POLICY BRIEF published: 19 May 2022 doi: 10.3389/fpubh.2022.893770 Dealing With Immunoglobulin Shortages: A Rationalization Plan From Evidence-Based and Data Collection Gerard Solís-Díez 1 , Marta Turu-Pedrola 1 , Marta Roig-Izquierdo 1 , Corinne Zara 1 , Antoni Vallano 1* and Caridad Pontes 1,2 1 Gerència del Medicament, Servei Català de la Salut, Generalitat de Catalunya, Barcelona, Spain, 2 Departament de Farmacologia, de Terapèutica i de Toxicologia, Unitat Docent Parc Taulí, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain Background: The demand and consumption of immunoglobulins (IgGs) are growing, and there are many difficulties in obtaining supplies. The aim of the study was to analyze Edited by: the evolution of IgG consumption and cost over a decade, describe the measures Pedro Ruiz-Lopez, implemented for clinical management in the context of regional public health system, Research Institute Hospital 12 de Octubre, Spain and evaluate the initial impact of these measures. Reviewed by: Methods: We performed a retrospective longitudinal study including patients of all Marianna Cavazza, public health systems in Catalonia. First, we analyzed data on consumption and cost CERGAS SDA Bocconi, Italy Pedro Pablo Rodríguez, of IgGs during a period between 1 January, 2010 and 31 December 2021. Second, University Hospital October 12, Spain we analyzed the impact of a set of regional measures in terms of annual consumption Carmen Garcia Muñoz, Hospital Universitario 12 de and cost of IgGs. Regional measures were based on rational evidence-based measures Octubre, Spain and computer registries. We compared the data of year before applying intervention *Correspondence: measures (1 January and 31 December 2020) with data of year after applying clinical Antoni Vallano management interventions (1 January and 31 December 2021). In addition, detailed avallano@catsalut.cat information on clinical indications of IgG use between 1 January and 31 December 2021 Specialty section: was collected. This article was submitted to Digital Public Health, Results: Overall, in terms of population, the consumption of IgGs (g/1,000 inhabitants) a section of the journal increased from 40.4 in 2010 to 94.6 in 2021. The mean cost per patient increased Frontiers in Public Health from e10,930 in 2010 to e15,595 in 2021. After implementing the measures, the Received: 10 March 2022 mean annual estimated consumption per patient in 2021 was statistically lower than Accepted: 13 April 2022 Published: 19 May 2022 the mean annual estimated consumption per patient in 2020 (mean difference −47 g, Citation: 95% CI −62.28 g, −31.72 g, p = 0.03). The mean annual estimated cost per patient Solís-Díez G, Turu-Pedrola M, in 2021 was also lower than the mean annual estimated cost per patient in 2020 Roig-Izquierdo M, Zara C, Vallano A and Pontes C (2022) Dealing With (the mean difference was –e1,492, 95% CI –e2,132.12, –e851.88; p = 0.027). In Immunoglobulin Shortages: A 2021, according to evidence-based classification, 75.66% treatments were prescribed Rationalization Plan From for a demonstrated therapeutic evidence-based indication, 12.17% for a developed Evidence-Based and Data Collection. Front. Public Health 10:893770. therapeutic evidence-based indication, 4.66% for non-evidence-based therapeutic doi: 10.3389/fpubh.2022.893770 role indication, and 8.1% could not be classified because of lack of information. Frontiers in Public Health | www.frontiersin.org 1 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages Conclusion: The annual consumption and cost of IgGs have grown steadily over the last decade in our regional public health system. After implementing a set of regional measures, the annual consumption of IgGs per patient and annual cost per patient decreased. However, the decrease has occurred in the context of the coronavirus disease 2019 (COVID-19) pandemic, which may have influenced their clinical use. Managing the use of IgGs through a rational plan with strategies including evidence-based and data collection may be useful in a shortage situation with growing demand. Registries play a key role in collection of systematic data to analyze, synthesize, and obtain valuable information for decision support. The action developed needs close monitoring in order to verify its effectiveness. Keywords: immunogolobulins, clinical management, evidence-based medicine, real-world data, shortages INTRODUCTION important variability in intravenous IG (IVIG) prescriptions between hospitals (11). As the number of both label and off-label Cell blood components and plasma-derived medicinal products indications increases, and because most of these therapeutic uses (PDMPs) are complex biologic therapies with multiple uses in are chronic in nature, the global demand for immunoglobulins is immumodulation and replacement treatments of constitutional growing by about 6 to 8% per year (12). or acquired diseases of hemostasis (1–3). Some of these In the last years, intermittent shortages due to limited supply conditions are chronic, severe, or rare diseases, but PDMPs of plasma to IgG producers are increasingly frequent. The stress are also used in emerging medical situations and in medical in availability has translated into what has been described as “the management of acute conditions. Plasma allows obtaining product follows the price”, that is, difficulties in access to supplies a dozen of protein products such as albumin, polyvalent in countries with lower acquisition prices (13). This is the case immunoglobulins (IgGs), coagulation factors, anti-proteases, and in Spain, where the reimbursement price for IgGs is among the biologic adhesives (4). The plasma used for manufacturing lowest in terms of