The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative

Abstract

Since the inception of industrial plasma fractionation during the Second World War, a succession of protein therapies isolated from plasma have determined the volume of plasma requiring collection, and have also shaped the economics of the industry. These so-called plasma drivers have successively included albumin, coagulation Factor VIII (FVIII) and, for the past thirty years, intravenously (IV) and subcutaneously (SC) administered immunoglobulin (IG) solutions. The sale of IG underpins the profitability of the industry and has experienced continuous growth over the past decades, as the result of growing clinical demand. Modelling this demand using decision analysis indicates that supplying the evidence-based indications for IG therapies will generate a need for IG which exceeds the current plasma collection capacity of most countries. A notable exception to this situation is the United States (US) of America, whose population of compensated plasma donors generates two thirds of the global supply of plasma for fractionation. The US is also the leading consumer of IG, and its health care providers pay the highest price for the product globally. Shortages of IG occur whenever the demand for the product outstrips the supply. Current shortages, following other historical periods of shortage, threaten the well-being of patients dependant on these products and incur heavy costs on health systems. In Italy, the national blood system, which is based on voluntary unpaid donors, reflects a policy of national self-sufficiency in blood-derived therapies (a strategic objective of the national blood system itself), based on solidarity as an ethical principle. This system has increased the collection of plasma for fractionation by 3.8% per annum over 2008–2017, in accordance to a plan for plasma procurement targeting a collection rate of 14.1 L of plasma per thousand (10³) population by 2020. Over the same period, IG usage has increased by 8.5/per annum, to 89.2 g IG/10³ population. In this paper, we review the factors which, increasingly, are causing an imbalance between the global supply and demand for IG, and we assess Italy’s capacity to ensure that increasing this level of independence is no longer simply an ethical, but also an economic imperative, with implications for the security of Italy’s health system.

Evolution and current status of IG therapies

The history of IG therapy has been reviewed¹. The treatment of infections using animal antisera proliferated following the work of Behring and Ehrlich, and was augmented by the use of human sera to treat diphtheria and tetanus. Over the 1930s, awareness regarding serum protein composition showed that antibody activity was located in the immunoglobulin compartment of plasma². In the early 1940s, Cohn’s team at Harvard University built on his work on the characterisation of plasma proteins to develop a scheme for the large scale manufacture of purified albumin solution, which was required by the US military as a stable plasma expander under battlefield conditions³. Cohn’s basic method for albumin yielded an IG-rich side fraction. This was used to prevent and treat infectious disease including measles, poliomyelitis and hepatitis A. This usage diminished greatly when vaccination programmes were developed for these diseases.

In 1952, Bruton⁴ reported the first case of an eight year old patient with undetectable serum gamma globulin accompanied by a long-term history of infections. Clinical improvement was obtained with the subcutaneous administration of a commercial immune serum globulin preparation. Despite this report, and others also utilising subcutaneous preparations⁵, intramuscular (IM) administration became the standard administrative route for patients with a- and hypogammaglobulinaemia. The discomfort, and the twenty four hours needed for maximum serum IG levels to be reached following IM injection, stimulated attempts to admonish IG IV, but this resulted in severe reactions in patients⁶, apparently due to IG aggregates in the product. Early attempts to reduce aggregates included papain or trypsin treatment, and resulted in preparations which were well tolerated but had a short (<24 hours) half-life. Subsequent methods were developed, utilising chemical or enzymatic modification of IG, which differed in their functional integrity¹. Gradually, modifications in the Cohn-based manufacture and developments in formulations allowed manufacture of 4–5% solutions of monomeric, intact IG which were stable. The ability to administer large doses of well-tolerated IVIG have contributed to significant improvements in survival and well-being in patients lacking IG, including diverse forms of a- and hypogammaglobulinaemia grouped as primary immune deficiency disorders (PIDD or PID)⁷. This improvement is accompanied by enhancements in patient assessments of their own condition, through some⁸, but not all⁹, Health Related Quality of Life (HRQoL) elicitations.

