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C Biologics in Pediatrics Joan Stachnik and Michael Gabay* B iologics have a long history of use as therapeutic agents in the United States (FDA, 2002). Vaccines, primarily derived from animal sources, were among the first biologics developed. The smallpox vaccine was introduced in 1800 (Barquet and Domingo, 1997), followed by other vaccines, such as the rabies and diphtheria vaccines (Junod, 2002). These vaccines were widely used but had little regulatory oversight. This changed in 1902 with the passage of the Biologics Control Act of 1902, which es- tablished regulations for vaccine production and licensing, following the deaths of 22 children in separate incidents involving contaminated diphthe- ria antitoxin and contaminated smallpox vaccine (Junod, 2002). Since the time that these early biological products began to be regu- lated, advances in science and technology have allowed more purified and complex biologics, including those derived from human blood components or produced using recombinant technology1 (Roque et al., 2004; Burnouf, 2011). Biologics are now used not only to prevent infectious conditions but also to treat a wide array of diseases, such as rheumatoid arthritis, cancers, * Joan Stachnik, M.Ed., Pharm.D., B.C.P.S., is clinical associate professor in the Drug Infor- mation Group, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago. Michael Gabay, Pharm.D., J.D., B.C.P.S., is director and clinical associate profes- sor in the Drug Information Group, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago. 1 Recombinant technology involves the combining of DNA sequences responsible for ex- pression of specific proteins or the fusion of target regions of antibodies, antibody fragments, or proteins. 285
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286 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN and other immune-mediated conditions. Although some of these diseases are diagnosed in the pediatric population, research with these age groups is limited. Since 1972, the Food and Drug Administration (FDA) has been respon- sible for the regulation of biologics. FDA licenses biological products under the Public Health Service Act licensing provisions and approves drugs under the federal Food, Drug, and Cosmetic (FDC) Act approval provisions. Un- der the FDC Act, certain old, relatively simple, biologically based products (e.g., insulin and human growth hormone) have long been regulated by the Center for Drug Evaluation and Research (CDER) through the New Drug Application process rather than through the Biologics License Application process of the Public Health Service Act (FDA, 2009c). In 2003, CDER also assumed responsibility for certain biologics. These are sometimes referred to as “therapeutic biologics,” although responsibility for regulation of other therapeutic biologics, such as intravenous immune globulins, remained with the Center for Biologics Evaluation and Research (CBER). CDER-regulated biologics include monoclonal antibodies for in vivo use, cytokines, growth factors, enzymes, immunomodulators, thrombolytics, certain therapeutic proteins, and nonvaccine immunotherapies (FDA, 2009d, 2010). Regula- tion of allergenics, blood and blood components (including recombinant proteins of blood components), gene therapy products, certain human cellular and tissue-based products (including stem cells and tissues for im- plantation or transplantation), vaccines, and nonhuman cells or tissues for transplantation remains under the authority of CBER (FDA, 2009a). This paper focuses on the biologics regulated by CDER and the CBER-regulated biologics that are derived from blood and blood components, with the exception of vaccines. DEFINITION AND REGULATION OF BIOLOGICS Generally described, biologics are “isolated from a variety of natural sources—human, animal, or microorganism—and may be produced by biotechnology methods and other cutting-edge technologies” (FDA, 2009e, unpaged). The regulatory definition provided in the Public Health Service Act (as amended in 2010) states that a biologic is “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, al- lergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound) applicable to the preven- tion, treatment, or cure of a disease or condition of human beings” (42 USC 262(i)). Biologics differ from conventional drugs in complexity and source. Un- like small-molecule drugs, which are produced by chemical reactions and
