Assessing Global Standards for Biologic Medicines
Richard Dolinar, MD
Endocrinologist
Chairman of the Alliance for Safe Biologic Medicines
Presented at the Center for Business Intelligence 8th Annual Biosimilars Summit
March 5 , 2013
Presentation Overview
Global Quality Standards for Biologics in Regulated and
Unregulated Markets - Why is this important?
• Patient safety must ALWAYS be placed first.
• Biosimilars must be introduced without incident, or their adoption
will be undermined.
• Physicians require confidence in the medication they prescribe.
• Manufacturers should be held accountable for their products.
• In this global market, there should be no “EASY point of approval”,
such as in an emerging market with lower standards, that can
jeopardize the above principles.
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Potential Areas For Creation of Global Standards
Approval Processes:
Should biosimilars have to undergo clinical trials?
Biosimilar Naming:
Should biosimilars have unique names?
Biosimilar Substitution:
When?
By whom?
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Approval Pathways for Biosimilars…
Currently No Global Standards.
• 2003 EU Biosimilar Pathway
• 2009 Canadian Biosimilar Pathway
• US in the process
• Colombia recently proposed a 3-tier approval pathway:
1. full dossier,
2. abbreviated dossier with comparability/biosimilary
demonstrated to an approved product,
3. approved in another jurisdiction w/ similar standards
(which are unspecified)
• Brazil similar pathway to (3), limited to certain jurisdictions.
• Thailand has a substantial spike in Pure Red Cell Aplasia, > 30 RBC
stimulating products. Which is the culprit?
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Global Standards on Naming Being Discussed
WHO Guidance on Naming:
WHO has been the leader on "developing,
establishing and promoting international
standards with respect to biological,
pharmaceutical and similar products".
International Nonproprietary Names (INN)
facilitate the identification of
pharmaceutical substances or active
pharmaceutical ingredients.
WHO will be discussing the need for
unique names in biosimilars at the 56th
Consultation on INNs for Pharmaceutical
Substances (April 15-17, 2013).
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ASBM/FDLI Whitepaper on Biosimilar Naming, Nov. 2012
1. All biologics should receive distinct nonproprietary names.
2. United States Pharmacopeia (USP) should
work with FDA to adapt the product
monograph system to accommodate the
unique attributes of structurally-related, but
distinct, biologic medicines.
3. The non-proprietary name of a reference
product and product/s biosimilar to it should
have a common, shared root but have distinct
and differentiating suffixes.
4. Products designated interchangeable should
have a distinct name from the reference
product for which they are considered
interchangeable to facilitate accurate
attribution of adverse events.
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How is substitution of biosimilars addressed?
• US has “interchangeability” and as a result the FDA has laid
out in its draft guidance substitution guidelines that differ
from those of the EMA, Health Canada, and the World Health
Organization, particularly in regard to the role played by the
physician.
• 15 U.S. States are currently considering legislation which
regulates biosimilar substitution: Virginia, Indiana, Texas,
Florida, North Dakota, Washington, Colorado, Arkansas,
Massachusetts, Oregon, Arizona, Maryland, Pennsylvania,
Utah, Illinois.
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About ASBM
The Alliance for Safe Biologic Medicines
• Founded 2010
• Advisory Board consists of
PATIENTS
PHYSICIANS
RESEARCHERS
PHARMACISTS
The Four Pillars:
• PRIORITIZING PATIENT SAFETY over cost savings, speed, or politics
• LEVERAGING WHAT WE HAVE LEARNED the EU’s science-based approach
• PROMOTING PHARMACOVIGILANCE: holding manufacturers accountable
for the quality of their product
• KEEPING DOCTORS RELEVANT: Physicians and their patients should
determine treatment, not a third party
ASBM:
Engaging Stakeholders to Shape the US Biosimilars Pathway
• APRIL 16: ASBM submits Formal
Comments to US FDA
• MAY 11: 9 ASBM members and ASBM
Chairman testify at FDA Hearing
• JUNE: ASBM Presented at Toronto Patient
Experts Conference
• AUGUST: 380-Physician Survey conducted
on Biosimilar Naming and
Interchangability
• SEPTEMBER: Presented at 3 Conferences
in US including
FDA/DIA Conference
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Why Are New Standards Needed?
