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APPENDIX 1: EXPERT PANEL TREATMENT GUIDELINES Level I evidence is lacking, and few level II, III or IV studies exist, therefore the treatment of patients with ITP is based upon expert opinion. The two sources for the following treatment recommendations are George et al13 and Andersen et al.12 Children with ITP A. Observation Appropriate if platelet count >20,000/μL with no bleeding, child should avoid: 1) activities that predispose the patient to trauma 2) medications that impair platelet function. B. Hospitalization is appropriate for patients with: 1) Severe, life-threatening bleeding, regardless of platelet count 2) Platelet counts <20,000/μL and mucous membrane bleeding 3) Platelet counts <20,000/μL and child is inaccessible or non-compliant.

Emergency treatment consists of multimodality therapy including: a) platelet transfusion, b) high-dose glucocorticoid steroids (30 mg/kg methylprednisolone for three days administered intravenously), and c) IVIg 0.8g/kg to 1g/kg with a 2nd dose within 48 hours if platelet count is still <20,000/μL.

C. Initial therapy to restore platelet counts in patients with: 1) Platelet counts <50,000/μL and life-threatening bleeding 2) Platelet counts <20,000/μL and mucous membrane bleeding 3) Platelet counts <10,000/μL and purpura bleeding. Drug Therapy: 1) oral glucocorticoid (prednisone/methylprednisolone), recommended dosing of a) 1.5 to 2 mg/kg/day for 14 to 21 days, or b) 60 mg/m2/day for 21 days, or c) 4 mg/kg/day for seven days followed by tapering dose to Day 21. 2) IVIg, recommended dosing of 1g/kg for one day. NOTE: no platelet count restriction required if child is experiencing life-threatening bleeding or is inaccessible or non-complaint. Surgical therapy Splenectomy is appropriate for patients who fail to respond to glucocorticoid therapy, where the procedure is not contraindicated and they have had: 1) ITP diagnosis for 12 months, platelet count <10,000/μL with bleeding symptoms (3 to 12 years old) 2) ITP diagnosis for 12 months, platelet count 10,000 – 30,000/μL with bleeding symptoms (8 to 12 years old).

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Adults with ITP A. Hospitalization is appropriate for patients with: 1) Severe, life-threatening bleeding, regardless of platelet count 2) Platelet counts <20,000/μL and mucous membrane bleeding 3) Platelet counts <20,000/μL and patient is inaccessible or non-compliant. Emergency treatment consists of multimodality therapy including: a) platelet transfusion, b) high-dose glucocorticoid steroids (30 mg/kg methylprednisolone for three days administered intravenously), and c) IVIg 0.8g/kg to 1g/kg with a 2nd dose within 48 hours if platelet count is still <20,000/μL. B. Initial therapy to restore platelet counts in patients with: 1) life-threatening bleeding regardless of platelet count 2) Platelet counts <30,000/μL and asymptomatic, significant mucous membrane bleeding or vaginal bleeding. Drug Therapy: 1) oral glucocorticoid (prednisone/methylprednisolone), recommended dosing: 1 to 2 mg/kg/day 2) IVIg when patient is unresponsive or slow to respond to glucocorticoid steroids, recommended dosing 1 g/kg for 2 days. Surgical therapy Splenectomy is appropriate for patients who fail to respond to glucocorticoid therapy where the procedure is not contraindicated and they have had: 1) ITP diagnosis for six weeks, platelet count <10,000/μL with no bleeding symptoms 2) ITP diagnosis for three months, platelet count <30,000/μL with or without no bleeding symptoms Example of a recommended management regimen for a 30-year-old female patient, platelet count <10,000/μL with bleeding symptoms of purpura, menorrhagia, and epistaxis: 1) initial treatment with 1 mg/kg/day prednisone 2) if patient is non-responsive to steroid alter treatment after two to four weeks by either: a) increasing dose of prednisone b) change therapy to dexamethasone c) change therapy to anti-D d) if platelet count is persistently <30,000/μL, use IVIg therapy. Splenectomy does consistently sustain normalization of platelet counts, but no recommendations can be made on the timing of the procedure when the platelet count is persistently low. If the patient is not bleeding but is thrombocytopenic, splenectomy is not appropriate. If the patient initially responded to an increased dose of prednisone but relapsed after three weeks of tapering, splenectomy is recommended within 1 to 10 weeks after relapse.

