C

Biologics in Pediatrics

Joan Stachnik and Michael Gabay*

Biologics 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 established regulations for vaccine production and licensing, following the deaths of 22 children in separate incidents involving contaminated diphtheria antitoxin and contaminated smallpox vaccine (Junod, 2002).

Since the time that these early biological products began to be regulated, 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, and other

images

* Joan Stachnik, M.Ed., Pharm.D., B.C.P.S., is clinical associate professor in the Drug Information 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 professor 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 expression of specific proteins or the fusion of target regions of antibodies, antibody fragments, or proteins.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 285
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

OCR for page 285
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

OCR for page 285
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

OCR for page 285
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;

OCR for page 285
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

OCR for page 285
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.

OCR for page 285
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

OCR for page 285
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

OCR for page 285
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).

OCR for page 285
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

OCR for page 285
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).

OCR for page 285
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-

OCR for page 285
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

OCR for page 285
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

OCR for page 285
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.

OCR for page 285
314 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Barquet N, Domingo P. Smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med. 1997;127(8):635-642. Bernstein ML. Targeted therapy in pediatric and adolescent oncology. Cancer. 2011;117(10 suppl):2268-2274. Bjorkman S, Berntrop E. Pharmacokinetics of coagulation factors. Clinical relevance for pa- tients with hemophilia. Clin Pharmacokinet. 2001;40(11):815-832. Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: diagnosis and management. Hematol Oncol Clin N Am. 2010;24(1):249-273. Bloom BJ. Development of diabetes mellitus during etanercept therapy in a child with systemic- onset juvenile rheumatoid arthritis. Arthritis Rheum. 2000;43(11):2606-2608. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5 suppl 1):S1-S63. Bout-Tabaku S, Rivas-Chacon R, Restrepo R. Systemic lupus erythematosus in a patient treated with etanercept for polyarticular juvenile rheumatoid arthritis. J Rheumatol. 2007;34(12):2503-2504. Bremmer MS, Bremmer SF, Baig-Lewis S, Simpson EL. Are biologics safe in the treatment of atopic dermatitis? A review with a focus on immediate hypersensitivity reactions. J Am Acad Dermatol. 2009;61(4):666-676. Bristol-Myers Squibb. Orencia package insert. Princeton, NJ: Bristol-Myers Squibb; 2009. Brooker M. Registry of clotting factor concentrations. Montreal, Quebec, Canada: World Feder- ation of Hemophilia; 2008. http://www.wfh.org/2/docs/Publications/Treatment_Products/ Monographs/FF6_Registry_8th_2008.pdf. Accessed July 24, 2011. Buka RL, Resh B, Roberts B, Cunningham BB, Friedlander S. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol. 2005;53(2):358-359. Burnouf T. Modern plasma fractionation. Transfus Med Rev. 2007;21(2):101-117. Burnouf T. Recombinant plasma proteins. Vox Sang. 2011;100(1):68-83. Centocor Ortho Biotech, Inc. Remicade package insert. Malvern, PA: Centocor Ortho Biotech, Inc; 2011. Cucchiara S, Morelty-Fletcher A. “New drugs: kids come first”: children should be included in trials of new biological treatments. Inflamm Bowel Dis. 2007;13(9):1165-1169. Daneman D. Type 1 diabetes. Lancet. 2006;367(9513):847-858. de Zoeten E, Mamula P. What are the guidelines for use of biologics in pediatric patients? Inflamm Bowel Dis. 2008;14(suppl 2):S259-S261. Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor α blockers and malignancy in children. Arthritis Rheum. 2010;62(8):2517-2524. DiMichele DM. Inhibitors in hemophilia: a primer. Montreal, Quebec, Canada: World Federation of Hemophilia; 2008. http://www.wfh.org/2/docs/Publications/Inhibitors/ TOH-7%20Inhibitor-Primer-Revised2008.pdf. Accessed July 14, 2011. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633-659. Dotson JL, Hyams JS, Markowitz J, et al. Extraintestinal manifestations of pediatric inflamma- tory bowel disease and their relation to disease type and severity. J Pediatr Gastroenterol Nutr. 2010;51(2):140-145. Duhem C, Dicato MA, Ries F. Side-effects of intravenous immune globulins. Clin Exp Im- munol. 1994;97(suppl 1):79-83. Epstein JS, Zoon KC. Acute renal failure associated with immune globulin intravenous (hu- man). Bethesda, MD: Centers for Biologics Evaluation and Research, FDA. September 24, 1999. Farnsworth NN, George SJ, Hsu S. Successful use of infliximab following a failed course of etanercept in a pediatric patient. Dermatol Online J. 2005;11(3):11.

