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Summary Basis for Regulatory Action, December 22, 2013 - Tretten

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Date

December 22, 2013

From

Zuben E. Sauna, Committee Chair 

Subject

Summary Basis for Regulatory Action

BLA #

STN 125398/0

Applicant

Novo Nordisk

Date of Submission

February 23, 2011 (1st CR issued December 23, 2011, second CR June 27, 2013)

Goal Date

December 25, 2013 (based on response to CR received on October 25, 2013)

Established name

TRETTEN

Dosage forms

N/A

Proposed Indication(s)

Routine prophylaxis of bleeding in adult and pediatric  patients with congenital Factor XIII A-subunit deficiency

Recommended Action:

Approval

 

Signatory Authority Action

 

Jay S. Epstein, MD ____________________________
Offices Signatory Authority:
I concur with the summary review
I concur with the summary review and include a separate review or addendum to add further analysis
I do not concur with the summary review and include a separate review or addendum

 

Signatory Authority Action

 

Mary Malarkey                                                                
Offices Signatory Authority:
□ I concur with the summary review
I concur with the summary review and include a separate review or addendum to add further analysis
I do not concur with the summary review and include a
separate review or addendum

 

Discipline

Reviewer

CMC / Product

Zuben E. Sauna, Roman Drews, Al Del-Grasso, , Karen Campbell

CMC / Facilities

Destry Sillivan

Administrative / Regulatory

Jiahua, Qian

Biostatistics

Jean Wang, Alan Ou

Labeling

Michael Brony

Establishment Inspection Report

Inspection Waived

Environmental Assessment

Categorical Exclusion Approved

Pharmacology / Toxicology

La’Nissa Brown-Baker

Clinical Pharmacology

Iftekhar Mahmood

Clinical

Charles Maplethorpe, Nisha Jain

Bioresearch Monitoring

Anthony Hawkins, Carla Jordan

Advisory Committee Transcript

N/A

1. Introduction

Novo Nordisk submitted a Biologics License Application (BLA) for Coagulation Factor XIII A-Subunit (Recombinant) (rFXIII A) on February 23, 2011 (BLA 125398/0). The product was granted Orphan Product designation (designation 03-1748). The proprietary name TRETTEN was found to be acceptable. TRETTEN is presented as a lyophilized powder to be reconstituted in sterile water for injection. It is indicated for the routine prophylaxis of bleeding in adults and pediatric patients with congenital Factor XIII A-subunit deficiency. The initial review of the BLA resulted in the issuance of a Complete Response (CR) letter on December 23, 2011 because of several unresolved deficiencies in Chemistry, Manufacturing and Controls (CMC) and Clinical information, and outstanding issues from the pre-license inspections of Novo Nordisk’s facilities.  Novo Nordisk responded to the CR letter on December 6, 2012. Most of the outstanding issues related to CMC and clinical information were resolved to the satisfaction of the review team. The remaining outstanding CMC issues along with pending inspectional issues from the -----------(b)(4)----------- inspection of the Novo Nordisk facility located at ------(b)(4)------------------------------------ were communicated to the applicant in a second CR letter, on June 27, 2013. Subsequently, Novo Nordisk satisfactorily addressed the inspectional and review issues and submitted their response to this CR letter on October 25, 2013.

Factor XIII (FXIII) plays a critical role in the generation of a viable hemostatic plug and is the terminal enzyme in the coagulation cascade.  FXIII, a pro-transglutaminase, circulates in plasma as a tetrameric glycoprotein (molecular weight ~ 320 kDa) composed of two FXIII A subunits and two FXIII B subunits. The FXIII A subunits exhibit catalytic activity while the FXIII B subunits, which have no catalytic activity, function as carrier molecules for the A subunits, prolonging the half-life of the A2/B2 tetramer and preventing spontaneous activation and clearance.

The FXIII A subunit catalyzes the cross-linking of the a- and g-chains of fibrin, thus stabilizing the fibrin clot. In addition, the A subunit catalyzes the cross-linking between a2-plasmin inhibitor and the a-chain of fibrin, which protects the clot from degradation by plasmin.  

2. Background

Coagulation Factor XIII A Subunit (Recombinant), TRETTEN is produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology. The product is manufactured as a homodimer consisting of two FXIII A Subunits (rFXIII A2), the amino acid sequence of which has no detectable difference to that of human plasma-derived FXIII A-Subunit. TRETTEN is supplied as a sterile lyophilized powder in a glass vial with a nominal potency of 2,500 IU (15 mg) of FXIII A2. Prior to intravenous administration, the lyophilized powder is reconstituted with ~3 mL of sterile Water for Injection (sWFI) supplied in a separate glass vial.

