D

Biologics Studied and Not
Studied in Children
*

To identify biologics that have been studied, were being studied, or were planned for study in children, the Institute of Medicine committee examined several sources of information about biologics that were approved by the Food and Drug Administration (FDA) between January 1, 1997, and December 31, 2010. FDA supplied the list of biologics for products now regulated by the Center for Drug Evaluation and Research (CDER). For the biologics that are regulated by the Center for Biologics Evaluation and Research (CBER), the committee relied on a website listing of biologics for which some supporting documentation was available. CBER staff were consulted to help the committee identify any relevant omitted products and exclude products that were approved under new drug applications (NDAs), were not being marketed, or were not new products.

As explained in Chapter 8, the committee excluded preventive vaccines and nontherapeutic biologics such as assays and reagents (e.g., products used for blood testing or blood grouping). In addition to excluding products approved before 1997, it also excluded products that were approved under new drug applications, were not approved for marketing in the United States, were not being marketed as of December 31, 2010, or were

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* Tables were prepared with the assistance of Lara Ellinger, Pharm.D., B.C.P.S., Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago.



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D Biologics Studied and Not Studied in Children* T o identify biologics that have been studied, were being studied, or were planned for study in children, the Institute of Medicine com- mittee examined several sources of information about biologics that were approved by the Food and Drug Administration (FDA) between Janu- ary 1, 1997, and December 31, 2010. FDA supplied the list of biologics for products now regulated by the Center for Drug Evaluation and Research (CDER). For the biologics that are regulated by the Center for Biologics Evaluation and Research (CBER), the committee relied on a website list- ing of biologics for which some supporting documentation was available. CBER staff were consulted to help the committee identify any relevant omitted products and exclude products that were approved under new drug applications (NDAs), were not being marketed, or were not new products. As explained in Chapter 8, the committee excluded preventive vaccines and nontherapeutic biologics such as assays and reagents (e.g., products used for blood testing or blood grouping). In addition to excluding prod- ucts approved before 1997, it also excluded products that were approved under new drug applications, were not approved for marketing in the United States, were not being marketed as of December 31, 2010, or were * Tables were prepared with the assistance of Lara Ellinger, Pharm.D., B.C.P.S., Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago. 321

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322 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN not new products.1 The final list included 96 biologics. Of these, 57 were regulated by CDER and 39 were regulated by CBER. This appendix reports information from the labeling of these products and from a government registry of clinical trials. Although the committee excluded vaccines for its more extensive analy- sis, it conducted a less intensive review of information on pediatric studies and labeling for vaccines. It identified 55 vaccines with supporting informa- tion that CBER had posted at http://www.fda.gov/BiologicsBloodVaccines/ ucm133705.htm. The vaccines listed include approximately 20 that appear to have been approved before 1997. A number of vaccines (e.g., vaccines for rotavirus and combination vaccines for diphtheria, tetanus, and pertussis) are labeled for pediatric use only. Of the 55 vaccines listed by CBER, three products (5 percent) were not labeled for pediatric use, had waivers of pediatric study requirements, and also did not have pediatric studies registered at ClinicalTrials.gov. • An adenovirus type 4 and type 7 vaccine (no brand name) was developed under contract with the U.S. Department of Defense and approved by FDA in 2011 for use with military personnel ages 17 to 50 years; an earlier product had been used by the military beginning in the 1980s and ending after the sole manufacturer stopped manufacturing the product (Schrager, 2011). FDA waived the pediatric study requirement because studies were impossible or impracticable (Malarkey and Baylor, 2011).2 • An anthrax vaccine (no brand name) was approved in 1970 for use by individuals ages 18 to 65 years who are at high risk of exposure to the disease. In a 2008 approval for a new dosing interval and route of administration, FDA waived the pediatric study require- ment on the grounds that studies were impossible or impracticable because the pediatric population is not at high risk of exposure (Sun, 2008). • A herpes zoster (shingles) vaccine (Zostamax) was approved by FDA in 2006 for use by individuals 60 years of age or older. FDA waived the requirement for pediatric studies because the product 1 The original approval dates and marketing status for biologics are not always easily de- termined. It is possible that one or more of the products listed had an original approval date prior to 1997. After the release of the prepublication manuscript at the end of February 2012, study staff determined that two products (Peginterferon alfa-2B; ribavirin [Pegintron/Rebetrol combo pack] and methoxy polyethylene glycol-epoetin beta [Mircera]) were not marketed as of December 31, 2010, and that one excluded product (drotrecogin alfa [Xigris]) was not discontinued until 2011. Tables D-1 and D-2 were revised to reflect this information. These revisions did not affect the report’s overall conclusions. 2 References cited in this appendix are included in the report’s reference list.

