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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.
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