Towards Safe and Effective Biosimilars

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Towards Safe and Effective Biosimilars

• Location, Date
• Experts Name

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Overview

• Value of biologics
• Science of biologics
• Implications for biosimilars
• Regulation of biosimilars
• Regulatory and healthcare system challenges
• Important take-aways

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Value of Biologics
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Cornerstones in biotechnology history which have
influenced the production of biologics 1953
Discovery of DNA structure 1973 Discovery of
DNA restriction enzymes 1977 Genentech, first
biotech-enterprise founded 1982 First
biopharmaceutical approved by FDA recombinant
human insulin 1986 First recombinant vaccine
(HepB) is approved for human use, first
recombinant anti-cancer drug (Interferon) is
produced 2003 Human genome sequenced
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Biologics Help Treat Severe Diseases
1- National Institute of Neurological Disorders
and Stroke. NINDS Multiple Sclerosis Information
Page. http//ms.about.com/od/treatments/a/ms_treat
ment.htm 2- http//www.enlivenservices.com/ra/get
tingstarted/results-side-effects/ 3-
http//www.cancer.org/docroot/ETO/content/ETO_1_4X
_Monoclonal_Antibody_Therapy_Passive_Immunotherapy
.asp 4- Israel Hartman. Insulin Analogs Impact
on Treatment Success, Satisfaction, Quality of
Life, and Adherence. Clinical Medicine and
Research. Vol 6 (2) 54-67. 2008.
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Trade name (US) Epogen Procrit Rebotron Intro
n-A Roferon Humulin Lantus Levemir Betasero
n Rebif Saizen Enbrel
Used to treat Anemia Hepatitis B,C,D Leukemia,
Lymphoma Diabetes Multiple
sclerosis Growth control Arthritis,
Psoriasis,
Developed by Amgen Schering-Plough Roche Eli
Lilly, Sanofi Aventis NovoNordisk Bayer Serono S
erono Amgen, Wyeth
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Biologics in Cancer therapy Clinical trials of
monoclonal antibody therapy are in progress for
almost every type of cancer. The U.S. FDA has
already approved several for the treatment of
certain cancers
www.cancer.org
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Biotech Medicines in Development
Source http//www.phrma.org/files/Biotech202008.
pdf
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• Science of Biologics

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Biologics are

• Derived from living material (plant, animal or
  microorganism)
• Derived from natural sources or engineered
• Usually based on a protein or nucleic acid
• Used for the treatment of diseases in humans

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Biologics are Different from Small Molecule Drugs

• Composition, Size, Structure
• Larger, more complex, more heterogeneous
• Manufacturing
• Genetic engineering vs. organic chemistry
• Synthesis by living cells/organisms
• Clinical Safety
• Species specificity limits standard pre-clinical
  models for safety testing
• Usually injected
• Immunogenicity

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Complexity of Biologics
Structure
Size
Epoetin
Aspirin
Stability
Modification
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Difference in Size Between Biologics and Small
Molecule Drugs
Behram, Rachel E. (2008, November 21) Follow-on
Biologics A Brief Overview. Presentation given
by the U.S. FDA at the U.S. Federal Trade
Commission workshop "Competition Issues Involving
Follow-on Biologic Drugs." 
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Manufacturing Process

• Chemically-based drugs are made by adding and
  mixing together known chemicals and reagents
  using a series of controlled and predictable
  chemical reactions
• This is Organic Chemistry
• Biologics are made by harvesting the substances
  produced and secreted by constructed cells
• This is Genetic Engineering

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Biologics Complex Manufacturing Process
BIOLOGICS MANUFACTURING PROCESS
Active ingredient derived from living cells
Purification and storage process
Materials used in the formulation process
Culture conditions
IMPURITY LEVELS
Unique characterization SAFETY, EFFICACY AND
QUALITY
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Central Dogma of Molecular Biology--Biotech
Revolution

• DNA makes RNA makes Protein
• Inside a cell
• Manipulate DNA Manipulate cells Make desired
  protein

Gene of Interest
GoI
Desired Protein
DNA Plasmid Insert Gene of Interest
Cell of choice
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Different cells will make slightly different
protein
Cells w/Gene of Interest
Protein of Interest
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Clinical Safety

• Species specificity limits standard pre-clinical
  models for safety testing
• Usually injected
• Immunogenicity

