summary basis for regulatory action review, chair . irwin m. feuerstein : facility review . cecily...

Summary Basis for Regulatory Action Date: 2014-10-14

From: Irwin M. Feuerstein, M.D., M.S., M.B.A., Chair of the BLA

BLA/STN#: 125264/1396

Applicant Name: Pfizer Incorporated / Wyeth Biopharma Division of Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.

Date of Submission: 2013-12-20

PDUFA Goal Date: 2014-10-20

Proprietary Name / Established Name: XYNTHA

Indication: XYNTHA is a recombinant antihemophilic factor indicated in adults and children with hemophilia A for control and prevention of bleeding episodes and for perioperative management.

Recommended Action: Approval

Signatory Authority’s Action:

Office’s Signatory Authority:

□ I concur with the summary review.

□ I concur with the summary review and include a separate review to add further analysis.

□ I do not concur with the summary review and include a separate review.

Material Reviewed Reviewer Name

Clinical Review, Chair Irwin M. Feuerstein

Facility Review Cecily M. Jones

BIMO Review Bhanumahti Kannan

Clinical Pharmacology Review Iftekhar Mahmood

Labeling Review Loan Nguyen

Regulatory Project Manager Leigh Pracht, Pratibha Rana

Biostatistics Review Boris Zaslavsky

Executive Summary STN 125264 is Pfizer/Wyeth’s application for XYNTHA B-domain-deleted recombinant factor VIII antihemophilic factor indicated for treatment of bleeding episodes. Supplement 1396 is a pediatric efficacy supplement submitted to include pediatric information in the label and to modify the indication to specify children.

Four clinical trials contribute data to the submission: Studies 310, 313, 3315, and 4418. Study 310 was the pivotal phase 3 trial for the original licensing application, which contained 17 pediatric subjects, aged 12-15, with safety, efficacy, and pharmacokinetic data. Study 313 was a phase 3 trial of pediatric subjects less than 6 years old that collected safety and efficacy data. At the time of data lock, there were 27 subjects available for analysis; 15 of 42 subjects had been removed from the analysis because of disqualification of their study site secondary to irregularities in data collection. As the study was not powered for efficacy or safety, removal of these subjects does not impact the data review. No safety concerns arose from any of these subjects. Studies 3315 and 4418 had only four subjects between them before the studies were discontinued for logistical reasons. Demographic subanalyses were not performed. All subjects were male, 96% were Caucasian, and 15% were Hispanic.

Safety data were pooled across all four studies. The product demonstrated acceptable safety in the evaluated population. The primary safety evaluation was for inhibitor formation. The one subject with inhibitor formation in Study 310 is already included in the label. Two subjects in Study 313 developed low-titer, transient factor VIII inhibitors that were neither confirmed with repeat inhibitor testing at a second laboratory, nor corroborated with anti-factor VIII (b)(4) testing. These subjects were withdrawn from the trials as mandated by protocol. Evaluations by the medical officer and the product reviewer accept the applicant’s analysis and conclusion that these two cases represent false-positive results. No new safety signals were identified. No other related, serious adverse reactions occurred in Study 313.

Efficacy data were evaluated from Studies 310 and 313 individually. The product demonstrated acceptable efficacy for treatment of bleeding episodes in the target population. Both studies demonstrated that bleeding episodes were controlled with one or two infusions of product in over 94% of episodes. Hemostatic efficacy of treatment for on-demand bleeding was rated as excellent or good in 58% of subjects in Study 310 and in 95% of subjects in Study 313.

Analysis of pharmacokinetic data demonstrated that XYNTHA in children has a shorter half-life, higher clearance, larger volume of distribution, and lower recovery. Recommendation for dose adjustment for the younger patient is included in the prescribing information.

The data show a favorable benefit-to-risk profile. The review team concludes that the application demonstrates acceptable safety and efficacy in the pediatric population and recommends approval of the pediatric efficacy supplement.

Regulatory History XYNTHA is a recombinant antihemophilic factor indicated for (1) control and prevention of bleeding episodes in patients with hemophilia A, and (2) surgical prophylaxis in patients with hemophilia A. The

product was approved in 2008 for use in all age groups, without limitations and with no clinical postmarketing requirements or commitments.

The active ingredient, moroctocog alfa (AF-CC), is a recombinant, B-domain-deleted factor VIII. The original active ingredient was approved as ReFacto, which used -------(b)(4)---------------------------------- in its manufacturing process. For XYNTHA, manufacturing changes were made to ReFacto to ---------------------------(b)(4)-------------------- reagents and manufacturing steps.

The submission references four NCT numbers on the 3674 form: NCT00141843, NCT00543439, NCT00759655, and NCT00765726.

The safety and efficacy of XYNTHA for initial licensure was established in two pivotal clinical trials. The first pivotal trial studied 94 previously treated subjects with hemophilia A for safety and efficacy to support the indication of control and prevention of bleeding episode. The second pivotal trial studied 30 previously treated subjects with hemophilia A for perioperative management during major surgery. Subjects were expected to receive XYNTHA for at least 6 days after surgery.

Orphan Designation and PREA XYNTHA is the same drug active ingredient as ReFacto, with manufacturing changes that include ---------------(b)(4)--------------------------------------------------------------------. ReFacto had orphan designation 95-944 granted in 1996. Because the active ingredient is the same, XYNTHA shares the orphan designation of ReFacto and does not trigger PREA.

Prior Correspondence In a correspondence of 2012-11-26, FDA agreed that pooled safety and pharmacokinetic data from ongoing Study 313 and completed Studies 310, 3315, and 4418 could be used to update the XYNTHA labeling. FDA also agreed that the pooled safety and pharmacokinetic data along with existing on-demand efficacy data from the four studies may be sufficient to support a pediatric indication for treatment of bleeding episodes, but that a final decision would be made on the review of the adequacy of the data.

Proposed, Revised Indication in Labeling The previously approved indication is as stated in the current label: XYNTHA is a recombinant antihemophilic factor indicated for (1) control and prevention of bleeding episodes in patients with hemophilia A, and (2) surgical prophylaxis in patients with hemophilia A. The newly approved indication was revised to state:

• XYNTHA is a recombinant antihemophilic factor indicated in adults and children with hemophilia A for control and prevention of bleeding episodes and for perioperative management.

• XYNTHA is not indicated in patients with von Willebrand’s disease.

Clinical Background Hemophilia A is the most common form of hemophilia, affecting 1 in 5,000 male births. Prevalence in the U.S. is estimated at 20,000 people. The condition is an X-linked hereditary disorder of blood coagulation secondary to decreased levels of Factor VIII:C and results in bleeding into joints, muscles, or internal organs. Median ages of diagnosis in the U.S. for moderate or severe hemophilia are 8 months or 1 month, respectively. Repeated bleeding episodes are common, often symptomatic, and can occur spontaneously or as a result of accidental or surgical trauma. In severe hemophilia, bleeding into joints can result in destructive hemophilic arthropathy with deformity, contractures, and muscle atrophy. One common categorization of deficiency is into severe, moderately severe, moderate, and mild, with factor VIII activity levels of < 1%, 1% to < 2%, 2% to 5%, and > 5% to 40%, respectively.

