國際生物相似性藥品法規及管理簡介
2017.10.19
許芷瑀 技士
食品藥物管理署 藥品組
2
報告大綱
生物藥品與生物相似性藥品基本概念
台灣生物相似性藥品法規管理與審查考量
國際生物相似性藥品管理簡介
適應症外推
上市後藥品可交換性
命名
仿單
Q & A
未來規劃
What are biologic products?
Bigger, and More Complex!!!
Post-translational modification affects bioactivity
• Glycosylation may increase activity or serum half-life
• Lipid attachment may affect membrane localization
• Phosphorylation may active or inhibit kinase.
Complexity of Biologics
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Not only does the translation from mRNA cause differences, but many proteins are also subjected to a wide variety of chemical modifications after
translation. Many of these post-translational modifications are critical to the protein's function.
Chemical medicines are chemicals made by chemists out of other chemicals.
That’s why they are also known as “small molecules” or “chemically-synthesized drugs”
Following the same “recipe” yields exactly the same product.
=
Aspirin
Biologics are grown from living organisms.
A biologic must be manufactured under precise conditions, following many exacting steps, to yield a consistent product.
Biologics are highly sensitive to manufacturing conditions.
Chemical Medicines Are Made ； Biologics Are Grown
Chemical Medicine vs Biologics
Parameter Chemical Medicine
(Small Molecules) Biologics Manufacturing Chemical Synthesis
- predictable
Living organisms (human, animal, microorganism)
- Inherent heterogeneity Active Ingredients Unique, well
defined
Complex mix of heterogeneous proteins and impurities
Characterization Well-defined structures
Limited characterization
Difficult to quantify often multiple Impurities Defined
Standards/Specs Difficult to define and quantify
Stability Stable Unstable; sensitive to external conditions
Immunogenicity Mostly
nonimmunogenic Immunogenic
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What is a Biosimilar Drug?
Generally, a biologic product highly similar to an already licensed biological product (reference product) in terms of quality, safety, purity, potency, activity, efficacy, etc.
Not expected that all structural aspects are identical to reference product
-Unlike small molecule generics where active ingredient is identical
Biosimilar amino acid sequence should match reference product, but there will likely be differences in post translational
modifications.
Despite any differences, biosimilar should behave the same as
reference product.
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“Highly Similar” but not Identical
This is true even if a biologic and its biosimilar start from the same genetic blueprint, in much the same way as identical twins, despite the same genes, have different fingerprints.
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Why Biosimilar is Popular ?
Many blockbuster biologics are now coming off patent, and the market volume worth about 2-4 billion USD.
Biosimilars are expected to relieve the burdens of patients’
medical costs and government’s health insurance budget pressure by offering same effectiveness at lower price than originals.
Relative Effort in Development Pathway
Clinical studies Clinical PK/PD
Nonclinical
Analytical
Goal: To establish safety and effectiveness of a new product
Goal: To demonstrate biosimilarity
New Biologics Biosimilars
CMC: Chemistry, Manufacture, Control P/T: Pharmacology/Toxicology
PK/PD: Pharmacokinetics/Pharmacodynamic
Clinical studies Clinical PK/PD
Nonclinical
Analytical
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Key Concept of Biosimilar Regulation
Non-clinical Quality
Clinical
Comprehensive comparison at quality level will provide a basis for reduction of non-
clinical/clinical data required for approval.
