Full Application for an Addition of a Test Categories in the EDL

Full application for an addition of a test categories in the EDL

Survey response 1

Response ID 71

Date submitted 1980-01-01 00:00:00

Last page 1

Start language en

1. Name of test category

Name of the test category addressed in the original submission: Serum and urine protein electrophoresis

2. Pre-submission information

Please indicate your pre-submission response ID: [Pre-submission ID] 131

3. Applicant’s information (primary contact person):

Contact person, name and information of the person submitting the application: [LAST NAME, First name] SOLIS, Leire

Contact person, name and information of the person submitting the application: [Email address (...@....)] [email protected]

Contact person, name and information of the person submitting the application: [Phone number (+country code) phone number no spaces] +351214075720

Contact person, name and information of the person submitting the application: [Other information] -

4. Applicant’s information (secondary contact person):

[LAST NAME, First name] PREVOT, Johan

[Email address (...@....)] [email protected]

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[Phone number (+country code) phone number no spaces] +351214075720

[Other information] -

5. Details of the organization making the submission (if applicable)

Name of the organization making the submission (if applicable): [Name of the organisation] International Patient Organisation for Primary Immunodeficiencies (IPOPI)

Name of the organization making the submission (if applicable): [Address] Rocky Bottom, Trerieve, Downderry, Cornwall PL11 3LY, UK

Name of the organization making the submission (if applicable): [Department]

Name of the organization making the submission (if applicable): [Website] www.ipopi.org

Name of the organization making the submission (if applicable): [Phone number] +351214075720

6. Details of the organizations supporting the application:

Please provide up to three organizations supporting your application including a. Organization name, b. Contact person, c. Email address: a. International Union of Immunological Societies (IUIS) b. Prof Stuart Tangye c. [email protected]

7. Public health impact of the disease/condition:

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Please detail the public health relevance of conditions addressed with the proposed test and add references: Myeloma: According to the International Myeloma Foundation, multiple myeloma is a cancer of the bone marrow plasma cells. It is synonymous with "myeloma" and "plasma cell myeloma." Plasma cells make antibodies against infectious agents such as viruses and bacteria. A cancerous or malignant plasma cell is called a myeloma cell. Myeloma is called “multiple” because there are frequently multiple patches or areas in bone marrow where it grows. It is important that multiple myeloma be diagnosed as early as possible to reduce the number of potential complications with more advanced myeloma. Myeloma can be slow-moving or more aggressive. 159,985 new cases are diagnosed yearly, worldwide. It is twice more likely to occur in people of African descent. Incidence of MM is highly variable among countries but has increased uniformly since 1990, with the largest increase in middle and low-middle SDI countries.

Literature: Ramsenthaler C et al. The impact of disease-related symptoms and palliative care concerns on health-related quality of life in multiple myeloma: a multi-centre study. BMC Cancer. 2016; 16: 427. doi: 10.1186/s12885-016-2410-2 Cook R. Economic and clinical impact of multiple myeloma to managed care. J Manag Care Pharm. 2008 Sep;14(7 Suppl):19-25. Pineli M et al. Multiple Myeloma: Epidemiology and Burden of Disease Analysis in Latin America. Value in Health Volume 20, Issue 9, Page A872. DOI: https://doi.org/10.1016/j.jval.2017.08.2558 Cowan A, Allen C, Barac A et al. Global Burden of Multiple Myeloma. A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. doi:10.1001/jamaoncol.2018.2128 Cowan A, Ballen C, Barac A, et al. Global Burden of Multiple Myeloma. A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. doi:10.1001/jamaoncol.2018.2128

