Download Cell Therapy: PROVENGE

Cell Therapy: PROVENGE®
Sipuleucel-T
Regulatory framework
Lysa ANGLES
Delphine CAZALEDES
Chloé DESPRES
Valentin RENAUX
Clémence ROYE
MASTER 2 AREIPS – March 2015
Disclaimer
This is an independent study performed by
students from the Master Degree « Affaires
Réglementaires Européennes et Internationales des
Produits de Santé ».
Opinions expressed in this presentation are
strictly personal and may not reflect those from
the University of Lille 2.
2
Introduction
 Manufactured by Dendreon Corporation
 Cancer vaccine
 For the treatment of asymptomatic or minimally symptomatic
metastatic castrate resistant (hormone refractory) prostate cancer
 FDA: MA April 29th, 2010
Launch May 2010
 EMA: MA September 6th, 2013
No launched
3
Content
 The natural history of prostate cancer
 Epidemiology & Physiopathology
 Diagnostic
 Therapeutic strategy
 Process of PROVENGE®
 Regulatory dossier
 Submission
 CMC
 Clinical studies
 Pharmaco-economic aspects of PROVENGE®
 Pricing
 Reimbursement
 Consequences
 PROVENGE® nowadays
 Conclusion
M2 AREIPS – March 2015
4
Part 1
The natural history of
prostate cancer
Epidemiology & Physiopathology
Diagnostic
Therapeutic strategy
5
Prostate cancer




Development of cancer cells in the prostate
95%: adenocarcinoma (glandular cancer)
Slow and predictable progression
The most common cancer and the second leading cause of cancer
deaths among males in most Western countries.
 Prostate cancer-related deaths occur as a result of complications
of metastatic disease.
6
Prostate cancer in figures
http://seer.cancer.gov/statfacts/html/prost.html
7
Prostate cancer in figures
http://seer.cancer.gov/statfacts/html/prost.html
8
Physiopathology
9
Part 1
The natural history of
prostate cancer
Epidemiology & Physiopathology
Diagnostic
Therapeutic strategy
10
Part 1
The natural history of
prostate cancer
Diagnostic
1. Digital rectum examination
2. Prostatic Specific Antigen (PSA)
3. Biopsy
Gleason score
11
1. Digital rectum examination
 The most common way of helping
to diagnose a prostate cancer
 Hard bumpy areas may suggest
prostate cancer
 >50 years, once a year
12
2. Prostate Specific Antigen (PSA)
 Protein produced by the prostate gland
 PSA test measures the level of PSA in a man’s blood
 Screen men for prostate cancer
 Monitor men who have been diagnosed with prostate cancer
 to see if their cancer has recurred after initial treatment
 To see if they are responding to therapy
13
2. Prostate Specific Antigen (PSA)
PSA (ng/mL)
Detection rate
Cancer stage and curability
3–7
25%
Very early, curable in more
than 8 cases out of 10
7 – 30
65%
Early, curable in less than 5
cases out of 10
30 – 100
90%
Advanced, non curable,
regional metastasis
100 – 1000
100%
Late, non curable, bone or
distant metastasis
14
3. Biopsy
 Remove small samples of prostate tissue
 Transrectal or transurethral biopsy
Normal prostate
Prostatic adenocarcinoma
15
Gleason Score
 Sums the pattern-number of the primary and secondary grades to
obtain the final Gleason score
 Gleason scores range from 2 to 10
16
Part 1
The natural history of
prostate cancer
Epidemiology & Physiopathology
Diagnostic
Therapeutic strategy
17
When is the right time for
Provenge®?
No metastasis cancer
Metastasis cancer
18
Part 2
Process of PROVENGE ®
19
The immunotherapeutic approaches
 2 types of immunotherapeutic approaches to treat a cancer
 Passive immunotherapy : antibodies produced in laboratory
 Bevacizumab
 Trastuzumab
 Active immunotherapy “vaccine therapy” : designed to elicit a
host immune response that specifically targets the tumor.
  The APC will process internalized intact protein into peptide fragments
which can stimulate a specific tumor response with memory capabilities
20
Principe of Provenge®
 The cells that comprise sipuleucel-T are not intended to have a
direct cytotoxic effect.
 The anti-tumor effect is generated by the presentation of the PAP
antigen by activated cells present in the population of cells
contained in sipuleucel-T to immune cells in the body such as T
cells which will then mount an immune attack against the
prostate tumor.
 Thus, this product
relies on the patient's
immune system to
develop a specific
response that can then
kill the tumor
21
How does it work?
22
Leukapheresis
 Leukapheresis involves having an intravenous catheter (IV) placed
in each arm. Blood is taken out of one of the IVs, filtered through a
machine that pulls out the necessary white blood cells, and the
rest of the blood is then given back to you through the second IV
after a step of centrifugation.
 This process takes about 3-4 hours and is done 3 days prior to the
infusion of Provenge®.