The applicant states “Xyntha is currently being used in pediatric patients at the discretion of physicians treating patients with hemophilia [off-label use, although the existing label does not have an age restriction]. Pfizer believes that it is in the best interest of patients to update the Xyntha labeling with the most relevant available data in pediatric subjects, as this will enable health care professionals to make better informed decisions regarding the use of this product.” The medical reviewer finds this clinical consideration and approach reasonable and acceptable.

Manufacturing and Controls Please refer to the review memo of the original application.

XYNTHA is presented as a sterile, lyophilized powder and diluent for intravenous injection. XYNTHA comes in two presentations: a product vial with prefilled diluent syringe, and a dual-chamber syringe with powder and diluent in a single unit. The diluent is normal saline.

The product packaged in vials comes in strengths of 250, 500, 1000, or 2000 IU; the SOLOFUSE dual-chamber syringe has an additional strength of 3000 IU. Excipients include sodium chloride, sucrose, L-histidine, calcium chloride, and polysorbate 80. Specific activity range is 5,500-9,900 IU per milligram of protein.

Nonclinical Pharmacology/Toxicology No nonclinical pharmacology or toxicology data were included in the application.

Study Designs and Demographics Data from four clinical trials are submitted in this supplement: Studies 310, 313, 3315, and 4418. Three of these are completed and one trial (Study 313) includes data as of data lock date 2012-12-31. The studies that included pediatric subjects are summarized in Table 1.

Table 1: Summary of Clinical Studies that Included Pediatric Subjects

Overall Sample Population and Disposition In the 155 subjects enrolled in the clinical trials, 48 were pediatric subjects. Of the 48 total pediatric subjects, 40 subjects from combined Studies 310 and 313 (83%, 40/48) had at least 50 exposure days. Fifteen of the 40 subjects with at least 50 exposure days between 12 and less than 16 years old were enrolled in study 310; these subjects were reviewed under the original BLA. The other 25 of 40 subjects with at least 50 exposure days come from Study 313.

No subgroup analyses were conducted for pediatric age, race, and gender. All subjects were male and 96% were Caucasian. Median age was 5 years (range 0-15 years). The overall demographics for the 48 subjects are presented in Table 2.

Table 2: Overall Pediatric Clinical Trials Demographics from Studies 310, 313, 3315, and 4418 (N=48)

Ages Studied 0 to less than 16 years

Subjects 48 pediatric subjects analyzed. Site 010 had 15 subjects which were excluded, so there were 63 enrolled prior to site disqualification.

0 to less than 6 years 28 pediatric subjects analyzed. Site 010 had 15 subjects which were excluded, so there were 43 enrolled prior to site disqualification.

6 to less than 12 years 0


Centers (n) 25 not including Site 010

Countries (centers, n) 10 Countries: Argentina (1 center, 2 subjects); Austria (1 center, 2 subjects); Columbia (1 center, 1 subject); Mexico (1 center, 2 subjects); New Zealand (2 centers, 4 subjects); Poland (2 centers, 10 subjects); Romania (1 center, 5 subjects); Turkey (5 centers, 7 subjects); US (10 centers, 14 subjects); Croatia (1 center, 1 subject)

Race, N (%)

Caucasian 46/48 (96%)

Other 1 Black (2%), 1 Other (2%)

Ethnicity 7 Hispanic (15%), 41 not Hispanic (85%)

Study 310: A Randomized Two-Way Blinded Crossover Design Study to Establish the Bioequivalence of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII, moroctog alfa [AF-CC]) With a Full-Length Recombinant Factor VIII Preparation (FLrFVIII, Advate), Followed by an Open-Label Trial of the Safety and Efficacy of Moroctocog Alfa (AF-CC) in Previously Treated Patients with Hemophilia A Study 310 was the pivotal phase 3 study for licensure of XYNTHA for patients with hemophilia A. The study population was 94 male previously treated patients, 12 years of age or older, with severe or moderately severe hemophilia A, with at least 150 days of exposure to any factor VIII product. FVIII:C activity levels included during pharmacokinetic and safety/efficacy components were ≤ 1% and ≤ 2%, respectively. Subjects had to test negative for factor VIII inhibitors. The study design included a pharmacokinetic bioequivalence study in 31 subjects followed by an open-label safety and efficacy clinical trial of subjects receiving either routine prophylaxis or on-demand treatments to obtain the 50 exposure days. Repeat single-dose pharmacokinetic study of XYNTHA was performed in the 31 subjects

6 months after the initial pharmacokinetic study. The primary efficacy objective was demonstration of bioequivalence between XYNTHA and another licensed product. The primary safety endpoint was incidence of inhibitor formation. Secondary objectives were to characterize the pharmacokinetics, efficacy, rate of responses with less-than-expected therapeutic effect (LETE), consumption over time, and compliance. Subjects in the crossover pharmacokinetics study were randomized to administration of sequential single doses of 50 IU per kg of one product followed by a washout period and administration of 50 IU per kg of the other product. The demographics of Study 310 are presented in Table 3.

Table 3: Pediatric Clinical Trial Demographics in Study 310

Study Types Phase 3, pivotal, pharmacokinetics, safety, and efficacy

Study Designs PK: Double-blind, randomized, crossover against ADVATE; repeat PK at 6 months

Safety and Efficacy: Open-label for prophylaxis and on-demand treatment


Subjects (n) 17




Centers (n) 7

Countries (centers, n) 3 countries: US (4 centers, 6 subjects); Poland (2 centers, 10 subjects); New Zealand (1 center, 1 subject)

Gender All male

Race, N (%)

Caucasian 17 (100%)

