Immunoglobulin utilization in Canada: a comparative analysis of provincial guidelines and a scoping review of the literature

Immunoglobulin (IG) is a plasma product prepared by purifying and pooling antibodies from thousands of healthy individuals [1, 2]. These products are prepared based on the route of administration as intravenous (IVIG) or subcutaneous (SCIG), both of which are available and widely used in Canada [3]. Unlike IVIG which requires administration by a healthcare professional, SCIG can be self-administered at home [4]. IG products are used to treat patients across a broad spectrum of illnesses [5], such as primary and secondary immune deficiencies (PID, SID), immune thrombocytopenia (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Canada is the 2nd highest global per capita consumer of IG products [5]. According to Canadian Blood Services (CBS), half of the patients who use IG products in Canada have no other treatments available for their condition and therefore depend on them to survive [5, 6]. However, due to the high levels of IG use across a range of indications and the shortage of production facilities in Canada, concerns have been raised regarding Canada's long-term ability to ensure the ongoing supply of IG for patients across the country [7].

In the last decade, Canada has experienced an 8% annual growth in the use of IG products [5, 8]. Some of the leading factors that have contributed to the increase in demand include off-label use [9], inappropriate dosing [10‐14], and the expansion of indications [15, 16]. The increased demand has made it exceedingly challenging for the Canadian blood product suppliers, the Canadian Blood Services and Hema-Québec (only for Québec), to meet the demand. Only 17% of the plasma required in Canada is produced using donated plasma within the country [5]. Thus, Canada highly depends on suppliers from other countries, mainly the United States, to meet the demands. The high dependency has resulted in towering expenses, with 66% of the total blood expenditure spent to supply these products [5]. To respond to the high demand for IG, the increase in use over time, the supply challenges, and the high costs associated with its use, and to ensure the receipt of IG products, several provincial guidelines for IG use have been developed [17]. However, no Canadian national standardized protocol is currently available, and there are considerable variations among the existing provincial guidelines. Such inconsistencies among the provincial IG guidelines could cause differences in IG utilization and treatment outcome, affecting demand and supply management [18‐20].

This study followed two main goals: We first collected and compared the existing provincial guidelines on using IG products in Canada to identify the consistencies and differences in provincial guidelines. Comparing the provincial guidelines can help develop a standardized approach to IVIG use across the country, which can help identify best practices, help improve patient outcomes, reduce variations in care, reduce costs, and support the development of new treatments. The second goal was to examine the existing literature on IG supply and utilization in Canada following the establishment of the IVIG and SCIG guidelines to understand the scope of existing research and pinpoint the gaps. Such studies at the national or local level can support the development of national utilization guidelines by providing valuable data on treatment outcomes, medication safety profiles, regional unique factors that may influence medication responses, cost-effectiveness, and resource availability. This study highlights the need for further research to assess the feasibility of the IVIG and SCIG infusion guidelines and to explore the factors influencing guideline adherence, costs, and comparative effectiveness. It also emphasizes the importance of evaluating the impact of updated guidelines on IG use and patient outcomes to ensure the continued availability of IG products for patients in Canada.

The scoping review included 29 studies which focused on IVIG utilization and audits, the switch from IVIG to SCIG, patient satisfaction with immunoglobulin therapies, and alternative therapies for IVIG. The review also provided a comprehensive analysis of Canadian IG guidelines across provinces.

We recognized two primary similarities by comparing Canadian IG guidelines across provinces. Firstly, the medical conditions delineated in the IG guidelines exhibited considerable overlap, with minor deviations due to disparities in recommendation categories. Secondly, dose calculations demonstrated relative uniformity among the guidelines. However, numerous differences exist between the provincial IG guidelines. The Atlantic guideline stands out as the only one offering a comprehensive list of dosing recommendations for relevant medical conditions. In contrast, the Prairie and Québec guidelines mention SCIG administration but lack information on dosing. Recommendation categories also exhibit high variations between guidelines, with a high percentage of indications for IG use falling into the categories of "possible treatment option" or "insufficient data" in Ontario, Prairies, Atlantic, and Québec. In contrast, British Columbia distinguishes between recommended and not recommended categories. Moreover, some guidelines group multiple conditions within a single category, while others list them separately (e.g., the Québec guideline enumerates conditions that fall under the PID or SID categories, whereas other guidelines use the general terms 'PID' and 'SID' instead). Other discrepancies include the inconsistent provision of pediatric dosing and divergent recommendations for identical conditions based on patient demographics. The meta-analysis reveals that approximately 50% of the medical indications were recommended for IVIG, with the remaining 50% being not recommended or having an ambiguous recommendation. The high overall heterogeneity (I² = 73%) underscores a significant inconsistency across different provincial guidelines. Furthermore, the proportion of indications recommended for IVIG varied among different medical specialties, ranging from 30% in neurology to 72% in immunology. Substantial heterogeneity was also observed within specialties across the guidelines. These variations in guidelines and recommendations may contribute to inconsistencies in IG use and adherence across the country. It is worth noting that the National Advisory Committee on Blood and Blood Products [53] has issued nationwide recommendations for the administration of fibrinogen [54] and prothrombin complex concentrates [55]. However, standardized national recommendations for the use of IVIG and SCIG are yet to be established.

