Wednesday, 20 November, 2013 Latin America Biotherapeutic Conference Day 2

1. International Federation
of Pharmaceutical
Manufacturers & Associations
Biotherapeutic medicines and
pharmacovigilance
Dr Gino Grampp, Amgen
On behalf of IFPMA Biotherapeutics Group
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© IFPMA 2013

2. Agenda
• Setting the scene
– Changing regulations – a brave new world
• Pharmacovigilance challenges related to
biotherapeutics
• Identification and traceability
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3. Pharmacovigilance today
•
•
Systems developing at different rates, with different requirements
– Many countries still without strong pharmacovigilance systems
– INN system for biotherapeutics weakening, different approaches to
naming at national levels
– Need for robust PV systems and consistent approach to naming to
allow countries to leverage global PV data
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. Policy-makers are emphasizing enhanced
pharmacovigilance of biotherapeutics
European Community 2011 PV
Legislation1
FDA is Considering Policies for
the U.S.2
“The Member States shall:
(e) Ensure […] that all
appropriate measures are taken
to identify clearly any biological
medicinal product prescribed,
dispensed, or sold in their
territory…”
“The FDA process for biosimilars
must include product specific
safety monitoring […] and
appropriate strategies must be
developed to ensure the
implementation of robust,
modern pharmacovigilance
programs for biologics.”
1. Article 102(e) of the Medicinal Products Directive 2011/83/EU, as amended by Directive 2010/84/EU.
2. Kozlowski S et al. N Engl J Med. 2011;365:385-388.
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5. Challenge 1: Biotherapeutics differ from
chemically-synthesized molecules in both
complexity & sensitivity
Biotherapeutics
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Small Molecules
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;
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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.
© IFPMA 2013

6. Challenge 2: Immunogenicity
• One of the key factors that distinguishes biotherapeutic
medicines from low-molecular-weight pharmaceuticals is their
capacity to elicit an immune response
• Immunogenicity is the production of host antibodies directed
against a therapeutic (anti-drug antibodies, ADA)
• Rates of immunogenicity vary by product and condition of use
(from <1% to >50%)1,2
• ADAs may have no clinical impact, may impact bioavailability,
or may impact safety and efficacy1,2,3
3.
Koren, E., et al. (2002). “Immune Responses to Therapeutic Proteins in Humans - Clinical Significance, Assessment and Prediction.” Current Pharmaceutical
Biotechnology 3(4): 349-360.
Purcell, RT and Lockey, RF. (2008). “Immunologic Responses to Therapeutic Biologic Agents.” Journal of Investigational Allergololgy & Clinical Immunology
8(5): 335-342
Chirmule, N., et al. (2012). "Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy." The AAPS Journal 14(2): 296-302.
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1.
2.
© IFPMA 2013

7. Challenge 3: Complex pharmacology
• Complex biotherapeutics (e.g. monoclonal antibodies) can
modulate immunological functions through multiple mechanisms
• 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)
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Hansel et al, Nat Rev Drug Discov. 2010
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8. Challenge 4: Limited predictability of
analytical and preclinical to clinical
Analytical and preclinical studies cannot reliably predict
immunogenicity, pharmacology or safety of biotherapeutics
• Immunogenicity: currently animal models cannot predict clinical
immune response to impurities (e.g. protein aggregates)1,2
• Pharmacology: animal models cannot reliably predict structural
effects on pharmacology (PK and PD)3
• Safety: Off-target and immunomodulatory effects are often species
specific
– Eg. Cytokine storm occurring in healthy volunteers treated with the superagonist
anti-CD28 monoclonal antibody TGN1412 (TeGenero)4
1.EMA Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use
2. Ponce et al. Regulatory Toxicology and Pharmacology 54 (2009) 164–182
3. Carter. Nat Rev Immunol. 2006;6:343-357.
4. Sathish et al. Nat Rev Drug Disc. 2013;12:306-324
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9. Challenge 5: Different regulatory pathways
Originator
Biotherapeutic
• Novel product, generally
with patent protection
• Marketing authorisation
through full regulatory
dossier
Similar
Biotherapeutic
Product (SBP)
• Product highly similar to
an originator
biotherapeutic that has
already been authorized
(reference medicinal
product)
• Subject to a tailored
regulatory data package
establishing biosimilarity
through comprehensive
comparability exercise
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Non-comparable
Biotherapeutic
• Product that is not
approved in accordance
with the WHO SBP
guidelines, e.g.
• Product developed on
its own and not directly
compared and analyzed
against a licensed
reference product
• May or may not have
been compared
clinically
• Can be subject to
regulatory approval, but
in some settings of a
more abbreviated
nature
• Products with unclear
approval standards
© IFPMA 2013