Other / Ethnicity 1 Hispanic

Study 313: An Open Label Study to Evaluate Prophylaxis Treatment and to Characterize the Efficacy, Safety, and Pharmacokinetics of B-Domain Deleted Recombinant Factor VIII Albumin Free (Moroctocog alfa [AF-CC]) in Children with Hemophilia A Study 313 was a phase 3, interventional, open-label clinical trial with the primary objective to evaluate the efficacy of prophylaxis treatment to reduce the frequency of bleeding episodes relative to on-

demand therapy in children less than 6 years of age with severe or moderately severe hemophilia A (level ≤ 2%) and with at least 20 prior exposure days. There were 27 subjects analyzed, 25 with more than 50 exposure days. All subjects tested negative for factor VIII inhibitors. Secondary objectives included comparison of efficacy between different prophylaxis regimens. Secondary objectives of the trial were to collect data on safety, efficacy, and pharmacokinetics of XYNTHA in children less than 6 years old. Data provided to this submission has a data lock date of 2012-12-31. The trial was planned for 72 subjects and, as of data lock, 43 subjects had enrolled and 42 had been treated. Only 8 subjects were assigned to on-demand therapy. Enrollment into the on-demand arm of the trial has been difficult since most subjects opted for prophylaxis. See above description of FDA communication of 2012-Nov-26 in Prior Correspondence section for agreement reached. Figure 1 shows the flow diagram for the trial design. In Segment 1, subjects could choose prophylaxis or on-demand treatment; in Segment 2, all subjects entered a study of two prophylaxis regimens. The high-frequency regimen dosed 25 IU per kg every other day and the low-frequency regimen dosed 45 IU per kg twice weekly. Subjects in the on-demand group for Segment 1 were placed in the high-frequency group for Segment 2. Subjects on prophylaxis for Segment 1 crossed over to the other group for Segment 2. Subjects could be escalated to a high-intensity group treated with 45 IU per kilogram every other day if they experienced sufficient numbers of bleeding episodes s in the absence of inhibitor formation. Subjects could go to an even higher intensity regimen if needed. The demographics of Study 313 are presented in Table 4.

Figure 1: Overview of Study 313

Table 4: Pediatric Clinical Trial Demographics for Study 313

Study Type Phase 3 safety, efficacy, and pharmacokinetics

Study Designs Prospective, interventional, open-label, uncontrolled


Subjects (n) 27




Centers (n) 15

Countries (centers, n) 9 countries, 10 if including disqualified site 010. Argentina (1 center, 2 subjects), Austria (1 center, 2 subjects), Columbia (1 center, 1 subject), Croatia (1 center, 1 subject), Mexico (1 center, 2 subjects), New Zealand (1 center, 3 subjects), Romania (1 center, 5 subjects), Turkey (5 centers, 7 subjects), USA (3 centers, 4 subjects)

Gender All male (100%)

Race, N (%)


Other / Ethnicity 1 Other Race (4%) 6/27 (22%) Hispanic, 21/27 (78%) not Hispanic

Study 3315: An Open-Label Study to Evaluate the Efficacy and Safety of XYNTHA in Children <6 Years of Age in Usual Care Settings Study 3315 was originally designed as a phase 3b/4, multicenter clinical trial. The emphasis was to collect data on 30 previously untreated patients. Inclusion criteria included male children less than 6 years old with severe or moderately severe hemophilia A, FVIII:C activity at most 2%, and under 50 days of exposure. The primary objective was to evaluate the safety of XYNTHA in children less than 6 years old. Secondary objectives included evaluation of annualized bleeding rates for prophylaxis and efficacy of on-demand treatment for incident hemorrhage. After a change in the inclusion criteria for Study 313, which then allowed enrollment of subjects with exposure as low as 20 days, Study 3315 was then in competition with Study 313 for subject enrollment. The applicant terminated Study 3315 to eliminate the competition for subjects between the two trials. The demographics of the single subject enrolled in Study 3315 are presented in Table 5.

Table 5: Pediatric Clinical Trial Demographics for Study 3315

Study Types Safety and efficacy

Study Designs Nonrandomized, uncontrolled, open-label, prospective, multicenter clinical trial


Subjects (n) 1




Centers (n) 1

Countries (centers, n) 1: USA (1 center, 1 subject)

Race, N (%)


Other / Ethnicity 0/0 (0%) Hispanic, 1/1 (100%) not Hispanic

Study 4418: A Post Authorization Safety Surveillance Study of XYNTHA in Usual Care Settings Study 4418 was a phase 4, nonrandomized, uncontrolled, open-label, multicenter, prospective clinical trial of XYNTHA. Inclusion criteria were male subjects, at least 12 years of age, negative for factor VIII inhibitors, previously treated with over 150 exposure days, and transitioning from ReFacto or other factor VIII products. The primary objective was to evaluate factor VIII inhibitor formation. The secondary objective was to characterize the overall safety profile of XYNTHA through collection of adverse reactions and less-than-therapeutic effect (LETE). Subjects could participate for up to 2 years. During the active surveillance phase, factor VIII inhibitor and recovery studies were performed at each visit. During the observational surveillance phase, subjects were managed with routine care. The demographics for the three subjects less than 16 years old in Study 4418 are presented in Table 6.

Table 6: Pediatric Clinical Trial Demographics in Study 4418

Study Types Safety and inhibitor development

Study Designs Phase 4, nonrandomized, uncontrolled, open-label, multicenter, prospective clinical trial


Subjects (n) 3




Centers (n) 2

Countries (centers, n) 1 Country: US (2 centers, 3 subjects)

Race, N (%)

Caucasian 2/3 (67%)

Other / Ethnicity 1/3 (33%) Black 0/0 (0%) Hispanic, 3/3 (100%) not Hispanic

Study 311 was the pivotal trial for the XYNTHA surgical prophylaxis indication approved under 125264/797/e0048. Because Study 311 included no subjects less than 16 years old, data from Study 311 are not included in this analysis. At the time of approval, Study 311 had enrolled 30 subjects. The final study report revealed that the youngest subject was 18 years old.

Clinical Pharmacology Pediatric pharmacokinetic parameters were studied in nine children, four children 14-15 years old and included in the original population for licensure, and five children 3 to less than 6 years old from the dedicated pediatric studies. In the pediatric population studied, the following differences were noted between adults and children: (a) pediatric half-lives are shorter, (b) pediatric volumes of distribution are larger, and (c) pediatric recovery is lower. Trends between children less than 6 years old and adolescents between 12 and less than 16 years old are provided in Table7.

The label will include the statement that “Larger or more frequent dosing may be needed.”

Table 7: Mean ± Standard Deviation for XYNTHA Pharmacokinetic Parameters in Previously Treated Pediatric Patients with Hemophilia A after Single 50 IU per kg Dose

Parameter Young Children (n = 5) Adolescents (n = 4)

Age (min-max, years) 3.7-5.8 14-15

Peak Concentration (IU per mL) 0.78 ± 0.34 0.97 ± 0.21

Area Under Curve∞ (IU-hr per mL) 12.2 ± 6.5 8.5 ± 4.0

Half-life (hours) 8.3 ± 2.7 6.9 ± 2.4

Clearance (mL per hour per kg) 6.29 ± 4.87 6.62 ± 2.1

Volume of Distribution (mL per kg) 66.9 ± 55.6 67.1 ± 13.6

Recovery (IU/dL per IU/kg) 1.52 ± 0.69 1.95 ± 0.41

In the pediatric population, individualization of dosing may be needed. Children may need relatively larger doses (higher IU per kg) or more frequent doses.

