The FDA approved Novoeight, a recombinant Factor VIII treatment for hemophilia A, in October 2013 based on positive results from clinical trials. Novoeight was found to effectively control and prevent bleeding episodes in adults and children with hemophilia A. The approval process involved reviewing manufacturing, clinical data, and inspections to ensure safety and efficacy. This approval expands treatment options for hemophilia A patients and represents continued innovation in the development of safer recombinant clotting factor therapies.

1. A STORY OF
NOVOEIGHT®
WITH THE FDA
Overview of the Approval of Novoeight by the FDA for
Hemophilia A management in Adults and Children's
Final Project Presentation for RGA 6200, Winter 2014 Class
Qinglin Che
Mach 20, 2014

2. What’s the Story
 On October 15th, 2013, The FDA approved Novoeight ®, a
recombinant Antihemophilic Factor developed by Novo Nordisk for
adult and children patients with hemophilia A for the following three
indications.
 Control & prevention of bleeding episodes
 Perioperative management
 Routine prophylaxis to prevent or reduce the frequency of
bleeding episodes.

3. Background: The Indications
 What is Hemophilia A? Hemophilia A is a chronic, inherited bleeding disorder
that mainly affects males. 1 of every 5,000 male births with Hemophila A.
 Global Patients Population: ~400,000
 U.S. Patients Population: ~20,000
 What Causes Hemophila A? Hemophia A patients has no or malfunctional
Factor VIII protein in the plasma. Classified based on FVIII activity in plasma.
 Sever (<1%)
 Moderate (1-5%)
 Mild (>5%)
 How to Manage? patient would take Factor VIII to replace the missed or
malfunctioning FVIII protein.

4. Background: About the Target FVIII
 Plasma based FVIII Concentrate
 widely used before 1990s,
 Safety Concern: viral contamination.
 Recombinant Full-Length FVIII
 First Gen. Using human albumin as stabilizer. Transmission issue remains.
 Second Gen. synthetic stabilizers, but human/animal proteins used in manuf.
 Third Gen. No human/animal plasma-based products used in process
 Recombinant B-Domain Deleted Recombinant FVIII (BDDrFVIII):
 Replaced heavy B-domain with a short amino acid sequence
 Reducing the size of the protein, making manufacturing much easier
 Greater stability, eliminating the need for human albumin as stabilizer, thus
reducing the risk of viral pathogen transmission.
 Safety Concern: Immunogenicity-development of inhibitor and antibody

5. Historical Evolution to FVIII products
 Plasma-derived FVIII concentrates become commercially available.
 HIV epidemic results in viral contamination of plasma-derived products
and widespread infection of more than half of all hemophiliacs with
HIV.
 Recombinant FVIII products become commercially available
 1st Generation: Recombinant (Baxter)
 2nd Generation: Advate (Baxter)
 3rd Generation: Kogenate FS (Bayer)
 ReFacto, the first BDDrFVIII is licensed by FDA: elimination of the B-
Domain
 Xyntha, a BDDrFVIII albumin-free cell culture product is licensed by
FDA and replaces ReFacto in the US market
 NovoNordisk submits BLA for NovoEight

6. Regulatory Chronology of NovoEight ®
Jun 15, 2009
• IND submitted
(BB-
IND14059)
July 9, 2009
• Telecon on
Study Design:
Immunogenicity
testing and
surgical study
evaluation
revised
July 16, 2009
• Telecon to
discuss
deficiencies;
study can’t
proceed until
revisions are
submitted and
approved by
FDA
August 14, 2009
• Study may
proceed; non-
hold items
communicated
June 13, 2012
• Pre-BLA meeting
response:
dataset to be
arranged by
study site
August 3, 2012
• 2012 Telecon to
discuss Pre-BLA
responses;
clarification on
the site-specific
data set format
requested by
sponsor
Oct 16, 2012
BLA
Submitted

7. BLA Review: CMC and PLI
 CMC Review. No use of any serum or other animal-derived
components in the manufacturing and formulation process
 Drug substance: cell culture, capture of protein, purification of protein.
 Durg product: Filtration, filling and lyophilization
 Pre-license Inspection
 Inspected the facility in Denmark for the manufacturing of NovoEight
 Form FDA 483 Issued with following observations
 Deficiencies in following aseptic tech in the seed lab
 Insufficient control over the cell culture process
 Lack of quantitative criteria in the qualification of purification
equipment
 Inadequate cleaning validation
 August 16, 2013. NovoNordisk response with corrective actions.
 FDA accepted the response, and considered it satisfactory