European prices (7). The COVID-19 pandemic medicinal products is recovered whole blood donated for has lowered surgical activity and donation, disrupting supply, transfusion purposes or collected by apheresis from donors in a and has increased product demand for investigational therapies proportions that varies depending on region and country (5). for COVID-19, leading to further stress on the system (14). Plasma for fractionation is considered a strategic resource, and Strategies to guarantee access to treatment with IgGs include plasma-derived medicines are considered essential medicines long-term measures to achieve self-sufficiency of countries, by the World Health Organization (WHO). The WHO has increased donation of plasma, and improved manufacturing. announced the implementation of a blood supply system On the other hand, the evidence of the efficacy and safety founded on voluntary non-remunerated blood donation of IgGs is available only for a number of indications, with (VNRBD) and the establishment of not-for-profit blood doubtful uses reported to represent up to 40% of total; thus, establishments with the aim of achieving self-sufficiency in blood rational and balanced use of the available product is also supply (6, 7). Furthermore, European union (EU) policies are required. If ever shortages lead to stock breakage, handling driven by principles of voluntary unpaid donation of blood and may require coordination and redistribution of the available blood components (8), although some countries have begun to product, avoiding stockpiling and prioritization to ensure that compensate donors directly or indirectly (9). the available product covers patients who are at serious risk, The need for IgGs is currently the most important driver avoiding use in weak off-label indications (10). of the plasma fractionation industry. IgGs are required for In Catalonia, the processing of plasma obtained from the chronic treatment of patients with primary and secondary VNRBD in hospitals and blood donor campaigns is immunodeficiencies (PIDs and SIDs). In particular, SIDs create performed by a private vendor, and the resulting domestic a growing demand, especially those derived from cancer immunoglobulin product is centrally managed by a public chemotherapy and stem cell transplantation. They are also healthcare center (BST) owned by the Catalan Health used as an immunomodulatory therapy for several disorders Service. This organization has commissioned the integral such as immune thrombocytopenia (ITP), Kawasaki disease, management of these products, including a model for Guillain-Barré syndrome, chronic inflammatory demyelinating commercialization to hospitals at a fixed rate. According polyneuropathy (CIDP), and multifocal motor neuropathy, with interim data in 2021 BST offered up 30.7% of the Catalan together with a large number of widely accepted off-label uses immunoglobulin consumption, fixing as a self-sufficiency and other indications under investigation (10). Previous studies CHS rate. carried out in our local environment showed that intravenous In Catalonia, the Catalan Healthcare System (CHS) is IgGs were prescribed for a significant number of non-authorized integrated in a single network for public use of all healthcare and non-accepted indications with a notable cost, as well as resources with a variety of providers and management formulas. Frontiers in Public Health | www.frontiersin.org 2 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages In 2000, the comprehensive health system for public use includes detailed information on indications and use of hospital in Catalonia (SISCAT) was created, involving all different drugs for outpatient use, data on pragmatic assessments on healthcare networks into a single public system. Some of effectiveness and safety are also collected for drugs that have been the entities in the system are owned by the Department of evaluated in the Catalan Pharmaco-Therapeutic Harmonization Health or Catalan Health Services (CatSalut), public companies Program (17, 18). The registry is available for SISCAT hospitals, (public law entities subject to the private legal system and so all eligible drugs used in the public system and reimbursed commercial companies), consortia, and foundations. SISCAT is by the Catalan Health Service must be registered for invoicing. currently composed of hospitals, primary care centers, social Data can be cross-referenced to administrative databases, such and health inpatient centers, in-patient mental health centers, as the Central Insurance Registry (RCA) and registries of billing, basic and advanced life support ambulances (SVB and SVA), in order to extract aggregated reports on patient characteristics and the medical emergency systems such as non-urgent medical and economical costs for management purposes (19). As in 2019, transport ambulances (rehabilitation, dialysis, etc.). the RPT was a suitable tool to collect both quantitative and In June 2019, the CHS received several inputs on concerns qualitative detailed information on clinical use, and recorded from several hospitals regarding growing difficulties in obtaining information on IgG use in the registry was agreed upon by immunoglobulin supplies. Posteriorly, Spanish Medicines all hospital centers prescribing these products. Variables were shortage registry published firsts reports about punctual chosen by consensus with hospital representatives and included availability problems for non-specific IgGs medicines (15). therapeutic indication, administration route, dates of start and There are reported previous experiences of IgGs shortage in end of treatment, patient’s weight, expected length of treatment other countries, but health