This document discusses pharmacovigilance challenges related to biotherapeutic medicines. It notes that biotherapeutics differ from chemically synthesized molecules in their complexity and sensitivity, posing challenges like immunogenicity and exaggerated pharmacology. Different regulatory pathways for biotherapeutics also require comprehensive pharmacovigilance planning. Effective pharmacovigilance requires identifying biotherapeutics, thorough record keeping and reporting, and ongoing safety monitoring due to factors like interchangeability of products and the potential for different safety profiles. The International Nonproprietary Name system also presents challenges for distinguishing biotherapeutics.

1. International Federation
of Pharmaceutical
Manufacturers & Associations
Pharmacovigilance Aspects of
Biotherapeutic medicines:
Nowadays and Perspectives
Dr Thomas Schreitmueller, F. Hoffmann - La Roche
On behalf of IFPMA Biotherapeutics Group
16 May 2013 © IFPMA 20131

2. Agenda
• Setting the scene
– Changing regulations – a brave new world
• Pharmacovigilance Challenges related to Biotherapeutics
– Biotherapeutics differ from chemically-synthesized
molecules
– Immunogenicity
– Exaggerated Pharmacology & Rare Events
– Different regulatory pathways
• Traceability
• Conclusions
16 May 2013 © IFPMA 20132

3. Pharmacovigilance today
• Systems developing at different rates, with different requirements
– Many countries still without strong pharmacovigilance systems
– INN system weakening, different approaches to naming at
national levels
• Focus on the development of comprehensive pharmacovigilance
systems including:
– Need to establish basic pharmacovigilance guidance to ensure
patient safety
– Improving identification, naming of products, record keeping
– Increased emphasis on robust adverse event
collection/reporting, surveillance, signal detection and evaluation
– Focus on risk in context of benefit
• Important to take the entire prescription/dispensing/using/ADR reporting chain
into consideration for traceability
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4. New pharmacovigilance legislation adopted in the EU in
December 2010 will promote and protect public health and
save potentially thousands of lives each year by:
•strengthening the European system for monitoring the
safety and use of medicines
•clarifying and simplifying tasks for the parties involved;
•improving decision-making procedures and reducing
administrative costs
•strengthening communication and transparency on the
safety of medicines
Patient Safety
Changing Regulations
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5. A brave new world of changing regulations:
Understanding benefit-risk
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More
Defined
Uncertain
Phase 3
Trial
Population Label Population
Off-label & Noncompliant
Population
Optimize
Individualized
Population
Personalized
Health Care
(biomarker,
Bioimaging, …)
Benefit/Risk
Efficacy-Effectiveness Gap
Lack of
communication
Lack of
external validity
How to Best
Manage This
Transition?
Benefit Risk Management Plans
Adapted from Thomas Lundgrenn (DIA QPPV Forum, 17-18 April 2013)

6. Challenge 1: Biotherapeutics differ from
chemically-synthesized molecules in both
complexity & sensitivity
Image Source: Tim Osslund photographer (Amgen staff); Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time. Images
not to scale.
1.Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework Br J Clin Pharmaco l.
2007;65:619-620;
2.Roger SD. Nephrology. 2006;11:341-346
3.Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56.
Biotherapeutics Small Molecules
6 © IFPMA 201316 May 2013

7. • One of the key factors that distinguishes both
biotherapeutic and biosimilar medicines from low-
molecular-weight pharmaceuticals and generic drugs is
their capacity to elicit an immune response
• Immunogenicity is the production of host anti-bodies
directed against a therapeutic (anti-therapeutic
antibodies, ATA = anti-drug antibodies, ADA)
Challenge 2: Immunogenicity
16 May 2013 © IFPMA 20137
Chirmule et al, The AAPS Journal 2012

8. Approaches to address
Immunogenicity
16 May 2013 © IFPMA 20138

9. Areas Potential clinical outcome
Safety • Hypersensitivity reactions
• Receptor signaling related to cross-linking
• Neutralizing activity of endogenous
counterpart
Efficacy • Neutralization
• Impact PK
• Change in biodistribution
None • Despite generation of antibodies, no
discernible impact
Potential Consequences of
Immunogenicity
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10. No predictability of Immunogenicity
from preclinical to clinical
• Immunogenicity - The immunogenicity of
mAbs is complex and there are a number
of often poorly understood factors which
make it difficult to predict with any
certainty whether a therapeutic or
diagnostic monoclonal antibody is likely to
provoke a clinically relevant immune
response*
16 May 2013 © IFPMA 201310
* EMA Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use