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287 APPENDIX C NO 2 O O2N O CH 2 CHCH2 O NO 2 C3H5N3O9 FIGURE C-1 Structures of nitroglycerin (C3H5N3O9), a conventional drug, and alteplase, a recombinant form of human tissue plasminogen activator. NOTE: EGF = epidermal growth factor. SOURCE: For alteplase, reproduced from Heart, T. K. Nordt and C. Bode, 89(11): 1358-1362, 2003 with permission from BMJ Publishing Group Ltd. have a known structure, biologics can be derived from human, microbio- logical, or animal sources and have complex structures consisting of amino Figure C-1.eps acids, sugars, and nucleic acids (Figure C-1 shows an approximation of landscape the difference in scale and complexity). Because of their higher complexity, stability is usually a greater issue with biologics than drugs (FDA, 2009e). OVERVIEW OF CHARACTERISTICS OF SELECTED BIOLOGICS Some biologics are derived from blood, primarily plasma proteins (Table C-1) or are produced via recombinant technology. Plasma, either re- covered from blood or donated directly, undergoes a fractionation process, which was first developed in the 1940s, to isolate proteins that can be used therapeutically (Burnouf, 2007). Isolation of a different protein occurs at each step of the fractionation process. For example, the first precipitate of the process—cryoprecipitate—is a rich source of coagulation proteins or factors (e.g., factor VIII and fibrinogen). Later in the fractionation process, other proteins such as albumin and immunoglobulins are separated out of the plasma after exposure to different ethanol concentrations and pHs. The safety of plasma-derived proteins is increased through the use of various
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288 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE C-1 Plasma-Derived Therapeutic Proteins Plasma-Derived Protein General Uses Coagulation factors (single factors Treatment or prevention of bleeding in patients with and prothrombin complex) factor deficiency Fibrinogen Control of acute bleeding in patients with congenital fibrinogen deficiency von Willebrand factor Treatment or prevention of bleeding in patients with von Willebrand disease Thrombin (human and bovine) Achievement of hemostasis during surgery Antithrombin Treatment or prevention of thromboembolism in patients with antithrombin deficiency α1-Antitrypsin (α1-protease Replacement therapy for patients with congenital α1- inhibitor) antitrypsin deficiency and emphysema C1-esterase inhibitor Prevention of angioedema in patients with hereditary angioedema Immunoglobulins Treatment of primary immunodeficiency diseases and immune thrombocytopenic purpura Albumin Treatment of fluid resuscitation and shock SOURCES: Burnouf (2007), McEvoy (2011). methods to reduce the risk of transmission of human immunodeficiency virus, hepatitis viruses, and other viruses. These methods include chro- matography (ion-exchange, affinity, and size-exclusion chromatography), filtration, solvent-detergent treatment, pasteurization, and heat treatment. Beginning in the early 1980s, advances in genetic engineering and cell expression systems allowed production of recombinant forms of some hu- man plasma proteins and the development of new biologics with specific cellular targets (Burnouf, 2011). Recombinant therapeutics generally in- clude monoclonal antibodies, fusion proteins, and recombinant versions of human proteins (e.g., recombinant-derived coagulation factors). In addition to the different methods of production, recombinant therapeutics can differ in action, with some blocking or preventing release of cytokines and others acting as replacement proteins for deficient endogenous human proteins (Grabenstein, 2011). Monoclonal antibodies represent the largest class of recombinant- derived therapeutics (An, 2010). Monoclonal antibodies have structures similar to those of immunoglobulins but are modified by recombinant technology to have a high specificity and affinity for a particular target, such as cytokines, cell markers, or their receptors, to prevent subsequent effects or production of inflammatory mediators (Table C-2) (An, 2010;
