This document summarizes a study comparing the therapeutic interchange of plasma-derived factor VIII (pdFVIII) and recombinant factor VIII (rFVIII) for the treatment of Hemophilia A. The study analyzed the safety, efficacy, and costs of various pdFVIII and rFVIII products. It found that while rFVIII products had a slightly higher risk of inhibitor development, the cost difference between rFVIII and pdFVIII products could amount to over $4 million more for rFVIII over a patient's lifetime. However, both classes of products showed similar efficacy in clinical trials. The study concluded that therapeutic interchange between pdFVIII and rFVIII is a viable option to reduce costs while maintaining patient outcomes for

1. Therapeutic Interchange in
Hemophilia A:
Is it worth it?
Roohee Peerzada, B.Pharm, MBA
Advisor – Dr. Robert Mueller Jr. , EdD
Director of the MBA Program
Assistant Professor of Pharmaceutical and Healthcare Business

2. Acknowledgements
Dr. Robert Mueller – Advisor
Dr. Patricia Audet
Dr. Ann Rogers
Dr. Patrick Collins
Cassandra Henderson
Mayes College Faculty and Staff

3. Agenda
Hypothesis
Introduction
Objectives & Methodology
Results
Conclusion
Recommendations

4. Hypothesis
“Therapeutic Interchange in Hemophilia A is a
safe, efficacious and cost-effective option and
should be adopted by the US healthcare system
more readily”

5. Introduction
Hemophilia A (HA) snapshot
400,000 patients globally
20,000 affected by HA in USA
30-40% of patients develop inhibitors
80-90% Total treatment cost – HA medications
Average annual treatment cost – $100,000
Mild (5-40% Clotting Factor) Moderate (1-5%) severe (>1%)
Treatment can be on-demand or prophylaxis
Two types of coagulation factors (CF) – Plasma-derived and
Recombinant

6. Inhibitors and Therapeutic
Interchange
Inhibitors
Therapeutic Interchange (TI)
Chief adverse event
Cost-containment strategy
Management options – Immune
Tolerance induction (ITI);
preferred, costs $1 M, use of bypassing agents, High-Dose Clotting
Factor Concentrates
Medication switched with a low
cost therapeutically equivalent
alternative
TI in hemophilia extremely low
Greatest inhibitor incidence in
Previously untreated Patients (PUPs)
Fear of inhibitors

7. Coagulation Factors’ Development
Timeline
Intermed
iate
purity
pdFVIII
concentr
ates
pdFVIII
Concent
rates
Early
70s
Late
70s
Donor/Pl
asma
screenin
g for
HBV
starts
Source: FDA workshop on FVIII inhibitors.
Early
80s
Heat
Treatme
nt starts
Mid 80s
Heat
treated
FVIII
plasma
concentr
ates
widely
available
High
purity
pdFVIII
concentr
ates
Late
80s
Expande
d donor
plasma/
plasma
screenin
g:
HIV/HC
Immuno
V
affinity,
solvent/d
etergent,
Ion
exchang
e
treatmen
t starts
Plasma/albumin free rFVIII
Recombinant
FVIII (rFVIII)
Early
90s
Late
90s
Early
00s
Improved donor/plasma screening:HIV, HCV,
NAT starts
Efforts to minimize presence of
animal or human derived
material in rFVIII agents

8. pdFVIII and rFVIII
Plasma-derived
Products containing
Von Willebrand Factor
(VWF)
Humate-P
Made from animal cells
Low cost
Hemofil M
rFVIIII
Made from human
blood
Immunoafinity
Purified
Koate-DVI
pdFVIII
Premium pricing
Contamination fearsfatal diseases like
Creutzfeldt-Jakob
(CJD)
Seen as less
immunogenic
Monoclate-P
Recombinant
First generation
Second generation
Third
generation
Recombinate
Kogenate FS
Advate
Kogenate
Helixate FS
Xyntha
Fear of inhibitor development

9. Methodology and Objectives
Main objective:
Explore TI possibilities between pdFVIII and rFVIII on the basis of their Safety,
Efiicacy and Cost
Objective
Analysis done on the basis of.
Source
Step I
Determine the cost of illness for HA
Outpatient drug claims, outpatient
service claims, inpatient service claims
and inpatient admission claims
1. Study published by Centers for
Disease Control and Prevention
[CDC]
(Market Scan commercial and
Medicare research databases)
Step II (Focus: COST)
Selection of potentially interchangeable
CF’s based on their cost profile
Annual cost, Annual sales and
Formulary status
1. Medicare Part B Drug and Biological
Average Sales Price Quarterly
Payment .files for calendar year
2013,
2. Annual reports
3. Insurance plans’ websites
Step III (Focus: Safety & Efficacy)
Determine whether the big gap in the
cost structure between the two classes
Prescribing information, clinical trials
and published clinical studies
1. Company websites
2. PubMed

