Hôpital Cochin, Paris, France
Correspondence to Loïc Guillevin, Department of Internal Medicine, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, 27, rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France. E-mail: firstname.lastname@example.org
Immunoglobulins for therapeutic use are derived from human plasma. As such, their production is constrained by the limitations of blood donation, and is costly enough to impact on resources of health insurance. Immunoglobulins are indicated in a wide range of conditions. Worldwide, three quarters of the IVIg produced are used in North America and Europe . In 2008, the average immunoglobulin use in Europe was 36 g per 1000 inhabitants and published data indicate wide variations in immunoglobulin use from one European country to another, which is, in part, due to governmental health policies. An in-depth assessment of immunoglobulin use in Europe revealed that the countries in which immunoglobulins are used the most include Sweden, Belgium, and France, whereas immunoglobulin use in the UK and Germany is lower (by half). These countries all have comparable standards of living and social welfare systems, indicating that the major differences in immunoglobulin use per inhabitant more likely reflect different prescribing practices. The worldwide immunoglobulin market could further evolve with the development of new indications, which could potentially lead to difficulties if these new indications generate a demand for immunoglobulins that exceeds supply . The worldwide immunoglobulin market is driven by supply and demand. In 2011, available quantities exceeded demand by 10%, which is equivalent to an immunoglobulin excess of 9 tonnes (Marketing Research Bureau, Union de Banques Suisses estimates examining US and EU derived IVIg versus global demand for US and EU IVIg, including global demand – i.e. global tradable market). These factors together indicate that appropriate use and cost control of immunoglobulins are important.
From a French perspective, the immunoglobulin market has grown an average of 9% per year from 1997 to 2004, and a further 12% per year from 2004 to 2010. Over this period, IVIg unit costs have increased considerably. Even though plasma obtained from blood donation is free in France, the cost of collecting and preparing the immunoglobulin is elevated. The budgetary impact of immunoglobulin use is important, which is why Parisian health authorities and hospitals (AP-HP) have implemented a supervisory programme to study trends in immunoglobulin use. Created in 1991 by the Comité d’étude des Innovations technologiques (CEDIT) of the AP-HP, the immunoglobulin expert group set out to achieve a three-tiered objective to establish a list of indications and dosing schedules for immunoglobulin use, and to assess their use in Parisian hospitals; evaluate administration routes; and encourage research on therapeutic strategies . With time, the expert committee has become a reference in defining lists of indications, thus contributing to the establishment of temporary therapeutic protocols and prioritizing immunoglobulin prescription per treatment indication in the event of shortages.
The use of immunoglobulins in France and in Paris (AP-HP) has steadily increased in the last few years. The total use of polyvalent human immunoglobulins, as calculated from data collated in the AP-HP registry of Parisian hospitals, was 39.6 kg in 2007 and 45 kg in 2008. This sustained increase is the result of new indications that are often broadly interpreted and of the increase in cost per gram, as a consequence of technological advances in the purification, calibration, and safety of products. The price of all immunoglobulins is fixed by health authorities, but competition between producing and commercializing laboratories allows for hospitals to obtain immunoglobulin batches at reduced costs. In the long run, market regulation is not an optimal method of limiting immunoglobulin price because the production costs are elevated and the source materials are by definition limited. The gratuity of blood donation in France, which is supported by blood donor associations, limits international plasma supplies because even foreign laboratories supplying the French market must implement collection centres in which plasma is donated free, in accordance with French legislation.
Based on the recommendations of the French CEDIT expert committee, immunoglobulin indications were classified into four groups, supported by the French health authorities (AFSSAPS). These are described as (I) labelled (approved) indications, (II) temporary therapeutic protocols, (III) off-label indications, and (IV) indications for which immunoglobulin use is not recommended. In terms of quantity of immunoglobulins used, the majority fell into categories I and II: 78 and 16% in 2007, and 77 and 17% in 2008, respectively (Table 1). Although categories III and IV only represent a small proportion of total indications, use of immunoglobulins in these indications has nevertheless increased in recent years.
Replacement therapy with immunoglobulins is used to treat primary and secondary immunodeficiency disorders. In France, compared with 2009, the quantity of immunoglobulins used to treat primary immunodeficiencies decreased by 6% in 2010, whereas the quantity used for the treatment of secondary immunodeficiencies increased by 22.6% during the same period. Of note, guidelines for prescription of immunoglobulins in secondary immunodeficiencies state that patients must not only have decreased immunoglobulins, but recurring infections, severe infections, and progressive disease . This 22.6% increase may be indicative of uncontrolled/unwise broad use of immunoglobulins. Approved neurological indications for immunoglobulins include chronic inflammatory demyelinating polyradiculoneuritis (CIDPs) and multifocal motor neuropathies (MMNs). In 2010, quantities of immunoglobulin used to treat CIDP increased by 9.7%, whereas they decreased by 4.2% in the treatment of MMN, compared with 2009. Prospective analyses are planned to optimize immunoglobulin prescription, particularly in CIDP, in which immunoglobulin use has increased. Even though immunoglobulin use is justified in this indication, questions on the timing of treatment initiation and duration remain.