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報告大綱
生物藥品與生物相似性藥品基本概念
台灣生物相似性藥品法規管理與審查考量
國際生物相似性藥品管理簡介
適應症外推
上市後藥品可交換性
命名
仿單
Q & A
未來規劃
Life Cycle Management
Consultation
ADR & Product Defect Reporting Registration
GLP GCP
GPvP IRB
GLP: Good Laboratory Practice GCP: Good Clinical Practice IRB: Institutional Review Board
SUSAR: Suspected Unexpected Serious Adverse Reactions
GMP: Good Manufacturing Practice ADR: Adverse Drug/Device Reaction GPvP: Good Pharmacovigilance Practices GDP: Good Distribution Practice
GVP: Good Vigilance Practice GPP: Good Pharmacy Practice RMP: Risk management plan
Lot release: Each lot must be tested for purity, potency, identity, and sterility
Pre-clinical
Studies IND
Clinical Trial
Postmarket Surveillance Basic
Research Product
Development NDA
Market licensing Production
GDP SUSAR
Reporting Insurance
PICS/GMP
RMP Drug injury relief
GPP
Pre-Market Approval Post-Market Control
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Lot release
Supplement (post-licensure changes, i.e., new indication or facility…)
Guidance for Review and Approval of Biosimilar Products
(2008; amend 2015)
Points to Consider for
Common Technical Documents (CTD) in Review and Approval of Biosimilar Products
(2010)
Guideline for Review and Approval of Biosimilar Monoclonal Antibodies (2013, amend 2015)
Current Regulatory Development
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生物相似性藥品 查驗登記基準
生物相似性藥品查 驗登記技術性資料 審查重點表
生物相似性單株
抗體藥品查驗登
記基準
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生物相似性藥品定義與範疇
定義
生物相似性藥品為生物技術衍生之生物藥品，於 品質、安全及療效，與我國核准之原開發廠商之 生物藥品 ( 或參考藥品 ) 相似。
範疇
以重組胜肽、重組蛋白質為活性成分的生物技術
衍生的藥品。疫苗、致敏原產品、血液或血漿衍
生製劑及其重組替代物，以及如基因或細胞治療
產品等其他未列入前項之生物醫藥產品。
生物相似性藥品查驗登記基準
Content
Anne x
General principle:
proof of similarity with a reference product as the basis approval
Quality Issues:
full dossier plus head-to-head comparison to reference product
Non-Clinical and Clinical Issues:
reduced dossier, head-to-head comparison to reference product
Insulin Somatropin G-CSF EPO INF-a
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Review of Biosimilars in CMC
Regarding quality requirement, identical characteristics is not possible, instead, only similarity could be achieved.
The biosimilar approach is based on a comparability exercise.
Both product-related and process-related characteristics are required.
Minor structural differences in active substance may be acceptable but must be justified.
To generate evidence to demonstrates similarity, using state- of-the-art methods (or analytical tools) is needed.
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Review of Biosimilars in Non-Clinical
CMC profile (quality) is demonstrated comparability or
acceptable similarity….it is acceptable to submit limited non- clinical efficacy & safety studies.
Usually reproductive performance, reprotoxicity &
developmental toxicity, genotoxicity, and carcinogenicity are not required.
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Review of Biosimilars in Clinical
Comparative PK/PD studies could be justified in the same study.
Clinical studies should be designed as equivalence trials and sufficiently powered to detect any difference in efficacy; in limited cases, a non-inferiority design may be used.
The immunogenicity of the biosimilar has to be tested using state-of-the-art methods to ascertain the effect of
immunogenicity on efficacy and safety (usually a 12-month study is expected).
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Review of Risk Management Plan
A comprehensive pharmacovigilance and risk management plan (RMP) is fundamental for all biotherapeutic products since even minor differences in the manufacturing process may affect the efficacy and/or safety profile.
Efficacy similar does not imply safety similar. Pre-approval clinical safety data are insufficient to identify all the potential safety profiles. Therefore, the long-term safety (and
effectiveness) must be monitored on an ongoing basis after marketing approval.
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Approved Biosimilar Products in Taiwan
許可證字號 品名 主成分 適應症
105/12/22 衛部菌疫輸字
第001035號
類希瑪
Remsima® Infliximab
1、克隆氏症：適用於對傳統治療無效之成人中度至 重度活動性克隆氏症，可減輕症狀與徵兆及誘導與維 持臨床緩解；適用於對傳統治療(包含抗生素、引流與 免疫抑制劑)反應不佳之成人活動性瘻管性克隆氏症。
2、小兒克隆氏症：適用於對皮質類固醇及免疫調節 劑(immunomodulators)反應不佳之小兒(6-17 歲)中 度至重度活動性克隆氏症，可減輕症狀與徵兆及誘導 與維持臨床緩解。
3、潰瘍性結腸炎：適用於皮質類固醇和6-
mercaptopurine (6-MP)或azathioprine (AZA)等傳 統治療無效、無法耐受或有醫療禁忌之中度至重度活 動性潰瘍性結腸炎成人病患。
4、小兒潰瘍性結腸炎：適用於對皮質類固醇和6- mercaptopurine (6-MP)或azathioprine (AZA)等傳 統治療無效、無法耐受或有醫療禁忌之中度至重度動 性潰瘍性結腸炎小兒(6-17歲)病患。
104/11/25 衛部菌疫輸字
第000986號
日胰穩注射劑 BASAGLAR®
Insulin
Glargine 成人、青少年及6歲以上(含6歲)之糖尿病
099/03/18
衛署菌疫輸字 第000893號
歐密拓“山德 士”注射液5毫
克/1.5毫升
Omnitrope® Recombinant Somatropin
腦下垂體之生長激素分泌不足所導致之生長干擾
;TURNER'S SYNDROME所導致之生長干擾;PRADER- WILLI SYNDROME所導致之生長干擾;慢性腎臟功能 不足所導致之生長干擾;低出生體重兒Small for Gestational Age(SGA)逾四歲者之生長障礙;成人生長 激素嚴重缺乏之補充療法。
衛署菌疫輸字 第000896號
歐密拓“山德 士”注射液10 毫克/1.5毫升 Omnitrope®
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報告大綱
生物相似性藥品基本概念
台灣生物相似性藥品法規管理與審查考量
國際生物相似性藥品管理簡介
適應症外推
上市後藥品可交換性
命名
仿單
Q & A
未來規劃
Global Regulatory Landscape
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Taiwan/ 2008
Japan/ 2009
Australia/ 2008 South Korea/ 2009
Malaysia/ 2008 Singapore/ 2011
EU/ 2005
Canada/ 2010
Switzerland/ 2008
Saudi Arabia/ 2010 Turkey/ 2008
US/ 2012 (draft)
Brazil/ 2010 Mexico/ 2012
WHO/ 2009
China/ 2015
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Major Biosimilar guidelines
European Medicines Agency (EMA) –11/23/2014
Guideline on Similar Biological Medicinal Products
Food and Drug Administration (FDA) –4/18/2015
Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product.