policy-makers did not respond to the and monthly dose (g/Kg), and required follow-up. Since August shortage in a timely and effective manner. Those experiences 2020, ongoing data collection and its inclusion in the RPT has indicated that shortages in IVIG would benefit from more been mandatory because of its link with invoicing of the product immediate and coordinated efforts to make the distribution of by the CHS. IgGs in a just manner, and to identify and remedy the sources A closed list of thirty-nine predetermined therapeutic of IgG supply problems (16). However, no experiences have been indications was populated in the registry to cover most reported on measures implemented to manage these situations of frequent uses (Supplementary Material). A free-text field IgG supply problems from public health systems and the impact was also enabled to register other different indications. of these measures. Therapeutic indications were grouped with a dimension table The aim of the study was to analyze the evolution of IgG according to different perspectives, such as overall therapeutic consumption and cost over a decade, describe the contingency objective (replacement therapy in PID, replacement therapy measures planned and implemented for clinical management in in SID, immunomodulation, and solid organ or hematological the context of public health system in Catalonia (CHS), and transplantation) and established clinical adequacy according evaluate the initial impact of these measures. to evidence. Periodic descriptive analysis, reporting of data, and methodology to do an assessment of clinical adequacy were MATERIALS AND METHODS agreed upon by consensus. For that purpose, three documents were taken into account that recommended or not the use of A retrospective longitudinal study including all patients of IgGs according to their degree of evidence and established SISCAT was carried out. First, we analyzed data on consumption clinical criteria for use (20–22). The clinical adequacy and cost of IgGs during a period between January 1, 2010 categorization method assigned the same evidence-category and December 31, 2021. Second, we analyzed the impact of if three documents were consistent, and the lowest category if the implementation of interventional measures in terms of those were inconsistent. annual consumption, doses, and cost of IgGs. We described Therapeutic indications were classified into five clinical use and compared the data of the year before applying intervention categories as follows: measures (1 January and 31 December 2020) with data of the year after applying clinical management interventions (1 January and • Demonstrated therapeutic role (category A): for this clinical 31 December 2021). In addition, detailed information on clinic indication, IgG use has reasonable-quality evidence support; indications of IgGs use between 1 January and 31 December 2021 • Developed therapeutic role (category B): IgGs use is supported was collected. in selected patients with specific conditions, although the Annual information about the following variables were quality of evidence is variable; recorded: number of patients, estimated annual consumption • Exceptional therapeutic role (category C): only exceptionally of IgGs (g), cost of IgGs (e), and type of IgGs classified as would require IgG therapy, either because there are alternative domestic IgG obtained from Catalan (VNRBD) and imported therapies or because the evidence of benefit does not justify use IgG obtained from remunerated blood donors (RBDs). This in most cases; information was obtained from billing registry. • Non-evidenced therapeutic role (category D): there is evidence Since 2012, Catalonia has been implementing a dedicated of no benefit, insufficient evidence of benefit, or some evidence registry, the Registry of Treatments and Patients (RPT), that of benefit but preferred alternative therapies are available; Frontiers in Public Health | www.frontiersin.org 3 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages • Non-classifiable: the category is used when information about minimum and territorial distribution is taken into account to a clinical indication narrowed down by a clinician was ensure covering the needs of smaller centers and/or with special insufficient to be classified. needs. A reserved amount is also allocated for emergencies. All territorial and emergency issues were overseen by the Besides all these, CatSalut distributed information to different working group and agreed upon by consensus with hospital SISCAT hospitals on the use of IgGs together with various healthcare providers. recommendations for use in order to prioritize and optimize To know the existing stock, trends, and IgG requirements ongoing treatments. in SISCAT hospitals, a stock registry, initially used to manage 1) Optimal clinical management was recommended in order supplies during the COVID-19 pandemic was, re-profiled. In to concentrate the use of IgGs as much as possible on June 2021, the registry became an IgG registry to inform weekly treatments with a higher degree of evidence, reconsidering about available units. This information permits the establishment the suitability of treatments with a low level of evidence. of categories to estimate the availability of IgGs by center, In addition, careful review of the use of IgGs in indications medicine, or administration route. with a lower degree of evidence by analyzing the availability All these measures were discussed by dedicated committees of other therapeutic alternatives in each of the indications involving hospital representatives (physicians, pharmacists, and is advised. managers) and members of the Catalan Health Service, and the 2) Lists of