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In patients who fail to respond to prednisone and splenectomy and have active bleeding, the recommended treatments include: IVIg, accessory splenectomy, high-dose glucocorticoid, danazol, and azathioprine.

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APPENDIX 2: SEARCH STRATEGY

OVERVIEW Interface: Ovid Databases: EMBASE <1980 to present>;

Ovid MEDLINE In-Process & Other Non-Indexed Citations; Ovid MEDLINE <1950 to present>; CINAHL <1982-present> * Note: Subject headings have been customized for each database.

Date of Search: 26 Feb 2008 Alerts: Monthly search updates will begin [26 Feb 2008] and run to [5 May

2008]. Study Types: Primary economic studies and reviews Limits: None SYNTAX GUIDE

/ At the end of a phrase, searches the phrase as a subject heading .sh At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading .fs Floating subheading exp Explode a subject heading $ Truncation symbol, or wildcard: retrieves plural or variations of a word * Focused term; indicates that the marked subject heading is a primary

topic ? Truncation symbol for one or no characters only ADJ Requires words are adjacent to each other (in any order) ADJ# Adjacency within # number of words (in any order) .ti Title .ab Abstract .hw Heading Word; usually includes subject headings and controlled

vocabulary .pt Publication type .tn Drug trade name (EMBASE)

MULTI-FILE STRATEGY FOR MEDLINE / EMBASE

EMBASE, Ovid MEDLINE(R) # Searches Results IVIg concept

1 Immunoglobulins, Intravenous/ [MEDLINE term] 44983

2 ((intravenous$ adj (antibod$ or gammaglobulin$ or gamma globulin$ or immunoglobulin? or immune globulin?)) or iv 13667

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immunoglobulin? or intravenous ig or modified immune globulin?).ti,ab.

3 (IVIG or igiv or igv or IVIGg or ivgg).ti,ab. 6837

4

(alphaglobin$ or baygam$ or endobulin$ or gamagard$ or gamimmune$ or gamimune$ or gamunex$ or gammimune$ or gammimmune$ or gammagard$ or gammaguard$ or gammaglobulin$ or gammonativ$ or (globulin adj n) or igivnex$ or intraglobin$ or intraglobulin$ or iveegam$ or octagam$ or polygam$ or sandoglobulin$ or venimmune$ or venoglobulin$).ti,ab,tn.

6071

5 Immunoglobulin/ [Embase term] 74254

6 or/1-5 87872 ITP concept

7 Purpura, Thrombocytopenic, Idiopathic/ [MEDLINE term] 6829

8 Purpura, Thrombocytopenic/ [MEDLINE term] 7124

9 limit 8 to yr="1966 - 1991" 4311

10 ((thrombocytop$ adj2 purpur$) or ((autoimmune or idiopathic or immun$) adj2 thrombocytop$) or ITP or (werlhof$ adj (disease or morbus))).ti,ab.

20369

11 Idiopathic Thrombocytopenic Purpura/ [EMBASE term] 6829

12 or/7,9-11 23484 CIDP concept

13 Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/ [MEDLINE term] 788

14 (chronic inflammatory demyelinating polyradiculoneuropath$ or chronic inflammatory polyradiculoneuropath$ or CIDP).ti,ab. 1656

15 Chronic Inflammatory Demyelinating Polyneuropathy/ [EMBASE term] 593

16 or/13-15 2305 17 12 or 16 25752 Economic evaluations concept

18 (Economics or Economics, Medical or Economics, Pharmaceutical or "Value of Life").sh. [MEDLINE terms]

43654

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19 exp "Costs and Cost Analysis"/ or exp Models, Economic/ [MEDLINE terms] 270314

20 ec.fs. [MEDLINE subheading] 2296094

21 (econom$ or cost$ or budget$ or pharmacoeconomic$ or pharmaco-economic$ or valu$).ti. 275442

22

((cost$ adj benefit$) or costbenefit$ or (cost adj effective$) or costeffective$ or econometric$ or life value or quality-adjusted life year$ or quality adjusted life year$ or quality-adjusted life expectanc$ or quality adjusted life expectanc$ or sensitivity analys$ or "value of life" or "willingness to pay").ti,ab.