Health Canada (HC)–11/14/2016
Information and Submission Requirements for Biosimilar Biologics Drugs.
Pharmaceuticals and Medical Devices Agency (PMDA) –4/19/2013
Guideline for the Quality, Safety, and Efficacy Assurance of Follow- on Biologics.
World Health Organization (WHO) –10/19-23/2009
Guidelines On Evaluation Of Similar Biotherapeutic Products.
Follow-On-Biologic (FOB) Biosimilar product (Biosimilar)
Similar Biotherapeutic Products (SBP)
Similar Biological Medicinal Product (Biosimilar)
Subsequent Entry Biologic (SEB) Biosimilar biologic drug (Biosimilar)
Follow-On-Biologic (FOB)
Biosimilars
Biosimilar Terminology 名稱
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定義
EMA (2005)
̶ A biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product .
̶ Similar to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise
US FDA(2012)
̶ A biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components; and
̶ No clinically meaningful differences exist between the biological product and the reference product in terms of the safety, purity, and potency .
WHO (2009)
̶ A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.
台灣(2008)
生物相似性藥品為生物技術衍之藥品，於品質、安全及療效，與我國核准之
原開發廠商之生物藥品 (或參考藥品 )相似。
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Common principles in establishing Biosimilarity
Highly similar between the reference product.
-Mostly in the context of analytical comparability with State-of- the-art technology
Stepwise approach
-To establish the biosimilarityin a sequential order
Totality-of-the-Evidence Approach
-The Biosimilarity based on comprehensive comparability data
Pharmacovigilance (PV) is particularly important
-Limited safety data due to the abbreviated licensure pathway
-Safety profile for extrapolated indication needs to be confirmed -Detect potential differences in safety signals between biosimilars and reference products.28
Stepwise approach
Apply a stepwise approach to data generation and the
evaluation of residual uncertainty in support to
demonstration of biosimilarity .
Stepwise approach is in a sequential order , starting
with a comprehensive physicochemical and biological
characterization. Move onto the next level to address a residual
uncertainty, the extent of the non-clinical and clinical
studies to be performed depend on the level of
evidence obtained in the previous step(s).
Physicochemical characterization
Biological characterizatio
n
Non- clinical
Clinical PK/PD
Clinical S & E trials
CMC
Non-Clinical Clinical RMP Comparative
studies in quality, safety and efficacy of biosimilar in a single disease or specific patient population (indication A).
Approval in indication A
Indication B
Indication C
Indication D
Indication Extrapolation-1
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Reference product has been approved for Indications A, B, C and D.
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Special considerations
Study population
Treatment regimen
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Indication Extrapolation-2
sensitive factors affect immune responses
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Indication Extrapolation may be possible, if
The clinically relevant mechanism of action and/or involved receptors are the same
The PK and bio-distribution in different patient population are justified.
Safety and immunogenicity of biosimilar product have been sufficiently characterized and there are no
unique/additional safety issues expected for the extrapolated indication
Scientific justification must be provided to support extrapolation to other conditions of use
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Indication Extrapolation-3
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Interchangeability-1
Demonstrating Interchangeability With a Reference Product Guidance for Industry (draft) ---on January 2017 by FDA
Interchangeable or Interchangeability means:
the biological product is biosimilar to the reference product;
it can be expected to produce the same clinical result as the reference product in any given patient; and
for a product that is administered more than once to an
individual, the risk in terms of safety or diminished efficacy of
alternating or switching between use of the product and its
reference product is not greater than the risk of using the reference product without such alternation or switch.33
Interchangeability-2
Guideline on similar biological medicinal products ---on October 2014 by EMA
EMA does not regulate interchangeability, switching and substitution of a reference medicine by its
biosimilar. These fall within the remit of EU Member States.
