final project

Yury Viknevich
Albany College of Pharmacy and Health Science
Pharmacy Candidate 2017
Fulfillment Room, 8/10/2016
New biosimilar regulations

Definition-Biologics
3
•Composed of either a single
component/combination of sugars,
proteins, nucleic acids, or may be
living entities
•Isolated from natural sources
Available from:
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm, 8/3/16

Biologics vs. small molecules: complexity
comparison
Available from:
https://www.google.com/search?q=zarxio&biw=1976&bih=1088&source=lnms&tbm=isch&sa=X&ved=0ahUKEwif_PTkobTOAhVIlR4KHdN_
A3YQ_AUIBygC&dpr=0.85#tbm=isch&q=filgrastim+molecular+structure&imgrc=U1a7NOgBRrJH0M%3A, 8/4/16

Definition-Biosimilars
5
•Biological product that is approved and is
highly similar to an FDA-approved
biological product (ie. reference product)
•Has no clinically meaningful differences in
terms of safety and efficacy from the
reference product
Available from:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Therapeutic
BiologicApplications/Biosimilars/, 8/3/16
.

Definition-Biosimilars
6
They are not generics
•Unique and can never be identical to the reference
product
FDA requires these products to meet rigorous
standards for safety and efficacy
Available from:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Therape
uticBiologicApplications/Biosimilars/, 8/3/16

FDA guidances: Biosimilars
| New biosimilar regulations | Yury Viknevich | 8/10/16| Novartis | Business Use OnlyAvailable from:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241720.ht
m, 8/9/16

Testing-required by FDA
•Comparative animal and human PK and PD data
- Demonstrate PK and PD similarity
- Assess clinically meaningful differences between the
proposed biosimilar and the reference product
•Support a demonstration of biosimilarity with the
assumption that similar exposure (and PD response)
provides similar efficacy and safety
Available from:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UC
M428732.pdf, 8/4/16

Overview of pre-clinical studies
Available from:
M428732.pdf, 8/3/16

Pre-clinical study-Demonstrating
biosimilarity
10
Structural analysis
• Demonstrate that the product is similar to the reference product
(notwithstanding minor differences)
 Functional assays
• Use in vitro and/or in vivo analysis
 Animal studies plus toxicity studies
• Can be used to support safety (this is good to do if there are still
uncertainties about the product)
Available from: http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
&http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf, 8/5/16

Pre-clinical study-Data analysis
Acceptance range of biosimilarity to reference
product: 80-125% similar (90% CI for PK and
PD), scientifically justify use of other ranges
•Similar PK/PD data assumes lower risk of clinical
differences (total evidence demonstrate
biosimilarity)
Choice of primary endpoints (ie. PK—AUC,
Cmax; PD—AUEC)
Available from:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicAp
plications/Biosimilars/UCM428732.pdf & http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf,
8/3/16

Pre-clinical study-Data analysis
Evaluation of residual uncertainty (pharmacology
data: pre-clinical)
• The FDA collects data in a step-wise fashion and considers the totality of
the evidence (use of risk-based approach)  additional data based on
residual uncertainty
 Analytic quality and similarity
• Analytic characterization between product and reference product using
meaningful fingerprint-like analysis algorithm
 Safety and immunogenicity studies
12
Available from:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf, 8/5/16

Pre-clinical study-Biological
variability
13
Inherent variability of the biologic system and the
manufacturing process OR microheterogeneity
•Small variability
Available from:
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf, 8/3/16

Pre-clinical study-Extrapolation
Potential to be approved for one or more conditions
based on reference product (based on sufficient
scientific justification)
•The MoA(s) in each condition of use for which
licensure is sought
•PK and bio-distribution of the product in different
patient populations
•Immunogenicity of the product in different patient
populations
•Differences in toxicities in each condition of use and
patient population
Available from:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplicati
ons/Biosimilars/UCM428732.pdf & http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf, 8/3/16

Clinical trial design
Clinical studies
•To show no clinical meaningful difference between the
product and the reference product in terms of purity,
safety, and potency (ex. Zarxio)
•To confirm similarity to reference product
Two phases of clinical studies are required – Phase I
and Phase III study (multiple studies per phase)
•At least 1 clinical study that includes a comparison of
the immunogenicity of the proposed reference product
Available from:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM4
28732.pdf & http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf, 8/4/16

Two types of particular relevance:
• Crossover design (generally preferred for PK similarity):
recommended for a product with a short half-life, a rapid PD
response, and a low incidence of immunogenicity. Issue with time
course of appearance and disappearance of immunogenicity and its
relation to the washout period.
• Parallel design: recommended for products with a long half-life or for
which repeated exposure can lead to an increased immune
response. Also, appropriate for diseases that exhibit time-related
changes associated with exposure to the drug.
17
Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf, 8/5/16

Study population: an adequately sensitive
population to detect any differences
PK and PD measure: reflect the effect(s) of the
drug
• PK sampling: frequent at early stages with decreased frequency
later
• PD sampling: variable
Route of administration: all routes vs. a single
route
18
Available from:
M428732.pdf & http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf, 8/4/16

Pharmacovigilance (post-marketing)
19
Fundamentally important to monitor safety issues
that are specific to a manufacturer
•A robust program is essential to help ensure patient
safety
Safety monitoring should also have adequate
mechanisms in place to differentiate between the
adverse events with the biosimilar and the
reference product
Available from: https://www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products &