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289 APPENDIX C TABLE C-2 Therapeutic Monoclonal Antibodies and Fusion Proteins Sourcea Biologic Target Monoclonal antibodies Abciximab (ReoPro) Glycoprotein IIb/IIIa receptor Chimeric Adalimumab (Humira) Human tumor necrosis factor alpha Human Certolizumab (Cimzia) Humanized Golimumab (Simponi) Humanized Infliximab (Remicade) Chimeric Alemtuzumab (Campath) CD52 surface antigen on B and T lymphocytes; Humanized most monocytes, macrophages, and natural killer cells; and some granulocytes Basiliximab (Simulect) Interleukin-2 receptor (CD25 surface antigen) on Humanized Daclizumab (Zenapax) activated lymphocytes Humanized Bevacizumab (Avastin) Human vascular endothelial growth factor-A Humanized Ranibizumab (Lucentis) receptor Humanized Interleukin-1β Canakinumab (Ilaris) Humanized Capromab (ProstaScint) Prostate-specific membrane antigen Murine Cetuximab (Erbitux) Human epidermal growth factor receptor Chimeric Panitumumab (Vectibix) expressed on normal and tumor cells Humanized Denosumab (Prolia/Xgeva) Human receptor activator for nuclear factor- Humanized kappa B ligand Eculizumab (Soliris) Complement protein C5 Humanized Ibritumomab tiuxetan CD20 surface antigen on B lymphocytes Murine (Zevalin) Ofatumumab (Arzerra) Humanized Rituximab (Rituxan) Chimeric Tositumomab, Iodine Murine I 131 tositumomab (Bexxar) Muronomab (Orthoclone CD3 surface antigen of T cells Humanized OKT3) α4-Integrin on the surface of all leukocytes Natalizumab (Tysabri) Humanized except neutrophils Omalizumab (Xolair) Human immunoglobulin E Humanized Palivizumab (Synagis) The A antigenic site of F protein of respiratory Humanized syncytial virus Tocilizumab (Actemra) Interleukin-6 receptor Humanized Trastuzumab (Herceptin) Human epithelial growth factor receptor-2 Humanized protein Ustekinumab (Stelara) p40 subunits of interleukin-12 and interleukin-23 Humanized continued
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290 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE C-2 Continued Biologic Target Fusion proteins Abatacept (Orencia) CD80 and CD86 surface antigens on T cells Alefacept (Amevive) CD2 surface antigens on T cells Etanercept (Enbrel) Human tumor necrosis factor Rilonacept (Arcalyst) Interleukin-1 receptor Denileukin (Ontak) Interleukin-2 receptor Romiplostim (Nplate) Thrombopoietin receptor a Sources of fragments used for monoclonal antibody production include human and nonhu- man species. A portion of chimeric monoclonal antibodies (25 percent) are murine derived, humanized monoclonal antibodies are 5 percent murine derived, and human monoclonal antibodies are fully human. Immunogenicity is decreased with more human monoclonal antibodies. SOURCES: An (2010), Lee and Ballow (2010), Burnouf (2011), Grabenstein (2011), McEvoy (2011), Wickersham (2011). Burnouf, 2011; Grabenstein, 2011). In addition to monoclonal antibodies, fusion proteins bind to cytokines or receptor sites to block the effects or production of cytokines (Table C-2). Fusion proteins consist of a portion of a native protein (e.g., a cell surface receptor) fused to another molecule, often via a portion of human immunoglobulin (Lee and Ballow, 2010). Finally, recombinant versions of human plasma proteins, as well as enzymes, have been developed for treatment of disorders resulting from qualitative or quantitative deficiencies of these substances. These prod- ucts are listed in Table C-3 (Rohrbach and Clarke, 2007; Brooker, 2008; Wickersham, 2011). The biologics described in Tables C-1 to C-3 are used for the treat- ment of a wide array of diseases and disorders (An, 2010; Burnouf, 2011). Because of their mechanisms of action, many of the monoclonal antibodies and fusion proteins are used for treatment of immune-mediated diseases, such as rheumatoid arthritis, Crohn’s disease, multiple sclerosis, cancers, and psoriasis. Most are classified as antineoplastics, disease-modifying antirheumatic drugs, biologic response modifiers, or immunosuppressive agents (McEvoy, 2011). The activities of recombinant-based versions of human plasma proteins (e.g., epoetin, pegfilgrastim, antihemophilic factor, palifermin, and drotrecogin alfa) and enzymes (e.g., rasburicase, laronidase, naglazyme, and alglucosidase alfa) as well as plasma-derived proteins (e.g., immunoglobulins, albumin, von Willebrand factor, and C1-esterase) gener- ally mimic the activity of the endogenous protein or enzyme to achieve a therapeutic effect.