10. Results

11. Step I: Cost of illness (COI) of HA
Characteristics of children with Hemophilia A by risk group
No. of people
Age group:N (%)
0 to 4
5 to 9
10 to 14
15 to 17
Clotting factor:
No. of people
Emergency department (ED) visits:
No. of people
Frequency among ED visitors
Types of care: N
Inpatient
Prescription
Total Expenditures ($):
Median
Mean
95th percentile
Expenditures for clotting factors ($):
Median
Mean
95th percentile
Characteristics of adults with Hemophilia A by risk group
Receiving no bypassing agent Receiving bypassing agent
452
14
87
112
170
83
6
3
3
2
386
14
163
2.3
10
5.7
44
164
6
0
$
$
$
73,659
142,057
527,944
$
$
$
461,527
831,866
4,674,076
$
$
$
52,287
124,752
489,393
$
$
$
375,384
728,737
4,141,157
Receiving no by-passing agentReceiving bypassing agent
No. of people
378
16
Age group:N (%)
18-29
187
2
30-39
42
3
40-49
52
4
50-59
48
3
60-69
33
2
70-79
8
1
808
48
Clotting factor:
No. of people
281
16
Emergency department (ED) visits:
No. of people
107
10
Frequency among ED visitors
1.7
2.3
Types of care: N
Inpatient
47
5
Prescription
121
5
Total Expenditures ($):
Median
$
43,968 $
176,218
Mean
$
125,861 $
577,640
95th percentile
$
520,976 $
2,459,207
Expenditures for clotting factors ($):
Median
$
27,561 $
111,147
Mean
$
107,985 $
438,155
95th percentile
$
440,717 $
2,434,958
Guh S, Grosse SD, McAlister S, Kessler CM, Soucie JM. Healthcare expenditures for males with haemophilia and
employer-sponsored insurance in the United States, Haemophilia. 2012 Mar;18(2):268-75.

12. Step I: Cost of illness (COI) of HA
Total expenditures vs. Clotting Factor costs
Key Takeaways:
Children
$900,000
$800,000
$700,000
$600,000
$500,000
$400,000
$300,000
$200,000
$100,000
$-
Children
$831,866
$728,737
Cost of clotting factors = 87% Total cost
With Inhibitors
6X
Without Inhibitors
87%
$142,057
Total expenditures
Total cost for patients with inhibitors six
times higher
$124,752
Adults
Clotting Factor Cost
Cost of clotting factors = 87% Total cost
Total cost for patients with inhibitors four
times higher
Adults
$700,000
$600,000
$577,640
$500,000
$400,000
$300,000
$438,155
4X
With Inhibitors
87%
$200,000
$100,000
Without Inhibitors
$125,861
$107,985
$Total expenditures
Clotting Factor Cost

13. Step II: Cost based comparisons
between rFVIII and pdFVIII
Recombinant products:
Recombinate
Kogenate
Advate
Xyntha
HCPCS code usage in
international units(IU)
1
1
1
1
Average IU/year
6000
6000
6000
6000
Payment limit ($)
1.128
1.128
1.128
1.136
Annual cost
(prophylaxis) ($)
338400
338400
338400
340800
1108
1659
506
Annual Sales (2011) in 553
MM
** XLS sheet: Double click to check formulas**
Detailed Calculation (Total Annual cost) for Recombinant products
Recombinate Kogenate/Helixate FS
Advate
Xyntha
International units (IU)
1
1
1
1
IU/year
6000
6000
6000
6000
Weight
50
50
50
50
IU/Weight required per year $
300,000 $
300,000 $
300,000 $ 300,000
Payment limit/IU
$
1.128 $
1.128 $
1.128 $
1.136
Total annual cost
$
338,400 $
338,400 $
338,400 $ 340,800
Difference
$
2,400
Calculations:
Based on average weight of a 15 year old boy (50 kg), undergoing prophylaxis
and getting 6000 IU of Factor VIII/kg/year
Total Annual cost= IU/weight required annually*Payment limit/IU
Healthcare Common Prrocedural Coding System codes and Average payment limit: Medicare Part B Drug and Biological Average Sales Price
Quarterly Payment .files