patients with low-evidence indications need to closely monitor the use and availability of IgGs was of IgGs have been distributed to hospitals in agreed upon. A working plan was designed with the following order to facilitate case review and encourage actions: (1) collect systematic data about IgGs treatments in prioritized use, adjusting to the current outpatients, further analyse it, and elaborate periodic reports; (2) product availability set up a working group responsible of design select adequacy, 3) Reassessment of diagnoses every 2-5 years. Diagnostic utilization indicators and evidence-based measures for rational confirmation and periodic reassessment of the treatment use and determine when each measure should be implemented, requirement is advised in immunodeficiencies of (3) disseminate data from periodic reports and main measure adults without a molecular diagnosis confirming to involved centers aiming to enhance clinical revision, access IgG deficiency. priority, establish interchangeable and alternatives strategy and 4) Adjustment of dosage by ideal weight in patients measure impact in consumption, and (4) coordinate and improve with indications of immunomodulation. In patients equitable access to the limited IgGs. with a BMI> 30, the dosage may be reviewed to the Information was presented to stakeholders with the aim of adjusted ideal weight (40% by weight). In the dosage raising awareness, and data were disseminated at pharmacy range adjusted for the doses of the presentations, services of SISCAT hospitals with the aim of supporting clinical in pediatric patients it may be adjusted upward, review cases of treatments with categories C and D and of patients and in adult patients, it may be adjusted downward with dosages above product information recommendations. (23, 24). A statistical analysis for categorical and continuous variables 5) Individual evaluation of the interchangeability of was conducted using frequencies, means, confidence intervals presentations. Although this particular strategy cannot of 95% (95% CI), or standard deviations (SDs). Statistical be applied systematically because of risks of associated mean differences were evaluated by Student t-test. A two- adverse reactions, this option could be considered tailed significance was set at level.05. The statistical analysis in the event of a supply failure (25, 26). It should was performed using SPSS 26 (IBM Corp. Armonk, NY, be noted that there are patients who do not tolerate United States). certain IgG brands, and those who tolerate must be maintained. 6) Dose reduction and temporary treatment discontinuation RESULTS in immunomodulatory indications when patients are The main steps taken involving RPT, IgG availability, in remission (10, 25, 27). This strategy has also been management measures, and trough time are summarized described as a feasible option for common variable in Figure 1. immunodeficiency but is controversial without unanimous Between 2010 and 2021, 5.94 million grams of non-specific agreement (28). IgGs were used for 6,925 patients at a cost of e232,835,146 and an 7) Available treatment alternative to IgG use is another average cost per patient in studied period of e33,391 (Figure 2). available option (27). A document is being developed In terms of population, the use in grams of IgGs for on potential therapeutic alternatives to IgGs in every 1,000 inhabitants has increased from 40.4 in 2010 therapeutic indications where they are available and to 94.6 in 2021, with an average annual increase of 7.3% with solid evidence. (Supplementary Material). Since July 2021, the allocation of the proportion of the lots The number of patients has grown annually from 1,151 in has been agreed to be based on the amount of use of IgGs 2010 to 1,940 in 2021, with an annual average of 4,5%. The cost for indications categorized as A and B. Likewise, criteria of per patient-year was the most variable indicator, ranging from Frontiers in Public Health | www.frontiersin.org 4 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages FIGURE 1 | Main steps taken with patients and treatments registry, immunoglobulin (IgG) availability and IgG management measures taken trough time. −3.29 to 7.4%. In the last 4 years, the increase has been positive the patients was 53.35 (22.1) years, and 1,007 (51.5%) and has grown by 6.24% on average (Figure 2). were women with variability in age and sex distribution by A total of 1,956 outpatients have been registered with therapeutic indications. According to the therapeutic objective immunoglobulin therapy in year 2021. Mean age (SD) of of the treatment, replacement therapy in PID represented Frontiers in Public Health | www.frontiersin.org 5 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages FIGURE 2 | Evolution of IgG consumption between 2010 and 2021. Source, Billing registry;Domestic IgG, immunoglobulins obtained from Catalan voluntary non-remunerated blood donor (VNRBD); Imported IgG, immunoglobulins obtained from remunerated blood donors (RBDs). 