Member States have access to the scientific
evaluation performed by the CHMP and all submitted data in order to substantiate their decisions.
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What’s the difference?
Interchangeability
• A designation given by the regulatory authority after the biosimilar has proven that it produces the same clinical result as the reference product in any given patient.
Substitution
• A process that allow a pharmacist to substitute a certain prescribed product by another equivalent product
Switching
• When a prescribing physician determines (in consultation with the patient) that changing a patient’s treatment is appropriate whether another biologic or biosimilar.
Nonproprietary Naming-1
WHO proposal
To provide a unique identification code (Biological
Qualifier or BQ), distinct from the INN, for all biological substances that are assigned INNs.
The code will consist of four random consonants and an optional two digits as a checksum.
-anonutropin alfa bxsh -anonutropin alfa bxsh08 - anonutropin alfra bx08sh
A combination of the core name and a distinguishing suffix is composed of four lowercase letters.
FDA suggests the proposed suffix be: unique devoid of meaning ,four lowercase letters of which at least three are distinct , nonproprietary attached to the core name with a hyphen, free of legal barriers that would restrict its usage.
FDA
January 2017
Nonproprietary Naming-2
EMA
Biosimilars with the same nonproprietary names as their reference biologics.
Prescription and dispensing controlled by 2D- barcoding and pharmacovigilance by enforcing use of tradename and batch number.
To use the reference product INN but
distinguishes it by adding BS1 and BS2 etc.
PMDA
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Labeling for Biosimilar
Incorporate relevant data and information from the reference product labeling, with appropriate product- specific modifications.
– Indication and Usage
Information and data from a clinical study of a proposed
biosimilar product：only when necessary to inform safe and effective use by a health care practitioner.
– Data from clinical studies designed to support a demonstration of biosimilarity potentially may cause confusion.
Biosimilarity statement
– the product is biosimilar to the reference product
Labeling for Biosimilar Products Guidance for Industry (draft) ---on March 2016 by FDA
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Labeling for Biosimilar
The summary of product characteristics (SmPC) of a biosimilar is aligned with that of the reference
medicine.
When a company does not apply for all the indications of the reference medicine, efficacy data on the additional indications are not included in the biosimilar’s SmPC, however safety data are reflected.
Biosimilarity statement
– Section 5.1 (pharmacodynamic properties) of the SmPC will identify a medicine as a biosimilar
Biosimilar in the EU-Information guide for healthcare professionals ---on April 2017 by EMA
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Q1：對於命名部分，台灣目前除了商品名和學名之外，
有沒有附加其他註記？
A1：目前台灣對命名部分沒有附加其他註記，與歐盟相同。
另外會在藥品許可證上用印「生物相似性藥品」章戳，同 時要求許可證持有藥商於仿單上(藥效學一節)註記生物相 似性藥品等字樣以做區分。
Q & A
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Q2：生物相似性藥品的仿單，是與學名藥一樣複製原廠 藥的仿單嗎？
A2：原則上，生物相似性藥品的仿單須參照參考藥品撰
寫，且使用方法(即包括劑量及給藥方法)及投予途徑應與 參考藥品相同。
若參考藥品適應症超過一種以上，須提出充分的解釋以說 明生物相似性藥品對其宣稱之適應症具備相似的療效和安 全性，必要時，須分別就每種宣稱適應症逐一證明。
Q & A
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Q & A
Q3 ：有關生物相似性藥品的可互換性，台灣這方面是與 歐盟還是美國的規範相似？
A3：台灣目前對生物相似藥品的可互換性，由醫師先與
病人充分諮詢溝通，進行臨床評估後為之。
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報告大綱
生物相似性藥品基本概念
台灣生物相似性藥品法規管理與審查考量
國際生物相似性藥品管理簡介
適應症外推
上市後藥品可交換性
命名
仿單
Q & A
未來規劃
43
Future prospect
Naming
whether the biosimilar should share the reference product’s exact nonproprietary name, or whether biosimilars should have distinct names.
• facilitates substitution/ switching
• public and prescriber acceptance
• adverse event report /Pharmacovigilance
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Triple-Win Situation
Consumer Protection
Industry
Competences Enhancement
Government
Smart
Administration
Win-Win-Win
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