23
24
Leukapheresis
 Leukapheresis involves having an intravenous catheter (IV) placed
in each arm. Blood is taken out of one of the IVs, filtered through a
machine that pulls out the necessary white blood cells, and the
rest of the blood is then given back to you through the second
IV. This process takes about 3-4 hours and is done 3 days prior to
the infusion of Provenge®.
 1,5-2 times patient’s blood volume
 There are some recommendations for patients who do
leukapheresis (hydration, calcium, no caffeine,…)
25
How does it work?
PA2024
26
PAP-GM-CSF
 In vitro
27
Role of each component
 PAP : Prostatic Acid Phosphatase : the target antigen
 Expressed in more than 95% of prostate adenocarcinomas
 Highly specific to prostate tissue
 Reported to be an effective target antigen in experimental models
 GM-CSF : Granulocyte Macrophage Colony Stimulating Factor
 The receptor for GM-CSF is expressed broadly on blood and bonemarrow derived APCs.
 Engagement of the GM- CSF receptor by ligand results in the
upregulation of the expression of a variety of molecules.
 The APC will bind PA2024 by way of the GM-CSF receptor and
internalize the fusion protein, process the PAP antigen portion, and
present it in context of class I and class II major histocompatibility
complex (MHC)
GM-CSF
© The Canadian Journal of UrologyTM: International Supplement, April 2014
28
Prostatic Acid Phosphatase
(PAP)
PAP-GM-CSF
 In vitro
The final cellular product is
suspended in lactated Ringer’s
and delivered for infusion within
18 hours of suspension
= date of manufacture
29
How does it work?
30
CD54 activation
 CD54 is a cell surface molecule that plays a role in the
immunologic interactions between APCs and T cells, and is
considered a marker of immune cell activation.
 The data presented show that CD54+ cells are responsible for T
cell stimulation and for PAP antigen presentation.
31
Calendar
CYCLE 1
CYCLE 2
CYCLE 3
Leukapheresis
Manufacturing of
PROVENGE®
32
PROVENGE®
Infusion
Part 3
Regulatory Dossier
Submission (FDA / EMA)
CMC
Clinical Studies
33
Part 3
Regulatory Dossier
Submission (FDA / EMA)
CMC
Clinical Studies
34
Submission - FDA
Different approaches
Different types of
applications
Speeding the availability of drugs
that treat serious diseases
NDA (New Drug Application)
Fast track
2005
ANDA (Abbreviated NDA)
Priority review
2007
OTC (Over-The-Counter drugs)
Breakthrought therapy
BLA (Biologic Licence Application)
Accelerated approval
2006
35
Submission - FDA
How to speed the availability of drugs ?
process designed to facilitate
the development, and expedite
the review of drugs to treat
serious conditions and fill an
unmet medical need
allowed drugs for serious
conditions that filled an unmet
medical need to be approved
based on a surrogate endpoint
process designed to expedite
the development and review of
drugs which may demonstrate
substantial improvement over
available therapy
FDA’s goal is to take action on
an application within 6 months
2005
2007
36
Submission – FDA summary
Jan 2005
Nov 2005
Jan 2007
…
Apr 2010
• Discussions with the FDA to determine the best way of obtaining
regulatory approval
• Fast Track Status
• Priority Review Status
•…
• Sipuleucel-T approval
37
Submission - UE
PROVENGE® REGULATORY STATUS ?
DIRECTIVE 2003/63/CE
du 25 Juin 2003, modifiant la Directive 2001/83/EC
Annexe I, Partie IV : Médicaments de thérapie innovante
…procédés de fabrication axés […] sur des cellules dont les propriétés biologiques
ont été modifiées et qui sont utilisées comme substances actives ou parties de
substances actives.
2. Médicaments de thérapie cellulaire somatique
…cellules vivantes somatiques autologues (émanant du patient lui-même),
allogéniques (provenant d'un autre être humain) ou xénogéniques (provenant
d'animaux) utilisées chez l'homme, dont les caractéristiques biologiques ont été
sensiblement modifiées sous l'effet de leur manipulation pour obtenir un effet
thérapeutique, diagnostique ou préventif s'exerçant par des moyens
métaboliques, pharmacologiques et immunologiques. Cette manipulation inclut
l'expansion ou l'activation de populations cellulaires autologues ex vivo…
38
Submission - UE
REGULATION (EC) No 1394/2007
Centralised procedure is compulsory for :
 human medicines for the treatment of human immunodeficiency virus
(HIV) or acquired immune deficiency syndrome (AIDS), cancer, diabetes,
neurodegenerative diseases, auto-immune and other immune
dysfunctions, and viral diseases
 veterinary medicines for use as growth or yield enhancers
 medicines derived from biotechnology processes, such as genetic
engineering
 advanced-therapy medicines, such as gene-therapy, somatic cell-therapy
or tissue-engineered medicines
 officially designated 'orphan medicines' (medicines used for rare human
diseases)
39
Submission – UE summary
2011
Jan 2012
…
Sept 2013
•Pre-submission meetings with EMA
•Filing submitted to the EMA validated
•…
•EC approved Sipuleucel-T in the EU, Norway, Iceland and
Liechtenstein
40
Submission : what is next ?
