Dennis M. Gross, MS, PhD
CEO & Treasurer, Professor of Pharmacology
Pennsylvania Drug Discovery Institute
Faculty, Jefferson College of Biomedical
Sciences, Sidney Kimmel College of Medicine, Th. Jefferson University
Medi ine Th Jefferson Uni ersit
© Dr. Dennis M. Gross 2016
1
“80% of success is showing‐up”
Woody Allen
2
1
Introduction
D fi iti
L
l l
Definitions: Large molecules
Differences: Drugs vs. Biologics
Vaccines
Case Studies from Production of Vaccines
p
Development
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Non‐clinical
Clinical
Future of Vaccines and Biologics
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3

Vaccines
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Attenuated: M‐M‐R, Rotavirus, Varicella, Zostavax
Killed or Inactivated: IPV, HepA
Toxoids: Diphtheria; Tetanus;
Sub‐unit: HepB; acellular Pertussis; VLP
Vector‐based vaccine: Canary pox, Adenovirus,
DNA: In research phase
Peptide vaccine: Epitope vaccine, peptide immunogens (HER‐2/neu); Antibodies: MAbs
Cytokines:
 Lymphokines (IFN, IL); monokines (IL,TNF); Interleukins (IL)


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Growth factors: Erythropoietin, VEGF
Hormones: Steroids (estrogens); Polypeptides (Insulin, endorphins); etc.
Gene Therapy
Stem Cells: Embryonic, Adult
4
2

Vaccine: A preparation of microorganisms (e.g., bacterium, virus), or their antigenic components administered for the prevention, amelioration or treatment of an infectious disease 
Biologic preparation that elicits immune response with memory

Generates humoral (antibody) and/or cellular (cytotoxic or killer T‐cell) response to eliminate pathogen or pathogen infected cell

The immune system is then primed to mount a secondary immune response with strong and immediate protection upon future exposure to ih
di
di
i
f
the pathogen
5
WHY??
6
3
7
8
4
9

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Drugs
Synthetic, organic compounds
Defined structure, physical & chemical characteristics
chemical characteristics

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
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

Chemical synthesis
Small molecule (±1,000)
Stable
Homogeneous
Biotransformed (metabolized)
Linear dose‐response
Activity not species specific
Acetaminophen Mw = 151 10
5
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

Drugs
Synthetic, organic compounds
Defined structure, physical & chemical characteristics
chemical characteristics







Chemical synthesis
Small molecule (±1,000)
Stable
Homogeneous
Biotransformed (metabolized)
Linear dose‐response
Activity not species specific
Acetaminophen Mw = 151 
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
Biologics
Protein‐, carbohydrate‐ or nucleic acid ‐based product
Extracted from living organism
Complex physicochemical structure
Less well‐characterized
Macromolecule (5,000 ‐>1,000,000)
Tertiary structure
Location, extent and type of glycosylation
Heat‐ & shear‐ sensitive
Non‐linear dose‐response
Monoclonal antibody, Mw = ~150,000 11
12
6
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Smallpox
Pertussis
Diphtheria
Polio Vaccines
Hepatitis B vaccine
13
1981
Hepatitis B
Ref. Hilleman, Nature Medicine, 4, 504, 1998
Maurice Hilleman
1919 - 2005
Albert Sabin
1906 - 1993
Jonas Salk
1914 - 1995
1923
Diphtheria
Louis Pasteur
1822 - 1895
Edward Jenner
1749 - 1823
1796
Smallpox
1780 1800
1926
Pertussis
1927
Tetanus
1840
1860
1880
1962
Oral Polio
1986
Hepatitis
B
p
(Recombinant)
1963, 1968
Measles
1989
Hib Conjugate
1965
Japanese
encephalitis
1995
Varicella
1967
Mumps
1996
Hepatitis A
1969
Rubella
1996
Hib-Hep B
1971, 1978
MMR
1996
DTacP
1974
Meningococcal
1998
Lyme
1977
1935
1956 Pneumococcal
Yellow Fever Adenovirus 14-valent
1885
Rabies
1820
1955
Polio
1900
1920
1940
1983
Pneumococcal
23-valent
1960
1999
Pneumococcal
conjugate
1980
2000
7
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Smallpox
Pertussis
Diphtheria
Polio Vaccines
Hepatitis B vaccine
15
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Smallpox
Pertussis
Diphtheria
Polio Vaccines
Hepatitis B vaccine
Protection from Cholera
Picture courtesy of Wellcome Library, London
16
8

17th century Chinese practice


Vaccinating with scabs from smallpox patients
smallpox patients
1796 ‐ Edward Jenner
Vaccine made from pus of cowpox patients and milk maids
 Coined the term “vaccination”  First recognized use of a vaccine


No purification!