102146

23 exp "Health Care Cost"/ or exp Health Economics/ or exp Resource Management/ [Embase terms]

251255

24 (Economic Aspect or Economics or Quality Adjusted Life Year or Socioeconomics or Statistical Model).sh. [Embase terms]

146249

25 or/18-22 2719910 26 or/21-24 631346 27 6 and 17 and 25 835

28 from 27 keep 778-835 [MEDLINE records] 58

29 6 and 17 and 26 187

30 from 29 keep 1-151 [Embase records] 151

31 28 or 30 209 32 remove duplicates from 31 182

OTHER DATABASES PubMed Same MeSH, keywords used as per MEDLINE search, with

appropriate syntax, limited to in process[sb] OR publisher[sb] OR pubmednotmedline[sb] records.

Biosis Previews (Thomson ) <1995-present>

Same keywords used as per MEDLINE search with appropriate syntax.

Cochrane Library (Wiley) <2008 Issue 1>

Same MeSH, keywords used as per MEDLINE search. Syntax adjusted for Cochrane Library databases.

Health Economic Evaluations

Same keywords used as per MEDLINE search with appropriate syntax.

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Database (Wiley) EconLit (Scholar’s Portal) <1969-present>

Same keywords used as per MEDLINE search with appropriate syntax.

Social Sciences Citation Index (Thomson) <1976-present>

Same keywords used as per MEDLINE search with appropriate syntax.

Grey Literature and Hand Searches Dates for Search: 2003 to 2008 Keywords: Included terms intravenous immunoglobulins, idiopathic

thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy

Limits: Publication years 2003 to present * NOTE: This section lists the main agencies, organizations, and websites searched; it is not a complete list. For a complete list of sources searched, contact CADTH (http://www.cadth.ca).

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Health Technology Assessment Agencies Alberta Heritage Foundation for Medical Research (AHFMR) http://www.ahfmr.ab.ca Agence d’évaluation des technologies et des modes d’intervention en santé (AETMIS). Québec http://www.aetmis.gouv.qc.ca Canadian Agency for Drugs and Technologies in Health (CADTH) http://www.cadth.ca Centre for Health Services and Policy Research, University of British Columbia http://www.chspr.ubc.ca/cgi-bin/pub Health Quality Council of Alberta (HQCA) http://www.hqca.ca Health Quality Council, Saskatchewan http://www.hqc.sk.ca/ Institute for Clinical Evaluative Sciences (ICES), Ontario http://www.ices.on.ca/h Institute of Health Economics (IHE), Alberta http://www.ihe.ca/ Manitoba Centre for Health Policy (MCHP) http://www.umanitoba.ca/medicine/units/mchp/ Ontario Ministry of Health and Long-Term Care, Health Technology Analyses and Recommendations http://www.health.gov.on.ca/english/providers/program/ohtac/tech/techlist_mn.html The Technology Assessment Unit of the McGill University Health Centre http://www.mcgill.ca/tau/ Therapeutics Initiative, University of British Columbia http://www.ti.ubc.ca Health Technology Assessment International (HTAi) http://www.htai.org International Network for Agencies of Health Technology Assessment (INAHTA) http://www.inahta.org