TRETTEN is indicated for routine prophylaxis of bleeding in adult and pediatric patients with congenital deficiency in Coagulation Factor XIII A subunit. Congenital deficiency in Factor XIII is a very rare condition, affecting only about 200 patients in the United States. A plasma-derived Factor XIII product, Corifact, manufactured by CSL Behring, was approved by the FDA on February 17, 2011. However, unlike Corifact, the active ingredient in TRETTEN is only FXIII A Subunit. Although this subunit contains the active, catalytic domain of the FXIII molecule, the FXIII B Subunit also plays a critical role as a carrier molecule. Thus, the endogenous FXIII B Subunit is necessary to stabilize and protect the rFXIII A Subunit from proteolysis. Therefore, TRETTEN should not be prescribed to patients with deficiencies in FXIII B Subunit. Most cases of deficiency are due to a deficiency in the A subunit.

3. Chemistry, Manufacturing and Controls (CMC)

CMC / PRODUCT

Manufacturing sites
Different activities for the manufacture of TRETTEN occur at the following locations in Denmark:

ADDRESS

ACTIVITY

Novo Nordisk A/S
Novo Alle
DK-2880 Bagsvaerd

------------------------(b)(4)------------------------------
-------------------------------------------------------------
---------------------------------------

-------(b)(4)---------
-------------
---------------------------

---------------------(b)(4)---------------------------------

-------(b)(4)---------
-------------------
-----------------------

---------------(b)(4)---------------------
----------------------------------------------------------
--------------------------------------------------------------

------(b)(4)----------
--------------------
-----------------------

---------------(b)(4)-----------------

The product
The rFXIII A Subunit is composed of 731 amino acids with a relative molecular mass of 83,179 Da. Characterization of this protein shows that there are no post-translational modifications or disulfide linkages, identical to its plasma-derived counterpart.

Development of host strains for manufacture
Recombinant FXIII A2 homodimer is expressed as an intracellular protein in baker’s yeast (Saccharomyces cerevisiae). Novo Nordisk has provided a detailed description of the Saccharomyces cerevisiae (S. cerevisiae ), -------(b)(4)-------, host strain that expresses rFXIII A2 using the pD16 vector. ----------------------------------------(b)(4)-----------------------------------------
-----------------------------------------------------------------------------------------------------------------     -------------------------------------------------------------------------------------------------------------------- -----------------------------------------------

----------------------------------(b)(4)--------------------------------------
------------------------------------------
---------------------------------------------------
------------------------------------------------------
---------------------------------------------
------------------------------------------------

The materials used in the clinical studies and the commercial product have been manufactured using multiple WCB’s generated from -(b)(4)- MCB. Both WCB and MCB are stored under well defined and controlled conditions.

---------(b)(4)------------
------------------------------------------------------------------------------------------------------------

---------------------------------------------------(b)(4)----------------------------------------------------         -------------------------------------------------------------------------------------------------------------------  ---------------------------------------------------------------------------------------------------------------       --------------------------------------------------------

--------------------------------------------(b)(4)----------------------------------------------------                  -----------------------------------------------------------------------------------------------------------------     ---------------------------------------------------------------------------------------------------------------       -----------------------------------------------------------------------------------------------------------------     ---------------------------------------------------------------------------------------------------------------       ----------------------------------------------------------- 

----------------------------------------------(b)(4)------------------------------------------------------             -------------------------------------------------------------------------------------------------------------------  -------------------------------------------------------------------------------------------------------------------------------------

[--(b)(4)--]
The definition of a batch of rFXIII A2 bulk drug substance (BDS) is the final material that is derived from ------------(b)(4)--------------. The batch size of rFXIII A2 BDS is between --(b)(4)-------------.

Analytical methods
All analytical methods have been satisfactorily validated, or covered by European or U.S. Pharmacopoeias.

Reference standards
Since no international standard for FXIII A2 activity exists, Novo Nordisk calibrated rFXIII A2 In-house Working Standard against the WHO 1st International Standard Factor XIII Plasma (NIBSC code 02/206) and adopted International Units (IU) to show traceability to the WHO standard.

Final Drug product
The composition of the final drug product is given below:

Component

Quantity per vial

Function

Reference standard

Before lyophilization

After lyophilization

After reconstitution*

 

Active substance

rFXIII A

-(b)(4)-

-(b)(4)-

15.0 mg

Active ingredient

Novo Nordisk

 

Excipients

L-Histidine

-(b)(4)-

-(b)(4)-

9.3 mg

Buffer

-(b)(4)-
---------

Sodium chloride

-(b)(4)-

-(b)(4)-

8.7 mg

Stabilizer

-(b)(4)-
---------

Sucrose

-(b)(4)-

-(b)(4)-

174 mg

Stabilizer

-(b)(4)-
---------

Polysorbate 20

-(b)(4)-

-(b)(4)-

0.30 mg

Surfactant

-(b)(4)-
---------

Water for injection

To final volume

 

To final volume

Solvent

-(b)(4)-
---------

 

----(b)(4)---------

--(b)(4)--

-

+

-

-(b)(4)-
---------

-(b)(4)-
---------

*Lyophilized drug is reconstituted in 3.2 mL water for injection and these values were calculated based on a withdrawal of 3 mL after reconstitution.

