In the UK, Health Minister Edwina Hart ruled that the Welsh Blood Service and NHS Blood and Transplant (which collects blood for North Wales and England) can sell discarded plasma for non-clinical use, with safeguards in place to ensure that products can be used only for ethical purposes and a policy is under development about the sale of plasma.
In August 2010, Octapharma announced successful completion of clinical development of Uniplas, a blood group independent, universally applicable, prion depleted, solvent/detergent treated, human pooled plasma for infusion. OctaplasLG is the only commercially available prion-reduced plasma for transfusion, manufactured by Octapharma and relying on PRDT’s prion capture technology used at industrial scale. This industrial application of the prion capture technology is also being expanded for use in Uniplas.
Strong activity and global interest in these important products continued throughout the year.
The FDA announced in August 2010 that Octapharma was voluntarily recalling selected batches of Octagam because of increased rates of thromboembolic events. Thirty-one batches were recalled. By 8 September the recall had been extended to a further five batches in France, two batches in Mexico and one batch in Germany. This was subsequently expanded to further EU nations.
By 22 September 2010, Sweden and France had quarantined or withdrawn the product and Germany had withdrawn its licence. The Octapharma IVIg product represented ~8 per cent of the USA market and ~13% of the global market. CSL and Baxter share prices rose on the assumption that their respective market shares would increase.
By late September 2010, Octapharma had withdrawn all its 5 per cent liquid preparation from the USA market at the request of the FDA, until a root cause of the previously reported thromboembolic events can be determined.
The EMA recommended suspending the marketing authorisation for Octagam 5 and 10 per cent throughout the EU and initiating a recall of all Octagam 5 and 10 per cent batches from the EU market. The suspension was to remain in place until the problem had been rectified.
Octapharma believed that an unexpected increase in Factor XIa in the final products played a role in the increase of the rate of thromboembolic events; and that, having identified the cause of the increased incidence, it could take prompt corrective action. The company said it assumed the issue could be resolved by the end of 2010.
On 31 May 2011, Octapharma announced that the European Commission had lifted the EU-wide suspension of the marketing authorisations of both Octagam 5 and 10 per cent subject to certain conditions including that each batch released would have a thrombin generation assay carried out and that post-marketing studies would be implemented in order to confirm the safety of the product.
There was a minor impact in Australia at that time (see page 49 & 59) or Australia’s response.
The USA FDA received post-marketing reports of serious thrombotic adverse events associated with use of Vivaglobin manufactured by CSL Behring. Vivaglobin was indicated for treatment of Primary Humoral Immunodeficiency and was administered subcutaneously. It was not approved for intravenous use and inadvertent intravenous use of Vivaglobin may carry a higher risk. CSL Behring informed the FDA that in-house research testing revealed procoagulant activity in Vivaglobin.
Risk factors identified in post-marketing thrombotic event reports for Vivaglobin included pre-existing cardiovascular disorders, prior thrombotic event, obesity, oral estrogen use, hyperlipoproteinemia, in-dwelling catheter and immobility.
Hyperviscosity, hypercoagulable disorders, and multiple cardiac risk factors may also confer thrombosis risk in the setting of immune globulin product administration. Marketing of the product in the USA was discontinued from 4 April 2011.
Activities in market coverage of leading immunoglobulin products included:
According to data presented at the XIVth Meeting of the European Society for Immunodeficiencies, CSL’s Privigen 10 per cent liquid intravenous immunoglobulin therapy stabilized with proline is effective and well tolerated in patients with several primary and secondary immunodeficiencies and offers significant protection against infection. Privigen is approved in the EU, Switzerland, Canada and the USA for treating patients diagnosed with PID and ITP. In Europe, Privigen is also approved for treating Guillain-Barre Syndrome and Kawasaki-Syndrome.
At the same meeting, Baxter presented interim data from a Phase III clinical trial of HyQ. HyQ is an immunoglobulin therapy facilitated subcutaneously by recombinant human hyaluronidase, a dispersion and permeation enhancer. Interim analyses showed that 28 out of 29 HyQ-treated study participants with PID were able to infuse immunoglobulin under the skin, using a single injection site, at infusion volumes, intervals and rates equivalent to their previous intravenous administration of immunoglobulin.
