of the study rather than reporting outcomes for CVID separately. When all PID patients have been pooled this is reflected in the table.Most adverse reactions experienced by the patients were mild and transient, occurring in 42% of patients overall (range per study 14% to 66.7%) and 8% of infusions overall (range per study 1.8% to 21.7%). Mild reactions included chills, flushing, fever, nausea, headache, muscle ache, mild anxiety, pharyngolaryngeal pain, fatigue and hypotension. These events were resolved by stopping or slowing the infusion rate. Discontinuation of Ig treatment was not required.Moderate adverse events including rash, severe headache, abdominal pain, joint pain, chest tightness, vomiting, wheezing and mild dyspnoea, occurred in 6.7% to 24% of patients and 0.2% to 1.5% of infusions. These reactions led to slowing of the infusion, discontinuation of the infusion, and in some cases a change in Ig brand. Treatment included antihistamines, corticosteroids and/or anti-inflammatory agents. Severe adverse events were rare, occurring in 0% to 5% of patients and 0% to 0.2% of infusions. Severe events included severe chest pain, severe wheezing/breathlessness, severe headache, severe dizziness, tightness of the throat, sensation of pressure in the chest and collapse. Moderate events that were persistent and could not be prevented by pre-infusion treatment with steroids and antihistamines were also included in this category. Treatment required adrenaline and in some cases hospitalisation. For at least some patients with severe reactions treatment was withdrawn or the patient was switch to subcutaneous Ig administration which was reportedly well tolerated (Quinti et al., 2008).Three studies reported similar adverse event rates for CIVD and other PIDs (Bayrakci et al., 2005, Berger et al., 2007, Bicuuetti-Silva et al., 2014,), while, two studies reported that the adverse event rate was higher for patients with CVID (23% vs 12.4% and 8.5% vs 3.5% respectively) (Aghamohammadi et al., 2004 and Dashti-Khavidaki et al., 2009). Berger et al. (2007) observed that the adverse event rate was highest for the first infusion compared to subsequent infusions (47.6% vs 22-38%).Table SEQ Table \* ARABIC 15Summary of safety dataAuthor (year)CountryNumber of patientsDuration of follow-upTotal AE rate Per patient Per infusionMild AEs Per Patient Per infusionModerate AEsPer patient Per infusionSevere AEsPer patient Per infusionDescription of AEs and treatmentAghamohammadi et al. (2003)Iran45 (all PID patients pooled)3 yrsPP: 25/45 (55.6%) PI: 50/955 (5.2%)PP: 22/45 (48.9%)PI: 40/955 (4.2%)PP: 3/45 (6.7%)PI: 10/955 (1%)PP: 0/45 (0%)Mild: Chills, flushing, fever, nausea, headacheAll subsided with slowed infusion rateModerate: Rash, severe headache, abdominal pain, joint pain, chest tightnessTreated with antihistamines and/or hydrocortisoneAghamohammadi et al. (2004)Iran71(all PID patients pooled)NR data collected over 7 yrsPP: 35/71 (49.3%)PI: 152/1231 (12.4%)PP: 33/71 (46.5%)PI: 131/1231 (10.6%)PP: 12/71 (16.9%)PI: 19/1231 (1.5%)PP: 2/71 (2.8%)PI: 2/1231 (0.2%)Mild: chills, fever, flushing, muscle aches, nausea, headache, anxietyAll subsided with slowed infusion rateModerate: vomiting, chest pain, wheezingTreated with antihistamines and/or hydrocortisoneSevere: severe chest pain, severe wheezing, severe headache.Treatment NRNote: AE rate for CVID per infusion was higher than for the rate of all PID infusions pooled (23% vs 12.4%)Bayrakci et al. (2005)TurkeyB46 (all PID patients pooled)Median 4.25 yrs (range 1.25-12.25PP: 3/46 (6.5%)PI: NRPP: NRPI: NR39 events totalPP: NRPI: NR12 events totalPP: NRPI: NR2 events totalMild/Moderate: type NR, resolved by changing infusion rate or switching Ig brandSevere: hospitalisation required for 2 patientsNote: no patient required therapy discontinuationNote: AE rate for CVID patients was similar to the rate of all PID infusions pooled (5.5% vs 5.8%)Berger et al. (2007)USA/Canada42 (ITT, all PID patients pooled)0.5 yrsPP: 25/42 (60%) PI: 100/314 (32%) PP: 23/42 (54.8%)PI: 69/42 (21.7%)NR PP: 0/42 (0%)Mild: headache (59.5%), pharyngolaryngeal pain (38.1%), sinusitis (28.8%), diarrhoea (23.8%), fatigue (23.8%), nausea (23.8%), pyrexia (23.8%)Moderate: mild dyspnoea resolved by stopping infusionNote: AE rate for CVID patients was similar to the rate of all PID infusions pooled (62% vs 60%).AE rates were higher for first infusion compared to subsequent ones (47.6% vs 22.2-37.5%)AE rates higher with higher doses of IgBichuetti-Silva et al. (2014)Brazil117 (all PID patients pooled)2 yrsPP: 28/117 (23.9%)PI: 38 /1765 (2.2%)PP: NRPI: 31/1765 (1.8%)PP: NRPI: 4/1765 (0.2%)PP: NRPI: 3/1765 (0.2%)Mild: headache, fever, chills, nausea, emesis, hypotension, muscle crampsModerate: reactions necessitating discontinuation of infusionSevere: moderate reactions that were persistent, tightness of throat, severe shaking, severe breathlessness or wheezing, severe dizziness, sensation of pressure in the chest, collapse. Severe reactions required adrenaline treatment.Note: AE rate for CVID patients was similar to the rate of all PID infusions pooled (2.3% vs 2.2%)Dashti-Khavidaki et al. (2009)Iran99 (all PID patients pooled)NR data collected over 13 yearsPP: 66/99 (66.7%)PI: 216/3004 (7.1%)PP: 66/99 (66.7%)PI: 172/3004 (5.7%)PP: 24/99 (24%)PI: 41/3004 (1.4%)PP: 3/99 (3%)PI: 3/3004 (0.1%)Mild: chills, fever, cold feeling, backache, headacheModerate: vomiting, chest pain, wheezingTreatment: infusion stopped or rate reduced, antihistamines, anti-inflammatory agents and/or corticosteroids administeredSevere: severe chest pain, severe wheezing, severe headacheNote: AE rates per infusion varied depending on PID: e.g. CVID = 8.5%, XLA = 3.35%, Ataxia-telangiectasia = 3.8%, IgG subclass deficiency = 17.4%De Garcia et al. (2004)Spain2424 moPP: NRPI: 61/888 (6.8%)NRNRNRType of AE NRNo AE required infusions to be discontinuedMartinez Garcia et al. (2001)Spain19Mean 7.5 yrsNRNRNRNRNote: 1 patient withdrawn due to anaphylactic reactionQuinti et al. (2008)Italy262Mean 7 years1,982 patient yearsNRNRNRPP: 13/262 (5.0%)PI: NRSevere: Ig treatment withdrawn due to AE that could not be prevented with premedication (steroids, antihistamines) or switching Ig brand. Patients were started on SCIg which was well tolerated by most patients.Singh et al. (1994)India14NRPP: 2/14 (14%)PI: NRPP: 2/14 (14%)PI: NRNone None Mild: nausea, joint pain, chillsAbbreviations: AEs: adverse events, CVID: common variable immunodeficiency, PID: primary immunodeficiency diseases, Ig: immunoglobulin, IgG: immunoglobulin G, ITT: intention to treat, PI: per infusion, PP: per patient, NR: not reported, yrs: years.Is it effective? Summary – What is the effectiveness of Ig in patients with PID?One comparative study was identified that retrospectively compared a group of patients on Ig treatment to a group of patients not on Ig treatment due to delayed diagnosis. IVIg treatment was associated with improved patient outcomes, including lower infection rates, hospital admissions, bronchiectasis and mortality. This study was assessed as being at high risk of bias.Data from single arm studies of patients with CVID comparing pre- and post-treatment outcomes, reported consistent findings. The post-Ig outcomes (infection rates, IgG levels and hospitalisation rates) were improved compared to those measured pre-Ig treatment.Data from three studies reporting a mean age similar to that of Australian patients receiving NBA-funded Ig were consistent with the overall results of the Assessment. All three studies reported that Ig use was associated with reductions in infection rate compared to pre-treatment rates.Key issues with the evidence base were identified, which may have a substantial impact on effectiveness results. Confounding factors and co-interventions were generally not reported and not investigated. It is unclear how these omissions influence results. Unadjusted co-intervention use may bias results in favour of Ig. Most studies were retrospective, and it was not clear if all patient information was captured consistently and comprehensively. It was also unclear if any eligible patients were excluded from analysis. The impact these issues may have on results is parative effectivenessNo studies were identified comparing the effectiveness of immunoglobulins (IVIg or SCIg) to other treatments, or to a placebo, for patients with any form of PID. Four studies were identified that compared—to varying degrees—the effectiveness of Ig treatment to no treatment. Aghamohammadi et al (2009) compared a range of effectiveness outcomes between 24 untreated CVID patients and 23 CVID patients regularly treated with Ig therapy (400–600 mg/kg every three to four weeks). Untreated patients were those who had experienced long diagnostic delays (more than six years), thus long diagnostic delay was considered the equivalent of being untreated. REF _Ref31806412 \h \* MERGEFORMAT Table 16 shows the total number of infections, hospital admissions, bronchiectasis, missed days from work or school, and deaths. Untreated patients had significantly more infections, hospital admissions and bronchiectasis, and a significantly higher mortality rate compared with Ig-treated patients. Table SEQ Table \* ARABIC 16 Number of infections, hospital admissions, bronchiectasis, missed days from school or work and deaths in Ig-treated and untreated CVID patientsVariableUntreated patients (diagnostic delay)N = 24Total treatment follow-up = 256 patient yearsIg treated patients (diagnosed early)N = 23Total treatment follow-up = 207 patient yearsp valueTotal number of infections during study period 500 75 0.048 (infection rate)Total number of hospital admissions 203 88 0.001 (hospitalisation rate)Total number of non-infectious complications during study period8539NRTotal number of infections that led to hospital admission105620.001Hospital admissions due to other causes9826NRBronchiectasis 14/24 (58%)8/23 (34%)0.032Missed days from work or school1563626NRDeath9/24 (40%)2/23 (8%)0.009Abbreviations: NR: not reportedComplication rates for infectious and non-infectious conditions are described in detail in REF _Ref31805196 \h \* MERGEFORMAT Table 17. For non-infectious complications, significantly higher rates were observed for obstructive lung disease, restrictive lung disease, hepato/splenomegaly and failure to thrive in the untreated patients compared with Ig treated patients. Rates of other non-infectious complications did not differ significantly between the untreated and Ig-treated patients. For infectious complications, significantly higher rates were observed in the untreated patients for all conditions except skin abscesses and mastoiditis. Probability of survival after CVID diagnosis (estimated from Kaplan-Meier life tables) showed that the mortality rate of untreated patients was significantly higher than that of Ig-treated patients (p = 0.005). Table SEQ Table \* ARABIC 17 Infectious and non-infectious complications among Ig-treated (early diagnosis) and untreated (delayed diagnosis) CVID patientsNon-infectious complication rate (per patient per year) Non-infectious complicationsIg treated patients (diagnosed early)N = 23Untreated patients (diagnostic delay)N = 24p valueObstructive lung disease00.0410.01Restrictive lung disease00.1660.032Bronchiectasis0.3910.54> 0.05Renal failure0.0430.083> 0.05Cirrhosis0.3470.291> 0.05Hepatitis0.0430.208> 0.05Hepato/splenomegaly0.1300.3750.046Inflammatory bowel disease00.083> 0.05Lymphoid hyperplasia0.0430.208> 0.05Deafness0.2600.333> 0.05Failure to thrive0.1300.6660.043Immune thrombo-cytopenic purpura0.080.208> 0.05Autoimmune haemolytic anaemia00.083> 0.05Neutropenia0.0430> 0.05Diabetes mellitus00.083> 0.05Rate of infections, hospitalisations and missed work/school days (per patient per year)InfectionsIg treated patients (diagnosed early)N = 23Untreated patients (diagnostic delay)N = 24P valueSinusitis/otitis media0.0820.6870.003Pneumonia0.1030.3820.001Septic meningitis00.0410.034Encephalitis00.0180.032Lung abcess00.0900.01Septic arthritis0.0020.0580.027Reactive arthritis0.0170.0610.031Visceral abscess00.0170.041Skin abscess0.0120.023> 0.05Chronic diarrhea0.1360.6120.005Mastoiditis0.0020.020> 0.05Liver diseases0.060.10.048Enteropathies0.130.6990.012Hospitalisation0.4300.9960.001Missed days from work/school0.423.90.002Abbreviations: Ig: immunoglobulin. Three additional studies compared baseline data of CVID patients previously on IMIg to those with no previous Ig treatment. All three studies reported higher IgG levels in patients treated with IMIg compared to those receiving no treatment (statistical testing not performed). However, the applicability of the results is unclear as IMIg does not reflect current clinical practice in Australia. Case series pre/post effectiveness dataEleven case series studies reported pre- and post-Ig effectiveness data for patients with CVID (summarised in REF _Ref34202933 \h \* MERGEFORMAT Table 18). Ten studies reported a change in infection-related outcomes pre- and post-Ig treatment. All reported that treatment with Ig lead to a reduction in the number of infections. Methodology and reporting varied between studies, with some studies reporting each infection separately and others reporting composite outcomes, e.g. serious infection (including pneumonia, sepsis, meningitis and pulmonary abscess). Similarly, some studies reported infection incidence (per patient per year) while others reported the percentage of patients who had at least one occurrence of the infection during the follow-up period. Considering each infection type separately where possible:Incidence of lower respiratory infections (including pneumonia) was lower post-Ig treatment in all eight studies reporting this outcome PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGthbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Alkan et al., 2017, Baris et al., 2011, Busse et al., 2002, de Gracia et al., 2004, Martinez Garcia et al., 2001, Pourpak et al., 2006, Quinti et al., 2007, Salehzadeh et al., 2010). Pre-treatment incidence ranged from 0.28 to 2.04 infections per patient per year. Post treatment incidence ranged from 0.16 to 0.34 per patient per year.Otitis media, sinusitis and diarrhoea rates were generally lower post-Ig treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2hhbW9oYW1tYWRpPC9BdXRob3I+PFllYXI+MjAwODwv

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ADDIN EN.CITE.DATA (Aghamohammadi et al., 2008, Baris et al., 2011, de Gracia et al., 2004, Quinti et al., 2007, Salehzadeh et al., 2010), although for Salehzadeh et al. (2010) this reduction was only statistically significant for recurrent infections (more than three infections per patient per year). Baris et al. (2011) reported no significant change in rates of diarrhoea pre- and post-treatment.Seven studies reported change in IgG levels following Ig treatment. Baseline IgG levels ranged from 195 mg/dl (SD NR) to 416 mg/dl (SD 196). Post-Ig treatment levels ranged from 455 mg/dl (SD 200) to 891 mg/dl (SD 132). Four studies reported a statistically significant increase PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2hhbW9oYW1tYWRpPC9BdXRob3I+PFllYXI+MjAwMzwv

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ADDIN EN.CITE.DATA (Aghamohammadi et al., 2003, Aghamohammadi et al., 2008, de Gracia et al., 2004, Pourpak et al., 2006) while three studies reported a numerical increase without commenting on the statistical significance of the results PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJpczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Baris et al., 2011, Quinti et al., 2007, Salehzadeh et al., 2010). In four studies, Ig treatment was associated with a reduction in the number of required per patient per year. Pre-Ig treatment patients were hospitalised an average of 1.35 to 3.4 times per year. Patients receiving Ig required an average of 0.13 to 0.7 hospitalisations per year.Two studies commented on the effect of Ig treatment on bronchiectasis. Bronchiectasis was associated with longer delays before diagnosis (Alkan et al., 2018, Baris et al. 2011) higher age at diagnosis, number of respiratory infections and frequency of antibiotic use (Baris et al., 2011).One study (Baris et al., 2011) reported that Ig use was associated with a reduction in antibiotic use. Pre-Ig treatment patients received an average of 8.27 courses of antibiotic per year, which reduced to 2.5 course (p = 0.0001) after starting Ig therapy. The only study (Baryakci et al., 2005) to investigate the impact of prophylactic antibiotics on outcomes, reported no change in infection frequency with antibiotic usage for patients with CVID. The impact of other co-interventions was not reported by any study.Three studies (Busse et al., 2002, De Garcia et al., 2004, Martinez Garcia et al., 2001) included patients with a mean age of 42 years, 45 years and 33 years, respectively, the most similar in patient-age demographics to Australian patients receiving Ig (NBA data from 2018/19 reported an average patient age of 53 years for CVID). Results from these studies were consistent with the overall results of the Assessment. All three studies reported that Ig use was associated with reductions in infection rate compared to pre-treatment rates. No other outcomes were reported by these studies. Table SEQ Table \* ARABIC 18Summary of effectiveness resultsAuthor (year)CountryNumber of patientsDuration of follow-upIgG trough levels (mg/dl)Infection rates (per patient per year)Antibiotic usage (per patient per year)PID-related hospitalisations (per patient per year)BronchiectasisOtherAghamohammadi et al. (2003)Iran353 yrsPre: 258.8 (SD 162.0) Post: 657.5 (SD 262.6)P < 0.001NRNRNRNRNRAghamohammadi et al. (2008)Iran64Median 3 yrs (range 0.1-18)Pre: 195.1 (SD NR)Post: 552.2 (SD NR)P < 0.001Median (range)Otitis media:Pre: 0.73 (0-10) Post: 0.12 (0-4)P = 0.004SinusitisPre: 1.0 (0-30) Post: 0.67 (0-6)P = 0.018NRNRNRNRAlkan et al. (2018)Turkey12NR, data collected over 11 yrsNRLower respiratory infection and gastroenteritis frequency significantly decreased at 1 year post-treatmentUpper respiratory infection significantly decreased at 5 years post-treatmentNRNRBronchiectasis was associated with increased diagnostic delay and higher rates of lower respiratory infectionsPathological sounds of the lung improved in 3 patients with this symptom at diagnosisBaris et al. (2011)Turkey29Mean 5.6 yrs (SD 3.5, range 1.3-14)Pre-Ig mean follow-up 1.1 yrs (SD 1.5)IgG serum levelsPre: 416.1 (SD 195.5)Post: 891.4 (SD 132.1)Upper respiratoryPre: 8.87 (SD NR)Post: 2.04 (SD NR)P = 0.0001Lower respiratoryPre: 2.23 (SD NR)Post: 0.50 (SD NR)P = 0.001 (SD NR)DiarrhoeaPre: 0.62 (SD NR)Post: 0.38 (SD NR)P > 0.05 (NS)Serious infectionAPre: n = 7Post: n = 0P = NRPre: 8.27 (SD NR)Post: 2.50 (SD NR)P = 0.0001Pre: 1.35 (SD NR)Post: 0.21 (SD NR)P = 0.0001Hospital stay was inversely correlated to IgG levels (r = -0.42m p = 0.03)Length of stay (days)Pre: 16.35 (SD NR)Post: 6.33 (SD NR)P = 0.0412 cases detected before Ig therapyDuring therapy, progression was marked in n= 5, regression observed in n = 4 and resolution in n = 3No new cases during Ig therapyDiagnostic delay, age at diagnosis, number of respiratory infections and frequency of antibiotic use were higher in patients with bronchiectasisNRBayrakci et al. (2005)TurkeyB20Median 4.25 yrs (range 1.25-12.25)NRSignificant reduction post-Ig (Data for CVID NR separately)NRSignificant reduction post-Ig (Data for CVID NR separately)NRIn patients with CVID prophylactic antibiotics did not change infection frequency (data NR)Busse et al. (2002)USA50Mean 6.6 yrs on IVIgCNRPneumonia prevalence (%)Pre: 42/50 (84%)Post: 11/50 (22%)NRNRNRNRDe Garcia et al. (2004)Spain242 yrsPre: 239 (SD 138)Post: 806 (SD 167)P < 0.0001Serious infectionBPre: 0.48 (SD 0.45)Post: 0.047 (SD 0.15)P = 0.001Mild infectionCPre: 4.9 (SD 4.1)Post: (2.2 (SD 2.0)P = 0.01NRNRNRPulmonary function No significant change in pulmonary function after 2 yrs Ig treatmentMartinez Garcia et al. (2001)Spain19Mean 7.5 yrsNRLower respiratory tract Pre: 0.28 (SD NR)Post: 0.16 (SD NR)P < 0.001NRNRPrevalence 11/19 (58%)No data on impact of treatmentNRPourpak et al. (2006)Iran26Mean 3.5 yrs (SD 3.0)Pre: 214.86 (SD 165.73)Post: 616.37 (SD 287.38)P = 0.001PneumoniaPre: 0.81 (SD NR)Post: 0.34 (SD NR)P = 0.0017NRPre: 3.4 (SD NR)Post: 0.7 (SD NR)P < 0.0005Hospitalisation due to pneumonia:Pre: 88.5% per yearPost: 46% per yearP = 0.0025NRNRQuinti et al. (2007)Italy224Mean 11.5 yrs (range 3-34)Pre: 258.12 (SD NR)Post: 579.49 (SD NR)Significant reduction in pneumonia, otitis observed (p < 0.001, data NR)Significant increase in sinusitis and chronic lung disease (p < 0.001, data NR)NRNRNRNRSalehzadeh et al. (2010)Iran24Mean 8 yrs (SD 4.6)Pre: 272.91 (SD 185.58)Post: 455.29 (SD 200.23)All % of patients with infectionRecurrentE Otitis mediaPre: 46%, Post: 4%,P = 0.002Recurrent SinusitisPre 25%, post: 4%P = 0.048Recurrent pneumoniaPre: 42%, post: 4%P = 0.006Recurrent diarrhoeaPre: 50, post: 4P = 0.001Note: % patients with any otitis media, any sinusitis was not significantly different pre- and post- treatmentNRPre: 1.21 (SD NR)Post: 0.125 (SD NR)P 0.008Documented in 7 patients, effect of IG NRNRAbbreviations: Ig: immunoglobulin, IgG: immunoglobulin G, NR: not reported, PID: primary immunodeficiency diseases, Pre: results from before immunoglobulin treatment, Post: results from after immunoglobulin treatment, SD: standard deviation. Notes: A = all values are mean (standard deviation) unless specified. B = Baris et al. (2011) defined serious infection as cellulitis, meningitis, sepsis. C = De Garcia et al. (2004) defined serious infection as pneumonia, sepsis, meningitis and/or pulmonary abscess. D = De Garcia et al. (2004) defined mild infection as bronchitis, otitis, sinusitis or fever. E = Salehzadeh et al. (2010) defined recurrent as more than three episodes of infection..Supplementary evidence: Studies comparing IVIg to IMIg or SCIg Three randomised controlled trials were identified that compared administration route of Ig (IMIg or SCIg compared to IVIg) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Chapel et al., 2000, Garbett et al., 1989, Nolte et al., 1979). Advice from the Immunoglobulin Review Reference Group is that, IMIg is no longer used as an Ig administration method. Therefore, evidence comparing IMIg to IVIg is outside the scope of this review. The comparison has been retained here as supplementary evidence only. Similarly, as the intervention is considered to be Ig (regardless of the route of administration), the comparison of SCIg to IVIg is outside the scope of this assessment and this comparison is presented as supplementary evidence only.The Supplementary evidence is presented only to acknowledge that these issues have been investigated and do not form the basis of the findings of this review. Chapel et al. (2000) randomised 30 patients to either IVIg or SCIg for 12 months. Patients were then crossed over to the alternate treatment for 12 months. A total of 22 patients completed the 24 months of the trial (four patients on SCIg therapy withdrew due to systemic reactions, pain at infection site, preferred intravenous administration or repeated local allergy). Four patients on or due to begin IVIg therapy withdrew due to product unavailability, fear of virus transmission or preferred SCIg therapy and refused intravenous administration. There were no significant differences in the rate of infection between the two groups (mean 4.12 per patient per year for IVIg, mean 3.82 for SCIg, p = NR). Similarly, there were no significant differences in the length of infection (mean 87 days IVIg vs mean 73 days SCIg) or number of days missed work/school (mean 12 days for both IVIg and SCIg). SCIg was associated with a higher number of adverse events overall (10.4% of infusions vs 5.5% for IVIg), however when pain or redness at infusion site was excluded the rate of systematic reactions for SCIg was 3.3%. Systematic adverse events included headache, fatigue rigors, hot flushes, urticaria/eczema, increased pulse, dizziness and nausea. No differences in trough IgG serum levels were found between the two groups (IVIg median 7.8-8.4 g/l vs SCIg median 8.0-9.1 g/l). Patient preference varied, with 16 patients preferring IVIg, 10 patients preferring SCIg and four patients reporting no preference.Two studies investigated the comparison between IMIg and IVIg, with both reporting better outcomes with IVIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJiZXR0PC9BdXRob3I+PFllYXI+MTk4OTwvWWVhcj48