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WHO Health Evidence Network http://www.euro.who.int/HEN Centre for Clinical Effectiveness, Monash University http://www.med.monash.edu.au/healthservices/cce/ Medical Services Advisory Committee, Department of Health and Ageing http://www.msac.gov.au/ NPS RADAR (National Prescribing Service Ltd.) http://www.npsradar.org.au/site.php?page=1&content=/npsradar%2Fcontent%2Farchive_alpha.html Institute of Technology Assessment (ITA) http://www.oeaw.ac.at/ita/index.htm Federaal Kenniscentrum voor de Gezondheidszorg http://www.kenniscentrum.fgov.be Danish Centre for Health Technology Assessment (DACEHTA), National Board of Health http://www.dihta.dk/ DSI Danish Institute for Health Services Research http://www.dsi.dk/engelsk.html Finnish Office for Health Technology Assessment (Finohta), National Research and Development Centre for Welfare and Health http://finohta.stakes.fi/EN/index.htm Haute Autorité de santé (HAS) [French National Authority for Health] http://www.has-sante.fr/portail/jcms/c_5443/english?cid=c_5443 Committee for Evaluation and Diffusion of Innovative Technologies (CEDIT) http://cedit.aphp.fr/english/index_present.html German Institute of Medical Documentation and Information (DIMDI), Federal Ministry of Health http://www.dimdi.de/static/de/hta/db/index.htm College voor zorgverzekeringen / Health Care Insurance Board (CVZ) http://www.cvz.nl Health Council of the Netherlands http://www.gr.nl

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New Zealand Health Technology Assessment (NZHTA) http://nzhta.chmeds.ac.nz/ Norwegian Centre for Health Technology Assessment (SMM) http://www.kunnskapssenteret.no/index.php?show=38&expand=14,38 Agencia de Evaluación de Tecnologías Sanitarias (AETS), Instituto de Salud “Carlos III” / Health Technology Assessment Agency http://www.isciii.es/htdocs/investigacion/Agencia_quees.jsp Basque Office for Health Technology Assessment (OSTEBA). Departamento de Sanidad http://www.osasun.ejgv.euskadi.net/r52-2536/es/ Catalan Agency for Health Technology Assessment and Research (CAHTA) http://www.gencat.net/salut/depsan/units/aatrm/html/en/Du8/index.html CMT — Center for Medical Technology Assessment http://www.cmt.liu.se/pub/jsp/polopoly.jsp?d=6199&l=en Swedish Council on Technology Assessment in Health Care (SBU) http://www.sbu.se/ Swiss Network for Health Technology Assessment http://www.snhta.ch/about/index.php European Information Network on New and Changing Health Technologies (EuroScan). University of Birmingham, National Horizon Scanning Centre http://www.euroscan.bham.ac.uk National Horizon Scanning Centre (NHSC) http://www.pcpoh.bham.ac.uk/publichealth/horizon National Institute for Health Research (NIHR) Health Technology Assessment programme / NIHR Coordinating Centre for Health Technology Assessment (NCCHTA) http://www.ncchta.org/ NHS National Institute for Clinical Excellence (NICE) http://www.nice.org.uk NHS Quality Improvement Scotland http://www.nhshealthquality.org University of York National Institute for Health Research Centre for Reviews and Dissemination (NIHR CRD) http://www.york.ac.uk/inst/crd

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Wessex Institute for Health Research and Development http://www.wihrd.soton.ac.uk/ West Midlands Health Technology Assessment Collaboration (WMHTAC) http://www.wmhtac.bham.ac.uk Agency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov/ United States Department of Veterans Affairs Research & Development http://www.research.va.gov/resources/pubs/default.cfm Veterans Affairs Technology Assessment Program(US) http://www.va.gov/vatap/ Institute for Clinical Systems Improvement http://www.icsi.org/index.asp Technology Evaluation Center (TEC). BlueCross BlueShield Association http://www.bluecares.com/tec/index.html University HealthSystem Consortium (UHC) http://www.uhc.edu/ Health Economic Centre for Health Economics and Policy Analysis (CHEPA), McMaster University http://www.chepa.org Health Economics Research Group (HERG), Brunel University http://www.brunel.ac.uk/about/acad/herg Health Economics Research Unit (HERU). University of Aberdeen http://www.abdn.ac.uk/heru/ Health Economic Evaluations Database (HEED) http://heed.wiley.com The Hospital for Sick Children (Toronto), PEDE Database http://pede.bioinfo.sickkids.on.ca/pede/index.jsp University of Connecticut, Department of Economics, RePEc database http://ideas.repec.org

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Search Engines Google http://www.google.ca/ AlltheWeb http://www.alltheweb.com/

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APPENDIX 3: DATA ABSTRACTION SHEETS FOR INCLUDED STUDIES REFID# 23 Citation Hollenberg JP, Subak LL, Ferry JJ, Jr., Bussel JB. Cost-

effectiveness of splenectomy versus intravenous gamma globulin in treatment of chronic immune thrombocytopenic purpura in childhood. J Pediatr 1988;112(4):530-9.

