Dialogue with Canada’s leading regulatory and assessment experts: Health Canada Bureau of Biologics and Genetic Therapies (BGTD) and Canadian Agency for Drugs and Technologies in Health (CADTH) Date: June 29, 2016 Time: 1:00pm to 3:00pm EST

1. Durhane Wong-Rieger, PhD
President - Canadian Organization for Rare Disorders
Webinar:
Access to biosimilars in Canada
June 2016
Cathy Parker
Director General – Biologics and Genetic Therapies
Directorate (Health Canada)
Chander Sehgal
Director – Common Drug Review and Optimal Use
at CADTH

2. Regulation of Biosimilars
(Subsequent Entry Biologics)
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
June 2016

3. Outline
• The Promise of Biosimilars
• Canadian Regulatory Approach
• Challenges

4. Biologic Drugs
Biologic
drugs
differ
from
chemically
synthesized
drugs
as
they
are
• derived
from
the
metabolic
ac8vity
of
living
organisms
• large,
structurally
complex
and
difficult
to
characterize
• inherently
more
variable
• sensi8ve
to
light,
temperature,
and
suscep8ble
to
contamina8on
Differences
between
pharmaceu8cals
and
biologics
require
differences
in
how
they
are
regulated

5. Revers
and
Furczon,
CPJ,
2010,
143:134
hKp://cph.sagepub.com/content/143/3/134
Chemical Drug vs. Biologic Drug

6. What is a Biosimilar?
• A biologic drug that
– enters the market subsequent to a version previously authorized in Canada
– has demonstrated similarity to a reference biologic drug
– has no clinically meaningful differences from the reference biologic drug
• A biosimilar relies in part on prior information regarding safety
and efficacy due to the demonstration of similarity to the
reference biologic drug.
• Biosimilars are not generic biologics
– Unlike generics, biosimilars are not pharmaceutically equivalent to their
reference drugs (i.e. in comparison with the reference product they do not
contain identical amounts of identical medicinal ingredients)
– Biosimilars can only be shown to be “similar” to a reference biologic drug

7. The Promise of Biosimilars
• Minister of Health Mandate Letter – expectations related to improving
access to necessary prescription medications and making them more
affordable http://pm.gc.ca/eng/minister-health-mandate-letter#sthash.0WH66z0X.dpuf
• The availability of biosimilars is anticipated to contribute to more
affordable biologic drugs, more secure supply and more treatment
options
• Influx of biosimilar submissions expected over next several years as
patents and data protection expire
• Today, there are numerous biosimilar development programs underway
and multiple programs for each of the top selling biologics

8. The Promise of Biosimilars
Rank
Leading
Products
Therapeutic
Subclass
2013
Sales
in
Canada1
($
millions)
Innovator
Company
Canadian
Patent
Expiry
Year
1
Remicade
(infliximab)
Anti-­‐arthritic
694.9
Janssen
Biosimilar
available
2
Humira
(adalimumab)
Anti-­‐arthritic
434.9
AbbVie
Majority
of
Canadian
patents
set
to
expire
between
2016
-­‐2020
for
leading
biologics
3
Lucentis
(ranibizumab)
Vision
loss
402.2
Novartis
4
Enbrel
(etanercept)
Anti-­‐arthritic
332.9
Amgen
5
Cipralex
Antidepressant
250.0
Lundbeck
6
Rituxan
(rituximab)
Autoimmune
217.6
Roche
1
Innovation,
Science
and
Economic
Development
Canada,
“Pharmaceutical
industry
profile.”
Accessed
2
May
2016
https://www.ic.gc.ca/eic/site/lsg-­‐pdsv.nsf/eng/h_hn01703.html
Red denotes biologic drugs
Top Selling Drugs (2013)
Biologics made up 5 of the top 10
Expiring patents for all 5

9. Canadian Regulatory Approach
• A biosimilar is a biologic drug that enters the market subsequent to
a version previously authorized in Canada, and has demonstrated
similarity to a reference biologic drug.
• The demonstration of similarity can be the basis for accepting a
reduced non-clinical and clinical data package.
– A biosimilar relies in part on prior information regarding safety and efficacy
due to the demonstration of similarity to the reference biologic drug.
• Biosimilars are not generic biologics
– Unlike generics, biosimilars are not pharmaceutically equivalent to their
reference drugs (i.e. in comparison with the reference product they do not
contain identical amounts of identical medicinal ingredients)
– Biosimilars can only be shown to be “similar” to a reference biologic drug

10. Food
and
Drugs
Act
Food
and
Drug
Regula2ons
Guidance
Document
Regulatory Approach
Biosimilars are regulated as new biologic drugs in Canada; they are subject
to the Food and Drugs Act and Part C, Division 8 of the Food and Drug
Regulations just like other new biologic drugs.
Regulatory approach is tailored to the concept of similarity.
A guidance document was published in 2010 to communicate submission
requirements to biosimilar sponsors. The document is under revision to
reflect experience gained by Health Canada over time.

