The contested market of plasma.

Voluntary, anonymous free gift-giving has become the dominant norm for blood donation for transfusion purposes, in view of its established ability to satisfy the needs for labile blood products that meet satisfactory conditions of safety and cost. But the economy of blood products is also the place for one of the main exceptions to the principle of non-commercialization of body parts. I show that there exists a genuine international plasma market, which provides the raw materials to produce blood protein products by pharmaceutical industries. The recent years have seen a considerable strengthening of the massive and globalized features of this market. I briefly describe the issues that this evolution raises, and I sketch some directions for a partial resolution of these issues. I explain why the development of contract fractionation appears both possible and desirable from an economic perspective in the present context.

[Plasma protein derivatives].

Plasma protein derivatives produced from human plasma include albumin, blood coagulation factors, immuno globulins, haptoglobin, and c1-inactivator and have been widely used clinically. However, the HIV-tainted blood scandal in which HIV was transmitted to many Japanese patients through blood coagulation factors, must be remembered. The safety of blood products has increased since then in response to that event. Because blood products are provided by volunteer donors, there is a risk of contamination by unknown pathogens and they must be used appropriately. In addition, blood products including plasma derivatives are defined as "special biological products" and regulated by the new Medicine Act. All physicians who prescribe plasma derivatives should understand not only their clinical use but also social expectations and legal regulations.

Can the supply and demand for plasma-derived products ever be reconciled? Self-sufficiency from the viewpoint of a blood transfusion service.

Sufficiency is the balance between supply and demand. The problems of estimating future demands and of maintaining adequate supplies of blood for the preparation of blood products, will be discussed from the viewpoint of a well-established blood transfusion service.

Can the supply and demand for plasma-derived products ever be reconciled?

With regard to self-sufficiency, supply and demand for plasma-derived products can only be reconciled if there is a free exchange of source materials and products with European harmonization of products. It is essential that safety aspects are agreed upon internationally and free access is guaranteed.

Is self-sufficiency financially viable and ethically justifiable?--legal aspects.

There is no legislation specifically designed to compensate haemophilia patients who have been damaged by defective blood products. But there is a general regime, created as a result of the thalidomide tragedy, which deals with defective 'products'. It was introduced at the European level by the European Directive on Product Liability in 1985 and has been given effect in England by the Consumer Protection Act 1987. The rights of haemophilia patients who are injured by defective blood products depends on this Directive.

Is self-sufficiency financially viable and ethically justifiable?--a commercial viewpoint.

Manufacturers of blood products have to maintain the highest possible standards for plasma screening and good manufacturing practices to ensure maximum purity and viral safety. The private sector companies have much experience in implementing and complying with national and international regulations. These requirements involve considerable cost in the areas of (1) plasma collection facilities, (2) research and clinical research, (3) manufacture, and (4) quality control. Total self-sufficiency would mean the loss of many existing resources. An alternative would be a collaboration between the public and private sectors to meet the needs of all patients who require plasma derived products. The current definition of self-sufficiency suggests that it is not financially viable.

Is self-sufficiency financially viable and ethically justifiable?--the role of the National Blood Authority.

The National Blood Authority is committed to the principle of self-sufficiency but also supports the principle of clinical freedom and aims to improve patient care. Methods of increasing plasma yields are being investigated. On-going discussions are being held with the commercial sector concerning the range of products available and methods of improving manufacturing efficiency. It is believed that the NBA can become largely self-sufficient using blood given by the 2,000,000 voluntary donors.

Should clinical freedom be constrained in the name of self-sufficiency?

Clinical freedom should enable a physician to decide in a free and unbiased manner which is the most appropriate therapy to use for a particular patient. In order to implement the four aims of the German Haemophilia Society an average of 4-4.5 units of Factor VIII per capita of the general population per year is needed. At present European countries do not produce this amount, but to reduce the consumption of F VIII in therapy lowers treatment levels. Until plasma collection services in Europe can be expanded it is necessary that the additional, imported, sources of plasma are available, otherwise clinical freedom will be curtailed.