620 (31.7%) treatments, replacement therapy in SID 299 consumption per patient in 2020 (mean difference −47 g.; 95% (15.29%) treatments; and immunomodulation 392 (20.04%) CI −62.28; −31.72; p =0.03). In addition, the mean annual treatments including multifocal motor neuropathy (MMN), estimated cost per patient (e) in 2021 was also lower than the CIDP, ITP, and Guillain-Barré syndrome, among others. In annual mean annual estimated cost per patient in 2020 (mean addition, 223 (11.4%) treatments were used for myasthenia difference –e1,492; 95% CI, −2,132.12; −851.88; p = 0.027) gravis and 101 (5.16%) for desensitization therapy or rejection (Table 2). treatments in solid organ or bone marrow transplants (Table 1). By therapeutic objective, the mean annual estimated According to the evidence-based classification consulted, 1,480 consumption per patient (g) in PID statistically decreased in (75.66%) treatments were prescribed for a demonstrated 2021 (mean difference −28 g.; 95% CI: −40.71; −15.29; p = therapeutic indication (category A), 224 (12.17%) treatments 0.037), and the mean monthly dose per patient in terms of g/kg for a developed therapeutic indication (category B), 93 (mean difference −0.05; 95% CI: = 0.003). The mean annual (4.66%) treatments for exceptional therapeutic or non-evidenced estimated consumption per patient in other objectives, mainly therapeutic role indication (categories C and D), and 157 (8.1%) due to myasthenia gravis, was also statistically lower in 2021 treatments could not be classified because of lack of information (mean difference −48 g.; 95% CI: −81.81; −14.19; p 0 0.029) (Supplementary Material). (Table 2). Prescription was for a chronic pathology (≥ 1 year of Since stock registry was ongoing, median estimated treatment) for 1,563 (79.91%) patients. The mean (SD) of availability was 19.7 days per month for IVIG and the estimated initial monthly dose was 1.07 (0.87) g/Kg per 25 days per month for subcutaneous IgGs (SCIG) month. The mean of estimated annual consumption per (Supplementary Material). patient was 435 (483.7) g of non-specific IgGs. According to the therapeutic objective of the immunoglobulin prescription, the mean (SD) of the monthly dose of IgGs was highest DISCUSSION for diseases not related with replacement therapy or immunomodulation, which stood at 1.69 (1.06) g/Kg, followed There has been a sustained and continued increase in the by immunomodulation with 1.68 (0.69) g/Kg and other non- demand for IgGs in recent years. A review looked at the classifiable indications due to lack of information, with 1.41 causes of the large increase in demand for immunoglobulins (1.02) g/Kg (Supplementary Material). by investigating guidelines, recommendations, Cochrane data Overall, the mean annual estimated consumption per patient analyses, and systematic reviews for clinical indications of IgGs (g) in 2021 was statistically lower than the mean annual estimated over time. No new evidence explaining the huge increase was Frontiers in Public Health | www.frontiersin.org 6 May 2022 | Volume 10 | Article 893770 Frontiers in Public Health | www.frontiersin.org Solís-Díez et al. TABLE 1 | Description of IgG use in year 2021. Medical condition Therapeutic area Clinical Patients Centers Total estimated Mean (SD) Mean cost per adequacy consumption monthly dose patient category N (%) N (%) Annual grams g/Kg e Replacement therapy in primary 620 (31, 7) 42 (87, 5) 228.856 0, 57 (0, 3) 15.568 immunodeficiencies diseases Congenital hypogammaglobulinemias Hematology B 54 (2, 76) 17 (35, 42) 16.256 0, 69 (0, 46) Common variable immunodeficiency disease (CVID) Immunology A 311 (15, 9) 35 (72, 92) 130.440 0, 59 (0, 25) IgG subclass deficiency (with recurrent infections) B 102 (5, 21) 22 (45, 83) 34.935 0, 47 (0, 22) Unspecified primary antibodies deficiencies C 69 (3, 53) 19 (39, 58) 25.917 0, 64 (0, 41) Agammaglobulinaemias A 61 (3, 12) 12 (25) 15.405 0, 49 (0, 31) Severe combined immunodeficiency (SCID) A 21 (1, 07) 12 (25) 5.275 0, 55 (0, 23) Replacement therapy in HIV/AIDS D 2 (0, 1) 3 (6, 25) 630 0, 42 (0) Immunomodulation 392 (20, 04) 42 (87, 5) 262.973 1, 68 (0, 69) 29.780 ITP in specific circumstances (surgery, other therapy Hematology A 50 (2, 56) 15 (31, 25) 10.155 1, 51 (0, 84) contraindicated, chronic ITP, concurrent risk factors) ITP with life-threatening hemorrhage or potential A 34 (1, 74) 14 (29, 17) 8.665 1, 64 (1, 05) lifethreatening hemorrhage Kawasaki disease Immunology A 4 (0, 2) 5 (10, 42) 295 2, 11 (1, 33) Chronic inflammatory demyelinating polyneuropathy Neurology A 205 (10, 48) 33 (68, 75) 168.276 1, 72 (0, 58) 7 (CIDP) Multifocal motor neuropathy (MMN) A 71 (3, 63) 17 (35, 42) 67.042 1, 69 (0, 45) Guillain–Barré syndrome (GBS) A 23 (1, 18) 13 (27, 08) 6.080 1, 66 (0, 73) Chronic inflammatory demyelinating A 3 (0, 15) 4 (8, 33) 1.565 1, 41 (1, 11) polyradiculoneuropathy Immune-mediated neuropathy (IMN) A 2 (0, 1) 2 (4, 17) 895 2, 78 (-) Other therapeutic objectives/diseases 388 (19, 84) 36 (75) 182.630 1, 69 (1, 06) 22.250 Dermatomyositis (DM) Dermatology A 46 (2, 35) 18 (37, 5) 45.235 1, 77 (0, 5) Autoimmune haemolytic anemia (AIHA) Hematology B 4 (0, 2) 5 (10, 42) 1.885 1, 24 (1) Haemolytic disease of the newborn (HDN) C 3 (0, 15) 2 (4, 17) 35 5, 28 (4, 11) Systemic lupus erythematosus (SLE) Immunology D 12 (0, 61) 8 (16, 67) 3.925 1, 28 (0, 74) Dealing With Immunoglobulin Shortages ANCA-positive systemic necrotising vasculitis B 11 (0, 56) 11 (22, 92) 8.338 1, 19 (0, 76) May 2022 | Volume 10 | Article 893770 Sjögren’s syndrome C 3 (0, 15) 4 (8, 33) 2.380 1, 42 (0, 74) Susac syndrome C 2 (0, 1) 2 (4, 17) 630 1, 26 (0, 26) Myasthenia gravis (MG) Neurology A 223 (11, 4) 30 (62, 5) 68.997 1, 61 (0, 92) Paraneoplasic encephalitis C 25 (1, 28) 13 (27, 08) 8.450 2, 35 (2) Inflammatory myopathies A 16 (0, 82) 10 (20, 83) 14.300 1, 63 (0, 51) (Continued) Frontiers in Public Health | www.frontiersin.org Solís-Díez et al. TABLE 1 | Continued Medical condition Therapeutic area Clinical Patients Centers Total estimated Mean (SD) Mean cost per adequacy consumption monthly dose patient category N (%) N (%) Annual grams g/Kg e Lambert–Eaton myasthenic syndrome (LEMS) A 12 (0, 61) 7 (14, 58) 5.250 1, 67 (0, 64) IgM paraproteinaemic demyelinating neuropathy B 9 (0, 46) 8 (16, 67) 9.215 1, 92 (0, 59) Stiff person syndrome A 9 (0, 46) 7 (14, 58) 5.060 1, 61 (0, 43) IgG and IgA paraproteinaemic demyelinating A 8 (0, 41) 