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Health Products and Food Branch
Visión Global de la Regulación de
Productos Biológicos y Biotecnológicos
Dr. Elwyn Griffiths
Health Canada, Ottawa
Buenos Aires 2008
Health Products and Food Branch
Outline
• Regulation of Biologics / Biotechnology
Products
• Fundamental issues with biotechnology
products
• Biosimilars / subsequent entry biologics
Health Products and Food Branch
What are they- terminolgy?
• Biologics (North America)
• Biological medicines
• Biologicals
• Include Biotechnology Products
• Used in prophylaxis, therapy or
diagnosis of human diseases
(in vitro diagnostics)
Health Products and Food Branch
History
• Traditional Biologicals - include vaccines,
products isolated from biological materials (eg
plasma -FactorViii)
• Early 1980s rDNA derived products came on
to the market called Biotechnology products,
including products from novel cell lines
(monoclonal antibodies)
• Regulated as biologicals
Health Products and Food Branch
Regulatory oversight
• REGULATORY MEASURES put in place very
early on in development of biotechnology
medicinal products - regulated as biologicals
(eg Canada, Europe, USA)
• GUIDELINES on production and quality
control rDNA derived proteins also developed
early on (EMEA, FDA,WHO, ICH)
• Provided framework for moving forward with
the newer technologies
Health Products and Food Branch
Biotechnology Products: What
are the issues?
• Differ from Chemical Drugs in many ways
• Biological starting materials and /or
manufacturing process - inherently variable
• Highly complex products – large protein
molecules
• Test methods needed to characterize product
are biological in nature (bioassays) – potency
(activity), immunogenicity, safety
Biotechnology Productsregulatory issues cover
Development genetics
Cell substrates
Cultivation and harvesting
Downstream processing
Viral validation studies
Detailed product characterization
Testing and release
Pre-clinical studies/toxicology
Clinical studies/several lots to be used
Health Products and Food Branch
Critical Points
• Cell bank / bacterial host / other expression
system
• Cell culture / fermentation
• Sequence/translation of gene
• Separation and purification of product
• Bulk product testing
• Characterization of resulting protein +
glycosylation or other modifications
• Final product testing
Health Products and Food Branch
Product characterization
• Means more than simple quality control tests
• Expect several parameters to be evaluated by
different techniques, not just one
• Protein sequence, secondary / tertiary
aspects, glycosylation, phosphorylation,
oxidation, lipidation, etc
• Product / host cell related impurities (
quantity, identification)
• Formulation implications and Stability
Health Products and Food Branch
Biotechnology productsother issues
• Residual host cell DNA from transformed
(continuous ) cell lines
• Concern - transfer of oncogenic DNA to
recipients
• WHO recommendations as to allowable levels
of DNA
• Viral safety- cell banks screened / validation
virus removal or clearance
Health Products and Food Branch
Biologics production In process controls critical
• Need to understand origin of materials
(production cells, seeds)
• Tests on starting materials
• Tests on intermediates
• Tests on final product
Health Products and Food Branch
Biotechnology derived products
• Led to concept of “well characterized
biologics”
• Best characterized biological products
• Safe and effective medicines
• But control procedures still in place cannot
FULLY predict biological properties and
clinical performance
• Consistency of production critical
• Production changes can lead to major
adverse effects
Health Products and Food Branch
Biotechnology products
• Very sensitive to production parameters
• Nature of cell substrate and growth
conditions / downstream processing
• Minor changes can have major effects on
biological activity: scale up major issue
• Key issue potential immunogenicity
Health Products and Food Branch
Potential immunogenicityimpacts product safety
• Most biologicals induce some antibodies
• Foreign proteins (streptokinase) induce
antibodies via classical vaccine-type reaction
• Human homologue proteins( interferon,
cytokines) induce antibodies by breaking B-cell
tolerance
• Various factors involved- impurities and
aggregates considered to be major cause
• Single or multiple dose also a consideration
Potential immunogenicity - key
event 2002
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Pure red cell aplasia related to use of
Erythropoetin (epoetin) – a major event
In 2002 , 13 cases noted all associated with
epoetin treatment – Antibodies to epoetin
Product Eprex had been safely used for many
years.