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Immunogenicity

• Human reaction to the introduction of a foreign
  protein
• Small molecule drugs rarely elicit immune
  responses
• Macromolecules (proteins) like biologic drugs are
  capable of triggering immune responses with
  varying consequences, e.g.,
• Antibodies may neutralize the molecule making it
  therapeutically ineffective
• There may be no clinical effect
• Rare but serious autoimmune responses can be
  life-threatening
• Immunogenicity of biologic drugs is
  unpredictable, unforeseeable
• Small changes in a macromolecule can completely
  shift its immunogenicity profile

H. Schelleken. Factors influencing the
immunogenicity of therapeutic proteins. Nephrol
Dial Transplant (2005). 20 (Suppl 6) vi3-vi9
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Key Points on the Science of Biologics

• Biologic drugs are orders of magnitude more
  complex than small molecule drugs
• Safety efficacy of final product is
  exceptionally sensitive to small changes in
  manufacturing process
• It is difficult to impossible to predict the
  effect of these small changesexperience counts
• Potential for dramatic negative health
  consequences

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Implications for Biosimilars
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What is a biosimilar?
A biological medicinal product referring to an
existing one and submitted to regulatory
authorities for marketing authorization by an
independent application after the time of the
protection of the data has expired for the
original product.
Source Dan Crommelin, et. Al. Pharmaceutical
evaluation of biosimilars important differences
from generic low-molecular-weight
pharmaceuticals. EJHP. Vol 11 (1)11-17. 2005.
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Importance of Similarity

• Similarity must be established at each stage of
  comparison with the reference product.
• Molecular analytical similarity need to conduct
  robust molecular analytical comparisons to prove
  similarity. Otherwise, different molecular
  characteristics could have potential clinical
  consequences in patients resulting in the
  approval of medicines with unknown clinical
  consequences, misinformation for physicians and
  potential mistreatment to patients.
• Clinical similarity without probing molecular
  similarity, there exists no scientific basis to
  support that safety and effectiveness of the
  reference product applies to the follow-on
  version. Likewise, head-to-head comparison
  showing non-inferiority would not apply for
  biosimilars because there could exist different
  clinical profiles between the reference and
  follow on products.
• Therefore, biosimilar manufacturers need to show
  similarity with both analytical methods and
  clinical studies to demonstrate that the
  biosimilar has the same outcomes of quality,
  safety, and efficacy as the reference product.

Source Letter from Dr. Ryoko Krause on behalf of
IFPMA to Dr. Ivana Knezevic of the World Health
Organization. July 17, 2008
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BiosimilarsScientific basis for abbreviated
pathway
Demonstrate Quality, Safety, Efficacy
Regulatory Approval
New Biologic
Extensive Characterization
Clinical
Surveillance
Pre-Clinical
Regulatory Approval
Clinical
Extensive Characterization
Clinical
Biosimilar
Surveillance
Extensive Comparison to Reference
Pre-Clinical
Pre-Clinical
Allows for abbreviated pre-clinical clinical
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Biosimilars Scientific Basis for Approval

• Similar ? Same
• Everything else follows from this
• Require clinical trials
• No current scientific basis for
  substitution/interchangeability
• Different names

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Different Protein Manufacturers Use...
....ATG Gene Sequence STOP...
Cloning into DNA Vector
ATG
Maybe the same gene sequence
Stop
(Probably) a different DNA vector
Different in-process controls
Transfer into Host Cell Expression Screening/Sele
ction
Different fermentation process
Fermentation
Downstreaming/ Purification
Different recombinant production cell
Different downstreaming protocol
e.g., bacterial or mammalian cell
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Need for Clinical Trials Immunogenicity Safety
GROWTH HORMONE
Omnitrope (somatropin) Innovative biologic
Genotropin (Pfizer)

• Up to 60 of enrolled patients developed
  antibodies to Omnitrope in the first study of
  phase III
• The problem was a high concentration of host cell
  protein in the host cell which are known to
  enhance antibody reaction against growth hormone.
  
• Introduced additional purification steps
• New phase III studies were conducted
• Antibody level was significantly reduced

EMEA Review Process
Source EMEAs Omnitrope EPAR http//www.emea.eur
opa.eu/humandocs/Humans/EPAR/omnitrope/omnitrope.h
tm
APPROVED
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Need for Clinical Trials - Efficacy and Safety
CHRONIC HEPATITIS C
Alpheon (interferon alfa-2a) Innovative biologic
Roferon-A (Roche)

• Differences in the qualitiative and quantitative
  impurity profile could not lead to similarity
  conclusion for Alpheon and Roferon-A.
• Clinical trials showed that patients using
  Alpheon had a higher relapse rate and higher rate
  of adverse events.