Primary immunodeficiencies: Primary immunodeficiencies (PIDs) are a large and growing group of over 350 different inherited disorders caused when some components of the immune system (mainly cells and proteins) do not work properly. Recent studies have shown that PIDs may be more common than previously estimated and that as many as 1% of the population may be affected with a PID when all types and varieties are considered. Because their immune systems do not work properly, people with PIDs are more prone than other people to repeated, severe and even fatal infections. When PIDs are left underdiagnosed or are misdiagnosed, the immune system remains defective, often leading to illness, disability, permanent organ damage or even death. Without treatment with Polyvalent Human Immunoglobulins, the morbidity and mortality rates of patients affected by PIDs are significantly higher and life expectancy is reduced from 50 years to 12 years. Clinical data have clearly demonstrated that appropriate treatment with Polyvalent Human Immunoglobulins of patients affected by these conditions can be lifesaving as well as greatly improve their quality of life. The evidence led to the inclusion of Polyvalent Human Immunoglobulins in the WHO Essential Medicines List in 2006 and WHO Model List of Essential Medicines for Children in 2007. Some PIDs do not require Ig replacement therapy but can be cured by allogeneic stem cell transplantation (or even gene therapy in a few limited instances as of today). In the case of PIDs, “although diverse, [they] share the common feature of susceptibility to infection and result in substantial morbidity and shortened life spans. Most importantly, prompt diagnosis and treatment can now lead to life-saving treatments (including antibiotics, replacement with stem cells and immunoglobulins) and result in marked improvements in the quality and length of life for persons with most primary immune diseases” (Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Reports. Applying Public Health Strategies to Primary Immunodeficiency Diseases, January 16, 2004 / 53(RR01);1-29). “Early recognition of primary immunodeficiency is essential to reduce morbidity and mortality, and yet failure to recognize these conditions is still a major problem for clinicians around the world” (Sewell, W. A. C, et al., Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects, 2006 Clinical and Experimental Immunology 145:201–203). One major problem is that many general practitioners, physicians and paediatricians not only lack familiarity with immunodeficiencies and but lack guidance on diagnostic tests. This is particularly applicable in developing countries. The use of the WHO List of Essential Medicines and formulary has helped in tackling this problem and helping raise the awareness of these treatable conditions. There are many types of PIDs, depending on which part of the immune system is affected. Antibody failure is the most common form but more severe forms, due to several immune defects in one individual, are easy to diagnose with the correct tools and fatal within 2 years of birth without diagnosis and replacement of stem cells. The largest clinical data collection comes from the UK Medical Research Council study, 1955 –1966. The study’s main aims were to collect information on the natural history of PIDs and to capture nearly all the cases occurring in the UK; 184 untreated patients were admitted to the study (ascertainment has risen > x100 since that time). Ten-year survival rates were 36%. This has been followed by a study of treated patients followed by Cunningham-Rundles and Bodian, diagnosed by the Immunodeficiency Clinic at the Mount Sinai Medical Centre from 1973 to 1998. This comprised 248 patients. Ten-year survival rates had risen to 78% but stilled lagged behind US general figures of 98% with more awareness and higher doses of replacement immunoglobulins, this has now improved further to 92%. Recent data from Iran has confirmed the hugely increased serious infection burden in those patients without immunoglobulin treatment compared with those receiving Polyvalent Human Immunoglobulins (Aghamohammadi A. et al. Efficacy of IVIg on the prevalence of pneumonia in patients with agammaglobulinaemia. 2004 FEMS Immunology & Med. Microbiology 40: 113-118). Social and economic impact Diagnostic delays are not only damaging to the patient with a deterioration of his/her condition and difficult for the family caring for their relative, they also have a negative impact on healthcare systems due to inappropriate use of health resources caused by avoidable visits/hospital admissions involving a variety of different specialists for recurring infections. A recent study showed that “early diagnosis resulted in lower costs postdiagnosis as compared to the year prior to diagnosis, even if regular immunoglobulin replacement therapy was required. The annual savings to the health care system for each diagnosed page 3 / 10