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291 APPENDIX C TABLE C-3 Additional Therapeutic Recombinant Human Proteins Biologic Description Recombinant human form of α-galactosidase Agalsidase beta (Fabrazyme) Alglucosidase alfa (Myozyme/ Recombinant human lysosomal glucogen-specific enzyme (α-glucosidase) Lumizyme) Alteplase (Activase) Recombinant human tissue-type plasminogen activator Anakinra (Kineret) Nonglycosylated interleukin-1 receptor antagonist Antithrombin alfa (ATryn) Recombinant human antithrombin III Becaplerin (Regranex) Recombinant human platelet-derived growth factor Darbepoetin alfa (Aranesp) Recombinant human erythropoietin (modified by the addition of two carbohydrate chains) Drotrecogin alfa (Xigris) Recombinant activated human protein C Ecallantide (Kalbitor) Recombinant human reversible inhibitor of plasma kallikrein Epoetin (Epogen) Recombinant human erythropoietin Factor IX (Benefix) Recombinant human coagulation factor IX Factor VIIa (NovoSeven-RT) Activated recombinant human coagulation factor VII Factor VIII, B domain deleted Recombinant human coagulation factor VIII with (Xyntha) deletion of the B domain Factor VIII, full length (Recombinate, Recombinant human coagulation factor VIII Helixate, Kogenate, Advate) (antihemophilic factor) Idursulfase (Elaprase) Recombinant human iduronate-2-sulfatase Interferon alfacon-1 (Infergen) Recombinant hybrid of human interferon alpha Interferon gamma 1B (Actimmune) Recombinant human interferon gamma Interferon beta (Betaseron, beta-1b; Recombinant human interferon beta Avonex, Rebif, beta-1a) Laronidase (Aldurazyme) Recombinant human lysosomal glucogen-specific enzyme (l-iduronidase) Naglazyme (Galsulfase) Recombinant human lysosomal enzyme (N-acetylgalactosamine-4-sulfatase) Oprelvekin (Neumega) Recombinant human interleukin-11 (thrombopoietic growth factor) Palifermin (Kepivance) Recombinant analog of human keratinocyte growth factor Pegfilgrastim (Neulasta) Covalent conjugate of filgrastim and monomethoxypolyethylene glycol continued
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292 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE C-3 Continued Biologic Description Peginterferon alfa (Pegasys [alfa-2a]; Recombinant human interferon alpha covalently PegIntron [alfa-2b]) bound to polyethylene glycol monomethoxy ether Pegloticase (Krystexxa) Pegylated recombinant human uric acid-specific enzyme Rasburicase (Elitek) Recombinant human of urate oxidase Reteplase (Retavase) Recombinant human tissue-type plasminogen activator Tenectaplase (TNKase) Recombinant human tissue-type plasminogen activator Thrombin alfa (Recothrom) Recombinant human thrombin SOURCES: Burnouf (2011), McEvoy (2011), Wickersham (2011). CLINICAL PHARMACOLOGY OF BIOLOGICS Well-established pharmacokinetic data for many drugs and biologics for the pediatric population are lacking. FDA has recognized the paucity of pediatric pharmacokinetic data and in response published draft guidance for industry in 1998 (FDA, 1998). The focus of the guidance was to elabo- rate on the pharmacokinetic information needed to determine appropriate medication doses in the pediatric population across all age groups, from neonates to adolescents. This determination is of particular concern in pediatrics because of growth and developmental changes that influence the absorption, distribution, metabolism, and excretion of drugs and biologics. Within the guidance, FDA recommended that pediatric pharmacokinetic studies evaluate how dosage regimens should be adjusted to attain “ap- proximately the same level of systemic exposure that is safe and effective in adults” (FDA, 1998, p. 4). If pediatric pharmacokinetic data are lacking for traditional drugs, these data are even scarcer for biologics, including monoclonal antibodies, although published data continue to expand (Dirks and Meibohm, 2010; Keizer et al., 2010). Monoclonal antibodies are immunoglobulins, which are used to treat a wide range of illnesses. Although there are five separate types of immunoglobulins in humans: immunoglobulin A (IgA), IgD, IgE, IgG, and IgM. An estimated 80 percent of all antibodies in humans are of the IgG family; all approved therapeutic monoclonal antibodies are of this family as well (Keizer et al., 2010). The primary route of administration for approved monoclonal anti- bodies is intravenous (IV); however, some agents may be administered via