Current status of IG therapy

With the development of well-tolerated concentrated solutions of IG by the early 2000s, the status of IG as a modality for the treatment of PID appeared stable and secure. Subsequent developments have progressed this therapeutic landscape considerably, and have established IG as a modality considered by the World Health Organization as an essential medicine¹⁰. Over the 1980s, early observations by Barandun¹¹ were developed by Imbach and co-workers to develop a role for IVIG in the treatment of idiopathic thrombocytopenic purpura (ITP)¹² intact immunoglobulin (Ig). This first use of IVIG as an immunomodulatory therapy was succeeded by its application in other diseases, including the autoimmune neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS), multifocal motor neuropathy (MMN) and others¹³. The increasing use of IVIG in these conditions has made them the major contributor for IVIG demand, and CIDP¹⁴ in particular, absorbs around a third of IVIG use in many surveys^15–17. The increasing demand for IVIG, fuelled particularly by the accrual of indications such as CIDP, has contributed to efforts by the plasma product manufacturers to improve the yield and presentation of IG products. These have included the development of more concentrated (10 vs 5%) IVIG solutions¹⁸, most of which are manufactured by significant variations and, indeed, departures from the Cohn methodology. In addition, the various products have been tested for the effect of rapid infusion speeds on patients¹⁹. Both of these developments have emanated as a convergence of several factors, including the higher IG yields obtainable from the new fractionation chemistries, the decrease in manufacturing costs for the fractionators from the production of 10 vs 5% solutions, and the decreased hospital/clinic stay time from infusing 10% solutions rapidly. This last factor is particularly important in the US. Attempts by the manufacturers to market these factors as benefiting patient quality of life are not supported by evidence, which indicates that patients are indifferent to these particular product features²⁰. It should be noted that the manufacturing products developed to allow these features have occasionally resulted in increased adverse events before the methods were optimised following post-approval clinical experience²¹.

In addition to the claimed improvements to IVIG, over the past years the development of IG solutions administered SC has assumed increasing importance in the treatment of the spectrum of diseases treated by IG. Staring with PID, these products have been shown to be efficacious, and a lower rate of adverse events have been reported by some investigators²². These solutions are administered into a subcutaneous deposit from which the IG moves into the vasculature, eventually resulting in a steady concentration of IG as intra- and extravascular passage equilibrates. The difference in pharmacokinetics (PK) between the two formulations results in higher peak levels of IG from the IV route, but a more sustained and steady level with SC²³. A SCIG product administered in combination with recombinant hyaluronidase in order to facilitate vascular access from the subcutaneous depot results in modified PK (Figure 1)^{24, 25}; the actual clinical benefit from this is uncertain. On the basis of PK data submitted by various manufacturers, the US Food and Drug Administration (FDA) has mandated that licensed SCIG product information for the dosage regimen when switching from IV to SC administration effectively increases the dose by up to 40% relative to the IV route²⁶. This aspect will be discussed below. Uptake of the SC formulations, which are now mostly 20% IG in this competitive landscape, is growing faster than IV products, and now stands at 15% of total IG use in the key US market²⁷, including 61% of the IG used for PIDD²⁸. This trend will increase with the approval of this modality for the high-dosage neurological indications²⁹.

Figure 1.

Immunoglobulin pharmacokinetics²⁵.

IVIg: intravenous immunoglobulin fSCIg: facilitated subcutaneous immunoglobulin; SCIg: subcutaneous immunoglobulin; IgG: immunoglobulin G.

Demand versus supply: the evolution of shortage

As outlined above, demand for IG, irrespective of formulation, geography, etc. has grown continuously since the commencement of records³⁰ (Figure 2).

Figure 2.

The world polyvalent IG market (Tons): 1986 to 2014³⁰.

IG: immunoglobulin.

The issue of which are the evidence-based indications of IG which should form the basis of clinical demand has been debated vigorously over the past twenty years³¹, but an evolving consensus has established which indications unequivocally benefit from IG therapy³². Throughout the years around this controversy, the issue of off-label use of the product has been mentioned repeatedly. The approval of an indication by a regulatory body, following review of the appropriate clinical studies for efficacy, is the basis for the indication on the label. In the case of IG, the provisions of most authorities require that the first indication to be approved should be for PID. Once the product is on the market for this indication, any use for other indications which are not yet approved specifically, such as CIDP, are, strictly speaking, off label. Each product has to acquire its own range of labelled indications, since regulatory agencies do not accept the concept of genericity for IG therapies. There is little evidence today’s generation of IG products vary in their efficacy for the current range of supported indications, irrespective of their presence on the label. In practice, this results in many IG products having been used off-label for e.g. CIDP, although most manufacturers have sought their own specific label. This attribution of “biosimilarity” to IG products is probably not justified for product tolerability³³, and to clinical areas involving specific antibody supplementation³⁴. In summary, all IG products with proven efficacy for PID are efficacious for the range of indications shown in Table I^32,35.

Table I.

