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Quality, Safety and Efficacy of Follow-on Biologics
Teruhide YAMAGUCHIDivision of Biological Chemistry and Biologicals
National Institute of Health Sciences
2009.9.28 London2009.9.28 London
Quality, Safety and Efficacy of Follow-on Biologics
• Current situation of follow-on biologics/biosimilar and Key issues to be discussed
• Key points to ensure the quality, safety and efficacy of Follow-on Biologics
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Regulatory Topics on Follow-on Biologics
• "Guidelines for the Quality, Safety and Efficacy Assurance of Follow onEfficacy Assurance of Follow-on Biologics“ (Yakushoku shinsahatu 0304007 by MHLW / March 4, 2009)
• “Revision of marketing approval application” (Yakushoku shinsahatu 0331015 by MHLW / ( yMarch 4, 2009)
• “Nonproprietary name and brand name of Follow-on Biologics“ (Yakushoku shinsahatu 0304011 by MHLW / March 4, 2009)
Development of Follow-on Protein (Biosimilar Medicines) Products in Japan (Sep. 2009)
Reference Biosimilar Companyproducts products
Approvedproducts products
Somatropin Genotropin Omnitrope Sandoz 2009
Epoetin kappa Jepo JCRUnder reviewing
Under development
Follitropin alpha Filgrastim
Interferon aInterferon b
Insulin
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N
aspirin human Growth Hormone
Biotechnological Products Have Complex Structure
100
94
92
106
34
9
128
184
Helix ⅠHelix Ⅱ
Helix Ⅲ
C189
primary / secondary / tertiary / quaternary structure
heterogeneity
molecular size, charge
posttranslational modification
3847 64
70
155 C165
C53
Helix ⅣC182
C189
C72
posttranslational modification such as glycosylation
heterogeneity in bioengineered structure such as pegylation
biological activity
immunogenicity
Some Biotechnological Products Have Multiple Domains
Each domain has its own function.
A set of relevant functional assays are required.
tissue Plasminogen Activator
FN domain EGF domain Kringle domain
A ti t
Kringle domain
tissue Plasminogen Activator(t-PA)
Serine protease domain
Plasminogen binding domain
Active center
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Biotechnological Products Consist of Multiple Components→Important Issues in Characterization of Follow-on Biologics
Product-related impurities-aggregates-degradation products
Process-related impurities- host cell proteins
Desired Product・heterogeneity (e.g. glycosylation)
Product-related substancesd id t d d t ost ce p ote s
- serum components- infectious agents- purification-process
related impurities
・deamidated products・oxidized products・N/C terminal deleted products
Can Q5E apply the comparability study of follow-on biologics?
Clone selection Production process of reference product is in “Black box”.H h ld l t th
Banking
Characterizations
Seed cell AHow should we evaluate the quality and safety of follow-on products including impurity profile?
Product A
Development of follow-on products
Follow-on product for Product A
Manufacture process change in a single manufacturer
？
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Human Growth Hormone (INN: somatropin)
Brand Name Indications/Cell Substrate Dwarfism Turner's Prader Willi hGH Weight
Innovator’s Products with Multi-indications
/Cell Substrate Dwarfism, Turner s, Prader-Willi, hGH- Weight-syndrome syndrome, deficiency, loss (HIV)
•Genotropin ○ ○ ○ ○/E.coli
•Norditropin ○ ○/E.coli
•Humatrope ○ ○ ○/E.coli
•Saizen ○ ○/CHO cell
•Growject ○ ○/E.coli
Key issues: Can follow-on biologics be approved for the multi-indication?