FDA guidances-Labeling
| New biosimilar regulations | Yury Viknevich | 8/10/16| Novartis | Business Use Only20
Labeling should be specific to the conditions of
use, dosing regimen(s), and language previously
approved for the reference product
If fewer conditions are approved than the
reference product, certain text would be used
•Exception: sometimes information that the
product is not approved for, but the reference
product is, can be used. This is in order to
ensure safe use
Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf, 8/3/16

21
Unique labeling:
•Incorporate “Biosimilarity Statement” describing
relationship to the reference product (under initial
US approval)
•Recommended to incorporate relevant data and
information from the FDA-approved labeling for
the reference product plus any appropriate
modifications specific to the product (NO
comparative data)
Available from: http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm & https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe707775-a0ae-41b5-a744-
28c41889fce8&type=display &http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf. 8/3/16

22
Under 21 CFR 201.56(c)(1), biosimilar product
labeling must meet the content and format
requirements of the physician labeling rule (PLR)
as described in 21 CFR 201.56(d) and 201.57
Biosimilar must meet the content and format
requirements of the pregnancy and lactation
labeling final rule (PLLR) as described in 21 CFR
201.57(c)(9)(i) through (iii)
Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf. 8/3/16

23
Statement:
•As with all therapeutic proteins, there is potential for
immunogenicity
Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf &
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf, 8/3/16

FDA guidances-Naming
24
Unique naming:
•Core name (adopted by USAN) proper name (from
public health service (PHS) act and 600.3(k))
•Suffix of four lowercase letters will be attached with
a hyphen, unique, and devoid of meaning (ex.
Filgrastim-sndz)
- Will help products being grouped together in electronic
databases and distinguish them from the reference
product
Available from: https://www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products &

25
Suffix (should not):
•Be promotional
•Include abbreviations commonly used in clinical
practice
•Contain or suggest any drug substance name or
core name designated by the USAN council
•Look similar to or be mistaken for the name of a
currently marketed product
•Be too similar to any other product’s suffix

26
Using the biosimilar name:
•The information described is specific to the product
•Directive statements and recommendations
(preventing, monitoring, managing, or mitigating
risks)
Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf &
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe707775-a0ae-41b5-a744-28c41889fce8&type=display, 8/3/16

Reference product labeling Biosimilar product labeling
Treatment with JUNEXANT
increases the risk of serious
infections involving various
organ systems and sites that
may lead to hospitalization or
death.
Treatment with replicamab
products increases the risk of
serious infections involving
various organ systems and
sites that may lead to
hospitalization or death.Available from:
Using the core name:
•Overall risk-benefit profile of the reference product is
relevant to the biosimilar
•Risk applies to both products: use the core name followed
by “products”

28
Reasons:
•The proper name of a biological product reflects
certain scientific characteristics of the product, such
as chemical structure and pharmacological
properties
•Proper name of a biological product helps health
care providers identify the product's drug substance
and distinguish biological products from one another
Available from: https://www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products, 8/4/16

29
Reasons (retrospectively):
• Prevent a patient from receiving the wrong product
• Facilitate manufacturer-specific pharmacovigilance
• Encourage routine use of designated suffixes in ordering,
prescribing, dispensing, and recordkeeping
• Advance accurate perceptions of biological products

Biosimilars in the pipeline: Sandoz
30
Project in filing chart Current phase Indications
Pegfilgrastim LA-
EP2006
Submitted (EU and US) Chemotherapy-induced
neutropenia, etc
Adalimumab GP2017 III Arthritidies, plaque
psoriasis and others
Etanercept GP2015 Submitted (EU and US) Arthritidies, plaque
psoriasis and others
Rituximab GP2013 III FL, II RA, III RA Lymphoma, chronic
lymphocytic leukemia,
RA
Epoetin-alfa HX575 III CKD, chemo induced
anemia, etc
Infliximab GP 1111 III Autoimmune diseases,
etc
Available from: http://www.sandoz-biosimilars.com/en/clinicaltrials/sandoz-clinical-trials.shtml, 8/5/16

News: updates with biosimilars
31

CVS health
32
Will remove 35 medications from 2017 formulary
• Lantus (insulin glargine)
• Neupogen (filgrastim)
Replace with biosimilars: Reduced drug costs (typically
10 – 15% cheaper than originator product)
• Basaglar (insulin glargine)
- Approved 2015
• Zarxio (filgrastim-sndz)
Available from: http://www.firstwordpharma.com/node/1404858#axzz4GO4IA4Jj & http://diatribe.org/fda-approves-new-insulin-glargine-basaglar-first-biosimilar-insulin-us, 8/5/16

References
33
 www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm
 www.google.com/search?q=biological+molecules
 www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/
 www.amgenbiosimilars.com/the-science/clinical-trial-design
 www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/UCM428732.pdf
 www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf
 www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf
 www.fda.gov/Drugs/NewsEvents/ucm493240.htm
 www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products
 www.sandoz-biosimilars.com/en/clinicaltrials/sandoz-clinical-trials.shtml
 www.firstwordpharma.com/node/1404858#axzz4GO4IA4Jj
 www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/
ucm241720.htm
 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosi
milars/

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