Release specifications
Given below are the test parameters, procedures used and acceptance criteria of TRETTEN FDP:


Test

Analytical Procedure 

Acceptance Criteria 

Release

Shelf

 

Before reconstitution  

Appearance of powder

Visual inspection

--(b)(4)--

--(b)(4)--

Reconstitution time

Visual inspection

--(b)(4)--

--(b)(4)--

Water content

----(b)(4)----

-(b)(4)-

-(b)(4)-

 

After reconstitution 

Appearance of solution

Visual inspection

--(b)(4)--

--(b)(4)--

pH

-----(b)(4)------

-(b)(4)-

-(b)(4)-

Identity

-(b)(4)-

--(b)(4)--

-(b)(4)-

Purity --(b)(4)--

-(b)(4)-

-(b)(4)-

-(b)(4)-

-----(b)(4)-----

-(b)(4)-

---(b)(4)---

-(b)(4)-

------(b)(4)-------
---------

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

-(b)(4)-

---(b)(4)---

-(b)(4)-

-(b)(4)-

-(b)(4)-

Content

-(b)(4)-

-----(b)(4)------

-----(b)(4)------

Total bioactivity

rFXIII bioactivity assay

-------(b)(4)-------

-(b)(4)-

Specific bioactivity

rFXIII bioactivity assay

----(b)(4)-----

-(b)(4)-

-----------------------------------(b)(4)----------------------

-----(b)(4)------

-(b)(4)-

-(b)(4)-

Polysorbate 20

-(b)(4)-

----(b)(4)----

-(b)(4)-

Particulate matter

-------(b)(4)--------

------(b)(4)-------    ---------------------- -----------------        ---------------          ----------------------

--------(b)(4)--------
---------------------
-----------------------
---------------------
----

-------(b)(4)-------
----------

------(b)(4)-----
-------------

------(b)(4)--------------------------

-(b)(4)-

Bacterial endotoxins

-(b)(4)-

----(b)(4)----

----(b)(4)----

Sterility

Membrane filtration

Complies

Complies

Stability
The results of the stability studies conducted and their statistical evaluation, support the proposed shelf-life for TRETTEN of 24 months at 5oC ± 3oC. Based on the results of the in-use studies, the reconstituted rFXIII A Subunit may be stored for -(b)(4)- hours at 5oC ± 3oC or 3 hours at a maximum temperature of 25oC. Stability studies also showed that the rFXIII A Subunit is sensitive to light, and must be protected from light if stored in the primary container closure system (glass vial). The secondary packaging (carton) protects the product from light.

Critical issues
During the review of the BLA, the review team communicated to Novo Nordisk several concerns and requested clarifications via information requests (IRs) (September 1, 2011 and September 16, 2011). At the end of the first review cycle, several CMC and clinical deficiencies remained unresolved and there were outstanding issues from the pre-approval inspections of Novo Nordisk’s facilities. Thus, the FDA issued a Complete Response (CR) letter to Novo Nordisk on December 23, 2011. Briefly, the unresolved CMC deficiencies were related to: (i) Process validation studies for the manufacture of the bulk drug substance; (ii) In-process controls for cell propagation and fermentation as well as purification of rFXIII; (iii) Release specifications of the bulk drug substance and final drug product; and (iv) Clearance for process related impurities. Additional deficiencies were related to the assays and reagents used to monitor anti-drug antibodies to FXIII during the clinical trials. Novo Nordisk’s responses to the CR letter (amendment dated December, 06, 2012) were deemed adequate except for specific review and inspectional deficiencies.  A second CR letter was issued on June 27th, 2013.  Subsequently, upon satisfactorily addressing these issues, Novo Nordisk submitted the response to this CR letter on October 25, 2013.  Novo Nordisk has committed to continue to evaluate the safety profile of TRETTEN by conducting a post-marketing observational study (NN1841-3868) via a pharmacovigilance plan.

TRETTEN is exempted from lot-by-lot release by CBER. TRETTEN is a well-characterized recombinant DNA-derived product. Under the provision described in Federal Register 58: 38771-38773; alternatives to official lot release are allowable. Furthermore, in the Federal Register Notice (60 FR 63048) published on 8 December 1995, the Director of CBER announced that routine lot-by-lot release by CBER is no longer required for licensure of this class of products. As part of the review of the BLA, conformance lots of TRETTEN were assayed by CBER and the results were acceptable. Other elements of the BLA support Novo Nordisk’s ability to adequately control the manufacturing process, and the exemption of TRETTEN from lot-by-lot release by CBER.

FACILITIES AND EQUIPMENT

Review of Manufacturing Facilities
The manufacture of TRETTEN is performed at four Novo Nordisk A/S facilities in Denmark (one facility in Bagsvaerd, and three -(b)(4)------). Additionally, storage of cell banks occurs in a facility in ----(b)(4)----.

Novo Nordisk A/S Bagsvaerd Facility
Bulk Manufacturing Facility Building -(b)(4)- is utilized for propagation, fermentation and purification. The facility is used for the manufacture of additional pharmaceutical products for non-clinical and clinical trials. This facility was inspected by the FDA for the TRETTEN BLA.