•Discussions
•Discussions with
with the
the FDA
FDA to
to determine
determine the
the
best way
way of
of obtaining
obtaining regulatory
regulatory approval
approval
Jan
Jan 2005
2005 best
Nov
Nov 2005
2005
Jan
Jan 2007
2007
•Fast
•Fast Track
Track Status
Status
2011
• Filing submitted to the EMA
validated
Jan 2012
•Priority
•Priority Review
Review Status
Status
•Cellular, tissue and Gene Therapies
•…
Advisory Committee review
Ma…
2007
Apr
Apr 2010
2010
• Pre-submission meetings with EMA
•Sipuleucel-T
•Sipuleucel-T approval
approval
June…2013
•…
CAT and CHMP review
•
• EC
EC approved
approved Sipuleucel-T
Sipuleucel-T in
in the
the EU,
EU,
Norway,
Iceland
and
Liechtenstein
Sept
Sept 2013
2013
41
Review and evaluation of the MAA dossier
Cellular, tissue and Gene Therapies
Advisory Committee
CHMP & CAT
What were the main
issues ?
 CMC
 Toxicology & Pharmacology
 Name
 Statistics
 Clinical studies
42
Part 3
Regulatory Dossier
Submission (FDA / EMA)
CMC
Clinical Studies
43
CMC
Main issues related to CMC
dossier ?
1. Product consistency
2. Lot release testing
3. Logistics
44
CMC
Main issues related to CMC
dossier ?
1. Product consistency
2. Lot release testing
3. Logistics
45
CMC – Product consistency
Sipuleucel-T process overview :
inherent
variability
Product is variable :
- From patient to patient
- From lot to lot
46
differences in :
 Total number of cells ?
 Cellular composition ?
 Level of activation of
monocytes ?
if yes
CMC – Product consistency
1. Variability in Total
Number Cell (TNC) ?
Pre-requisites
Leukapheresis
( 2 x buoyant density centrifugation)
TNC could impact the
dose of the product
47
CMC – Product consistency
1. Variability in Total
Number Cell (TNC) ?
APH = leukapheresis
FP = final product
Data based on 526 lots
 Process significantly reduces TNC
 Broad range in TNC
 Due to variability in the apheresis material
 Will impact the TNC administered per dose
 No upper or lower limit for TNC in the final
product
FDA briefing information (part 2)
48
CMC – Product consistency
Sipuleucel-T process overview :
inherent
variability
Product is variable :
- From patient to patient
- From lot to lot
49
differences in :
 Total number of cells ?
 Cellular composition ?
 Level of activation of
monocytes ?
if yes
CMC – Product consistency
2. Variability in cellular
composition ?
 Mixed population of leukocytes
Will the cellular composition
be variable :
- From one lot to an other
one ?
- Across the manufacturing
process ?
50
CMC – product consistency
2. Variability in cellular
composition ?
Sponsor briefing document
Variability from a lot to an other one ?
51
CMC – Product consistency
2. Variability in cellular
composition ?
Sponsor briefing document
Variability across the manufacturing process ?
52
CMC – Product consistency
To sum up 1. & 2.
1. Variability in Total
Number Cell (TNC) ?
2. Variability in cellular
composition ?
YES
Variability from a lot to an other one : YES
Variability across the manufacturing process : NO
How to be sure the product is well manufactured and will be effective ?
Level of activation of monocytes
= product potency
53
CMC – Product consistency
Sipuleucel-T process overview :
inherent
variability
Product is variable :
- From patient to patient
- From lot to lot
54
differences in :
 Total number of cells ?
 Cellular composition ?
 Level of activation of
monocytes ?
if yes
CMC – Product consistency
3. Variability in product
potency ?
 The APCs are not expected to
directly kill tumor cells, but instead
are expected to activate antigenspecific T cells.
 The ideal potency assay for a product
with this proposed mechanism of
action would be to measure the
ability of the APCs to induce
antigen-specific T cells in vitro. This
is not feasible for sipuleucel-T
because of its shelf-life and the
duration needed for this assay.
How to measure product potency ?
55
CD54 activation
 CD54 is a cell surface molecule that plays a role in the
immunologic interactions between APCs and T cells, and is
considered a marker of immune cell activation.
 The data presented show that CD54+ cells are responsible for T
cell stimulation and for PAP antigen presentation, with no
presentation by T cells and B cells, and very low levels by NK cells
56
CMC – Product consistency
3. Variability in product
potency ?
How to measure product potency ?
-> detect APCs
 Number of CD54+ cells (indirect indication that cells can
process and present Ag)
 CD54 upregulation = ratio of CD54 expression before and
after culture with PA2024 (direct mesure of cellular
activation)
57
CMC – Product consistency
3. Variability in product
potency ?
1. Number of CD54+ Cells
- Data from each of the 3 doses of the treatment
cycle
- Number of CD54 positive cells present in the final
product did not increase with subsequent
vaccinations
FDA briefing information part 2
58
CMC – Product consistency
3. Variability in product
potency ?
