yvonne khoo, ph.d national pharmaceutical control bureau
TRANSCRIPT
*The opinions expressed by the presenter do not always represent the opinions of NPCB
Yvonne Khoo, Ph.D
National Pharmaceutical Control Bureau,
Ministry of Health Malaysia
Subang Jaya, 15th November 2015
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Aim of this Talk….
The Message
• Differences between biotherapeutics and chemically synthesised medicines
• Scientific and regulatory challenges in development and registration of biosimilars
• Malaysian perspective on biosimilar regulation
• Important considerations on clinical use of biosimilars
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Originators vs. Biosimilars
BIOTHERAPEUTICS
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A medicine whose active substance is made by or derived from a living organism and may
be produced by biotechnology methods
Biotherapeutic
5 Ref.: NPCB, Drug Registration Guidance Document (DRGD), revised July 2015. Available at: http://portal.bpfk.gov.my/index.php/guidelines-central
Generally the product that was first authorised worldwide for marketing, normally as a patented product, on the basis of the documentation of its
efficacy, safety and quality, according to requirements at the time of authorisation
Originator
6 Ref.: WHO definition of generics. Available at: http://gabionline.net/Generics/General/WHO-definitions-of-generics
A new biological medicinal product developed to be similar in terms of quality, safety and efficacy to an
already registered, well established medicinal product
Biosimilar
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Ref.: NPCB. Guidance Document and Guidelines for Registration of Biosimilars in Malaysia. August 2008. Available at: http:portal.bpfk.gov.my/images/Guidelines_Central/Guidelines_on_Regulatory/GUIDELINES%20FOR%20REGISTRATION%20OF%20BIOSIMILAR%20(1).pdf
QUESTION: Are Biosimilars different from Originators?
• YES
• “Reference Biotherapeutic Product, RBP”
• Similar, NOT identical
• Biosimilar, NOT bio-generic
• Biosimilars are intended to be used at the same doses and dosing regimens to treat the same disease as their RBPs
• Philosophy of biosimilars: comparability; science 8
Complexity of Biotherapeutics Amino acid
sequence
Protein folds
Higher order
structure
Cloning & Protein expression
Cell expansion
Protein recovery
Purification
9 Figure adapted from Dranitsaris G, et al., Invest. New Drugs, 2013; 31: 479-87
QC & Stability
Why Develop Biosimilars?
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End of patent protection for
originators
Market share of blockbuster
biologics
Special considerations
in product registration
Potential cost saving to
increase access to medicines
Biosimilar Registration Malaysian Perspective
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Why Not Register as Bio-generics?
• Quality – Complexity – Size & structure – Manufacturing process
• Efficacy – Potency • Safety – Immunogenicity
- “unwanted immune response”
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Factors Influencing Immune Responses Against Therapeutic Proteins
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PATIENT
Genetic
Age
Disease
Concomitant Treatment
Duration & route of treatment
Previous exposure
PRODUCT
Protein structure
Formulation
Aggregation
Impurities
Ref.: EMA CHMP: Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (2007)
Potential Clinical Consequences of Immunogenicity
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SAFETY
Infusion-related
reactions
Delayed hypersensitivity
Cross-reactivity
EFFICACY
Altered pharmaco-
kinetics
Loss of efficacy
Ref.: EMA CHMP: Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins (2007)
Registration of Biosimilars in Malaysia
• Legal framework:
– Sale of Drugs Act 1952
– Control of Drugs and Cosmetics Regulations 1984
• NPCB:
– Guidance Document and Guidelines for Registration of Biosimilars in Malaysia (2008)
• Biosimilar product evaluation & registration at NPCB:
– Biologic Product Registration Section
– Centre for Quality Control [QC]
– Centre for Compliance & Licensing [QA]
– Centre for Post-Registration [Risk management]
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Principles of Regulation
• Evaluated as new biological products • Generic approach is scientifically not sufficient • Additional nonclinical and clinical comparability data required
Ref.: Abas A, Biologicals 2011; 39: 339-42
The world turned upside down
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Clinical studies
Clin. pharmacology
Nonclinical
Quality
Novel Biologic
Clinical studies
Clin. pharmacology
Nonclinical
Quality & Comparability
Biosimilar
Regulatory Evolution of Biosimilars
Principles of regulation: • Comparability vs. Reference Biotherapeutic Products
(RBPs)
• Stepwise comparison on quality characteristics, safety, PK/PD and efficacy
• Orthogonal analytical methods, based on “state-of-the-art” technologies
Challenges: • Proprietary process
• Process changes
• Source & availability of RBPs
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Regulatory Experience in Malaysia
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Active substance Product brand name Company
Somatropin SciTropin Sandoz
Epoetin alfa Binocrit Sandoz
Epoetin zeta EPO STADA Stada
Filgrastim
Zarzio Sandoz
Nivestim Hospira
Recombinant Human Insulin
Insugen Biocon
Infliximab Remsima
Celltrion
Abas A and Khoo YSK, GaBI Journal 2014; 3(4): 193-8 [updated]
Table: Biosimilar products registered in Malaysia (2010-2015)
Case Study on EPOs
• Recombinant human EPO displaced RBC transfusion in kidney failure patients (approved in the late ‘80’s)
• Antibody formation against non-self and self EPOs causing neutralisation of all EPOs in the body – Rare adverse event: Pure red-cell aplasia (PRCA)
– Surge of cases (1998-2003) [Casadevall N, et al., 2005]
– Implication on approval of biosimilar EPOs
• THAILAND’S EXPERIENCE WITH PRCA – 14 copy EPOs products registered as generics by 2009
[Praditpornsilpa K, et al., 2011]
• Malaysian Adverse Drug Reaction Advisory Committee (MADRAC)’s advice
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Important Considerations in Clinical Practice
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What’s in a name?