14. Step II: Cost based comparisons
between rFVIII and pdFVIII
Plasma-derived products:
Koate
Alphanate
Humate
Monoclate Hemofil-M
-P
HCPCS code
usage in
international
units(IU)
1
1
1
1
1
Average IU/year
6000
6000
6000
6000
6000
Payment limit
($)
0.920
0.930
0.904
0.920
0.920
Annual cost
(prophylaxis) ($)
276000
279000
271200
276000
276000
Detailed Calculation (Total Annual cost) for Plasma derived products
Annual Sales
100
225
350
350
Koate
Alphanate
Humate-P
Monoclonate Hemofil
(2011) in MM
IU
1
1
1
1
1
IU/year
6000
6000
6000
6000
6000
Weight
50
50
50
50
50
IU/Weight in year
$
300,000 $
300,000 $
300,000 $ 300,000 $ 300,000
Payment limit/IU
$
0.920 $
0.930 $
0.904 $
0.920 $ 0.920
Total annual cost
$
276,000 $
279,000 $
271,200 $ 276,000 $ 276,000
Difference
$
7,800
Alphanate-Humate-P
300
Calculations:
Total Annual cost= IU/weight required annually*Payment limit/IU

15. Step II: Cost based comparisons
between rFVIII and pdFVIII
Formulary status comparisons for rFVIII and Plasma derived factors
Recombinant products:
Formulary Plans
Recombinate
Tier
Kogenate
Advate
Xyntha
Res trictions Tier
Res trictions Tier
Res trictions
none
Aetna Medicare Advantage – NC
PA
Res trictions Tier
none
none
none
NC
NC
NC
Capital Blue Cros s -PA
3 none
3 none
3 none
4 none
Penns ylvania s tate medicaid
2 none
2 none
2 none
2 none
Plasma derived products:
Formulary Plans
Koate-DVI
Alphanate
Humate-P
Monoclonate
Hemofil
Restricti
Restric
Restrictio
Restriction
Restricti
Tier ons
Tier tions Tier ns
Tier s
Tier ons
Aetna Medicare Advantage Not covered (NC)NC none
none
Capital Blue
3 none
3 none
Pennsylvania state
medicaid
2 none
2 none
Plans. (n.d.). Capital BlueCross. Retrieved November 20, 2013, from
https://www.capbluecross.com/
Medicaid State Plan. (n.d.). Medicaid State Plan. Retrieved November 20, 2013, from
http://www.dpw.state.pa.us/publications/medicaidstateplan/index.htm
Medicare Advantage. (n.d.). , Plans. Retrieved November 20, 2013, from
http://www.aetnamedicare.com/plan_choices/aetna_medicare_advantage.jsp
NC
none
NC none
3 none
3 none
3 none
2 none
2 none
2 none
NC
none

16. Step III: Safety and Efficacy analysis
–
Advate and Monoclate-P
Advate’s annual treatment is $60K higher than Monoclate-P
Average male with Hemophilia A with a life expectancy of 76 years:
Annual cost
Rough lifetime cost(76 years)
Difference
Advate
Monoclate
$338,400
$276,000
$25,718,400 $20,976,000
$4,742,400

