Considering the demand for and prioritization of intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is an essential therapy for a wide variety of conditions. The number of indications and potential applications for immunoglobulin (Ig) has been rising steadily during the past 20 years and insight into therapeutic mechanisms has helped to substantiate this expansion. Improved evidence as to how best to apply Ig within specific indications has also led to more targeted, rational and, in some cases, an increased and appropriate usage of Ig.

In the United States, Ig is available to physicians, hospitals and speciality pharmacies via a complex network for use in indications that are Food and Drug Administration (FDA)-approved, or are supported by robust widely accepted evidence. This same network is utilized for Ig that is applied in experimental indications. It is theoretically possible that an increase in the number of FDA-approved indications [e.g. IVIg in chronic inflammatory demyelinating polyneuropathy (CIDP), and a potential indication in a subset of patients with Alzheimer's disease], as well as other indications supported by high-quality evidence, could place a burden on the existing Ig pool that is available for therapeutic application. Similarly, increasing usage of Ig in any of these three categories of indications could also lead to strain on the supply of Ig. This is especially challenging, because there is a significant and necessary lag in assessment of Ig usage from physician prescription to a manufacturer being able to increase production in order to be able to meet any increased demands.

To estimate the underlying demand for Ig in the setting of competing demands for this resource, a decision model was developed in collaboration with the European Society for Immunodeficiencies (ESID) Registry Working Party and the Plasma Protein Therapeutics Association (PPTA), to better inform payors and to anticipate and prepare for patients' future needs 1. The assessment of latent therapeutic demand (LTD) for Ig in the treatment of common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA) was made using decision analysis methodology, and compared with actual Ig use in different countries. Estimates were performed based on 948 clinical records of CVID and 419 clinical records of XLA obtained from the ESID Registry. Data for the epidemiological- and treatment-related variables were extracted from peer-reviewed publications, clinical registries and publicly available patient surveys. Based on probabilistic distributions and Monte Carlo simulation, treatment dosage, prevalence and treatment frequency were identified as the main driving forces of LTD. In contrast, patient gender, treatment rate, age group of patients and route of administration had substantially less effect on the LTD for CVID and XLA. The study concluded that the average potential usage of Ig for CVID and XLA was approximately 72 g per 1000 population. This was higher than the actual Ig usage in CVID and XLA of approximately 27–41 g per 1000 population in the United States, and also higher than the actual total Ig usage for all indications in many countries. Hence, the potential demand for Ig for the treatment of CVID and XLA exceeds the currently observed Ig usage in these disorders 1. Given the efforts to improve diagnosis 2–4 and promote optimal treatment 5,6, it is prudent for the Ig community overall to be prepared for increased demand for therapeutic Ig preparations.

Given the LTD for Ig within a finite production environment, the concept of prioritization of Ig use within indications is a necessary consideration. While several countries have prioritization programmes and demand models in place for therapeutic Ig, in the United States there is no national, but many institution-specific programmes. The current American Academy of Allergy, Asthma and Immunology recommendations for managing Ig demand are based on evaluation of the published evidence for Ig use in multiple indications 7. However, it may be necessary to consider more than one axis within the concept of evidence-based medicine (EBM) when evaluating a costly and limited resource. Data from a 2006 survey of pharmacy directors, conducted by the Immune Deficiency Foundation on hospital usage of IVIg, showed that many organizations prioritize individually how Ig is utilized 8, which are likely variable in application. Further national and regional recommendations are available with regard to acceptable indications, notably through the US Department of Health and Human Services (HHS) Center for Medicare Services (CMS) contractor IVIg Local Coverage Determinations. Private insurers in the United States also have their own coverage polices applicable to therapeutic Ig, most of which are based upon data supporting applicability to a particular clinical indication. This results in a relatively large number of different operating practices in the United States, which have been derived from a variety of means.