The findings on IVIG utilization not only revealed an increasing trend in IVIG use but also highlighted the limitations in current interventions and guidelines to control its use [17, 26, 27]. This suggests the need for reinforcement strategies, a better understanding of guideline adherence factors, and exploring other explanations for changes in IVIG use. The audit studies identified challenges in ensuring appropriate IVIG use, with insufficient documentation and low compliance with the Ontario IVIG Utilization Management Strategy [9, 28] or high rates of inappropriate treatments when measured against a robust benchmark [29]. These results call for a comprehensive, evidence-based active surveillance process and the development of clinical guidelines to ensure appropriate and cost-effective treatment.

The studies on chronic IG therapy demonstrated the potential benefits of SCIG, including improvements in disease outcomes, reductions in the use of other medications, and fewer side effects compared to IVIG [31‐33]. However, they also suggested areas for further research, such as the need for prospective randomized studies to clarify costs and comparative effectiveness [32] or longer follow-up periods and specific IVIG to SCIG conversion ratios for certain patient populations [33].

The cost-saving analysis studies showed the potential for reduced healthcare resource utilization when switching patients from IVIG to home-based SCIG therapy [34‐36]. Furthermore, the availability of several SCIG home infusion programs, entirely funded by pharmaceutical companies [24, 25], contributes to the advantages of home-based SCIG treatments concerning healthcare expenses. These findings help justify the provision of home-based therapy training to suitable patients and can encourage healthcare professionals to consider advocating for home-based SCIG therapy for PID/SID patients when clinically appropriate. The patient satisfaction studies [38, 39, 41] provided insights into patient satisfaction regarding IVIG and SCIG treatments. IVIG was found to be satisfactory in tolerability but inconvenient, while SCIG was generally well-received with improved quality of life and lower risk for systemic adverse effects [56‐58]. The studies that compared the efficacy and cost-benefits of alternative treatments to IG products can provide alternative reasonable treatment options, especially in light of IG product supply limitations [50, 51]. This information could be valuable in guiding healthcare providers and policymakers to tailor IG treatment strategies to better suit patients' needs and preferences.

Nevertheless, the existing studies have several limitations: (1) Several studies were conducted at single sites and might not be representative of other regions in Canada. (2) Most studies have small sample sizes, which could limit the generalizability of their results to larger populations. (3) The focus on specific medical conditions, such as ITP, PID, MG, and immune-mediated neurological disorders, means that the results may not be applicable to other medical conditions. (4) Some of the studies are conducted over a relatively short period, which could limit the ability to draw long-term conclusions. (5) Studies with retrospective design can be subject to selection and recall bias (e.g., underreporting of adverse events, unclear principal diagnosis for IG use, reliance on chart reviews for symptom assessment).

This scoping review also has some limitations. The primary focus of our research was to examine the research on IG utilization in Canada, along with its corresponding provincial guidelines. Although other countries might face similar ongoing issues regarding IG supply, it is crucial to recognize that the applicability of our findings and conclusions to different countries or healthcare systems could be restricted. Moreover, the review included a relatively small number of studies, which may not fully reflect the Canadian context. The review focused solely on published literature and conference abstracts, which did not consider gray literature such as unpublished reports or government documents, which may contain important information not published in peer-reviewed journals. Furthermore, the time frame of 2014 to 2023 may result in the omission of relevant papers published before 2014, such as the study by Chow et al. [59]. However, the utilization of IG products was limited before that time.

In conclusion, this study highlights the differences in Canadian IG guidelines across provinces and the various factors influencing IVIG and SCIG use, patient satisfaction, cost savings, and alternative therapies for IVIG. The findings of this review may inform healthcare professionals, policymakers, and guideline developers in their efforts to unify and optimize immunoglobulin therapy practices in Canada. Future research may focus on conducting prospective randomized studies to clarify costs and comparative effectiveness, exploring factors influencing guideline adherence, evaluating the impact of updated guidelines on IG use and patient outcomes, and establishing a unified national IG guideline.