2. CD54 Upregulation
- Data from each of the 3 doses of the treatment
cycle
- Median level of CD54 Upregulation did increase
between the fist vaccination and the week 2
vaccination
This indicates that the response to PA2024, at least
in vitro, is increasing with subsequent doses of
product.
FDA briefing information part 2
59
CMC – Product consistency
TNC
Cellular Composition
Product potency
SUMMARY
 Data on product cellular composition and cell number demonstrates very large
inherent product variability
will impact the total number
of cells administered/dose
 Lot to lot variations
 Even from the same patient
 Manufacturing process is consistent
 No criteria for minimal or maximal TNC dose in the final product.
The only requirement for TNC is the minimum limit established for the
apheresis material.
 A dose of sipuleucel-T is based on a minimum number of CD54 positive cells.
60
CMC
Main issues related to CMC
dossier ?
1. Product consistency
2. Lot release testing
3. Logistics
61
CMC - Lot release testing
1.
Identity :
adequately identify the product as that designated on the final container and package
labels and distinguish it from other products being processed in the same facility
2.
Purity/Impurity :
measurement of pyrogenic substances, and any extraneous material that is
unavoidable in the manufacturing process. For cellular products this may include
measurement of populations of cells in the final product that are not proposed to be
the active cells
3.
Potency :
the sipuleucel-T product dose is based on the total number of CD54+ cells :
Minimum of 50 million CD54+ cells
FDA briefing information part 2
62
CMC
Main issues related to CMC
dossier ?
1. Product consistency
2. Lot release testing
3. Logistics
63
Stability issues
 Shelf life : 18 H
 Temperature storage : 2-8°C
 Challenge : shipping
CMC review FDA
64
Logistic
 4 majors steps
Contact Dendreon
HQ : management
scheduling
Scheduling
Cell
collection
Manufacturing
Follows by HQ
Infusion
Dendreon.com
65
Barecoded and
pakaged / follows
by HQ
Packaging
 1 : infusion bag
 2 : secondary packaging
 shipment bag (leak-proof,
tamper-evident polypropylene
pouch)
 insulated polyurethane
container (which protects the
product from physical stresses,
 and cools and maintains the
product within the validated
temperature range of 2 to 8°C
with gel packs
 3 : shipping package (cardboard
box)
66
Maintain identity of the product
 Barcode on all samples
 LIMS : Laboratory Information Management Systems
 Track all samples
 Barcode on infusion bag
 Barcode on container
 Cardboard shipping carton will not contain any product or patient specific
label. A shipping label with the site contact name, site address, and the lot
number, will be affixed to the cardboard shipping carton.
67
Part 3
Regulatory Dossier
Submission (FDA / EMA)
CMC
Clinical Studies
68
How to treat placebo patients?
Provenge® group
Placebo group
Leukapheresis
Leukapheresis
APCs cultured with
PAP-GMCSF
Reinfusion of cells :
PROVENGE®
1/3 of cells
Held at 2-8°C
during 36-44h
Reinfusion of
cells
2/3 of cells
cryoconserved
Open-label
Salvage
protocol
APCs cultured
with APC8015F
Reinfusion of cells :
SIMILI-PROVENGE®
D9901 study
Involvement of 19
centers in the US
127 patients
2:1 ratio
(sipuleucel-T: placebo)
Crossover to open-label
APC8015F for patients
treated with placebo.
Observations every 8
to 12 after treatment
70
D 9901 study
Primary Endpoint : Time To Progress
The median TTP was 11.7 weeks
(95% CI, 9.1 to 16.6) in sipuleucelT-treated patients and 10.0
weeks (95% CI, 8.7 to 13.1) in
placebo-treated patients.
This phase III trial did not demonstrate an improvement in the primary
end point (TTP) with sipuleucel-T compared with placebo.
© The Canadian Journal of UrologyTM: International Supplement, April 2014
71
D9901 study
Secondary Endpoint : Overall Survival
Nevertheless : In an ITT
(Intention to treat) analysis, the
median overall survival was 25.9
months (95% CI, 20.0 to 31.9) in
sipuleucel-T-treated patients
compared with 21.4 months (95%
CI, 12.3 to 25.8) in placebotreated patients.
 The use of sipuleucel-T demonstrated a 4.5-month improvement in
overall survival, which achieved statistical significance.
© The Canadian Journal of UrologyTM: International Supplement, April 2014
72
IMPACT study
IMPACT (Immunotherapy for Prostate AdenoCarcinoma Treatment)
Involvement of 75
centers in the US
512 patients
2:1 ratio
(sipuleucel-T: placebo)
Crossover to open-label
APC8015F for patients
treated with placebo.
Observations every 8
to 12 after treatment
73
IMPACT study
Primary Endpoint : Overall Survival
 Results
 92,2% of patients received
all three infusions
 The median OS was 25,8
months for men receiving
sipuleucel-T vs 21,7 months
for patients receiving
placebo  4,1 months
longer
NEJM Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer, Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore et all
74
IMPACT study
Adverse events were reported for 496 of 506 patients (98.0%) in the
safety population and were mild to moderate (grade 1 or 2) for 330
patients (65.2%).