Pharmacokinetics and Dosing A total of 7150 infusions were administered to 48 pediatric subjects. The median dose per infusion was 29 IU per kg, with range of 9-108 IU per kg per infusion.

Pharmacokinetic data is available for nine children, four aged 14-15 years old and five aged 3.7-5.8 years old. Profiles were obtained after single 50 IU per kg doses. In children, the half-life of XYNTHA is shorter, and the clearance per kg body weight is 40% higher, than in adults. Larger or more frequent doses may be needed. Other factor VIII product labels have similar statements. Trends between the various studies of XYNTHA are displayed in Table 8.

Table 8: Pharmacokinetic Parameters from Studies of XYNTHA in Different Populations

Parameter Young Children Adolescents Pivotal Trial Surgery Trial

C(max) (IU/mL) 0.78 ± 0.34 0.97 ± 0.21 1.08 ± 0.22 1.08 ± 0.24

AUC(∞) (IU x hr/mL)

12.2 ± 6.50 8.5 ± 4.0 13.5 ± 5.6 16.0 ± 5.2

t(1/2) (hours) 8.3 ± 2.7 6.9 ± 2.4 11.2 ± 5.0 16.7 ± 5.4

CL (mL/hr/kg) 6.29 ± 4.87 6.62 ± 2.16 4.51 ± 2.23 3.48 ± 1.25

Vss (mL/kg) 66.9 ± 55.6 67.1 ± 13.6 66.1 ± 33.0 69.0 ± 20.1

Recovery (IU/dL per IU/kg)

1.52 ± 0.69 1.95 ± 0.41 2.15 ± 0.44 2.17 ± 0.47

AUC(∞) = Area under the plasma concentration-time curve from zero to infinity; C(max) = Peak concentration; t(1/2) = Plasma elimination half-life; CL = Clearance; Vss = Volume of distribution at steady state

Regarding the assessment of factor VIII:C pharmacokinetics over time, one pediatric subject in Study 310 had full pharmacokinetic profiles twice, and three pediatric subjects in Study 4418 had recovery studies repeatedly for up to 24 months. In Study 310, bioequivalence was defined as ratios of month-6/baseline geometric means for AUC and recovery (K) within 80-125%. In Study 4418, recovery was assessed using summary statistics. No significant changes in the full profile or recovery were reported.

Efficacy Efficacy in pediatric subjects was determined using the number of infusions per bleed and a 4-point hemostatic efficacy scale to assess response to on-demand treatment. The hemostatic efficacy scale is a 4-point ordinal scale with ratings of excellent, good, moderate, and no response. The scale takes into account pain relief, time course, and number of infusions.

• Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered.

• Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode; OR Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following the infusion, with no additional infusion administered.

• Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode.

• No response: No improvement at all between infusions or during the 24 hour interval following an infusion, or condition worsens.

Efficacy was determined from Studies 310 and 313, which studied efficacy in their pediatric populations. Studies 3315 and 4418 did not study efficacy. In the efficacy trials, the treatment of bleeding episodes

was at the discretion of the caregiver or investigator. Studies 310 and 313 enrolled 44 subjects at risk for bleeding (27 subjects from Study 313 and 17 subjects from Study 310). Of the 44 subjects at risk, 35 subjects received on-demand treatment (25 subjects from Study 313 and 10 from Study 310). Efficacy data were presented separately for the two trials. Data from the two trials, plus pooled demographic data, are presented below.

Pooled Demographic Data from the Efficacy Population Data for efficacy derive from Studies 310 and 313. Pooled demographic data from these two clinical trials are presented in Table 9.

Table 9: Demographics from Subjects who Received at Least One Dose of XYNTHA in Efficacy Trials 310 and 313

Demographic Data Study 310 (N=17) Study 313 (N=27) Pooled (N=44) Age (years) Mean = 14

Median = 14 Range 12-15

Mean = 5 Median = 5 Range 2-5.9

Mean 8 years Range 2-15

Gender 100% male 100% male 100% male Race, % (n) Caucasian 100% (17/17) Caucasian 96% (26)

Other 4% (1) Caucasian 98% (43/44) Other 2% (1)

Ethnicity, % (n) Hispanic 6% (1) Not Hispanic 94% (16)

Hispanic 22% (6) Not Hispanic 78% (21)

Hispanic 16% (7) Not Hispanic 84% (37)

Efficacy Data from Individual Studies In both Studies 310 and 313, the large majority (96% in Study 310 and 94% in Study 313) of bleeding episodes resolved with one or two infusions. Details of individual trial efficacy data are provided below.

Study 310 A subset of 10 subjects out of the 17 total pediatric subjects received on-demand therapy for at least one bleeding episode. There were 66 bleeding episodes, all with assessments. Bleeding resolved with one or two infusions in 96% (63/66) of episodes. Bleeding resolved with one infusion in 79% (52/66) or two infusions in 17% (11/66). On a 4-point scale of hemostatic efficacy (excellent, good, moderate, or no response), 58% (38/66) were rated as excellent or good, 36% (24/66) were rated as moderate, and 0% (0/66) were rated as no response.

Study 313 Of the 27 subjects who received at least one dose of XYNTHA, 25 experienced at least one bleeding episode that necessitated on-demand treatment. Bleeding included episodes both spontaneous and traumatic. Demonstration of efficacy for the currently approved indication, treatment of bleeding episodes, was a secondary efficacy endpoint for the trial. Bleeding assessments were available for 24 of the 25 subjects with bleeds. In one subject, the initial bleed was treated with Advate and the first infusion is not evaluable. In the 24 subjects with assessments, there were 493 bleeds. Bleeding resolved with one or two infusions in 94% (462/493, mean 1.4 infusions for resolution) of episodes.

Bleeding resolved with one infusion in 78% (386/493) or two infusions in 15% (76/493). On a 4-point scale for subject-rated efficacy (excellent, good, moderate, or no response), 95% (468/493) of responses to initial treatment for bleeding episodes were rated as excellent (69%, 339/493) or good (26%, 129/493), 5% (22/493) were rated as moderate, and 0.4% (2/493) were rated as no response.

Safety Pooled Safety data was pooled across four studies: 313 (locked), 310 (completed), 3315 (terminated by applicant), and 4418 (terminated by applicant). A total of 48 pediatric subjects were evaluated for safety. Of the 48 subjects, 28 were less than 6 years old and 20 were between 12 to less than 16 years old (12 years inclusive). Of the 40 subjects with greater than 50 exposure days, 25 were less than 6 years old and 15 were 12 to less than 16 years old.

Overall Population A total of 48 subjects were included after the 15 subjects from disqualified Site 010 were excluded. All subjects were male, 96% (n=46) were Caucasian, and 15% (n=7) were Hispanic. No analyses of race were conducted. Data were also analyzed by age groups less than 6 years (n=28) and 12 to under 16 years old (n=20). Median age was 5 years (mean 8, range 0-15). Half (50%, 24/48) of subjects had at least one target joint, and 67% (32/48) had at least 150 previous exposure days to factor VIII products.