patient is $85,882. Even for patients that are diagnosed and treated with immunoglobulin, this amount remains at $55,882 saved annually”. (Modell V et all. Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes. Immunologic Research (2018) 66:367–380). Additionally, a 2009 peer-reviewed study documenting the financial impact associated with early diagnosis and management of PIDs in the US found that costs to the healthcare system for each undiagnosed patient with an underlying PID amount to an average of $102,552 (€75,587.40) annually, while diagnosis and treatment yielded average savings of $79,942 (€589,223) per patient per year. (Condino-Neto A and Espinosa-Rosales FJ (2018) Changing the Lives of People With Primary Immunodeficiencies (PI) With Early Testing and Diagnosis. Front. Immunol. 9:1439. doi: 10.3389/fimmu.2018.01439).

8. Potential public health impact of the test:

Please explain in which way the proposed test benefits public health. Please detail your response and add references: Public health impact of test on myeloma: Myeloma is unique as a cancer because basic diagnostic testing includes only a complete blood cell count with differential, basic metabolic panel; serum calcium, serum and urine protein electrophoresis; and osseous survey, all of which should be accessible in low- and middle-income countries (LMICs). references: Fleming KA, Naidoo M, Wilson M, et al. An essential pathology package for low- and middle-income countries. Am J Clin Pathol. 2017;147(1):15-32. Tan D, Chng WJ, Chou T, et al. Management of multiple myeloma in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14(12):e571-e581

Public health impact on PIDs: Primary antibody deficiency is a diagnosis of exclusion in younger and adult patients whose immune systems fail for unknown reasons (without haematological malignancy). This test is on the list for the haematology section of the EDL, and should be recognized as essential for PIDs especially in adults. Plasma and urine protein electrophoresis should be performed as part of the diagnostic investigation of suspected primary immunodeficiencies and secondary immunodeficiencies, as well as other diseases (plasma cell dyscrasias such as myeloma, lymphoma, chronic lymphatic leukaemia, etc). Given that protein and urine electrophoresis are widely used in almost all countries, particularly the poorer ones. It is important for adult PID patients (represent >80% of all PIDs) and for less well-resourced countries. • These tests are very much used in Russia (adult hospital, 100%), Benin (plasma protein electrophoresis 50%), Kenya (less than 50%), Uruguay (100% of diagnosis), Bolivia (maybe 40%), Paraguay (70%), Sudan (about 50%-80%). Many of the others hospitals consulted did not use this technique as it is mainly used for the diagnosis of adult patients and the reference hospitals consulted were mainly working with children. • From one of the two experts consulted in Vietnam we have received the following statement: “We do not use these tests in our hospital since we can do Immunoglobulin level. But I often suggest doctors in provincial hospitals to do protein electrophoresis when they have a PID suspected patient, as they cannot do other tests. The price is around $15”. • We have also received similar comments from contacts in India, where the hospital consulted used to use these tests when “immunoglobulin assay kits were not readily available or expensive. (…) a good screening modality to screen PID patients at risk for B cell lymphomas producing a monoclonal immunoglobulin.” There are a number of international guidelines (listed below) which recommend the measurement of immunoglobulins and immunofixation in the diagnosis of myeloma and other conditions. For example, NICE recommend serum protein electrophoresis to confirm the presence of a paraprotein. The same applies to the diagnosis of an immunodeficiency, in guidelines from ESID that are used all over the world (de Vries, E. for the Clinical Working Party of the European Society for Immunodeficiencies. Patientcentred screening for primary immunodeficiency: a multi-stage diagnostic protocol designed for non- immunologists Clinical & Experimental Immunology 2006; 145: 204-214) and the international “Primary Immune deficiencies - Principles of Care” (Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L, Drabwell J; Editorial Board for Working Party on Principles of Care at IPOPI. Primary immune deficiencies - principles of care. Front Immunol. 2014 Dec 15;5:627)