Except for groin pain,
most of these events
occurred with- in 1 day
after infusion and
resolved within 1 to 2
days.
NEJM Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer, Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore et all
75
A bit more complicated…
D9901
D9902
Time to Disease
Progression
Time to Disease
Progression
2002
Negative results
2004
Post-hoc
analysis on OS
positive
D9902 A :
enrollement stoped
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
2000
D9902 B : IMPACT
TODP - TDRP
OS primary criteria
77
TODP : Time to Objective Disease Progression
TDRP : Time to Disease Related Pain
IMPACT Design
Randomize
Sipuleucel-T
Week 0, 2, 4
Placebo
Objective Disease Progression = Secondary criteria
Docetaxel +
Salvage
treatment
Docetaxel
Overall Survival = primary criteria
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
78
Controversal
Placebo ?
Salvage therapy ?
Docetaxel ?
79
Controversal
Placebo ?
Salvage therapy ?
Docetaxel ?
80
Placebo
Placebo group
Leukapheresis
1/3 of cells reinfused ?
Thus, given the greater than
65% (median) of cells lost in
processing and the further
two-thirds
removed
for
freezing, less than 12% of the
original pheresed cell load
was left for reinfusion into the
placebo patients.
1/3 of
1/3 of cells
cells
Held at 2-8°C
during 36-44h
Reinfusion of
cells
Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in CastrationResistant Prostate Cancer . Marie L. et al.Manuscript received July 11, 2011
81
2/3 of cells
cryoconserved
Open-label
Salvage
protocol
APCs cultured
with APC8015F
Reinfusion of cells :
SIMILI-PROVENGE®
Placebo
Placebo group
Leukapheresis
No GM-CSF ?
1/3 of cells
GM-CSF is a cytokine that
functions as a white blood
cell growth factor, and
furthermore, may have
antitumor activity as a
single agent in prostate
cancer.
Held at 2-8°C
during 36-44h
Reinfusion of
cells
Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in CastrationResistant Prostate Cancer . Marie L. et al.Manuscript received July 11, 2011
82
2/3 of cells
cryoconserved
Open-label
Salvage
protocol
APCs cultured
with APC8015F
Reinfusion of cells :
SIMILI-PROVENGE®
Placebo
Placebo group
Leukapheresis
Storage at 2-8°C
during 36-44h?
1/3 of cells
Storage at 2°C–8°C for
36–44 hours can result
in the death of most of
those cells.
Held at 2Held at 2-8°C
8°C during
during 36-44h
36-44h
Reinfusion of
cells
Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in CastrationResistant Prostate Cancer . Marie L. et al.Manuscript received July 11, 201
83
2/3 of cells
cryoconserved
Open-label
Salvage
protocol
APCs cultured
with APC8015F
Reinfusion of cells :
SIMILI-PROVENGE®
Placebo
1/3 reinfused ?
No GM-CSF ?
Storage at 2-8°C
during 36-44h?
Conclusion : No impact on OS in placebo population BUT The IMPACT placebo
constituted a biologically significantly different intervention that could have
had distinct clinical properties and was therefore an inappropriate control
for sipuleucel-T.
Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in CastrationResistant Prostate Cancer . Marie L. et al.Manuscript received July 11, 201
84
Controversal
Placebo ?
Salvage therapy ?
Efficacy ?
85
Context
2002
D9901
D9902
Time to Disease
Progression
Time to Disease
Progression
Negative results
D9902 A :
enrollement stoped
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
86
2000
D9902 B : IMPACT
TODP - TDRP
TODP : Time to Objective Disease Progression
TDRP : Time to Disease Related Pain
Salvage therapy
Randomize
Supportive study D9901
I : TDP
Post-hoc analysis : OS
Supportive study D9902A
I : TDP
Post-hoc analysis : OS
Sipuleucel-T
Week 0, 2, 4
Placebo
Objective Disease Progression
Positive effect on OS
Docetaxel
Bias ?
Docetaxel +
Salvage
treatment
Overall Survival = primary criteria
ANSM CR 04/07/14
87
Salvage therapy
 Post-hoc studies have been performed
 Not interpretable : not on randomized groups
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
88
Controversal
Placebo ?
Salvage therapy ?
Docetaxel ?
89
Docetaxel ?
 Consequences of Docetaxel ?
 57 % in Sipuleucel-T arm
 50% in placebo arm
 Applied 1,6 months later
in placebo arm
Randomize
Sipuleucel-T
Week 0, 2, 4
Placebo
Objective Disease Progression = Secondary criteria
Docetaxel
Docetaxel +
Salvage
treatment
Overall Survival = primary criteria
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
90
Docetaxel ?
 Post-hoc study has been performed :
 Not interpretable : not on randomized groups
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
91
Conclusion on IMPACT study
Is Provenge® really effective ?