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ADDIN EN.CITE.DATA (Garbett et al., 1989, Nolte et al., 1979). Garbett et al. (1989) compared IMIg to IVIg in a RCT of 12 patients. Trough serum levels of IgG were higher with IVIg than IMIg (even higher with 3-weekly doses of IVIg than 4-weekly) (mean values not reported, p = 0.004 and p = 0.001, respectively). Patients reported significantly improved infection indices on IVIg compared to IMIg including fewer days feeling unwell (225 vs 407, p = 0.002), reduced antibiotic usage (296 vs 511, p = 0.03), fewer days with increased temperature (10 vs 30, p = not reported) and fewer days with acute respiratory tract symptoms (236 vs 388, p = 0.009). Further, these outcomes were significantly improved when using three-weekly IVIg dosing compared to four-weekly (p = 0.02). Nolte et al. (1979) randomised 20 patients to either IMIg or IVIg. Serum IgG levels increased from baseline by a higher proportion following IVIg treatment (248% increase vs 90%). Infection rates were lower in patients treated with IVIg (0.103 infections per patient per month vs 0.295).Supplementary evidence: What do existing systematic reviews say?Five systematic reviews were identified investigating the effectiveness of Ig in patients with PID PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYm9saGFzc2FuaTwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

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ADDIN EN.CITE.DATA (Abolhassani et al., 2012, Jones et al., 2018, Lingman-Framme and Fasth, 2013, Shabaninejad et al., 2016, Shrestha et al., 2019b). These reviews were pearled to ensure all relevant studies were captured in our review of primary evidence. The findings of these reviews are discussed below and summarised in REF _Ref34054687 \h \* MERGEFORMAT Table 19. The identified systematic reviews all compared IVIg to SCIg. Reviews were based on searches conducted between January 2012 and May 2018 and included patients with any type of PID. Results for each type of PID were analysed together. IgG trough levels, infections rates and adverse events were the most commonly reported outcomes. The studies varied with respect to the comparison between SCIg and IVIg. Three reviews found IgG levels were higher with SCIg treatment than with IVIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbWFuLUZyYW1tZTwvQXV0aG9yPjxZZWFyPjIwMTM8

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ADDIN EN.CITE.DATA (Lingman-Framme and Fasth, 2013, Shabaninejad et al., 2016, Shrestha et al., 2019b), while Abolhassani et al. (2012) reported equivalent levels between the two administration routes. All four reviews reporting comparative infection levels found no difference between the administration routes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYm9saGFzc2FuaTwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll

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ADDIN EN.CITE.DATA (Abolhassani et al., 2012, Lingman-Framme and Fasth, 2013, Shabaninejad et al., 2016, Shrestha et al., 2019b). Shabaninejad et al. (2016) reported no difference in systemic adverse events between IVIg and SCIg, conversely Abolhassani et al. (2012) reported SCIg was associated with lower adverse events. Lingman-Framme and Fasth (2013) noted that systemic events were rare and it was not possible to draw any conclusions as to the comparative safety of the two administration routes. All reviews noted the low quality of the evidence base which limited the findings of the reviews. Calls for further research to be conducted were made by all reviews.While some studies noted there may be benefits associated with SCIg use, no study found IVIg was associated with improved outcomes. Therefore, extrapolation of the results in Section B.6 to patients treated with SCIg is unlikely to overestimate the effectiveness of SCIg in the Australian clinical context. Table SEQ Table \* ARABIC 19Characteristics of the systematic reviewsAuthor (year)Search dateNumber of studiesNumber of patientsStudy characteristicsPurpose of the reviewPatient characteristicsKey safety outcomesKey effectiveness outcomesConclusions of the reviewAbolhassani et al. (2012)January 2012471,484 (1,028 unique patients)10 clinical trials, 17 prospective cohorts, 20 retrospective cohortsCompare the safety and efficacy of SCIg to IVIgAdult and paediatric patients with any form of PIDDecreased systemic events with SCIg (OR 0.09 (95% CI = 0.07, 0.11)Trough IgG levels: comparableInfection rate: no significant difference in odds of infectionSCIg may offer a benefit over IVIgResults may be biased by lack of RCTs, and enrichment of patients who cannot tolerate IVIgJones et al. (2018)August 2015171,8581 RCT, 7 prospective case series, 9 cross-sectional studiesTo investigate the burden of Ig treatment in relation to administration routeAdult and paediatric patients with any form of PIDNRIg was not associated with high burden and patients were generally satisfied with either administration routePatients preferred in-the-home delivery and generally patients preferred SCIgLack of control groups in most studies may have influenced resultsPID patients satisfied with either treatment modalityMore research required in this areaLingman-Framme and Fasth (2013)June 2012192842 RCTs, 17 observational studiesCompare the safety, efficacy, HRQoL and cost-effectiveness of SCIg to IVIgNRSerious adverse events: none reported for either groupSystemic events: rare, not possible to comment on comparative ratesLocal events: higher for SCIg, mildTrough IgG levels: higher for SCIgInfection rate: no significant differenceHRQoL: improved with SCIgCost-effectiveness: SCIg more cost effective mostly due to reduced days of work/school lost SCIg is safe and efficacious and at least non-inferior to IVIg. Good quality studies are lacking.Shabaninejad et al. (2016)March 2015249456 clinical trials, 12 prospective studies, 6 retrospective studiesCompare the safety and efficacy of SCIg to IVIgAdult and paediatric patients with any form of PIDNo statistical difference in systemic adverse events (OR 0.497, 95% CI = 0.180, 1.371) Trough IgG levels: higher in SCIg, mean 9.59 vs 8.54, SMD 0.339 (95% CI = 0.2, 0.47)Infection: no difference in infection rateShifting from IVIg to SCIg can have clinical benefit for PID patientsMore research in this area would be beneficialStrestha et al. (2019)May 20182421 prospective studies, 2 ambispective, 2 retrospective studiesInvestigate the relationship between IgG trough levels, route of administration and infection incidence.Adult and paediatric patients with any form of PIDMean patient age 23.8 yrs, majority male patients, predominantly CVID (> 80%)NRTrough IgG levels: higher for SCIg (MD 75.43, 95% CI 31.67, 119.19)Infection: No difference in overall risk of infection (RD 1.58, 95% CI = 0.75, 3.33)No difference in serious infection (OR 1.94, 95% CI = 0.59, 6.32)SCig associate with higher IgG trough levels. Higher SCIg trough levels associate with reduced infection. For IVIg, no relationship between trough Ig and infection levels was found.More RCTs required to investigate relationship between IgG levels and infection.Abbreviations: CI: confidence interval, HRQoL: health related quality of life, Ig: immunoglobulin, IgG: immunoglobulin G, IVIg: intravenous immunoglobulin, MD: mean difference, NR: not reported, OR: odds ratio, PID: primary immunodeficiency diseases, RCT: randomised controlled trials, RD: risk difference, SCIg: subcutaneous immunoglobulin, SMD: standard mean difference.Extended Assessment of HarmsThe Database of Adverse Event Notification (DAEN) of the TGA was searched on 2 March 2020 for all medicines listed as “normal immunoglobulin” ADDIN EN.CITE <EndNote><Cite><Author>TGA</Author><Year>2020</Year><RecNum>43</RecNum><DisplayText>(TGA, 2020)</DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1583273916">43</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>TGA,</author></authors></contributors><titles><title>Database of Adverse Event Notifications (DAEN)</title></titles><volume>2020</volume><number>4 March</number><dates><year>2020</year></dates><publisher>Australian Government Department of Health, Therapeutic Goods Administration</publisher><urls><related-urls><url>;(TGA, 2020).A total of 2,035 cases of reaction were reported. The most common events (occurring in 100 or more patients) were:Chills (n = 403)Fever (n = 321)Headache (n = 305)Nausea (n = 223)Shortness of breath (n = 209)Tachycardia (n = 156)Hypertension (n = 153)Rash (n = 149)Urticaria (n = 129)Back pain (n = 125)Vomiting (n = 125)Pruritus (n = 109)Chest pain (n = 101)Hypotension (n = 101)Aseptic meningitis (n = 100)These are consistent with the events reported in Section B.6, with the exception of aseptic meningitis which was not reported as an adverse event by any study (but may have been captured in effectiveness data in a single study).Ig therapy is known to be associated with rare, but potentially serious adverse events including serious allergic reaction, thrombotic events (stroke and myocardial infarction), seizures, posterior reversible encephalopathy syndrome, renal impairment, haemolysis and neutropenia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW88L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Guo et al., 2018). Considering only these potentially serious events, the DAEN database reported the following number of these potentially serious rare events occurring with Ig use (for any indication):Anaphylaxis (n = 70)Thrombotic stroke (n = 4)Myocardial infarction (n = 10)Seizure (n = 18)Renal impairment (n = 12)Haemolysis (n = 54)Neutropenia (32)The FDA has noted that immunoglobulins are associated with an increased risk of thrombosis and have issued a black box warning for all human immunoglobulins to reflect this ADDIN EN.CITE <EndNote><Cite><Author>IDF</Author><Year>2013</Year><RecNum>37</RecNum><DisplayText>(IDF, 2013)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1583122565">37</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>IDF,</author></authors></contributors><titles><title>FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products.</title></titles><volume>2020</volume><number>2 March</number><dates><year>2013</year></dates><publisher>Immune Deficiency Foundation</publisher><urls><related-urls><url>;(IDF, 2013). We note that these reports indicate that severe adverse events, although rare, can occur with Ig use. It is not clear to what extent these events occur in patients with PID. Interpretation of the Clinical EvidenceOn the basis of the evidence profile (summarised in REF _Ref399239890 \h \* MERGEFORMAT Table 20), it is suggested that, relative to no treatment, Ig has inferior safety and may have superior effectiveness noting that there is only low to very low quality evidence available to support these conclusions.Ig is accepted as a safe therapy in Australia and is generally associated with mild adverse events. Severe events are rare and mostly resolved by treatment cessation. Overall it is estimated that approximately 44% of patients will experience an adverse event at some point during their treatment. Approximately 4% of patients are estimated to suffer a serious adverse event at some point during treatment. Considering effectiveness, Ig is associated with lowered infection rates (including upper and lower respiratory tract infections, pneumonia, otitis media, sinusitis and diarrhoea), lower hospitalisation rates and higher IgG levels. However, these effectiveness results have been assessed as being low to very low quality due to the high risk of bias associated with the studies and the potential impact of confounding influencing the results (particularly the use of prophylactic antibiotic usage). Advice from the Immunoglobulin Review Reference Group is that it is difficult to separate the effect of Ig and any co-interventions.On the other hand, for patients with CVID, The Criteria Version 3 requires review by an immunologist after six months of therapy and documented evidence of clinical effectiveness is required to continue therapy. None of the studies reported whether such a review was undertaken for included patients. However, advice from the Immunoglobulin Review Reference Group is that it is unlikely that patients with CVID who start Ig therapy would cease the therapy due to absence of effect; therefore, this issue is considered unlikely to have impacted the results of this review substantially. Generally, the patients included in the studies and the way Ig was used were considered applicable to the Australian context. Three further potential issues with the evidence base were identified:The findings of this review are limited to patients with CVID. The effectiveness of Ig in patients with another form of PID is not known. CVID does represent most Ig use in Australia for primary immunodeficiency conditions (86% according to NBA data); therefore, the findings of this review are applicable to the majority of patients on the proposed population. The average age of patients in the evidence base was lower than for patients receiving Ig treatment for CVID in Australia (average age 56 years in 2018/19, NBA data). A subgroup of three studies with similar patient demographic to the Australian data was assessed separately and no differences in results compared to the overall evidence base were identified. Therefore, the age discrepancy noted does not appear to impact the generalisability of this review to the Australian CVID population.The findings of this review are based on evidence conducted using IVIg as the treatment. One RCT and five systematic reviews of observational studies found SCIg was at least non-inferior to IVIg. SCIg may be associated with high rates of minor local adverse events at the infusion site but lower rates of systemic adverse events. Therefore, it is considered reasonable to extrapolate the results of this review to patients on SCIg therapy for CVID. Despite the significant limitations associated with the evidence base, it is unlikely that higher quality studies will be forthcoming to investigate the comparative effectiveness of Ig therapy in patients with PID. No relevant upcoming clinical trials were identified, and due to the low incidence of PID, recruiting enough patients for a large prospective trial may not be feasible (for example, a Melbourne study included all patients with any form of PID treated over a period of 16 years and included 179 patients). Further, based on the literature screening performed for this review, there does not appear to be any other treatment routinely available for patients with PID other than Ig therapy, therefore a trial comparing Ig to another active treatment for PID is unlikely to be feasible at this point in time. A trial comparing Ig treatment to no treatment/placebo may not be ethical given there is (limited, low quality) evidence that delaying Ig treatment may lead to worse outcomes for patients (for example a delay may increase the risk of bronchiectasis). Table SEQ Table \* ARABIC 20Balance of clinical benefits and harms of intervention, relative to comparator, and as measured by the critical patient-relevant outcomes in the key studies Outcome(units, follow-up)No. of studies and study designRisk of biasEffect Ig Effect no treatment QualityImportanceAdverse eventsfollow up: range 1 years to 12 years (count)8 observational studiesSerious184/434 (42.4%)NA????Moderate qualityCriticalSerious adverse events (count)5 observational studiesSerious20/519 (3.9%)NA????Moderate qualityCriticalLower respiratory infection rates (per patient per year)8 observational studiesVery seriousRange of means0.16-0.34Range of means0.28-2.04????Very low qualityCriticalIgG trough levels (mg/dl)7 observational studiesSeriousRange of means455-891Range of means195-416????Low qualityCriticalHospitalisations (per patient per year)4 observational studiesVery seriousRange of means0.13-0.7Range of means1.35-3.4????Very low qualityCriticalAbbreviations: Ig: immunoglobulin, IgG: immunoglobulin G, NA: not applicable. Source: GRADE Working Group grades of evidence (Guyatt et al., 2013)???? High quality: We are very confident that the true effect lies close to that of the estimate of effect. ???? Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ???? Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. ???? Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.Section CTranslation IssuesWith the agreement of the Immunoglobulin Review Reference Group, translation of the clinical evidence was not undertaken.Section DReview of Economic EvaluationsOverviewTo understand the cost-effectiveness profile of Ig replacement therapy for PID patients, a review of literature on published economic evaluations was conducted. Results of the literature review informed consideration of the feasibility of performing a model-based economic evaluation. The literature searches and selection criteria resulted in the identification of 15 relevant studies. Six of these studies were model-based economic evaluations, six were cost analyses of disease burden and budgetary impact, and the remaining three were reviews of economic studies. None of the identified studies compared Ig use to non-Ig standard care for PID patients. All comparative studies were focused on how IVIg and SCIg compare in terms of clinical and economic outcomes. Despite the diversity in modelling approaches and evaluation results, there was a consistent finding across all studies: SCIg is likely to be substantially more cost-effective compared to IVIg. Given the available evidence, it is unlikely to be feasible to conduct model-based economic evaluation to compare Ig and non-Ig standard of care due to the lack of data on the comparator. Ig use for patients with PID is routine and considered the standard clinical management strategy, particularly for patients with common subtypes of PID, including common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). Existing evidenceLiterature search and selectionA targeted search was undertaken to identify existing economic evaluations of the cost-effectiveness of Ig therapy in PID. Keywords used in the search are provided in Appendix B. The search was designed to identify any economic evaluation involving the use of Ig in any form for patients with PID without limiting to any subtypes of PID. Further, the search did not limit specific types of economic evaluations. Literature reviews and health technology assessments with an economic evaluation component were also included for comprehensiveness. The search was performed in PubMed, and was limited to studies published in the last 10 years. Literature screening and selection were conducted using the specific inclusion and exclusion criteria listed below ( REF _Ref41571932 \h Table 21). Table SEQ Table \* ARABIC 21Selection criteria for literature reviewSelection criteriaInclusion criteriaThe investigation of Ig therapeutic use;Treatment of primary immunodeficiency (PID), not limited to any subtypes;’Economic evaluation with or without using a modelled approach;For studies using a modelled approach, any types of economic evaluation including CMA, CEA, CUA or CCA Reviews of economic evaluations or HTAs with an economic evaluation componentExclusion criteriaAcquired immunodeficiency due to HIV or others;Patients having secondary immunodeficiency;Studies focused on the PID diagnosis instead of therapy;Studies investigating non-human subjects;Studies in foreign languagesStudies published over ten yearsAbbreviations: PID = primary immunodeficiency; CEA = cost-effectiveness analysis; CUA = cost-utility analysis; CMA = cost-minimisation analysis; CCA = cost-consequence analysis; HIV = human immunodeficiency virus;The search yielded 83 potentially relevant studies and the application of the above selection criteria narrowed down the selection to 15 studies for review. Among the 15 studies, there were six modelled economic evaluations: one study conducted a cost-effectiveness analysis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFiYW5pbmVqYWQ8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

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ADDIN EN.CITE.DATA (Shabaninejad et al., 2017), one study was a cost-utility analysis ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2020</Year><RecNum>87</RecNum><DisplayText>(Windegger et al., 2020)</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T. M.</author><author>Nghiem, S.</author><author>Nguyen, K. H.</author><author>Fung, Y. L.</author><author>Scuffham, P. A.</author></authors></contributors><auth-address>School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Down, QLD, Australia.&#xD;Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.&#xD;Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia.&#xD;Health Service Strategy and Planning, Metro North Hospital and Health Services, Brisbane, QLD, Australia.</auth-address><titles><title>Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia</title><secondary-title>Blood Transfus</secondary-title></titles><periodical><full-title>Blood Transfus</full-title></periodical><pages>96-105</pages><volume>18</volume><number>2</number><edition>2020/04/10</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1723-2007</isbn><accession-num>32271703</accession-num><urls><related-urls><url>;(Windegger et al., 2020), and the other four studies were cost-minimisation analyses PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWF1dGU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Beaute et al., 2010, Igarashi et al., 2014, Martin et al., 2013, Perraudin et al., 2016). A further six cost and budgetary impact analyses were identified in various settings and countries. All of them considered different Ig administration methods for PID patients in a specific health settings (e.g. the health system or a hospital) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA (Fu et al., 2018, Menzin et al., 2014, Pollock and Meckley, 2018, Sadeghi et al., 2015, Gholami et al., 2017, Viti et al., 2018). Two of these studies examined the CVID subtype of PID PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWRlZ2hpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA (Sadeghi et al., 2015, Viti et al., 2018). Finally, three review-type studies were also identified and included. However, the scope of these reviews is larger than the current assessment. For example, one review of economic studies included both the treatment and (early) diagnosis of PID PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbHNpbms8L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Elsink et al., 2020). All primary studies identified in that review were also identified and included by the current search. The second review was a comprehensive review of subcutaneous Ig only, and the investigated both primary and secondary immunodeficiencies ADDIN EN.CITE <EndNote><Cite><Author>Lingman-Framme</Author><Year>2013</Year><RecNum>8024</RecNum><DisplayText>(Lingman-Framme and Fasth, 2013)</DisplayText><record><rec-number>8024</rec-number><foreign-keys><key app="EN" db-id="w0x0ef2w7df5z8ez9ptp0aaj25z0fe59dv5e" timestamp="1581396199">8024</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lingman-Framme, J.</author><author>Fasth, A.</author></authors></contributors><auth-address>Department of Pediatrics, Halland Hospital, Sweden.