In June 2011, Baxter announced that the Committee for Medicinal Products for Human Use of the EMA had issued a positive opinion for extension of the therapeutic indications of KIOVIG33 to include a new indication for multifocal motor neuropathy (MMN), a severe, debilitating disorder requiring lifelong treatment. Baxter has been granted Orphan Drug Designation for this indication in the USA.
Immunoglobulin is used to treat a range of conditions. The NBA follows with interest any alternative treatments that are developed as they may reduce pressure on supply and price. This year we have specifically focused on developments for the treatment of chronic immune thrombocytopaenia.
During 2010–11 a number of studies were released:
NICE did however agree that Nplate could be used on the NHS in England and Scotland to treat adults: with chronic forms of the condition when they are unresponsive to standard active treatments and rescue therapies; in patients who have severe disease; or those at high risk of bleeding requiring frequent courses of rescue therapies. The product had already been approved in the USA Europe and Japan.
However, GSK and the FDA notified a new safety finding in patients with chronic liver disease whose thrombocytopenia was treated with eltrombopag. The ELEVATE study was terminated following the identification of an imbalance of thrombosis of the portal venous system in the patients treated with eltrombopag versus matching placebo. Healthcare professionals were reminded that Promacta was not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.
In June 2011, Shire announced that the Pulmonary-Allergy Drugs Advisory Committee of the FDA recommended, that the efficacy and safety data provides substantial evidence to support approval of Firazyr (icatibant) for the treatment of acute attacks of hereditary angioedema in patients 18 years and older. The Committee also recommended self-administration of the drug by patients.
The interest in proving efficacy of immunoglobulin for AD continued. Baxter released positive results from a Phase II clinical study of Gammagard in patients with mild-to-moderate AD, and its Phase III clinical trial will run into 2012. Grifols is trialling therapeutic plasmapheresis and the administration of human albumin and IVIg at different doses and frequencies. The preliminary results suggested a trend toward disease stability in the treatment group.
A positive result from either or both of these studies could have a major impact on global demand for immunoglobulin, with consequent supply shortages and price rises. However it is interesting to note that USA companies alone currently have around 100 drugs, not just immunoglobulins, for use in the treatment of AD either in clinical trials or awaiting regulatory review. The NBA is following all of the activities around alternative therapies for AD because of their potential effect on the market.
Scientists developing treatments for Creutzfeldt-Jakob Disease (CJD) have unexpectedly blocked the onset of AD. Two antibodies studied in relation to CJD may also have an effect on AD35, by blocking the damaging effects of the toxic protein ‘amyloid beta’, which accumulates and becomes attached to the nerve cells in the brain.
GBI Research recently estimated that by 2016 the world coagulation disorders market will reach $US 7.7 billion, demonstrating a cumulative annual growth rate of 5 per cent between 2009–16.
The same report notes that Baxter and Bayer control 56 per cent of the market. Novo Nordisk has third position with Pfizer and CSL Behring controlling 15 per cent and 8 per cent respectively. On future developments, GBI reports that the current coagulation disorders pipeline contains 90 projects across five major indications. Haemophilia A and haemophilia B, currently accounting for more than two-thirds of the total coagulation disorders market, are the key therapy areas of focus in the current pipeline, with approximately 64% of the current coagulation disorders pipeline concentrating on these two indications. About 20 molecules, representing 22% of the current coagulation disorders pipeline, are in early stages of development for haemophilia.
In July 2010, the World Federation of Haemophilia Congress was held in Buenos Aires. Suppliers used the occasion to describe their projects.
Biogen Idec and Swedish Orphan Biovitrum AB announced results from a Phase I/IIa study of their long-lasting, fully-recombinant FIX Fc fusion protein (rFIXFc) in haemophilia B patients. The product demonstrated a threefold increase in half-life compared with historical data for BeneFIX. The product is now in Phase III development, along with a FVIII product. This long-lasting, fully-recombinant Factor VIII Fc fusion protein (rFVIIIFc) has been granted orphan drug designation by the European Commission.
