Plasma-derived medicines: access and usage issues.

Abstract

Background to plasma-derived medicines Although the first plasma-derived medicines were anti-toxins, raised in horses against pathogens (diphtheria, tetanus)1, the inception of plasma protein therapy occurred when Edwin Cohn developed his fractional ethanol precipitation scheme to isolate a stable albumin solution for the treatment of battle fi eld injury and blood loss2. The Cohn scheme yielded albumin as a fi nal product while producing, among others, therapeutically useful fractions of fi brinogen and immunoglobulins which could not be employed widely because of safety issues. Following initial safety problems, albumin gained widespread medical acceptance because of its dramatic effectiveness reported in victims of shock3, and was the plasma industry's staple product until the 1970s. Its position as a safe and effective plasma expander went unchallenged up to the 1990s, when the introduction of cheaper synthetic colloids and a Cochrane metaanalysis4 threw doubts on its use, which were subsequently dispelled through clinical trials5. While studies showed that careful plasma processing of Cohn's Fraction I could yield a product which was therapeutically useful in haemophilia A6, it took Judith Pool's widespread adoption of cryoprecipitate from blood bank plasma7 to result in the next milestone in the history of plasma protein therapies. Pool's technique was rapidly adapted for large-scale fractionation without affecting the Cohn method8 and resulted in the fi rst industrial scale production of haemophilia therapy. The capacity to treat a previously life-limiting disease effectively made the manufacture of factor VIII (FVIII) concentrate the driver for the plasma industry in the 1970s, usurping albumin's historical position. The revolution this produced in the life of haemophiliacs cannot be underestimated, just as the effects, on patients and industry alike, of viral transmission by the products cannot be underappreciated, although in the heady days of the 1970s this risk of this transmission was under recognised. While industry hastened to introduce enhanced safety measures, particularly viral inactivation which by the mid 1980s had made haemophilia products safe, an effect of this tragedy was the rapid development of recombinant FVIII concentrates, once the F8 gene had been cloned in 19849. The results of clinical trials, published in 198910, rapidly led to widespread acceptance of this therapy to its current position as the dominant haemophilia treatment modality in many countries of the developed world, including the United States, the United Kingdom, Canada and Australia, and greatly increased the market and the availability of FVIII, allowing interventions such as prophylaxis and tolerisation. In some other, mostly European countries, plasma-derived FVIII has retained a strong presence, due, primarily, to the continuing debate regarding the different capacity of different FVIII products to result in inhibitors to FVIII11. This development would have had a profound effect on the economic, and indeed, the viability of the industry, but other developments in the fi eld of immunotherapy obviated it. Cohn's original method allowed the harvesting of immunoglobulin (Ig) fractions which could be concentrated into solutions and used to treat patients with Ig defi ciencies12. In addition, Ig solutions from the plasma of donors immunised to specifi c antigens could be used for the treatment or prophylaxis of various diseases; the use of the Rh Ig fraction is the most famous of these applications13. However, early clinical observations that intravenous administration of Ig solutions led to severe reactions meant that Ig administration was limited to the intramuscular route, limiting dosage and patients' comfort. Efforts to address this problem led to several imperfect intravenously administrable Ig products, in which measures, such as enzymatic digestion of the entities