17. Advate (rFVIII)
Company
Baxter
Cost
$
formulary status
Monoclate-P (Plasma)
same
Type of molecule
Patients studied in trials
median ABR (Annualized
bleed rate)
zero bleeds
CSL Behring
338,400
$
276,000
Advate's annual treatment cost is $62,400 more than monoclate-P
same
Pasteurized, monoclonal antibody purified
lyphillized concentrate of Factor VIII with
protein free full length rFVIII
reduced amounts of VWF:Ag
5 completed studies in previously treated
2 open label studies in PUPs (moderate to
patients (PTPs) and one on going study in
severe HA). No patients seroconverted to
previously untreated patients (PUPs)
HIV, Hepatitis nonA/non B, or hepatitis B.
1.0 (both standard prophylaxis and PK driven
prophylaxis) vs 44 for on demand patients
NA
42% of patients on prophylaxis (0% on demand) NA
The dose and frequency of use of this
medication will be determined by your
every three days
condition, weight and situation
dosing frequency
anaphylaxis/hypersensitivi
ty
can occur (trace mouxse proteins)
inhibitors
can occur ( trace mouse proteins)
mild chills, nausea or stinging at the
infusion site. In some cases, inhibitors of
more than 10% of patients saw pyrexia,
FVIII may occur. Carries a risk of
headache, cough, nasopharyngitis,
transmitting Creutzfeldt-Jakob disease(CJD)
vomiting, arthralgia, and limb injury
agent
Clinical trial was conducted in nine
patients. IgE antibodies to
mouse IgG were undetectable (519 ng ML71)
at all time
3/182 pts saw upward trend in CHO antibodies, points.Lack of immunogenicity of traces of
10/182 upward trend in
mouse protein in these preparations is
muIgG (mouse immunoglobulin) antibodies.
supported in that
Could lead to urticaria, pruritus,
none of the patients assessed developed
rash, and slight eosinophil count elevations,
anaphylactoid
but repeat admin without
reactions during treatment. Unreliable due
recurrence of side effects.
to small sample size
0.3% overall inhibitor rate. 5/25 previously
untreated patients developed
antibodies in median 11 exposure days, 4 high
titer 1 low titer. In previously
treated patients, 1 of 198 older than age 10
developed low-titer antibody in
23% overall inhibitor rate. 7/30 previously
26 exposure days, or 0.51% frequency (no
untreated patients developed antibodies
longer detectable after 8 weeks).
with 3 being high (>10BU) titer. The majority
none of 53 pediatric (<6) previously treated
of patients who developed inhibitors had
patients developed inhibitors
severe hemophilia A (n=6) [details in Table ]
half life
12.4 hours
other adverse reactions
immunogenicity
17.5 hours
Key Takeaways:
Inhibitor rates in PUPs for both
drugs very close – Advate
(20%) and Monoclate (23%)
Negligible inhibitor development
in PTPs
Sample size very small
EPIC study conducted by
Baxter
"Advate." Prescribing Information. N.p., n.d. Web. 8 Dec. 2013.
"Monoclate-P." Prescribing Information. N.p., n.d. Web. 8 Dec. 2013.

18. Step III: Safety and Efficacy analysis
–
Advate and Monoclate-P
Monoclate-P Clinical studies
Study design
Number of patients
Results
Inhibitors to FVIII were
detected in seven of the
Aim: To study the efficacy and asafety of
30 previously untreated
30 (23%) treated patients
1
Monoclate-P
patients, 18 with severe
after a mean of 418 days.
Two multicentre, prospective, open label (<1% FVIII:C activity) and 12 The majority of patients
trials were conducted in four medical
with moderate (!% to 5%
who developed
centres in the US (Sudy I) and in 11 medical FVIII:C activity) hemophilia
inhibitors had severe
centres in Europe (Study II).
A.
hemophilia A (n=6)
A Post-Marketing Safety and Efficacy
97 patients with
Assessment of a Monoclonal Antibody
haemophilia A, attending
Purified High-Purity Factor VIII
three haemophilia centres,
Concentrate. 2
The identification of infrequent sideeffects of clotting factor concentrates,
undetected by clinical trials, is facilitated
by post-marketing surveillance.
were treated over a
median follow-up period
of 284 days (range 1-1074), No new inhibitors were
and a total follow-up
observed during the
period of 30,080 days,
study
1. CS, P. (n.d.). Viral safety of a pasteurized, monoclonal antibody-purified factor VIII concentrate in previously untreated haemophilia A patients . National Center for Biotechnology
Information.
2. Lee, C., Savidge, G., & Hay, C. (n.d.). "A Post-Marketing Safety and Efficacy Assessment of a Monoclonal Antibody Purified High-Purity Factor VIII Concentrate.". Post Marketing

19. Step III: Safety and Efficacy analysis
–
Advate and Monoclate-P
Advate
Monoclate-P
Total number of patients
198 (PUPs+PTPs)
30PUPs
Inhibitor rate
5/25 (20%)
7/30 (23%)
Overall inhibitor rate
0.3%
23%
Tests on PTP’s
1/173
0/97 patients
Phase IV (no inhibitor
development was
reported)
Immunogenicity
3/182 upward trend in
CHO antibodies
10/182- mouse ulgG
antibodies
Conducted in 9 patients.
Any antibody formation
was undetectable