7 (14, 58) 6.610 1, 38 (0, 46) neuropathies Epilepsy C 5 (0, 26) 4 (8, 33) 2.320 1, 54 (0, 53) Replacement therapy in secondary 299 (15, 29) 34 (70, 83) 61.362 0, 54 (0, 51) 8.910 immunodeficiencies diseases Replacement therapy in chronic lymphocytic leukemia Hematology A 94 (4, 81) 22 (45, 83) 16.050 0, 4 (0, 14) and severe recurrent infections Replacement therapy in multiple myeloma and severe A 50 (2, 56) 10 (20, 83) 7.245 0, 49 (0, 52) recurrent infections Replacement therapy in chronic lymphocytic leukemia A 2 (0, 1) 3 (6, 25) 145 0, 38 (0, 15) and recurrent infections Secondary hypogammaglobulinaemia (excluding Immunology B 127 (6, 49) 22 (45, 83) 28.994 0, 66 (0, 67) hematological malignancies) 8 Replacement therapy patients with severe or recurrent B 26 (1, 33) 17 (35, 42) 8.928 0, 56 (0, 2) infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) Transplantation related therapy 101 (5, 16) 11 (22, 92) 12.451 0, 75 (0, 52) 5.397 Replacement therapy pre or post allogenic stem cell Transplant B 48 (2, 45) 6 (12, 5) 5.046 0, 48 (0, 19) transplantation with hypogammaglobulienemia Medicine Treatment of antibody mediated solid organ transplant A 37 (1, 89) 10 (20, 83) 4.955 0, 93 (0, 54) rejection Ongoing desensitization of patients to improve the A 13 (0, 66) 3 (6, 25) 2.100 1, 22 (0, 69) likelihood of non-compatible ABO or HLA transplantation Ongoing desensitization of patients to improve the A 3 (0, 15) 2 (4, 17) 350 1, 44 (0, 54) likelihood of solid transplantation with highimmunologic risk Dealing With Immunoglobulin Shortages May 2022 | Volume 10 | Article 893770 Non-classifiable E 156 (7, 98) 26 (54, 17) 67.979 1, 41 (1, 02) 18.812 Total 1956 (100) 48 (100) 816.251 1, 07 (0, 87) 18.305 A, Demonstrated therapeutic role; B, Developed therapeutic role; C, Exceptional therapeutic role; D, Non-evidenced therapeutic role (category D); E, Non-classifiable. Bold values are superior categories that aggregate several indications showed below. Frontiers in Public Health | www.frontiersin.org Solís-Díez et al. TABLE 2 | Main differences between 2020 and 2021 trends in IgG consumption. Therapeutic objective Key indicator Year 2020 Year 2021 Mean differences (CI95%) p-value mean (CI95%) mean (CI95%) Replacement therapy in primary Number of patients 665 620 immunodeficiencies diseases Annual estimated consumption (g) 402 (382.62; 421.38) 374 (356.53; 391.47) −28 (−40.71;−15.29) 0.037 Monthly dose (g/Kg) 0.62 (0.6; 0.64) 0.57 (0.55; 0.59) −0.05 (−0.07;−0.03) 0.003 Estimated annual cost (e) 16,722 (15,910.12; 17,533.88) 15,533 (14,796.71; 16,269.29) −1189 (−1722.71;−655.29) 0.106 Immunomodulation Number of patients 434 392 Annual estimated consumption (g) 785 (708.23; 861.77) 704 (630.75; 777.25) −81 (−132.69;−29.31) 0.1 Monthly dose (g/Kg) 1.74 (1.68; 1.8) 1.68 (1.61; 1.75) −0.06 (−0.1;−0.02) 0.202 Estimated annual cost (e) 32,149 (28,968.58; 35,329.42) 30,188 (27,052.69; 33,323.31) −1,961 (−4,132.87;210.87) 0.39 Other therapeutic Number of patients 414 388 objectives/diseases Annual estimated consumption (g) 558 (509.07; 606.93) 510 (460.35; 559.65) −48 (−81.81;−14.19) 0.029 Monthly dose (g/Kg) 1.7 (1.56; 1.84) 1.69 (1.58; 1.8) −0.01 (−0.1;0.08) 0.913 Estimated annual cost (e) 22,813 (20,790.04; 24,835.96) 22,547 (20,387.11; 24,706.89) −266 (−1,698.85;1,166.85) 0.86 Replacement therapy in Number of patients 274 299 secondary immunodeficiencies Annual estimated consumption (g) 236 (208.17; 263.83) 211 (184.59; 237.41) −25 (−43.59;−6.41) 0.202 diseases Monthly dose (g/Kg) 0.56 (0.5; 0.62) 0.54 (0.48; 0.6) −0.02 (−0.06;0.02) 0.646 Estimated annual cost (e) 9,745 (8,576.22; 10,913.78) 8,759 (7,647.97; 9,870.03) −986 (−1,767.39;−204.61) 0.231 Transplantation related therapy Number of patients 118 101 9 Annual estimated consumption (g) 137 (104.7; 169.3) 131 (104.28; 157.72) −6 (−26.73;14.73) 0.784 Monthly dose (g/Kg) 0.83 (0.7; 0.96) 0.75 (0.65; 0.85) −0.08 (−0.16;0) 0.345 Estimated annual cost (e) 5,776 (4,402.03; 7,149.97) 5,483 (4,327.29; 6,638.71) −293 (−1,180.07;594.07) 0.754 Non-classifiable Number of patients 129 156 Annual estimated consumption (g) 507 (399.84; 614.16) 453 (372.5; 533.5) −54 (−117.81;9.81) 0.422 Monthly dose (g/Kg) 1.42 (1.26; 1.58) 1.41 (1.25; 1.57) −0.01 (−0.12;0.1) 0.931 Estimated annual cost (e) 20,834 (16,312.62; 25,355.38) 18,542 (15,233.13; 21,850.87) −2,292 (−4,953.04;369.04) 0.409 All therapeutic objectives Number of patients 2034 1956 Annual estimated consumption (g) 483 (459.97; 506.03) 436 (414.55; 457.45) −47 (−62.28;−31.72) 0.03 Monthly dose (g/Kg) 1.1 (1.06; 1.14) 1.07 (1.03; 1.11) −0.03 (−0.06;0) 0.301 Estimated annual cost (e) 19,890 (18,935.35; 20,844.65) 18,398 (17,487.96; 19,308.04) −1,492 (−2,132.12;−851.88) 0.027 Dealing With Immunoglobulin Shortages May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages found, and market profitability seems to be the dominant driving by collecting information on indication and, eventually, results. force that explains this large increase in demand. This situation is A benefit of this information when it is rapidly transformed likely to continue in the absence of good clinical studies analyzing into reports is in helping decision-making in health. However, the place of IgG therapy vs. other treatments (10). an important finding was the consumption growth of IgGs in Product shortages during the COVID-19 pandemic caused non-classifiable therapeutic indications. Therefore, more actions sudden increases in demand or disruptions in supply chains should be designed and implemented in order to improve the of different products such as IgGs. Experiences describe how quality of recorded information. health systems have handled shortages in essential products by A very important aspect