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323 APPENDIX D did not offer a meaningful therapeutic benefit over existing prod- ucts and was unlikely to be used by a substantial number of chil- dren (Baylor, 2006). In addition, FDA waived pediatric studies (without explanation) in ap- proving a vaccine (Twinrix) for prevention of hepatitis A and B (Richman, 2007). For this product, however, ClinicalTrials.gov lists pediatric studies (see, e.g., ClinicalTrials.gov identifier: NCT00107042). For an intradermal formulation of an influenza vaccine (Fluzone), FDA waived pediatric stud- ies because the product did not offer a meaningful therapeutic benefit over existing products and was unlikely to be used by a substantial number of children (Sun, 2011). ClinicalTrials.gov also lists pediatric studies of this product (see, e.g., ClinicalTrials.gov identifier: NCT00391391). For the biologics including in the committee’s more extensive investiga- tion, the committee consulted the current product labeling for references to pediatric studies; examined approval letters, if available, for references to required pediatric studies; checked FDA’s tracking database for postmarket study requirements and commitments for required studies; and searched ClinicalTrials.gov. ClinicalTrials.gov is a registry of publicly and privately supported clinical trials that is administered by the National Institutes of Health. Table D-1, which groups CDER- and CBER-regulated products to- gether, summarizes pediatric information found in the manufacturer’s prod- uct labeling. This information includes any pediatric use(s) for which the product is labeled; descriptions in the labeling of pediatric studies of the product (including studies that did not demonstrate efficacy); and, espe- cially for any products without such labeling information, any warnings against pediatric use based on FDA or other analyses of adverse event re- ports or similar data. Information relevant to use of a product by pediatric populations may be located in several sections of the structured label (e.g., in sections on dosage, clinical pharmacology, and adverse reactions as well as in the highlights section that now appears at the start of prescription labeling). This can complicate efforts to find and summarize this informa- tion. Most of the review of labeling occurred in July and August 2011.3 Table D-2 summarizes information about pediatric studies registered at the ClinicalTrials.gov database. It first presents the information for CDER- regulated products and then presents the information for CBER-regulated 3 After the release of the prepublication manuscript, study staff determined that Table D-1 should be revised to categorize two products (basiliximab [Simulect] and digoxin immune Fab [DigiFab]) as labeled for pediatric use. Some other summary information was edited for specificity. These revisions, based on reexamination of the manufacturer’s labeling, did not affect the report’s overall conclusions.

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324 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN products. For this table, products in certain classes (e.g., intravenous im- mune globulins) that are often treated as interchangeable for certain uses were grouped together because database entries often did not identify stud- ied products by brand name. Trials for which the lower end of a participant age range was 16 years are not included. The database was checked from July to December 2011. The brief summaries in the trials database were sometimes incorrect in indicating that a trial included children, particularly when the more detailed trial descriptions did not include an overview description of the age range but did make clear in the inclusion or exclusion criteria that only adults were eligible. These brief summaries could also be misleading about the condition to be studied, for example, by specifying transplantation rather than transplantation-related complications or disorders. A study catego- rized in the database as a Phase IV study, particularly one requested under the Best Pharmaceuticals for Children Act or required under the Pediatric Research Equity Act, might also fit the definition of a Phase I, II, or III study.