Whooping cough caused by B. pertussis, a small gram negative bacteria

Vaccine ‐ suspension of killed whole cells of bacteria 
Whole cell pertussis vaccine first licensed in the US in 1914
 Later combined with diphtheria and tetanus toxoids (DTP) in 1942
tetan s to oids (DTP) in 1942

Lack of purity caused some side effects
 Led to the development of acellular pertussis (subunit vaccine)
Ref. Aunins, Lee and Volkin, in The Biomedical Engineering Handbook, CRC Press, Boca
Raton, 1995
9

Respiratory infection caused by C. diphtheriae, a gram‐positive bacteria

Diphtheria toxin, a polypeptide of 62 kDa MW, is formaldehyde treated to form toxoid

First protein purified for active immunization

Purity < 60%
P it 60%
 protein impurities can crosslink with toxoid
Ref. Rappuoli and Pizza in Vaccines, Eds. Perlman, P.
and Wigzell, H., Springer, Heidelberg, 1999
20
10
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

Enders successfully cultivated virus in tissue culture (1949)
Inactivated virus developed by Salk (1955)
Oral polio (Live virus) developed by Sabin (1963) (1963)
Oral polio (Live virus) developed by Sabin

Less expensive and simple to use
IPV
Ref. Salk, JAMA, 151, 1081, 1953
OPV
Ref. Aunins, in Encyclopedia of Cell Tech., Ed. Spier, Wiley & Sons, NY, 2000
21

RECOMBIVAX HB® was the first US licensed recombinant ®, a plasma‐derived vaccine vaccine (1986) replacing HEPTAVAX
(
) p
g
p
(1981) which was removed from the market in 1986.

HBsAg is expressed in yeast; intracellular product

~100 copies of 24 kD polypeptide assembles with host‐derived lipids into 22‐nm spherical particles

Particle held together by hydrophobic interactions in lysate; disulfide bonds form during purification process
22
11
Yeast
Fermentation
MF
Homogenization
MF
UF
XAD Treatment
Aerosil
Adsorption
Butyl Agarose
Chromatography
KSCN treatment
Sterile filtration
Ref. Sitrin et al., in Hepatitis B Vaccines in
Clinical Practice, Ed. Ellis, R. W., Marcel Dekker, NY, 1993
Alum treatment
23
How do you grow all those cells to infect?
o do you g o a t ose ce s to ect?
24
12
 Small‐scale (<10 L)


