key: cord-0684397-0zmz9wg9 authors: Hartmann, Jan; Klein, Harvey G. title: Supply and demand for plasma‐derived medicinal products – a critical re‐assessment amidst the COVID‐19 pandemic date: 2020-08-28 journal: Transfusion DOI: 10.1111/trf.16078 sha: e3f5abf082eb45b2b6474db457d82a9b40fdb601 doc_id: 684397 cord_uid: 0zmz9wg9 Plasma‐derived medicinal products (PDMP) play an integral role in medical treatment and prophylaxis. Most plasma used for manufacturing medicinal products is collected as source plasma by apheresis from donors in dedicated plasma collection centers. The United States is the largest contributor to the global source plasma supply; most other countries depend on the import of plasma or plasma‐derived medicinal products. Plasma supply and demand are held in a fine balance. The 2019 shortage of IVIG showed the fragility of the system. The COVID‐19 pandemic has introduced additional stress on the plasma supply. At the same time demand for plasma‐derived medicinal products has further increased as they are tested as a potential treatment for this new disease. Transfusions of convalescent plasma, hyperimmune globulins derived from convalescent plasma and immunoglobulins are under investigation, with promising early safety and efficacy signals. Supply will have to be protected and boosted and demand will have to be managed fairly and effectively. If this issue is unaddressed, shortages of plasma‐derived medicinal products, such as IVIG, have to be expected by the beginning of 2021. Plasma-derived medicinal products (PDMP) play an integral role in medical treatment and prophylaxis. Plasma products are critical for managing bleeding emergencies, autoimmune disorders, as well as a number of chronic conditions, such as hemophilia, congenital and acquired immunodeficiencies, and other inherited protein disorders. Driven by increased access to medical care, new products and applications, and diagnostic advances, the demand for plasma-derived medicinal products has been steadily growing. Plasma for fractionation, the raw material for PDMPs, is considered a strategic resource and plasma-derived medicinal products are listed by the World Health Organization (https://www.who.int/health-topics/essentialmedicines) as essential medicines. [1] 85-90% of plasma used for manufacturing medicinal products is collected as source plasma by apheresis from donors in dedicated plasma collection centers. A small fraction (~10-15%) is contributed by recovered plasma, unused plasma derived from whole blood donated for transfusion purposes. With the decline in red blood cell transfusions worldwide [2] , the amount of available recovered plasma appears to be stable to declining. Source plasma collections on the other hand have increased by a factor of 3. Plasma supply and demand are held in a fine balance. If demand outpaces supply, or in cases of disruptions to the supply chain, shortages of PDMP can occur. In the past, shortages of plasmaderived coagulation factors and albumin concentrates have altered medical practice. More recently, intravenous immunoglobulin (IVIG) has been in short supply. In 2019 a significant scarcity of IVIG resulted in local shortages and rationing. [3, 4] The COVID-19 pandemic has introduced additional stress on the plasma supply. At the same time, because of the absence of a vaccine or other specific drugs, plasma-derived medicinal products have been proposed for the treatment of this new disease. [5] Transfusions of convalescent plasma are under investigation, with promising early safety and efficacy signals. [6, 7] Likewise, hyperimmune globulins derived from convalescent plasma have been produced for Given the criticality of the plasma supply in general and the potential application for experimental treatments for COVID-19 specifically, plasma collections have been deemed an essential component of the critical infrastructure during this pandemic. Like whole blood donations, plasma collections were allowed to continue through all phases of the pandemic response by both the U.S. Department of Homeland Security (https://www.cisa.gov/sites/default/files/publications/CISA-Guidance-on-Essential-Critical-Infrastructure-Workers-1-20-508c.pdf ) and the European Commission (https://ec.europa.eu/health/sites/health/files/blood_tissues_organs/docs/2020_soho_crossb ordershipments_en.pdf). Fractionation of human plasma provides a range of more than two dozen therapeutic proteins used worldwide. [9, 10] For major bleeding, prothrombin complex (PCC) is used to treat patients anticoagulated with vitamin -K antagonists as well as factor Xa related inhibitors. While currently only approved for congenital hypofibrinogenemia in the U.S., fibrinogen has been proposed as an alternative to cryoprecipitate for severe acquired hypofibrinogenemia, e.g., in trauma, post-partum hemorrhage or cardiac surgery. The recent FIBRES trial in the cardiovascular treatment space may lead to a broadened regulatory approval in the U.S. [11] Many European countries have already allowed the use of fibrinogen in acquired hypofibrinogenemia and bleeding. Use of plasma-derived medicinal products in chronic conditions is extensive and growing. Specific plasma fractions are used to replace congenital protein deficiencies such as Accepted Article antithrombin deficiency, protein C deficiency, and C1-esterase deficiency. Even for the hemophilias, where recombinant factor concentrates and novel antibody-based medications have been developed, human factor concentrates remain important, e.g., plasma-derived factor VIII