Pfizer presented the results of a pre-clinical study in mice indicating that recombinant FXa therapy may provide a unique way to bypass deficiencies in the intrinsic pathway. Other results suggest that a recombinant FVIIa molecule with increased activity and duration may improve inhibitor outcomes. Other haemophilia research outlined by Pfizer included:
Bayer HealthCare presented data from a Phase I study of its rFVIIa variant (BAY 86-6150) in haemophilia A or B, with or without inhibitors. Novo Nordisk researchers advised that N7-GP, now in Phase II clinical trials, may offer a less frequent dosing schedule for prophylaxis in haemophilia patients with inhibitors.
According to pooled results from four studies, an ultrapure form of plasma-derived FIX concentrate (Nonafact) appears to stop bleeding in haemophilia patients, whether bleeding occurs spontaneously or due to surgery.
In other developments:
At the annual meeting of the American Society of Hematology researchers reported that about two-thirds of patients with acquired haemophilia appear to find the disorder resolves itself38.
Results from the European Acquired Hemophilia Registry indicate that more than 70 per cent of patients diagnosed with acquired haemophilia who successfully eradicate FVIII inhibitors survive for at least five years39.
A survey of haemophilia treatment centres suggested that only half were treating children according to guidelines, with prophylaxis three times a week40.
Novo Nordisk reported rFVIII shows the potential to become a safe and effective treatment. The company submitted a Biologic License Application to the FDA seeking approval of its rFXIII compound for congenital factor XIII deficiency.
Baxter reported that recombinant von Willebrand factor or rVWF may be safe and well tolerated in patients with type 3 and severe type 1 von Willebrand disease, the most common inherited bleeding disorder worldwide.
In Israel, Prolor’s Factor IX-CTP demonstrated a significantly longer duration of clotting activity in the haemophilic mice model compared with commercially available Factor IX.
The USA FDA recently approved revised labelling for Grifol’s Alphanate blood-clotting agent to show steps taken to prevent the compound leading to infections of vCJD.
According to Jerzy Windyga of the Institute of Hematology and Transfusion Medicine in Warsaw41, the improved rFVIII Xyntha is safe and effective for surgical haemostasis in patients with haemophilia A undergoing major orthopaedic surgery.
A European registry that enrolled patients with haemophilia B being treated with rFIX (Benefix) found that the reformulated version of the product was associated with fewer adverse events compared with the original formulation42.
Pfizer received approval from the FDA for the use of a prefilled dual-chamber syringe for administration of XYNTHA Antihemophilic Factor (Recombinant) Plasma/Albumin-Free for haemophilia A.
Novo Nordisk announced that the FDA had approved NovoSeven RT rfVIIa (room temperature stable) in an 8 mg vial size. The FDA extended the shelf life for all vial sizes from 24 to 36 months at room temperature (at/below 77 degrees Fahrenheit).
Significant changes in market access included:
A Danish study claimed that expensive treatments for AAT deficiency should be withdrawn because the drugs have no benefit. The study reviewed data from two trials on 140 patients. It considered treatments developed by Kamada, Talecris, CSL, and Baxter. The report called recommendations by the American Thoracic Society and European Respiratory Society ‘misguided’, however, Talecris funded a study43 which it says demonstrates that augmentation therapy with Alpha(1)-Proteinase Inhibitor (Human) (A1PI) significantly reduces lung tissue loss in patients with emphysema related to AAT deficiency.
The FDA approved Octapharma USA’s Investigational New Drug Application for Octaplex (human prothrombin complex, freeze dried) as a fast track product for ‘reversal of anticoagulation therapy in patients under vitamin K antagonist therapy with the need for urgent surgery or invasive procedures’. The FDA had previously granted orphan drug exclusivity for Octaplex in this indication. Octaplex is a double virus-inactivated concentrate with a balanced level of Vitamin K-dependent coagulation factors and protein C and S.
A blood clot treatment being developed by Talecris Biotherapeutics received an Orphan Drug Designation from European regulators. Talecris is studying Plasmin in Phase II clinical trials to assess its ability to treat acute peripheral arterial occlusion. The condition occurs when blood flow to the extremities, usually the legs, is blocked by a blood clot. It is most common in people with underlying peripheral artery disease.