Industry Sponsorship No Study Perspective Not stated Population 10 year old, 35-kg children with chronic ITP (over 6 months)

requiring daily corticosteroids therapy to maintain platelet levels >30,000.

Interventions and Comparators

1) Splenectomy 2) IVIg (2 g/kg for introduction, 1 g/kg maintenance)

Study Design 10-year Markov model. Immediate splenectomy group:

• Patients at risk of immediate operative death and post-surgery sepsis and sepsis-related death.

• Proportion of patients are cured, those who are not switch to IVIg therapy.

Immediate IVIg treatment group: • Patients who were responsive to initial IVIg infusion

received maintenance IVIg infusions until they were cured or needed a salvage splenectomy after 2 years.

• Patients who were unresponsive to initial IVIg were immediately given a splenectomy.

• Patients who are not cured by either splenectomy or IVIg therapy are at risk of trauma that would necessitate a hospitalization and an additional IVIg infusion to prevent hemorrhage.

Location US Outcome and Sources ● Main outcome: % of patients surviving

Sources of clinical inputs parameters of the model included published literature (no systematic review), an unpublished survey, and expert opinion. Cost parameters were based on “Actual charges and present reimbursement rates in New York City.” The unit cost of IVIg was based on the “wholesale price.” No source of the price was given. The length of stay of hospitalizations was based on expert opinion. Costs discounted at 5% annually

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Currency and Year 1986 US Estimate of cost-effectiveness

IVIg=intravenous immunoglobulin. Sensitivity analysis: Multiple sensitivity analysis conducted. Changing the proportion of patients curable by IVIg +- 25 varied ICER from $166,000/death avoided to $1,200,000/death avoided. Changing cost of IVIg from $35/g to $21/g made IVIg dominant. If cost of splenectomy increased from $10,000 to $16,380, IVIg becomes dominant. If children ≤ 6 years old, IVIg less costly and dominant (they require less IVIg because they weigh less).

IVIg Splenectomy Difference Cost $20,964 $16,913 4,051 % alive 0.9863 0.9789 0.0075 $/death avoided $540,130

Conclusions No conclusion on base-case cost-effectiveness provided. “Initial IVGG treatment of younger children with chronic ITP is clearly a cost-effective strategy.”

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REFID# 24 Citation Kumar M, Vik TA, Johnson CS, Southwood ME, Croop

JM. Treatment, outcome, and cost of care in children with idiopathic thrombocytopenic purpura. Am J Hematol 2005;78(3):181-7.

Industry Sponsorship No Study Perspective Not stated Population Children <18 years of age with ITP Interventions and Comparators

1) Anti-D (n=60) IVIg (n=42) Steroids (n=42) Observation (n=27)

Study Design Retrospective chart review of acute ITP patients seen at a hospital in Indiana between 1997 and 2001. Baseline characteristics and clinical outcomes recorded from chart.

Location US Outcome and Sources Main outcome was number of days patients reached

platelet counts >20,000. Outcome recorded from chart. Costs based on actual physician bills and hospital charges of each patient encounter.

Currency and Year US; year depends on year of admission. No common year given.

Estimate of cost-effectiveness

The paper did not calculate cost-effectiveness ratios; however, based on costs and outcomes, cost-effectiveness can be calculated as: Incremental Costs Effects Costs Avoided $/Effect Observation 595 n/a Steroids 1,737 6 Reference Reference Anti-D 2,037 4 300 2 150 IVIg 2,926 3 889 1 889 IVIg=intravenous immunoglobulin.

Conclusions No conclusions on cost-effectiveness are provided.