Quality, Safety and Efficacy of Follow-on Biologics
• Current situation of follow-on biologics/biosimilar and Key issues to be discussed
• Key points to ensure the quality safety• Key points to ensure the quality, safety and efficacy of Follow-on Biologics
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Dossiers of the innovator product Dossiers of the biosimilar product
Manufacturing Process
Dossiers of Follow-on Biologics to be Submitted
To establish stable and robust manufacturing
Manufacturing Process
Characterization of Quality Attributes
Non-clinical studyComparability study
＋
process
To analyze the quality attributes individually
Characterization of Quality Attributes
Non-clinical study
Clinical study
＋Individual study
＋Information
Non-clinical study
Clinical study
Guideline on Follow-on Biologics:Quality, Safety and Efficacy Issues
Published by MHLWMarch 4, 2009
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Contents1. Introduction2. Scope (Well-characterized recombinant protein products)3 G l i i l f th d l t f3. General principles for the development of
follow-on biologics4. Manufacturing process and quality characterization5. Comparability studies on quality attributes6. Specifications6. Specifications7. Non-clinical studies8. Clinical studies9. Post-marketing surveillance10.Glossary
Definition of Follow-on Biologics
A “follow-on” biologic is a biotechnological drug product developed by a company to be comparable to an
d bi t h l d i d d t (h i ftapproved biotechnology-derived product (hereinafter “original biologic”) of a different company.
A follow-on biologics can generally be developed on the basis of data that demonstrates comparability between the two biologics with respect to quality, safety andthe two biologics with respect to quality, safety and efficacy, or other relevant data.
It is recommended to adopt the manufacturing processes which potentially improve safety of the product.
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Scope of Follow-on Biologics (1)The guideline applies to recombinant proteins and polypeptides their derivatives andand polypeptides, their derivatives, and products of which they are components, (e.g., conjugates).
These proteins and polypeptides are produced from recombinant cell cultureproduced from recombinant cell-culture expression systems and can be highly purified and characterized using an appropriate set of analytical procedures.
Decision Products Reasons NotesYes Recombinant
plasma proteins
There is no reason to exclude recombinant plasma proteins from the scope, even though some
Some patients might prefer non-recombinant products. Blood product supply might be affected, even though
Scope of the guideline (2)
proteins the scope, even though some proteins have highly complicated structure.
supply might be affected, even though overlapped product development ensures the consistent supply.
Recombinant vaccines
Well characterized recombinant vaccine can be possibly developed as follow-on biologics.
Vaccine is administrated to healthy humans.Lot-to-lot variation of adjuvant activity is relatively large.
PEGylated recombinant proteins
Conjugates are in the scope as is in ICH Q6B.
Development of PEGylated protein as follow-on biologics might be difficult due to the structural complexity.
No Synthetic peptides
Impurity profile is different from that of recombinant proteins.
Synthetic peptides can be generic drugs, because desired product can be easily defined by structural analyses.
Polyglycans Characterization is difficult. Several polyglycan products have been approved as generic drugs in Japan.
Case by case
Non-recombinant proteins*
Proteins that are highly purified and characterized could be developed as follow-on biologics.
Several urine-derived protein products have been approved as generic drugs in Japan.
* e.g. proteins such as isolated from tissues or body fluids
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General Principles for the Development of Follow-on Biologics (1)As with new biotechnological products, establishment of the well-defined manufacturing process andof the well defined manufacturing process, and extensive characterization studies to reveal the molecular and quality attributes of the follow-on biologics are required.
Demonstration of the high similarity in quality attributes with the reference medicinal product is also requiredwith the reference medicinal product is also required.
Comparability between the follow-on biologics and reference medicinal product should be evaluated based on the data from non-clinical and clinical studies in addition to the data of quality characteristics.
General Principles for the Development of Follow-on Biologics (2)The objective of ICH Q5E guideline is to provide the principles for assessing the comparability of biotechnological /bi l i l d t h h d/biological products where changes are made on manufacturing processes. Manufacturers can compare the both products head-to-head in such a case.
Since the information of innovator’s products are generally not disclosed, approaches by ICH Q5E can not always be applied to the evaluation of follow-on biologicsapplied to the evaluation of follow on biologics.
Based on the concept of Q5E, sponsors intending to develop the follow-on biologics should consider the comprehensive approach including comparability studies and other approaches that utilize public information or existing experiences.