Novo Nordisk A/S --(b)(4)-- Facilities
The Novo Nordisk A/S -(b)(4)- Facility (------------------------(b)(4)------------------------) and the Novo Nordisk A/S -(b)(4)- Facility (-------------------------(b)(4)---------------------------) are both involved in the further purification of TRETTEN, and Building -(b)(4)- is also involved in quality control. The -(b)(4)- facility is where --------(b)(4)-------- are performed, and ----(b)(4)------ takes place in building -(b)(4)-. These facilities are used for the manufacture of additional pharmaceutical products for non-clinical and clinical trials.  These facilities were inspected by the FDA for the TRETTEN BLA.

The Novo Nordisk A/S -(b)(4)- Facility in ---------------------(b)(4)------------------------ is used for the formulation, filling, lyophilization, and inspection of the drug product.  This facility was not inspected for this BLA (see below).

Inspection of the Manufacturing Facilities

CBER performed pre-license inspections (PLI) for the following facilities: -----(b)(4)-----            ------------------------------------------------- and -------------------------(b)(4)-------------------------------------------, from -------------(b)(4)-----------------. Two FDA form 483s were issued to the firm, one for Building -(b)(4)- and one was combined for the --------------(b)(4)-------------------            ------------ facility and ---------------------------------(b)(4)--------------------------------------. Issues identified included: deficiencies in analytical procedures documentation, environmental monitoring and cleaning validation.

The finish and filling facility in -------(b)(4)--------- was not inspected for this BLA, as the facility is a licensed multi-product facility and was last inspected by Team Biologics from -----------(b)(4)-----------.  Issues identified during this inspection and related review issues were the subject of the June 27, 2013, CR letter,

Novo Nordisk implemented appropriate corrective actions to address all 483 items.  All inspectional issues are considered satisfactorily resolved.

Environmental Assessment

Novo Nordisk submitted a request for a Categorical Exclusion to omit preparation of an environmental assessment pursuant to 21 CFR 25.31(c). Based on the submitted information and the nature of this product, the Division of Manufacturing and Product Quality concluded that the Applicant’s request for Categorical Exclusion from an Environmental Assessment under 21 CFR 25.31(c) is justified as this product is composed of naturally occurring substances. Manufacturing of this product will not significantly alter the concentration and distribution of the natural substance, its metabolites, or degradation products in the environment and no extraordinary circumstances exist that might cause this action to have a significant effect on the quality of the human environment.

CMC CONCLUSION

The process and analytical method validations and product characterization are sufficient to support product quality, purity, identity, potency and safety. The results of the stability studies support the proposed shelf-life of the product for 24 months at 5 oC ± 3 oC.

4. Nonclinical Pharmacology/Toxicology

Pharmacological/Toxicological Findings
The Applicant has completed an extensive nonclinical program to demonstrate the safety and effectiveness of TRETTEN.  Good Laboratory Practice (GLP) and non-GLP compliant nonclinical studies were conducted, Completed nonclinical studies included dose range-finding studies in rabbits, safety pharmacology studies in monkeys, pharmacodynamic and efficacy studies in rabbits and monkeys, pharmacokinetic profiles in monkeys, local tolerance studies in rabbits, and acute, subacute, repeat-dose and subchronic toxicity studies (including toxicokinetics) in rats, dogs and in monkeys for up to 27 weeks. Reported toxicities in animals dosed with TRETTEN were local irritation at the injection site, systemic hemorrhage, immunogenic responses (antibody formation) and exaggerated pharmacologic effects including alterations in the hematology panel, general thrombosis, ischemic necrosis, and mortality, at doses approximately 16- to 48-fold in excess of the recommended clinical dose. Similar toxicity profiles were observed in nonclinical studies with TRETTEN and non-proteolytically activated recombinant FXIII.  TRETTEN toxicities in animal studies were reported after a single intravenous dose of 10 mg per kg body weight [1670 IU/kg, i.v.], or an approximately 48-fold greater dose than the expected, maximum recommended clinical dose of 210 micrograms per kilogram (35 IU per kilogram) of body weight.  These adverse events were expected based on the pharmacologic activity of TRETTEN.

In a monkey cardiovascular safety pharmacology model evaluating the combination of excessive doses of TRETTEN  [i.e. 3.5 mg per kg bodyweight (585 IU per kilogram); 17 times the expected human dose] in combination with rFVIIa (1000 mcg/kg, 11 times the expected human dose), one out of twelve monkeys died 4 hours after treatment, due to thrombosis. Procoagulant risk factors, including 6 indwelling catheters per monkey and the induction of anesthesia may have complicated the study results. It is unclear whether the mortality was related to the overdose of one or both products, or to a specific interaction between them. Nonclinical or clinical studies with the combination of TRETTEN and other coagulation factors including rFVIIa at the intended human dose levels have not been performed.  This potential safety issue has been identified in Section 13.2 (Nonclinical Toxicology and Pharmacology) of the labeling.