</auth-address><titles><title>Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review</title><secondary-title>Drugs</secondary-title><alt-title>Drugs</alt-title></titles><periodical><full-title>Drugs</full-title></periodical><alt-periodical><full-title>Drugs</full-title></alt-periodical><pages>1307-19</pages><volume>73</volume><number>12</number><edition>2013/07/19</edition><keywords><keyword>Administration, Intravenous/methods</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Home Care Services</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/*administration &amp; dosage/adverse effects</keyword><keyword>Immunologic Deficiency Syndromes/*drug therapy</keyword><keyword>Infusions, Subcutaneous/methods</keyword><keyword>Quality of Life</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0012-6667</isbn><accession-num>23861187</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"> not only compares SCIg to IVIg</research-notes><language>eng</language></record></Cite></EndNote>(Lingman-Framme and Fasth, 2013). As this review was published in 2013, it did capture economics studies which were outside the current inclusion limit of 10-years. The final review was an HTA conducted by Health Quality Ontario in Canada ADDIN EN.CITE <EndNote><Cite><Author>Health Quality Ontario</Author><Year>2017</Year><RecNum>103</RecNum><DisplayText>(Health Quality Ontario, 2017)</DisplayText><record><rec-number>103</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">103</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Health Quality Ontario,</author></authors></contributors><titles><title>Home-Based Subcutaneous Infusion of Immunoglobulin for Primary and Secondary Immunodeficiencies: A Health Technology Assessment</title><secondary-title>Ont Health Technol Assess Ser</secondary-title></titles><periodical><full-title>Ont Health Technol Assess Ser</full-title></periodical><pages>1-86</pages><volume>17</volume><number>16</number><edition>2017/11/01</edition><dates><year>2017</year></dates><isbn>1915-7398</isbn><accession-num>31210833</accession-num><urls></urls><custom2>PMC6548531</custom2><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Health Quality Ontario, 2017). This study comprehensively analysed the clinical evidence comparing IVIg and SCIg, but only narratively reviewed the health economic literature identified. It should be noted that, for all the studies identified above, none of the articles investigated the economic outcomes of comparing the use of Ig (IVIg or SCIg) against standard of care (without Ig). For most comparisons, the studies analysed economic outcomes comparing IVIg and SCIg; most using a cost minimisation analysis (CMA). All the CMAs assumed that clinically there was no significant difference in administration routes or settings: i.e., intravenous versus subcutaneous route; administration in hospital or at home. As this may lead to significant cost advantage of SCIg, they investigated whether the Ig administration in home setting via subcutaneous route could be cost-saving. No cost-consequence analyses were identified.While the current evidence base does not directly address the question of the cost-effectiveness between Ig and non-Ig standard care, information presented in these included studies could still be relevant. Therefore, relevant information such as study settings, costs and evaluation approaches as well as evaluation methodologies have been extracted and appraised. The applicability of the published information to the Australian context has also been explored. Key characteristics of the costing studies includedTo provide a clear profile of the evidence base currently available, key study information was categorised from the three types of economics studies included in the current review: 1) studies with economic modelling approaches (n = 6), 2) costing studies on budgetary impact (n = 6), and 3) review studies (n = 3). Model-based economic evaluationsThere are in total of six model-based studies. As previously described, most were cost-minimisation analyses due to the presumed clinical equivalency between IVIg and SCIg. It was understood that SCIg, which was administered at a home setting with a potential better safety profile, may have cost advantages over the conventional hospital administered IVIg. The cost benefits are primarily attributable to savings around reduced requirements for professional care (e.g. nurses) and avoidance of potential adverse events associated with intravenous infusions. Key study characteristics, methodologies and evaluation results are shown in REF _Ref41571963 \h Table 22 below. It should be highlighted that the studies included in this review were comparing IVIg and SCIg, hence do not directly inform the comparative cost-effectiveness of Ig against no Ig and BSC. Table SEQ Table \* ARABIC 22The key characteristics and evidence profile presented in the included model-based studies AuthorPublish year CountryModel settingsData sourcesPopulationComparisonEconomic OutcomeModelling approachSensitivity analysisResults andConclusionShabaninejad et al2017IranHealthcare payer perspectiveIran health administration dataPID patients NOSIVIg in hospitals and SCIg at homeIncremental costs per 1% increase in Ig serum level and reduction in adverse eventsCEA via decision tree, with 1-year THDSA variables tested: Ig cost, infusion period, hospital, material and personnel costsIncremental costs per 1% increase in Ig serum level with SCIg compared to IVIg = -$4,348Incremental costs per 1% reduction in adverse events with SCIg compared IVIg = $2,939SCIg is more cost effective than IVIgWindegger et al. 2020AustraliaAustralian healthcare system perspectiveData from Sunshine Coast Hospital and Health Services PID patients NOSIVIg in hospitals and SCIg at homeIncremental costs per QALY gainedCUA via Markov cohort transition model with six health states with 10-year TH and weekly cycle;Both DSA and PSA to identify key drivers of the modelIncremental cost = $45,835;Incremental QALY = -0.021; SCIG dominantPerraudin et al. 2016SwitzerlandHealthcare provider perspectivePharmaceutical companies and Government statisticsPID patients NOSIVIg in hospitals and SCIg at homeCost differencesCMA via decision tree with 3-year THDSA only on uncertain cost items; the main drivers were all related to Ig dosage and frequency of administrationsSCIg = $36,595 in the 1st year and $30,309 in subsequent years;IVIg = $35,370 per yearCost saving = $9,828 over 3 yearsIgarashi et al. 2014JapanSocietal perspectiveOnly included non-medical costs by assuming equivalent medical expensePID patients NOSIVIg in hospitals and SCIg at homeLife quality index (LQI) score, productivity loss and hospital-related absenteeismCMA was indicated but method not reported in detail;No sensitivity analysisSCIg demonstrated Higher LQI 60% reduction in productivity loss, saving about JPY 10,875Less hospital-related absenteeism for patients and carersMartin et al. 2012CanadaCanadian healthcare perspectiveSt Paul’s Hospital, Vancouver, CanadaPID patients NOSIVIg in hospitals and SCIg at homeCost differences per patient and to overall national health budgetCMA via decision tree with 3-year TH, also a budgetary impact analysis (BIA) modelDSA on numbers of hospital visits for IVIg and scenario of SCIg switching in both CMA and BIACost reduction of $5,736 per patient over 3 years by CMA modelCost saving of 1.308 million (37%) in the first 3 years from the national health budgetBeaute et al. 2010FranceFrench social insurance perspectiveSpecific source of data used not provided, but verified by field data through questionnairesPID patients with subtypes of agammaglobulinemia or hyper-IgM syndrome.IVIg in hospitals or home and SCIg at homeCost differencesCMA, 1-year THDSA on infusion period, nurse costs and related medical equipment and materialSCIg was 25% less expensive based on field data analysis due to lower doseAbbreviations: PID = primary immunodeficiency; NOS = no otherwise specified; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; CEA = cost-effectiveness analysis; CUA = cost-utility analysis DSA = deterministic sensitivity analysis; TH = time horizon; JPY = Japanese YinThe six model-based health economic evaluations demonstrated a consistent cost advantage of SCIg over IVIg. All of the four-cost minimisation analysis presented the cost-saving result in the base-case scenario, where the other two studies also showed that SCIg is more cost-effective than IVIg. In the CMA, the main driver of the economic evaluation outcomes seems to be the cost of Ig administration where the saving was due to the avoidance of hospital-related costs. Due to the nature of these evaluations, the time horizons in these studies are very short. The only long-term studies were the cost-utility analysis by Windegger et al. (2020). This cost-utility model extrapolated the evaluation to 10-years, and also showed the SCIg being dominant over IVIg due to reduced costs. From the included CMA studies, costs incurred by IVIg within the hospital setting were relatively stable over time, and additional costs associated with SCIg, such as medical equipment and training, tended to only occur in initial years. Regular costs of SCIg in the longer-term were also relatively stable. Therefore, although few studies looked at the long-term economic outcome of different forms of administration for Ig, the evaluation results in the studies with short time horizons may also be applicable to a longer time horison. This should be however, established on the premise of patients using SCIg and IVIg having similar clinical characteristics.Budgetary impact analysis Various costing studies were also identified and included in the current assessment. Although they are not comparative in nature, they provide valuable information regarding PID prevalence, clinical management strategies, and the cost burden of disease. On the other hand, the information presented in this type of study is diverse due to significant differences in health system across countries and settings. Also, the methodologies used across the modelling and non-modelling studies were highly variable. To ensure the extraction of useful information, only high-level data extractions were undertaken focusing on key data from the studies. The key information is tabulated below in REF _Ref41571985 \h Table 23.Table SEQ Table \* ARABIC 23Key study characteristics for budgetary analysis for PID patientsAuthorPublish year Country-Population-Prevalence -% treated by Ig -IVIg and SCIg splitCosts involved-direct costs-indirect costs-Estimating approach-Sensitivity analysisResults andConclusionViti et al. 2018ItalyPID with CVID and XLA subtype CVID = 3.17 per 100k, XLA = 0.22 per 100kCVID = 85%, XLA = 91.5%CVID: 69.5% vs. 30.5%; XLA: 66.5% vs. 33.5%Direct costs including Ig drugs, personnel, pre-medications, adverse events, administration and diagnosis; Indirect costs including productive loss and absenteeism due to IVIg (all estimated)Combination of epidemiological and market share approach PSA on all population related variablesPopulation size: CVID = 1,885 and XLA = 133;Total annual estimated costs = € 42.68 million Pollock and Meckley 2018SwitzerlandPID NOSPopulation size: PID = 338, 42.1% treated with IgIg use,Healthcare professional (HCP) costsAncillary usage (pump etc.)Combination of epidemiological and market share approachDSA on Ig dosage, frequency, PID prevalence, HCP involvement and Ig administration splits142 treated with IgWith SCIg (Ig20Gly), 11.151 million CHF by year 3;Without SCIg (Ig20Gly), 11.163 million by year 3Fu et al. 2018CanadaPID with CVID and XLA subtype, subtype specific detail not reportedIVIg and SCIg split = 30:27Ig usePhysician visitsHospital costsObservational study at a hospital levelSensitivity analysis not performedUnadjusted average total costs for SCIg ($1,836) is significantly lower than IVIg ($4,187) at hospital level (diff = $2,351)Adjusted (for age, sex, weight and comorbidities) the incremental difference at hospital level is $2,103.Gholami et al. 2017IranPaediatric PID patients with 10 subtypes based on the ICD-10 codes, including CVID and XLAAll direct costs around hospital admission, medical equipment and tests plus interventional procedures including surgery or bronchoscopyObservational study at one specific local hospital in IranSensitivity analyses not performed, but uncertainty ranges were estimated and provided Mean admission cost = $7,090 per patients, costs for specific medication categories (e.g. anti-infective drugs) also reported, which accounted 4.6% to 28.1% of all costs Sadeghi et al. 2015IranPID with CVID subtypeEpidemiological data used for cost modelling via the PID registry, but no detail reported.Direct costs = physicians and ambulatory care, hospital admission, medications (including Ig and others), outpatient care, laboratory tests and ambulatory transport are included;Indirect costs = loss of productivity and premature deathCost modelling using hidden Markov model PSA performed on all variables includedCost of diagnoses per patients = $6,500, the cost of hospital admission = $25,000, and medication costs = $40,600Total annual costs per patient = $274,200Menzin et al. 2014The USPID NOSEpidemiological data not relevantAll direct costs including hospitalisation, ER visits, outpatient visits, allied healthcare professionalsRetrospective observational study using market share approach Sensitivity not performed, but uncertainty ranges estimated and reported.Infection was the most expensive resource used, and costed $11,925 on average per patients over the 7 months period;Hospitalised patients due to infection cost significantly more, around $38,574 per patientsAbbreviations: PID = primary immunodeficiency; XLA = X-linked agammaglobulinemia; NOS = no otherwise specified; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; CEA = cost-effectiveness analysis; CUA = cost-utility analysis DSA = deterministic sensitivity analysis; TH = time horizon; JPY = Japanese YinThree studies reviewed the budgetary impact or cost burden at a national level PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXRpPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Viti et al., 2018, Pollock and Meckley, 2018, Sadeghi et al., 2015), and the other three examined the cost burden at a local level PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051

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ZE5vdGU+AG==

ADDIN EN.CITE.DATA (Fu et al., 2018, Gholami et al., 2017, Menzin et al., 2014). The observation shared across all the included studies is that Ig replacement therapy for PID is expensive but there is room to gain more efficiency in its administration. Studies which evaluated cost burden at national levels were difficult to compare due to differences in health systems and diversity in how health services and goods were costed. In contrast, for the costing studies at local levels, it appears that Ig treatment is a significant cost burden. A common finding shared across all studies was that, in the absence of Ig treatment, increased infection rates leading to hospitalisations will lead to increased costs. Four of the six budgetary impact studies discussed specific subtypes of PIDs in their publication PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXRpPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Viti et al., 2018, Fu et al., 2018, Gholami et al., 2017, Sadeghi et al., 2015), and three of these were limited to specific PID subtypes of CVID and XLA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXRpPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Viti et al., 2018, Fu et al., 2018, Sadeghi et al., 2015). The remaining two budgetary impact studies reported the coverage rate of Ig as a therapy options for patients with any form of PID PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXRpPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Viti et al., 2018, Pollock and Meckley, 2018). There was some variation as to how PID patients were managed using Ig due to the inclusion of different PID subtypes. The coverage rate ranged from very high (91.5% of XLA patients in Italy treated with Ig) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaXRpPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Viti et al., 2018) to less than half (42.1% of the PID patients in Switzerland) ADDIN EN.CITE <EndNote><Cite><Author>Pollock</Author><Year>2018</Year><RecNum>97</RecNum><DisplayText>(Pollock and Meckley, 2018)</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pollock, R. F.</author><author>Meckley, L. M.</author></authors></contributors><auth-address>Ossian Health Economics and Communications GmbH, Health Economics and Outcomes Research, Basel, Switzerland.&#xD;Shire Plc, Outcomes Research and Epidemiology, Cambridge, MA, USA.</auth-address><titles><title>An evaluation of the budget impact of a new 20% subcutaneous immunoglobulin (Ig20Gly) for the management of primary immunodeficiency diseases in Switzerland</title><secondary-title>Clinicoecon Outcomes Res</secondary-title></titles><periodical><full-title>Clinicoecon Outcomes Res</full-title></periodical><pages>223-229</pages><volume>10</volume><edition>2018/04/26</edition><keywords><keyword>Switzerland</keyword><keyword>costs and cost analysis</keyword><keyword>immune system diseases</keyword><keyword>immunoglobulin</keyword><keyword>and Communications GmbH, which received consultancy fees from Shire to conduct</keyword><keyword>the analyses and write the manuscript. Lisa M Meckley is an employee and</keyword><keyword>shareholder of Shire Plc, the manufacturer and marketing authorization holder for</keyword><keyword>Ig20Gly. The authors report no other conflicts of interest in this work.</keyword></keywords><dates><year>2018</year></dates><isbn>1178-6981 (Print)&#xD;1178-6981</isbn><accession-num>29692618</accession-num><urls><related-urls><url>;(Pollock and Meckley, 2018). The low coverage rate reported by the Swiss study was not explained in their report, and the percentage figure was referenced from an external study. When the original study was examined, it appeared the common types of PIDs, including CVID and XLA, had high coverage rates PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsb3c8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Elsink et al., 2020). The review found that patients with CVID and XLA were most commonly treated with Ig replacement therapy, in form of either IVIg or SCIg. However, due to some of the included studies not specifying PID subtypes in their investigated population, a consistent result was difficult to find. Further, the review found that the economic consequences of Ig treatment are heavily reliant on disease duration and treatment time span. Therefore, the review recommended interpreting the economic evaluation outcomes with caution. The assessment by Health Quality Ontario conducted a review of economic literature as a part of their comprehensive HTA, similar to the current assessment. The HTA review included a smaller number of studies (n = 3), and it addressed the comparison between IVIg and SCIg ADDIN EN.CITE <EndNote><Cite><Author>Health Quality Ontario</Author><Year>2017</Year><RecNum>103</RecNum><DisplayText>(Health Quality Ontario, 2017)</DisplayText><record><rec-number>103</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">103</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Health Quality Ontario,</author></authors></contributors><titles><title>Home-Based Subcutaneous Infusion of Immunoglobulin for Primary and Secondary Immunodeficiencies: A Health Technology Assessment</title><secondary-title>Ont Health Technol Assess Ser</secondary-title></titles><periodical><full-title>Ont Health Technol Assess Ser</full-title></periodical><pages>1-86</pages><volume>17</volume><number>16</number><edition>2017/11/01</edition><dates><year>2017</year></dates><isbn>1915-7398</isbn><accession-num>31210833</accession-num><urls></urls><custom2>PMC6548531</custom2><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Health Quality Ontario, 2017). Therefore, the information available in the publication was of limited relevance to this Assessment (comparing Ig to no Ig treatment). Nevertheless, the HTA found that SCIg was associated with substantial cost-savings compared to IVIg due to the reduction in nursing care required. This is consistent with the findings described above. The 2013 review by Lingman et al. reviewed both clinical and economic aspects of Ig use via the either intravenous or subcutaneous route ADDIN EN.CITE <EndNote><Cite><Author>Lingman-Framme</Author><Year>2013</Year><RecNum>8024</RecNum><DisplayText>(Lingman-Framme and Fasth, 2013)</DisplayText><record><rec-number>8024</rec-number><foreign-keys><key app="EN" db-id="w0x0ef2w7df5z8ez9ptp0aaj25z0fe59dv5e" timestamp="1581396199">8024</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lingman-Framme, J.</author><author>Fasth, A.</author></authors></contributors><auth-address>Department of Pediatrics, Halland Hospital, Sweden.</auth-address><titles><title>Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review</title><secondary-title>Drugs</secondary-title><alt-title>Drugs</alt-title></titles><periodical><full-title>Drugs</full-title></periodical><alt-periodical><full-title>Drugs</full-title></alt-periodical><pages>1307-19</pages><volume>73</volume><number>12</number><edition>2013/07/19</edition><keywords><keyword>Administration, Intravenous/methods</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Home Care Services</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/*administration &amp; dosage/adverse effects</keyword><keyword>Immunologic Deficiency Syndromes/*drug therapy</keyword><keyword>Infusions, Subcutaneous/methods</keyword><keyword>Quality of Life</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0012-6667</isbn><accession-num>23861187</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%"> not only compares SCIg to IVIg</research-notes><language>eng</language></record></Cite></EndNote>(Lingman-Framme and Fasth, 2013). The review found that published studies up to the end of 2012 demonstrated the SCIg could introduce substantial cost savings to patients compared to IVIg while sharing similar safety and effectiveness profile. However, this cost-saving was primarily derived from societal benefits such as the avoidance of unnecessary productivity loss. Applicability to the Australian clinical contextAs described above, none of the included economic studies is directly relevant to the main question of the current report, regarding the relative cost, effectiveness, and cost-effectiveness of Ig use compared with non-Ig use in patients with PID. Consequently, it is not possible to draw any conclusions from the economic literature regarding the cost-effectiveness of Ig: the incremental cost-effectiveness of Ig versus no Ig can neither be confirmed nor dismissed. Based on the clinical and economic studies discussed herein, it is possible to infer that Ig (especially SCIg) may be cost-effective for the management of PID.Consequently, the potential cost-effectiveness of Ig in PID has been explored using three indirect approaches. These three approaches are discussed in more detail below. It should be noted that, in the absence of detailed modelling work, the analyses below are exploratory, and the cost-effectiveness of Ig compared to no Ig in PID remains uncertain. Impact of Ig on serious infections and bronchiectasis From the clinical evaluation in Section B, it is apparent that Ig is effective in improving patient outcomes such as reducing infections, controlling the onset of bronchiectasis, and avoiding general hospital admissions (noting the low-quality evidence to support these conclusions). The cost-utility analysis by Windegger et al. showed that the costs of bronchiectasis and infections were the two greatest drivers of their model ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2020</Year><RecNum>87</RecNum><DisplayText>(Windegger et al., 2020)</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T. M.</author><author>Nghiem, S.</author><author>Nguyen, K. H.</author><author>Fung, Y. L.</author><author>Scuffham, P. A.</author></authors></contributors><auth-address>School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Down, QLD, Australia.&#xD;Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.&#xD;Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia.&#xD;Health Service Strategy and Planning, Metro North Hospital and Health Services, Brisbane, QLD, Australia.</auth-address><titles><title>Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia</title><secondary-title>Blood Transfus</secondary-title></titles><periodical><full-title>Blood Transfus</full-title></periodical><pages>96-105</pages><volume>18</volume><number>2</number><edition>2020/04/10</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1723-2007</isbn><accession-num>32271703</accession-num><urls><related-urls><url>;(Windegger et al., 2020). This finding provides strong support for the use of Ig from an economic perspective: in the absence of Ig therapy, patients may experience significantly higher rates of infections and/or exacerbated bronchiectasis. These conditions are potentially expensive to treat, and they are likely to remain as long-term issues. Therefore, any Ig-related reduction in PID-associated disease burden is likely to have cost benefits, which may in the long-term, partially offset Ig treatment costs. Adverse events associated with IgOne of the concerns regarding Ig use for PID is the potential for Ig-related adverse events. Adverse events by route of Ig administration were not considered as a part of the modelling work in most of the economic studies above. Windegger et al. did not include costs of adverse event management and acknowledged that some mild adverse events due to IVIg such as headaches, muscle aches, and itching or pain were mitigated or managed preventatively by appropriate OTC drugs, and no serious adverse events requiring hospital admissions were reported ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2020</Year><RecNum>87</RecNum><DisplayText>(Windegger et al., 2020)</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1589206097">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T. M.</author><author>Nghiem, S.</author><author>Nguyen, K. H.</author><author>Fung, Y. L.</author><author>Scuffham, P. A.</author></authors></contributors><auth-address>School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Down, QLD, Australia.&#xD;Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.&#xD;Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia.&#xD;Health Service Strategy and Planning, Metro North Hospital and Health Services, Brisbane, QLD, Australia.</auth-address><titles><title>Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia</title><secondary-title>Blood Transfus</secondary-title></titles><periodical><full-title>Blood Transfus</full-title></periodical><pages>96-105</pages><volume>18</volume><number>2</number><edition>2020/04/10</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1723-2007</isbn><accession-num>32271703</accession-num><urls><related-urls><url>;(Windegger et al., 2020). Although the study in Iran by Shabaninejad et al. reported the incremental cost reduction ($2,939) per percentage reduction in adverse events when using SCIg compared to IVIg, the study did not provide any specific details of theses adverse events PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFiYW5pbmVqYWQ8L0F1dGhvcj48WWVhcj4yMDE3PC9Z