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325 APPENDIX D TABLE D-1 Labeling Information on Pediatric Uses, Studies, and Certain Safety Warnings for Biologics Initially Approved by FDA Between January 1, 1997, and December 31, 2010 (listing for CDER- and CBER- regulated products combined) Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 1. Abatacept • dult rheumatoid A Labeled pediatric use(s) ≥ (Orencia) arthritis • 6 yr with moderately to severely (125118) • uvenile idiopathic J active polyarticular JIA; may 12/23/2005 arthritis (JIA) be used as monotherapy or concomitantly with methotrexate • ot established in patients <6 yr N • ot established for diseases other N than JIA Study information • afety and efficacy were assessed S in patients 6 to 17 yr (n = 190). • indings showed that the risk F of disease flare in patients on Orencia was <1/3 the risk for flare in patients withdrawing from Orencia. • nfections were the most frequent I adverse events. 2. AbobotulinumtoxinA • ervical dystonia C Cervical dystonia: Safety and (Dysport) • emporary T effectiveness not established in (125274) improvement in pediatric patients 04/29/2009 glabellar lines Glabellar lines: Not recommended for pediatric patients <18 yr continued

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326 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 3. Adalimumab • heumatoid arthritis R Labeled pediatric use(s) (Humira) • uvenile idiopathic J • atients 4 to 17 yr for JIA P (125057) arthritis (JIA) • afety and efficacy not established S 12/31/2002 • soriatic arthritis P for children weighing <15 kg and • nkylosing A for conditions other than JIA spondylitis Study information • rohn’s disease C • afety and efficacy were assessed S • laque psoriasis P in patients 4 to 17 yr (n = 171). • indings showed fewer patients F in the adalimumab group than in placebo group experienced disease flare, regardless of methotrexate use. • alignancies have been reported M in children and adolescent patients receiving treatment with tumor necrosis factor blockers, of which adalimumab is a member. • njection site reactions and I infections are common adverse events. 4. Agalsidase beta Fabry disease Labeled pediatric use(s) (Fabrazyme) • atients 8 to 16 yr with Fabry P (103979) disease 04/24/2003 • afety and efficacy have not been S evaluated in children <8 yr. Study information • afety, pharmacokinetics, and S pharmacodynamics were assessed in patients 8 to 16 yr (n = 16). • en of 12 patients taking T agalsidase beta had a reduction in globotriaosylceramide to normal levels. • o new safety concerns were N identified in pediatric patients. • nfusion reactions were the most I common adverse event.

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327 APPENDIX D TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 5. Albumin (human) • ypovolemia H Labeled pediatric use(s) (Albumin), 5%, 25% • ypoalbuminemia H • ypovolemia H (125154) • revention of central P • emolytic disease of the newborn H 10/17/2006 volume depletion (25%) after paracentesis The product should only be • varian O administered to pediatric patients if hyperstimulation needed. syndrome (25% only) Study information • dult respiratory A • ata on use of albumin in D distress syndrome children, including premature (25%) babies, are very limited. • cute nephrosis A (25%) • emolytic disease of H the newborn (25%) 6. Alefacept Chronic plaque Safety and efficacy of Amevive in (Amevive) psoriasis in adult pediatric patients have not been (125036) patients studied. 01/30/2003 7. Alemtuzumab B-cell chronic Safety and effectiveness in pediatric (Campath) lymphocytic leukemia patients have not been established. (103948) 05/07/2001 8. Alglucosidase alfa Late-onset Pompe Labeled pediatric use(s) disease (α-glucosidase (Lumizyme) • atients >8 yr with late-onset P (125291) deficiency) Pompe disease 05/24/2010 • afety and efficacy in pediatric S patients <8 yrs have not been evaluated in clinical trials. Study information • afety and efficacy were assessed S in 90 patients with late-onset Pompe disease, ages 10 to 70 years, in a randomized double- blind, placebo-controlled study designed to enroll patients age 8-70 years. The youngest Lumizyme-treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. continued