EMEA Review Process
Source EMEAs Alpheon EPAR http//www.emea.euro
pa.eu/humandocs/PDFs/EPAR/alpheon/H-585-RAR-en.pdf
Not approved
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Biosimilars should not be Subject toAutomatic
Substitution

• Generic drugs may be substituted for reference
  drugs because they are the SAME
• Biosimilars are similar to the reference, i.e.,
  DIFFERENT
• There is currently no scientific basis to
  substitute different products

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Different things should have different names

• Generic drugs have the same non-proprietary name
  as their reference drug because they have the
  SAME active ingredient
• Biosimilars will be similar to (i.e., DIFFERENT
  from) their reference product

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Unique names for patient safety and
pharmacovigilance

• Unique names are needed to facilitate clear
  prescribing and dispensing and to ensure a
  biosimilar is not automatically substituted
  without physicians knowledge and approval.
• Unique names are needed for pharmacovigilance
  because they provide a mechanism to track and
  attribute adverse events to the appropriate
  product.

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Regulation of Biosimilars
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No Harmonized Worldwide Regulatory Framework for
Biosimilars

• Small molecule generics model is inappropriate
• In many regions limited or no regulatory
  processes exist
• Lack of minimum regulatory standards presents a
  risk for patients because of the potential issues
  relating to the quality, efficacy and safety of
  biosimilars developed and approved without
  defined requirements

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European Union

• European law recognizes Similar Biological
  Medicinal Products (Biosimilars) as a category
  distinct from generic drugs
• EMEA has published General Guidelines and Concept
  Papers on Similar Biological Medicinal Products

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United States

• There is currently no regulatory approval pathway
  in the U.S. for the approval of biosimilars.
• A regulatory approval pathway for biosimilars in
  the U.S. requires legislation by Congress.

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Need for a Legal and Regulatory Pathway in
Region

• Lack of a differentiated legal pathway
• Lack of strict safety and efficacy requirements
  for biosimilars
• Local example
• Importation of biosimilars from countries with
  lax safety and efficacy controls
• Regional example

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Biosimilars Approval Pathway

• Generic drug approval pathway is premised on
  ability to make and show that generic drug is the
  same as the innovator drug
• Biologics from different manufacturers may be
  similar, not the same
• Therefore you need a different regulatory
  pathway, with different scientific standards
• Biosimilars are not generics
• The regulatory pathway should reflect this in the
  rigor of the approval standards.

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Regulatory and HealthCare System Challenges
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Public Health Challenges

• Constraints in health care budget
• Safety concerns
• Consideration of all patients health care needs
• Access to all types of safe and effective health
  care services and drugs
• Pharmacovigilance
• Open transparent regulatory process
• Government more direct support for innovation and
  encouraging development of new cures

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Physicians Role

• Advise governments to ensure that all approved
  therapies are effective and safe for patients.
• Ensure that all patients health care needs are
  considered.
• Make sure that patients have information and
  access to all types of safe and effective health
  care.
• Educate patients about their ability to go to the
  government to make sure they have access to safe
  and effective medicines.
• Contribute to monitoring of adverse effects.
• Support innovation and development of new cures.

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Important take-aways
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Biosimilars - Summary

• The issues and the science are complex and
  multi-faceted.
• Patient safety and sound science are fundamental
  biologics raise unique concerns because of the
  close relationship between a products
  manufacturing process and its clinical
  attributes.
• Strong intellectual property protections are
  essential to promoting innovation that meets
  patients needs through new biologics medicines.
• Extensive fact-finding through rigorous and
  transparent processes is needed.

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Understand the science

• Complex science of biologics makes each protein
  product unique, not reproducible nor
  interchangeable

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Place Patients Safety First

• Patients safety requires that standards for
  regulatory approval of biosimilar remain high

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Develop Science-Based Regulations

• In Region, there is a need to develop proper,
  differentiated regulatory frameworks to protect
  patients from unnecessary health risks from
  biosimilars

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Be Able to Distinguish Products

• Each biological product, including biosimilars,
  should have a distinct non-proprietary name for
  patient safety and pharmacovigilance

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Integrate Stakeholders

• Integrate patients and health experts in the
  decision-making process for policies and
  regulations of biosimilars

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Thank you