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293 APPENDIX C the subcutaneous (SC) or intramuscular (IM) route (Keizer et al., 2010). Absorption via these secondary routes is facilitated by the lymphatic sys- tem, which often results in low to intermediate bioavailability. Peak con- centrations in serum generally do not occur until a few days after SC or IM administration because of slow absorption into the systemic circulation. Effective systemic therapy with monoclonal antibodies via the oral route is not currently possible because of their size, polarity, and the occurrence of gastrointestinal degradation. Monoclonal antibodies generally have low volumes of distribution primarily because of their large size and hydrophilic nature. Also, their bulky molecular size does not allow urinary excretion. Rather, monoclonal antibodies are metabolized to peptides and amino ac- ids that are then either reused by the body or excreted by the kidney. The specific mechanisms of elimination of monoclonal antibodies are not well understood. In pediatric populations, specific pharmacokinetic parameters for monoclonal antibodies are not well studied. The clearance of monoclonal antibodies from the body may be length- ened through a process called pegylation (i.e., the attachment of polyeth- ylene glycol polymer chains to another molecule like a drug or therapeutic protein). Prolonging the half-life may allow reduced dosing or less frequent administration; however, this manipulation may also cause increased toxici- ties, such as a greater risk of allergic reactions. The formation of antibod- ies against monoclonal antibodies can have a significant impact on their efficacy in pediatric populations through effects on pharmacokinetics. The development of anti-monoclonal antibodies has been linked to a reduction in levels in serum and an increase in antibody clearance correlating to a reduced clinical response (Keizer et al., 2010). For plasma-derived therapeutics, such as hemophilia factor concen- trates and immune globulin intravenous (IGIV),2 more specific, yet limited, pediatric pharmacokinetic data are available. In the pediatric population, both the clearance and volume of distribution of factor concentrates ap- pear to increase with age and body weight (Bjorkman and Berntrop, 2001). In neonates administered IGIV for prevention of infection, the estimated elimination of IGIV was found to be quite prolonged: 16 to 36 days across various studies (Koleba and Ensom, 2006). In 2008, the FDA published guidance regarding safety, efficacy, and pharmacokinetic studies to support marketing of IGIV as replacement therapy for primary humoral immunode- ficiency (FDA, 2008). Within this guidance, the FDA recommended that “if possible and needed, the pharmacokinetic study of an IGIV product should be conducted across all pediatric age groups” (p. 10). 2 Although immune globulin intravenous (IGIV) is the official name of these products, many clinicians continue to refer to these plasma-derived therapeutics as intravenous immune globulin (IVIG).
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294 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN SAFETY CONCERNS IN PEDIATRIC POPULATIONS Plasma-derived proteins such as coagulation factors and IGIV are com- monly used to treat hemophilia and immune deficiency disorders in chil- dren, respectively. Historically, the major safety concern with these proteins was the risk of blood-borne infections; however, donor screening, improved testing methods (e.g., nucleic acid amplification), and viral inactivation pro- cedures in the manufacturing process have made the potential for infection less of a concern (Tarantino et al., 2007; Radosevich and Burnouf, 2010). Today, there are different safety concerns with each of these products. For pediatric patients with hemophilia, inhibitor development may be a serious roadblock to successful therapy. An inhibitor is a type of antibody, and in the case of hemophiliacs, these antibodies attach to coagulation factor VIII or factor IX and inhibit the ability of the factor to stop bleed- ing (DiMichele, 2008). As opposed to patients without inhibitors, hemo- philiacs who develop inhibitors to factor products experience orthopedic and life-threatening bleeding complications more frequently because of the difficulties with the treatment of such patients (DiMichele, 2008). In addi- tion, these individuals experience more disability in their everyday activities (DiMichele, 2008). A variety of potential safety concerns arise with the administration of IGIV, with infusion-related reactions (arising from the triggering of an inflammatory response by components within an IGIV preparation) of various severities being the most common (Duhem et al., 1994; Nydegger and Sturzenegger, 1999). These reactions are often mild, self-limiting, and more common in IGIV-naïve patients and generally occur within 30 to 60 minutes after the start of an infusion. This reaction may manifest itself clini- cally as a low-grade fever, chills, mild headache, myalgias, and backache. Anaphylactic reactions occur rarely (<5 percent of IGIV recipients) and are most commonly observed in patients with IgA deficiency. The use of prod- ucts that contain large amounts of IgA should be avoided in these patients (Nydegger and Sturzenegger, 1999). Other rare, but serious, adverse events that can occur with IGIV administration include renal failure, aseptic meningitis, hemolysis, transfusion-related acute lung injury, and thrombotic events. Renal failure most commonly occurs with the use of sucrose-containing IGIV products (Epstein and Zoon, 1999). Long-term safety concerns for certain biologics—in particular, the chronic administration of human tumor necrosis factor (TNF) inhibitors such as adalimumab, etanercept, and infliximab—may be quite serious (Hashkes et al., 2010). These concerns, which are controversial, include the possible occurrence of malignancies; an increased risk of serious infections; and the development of autoimmune phenomena such as demyelinating