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328 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 9. Alglucosidase alfa Pompe disease Labeled pediatric use(s) (α-glucosidase (Myozyme) • nfantile-onset Pompe disease I (125141) deficiency) (improvement in ventilator-free 04/28/2006 survival) • isks and benefits have not been R established in the juvenile-onset Pompe disease population. Study information • ne trial assessed efficacy in O patients ≤7 mo with infantile- onset Pompe disease (n = 18). A greater survival without invasive ventilator support was seen in patients receiving alglucosidase alfa vs. historical control. • second trial assessed efficacy in A patients 3 mo to 3.5 yr (n = 21). No effect of alglucosidase alfa compared with historical control could be determined. • ost common adverse reactions M were infusion related. • naphylactic reactions, A cardiorespiratory failure, and cardiac arrest have also occurred. • pen-label clinical trials have O been performed in older pediatric patients ranging from 2 to 16 years at the initiation of treatment juvenile-onset Pompe disease). 10. Alpha1-proteinase Congenital deficiency of Safety and effectiveness in pediatric α1-proteinase inhibitor inhibitor (human) patients have not been established. (Aralast NP) with clinically evident (125039) emphysema 05/04/2007 11. Alpha1-proteinase Emphysema due to Safety and effectiveness in pediatric inhibitor (human) congenital deficiency of patients have not been established. α1-proteinase inhibitor (Glassia) (125325) 07/01/2010

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329 APPENDIX D TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 12. Alpha1-proteinase Congenital deficiency of Safety and effectiveness in pediatric α1-proteinase inhibitor inhibitor (human) patients have not been established. (Zemaira) with clinically evident (125078) emphysema 07/08/2003 13. Anakinra Rheumatoid arthritis in Not recommended because prefilled (Kineret) adults syringes do not allow accurate (103950) dosing below 100 mg and efficacy 11/14/2001 could not be demonstrated in study because of low enrollment Study information • fficacy was assessed in patients E 2 to 17 yr (n = 86) with juvenile rheumatoid arthritis. • fficacy was not demonstrated. E An adverse event profile similar to that seen in adult patients with rheumatoid arthritis was observed. 14. Antihemophilic • ontrol and C Labeled pediatric use(s) factor (recombinant) prevention of • ppropriate for use in children A (ReFacto) hemorrhagic of all ages with hemophilia A, (103779) episodes and for including newborns 03/06/2000 surgical prophylaxis Study information in patients with • afety and efficacy studies have S hemophilia A been performed with previously • hort-term S untreated neonates, infants, and prophylaxis of children <1 to 52 mo (n = 101). spontaneous bleeding • tudies were also performed with S episodes in patients previously treated children and with hemophilia A adolescents 5 to 18 yr (n = 31). continued

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330 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 15. Antihemophilic • ontrol and C Labeled pediatric use(s) factor (recombinant), prevention of • ontrol and prevention of C plasma/albumin-free bleeding episodes in bleeding episodes in adults and method adults and children children with hemophilia A (Advate) with hemophilia A • erioperative management P (125063) • erioperative P in adults and children with 07/25/2003 management in adults hemophilia A and children with Study information hemophilia A • harmacokinetic studies were P performed in patients 1 mo to <16 yr (n = 51). • n comparison with adults, I children had higher Factor VIII clearance values and thus lower half-lives and recovery of Factor VIII. • arger or more frequent doses L should be considered in a pediatric patient population. 16. Antihemophilic • ontrol and C Labeled pediatric use(s) factor (recombinant), prevention of • leeding episodes in hemophilia A B plasma/albumin free bleeding episodes • urgical prophylaxis in S (Xyntha) in patients with hemophilia A (125264) hemophilia A • escription of indicated uses does D 02/21/2008 • urgical prophylaxis S not mention pediatric population in patients with explicitly. hemophilia A Study information • harmacokinetics were studied in P previously treated patients 12 to 16 yr (n = 7). • harmacokinetic parameters were P similar to those observed in adults.

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331 APPENDIX D TABLE D-1 Continued Generic Name (Trade Name) (BLA Number) Highlights of Pediatric Information Original Approval Date Approved Indication(s) in Labeling 17. Antithrombin • revention of P Safety and effectiveness in pediatric (recombinant) perioperative patients have not been established. (ATryn) and peripartum (125284) thromboembolic 02/06/2009 events in hereditary antithrombin-deficient patients • ot indicated N for treatment of thromboembolic events in hereditary antithrombin-deficient patients 18. Anti-thymocyte Acute rejection in renal Safety and effectiveness in pediatric globulin (rabbit) transplant patients patients have not been established in (Thymoglobulin) controlled trials. (103869) Study information 12/30/1998 • ose, efficacy, and adverse event D profile are thought to be similar to those in adults, based on limited European studies and U.S. compassionate use. 19. Autologous cultured Repair of symptomatic Safety and effectiveness in pediatric chondrocytes cartilage defects of the patients have not been established. (Carticel) femoral condyle (103661) 08/22/1997 continued