11. Challenge 3: Exaggerated Pharmacology
11
Hansel et al, Nat Rev Drug Discov. 2010 16 May 2013 © IFPMA 2013
• The nature of safety problems identified after approval for
biologicals is often related to the immunomodulatory effect
e.g infections (Giezen et al. JAMA 2008)
• Adverse events are related to exaggerated pharmacology,
e.g TB with Infliximab (Giezen et al, Drug Safety 2009)
11

12. Exaggerated Pharmacology
Safety Issue Explanation
tuberculosis with the use of
tumour necrosis factor (TNF)-a
inhibitors, especially Infliximab
TNFa has a role in the immune
response to the mycobacteria
responsible for tuberculosis.
Inhibition of TNFa will lead to an
increase of the activity of the bacilli
and cause disease
dramatically increased incidence of
pure red cell aplasia in patients
treated with one particular
formulation of recombinant human
epoetin
immunogenic response to
endogenous
molecules, which occurred
following changes in the
manufacturing of epoetin alfa
Giezen et al. Drug Safety 2009
16 May 2013 © IFPMA 201312

13. Challenge 4: Different regulatory pathways
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14. Comprehensive pharmacovigilance and
risk management planning needed for
all biotherapeutics
• Even minor differences in the manufacturing
process may affect the efficacy and/or safety
profile
– Innovator Products
– SBPs may have potential for different safety profile than
innovator
– Non-comparable biotherapeutics - different safety and efficacy
profiles compared to other biotherapeutics of the same product
class possibly due to lack of comparability information, i.e.
unknown whether and which physicochemical differences exist
(Weise, M., et al.)
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15. Different regulatory pathways
Interchangeability/Substitution
• Not all products will be approved for all
indications
• Automatic substitution of biological products
is not compatible with high levels of patient
safety
• Right of the prescriber (physician) and of the
patient to choose appropriate product based
on proper and transparent information
16 May 2013 © IFPMA 201315

16. Different regulatory pathways
Importance to “track & trace”
• Mix of biotherapeutics in use for the same
treatment, some with the same INN
• Biotherapeutics with the same INN could have
– Different posology
– Different indications
How to track and trace the medicine which any
given patient has received?
 Identification
 Records
 Physician and patient awareness
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17. Acknowledged by the regulators: Increased
emphasis on identification and tracking of
biotherapeutics in pharmacovigilance systems
Article 102(e) of the Medicinal Products Directive 2011/83/EU, as amended by
Directive 2010/84/EU, deals with the identification of medicinal products when
reporting adverse events. Article 102(e) provides clarification specifically for
biological medicinal products.
The Member States shall:
(e) Ensure, through the methods for collecting information and where necessary
through the follow-up of suspected adverse reaction reports, that all appropriate
measures are taken to identify clearly any biological medicinal product
prescribed, dispensed, or sold in their territory which is the subject of a
suspected adverse reaction report, with due regard to the name of the medicinal
product, in accordance with Article 1(20), and the batch number [Emphasis added].
Example: New EU Requirement in EU
GVP Module VI requires MAH to follow up until batch number,
brand name and active substance are known
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18. Traceability
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19. Issues in practice also emphasize
importance of PV for biotherapeutics
• Biotherapeutics often used for chronic
treatment
– Switching therapies
• Physician and patient awareness
• PV system requirements – necessary details to record
beyond INN (e.g. brand name, unique identifier, batch
number, etc)
– Implications for effective pharmacovigilance
• Frequency of switches
• Managing track and trace, analysis
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20. Tracking and tracing
biotherapeutics – challenges for the
INN system
• INN plays a central role in:
– National pharmacovigilance and traceability systems
– National systems for substituting medicines
• Limited control over use of existing INNs
– Applicant decides if new INN wanted/required
– If existing INN is chosen, National Regulators need to ensure
implementation of WHO naming system
• Under current WHO criteria, possible for multiple
biologics to have the same INN with different clinical
characteristics
• As a result: no clear INN differentiation between
similar products22 16 May 2013 © IFPMA 2013

21. In Summary
• Due to their unique product characteristics and practices
in prescribing and use, all biotherapeutics – innovator,
SBPs and non-comparable biotherapeutics – require
comprehensive pharmacovigilance guidance and
systems
• Effective, global pharmacovigilance for patient safety
requires that we:
1. Identify
Naming,
distinguishable
INN
2.
Recordation
/Reporting
Spontaneous
reporting,
Periodic reports
Robust data
Patient Records
3. Monitor and Assess
Safety signals identified, explored
23 © IFPMA 201316 May 2013

22. International Federation
of Pharmaceutical
Manufacturers & Associations
Thank you!
16 May 2013 © IFPMA 201324