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REFID# 7 Citation O'Brien SH, Ritchey AK, Smith KJ. A cost-utility

analysis of treatment for acute childhood idiopathic thrombocytopenic purpura (ITP). Pediatr Blood Cancer 2007;48(2):173-80.

Industry Sponsorship No Study Perspective Societal perspective (both direct and indirect costs). Population Children with acute ITP and a platelet count <20,000.

Hospitalized assumed weight of 20 kg. Interventions and Comparators

1) IVIg (single dose 0.8 g/kg) 2) Anti-D (single dose 75 μg/kg) 3) Intravenous methylprednisolone 30 mg/kg dose over

3 days 4) Oral prednisone 4 mg/kg/day given for 4 days

Study Design A cost-utility analysis using a decision analytic model. Patients were at risk of developing treatment side effects and ICH during their hospitalization. The probability of side effects varied between treatment strategies. Costs and utility decrements were applied to patients with side effects. For the base-case analysis, the model assumed that the probability of ICH was the same for all strategies (0.1%). In sensitivity analysis, it was assumed that the probability of ICH was 0.1% per day that platelets <20,000. The model assumed that one parent would have to take time of work during their children’s’ hospitalization. Costs were assigned to time of work. Disutilities were assigned to each day patients were in hospital.

Location US Outcome and Sources The primary economic outcome was the incremental

cost per (QALD). The main clinical outcomes that drove the model were the number of days to reach platelet counts >20,000 and the probability of side effects associated with each treatment. The authors stated that a literature search was conducted to estimate that time to reach platelet counts >20,000 and the probability of side effects. The estimated days with platelet counts <20,000 was 0.7, 1.4, 1.6 and 2.4 for anti-D, IVIg, oral prednisone, and methylprednisolone respectively. A literature search was also undertaken to determine

the probability of side effects for each treatment.

The authors state that the disutilities associated with hospital stay, side effects, and ICH were derived using the Health and Activity Limitation Index.

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Medication costs were based 2004 Red Book average wholesale prices. A local hospital finance system was used to estimate hospital bed costs and infusions costs. The authors stated that Medicare reimbursement data was used to estimate the cost of an ICH. The average hourly wage of a US non-farm production worker in 2004 was used to estimate the cost of time off work of parents.

Currency and Year $US 2004 Estimate of cost-effectiveness

Cost-effectiveness:

Cost-effectiveness of $7,616 equivalent of $2.8, million dollars per QALY of anti-D compared with oral prednisolone.

Sensitivity analysis: Sensitivity analyses were conducted around all model parameters with the focus on the impact of varying assumptions of the incremental cost-effectiveness of anti-D compared with oral prednisolone. The lowest cost per QALD for anti-D compared with oral prednisolone was $1,678, the equivalent of $612,000 per QALY.

Costs Utilities Lost $/QALD Prednisone $786 -0.33 Reference Methlyprednisolone $1,346 -0.496 Dominated Anti-D $2,035 -0.166 $7,616 IVIg $2,926 -0.308 Dominated IVIg=intravenous immunoglobulin; QALD=quality-adjusted life day.

Conclusions The authors state that the cost per QALY of anti-D far exceeds “the often quoted values of $50,000/QALY-$100,000/QALY.”

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APPENDIX 4: EXCLUDED STUDIES AND REASONS FOR EXCLUSION Commentary on primary economic evaluations 1. Benesch M. How far should we go with cost-utility analysis when treating children with

acute idiopathic thrombocytopenic purpura? Pediatr Blood Cancer 2008;50(2):433. 2. Buchanan GR. What is the “cost” of acute ITP? Pediatr Blood Cancer 2007;48(2):119-20. Conference abstract, duplicate of included primary economic evaluation 1. O'Brien SH, Ritchey A, Smith KJ. Treatment of acute childhood idiopathic

thrombocytopenic purpura (ITP): a cost-utility analysis [abstract]. Blood 2005;106(11 Part 1):388A.

2. Kumar M, Vik TA, Calley CS, Southwood M, Croop JM. Cost of care and outcomes in children with idiopathic thrombocytopenic purpura [abstract]. Pediatr Res 2003;53(4 Part 2):285A.