Italian approved indications for the therapeutical usage of polyvalent human immunoglobulins (updated from Quinti et al.³²).

Clinical condition	Notes
Primary immune deficiencies	Primary antibody and combined immunodeficiencies
Idiopathic thrombocytopenic purpura	Risk of bleeding
Kawasaki syndrome	Prevention of aneurysms formation
Chronic lymphocitic leukaemia and myeloma	Prevention of bacterial infections in patients with hypogammaglobulinaemias
HIV infection	Paediatric HIV
Bone marrow transplantation	In patients >20 years during the first 100 days post-BMT
Guillain-Barré syndrome	Clinical efficacy overlapping plasmapheresis
Multifocal motor neuropathy	Condition approved for only one brand of commercially available products in Italy
Chronic inflammatory demyelinating polyneuropathy	-
Secondary immune deficiency	In patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF) or serum IgG level of <4 g/L36

BMT: bone marrow transplantation HIV: human immunodeficiency virus; IgG: immunoglobulin G.

Estimating the potential demand for IG has to focus on these indications. Given the variability around many of the factors shaping demand, which include disease prevalence, dosage, patient age and weight etc.³⁶, a high level of uncertainty inevitably surrounds such estimates. Using decision analysis in order to address these uncertainties has yielded estimates of potential (latent) therapeutic demand (LTD) in the principal PIDDs³⁶ and in the main neurological conditions³⁷ responsive to IG. These studies estimated that LTD for these indications in the US is 105 g/10³ population for PIDDs and a combined total of 138 g/10³ population for the main neurological conditions, respectively. Hence, the combined LTD for these indications, which comprise the majority of evidence-based clinical use, approximates 250 g/10³ population, which reflects the current IG usage in the USA and other countries such as Canada and Australia²⁸ (Figure 3).

Figure 3.

Immunoglobulin use in some countries, 2014–2018.

IG: immunoglobulin.

It is notable that Canada and Australia, delivering IG through publicly funded systems with strict adherence to guideline-driven allocation³⁸, are not comparable to the market-driven health system of the US. Despite this, IG usage levels, based on evidence-based delivery, are similar. In the case of the usage of IG for the commonest PIDDs, indications which are unequivocally appropriate, the decision analysis approach estimates IG levels which approximate those in the US, Canada and Australia for these patients, but which exceed the total IG usage in many European countries (Figure 4)³⁹. Clearly, such analyses, performed on population-based estimates and using guideline-based dosages, have limitations in the current era of personalised treatment, which will be further discussed below.

Figure 4.

Probability distribution of LTD the commonest PIDDs when compared to the total observed IG usage for various countries (shown as dots).

The median is 64 g/10³ population. LTD: latent therapeutic demand; PIDDs: primary immune deficiency disorders.

In the interim, the demand for IG continues to grow, and may be expected to trend towards the 250–300 g/10³ population predicted by modelling. In order to meet this demand, increasing amounts of IG products have to be manufactured and, through reimbursement mechanisms, supplied to patients. The volume of plasma available for fractionation globally grew annually at 8.3% over 2004–2014 (Figure 5)³⁰, while IG sales grew at 9.2% over the same period.

Figure 5.

Global plasma collection (millions of litres) over time.

Recovered and Source plasma.

Over this time, the industry’s IG yields also increased, for many manufacturers, contributing to maintaining a balance between supply and demand. The system has been finely balanced, and any perturbation in the supply-demand equation, such as manufacturing problems, new indications etc, will put pressure on supply and predicate to shortages. The industry needs to maintain a fine balance between increasing sales through increased volumes and increasing prices to enhance profit. Any oversupply will generate a glut which would put downward pressure on price, as happened in the early 2000s^40,41.

IG: the Italian dimension

IG in Italy is delivered through the National Health Service, which is devolved to the 20 Italian Regions^42,43. Two sources of supply are in play:

1. as a result of the Italian policy of national self-sufficiency in blood-derived therapeutics⁴⁴, plasma donated by Italian voluntary donors is suppled as a raw material for fractionation to commercial agencies, which manufacture it to the required products under contract to the Italian Regions. As of the implementation of the Ministerial Decree of 5 December 2014⁴⁵, these arrangements have allowed a number of companies to compete for the fractionation business of the 20 Regions, which are organised into four consortia⁴⁶. Before the introduction of competitive tendering, the monopolistic contract with an Italian manufacturer was supplying 74% of a self-sufficiency level, defined as the “actual” rather than the “latent” clinical demand, of 61 g of IG per 10³ population⁴⁷. Recent estimates based on the performance of the new competitive system indicate that the self-sufficiency level is now at 77%, for a clinical demand which had risen to 76.2 g/10³ population.