‐ Flasks (T‐flasks, Erlenmeyer, Spinners)
‐ Roller Bottles
 Mid‐scale (10 ‐ 250 L)
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
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‐ Roller Bottles (automated handling)
‐ Nunc Cell Factories and Costar Cell cubes
‐ “Small” continuous stirred reactors
‐ Wave Bioreactors
25
Large scale (> 250 L) engineered systems.
Images: Copyright Sanofi Pasteur , Amgen,
and New York Times
26
13
27
Source: Xcellerex, Sartorius
28
14
ProtA-Equi il .
ProtA-Wash
S-001
Inoculum Prep
S-003
S-107
ProtA-El ut.
S-108
Primary Recovery
Protein-A
ProtA-Reg.
15.15 L/batch
3.64 L/batch
S-034
S-031
S-002
P-1 / T FR-101
Roller Bottle (2.2 L)
T -Flask (225 m L)
S-037
3836.66 L/batch
S-032
P-2 / RBR-101
P-14 / V-101
S-004
P-16 / DE-108
P-15 / DS-101
Surge T ank
S-036
P-17 / V-103
Polishing Fi tl er
Centrifugation
P-18 / C-101
P-19 / DE-109
PBA Chromatography
Centri fugati on Pool T ank
Pol ishi ng Fitler
ProtA-Waste
S-008
S-033
S-009
S-006
59.11 L/batch
S-038
46590.92 L/batch
S-035
S-039
235.91 L/batch
S-007
P-3 / BBS-101
P-4 / BBS-102
Bag Bioreactor (20 L)
S-05
S-043
S-109
Bag Bi oreactor (100 L)
Chemical Virus Inactivation
S-041
S-010
S-110
S-045
S-011
S-102
S-103
S-101
Vent-3
S-044
P-20 / V-107
P-21 / DF-101
P-22 / V-111
Storage
Di afil tration
Virus Inactivation
S-046
P-23 / DE-110
Polishing FIl ter
S-015
S-012
S-042
767.42 L/batch
945.69 L/batch
P-6 / M P-101
S-013
P-7 / DE-101
M edi a Prep
S-048
P-5 / SBR1
Steri le Fi ltrati on
767.59 L/batch
First Seed Bioreactor (1000 L)
S-047
S-017
S-016
S-014
S-030
HIC-Equil
IEX-Equil
Amm. Sulfate
S-018
HIC-Wash
IEX-Wash
Vent-4
HIC Chrom
IEX Chrom
IEX-WFI
HIC-El
S-021
IEX-El
S-019
IEX-Stri p
P-9 / MP-102
3798.91 L/batch
S-020
1142.85 L/batch
S-049
HIC-Reg
P-27 / DE-106
P-25 / V-109
P-8 / SBR2
Steril e Fil tration
S-051
IEX-Ri nse
P 10 / DE
P-10
DE-102
102
Media Prep
P-24 / C-102
Second Seed Bi oreactor (4000 L)
S-050
1345.25 L/batch
IEX Pool Tank
Dead-End Fil tration
P-26 / C-103
HIC Chrom atography
IEX Chromatography
S-052
S-022
HIC-Waste
S-023
IEX-Waste
S-025
S-172
9743.99 L/batch
12594.01 L/batch
Bioreaction
Vent-5
S-024
Viral Exclusion
Final Filtration
S-026
S-025b
P-12 / MP-103
P-13 / DE-103
M edi a Prep
Sterile Filtration
S-028
S-106
S-058
S-057
S-054
S-027
15185.02 L/batch
S-028b
P-11 / PBR1
Production Bioreactor (15000 L)
S-024b
P-34 / MP-104
Media Prep
P-28 / V-108
HIC Pool T ank
761.97 L/batch
S-056
S-053
S-062
P-30 / V-110
P-29 / DE-105
Storage
P-35 / DE-104
Sterile Filtration
S-105
S-104
Viral Excl usion Filtration
S-026b
S-059
P-31 / DF-102
761.97 L/batch
Diafiltration
P-32 / DE-107
P-33 / DCS-101
Final Pol ishi ng Filtration
Freeze in 50L Plastic Bags
Final Product
S-061
S-029
S-055
S-060
S-027b
29
CAPD = Computer
Aided
p
Process Design
Source: Intelligen Suite
30
15
31
32
16
33
34
17
35
36
18
37
38
19
39
40
20
41
42
21
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Fever and jaundice of 2‐3
weeks duration
Fever and jaundice of 2
3 weeks duration
Transmitted by fecal oral route
In US, spread through day care centers, residential institutions, restaurant food handlers
Endemic in developing countries
Vaccine development undertaken to minimize spread of disease
43
Ref. Aboud et al. (Merck & Co. Inc.), PCT WO 94/03589, 1994
44
22
Cell Growth and Viability
viable
v
cell density (x 10 c
cells/ml)
100
6
80
40
viability
60
20
infection
0
time (hours)
45
Cell Culture
Lysate
Nuclease treatment
Capture chromatography
PEG precipitation
Solvent extraction
1
2
3
4
5
6
7
Ion exchange chromatography
8 9
Size exclusion chromatography
Formaldehyde
Alum adsorption
1. LOW MW STANDARDS
2. LYSATE
3. LYSATE + BENZONASE
4. CAPTURE PRODUCT
5. PEG PELLET
6. SOLVENT EXTRACT
7. ION EXCHANGE PRODUCT
8. SIZE EXCLUSION PRODUCT
9. SIZE EXCLUSION PRODUCT
12% GEL WITH 200NG HAV ANTIGEN PER LANE
46
23
Resuspended PEG Pellet Sample
Ion-Exchange Chromatography Product
660kDA Protein
Hepatitis A
Hepatitis A
Aggregate
660kDA
Protein
Aggregate
A 214nm
0
A 214nm
10
20
30
40
0
Solvent Extracted Aqueous Phase Sample
10
20
30
40
Size-Exclusion Chromatography Product
Hepatitis A
Hepatitis A
660kDA
Protein
Aggregate
A 214nm
0
A 214nm
10
20
Minutes
30
40
0
10
20
Minutes
30
40
Hardware: Rainin HPLC system, TosoHaas TSK PW4000xl, 7.8 x 300 mm column
Mobile phase: PBS, 0.32 ml/min, 50
l injection. Detection UV 214 nm
47
48
24
49
50
25