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ADDIN EN.CITE.DATA (Shabaninejad et al., 2017). None of the four cost minimisation analyses included any costs of adverse event management due to Ig use. Two of the analyses commented that Ig-related adverse events were rare and negligible, and the use of SCIg would further reduce the chances of adverse reactions due to the avoidance of intravenous infusion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWF1dGU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (Beaute et al., 2010, Igarashi et al., 2014). These findings are consistent with the safety data presented in Section B. Therefore, it is assumed that adverse events associated with Ig use are unlikely to be an issue from either a clinical or economic perspective. Current Ig treatment for PIDIt is clear, especially for PID patients with common subtypes of CVID or XLA, that Ig replacement therapy is a standard treatment in Australia. The lack of data for PID patients not on Ig replacement therapy poses significant challenges when populating a cost-effectiveness model (as noted above, given the limited data available for PID in general and for CVID in particular, it was the view of the Assessment Group and the Immunoglobulin Review Refernece Group that there is likely to be little value developing a comparative cost-effectiveness analysis).Further, clinical management changes are happening around how Ig could be safely and more conveniently administered. As SCIg has been proven to be an attractive option for patients and providers, the paradigm in Ig replacement therapy is experiencing a shift from IVIg to SCIg. Due to the cost benefits likely to be realised with SCIg, the overall economic profile of Ig replacement therapy for PID may be significantly reduced in the future.Feasibility of conducting model-based economic evaluationTo directly answer the question of how cost-effective Ig replacement therapy is compared to non-Ig therapy for PID patients, a model-based health economic evaluation would be required. General model design and structure could be informed by existing evaluations such as the study by Windegger et al. (2020). From this perspective, it is feasible to conduct the model. However, from an execution perspective, the proposed model may encounter substantial difficulties. Based on the review and evidence available in the published literature so far, the lack of reliable model input parameters for PID patients on non-Ig therapy would make the model unreliable. Finally, the model-based evaluation would require assumptions to be made on how IVIg and SCIg are used currently and how this may change in the future. Due to the significant difference in cost between IVIg and SCIg, an unreliable estimate in future split between these administration routes will introduce significant uncertainty to the model. Whether or not the results derived from such an economic model would be sufficiently reliable to inform funding decision is highly uncertain. Therefore, a comparative economic evaluation to compare Ig and non-Ig standard care for PID patients is not recommended.Due to the lack of available clinical information and the high level of uncertainty surrounding the currently available data, a cost-consequences analysis was proposed to evaluate the incremental costs and outcomes of Ig for PID. This cost consequence analysis takes a one-year time horizon. This is justified as the Ig therapy is likely to follow a routine for PID patients, and it is unlikely to significantly change over time. Therefore, all costs presented in the cost-consequence analysis are annual costs. Variables used in the cost consequence analysisThe cost of Ig and its administrationThe cost of Ig therapy mainly involves two categories of cost: the acquisition of Ig product and the costs associated with its administration. These two categories of cost are calculated separately at an individual patient level, and the results are presented in the cost consequence analysis. The unit cost of Ig productThe acquisition cost of Ig depends on the Ig unit cost as well as the dosage when applied to patients. Although Ig can be sourced either domestically or from the overseas, and the administration method can be either from intravenous (IVIg) or subcutaneous (SCIg) pathways, the unit cost of Ig (i.e. cost per gram) is under a fix-price schedule provided by the NBA. The cost per gram of Ig used in the base case analysis is $60.41. This cost was provided by the Applicant to inform the economic and financial analyses in all the pilot Ig reviews. The base case cost/gram was estimated retrospectively based on the reported total domestic product cost in 2017/18 ($195 million) minus domestic SCIg product costs ($4 million) in that same year, divided by the number of IVIg domestic grams issued (3,161,673) as published in the National Report on the Issues and Use of Ig in 2017/18. Additional estimates are presented assuming:The highest cost of Ig (i.e. domestic IVIg, including the cost of plasma collection and fractionation), $140.18The lowest cost of Ig (i.e. imported IVIg), $44.94The weighted average cost of Ig across all indications, $94.51While there are slight variations between the prices per gram used in the DCAR to that published on the NBA website in 2020, as all costs above (including that of plasma fractionation) could be sourced from the same year and for consistency these prices have been used in all of the pilot Ig reviews. The Ig dosageThe Ig dosage is determined by patients’ body weight. Heavier patients would receive higher doses to ensure treatment effectiveness. However, due to the lack of data on patient characteristics, the Ig dosage information is not estimated based on the treatment regimen but derived from the usage data provided by the NBA. The NBA BloodSTAR data documented the total annual quantity of Ig used in 2018 to 2019 financial year, as well as the number of patients, who received the therapy during this period of time. The per patient dosage is hence derived and presented below in REF _Ref44629697 \h Error! Reference source not found.. The per patient dosages derived here are the mean value across all PID patients in Australia. The uncertainty measures (e.g. confidence intervals) of these point estimates over the entire PID population in Australia were not estimated based on population characteristics but assumed with 10% upper and lower thresholds for sensitivity analyses. Table D.2. SEQ Table_D.2. \* ARABIC 1Ig dosage calculation based on NBA dataRow2018 – 2019 DataDomestic IVIg Imported IVIgDomestic SCIgImported SCIgSource or calculation 1Total annual usage (gram) 546,781 41,647 46,426 111,451 NBA2Annual patient count 1,738 131 207 384 NBA3Per patient dosage (gram per patient)315318224290Row 1 ÷ Row 2Abbreviations: PID = primary immunodeficiency; NBA = National Blood Authority; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; As Ig is sourced and delivered differently in Australia, the NBA data are used to derive a global weighting on how different Ig therapies are sourced and administered at the population level. Based on the data available from BloodSTAR, the IVIg and SCIg split for PID in 2018-2019 financial year was 76% and 24%, respectively. For IVIg, approximately 97% of Ig was produced domestically whereas only 3% were imported from overseas. In contrast, more than half of the SCIg were imported (65%) compared to the domestically produced counterpart (35%). Combining the Ig sources and administration pathways, the global weights for Ig use are derived, and its proportional distribution is tabulated below in REF _Ref44668988 \h \* MERGEFORMAT Table D.2. 2. The more detailed calculations can also be found in the Excel spreadsheet for cost consequence analysis.Table D.2. SEQ Table_D.2. \* ARABIC 2Ig use by its source and administration methodSource: domesticSource: importedIVIg 70.68%5.32%SCIg8.40%15.60%Abbreviations: PID = primary immunodeficiency; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; The calculation below is presented to estimate the annual patient cost of Ig product by itself.Table D.2. SEQ Table_D.2. \* ARABIC 3Annual Ig dosage and cost estimation. Row2018 – 2019 DataDomestic IVIg Imported IVIgDomestic SCIgImported SCIgSource or calculation 1Per patient dosage (gram per patient)315318224290 REF _Ref44629697 \h \* MERGEFORMAT Error! Reference source not found.2Unit cost of Ig ($)60.4160.4160.4160.41NBA3Global weighting 70.68%5.32%8.40%15.60%Derived via NBA data4Weighted dosage (gram per patient)222.3616.9118.8445.28Row 2 × Row 35Annual dosage 303.39gram / patientSum of Row 46Total cost per patient$18,327.88Row 5 × $60.41Abbreviations: PID = primary immunodeficiency; NBA = National Blood Authority; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; Based on the calculation above, the weighted average quantity of Ig at an individual patient level is 303.39 gram per patient annually. Using the base case fixed price of Ig at $60.41, the annual cost of Ig product is estimated at $18,327.88per patient. The cost of Ig administration Healthcare resource utilisation and procedures involved in delivering Ig therapy via the intravenous or the subcutaneous pathways are different. Therefore, the cost of Ig administration varies as well. IVIg delivery involves a more consistent regimen due to the product being administered in a hospital setting. In comparison, SCIg has a two-step arrangement to firstly allow patients to receive some training and education for several months with help from professional medical staff, then to self-administer the medicine at home. Also, the SCIg involves the purchase of pump and various consumables suitable for the home-setting administration. Therefore, the cost of Ig delivery needs to be calculated separately for the IVIg and SCIg. The administration cost of IVIg is tabulated below in REF _Ref44635948 \h \* MERGEFORMAT Error! Reference source not found.. It should be noted that the cost of IVIg delivery is calculated as the annual cost at the individual patient level. Also, the healthcare resource use is collected at the wider Australia health system perspective, which involves PBS, MBS and state hospital costs. Table D.2. SEQ Table_D.2. \* ARABIC 4Ig administration costs (annually per patient)Costing ItemsProvider Price per unit Per year% of PatientsTotal costCosts to the Australian health system (%)Costs to the Australian health system($)SourceAntihistamine, Cetirizine hydrochloride 10mg tablet,PBS$0.9013.210%$1.20100%$1.20PBS website. Pack cost divided by 30Immunologists Specialist Consultations.MBS$267.901100%$267.9075%$200.90MBS 132. Professional attendanceImmunologist Follow-up Consultations.MBS$136.301100%$136.3075%$102.20MBS 133. Professional attendanceConsumables (syringes, needles and lines etc.), IVIgState hospital$4.945276%$195.23100%$195.23Windegger et al. (2020)Consumables (syringes, needles and lines etc.) SCIgState hospital$20.885224%$260.58100%$260.58Windegger et al. (2020)Pump for SCIgState hospital$1.295224%$16.10100%$16.10Windegger et al. (2020)Ward costs (IVIg)State hospital$46.335276%$1,830.96100%$1,830.96Windegger et al. (2020)Ward costs (SCIg)State hospital$23.165224%$289.04100%$289.04Windegger et al. (2020)Total$2,896.21Abbreviations: PID = primary immunodeficiency; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; The cost of Management of PID Related conditionsThe management of PID related illness could be broadly grouped into two categories: 1) management and treatment of serious infections; and2) the management of bronchiectasis; and Cost for infection-related conditionsInfections due to PID can include conditions with different origins including bacterial, viral or fungal infections ADDIN EN.CITE <EndNote><Cite><Author>Menzin</Author><Year>2014</Year><RecNum>38</RecNum><DisplayText>(Menzin et al., 2014)</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="fwavdefz3spx9te2zso5wz2uezp2fxtxzs0w" timestamp="1594873833">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menzin, J.</author><author>Sussman, M.</author><author>Munsell, M.</author><author>Zbrozek, A.</author></authors></contributors><auth-address>Boston Health Economics, Inc., Waltham, MA, USA.&#xD;CSL Behring, LLC, King of Prussia, PA, USA.</auth-address><titles><title>Economic impact of infections among patients with primary immunodeficiency disease receiving IVIG therapy</title><secondary-title>Clinicoecon Outcomes Res</secondary-title><alt-title>ClinicoEconomics and outcomes research : CEOR</alt-title></titles><pages>297-302</pages><volume>6</volume><edition>2014/06/25</edition><keywords><keyword>economics</keyword><keyword>immunoglobulin replacement therapy</keyword><keyword>immunology</keyword><keyword>outcomes research</keyword><keyword>resource utilization</keyword><keyword>treatment</keyword></keywords><dates><year>2014</year></dates><isbn>1178-6981 (Print)&#xD;1178-6981</isbn><accession-num>24959089</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">;(Menzin et al., 2014). Different medications with various regimens will be used to treat these infections, depending on the origin and the severity of the disease. The current consideration of infections in the cost consequence analysis only accounts for patients to have severe symptoms which need medical attention by hospitalisation. A broad range of information source was searched to identify relevant information on the rate of infection due to PID, as well as the associated costs. Information on these parameters is scarce with significant limitations. Therefore, there might be significant uncertainties and applicability issues surrounding these estimates. The sources of information on infections rates and the associated costs were tabulated below. Table D.2. SEQ Table_D.2. \* ARABIC 5Probability of infections and associated costsAghamohammadi et al (2009)Windegger et al. (2020)Infection under IVIgInfection rate: 62/207 = 0.30Converted to the annual probability = 0.259Probability of infection (weekly): 0.054Estimated infection cost per hospitalisation episode: $7910.10Infection under SCIgProbability of infection (weekly): 0.039Estimated infection cost per hospitalisation episode: $6732.00Infection under no IgInfection rate: 105/256 = 0.41Converted to annual probability = 0.336Not applicableAbbreviations: PID = primary immunodeficiency; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; The likelihood of infection among PID patients was reported in one comparative study, and the results were extracted and summarised in Section B.6 with more detail. However, the data is significantly limited for calculating the cost due to the variability of how infections were defined and the lack of specific detail regarding the severity leading to hospitalisation. The cost-utility analysis performed in the study by Windegger et al. (2020) provided the (transition) probabilities of infection for one week as well as the estimated costs under a local hospital perspective. However, as the study was comparing IVIg and SCIg, the probability of infection under no Ig treatment was not relevant to the study. Further, the weekly probability needs to be converted to the annual value for the current cost consequence analysis, yet this conversion would not be appropriate to use in the absence of information on the duration of the infection management. Therefore, a basic weighted cost for both IVIg and SCIg on infection requiring hospitalisation was derived as a weekly cost, then multiplied by 52 to estimate the annual cost. Then the weighted average cost for Ig is compared against no Ig using infection rates reported by Aghamohammadi et al. (2009). An alternative cost estimate on infection treatment is also sourced from a parallel HTA of Ig (MSAC 1565) for acquired hypogammaglobulinemia. Although the HTA is investigating a different immunodeficiency disease, the management of common infection due to immunodeficiency was considered relevant. The cost calculation procedures are summarised below in REF _Ref45673952 \h Table D.2. 6 below. Table D.2. SEQ Table_D.2. \* ARABIC 6Estimates of incremental costs for infection management Windegger et al. (2020)Aghamohammadi et al (2009), base caseInfection cost variationCost and rateIVIg = 0.054 × $7910.10= $427.14SCIg = 0.039 × $6732.00 = $262.55Weighted weekly cost = $689.69Annual cost = $689.69 × 52 = $35,863.78Infection with Ig = 0.259Infection with no Ig = 0.336Serious infection episode cost = $12,852Infection cost with Ig0.259 × $35,863.78 = $9,282.470.259 × $12,852 = $3,326.40Infection cost with no Ig0.336 × $35,863.78 $12,066.590.336 × $12,852 = $4,324.10Incremental -$2,784.11-$997.70Abbreviations: PID = primary immunodeficiency; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; CEA = cost-effectiveness analysis; Based on the calculations, in the base case the incremental cost for serious infection management by hospitalisation for Ig compared to no Ig treatment is estimated as a cost-saving of $2,784.11 per year. The result from the alternative scenario estimated using cost data from the HTA (for acquired hypogammaglobulinemia) is lower than the base case, yielding at a difference of $997.70 in costs saved. As the alternative cost for infection is the per episode cost, the annual total cost may be subject to underestimation due to the possibility of patients suffering multiple episodes of infection within one calendar year. Cost of management of bronchiectasis Bronchiectasis is the permanent enlargement of the airway in the lung. The expansion in the air passage could lead to symptoms such as chronic coughing, shortness of breath and potential chest pain. Also, bronchiectasis is susceptible to a range of acute and chronic infections. Among many infections, patients are particularly at risk of suffering from chronic P. aeruginosa infection. The key role of Ig relevant to bronchiectasis is to prevent infections in the lung. However, Aghamohammadi and colleagues pointed out that a small proportion of patients would still develop chronic conditions in the lung, including bronchiectasis, despite being treated with Ig ADDIN EN.CITE <EndNote><Cite><Author>Aghamohammadi</Author><Year>2009</Year><RecNum>299</RecNum><DisplayText>(Aghamohammadi et al., 2009a)</DisplayText><record><rec-number>299</rec-number><foreign-keys><key app="EN" db-id="0eeax0efkst5axe0t9nptxpar2avpvvra0ss" timestamp="1593845981">299</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aghamohammadi, Asghar</author><author>TAVASOLI, MAHMOUD</author><author>ABOU ALHASANI, HASAN</author><author>Parvaneh, Nima</author><author>MOAZAMI, K</author><author>ALAHVERDI, AAR</author><author>MAHDAVIANI, SAR</author><author>Atarod, Lida</author><author>Rezaei, Nima</author></authors></contributors><titles><title>Infectious and non-infectious complications among undiagnosed patients with common variable immunodeficiency</title></titles><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>(Aghamohammadi et al., 2009a). The comparative data between Ig and no Ig treatment on the rate of bronchiectasis due to PID is very limited. In Section B, the comparative rate of bronchiectasis without infection was extracted from the study by Aghamohammadi et al. (2009). The reported prevalence data have been converted to annual probabilities to derive the cost of bronchiectasis management and monitoring. The result of the converted probabilities is tabulated below in REF _Ref45751801 \h Table D.2. 7. Here it should be acknowledged that the bronchiectasis rate is for CVID patients, and while this is a large subgroup of the general PID population, there is still uncertainty regarding the estimation of rates and costs for this outcome. There is a routine but limited treatment for bronchiectasis. The cost of bronchiectasis ongoing monitoring and management include regular clinic visits, respiratory function test, imaging tests for the lung plus some other routine consultations with haematologists to monitor the Ig level on a regular basis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2hhbW9oYW1tYWRpPC9BdXRob3I+PFllYXI+MjAwOTwv