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295 APPENDIX C disease, autoantibodies, uveitis, lupus-like syndrome, inflammatory bowel disease, and psoriasis. A search of FDA’s Adverse Event Reporting System (through April 29, 2008) revealed 48 cases of malignancy among pediat- ric patients prescribed TNF inhibitors, primarily for inflammatory bowel disease (Diak et al., 2010). Although the reported malignancy rates among children who received infliximab and etanercept were found to be higher than the background rates in the general pediatric population, a clear causal connection could not be established due to confounding factors such as con- current immunosuppressant therapy and the potential risk of malignancy associated with underlying illnesses. Administration of TNF inhibitors had been associated with an in- crease in granulomatous infections, particularly tuberculosis, prior to the widespread implementation of pretreatment screening and administration of appropriate prophylactic medications (Keane et al., 2001; Wallis et al., 2004; Hashkes et al., 2010). Reports of such infections in children admin- istered these agents have subsequently decreased since 2000, with only a few case reports demonstrating development of tuberculosis (Myers et al., 2002; Armbrust et al., 2004) and histoplasmosis (Lee et al., 2002) being published. Because of the complex effects of TNF in the immune system, inhibition may lead to autoimmune phenomena, including the development of autoim- mune disorders for which TNF inhibitors are standard treatments, though a definitive association of autoimmune disorders with TNF inhibitors has not been shown. Published case reports have documented the occurrence of a variety of these phenomena in children prescribed TNF inhibitors, including psoriasis (Peek et al., 2006), demyelination (Mohan et al., 2001), uveitis (Hashkes and Shajrawi, 2003), autoantibody development (Kanakoudi- Tsakalidou et al., 2008), diabetes mellitus (Bloom, 2000), systemic lupus erythematosus (Lepore et al., 2003; Bout-Tabaku et al., 2007), autoimmune hepatitis (Fathalla et al., 2008), and Crohn’s disease (Ruemmele et al., 2004; Wiegering et al., 2010). Infusion or injection-site reactions are common with administration of TNF inhibitors and other biologics such as interleukin-1 receptor antago- nists (i.e., anakinra) and fusion proteins (Hashkes et al., 2010). Injection- site reactions (erythema, pruritus, pain, edema) occur frequently with the TNF inhibitors etanercept and adalimumab (28 to 39 percent) but do not often result in discontinuation of therapy. In contrast, infusion-related re- actions with infliximab (fever, chills, dyspnea, urticaria, and hypotension, which may be due to anaphylaxis or the development of antibodies to infliximab) have been reported to result in cessation of therapy in approxi- mately 20 percent of pediatric patients with juvenile idiopathic arthritis in a long-term prospective study (Gerloni et al., 2008).
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310 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Targeted therapies with biologics have the potential to improve the prognosis of childhood cancers with historically poor outcomes (Bernstein, 2011). However, there are many unknowns regarding the use of biologics in childhood cancers. As noted above, cancers in children differ from those in adults, and these differences can alter the effects of biologics, in terms of both efficacy and adverse events. Additionally, exposure to conventional chemotherapy has long-term effects in adult survivors of childhood cancer. An important question for long-term investigation is whether exposure to biologics during childhood predisposes pediatric patients to adult-onset chronic conditions or to other cancers to a similar degree. In addition, the impact of biologics on the growth and development of children is unknown. Endocrinology: Diabetes Both type 1 and type 2 diabetes can have a significant impact on qual- ity of life in children (American Diabetes Association, 2011). Although the incidence of type 2 diabetes in children is increasing, in part because of the rise in the incidence of obesity among children, the onset is more common in adulthood. In contrast, the onset of type 1 diabetes is frequently seen during childhood. One epidemiologic study reported that approximately 26 percent of cases of type 1 diabetes presented in children less than 4 years of age and 37 percent presented at 5 to 14 years of age (Harjutsalo et al., 2008). However, the frequency of diabetic ketoacidosis at onset of the disease is higher in younger children (40 to 50 percent for ages 0 to 4 years) than in older adolescents (12 to 15 percent for ages 15 to 21 years) (Daneman, 2006). Type 1 diabetes accounts