OCR for page 285
315 APPENDIX C Fathalla BM, Goldsmith DP, Pascasio JMC, Baldridge A. Development of autoimmune hepa- titis in a child with systemic-onset juvenile idiopathic arthritis during therapy with etan- ercept. J Clin Rheumatol. 2008;14(5):297-298. FDA (Food and Drug Administration). Guidance for industry. General considerations for pediatric pharmacokinetic studies for drugs and biological products. Rockville, MD: FDA; 1998. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm072114.pdf. Accessed July 11, 2011. FDA. Science and the regulation of biological products. Rockville, MD: FDA; 2002. http:// www.fda.gov/downloads/AboutFDA/WhatWeDo/History/ProductRegulation/100Yearsof BiologicsRegulation/UCM070313.pdf. Accessed July 20, 2011. FDA. Guidance for industry. Safety, efficacy, and pharmacokinetic studies to support mar- keting of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. Rockville, MD: FDA; June 2008. http://www.fda.gov/down loads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/ Blood/ucm078526.pdf. Accessed July 11, 2011. FDA. Biologics regulated products. Rockville, MD: FDA; 2009a. http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm123205.htm. Accessed July 20, 2011. FDA. Follow-up to the June 4, 2008 early communication about the ongoing safety review of tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). Rockville, MD: FDA; 2009b. http://www.fda.gov/Drugs/DrugSafety/Post marketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHealth careProfessionals/ucm174449.htm. August 4, 2009. Accessed November 28, 2011. FDA. Regulatory information. Federal Food, Drug, and Cosmetic Act (FD&C Act). SEC. 201. [21 U.S.C. § 321] Chapter II—Definitions 1. Rockville, MD: FDA; 2009c. http://www. fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/ FDCActChaptersIandIIShortTitleandDefinitions/ucm086297.htm. Accessed July 20, 2011. FDA. Therapeutic biological applications (BLA). Rockville, MD: FDA; 2009d. http://www.fda. gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approval Applications/TherapeuticBiologicApplications/default.htm. Accessed July 20, 2011. FDA. What are “biologics” questions and answers. Washington, DC: FDA; 2009e. http:// www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ ucm133077.htm. Accessed July 20, 2011. FDA. Transfer of therapeutic products to the Center for Drug Evaluation and Research. Wash- ington, DC: FDA; 2010. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedical ProductsandTobacco/CBER/ucm133463.htm. Accessed July 20, 2011. Floristan U, Feltes R, Ramirez P, Alonso ML, de Lucas R. Recalcitrant palmoplantar pustular psoriasis treated with etanercept. Pediatr Dermatol. 2011;28(3):349-350. Ford A, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):644-659. Gare BA. Juvenile arthritis—who gets it, where and when? A review of current data on inci- dence and prevalence. Clin Exp Rheumatol. 1999;17(3):367-374. Genentech. Actemra package insert. South San Francisco, CA: Genentech; 2011. Gerloni V, Pontikaki I, Gattinara M, Fantini F. Focus on adverse events of tumour necrosis factor α blockade in juvenile idiopathic arthritis in an open monocentric long-term pro- spective study of 163 patients. Ann Rheum Dis. 2008;67(8):1145-1152. Glade-Bender JL, Adamson PC, Reid JM, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol. 2008;26(3):399-405.

