The risk with using untested biologics is an immunogenic reaction. It's already happened with Eprex, a generic eythropoietin, when patients developed pure red cell aplasia and anti-erythropoietin antibodies. The risk of developing immunogenicity, no matter how slight, is the reason I won't use generic GH products.
Nephrol Dial Transplant. 2003 Nov;18 Suppl 8:viii37-41.
Pure red cell aplasia and anti-erythropoietin antibodies in patients treated with epoetin.
Casadevall N1.
Abstract
Recombinant human erythropoietin (epoetin) was first used for the treatment of renal anaemia in 1986. During the first 10 years of its use, epoetin-induced antibodies were a rare complication and only three cases of patients with epoetin-induced antibodies associated with pure red cell aplasia (PRCA) were published. Since 1998, however, there has been a significant increase in the number of patients developing severe anaemia during the course of epoetin treatment due to neutralizing antibodies. Patients with PRCA present with an absolute resistance to epoetin therapy and then rapidly develop severe anaemia with a very low reticulocyte count (<10 000/mm(3)). Consequently, patients become dependent on blood transfusions to maintain an acceptable level of haemoglobin. By December 2002, approximately 142 patients worldwide had been diagnosed with antibody-positive PRCA after receiving epoetin. The vast majority of these patients had been treated with the Eprex/Erypo brand of epoetin alfa, but there were also some cases in which patients had been receiving epoetin beta (NeoRecormon). To date, there have been no cases of antibody-mediated PRCA reported with the sole use of darbepoetin alfa (Aranesp). All patients with epoetin-induced anti-erythropoietin antibodies had received the drug subcutaneously (s.c.), and almost all had chronic kidney disease-related anaemia. To our knowledge, no patient treated exclusively by intravenous (i.v.) administration has developed anti-erythropoietin antibodies. The increase in reported cases coincides with the removal of human serum albumin from the ex-US formulation of epoetin alfa, in order to comply with new regulations from the European regulatory authorities. It has been proposed that the new formulation is less stable, allowing aggregates of erythropoietin molecules to form, which increases the probability of antibody formation. Treatment with epoetin must be discontinued if PRCA is suspected. Patients do not respond to an increase in dose. Furthermore, patients must not be switched to another form of erythropoietic therapy as the antibodies cross-react with all erythropoietic therapies available. In around 70% of cases, immunosuppressive regimens are effective in eliminating the antibodies; cessation of epoetin therapy without concomitant immunosuppression is rarely effective. Kidney transplantation seems to provide an immediate and effective cure.
Arch Immunol Ther Exp (Warsz). 2012 Oct;60(5):331-44.
Immunogenicity to biologics: mechanisms, prediction and reduction.
Sethu S1,
Govindappa K,
Alhaidari M,
Pirmohamed M,
Park K,
Sathish J.
Abstract
Currently, there is a significant rise in the development and clinical use of a unique class of pharmaceuticals termed as Biopharmaceuticals or Biologics, in the management of a range of disease conditions with, remarkable therapeutic benefits. However, there is an equally growing concern regarding development of adverse effects like immunogenicity in the form of anti-drug antibodies (ADA) production and hypersensitivity. Immunogenicity to biologics represents a significant hurdle in the continuing therapy of patients in a number of disease settings. Efforts focussed on the identification of factors that contribute towards the onset of immunogenic response to biologics have led to reductions in the incidence of immunogenicity. An in-depth understanding of the cellular and molecular mechanism underpinning immunogenic responses will likely improve the safety profile of biologics. This review addresses the mechanistic basis of ADA generation to biologics, with emphasis on the role of antigen processing and presentation in this process. The article also addresses the potential contribution of complement system in augmenting or modulating this response. Identifying specific factors that influences processing and presentation of biologic-derived antigens in different genotype and disease background may offer additional options for intervention in the immunogenic process and consequently, the management of immunogenicity to biologics.
Ther Clin Risk Manag. 2011;7:489-93. doi: 10.2147/TCRM.S27495. Epub 2011 Dec 7.
Emerging patient safety issues under health care reform: follow-on biologics and immunogenicity.
Liang BA1,
Mackey T.
Abstract
US health care reform includes an abbreviated pathway for follow-on biologics, also known as biosimilars, in an effort to speed up access to these complex therapeutics. However, a key patient safety challenge emerges from such an abbreviated pathway: immunogenicity reactions. Yet immunogenicity is notoriously difficult to predict, and even cooperative approaches in licensing between companies have resulted in patient safety concerns, injury, and death. Because approval pathways for follow-on forms do not involve cooperative disclosure of methods and manufacturing processes by innovator companies and follow-on manufacturers, the potential for expanded immunogenicity must be taken into account from a risk management and patient safety perspective. The US Institute of Safe Medication Practices (ISMP) has principles of medication safety that have been applied in the past to high-risk drugs. We propose adapting ISMP principles to follow-on biologic forms and creating systems approaches to warn, rapidly identify, and alert providers regarding this emerging patient safety risk. This type of system can be built upon and provide lessons learned as these new drug forms are developed and marketed more broadly.