• WHO International Non-proprietary Name (INN) – Suitable for biosimilars (as for generics)?
• Malaysia – INN + brandname, until further decision by WHO
• Pharmacist:
– Dispenses as prescribed
– Records Brandname, manufacturer, batch no.
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What’s in a name?
• Advice to Physicians:
– Prescribes by INN + Brandname
– Factors to consider in substitution
• Previously-treated vs. untreated patients
• Clinical data on interchangeability
• Treatment monitoring
• Advice to Patients:
– Learn to recognise product
– Aware of biosimilars
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Labelling
• On the product label for Malaysian market: CRITERION: “A clear indication that the medicine is a biosimilar of a specific reference product.” E.g.: “Binocrit® is a biosimilar of Eprex®”
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Labelling
• In the Malaysian biosimilar package insert: CRITERION: “Should clearly and prominently state that the biosimilar is not interchangeable or substitutable with the reference product.”
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Automatic Substitution
• “Levels of responsibility” in allowing/using biosimilars need to be defined – Regulatory agency? Doctors? Pharmacists?
• Automatic substitution at pharmacy level is not allowed without interchangeability study data
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Education & Awareness
• Strict licensing requirements
• Prescribing – INN + Brandname (originator/biosimilar)
– Do not switch existing patients (subject to clinical data)
• Dispensing – No automatic substitution
• Identity & traceability – Manufacturer
– Batch number
• Pharmacovigilance – Adverse Drug Reaction (ADR) reporting
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Take Home Message
• Complexity of biotherapeutics: A biosimilar is not identical to its reference biotherapeutic product. It is only similar based on sensitivity limits of current analytical methods
• Malaysia has established a biosimilar registration process based on sound scientific principles and aligned with international standards since 2008 to allow market access only to products of acceptable quality, safety and efficacy
• HCPs need to be aware of integration of biosimilar into therapy, incl. issues on interchangeability, automatic substitution, immunogenicity and pharmacovigilance* [*Role of Pharmacists]
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Reading List for Biosimilars in Nephrology
1. Bogaert P, Lietzan E and Sim L. Biosimilar regulation: important considerations and global developments. Life Sciences Handbook 2011; 1-11.
Background on important considerations in biosimilar regulation; worldwide comparison
2. Weise M, Bielsky M-C, De Smet K, Ehmann F, Ekman N, Giezen TJ, Gravanis I, Heim H-K, Heinonen E, How K, Moreau A, Narayanan G, Kruse NA, Reichmann G, Thorpe R, van Aerts L, Vieminckx C, Wadhwa M and Schneider CK. Biosimilars: What clinicians should know. Blood 2012; 120 (26): 5111-7.
Regulatory perspective on biosimilar products
3. Covic A, Cannata-Andia J, Cancarini G, Coppo R, Frazão JM, Goldsmith D, Ronco P, Spasovski GB, Stenvinkel P, Utas C, Wiecek A, Zoccali C and London G. Nephrol. Biosimilars and biopharmaceuticals: what the nephrologists need to know—a position paper by the ERA-EDTA Council. Dial. Transplant. 2008; 23: 3731-7.
4. Locatelli F and Becker H. Update on anemia management in nephrology, including current guidelines on the use of erythropoiesis-stimulating agents and implications of the introduction of “biosimilars”. The Oncologist 2009;14(suppl1): 16–21.
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