OCR for page 285
316 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Grabenstein JD, editor. Immunofacts 2011. St. Louis, MO: Wolters Kluwer Health; 2011. Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non- Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;52(2):177-181. Griffiths A. Growth retardation in early-onset inflammatory bowel disease: should we monitor and treat these patients differently? Dig Dis. 2009;27(3):404-411. Gururangan S, Chi SN, Young Poussaint T, et al. Lack of efficacy of bevacizumab plus irinote- can in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010;28(18):3069-3075. Harjutsalo V, Sjöberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finn- ish children: a cohort study. Lancet. 2008;371(9626):1777-1782. Hashkes PJ, Shajrawi I. Sarcoid-related uveitis occurring during etanercept therapy. Clin Exp Rheumatol. 2003;21(5):645-646. Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol. 2010;6(10):561-571. Hassan AD, Kaelin U, Braathen LR, Yawalkar N. Clinical and immunopathologic findings during treatment of recalcitrant atopic eczema with efalizumab. J Am Acad Dermatol. 2007;56(2):217-221. Hawrot AC, Metry DW, Theos AJ, Levy ML. Etanercept for psoriasis in the pediatric popula- tion: experience in nine patients. Pediatr Dermatol. 2006;23(1):67-71. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692-1698. Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3g1(Ala-Ala) results in improvement in C-peptide responses and clini- cal parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005; 54(6):1763-1769. Herold KC, Gitelman S, Greenbaum C, et al. Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years. Clin Immunol. 2009;132(2):166-173. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132(3):863-873. Hyams JS, Lerer T, Griffiths A, et al. Long-term outcome of maintenance infliximab therapy in children with Crohn’s disease. Inflamm Bowel Dis. 2009;15(6):816-822. Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52(3):522-526. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300. Junod SW. Biologics centennial: 100 years of biologics regulation. Update. Silver Spring, MD: Food and Drug Administration; November-December 2002. Available at http://www. fda.gov/aboutfda/whatwedo/history/productregulation/selectionsfromfdliupdateserieson fdahistory/ucm091754.htm Accessed July 20, 2011. Kanakoudi-Tsakalidou F, Tzimouli V, Pratsidou-Gertsi P, Chronopoulou E, Trachana M. The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment. Cytokine. 2008;42(3):293-297. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distri- bution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5(12):1424-1429. Kaufman A, Herold KC. Anti-CD3 mAbs for treatment of type 1 diabetes. Diabetes Metab Res Rev. 2009;25(4):302-306. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med. 2001;345(15):1098-1104.

OCR for page 285
317 APPENDIX C Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat hemophilia and other hereditary disorders. Haemophilia. 2008;14(4):671-684. Keizer RJ, Huitema ADR, Schelllens JHM, Beijnen JH. Clinical pharmacokinetics of therapeu- tic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493-507. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(52):2598-2608. Koleba T, Ensom MHH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26(6):813-827. Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol. 2005;53(2):338-340. Kress DW. Etanercept therapy improves symptoms and allows tapering of other medications in children and adolescents with moderate to severe psoriasis. J Am Acad Dermatol. 2006;54(3):S126-S128. Lane JE, Cheyney JM, Lane TN, Kent DE, Cohen DJ. Treatment of recalcitrant atopic derma- titis with omalizumab. J Am Acad Dermatol. 2006;54(1):68-72. Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immu- notherapy with tumor necrosis factor α antagonists infliximab and etanercept. Arthritis Rheum. 2002;46(10):2565-2570. Lee S, Ballow M. Monoclonal antibodies and fusion proteins and their complications: target- ing B cells in autoimmune diseases. J Allergy Clin Immunol. 2010;125(4):814-820. Lepore L, Leone V, Marchetti F, Ventura A, Facchini S. Drug-induced systemic lupus erythe- matosus associated with etanercept therapy in a child with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2003;21(2):276-277. Levine D, Gottlieb A. Evaluation and management of psoriasis: an internist’s guide. Med Clin N Am. 2009;93(6):1291-1303. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342(11):763-769. Lovell DJ, Reiff A, Ilowite NT, et al. Safety and efficacy of up to eight years of continu- ous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008a;58(5):1496-1504. Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juve- nile rheumatoid arthritis. N Engl J Med. 2008b;359(8):810-820. Mackey A, Green L, Leptak C, Avigan M. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update. J Pediatr Gastroenterol Nutr. 2009;48(3):386-388. Maguire A, Craig M, Chan A, et al. The case for biennial retinopathy screening in children and adolescents. Diabetes Care. 2005;28(3):509-513. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis—why does it vary so much? J Rheumatol. 2002;29(7):1520-1530. Marji JS, Marcus R, Moennich J, et al. Use of biologic agents in pediatric psoriasis. J Drugs Dermatol. 2010;9(8):975-986. McEvoy GK, editor. AHFS Drug Information 2011. In STAT!Ref Online Electronic Medical Li- brary [online database]. Jackson, WY: Teton Data Systems; 2011. http://online.statref.com. proxy.cc.uic.edu/Document/Document.aspx?docAddress=pDsr3ldZEAdtFTdz9Db3Dw %3d%3d&offset=81&SessionId=15854A2CXDYSQQRR. Accessed July 24, 2011. Meinhardt A, Burkhardt B, Zimmermann M, et al. Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia. J Clin Oncol. 2010;28(19):3115-3121. Menter M, Cush JM. Successful treatment of pediatric psoriasis with infliximab. Pediatr Dermatol. 2004;21(1):87-88.