FDA and CHMP concluded that the clinical efficacy has been established
92
Regulatory Dossier - Summary
FDA
•Discussions with the FDA to determine the
Jan 2005 best way of obtaining regulatory approval
EMA
•Pre-submission meetings with EMA
2011
•Fast Track Status
Nov 2005
•Filing submitted to the EMA validated
Jan 2012
•Priority Review Status
Jan 2007
•Cellular, tissue and Gene Therapies Advisory
Mar 2007 Committee recommended approval for HRPC
•Sipuleucel-T approval
Apr 2010
June 2013
Sept 2013
93
•CAT adopted a draft opinion recommending
approval
•CHMP adopted a positive opinion for approval
•EC approved Sipuleucel-T in the EU, Norway,
Iceland and Liechtenstein
What happened ?
 In 2007 FDA : submitted application deemed insufficient to
support licensure
https://www.youtube.com/watch?v=f30cedqwQUQ
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
94
What happened ?
D9901
D9902 B : IMPACT
2004
Post-hoc
analysis on OS
positive
OS primary criteria
2006
BLA submitted
2007
FDA defer
licensure
decision
2009/
2010
http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTher
apyProducts/ApprovedProducts/UCM214540.pdf
TODP - TDRP
Approval
95
End of the study
TODP : Time to Objective Disease Progression
TDRP : Time to Disease Related Pain
Part 4
Pharmaco-economic aspects of
PROVENGE®
Pricing
Reimbursement
Consequences
96
Main issues
 New cancer medicines
→ More selective
→ More expensive
→ Put pressure on health care budgets
 Question : What minimum amount of benefit (and maximum cost)
is acceptable for adoption of a new cancer medicine?
→ Pharmacoeconomic evaluation : increasingly used by government
agencies, insurance companies and health care professionals to
assess the cost-effectiveness of a (cancer) medicine
M2 AREIPS – March 2015
97
Part 4
Pharmaco-economic aspects of
PROVENGE®
Pricing
Reimbursement
Consequences
98
Pricing
 Price : a wider range of factors in decision making
 High costs of production
 Manufacturing costs
 Manufacturing facilities
 Leukapheresis providers
 Physician infusion centers
 Transportation
 R&D
 Support functions
 Difficult to forecast a price for a first active immunotherapy in
prostate cancer
M2 AREIPS – March 2015
99
Estimated sales (USA)
Cost of goods/treatment (2015) = 11,400$
Cost of goods/sales (2015) = 30%
M2 AREIPS – March 2015
Total expenses/sales
(2015) = 47%
100
Pricing
 USA
 UK
 $31,000 per infusion
=
 $93,000 per patient
 Almost $23,000 per extra month of life
 20-30% of men diagnosed with early
stage prostate cancer
 benchmarking not just against
competitors’ prices
 Acquisition cost of £47,132.68 based on
an average of 2.92 infusions
 Almost 4600 patients in England
 Competitor’s price: £58,600 for
abiraterone, Zytiga® (20 months/
discount patient access scheme)
 Additional costs? a limited number of
treatment centres, high travel costs
for the individual or the NHS…
 “Our price compares favorably to
other cancer drugs,” Hans Bishop
Dendreon’s chief operating officer
 Conditional on the treatment being
launched
http://www.xconomy.com/seattle/2010/04/29/dendreon-sets-provenge-price-at93000-says-only-2000-people-will-get-it-in-first-year/
101
http://www.pharmatimes.com/Article/14-1016/Dendreon_s_Provenge_too_expensive_for_NHS_use_says_NICE.
aspx
Part 4
Pharmaco-economic aspects of
PROVENGE®
Pricing
Reimbursement
Consequences
102
Reimbursement
 Coverage by social welfare :
→ Specific features of Sipuleucel-T = innovative reimbursement
mechanisms to consider
 Uncertainty surrounding the clinical benefit of Sipuleucel-T and its
effectiveness in a real-world setting
→ Coverage with evidence development scheme?
→ Implementation of a risk-sharing arrangement ?
 High price for a modest effectiveness
→ Unlikely to be cost-effective ?
→ Medicare Program & NICE = two opposing views
M2 AREIPS – March 2015
103
The Medicare Program
1. Provenge® and The
Medicare Program
‘Medicare must cover medical
products and services that are
“reasonable and necessary,”
without regard for cost’
http://www.cms.gov/
104
The Medicare Program
 Cost effectiveness / Back-of-the-envelope calculation (simplistic
calculation)
→ An increase of life expectancy by 4.1 month at an additional cost of a
one-month course of $93,000
→ Cost-effectiveness ratio : $272,000 per year of life saved
→ Without taking into account the cost of subsequent chemotherapy
regimens etc.
 Sipuleucel-T compare with other health technologies for
prostate cancer?