8. BLA Review: Clinical Programs
Based on 3 clinical trials including a pivotal and an expansion trials
Trial ID
Number of
subjects
Study design Regimen
NN7008-3543
150 adolescents
and adults
Pivotal trial
For prevention and
treatment of bleeds
Prevention: 20-50 IU/kg every second day or 20-
60 IU/kg 3 times weekly
Treatment: per guidelines
Surgery: based on individual PK
PK: 50 IU/kg (single dose)
NN7008-3545
63 children <12
years
Pediatric study,
previously treated
patients with hemophilia
A
Prevention: same as NN7008-3543
Treatment: per guidelines
Surgery: based on individual PK
PK: 50 IU/kg (single dose)
NN7008-3568
188 pediatric,
adolescent or
adult
Extension trial
For prevention and
treatment of bleeds
Routine prophylaxis: 20-50 IU/kg every second
day or 20-60 IU/kg 3 times weekly
Treatment: per guidelines
Surgery: based on individual PK

9. BLA Review: Efficacy Assessment
 Objectives: assess the efficacy for reducing the number of acute bleeding
events per year on prophylactic treatment when compared to on demand treatment
and for treatment of breakthrough bleeds using the following endpoints:
 Annualized bleeding rate of prophylactic vs on-demand treatment
 Hemostatic effect for intra- and post-operative management and for
treatment of spontaneous and traumatic bleeding episodes
 The number of infusions required per bleeding episode
 Efficacy Conclusion: The outcomes of the study support the efficacy of
Novoeight in adults with hemophilia A for control and prevention of bleeding,
perioperative management, and routine prophylaxis to prevent or reduce the
frequency of bleeding episodes.
Reviewer Comment: A success rate was not pre-specified in the protocol; however, a response rate
of >80% is clinically significant. The success rate of 80.8% is lower than the sponsor’s report of
84.5%, which was calculated with missing data excluded. The protocol did not specify how missing
data would be handled, therefore in my analysis all missing data were considered failures.

10. BLA Review: Safety Assessment
 Endpoints: The safety concerns for this product are hypersensitivity and
allergic reactions, thromboembolic events, and inhibitor development. The safety
was assessed using the endpoints:
 • Frequency of adverse events
 • Vital signs (blood pressure, pulse, temperature, and respiratory rate)
 • Clinical laboratory tests
 Results: 783 AEs reported in 179 subjects (2.29/subject); 30 were evaluated as
related to the product by the investigator. The majority of the AEs were mild or
moderate; 28 severe AEs in 22 subjects were all unrelated. No confirmed inhibitor
development.
 Safety Conclusion: Data from the three efficacy and safety trials and from
the three PK studies were pooled to allow for an integrated prioritized review of
safety topics. The product appears well-tolerated. No new safety concerns were
identified.

11. Compliance with GCP: BIMO Inspection
 Who were inspected?
 Four clinical sites were chosen. Selection of sites was based on
 Highest No. of subject enrolled (6,6,6,10, totally 28, 22% of total), &
 Previous inspection history
 What were Inspected? Focused on
 the study protocol
 comparison of data submitted in the BLA to source
 Results:
 Form FDA 483 was issued notifying NovoNordisk of objectionable
conditions were issued at the sites.
 A number of deviations from protocol adherence, &
 Data discrepancies between the source document and BLA.
 However, the FDA consider that the inspections did not reveal any
issue that would impact the data submitted in the BLA.

12. BLA Review: PeRC Assessment
 PREA requirements were triggered as a new indication was being sought.
 Subjects: From the pivotal and pediatric trials, the safety and efficacy of
Novoeight was evaluated in 79 children between 0 and <16 years, including 4 from
0 to <2 years, 27 from 2 to <6 years, 32 from 6 to <12 years, and 16 from 12 to
<16 years of age.
 Reviews: Sep 11, 2013. The data from the pediatric trial and pediatric patients in
the pivotal trial were presented to the Pediatric Review Committee (PeRC)
PeRC: Pediatric Research Equity Act
Conclusion: No confirmed inhibitors were reported in any
pediatric subject. Hemostatic response in 54 subjects was
excellent or good for 210/244 (86%) of bleeds. The ABR (95%
CI) for the 79 subjects was 4.8. Based on these data, PeRC
agreed with the review decision that Novoeight is safe and
efficacious for children with hemophilia A.