One Example: Immunogenicity
FDA released draft guidance February 2013, saying:
“Immune responses to therapeutic
protein products may pose
problems for both patient safety
and product efficacy.
[Immunological adverse events]
have caused sponsors to terminate
the development of therapeutic
protein products or limited the use
of what might otherwise be
effective therapies.”
-FDA Center for Drug Evaluation and Research,
in-PharmaTechnologist.com, 2/25/2013
Guidance fo
Immunogenic r Industry
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Therapeutic
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This guidanc
DRAFT GU
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Services
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Center for Bio ug Evaluation and Resea
rch (CDER)
logics Evalu
ation and Re
search (CBE
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February 20
13
Clinical/Med
ical
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Biologic vs. Chemical Medicines: Differences
SIZE: significantly larger, more complex
STRUCTURE: Highly complex, minor
manufacturing differences can cause
adverse effects
DRIFT: biologics can change with time
STABILITY: Biologic medicines are sensitive
to light, heat, denaturing or degradation
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Key differences between chemical drugs and biologics
SIZE
ASPIRIN
• ~180 daltons
• 21 atoms
HUMAN GROWTH HORMONE
• 191 amino acids
• ~22,000 daltons
• 3091 atoms
lgL1 ANTIBODY
• >1000 amino acids
• ~150,000 daltons
• >20,000 atoms
Source: Genentech
Molecular Comparison:
Aspirin vs. Biologic Monoclonal Antibody
Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011
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A Highly Complex Manufacturing Process
Fermentation –
cells produce the
protein defined
by the vector
Purification –
removing the
impurities
Highly complex
protein with 3 or
4 levels of
structure
Place vector
inside a specific
cell
Design the gene
sequence
Place gene
sequence inside
a vector
IgG1 antibody
>1000 amino acids
~150,000 daltons
>20,000 atoms
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Degree of Manufacturing Change
The degree of change determines the level of risk and thus the data
required to demonstrate the product remains equally safe and effective:
Higher risk / less common changes =
Maximal Data Required
(Clinical Testing, Analytical and Process)
Low risk and common change =
Minimal data required
Supplier
for tubing
changed
Relocate
equipment
within same
facility
Relocate to
new facility
Manufacturing
scaled up to
production level
*It is not scientifically possible to exactly copy biologic medicines at this time.
New cell line
New process*
Small Differences
CH3
CH3
OH
COCH3
CH3
CH3
O
O
CH3
OH
OH
Source: Bilao LLC, 2008
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Small Differences = Large Impact
CH3
CH3
OH
CH3
CH3
O
O
COCH3
CH3
Progesterone
OH
Testosterone
OH
Source: Bilao LLC, 2008
Estradiol
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What are Biosimilars?
•
Biosimilars are often referred to as “follow-on biologics” or “follow-on
proteins”.
•
Biosimilars are copies of existing trade-name biological products whose
patents have expired.
•
While “highly similar” biosimilars are not “identical” to the reference product.
•
They do not utilize the same living cell line, production process, or raw
material as the innovator drug.
SIMILAR, BUT
NOT IDENTICAL
≠
INNOVATOR MEDICINE
EU-APPROVED BIOSIMILAR
Creating a US Biosimilars Pathway
• 1984 – Hatch-Waxman Act
• March 23, 2010 – Patient
Protection and Affordable Care
Act
• Biologics Price, Competition,
and Innovation Act (BPCIA)
• November 2010 – FDA began
consulting with various
individuals and groups
• February 9, 2012 – FDA draft guidance issued
• February 27, 2012 – ASBM hosts Capitol Hill Biosimilars Forum
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