Overall disposition Of the 48 total subjects at the data lock date, 33 (69%) completed their respective studies, 9 (19% including the 4 subjects from terminated trials) withdrew, and 6 (13%) were locked. After data lock, two subjects in Study 313 with low-titer, transient, probably false-positive inhibitors were withdrawn as mandated by protocol, for a total of 11 (23%) withdrawals. In Study 313, three of 27 (11%) withdrew initially, with two more after data lock totaling five (19%). In Study 310, two of 17 (12%) withdrew. Four subjects were withdrawn because Studies 3315 and 4418 were terminated for logistical reasons. Three subjects overall withdrew with inhibitors, although two are agreed to be false-positive. Study subject disposition is detailed in Table 10.

Table 10: Subject Disposition by Study

Disposition Data Study 310 (N=17)

Study 313 (N=27)

Study 3315 Study 4418

Locked 0% (0) 22% (6); 15% (4) if withdraw 2 inhibitors

0% (0) 0% (0)

Completed 88% (15) 67% (18) Withdrew or withdrawn

12% (2) 11% (3); 19% (5) if include both inhibitors)

100% (1) 100% (3)

Lack of Efficacy, Death, Lost to Follow Up

0% (0) 0% (0) 0% (0) 0% (0)

Subject Request 0% (0) 4% (1) Investigator Request

6% (1) 4% (1)

Protocol Violoation

0% (0) 4% (1)

Early withdrawal for inhibitors before data lock

6% (1) 0% (0)

Late Withdrawal for Inhibitors

0% (0) 7% (2)

Discontinuation of Study by Sponsor

Yes Yes

Exposure For all types of exposures in all available studies, including prophylaxis and on demand, a total of 7150 infusions of product (does not include Study 4418) were administered over 7486 exposure days (includes Study 4418). The median dose was 29 IU/kg (mean 32 IU/kg, range 9-108 IU/kg or 253-5205 IU absolute), median number of infusions was 120 per subject (mean 159, range 10-309), and median exposure was 114 days (mean 156, range 10-342 days).

For exposures specifically for on-demand and follow-up treatments in all trials, a total of 803 infusions of product were administered over 788 exposure days. The median dose in Studies 310, 313, and 3315 was 28 IU/kg (mean 33 IU/kg, range 10-108 or 253-4164 IU absolute), median number of infusions was 16 per subject (mean 22, range 1-95), and median exposure was 14 days (mean 21, range 1-95)

In Study 310 for on-demand and follow-up treatment, the median dose per infusion was 47 IU per kg (mean 44 IU/kg, range 24-74 IU/kg or 1506-4164 absolute), median number of infusions per subject was 6 (mean 9 infusions, range 1-26), and the median exposure per subject was 6 days (mean 9 days, range 1-26 days).

In Study 313 for on-demand and follow-up treatment, the median dose per infusion was 28 IU per kg (mean 32 IU/kg, range 10-96 IU/kg or 253-2880 absolute), median number of infusions per subject was 18 (mean 29, range 2-95) and the median exposure per subject was 16 days (mean 27 days, range 2-95 days).

For the single subject in Study 3315 that was terminated early, he had 10 days of exposure over 26 weeks, including the first exposure which was from pharmacy stock and not study test article (a protocol violation of no clinical significance).

In Study 4418, the exposures for the three pediatric subjects were 18, 48, and 342 days.

Deaths, Serious Adverse Reactions No deaths occurred in any of the four included clinical trials: Studies 310, 313, 3315, or 4418. Serious adverse events occurred in 17% (8/48) of subjects. The only related serious adverse reactions were factor VIII inhibitors in three subjects. None of the other serious adverse events were considered related to product.

The primary determinants of safety in this population were the formation of factor VIII inhibitors, and factor VIII inhibitors were considered serious adverse reactions as well as adverse events of special interest. Inhibitors were present in three subjects, two (4%) in subjects detected before data lock and one in a sample run drawn before but reported to the applicant after data lock. All three subjects were withdrawn from their respective trials.

There were five subjects with serious adverse events not related to the study medication, for a total of eight subjects with serious adverse events. The other SAEs were anal abscess and anal fistula; tonsillitis; hemarthrosis; muscle hemorrhage; medical device complication; post-procedural hemorrhage; and convulsions and paralysis. All serious adverse events resolved.

Study Withdrawals and Subjects with Factor VIII Inhibitor Formation

Nine subjects withdrew from the study (19% of 48 total) prior to the data lock date of 2012-12-31 and increased to 11 (23%) after data lock. Three subjects out of the 48 subjects (6.25%) under 16 years of age discontinued for the adverse reaction of inhibitor formation and are the only withdrawals secondary to adverse reactions. As the three subjects who withdrew because of an adverse reaction are the same as the three with inhibitors, they are discussed together in the immunogenicity section below. Eight subjects withdrew for reasons other than adverse reactions. Four withdrew because their study was terminated by the applicant, one discontinued because of a protocol violation, two were terminated at the investigator request, and one was terminated at the subject request. No subjects were withdrawn for lack of efficacy. Table 11 shows the incidences and percentages of withdrawals for each clinical trial.

Table 11: Number and Rate of Inhibitor formation in Each Clinical Trial for Subjects Less than 16 Years of Age Who Received XYNTHA

Study Number of

Subjects with Inhibitors

Number who Received at Least

One Dose

Incidence Rate with at least One

Dose

Number with at least 50

Exposure Days

Incidence Rate with at least 50 Exposure Days

310 1 17 5.88% 15 6.67%

313 2 27 7.41% 25 8.00%

3315 0 1 0.00% - 0.00%

4418 0 3 0.00% - 0.00%

Total 3 48 6.25% 40 7.50%

In study 310, 15 of 17 subjects completed the clinical trial and two withdrew. One was withdrawn because of inhibitor formation and one was withdrawn by the investigator for noncompliance. In Study 313, three subjects terminated prior to the data lock date. One withdrew because of subject request because he didn’t want to switch regimens secondary to the adverse experience on a prior regimen, one was withdrawn by the investigator because the subject was unwilling to follow the protocol, and another was withdrawn because the parents would not follow the dosing regimen. The medical officer requested information regarding withdrawal from the adverse experience on a prior regimen and reviewed the submitted narrative. The 5.8 year old subject experienced 33 adverse events, all considered not related and all resolved. Many were musculoskeletal pain while on prophylaxis, although whether they were bleeds was not specified. Since the applicant is not pursing a prophylaxis indication, and there was no indication that on-demand treatment was compromised, the response was considered acceptable. After data lock, two subjects were withdrawn because of low-titer, transient, probably false-positive inhibitor measurements.