13. Advisory Committee? Not this time!
FDA didn’t refer to the Blood Products Advisory Committee (BPAC) for
approval recommendation, because:
 NovoEight is not a NME (new molecular entity). Sveral products already been
licensed in the U.S. since 1992.
 The MOA (mechanism of action) of FVIII and its function in blood coagulation is
well studied and understood.
 Novoeight is identical to human plasma derived FVIII in heavy and light chain
amino acid sequence and major post-translational modifications.
 The Manufacturing process already includes two viral clearance steps.
 The proposed indication are identical or similar
to those of other US licensed FVIII products.
 The clinical PK data indicated bioequivalence
with a licensed full-length recombinant FVIII
 No safety Concern revealed from the clinical data

14. Other Regulatory Related Items
 Pharmacovigilance and Post-marketing Commitments
 Stated in NDAAmendments (STN 125466/0.26 and STN 125466/0.34)
 To conduct additional stability studies for the commercial batches.
 To conduct an trial of 50 subjects for a minimum of 100 Eds over four years
 To conduct a trial in at least 50 PUPs who will be treated for a minimum of 50
Eds over 3.5 years,
 To submitted the final study report by March 31, 2017, and March 31, 2009,
respectively.
 Labeling
 The proposed proprietary name, Novoeight, was reviewed by APLB
(Advertising and Promotional Labeling Branch) and accepted.
 The FPI (Full Prescribing Information) was reviewed by BLA committee,
comments conveyed to NovoNordisk, modification accepted.

15. Review Conclusions
 Novoeight appears reasonably safe and likely to provide therapeutic benefit
to patients with hemophilia A.
 No reports of hypersensitivity/allergic reactions, thromboembolic events or
confirmed inhibitor development were reported.
 Hemostasis was successfully achieved in the treatment of acute bleeds and
during surgery.
 Prophylaxis reduced the ABR for subjects previously treated with on-
demand therapy by greater than fifty percent.

16. Post-Approval Activities
Global Approval Landmarks
 Sep. 2013, NovoEight was approved by EMA
 Oct 16, 2013, NovoEight was approved by FDA
 Nov 18, 2013, NovoEight passed the review by the Committee on Drugs of
Pharmaceutical Affairs in Japan
 Wait until April 2014 to launch in Europe
 Wait until Early 2015 to launch in the U.S.
Why not launch immediately after approval?
 Novo Nordisk is afraid of stepping on some unspecified
third-party patents, would wait until the expiration of the
patent before launch.

17. Why Not Biosimilar?
As an follow-on BDDrFVIII drug, why not go through biosimilar
pathway?
 To date, no application submitted via abbreviated BLA pathway yet.
 Unclear requirement for clinical Data in 2009 when IND initiated
 Need for public disclosure with originator drug company (patent
dance)
 No extended exclusion right
 Price dropped to ~70% of originator biologic
Why Normal BLA Pathway?
 Treated as innovator drug, not copycat, can keep
manuf. Process confidential
 Huge pricing advantage, still Brand-Name
 12-year exclusion benefit

18. What Does NovoEight Mean to NovoNordisk
Aiming to be a leader in Hemophilia Management
 Current lead product NovoSeven for Hemophilia A & B management.
 2012 Sale of Novoseven reached 1.5 Billion.
 Patent expiring in US and EU, sale from NovoSeven will decline.
What’s Next? NovoNordisk’s long-acting FVIII product (N8-GP) is in Phase
III clinical trial now. This is next generation of FVIII products that can work longer
in the body (with extended T-half).
 NovoNordisk approach: glyco-PEGylated rFVIII
 Intensed Competition. Rivols include include Baxter, Bayer and Biogen Idec.
BAX 855
PhIII Trail
ELOCTATETM BLA reviewBAY 94-9027
PhI Trial
N8-GP, Phase III Trail

19. What We Learned from NovoEight Story?
 A up-to-date case study on how biologics are developed and approved in the U.S.
 The historical evolution of NovoEight and other FVIII products demonstrated that
scientific Innovation drives the development of safer and more efficient therapeutics.
 Safety and efficacy are the two major aspects that the review focuses on. They are
the basis of risk/benefit assessment which determines the fate of the BLA
application.
 For the sponsor, intelligent properties consideration is very important in the process
of drug development. Protect your own, not step on the others.
 Biosimilar pathway in the U.S. is still immature, additional efforts from the regulator
are needed to accelerate the progress.

20. References & Additional Readings
 Final Review Memo of Original Application
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/License
dProductsBLAs/FractionatedPlasmaProducts/UCM375275.pdf
 Long-lasting recombinant factor VIII proteins for hemophilia A
http://asheducationbook.hematologylibrary.org/content/2013/1/37.full.pdf
 The Hemophilia Market: Steep but Surmountable Barriers for New Entrants
http://corporate.morningstar.com/us/html/pdf/Healthcare-Observer-Jan-2013.pdf
 Biologics License Application Memo, March 28, 2013 - Novoeight (PDF - 232KB)
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/License
dProductsBLAs/FractionatedPlasmaProducts/UCM374795.pdf
 Approval History, Letters, Reviews and Related Documents for Novoeight
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsB
LAs/FractionatedPlasmaProducts/ucm374010.htm
 NovoEight (turotocog alfa) page on European Medicines Agency
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002719/human_med
_001701.jsp&mid=WC0b01ac058001d124