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Development of Manufacturing ProcessIt is necessary to establish the highly consistent and robust manufacturing process.
If the host cell line used for the production ofIf the host cell line used for the production of reference medicinal product is disclosed, it is desired to use the same cell line.
For the establishment and characterization of the cell banks, ICH Q5A, Q5B, Q5D guidelines should gbe referred.
It is recommended to adopt the manufacturing processes potentially improve the safety of the product insofar as these do not affect efficacy.
Optimization of manufacturing process according to the comparability studies (1)
Profiling of sugar chainIEF
0 10 20 30 40 50 60 700
100
1001200 1250 1300
0
10
10
Profiling of sugar chainIEF
RBP
Candidate A of FBP
Time (min)
0 10 20 30 40 50 60 700
0 10 20 30 40 50 60 700
100 1200 1250 1300m/z
0
Some differences
Candidate B of FBP
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Characterization of eluted fractions
Optimization of manufacturing process according to the comparability studies (2)
Optimization of
RBP
Optimization of chromatography
RBP
Drug Product DesignIn principle, it is necessary for the dosage form and route ofdosage form and route of administration to be the same as that of reference medicinal product. Provided that safety and efficacy are
t ff t d it i t ti l f thnot affected, it is not essential for the follow-on biologics to have the same formulation as the reference medicinal product.
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Long-term, real-time, real-condition stability studies are required. The expiration dating of follow-on biologics should be determined
Stability Testing
follow on biologics should be determined based on the data of real-time/real-temperature studies. Since identical storage condition and storage period to the reference medicinal product are not prerequisite a comparison of stability withnot prerequisite, a comparison of stability with reference medicinal product therewith will not necessarily be required.These stability tests should follow the ICH Q5C Guideline.
Comparability Studies on Quality Attributes
In addition to elucidating the quality attributes of the follow on biologics comparability exercisesthe follow-on biologics, comparability exercises about quality attributes between the follow-on biologics and the reference medicinal productshould be conducted. For example, comparability exercises are conducted to examine the following aspects:
(1) Structural characterization and physicochemical properties
(2) Biological activities (3) Others
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D i d
Quality Attributes of Biologics
Desired Product
Product-related impurity
Product Related Substances
HCP etc.
InfectiousAgents
Evaluation of extraction method on active ingredient from product
RBP from marketingredient
Analysis of formulation
ingredientmannitolbuffersalt
Manufacturing of drug products similar to RBP
Drug substance of FBP candidateSB
P
on m
etho
d A
on m
etho
d B
mannitolbuffersalt
FBP candidate
pI
5.0
4.0
DS
of S
Extr
acti
Extr
acti
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Immunogenicity • Non-clinical study can not fully predict
immunogenicity of follow-on biologics in humanhuman.
• Comparative study on immune-reactivity during the repeated toxicity study will provide useful information as follows;– Difference of quality attributesDifference of quality attributes– Effect of antibody production on data
interpretation of toxicity and pharmacological studies
– Impact of antibody on clinical studies
Specifications
Setting of specifications is required principally based on the results of characterization and lotbased on the results of characterization and lot analyses. It also be considered to reflect the results of the comparability studies between follow-on biologics and reference medicinal product appropriately. For this it may be useful to conduct comparability studies using severalto conduct comparability studies using several lots of the products if applicable. In setting the specifications, the ICH Q6B guideline should be followed.
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Non-clinical studies that can ensure the safety for administration to humans should be
f d d l t d i t i iti ti f
Non-clinical Studies
performed and completed prior to initiation of the clinical studies.
Both “comparability assessment” and “individual assessment” are applicable, depending the purpose of the study Fordepending the purpose of the study. For example, comparability assessment may be conducted for pharmacological activity studies, whereas individual assessment is made to address the safety issues on impurities.