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370 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Drug Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 45. Peginterferon alfa-2B Neurofibromatosis 18 mo to II (Pegintron) 21 yr (103949) Malignant melanoma Up to 21 yr II 01/19/2001 Sarcoma 5 to 40 yr III HIV infection 3 mo to 16 yr I Plexiform neurofibroma 1 to 21 yr I Plexiform neurofibroma 18 mo to II 21 yr Neurofibromatosis 2 to 30 yr II ≥12 yr Chronic myeloid leukemia I Hepatitis C 3 to 24 yr III ≥15 yr HIV infection II Glioma Up to 21 yr II 46. Pegloticase None (Krystexxa) (125293) 09/14/2010 47. Ranibizumab None (Lucentis) (125156) 06/30/2006 48. Rasburicase Hyperuricemia Up to 18 yr IV (Elitek) Leukemia; lymphoma 1 to 29 yr II (103946) Malignancy-induced hyperuricemia Age not IV 07/12/2002 specified Tumor lysis syndrome Up to 18 yr IV ≥2 yr Tumor lysis syndrome n/s Nutritional and metabolic diseases Up to 18 yr II ≥15 yr Leukemia; lymphoma III Hyperuricemia 1 to 75 yr III Mature B-cell lymphoma Up to 20 yr II/III 49. Rilonacept Juvenile idiopathic arthritis 18 mo to II (Arcalyst) 19 yr ≥4 (125249) Familial Mediterranean fever yr II ≥7 02/27/2008 Cryopyrin-associated periodic yr III syndromes 50. RimabotulinumtoxinB Cerebral palsy (hand functioning) 2 to 18 yr I/II (Myobloc) (103846) 12/08/2000

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371 APPENDIX D TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Drug Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 51. Rituximab Leukemia; lymphoma Six trials (Rituxan) Lymphoproliferative disorder specifically (103705) include young 11/26/1997 patients; others include patients of any age Neuroblastoma 6 mo to 21 yr n/s 2 mo to 18 yr ≥18 mo Hemophilia II ≥12 yr Thrombotic thrombocytopenic III purpura >12 yr II/II ≥12 yr II Focal segmental glomerulosclerosis 5 to 60 yr II 2 to 80 yr Transplant-related complications, Various age II, multiple trials ranges across III, pediatric IV population Type 1 diabetes mellitus 8 to 45 yr II/III 8 to 45 yr IV ≥5 yr Myositis II ≥5 yr Immunoglobulin A nephropathy IV Nephrotic syndrome 2 to 18 yr II/III ≥15 yr Wegener’s granulomatosis II/III ≥12 mo Aplastic anemia n/s ≥2 yr II Neuromyelitis optica 12 to 86 yr I Central nervous system tumor 18 mo to II 75 yr Opsoclonus-myoclonus syndrome 6 mo to 19 yr I/II Chronic focal encephalitis 5 to 25 yr I Systemic lupus erythematosus 15 to 40 yr II ≥12 yr Lymphomatoid granulomatosis n/s 52. Romiplostim Idiopathic thrombocytopenic purpura 12 mo to III (Nplate) 17 yr (125268) Idiopathic thrombocytopenic purpura 12 mo to I/II 08/22/2008 17 yr Idiopathic thrombocytopenic purpura 1 to 18 yr III ≥1 yr Idiopathic thrombocytopenic purpura III continued