Pre‐clinical





Drugs
Toxicology in rodent and something else
Hepatic microsome for CYP enzyme metabolism
Safety pharmacology (CNS, cardiovascular, respiratory studies ICH S7)
Carcinogenicity (Ames Test)
Clinical



Drug‐drug interactions
Food‐drug interactions for oral administration
Effect on QT/QTc & arrhythmic potential


Pre‐Clinical




Biologics
T i l
i
l
t i l
Toxicology in relevant animal species
Very difficult learning curve at the moment
Don’t always get NOAEL (No Observed Adverse Event Level)
Clinical



PK and bioavailability but not metabolism
Concomitant use (vaccines) Off‐target incorporation of material (DNA Vaccines)
51





Inherent toxicity of the vaccine
Inherent toxicity of the vaccine
Toxicity of impurities/contaminants
Toxicity due to interaction of components
Toxicity linked to the immune response T i it li k d t th i
induced
Unknown unknowns (Black Swans)
52
26

“Relevant” animal species

An animal species susceptible to respond to the test article activity, e.g., development of an immune response after vaccination
 Ideally, species should be sensitive to the pathogenic organism or toxin

One relevant animal species in general is sufficient
 Exceptions on a case‐by‐case
 Non‐human primates not generally necessary

Group size dependent on the animal model
53

Route of administration (ROA) and dose should correspond to clinically intended ROA and dose(s), e.g., oral, SC, IM, Nasal

Total number of doses equal to or exceed number of clinically administered doses


[“N plus 1”]
Episodic dosing, e.g., weeks between doses
54
27
55
IND/
CTA



NDA/
WMA/
BLA 

Phase I – First‐into‐Human
 20‐100 normal healthy volunteers
Determine safety and tolerability
 Determine safety and tolerability
Phase IIa/IIb – Therapeutic Exploration
 100‐300 patients
 Evaluate efficacy
 Determine dose range and adverse events (AEs)
Phase III – Therapeutic Confirmation
 1,000 to 15,000 patients
 Verify efficacy, monitor AEs and effect in usual therapy and special populations
Phase IV – Post‐Approval
 Postmarketing surveillance
 Monitor long term risks and benefits, outcomes and pharmacoeconomics
Phase V
 Postmarketing studies (Potentially thousands of patients)
 New indications: “Megatrials”
56
28
Sources: Clemens et al. JAMA 1996;275:390‐7
Levine MM. British Medical Bulletin 2002;62:1‐13
Promising vaccine candidate
IND
Phase I: Well‐tolerated and immunogenic in healthy adults?
No
Yes
Phase II: Well‐tolerated and immunogenic in the target population?
Yes
No
Phase III: Well‐tolerated and efficacious in the target population?
57
Phase III: Well‐tolerated and efficacious in the target population?
No
Subset assessed for immunogenicity
y
y
p
Antibody level may link with protection = CORRELATE OF PROTECTION
Yes
Phase IV: Assess effectiveness
Sources: VacciNews 2002;1(6):1‐4 Clemens et al. JAMA 1996;275:390‐7
Levine MM. British Medical Bulletin 2002;62:1‐13
58
29

trial provides a more direct
An Efficacy trial provides a more direct
measurement of protection

