Plasma-derived medicinal products: demand and clinical use

Plasma-derived medicinal products (PDMPs) are prepared industrially from human plasma by pharmaceutical companies¹ and include products such as albumin, coagulation factors and immunoglobulins, which are life-saving therapeutics for several chronic and acute life-threatening diseases^2–4. The relevance of some of these products is confirmed by their inclusion in the World Health Organisation Essential Medicines Lists^5,6.

Plasma collected by Italian Blood Establishments derives from voluntary non-remunerated blood donations⁷. The Italian Regions and Autonomous Provinces (RAPs), individually or in association, send plasma produced according to regional and national plans to Kedrion Biopharma (Kedrion SpA, Castelvecchio Pascoli, Lucca, Italy), which is currently the only manufacturer authorised to fractionate national plasma upon toll fractionation agreements⁸. Importantly, RAPs remain the owners of plasma sent for fractionation, as well as of manufactured PDMPs and of the residual raw material, including discards. According to current contracts, Kedrion Biopharma provides for the manufacturing of the following PDMPs: human albumin solution (albumin), polyvalent immunoglobulin for intravenous administration (IVIG), factor VIII concentrates (FVIII), factor IX concentrates (FIX), prothrombin complex concentrates (PCCs) and antithrombin (AT).

For the purpose of a systematic analysis of the Italian demand for PDMPs, the National Blood Centre (NBC) developed a collaboration with the Information Systems Office of the Ministry of Health (MoH) resulting in the production of a full report on the “Demand for the main plasma derived medicinal products in Italy, Years 2007–2011”⁹.

The NBC -designated as the Italian blood and blood product competent authority operating on behalf of the MoH- coordinates and supervises the 21 Regional Blood Centres, with the goal of guaranteeing blood and blood component self-sufficiency and a homogeneous and standardised application of national and European blood regulations throughout the blood supply and transfusion chain, particularly as concerns quality and safety^7,10–13. The achievement of self-sufficiency is recognised as “a national, supra-regional, supra-local indivisible interest of the National Health Service” to be pursued with the contribution of the regional health authorities⁷. Every year, the NBC must provide technical indications to the MoH for the definition of an Annual National Programme for Self-sufficiency^14–16. Moreover, it must provide technical indications for a programme on the development of plasma collection and the promotion of an appropriate and rational use of PDMPs¹⁷. To facilitate the latter objective, a complete assessment of population needs and an in-depth analysis of PDMP utilisation at regional and national level are required as preliminary steps.

The above mentioned report⁹, the first document ever produced in Italy utilising institutional data, analyses the regional and national demand for the main PDMPs from 2007 to 2011, including those obtained from the toll fractionation contracts currently in place. Hence, the report provides the information required to support planning and adoption of national PDMP self-sufficiency policies¹⁸, also considering that it will be systematically updated.

The eighteen articles published in this Special Issue of Blood Transfusion represent a commendable initiative so far lacking in the transfusion medicine scenario. In fact, this Issue deals not only with the demand, the challenges and perspectives of PDMP clinical use^{2–4,19–26} but also focuses on the evolution of the Italian regulatory framework for PDMPs²⁷ as well as the hot topics in the drive for blood product self-sufficiency^8,28. In addition, an estimate of public expenditure for PDMPs and inherent recombinant medicinal products is thoroughly addressed^29,30, and an article showing that a national programme for PDMP self-sufficiency developed and governed by the public blood system can be economically sustainable (provided standard costs of blood component production are appropriately pursued and maintained) concludes the series of contributions³¹.

In Italy, the demand for PDMPs is significantly, though partially, met by the products supplied by toll fractionation contracts⁸. National self-sufficiency in PDMPs depends heavily both on the appropriate clinical use of plasma³², which allows an adequate supply of raw material for industrial fractionation, and on the appropriate clinical use of the PDMPs themselves. Importantly, in Italy there exists a significant variability of the quantity and quality of plasma sent for fractionation by RAPs with a decreasing north-to-south gradient⁸. Therefore, the analysis of five-year national PDMP utilisation data stimulates considerations that also pave the way to tackle the appropriateness of their clinical use as well as their shortage or surplus management, when necessary.