OCR for page 285
318 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826-850. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869. Morgan B. The search for child cancer drugs grows up. Nat Med. 2011;17(3):267. Moul DK, Routhouska SB, Robinson MR, Korman NJ. Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol. 2008;58(6):984-989. Myers A, Clark J, Foster H. Tuberculosis and treatment with infliximab. N Engl J Med. 2002;346(8):625. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Pro- gram Expert Panel Report 3. Guidelines for the diagnosis and management of asthma. Summary report. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. http:// www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf. Accessed July 14, 2011. National Psoriasis Foundation. About psoriasis. Statistics. Portland, OR: National Psoriasis Foundation. http://www.psoriasis.org/learn_statistics. Accessed July 16, 2011. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term man- agement of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114(6):1708-1733. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medi- cine. Heart. 2003;89(11):1358-1362. Nydegger UE, Sturzenegger M. Adverse effects of intravenous immunoglobulin therapy. Drug Saf. 1999;21(3):171-185. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572-1582. Pain CE, McCann LJ. Challenges in the management of juvenile idiopathic arthritis with etanercept. Biologics. 2009;3:127-139. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241-251. Papoutsaki M, Costanzo A, Mazzotta A, Gramiccia T, Soda R, Chimenti S. Etanercept for the treatment of severe childhood psoriasis. Br J Dermatol. 2006;154(1):181-183. Pappa H, Thayu M, Sylvester F, Leonard M, Zemal B, Gordon C. Skeletal health of chil- dren and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2011;53(1):11-25. Peek R, Scott-Jupp R, Strike H, Clinch J, Ramanan AV. Psoriasis after treatment of juvenile idiopathic arthritis with etanercept. Ann Rheum Dis. 2006;65(9):1259. Peskovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143-2152. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheuma- tology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-392. Pfefferkorn M, Burke G, Griffiths A, et al. Growth abnormalities persist in newly diagnosed children with Crohn’s disease despite current treatment paradigms. J Pediatr Gastroen- terol Nutr. 2009;48(2):168-174. Pigneur B, Seksik P, Viola S, et al. Natural history of Crohn’s disease: comparison between childhood- and adult-onset disease. Inflamm Bowel Dis. 2010;16(6):953-961. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186.

OCR for page 285
319 APPENDIX C Quartier P, Allantaz F, Cimaz R, et al. A multicenter, randomized, double-blind, placebo- controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70(5): 747-754. Radosevich M, Burnouf T. Intravenous immunoglobulin G: trends in production methods, quality control, and quality assurance. Vox Sang. 2010;98(1):12-28. Rohrbach M, Clarke JTR. Treatment of lysosomal storage disorders. Drugs. 2007;67(18): 2697-2716. Roifman CM, Berger M, Notarangelo LD. Management of primary antibody deficiency with replacement therapy: summary of guidelines. Immunol Allergy Clin N Am. 2008;28(4): 875-876. Roque AC, Lowe CR, Taipa MA. Antibodies and genetically engineered related molecules: production and purification. Biotechnol Prog. 2004;20(3):639-654. Rosh JR. Use of biologic agents in pediatric inflammatory bowel disease. Curr Opin Pediatr. 2009;21(5):646-650. Rosh JR, Lerer T, Markowitz J, et al. Retrospective evaluation of the safety and effect of adalimumab therapy (RESEAT) in pediatric Crohn’s disease. Am J Gastroenterol. 2009;104(12):3042-3049. Ruemmele FM, Prieur AM, Talbotec C, Goulet O, Schmitz J. Development of Crohn disease during anti-TNF-α therapy in a child with juvenile idiopathic arthritis. J Pediatr Gastro- enterol Nutr. 2004;39(2):203-206. Ruperto N, Lovell DJ, Cuttica R, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007;56(9):3096-3106. Ruperto N, Lovell DJ, Quartier P, et al. Abatacept in children with juvenile idiopathic ar- thritis: a randomized, double-blind, placebo-controlled withdrawal trial. Lancet. 2008; 372(9636):383-391. Saeki H, Furue M, Furukawa F, et al. Guidelines for management of atopic dermatitis. J Der- matol. 2009;36(10):563-577. Safa G, Loppin M, Bousser AM, Barbarot S. Etanercept in a 7-year-old boy with severe and recalcitrant psoriasis. J Am Acad Dermatol. 2007;56(2 suppl):S19-S20. Sandhu BK, Fell JME, Beattie M, et al. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. J Pediatr Gastroenterol Nutr. 2010;50(suppl 1):S1-S13. Sauer CG, Kugathasan S. Pediatric inflammatory bowel disease: highlighting pediatric differ- ences in IBD. Med Clin N Am. 2010;94(1):35-52. Sawczenko A, Ballinger AB, Savage MO, Sanderson IR. Clinical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics. 2006;118:124. Sherry N, Hagopian W, Ludvigsson H, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378 (9780):487-497. Shikhare G, Kugathasan S. Inflammatory bowel disease in children: current trends. J Gastro- enterol. 2010;45(7):673-682. Siegel J. IVIG medication safety: a stepwise guide to product selection and use. Pharmacy Practice News. 2010;1-8. Siegfried EC. Long-term follow-up of a child treated with efalizumab for atopic dermatitis. Arch Dermatol. 2007;143(8):1077-1078. Simon D, Hosli S, Kostylina G, Yawalker N, Simon HU. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008;121(1):122-128. Soucie JM, Evatt B, Jackson D, and the Hemophilia Surveillance System Project Investigators. Occurrence of hemophilia in the United States. Am J Hematol. 1998;59(4):288-294.