is the variability observed between estimating the clinical demand, assessing product supply and the centers in patterns of use of non-specific domestic IgGs and potential inequities in access, and enacting policies grounded in patterns of clinical use of therapeutic indication as in dosages, as an ethical framework for drug allocation (29, 30). well as economic expense. Therefore, a key issue is addressing In a shortage situation, contingency planning includes the variability of usage. Measures for the dissemination of prioritization policies for patients in the event of predicted this information among the centers for benchmarking allow shortage. A range of strategies tries to maintain ongoing identifying and sharing best practices aimed to improve IgG equitable access to blood for transfusion, sharing experience, use. Finally, it is also useful to establish common proposals and and developing expert consensus on the basis of evolving recommendations for all the centers to reduce the variability. publications, have all been proposed as useful tools in helping Thus, it is very important to establish good communication transfusion services and hospitals (31). Globally, national and with all centers, and to achieve the participation and co- regional health systems have designed IgG shortage management responsibility of the centers in the management of the use plans in last years to deal with possible critical scenarios (32– of IgGs. 34). All agents must be implicated in the importance of the good In a situation of scarcity, the concept of using biological agents clinical use of IgGs, in particular, and cell blood components and at the lowest effective dose is logical and may help minimize PDMP in general. This limited resource is vital in many medical side effects, some of which may be dose-related. This also saves areas, and major conclusions should be established to assess their significant amounts of IgGs. The use of immunoglobulin dose clinical use. adjusted for ideal body weight (IBW) may be a rational approach. The categories of adequacy were agreed upon as a surrogate of In our experience, managing the use of IgGs through multiple appropriate use, so the proportion of prescription in category A strategies may be useful; however, we must take into account could be used as an element to prioritize access to available stocks that observed reduction in the use of IgGs is also coincident whenever coordinated distribution was advised. with the pandemic period where other circumstances may have Regarding dose optimization, use of IgG dose adjusted for influenced their clinical use. Either increased use for COVID-19 ideal body weight (IBW) is a desired option, since biological related conditions or reduced use due to difficulties in healthcare drugs are mainly distributed to the central compartment; thus, it access during epidemic waves have disrupt IgG consumption. is sensible to account for the excess of poorly perfused adipose The effectiveness of these policies should be appraised to know tissue when body-weight adjustment of dosing is done. This their impact on the heterogeneity of their availability, their is not only rational but also helps saving significant amounts use, and their clinical outcomes in patients treated with IgGs; of IgGs. The main guidelines for clinical use of IgGs include furthermore, less consumption should be observed. In addition, recommendations for the use of IBW in the calculation of shortage alert systems should be improved providing information the dosage weight (DW) of immunoglobulins. In all of them, in real-time and predicting shortage trends and if this manner a compromise is reached between current weight (CW) and could advance at critical situations and prepare responses with IBW to determine the DW (23, 24). The working group is enough time. The actions developed need close follow-up. also developing guidance on therapeutic alternatives to IgGs in Continuous monitoring of proposed indicators is needed in the therapeutic indications where they are available and with solid near future to verify its effectiveness. evidence (24). Different studies on interventions to reduce low-value care Medicine regulatory agencies have developed national have been carried out. However, little is known about how shortage registries, but they generally inform once the supply the effects of such interventions are measured. Most published has been compromised instead of early detecting misbalances studies were focused on reduction in utilization. The effectiveness between use and supply in real-time, thus predicting shortages of these interventions have been variable (35). Audit and and allowing early action to avoid or manage them (12). feedback, computerized advice, point-of-care reminders, practice One of the first proposals of the group was to prospectively facilitation, educational outreach, and processes for patient collect information about therapeutic indications for which IgGs review and follow-up all demonstrated evidence of a quality were prescribed, as well as dosages and posology, in order to improvement effect. Evidence of an improvement effect was analyze clinical adequacy and potential areas of improvement higher where baseline performance was low and was particularly and efficiency. demonstrated across process measures and measures related Data availability on the use of IgGs from clinical records is a to prescribing. Evidence has not been sufficient to suggest useful source of information on how to manage the use of IgGs. that multifaceted approaches were more effective than single In that sense, therapeutic registries may also be useful, since they interventions (36). However, no study reports the cost-benefit can