ProFibrix, of the Netherlands, contracted with CSL Behring for clinical and commercial supply of plasma-based fibrinogen and thrombin. Its product Fibrocaps is currently being studied for treatment of bleeding during surgery and after trauma. A dry powder based on a mixture of fibrinogen and thrombin, Fibrocaps is a ready-to-use preparation designed to be stable at room temperature and applied in different formats, including sprays and bandages. A large Phase II trial is currently underway with final results expected in 2011.
Platelet-rich plasma (PRP) is a promising biologic treatment for myocardial infarction according to researchers at the Stanford University School of Medicine. PRP has already been identified as a novel biologic treatment for wound healing and sports-related injuries but it was only recently that scientists began studying PRP’s potential in repairing damaged cardiovascular tissue. Studies indicate PRP stimulates cell repair via growth factor release and by attracting reparative cells44.
The NBA undertakes the procurement of imported IVIg and other plasma and recombinant products within a global market of multinational suppliers. The industry remains active and expanding, in both production capacity and new product development, and is generally seen as a strong sector for investment.
In June 2010, Grifols, Europe’s largest maker of plasma products, agreed to buy Talecris Biotherapeutics for over $US3 billion to expand its share of the $US7 billion market to almost a third, the same as Baxter’s and more than CSL’s 29 per cent share45. However, the agreement was subject to approval by Spanish and USA regulatory authorities, as well as shareholders and the USA Federal Trade Commission (FTC). The approval took a year and was subject to a consent agreement regarding disposal of assets. The FTC was said to fear the merger would reduce supplies and raise prices. The three products for which the FTC had concern were immunoglobulin, albumin and plasma-derived factor VIII (pdFVIII)46.
The FTC conditions for approval introduced Italian company Kedrion to increased competition in the USA market. Grifols will sell both the Talecris fractionation facility in Melville, New York, and Grifols’ plasma collection centres in Mobile, Alabama, and Winston-Salem, North Carolina, to Italian company Kedrion. Grifols is required to sell Talecris’ Koate pdFVIII business, including the Koate brand name in the USA, to Kedrion, and to manufacture private-label immunoglobulin, private-label albumin and Koate for seven years for Kedrion to sell in the USA.
Grifols is starting construction of a new plant in Barcelona with the capacity to fractionate one million litres of plasma a year (with potential to expand to two million) allowing the group to double its existing fractionation capacity in Spain. The construction work is scheduled to take 18 months after which the process of obtaining licenses from the FDA and EMA will begin. The Grifols plant in Los Angeles currently has a capacity of 2.2 million litres, giving group total capacity of 6.3 million litres in 2014. The combined company’s USA and Spanish fractionation plants will receive plasma from about 150 plasma collection centres.
CSL is spending $A235 million over five years on a large scale biotechnology facility at its Victorian Broadmeadows site, focussed on the late-stage development of new therapies for cancer, bleeding disorders, inflammation and infection.
In mid-February 2011, CSL reported a 19 per cent drop in first half net profit from a year earlier because of the much stronger Australia dollar47. The CEO, Brian McNamee, said the company’s underlying business had continued to grow, including licensing into new geographic and patient markets. In the CSL Behring business, sales grew 8 per cent from a year ago on a constant-currency basis to $US1.6 billion.
Analysts said Baxter had benefited from the temporary absence of Octagam from the market and its return could mean Baxter could not maintain its growth.
Baxter acquired the haemophilia-related assets of Archemix. The lead product is ARC19499, a synthetic, subcutaneously-administered haemophilia therapy whose Phase I clinical trial was conducted in the UK.
Novo Nordisk plans to invest in a new biologics manufacturing facility at its Kalundborg site, the largest in the group’s production network. The new capacity will be used to manufacture biopharmaceuticals such as FVIIa and will be available for manufacturing haemophilia drugs in the pipeline.
Nearest to the market is Novo’s recombinant factor XIII drug NN1841, designed to treat a rare bleeding disorder that affects about 600–1,000 patients worldwide. The drug was filed for approval in the USA in February. An improved FVIII called N8 is in Phase III trials for haemophilia A, as is a long-acting formulation of FIX for haemophilia B.
Terumo Corporation of Tokyo announced its acquisition of CaridianBCT. Terumo entered the blood transfusion market in the 1960s and has grown into the number five blood transfusion player globally. The rising global demand for blood transfusion products is in part due to the ageing of the population in developed nations and, in emerging economies, the rapid development of healthcare infrastructure. The transaction will allow Terumo to offer a wider range of blood processing technologies and greatly expand Terumo’s geographic presence, particularly in North America.
