Biosimilars:
A Framework to Ensure Safe Substitution
Richard Dolinar, MD
Endocrinologist, Chairman of the Alliance for Safe Biologic Medicines
Presented at the University of Rhode Island College of Pharmacy
December 13, 2012
The Alliance for Safe Biologic Medicines
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Patients
Physicians
Scientists
CROs
Innovator industry
ASBM MEMBERS
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Biologics 101
Role of Biotechnology in Medicine
Advancements in science have increased the number of biotechnology products, revolutionizing the
diagnosis, prevention, cure and management of many serious diseases.
RHEUMATOID ARTHRITIS
This disorder attacks healthy
parts of the body, including
its own joints, causing
swelling, pain and even
disfigurement. New biotech
drugs target the affected
area without suppressing
the entire immune system.
HIV/AIDS
Some antiretroviral
therapies like Infuvirtide
(Fuzeon) stop the HIV
virus from infecting cells
while others treat HIVrelated anemia and
other complications.
DIABETES
Synthetically made
Human insulin was made
available in the 1980’s.
Before then, it was made
from cows and pigs.
CANCER
Several biologics
including this image of
Trastuzumab
(a monoclonal antibody)
treat cancers.
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Examples of Biologic Medicines
Product
Manufacturer
Condition
HumulinR (Insulin Injection, Human
Recombinant)
Eli Lilly
Diabetes
Betaseron (Interferon beta-1b)
Bayer
Multiple Sclerosis
Genotropic (Somatropin)
Pfizer
Children with growth hormone deficiency; Prader-Willi syndrome,
girls with Turner syndrome
Follistim (Follitropin Beta)
Organon
NovSeven (Coagulation Factor VIIa)
Novo Nordisk
Infertility
Hemophilia
Enbrel (Etanercept)
Amgen
Rheumatoid Arthritis, Psoriasis
Epogen (Epeotin alfa)
Amgen
Anemia caused by chronic kidney disease
Rituxan (Rituximab)
Genentech
Non-Hodgkin’s lymphoma, Rheumatoid Arthritis
Humira (Adalimumab injection)
Abbot Labs
Rheumatoid Arthritis, Crone’s disease,
ankylosing spondylitis, psoriatic arthritis
Erbitux (Cetuximab injection)
Pegasys (Peginterferon alfa-2a)
Bristol-Meyers
Squibb
Roche
Head & Neck Cancer, Colorectal Cancer
By 2014, it is
projected that six
out of the 10 topselling drugs in
the U.S. will be
biologics, some of
which may face
biosimilar entry.
Analysis Group Health Care
Consulting Bulletin (Fall/Winter
2010)
Hepatitis C, Hepatitis B
Herceptin (Trastuzumab injection)
Genentech
Metastatic Breast Cancer
Avastin (Bevacizumab)
Genentech
Colorectal Cancer, Lung Cancer, Metastatic Breast Cancer,
Gliobastoma, Metastatic Kidney Cancer
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The differences between Chemical Drugs and Biotech
Medicines you can see
CHEMICAL DRUGS:
BIOTECH MEDICINES:
• Made by chemical synthesis
• Made by living cells-unique cell lines,
from bacteria, yeast, or mammals
• Defined structure, easy to characterize
• Usually taken by mouth, prescribed by
general practitioner
• Heterogenous structure, difficult to
characterize
• Usually injected, prescribed by
specialists
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Biologic vs. Chemical Medicines - Differences that Matter:
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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What are Biosimilars?
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Biosimilars are often referred to as “follow-on biologics” or “follow-on
proteins”.
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Biosimilars are copies of existing trade-name biological products whose
patents have expired.
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While “highly similar” biosimilars are not “identical” to the reference product
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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
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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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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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*
Creating a U.S. 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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ASBM Recommendations made at FDA May 11 Hearing
• Clinical testing
• Thorough evaluation and
understanding of biosimilar
before designation as
“interchangeable”
• Only biosimilars determined
to be “interchangeable”
should be substituted
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Safe Substitution of Biologics
What is substitution?
1) Physician writes a prescription
2) Pharmacist is allowed, or
required, to provide a different
medicine to the patient
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Congress defined 2 different levels of biologic copies
BIOSIMILARS:
• HIGHLY Similar
INTERCHANGEABLE
BIOSIMILARS:
• HIGHLY Similar
• SAME EFFECT in any given
patient is expected
• NO ADDED RISK from switching
Is biologic substitution [no doctor involvement]
scientifically appropriate?
X
NEVER
Different medicine
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Different molecule
Different safety and
efficacy profile
X
NEVER
Only Similar. FDA has not
approved as safe for
substitution.
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Highly Similar but …
Not expected to have
same effect in any given
patient
Not determined to have
the same risk if patient is
switched.
✓SOMETIMES
FDA has determined safe for
substitution
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Highly Similar
• Safe effect in any given patient
• No greater risk if switch vs no
switch
• OK to switch UNLESS Dr. has
specified no switching
Who decides if substitution is allowed?
• Congress said “interchangeable” means
switching without physician involvement
• FDA determines if a product meets the criteria
for “interchangeable” – this is a scientific
decision.
• States historically have decided what
pharmacists are allowed to do.
States handle generic drug substitution in
different ways
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2/3rds reference the orange book in some way
Some require substitution
Some permit substitution
Some prohibit substitution
When will doctors and patients face substitution
questions for biologics?
• 1st biosimilars expected to
be approved in 2013
Providing a Biosimilar-Substitution Framework
for States
Goal: Have legislation in place when the first
biosimilars are approved in 2013
• Avoid substitution of biologics that are not
designated “interchangeable”
• Prevent a potentially harmful substitution
from occurring
Principal Safeguards for State Policy
1. Substitution should only occur when FDA has
designated a biosimilar “interchangeable”
2. The prescribing physician should be notified when a
substitution has occurred.
3. The prescribing physician should be able to prevent
substitution by writing “Dispense as Written” (DAW)
or “Brand Medically Necessary” (BMN) instruction.
May 24: Physician Notification Working Group
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Meeting of ASBM National
Advisory Board members, most of
whom are practicing physicians.
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Overwhelming concern about
harm to patients if prescribed
product is substituted.
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Outgrowth of the call was to
commission a SURVEY of
physicians regarding physician
notification of medication
switching, for use in promotion of
our policies on naming and
interchangeability.
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Importance of Physician Notification of
Medication Switching, with or without known risks
ASBM September Survey:
376 U.S. physicians,
distributed equally across:
• Endocrinology
80%
80%
70%
60%
• Oncology
50%
• Rheumatology
40%
• Nephrology
30%
Confidence interval is + or - 5%
88%
90%
• Dermatology
• Neurology
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100%
% Very important or Critical
20%
10%
0%
No risks specified
Risks specified
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Upcoming Pharmacist Survey
• Pharmacist Survey
Scheduled for January 2013
– Follow-up to ASBM’s
September Physician
Survey
– Designed to inform our
recommendations with
hard data from an
additional, vital
constituency
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Learn More at www.SafeBiologics.com
• Issue Background
• FDA Process
• The EU Experience
• Policy Resources
• FAQs
• Comments Submitted to FDA
• Additional Regulatory Outreach
• Recent News
• Event Calendar
• In the States
• European Product Assessment
Reports (EPARs) for Biosimilar
www.SafeBiologics.com
Products Documents
• Key Websites
• Biosimilar Laws and Regulations Around The World
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