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ADDIN EN.CITE.DATA (Aghamohammadi et al., 2009a, Windegger et al., 2020) The cost of bronchiectasis were estimated in the study by Windegger et al. (2020) for the comparison of IVIg and SCIg. ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2020</Year><RecNum>32</RecNum><DisplayText>(Windegger et al., 2020)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="fwavdefz3spx9te2zso5wz2uezp2fxtxzs0w" timestamp="1594873832">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T. M.</author><author>Nghiem, S.</author><author>Nguyen, K. H.</author><author>Fung, Y. L.</author><author>Scuffham, P. A.</author></authors></contributors><auth-address>School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Down, QLD, Australia.&#xD;Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.&#xD;Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia.&#xD;Health Service Strategy and Planning, Metro North Hospital and Health Services, Brisbane, QLD, Australia.</auth-address><titles><title>Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia</title><secondary-title>Blood Transfus</secondary-title></titles><pages>96-105</pages><volume>18</volume><number>2</number><edition>2020/04/10</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1723-2007</isbn><accession-num>32271703</accession-num><urls><related-urls><url>;(Windegger et al., 2020) The study provided the delineated costs for bronchiectasis with or without common infections, as well as with or without p. aeruginosa infection specifically. For simplicity, the CCA only considers patients with simple bronchiectasis without any infection, as the non-infectious bronchiectasis rates are the only available data. For IVIg and SCIg, it appears the ongoing management of bronchiectasis was estimated using similar methods in the study by Windegger et al. (2020). ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2020</Year><RecNum>32</RecNum><DisplayText>(Windegger et al., 2020)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="fwavdefz3spx9te2zso5wz2uezp2fxtxzs0w" timestamp="1594873832">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T. M.</author><author>Nghiem, S.</author><author>Nguyen, K. H.</author><author>Fung, Y. L.</author><author>Scuffham, P. A.</author></authors></contributors><auth-address>School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Down, QLD, Australia.&#xD;Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.&#xD;Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia.&#xD;Health Service Strategy and Planning, Metro North Hospital and Health Services, Brisbane, QLD, Australia.</auth-address><titles><title>Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia</title><secondary-title>Blood Transfus</secondary-title></titles><pages>96-105</pages><volume>18</volume><number>2</number><edition>2020/04/10</edition><dates><year>2020</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1723-2007</isbn><accession-num>32271703</accession-num><urls><related-urls><url>;(Windegger et al., 2020). In the current analysis, the weekly cost of managing bronchiectasis was estimated at $32.65, yielding an annual cost is $1,697.80. Similar to infections, Windegger and colleagues only considered patients receiving Ig, hence the cost of ongoing bronchiectasis for non-Ig recipients were not provided. It is reasonable to assume the basic ongoing monitoring and management strategy for bronchiectasis would be similar, if not the same for the Ig patients compared non-Ig patients. Therefore, the total cost of managing bronchiectasis for non-Ig (?) patients experiencing this outcome is also assumed to be $1697.80. Table D.2. SEQ Table_D.2. \* ARABIC 7Cost of management for bronchiectasisPID infectionsRate from literature dataWindegger et al. (2020)Cost estimateInfection under no IgEstimated prevalence = 0.54Annual probability = 0.417Estimated cost for ongoing management: $32.65 per week The annual cost is $1,697.800.417 × 1,697.80 = $708.41Infection under Ig (IVIg or SCIg)Estimated prevalence = 0.391Annual probability = 0.324Not applicable0.324 × 1,697.80 = $549.44Incremental- $158.97Abbreviations: PID = primary immunodeficiency; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; CEA = cost-effectiveness analysis; Results of the cost consequence analysisCost consequence analysis The cost consequence analysis comparing the total annual cost of Ig versus no Ig per PID patient is summarised below in REF _Ref45696199 \h Table D.3. 1. The reduction in PID associated illnesses (summarised in the table below) was derived from literuature where calculation was described in detail in the previous section. The reduction in probabilities between the two arms were calculated to produce the incremental differences. The cost included the Ig acquisition cost with the associated delivery and management costs, plus the costs of managing PID related infections and bronchiectasis. The incremental cost between the Ig versus no Ig treatment regimen is estimated to be $18,281.01 per patient per year, and the greatest contributor of this cost difference is the Ig product cost, which is estimated at around $18,327.88 per patient per year. In this analysis, the additional cost of Ig administration is partially offset by cost savings gained through better infection control as well as treatment and management of bronchiectasis. Table D.3. SEQ Table_D.3. \* ARABIC 1Result of the cost consequence analysis (base case)PID outcomesThe intervention armIg therapyThe comparator armNo Ig treatmentIncremental effectiveness or costsEffectivenessAnnual probability of serious infections and the number of patients estimated*0.259637 per year0.336828 per year190 avoidedAnnual probability of bronchiectasis and the number of patients estimated*0.324796 per year0.4171,026 per year230 avoidedCostsCost of product (Ig cost alone)$18,327.88-$18,327.88Cost of Ig administration$2,896.21-$2,896.21Hospitalisation due to infection$9,282.47$12,066.59-$2,784.11Treatment and management of bronchiectasis$549.44 $708.41 -$158.97 Total annual incremental cost$18,281.01Abbreviations: PID = primary immunodeficiency; Note: The calculation of the number of patients avoiding associated illnesses was based on the estimate annual PID patient number of 2,460 ( REF _Ref48005946 \h Table D.2. 1). However, these numbers have NOT been directly used as the basis of calculating Ig product costSensitivity analyses on the cost consequence analysis A range of sensitivity analyses were performed over the base case of the cost consequence analysis to capture some of the uncertainties of the evaluation. Firstly, the Ig product cost are tested sensitivity analysed using the Reference Group agreed unit cost. The one-way sensitivity analyses were undertaken, and the result is presented below. A standard 10% increase or decrease in values for (non-Ig) costs or probabilities has been undertaken and the results are compared to the base case. Finally, when alternative scenarios are available, the results from the alternative scenarios are also evaluated and presented below in REF _Ref45755617 \h Table D.3. 3. It should be noted that the sensitivity was only performed on the cost of severe infection needing hospitalisation and the ongoing monitoring and management of bronchiectasis. Table D.3. SEQ Table_D.3. \* ARABIC 2One-way sensitivity analysis on Ig product unit costIntervention Ig therapyComparatorNo Ig therapy Incremental costCost breakdownBase case ($60.41)$18,327.88-$18,327.88High Ig unit cost ($140.18)$42,529.41-$42,529.41Low Ig unit cost ($44.94)$13,634.41-$13,634.41Weighted Ig unit cost ($94.51)$28,673.52-$28,673.52Cost of Ig administration$2,896.21-$2,896.21Hospitalisation due to infection$9,282.47$12,066.59 -$2,784.11 Treatment and management of bronchiectasis$549.44$708.41 -$158.97 Total annual incremental cost (by different Ig unit cost scenarios)Base case Ig unit cost$18,281.01High Ig unit cost ($140.18)$42,482.54Low Ig unit cost ($44.94)$13,587.54Weighted Ig unit cost ($94.51)$28,626.65As shown in the table above, the incremental cost between Ig and no Ig is very sensitive to the Ig product cost. With the higher Ig product costs, the incremental cost has increased by more than two-fold, and such increase is directly translated from the similar two-fold increase in the Ig unit cost. This observation highlights that the incremental cost of Ig therapy is essentially the direct cost Ig product since the administration costs are mostly offset by the reduction in serious infections and bronchiectasis. Table D.3. SEQ Table_D.3. \* ARABIC 3Sensitivity analysis on generic variations and alternative scenariosOutcome specificTotalIncremental base case10% increase10% decreaseIncremental base case10% increase10% decreaseInfections requiring hospitalisationRate of hospitalisation due to infection-$2,784.11-$3,368.78-$2,255.13$18,281.01$17,696.35$18,809.99Cost of infection in general-$2,784.11-$2,505.70-$3,062.52$18,281.01$18,002.60$18,559.42Alternative scenario: Lower cost of infection-$2,784.11-$997.70$18,281.01 $20,067.43 BronchiectasisRate of bronchiectasis without infection-$158.97-$166.94-$149.86$18,281.01$18,273.04$18,290.12As shown in the table above, uncertainties over the rate and the cost of infection and bronchiectasis are tested via one-way sensitivity analyses. Due to the relatively low proportion of costs contributed by the infection and bronchiectasis to the overall cost-consequence outcome, the impact of these uncertainties is relatively limited. Between the infection and bronchiectasis, the impact of uncertain infection rate seems to be larger. This is reasonable due to the relatively higher costs associated with the serious infections requiring hospital care. Also, the lower cost scenario of infection also has a relatively larger impact to the overall cost-consequence outcome. The smaller offset in costs of treating infection leads to an overall higher incremental cost between the Ig and no Ig arm. Therefore, the overall incremental cost is relatively more susceptible to the uncertainties around infection rates and costs. Section EFinancial ImplicationsE.1Justification of the Selection of Sources of DataThis section of the report provides an evidence-based projection of the financial implications of the use of Ig for PID from 2021 to 2025. These estimates are primarily based on the Ig usage figures from the past two financial years (2017 to 2019) provided by the NBA, as well as externally sourced epidemiological studies conducted in Australia. Version 3 of the Criteria was introduced in October 2018. It is not clear how Ig usage will change under Version 3 as only a single year of data is available; therefore, the projections of future usage are uncertain. Two studies were identified through a targeted literature search, which were published ten years apart. The study by Baumgart and colleagues in 1997 estimated that in Australia the prevalence of PID was 2.1 per 100,000 population with uncertain range of 1.18 to 4.57 per 100,000 population ADDIN EN.CITE <EndNote><Cite><Author>Baumgart</Author><Year>1997</Year><RecNum>4</RecNum><DisplayText>(Baumgart et al., 1997)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="wexfxetp6ftp06eerfnx950ap2fd9w2ssxsf" timestamp="1583845961">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baumgart, Karl W</author><author>Britton, Warwick J</author><author>Kemp, Andrew</author><author>French, Martyn</author><author>Roberton, Don</author></authors></contributors><titles><title>The spectrum of primary immunodeficiency disorders in Australia</title><secondary-title>Journal of allergy and clinical immunology</secondary-title></titles><periodical><full-title>Journal of allergy and clinical immunology</full-title></periodical><pages>415-423</pages><volume>100</volume><number>3</number><dates><year>1997</year></dates><isbn>0091-6749</isbn><urls></urls></record></Cite></EndNote>(Baumgart et al., 1997). Approximately ten years later the publication by Kirkpatrick and colleagues estimated that PID prevalence was around 5.6 per 100,000, and the study also claimed that the adjusted prevalence estimates were much higher, ranging between 13.2 to 14.5 per 100,000 ADDIN EN.CITE <EndNote><Cite><Author>Kirkpatrick</Author><Year>2007</Year><RecNum>7</RecNum><DisplayText>(Kirkpatrick and Riminton, 2007a)</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1576628253">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkpatrick, Philippa</author><author>Riminton, Sean</author></authors></contributors><titles><title>Primary Immunodeficiency Diseases in Australia and New Zealand</title><secondary-title>Journal of Clinical Immunology</secondary-title></titles><periodical><full-title>Journal of Clinical Immunology</full-title></periodical><pages>517-524</pages><volume>27</volume><number>5</number><dates><year>2007</year><pub-dates><date>2007/09/01</date></pub-dates></dates><isbn>1573-2592</isbn><urls><related-urls><url>;(Kirkpatrick and Riminton, 2007a). Using the PID data provided by the NBA based on Ig use, the prevalence of PID was approximately 9.09 per 100,000 population in 2018-2019 financial year. These changes to the population prevalence estimates over the past 20 years may be due to various reasons including increasing diagnostic capabilities, changes in disease definitions, improved access to treatments and improved study performance in relation to patient recruitment. It is important to note that the NBA provided data in financial year figures on Ig use for PID. PID patients (diagnosed or otherwise) who are not on Ig therapy are not included in the NBA data calculation. Therefore, the 9.09 per 100,000 population treated prevalence rate is likely to be less than the true population prevalence for PID. For the purpose of estimating the financial implications of Ig use for PID patients, the data provided by the NBA are considered the primary source. While Australian population based PID epidemiological studies are not available, the PID patient number ascertained through a therapeutic channel (i.e. Ig usage) are considered the most relevant. Historical studies can be used to safeguard the estimation through sensitivity analyses. Further, the administration of Ig is a personalised dosage scheme determined by patients’ body weight and other factors (e.g. height, gender, general health status, as well as treatment frequencies), ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>National Blood Authority</Author><RecNum>2</RecNum><DisplayText>(National Blood Authority)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="wexfxetp6ftp06eerfnx950ap2fd9w2ssxsf" timestamp="1583845857">2</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>National Blood Authority,</author></authors></contributors><titles><title>Criteria for Clinical Use of Immunoglobulin in Australia</title></titles><volume>2020</volume><number>3 March</number><dates></dates><urls><related-urls><url>;(National Blood Authority) hence patients will receive different dosages adjusted to their personal circumstances. Administration method of Ig also includes intravenous or subcutaneous administration, and dosage and costs associated with these two routes of administration are different. As the NBA provided the Ig usage data, the annual Ig consumption will also be used as an alternative method to project costs. The financial implications of Ig use for PID patients in this section will include the cost of Ig itself and costs associated with Ig delivery, particularly around intravenous delivery. The unit cost of intravenous Ig (IVIg) and subcutaneous Ig (SCIg) are both priced at $60.41 per gram as the base cost. This cost per gram of Ig was provided by the Applicant and accepted by the Immunoglobulin Review Reference Group to be used in the base case across each of the Ig Reviews.It should be noted that due to the limitation in the clinical data; the financial estimates do not take into account any costs associated with other PID treatment requirements, including hospitalisations due to infection. The financial estimates also have not considered costs associated with adverse events arising from Ig usage as rates and consequences of these are uncertain for the PID population but estimated to be of minor consequence in our review of safety data and in other identified economic analyses. E.2 Use and cost of Ig for PIDE.2.1Number of patients with the medical conditionThe PID patient numbers in the 2017-18 and 2018-19 financial years (FY) were provided by the NBA. Specific disease subtypes were also provided to stratify the total PID numbers further. A total of six subtypes of PID were reported in the 2017-2018 FY while twelve subtypes (inclusive of the previous six) were reported in 2018-19. Therefore, the cross-FY comparisons were made only among the reported PID disease subtypes. As the two years’ of PID patient counts are the only data available, the projection on patient numbers is likely to be very uncertain. Four methods are used to estimate how many patients are likely to be diagnosed with PID from 2021 to 2025. These estimates were generated to cross-validate the projection and provide the best and worst-case scenarios. PID subtypes (based on the six reported ones) are analysed where their trends are derived to predict patient numbers at the subtype level. For disease subtypes which were not reported from the first FY, the patient counts were carried forward (Last Observation Carry Forward, LOCF) assuming no change. The six reported PID subtypes and associated predictions were plotted in REF _Ref41572066 \h \* MERGEFORMAT Figure 5, with the detailed calculation provided in the Excel file. It is not clear whether the reduction in patient number is due to changes in eligibility criteria, and whether this trend will continue over time. Therefore, this method was not used as the base case.The annual change in PID patient counts was derived based on each of the PID subtypes. The same assumption regarding LOCF in the above scenario is also used here. Based on the data provided, the most significant decline was seen for the common variable immunodeficiency disease (CVID) subtype with a 29-patient drop. Only three disease subtypes were increasing in the second FY compared to the previous one, and the maximum increase was the X-linked agammaglobulinemia with two more patients counted over the year. This resulted in an averaged reduction of 2.58 patients annually. Results of this projection were reported in REF _Ref41572110 \h \* MERGEFORMAT Table 24.A na?ve patient number change was observed comparing the 2018 FY and the 2019 FY with an increase of 107 patients. This was also applied to derive the projection, and the estimated patient counts are provided in REF _Ref41572110 \h \* MERGEFORMAT Table 24.Based on the data provided, the use of Ig at the population level was also calculated. It was estimated that approximately 9.09 per 100,000 Australians would receive Ig therapy due to PID. Assuming this prevalence is not going to change substantially, the PID patient projection was then based on the Australia population, which is experiencing approximately 1.5% growth annually. The estimated population and PID patient numbers are also provided in REF _Ref41572110 \h \* MERGEFORMAT Table 24. This is considered to be the most stable estimates for PID numbers, and hence is used as the base case for budgetary projection in this section. It is clear that all the methods above are associated with some uncertainty. To illustrate this, results of projection from all the four methods were plotted in the same graph ( REF _Ref41572220 \h Figure 6). Among the four methods used, Method 2 (average reduction of 2.58 patients annually) seems reasonable, and Method 4 was also considered appropriate. Methods 1 and 3 were considered as the lower and upper boundaries of the estimates, which are represented by error bars. Figure SEQ Figure \* ARABIC 5PID patient numbers projected by specific PID subtypesAbbreviations: CVID = Common variable immunodeficiency disease; PID = Primary immunodeficiency diseases; SCID = Severe combined immunodeficiency; W-A = Wiskott–Aldrich; AGA = agammaglobulinemia; FY = financial yearFigure SEQ Figure \* ARABIC 6Total PID patient projection via different methodsAbbreviations: FY = financial yearBased on the four methods described above, the patient number projection from 2021 to 2025 is tabulated below in REF _Ref41572110 \h Table 24. The results from Method 4 are considered most likely and were chosen to be the base case scenario; advice from the Immunoglobulin Review Reference Group is that the choice of method for the base case is appropriate (Immunoglobulin Review Reference Group Meeting 25 March 2020). Estimates from Method 2 are considered as an alternative scenario for sensitivity analyses, plus further sensitivity analyses on Method 1 and 3 are presented as the best- and worst-case scenarios. Table SEQ Table \* ARABIC 24PID population projected via different methodsYear20212022202320242025SourceAustralian population26,130,93626,522,90026,920,74427,324,55527,734,423ABS ADDIN EN.CITE <EndNote><Cite><Author>Australian Bureau of Statistics</Author><Year>2019</Year><RecNum>1</RecNum><DisplayText>(Australian Bureau of Statistics, 2019)</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="wexfxetp6ftp06eerfnx950ap2fd9w2ssxsf" timestamp="1583845705">1</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Australian Bureau of Statistics,</author></authors></contributors><titles><title>3101.0 - Australian Demographic Statistics, Jun 2019</title></titles><volume>2020</volume><number>March 5</number><dates><year>2019</year></dates><pub-location>Canberra</pub-location><urls><related-urls><url>;(Australian Bureau of Statistics, 2019)PID estimates via pure changes in counts26132720282729343041107 more cases each yearMethod 3PID estimates via Ig use (Base case)237524112447248425219.09 per 100K Aus. Population, Method 4PID estimates via average changes 228422822279227722742.58 case reduction per year, Method 2PID estimates via trends in subtypes22082181215421272100Extrapolation and LOCF, Method 1Abbreviations: PID = primary immunodeficiency diseases; Ig = immunoglobulin; ABS = Australian Bureau of Statistics, LOCF = last-observation-carry-forwardThe Ig use to treat PID varies based on its administration route, intravenous or subcutaneous, and is either collected from Australian blood sources such as domestic volunteer donors or imported from other countries. Variations regarding the Ig administration methods and product sources exist in Australia. However, due to applying a consistent unit cost on Ig regardless, these variations are not going to affect the financial estimates. The Ig use split regarding the source and administration methods are provided below for demonstration only ( REF _Ref41572303 \h Table 25). Table SEQ Table \* ARABIC 25Ig usage split for PID patientsIg usage splitIVIgSCIgSourceAdministration route split76%24%NBA 2018-2019 FY dataDomestic sourced93%35%Imported 7%65%Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearThe average dosage per person was derived from the 2018-2019 FY data provided by the NBA. As the use of Ig for PID is a weight-based scheme, to use the average dose at the population level is a crude approximation. The approximation was considered appropriate under the assumption that:there would be no significant or foreseeable changes in how Ig would be used across PID patients, patient demographics will remain relatively stable. Based on how patients are diagnosed and managed, these two assumptions are likely to be reasonable in the short term. On the other hand, the use of average dosage at the population level does not account for wastage. Wastage is likely to occur when a patient does not exhaust the entire Ig vial based on their weighted dose, and a certain volume of Ig is discarded. Given the various vial sizes available for Ig (ranged from 0.5g to 20g), wastage may or may not be a significant issue. Also, at the time of requesting Ig in BloodSTAR, there is scope to make adjustment between patients’ weight and vial size, hence there should be very little to no wastage. Average dosages in gram per person stratified by administration routes and sources are REF _Ref41572435 \h Table 26 below. These values are used in the calculation of Ig cost projections. It should be noted that this is not going to affect the financial estimates due to the same unit cost of Ig across different sources and administration methods.Table SEQ Table \* ARABIC 26Average dosage per person of Ig by sources and typesAverage dosage in gram per personIVIgSCIgSourceDomestic sourced315g/pp224g/ppNBA 2018-2019 FY dataImported 318g/pp290g/ppAbbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearNotes: The dosage was estimated at the population level using the NBA data provided;The cost of Ig was informed by the NBA and agreed with the Ig Review Reference Group to be $60.41 per gram as a base case regardless of its administration routes or sources (domestically sourced or imported). It was acknowledged that the cost of Ig might vary depending on a range of factors such as manufacturers, administration methods and sources and the allocation of domestic and imported product to each medical condition changes frequently. Therefore, the base case price of $60.41 is considered the most appropriate price to use for consistency across each of the Ig Reviews. Alternative pricing arrangements have been tested in sensitivity analyses.Table SEQ Table \* ARABIC 27Unit cost of Ig by sources and typesUnit cost (per gram)IVIgSCIgSourceDomestic sourced$60.41$60.41NBA Imported $60.41$60.41Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; Notes: This pricing is provided by the NBA. With the information obtained above, cost projection of Ig for PID can be calculated. The total cost projection of Ig use was evaluated separately by the intravenous (i.e. IVIg) and the subcutaneous (SCIg) pathways, then combined. The calculating procedures and results are presented in REF _Ref41572568 \h Table 28 to REF _Ref41572655 \h Table 30. The model predicts that the cost of Ig use in treatment of PID patients starts from $43.8 million in 2021, rising to $46.2 million in 2025 with about 1.5% growth annually.Table SEQ Table \* ARABIC 28Cost projection of IVIg for PID from 2021 to 2025FY20212022202320242025SourceCalculation referenceTotal PID estimates237524112447248425219.09 per 100KAIVIg patient numbers18051832186018881916 REF _Ref41572303 \h Table 25B = A × 0.76IVIg domestic16791704173017561782 REF _Ref41572303 \h Table 25C1 = B × 0.93IVIg Imported126128130132134 REF _Ref41572303 \h Table 25C2 = B × 0.07Domestic IVIg consumption528842536775544826552999561294 REF _Ref41572435 \h Table 26D1 = C1 × 315Imported IVIg consumption4018440787413994202042650 REF _Ref41572435 \h Table 26D2 = C2 × 318Cost of IVIg domestic$31,947,346$32,426,556$32,912,954$33,406,648$33,907,748 REF _Ref41572513 \h Table 27E1 = D1 × 60.41Cost of IVIg imported$2,427,540$2,463,953$2,500,913$2,538,426$2,576,503 REF _Ref41572513 \h Table 27E2 = D2 × 60.41Total cost of IVIg$34,374,886$34,890,509$35,413,867$35,945,075$36,484,251F = E1 + E2Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; FY = financial yearTable SEQ Table \* ARABIC 29Cost projection of SCIg for PID from 2021 to 2025FY20212022202320242025SourceCalculation referenceTotal PID estimates237524112447248425219.09 per 100KASCIg patient numbers57057958759660524% use SC routeB = A × 0.76SCIg domestic20020320620921235% domesticC1 = B × 0.35SCIg Imported37137638238839365% importedC2 = B × 0.65Domestic SCIg consumption 4468845365460434673947435 REF _Ref41572435 \h Table 26D1 = C1 × 224Imported SCIg consumption107445109074110702112376114050 REF _Ref41572435 \h Table 26D2 = C2 × 290Cost of SCIg domestic$2,699,602$2,740,522$2,781,443$2,823,500$2,865,557 REF _Ref41572513 \h Table 27E1 = D1 × 60.41Cost of SCIg imported$6,490,752$6,589,139$6,687,525$6,788,644$6,889,763 REF _Ref41572513 \h Table 27E2 = D2 × 60.41Total cost of SCIg$9,190,355$9,329,661$9,468,967$9,612,143$9,755,319F = E1 + E2Abbreviations: PID = primary immunodeficiency diseases; SCIg = subcutaneous immunoglobulin; FY = financial yearTable SEQ Table \* ARABIC 30Total Ig cost projection from 2021 to 2025FY20212022202320242025SourceCalculation referenceTotal cost