Bayer Schering Pharma aims to deliver a successor to its Factor VIII product and to create drugs to treat bleeding and optimise bypass therapy. The rFVIIa compound BAY 86-6150 shows promise in this respect with a pivotal Phase II/III study of the drug.
Cangene has merged and rebranded its USA subsidiaries as Cangene Plasma Resources. The company owns and operates three FDA licensed plasma-collection facilities and Cangene Plasma Resources Winnipeg. Cangene recently announced that the Biomedical Advanced Research and Development Authority (BARDA), the agency within the HHS that administers its bio-defence stockpiling contracts, will exercise options under a botulism antitoxin supply contract. This should generate $US61million in additional revenue for Cangene over three to four years.
Germany’s Biotest AG acquired Brazil’s Marcos Pedrilson Produtos Hospitalares Ltda. The Brazilian company, located in Rio de Janeiro, was Biotest’s distributor and holds all plasma protein registrations of Biotest for the Brazilian market. Biotest contracted to sell its global Microbiological Monitoring business to Merck, so it can focus on its plasma proteins business.
GTC Biotherapeutics, developer of ATryn, the first product developed, approved and manufactured in the USA and EU using GTC’s transgenic technology, is now a subsidiary of LFB Biotechnologies. Interest continues in the FVIIa development.
Bio Products Laboratory in the UK changed ownership status following the completion of its transfer to a limited company. This follows a transfer of the business away from NHS Blood and Transplant into Plasma Resources UK, a Department of Health-owned entity. The Bio Products Laboratory is now run by the same holding company and operational board as its plasma supplier DCI.
ProMetic, via its new subsidiary, NewCo, entered into a long-term lease with Quebec’s Institut National de la Recherche Scientifique for an existing state-of-the-art facility. NewCo will undertake the development and manufacturing of high-value plasma-derived therapeutic biosimilars for ProMetic’s current and future clients. This facility will have a targeted processing capacity of 150,000 litres. The plant is expected to begin operations by the end of 2011 and reach full capacity by 2014.
1 Lambrechts L, Paaijmans KP, Fansiri T, Carrington LB, Kramer LD, Thomas MB, Scott TW 2011, ‘Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti’. Proc Natl Acad Sci U S A. May 3; vol. 108, no. 18 pages 7460–5, Epub 2011 Apr 18
2 Kumar NC, Nadimpalli M, Vardhan VR, Gopal SD, Jun 2010. ‘Association of ABO blood groups with Chikungunya virus’. Virol J. vol. 25, no. 7, page 140.
3 Warter L, Lee CY, Thiagarajan R, Grandadam M, Lebecque S, Lin RT, Bertin-Maghit S, Ng LF, Abastado JP, Desprès P, Wang CI, Nardin A, 1 Mar 2011 ‘Chikungunya virus envelope-specific human monoclonal antibodies with broad neutralization potency’. J Immunol., vol. 186, no. 5, pages 3258–64, Epub 2011 Jan 28.
4 Wu B, Wang C, Dong G, Guo Y, Nolte DL, Deliberto TJ, Xu J, Duan M, He H, 15 Aug 2010, ‘New evidence suggests Southern China as a common source of multiple clusters of highly pathogenic H5N1 avian influenza virus’. J Infect Dis., vol. 202, no. 3, pages 452–8.
5 Nidom CA, Takano R, Yamada S, Sakai-Tagawa Y, Daulay S, Aswadi, D, Suzuki T, Suzuki Y, Shinya K, Iwatsuki-Horimoto K, Muramoto Y, Kawaoka Y, Oct 2010, ‘Influenza A (H5N1) viruses from pigs, Indonesia’, Emerg Infect Dis. vol. 6 no. 10, pages 1515–23.
6 Derdowski A, Sindi SS, Klaips CL, DiSalvo S, Serio TR, 29 Oct 2010, ‘A size threshold limits prion transmission and establishes phenotypic diversity’, Science, vol. 330, no. 6004, pages 680–3.