2. The clinical demand residual to the supply of IG from the domestic blood supply is provided through purchase of commercially available IG from suppliers whose products are approved by the Italian Pharmaceutical Authority (AIFA). Estimates based on volumes purchased and total reimbursements extracted from⁴⁷ indicates that the price of commercially purchased IG in 2014 was ca € 46 per g.

Estimates for demand vary, and the most widely utilised source for plasma product data, the Market Research Bureau (MRB), estimated that the demand for IG in Italy in 2017 was 90.7 g/10³ population. It is certain that IG demand, in common with other developed health care systems, is increasing. The MRB reports an increase of 52.5 to 90.7 g/10³ over the period 2008–2017⁴⁸. The Italian Organisation for patients with Immunodeficiencies (AIP | Associazione Immunodeficienze Primitive; Gressani A, personal communication 2019) report they are experiencing the same IG shortage which has been affecting the global market for over the past years⁴⁹, raising concerns in the patient community worldwide⁵⁰.

Why a shortage? Global and Italian perspectives

The essential raw material for IG manufacture is plasma collected for fractionation. For the past ca 25 years, the driver for collection has been the need for IG, meaning that IG is extracted from all the plasma collected. The MRB reports that 152 tonnes of IG was extracted from 45 million litres of plasma in 2014³⁰, reflecting an average of 3.4 IG/L of plasma at this time. The MRB estimates that a global requirement of 300 tonnes of IG by 2022 will require 75 million litres of plasma to be collected, assuming that current yields are higher, at an average of 4 g/L than in 2015, due to the modifications in Cohn fractionation noted above. On the face of it, if the industry maintains its capacity to collect plasma at the current Compound Annual Growth Rate (CAGR) of ca 8%, this volume is attainable. The issue of the IG shortage requires deeper reflection. Some factors contributing may include:

1. The transformation of latent to actual clinical demand. As outlined above, an IG usage of 250–300 g/10³ population is required to meet the LTD from the major immunological and neurological indications. This level of usage has already been reached in the USA, Canada and Australia, so it is unlikely that any shortages in these countries is ensuing from a release in pent-up demand. The effect of the underpinning assumptions on these estimates in increasing the demand in lower usage countries such as Italy will be discussed below. It is possible that supply pressures in such countries are ensuing from treatment progression along the conventional path assumed by this modelling.

2. The conversion of treatment plans from IVIG to SCIG. The adoption of SCIG as an alternative to IVIG, as discussed above, has resulted in the majority of patients with PID in the US converting to this modality²⁸. Because of the lower bioavailability of SCIG compared to an equivalent dose of IVIG, the US FDA requires manufacturers of approved SCIG products to estimate a dose-adjustment coefficient (DAC) between SC and IV preparations to result in equivalent systemic levels. Studies using a leading 20% SCIG indicate that the DAC to achieve this equivalence is ca 1.5^51,52. More recently, the FDA has approved an adjusted DAC of 1.37, on the basis of manufacturer data²⁶. Despite the minor status of PID in the IG market, the size of the US sector results in a disproportionate allocation of product due to the increasing conversion of PID patients to the SCIG route. This DAC is not required for the use of SCIG for CIDP, and comparison of the dosage regimens of SCIG vs IVIG for CIDP as specified in the relevant approved product information suggests that lower dosages are possible for the SCIG route. The SCIG route, while approved for CIDP for one product as of 2019, is considered by one manufacturer to be unattractive to CIDP patients because of the multiplicity of injection sites required⁵³.

3. The relative prices of IG in different markets. The price of IG products varies between different countries (Figure 6)⁵⁴. This is due to the different insurance and reimbursement mechanisms in play. It should be noted that manufacturers allocate their products to specific countries according to the price obtained in that market i.e. the product follows the price. This results in higher priced markets receiving preferential allocation. Companies seek the highly priced US market and any products approved for this market will be drawn into it before any other markets are satisfied. In the current period when the US market is also experiencing shortage, which may be expected, if anything, to raise prices in this country, IG will be absorbed preferentially in the US, exacerbating shortages in lower priced markets, including Italy, where the official reimbursement price for commercially purchased IG is reported at ca € 40 per g⁵⁵.