for only 5 to 10 percent of all cases of diabetes; but its early onset, faster and more intense destruction of pancreatic β cells (compared with type 2 diabetes), and association with short- and long-term complications make it a serious, chronic disorder of importance among children. Type 1 diabetes results from destruction of pancreatic β cells resulting from a cell-mediated autoimmune reaction (Daneman, 2006). This then causes a progressive loss of insulin production; patients eventually have an absolute insulin deficiency, requiring exogenous insulin to maintain glucose hemostasis. Although insulin is an effective treatment and the new analog insulins allow greater physiologic control of glucose, complications from treatment can still frequently occur. In the short term, hypoglycemia is likely the most important complication of type 1 diabetes, which can be life-threatening and can interfere with effective glucose control. Side effects of insulin in both adults and children can include hypersensitivity reactions, lipohypertrophy or -atrophy, and pain at the injection site (Bangstad et al., 2007). Long-term diabetes is associated with micro- and macrovascular complications, including nephropathy, retinopathy, and cardiovascular dis-
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311 APPENDIX C ease (Daneman, 2006). Some of these complications, such as retinopathy, may be seen early in the course of the disease (Maguire et al., 2005). Given the role of the immune system in the development of type 1 diabetes, studies have looked at the effects of monoclonal antibodies— primarily CD3-specific antibodies—on the preservation of β-cell function (Kaufman and Herold, 2009). Otelixizumab, an investigational CD3 sur- face antigen antibody, was evaluated for its effects on new-onset type 1 diabetes (Keymeulen et al., 2005). The CD3 surface antigen was targeted because of the T-cell-mediated autoimmune mechanism of type 1 diabetes. Residual β-cell function (as measured by C-peptide release) was maintained among patients given otelixizumab and returned to baseline at 18 months after treatment. Patients given placebo had reductions in β-cell function of just over 30 percent during the same time period. In addition, treatment with the monoclonal antibody had a greater effect in patients with higher residual β-cell function at baseline (≥50th percentile). Adverse effects of treatment were transient but significant, with nearly all treated patients experiencing fever, headache, gastrointestinal events, arthralgia, myalgia, rash, and an acute mononucleosis-like syndrome. A second investigational anti-CD3 monoclonal antibody, teplizumab, was evaluated in 24 patients with a diagnosis of type 1 diabetes of 6 weeks or less (Herold et al., 2002). Teplizumab or placebo was given as a 14-day course of treatment, and patients were assessed after 1 year. The mono- clonal antibody significantly attenuated the decline in C-peptide response compared with placebo. A decline in both glycosylated hemoglobin (A1C) levels and insulin dose were also seen with teplizumab. Similar results were reported in a 2-year follow-up; the effects of teplizumab were maintained (Herold et al., 2005). A second trial of teplizumab was initiated with patients with recent- onset type 1 diabetes (Herold et al., 2009). This study, however, was stopped after enrollment of 10 patients (6 given teplizumab) due to a substantially higher rate of adverse events than previously seen, despite use of the same dosage regimen (Herold et al., 2002, 2005). It was later determined that a change in the manufacturing of teplizumab—use of a stoppered vial in- stead of a glass ampoule—resulted in a 40 percent increase in the dose of teplizumab over previous trials and a subsequent increase in adverse events (Herold et al., 2009). During preparation for administration, the contents of the glass ampoule were filtered, whereas a filter was not used when the agent was packaged in a stoppered vial. An extended follow-up of patients given teplizumab was conducted. At 60 months, the mean loss of baseline function (based on C-peptide response) was 63.8 percent, indicating that the monoclonal antibody had a prolonged effect. A more recent, larger study of teplizumab enrolled 516 patients (ages 8 to 35 years) with type 1 diabetes within 12 weeks from diagnosis (Sherry