Factors thought involved formation of
micelles associated with epoetin, silicon
droplets in prefilled syringes
Major changes in formulation
Potential immunogenicity
Such adverse events cannot be
predicted
 Need for vigilance especially after
manufacturing changes or new products
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Health Products and Food Branch
Biotechnology Products
• On the market since the early 1980s
(rDNA derived medicinal products /
products from novel cell lines)
• Regulatory oversight (guidelines) put in
place early on during their developmentmaximized their safety and efficacy
• Best characterized biological medicines
• Much production and clinical experience
Health Products and Food Branch
Recent Developments
• Increasing number of patents/data
protection expiring
• Products “similar” to the originals
(innovator) coming to the market
• Intention that licensing rely, in part, on
data from an approved innovator product
• Much manufacturer and regulatory
interest worldwide
Health Products and Food Branch
Drivers
• Alternatives to innovator products expected
more affordable – may contribute to increased
access
• Global markets for biologicals growing and
attractive - so considerable global interest
• Difficult and contentious issues
• Key question is how to handle the licensing
of these products if relying, in part, on data
from innovator product
Health Products and Food Branch
Request to WHO for Action
• International Conference of Drug Regulatory
Authorities , Seoul, 2006
• WHO requested to develop global
regulatory consensus and guidance
• WHO Consultations on nomenclature and
regulatory evaluation for “Biosimilars” 2006,
2007,2008- regulators and manufacturers
• WHO Expert Committee on Biological
Standardization (2006, 2007)
Health Products and Food Branch
WHO Consultations
outcomes
• Better understanding of directions and
challenges in the regulatory evaluation of the
quality, safety and efficacy of “biosimilars”
• Exchange of information between regulators,
the identification of key issues and gaps, and
recommendations on the next steps
• Wide range of regulatory preparedness
• Clear need for global road map
• Decision on INNs
• WHO Guideline Drafting Group established
Health Products and Food Branch
What should they be called?
• Different NAMES given by different
jurisdictions
• Follow-on Biologics/protein products (USA,
Japan)
• Biosimilar Products (EU)
• Subsequent-entry Biologics (Canada)
• Biogeneric products (others)
Health Products and Food Branch
Not Generics
• Agreed – biotechonolgy products do not
meet criteria for true GENERICS should not be regulated under generic
(chemical ) drugs regulations
• Biologicals / biotechnology products, by
definition, are not “identical”
• They are highly complex in nature and
production
Health Products and Food Branch
Key Consensus Points
• Possibility of licensing a new biotechnology
product on basis of “similarity” with a well
established licensed product agreed
• Extensive characterization of new product
• Abridged non clinical and clinical data package
possible (case by case)
• But what type of regulatory pathway to use?
Health Products and Food Branch
Which regulatory pathway?
• Some authorities already established
regulatory pathway (Europe/EMEA)
• Others close to doing so (Canada)
• Yet others do not have a regulatory
framework for such products
• Sometimes legal framework problem
• Generally same issues highlighted
Health Products and Food Branch
Issues
• Definitions and terminology
• Type of regulatory pathway
• Scope of products – only rDNA proteins ?
monclonals? Polysaccharides (Heparins)?
• Degree of “similarity” – potential
immunogenicity
• Demonstration of “similarity”
• Defined comparator / reference product
• Extrapolation of indications from originator
• Interchangeability / substitutability
Health Products and Food Branch
WHO Draft Guidelines developed
• By WHO Drafting Group
• Consultation, Seoul, May 2008, public
consultation/comments
• PAHO Consultation of Regulatory Authorities,
Dominican Republic, June 2008
• Presented to WHO Expert Committee on
Biological Standardization, October 2008
• Immense global interest – regulatory agencies,
industry, media
Health Products and Food Branch
WHO Draft Guidelines
• Intention- globally acceptable set of
principles for abbreviated/abridged
licensing pathways for biological
therapeutic products
• Intention - not to resolve all issues
• Need for implementation strategy
• Need for transition period
Health Products and Food Branch
Current WHO Draft Guideline
Considered 3 Regulatory Pathways
• Full license application : no reliance on any
data from already licensed product
• Two Abbreviated licensing approaches:
-reliance on demonstrated “similarity” of new
product with an innovator product :
-reliance on knowledge and experience of
product class
• Both have extensive quality dossier
Health Products and Food Branch
Abbreviated pathway 1
Biosimilar approach (like EMEA)
• Reliance on head to head