European regulatory issues.

Current EU regulations do not cover all aspects of the manufacture and control of blood products. Recent legislation coming into force on 1 January 1995 has established the European Medicines Evaluation Agency and introduced revised systems for approving pharmaceutical products, including blood products. There remains a need for comprehensive harmonized legislation covering plasma collection and screening, virus validation studies, and batch release.

Economic issues in European self-sufficiency.

Future clinical practice in haemophilia care must make optimum use of resources and provide the highest quality products and services in an efficient and effective manner. Studies show that prophylactic therapy, compared with on-demand therapy, results in less time off work--that is, a smaller loss in productivity. However, prophylactic therapy requires a three- to five-fold greater annual amount of factor VIII than does on-demand therapy. Further study is needed to determine the optimum therapeutic strategy that gives the best cost v. benefit situation.

Do safety issues of plasma products constrain self-sufficiency?

The ultimate responsibility for selecting and administering plasma products to patients rests with the prescribing physician, and it is for him/her to choose the safest product available. However, liability for a product with a full licence rests exclusively with the licence holder. After the problems of HIV and hepatitis C the safety of plasma-derived products has become of paramount importance. Particularly in the public sector, financial, strategic and political obstacles may adversely influence the quantity, quality and safety of plasma collection. The safety of blood products can be substantially enhanced by the harmonization of technical standards across both public and private sectors, thus supporting EC Directive 89/381. Additionally, the goal of European rather than national self-sufficiency should be encouraged.

[Recent circumstances in the supply and demand of various blood products in Japan, and appropriate use of blood components or plasma protein derivatives].

In Japan, as in the United States and several other advanced countries, the use of fresh frozen plasma (FFP) and albumin has increased dramatically over the past 10 years. Especially in Japan the increase has been at least tenfold, and half of this usage has been for surgery. Most reviews of albumin usage acknowledge that there is a high ratio of wastage, or use in clinical circumstances without a firm scientific basis. Recently Japan has imported an enormous volume of various plasma fraction products such as albumin, Factor VIII etc., or plasma as raw material from foreign countries, especially the United States. As a result, Japan has come to monopolized a quarter of the albumin manufactured in the world, and has therefore received much internal and external criticism from or ethical standpoint. As countermeasures against shortage of these blood products, it will be necessary for doctors to use these blood products more sparingly and to increase the yield of volunteer donor's blood, especially plasma. More red blood cell concentrate should be utilized for hemorrhage in routine surgical operations. Because whole blood transfusion is rarely used except in cases of massive bleeding that cannot be stopped immediately, exchange transfusion has been performed in the United States and European countries recently. Transfusion of FFP is appropriately used only for replacement of coagulation factor deficiencies, massive transfusion etc. in the United States. It should be particularly noted that these carry the risk of transmission of diseases such as hepatitis and possibly AIDS. Albumin is an effective oncotic agent in the treatment of acute shock and in the maintenance of intravascular volume and cardiac output. However, albumin and FFP have no demonstrable effect in the general supportive management of chronic hypoproteinemia and undernutrition.

Pharmaceutical protein production by yeast: towards production of human blood proteins by microbial fermentation.

Since the approval of recombinant insulin from Escherichia coli for its clinical use in the early 1980s, the amount of recombinant pharmaceutical proteins obtained by microbial fermentations has significantly increased. The recent advances in genomics together with high throughput analysis techniques (the so-called-omics approaches) and integrative approaches (systems biology) allow the development of novel microbial cell factories as valuable platforms for large scale production of therapeutic proteins. This review summarizes the main achievements and the current situation in the field of recombinant therapeutics using yeast Saccharomyces cerevisiae as a model platform, and discusses the future potential of this platform for production of blood proteins and substitutes.