7 Edgeworth JA, Farmer M, Sicilia A, Tavares P, Beck J, Campbell T, Lowe J, Mead S, Rudge P, Collinge J, Jackson GS, 5 Feb 2011, ‘Detection of prion infection in variant Creutzfeldt-Jakobdisease: a blood-based assay’ Lancet, vol. 377, no. 9764, pages 487–93; Gregori L, 5 Feb 2011, ‘A prototype assay to detect vCJD-infected blood’, Lancet, vol. 377, no. 9764, pages 444–6.
8 Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtaq S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM, Woodford N, Sep 2010, Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study, Lancet Infect Dis. vol. 10, no. 9, pages 597–602, Epub 2010 Aug 10 <http://www.thelancet.com/journals/laninf/article/PIIS1473–3099(10)70143-2/fulltext>; Pitout JD, Sept 2010, ‘The latest threat in the war on antimicrobial resistance’, Lancet Infect Dis. vol. 10, no. 9, page 578–9, Epub 2010 Aug 10.<http://www.thelancet.com/journals/laninf/article/PIIS1473–3099(10)70168–7/fulltext>
9 Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA, 23 Oct 2009, ‘Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome’, Science vol. 326, no. 5952, pages 585–9, Epub 2009 Oct 8.
10 Principles to apply to the collection and provision of blood components and plasma-derived medicinal products, March 2011.
11 Sampson J, de Korte D, Apr 2011, ‘DEHP-plasticised PVC: relevance to blood services’ Transfus Med. vol. 21, no. 2, pages 73–83, Epub 2010 Dec 8.
12 The summary of a comprehensive European risk assessment, involving nearly 15 years of extensive scientific evaluation by EU regulators, was published in the EU Official Journal on February 7 2008 (Commission Communication C/2008 34/1 and Commission Recommendation L 33/8).
13 Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR), Opinion on the Safety of Medical Devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk. Adopted after public consultation by the SCENIHR during the 22nd Plenary of 6 February 2008. http://www.dehp-facts.com/upload/documents/webpage/SCENIHR%20medical%20devices.pdf
14 “CE” stands for “Conformité Européenne» («European Conformity»).
15 Morris SR, Little SJ, Cunningham T, Garfein RS, Richman DD, Smith DM, Jun 2010, ‘Evaluation of an HIV nucleic acid testing program with automated Internet and voicemail systems to deliver results’, Ann Intern Med, vol. 152, no. 12, pages 778–85.
16 Eikelboom JW, Cook RJ, Liu Y, Heddle NM, May 2010, ‘Duration of red cell storage before transfusion and in-hospital mortality’, Am Heart J. vol. 159 no. 5, pages 737–743.e1.
17 Edgren G, Kamper-Jørgensen M, Eloranta S, Rostgaard K, Custer B, Ullum H, Murphy EL, Busch MP, Reilly M, Melbye M, Hjalgrim H, Nyrén O, Jun 2010, ‘Duration of red blood cell storage and survival of transfused patients (CME)’, Transfusion, vol. 50, no. 6, pages 1185–95. Epub 2010 Feb 12.
18 Recent clinical studies have raised concerns that transfusions using blood stored longer than 14 days may increase the risk for cardiovascular events and organ failure, particularly in certain patients who receive multiple units of aged blood, such as those who have had coronary artery bypass or heart-valve surgery. Scientists call the blood-degradation problem the “storage lesion.” Currently, FDA regulations allow facilities to store red blood cells for up to 42 days before being transfused. The average age of transfused red blood cells in the United States is estimated to be a little more than 16 days, according to the NHLBI.
19 van Straten AH, Soliman Hamad MA, van Zundert AA, Martens EJ, ter Woorst JF, de Wolf AM, Scharnhorst V, Jan 2011, ‘Effect of duration of red blood cell storage on early and late mortality after coronary artery bypass grafting’, J Thorac Cardiovasc Surg., vol. 141, no. 1, pages 231–7.
20 Huang YX, Wu ZJ, Mehrishi J, Huang BT, Chen XY, Zheng XJ, Liu WJ, Luo M, 21 Mar 2011 ‘Human Red Blood Cell Aging: Correlative changes in surface charge and cell properties’, J Cell Mol Med., doi: 10.1111/j.1582–4934.2011.01310.x. [Epub ahead of print].