11. Regulatory Decision-making
• A final determination to issue an authorization (Notice of
Compliance) is based upon a benefit/risk decision after
considering all of the supporting quality, safety, and efficacy
data.
Note: This does not differ from any other new drug
v SEBs are considered in new drug status, subject to all the provisions of the
new drug regulations
v Post-market requirements apply
v No declaration of equivalence, interchangeability or substitutability: these
are within the purview of the health care system/s in the provinces

12. Guidance document
• The 2010 Guidance for Sponsors: Information and Submission Requirements
for Subsequent Entry Biologics (SEBs) was updated in 2015 to reflect
experience gained over the last 5 years.
• Many of the proposed revisions reflect guidance provided by Health Canada to
sponsors in relation to submissions or queries.
• More than 20 unique stakeholders/groups responded
– Individual drug companies, industry associations, patient, healthcare, scientific and
clinical research organizations, law firms
• Stakeholder comments are actively being reviewed by an internal
Health Canada working group.
• BGTD also launched a three year pilot for SEB Scientific Advice Meetings to
allow for discussion and review of quality package by Health Canada early in
the development process.

13. Subsequent Entry Biologics (SEBs)
Generic Pharmaceuticals
Nature/Manufacturing
process
Biological; derived from living organisms
Chemically synthesized
Size, Structure, and
Complexity
Large and structurally complex molecules; difficult to
characterize
Small molecules, simple and well-defined;
easy to characterize
Type of drug
submission
New Drug Submission
Abbreviated New Drug Submission
Similarity/Equivalence
“Similar” to Reference Biologic Drug (Canadian or non-
Canadian)
Equivalent to Canadian reference product
Chemistry and
manufacturing data
requirements
Full quality data plus extensive comparability exercise to
show similarity
Full quality data
Clinical data
requirements
Clinical trials in patients required comparing SEB to
reference product
“Bioequivalence” trials (small trials in
healthy volunteers to show that the drug
behaves the same way in the body as the
reference product)
Extrapolation of
indications
Review-based decision on whether to allow for
extrapolation to indications held by the Canadian reference
biologic drug based on review of detailed scientific
rationale or data to support the extrapolation
Automatic extrapolation to all indications of
the Canadian reference product
Additional regulatory
oversight
Additional regulatory oversight applied to biologic drugs,
including SEBs
• On site evaluations (inspection of the manufacturing site
and drug production)
• Lot Release Program
Regulatory review
timelines
300 calendar day performance target standard
180 calendar day performance target
standard
Interchangeability
Authorization is not a declaration of bioequivalence
Authorization constitutes a declaration of
bioequivalence

14. International Context
Health Canada EMA FDA
Number of biosimilars authorized (as of March 1, 2016)
5
(1st authorized 2009)
22
(1st authorized 2006)
2
(1st authorized 2015)
• The European Medicines Agency (EMA) and Health Canada were leaders in
the initial development of regulatory frameworks for biosimilars.
• The US Food and Drug Administration (FDA) has lagged behind other
regulators and is now implementing its regulatory framework. There are > 50
biosimilar development consultations underway with FDA.
• Health Canada works closely with the WHO and other regulators to enable
information sharing and to promote regulatory convergence. Regular “cluster”
teleconferences with the FDA, EMA, and Japan to discuss specific issues.

15. Biosimilars
authorized
in
Canada
(as
of
June
2016)
Biosimilar
Reference
Biologic Drug
Therapeutic area Date of NOC
Omnitrope
(Somatropin – Human
Growth Hormone)
Genotropin Growth Hormone Deficiency in Children and
Adult Growth Hormone Deficiency
April 20, 2009
Omnitrope Genotropin Additional indications for Small for Gestational
Age, Idiopathic Short Stature and Turner
Syndrome
May 8, 2015
Inflectra
(Infliximab – Monoclonal
Antibody)
Remicade Rheumatoid Arthritis, Ankylosing Spondylitis,
Psoriatic Arthritis and Plaque Psoriasis
Crohn’s, ulcerative colitis
January 15, 2014
June 10, 2016
Remsima
(Infliximab – Monoclonal
Antibody)
Remicade Rheumatoid Arthritis, Ankylosing Spondylitis,
Psoriatic Arthritis and Plaque Psoriasis
January 15, 2014
Basaglar
(Insulin Glargine -
Recombinant Human
Insulin Analogue)
Lantus Treatment of pediatric (>6 years) and adult
patients with Type 1 diabetes mellitus, and
adult patients with type 2 diabetes mellitus
September 1,
2015
Grastofil (filgrastim) Neupogen Prevention or treatment of neutropenia December 7, 2015