9. Clinical utility of the proposed test/potential impact of the test on patient management and care

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Please provide your answer as described in the guidance document: Protein electrophoresis (PEP) is an inexpensive and easy-to-perform medical technique that allows the separation and identification of proteins on basis of their electrical charges PEP may display monoclonal, polyclonal or oligoclonal bands which are usually seen in the γ zone, but may be seen in proximity of the β band or, rarely, in the α2 region [Amer Wahed 2015]. PEP aims to screen for gammopathy, hypergammaglobulinemia, and hypogammaglobulinemia [Lassoued K]. PEP is performed for a presumptive diagnosis of monoclonal or polyclonal gammopathies or hypogammaglobulinemia. In the suspicion of gammopathy, mainly the multiple myeloma, the clinician intends to: • Check for monoclonal protein; • Determine the isotype and the concentration of the immunoglobulin • Assess the response to the therapy and to monitor the progression of disease or relapse • Consider any progress that has been made in the diagnostic criteria, diagnostic workup, prognosis, and treatment of patients with multiple myeloma [Huong Yew Ting. 2019] On the other hand, a wide variety of congenital and acquired immunodeficiency conditions have been associated with the presence of oligoclonal and monoclonal gammopathies [David F Keren 2003]. Actually, it was pointed out that monoclonal gammopathies (homogeneous immunoglobulin components) in the elderly may represent a loss of immune regulatory function with T < B immune system imbalance [Radl J. 1985] Monoclonal gammopathies in children are exceedingly rare but, when present, may indicate either a transient or congenital immune dysfunction [Koliakos G 2001, Schreiber S. 1997]. Hypogammaglobulinemia is also a common situation in clinical practice; it must evoke the possibility of a primary immunodeficiency (PID). Before that, it’s necessary to rule out acquired causes of hypogammaglobulinemia. To well assess the hypogammaglobulinemia, SPE should be performed. In fact Nephelometric methods are not accurate enough for the immunoglobulins, their concentrations may be overestimated [Lassoued K. 2001]. SPE distinguishes the hypogammaglobulinemia associated with hypo-albuminemia, generally related to malabsorption, acute (transient) infection, capillary leak syndrome (intermittent), nephrotic syndrome or exudative enteropathy (persistent), and the hypogammaglobulinemia without hypo-albuminemia, related to many conditions such as immunosuppressive therapy, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, myeloma, autoimmune diseases (Lupus, Sjögren syndrome, Rheumatoid arthritis), infections (HIV, EBV, CMV, VBH, VHC, salmonellosis leptospirosis, malaria, toxoplasma, ..), intestinal bowel diseases, cirrhosis and hepatopathies, and PID as well [Couderc 2006]. Congenital immunodeficiency diseases such as Wiskott–Aldrich Syndrome, DiGeorge Syndrome, Nezelof Syndrome and severe combined immunodeficiency (SCID) are frequently associated with the presence of monoclonal immunoglobulins. Therefore, in addition to the conditions described above, immune dysfunction may be the underlying cause of monoclonal and oligoclonal gammopathies [David F Keren 2003]. PID with hypogammaglobulinemia correspond predominantly to humoral immunodeficiency including the following categories: X- linked agammaglobulinemia (Bruton's disease) or autosomal recessive disorder, CVID (Variable Common Immune Deficiency), Hyper-IgM syndrome, IgA Deficiency, IgG subclass deficiency, Hypogammaglobulinemia with thymoma (Good syndrome), X- linked proliferative disease (Duncan disease) [Couderc 2006].. Amer Wahed, Amitava Dasgupta. Monoclonal Gammopathy and Its Detection. In Hematology and Coagulation. 2015. Lassoued K, Coppo P : Conduite à tenir devant une hypogammaglobulinémie. Med Ther 2001 ; 8: 694-9. David F Keren. Protein Electrophoresis in Clinical Diagnosis. 2003. In Edward Arnold (Publishers) Ltd. Huong Yew Ting, Pavai Sthaneshwar, Ping Chong Bee, Hemalatha Shanmugam, Merrell Lim, Heavy/light chain assay in the monitoring of multiple myeloma. Pathology 2019, 51(5):507-511] Radl J. Monoclonal gammapathies. An attempt at a new classification. Neth J Med 1985;28: 134–137. Koliakos G, Papachristou F, Papadopoulou M, Trachana V, Gaitatzi M, Sotiriou I. Electrophoretic analysis of urinary proteins in diabetic adolescents. J Clin Lab Anal 2001;15: 178–183. Schreiber S, Hamling J, Zehnter E, et al. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997;40:761–766. Couderc L-J, Catherinot E. Granulomatose non sarcoïdienne. Rev Mal Respir 2006; 23: 5S62-5S67. Doi : 10.1019/20064032