approach effectiveness and utilization of registered medicines ratio of documented interventions. Future intervention studies Frontiers in Public Health | www.frontiersin.org 10 May 2022 | Volume 10 | Article 893770 Solís-Díez et al. Dealing With Immunoglobulin Shortages should incorporate economic variables to documents and needed to better analyse the impact of the established measures. disseminate the cost-benefit ratio. Registries play a key role in collection of systematic data to The main limitations in analyzing the effect of the analyze, synthetize, and extract valuable information for decision intervention were related to the study period and the lack support. More research is required to determine the use and of a control group. On the one hand, the study period coincided impact of quality improvement interventions using theoretical with the COVID-19 pandemic. Therefore, the main limitation frameworks and by cost-effectiveness analysis. was related to the effect of this disease, which has had a great influence on the observed results. On the other hand, the data are observational and are limited to comparing two periods with AUTHOR CONTRIBUTIONS a very short time interval; therefore, it is difficult to analyze the CP, AV, and GS-D conceptualized and designed the article and effect in such a short time. A concurrent control group was not verified data. GS-D and MT-P collected the data, analyzed the included to be able to analyze the causal relationship between data, and created the tables and graphs. GS-D drafted and the intervention and the observed effect. Although different wrote the manuscript. MR-I, CZ, MT-P, and AV reviewed the health systems have developed evidence-based management manuscript for important intellectual content. CP revised the plans for situations of immunoglobulin deficiency, there are no final version of the manuscript and is guarantor for the article descriptions of the effect of these management plans. Therefore, and expert in public health. All authors contributed to the article it should be noted as strength that an initial experience has and approved the submitted version. been presented on the effect of the implementation of specific measures for the clinical management of IgGs in the context of a regional health system. Nevertheless, a long-term follow-up is ACKNOWLEDGMENTS necessary to verify the effectiveness of these measures. This policy has been possible thanks to the countless hours of dedication and effort by health professionals and registration CONCLUSIONS support technicians in different SISCAT hospitals, and thanks The annual consumption and cost of IgGs increased in the to the farsightedness of the registry creators. Technicians of last decade. After identifying a potential serious health problem the Management of Information Systems of CatSalut and consisting of increasing supply problems of IgGs, a set of Technicians of the Medicines Area of the CatSalut allowed the pharmaceutical policies has been drawn up in conjunction with continuity and future development of the project with their daily stakeholders. A multifaceted intervention based on evidence contribution to the continuous improvement of the registry and focused on assessing the clinical adequacy of actual treatments, to the solution of problems. optimizing indications and dosing, to ensure an equitable supply in centers was done. We used previous records and set up new SUPPLEMENTARY MATERIAL ad hoc registries to evaluate the effect of this intervention on the use of IgGs. In a short period after the intervention, we observed a The Supplementary Material for this article can be found decrease in consumption of IgGs and in cost per patient but in the online at: https://www.frontiersin.org/articles/10.3389/fpubh. context of COVID-19. Therefore, long-term follow-up would be 2022.893770/full#supplementary-material REFERENCES 6. World Health Organization. Resolution WHA63.12: Availability, Safety and Quality of Blood Products. (2010). https://apps.who.int/gb/ebwha/pdf_files/ 1. Caraceni P, Tufoni M, Bonavita ME. Clinical use of albumin. Blood Transfus. WHA63/A63_R12-en.pdf (accessed April 9, 2022). (2013) 11(Supl4):s18–25. doi: 10.2450/2013.005s 7. WHO Expert Group. Expert Consensus Statement on achieving self- 2. Morfini M, Coppola A, Franchini M, Di Minno G. 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Any product that may be evaluated in 9, 2022). this article, or claim that may be made by its manufacturer, is not guaranteed or 22. Grupo Español de Medicamentos Hemoderivados (GEMEH), Sociedad endorsed by the publisher. Española de Farmacia Hospitalaria (SEFH). Guíaclínica Para el uso de Inmunoglobulinas. Adaptación Para España. (2011). Available online Copyright © 2022 Solís-Díez, Turu-Pedrola, Roig-Izquierdo, Zara, Vallano and at: https://www.sefh.es/bibliotecavirtual/Guia_Igb/Guia_Imnunoglobulinas. Pontes. This is an open-access article distributed under the terms of the Creative pdf (accessed April 9, 2022). Commons Attribution License (CC BY). The use, distribution or reproduction in 23. Grindeland JW, Grindeland CJ, Moen C, Leedahl ND, Leedahl DD. Outcomes other forums is permitted, provided the original author(s) and the copyright owner(s) associated with standardized ideal body weight dosing of intravenous immune are credited and that the original publication in this journal is cited, in accordance globulin in hospitalized patients: a multicenter study. Ann Pharmacother. with accepted academic practice. No use, distribution or reproduction is permitted (2019) 54:205–12. doi: 10.1177/1060028019880300 which does not comply with these terms. Frontiers in Public Health | www.frontiersin.org 12 May 2022 | Volume 10 | Article 893770