16. Challenges - Rapidly Evolving Field
• Ongoing challenge of regulatory frameworks keeping pace with science
• Close interactions with other regulators and participation in WHO
guideline drafting groups extremely helpful
• Regular review of regulatory guidance document for biosimilars

17. Challenges - Interchangeability
• Biosimilars are not linked to their reference products in the way
of generic pharmaceuticals. Regulatory authorization is not a
declaration of equivalence.
• Pressures from various stakeholders to provide direction
• Increased focus on the concept of switching?
• Confusion in terminology and understanding amongst
stakeholders
Subs2tu2on
Automa2c
Subs2tu2on
Interchangeability
Switching

18. Other Challenges
• Patient and Health Care Provider Confidence
– Perception that biosimilars have less rigid pre and post market data
requirements
– As a new category of drug products there is a need to educate on
their safety and efficacy
• Naming
– Controversy over whether biosimilars should have unique identifier
– No international consensus. US and Canada support extension to
INN name identifying biosimilars and biologics, EU does not support
• Labelling
– How much information from reference product’s monograph should
be used in labelling of biosimilar?

19. Transparency
• Regulatory Transparency and Openness Framework – one of the
objectives is to help Canadians to better understand how and
why our decisions are made.
• Submissions under Review
– Biosimilars accepted for review are now published on the website
• Regulatory Decision Summaries and Summary Basis of Decision
documents also published
• Stakeholder registry – to help you stay informed of the latest
consultations and participate in any engagement activities.
– Consultation and Stakeholder Information Management System
– Onus to register is on the stakeholder

20. Contact:
Stephanie Hardy
Office of Policy and International Collaboration
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Stephanie.hardy@hc-sc.gc.ca
Or
Catherine Parker
Director General
Cathy.parker@hc-sc.gc.ca

21. Key reference documents
• (Draft) revised Health Canada Guidance Document – Submission and
Information Requirements for Subsequent Entry Biologics
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/consultation/biolog/submission-seb-exigences-pbu-
eng.pdf
• Subsequent Entry Biologics Scientific Advice Meetings Pilot
http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/subsequent-entry-biologics-
produits-bio-ulterieurs-eng.php
• Summary Basis of Decision documents
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/index-eng.php
• Regulatory Decision Summaries
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/index-eng.php
• Submissions under Review
http://www.healthycanadians.gc.ca/drugs-products-medicaments-produits/authorizing-manufacturing-
autorisation-fabrication/review-approvals-evaluation-approbations/submissions-under-review-
presentations-cours-examen-eng.php
• Stakeholder Registry
http://www.hc-sc.gc.ca/ahc-asc/public-consult/stakeholder-intervenants/index-eng.php

22. Chander Sehgal
Director – Common Drug Review and Optimal Use
at CADTH

23. Patients’ Knowledge and
Beliefs about Biosimilars
Durhane Wong-Rieger, PhD
Consumer Advocare Network

24. Patient
Survey
on
Biosimilars
§ WHAT
is
current
status
of
biosimilars?
§ Increasing
number
of
biosimilars
approved
and
available
for
use
§ Increasing
evidence
about
safety,
effec8veness,
and
quality
§ Uncertainty
about
long-­‐term
outcomes
and
interchangeability
§ WHY
were
pa8ents
surveyed
about
biosimilars?
§ Learn
pa8ent
knowledge,
beliefs,
and
opinions
about
biosimilars
§ Iden8fy
sources
of
pa8ent
and
public
informa8on
§ Engage
pa8ents
to
contribute
to
evolving
understanding
of
biosimilars
§ HOW
will
learning
from
survey
be
used
to
engage
pa8ents?
§ Develop
up-­‐to-­‐date
informa8on
accessible
by
pa8ents
and
public
§ Assure
balanced
approach
to
promote
informed
decision
making

25. How was Survey Implemented
§ Canada-wide Web-based survey
§ Directed to existing patient cohort of 2,000+
§ Secondary distribution to patient organizations
and umbrella associations
§ Promoted through Facebook and Twitter
§ Preliminary Findings (May-June 2016)
§ Respondents = 320; Complete survey = 200
§ Conditions = inflammatory, blood disorders,
immune-related, diabetes, cancers, multi-
systemic, lysosomal storage, cardiovascular

26. Biosimilar Information Sources
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Workshop or
education forum
about
biosimilars
Conference,
workshop or
forum that
INCLUDED
information on
biosimilars
Web-based
information
about
biosimilars
Written
materials about
biosimilars
Public media
(newspaper,
magazine, TV,
or radio) about
biosimilars
Information
from healthcare
providers or
healthcare
facility about
biosimilars
Which information sources have you used to learn about biosimilars?
Yes
No
Not Sure