→ Review of 22 economic evaluations reporting
→ Median cost per quality-adjusted life year gained : $34,500
Unlikely to be cost-effective (reasonable?) but…
Greenberg et al. When is cancer care cost-effective? A systematic overview of
cost-utility analyses in oncology.J Natl Cancer Inst 2010
105
The Medicare Program
 On March 30, 2011 the CMS announced their decision to cover
Provenge®, under Medicare
 $93,000 for each treatment-without including the associated costs
 Only for FDA approved conditions, "local" Medicare carriers are going to
decide whether or not to pay for Provenge® off-label therapy
 Main arguments :
 Medicare covers some cancer treatments where the survival benefit is
less than it is for Provenge®
 Media influence and political issues?
“Leaving The Battle Over Cost And Value To Be Fought Another Day”
www.cancer.org/aboutus/drlensblog/post/2011/03/30/medicare-decides-to-pay-for106
provenge-leaving-the-battle-over-cost-and-value-to-be-fought-another-day.aspx
The Medicare Program
But… some unusual specificities
 A national coverage review by the Coverage and Analysis Group for a
for a national coverage determination (NCD)
 Referral to the Medicare Evidence Development & Coverage Advisory
Committee (MEDCAC)
 Reservations about the evidence : 3.6 of 5 for its FDA on-label use
 Collect postapproval outcomes data
 Technology assessment, commissioned by the Agency for Healthcare
Research and Quality (AHRQ)
 Concerns about the design of clinical studies
 Interactions between Sipuleucel-T and subsequent treatment?
 Adverse events : Strokes
http://jnci.oxfordjournals.org/ : Goozner .M, Concerns About Provenge Simmer
as CMS Ponders Coverage, 2011
107
The Medicare Program
Commitments for coverage
 A ‘coverage-with-evidence-development’ program
 An expanded registry to monitor outcomes such as mortality, time to
progression, and side effects
 Side effects
 Strokes measure cerebral – vascular outcomes from 1,500 patients
 Uncertainty in clinical efficacy
 Not recommended when the life expectancy is less than 6 months
 Additional post approval clinical trials?
http://jnci.oxfordjournals.org/ : Goozner .M, Concerns About Provenge Simmer
as CMS Ponders Coverage, 2011
108
The Medicare Program
60% of the men diagnosed with prostate cancer are 65 or older
Drendreon’s patient assistance programs:
 Co-pay Assistance for Patients With Medicare
 PROvide : assistance program for patients with commercial
insurance
 Support for Patients Without Coverage for PROVENGE®
 Travel Cost Assistance
http://www.provenge.com/reimbursement.aspx
109
NICE recommendation
2. Provenge® and The
NICE’s recommendation
http://www.nice.org.uk/
110
NICE recommendation
 Oct 2014 : NICE issues preliminary draft guidance
 Shown to prolong overall survival VS placebo
 But… some uncertainties in the clinical evidence VS other
existing treatments
 Costs per QALY
 Compared with abiraterone : £512,000 (company’s analyses) or
£244,000 (Evidence Review Group’s analyses)
 Compared with best supportive care : £112,000 (or £61,400 for a
subgroup of patients with certain levels of PSA)
Well above normal cost-effectiveness thresholds
https://www.nice.org.uk/news/press-and-media/sipuleucel-t-cost-too-highfor-nhs-draft-guidance
111
NICE recommendation
Cost-effectiveness assessment : a questionable model
 A cost-utility Markov model comparing Sipuleucel-T with BSC and abiraterone
 3 main health states :
 Pre-docetaxel use (4 sub-states, defined by opioids and/or adverse events)
 Death
 and a single state that included both docetaxel use and post-docetaxel use
 The modelled population :
 The ITT population of the IMPACT trial (= base-case analysis)
 + a subgroup analysis of patients with a baseline PSA concentration of 22.1
nanogram/ml or below
 No measure of health-related quality of life in the Sipuleucel-T trials
 The model used utility values taken from published studies
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic or
minimally symptomatic metastatic hormone-relapsed prostate cancer
112
NICE recommendation
Cost-effectiveness assessment : a questionable model
10yrs
docetaxel and
post-docetaxel use
Pre-docetaxel use
No opioids
Opioids
No
adverse
events
No
adverse
events
0.760
0.691
Opioids
and ↗
adverse
events
Opioids
and
adverse
events
Average
0.538 0.691
Death
No longer adequately controlled
with sipuleucel-T, BSC or abiraterone
Do not adequately reflect the treatment pathway and course
of disease
M2 AREIPS – March 2015
113
NICE recommendation
Results of the company’s economic analyses
 Company’s base-case analysis : more QALY and higher costs than
BSC
 Incremental cost-effectiveness ratio (ICER) : between £130,985 and
£141,330 per QALY gained
 Company’s analysis of sipuleucel-T compared with abiraterone
Sipuleucel-T dominated abiraterone at list price :
 More QALYs and lower costs
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic
or minimally symptomatic metastatic hormone-relapsed prostate cancer
114
NICE recommendation
Appraisal Committee’s key conclusions
“Sipuleucel-T is not recommended within its marketing
authorisation for treating adults who have asymptomatic or
minimally symptomatic metastatic non-visceral hormone-relapsed
prostate cancer for which chemotherapy is not yet clinically
indicated.”