10. What is an SBP (aka “biosimilar”)?
•
As their name implies, SBPs are “similar” but not identical versions of their innovative
reference biotherapeutic product (RBP)
•
Whereas producing generic versions of off-patent chemically-synthesized medicines
is relatively easy, producing an SBP is far more complicated due to the complex
molecular structure and the unique manufacturing process required for
biotherapeutic medicines
•
Due to their manufacturing process and complexity, all SBPs differ from the
originator product and from each other and therefore regulatory assessment should
ensure that the inevitable differences do not lead to clinically meaningful differences.
Original
Biotherapeutic
1.
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SBPs
Neiderwieser D, Schmitz S. Biosimlar agents in oncology/haematology; from approval to practice. Eur J Haematol. 2011 Apr;86(4):277-88
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11. Different regulatory pathways Implications for pharmacovigilance
•
•
Many countries now have regulatory pathways for biologics and biosimilars which are
aligned with WHO related guidelines
– However, some jurisdictions have stand alone pathways defined differently
– For example, stand alone pathways for related biologics, but without comparability
This results in multiple sources of biotherapeutics in use for the same treatment,
some with the same INN
–
•
E.g. Interferon beta-1a, interferon beta-1b
Biotherapeutics using the same INN could have
– Different posology
– Different indications
– Different safety profiles
How to identify and trace the medicine which any given
patient has received?
 Identification
 Records
 Physician and patient awareness
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12. Comprehensive pharmacovigilance and
risk management planning needed for
biotherapeutics
• Even minor differences in the manufacturing
process may affect the efficacy and/or safety profile
– Originator Products
– SBPs may have potential for different safety profile than originator
– 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.)2
• Biotherapeutics often used for chronic treatment
– Switching therapies can confound pharmacovigilance,
especially in the case of latent immunogenicity2
1. Wiese M et al. Biosimilars – why terminology matters. Nat. Biotech. 2011;29:690-693
2. Wieser C, Rosenkranz A. Clin. Kidney J. 2013;6:164–182
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13. Example: Important differences in
Interferon beta-1a
•
Published reports show differences in purity and potency among originator and
non-comparable versions of interferon beta-1a
•
Recall non-comparables have not been assessed through WHO-aligned SBP
pathway
Purity by SDS-PAGE
Potency by In vivo Bioassay
Originators
Non-comparables
Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012
and Adapted from Meager et al. J of Interferon and Cytokine Research 2011;31:383-392
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14. Do interferon beta-1a differences matter?
Interim analysis of an observational study
• MATRIX phase 4 study performed in 2 Latin American countries
comparing antibodies (NAbs), PD markers, and treatment-related events
in originator (A) and non-comparable (B) IFN-beta
• Enrolment targets: 90 MS patients per arm, with 1-3 years prior exclusive
use of either A or B
Some study findings:
• Low enrolment due to common
pharmacy substitution of (B) for (A)
• NAbs not detected – probably due to
low patient numbers
• PD marker higher in cohort A
(P<0.01)
• Flu like symptoms higher in cohort A
(P<0.01)
Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012
Abstract by C. Cuevas at 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 10-13 October 2012, Lyon, France
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15. Traceability
Systems should encourage recording details beyond INN
(e.g. brand name, unique identifier, batch number, etc)
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16. IFPMA supports the goal of the INN
system
•
IFPMA continues to share WHO's goal in preserving the objectives of the INN
system:
•
•
•
•
Unique and universally-available designated name for each active substance to be marketed
as a pharmaceutical
Clear identification; and
Safe prescribing and dispensing
Biotherapeutic medicines need to be identifiable throughout the prescribing
and dispensing processes to promote patient safety
•
•
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In practice this is not occurring with the current INN system
IFPMA welcomes WHO action on this issue to promote a globally harmonized &
distinguishable naming system for biotherapeutics to promote clear identification and
effective track-and-trace of each distinct biotherapeutic medicine
•
IFPMA supports publication of a proposal for implementation of a distinguishable INN for
© IFPMA 2013
all biotherapeutics, including a unique product identifier

17. In Summary
• Due to their unique product characteristics and
practices in prescribing and use, all biotherapeutics –
originator, SBPs and non-comparable biotherapeutics –
require comprehensive pharmacovigilance
guidance and systems
• Regulatory authorities can support effective pharmacovigilance
through:
Nomenclature
1. Identification
Brand name
prescribing and/or
distinguishable INN for
biotherapeutics
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Systems
Advocacy
2. Reporting & analysis
3. Build Support
Spontaneous reporting;
Multiple identifiers
Periodic reports
Safety signals identified,
explored
Education;
Active participation with
stakeholders
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18. International Federation
of Pharmaceutical
Manufacturers & Associations
Thank you!
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19. Industry support for unique identifier
Presented by IFPMA at Open Session to Stakeholders: 57th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances, October 22, 2013

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 products
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© IFPMA 2013