10. Systematic reviews of the clinical accuracy of the test

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Please describe or comment as requested in guidance document or state if no systematic review of clinical accuracy studies exists: Serum free light chain quantification Optilite User Training Manual APDOC39 v3 Optilite Operations Manual INS700.OPT v6.0A Oct 2016 Serum Free Light Chain Analysis (and Hevylite) 6th Edition, Bradwell AR 2010, The Binding Site Ltd. Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ, Drayson MT, Drew R. Highly sensitive automated immunoassay for Ig light chains in serum and urine. Clin. Chem. 2003; 47:4 673-680 Katzmann JA1, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, Kyle RA. Serum reference intervals and diagnostic ranges for free Kappa and free Lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin. Chem. 2002; 48 (9):1437 -1444 Laboratory standard operating procedure for Freelite assays, Gambro Dialyser study protocol, The Binding Site Limited Capillary Zone Electrophoresis Guinan JE1, Kenny DF, Gatenby PA. Detection and typing of paraproteins: a comparison between different methods in a routine diagnostic laboratory. Pathology 1989; 21: 35-41 Keren, D.F. High resolution electrophoresis and immunofixation, techniques and interpretation 2nd Edition, Butterworh Heinmann, Woburn M.A. USA (1994) Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26. Caers J et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when. Haematologica 2018 Nov;103(11):1772-1784. doi: 10.3324/haematol.2018.189159. Epub 2018 Aug 31. Smellie, W. S., & Spickett, G. P. (2006). Paraprotein management. BMJ (Clinical research ed.), 333(7560), 185–187. doi:10.1136/bmj.333.7560.185 Please attach the reviews you make reference to:

filecount - Please attach the reviews you make reference to: 0

11. Primary studies of clinical accuracy of the test

Please describe or comment as requested in the guidance document or state if no primary studies of clinical accuracy are available: CVID is a primary humoral immunodeficiency disorder characterized by reduced serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) or immunoglobulin M (IgM) Hypogammaglobulinemia, even with at least one Ig reduction, can be detected at electrophoresis in 93.1% cases (1). Protein electrophoresis has less accuracy at detecting low concentration of non-IgG antibodies ( Please attach the publications you make reference to:

filecount - Please attach the publications you make reference to: 0

12. Systematic reviews of the clinical utility/impact of the test on patient management and care

Please describe any systematic reviews of studies on the impact of the test result in clinical practice on diagnosis, treatment and patient outcomes or state if none are available (please refer to the guidance document) Moreau P et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv52-iv61. doi: 10.1093/annonc/mdx096. NICE: Guideline on myeloma – Diagnosis and management (2016, updated 2018) Medical Scientific Advisory Group to the Myeloma Foundation of Australia (MSAG MFA): Clinical practice guideline on multiple myeloma (2017) Please attach the reviews you make reference to:

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filecount - Please attach the reviews you make reference to: 0