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372 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Drug Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 53. Tenecteplase Restoration of function in n/s III (Tnkase) dysfunctional central venous (103909) catheters (2 studies, including 06/02/2000 subjects weighing <10 kg) 54. Tocilizumab Systemic juvenile idiopathic arthritis Up to 19 yr III (Actemra) Systemic juvenile idiopathic arthritis 2 to 17 yr III (125276) Systemic juvenile idiopathic arthritis Up to 24 mo I 01/08/2010 55. Tositumomab; iodine None I 131 tositumomab (Bexxar) (125011) 06/27/2003 56. Trastuzumab Osteosarcoma <30 yr II (Herceptin) Recurrent osteosarcoma Any age II (103792) 10/25/1998 57. Ustekinumab Psoriasis 12 to 18 yr III (Stelara) (125261) 09/25/2009 Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 1. Albumin (human) Cardiac surgery 2 to 12 yr IV (Albumin) Cardiac surgery Up to 36 mo n/s (125154) 10/17/2006 2. Alpha1-proteinase Type 1 diabetes mellitus 8 to 35 yr II inhibitor (human) Type 1 diabetes mellitus 8 to 35 yr II (Aralast NP) Type 1 diabetes mellitus 6 to 45 yr I (125039) 05/04/2007

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373 APPENDIX D TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 3. Alpha1-proteinase Type 1 diabetes mellitus 10 to 25 yr I/II inhibitor (human) (Glassia) (125325) 07/01/2010 4. Alpha1-proteinase None inhibitor (human) (Zemaira) (125078) 07/08/2003 5. Antihemophilic Hemophilia A (multiple studies) Age ranges I, II, factor (recombinant), vary for III, plasma/albumin free specific IV method studies but (Advate) collectively (125063) cover the 07/25/2003 pediatric age range 6. Antihemophilic factor (recombinant) (ReFacto) (103779) 03/06/2000 7. Antihemophilic factor (recombinant), plasma/albumin free (Xyntha) (125264) 02/21/2008 8. Antithrombin Postoperative hemorrhage in Up to 30 I (recombinant) cardiopulmonary bypass surgery days (ATryn) Postoperative hemorrhage in Up to 30 III (125284) cardiopulmonary bypass surgery days 02/06/2009 continued

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374 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 9. Anti-thymocyte Transplant-related complications, Various age I, II, globulin (rabbit) multiple trials ranges across III, (thymoglobulin) pediatric IV (103869) population 12/30/1998 Type 1 diabetes mellitus 12 to 45 yr I, II 12 to 35 yr II ≥2 yr Aplastic anemia II ≥12 yr II ≥15 yr II Systemic sclerosis Up to 64 yr II Myelodysplastic syndrome All ages II Toxicities of total body irradiation Up to 21 yr IV 10. Autologous cultured None chondrocytes (Carticel) (103661) 08/22/1997 11. Botulism immune Infant botulism Up to 1 yr n/s globulin intravenous (human) (BabyBIG) (125034) 10/23/2003 ≥6 yr 12. C1 esterase inhibitor Hereditary angioedema II/III ≥6 yr (human) Hereditary angioedema III (Berinert) (125287) 10/09/2009 13. C1 esterase inhibitor Hereditary angioedema 2 to 11 yr II ≥6 yr (Cinryze) Hereditary angioedema II (125267) 10/10/2008 14. Coagulation factor Hemophilia A Up to 8 yr II VIIa (recombinant) Cardiopulmonary bypass Up to 30 n/s (NovoSeven) days ≥2 yr (103665) Hemophilia A n/s 03/25/1999 Hemophilia Up to 20 yr IV ≥2 yr Hemophilia A, B II ≥2 yr Hemophilia A, B n/s Factor VII deficiency Up to 90 yr n/s

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375 APPENDIX D TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 15. Coagulation factor IX Hemophilia B (multiple studies) Age ranges III, (recombinant) vary for IV (Benefix) specific (103677) studies but 02/01/1997 collectively cover the pediatric age range 16. Crotalidae polyvalent Snakebite 2 to 80 yr III ≥1 yr immune Fab (ovine) Snakebite IV (CroFab) (103788) 10/02/2000 17. Digoxin immune Fab None (ovine) (DigiFab) (103910) 08/31/2001 18. Fibrin sealant None (human) (Artiss) (125266) 03/21/2008 19. Fibrin sealant Surgical blood loss n/s III (human) (Evicel) (125010) 03/21/2003 20. Fibrin sealant Local bleeding, liver surgery Up to 6 yr II/III (TachoSil) Local bleeding, liver surgery All ages III (125351) (04/02/2010) ≥6 yr 21. Fibrin sealant Burns I/II (Tisseel) Burns Up to 65 yr III Baxter (103980) 05/01/1998 continued