The objective of self-sufficiency in albumin and IVIG has not yet been achieved although they are the driving products in the plans for PDMP national manufacturing⁷. Indeed, their demand is still only partially met by the toll fractionation supply.

The self-sufficiency level of albumin is very significantly influenced by the questionable level of appropriateness of the clinical use of albumin. The need for improving the appropriateness of clinical use of albumin mainly emerges from international benchmarking that ranks Italy at the very top of albumin consumers in the world with a huge average standardised demand of 601 grams per 1,000 population¹⁹. Furthermore, an enormous utilisation of albumin is recorded in some Italian Regions; in fact, in 2011, Sardinia, Apulia and Campania recorded the highest per 1,000 population standardised demand of 1,222, 920 and 742 grams, respectively, in comparison with 238, 148 and 82 grams per 1,000 population respectively reported in France, Germany and the United Kingdom³³. In addition, an important amount of albumin is distributed out of hospitals, in accredited pharmacies, making appropriate use evaluation very difficult. In addition, in the opinion of the authors, should human albumin no longer be sold in pharmacies open to the public, the patients would profit of safer and more appropriate treatments, as well as improved outcomes, which are the key objectives a national public health service should pursue to really act as a healthcare provider. Finally, evaluation of the appropriateness of albumin prescription is becoming even more critical given the risk of an increase of its inappropriate utilisation related to the recent ban on hydroxyethyl starch³⁴.

The increasing demand for polyvalent immunoglobulin is the real challenge for the future for all the stakeholders involved in plasma production and fractionation. In fact, over the last decade, scientific literature on this PDMP has been increasingly published bringing about new evidence and new therapeutic indications (e.g. chronic inflammatory demyelinating polyneuropathy), even though the levels of supportive evidence are sometimes controversial^3,20,21. Moreover, the increased use of polyvalent immunoglobulin for subcutaneous administration suggests including this preparation in the toll fractionation contracts²¹.

The extension of the toll fractionation market to other European fractionators beyond Kedrion Biopharma envisaged by recent national provisions is expected to provide Regions with a wider product portfolio. Concerning FVIII and FIX, this should allow this should allow an adequate management of the current FVIII surplus and a progressive normalisation of its production^8,22,27. In the meanwhile, regional and national policies suggest the highest possible use of toll fractionation FVIII in order to maximise the coverage of the national demand for these products. Importantly, given the considerable expenditure for recombinant clotting factors sustained by the NHS³⁰, revisions of the procurement policies currently adopted by RAPs and of the maximum reference sale prices established by the Italian Medicines Agency (AIFA)^23,30,35 are envisaged. Very recently, AIFA chose to initiate the procedure to tackle this issue. In this perspective, a newly organised network of accredited Haemophilia Centres should be implemented in order to maximise the appropriateness of clotting factor prescriptions and guarantee optimal patients’ outcomes^36–38.

International benchmarking of AT usage highlights that Italy is one of the first countries in the ranking (2 per capita I.U.), preceded only by Japan (3 per capita I.U.) and followed by Germany and France (1 and 0.3 per capita I.U., respectively)^24,33.

As far as PCCs are concerned, the uncertainty in the possible differences in efficacy and safety between three- and four-factor PCC, as well as the differences in recent international recommendations on their use for the urgent reversal of anticoagulation produced by vitamin K antagonists, could explain non-homogeneous therapeutic approaches in clinical practice and justify a variability of their utilisation^25,33.

This is the first report providing comprehensive information on the national demand for and usage of PDMPs in a five-year period (2007–2011). Reported evidence and comments on the level of appropriateness of PDMP clinical use and on the associated economic implications are fully coherent with the current historical timeframe. Indeed, at present, most high-income countries are united by the common need for sustainable healthcare and by strong efforts to cope with steadily growing healthcare costs. Therefore, we hope this Special Issue of Blood Transfusion will prove useful reading not only for clinicians and transfusion medicine specialists involved in the clinical governance of blood resources on a daily basis, but also for hospital managers, policy makers and all professionals contributing to an appropriate and equitable allocation of financial resources and to the pursuit of accountable and sustainable models of public healthcare.