To reduce inconsistency, consider potential demand issues and promote best practice, a theoretical Ig prioritization algorithm was proposed for strong evidence-based indications 9. In addition to the evidence supporting use in the indication, disease severity and efficacy of therapeutic alternatives were included as additional axes within the algorithm. Three immunology experts whose main clinical focus is primary immunodeficiencies rated 17 indications using the three axes. There were a few areas of consensus (e.g. rating of CVID) but, more commonly, minor differences in opinion. In a few cases there were considerable differences, such as the rating of efficacy of therapeutic alternatives of severe combined immunodeficiency and toxic epidermal necrolysis 9.

One of the stated limitations of this effort was the lack of discussion, after collating the responses, to mitigate misunderstandings or individual perspectives. An additional limitation of the proposed algorithm included the single-speciality background of the participants and the consideration of only three variables. In the future, additional variables such as the onset (acuity), chronicity, number of doses needed and pharmacoeconomics could be considered.

The large multi-speciality, multi-national audience assembled at the 7^th International Immunoglobulin Conference provided the opportunity to invite attendees to rate six Ig indications according to severity and the efficacy of therapeutic alternatives (Fig. 1). The aim of this exercise was to gain an additional perspective on the level of consensus or discrepancy among specialists when considering prioritization of Ig use. There were 221 attendees at the Conference, and each was given a form to rate two axes for the six indications. A total of 91 forms were returned for a lowest-possible response rate of 41·2%. Although the forms were anonymous, the distribution of the respondents' self-reported specialties is outlined in Fig. 2. The frequency of ratings of immunological and neurological conditions is shown in Figs 3 and 4, respectively.

Figure 1.

Immunoglobulin (Ig) prioritization algorithm (modified with permission from 9, copyright 2013, open source). Indications for Ig were considered according to the severity of the disease and the efficacy of therapeutic alternatives to Ig. Each variable was based on a four-point scale leading to 16 potential ratings for each indication listed.

Figure 2.

Distribution of the speciality of audience participants. A total of 91 participants completed the questionnaire; n: number of respondents.

Figure 3.

Participant ratings of disease severity and efficacy of therapeutic alternatives of immunological indications. (a) Common variable immunodeficiency; (b) Specific antibody deficiency. Comparison of severity ratings and efficacy ratings between specialities was performed by Kruskal-Wallis test and Fisher's exact test (significance level <0·05; only significant values are stated); n: number of respondents.

Figure 4.

Participant ratings of disease severity and efficacy of therapeutic alternatives of neurological indications. (a) Guillain-Barré syndrome; (b) Chronic inflammatory demyelinating polyneuropathy; (c) Idiopathic thrombocytopenic purpura/immune thrombocytopenia; (d) Alzheimer's disease. Comparison of severity ratings and efficacy ratings between specialities was performed by Kruskal-Wallis test and Fisher's exact test (significance level <0·05, only significant values are stated); n: number of respondents.

Despite an overall consensus among ratings of disease severity, with minor differences in opinion regarding the efficacy of therapeutic alternatives (Figs 3 and 4), there was a statistically significant difference in the disease severity ratings of specific antibody deficiency among different specialities (P = 0·03, Fig. 3a) and in the ratings of the efficacy of therapeutic alternatives of idiopathic thrombocytopenic purpura/immune thrombocytopenia (P = 0·04, Fig. 4c). Additional multi-speciality dialogue could have the potential to promote further alignment in perspective once speciality-specific perspectives are defined appropriately. The overall high consensus, however, could suggest the role of experts in working with administrative stakeholders in proactively supporting patient needs.

In conclusion, despite the recognized limitations of the proposed algorithm 9, consideration of additional variables other than simple EBM may help to inform best application of the limited therapeutic Ig resource, and ultimately assist stakeholders in ensuring that patients who will benefit most from Ig therapy receive it.

Disclosures

J. S. O. has received consulting honoraria from CSL Behring, Baxter, ASD and Atlantic Research Group, and a research grant from CSL Behring.