concentrate [12, 13] , particularly in developing countries and where cost is a deciding factor. The need for polyvalent IVIG is the most substantial driver of the plasma fractionation industry. IVIG and subcutaneous immunoglobulin (SCIG) are essential therapeutic products for chronic treatment of patients with primary and secondary immune deficiencies, such as those resulting from cancer chemotherapy and stem cell transplant. IVIG has numerous applications as an immunomodulatory therapy in such diverse disorders as idiopathic thrombocytopenic purpura (ITP), myasthenia gravis [9, 10] and chronic inflammatory demyelinating polyneuropathy (CIDP). In addition, there are a number of investigational uses under study including Alzheimer's Disease. [14] The COVID-19 pandemic has introduced an additional need for plasma that threatens an already strained system. Given the absence of proven and effective therapies for the syndromes caused by the SARS-CoV-2 virus and given the long lead time to develop effective vaccines or drug treatments, researchers have begun exploring the therapeutic use of convalescent plasma, a therapy first described during the Spanish Flu of 1918. Since then, convalescent plasma has been tried during various pandemics. [5, 15, 16] While it has been difficult to confirm effectiveness in some diseases such as Ebola [17] , some patients treated during influenza and particularly other coronavirus related pandemics seemed to improve. A Accepted Article systematic review and exploratory meta-analysis of the use of convalescent plasma and hyperimmune globulins suggested some efficacy and an acceptable safety profile. [18] Early reports specifically on COVID-19 patients from China were likewise encouraging [19, 20] and led to intense research efforts in the U.S. and Europe. First results are now emerging from trials in the U.S. and seem to indicate an acceptable safety profile and encouraging efficacy data [6, 7, 21] . A first randomized controlled trial from China [22] showed no significant improvement with convalescent plasma therapy. However, this study was terminated prematurely due to enrolment issues and was underpowered. The authors did report positive trends particularly for severe cases. In addition to the transfusion-based use of convalescent plasma there are also studies on-going to understand the therapeutic potential of hyperimmune globulins for COVID-19 patients. Lastly, regular healthy donor derived IVIG has been proposed as a potential therapeutic option in COVID-19 patients as well. [23, 24] All these treatments acutely raise the demand for (convalescent) plasma. Unlike for small molecule pharmaceuticals, the most challenging aspect of manufacturing plasma-derived medicinal products is provision of the raw material, plasma. Most plasma for medicinal products is derived from source plasma collection. Recovered plasma adds to the supply, but its collection volume has at best been stable and is declining in several countries as whole blood collections decline. Source plasma collection is the only practical way to meet increasing demand. This article is protected by copyright. All rights reserved. The United States is the major global supplier of (source) plasma, in part due to local regulations that allow for source plasma donations to be compensated. Only four European countries (Germany, Austria, Czech Republic and Hungary) accept remuneration for plasma donors. Likewise, China allows for donor compensation and collects a significant portion of the global plasma supply, although retained within China. Other countries are dependent on the import of plasma, or the derived products to meet their demand, while self-sufficiency remains a declared goal of many countries, particularly in Europe. That nomogram was instituted to simplify the multitude of available nomograms at different centers and for different devices from different manufacturers, and to thereby reduce the risk of human error. Over time this nomogram has served donors well and has proved safe. While the simplicity reduced the risk of human errors, it came with the limitation of focusing only on weight, ignoring other important factors, such as hematocrit, weight, height or body mass index (BMI) that are known to influence the total plasma volume of a donor. [26] Moreover it created a paradoxical situation where low weight donors with the lowest total plasma volume are allowed to donate up to twice the percentage of their total plasma volume compared to heavier donors at the other end of the spectrum. [27] Given that collection technology has advanced and current apheresis devices allow automated entry of such data as physical measurements, laboratory information, and target collection setting , it seems appropriate to rethink the current approach, and to potentially introduce a more personalized method focused on the individual donor's total plasma volume (TPV). Such Accepted Article strategy could potentially reduce the volume challenge for some donors while allowing others to safely donate larger volumes of plasma. Clinical trials will be needed to test this hypothesis. From time to time clinical demand has outgrown the available supply. Shortages can also occur in the event of a supply disruption, e.g., a natural disaster at a key production site. [4] Last year, a significant shortage developed in the United States that led to rationing of IVIG products and necessary triaging and prioritization of patients' demands. Under these circumstances many investigational uses were limited, but also in approved key