20. Step III: Safety and Efficacy analysis
–
Advate and Monoclate-P
Heterogeneous nature of clinical studies makes it difficult to evaluate rates of inhibitor
development
Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET ) study- Advate vs.
Advate
Monoclate-P
Alphanate
The advantages include:
 Better S&E profile
 Contains no human or animal plasma or
albumin;
 Recently approved
 Recombinant proteins are generally
perceived as less immunogenic
Advantages:
 Lower cost
 Improved viral inactivation processes and
testing of donor plasma
 Patient switch among PUPs in Hemophilia A
is almost nil while in that of PTPs is
generally low
While the major disadvantage in Advate is the
premium pricing.
Disadvantages:
 Transmission risk of fatal infectious diseases
like CJD
 Not enough published data on clinical
studies
 Approved in 1988 with a different regulatory
protocol than today which make the

21. Conclusion
Results do not support initial hypothesis
High magnitude of risks
Lack of published evidences
Uncertainty can lead to higher costs, fatal infectious diseases & unknown
immunogenic reactions
Comparing apples to oranges need to be stopped
Results lean in the favor of Advate – PUPs regimen

22. Recommendations
Studies focused on providing more information about the long term natural
history of inhibitor incidence, either or just-appearing inhibitors
Careful follow up of patients during a switch to a new product
Pharmacovigilance registry

23. References
Johnson, K. A., & Zhou, Z. (n.d.). Costs of care in hemophilia and possible implications of health care reform.
National Center for Biotechnology Information. Retrieved November 28, 2013, from
http://www.ncbi.nlm.nih.gov/pubmed/22160067
Lorio, A., Pucetti, P., & Makris, M. (n.d.). Alfonso Iorio1, Paolo Puccetti2, and Mike Makris3. PubMed.gov. Retrieved
November 22, 2013, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702179/
FDA workshop on FVIII inhibitors. (n.d.). DEPARTMENT OF HEALTH AND HUMAN SERVICES . Retrieved
December 15, 2013, from
http://www.fda.gov/downloads/biologicsbloodvaccines/newsevents/workshopsmeetingsconferences/transcriptsminut
es/ucm054451.pdf
Aledort LM Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia a
treatment. J Thromb Haemost 2011;9(3):423-427
Neugebauer B, Drai C, Haase M, et al. Factor VIII products and inhibitor development: concepts for revision of
European regulatory guidelines.Haemophilia 2008;14(1):142-144.
Guh S, Grosse SD, McAlister S, Kessler CM, Soucie JM. Healthcare expenditures for males with haemophilia and
employer-sponsored insurance in the United States, 2008. Haemophilia. 2012 Mar;18(2):268-75.
2013 ASP Drug Pricing Files. (n.d.). - Centers for Medicare & Medicaid Services. Retrieved November 1, 2013, from
http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-BDrugs/McrPartBDrugAvgSalesPrice/2013ASPFiles.html
Medicaid State Plan. (n.d.). Medicaid State Plan. Retrieved November 20, 2013, from
http://www.dpw.state.pa.us/publications/medicaidstateplan/index.htm
Medicare Advantage. (n.d.). , Plans. Retrieved November 20, 2013, from
http://www.aetnamedicare.com/plan_choices/aetna_medicare_advantage.jsp

24. References
Plans. (n.d.). Capital BlueCross. Retrieved November 20, 2013, from
https://www.capbluecross.com/
"Advate." Prescribing Information. N.p., n.d. Web. 8 Dec. 2013.
<http://www.baxter.com/downloads/healthcare_professionals/products/ADVATE_PI.pdf>
"Monoclate-P." Prescribing Information. N.p., n.d. Web. 8 Dec. 2013.
<http://www.CSLBehring.com/docs/2012-MonoclateP-PI.pdf>.
CS, P. (n.d.). Viral safety of a pasteurized, monoclonal antibody-purified factor VIII concentrate in
previously untreated haemophilia A patients . National Center for Biotechnology Information.
Retrieved January 11, 2014, from http://www.ncbi.nlm.nih.gov/pubmed/11260273
Lee, C., Savidge, G., & Hay, C. (n.d.). "A Post-Marketing Safety and Efficacy Assessment of a
Monoclonal Antibody Purified High-Purity Factor VIII Concentrate.". Post Marketing Surveillance .
Retrieved November 24, 2013, from
https://www.newsrx.com/purchased_articles.php?accessID=14c1ffc154d79679c059e69876e7a6c
6
Life Expectancy FASTSTAT. (2013, November 21). Centers for Disease Control and Prevention.
Retrieved January 11, 2014, from http://www.cdc.gov/nchs/fastats/lifexpec.htm
Sippet Study. (n.d.). Sippet Study. Retrieved January 11, 2014, from
http://www.sippet.org/Source/SippetStudy.aspx

25. Thank you