Study 3315 was terminated with one ongoing subject. Study 4418 was administratively terminated by the applicant because other ongoing studies were collecting similar data. One subject completed the study, one was withdrawn at study termination, and one requested to be withdrawn.

Withdrawals for Immunogenicity: Case Narratives

Study 310: One Subject Prior to data lock, one subject was withdrawn from Study 310 because of a transient inhibitor. This subject was a 12-year-old Caucasian male with severe hemophilia A (FVIII activity < 1%), a reported history of 2050 EDs to FVIII, and past medical history negative for a FVIII inhibitor. Results from this subject’s central laboratory value at visit 7 (month 3), after 38 EDs to XYNTHA, revealed a low-titer inhibitor of 0.9807 BU/ml. The subject was asymptomatic at this time. Central laboratory results from inhibitor assays performed at visits immediately before and after inhibitor detection were negative. Repeat testing at his final visit reported a negative result of < 0.6 BU/mL. There were no reports of lack of therapeutic effect, no dose escalation, no instances of spontaneous breakthrough bleeds on prophylaxis, no bleeds within 72 hours of a prophylactic dose, and no other clinical evidence of treatment failure. A subsequent -(b)(4) anti-FVIII test was negative. The subject was considered to have recovered from the adverse reaction. The subject received 28 EDs to the study drug between the date the initial positive sample was drawn and the final study visit. He was withdrawn after 66 EDs (153 days on routine prophylaxis) due to this development of an inhibitor to factor VIII. In the 5 months after the final study visit, the subject was seen at the clinical site ten times. During this time, the subject received prophylaxis with approximately 15-20 IU per kg, 2-3 times per week, and has had two bleeding episodes treated with commercial factor VIII concentrate.

Study 313: Two Subjects After data lock of 2012-12-31, two subjects were withdrawn from Study 313 per protocol because of evidence of inhibitors to FVIII. Both had transient, low-titer, clinically silent inhibitors. Both had the

inhibitors discovered on specimens that were drawn before data lock, but the laboratory results were not confirmed until after data lock, in 2013-03. The subjects were withdrawn in 2013-03.

Subject #1

Subject #1 was a 4-year-old male child with severe hemophilia and prior exposure of 362 days. Four bleeds had occurred in the prior year. Blood samples from Visits 7 and 9 were reported as positive for factor VIII inhibitor. Immunogenicity evaluations are presented in Table 12 and laboratory assessment are tabulated in Table 13. During the time period around and after the transient inhibitor development, he never experienced any clinical bleeding or bruising despite being very active. No increase in prophylaxis dose was required and no lack of therapeutic effect was identified. There were no relevant concomitant medications required. The positive inhibitor results were not confirmed by an outside laboratory and anti-factor VIII antibody (b)(4) was negative. This case was discussed internally and the root cause document was reviewed with a product reviewer. We agree with the applicant assessment that this case represents a false-positive instance of low-titer, transient inhibitor development.

Table 12: Immunogenicity Evaluations for Subject #1

Date Description

2011-12-05 Screened, no significant medical history other than severe hemophilia.

2012-01-02 First dose of XYNTHA. Assigned to prophylaxis regimen 45 IU/kg twice weekly for 12 months, then planned switch to 25 IU/kg every other day until end of study.

2012-07-04, 68 ED, Visit 7, Month 6

Inhibitor assays positive at 1.84 BU/mL and 1.86 BU/mL, initially and retested, respectively, tested by --(b)(4)-. Anti-factor VIII antibody evaluation of another sample from the same day was negative.

2012-10-03, Visit 9, Month 9

Inhibitor assays positive and negative at 3.20 BU/mL and < 0.6 BU/mL, initially and retested, respectively, tested by --(b)(4)-. Same sample retested by another laboratory --(b)(4)-- and negative at < 0.6 BU/mL. Anti-factor VIII antibody evaluation of another sample from the same day was negative.

2012-11-21 Recovery assay was done and was normal. A blood sample tested for inhibitors locally and at the central --(b)(4)- laboratory was normal at < 0.6 BU/mL.

Subsequently All subsequent inhibitor tests were negative. See Table 13 below.

2013-03-13 Delayed confirmation of --(b)(4)- central laboratory results, delayed because of technical issues.

2013-03-24 Last dose administered, then permanently withdrawn.

2013-03-27 Early termination visit because of positive results of 2012-07-04 and 2012-10-03.

Table 13: Laboratory Results from Immunogenicity Evaluation for Subject #1

Date

--(b)(4)-- FVIII Inhibitor (BU/mL)

Retest --(b)(4)- FVIII

Inhibitor (BU/mL)

Local Laboratory

FVIII Inhibitor

--(b)(4)- FVIII Inhibitor Titer

(BU/mL) Anti-FVIII Antibody

2012-07-04 1.84 1.86 < 0.6 Negative

2012-10-03 3.20 0 < 0.6 Negative

2012-11-21 < 0.6 Negative

2013-01-09 < 0.6

2013-02-20 < 0.6 Negative

2013-03-27 < 0.6 Negative

Subject #2

Subject #2 was a 4-year-old male child with severe hemophilia and over 50 exposure days of on-demand therapy. Twelve bleeds were reported in the prior year. A blood samples from Visit 5 was reported as positive for factor VIII inhibitor. Immunogenicity evaluations are presented in Table 14 and laboratory assessment are tabulated in Table 15. During the time around and after the transient inhibitor development, he never experienced clinical bleeding or lack of efficacy. No increase in prophylaxis dose was required and there were no concomitant medications needed. Similar to Subject #1, the positive inhibitor results were not confirmed by an outside laboratory and anti-factor VIII antibody (b)(4) was negative. This case was discussed internally and the root cause document was reviewed with a product reviewer. We agree with the applicant assessment that this case represents a false-positive instance of low-titer, transient inhibitor development.

Table 14: Immunogenicity Evaluations for Subject #2

Date Description

2012-02-08 Screened, no significant medical history other than severe hemophilia.

2012-03-13 First dose of XYNTHA. Assigned to prophylaxis regimen 25 IU/kg every other day for 12 months, then 45 IU/kg twice weekly for rest of study.

2012-06-13, Visit 5, Month 3

Inhibitor assay positive at 1.61 BU/mL and 2.11 BU/mL, initially and retested on same sample, respectively, tested by --(b)(4)-. Same sample was retested by another laboratory --(b)(4)--- and was negative at < 0.6 BU/mL. Anti-factor VIII antibody evaluation of another sample from the same day was negative.

2012-08-28 Sample was negative for factor VIII inhibitor by --(b)(4)-.

Subsequently All --(b)(4)- and local samples tested negative for inhibitors. See Table 15.

2013-03-13 Delayed confirmation of positive result for inhibitors on sample taken 2012-06-13.

2013-03-14 Last dose administered, then permanently withdrawn.