demonstration of “similarity” of new
product characteristics (physico chemical
/ biological activity) to a chosen licensed
reference product (innovator product)
• Reduced non-clinical and clinical data
but including head to head comparison
with the same reference product
Health Products and Food Branch
Biosimilar Approach
Choice of Reference Product
• Reference must be a licensed product
• Object of comparability studies is to
demonstrate product “similarity”
• Same reference throughout studies
• Extrapolation- of indications of the
Reference Product to the biosimilar
possible on basis of one clinical study on
justification
Health Products and Food Branch
Biosimilar Approach
Choice of Reference Product
• Unavailability of reference drug
substance, only formulated product
• Need to extract from formulated
product for physico chemical studies
• Verification that extraction does not
affect drug substance properties
Health Products and Food Branch
Abbreviated pathway 2
Clinical comparability approach
• Reliance on belonging to product class;
no head to head quality comparison
with a reference product
• Reduced non-clinical data package
• Reduced clinical data possible on
justification but including head to head
comparison with reference product
Health Products and Food Branch
Clinical comparability approach
Reference Product
• No need to extract drug substance since
formulated product used in clinical studies
• Comparator should be well established
product in product class
• Extrapolation- of indications of the Reference
Product to the new one not to be considered
on basis of one clinical study
Health Products and Food Branch
WHO Guidelines -Abbreviated
licensing approaches
• Both approaches have same
requirement for an extensive
immunogenicity studies in comparison
with the reference products prior to
licensing.
• Both require a post marketing
pharmacovigilance plan to be developed
Health Products and Food Branch
Regulatory approaches for biotherapeutics
following licensing of the originator
Full licensing
application
Full dossier (no
data reduction)
Abbreviated licensing pathways
Biosimilar approach
1) Full quality dossier
with a comparability
exercise
2) Reduced non-clinical
and clinical data
(comparative)
1)
2)
3)
Clinical comparability
approach
Full Quality dossier
Reduced nonclinical data
Clinical data (head to head
comparison with
reference product)
Stand alone
product
Biosimilar product
Clinically comparable product
Extrapolation of
indications possible on
justification
No extrapolation of indication(s)
To be considered
Health Products and Food Branch
WHO Expert Committee - Concerns
expressed over first official draft
• Concerns of IFPMA, manufacturers, number of
regulatory agencies (FDA,EMEA,TGA)
• Perception Clinical Comparability approach
lower standard than “biosimilar pathway”. Two
standards which may compromise safety
• Agreed parts of a complete/full licensing
approach can be reduced on consideration of
knowledge and experience of product class
(IFPMA letter to WHO)
Health Products and Food Branch
WHO Expert Committee 2008
Proposed Guidelines
• Intensive discussion over several sessions
• Document not adopted
• Many proposals made for improvements
• Document now being revised
• To be submitted to Expert Committee in draft
for general agreement prior to posting on
internet in first quarter 2009.
• To undergo further public consultation; revised
version will go to the WHO Expert Committee
in 2009
Health Products and Food Branch
WHO Expert Committee 2009
Proposed Revised Guidelines
• Issues to be reviewed/revised: Scope (agreed
not vaccines); Non-inferiority/clinical
equivalence; extrapolation of indications
• To cover “biosimilar” approach and full
licensing approach with considerations for
reduction of non-clinical and clinical package
based on knowledge of product class and
experience of use.
• Focus on principles not regulatory pathways
Health Products and Food Branch
WHO Expert Committee 2009
Proposed Revised Guidelines
• Possibility of further consultation in 2009
being considered prior to ECBS
• Need for clarity
• Difficulties will be terminology /
nomenclature
• Time to prepare/brief manufacturers and
National Regulatory Authorities (NRAs)
regarding future developments and
directions – feedback on revision
Health Products and Food Branch
Preparation and Implementation
• Additional consultations with other stakeholders
(relevant government representatives,
physicians, patients groups) also needed
concerning
 adoption of “biosimilars” by drug formularies
 Interchangeability and substitutability
 Post-market surveillance issues which are
an important component of the draft
guideline
Health Products and Food Branch
Next 12 months
• Share information on issues and options
with national regulatory authoriites
• Stimulate broad discssion as ot how to
handle licensing in PAHO countries
• Need for expertise
• Feedback to WHO on next draft of
guidelines – clear ? useful?
Health Products and Food Branch