of IVIg$34,374,886$34,890,509$35,413,867$35,945,075$36,484,251Row F in REF _Ref41572568 \h Table 28ATotal cost of SCIg$9,190,355$9,329,661$9,468,967$9,612,143$9,755,319Row F in REF _Ref41572620 \h Table 29BTotal Ig cost $43,566,409$44,219,905$44,883,204$45,556,452$46,239,799A + BAbbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearE.2.2 Costs of Ig deliveryIg delivery is via the intravenous or subcutaneous route. Both of these administration pathways will incur some costs due to the utilisation of therapeutic goods or services. These associated costs are mostly covered by MBS, PBS or state governments, and they form the totality of the Ig therapy for PID patients. Costs associated with Ig use are extracted and tabulated below in REF _Ref41572708 \h Table 31 REF _Ref34748322 \h Error! Reference source not found.. Some of these costs are incurred for generic Ig usage, which is non-specific to PID patients. Also, the inclusion of these costs is considered conservative. In the absence of expert advice regarding the inclusion/exclusion of the use of specialised drugs use or services for PID treatment option, these associated costs are likely to be underestimated. Table SEQ Table \* ARABIC 31Costs associated with Ig delivery via the intravenous route (IVIg)Costing ItemsProvider Price per unit Per year% of PatientsTotal cost% cost incurredCosts to the Australian health systemSourceAntihistamine, Cetirizine hydrochloride 10mg tablet PBS$0.913.210%$1.2100%$1.2PBS website. Pack cost divided by 30Immunologists Specialist Consultations.MBS$267.91.0100%$267.975%$200.9MBS 132. Professional attendance Immunologist Follow-up Consultations.MBS$136.31.0100%$136.375%$102.2MBS 133. Professional attendance Consumables (syringes, needles and lines etc.)State hospitalsIVIg = $4.94;SCIg = $20.88per week52IVIg = 76%SCIg = 24%100%IVIg = $195.23SCIg = $260.58Total = $455.81Windegger et al. (2020)Pump for SCIgState hospitals$1.29SCIg onlyper week52SCIg only, 24%100%$16.10Windegger et al. (2020)Ward costsState hospitalsIVIg = $46.33SCIg = $23.16per week52IVIg = 76%SCIg = 24%100%IVIg = $1,830.96SCIg = $289.04Total = $2120.00Windegger et al. (2020)Total$2,896.21Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; PBS = pharmaceutical benefit scheme; MBS = medical benefit scheme; IV = intravenous The costs for IVIg delivery was estimated at $5,202 per patient per year, whereas SCIg delivery incurred much lower costs at $1,404.20. It should be noted that the annual cost of SCIg administration was derived with the exclusion of the initial training of new patients. As the current PID patient numbers were prevalence estimates, it was not clear how many patients were new to Ig use due to new diagnoses and how many patients were off Ig. Therefore, excluding initial training costs was to reduce this uncertainty, and this could be considered as a conservative approach, and likely to result in a low level of underestimation. The annual costs of Ig delivery were then calculated, and the results are presented in REF _Ref41572760 \h Table 32.Table SEQ Table \* ARABIC 32Total Ig costs including delivery FY20212022202320242025SourceCalculation referenceIVIg number18051832186018881916 REF _Ref41572303 \h Table 25ASCIg number570579587596605 REF _Ref41572303 \h Table 25BTotal cost of Ig delivery$6,879,371$6,982,561$7,087,300$7,193,609$7,301,513CalculatedCIg product costs $43,566,409$44,219,905$44,883,204$45,556,452$46,239,799 REF _Ref41572655 \h Table 30DGrand total of Ig for PID patients$50,445,780$51,202,467$51,970,504$52,750,061$53,541,312Calculated E = C + D% of delivery from the total 13.64%13.64%13.64%13.64%13.64%Calculated F = C ÷ EAbbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearThe total Ig cost, including delivery, was estimated at $66.7 million in 2021 and increasing to $70.7 million in 2025. The delivery cost of Ig for PID patients accounted for approximately 13.64% of the total costs, and this proportion was stable over the five projected years. E.3 Sensitivity analysesDue to the uncertainty in PID patient number estimates and how Ig is used, the projected costs from 2021 to 2025 are likely to also be uncertain. A range of sensitivity analyses were performed to test several assumptions and elicit the impact of these uncertainties. Variables tested by sensitivity analyses include: Patient number estimates from 2021 to 2025 via different methods:Method 2 was used to provide alternative scenarios for PID patient number estimates. In contrast, the other two methods were used to provide the lower and upper limits for the best- and worst-case scenarios. Price of Ig for PID treatment using other agreed values:Three alternative Ig unit costs were provided besides the agreed base-case value of $60.41. The highest cost of Ig is $140.18 per gram, and the the lowest possible Ig is at $44.94 per gram. Also, a weighted average cost of Ig across all indications was estimated at $94.51 per gram. These alternative values were estimated by the Applicant, and the calculation was based on the 2017/18 National Report on the issues and use of Ig in Australia. Detailed derivation of these Ig unit costs was discussed in Section D.3. These costs are used to estimate the budgetary impact for sensitivity analyses. Ig dosage increase or decrease by 10% at the population level:As the Ig dosage was estimated at a population level, it could be subject to high levels of uncertainty, attributable to patient weights, personal circumstance and potential wastage. Therefore a 10% variation was tested in sensitivity analysis. Results of the sensitivity analyses are provided below in REF _Ref41572800 \h Table 33. It appears the greatest impact was the unit cost of Ig; the $140.18 per gram pricing arrangement increases costs significantly. Table SEQ Table \* ARABIC 33Sensitivity analyses considering only Ig costs (not delivery)Year20212022202320242025Base caseIg cost alone$43,566,409$44,219,905$44,883,204$45,556,452$46,239,799Ig cost aloneSensitivity analysisPID patients via Method 2Uncertainty range by Method 1 and Method 3$41,896,385($40.5m, $47.9m)$41,849,003($40.0m, $49.9m)$41,801,621($39.5m, $51.9m) $41,754,239($39.1m, $53.8m)$41,706,857($38.5m, $55.8m)Price of Ig at lowest cost ($44.94)$32,409,774$32,895,920$33,389,359$33,890,200$34,398,553Price of Ig at highest ($140.18)$101,094,839$102,611,262$104,150,431$105,712,687$107,298,378Price of Ig at weighted average ($94.51)$68,158,605$69,180,984$70,218,699$71,271,980$72,341,05910% increase in dosage$47,923,050$48,641,896$49,371,524$50,112,097$50,863,77910% decrease in dosage$39,209,768$39,797,915$40,394,884$41,000,807$41,615,819Abbreviations: PID = primary immunodeficiency diseases; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin; FY = financial yearSection FOther relevant considerationsThe Assessment group has identified the following areas for potential future research on PID in Australia:Currently, most evidence considers all forms of PID together, having studies that report data separately for each subtype would be informative. This may be difficult due to the rare nature of these conditions. From a clinical effectiveness point of view, research into the impact of co-interventions on outcomes would be helpful to resolve the confounding issues identified in the evidence base. More broadly, it may be useful to establish a registry or database for PID patients and document the treatment(s) they are receiving. This would be helpful to understand Ig therapy coverage and true population prevalence in Australia.It would be beneficial to have more granular information on how Ig is used for PID in Australia. Ideally, future research would focus on each PID subgroup separately and be aimed to answer the questions such as:Is there any difference is usage patterns for children compared to adults? Does severity of disease impact Ig usage? Which patients are trialling periods of Ig and which of these patients are able to successful stop or reduce Ig usage? Is the pattern of Ig usage consistent over time for each PID subtype?Appendix SEQ Appendix \* ALPHABETIC AClinical Experts and Assessment GroupAssessment group RACS Research and Evaluation (ASERNIP-S)NamePositionDavid Tivey ManagerJoanna Duncan Team LeaderNing Ma Team LeaderDeanne Forel Senior Research OfficerVirginie Gaget Research OfficerMeegan Vandepeer Research OfficerNoted conflicts of interestThere were no conflicts of interest.Appendix SEQ Appendix \* ALPHABETIC BSearch strategiesBibliographic databasesElectronic databaseTime period searchedEmbase Inception to 25/11/2019PubMedInception to 20/11/2019Notes: It is worth noting that two subject headings in Embase, namely “combined immunodeficiency” and “lymphoproliferative disease”, provided a very high number of hits compared to the Pubmed search (i.e. 161,859 vs 3,928 hits for combined immunodeficiency and 427,086 vs 349,407 hits for lymphoproliferative disease). In the light of these results, the assessors opted to eliminate these two subject headings but added these two terms as text words in the search. The Pubmed and Embase searches returned a similar number of hits with 7,234 and 8,461 references respectively. When combining the two libraries, 462 references were accidentally added in duplicate (verified posteriori), which provided an original database of 16,157 references to screen. Duplicates and foreign languages records (n = 3,973) were excluded to obtain 12,200 references, which were then screened by title and abstract by three reviewers.Additional sources of literatureSourceLocationAustralian and New Zealand Clinical Trials Registry Trials Terms Used in Economic ReviewSearchQueryItems found#25 ((((((((immunoglobulins[MeSH Terms]) OR (((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulin*[Title/Abstract])) AND (((((immunologic deficiency syndrome[MeSH Terms]) OR (((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract])) OR ((primary[Title/Abstract]) AND immunodeficienc*)) OR (((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR ((((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract]))))) NOT (HIV[Title/Abstract] OR AIDS[Title/Abstract]))) AND (((((economic[Title/Abstract]) AND (model*[Title/Abstract] OR evaluat*[Title/Abstract]))) OR ((((((utility[Title/Abstract]) OR consequence[Title/Abstract]) OR effectiveness[Title/Abstract]) OR (minimization[Title/Abstract] OR minimisation[Title/Abstract]))) AND cost[Title/Abstract])) OR (((benefit and cost[MeSH Terms])) OR cost benefit analysis[MeSH Terms]))83#24 ((((economic[Title/Abstract]) AND (model*[Title/Abstract] OR evaluat*[Title/Abstract]))) OR ((((((utility[Title/Abstract]) OR consequence[Title/Abstract]) OR effectiveness[Title/Abstract]) OR (minimization[Title/Abstract] OR minimisation[Title/Abstract]))) AND cost[Title/Abstract])) OR (((benefit and cost[MeSH Terms])) OR cost benefit analysis[MeSH Terms])203182#23 (economic[Title/Abstract]) AND (model*[Title/Abstract] OR evaluat*[Title/Abstract])79165#22 (((((utility[Title/Abstract]) OR consequence[Title/Abstract]) OR effectiveness[Title/Abstract]) OR (minimization[Title/Abstract] OR minimisation[Title/Abstract]))) AND cost[Title/Abstract]88166#21 (((utility[Title/Abstract]) OR consequence[Title/Abstract]) OR effectiveness[Title/Abstract]) OR (minimization[Title/Abstract] OR minimisation[Title/Abstract])797308#20 ((benefit and cost[MeSH Terms])) OR cost benefit analysis[MeSH Terms]88900#19 ((((((immunoglobulins[MeSH Terms]) OR (((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulin*[Title/Abstract])) AND (((((immunologic deficiency syndrome[MeSH Terms]) OR (((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract])) OR ((primary[Title/Abstract]) AND immunodeficienc*)) OR (((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR ((((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract]))))) NOT (HIV[Title/Abstract] OR AIDS[Title/Abstract])19905#18(((((benefits and costs[MeSH Terms])) OR cost[Title/Abstract]) OR economic[Title/Abstract])) AND (((((immunoglobulins[MeSH Terms]) OR (((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulin*[Title/Abstract])) AND (((((immunologic deficiency syndrome[MeSH Terms]) OR (((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract])) OR ((primary[Title/Abstract]) AND immunodeficienc*)) OR (((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR ((((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract]))))543#17(((benefits and costs[MeSH Terms])) OR cost[Title/Abstract]) OR economic[Title/Abstract]621000#16((((immunoglobulins[MeSH Terms]) OR (((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulin*[Title/Abstract])) AND (((((immunologic deficiency syndrome[MeSH Terms]) OR (((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract])) OR ((primary[Title/Abstract]) AND immunodeficienc*)) OR (((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR ((((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract])))36346#15((immunoglobulins[MeSH Terms]) OR (((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulin*[Title/Abstract]945020#14immunoglobulin*[Title/Abstract]154329#13((((immunologic deficiency syndrome[MeSH Terms]) OR (((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract])) OR ((primary[Title/Abstract]) AND immunodeficienc*)) OR (((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR ((((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract]))359999#12(((combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract]))) AND ((((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract])14063#11(combine*[Title/Abstract]) OR (common[Title/Abstract] AND variable[Title/Abstract])889168#10(((immune[Title/Abstract]) AND deficienc*[Title/Abstract])) OR immunodeficienc*[Title/Abstract]154117#9(immune[Title/Abstract]) AND deficienc*[Title/Abstract]28111#8immunodeficienc*[Title/Abstract]131589#7((primary[Title/Abstract]) AND immune[Title/Abstract]) AND deficienc*[Title/Abstract]3425#6(primary[Title/Abstract]) AND immunodeficienc*20039#5((PID[Title/Abstract]) OR CVID[Title/Abstract]) OR SCID[Title/Abstract]24651#4immunologic deficiency syndrome[MeSH Terms]326964#3((((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract])) OR immunoglobulins[MeSH Terms]898214#2((ig[Title/Abstract]) OR ivig[Title/Abstract]) OR scig[Title/Abstract]43432#1immunoglobulins[MeSH Terms]881128Appendix SEQ Appendix \* ALPHABETIC CStudies included in the Systematic Review Table SEQ Table \* ARABIC 34Profiles of comparative studies on Ig replacement therapy in patients with PID included in the systematic literature reviewAuthor (year)CountryStudy designRoBDuration of follow-upNumber of patientsPatient populationDiagnostic criteriaPatient baseline characteristicsInterventionComparatorKey outcome(s)Measurement of outcomes and analysisAghamohammadi et al. (2009)IranComp, RetroSCHighI: median 7 years (range 4-21) C: median 5 years (range 1–15) I: n = 23C: n = 24CVID patients aged > 2 years referred to a medical centre between 1984–2009.I: Patients diagnosed within 6 years of onset and received appropriate treatment for at least 5 yearsC: Patients with a diagnostic delay > 6 years matched for age and gender with the I groupCriteria: ESID/.PAGIDI groupM = 10, F = 13Median age = 15.6 yrs (range 7-50)Onset age: NRDiagnostic delay: median 2.6 yrs (range 0.5-5)C groupM = 12, F = 12Median age = 14.6 yrs (range 8-42)Onset age: NRDiagnostic delay: median 8.4 yrs (range 6-32)IVIg (400-600 mg/kg, every 3-4 weeks).Prophylactic antibiotics, antibiotics at first sign of infection, regular outpatient visits. No Ig or prophylactic treatment due to delayed diagnosisInfections, hospital admissions, non-infectious complications, bronchiectasis, missed days from work or school, mortalityData was obtained by reviewing patients’ hospital records and interviewing. Survival was estimated from Kaplan-Meier life tables.Cunningham-Rundles (1989)USAComp, RetroSCNANRI: n = 46C: n = 57Consecutive CVID patients aged > 2 yearsCriteria: March of Dimes Birth Defects CriteriaI + C combinedM = 51, F = 52Age mean 29 yrs (range 3-71)Onset age: mean 25 yrsDiagnostic delay: mean 3 yrsIMIg (dose NR)No treatmentTrough IgG, IgA and IgM levelsRadial immunodiffusion was used to quantify serum Ig levels were quantitated by radial immunodiffusion. The serum Ig were also examined for monoclonal proteins using an immunoelectrophoresis approach.To analyse immunologic parameters a χ2 test and a test of correlation were applied to the data obtained (Pearson).Gardulf et al. (1993)SwedenComp, RetroMCNANRI: n = 15C: n = 10Consecutive patients aged ≥ 18 years with CVID (n = 23), XLA (n = 1), thymoma with hypogammaglobulinemia (n = 1)Criteria: NRI + C combinedM = 12, F = 13Age mean 43 yrs (SD 16)Onset age: mean 25 yrsDiagnostic delay: median 10 yrs (range 1-56)IMIg (n = 13) or IVIg (n = 2) for mean of 78 months (dose NR)No treatmentFunctional status, Recreational activity, IgG trough levelsQuestionnaire based.Non-parametric statistical methods applied.A Wilcoxon-Mann-Whitney test was used to determine the difference between groups.A Spearm rank-order approach was used to express the relations between variables in correlation coefficients.Fisher’s exact test was applied to treat nominal data.Waniewski et al. (1994)PolandComp, RetroSCNANRI: n = 17C: n = 6Patients with CVID and increased infection rate aged ≥ 18 yearsCriteria: WHOI + C combinedM = 9, F = 14Age, onset age and diagnostic delay NRIMIg (dose NR)No treatmentSerum IgG levelsIgG levels from the time of diagnosis were obtained from patients’medical reports.Blood samples were collected at follow-up for analysis.Results were summarized using descriptive statistics. Two non-parametric tests, namely the Kruskall-Wallis test and the Mann-Whitney test, were used to compare different patient groups. To compare IgG levels across time and groups, the paired t test was applied to the data obtained.Abbreviations: C: comparator group; Comp: comparative study; Criteria: refers to the diagnostic criteria used to identify patients; CVID: common variable immunodeficiency, F: female patients, I: intervention group; Ig: immunoglobulin; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; IMIg: intramuscular immunoglobulin; IVIg: intravenous immunoglobulin; M: male patients, MC: multicentre study, n: number of patients; NA: not assessed, NR: not reported; PAGID/ESID: Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, PID: Primary Immunodeficiency Disease; Retro: retrospective study; SC: single centre study, SCIg: subcutaneous immunoglobulin; SD: standard deviation,.XLA: X-linked agammaglobulinaemia.Table SEQ Table \* ARABIC 35Profiles of single arm cohort studies assessing the safety and effectiveness of Ig replacement therapy for patients diagnosed with CVIDAuthor (year)CountryStudy designRoBDuration of follow-upNumber of patients CVIDTotal CVID patient populationPatients baseline characteristicsInterventionCo-interventionsKey outcome(s)Aghamohammadi et al. (2003)IranCS, Pros, SCHigh36 months2545CVID patients receiving IVIg at a single referral centre from 1997-2000 Criteria: WHOM = 13, F = 12Mean age = 15.8 yrs (SD 6.5)Onset age, diagnostic delay, both NRIVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRTrough IgG levelsAEsAghamohammadi et al. (2004)IranCS, Retro, SCHighNR data collected over 7 yrs3171CVID patients receiving IVIg at a single referral centre from 1995-2002 Criteria: WHOM = 51, F = 20Mean age: 13.8 yrs (SD 5.5)Onset age, diagnostic delay, both NRIVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRAEsAghamohammadi et al. (2008)IranCS, Retro, SCHighMedian 3 years (range 0.1-18)64109CVID patients diagnosed and treated at a single referral centre from1980-2004Criteria: PAGID/ESIDM = 33, F = 31Median age 12.5 yrs (range 2.3-56)Onset age: median 2 yrs (range 0.5-46)Diagnostic delay median 3.25 yrs (range 0.5-39)IVIg 400-500 mg/kg every 3-4 weeksCo-interventions: NRIgG serum levelInfection (otitis media and sinusitis)Alkan et al. (2018)TurkeyCS, Retro, SCHighNR, data collected over 11 yrs1212CVID patients diagnosed at a single centre from 2001-2012Criteria: PAGID/ESIDM = 7, F = 5Median age 11.6 (SD 3.7)Onset age: median 7.2 yrs (SD 4.1)Diagnostic delay: median 4.3 yrs (SD 2.6)IVIg 500 mg/kg every 3 weeksCo-interventions: NRInfection (upper respiratory, lower respiratory)Bronchiectasis (rates and prognosis)Baris et al. (2011)TurkeyCS, Retro, SCHighMean 5.6 yrs (SD 3.5, range 1.3-14)Pre-Ig mean follow-up 1.1 yrs (SD 1.5)2929Paediatric CVID patients diagnosed at a single centre and monitored for at least 12 months pre/post Ig treatment from 1994-2009Criteria: PAGID/ESIDM = 22, F = 7Mean age: 1.8 yrs (SD 6.1)Onset age: mean 21 mo (SD 26.4)Diagnostic delay: mean 3.9 yrs (SD 3.3)IVIg 500 mg/kg every 3 weeksCo-interventions: Antibacterial prophylaxis (patients with upper respiratory infections >1 per mo), daily chest therapy, inhaled corticosteroids, bronchodilators (patients with bronchiectasis)Serum IgG levelsInfections (respiratory, gastrointestinal) Bronchiectasis (rates and prognosis)Hospital stays (length and number)Antibiotic usageGrowthBayrakci et al. (2005)TurkeyACS, Retro, SCHighMedian 4.25 yrs (range 1.25-12.25)2046CVID patients treated at a single centre from 1984-2000Criteria: WHOM = 20, F = 30Median age: 13.8 yrs (range 7.8-22.3)Onset age: median 1.8 yrs (range 0.1-5)Diagnostic delay: median 4.5 yrs range 0.25-11.4)IIVIg orIMIg median dose 370 mg/kgCo-interventions: Antibacterial prophylaxis (patients with upper respiratory infections >1 per mo)Trough Ig levelsInfection and hospitalisation ratesAEsBerger et al. (2007)USA/CanadaCS, Pros, MCHigh0.5 yrs32 (ITT)42Patients treated with stable IVIg therapy for > 6 mo at 11 sites in USA and 2 sites in Canada from 2004-2005Criteria: PAGID/ESIDBaseline data for CVID patients NRIVIg 200-800 mg/kg every 3-4 weeksCo-interventions: NRAEsBichuetti-Silva et al. (2014)BrazilCS, Pros, SCHigh2 yrs50117All patients with CVID who had received at least one dose of IVIg from August 2011-August 2013.Criteria: PAGID/ESIDBaseline data for CVID patients NRIVIg median dose 600 mg/kg every 3-4 weeksCo-interventions: NRAEsBusse et al. (2002)USACS, Retro, SCHighMean 6.6 yrs on IVIgB5050Most recently referred patients with CVID Criteria: PAGID/ESIDM = 20, F = 30Mean age: 42.0 yrs (SD 16.3)Age at onset, diagnostic delay NRIVIg 300-400 m/kg every 3-4 weeksCo-interventions: NRInfection rates (pneumonia)Dashti-Khavidaki et al. (2009)IranCS, Retro, SCHighNR data collected over 13 years5499Patients with CVID on stable IVIg treatment who had received at least 4 infusionsCriteria: PAGID/ESIDBaseline data for CVID patients NRIVIg 300-600 mg/kg every 3-4 weeksCo-interventions: NRAEsDe Garcia et al. (2004)SpainCS, Retro, SCHigh2 yrs2424Consecutive adult patients with CIVD diagnosed 1994-2001Criteria: WHOM = 10, F = 14Mean age: 45 yrs (SD 18)Onset age: NRDiagnostic delay: NRIVIg 200-300 mg/kg weekly for 3 weeks then every 3 weeks. Additional IVIg given if trough Ig levels < 600 mg/kg or if bacterial infections persistedCo-interventions:Postural drainage, chest percussion, bronchodilators, inhaled steroids and antibiotics considered if CPD presentIgG levels, Infection (serious and mild)AEsMartinez Garcia et al. (2001)SpainCS, Retro, SCHighMean 7.5 yrs1919Patients diagnosed with CVID on Ig replacement therapyCriteria: NRM = 12, F = 7Mean age: 33 yrs (SD 17.1)Onset age: mean 14.7 yrsDiagnostic delay: mean 8.5 yrsIVIg 300-600 mg/kg every 3 weeksCo-interventions: NRInfection (upper respiratory, pneumonia, sinusitis, otitis media) chronic pulmonary conditions (bronchiectasis, COPD, tuberculosis, asthma)Pourpak et al. (2006)IranCS, Retro SCHighMean 3.5 yrs (SD 2.95)2626Patients diagnosed with CVID from 1999-2002 receiving IVIg who had been observed for at least 9 moCriteria: WHOM = 14, F = 12Mean age: 12.4 yrs (SD 5.6)Onset age: mean 2.5 yrs (SD 3)Diagnostic delay: mean 5.7 yrs (SD 3.9)IVIg 400 mg/kg every 3-4 weeksCo-interventions: NRInfection (pneumonia)Hospital admission IgG levelsQuinti et al. (2008)ItalyCS, Pros, MCHigh1982 patient years262262Patients diagnosed with CVID in the Italian Primary Immunodeficiency Network (26 centres) from 1999-2007Criteria: PAGID/ESIDNRIVIg 400 mg/kg 2-3 weeklyCo-interventions: antibiotic prophylaxis (11.6% of patients)AEsQuinti et al. (2007)ItalyCS, Pros, MCHighMean 11.5 yrs (range 3-34)224224Patients diagnosed with CVID in the Italian Primary Immunodeficiency Network (26 centres) from 1999-2007Criteria: PAGID/ESIDM = 111, F = 113Mean age: 26.6 yrs (range 2-73)Onset age: mean 16.9 yrs (range 2-66)Diagnostic delay: mean 8.9 yrsIVIg 400 mg/kg 2-3 weeklyCo-interventions: antibiotic prophylaxis (11.6% of patients)Serum IgG levelsInfection (prevalence)Salehzadeh et al. (2010)IranCS, Retro, SCHighMean 8 yrs (SD 4.6)2424Patients aged >= 2 yrs with CVID diagnosed Criteria: PAGID/ESIDM = 17, F = 7Mean age 19.5 yrs (SD 12.6)Onset age: NRDiagnostic delay: median 5.3 yrs (0.25-39.75)IVIg 300-600 mg/kg every 3-4 weeksCo-interventions: NRSerum IgG levelsInfection (prevalence)Hospital admission ratesSingh et al. (1994)IndiaCS, Retro, SCHighNR1414Patients with CVIDCriteria: NRM = 10, F = 4Age range 2-40 yrsOnset age: NRDiagnostic delay: NRIVIg 10 ml/kg or IMIg 100 mg/kg at an interval to prevent diarrhoea and chest infectionsCo-interventions: prophylactic antibiotics usedAEsAbbreviations: AEs: adverse events; CS: case series study; Consec: consecutive patients; COPD: chronic obstructive pulmonary disease; CPD: chronic pulmonary disease; CVID: common variable immunodeficiency; F: number of female patients; IgG: immunoglobulin G; IMIg: intramuscular immunoglobulin, IVIg: intravenous immunoglobulin; ITT: intention to treat population; M: number of male patients; MC: multicentre; Mo: months; NR: not reported, PAGID/ESID: Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, PP: per protocol population; Pros: prospective study design; Retro: retrospective study design; SC: single centre; SD: standard deviation), USA: United States of America, WHO: World Health Organisation, Yrs: years.Note: A = Bayrakci et al. (2005) data was reported in trimesters, one trimester calculated to be 3 months based on total length of follow-up of 2733 months equating to 911 trimesters); B = Busse et al. (2002) note 3 patients began treatment on IMIg then switched to IVIgTable SEQ Table \* ARABIC 36Risk of bias of the comparative study Aghamohammadi et al. (2009) using the ROBINS-1 tool ADDIN EN.CITE <EndNote><Cite><Author>Sterne</Author><Year>2016</Year><RecNum>41</RecNum><DisplayText>(Sterne et al., 2016)</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="at909z2f2a20z7estdop5fzd2wxzs2sx5v9d" timestamp="1583189733">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sterne, Jonathan AC</author><author>Hernán, Miguel A</author><author>Reeves, Barnaby C</author><author>Savovi?, Jelena</author><author>Berkman, Nancy D</author><author>Viswanathan, Meera</author><author>Henry, David</author><author>Altman, Douglas G</author><author>Ansari, Mohammed T</author><author>Boutron, Isabelle</author><author>Carpenter, James R</author><author>Chan, An-Wen</author><author>Churchill, Rachel</author><author>Deeks, Jonathan J</author><author>Hróbjartsson, Asbj?rn</author><author>Kirkham, Jamie</author><author>Jüni, Peter</author><author>Loke, Yoon K</author><author>Pigott, Theresa D</author><author>Ramsay, Craig R</author><author>Regidor, Deborah</author><author>Rothstein, Hannah R</author><author>Sandhu, Lakhbir</author><author>Santaguida, Pasqualina L</author><author>Schünemann, Holger J</author><author>Shea, Beverly</author><author>Shrier, Ian</author><author>Tugwell, Peter</author><author>Turner, Lucy</author><author>Valentine, Jeffrey C</author><author>Waddington, Hugh</author><author>Waters, Elizabeth</author><author>Wells, George A</author><author>Whiting, Penny F</author><author>Higgins, Julian PT</author></authors></contributors><titles><title>ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions</title></titles><pages>i4919</pages><volume>355</volume><dates><year>2016</year></dates><urls><related-urls><url> %J BMJ</electronic-resource-num></record></Cite></EndNote>(Sterne et al., 2016):DomainRisk of biasReasonsBias due to confoundingSeriousStudy did not report or consider disease severity or co-interventions as potential confounds. This may favour either the intervention or the control.Bias in selection of participants into the studySeriousPatients were potentially selected based on characteristics observed after start of the intervention. Selection bias was not adjusted for. This may favour either the intervention or the control.Bias in classification of interventionsLowBias due to deviations from intended interventionsModerateTreatment adherence was not reported. This may favour comparator.Bias due to missing dataSeriousIt was not clear if data was missing and if patients were excluded due to missing data. This may favour either the intervention or the control.Bias in measurement of outcomesModerateIt was not clear that data were collected in a consistent way for all patients. Due to retrospective study design some elements of patient history may be missing. This may favour either the intervention or the control.Bias in selection of the reported resultLowOverall risk of biasSeriousIt is not clear whether the predicted bias will favour the intervention or control overall. Table SEQ Table \* ARABIC 37Quality appraisal of the selected case series studies using the IHE assessment tool.Aghamohammadi et al. (2003)Aghomahammadi et al. (2004)Aghomahammadi et al. (2008)Alkan et al. (2018)Baris et al. (2011)Bayrakci et al. (2005)Berger et al. (2007)Bichuetti-silva et al. (2014)Busse et al. (2002)Dashti-Khavidaki et al. (2009)De Garcia et al. (2004)Martinez Garcia et al. (2001)Pourpak et al. (2006)Quinti et al. (2008)Quinti et al. (2007)Salehzadeh et al. (2010)Singh et al. (1994)Study objective1. Objective clearly statedYYYYYYYYYYYYYYYYYStudy design2. ProspectiveYNNNNNYYNNNNNYYNN3. MulticentreNNNNNNYNNNNNNYYNN4. Consecutive recruitmentNNNNNNNYYNYNNNNNNStudy population5. Were patient characteristics included?PPYYYYNNPNPYYNYYP6. Eligibility criteria clearly statedYYYYYYYYYYYYYYYYY7. Did patient enter the study at a similar point in the disease?????????????????Intervention and co-intervention8. Was the intervention of interest clearly described?YYIYYPYYYYYYYYYYP9. Were additional interventions clearly described?NNNNYYNNNNYNNYYNYOutcome measure10. Were relevant outcome measures established a priori*YYYYTYYYYYYYYYYYYY11. Were outcome assessors blinded to the intervention?NNNNNNNNNNNNNNNNN12. Were the outcomes measured using appropriate objective methods?YYYYYYYYYYYYYYYYY13. Were the relevant outcome measures made before and after the intervention?YNYYYYNNYNYYYNYYNStatistical analysis14. Were the statistical tests used to assess the relevant outcomes appropriate?YYYYYYYYYYYYYYYYYResults and conclusions15. Was follow-up long enough for important events and outcomes to occur?YYYYYYYYYYYYYYYYY16. Were losses to follow-up reportedNNNNNNYNNNNNNNNNN17. Did study provide estimates of random variability in the data analysis of relevant outcomes?YYNNNNN/AN/AN/AN/AYNNNANNNA18. Were the adverse events reported?YYNNNYYYNYYNNYNNY19. Were the conclusions supported by results?YYYYYYYYYYYYYYYYYCompeting interest and sources of support20. Were both competing interests and sources of support for the study reported?NNYPNNYNNNNNNNNPNAppendix SEQ Appendix \* ALPHABETIC DEvidence Profile Tables Table SEQ Table \* ARABIC 38Evidence profile table example 1 for Ig compared to no treatment for patients with CVIDOutcome(units, follow-up)No. of studies and study designRisk of biasInconsistencyIndirectnessImprecisionOther considerations Effect Ig Effect no treatment QualityImportanceAdverse eventsfollow up: range 1 years to 12 years (count)8 observational studiesSeriousNot seriousNot seriousNot seriousNone184/434 (42.4%)N/A????Moderate qualityCriticalSerious adverse events (count)5 observational studiesSeriousNot seriousNot seriousNot seriousNone20/519 (3.9%)N/A????Moderate qualityCriticalLower respiratory infection rates (per patient per year)8 observational studiesVery seriousNot seriousNot seriousNot seriousPlausible residual confounding may reduce the effectRange of means0.16-0.34Range of means0.28-2.04????Very low qualityCriticalIgG trough levels (mg/dl)7 observational studiesSeriousNot seriousNot seriousNot seriousnoneRange of means455-891Range of means195-416????Low qualityCriticalHospitalisations (per patient per year)4 observational studiesVery seriousNot seriousNot seriousNot seriousPlausible residual confounding may reduce the effectRange of means0.13-0.7Range of means1.35-3.4????Very low qualityCriticalRisk of bias is discussed in Section B.3. Hospitalisations and infection rates were assessed to be at higher risk of bias due to the potential for confounding for these outcomes.???? High quality: We are very confident that the true effect lies close to that of the estimate of effect. ???? Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.???? Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.???? Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.Appendix SEQ Appendix \* ALPHABETIC EExcluded StudiesCohort studies not reporting Ig outcomes (n = 10)Jones, C. A., Rojavin, M. & Baggish, J. S. 2012. Patients with primary immunodeficiency receiving subcutaneous immune globulin Hizentra maintain health-related quality of life and treatment satisfaction in a multicentre extension study of efficacy, tolerability and safety. Journal of Pharmaceutical Health Services Research, 3, 41-47.Lucas, M., Lee, M., Lortan, J., Lopez-Granados, E., Misbah, S. & Chapel, H. 2010. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol, 125, 1354-1360.e4.Quinti, I., Soresina, A., Guerra, A., Rondelli, R., Spadaro, G., Agostini, C., Milito, C., Trombetta, A. C., Visentini, M., Martini, H., Plebani, A. & Fiorilli, M. 2011. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol, 31, 315-22.Ramirez-Vargas, N., Arablin-Oropeza, S. 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M., Matucci, A., Pecoraro, A., Spadaro, G., Vultaggio, A. & Azzari, C. 2019. Subcutaneous Immunoglobulin Twenty Percent Every Two Weeks in Pediatric Patients with Primary Immunodeficiencies: Subcohort Analysis of the IBIS Study. Pediatr Allergy Immunol Pulmonol, 32, 70-75.Canessa, C., Iacopelli, J., Pecoraro, A., Spadaro, G., Matucci, A., Milito, C., Vultaggio, A., Agostini, C., Cinetto, F., Danieli, M. G., Gambini, S., Marasco, C., Trizzino, A., Vacca, A., De Mattia, D., Martire, B., Plebani, A., Di Gioacchino, M., Gatta, A., Finocchi, A., Licciardi, F., Martino, S., De Carli, M., Moschese, V. & Azzari, C. 2017. Shift from intravenous or 16% subcutaneous replacement therapy to 20% subcutaneous immunoglobulin in patients with primary antibody deficiencies. Int J Immunopathol Pharmacol, 30, 73-82.Chouksey, A., Duff, K., Wasserbauer, N. & Berger, M. 2005. 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Appendix F Clinical Trials SearchesTable SEQ Table \* ARABIC 39Search terms used for and ANZCTR searchesSearch TermSourceTotal TrialsDatePrimary ImmunodeficiencyClinical 16328/02/2020Common variable immunodeficiencyClinical 4629/02/2020X-linked agammaglobulinaemiaClinical 121/03/2020Severe immunodeficiencyClinical 882/03/2020Wiskott-Aldrich syndromeClinical 362/03/2020Table SEQ Table \* ARABIC 40Identified trials in patients with PID.Trial identifierConditionsInterventionComparatorStudy design (Allocation, Intervention/Observational model, Masking, Location, Primary purpose, Time perspective)Country(s)Status, Completion dateNCT02881437Primary ImmunodeficiencyIgHy10Single Group Assignment, Open Label, Multi-centre, TreatmentFranceCompleted, November 2018NCT01150240Primary ImmunodeficiencyCohort, multi-centreSwitzerlandUnknown, December 2018NCT02123615Primary ImmunodeficiencyGammagard via injection deviceGammagard via subcutaneous injectionRCT, Parallel Assignment, Double-blinded, single-centre, treatmentUSAUnknown, June 2018?NCT03896932Primary Immunodeficiencyminipooled- Intravenous immunoglobulin(MP-IVIG)Single Group Assignment, Open Label, single-centre, TreatmentEgyptNot yet recruiting,December 2021NCT03610802Primary ImmunodeficiencyCohort, multi-centre, ProspectiveUSATurkeyRecruiting, March 2038NCT03814798Primary ImmunodeficiencyIGSC 20% dose schedule comparisonIGSC 20% dose schedule comparisonRCT, Crossover Assignment (Cohort), Open Label, Multi-centre, Treatment, Prospective USANot yet recruiting, September 2020NCT03907241Primary ImmunodeficiencyOctanorm 16.5%Single Group Assignment, Open Label, single-centre, TreatmentCanadaCompleted, August 2019NCT03394053Primary ImmunodeficiencyFamily-Based, multi-centre, ProspectiveUSARecruiting, December 2042NCT03252548Primary ImmunodeficiencyCase-Only, multi-centre, ProspectiveChinaNot yet recruiting, August 2022NCT03339778Primary ImmunodeficiencyOctagam 5%IVIG 10%Cohort, ProspectiveUSACompleted, September 2017NCT03033745Primary ImmunodeficiencyIgPro20 (Hizentra) dose schedule comparisonIgPro20 (Hizentra) dose schedule comparisonNon-RCT, Parallel Assignment, Open Label, Multi-centre, Treatment USACanadaCompleted, December 2018NCT02806986Primary ImmunodeficiencyIGSC 20%Single Group Assignment, Open Label, Multi-centre, TreatmentAustralia, Czechia, France, Germany, Hungary, Poland, Spain, Sweden, UKCompleted, May 2019NCT02604810Primary ImmunodeficiencyIGSC 20%IGIV-C 10%Non-RCT, Sequential Assignment, Open Label, Multi-centre, Treatment USACanadaCompleted, December 2017NCT03961009Primary ImmunodeficiencyKedrion IVIG 10%Single Group Assignment, Open Label, Multi-centre, Treatment, Prospective USACanadaRecruiting, February 2021NCT01465958Primary ImmunodeficiencyGAMUNEX-C IVGAMUNEX-C SCNon-RCT, Crossover Assignment, Open Label, Multi-centre, TreatmentUSACompleted, October 2013NCT02627300Primary ImmunodeficiencyOctanorm 16.5%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, September 2019NCT01012323Primary ImmunodeficiencyNewGamSingle Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, June 2012NCT02176239Primary ImmunodeficiencyGammaplex IVIg 5%Cohort, Multi-centre, ProspectiveUSACompleted, August 2019NCT00546871Primary ImmunodeficiencyIGIV 10%SCIG 10%Non-RCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSACompleted, September 2009NCT03618147Primary ImmunodeficiencyCohort, single-centre, Other (time perspective)KuwaitCompleted, May 2019NCT02490956Primary ImmunodeficiencyVerorabSingle Group Assignment, Open Label, single-centre, DiagnosticThailandUnknown, September 2016NCT01883921Primary ImmunodeficiencyGamma GlobulinCohort, single-centre, ProspectiveUSATerminated, August 2019NCT03988426Primary ImmunodeficiencyOctanormSingle Group Assignment, Open Label, Multi-centre, TreatmentRussiaCompleted, January 2018NCT01313507Primary ImmunodeficiencyNewGamSingle Group Assignment, Open Label Multi-centre, TreatmentUSACompleted, September 2012NCT03939533Primary ImmunodeficiencyCUTAQUIG – dose studyCUTAQUIG – dose studyRCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, March 2021NCT03037359Primary ImmunodeficiencyBivigamOther IGIVCohort, multi-centre, ProspectiveUSARecruiting, March 2021NCT01814800Primary ImmunodeficiencyRI-002Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, January 2015NCT01131858Primary ImmunodeficiencyVigantol (vitamin D supplementation)PlaceboRCT, Single Group Assignment, Quadruple , PreventionSwedenCompleted, June 2011NCT02269163Primary ImmunodeficiencyPrometic IGIV 10%IVIgNon-RCT, Sequential Assignment, Open Label, Multi-centre, TreatmentUSACompleted, January 2019NCT00751621Primary ImmunodeficiencyIgPro20Single Group Assignment, Open Label,Multi-centre, TreatmentFrance, Germany, Poland, Romania, Spain, Sweden, Switzerland, UKCompleted, December 2011NCT03277313Primary ImmunodeficiencyHYQVIA 10%GAMMAGARD LIQUID 10%Non-RCT, Single Group Assignment, Open Label, Multi-centre, PreventionUSAActive, not recruiting, October 2023NCT03116347Primary ImmunodeficiencyHYQVIA 10%KIOVIG 10%Cuvitru 20%Non-RCT, Single Group Assignment, Open Label, Multi-centre, TreatmentCzechia, Denmark, France, Greece, Slovakia, Sweden, UKRecruiting, April 2023NCT01412385Primary ImmunodeficiencyIGSC 20%GAMMAGARD LIQUID 10%KIOVIG 10%SUBCUVIANon-RCT, Parallel Assignment, Open Label, Multi-centre, TreatmentAustria, Germany, Hungary, Sweden, UKCompleted, May 2014NCT00391131Primary ImmunodeficiencyIgNextGen 16%Single Group Assignment, Open Label, Multi-centre, TreatmentAustraliaNew ZealandCompleted, October 2009NCT01485796Primary ImmunodeficiencyIGI 10% +rHuPH20Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, January 2013NCT01218438Primary ImmunodeficiencyIGIV 10%IGSC 20%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACanadaCompleted, March 2015NCT01175213Primary ImmunodeficiencyHYQVIAGAMMAGARD LIQUIDKIOVIGNon-RCT, Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, August 2013NCT00782106Primary ImmunodeficiencyIGIV 10% +rHuPH20Parallel Assignment, Open Label, Multi-centre, TreatmentUSACompleted, November 2007NCT00814320Primary ImmunodeficiencyIGIV 10% +rHuPH20Non-RCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSACompleted, November 2010NCT00157079Primary Immunodeficiency,Immune Thrombocytopenic Purpura (ITP),Kawasaki SyndromeIGIV 10%RCT, Crossover Assignment, Multi-centre, TreatmentUSACompleted, December 2013NCT02180763Primary ImmunodeficiencyGammanormSingle Group Assignment, Open Label, Multi-centre, TreatmentFranceCompleted, August 2017NCT00538915Primary ImmunodeficiencyNabi-IGIV 10%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, July 20109NCT00579137Severe Combined Immunodeficiency DiseaseSevere Primary Immunodeficiency DisorderUndefined T Cell Deficiency DisorderWiskott-Aldrick SyndromeFludarabineStem cell infusion (Anti-CD45)Campath -1HSingle Group Assignment, Open Label, Single-centre, TreatmentUSATerminated, October 2009NCT01458171Primary ImmunodeficiencyIgPro20Single Group Assignment, Open Label, Multi-centre, TreatmentJapanCompleted, April 2012NCT02503293Primary ImmunodeficiencyChrono Super PID + Gammanorm – delivery device comparisonRCT, Crossover Assignment, Open Label, Multi-centre, TreatmentAustraliaGermanyItalyUKCompleted, December 2017NCT02810444Primary ImmunodeficiencyBT595Single Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, April 2020NCT01888484Primary ImmunodeficiencyOctanorm 16.5%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACanadaCzechiaHungaryPolandRussiaSlovakiaActive, not recruiting, July 2020NCT01985373Primary ImmunodeficiencyIVIG NanogamSingle Group Assignment, Open Label, Multi-centre, TreatmentNetherlandsCompleted, March 2015NCT03668288Secondary or Primary ImmunodeficiencyIGHyCohort, Single-centre, ProspectiveFranceRecruiting, August 2021NCT01354587Primary ImmunodeficiencyVivaglobin + HizentraNon-RCT, Single Group Assignment, Open Label, single-centre, TreatmentUSAUnknown, August 2012NCT03716700Primary ImmunodeficiencyCUVITRU (IGSC 20%)Cohort, Multi-centre, ProspectiveCanadaRecruiting, July 2020NCT01461018Primary ImmunodeficiencyIgPro20 (Hizentra)Single Group Assignment, Open Label, Multi-centre, TreatmentJapanCompleted, July 2014NCT02593188Primary ImmunodeficiencyHYQVIACohort, Multi-centre, ProspectiveUSARecruiting, June 2021 NCT03148028Inflammatory Bowel DiseasesPrimary Immune Deficiency DisorderCohort, Multi-centre, OtherIsraelRecruiting, December 2020NCT02327351Primary Immune Deficiency DisorderHematopoietic Stem Cell TransplantationTCR alfa beta T cell depletionSingle Group Assignment, Open Label, single-centre, TreatmentRussiaUnknown, December 2018NCT00001788Primary ImmunodeficiencyCohort, Single-centre, RetrospectiveUSARecruiting NCT00113464Immune System DiseasesUSACompleted, April 2007NCT02868333Primary ImmunodeficiencyCohort, Multi-centre, ProspectiveFranceUnknown, January 2017NCT02579967Primary T-cell Immunodeficiency DisordersCommon Variable ImmunodeficiencyImmune System DiseasesAutoimmune LymphoproliferativeLymphoproliferative DisordersPentostatinGVHD ProphylaxisNon-RCT, Parallel Assignment, Open Label, single-centre, TreatmentUSARecruiting, December 2028NCT02735824Immunologic Deficiency Syndromesblood sampling and skin biopsyCase-Only, Multi-centre, ProspectiveSwitzerlandRecruiting, July 2022NCT00680446Primary Immune DeficiencyIg NextGen 16%Single Group Assignment, Open Label, Multi-centre, TreatmentAustraliaNew ZealandCompleted, May 2013NCT00266513Hyper-IgM SyndromeEctodermal DysplasiaUSATerminated, July 2013NCT02990819ImmunodeficienciesImmune Dysregulation SyndromesApha/beta T and CD19+ cell depletionNon-RCT, Parallel Assignment, Open Label, single-centre, TreatmentUSARecruiting, December 2023 NCT00719680Primary Immune DeficiencyIgPro20Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, June 2010NCT00811174Immunologic Deficiency SyndromesOctagam 10%Octagam 5%Single Group Assignment, Open Label, Single-centre, TreatmentAustriaTerminated, September 2010NCT01406470Immunologic Deficiency SyndromeIVIG-SN 5%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACanadaCompleted, July 2013NCT00006319Wiskott- Aldrich SyndromeADA Deficient SCIDCohort, Single-centre, ProspectiveUSAActive, not recruitingNCT00389324Immunologic Deficiency SyndromeGamunex (IGIV 10%)Non-RCT, Crossover Assignment, Open Label, Multi-centre, TreatmentUSACanadaCompleted, August 2008NCT01859754Primary Immune Deficiency DisorderOctagam 5%Other IVIG productCohort, Multi-centre, ProspectiveUSACompleted, May 2019NCT00895271Primary ImmunodeficiencyDOCK8Cohort, single-centre, ProspectiveUSAEnrolling by invitationNCT02888535Primary Immune Deficiency DisorderInternal Medicine consultationCohort, single-centre, ProspectiveFranceUnknown, December 2019NCT00358657Immunodeficiency SyndromeNon-Cancer DiagnosisSevere Aplastic AnemiaDonorCyclophosphamideFludarabine PhosphateMycophenolate MofetilSirolimusTacrolimusSingle Group Assignment, Open Label, Multi-centre, TreatmentUSAActive, not recruiting, December 2023NCT03054181Primary ImmunodeficiencySecondary Immune DeficiencyHyQviaCohort, Multi-centre, ProspectiveFranceGermanyItalyRecruiting, March 31, 2020NCT03330795Primary ImmunodeficiencyCD3/CD19 neg allogeneic BMTSingle Group Assignment, Open Label, single-centre, TreatmentUSARecruiting, November 2024NCT01856582Waning Donor ChimerismWaning Immune FunctionPrimary Immunodeficiency Disease(s)Bone Marrow FailureCD34+Single Group Assignment, Open Label, single-centre, TreatmentUSATerminated, August 2018NCT03492710Primary Immune Deficiency DisorderIGIV-SNSingle Group Assignment, Open Label, Multi-centre, Treatment, ProspectiveNot yet recruiting, December 2021NCT04197596Viral InfectionPrimary Immune Deficiency DisorderBK CTLSingle Group Assignment, Open Label, Multi-centre, TreatmentUSANot yet recruiting, June 30, 2024 NCT03266640Cytomegalovirus InfectionsPrimary Immune Deficiency DisorderCMV CTLsSingle Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, December 2021NCT01199705Primary Immune DeficiencyIgPro20Single Group Assignment, Open Label, Multi-centre, TreatmentJapanCompleted, November 2011NCT03266653Epstein-Barr Virus InfectionsPrimary Immune Deficiency DisorderCTLsSingle Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, December 2021NCT00419341Primary Immune DeficiencyIgPro20Single Group Assignment, Open Label, Multi-centre, Treatment, ProspectiveUSACompleted, October 2008NCT01287689Primary Immunodeficiency (PID)Secondary Immunodeficiency (SID)Neurological Autoimmune Diseaseany IgGCohort, Multi-centre, ProspectiveGermanyCompleted, December 2016NCT00634569Primary Immune Deficiency DiseaseFlebogamma 5% DIFSingle Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, May 2011NCT01196702Common Variable ImmunodeficiencyGranulomatous DiseaseBronchiectasisImmunoglobulin TreatmentCase control, Single-centre, Cross-sectionalUKUnknown, July 2011 NCT00553098Immunodeficiency SyndromeNon-Cancer DiagnosisAlemtuzumabCyclosporineFludarabine PhosphateMycophenolate MofetilSingle Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, March 2015NCT04232085Primary Immune Deficiency DisorderImmune Deficiency DiseaseBone Marrow FailureAlemtuzumabFludarabineMelphalanCyclophosphamideTacrolimusMycophenolate MofetilNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSARecruiting, December 2026NCT02349906Primary ImmunodeficienciesInborn Errors of MetabolismHaemoglobinopathiesBone Marrow Failure SyndromesTreosulfanBusilvexRCT, Parallel Assignment, Open Label, Multi-centre, TreatmentCzechiaGermanyItalyPolandActive, not recruiting, December 2022NCT03335605Common Variable ImmunodeficiencyCase-control, Single-centre, ProspectiveUSARecruiting, May 2020NCT01962415Primary Immunodeficiency (PID)Congenital Bone Marrow Failure SyndromesInherited Metabolic Disorders (IMD)Hereditary AnemiasInflammatory ConditionsHydroxyureaAlemtuzumabFludarabineMelphalanThiotepaNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSARecruiting, November 2021NCT02231710Primary Immune Deficiency DisordersHemophagocytic LymphohistiocytosisInherited Bone Marrow Failure SyndromeHemoglobinopathiesMetabolic DisordersBPX-501 + AP1903Single Group Assignment, Open Label, Single-centre, TreatmentUSAActive, not recruiting, July 2030NCT01966367Bone Marrow Failure SyndromeSevere Aplastic AnemiaSevere Congenital NeutropeniaAmegakaryocytic ThrombocytopeniaDiamond-Blackfan AnemiaSchwachman Diamond SyndromePrimary Immunodeficiency SyndromesAcquired Immunodeficiency SyndromesHistiocytic SyndromeFamilial Hemophagocytic LymphocytosisLymphohistiocytosisMacrophage Activation SyndromeLangerhans Cell Histiocytosis (LCH)HemoglobinopathiesSickle Cell DiseaseSickle Cell-beta-thalassemiaCD34 Stem Cell Selection TherapySingle Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, December 