27. Respondents’ Use of Biologics

28. Familiar with Definition of Biosimilars

29. Patient Perceptions of Biosimilars
To what degree do you agree that biosimilars compared to original …?

30. Patient Perceptions of Biosimilars
To what degree do you agree a biosimilar as compared to the original …?

31. Patient Perceptions of Biosimilars
Should government regulator, drug plan, HTA, or payer do following?

32. Attitudes About Use of Biosimilar
Do you agree with statement regarding switching … Avg (1-5)
Same scientific name (INN) implies identical drug 3.3
All biologics should have unique INN or suffix 2.7
Patient should receive exact biologic prescribed 3.1
Patient MAY be switched to biosimilar with consent 3.2
Patient SHOULD be switched if biosimilar lower price 2.1
Patient NOT on original MAY be given biosimilar 3.1
Patient NOT on original SHOULD be given biosimilar 2.7
OK to use biologic for indicators other than approved 2.7
Need monitoring plan to track adverse events 3.5
OK to promote preferential use of biosimilars 1.8
Collect real-world data to update usage guidelines 3.7
Biosimilars save money to allocate to other needs 2.9
1 = disagree completely; 3 = neither agree nor disagree; 5 = agree completely

33. Summary Patient Attitudes re:
Biosimilars - 1
§ Web is most frequent source of information about
biosimilars (65%); healthcare provider least frequent
(25%)
§ More than half now, in past or in future use biologic
medicines; one-fourth will not
§ 2/5 respondents were unfamiliar with biosimilars; 1/5 very
familiar
§ About 3/4 to 4/5 believe biosimilars are different and will
have different adverse effects than originator
§ About 2/5 believe may substitute biosimilar for originator;
about 2/5 believe may NOT substitute
§ About ¼ say okay to extrapolate biosimilar use to other
indications of originator even without clinical trials; about
¼ say not okay to extrapolate

34. Summary Patient Attitudes re:
Biosimilars - 2
§ About ½ agree biosimilar as safe and effective as
originator; about 1/3 disagree
§ About 2/3 agree biosimilar could have a different effect
than originator
§ More than 4/5 agree could have different adverse effects
than originator
§ About 2/5 believe patients should accept a biosimilar if it
is much cheaper than originator; 2/5 believe patients
should not accept on basis of price
§ About 3/5 would be UNWILLING to switch from originator
to biosimilar
§ About 3/5 say it is OKAY to prescribe biosimilar if patient
has no experience with originator

35. Summary Patient Attitudes re:
Biosimilars - 3
§ About 3/5 agree government should approve more
biosimilars
§ One-half say should NOT approve biosimilar if originator
not approved for use in country
§ Almost 9/10 say government (drug plans) should assure
NO interchangeability
§ Almost 8/10 say government (HTA) should NOT
recommend switching from originator to biosimilar
§ Almost 100% say patients have right to informed consent
§ Almost one-half say governments should NOT encourage
switching on basis of “cheaper” cost; about ¼ agree
should encourage switching based on cost

36. Recommendations
¥ Develop and make available to all patients accurate, balanced
and evidence-based information about biosimilars.
¥ Establish means to address patients’ concerns in open and
honest ways.
¥ Provide tools to monitor patient use of biologics that can
track outcomes to specific biologic.
¥ Develop and implement platforms to collect and analyze real-
world evidence to support and update appropriate use
guidelines.
¥ Engage patients as partners in every step of the process

37. Resources
§ Market Access and Uptake of Biosimilars (Steering Group of the Process for Corporate
Responsibility in the field of Pharmaceutical)
http://ec.europa.eu/enterprise/sectors/healthcare/competitiveness/
process_on_corporate_responsibility/platform_access/index_en.htm
§ European Medicines Agency
Biosimilars
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/
document_listing_000318.jsp&mid=WC0b01ac0580281bf0
§ Medicines Safety Monitoring
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/
general_content_000456.jsp&mid=WC0b01ac05801ae8fb
§ Guidance document for patient organisations on EU pharmacovigilance legislation:
http://www.eu-patient.eu/Initatives-Policy/Policy/Pharmaceutical-Package/
Pharmacovigiliance/
§ Patient Organisations’ Resources
The International Alliance of Patients’ Organisations Biosimilars Toolkit
https://www.iapo.org.uk/biosimilars-toolkit
§ National Rheumatoid Arthritis Society (UK) Position Paper on Biosimilars
http://www.nras.org.uk/data/files/About%20RA/How%20is%20RA%20managed/NRAS
%20Biosimilars%20Position%20Paper%20Final.pdf

38. Contact:
Durhane Wong-Rieger
Consumer Advocare Network
www.consumeradvocare.org
416-969-7435
durhane@sympatico.ca