13. Primary studies of the clinical utility/impact of the test on patient management and care

Please briefly describe any primary studies of the clinical utility/impact of the test on patient management and care, or state if none are available (please refer to the guidance document): A first severe bacterial infection in a young person without a predisposing factor should evoke a CVID and then requires an electrophoresis of serum proteins. In fact, bronchitis and infectious pneumopathies are observed in 69% and 40 to 58% of patients with CVID respectively [4,5]. Serum protein electrophoresis allows the diagnosis of hypogammaglobulinemia. In the series of electrophoresis studies, hypogammaglobulinemias are found from 8 to 14% of the series [1, 2, 3]. 31% of these hypogammaglobulinemias detected with protein electrophoresis remain without aetiology and therefore probably have a primary cause (3). In the diagnosis of CVID the serum protein electrophoresis also has a role of exclusion of secondary causes (such as myeloma, nephrotic syndrome). References: “marked decrease of IgG and marked decrease of IgA with or without low IgM levels” is one of the clinical criteria for diagnosis of CVID. www.esid.org [4] Resnick ES, Moshier EL, Godbold JH, et al. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119: 1650-7. [5] Oksenhendler E, Gérard L, Fieschi C, et al. Infections in 252patients with common variable immunodeficiency. Clin InfectDis 2008;46:1547—54. 1. Bouayadi O, Bensalah M, Rahmani N and al. Serum protein electrophoresis: study of 410 electrophoretic profiles. Pan African Medical Journal. 2019;32:161. 2. Chan PC and Chen J. Value of reflex testing based on hypogammaglobulinemia as demonstrated in serum protein electrophoresis. Clin Biochem. 2015 Jul;48(10-11):674-8. 3. Blot M, Boyer P, Samson M and al. Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia. Eur J Intern Med. 2014 Nov;25(9):837-42 Please include the articles/documents of key primary studies and all publications you make reference to:

filecount - Please include the articles/documents of key primary studies and all publications you make reference to: 0

14. Details of any guideline recommendations concerning use of the test

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Briefly describe the specific recommendation (indicate where it can be found in the guideline) and summarise the evidence upon which it is based (indicating where it can be found in the evidence summaries): Summary of consensus recommendations about use of the test: 1. Information to be included in reports of SPE : • Laboratories should report the same quantity of information in the same format • Reports should be consistent between interpreters • SPE reports that indicate the presence of a monoclonal immunoglobulin should include its isotype (when previously known), and its concentration • When confirmation testing (e.g. IFE) is not possible/available, it should be stated that there is an abnormality present and additional testing is recommended 2. Fraction reporting : • SPE reports should include protein fraction quantitation • Monoclonal proteins (when present) should be quantified and reported independent of other fractions • Protein and monoclonal fractions should be reported in g/L • Normal protein fractions should be reported with a healthy population-based reference interval 3. Interferences : • Interpreters should be educated about types of interferences and options to resolve them • Clinicians receiving reports from samples with interferences should be explicitly informed in the interpretative comments about limitations (e.g. quantization accuracy, false positive bands) • Interpreters and clinicians should communicate about consistent approaches to reporting results in patients receiving monoclonal therapies [Ronald A et al. 2018] Ronald A. Booth, Christopher R. McCudden, Cynthia M. Balion, Ivan M. Blasutig, Ihssan Bouhtiauy, Karina Rodriguez-Capote, Peter Catomeris, Pak Cheung Chan, Yu Chen, Christine Collier, Kristin Hauff, Jawahar Kalra, Dailin Li, Dan C. Lin, Amy H. Lou, Qing H. Meng, Tracy Morrison, Maria D. Pasic, Mabood Qureshi, Ed Randell, Kun-Young Sohn, Vinita Thakur, Dylan Thomas, Andrea Thoni, Cheryl Tomalty, Mohebullah Zamkanei. Candidate recommendations for protein electrophoresis reporting from the Canadian Society of Clinical Chemists Monoclonal Gammopathy Working Group. Clinical Biochemistry 51(2018);10-20 Please attach the guidelines that you are refering to:

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15. Examples of commercially available IVD products in the proposed new category