2019NCT04172181Severe Combined Immunodeficiency Diseasecord blood stem cell transplantationCohort, Multi-centre, ProspectiveChinaActive, not recruiting, October 2023NCT03733249Acute Lymphoblastic LeukemiaLeukemia, Acute Myeloid (AML), ChildLymphoma, Non-HodgkinMyelodysplastic SyndromesPrimary ImmunodeficiencyAnemia, AplasticHemoglobinopathiesCytopeniaFanconi AnemiaDiamond Blackfan AnemiaThalassemiaAnemia, Sickle CellRimiducidSingle Group Assignment, Open Label, Multi-centre, TreatmentItalySaudi ArabiaUKEnrolling by invitation, June 2035NCT02065869Acute Lymphoblastic LeukemiaLeukemia, Acute Myeloid (AML), ChildLymphoma, Non-HodgkinMyelodysplastic SyndromePrimary ImmunodeficiencyAnemia, AplasticOsteopetrosisHemoglobinopathiesCytopeniaFanconi AnemiaDiamond Blackfan AnemiaThalassemiaAnemia, Sickle CellrimiducidSingle Group Assignment, Open Label, Multi-centre, TreatmentItalyUKActive, not recruiting, December 2034NCT03301168Acute Lymphoblastic LeukemiaLeukemia, Acute Myeloid (AML), ChildLymphoma, Non-HodgkinMyelodysplastic SyndromesPrimary Immune Deficiency DisorderOsteopetrosisCytopeniaHemoglobinopathy in ChildrenAnemia, AplasticBPX-501 T cells and AP1903Single Group Assignment, Open Label, Multi-centre, TreatmentUSAActive, not recruiting, February 2035NCT00004695Common Variable ImmunodeficiencyPEG-interleukin-2RCT, Open Label, TreatmentCompleted, March 2000NCT00001467DOK 8STAT1GATA2ImmunodeficiencySTAT3Other, Single-centre, Cross sectionalUSAEnrolling by invitationNCT00845416Severe Combined ImmunodeficiencyT Cell LymphocytopeniaCohort, Multi-centre, ProspectiveUSACompleted, November 2011NCT00919503Non-Neoplastic HematologicLymphocytic DisorderTransplantationCyclosporineFludarabine PhosphateMethotrexateMycophenolate MofetilTacrolimusTotal-Body IrradiationTreosulfanAnti-Thymocyte GlobulinAllogeneic Bone MarrowPeripheral Blood Stem Cell TransplantationUmbilical Cord Blood TransplantationNon-RCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, February 2027NCT00405184Primary Immune Deficiency (PID)IntragamPIg NextGen 10%Single Group Assignment, Open Label, Multi-centre, TreatmentAustraliaCompleted, July 2008NCT00576407DiGeorge SyndromeComplete Typical DiGeorge AnomalyCultured Thymus Tissue for ImplantationSingle Group Assignment, Open Label, Single-centre, TreatmentUSACompleted, December 2017NCT02061800Chronic Myeloid Leukemia (CML)Acute Myelogenous Leukemia (AML)Myelodysplastic Syndrome (MDS)Juvenile Myelomonocytic Leukemia (JMML)Acute Lymphoblastic Leukemia (ALL)Lymphoma (Hodgkin's and Non-Hodgkin's)AlemtuzumabCyclophosphamideThiotepaTacrolimusMelphalanBusulfanFludarabineMethylprednisolonefull intensity with total body irradiationNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSARecruiting, December 2019NCT00006056Chediak-Higashi SyndromeGraft Versus Host DiseaseX-Linked Lymphoproliferative SyndromeFamilial Erythrophagocytic LymphohistiocytosisHemophagocytic LymphohistiocytosisVirus-Associated Hemophagocytic SyndromeAnti-thymocyte globulinBusulfanCyclophosphamideCyclosporineEtoposideFilgrastimMethotrexateAllogeneic hematopoietic stem cell transplantationTreatmentUSAUnknownNCT01617122Primary Immune Deficiency DiseasesBacteriophage OX174Single Group Assignment, Open Label, Single-centre, DiagnosticUSAUnknown, December 2015NCT03721146Immune DeficiencyCohort, Single-centre, ProspectiveFranceRecruiting, September 2021NCT03238079Primary Immune Deficiency DiseasesIGIV 10%Single Group Assignment, Open Label, Multi-centre, TreatmentUSACanadaRecruiting, May 2020 NCT02783482Immunologic Deficiency SyndromesGC5107 (IGIV 10%)Single Group Assignment, Open Label, Multi-centre, TreatmentUSACanadaUnknown, January 2018NCT00023504Primary Immune DeficiencyPneumovaxPrevnarTetanus diphtheria toxoidRabavertNon-RCT, Sequential Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, September 2026NCT02711228Primary Immune DeficiencySecondary Immune DeficiencyIgPro20 (Hizentra)Single Group Assignment, Open Label, Multi-centre, PreventionCanadaCompleted, January 30, 2018NCT03677557Primary or Secondary Immunodeficiency Disease16.5% CutaquigSingle Group Assignment, Open Label, Single-centre, TreatmentCanadaNot yet recruiting, July 2019NCT03188419Primary T-cell Immunodeficiency DisordersCommon Variable Immunodeficiencyallogeneic hematopoietic stem cell transplantCohort, Single-centre, RetrospectiveUSACompleted, February 2020NCT02303093Primary and Secondary Immunodeficiency and Other ConditionsOctagam IVIG 5%Octagam IVIG 10%panzygaCohort, multi-centre, ProspectiveAustriaCanadaFranceSpainUKRecruiting, December 2019NCT01166074Primary Immune DeficiencySCIGCohort, multi-centre, RetrospectiveUSACompleted, December 2010NCT01652092SCIDOmenn's SyndromeReticular DysgenesisWiskott-Aldrich SyndromeBare Lymphocyte SyndromeCommon Variable ImmunodeficiencyChronic Granulomatous DiseaseCD40 Ligand DeficiencyHyper IgM SyndromeX-linked Lymphoproliferative DiseaseHemophagocytic LymphohistiocytosisGriscelli SyndromeChediak-Higashi SyndromeLangerhan's Cell HistiocytosisAlemtuzumabCyclophosphamideBusulfanFludarabine phosphateMelphalanMESNAStem Cell TransplantationNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, December 2022NCT00246857Primary Immune DeficiencyOther, Multi-centre, ProspectiveUSATurkeyRecruitingNCT02542228Immune Deficiency, AntibodyCohort, ProspectiveCompleted, September 2016NCT02247141Primary Antibody DeficiencySubgamOpen Label, Multi-centre, ProspectiveUKCompleted, January 2005NCT01793506ImmunodeficienciesCohort, Single-centre, ProspectiveUSAWithdrawn, June 2017NCT01998633Hemophagocytic LymphohistiocytosisChronic Active Epstein-Barr Virus InfectionChronic Granulomatous DiseaseHIGM-1Leukocyte Adhesion DeficiencyIPEXHematopoietic Stem Cell TransplantAlemtuzumabFludarabineMelphalanSingle Group Assignment, Open Label, Single-centre, TreatmentUSACanadaCompleted, December 2016NCT01222741Fungal InfectionsPrimary Immune DeficienciesFamily-Based, Single-centre, ProspectiveUSARecruitingNCT00468273Immunologic Deficiency SyndromesOmr-IgG-am IGIVSingle Group Assignment, Open Label, Multi-centre, PreventionUSACanadaCompletedNCT01489618Common Variable ImmunodeficiencyPrimeboost Conjugated anti- Pneumococcal (PnCJ)Polysaccharide anti- Pneumococcal (PPS)RCT, Parallel Assignment, Open Label, Multi-centre, PreventionFranceTerminated, March 2013NCT00263237Common Variable ImmunodeficiencySTA-5326Single-centre, TreatmentUSACompleted, July 2008NCT00015431Common Variable ImmunodeficiencyUSACompleted, July 2013NCT03335605Common Variable ImmunodeficiencyCase-Control, Single-centre, ProspectiveUSARecruiting, December 2019NCT00004695Common Variable ImmunodeficiencyPEG-interleukin-2placeboRCT, Open Label, Multi-centre, TreatmentCompleted, March 2000NCT01946906Common Variable ImmunodeficiencyRifaximinNo treatmentRCT, Parallel Assignment, Open Label, Single-centre, Basic ScienceNorwayCompleted, December 2014NCT03534479Common Variable ImmunodeficiencyPolyclonal IgGRCT, Parallel Assignment, Open Label, Single-centre, Basic ScienceItalyCompleted, April 2013NCT03576469Common Variable ImmunodeficiencyC1-esterase inhibitorSingle Group Assignment, Open Label, Single-centre, PreventionUSARecruiting, March 2020NCT02680652Common Variable Immune DeficiencyCase-Control, ProspectiveUnknown, July 2018NCT02435173Common Variable Immunodeficiency (CVID) More Specifically Activated PI3Kdelta Syndrome (APDS) p110delta-activating Mutation Causing Senescent T CellsLymphadenopathy and Immunodeficiency (PASLI)CDZ173placeboNon-RCT, Single Group Assignment, Triple, Multi-centre, TreatmentUSACzechiaIrelandItalyNetherlandsRussiaUKRecruiting, June 2021NCT02960399Common Variable Immune DeficiencySpecific Antibody DeficiencyX-linked AgammaglobulinemiaZostavaxNon-RCT, Parallel Assignment, Open Label, Single-centre, PreventionUSATerminated, December 2017NCT00943514BronchiectasisCystic FibrosisAutoimmune DiseaseCommon Variable ImmunodeficiencyOther, Single-centre, ProspectiveUSARecruitingNCT03663933Lymphoproliferative DisordersAutoimmune LymphoproliferativePrimary T-cell Immunodeficiency DisordersImmune System DiseasesCommon Variable ImmunodeficiencyImmunosuppression Only ConditioningReduced Intensity ConditioningGVHD ProphylaxisAllogeneic HSCNo treatmentNon-RCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, May 2024NCT03513328Bone Marrow Failure SyndromeThalassemiaSickle Cell DiseaseDiamond Blackfan AnemiaAcquired Neutropenia in NewbornAcquired Anemia HemolyticAcquired ThrombocytopeniaHemophagocytic LymphohistiocytosesWiskott-Aldrich SyndromeChronic Granulomatous DiseaseCommon Variable ImmunodeficiencyX-linked Lymphoproliferative DiseaseSevere Combined ImmunodeficiencyHurler SyndromeMannosidosisAdrenoleukodystrophyThiotepa--single daily doseThiotepa--escalated doseRCT, Sequential Assignment, Open Label, Single-centre, TreatmentUSARecruiting, June 2022NCT01821781Immune Deficiency DisordersSevere Combined ImmunodeficiencyChronic Granulomatous DiseaseX-linked AgammaglobulinemiaWiskott-Aldrich SyndromeHyper-IgMDiGeorge SyndromeChediak-Higashi SyndromeCommon Variable Immune DeficiencyImmune Dysregulatory DisordersHemophagocytic LymphohistiocytosisIPEXAutoimmune Lymphoproliferative SyndromeX-linked Lymphoproliferative SyndromeAlemtuzumabFludarabineThiotepaMelphalanSingle Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, March 2024NCT01852370Severe Combined Immunodeficiency (SCID)Immunodeficiency with Predominant T-cell Defect, UnspecifiedSevere Chronic NeutropeniaChronic Granulomatous Disease (CGD)Hyper IgE SyndromesHyper IgM DeficienciesWiskott-Aldrich SyndromeMendelian Susceptibility to Mycobacterial DiseaseCommon Variable Immune Deficiency (CVID)CD3/CD19 negative allogeneic hematopoietic stem cellsSingle Group Assignment, Open Label, Single-centre, TreatmentUSAEnrolling by invitation, November 2024NCT02234791Agammaglobulinemia, BTKCohort, Single-centre, ProspectiveChinaUnknown, December 2016NCT01884311Primary Immune Deficiency DisordersCommon Variable ImmunodeficiencyX-linked AgammaglobulinaemiaHyperimmunoglobulin M SyndromeSingle Group Assignment, Open Label, Multi-centre, OtherUSACompleted, May 2017 NCT00004341X-Linked AgammaglobulinemiaX-Linked Hyper IgM SyndromeWiskott-Aldrich SyndromeLeukocyte Adhesion Deficiency SyndromeSingle- centre, ScreeningUSAUnknownNCT01963143Primary Immune Deficiency DisordersCommon Variable ImmunodeficiencyX-linked AgammaglobulinaemiaHyper-IgM SyndromeGammaplex (5%)Gammaplex (10%)RCT, Crossover Assignment, Open Label, Multi-centre, TreatmentUSAHungaryUKCompleted, May 2016NCT01289847Primary Immune Deficiency DisordersCommon Variable ImmunodeficiencyX-linked AgammaglobulinemiaHyper-IgM SyndromeWiskott-Aldrich SyndromeGammaplexSingle Group Assignment, Open Label, Multi-centre, PreventionUSAChileIsraelCompletedNCT00006054Immunologic Deficiency SyndromesChediak-Higashi SyndromeCommon Variable ImmunodeficiencyGraft Versus Host DiseaseX-Linked Lymphoproliferative SyndromeFamilial Erythrophagocytic LymphohistiocytosisHemophagocytic LymphohistiocytosisX-linked AgammaglobulinemiaWiskott-Aldrich SyndromeChronic Granulomatous DiseaseX-linked Hyper IgM SyndromeSevere Combined ImmunodeficiencyLeukocyte Adhesion Deficiency SyndromeVirus-Associated Hemophagocytic SyndromeAnti-thymocyte globulinBusulfanCyclophosphamideCyclosporineEtoposideMethotrexateMethylprednisolonePrednisoneAllogeneic bone marrow transplantationSingle-centre, TreatmentUSATerminated, December 2002NCT00613561Severe Immunodeficiency DiseasesFludarabineBusulfanAnti-Thymocyte GlobulinNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSAUnknown, December 2012NCT00295971Congenital Amegakaryocytic ThrombocytopeniaLeukemiaMyelodysplastic SyndromesSevere Congenital NeutropeniaAnti-thymocyte globulinTherapeutic allogeneic lymphocytesFludarabine phosphateThiotepaAllogeneic bone marrow transplantationAllogeneic hematopoietic stem cell transplantationIn vitro-treated peripheral blood stem cell transplantationTotal-body irradiationSingle Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, December 2011NCT02860559Severe Combined ImmunodeficiencyTBX-1400Single Group Assignment, Open Label, Multi-centre, TreatmentIsraelNot yet recruiting, March 2023NCT02244450Severe Combined Immunodeficiency, AtypicalSCID screeningNon-RCT, Parallel Assignment, Open Label, Multi-centre, ScreeningFranceCompleted, April 2018NCT00152100Severe Combined ImmunodeficiencyStem cell transplantFilgrastimAlemtuzumabNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSACompleted, August 2007NCT03597594Severe Combined ImmunodeficiencyAnti-thymocyte globulinBusulfanFludarabineThiotepaNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSANot yet recruiting, July 2027NCT02231983Severe Combined Immunodeficiencygene sequencingCohort, Single-centre, ProspectiveChinaUnknown, September 2016NCT01410019X-linked Severe Combined ImmunodeficiencyGene transferSingle Group Assignment, Open Label, Single-centre, TreatmentFranceUnknown, July 2015NCT02999984Severe Combined Immunodeficiency Due to ADA DeficiencyInfusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101)Single Group Assignment, Open Label, Single-centre, TreatmentUSACompleted, September 2019NCT00028236Severe Combined ImmunodeficiencyGene-Transduced Autologous CD34+ Stem CellsSingle-centre, TreatmentUSACompleted, July 2011NCT02590328Severe Combined ImmunodeficiencyNeonatal ScreeningCohort, Single-centre, ProspectiveChinaRecruiting, December 2020NCT01512888Severe Combined Immunodeficiency DiseaseX-linkedBusulfanSingle Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, August 2034NCT00228852T-Cell Immune Deficiency DiseasesSevere Combined ImmunodeficiencyBusulfanFludarabineATGNon-RCT, Single Group Assignment, Open Label, Single-centreUSACompleted, November 2006NCT00001255Severe Combined ImmunodeficiencyADA PBSCADA Umbilical Cord Blood CellsTransduced LymphocytesUSACompleted, July 2002NCT01129544Severe Combined ImmunodeficiencyGene transferSingle Group Assignment, Open Label, Multi-centre, TreatmentUSAActive, not recruiting, March 2023 NCT03645460 (17)Adenosine DeAminase Severe Combined ImmunoDeficiency (ADA-SCID)TYF-ADA gene-modified autologous stem cellsSingle Group Assignment, Open Label, Single-centre, TreatmentChinaRecruiting, December 2021NCT03538899Severe Combined ImmunodeficiencyBusulfanAProArtSingle Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, June 2038NCT01306019X-Linked Severe Combined Immune DeficiencyPaliferminBusulfanCD34+ HSCSingle Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, December 2030NCT01175239X-linked Severe Combined Immunodeficiencyautologous CD34+ cellsSingle Group Assignment, Open Label, Single-centre, TreatmentUKUnknown, December 2018NCT02127892Severe Combined ImmunodeficiencyUnrelated BM with T cell depletionHaplo BM with T cell depletionNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSATerminated, August 2016NCT00794508Severe Combined ImmunodeficiencyCD34+ cells ADA gene transfer Single Group Assignment, Open Label, Single-centre, TreatmentUSACompleted, January 2015, December 2012NCT04246840Severe Combined ImmunodeficiencyCase-Control, ProspectiveNot yet recruiting, February 2021NCT00006335Severe Combined ImmunodeficiencyUSACompleted, September 2008NCT01182675Severe Combined ImmunodeficiencyTransplant Conditioning with Mobilization + AlemtuzumabTransplant Conditioning with Mobilization OnlyNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSATerminated, September 2013NCT00055172Severe Combined ImmunodeficiencyFamily-Based, Multi-centre, Cross-sectionalChileUSANCT03601286Severe Combined ImmunodeficiencyX-LinkedLentiviral vector transduced CD34+ cellsSingle Group Assignment, Open Label, Single-centre, TreatmentUKRecruiting, December 2024NCT04140539Severe Combined Immunodeficiency Due to ADA DeficiencyOTL-101Single Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, February 2021NCT00490100Growth FailureX-linked Severe Combined Immunodeficiency (XSCID)Growth Hormone ResistanceIncrelexSingle Group Assignment, Open Label, Single-centre, TreatmentUSATerminated, December 2012NCT00018018Severe Combined Immunodeficiency SyndromeCD34+ cells transduced with ADA retrovirSingle-Centre, TreatmentUSACompleted, September 2014NCT03478670Immunologic Deficiency SyndromesStrimvelisCohort, Single-centre, ProspectiveItalyEnrolling by invitation, May 2037NCT03232203Severe Combined Immunodeficiency Due to ADA DeficiencySTRIMVELISCohort, Single-centre, Cross-sectionalItalyRecruiting, September 2020NCT02177760Severe Combined ImmunodeficiencyTransplacental Maternal EngraftmentStem Cell TransplantSirolimusSingle Group Assignment, Open Label, Single-centre, PreventionUSAWithdrawn, November 2015NCT04286815Gene TherapyLentiviral Vector Gene TherapySingle Group Assignment, Open Label, Single-centre, TreatmentChinaRecruiting, March 2025NCT01852071ADA-SCIDautologous EFS-ADA LV CD34+ (OTL-101)Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, August 2018NCT00599781Severe Combined Immunodeficiency Syndromegene transduced PBL and/or gene transduced HSCNon-RCT, Single Group Assignment, Open Label, Multi-centre, TreatmentCompleted, January 2007NCT03878069Adenosine Deaminase DeficiencySevere Combined Immunodeficiencyelapegademase-lvlrCohort, Open Label, Multi-centre, ProspectiveUSARecruiting, July 2023NCT00008450Adenosine Deaminase DeficiencyAutosomal Recessive DisorderImmune System DisorderPurine-Nucleoside Phosphorylase DeficiencySevere Combined ImmunodeficiencySevere Combined Immunodeficiency With Absence of T and B CellsX-Linked Severe Combined ImmunodeficiencyCyclosporineMycophenolate MofetilAllogeneic Bone Marrow TransplantationSingle Group Assignment, Open Label, Single-centre, TreatmentUSACompleted, December 2018NCT01380990Adenosine Deaminase DeficiencySevere Combined Immunodeficiencies (SCID)EF1αS-ADA lentiviral vector transduced patient Cd34+ cellsSingle Group Assignment, Open Label, Single-centre, TreatmentUKActive, not recruiting, December 2018NCT03311503Severe Combined ImmunodeficiencyX LinkedGene Therapyautologous CD34+ cell transduced with G2SCID vectorSingle Group Assignment, Open Label, Multi-centre, TreatmentUSAUKRecruiting, January 2024NCT01420627Adenosine Deaminase DeficiencySevere Combined ImmunodeficiencyEZN-2279AdagenNon-RCT, Crossover Assignment, Open Label, Multi-centre, TreatmentUSACompleted, May 2019NCT03879876Any Type of Severe Combined Immunodeficiency (SCID)Partial HLA Incompatible Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)Human T Lymphoid Progenitor (HTLP)Single Group Assignment, Open Label, Single-centre, TreatmentFranceNot yet recruiting, April 2024NCT03217617SCID, X LinkedTYF-IL-2Rg gene-modified autologous stem cellsSingle Group Assignment, Open Label, Multi-centre, TreatmentChinaRecruiting, December 2020NCT01019876Bone Marrow FailureOsteopetrosisFanconi AnemiaSevere Combined ImmunodeficiencyFludarabineCyclophosphamideNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSAUnknown, May 2013NCT02963064Severe Combined ImmunodeficiencyHumanized anti-CD117 Monoclonal AntibodyBlood Forming Stem Cell Transplant (CD34+CD90+)Single Group Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, August 2020NCT01346150SCIDADA-SCIDXSCIDLeaky SCIDOmenn SyndromeReticular DysgenesisCohort, Multi-centre, RetrospectiveCanadaUSARecruiting, August 2019NCT00695279Severe Combined ImmunodeficiencyMalignancy, HematologicNeuroblastomaNeoplasmMucopolysaccharidosis IVenipunctureCohort, Single-centre, ProspectiveUSARecruiting, December 2036NCT01182857ADA-SCIDProspectiveWithdrawn, September 2014NCT03619551SCIDBusulfanRCT, Parallel Assignment, Open Label, Multi-centre, TreatmentUSARecruiting, August 2026NCT01279720Adenosine Deaminase DeficiencyIntravenous infusion of transduced cellsNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUKCompleted, November 2013NCT00000603Anemia, AplasticFanconi AnemiaHematologic DiseasesLeukemiaNeoplasmsSevere Combined ImmunodeficiencyHematopoietic Stem Cell TransplantationMyelodysplastic Syndromesstem cell transplantationCompleted, October 2007NCT02064933Wiskott-Aldrich SyndromeCohort, Multi-centre, OtherCanadaUSAActive, not recruiting, August 2019NCT03198195Wiskott-Aldrich SyndromecyclophosphamideOther, ProspectiveEnrolling by invitation, July 2020NCT00885833FludarabineBusulfanThymoglobulinSingle Group Assignment, Open Label, Single-centre, TreatmentKorea RepublicCompleted, March 2012NCT03837483Wiskott-Aldrich SyndromeOTL-103Single Group Assignment, Open Label, Single-centre, TreatmentItalyRecruiting, December 2022NCT01347242Wiskott-Aldrich SyndromeCD34+ cells transduced with a lentiviral vector + human WASP geneSingle Group Assignment, Open Label, Multi-centre, TreatmentUKCompleted, November 2019NCT02333760Wiskott-Aldrich SyndromeAutologous CD34+ cells transduced with WASP lentiviral vectorSingle Group Assignment, Open Label, Multi-centre, OtherUKRecruiting, December 2027NCT01515462Wiskott-Aldrich SyndromeOTL-103Single Group Assignment, Open Label, Single-centre, TreatmentItalyCompleted, February 2009NCT01410825Wiskott-Aldrich SyndromeRetrovirus-mediated gene transferSingle Group Assignment, Open Label, Single-centre, TreatmentUSAActive, not recruiting, July 2023NCT01347346Wiskott-Aldrich SyndromeAutologous CD34 positive cells transduced with a lentiviral vector containing human WAS geneNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentFranceCompleted, January 2017NCT00774358Wiskott-Aldrich Syndrome (WAS)X-linked ThrombocytopeniaInterleukin-2Single Group Assignment, Open Label, Multi-centre, TreatmentUSACompleted, September 2016NCT00909363Wiskott-Aldrich SyndromeThrombocytopeniaBleedingPromactaNon-RCT, Single Group Assignment, Open Label, Single-centre, TreatmentUSATerminated, June 2017NCT03019809Wiskott-Aldrich SyndromeHematopoietic Stem Cell TransplantationGraft FailureG-CSF for Conditioning before HSCTPlerixafor for Conditioning before HSCTSingle Group Assignment, Open Label, Multi-centre, TreatmentRussiaRecruiting, July 2019NCT01319851ThalassemiaSickle Cell DiseaseGlanzmann ThrombastheniaWiskott-Aldrich SyndromeChronic-granulomatous DiseaseSevere Congenital NeutropeniaLeukocyte Adhesion DeficiencySchwachman-Diamond SyndromeDiamond-Blackfan AnemiaFanconi AnemiaDyskeratosis-congenitaChediak-Higashi SyndromeSevere Aplastic AnemiaAlefaceptSingle Group Assignment, Open Label, Single-centre, TreatmentUSATerminated, September 2013NCT00730314Sickle Cell DiseaseThalassemiaAnemiaGranulomaWiskott-Aldrich SyndromeChediak Higashi SyndromeOsteopetrosisNeutropeniaThrombocytopeniaHurler DiseaseNiemann-Pick DiseaseFucosidosisHematopoietic stem cell transplantationNon-RCT, Parallel Assignment, Open Label, Single-centre, TreatmentUSACompleted, August 2015NCT01917708Hurler SyndromeFanconi AnemiaGlanzmann ThrombastheniaWiskott-Aldrich SyndromeChronic Granulomatous DiseaseSevere Congenital NeutropeniaLeukocyte Adhesion DeficiencyShwachman-Diamond SyndromeDiamond-Blackfan AnemiaDyskeratosis-congenitaChediak-Higashi SyndromeSevere Aplastic AnemiaThalassemia MajorHemophagocytic LymphohistiocytosisSickle Cell DiseaseAbataceptSingle Group Assignment, Open Label, Single-centre, Supportive careUSACompleted, September 2019NCT03333486Wiskott-Aldrich SyndromeImmunodeficiency SyndromeCyclophosphamideFludarabine PhosphatePeripheral Blood Stem Cell TransplantationTotal-Body IrradiationSingle Group Assignment, Open Label, Single-centre, TreatmentUSARecruiting, September 2022NCT02512679Stem Cell TransplantationBone Marrow TransplantationPeripheral Blood Stem Cell TransplantationAllogeneic TransplantationGenetic DiseasesThalassemiaPediatricsDiamond-Blackfan AnemiaCombined Immune DeficiencyWiskott-Aldrich SyndromeChronic Granulomatous DiseaseX-linked Lymphoproliferative DiseaseMetabolic DiseasesCyclophosphamideNon-RCT, Single Group Assignment, Open Label, TreatmentTerminated, February 2014 ACTRN12620000264987Immune-mediated dermatological diseasesPRN473 TopicalPlaceboRCT, Double-Blind, ProspectiveAusatraliaNot yet recruiting, ACTRN12619001322123Autoimmune diseaseInflammatory bowel diseaseLupusbDMARDsOther types of immune-suppressing medicationsNo treatmentPlaceboRetrospectiveAustraliaRecruitingACTRN12618001511224Immunoglobulin A NephropathySparsentanIrbesartanRCT, Parallel assignment, Double-blind, multi-centre, treatment Australia USAUKBelgiumCzech RepublicFranceGermanyItalyLithuaniaPolandPortugalNew ZealandTaiwan China CroatiaEstoniaHong KongSpainKorea DRNot yet recruitingACTRN12618001502224Auto-Immune DiseasesHL161BKNPlaceboRCTAustraliaTerminatedACTRN12618001394235Lung TransplantationIntravenous immunoglobulinPlacebo (Human Albumin)RCT, Double-blind, treatmentAustraliaRecruitingReferences Guyatt, G, Oxman, AD, Sultan, S, Brozek, J, Glasziou, P, Alonso-Coello, P, Atkins, D, Kunz, R, Montori, V, Jaeschke, R, Rind, D, Dahm, P, Akl, EA, Meerpohl, J, Vist, G, Berliner, E, Norris, S, Falck-Ytter, Y & Schunemann, HJ 2013, 'GRADE guidelines: 11. 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