Efficacy‐ the protective effect of a vaccine against the target disease
Protective Efficacy =
incidence of disease in vaccinees
1- incidence
of disease in nonvaccinees X 100%
Sources: VacciNews 2002;1(6):1-4 Clemens et al. JAMA 1996;275:390-7
60
30
IND/
CTA



NDA/
WMA/
BLA 

Phase I – First‐into‐Human
 20‐100 normal healthy volunteers
Determine safety and tolerability
 Determine safety and tolerability
Phase IIa/IIb – Therapeutic Exploration
 100‐300 patients
 Evaluate efficacy
 Determine dose range and adverse events (AEs)
Phase III – Therapeutic Confirmation
 1,000 to 15,000 patients
 Verify efficacy, monitor AEs and effect in usual therapy and special populations
Phase IV – Post‐Approval
 Postmarketing surveillance
 Monitor long term risks and benefits, outcomes and pharmacoeconomics
Phase V
 Postmarketing studies (Potentially thousands of patients)
 New indications: “Megatrials”
61
DRUG
INDICATION
PHASE I
PHASE II
PHASE III
TOTAL
TRIALS/
SUBJECTS
TRIALS/
SUBJECTS
TRIALS/
SUBJECTS
TRIALS/
SUBJECTS
3/48
8/532
1/469
12/1069
6 ‐ 7
8/163
23/503
23/1381
34/2048
4 ‐ 5
18/446
3/3275
3/1588
28/5309
5
42/905
13/498
13/4679
68/6082
4 ‐ 5
31/940
2/1855
13/5733
46/8528
FIH‐NDA FILE
(YEARS)
HERCEPTIN®
BREAST CA
ENBREL®
RHEUM. ARTHRITIS
RELENZA®
INFLUENZA
VIAGRA®
ERECT. DYSFUNCT.
VIOXX®
OA & PAIN
•Grudzinskas C. Design of clinical development programs in Atkinson AJ Jr, et al. Principles of Clinical Pharmacology
62
31
IND/
CTA



NDA/
WMA/
BLA 

Phase I – First‐into‐Human
 20‐100 normal healthy volunteers
Determine safety and tolerability
 Determine safety and tolerability
Phase IIa/IIb – Therapeutic Exploration
 100‐300 patients
 Evaluate efficacy
 Determine dose range and adverse events (AEs)
Phase III – Therapeutic Confirmation
 Possibly 60‐70,000 for a vaccine
 Verify efficacy, monitor AEs and effect in usual therapy and special populations
Phase IV – Post‐Approval
 Postmarketing surveillance
 Monitor long term risks and benefits, outcomes and pharmacoeconomics
Phase V
 Postmarketing studies (Potentially thousands of patients)
 New indications: “Megatrials”
63


: Rotavirus vaccine‐ 70,000 patients in 70 000 patients in
ROTATEQ® : Rotavirus vaccine
the pivotal trials worldwide
ZOSTAVAX® : Shingles vaccine‐ 68,000 patients in the pivotal trials worldwide.
64
32
65
66
33
Biosimilars are to biologics what generics are to chemical
Biosimilars are to biologics what generics are to chemical
drugs
Reference
product
g
g
Biological
drug
PATENT EXPIRY
E
Chemical drug
Follow-on
version
Generic
Biosimilars ((EU))
Follow-on Biologics (FOB, US)
Subsequent-entry Biologic (SEB, Canada)
Biotechnology Follow-on Product (Japan)
Similar Biotherapeutic Product (SBP, WHO)
Follow‐on versions are generally expected to deliver price discounts.
67 | DRA NBx Training - Biosimilars | Ulrike Jägle | 28 Oct 2009 | Business Use Only


Reduced cost of patient care – Political agenda
Business opportunity pp
y



Worldwide revenues for biotech drugs in 2014= $73.3
billion from sales on the top 10 approved products
Average gross margins > 75% Expanding patient care