4. Financial pressures in government reimbursement. In several countries supplying medicines via public outlays, payback or “clawback” schemes are implemented increasingly on sellers. In these schemes, an additional tax is effectively levied on manufacturers after sales of medicines are finalised, so that part of the profit from sales returns to the government. A “clawback” on medicines in Romania led to the withdrawal of all IG manufacturers from that country, resulting in severe consequences for patients⁵⁶. Such a scheme is increasingly implemented in Italy⁵⁷, where it might also influence IG availability.

Figure 6.

Global immunoglobulin prices per gram.

The Italian IG shortfall: suggested measures

The Italian policy of self-sufficiency in blood product therapies has included a steady and impressive increase in the volume of plasma collected for fractionation (Figure 7)⁴⁷. This volume represents 14 L/10³ population. This programme has resulted in a level of self-sufficiency in IG of 73%, relative to actual clinical usage, by 2017⁵⁸. Included in this plan is a target usage of IG of 110 g/10³ population, as part of a policy for the promotion of the appropriate use of plasma products “in the absence of documented epidemiological and clinical (evidence)”. In the context of the tensions underpinning the global IG supply, the Italian system is placed under similar pressures. While over the period 2008–2017 the collection of plasma for manufacture grew by 3.8% per annum, the consumption of IG grew by 8.9% per annum over the same period. These realities demand careful policy and clinical considerations, and we suggest including the following measures in order to position the Italian health service optimally in the face of this challenge:

Figure 7.

Collection of plasma for fractionation by the Italian Regions (projections to 2020).

1. the amount of IG is determined by the volume collected and, importantly, by the yield of IG over manufacture. The yield depends on the scale and method of manufacture. Large scale manufacture generally improves yields as inevitable losses of protein on equipment etc are proportionately higher in smaller batches, as is the amount of intermediate and product sacrificed for in-process and quality control. IG produced by the classic Cohn scheme is obtained at the relatively low yield of ca 3 g/L of plasma⁵⁹, as this scheme was designed and optimised for the manufacture of albumin not IG. Modifications of the basic scheme can increase this to ca 3.5 g/L and the current generation of IG products are obtained at yields of 3.5–5.4 g/L^59,60. A recent article⁴⁶ has reported on the IG yields from the four manufacturers now present in Italy, as a result of the opening of the Italian contract fractionation market. The yield required by the several Italian consortia in the relevant tenders is ca 4.0–4.5 g/L, which is the lower reasonable expectations of current modern manufacture. We note that the contract for manufacture in Australia includes IG yield as a Key Performance Indicator (KPI) with reported yields of ca 4.7 g/L of plasma⁶¹. It behoves the Italian regions to ensure that:

   • - the yield of IG is required by the contractor is reflective of industry best practice;

   • - independent expert advice is solicited regarding the different technology and records of the several tenderers;

   • - the IG yield is instituted as a KPI and production is monitored to ensure adherence.

2. The possible effect of the adoption of SCIG has been outlined above. The FDA’s requirement of the use of a DAC, currently set at 1.37, is not included in the European Medicine Agency’s (EMA) approval of these products⁶², which emphasises dosage based on trough IG levels and personal patient PK. The Italian prescribers of SCIG are therefore not compelled to follow the FDA’s DAC and may dose according to the EMA’s guidelines and their own clinical judgement. It would be appropriate for the relevant scientific societies and patient organisations in Italy to use their global networks to point out to the FDA that real world evidence demonstrates that the DAC may be safely lowered to 1.14 and less⁶³. This would spare the IG supply through SCIG.

3. Personalising treatment is crucial in optimising IG use and supply. It is possible that IG clinical demand will exceed the targeted 110 g/10³ population if LTD is the basis for supply planning. LTD is derived from epidemiological estimates and guideline-driven IG dosage. These approximations are based on the inherent assumption of uniformity in the clinical response to IG, on a population-based approach contrasting with the modern principles of personalised medicine. In addition, the crucial issue of dosage is still controversial⁶⁴, with assumptions of increasing benefit for PID outcomes with increasing dose only partially supported by real world data⁶⁵. The concept of a linear relationship between IG dose and clinical benefit, implying a continuous benefit as long as more IG is infused, may be viewed as conceiving as IG as fuel in the tank of a car, rather than a complex therapeutic for heterogenous patient populations. In the current era of personalised medicine, this is clearly an incomplete perspective, with which we disagree.

   Rather than the guideline-driven allocation of IG which forms the basis of LTD, personalised treatment drawing on the full spectrum of clinical and immunological individual patient features has been developed by a number of clinical investigators^42,66,67, drawing on the experience of extensively monitored groups of PID patients. The algorithms developed for initiating IG treatment have also been used to stratify patients according to their level of clinical risk, in order to modify treatment regimens which achieved outcomes without increasing total IG usage or cost⁶⁸.