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312 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN et al., 2011). Results of the trial did not show an effect on β-cell preserva- tion at 1 year. However, an exploratory analysis on the effect of teplizumab in the children suggested a better C-peptide response, findings that need to be confirmed. In addition to CD3-specific antibodies, rituximab, an anti-CD20 mono- clonal antibody, has been evaluated for preservation of β-cell function (Pescovitz et al., 2009). At 1 year after treatment, a significantly lesser de- cline in the level of C peptide (as a marker of β-cell function) from baseline was seen with rituximab than placebo, and the decline was accompanied by reductions in both A1C and total insulin use. Adverse events occurred significantly more often with the use of rituximab than placebo, including fever, rash, hypotension, nausea, fever, and tachycardia. Overall, immunotherapy seems to be a promising area for research. As a life-long disease, the safety of biologics in the treatment of type 1 diabetes in children is of utmost importance. On the basis of the available data, treatment must be initiated shortly after diagnosis (before extensive loss of β-cell function) to preserve endogenous insulin production. How- ever, the effects of biologics on growth and development of young children are largely unknown. Additionally, since a single course of therapy with a biologic may have a prolonged effect on β-cell preservation, the optimal frequency of treatment needs to be established. Finally, another critical question for evaluation is whether the risks associated with biologics out- weigh the benefits of delaying or minimizing the long-term complications of type 1 diabetes. CONCLUSION For many disease states, biologics represent the most advanced thera- peutic approach. The use of biologics for chronic conditions such as rheu- matoid arthritis, psoriasis, and IBD has been established in adults. These agents have improved the quality of life of adult patients with these and similar immune-mediated diseases and induce a remission of symptoms for some diseases. However, the role of biologics (excluding plasma-derived or recombinant factor proteins) in many pediatric disease states is less clear. Most data on biologics appear to be for JIA, with some biologics approved for children as young as 2 years of age. IBD, atopic dermatitis, psoriasis, childhood cancers, and type 1 diabetes—the conditions discussed in this paper—all have a significant impact on the quality of life of children, which in many cases extends to adulthood. Taking prevalence, burden of disease, and life expectancy as well as a lack of pediatric studies into account, the two areas in which research in biologics may be the most needed are child- hood cancers and type 1 diabetes. For childhood cancers, use of many therapies is extrapolated from data
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313 APPENDIX C for adults because of the limited availability of data for the pediatric popu- lation. Although childhood cancers represent only about 1 percent of all cancers, they are the leading medical cause of death among children, mak- ing improvements to the survival of these patients a priority. Additionally, the cure of a childhood cancer prolongs life not by 10 or 20 years, as in adults, but potentially by 60 or 70 years, balancing any higher therapeutic costs with a substantial gain in life-years. Also important is type 1 diabetes. Although type 1 diabetes accounts for only 5 to 10 percent of cases of diabetes, nearly half of these cases are diagnosed in childhood. The only effective therapy is insulin, and despite appropriate treatment, type 1 diabetes is associated with significant morbid- ity and mortality from micro- and macrovascular complications. Prelimi- nary data suggest that early intervention with biologics has the potential to preserve β-cell function and endogenous insulin secretion (Herold et al., 2005; Keymeulen et al., 2005; Kaufman and Herold, 2009; Pescovitz et al., 2009). This could potentially prevent or limit the long-term complications of the disease and greatly improve the quality of life of patients with type 1 diabetes. Although biologic therapy is likely to be more costly than current insulin therapies, the cost of biologic therapy in childhood may be offset by the benefits of decreased morbidity in adulthood. A major concern about which little is known is the effect, if any, that biologics can have on childhood development and growth or if negative effects of treatment may be seen in adulthood. As noted above, some es- tablished treatments used with children may potentially increase the risk of subsequent malignancies. In addition to well-designed clinical trials, estab- lishment and continued use of registry data are important for investigation of the long-term effects of biologics. REFERENCES Abbott Laboratories. Humira package insert. North Chicago, IL: Abbott Laboratories; 2011. Abramson O, Durant M, Mow W, et al. Incidence, prevalence, and time trends of pedi- atric inflammatory bowel disease in Northern California, 1996 to 2006. J Pediatr. 2010;157(2):233-239. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011;34(suppl 1):S62-S69. Amgen. Enbrel package insert. Thousand Oaks, CA: Amgen; 2011. An Z. Monoclonal antibodies—a proven and rapidly expanding therapeutic modality for hu- man diseases. Protein Cell. 2010;1(4):319-330. Armbrust W, Kamphuis SSM, Wolfs TWF, et al. Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2004; 43(4):527-529. Bangstad HJ, Danne T, Deeb LC, Jarosz-Chobot P, Urakami T, Hanas R. ISPAD Clini- cal Practice Consensus Guidelines 2006-2007. Insulin treatment. Pediatric Diabetes. 2007;8(2):88-102.
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