2013-03-19 Early termination visit because of positive results of 2012-06-13.

Table 15: Laboratory Results from Immunogenicity Evaluation for Subject #2

Date

--(b)(4)- FVIII Inhibitor (BU/mL)

Retest --(b)(4)- FVIII

Inhibitor (BU/mL)

Local Laboratory

FVIII Inhibitor

--(b)(4)- FVIII Inhibitor Titer

(BU/mL) Anti-FVIII Antibody

2012-06-13 1.61 2.11 < 0.6 Negative

2012-08-28 < 0.6

2012-11-14 < 0.6 Negative

2013-02-07 < 0.6

Conclusion Regarding Factor VIII Inhibitors in Study 313

In summary, these two cases were discussed internally and the root cause document was reviewed with a product reviewer. We agree with the applicant assessment that both of these cases represent false-positive instances of low-titer, transient inhibitor development. Both instances of factor VIII inhibitor were listed as serious and severe, even though they were low titer and asymptomatic.

Studies 3315 and 4418 No factor VIII inhibitors were detected and no withdrawals because of adverse reactions occurred in Study 3315 or Study 4418.

Noninhibitory Binding Antibodies and Other Antibodies Noninibitory antibodies against factor VIII: Subjects did on occasion develop noninhibitory antibodies detected by (b)(4). One subject in Study 310 had noninhibitory antibodies at final Visit 10 without functional inhibitor. Another subject in Study 313 had noninhibitory antibodies at Visit 5 without functional inhibitor. These antibodies are clinically silent, have no known clinical significance, and do not impact the regulatory decision.

Antibodies to Chinese hamster ovary proteins (CHOP) or TN8.2: To date, no antibodies against CHOP or TN8.2 have been detected, although the results were not available for Study 313. The medical officer did request the results again prior to approval but the results are still not available.

General Adverse Reactions

Adverse Reactions In the prescribing information, the list of adverse reactions did not change as no new adverse reactions or safety signals were detected with the addition of the pediatric data. The adverse reactions most frequently reported in all previously treated subjects were headaches (24%), nausea (6%), diarrhea (5%), asthenia (5%), and pyrexia (5%). The adverse reactions most frequently reported in surgical subjects were pyrexia (43%), headache (13%), nausea (13%), and vomiting (7%).

Only four adverse events were considered related to treatment and thus adverse reactions. Three were factor VIII inhibitors, including the two false positives. One adverse reaction was an ALT increase. None of these adverse reactions occured with sufficient frequency to make the list of common adverse reactions, especially if the false positives are not included.

Adverse Events Adverse events were broken down into treatment-emergent adverse events (TEAEs), treatment-emergent hemophilia events (TEHE), and adverse reactions. TEAEs include events of all causality. TEAEs were reported for 83% (40/48) of subjects. Treatment-emergent hemophilia events were reported in 33% (16/48) subjects. The most frequently reported adverse events were cough (27%), pyrexia (25%), headache (23%), arthralgia (23%), vomiting (19%), diarrhea (17%), abdominal pain (13%), asthenia (13%), and nausea (6%). The most common TEAEs reported per subject were pyrexia (22%), nasopharyngitis (21%), vomiting (19%), cough (19%), headache (19%), and diarrhea (17%). These percentages of adverse events (not reactions) are substantially different than the list of adverse reactions presented in labeling for the population which was not specifically pediatric. However, the adverse events reported in this supplement are quite typical for subjects in the pediatric age group, would be expected to occur in different proportions from older trial participants, were considered not related to product administration, and did not lead to withdrawal or discontinuation. The most common treatment-emergent adverse events are presented in Table 16.

Table 16: Treatment-Emergent Adverse Events Reported in Studies 310, 313, 3315, and 4418.

Adverse event Treatment-emergent adverse events, all causality, all ages % subjects (n), N=48

Treatment-emergent adverse events, all causality, < 6 years % subjects (n), N=28

Treatment-emergent adverse events, all causality, 12-15 yrs % subjects (n), N=20

Any event 83% (40) 96% (27) 65% (13)

Pyrexia 22% (11) 39% (11) 0% (0)

Nasopharyngitis 21% (10) 29% (8) 10% (2)

Vomiting 19% (9) 21% (6) 15% (3)

Cough 19% (9) 32% (9) 0% (0)

Headache 19% (9) 14% (4) 25% (5)

Diarrhea 17% (8) 21% (6) 10% (2)

Upper respiratory infection

15% (7) 21% (6) 5% (1)

Extremity pain (non-TEHE)

15% (7) 18% (5) 10% (2)

Acute tonsillitis 13% (6) 21% (6) 0% (0)

Influenza 13% (6) 14% (4) 10% (2)

Head injury 13% (6) 18% (5) 5% (1)

Arthralgia (non-TEHE) 10% (5) 14% (4) 5% (1)

Fatigue 10% (5) 14% (4) 5% (1)

Fall 10% (5) 14% (4) 5% (1)

Limb injury 10% (5) 18% (5) 0% (0)

Rhinorrhea 10% (5) 18% (5) 0% (0)

None of the adverse events were considered allergic in nature and causally related to product. No anaphylactic or serious adverse allergic events were identified. Events that might have been plausibly considered allergic were rhinitis (n=2, 4%), lip swelling (n=1, 2%), pyrexia (n=11, 23%), wheezing (n=2, 4%), nasal congestion (n=1, 2%), rash (n=1, 2%), facial edema (n=1, 2%), urticaria (n=1, 2%), ocular swelling (n=1, 2%), hypersensitivity (n=1, 2%). However, none of these were considered related to study drug by the investigators. One subject in Study 310 experienced mild hypersensitivity (verbatim: allergies) that was treated and resolved, and was considered not related.

Medical officer review shows no pattern of allergic manifestation and mostly single events without clustering. None required discontinuation. Thus, allergic manifestations are concluded to not be a significant aspect of administration.

The most frequent TEHEs per subject were arthralgia (10%), extremity pain (8%), contusion (6%), and pain (6%). The most common TEHEs are presented in Table 17. None of the hemophilia events are considered related to administration of product.

Table 17: Treatment-Emergent Hemophilia Events Reported in Studies 310, 313, 3315, and 4418.

Hemophilia adverse event

Treatment-emergent hemophilia events, all causality, all ages % subjects (n), N=48

Treatment-emergent hemophilia events, all causality, < 6 years % subjects (n), N=28

Treatment-emergent hemophilia events, all causality, 12-15 yrs % subjects (n), N=20

Any event 33% (16) 29% (8) 40% (8)

Arthralgia 10% (5) 7% (2) 15% (3)

Extremity pain 8% (4) 7% (2) 10% (2)

Contusion 6% (3) 4% (1) 10% (2)

Pain 6% (3) 0% (0) 15% (3)

Hemarthrosis 4% (2) 7% (2) 0% (0)

Severity of Adverse Events and Reactions

There were no life-threatening events. There were eight severe events, all in Study 313. These were factor VIII inhibitor, varicella, medical device complication, post-procedural hemorrhage, hemarthrosis, muscle hemorrhage, convulsion, and paralysis. All other adverse events were mild or moderate.