Cost analysis only 1. Mahadevia PJ. The pocketbook: pharmacoeconomic issues related to intravenous

immunoglobulin therapy. Pharmacotherapy 2005;25(11 Pt 2):94-100S.

2. Sandler S, Novak S, Reinhold P. Cost of treating immune thrombocytopenic purpura using IV RhIG versus IVIG [abstract]. Transfusion (Bethesda) 1999;39(10 Suppl):120S.

Cost study (burden of illness) 1. Saleh MN, Grotzinger K. Burden of illness of chronic, adult idiopathic thrombocytopenic

purpura (ITP): a retrospective, longitudinal, cohort study [abstract]. Blood 2006;108(11 Part 1):939A.

Critical appraisal of primary economic evaluations 1. Centre for Reviews and Dissemination, University of York. Treatment, outcome, and cost of

care in children with idiopathic thrombocytopenic purpura [structured abstract]. In: NHS Economic Evaluation Database [database online]. York (UK): The University; 2008 (accessed 2008 Mar 5).

2. Centre for Reviews and Dissemination, University of York. A cost-utility analysis of

treatment for acute childhood idiopathic thrombocytopenic purpura (ITP) [structured abstract]. In: NHS Economic Evaluation Database [database online]. York (UK): The University; 2008 (accessed 2008 Mar 5).

3. Centre for Reviews and Dissemination, University of York. Cost-utility analysis of

intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy [structured abstract]. In: NHS Economic Evaluation Database [database online]. York (UK): The University; 2008 (accessed 2008 Mar 5).

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IvIg not included as a comparator 1. Bennett CL, Weinberg PD, Golub RM, Bussel JB. The potential for treatment of idiopathic

thrombocytopenic purpura with anti-D to prevent splenectomy: a predictive cost analysis. Semin Hematol 2000;37(1 Suppl 1):26-30.

Neither costs nor effects evaluated 1. Ochi K, Kohriyama T, Higaki M, Ikeda J, Harada A, Nakamura S. Changes in serum

macrophage-related factors in patients with chronic inflammatory demyelinating polyneuropathy caused by intravenous immunoglobulin therapy. J Neurol Sci 2003;208(1-2):43-50.

2. Watson DI, Coventry BJ, Chin T, Gill PG, Malycha P. Laparoscopic versus open

splenectomy for immune thrombocytopenic purpura. Surgery 1997;121(1):18-22. No cost analysis 1. Laosombat V, Wiriyasateinkul A, Wongchanchailert M. Intravenous gamma globulin for

treatment of chronic idiopathic thrombocytopenic purpura in children. J Med Assoc Thai 2000;83(2):160-8.

Not disease of interest 1. IGIV therapy not cost-effective for HIV-associated thrombocytopenia. Hosp Formul

1994;29(4):244.

2. McCrone P, Chisholm D, Knapp M, Hughes R, Comi G, Dalakas MC, et al. Cost-utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2003;10(6):687-94.

Review of cost studies 1. Adams JR, Nathan DP, Bennett CL. Pharmacoeconomics of therapy for ITP: steroids, i.v.Ig,

anti-D, and splenectomy. Blood Rev 2002;16(1):65-7. Review of existing cost-effectiveness studies 1. Rieckmann P. Socio-economic aspects of neuroimmunological diseases. J Neurol

2006;253(Suppl 5):V/87-90. Unable to translate 1. Akarsu S, Kilic M, Taskin E, Kurt A, Yilmaz E, Aygun AD. Comparison of efficacy and cost

of different doses of steroids and immunoglobulin treatments for acute immune thrombocytopenic purpura [in Turkish]. Cocuk Sagligi ve Hastaliklari Dergisi 2005;48(3):209-14.

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APPENDIX 5: GRAPHICAL MODEL STRUCTURE FOR ACUTE CHILDHOOD ITP ECONOMIC EVALUATION

ICH=intracranial hemmorrhage; ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin.

IVIg

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APPENDIX 6: STUDIES AND DATA USED FOR ESTIMATING TIME WITH PLATELETS <20,000/µL

IVIg=intravenous immunoglobulin; Methyl=methylprednisolone.