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376 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 22. Fibrinogen Cardiac surgical procedures Up to 18 yr II ≥6 yr concentrate (human) Fibrinogen deficiency II (RiaSTAP) (125317) 01/16/2009 Nonea 23. Hepatitis B immune globulin intravenous (human) (HepaGam B) (125237) 04/06/2007 Nonea 24. Hepatitis B immune globulin (human) (Nabi-HB) (103945) 10/23/2001 25. Immune globulin Trials for infections (both bacterial Various age I, II, intravenous (human) and viral); pediatric autoimmune ranges across III, (Flebogamma 5% neuropsychiatric disorders the pediatric IV DIF [dual inactivation associated with streptococcal age spectrum plus nanofiltration]) infections; neonatal infection; (125077) recurrent infections and 12/15/2003 immunoglobulin G subclass deficiency; HIV infection; 26. Immune globulin Rasmussen encephalitis intravenous (human) 10% solution Multiple trials for primary (Gammagard liquid) immunodeficiencies (125105) Trials for transplantation-related 04/27/2005 complications 27. Immune globulin Other trials for abnormal muscle intravenous (human) movement in neuroblastoma; sickle 5% liquid cell pain crisis; hyperbilirubinemia; (Gammaplex) idiopathic thrombocytopenic (125329) purpura; postpolio syndrome 09/17/2009

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377 APPENDIX D TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 28. Immune globulin injection (human) 10% caprylate/ chromatography purified (Gamunex-C) (125046) 08/27/2003 29. Immune globulin subcutaneous (human) (IGSC) 20% liquid (Hizentra) (125350) 03/04/2010 30. Immune globulin intravenous (human) 5% liquid (Octagam) (125062) 05/21/2004 31. Immune globulin intravenous (human) 10% liquid (Privigen) (125201) 07/26/2007 32. Immune globulin subcutaneous (human) (Vivaglobin) (125115) 01/09/2006 ≤6 mo 33. Protein C concentrate Protein C deficiency II/III (human) Protein C deficiency n/s IV (Ceprotin) (125234) 03/30/2007 continued

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378 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase 34. Rho(D) immune None globulin intravenous (human) (Rhophylac) (125070) 02/12/2004 35. Sipuleucel T None (Provenge) (125197) 04/29/2010 36. Thrombin, topical Aid to hemostasis during surgery Up to 17 yr IV (human) Aid to hemostasis during skin graft 2 to 75 yr II (Evithrom, a surgery component of Evicel) (125247) 08/27/2007 37. Thrombin, topical (recombinant) (Recothrom) (125248) 01/17/2008 ≥1 yr 38. Vaccinia immune Corneal scarring associated with II globulin intravenous vaccinia complication (CNJ-016) Prevention of vaccinal infection n/s I (125109) 05/02/2005

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379 APPENDIX D TABLE D-2 Continued Biologics Under the Jurisdiction of the Center for Biologics Evaluation and Research Generic Name (Trade Name) (BLA Number) Ages of Trial Trial Original Approval Date Condition Participants Phase ≥6 yr 39. von Willebrand Bleeding prevention in surgery III factor/coagulation Von Willebrand disease n/s n/s factor VIII complex Hemophilia A Any age n/s (human) (Wilate) (125251) 12/04/2009 a For the hepatitis B immune globulin products, none of the pediatric study listings involving this type of product cited either brand name. NOTES: For age, n/s indicates a study for which the trial description did not state age explic- itly but included children’s hospital sites or had inclusion criteria or other information text that indicated the inclusion of pediatric patients (e.g., references to trial patients <10 kg). For trial phase, n/s indicates that the phase was not specified in the description. Search terms included a combination of the generic “biologic name AND children” or the “trade name AND children” to capture all registered studies that used that agent. Some biologic agents that are often treated as interchangeable have been grouped together by their generic name (e.g., immune globulin intravenous). For each product that has relevant studies for the class of drug, at least one study identifies that brand name. The listings for each product may not be exhaustive of trials for the same condition, age group, and phase.

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