21 Kerkhoffs JL, van Putten WL, Novotny VM, Te Boekhorst PA, Schipperus MR, Zwaginga JJ, van Pampus LC, de Greef GE, Luten M, Huijgens PC, Brand A, van Rhenen DJ; Dutch–Belgian HOVON cooperative group, Jul 2010, ‘Clinical effectiveness of leucoreduced, pooled donor platelet concentrates, stored in plasma or additive solution with and without pathogen reduction’, Br J Haematol., vol. 150, no. 2, pages 209–17, Epub 2010 May 9.
22 Greco CA, Zhang JG, Kalab M, Yi QL, Ramirez-Arcos SM, Gyongyossy-Issa MI, Nov 2010, ‘Effect of platelet additive solution on bacterial dynamics and their influence on platelet quality in stored platelet concentrates’, Transfusion, vol. 50, no. 11, pages 2344–52.
23 Bovine haemoglobin: HemoBioTech announced its new patent. Simoni JS, Simoni G, Feola MJ, 2010, Methods of treating acute blood loss, US Patent 7,759,306. HemoBioTech has an exclusive worldwide license from Texas Tech University to commercialise the technology.
24 Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; American Society of Hematology and the American Society of Clinical Oncology Practice Guideline Update Committee, 18 Nov 2010, ‘American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer’, Blood, vol. 116, no. 20, pages 4045–59, Epub 2010 Oct 25; Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR; American Society of Clinical Oncology; American Society of Hematology. 20 Nov 2010, ‘American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer’. J Clin Oncol., vol. 28, no. 33, pages 4996–5010, Epub 2010 Oct 25.
25 November 8, 2010, HemOnc Today
26 Charnow JA, 18 November 2010, ‘Transfusions Linked to Worse Outcomes in Transplant Recipients’, Renal and Urology News, http://www.renalandurologynews.com/transfusions-linked-to-worse-outcomes-in-transplant-recipients/article/191142/.
27 Lin Y, Stanworth S, Birchall J, Doree C, Hyde C, 11 Jan 2011, ‘Use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without hemophilia: a systematic review and meta-analysis’, CMAJ, vol. 183, no. 1, pages E9–19, Epub 2010 Nov 15.
28 Logan AC, Yank V, Stafford RS, 19 Apr 2011, ‘Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records’, Ann Intern Med., vol. 154, no. 8, pages 516–22; Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, Sundaram V, McMahon D, Olkin I, McDonald KM, Owens DK, Stafford RS, 19 Apr 2011, Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications, Ann Intern Med, vol. 154, no. 8, pages 529–40.
29 Shander AS, Goodnough LT, 13 Oct 2010, ‘Blood transfusion as a quality indicator in cardiac surgery’, JAMA, vol. 304, no. 14, pages 1610–1.
30 Dries DJ, 24 Nov 2010, ‘The contemporary role of blood products and components used in trauma resuscitation’, Scand J Trauma Resusc Emerg Med, vol. 18, page 63.
31 Dr Jeffrey Traina, an orthopaedic surgeon at Natchez (Miss.) Community Hospital, gave his presentation on platelet-rich plasma at the annual International Arthroplasty Conference in Sharm Elsheikh, Egypt, and at the International Society for Technical Arthroplasty congress in Dubai, from Orthopedic, Spine and Pain Management Review, http://www.beckersorthopedicandspine.com/sports-medicine/item/3032-dr-jeffrey-traina-prp-after-total-knee-replacement-could-reduce-blood-loss.
32 American Congress of Obstetricians and Gynecologists (ACOG) 59th Annual Clinical Meeting: Abstract 33, presented May 3, 2011, http://www.medscape.com/viewarticle/742841
33 KIOVIG was approved in Europe in 2006 and has been available in the United States since 2005 (marketed as GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)]). KIOVIG is a human normal immunoglobulin (IVIg), 10% solution
34 Kuter DJ, Bussel JB, Newland A, Wasser JS, Lyons RM, George JN, Macik G, Nie K, Jun S, ‘Long-term efficacy and safety of romiplostim treatment of adult patients with chronic immune thrombocytopenia (ITP): Final report from an open-label extension study’, ASH, Abstract 68, http://www.oncuview.tv/portals/0/linkedfiles/ASH%20Abstract%2068%20Kuter.pdf; Saleh MN, Cheng G, Bussel JB, Sun H, Mayer B, Bailey C, Brainsky A, ‘EXTEND Study update: Safety and efficacy of eltrombopag in adults with chronic immune thrombocytopenia (ITP) from June 2006 to February 2010 “ ASH, Abstract 67, http://ash.confex.com/ash/2010/webprogram/Paper27183.html.