   We would propose that the inclusion of Italy’s community of clinical treaters in planning IG self-sufficiency is essential for optimising outcomes. The substitution of formula-driven by personalised treatment will be this approach.

4. Continued improvement of the plasma supply is essential for self-sufficiency in IG. The Italian plasma supply has grown successively and, through generating 860 tonnes of plasma by 2020, is expected to contribute 64.5 g/10³ population for the Italian health system. This is clearly less than the targeted 110 g/10³, and hence an increased level of self-sufficiency is needed. The Italian achievement of 14 L/10³ population lags behind that of other social market plasma collectors⁵⁴ and hence further increases in collection are not impossible for Italy’s system of unpaid plasma collection.

   The principal feature of highly efficient plasma procurement is the collection of plasma by apheresis. The Australian blood service generates 26 L/10³ population, which has been possible, in an era of decreasing whole blood donation and red cell usage, by a conversion of recovered to pheresis plasma to a current rate of 74% of all collected plasma by pheresis. It is emphasised that this is achieved through a population of committed voluntary donors, as a component of a policy of self-sufficiency⁶⁹. Italy’s collection rate of 8 plasmapheresis donations/10³ population/year in 2009⁷⁰, which comprised all types of pheresis, including mono- and multicomponent, is targeted to increase to 24 donations by 2020⁵⁸. The importance of this programme success cannot be over-emphasised.

5. Given the fragility of the global IG supply and the possible vulnerability of the Italian health system to these pressures, it is important to keep under consideration the options available for treating patients using alternatives to IG. The key to this continues to be the personalisation of treatment. Prophylactic use of antibiotics for PID before and as an adjunct to IG is described in a proposed algorithm by Jolles⁶⁶ to ensure that treatment allocation is aligned to individual patient clinical features. Irrespective of the effect on IG supply, practicing individual treatment will improve clinical outcomes. In the area of IG use for CIDP, the evidence synthesised by the Cochrane Collaboration indicates that, overall, alternative treatments including steroids and plasma exchange are equally effective^71,72. The issue of which treatment is more cost-effective is uncertain, with analyses yielding opposing results^73,74.

   In addition, authorities should monitor continuously scientific and commercial developments in alternatives to IG, particularly in the autoimmune disorders. The main approaches have been reviewed^75,76 and there has been a surge in the research and development of novel molecules, as potential therapeutic alternatives to traditional treatments, such as intravenous immunoglobulins, including their current status, development and target indications⁷⁵. The major plasma fractionators have all engaged in these developments. It would be premature to predict which and when these technologies will enter the market. The example of haemophilia therapies, which have revolutionised treatment over the past five years, should be kept in mind.

6. The changes in the Italian framework which have resulted in comparative tendering for the contract fractionation of Italian plasma obviate the disadvantages of a single supplier⁷⁷, and have the potential to enhance significantly the supply of IG and the level of self-sufficiency⁴⁶. However, the need for the commercial acquisition of IG sourced from non-Italian plasma is expected to continue, and this procurement is delegated to smaller purchasers, including the individual Regione, than the four consortia engaged in domestic contract fractionation. The prices paid by these purchasers hover around € 40–45 per g of IG. We point out that the price of similarly externally sourced IG for the Australian health system is ca € 28 per g⁶¹, obtained through yearly competitive tendering for a population of 25 million. The decreased buying power from a process for smaller amounts limits the possibility of accessing better prices for Italy. If the procurement of commercial IG were to be delegated to the consortia, each of which represents ca 25% of the Italian population, better financial outcomes may be achieved. A nationwide tender process might be expected to further generate more traction for the Italian system.

Summary and conclusions

Italy’s commitment to national self-sufficiency in blood has historically been presented as a strategic objective of the System also based on ethical and moral obligations, both worthy goals. In this work, we have built on the concepts of Strengers and Klein⁷⁸, to propose that, in the current environment dominated by commercial interests, the need for self-sufficiency has morphed into an economic imperative linked strongly to the security of access to an essential medicine. We suggest that a national endeavour, bringing together all the public health authorities of Italy, is needed to counter the harm which will be experienced by patients if Italy is unable to access IG. The increasing globalisation of the commercial IG market, with the possibility of expansion into currently low usage countries such as China, sharpens the urgency of this issue. E, allora, avanti insieme.