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10
64
2
△
●
○
●A2
NG(2)
A1
C1
0.4
10.6
0.2
0.1
2△
●A3NG(1)
0.02
0.040.06
N.Imai, et al; Eur.J.Biochem. 194, 457-462 (1990)
Sialic acid (mol/mol erythropoietin)121086420
△
A7
NG(0) A5
●
● C1; Intact erythropoietinA1~A7; Desialylated erythropoietinsNG(0),(1),(2); De-N-glycosylated erythropoietins
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Follow-on biologics – Effect of heterogeneity on efficacy and PK
pI
RBP
Candidates of SBPA B C
5.0
4.0
ARBP
AUC
A
BCRBP
In vitro activity
B
C
Difference between in vitro and in vivo activities
Tissue Distribution of Radioactivity After a Single Intravenous Administration of Radioiodinated
Control EPO or EPO-bi in Male Rats
20 min 1 hr 4 hrPlasma
Bone Marrow
Kidney
Spleen
Liver
Lung
20 min 1 hr 4 hr
Adrenal
Heart
Blood、86（1995）
■ EPO
■ EPO-bi
0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10
Concentration of radioactivity （ng eq. /mL or g)
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Non-clinical Studies - impuritiesFor product- and process-related impurities, it may be more rational to assess safety on themay be more rational to assess safety on the basis of an established manufacturing process per se and characteristics of impurities than simply to compare impurities of follow-on biologics with reference medicinal products.p oductsIt may be acceptable to compare the toxicity profiles between follow-on biologics with reference medicinal products in spite of difference of impurities.
Desired
Target for comparability study of Follow-on Biologics
P d t R l t d
Desired Product Product-related impurity
HCP tProduct Related Substances
HCP etc.Infectious
AgentsProcess-related impurity could be different between FBP and the innovator products
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Clinical Studies (1)In general, clinical studies are required in development of follow on biologics sincedevelopment of follow-on biologics since the data from quality characterization and non-clinical studies will be insufficient to evaluate the comparability with reference medicinal product.Clinical studies should be designed based on the data of quality characterizations, non-clinical studies and comparability studies.
Clinical Studies (2)Where the data sufficient to assure the comparability in clinical endpoint has been obtained through the clinical pharmacokinetic (PK), pharmacodynamic (PD) or PK/PD studies, further clinical studies could be reduced in some cases.
In general, the well-designed cross-over study should be consider to evaluate the comparability between follow-on biologics and reference medicinalbetween follow on biologics and reference medicinal products.
However, the cross-over study may not be suitable for the long half-life products or products which may cause the antibody formation.
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Clinical Studies (3) Indications• In the case of an originator biologics with more
than one indication• The efficacy and pharmacological effects of the
follow-on have been demonstrated to be comparable to the originator biologics
• In certain case it may be possible to extrapolate from one indication to the other indications of the originator biologics used as the reference product.
Genotropin, Omnitrope Omnitrope OmnitropeIndications in EU in USA in Japan
Approval of multi-indications for follow-on biologics
•Growth hormone deficiency ○ ○ ○ ○in children (CGHD),
•Growth hormone deficiency ○ ○ ○in adult (AGHD),
•Turner syndrome (TS), ○ ○ ○
•Chronic renal insufficiency ○ ○ ○deficiency
Prader-Willi syndrome ○ ○
Short for gestational age ○ ○
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Data from pre-authorization clinical studies normally are insufficient to identify the all potential safety
fil t k ti ill (PMS) f th
Post-marketing Surveillance
profiles, post-marketing surveillance (PMS) of the safety profile including immunogenicity is required.
The specific method and design of the PMS study and risk management plan should be discussed with the regulatory authorities and be submitted g ytogether with the application for approval.
The findings of the PMS should be reported to the regulatory authorities.
Clinical data about Turner syndrome and Chronic renal insufficiency of omnitrope are
PMS for Omnitrope
Chronic renal insufficiency of omnitrope are required during PMS.
The sponsor should analyze adverse effects possibly due to expression of antibodies against either somatropin or host cell proteinagainst either somatropin or host cell protein.
All patient data should be collected for 2 years as PMS.
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Thank you for your attentions!