35 Freir DB, Nicoll AJ, Klyubin I, Panico S, Mc Donald JM, Risse E, Asante EA, Farrow MA, Sessions RB, Saibil HR, Clarke AR, Rowan MJ, Walsh DM, Collinge J, Jun 2011, ‘Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites’, Nat Commun., vol. 7, no. 2, page 336.
36 The EU legislative framework for orphan medicines The orphan drug designation was mentioned earlier and this may need to go there provides incentives for the development of products intended to diagnose, prevent and treat rare life-threatening or chronically-debilitating conditions that affect up to 5 in 10,000 people.
37 Haemophilia patients who are coagulation-factor deficient are treated with replacement factor therapy. Some develop inhibitors, factor VIII or IX neutralizing antibodies which make further replacement therapy ineffective. Up to 33% of severe haemophilia A and up to 6% of all severe haemophilia B patients develop inhibitors. They can be treated with recombinant human factor VIIa. This is an enzyme that can initiate blood clotting. At high dose, it can “bypass” the factor VIII and IX dependent steps involved in effective coagulation. With the short half-life of the recombinant product currently available, frequent injections are needed to control or prevent bleeding.
38 Lentz S, Tandra A, Peters TJ, Cooper, DL, 2010, ‘The Acquired Hemophilia Surveillance (AHS) project: A novel mechanism of capturing post-marketing safety information on rFVIIa (NovoSeven®RT) in acquired hemophilia’, ASH, Abstract 3674.
39 Marco P, Collins PW, Knoebl P, Levesque H, Baudo F, Nemes L, Tengborn L, Huth-Kuehne A, Pellegrini F, 2010, ‘Acquired haemophilia: clinical and demographic data. Results of European Acquired Haemophilia Registry (EACH2)’ ASH, Abstract 1398.
40 Ragni MV, Fogarty PF, Josephson NC, Neff AT, Raffini L, Kessler CM, 2010, ‘Survey of current prophylaxis practices and bleeding characteristics of children with severe hemophilia A in U.S. hemophilia treatment centers’, ASH, Abstract 3653.
41 Windyga J, Rusen L, O’Brien AC, Hayward B, Arkin S, Roth DA, 2010, ‘BDDrFVIII (moroctocog alfa [AF-CC]) for surgical hemostasis in patients with hemophilia A undergoing total knee replacement or synovectomy’, NHF, Abstract CF5.
42 Rendo P, et al “A prospective registry of European hemophilia B patients receiving BeneFIX (nonacog alfa, recombinant human factor IX) for usual use” NHF, Abstract CR1.
43 Results of the studies, published as an integrated analysis of the raw data from two similar pilot trials, were published in the journal Respiratory Research. (http://respiratory-research.com/content/11/1/136)
44 Mishra A, Velotta J, Brinton TJ, Wang X, Chang S, Palmer O, Sheikh A, Chung J, Yang PC, Robbins R, Fischbein M, 2011, ‘RevaTen platelet-rich plasma improves cardiac function after myocardial injury’, Cardiovasc Revasc Med., vol. 12, no. 3, pages 158–63, Epub 2010 Oct 20.
45 Grifols, headquartered in Barcelona, has manufacturing facilities in Barcelona and Los Angeles. Talecris is based in Research Triangle Park, North Carolina
46 According to the FTC, Grifols and Talecris had around 8.4 percent and 22.8 percent of the US immunoglobulin market, respectively, and their merger would have meant effectively only three manufacturers with nearly all US sales. In albumin, the companies had US market shares of approximately 13 percent each, and the acquisition would have left four significant competitors. In the market for pdFVIII, Grifols and Talecris accounted for 23 percent and 3.6 percent respectively and after their merger there would have been only three main competitors
47 In April, CSL’s CEO was reported to have warned that the rising Australian dollar could see Australian companies send jobs offshore.