Adverse Events in Individual Clinical Trials

Adverse Events in Study 310

One subject was withdrawn because of an inhibitor, and one was withdrawn by the investigator for noncompliance. The one instance of factor VIII inhibitor is already in the existing label. Adverse events were reported in 65% (11/17) of subjects and are presented in Table 18. Hemophilia adverse events were reported in 41% (7/17) of subjects and are presented in Table 19. All AEs were mild or moderate in severity. The one treatment-related AE was the factor VIII inhibitor. The inhibitor was also listed as a hemophilia event.

Table 18: Treatment-Emergent Adverse Events Reported in Study 310

Adverse events, excluding hemophilia events

Treatment-emergent adverse events, all causality, 12-15 years old % of subjects (n), N=17, Study 310

Any event 65% (11)

Headache 29% (5)

Nasopharyngitis 12% (2)

Vomiting 12% (2)

Oral pain 12% (2)

Pain (non-TEHE) 12% (2)

Influenza 12% (2)

Table 19: Treatment-Emergent Hemophilia Events Reported in Study 310

Hemophilia adverse events

Treatment-emergent hemophilia events, all causality, 12-15 years old % of subjects (n), N=17, Study 310

Any hemophilia event 41% (7)

Pain 18% (3)

Arthralgia 12% (2)

Extremity pain 12% (2)

Contusion 12% (2)

Adverse Events in Study 313 In Study 313, there were eight severe adverse events in 5 of 27 subjects (19%), including hemophilia events. There were eight serious AEs in 5 of 27 subjects (19%) including single subjects with hemarthrosis; factor VIII inhibition; tonsillitis; muscle hemorrhage and medical device complication; and paralysis, post-procedural hemorrhage, and four convulsions. Treatment-emergent adverse events were reported in 96% (26/27) of subjects and are displayed in Table 20. Treatment-emergent hemophilia events were reported in 26% (7/27) of subjects and are displayed in Table 21.

Table 20: Treatment-Emergent Adverse Events Reported in Study 313

Adverse events, excluding hemophilia events

Treatment-emergent adverse events, all causality, < 6 years old % of subjects (n), N=27, Study 313

Any event 96% (26)

Pyrexia 41% (11)

Cough 33% (9)

Nasopharyngitis 30% (8)

Vomiting 22% (6)

Diarrhea 22% (6)

Acute tonsillitis 22% (6)

Upper respiratory infection 19% (5)

Extremity pain (non-TEHE) 19% (5)

Head injury 19% (5)

Limb injury 19% (5)

Rhinorrhea 19% (5)

Table 21: Treatment-Emergent Hemophilia Events Reported in Study 313

Hemophilia adverse events Treatment-emergent hemophilia events, all causality, < 6 years old % of subjects (n), N=27, Study 313

Any hemophilia event 26% (7)

Arthralgia 7% (2)

Extremity pain 7% (2)

Hemarthrosis 7% (2)

The adverse events and serious adverse events reported from Site 010 were not included in the analysis but were reviewed by the medical officer. They were similar to the other sites except for an SAE of Henoch-Schonlein purpura. All SAE were considered unrelated to product and the medical officer agrees.


One subject enrolled and received product. He was a young boy, 1 month old, with severe hemophilia (FVIII:C activity < 1%), white, and not Hispanic. He participated for 26 weeks with 10 exposure days. This one subject, during 26 weeks of participation, experienced 11 adverse events, three of which were serious although none were severe. He did not die during the trial so there were no deaths. None of the events were considered related to the product. Adverse events included anal fistula (two episodes),

anal abscess (two episodes), procedural pain (two episodes), infusion site extravasations, otitis media, influenza, hematoma (TEHE), and contusion (TEHE). All events were mild or moderate intensity. Three of the events were considered serious: both episodes of anal fistula and one event of anal abscess. No factor VIII inhibitors, aberrant vital signs, or clinically significant laboratory results were identified.


There were no deaths, no serious adverse events, and no severe adverse events among the three pediatric subjects. No inhibitor formation was identified. Two of the three subjects reported six TEAEs. Single events of diarrhea, vomiting, nausea, sinusitis, and head injury were reported, along with a single event of arthralgia. All six events were mild intensity and resolved.

Clinical laboratory

Laboratory panels typically included hematology, clinical chemistry, and immunogenicity. Immunogenicity testing assessed for anti-factor VIII, anti-Chinese hamster ovary, and anti-TN8.2 antibodies. One report of elevated ALT level was considered a mild, treatment-related adverse reaction from which the subject recovered with no action taken. No other clinically significant patterns in the clinical laboratory were identified.

Advisory Committee and PREA/PeRC No advisory committee was convened.

XYNTHA has orphan designation. Therefore, the application does not trigger PREA and was not presented to the Pediatric Review Committee.

Labeling Labeling review is ongoing, but the prescribing information has been updated with revisions including, but not limited to, the following sections: (a) Highlights - Recent Major Changes, Adverse Reactions, Use in Specific Populations, (b) Section 6.1 - Clinical Trials Experience, (c) Section 6.2 - Immunogenicity Information, (d) Section 8.4 - Pediatric Use, (e) Section 12.3 - Pharmacokinetics, and (f) Section 14 - Clinical Studies.

Recommendations and Risk/Benefit Assessment

a) Recommended regulatory action The review team recommends approval of the pediatric efficacy supplement.

b) Benefit / risk analysis Recombinant factor VIII products are the standard of care for congenital hemophilia A without inhibitors. XYNTHA has been marketed in the U.S. for many years. The current approved indications are (1) control and prevention of bleeding episodes in patients with hemophilia A, and (2) surgical

prophylaxis in patients with hemophilia A. This pediatric efficacy supplement requests extension of the age range for these same indications and no new indications are requested. The applicant states that the product is already being used extensively off-label in children. Nevertheless, having more information in the label could be beneficial for prescribers and for patients. The risk of extending the age range to include pediatric patients of all ages appears acceptable. No new safety signals or adverse event/reaction profiles are identified that increase the risk to this subset of patients. Therefore, the increased availability of product and improved information in labeling, compared with the small risk, indicates a favorable benefit-to-risk for approval of the pediatric efficacy supplement.

c) Recommendations for postmarketing risk management activities Specific postmarketing risk management activities are not necessary and not recommended.

d) Recommendations for postmarketing activities Specific postmarketing activities are not necessary and not recommended.

summary basis for regulatory action review, chair . irwin m. feuerstein : facility review . cecily...

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