Please download and complete the table in Annex I with commercially available IVD products in the test category, and include the information listed for each one. Please upload the completed file back and all the relevant test Instructions For Use (Package Inserts): [{ "title":"Helena Laboratories package insert","comment":"","size":"1662.757","name":"Helena%20Laboratories%20package%20in sert.pdf","filename":"fu_qrnty372cr2m9bq","ext":"pdf" },{ "title":"Annex I - PIDs & myeloma","comment":"","size":"16.843","name":"A nnex-I-Full-submission%20131%20PIDs%20%26%20myeloma.docx","filename":"fu_gngcdj7rkmk4xdp","ext":"docx" }] filecount - Please download and complete the table in Annex I with commercially available IVD products in the test category, and include the information listed for each one. Please upload the completed file back and all the relevant test Instructions For Use (Package Inserts): 2

16. Training requirements

Considering the tests mentioned in 15 above, what in general are the training requirements?: On-site training for clinical and technical staff

17. Equipment required

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Considering the tests mentioned in 15 above, please describe in general terms what, if any, equipment is required other than that provided with the test: For agarose gel zone electrophoresis and for capillary zone electrophoresis reagents to perform the tests are normally supplied by the manufacturer (i.e. Sebia Society, Helena Biosciences). Additional materials needed, but not provided: 5% acetic acid (v/v): Add 50 mL of glacial acetic acid to 950 mL of deionized water. Absolute methanol, reagent grade

18. Energy requirements

Considering the tests mentioned in 15 above, what, if any energy source is required for performance of the tests?: Continuous electrical power

Considering the tests mentioned in 15 above, what, if any energy source is required for performance of the tests?: [Other]

19. Landscape reviews

Please list any landscape reviews describing the different test technologies and their use or state if none available: -

Please attach the documents refered to in this question:

filecount - Please attach the documents refered to in this question: 0

20. Cost and Cost-effectiveness

Please provide a summary of data on comparative cost and cost-effectiveness or state if not available: Fatima S et al. Cost-effectiveness of Screening and Confirmatory Tests for Multiple Myeloma in Pakistani Population: An Audit Report. J Coll Physicians Surg Pak. 2018 Jul;28(7):560-563. doi: 10.29271/jcpsp.2018.07.560. Anand M, Kumar R, Sharma OD. Economical choices in setting up a diagnostic myeloma laboratory. Indian J Pathol Microbiol. 2004 Oct;47(4):506-8. McTaggart, et al. Replacing Urine Protein Electrophoresis With Serum Free Light Chain Analysis as a First-Line Test for Detecting Plasma Cell Disorders Offers Increased Diagnostic Accuracy and Potential Health Benefit to Patients. American Journal of Clinical Pathology, Volume 140, Issue 6, December 2013, Pages 890–897, https://doi.org/10.1309/AJCP25IHYLEWCAHJ

21. Ethical issues

Please detail any important ethical considerations related to the proposed test category and any consequences of its use: There are not ethical issues related to the test, as long as the patient is informed that by using it, results may show other potential diseases than those initially thought. Informed consent should also be provided.

22. Equity and human rights issues

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Please indicate if it reduces inequities and increases accessibility or if the test may prove inaccessible to some populations: For PID diagnosis: This test would help those countries in which access to a test to measure Immunoglobulin plasma levels (IgA, IgG and IgM) is not possible or too expensive. It is of special interest in the diagnosis of adult patients with primary immunodeficiencies.

For myeloma diagnosis: myeloma incidence is increasing steadily, but the largest increase is visibile in middle and low-middle income countries. It should also be considered that it is twice more likely to occur in people of African descent. By including this test in the diagnosis of multiple myeloma, the WHO would be increasing the chances of people living in middle income countries to have access to the diagnosis they need.

Signature

Through the electronic signature below, I acknowledge that I have provided appropriate information to support this submission. I acknowledge that WHO reserves the right to format and select the information provided as necessary and agree that the information will be publicly disclosed by WHO. [Electronic Signature (type your full name to sign):] Leire Solis

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