indications like primary immunodeficiency (PI) painful restrictions and modification of approved therapy had to be implemented. [3] With the COVID-19 pandemic the global plasma supply has come under additional pressure. Collection centers put a strong emphasis on safety and have rapidly adopted social distancing and other safety measures (e.g., use of face masks, enhanced cleaning standards) as the crisis unfolded. As a result, collection capacity at the center level is reduced. Convalescent plasma for transfusion is currently almost exclusively collected in blood centers and hospital-based transfusion medicine departments, using multi-component collection devices for plasmapheresis. In contrast, the production of hyperimmune globulins based on Accepted Article convalescent plasma is mostly driven by a consortium of commercial plasma collectors who use specialized plasma collection systems that were designed for efficient plasmapheresis. Independent of the setting, the frequency and number of donations are closely regulated by the same FDA guidance mentioned above. The current nomogram allows to collect up to 800ml of plasma. [27] That way, a donation from a single convalescent donor can yield up to three units of convalescent plasma product (~200-250ml). Driven by constantly increasing organic demand in core indications as well as growing investigational uses, the system for plasma-derived therapeutics has been under pressure for a while. Last year's IVIG shortage painfully demonstrated the fragility of this system. [3] With the onset of the COVID-19 pandemic, further stress has been applied to the system by both increasing demand for investigational therapies for COVID-19, and by disrupting supply. If unaddressed, this will soon lead to shortages. The plasma fractionation process takes months, and supply disruptions are expected to become apparent by early 2021. The time to act is now. Action should be focused on boosting plasma supply and on planning for potential shortages. On-going efforts of donor recruitment and retention need to be intensified. Countries that currently do not allow the remuneration of plasma donors should critically rethink that approach (at least temporarily) to add to the global supply. Protocols to assure donors of the safety of collection facilities and of the collection process in the midst of the pandemic are essential. Donor satisfaction should be improved to increase donation frequencies and duration Accepted Article of active donor status. Lastly, it will be key to optimize the collection from each individual donor. Some solutions are already in place, e.g., technology to safely collect the maximum allowable collection volume (without anticoagulant) and technology to reduce the wastage in the collection disposable sets. Also, clinical studies with intensified donations schemes demonstrated the potential to safely collect more plasma in individual donors. [28] Findings from a real-world data analysis of plasma donations demonstrated that the percentage of donated plasma can differ by more than factor two, and that donors with low total plasma volume (TPV) give on average higher percentages, while donors with high TPV only give a low percentage and may be able to donate more. [27] Clinical trials should be conducted to test the safety and effectiveness of more personalized approaches to determine the individual target collection volume. While maximizing the plasma supply, every effort should be made to anticipate and identify potential shortages early and to put mitigation plans in place. This could include clear guidance for triaging and prioritizing of available immunoglobulin by indication and severity of disease, which should be driven by clinical, health-economic and ethical considerations. Expert representatives from all these groups should be involved. This article is protected by copyright. All rights reserved. Plasma is a strategic resource Slowing decline in blood collection and transfusion in the United States -2017 Google Trends as an early indicator for shortages of intravenous immunoglobulin (IVIG). Transfusion Shortage of human intravenous immunoglobulin--reasons and possible solutions Deployment of convalescent plasma for the prevention and treatment of COVID-19 Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients. medRxiv Treatment of COVID-19 Patients with Convalescent Plasma in SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children An overview of plasma fractionation Evidence-based clinical indications of plasma products and future prospects Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A Clinical trials update: Innovations in hemophilia therapy Plasma exchange for Alzheimer's disease Management by Albumin Replacement (AMBAR) trial: Study design and progress The convalescent sera option for containing COVID-19 Convalescent plasma as a potential therapy for COVID-19 Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis Effectiveness of convalescent plasma therapy in severe COVID-19 patients Convalescent plasma for patients with COVID-19 Convalescent plasma treatment of severe COVID-19: A matched control study. medRxiv Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19 Abstract Presentations from the AABB Annual Meeting San Diego, CA ctober 7-10 Plasma volume nomograms for use in therapeutic plasma exchange Source plasma collection in the United States: Toward a more personalized approach A prospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA). Vox Sang This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.