OCR for page 285
320 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy Clin N Am. 2010;30(3):269-280. Sukhatme SV, Gottlieb AB. Pediatric psoriasis: updates in biologic therapies. Dermatol Ther. 2009;22(1):34-39. Takiguchi R, Tofte S, Simpson B, et al. Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol. 2007;56(2):222-226. Tarantino M, Ma A, Aledort L. Safety of human plasma-derived clotting factor products and their role in hemostasis in patients with hemophilia: meeting report. Haemophilia. 2007;13(5):663-669. Thayu M, Leonard MB, Hyams JS, et al. Improvement in biomarkers of bone formation dur- ing infliximab therapy in pediatric Crohn’s disease: results of the REACH study. Clin Gastroenterol Hepatol. 2008;6(12):1378-1384. Tollefson MM, Crowson CS, McEvoy MT, Kremers HM. Incidence of psoriasis in children: a population-based study. J Am Acad Dermatol. 2010;62(6):979-987. Torpy JM, Campbell A, Glass RM. Chronic diseases of children. JAMA. 2010;303(7):682. Trippett TM, Herzog C, Whitlock JA, et al. Phase I and pharmacokinetic study of cetux- imab and irinotecan in children with refractory solid tumors: a study of the pediat- ric oncology experimental therapeutic investigators’ consortium. J Clin Oncol. 2009; 27(30):5102-5108. Turunen P, Ashorn M, Auvinen A, Iltanen S, Huhtala H, Kolho K. Long-term health outcomes in pediatric inflammatory bowel disease: a population-based study. Inflamm Bowel Dis. 2009;15(1):56-62. Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol. 2006;55(1):168-170. Viola F, Civitelli F, DiNardo G, et al. Efficacy of adalimumab in moderate-to-severe pediatric Crohn’s disease. Am J Gastroenterol. 2009;104(10):2566-2571. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious disease associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38(9): 1261-1265. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab ther- apy in children with chronically active severe Crohn’s disease. Inflamm Bowel Dis. 2007;13(4):424-430. Weinberg JM, Siegfried EC. Successful treatment of severe atopic dermatitis in a child and an adult with the T-cell modulator efalizumab. Arch Dermatol. 2006;142(5):555-558. Wickersham RM, editor. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2011. Wiegering V, Morbach H, Dick A, Girschick HJ. Crohn’s disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature. Rheumatol Int. 2010:30(6):801-804. World Federation of Hemophilia. Guidelines for the management of hemophilia. Montreal, Quebec, Canada: World Federation of Hemophilia; 2005. http://www.wfh.org/2/docs/ Publications/Diagnosis_and_Treatment/Guidelines_Mng_Hemophilia.pdf. Accessed July 14, 2011. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo- controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998-1006.