The Applicant has not conducted in vitro or animal studies for carcinogenicity, mutagenicity, fertility, reproductive toxicity or teratogenicity evaluations of TRETTEN.  Based on the intended use of TRETTEN and on the recommendations provided in the ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals guidance, no animal reproductive or developmental toxicity studies were recommended. Long-term animal studies to evaluate the carcinogenic potential of TRETTEN or studies to determine its genotoxicity or effects on fertility are also not recommended according to the current ICH S6(R1) guidance, and the indication sought by the Applicant.  The lack of this information has been appropriately communicated in Sections 8.1 (Use in Pregnancy) and 13.1 (Carcinogenesis, Mutagenesis and Fertility) of the labeling for TRETTEN.

There were no toxicity concerns identified for this product regarding impurities, or unexpected toxic effects that would have warranted additional nonclinical toxicity testing. A toxicological risk assessment analysis was completed on the leachables and extractables associated with TRETTEN manufacturing and container closure systems. The results of this risk analysis indicated that the levels of potential leachable/extractable impurities were within the range of the Applicant’s specifications, and are at acceptable levels based on extensive clinical experience with other currently licensed products.  These results and the results of extractables/leachables nonclinical studies were found acceptable and support licensure of TRETTEN.

TOXICOLOGY CONCLUSION:

Overall results from nonclinical studies and from risk assessment of any potential impurities are adequate to support the licensure of TRETTEN for its proposed indication.

5. Clinical Pharmacology

Study F13-1663 was an open label pilot PK and safety study  in congenital FXIII  A subunit deficient patients.   This study also investigated the relationship between circulating plasma levels of FXIII, FXIII activity and clot strength. The study was designed to enroll a minimum of two subjects in each of the 5 dose cohorts (2, 6, 20, 50 and 75U/kg). Each subject received a single dose of TRETTEN.  Of the total 11 subjects enrolled, 9 (M=6; F=5) were Caucasians with a median age of 21 years. PK analyses, using the Berichrom activity assay, showed a terminal half life of approximately 5 days. Relationship between FXIII activity and clot stability as measured by urea clot solubility showed that subjects in the 50 and 75 IU/kg maintained normal clot solubility through Day 28.  The dose of 50 and 75 IU/kg appears to exert the PD effect in vitro and has not been studied in congenital A-Subunit deficient patients with bleeding.  Because of the small sample size in each dose cohort, the interpretation of the PK/PD results is limited.  No safety concerns were identified in this first study in the target population.

Study F13CD 3720 was a multi-center, multi-national, open-label, single-arm, repeat dose phase 3b study to evaluate the safety of monthly replacement therapy with TRETTEN in patients with congenital FXIII A-subunit deficiency. There were 23 subjects in this study (5 females and 18 males, 7-58 years of age, 22-100 kg of body weight).  The patients received a monthly (28 ± 2 days) intravenous (IV) injection of TRETTEN (35 IU/kg). Blood samples for PK assessments were collected at the following time points: Pre-dose, 1 hour, 2 hours, 3, 7, 14, 21 and 28 days post-dose. The PK parameters were calculated using a non-compartmental method with baseline adjustment.  The calculated PK parameters were based on the data obtained from the Berichrom activity assay.  The half-life and clearance of FXIII were 122 ± 62 hours (5.1 days) and 0.33 ± 0.11 mL/hr per kg. This study does not indicate if the pharmacokinetics of rFXIII at steady state is different than that of a single dose. 

Study F13CD-3760 was a phase 3b study investigating the pharmacokinetics and safety profile of a single intravenous dose of rFXIII in pediatric subjects (1 to less than 6 years old) with congenital FXIII A-subunit deficiency. This study was a multi-national, open-label, single-dose study in which 35 IU/kg was administered as an IV injection (at a rate not exceeding 1-2 mL per minute) to pediatric subjects with congenital FXIII A-subunit deficiency. Six young children (three boys and three girls) participated in the study.  The mean age was 2.7 years (range: 1 to 4 years). All children had been on monthly prophylactic treatment with a plasma derived FXIII containing product (prior to inclusion in the study), receiving their last dose of their previous prophylactic treatment approximately four weeks prior to the single dose of rFXIII 35 IU/kg. Blood samples were taken pre-dose, at 30 minutes, 24 hours, and days 7, 14, 21 and 30.  Concentrations of FXIII were measured by the Berichrom activity assay. Pharmacokinetic parameters of FXIII were calculated by non-compartmental analysis (baseline corrected).  The half-life and clearance of rFXIII were 171 ± 65 hours (7.1 days) and 0.41 ± 0.20 mL/hr per kg.  Compared to adults, the half-life of FXIII was longer and clearance on per kg body weight was higher in children.  

PHARMACOKINETIC CONCLUSION:

The pharmacokinetic study design and interpretation of data are acceptable.