67
New products –
New products 370 biotech drugs in clinical trials
370 biotech drugs in clinical trials
New markets – global expansion
Political Pressure !
68
34
The Patent Cliff
P A T E
2012
2013
2014
2015
2016
2017
2018
Enbrel
Epogen/
Procrit
Remicade
Neulasta
Aranesp
Avastin
Caduet
Neupogen NovoLog
Rituxan
Humira
Pegasys
CabillyII
Avonex
Lantus
Humalog
Herceptin
Rebif
Synagis
Byetta
PegIntron
Xolair
Actemra
35
Humira (AbbVie)
$12.5
Remicade (J&J)
Remicade (J&J)
$9 2
$9.2
Rituxn (Biogen)
$8.7
Enbel (Amgen)
$8.5
Lantus (Sanofi)
$7.3
Avastin (Roche)
$7.0
Herceptin (Roche)
$6.8
Neulasta (Amgen)
l
(A
)
$5.9
$
Prevnar (Pfizer)
$4.5
Avonex (Biogen)
$3.0
$0
Source: Statista
$2
$4
$6
$8
$10
$12
$14
Revenue in Billions (US$)
36
Source: EvaluatePharma
74
37

To date, Europe has approved 22 biosimilars with no significant safety issues in three classes:
Human growth hormones
Erythropoietins
 Recombinant Insulin






The US FDA received on 24 July 2014 the BLA via the 351(k) pathway for a biosimilar for Amgen’s Neupogen (filgrastim) from Sandoz which following court challenges was launched on 3 September 2015. Still being challenged
Korea approved (8 Sept. 2015) a biosimilar for Amgen’s Enbrel
that was developed by Merck/Samsung. Launched in December 2015.
2015
The US FDA accepted on 5 October 2015 the BLA under the 351(k) pathway for a biosimilar to Amgen’s Enbrel (etanercept). EU approved 18 January 2016
The biosimilar market in the US will not take shape until the 2017+ timeframe. One drug does not make a market.
75




Biosimilarity – What is it?
I t h
bilit (G
i
b tit ti ?)
Interchangeability (Generic substitution?)
Patient Safety and Pharmacovigilance
Naming Convention: Draft suggestion‐> Zarxio
(filgrastim‐sndz)
76
38




Biosimilarity – What is it?
I t h
bilit (G
i
b tit ti ?)
Interchangeability (Generic substitution?)
Patient Safety and Pharmacovigilance
Naming Convention: Draft suggestion‐> Zarxio
(filgrastim‐sndz)
77
“li”: Immune Target
Monoclonal Ab
“xi”: Chimeric

Remicade® by Johnson & Johnson

Chimeric mAb
Anti TNF‐α
Approved by the FDA in 1998
Administered intravenously
Designated for use in patients who did not respond to methotrexate
h
Proven to slow the clinical and radiological progression of rheumatoid arthritis





78
39





Biosimilarity – What is it?
I t h
bilit (G
i
b tit ti ?)
Interchangeability (Generic substitution?)
Patient Safety and Pharmacovigilance
Naming Convention: Draft suggestion‐> Zarxio
(filgrastim‐sndz)
Use of Supportive Data and Information


Whose data?
What is the reference product (RP) with multiple entries
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DRUG
Branded
Product
Generic #2
Generic #2
Generic #1
Branded
Product
?
BIOSIMILAR
Biosimilar #1
Biosimilar #2
?
80
40





Biosimilarity – What is it?
Interchangeability (Generic substitution?)
Interchangeability (Generic substitution?)
Patient Safety and Pharmacovigilance
Naming Convention: Draft suggestion‐> Zarxio
(filgrastim‐sndz)
Use of Supportive Data and Information
Whose data?
 What is the reference product (RP) with multiple entries


Guidances
EMA [2005]
 FDA [2012 draft document]

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Year of Publication
Country with Specific Guidelines
2005
EU
2007
Australia
2008
Malaysia, Turkey, Taiwan
2009
Japan, Korea, Singapore, WHO
2010
Brazil, Canada, Saudi Arabia, South Africa
2011
Argentina, Cuba, India, Iran, Mexico, Peru
2012
Colombia (draft), Egypt (draft), Jordan (draft),
Thailand (draft) US (draft)
2014
EU (revised guidelines)
2015
China
Source: Boren, J., Contract Pharma 17(5): 58 (2015)
82
41
83

