Safe and Effective Medicines for Children Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (2012) / Chapter Skim
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Appendix C: Biologics in Pediatrics
Appendix C: Biologics in Pediatrics
Pages 285-320
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From page 285... ...
. 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)
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From page 286... ...
. 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)
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From page 287... ...
For example, the first precipitate of the process -- cryoprecipitate -- is a rich source of coagulation proteins or factors (e.g., factor VIII and fibrinogen)
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From page 288... ...
. Recombinant therapeutics generally include monoclonal antibodies, fusion proteins, and recombinant versions of human proteins (e.g., recombinant-derived coagulation factors)
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From page 289... ...
Human tumor necrosis factor alpha Human Certolizumab (Cimzia) Humanized Golimumab (Simponi)
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From page 290... ...
. 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.
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From page 291... ...
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)
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From page 292... ...
. 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)
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From page 293... ...
The formation of antibodies 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)
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From page 294... ...
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 bleeding (DiMichele, 2008)
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From page 295... ...
revealed 48 cases of malignancy among pediatric patients prescribed TNF inhibitors, primarily for inflammatory bowel disease (Diak et al., 2010)
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From page 296... ...
Biologics as the Treatment of Choice for Certain Disorders Some diseases, although not widespread among children, commonly employ biologics, particularly plasma-derived or recombinant products, as treatment options. Examples of these diseases include hemophilia/bleeding disorders, immune deficiency syndromes, Kawasaki disease, and immune thrombocytopenic purpura (ITP)
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From page 297... ...
The purity of the factor VIII product does not appear to enhance safety for patients with hemophilia A; therefore, this product characteristic does not affect factor VIII product selection. With regard to viral inactivation/elimination, the World Federation of Hemophilia simply states that plasma quality and testing of the factor concentrate should definitely be considered but does not firmly recommend a particular coagulation factor product as being a safer option.
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From page 298... ...
. A variety of IGIV products for treatment of primary immune deficiency syndrome are currently commercially available.
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From page 299... ...
. Potential Therapeutic Options for Other Selected Pediatric Disorders Rheumatology: Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA)
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From page 300... ...
The efficacy and safety of adalimumab for JIA were established through the results of a randomized, double-blind, stratified, placebo-controlled study enrolling 171 pediatric patients (ages 4 to 17 years) (Lovell et al., 2008b)
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From page 301... ...
. The number of pediatric patients who had ACR Pedi 30, 50, 70, or 90 responses was significantly greater for those receiving adalimumab in combination with methotrexate than those receiving methotrexate therapy alone.
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From page 302... ...
In contrast to many other pediatric diseases, several biologics are approved for use by pediatric patients with JIA; however, various unanswered, challenging questions that can be addressed only through rigorous clinical trials remain. These issues include the following (Pain and McCann, 2009)
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From page 303... ...
Many of the currently available systemic therapies for severe disease have potential toxicities and modest efficacy; therefore, biologics may be another option for children with severe atopic dermatitis, though none have been approved by the FDA as safe and effective treatments (Bremmer et al., 2009)
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From page 304... ...
. Although the exact incidence of moderate to severe psoriasis among the pediatric population is unknown, it has been reported that approximately 8 percent of pediatric patients with psoriasis require phototherapy or systemic medications (Sukhatme and Gottlieb, 2009)
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From page 305... ...
. Gastroenterology: Inflammatory Bowel Disease Crohn's disease and ulcerative colitis, the two major types of inflammatory bowel diseases (IBDs)
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From page 306... ...
. Data for the indication for Crohn's disease are primarily from the REACH trial, an open-label study enrolling 112 pediatric patients with moderate to severe, active Crohn's disease (Hyams et al., 2007; Centocor Ortho Biotech, Inc., 2011)
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From page 307... ...
A retrospective review (the RESEAT trial) of data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group included 115 patients who were given at least one dose of adalimumab (Rosh et al., 2009)
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From page 308... ...
The cytotoxic effects of conventional cancer therapies (e.g., alkylating agents, anthracyclines, and radiation) may have a greater impact on pediatric patients than adults and may manifest as chronic conditions (also referred to as "late effects")
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From page 309... ...
Follow-up data reported that five patients were alive at 14 to 30 months following stem cell transplant, and four of these five patients were free of disease. Bevacizumab has been studied in two trials for treatment of refractory solid tumors, including recurrent malignant gliomas (Glade-Bender et al., 2008; Gururangan et al., 2010)
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From page 310... ...
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.
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From page 311... ...
. 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)
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From page 312... ...
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.
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From page 313... ...
Incidence, prevalence, and time trends of pedi atric inflammatory bowel disease in Northern California, 1996 to 2006. J Pediatr.
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From page 314... ...
Dirks NL, Meibohm B Population pharmacokinetics of therapeutic monoclonal antibodies.
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From page 315... ...
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.
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From page 316... ...
The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol.
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From page 317... ...
Drug-induced systemic lupus erythe matosus associated with etanercept therapy in a child with juvenile idiopathic arthritis. Clin Exp Rheumatol.
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From page 318... ...
Skeletal health of chil dren and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr.
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From page 319... ...
Rosh JR. Use of biologic agents in pediatric inflammatory bowel disease.
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From page 320... ...
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.
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