6. Clinical/Statistical-Efficacy

The clinical development plan to support the proposed indication consisted of the following studies:

  • F13-1663 US (2004) -- Safety and pharmacokinetics of rFXIII in patients with congenital factor XIII deficiency
  • F13CD-1725 (2010) Europe, Canada, US -- Phase 3 efficacy and safety
  • F13CD-3720 (Ongoing) Europe, Canada, US -- Safety extension trial to the phase 3 F13CD-1725 trial

Regulatory History related to clinical development:

  • ------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------
  • IND 10674 for TRETTEN was filed in September 2002, with pending results for a 28-day repeat-dose ---(b)(4)---- study.  When the results were submitted they showed the expected anti-TRETTEN antibody response, along with a prolonged depression of endogenous Factor XIII activity levels, which would be expected if anti-TRETTEN antibodies cross-reacted on ---(b)(4)----  Factor XIII. Autoantibody formation has been seen in nonclinical studies of other coagulation products, with no clinical consequences; however, in the interest of caution, IND 10674 was placed on clinical hold until additional information could be submitted, including modification of the clinical trial design to carefully monitor for autoantibody formation.

Pivotal Study design and efficacy results (study F13-CD1725)

The phase 3 study was a 12-month repeat-dose (once a month) routine prophylaxis study in subjects who were congenitally Factor XIII A-subunit deficient. Subjects were dosed with TRETTEN 35 IU/kg intravenously monthly (every 28 ± 2 days).  Blood samples for FXIII activity levels (by the Berichrom assay) and for anti-TRETTEN antibody levels were taken immediately pre-dose and 1 hour post-dose.  

To obtain historical  control for the annual bleed rate, Novo Nordisk conducted a patient survey in 92 congenitally Factor XIII deficient patients in Australia, Brazil, Europe, Israel, Saudi Arabia, and South Africa; 23 of these patients said they did not use FXIII prophylaxis treatments, and their reported bleeding rates were used to derive the control bleeding rate.  The annual bleeding rate for the control cohort was 1.68 bleeds per year (after excluding two patients who were considered outliers because of a large number of bleeds (11 and 12)

The efficacy results for the 41 subjects enrolled in study F13-CD1725 are shown in the following table, by age group:

Study F13-CD1725 Estimated Bleeding Rates by Age


Group

N

Estimated Bleeding Rate (bleeds/subject/year)

95% CI

Historical Control Group Estimated Bleeding Rate
(bleeds/subject/year)

All

41

0.138

[0.058; 0.332]

1.68

< 18 years

15

0.362

[0.136; 0.963]

2.00

≥ 18 years

26

0.040

[0.006; 0.283]

1.59

 

TRETTEN is effective for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency.

7. Safety

In study F13CD-1725, there were 231 treatment-emergent adverse events reported for 32 subjects. The most common adverse reactions reported in the clinical trials (≥1%)
were headache, pain in the extremities, injection site pain, D dimmer increase ( of no clinical significance). There were no thrombotic adverse events.  

The most commonly reported events were headache (21 events in 12 subjects), incorrect dosing (14 events in 7 subjects), nasopharyngitis (11 events in 8 subjects) and pyrexia (7 events in 7 subjects).

There were 13 adverse events in 9 subjects that were classified by the investigator or sponsor as possibly or probably related to the study agent, as shown in the following table:

Treatment-emergent Adverse Events with Possible or Probable Relation to Trial Product - Full Analysis Set


Subject ID

Age

Preferred Term

Severity

Serious

Latency in days

Relation

Outcome

  -(b)(6)- 

7

Antibody test positive 

 Mild 

 Y 

 14 

 Probable 

 Recovered 

 -(b)(6)- 

25

Pain in extremity 

 Mild 

 N 

 22 

 Possible 

 Not Recov.*** 

 -(b)(6)- 

26

Headache 

 Mild 

 N 

 0 

 Possible 

 Recovered 

 -(b)(6)- 

8

Leukopenia**** 

 Mild 

 N 

 32 

 Possible 

 Recovered 

 

 

Neutropenia**** 

 Mild 

 N 

 32 

 Possible 

 Recovered 

-(b)(6)-

7

Incorrect dose administered 

 Mild 

 N 

 0 

 Probable 

 Recovered 

 

 

Incorrect dose administered 

 Mild 

 N 

 0 

 Probable 

 Recovered 

 

 

Antibody test positive 

 Severe 

 N 

 28 

 Probable 

 Recovered 

 -(b)(6)- 

60

Incorrect dose administered 

 Mild 

 N 

 0 

 Probable 

 Recovered 

 -(b)(6)- 

16

Antibody test positive 

 Mild 

 Y 

 16 

 Possible 

 Recovered 

-(b)(6)-

14

Antibody test positive 

 Mild 

 Y 

 16 

 Possible 

 Recovered 

 -(b)(6)- 

8

Injection site pain 

 Mild 

 N 

 2 

 Possible 

 Recovered 

 

 

Fibrin D dimer increased 

 Mild 

 N 

 14 

 Probable 

 Recovered 

SOC:System Organ Class PT:Preferred Term Not recov.: Not recovered
* Age at baseline
**Days since the preceding dose of rFXIII
*** Outcome as recorded at the end-of-trial visit approximately two months after onset of the event
**** Worsening of mild neutropenia initially diagnosed before first trial drug administration.
Source: Original BLA 125398; Clinical Study Report module 5.3.4.3, p.60 Table 12-3