Requirements for extensive




Analytical
Physico‐chemical
Biological characterization
The FDA will consider multiple factors in making study determinations:






Product complexity
Formulation
Product stability
Structure‐function relationships
Manufacturing process
Clinical experience with the reference product
42

The 351(k) Biosimilar Pathway

C
h i d t
k
th t i l d
Comprehensive data package that includes:
 Analytical studies
 Functional studies
 Preclinical evaluation
 Clinical evaluation including pivotal studies
 PK Studies
 Studies in healthy volunteers
 Studies in patients with target disease(s).
86
43
Erythropoietin (MW = 34,000)
87
Erythropoietin
88
44
KEY CONCERNS:
2013
2015
I th
i il for
f Remicade
R i d interchangeable
i t h
bl
Is
the bi
biosimilar
YES 6%
YES:
YES 44
4%
YES:
44.4%
Little or no confidence in biosimilars
YES: 63%
YES: 19.5%
Require distinctive labeling
YES: 66%
Disagree with automatic substitution
YES: 35%
YES: 89.8%
Driver: Cost is main advantage
92.40%
More Pharmacovigilance
30.50%
Well designed RCT as concern
27.00%
Further assessment of risk profile
32.20%
Source: Abstract from S. Danese, G. Fiorino, P. Michetti, European Crohn’s and Collitis Organisation conference – 2016
89
90
45
91
•
•
•
•
The term refers to a rProtein that is in the same class as an existing biopharmaceutical but is not identical: It is i
d
th
i i l
improved over the original.
Biobetters are not entirely new drugs and they aren’t generic versions of drugs, either. Biobetters are being developed using protein or glyco‐
engineering which it is hoped will reduce the risk of immunogenicity making the drug safer, more effective and requiring a lower dose.
d
ii
l
d
A biobetter has the same target as the original but its effect on the target will hopefully last for an extended period of time.
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46
Early vaccines were based on the large and
• Early vaccines were based on the large and complex carbohydrate (sugar) based polymers produced by the bacteria. • More recently new glycoconjugate vaccines have been developed which involves 'fusing' the complex carbohydrates ‐‐ the sugar polymer tails ‐‐ onto carrier proteins. • These sugar‐protein complexes improve the effectiveness and longevity of the vaccine. effectiveness and longevity of the vaccine.
• However, there are still problems concerning the stability of formulations they are prepared in.
93
POTENTIAL IMPEDIMENTS TO BIOSIMILAR MARKET UPTAKE INCLUDE:

Regulatory Burden
 Name convention
 Clinical testing the FDA requires biosimilars to repeat
 Slow patient enrollment in studies

Statutory Burden
 State laws intended to restrict substitution could have the effect of hindering market uptake of biosimilars

Market Risks
Market Risks
 It is unclear how insurance companies and government health care programs will handle coverage and reimbursement
 The perception of biosimilars and the general public will play a substantial role in determining biosimilar utilization.
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47
POTENTIAL IMPACT ON BIOSIMILAR MARKET
•
Merck’ss biosimilar for Remicade
biosimilar for Remicade has been discounted 45% in Korea
has been discounted 45% in Korea
Merck
•
Discounted in Europe by a Finnish firm by 70% and 25‐30% by Napp
Pharma and Hospira
•
Average discounts in all markets for biosimilar Remicade = 45%
•
In the UK, biosimilar Remicade
In the UK, biosimilar Remicade already has a 5% market share
already has a 5% market share
•
Biosimilars for Remicade have already produced a 25% reduction in 2nd
Quarter sales for J&J which is significant as total sales in 2014 were $9.2B
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•
•
Major advantage is that you are already pursuing a mechanism of action that is known and because they are considered a new drug, they will enjoy 12 years of market protection in the US unlike a biosimilar.
However, it is not clear how much payors are willing to pay for biobetters benefits especially with the significant discounts already in the marketplace for biosimilars.
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48
97
“Predictions are difficult to make, especially about the future”
Yogi Berra
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49
“The only thing we know about the future is that it will be different”
W. Edwards Deming
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dgross@padrugdiscovey.org
+1.267.893.6777
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