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Final appraisal determination
M2 AREIPS – March 2015
115
NICE recommendation
Appraisal Committee’s argument : ICER
 Well above the range usually considered a cost-effective use of NHS
resources (£20,000- £30,000 per QALY)
 However… other societal considerations may matter when evaluating
end-of-life treatment
 The NICE recommends that a weight of 1.7 be assigned to QALY
accrued in the later stages of terminal diseases
 3 conditions:
 life expectancy extended by at least three months
 small patient populations
 patients with a life expectancy of less than one year
Sipuleucel T did not meet the criteria for end-of-life consideration
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic
or minimally symptomatic metastatic hormone-relapsed prostate cancer
116
NICE recommendation
Appraisal Committee’s argument : Evidence for clinical
effectiveness
 Uncertainty about :
→ When to administer Sipuleucel-T
→ Extension of survival without a measurable anti-tumor effect
→ Impact on clinical outcomes of differences in subsequent chemotherapy
regimens
→ Not proven to delay the progression of the disease unlike current treatments
→…
 Clinical benefit of Sipuleucel-T explored in patients satisfiing strict trial
inclusion criteria
→ Not be generalizable to a real-world patient population?
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic
or minimally symptomatic metastatic hormone-relapsed prostate cancer
117
NICE recommendation
Appraisal Committee’s argument : Evidence for clinical
effectiveness
 ‘Coverage with evidence development’ scheme?
 Why not ?
Problem with new medicines (abiraterone, Zytiga®) or other
immunization strategies
 Cost-effectiveness of one medicine relative to another medicine?
 Cost-effectiveness of combinations of medicines?
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic
or minimally symptomatic metastatic hormone-relapsed prostate cancer
118
NICE recommendation
Appraisal Committee’s argument : Evidence for clinical
effectiveness
Others reimbursement mechanisms to consider :
 Risk sharing arrangements
 The manufacturer shares the risk with the third-party payer that the product
may not be effective for a particular patient
 If the product does not have the expected effect, the company
 may loose some or all product revenue
 needs to provide a replacement product
 Require some markers to identify patients most likely to benefit from/
to respond to the treatment
 Such markers are not available for Sipuleucel T
NICE Final appraisal determination Sipuleucel-T for treating asymptomatic
or minimally symptomatic metastatic hormone-relapsed prostate cancer
119
Part 4
Pharmaco-economic aspects of
PROVENGE®
Pricing
Reimbursement
Consequences
120
Consequences
Medicare, a surprising decision unprecedented so soon
after FDA approval (April 2010)
 Causes : Media influence and political issue
 “While the cost of Provenge® was not an issue in our coverage
determination, (…) the cost of Provenge® created a public buzz around
this particular product, which then made it a higher-profile issue” Louis
Jacques, CMS
 Media reports asserting Provenge® was a “vaccine”
 Classification and coverage decision left to regional contrators
To warrant a nationally consistent policy for Provenge®
under the pressure of the Congress
Usdin .S, Provenge politics, BioCentury, Vol 19, Nov 2011
121
Consequences
Refusal of Coverage by the NHS
 Causes :
 Delay in the European MA approval (Sept 2013)
 Launch of new oral medicines in Prostate Cancer
Impact on Provenge® cost-effectiveness
 Consequences :
Failure of the introduction of Provenge® on the European
market
Support for innovation and research for new Cancer
therapies?
122
Part 5
Provenge® nowadays
123
Provenge ® Nowadays
 Efficacy uncertainty
 Marketing authorisation and reimboursement problem
 Cost efficiency uncertainty
 High price ($93,000)
 High cost of manufacturing
 Complexity of customizing the therapy for each patient
 Competition:
 Xtandi ®
 Zytiga ®
124
Prostate Cancer : new treatments
•Androgen biosynthesis
inhibitor
•Androgen receptor
inhibitor
•Centralised marketing
authorisation, September
2011
•Centralised marketing
authorisation, June 2013
•Per os, once daily
•Patients with mCRPC
•Per os, once daily
•Patients with mCRPC +
prednisone
•5,2 months improvement
in median OS
•4,8 months improvement
in median OS
125
Provenge ® Nowadays
 Efficacy uncertainty
 Marketing authorisation and reimboursement problem
 Cost efficiency uncertainty
 High cost of $93,000
 High cost of manufacturing
 Complexity of customizing the therapy for each patient
 Competition:
 Xtandi ®
 Zytiga ®
 Emergence of Bavarian Nordic A/S's experimental prostate cancer vaccines:
PROSTVAC ®
cheaper to manufacture
price expected to be in line with rival therapies
126
Conclusion
127
Dendreon’s bankruptcy
 November 10th, 2014  financial reconstruction
 Article 11, Chapter 11 bankruptcy protection
 $57.67 a share in April 2010 to 24 cents a share on November 2014
 Continue making Provenge ® without interruption
 Valeant has acquired in February 2015 the world-wide rights of
PROVENGE® and certain other Dendreon assets for $400 million.
128
Thanks for your attention
Any questions ?
129