Potential Risk for Immunogenicity

There were 4 subjects [--------------(b)(6)-------------------] who demonstrated antibody reactivity to TRETTEN in scheduled pre-dosing antibody tests. These antibody responses were observed after 2 or 3 product doses.  Three of these antibody-forming subjects [------------(b)(6)------------] were discontinued from further treatment, but were followed for safety for the duration of the study.  None of these subjects demonstrated clinically-apparent FXIII inhibitors. .  It was also noted that the day 28 FXIII activity values were at or below the presumed protective level for many of the 41 subjects in study F13-CD1725 . Some of these subjects had positive antibody responses during the treatment period, but there were no submitted data to show that the FXIII activity remained above the presumed protective level during the entire period between prophylactic doses; only data for the 1-hour post-dose time point were available. This was one of the findings that led to the issuance of the Complete Response Letter (December 23, 2011).   Among the requests in the CR letter was a request for a pharmacokinetics study of subjects who have had repeat exposure to TRETTEN to evaluate time points between 1-hour post-dose and day 28 to assure that intermediate time points have protective levels of Factor XIII activity in the plasma.   Given that there is no approved anti-FXIII antibody test on the U.S. market that could be used to monitor for FXIII inhibitors, it was deemed prudent to request additional PK data on subjects who had undergone repeat-dosing and who had anti-FXIII antibody responses that were judged by the applicant to be not clinically important.

The applicant responded to the CR letter in a December 27, 2012, submission containing the clinical report for a PK study of selected subjects in study F13CD-3720 in response to the request for a pharmacokinetics study of subjects who have had repeat exposure to TRETTEN to evaluate time points between 1-hour post-dose and day 28.  The report described the full 28 day pharmacokinetics for 9 subjects from study F13-CD1725, who were identified by FDA as possibly having anti-FXIII antibodies that may affect the FXIII activity level, and an additional 15 subjects identified by the applicant.  The 28-day PK profiles for these subjects show the presumed protective FXIII levels are obtained over the 28-day time period for all subjects.

It was concluded that the immunogenicity profile of TRETTEN is acceptable for licensure.

Post-marketing surveillance will monitor for clinical signs that could be attributed to immunogenicity, with follow-up investigative studies to be conducted by Novo Nordisk.

Bioresearch Monitoring (BIMO)

CBER BIMO issued five high-priority inspection assignments covering four clinical investigators and one contract laboratory.  The inspections did not reveal problems that impact the data submitted in the BLA.

Four clinical investigator inspections and one laboratory inspection were performed in support of this BLA. Study subject enrollment and previous inspection history related to this product were among the factors used to select the inspected sites.  The inspections focused on specific questions concerning the study protocol and the comparison of information from the BLA to source documents.  The contract laboratory was inspected, at the request of the committee, to review the raw data used to produce the final -(b)(4)- results for the anti-FXIII antibodies.

Inspection sites:


Location

Site #

# of Subjects

FDA 483

Petah-Tikva, Israel

201 IL_025

7

No

Toronto, Canada

120

3

Yes

Bonn, Germany

180 DE_546

3

No

Boston, Massachusetts

304

2

No

Indianapolis, Indiana

Central laboratory

629 samples (sent in from all 31 subjects)

No

The Clinical Investigator Compliance Program directs the FDA investigator to ask the clinical
investigator if and when he/she disclosed information about his/her financial interests to the sponsor and also the interests of any sub-investigators, spouse(s) and dependent children, and if and when the information was updated.  The four clinical investigators provided copies of the financial disclosure forms to the FDA investigators.  The information submitted to the BLA was verified for each investigator. 

The FDA investigator observed several discrepancies between the sponsor’s data listings submitted in the BLA and the study records, i.e. laboratory source documents and case report forms (CRFs), at the Petah-Tikva site. The data listings in the BLA did not match the corresponding study records for the following subjects.

 

Subject

Visit

Laboratory Test

Source Document/Case Report Form

BLA Data Listing

-(b)(6)-

6

Pre-dose rFXIII Ammonia Activity

0.110

0.127

-(b)(6)-

13

Post-dose rFXIII A2 subunit

17.04

3.60

-(b)(6)-

2

Pre-dose rFXIII Ammonia Activity

0.154

0.184

5

Pre-dose rFXIII Ammonia Activity

0.109

0.107

-(b)(6)-

1

rFXIII Ammonia Activity

0.169

0.159

4

Pre-dose rFXIII Ammonia Activity

0.191

0.158

8

Post-dose rFXIII B Subunit

0.23

1.79

-(b)(6)-

2

Hematocrit

40.9

40.0

2

Neutrophils

2.90

2.70

12

Monocytes

0.29

0.79

There were a few other minor problems noted during the inspection. 