Day 1 Day 2 Day 3 Day 7

Study Treatment n Platelets >20,000 % n

Platelets >20,000 % N

Platelets >20,000 % n

Platelets >20,000 %

Newman et al.82 Anti D 75 8 6 75.00% Blanchette et al., 199465 Anti-D 50 38 10 26.32% 38 27 71.05% 38 31 81.58% 38 34 89.47% Tarantino et al.80 Anti-D 50 35 17 48.00% 35 31 89.00% Tarantino et al.80 Anti-D 75 35 25 73.00% 35 33.6 96.00% Moser et al.83 Anti-D 75 25 19 76.00% Duru et al.70 IVIg 12 8 67.00% 12 11 92.00% 12 11 92.00% Erurden et al.72 IVIg 22 19 86.36% 22 21 95.00% Tarantino et al.80 IVIg 35 27 77.00% 35 32 90.00% Blanchette et al., 199465 IVIg 0.8 g/kg 35 24 68.57% 35 31 88.57% 35 34 97.14% 35 34 97.14% Ancona et al.63 IVIg 1 g/kg 42 23 55.00% 42 30 71.00% 42 40 95.00% Benesch et al.64 IVIg 1 g/kg 17 15 88.20% Blanchette et al., 199366 IVIg 1 g/kg 19 11 57.89% 19 18 94.74% 19 18 94.74% 19 18 94.74% Blanchette et al., 199465 IVIg 1 g/kg 34 13 38.24% 34 29 85.29% 34 32 94.12% 34 32 94.12% Erurden et al.72 Methyl oral 20 10 50.00% 20 19 95.00% Ancona et al.63 Methyl 1 g/kg 35 13 37.00% 35 20 57.00% 35 26 74.00% Duru et al.70 Methyl Oral 12 8 67.00% 12 11 92.00% 12 11 92.00% Duru et al.70 No therapy 26 11 42.00% 26 21 81.00% 26 23 88.00% Blanchette et al., 199465 No therapy 15 2 13.33% 15 3 20.00% 15 7 46.67% 15 10 66.67% Blanchette et al., 199465 Prednisone 39 12 30.77% 39 28 71.79% 39 31 79.49% 39 36 92.31% Blanchette et al., 199366 Prednisone 18 6 33.33% 18 12 66.67% 18 15 83.33% 18 17 94.44%

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IVIg

APPENDIX 7: GRAPHICAL REPRESENTATION OF ADULT ITP MODEL

ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin.

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APPENDIX 8: IVIg PLANNING, IMPLEMENTATION, UTILIZATION, LEGAL, REGULATORY, ETHICAL AND PSYCHOSOCIAL ISSUES ABSTRACTION FORM Date: Reviewer’s initials: ID number:

Article identification: (author, year)

Full citation: Geographic location: Time period: Study objective: (design, population, intervention, comparator)

Setting: (e.g., hospital-based, clinic-based, community-based, referral criteria or process, other)

PLANNING, IMPLEMENTATION, UTILIZATION, AND EQUITY ISSUES (e.g., limited resource, therefore product shortages; related challenges re: gathering enough evidence in light of rarity of some conditions)

Intervention Group Control Group

LEGAL AND REGULATORY ISSUES (e.g., issues with pooled blood products such as potential transmission of blood borne viruses/diseases; batch-to-batch variations; manufacturer-to-manufacturer differences; variation in plasma source; informed consent to ensure patients are aware that IVIg is a blood product, and of small risk of an as yet unidentified pathogen)

Intervention Group Control Group

ETHICAL ISSUES (e.g., issues with pooled blood products such as potential transmission of blood borne viruses/diseases; batch-to-batch variations; manufacturer-to-manufacturer differences; variation in plasma source; informed consent to ensure patients are aware that IVIg is a blood product, and of small risk of an as yet unidentified pathogen)

Intervention Group Control Group

PSYCHOSOCIAL ISSUES (e.g., psychological impact of treatment; social and family context)

Intervention Group Control Group