Immunoglobulins are also used in the context of renal transplantation, as both curative and prophylactic treatment for renal graft rejection, and also as part of desensitization ahead of transplantation. Compared with 2009, quantities of immunoglobulin used in 2010 to treat renal graft rejection in the curative and prophylactic settings increased by 8.1 and 12.2%, respectively. For desensitization, however, immunoglobulin use decreased by 8.1%. In the field of renal transplantation, several other treatment options to prevent graft rejection are available to patients in addition to immunoglobulins, including plasma exchange, and numerous drugs. A programme to monitor immunoglobulin use and efficacy in these indications is in progress. For instance, immunoglobulin supplementation is sometimes used at the end of plasma exchange, which may be a questionable approach in terms of efficacy because the immunoglobulins are washed out the following day. To date, there have been no clinical trials, but a registry has been implemented by the French health authorities, into which nephrologists are encouraged to register their patients.
Approved indications generating IVIg use that exceeds 10 kg/year include primary and secondary immunodeficiency disorders, CIDP, MMN, immune thrombocytopenic purpura, curative or prophylactic treatment for renal graft rejection, and Guillain–Barré syndrome. Temporary therapeutic protocols generating IVIg use superior to 10 kg/year include treatment of corticoresistant dermatomyositis and acute myasthenia. Off-label use of immunoglobulins in 2010 increased by 25.1% compared with 2009, in indications such as organ transplantation (heart, lung, liver, and small intestine), neurology (encephalitis, paraneoplastic syndromes, cerebellitis, narcolepsy, ataxias, opsomyoclonus syndrome, etc.), various alloimmunizations, autoimmune erythroblastopenia, autoimmune haemolytic anaemia, and capillary leak syndrome (which will likely become an indication for a temporary immunoglobulin treatment).
An attractive method of regulating immunoglobulin prescription and costs would be to monitor the indications for which immunoglobulins are used, along with their route of administration. A number of indications are widely accepted and have market approval. In addition to these indications, some diseases under study would also benefit from market approval. In the meantime, health authorities have allowed the use of immunoglobulins in these indications, as part of temporary treatment procedures. This temporary period of 3–4 years is intended to allow industry and prescribing clinicians to design studies to evaluate the therapeutic efficacy of immunoglobulins in these indications. Unfortunately, the approach is flawed, as the period afforded to temporary treatment procedures has not consistently been used to conduct the required studies. This has led to complicated situations in which the health authorities (AFSSAPS) have terminated temporary treatment protocols due to a perceived lack of clinical efficacy.
Limiting costs without withholding efficacious treatments from patients requires a rethink of immunoglobulin prescribing. Suggestions and future perspectives include the following:
- The strict application of approved labelling indications. The realization that immunoglobulins may not be used as a panacea in off-label indications would save a considerable amount of resources. The classification of indications by group proposed by the AH-HP immunoglobulin expert committee and implemented by the AFSSAPS highlights ‘atypical’ and contraindicated indication categories (III and IV) and the increased use of immunoglobulins in these indications (Table 1).
- The optimization of doses prescribed. In the treatment of immune deficiencies, immunoglobulin doses are well established. However, in the context of immunomodulation, required doses would benefit from additional study. These are usually 2 g/kg per treatment cycle, but could be lower: in cases of immune thrombopenia, an initial dose of 0.8 g/kg may be sufficient to normalize platelet counts. A double-blinded, randomized study found no significant superiority of 2 over 1 g/kg of IVIg in the treatment of myasthenia gravis exacerbation . Reduction of treatment doses should be studied in the majority of immunomodulatory indications.
- Treatment duration is also somewhat arbitrary, depending on the participant and the disease. There is no consensus on treatment duration/cessation. Prospective studies should be initiated to address this aspect of immunoglobulin treatment.
- Immunoglobulins are available as formulations for intravenous (IVIg) or subcutaneous (SCIg) administration. SCIgs are indicated for supplementation, and IVIgs for immunomodulation. A reduction of doses required to achieve immunomodulation may permit the use of SCIg in this indication. However, this route of administration requires careful consideration before generalization.
- Another approach for limiting immunoglobulin use is to prescribe alternative treatments when possible. Health authorities have drawn up lists of available alternative therapies to immunoglobulins. For instance, plasmapheresis may be used in Guillain–Barré syndrome and other autoimmune disorders. This list was established to address shortfalls in immunoglobulin supplies, and could also be integrated as part of a plan to improve management of immunoglobulin supplies.
In summary, the increasing use of immunoglobulins must be managed with both flexibility and rigour. The responsibility of maintaining adequate supplies of immunoglobulins must be shared by both the pharmaceutical industry and prescribing clinicians. The immunoglobulin market cannot be managed on a short-term basis by simply increasing production and mobilizing health insurance and industrial resources. The immunoglobulin market is global, and new users will come to the fore. Even if emerging economies also become producers, immunoglobulin shortages are still possible. Immunoglobulins are efficacious and essential therapeutic agents, when the indications are well defined. Their elevated rate of prescription and use in France, compared with other European countries should encourage reflexion on whether their use is valid in many indications and on the safeguarding of good prescribing practices. Emerging indications must be seriously evaluated and therapeutic trials should be carried out, in both a medical and pharmacoeconomic context. Temporary therapeutic protocols should not replace on-label prescribing, and follow-up of temporary treatments is required to validate the indication. The best way to address these issues is via the multiplication of scientific research to evaluate the rational use of immunoglobulins and to enable their use in novel indications. The clinical ‘leads’ are known and remain to be implemented.