  • Laboratory Testing –------------(b)(4)--------------- did not report results from all samples with coefficients of variation greater than 20% between duplicates in the Final Report used to determine adequate validation of --(b)(4)-- used to test subject samples.  
  • Serious Adverse Event (SAE) Reporting - Subject -(b)(6)- reported having a sprained ankle at Study Visit #14, week 44; however, this AE was not reported to the Sponsor. (Site 120)

These findings do not impact overall data assessment

8. Advisory Committee Meeting

OBRR reviewed information from this application and determined that referral to the Blood Products Advisory Committee (BPAC) prior to licensure is not needed for the following reasons (FDAAA [HR 3580-138 SEC. 918: REFERRAL TO ADVISORY COMMITTEE]):

  • The mechanisms of action of Coagulation Factor XIII and its role in blood coagulation are well understood.
  • The safety profile of a comparable plasma-derived Coagulation Factor XIII product, CorifactTM, is well established as it has been used widely outside the U.S. since 1993.  The BLA for Corifact was thoroughly reviewed by the FDA and approved on 17 February 2011 without presentation at an advisory committee.
  • As a recombinant product, TRETTEN is considered to have a favorable safety profile related to known infectious agents and impurities.
  • BPAC discussion of this application is unlikely to change the outcome of the review of this file from a regulatory standpoint.

9. Pediatrics

PREA does not apply because TRETTEN® received orphan product designation in May 2003.

Pediatric subjects were included in the study and consisted of 6 children in the age range 0-5, 12 children in the age range 6-12, and 9 adolescents in the age range 13-17 who were treated with TRETTEN for a total of 652 exposures. Three patients under 18 years who experienced non-neutralizing antibodies were withdrawn from the study.  A fourth patient less than 18 years old  who experienced non-neutralizing antibody remained in the trial. No dose adjustment is required for the pediatric age group.

10. Other Relevant Regulatory Issues

None

11. Labeling

Proprietary Name
The Advertising and Promotional Labeling Branch (APLB) performed an evaluation of the proposed proprietary name, TRETTEN, for Coagulation Factor XIII A-Subunit (Recombinant), to determine if any new products had been approved since the primary review. No such products were identified and the proprietary name was found to be acceptable

Conclusion:

The proposed prescribing information and the patient information leaflet submitted on December 11, 2013 are acceptable. Carton and immediate container labels submitted in the original application were reviewed by APLB and found to be acceptable.

12. Recommendations/Risk Benefit Assessment

a) Recommended Regulatory Action

The CBER review committee unanimously recommends approval of this BLA.

b) Risk/ Benefit Assessment

Patients with FXIII A-subunit deficiency are at risk for life-threatening bleeding. The applicant has shown that TRETTEN is effective for the routine prophylaxis of bleeding in adult and pediatric patients who are congenitally deficient in Factor XIII A-subunit. A  phase 3, 12 month, repeat dose study of TRETTEN administered once monthly as routine prophylaxis was conducted in15 patients < 18years of age and 26 adults. The annual bleeding rate decreased from an estimate of 1.68 bleeds per year in a control cohort to 0.138 bleeds per year in treated patients. A small number of treated patients developed antibodies to FXIII.  All antibodies detected in clinical studies were non-neutralizing and were not associated with clinical events upon patient follow-up.

Animal studies suggest that thrombosis may be a risk in treated patients. The package insert recommends monitoring of patients for thrombotic events. Patients receiving TRETTEN are also at risk for the development of allergic reactions. No thrombotic or allergic reactions were observed in the clinical studies.

The number of subjects enrolled in clinical studies was small because of the rarity of congenital FXIII deficiency. Based on the safety and efficacy data available at the time of licensure, the benefit of treatment with TRETTEN outweighs the risk. The safety profile of the product will be further evaluated  in an observational  post-marketing study. The data derived from this study will further inform the safety profile of TRETTEN.

c) Recommendation for Postmarketing Risk Management Activities
There are currently no recommendations for postmarketing risk management activities.

d) Recommendation for Postmarketing Activities
Novo Nordisk is conducting a post-marketing commitment (PMC) observational study [Post-Authorization Safety Study (PASS) NN1841-3868] to further evaluate the safety profile of TRETTEN, particularly with respect to immunogenicity.  This study will investigate the incidence of specific adverse drug reactions associated with the use of TRETTEN in patients with congenital Factor XIII A-subunit deficiency. Specific adverse drug reactions to be investigated include anti-FXIII antibodies, allergic reactions, thromboembolic events and lack of therapeutic effect.  The sponsor has proposed the following action plan for patients who form anti-TRETTEN antibodies to determine clinical significance:

  • Continued analysis of safety data from clinical trials that may be initiated in the future, and safety data collected during the post-marketing period, including (PASS) NN1841-3868.
  • Structured follow-up of reports where clinical findings or laboratory findings may indicate a lack of expected effect in order to determine the cause.
  • Analysis of blood samples for formation of antibodies when there is lack of effect indicated by clinical signs or laboratory findings reported in the post-marketing period from both spontaneous sources and also from non-interventional studies.
  • Cases of antibodies to rFXIII will be reported on an expedited basis regardless of case type (seriousness and expectedness).