Presented by:Dr/Kholoud Mamdouh
Biologicals Marketing Authorization Directorate
Central Administration for Pharmaceutical Affairs www.eda.mohealth.gov.eg
biologicals@eda.mohealth.gov.eg

Pharmaceutical product
Innovator Generic
Biosimilars are not generics
Biological product
Innovator Biosimilar
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Generic
• The applicant is not required to provide the results of preclinical tests and clinical trials if he can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product which is or has been authorised a Member State or in the Union
• A generic medicinal product is defined as a medicinal product that has:
• the same qualitative and quantitative composition in active substance(s) as the reference product,
• the same pharmaceutical form as the reference medicinal product,
• and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
Hybrid
•differ from generic applications in that the results of appropriate preclinical tests and clinical trials will be necessary in the following three circumstances:
•In case were the medicinal product doesn’t fall in definition of a ‘generic medicinal product’
•where the bioavailability studies cannot be used to demonstrate bioequivalence;
•where there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference medicinal product.
Biosimilar
•A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine (the ‘reference medicine’).
•The active substance of a biosimilar and its reference medicine is essentially the same biological substance, though there may be minor differences due to their complex nature and production methods. Like the reference medicine, the biosimilar has a degree of natural variability. When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness.
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Vs
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sameness profile
Quality
Preclinical Complete preclinical studies
Clinical
Innovator
Complete and independant product information
Complete clinical studies
Generic Biosimilar
A generic drug is
identical to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use
Complete and independant product information meet the same specifications as brand
A biosimilar product is similar to a reference biological product in the active substance, dosage form, Strength and route of administration and proved that its quality, safety and efficacy is similar to a reference biological product when prescribed in a claimed indication
Complete and independant product information with comprehensive comparability with reference
Bioequivalence study
Reduced preclinical comparability
-In vitro PD
- In vivo repeat dose toxicity
Reduced clinical comparability
-Phase 1 PK/PD
Phase III
- Immunogenicity
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Aspirin Vs Monoclonal antibody
Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011

Product characteristic
Chemical Biological
Small, simple molecule Large complex molecules,
Higher order structures, post translational modifications
Production Produced by chemical synthesis
Analytical testing Well defined chemical structure
Process dependence
Not sensitive to manufacturing process changes
Identity and purity Often meeting pharmacopeia or other standards of identity
Produced from biological origin
Heterogenous, difficult to characterize
Sensitive to minor changes in manufacturing process
Most have no pharmacopeia monographs
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The Rule in Biologicals
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Guidelines addressing the changes in the manufacturing process for biological product
Guidance for Industry
Comparability Protocols Protein
Drug Products and Biological
Products - Chemistry,
Manufacturing, and Controls
Information
ICH (June 2005)
Comparability of biotechnological/biological products subject to changes in their manufacturing process
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Comparability of biotechnological/biological products subject to changes in their manufacturing process
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Comparability of biotechnological/biological products subject to changes in their manufacturing process
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Guidance for Industry Comparability Protocols Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls
Information
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Eprex formulations
With Human serum albumin (HSA) With Polysorbate 80 (Tween )
Diagnosis EPO antibody mediated PRCA cases
• Unexplained loss of effect
(LOE)
• Anaemia (Hb decreases by about 0.1 g/dl/day)
• Low reticulocyte count (<
10 000/μl)
• Platelets. White blood cells : normal
• Bone marrow (strongly recommended)
– Normal cellularity
– Erythroblasts very rare (< 5
%)
• Positive Epo antibody test
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Immune-response and adverse reactions: PRCA case example Nicole Casadevall - EMA
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The interaction of Tween and the uncoated rubber in pre-filled syringes appears to cause leachates. These leachates have been implicated in causing aggregation of epoetin molecules that then enhance their antigencity.
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Health Authority
EMA
WHO
MHLW(Japan)
HC
KFDA
FDA
SFDA
CDSCO (India)
Date of guidance release
2005
2009
2009
2010
2010
Draft 2012
2012
2012
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• First guide line 2005
• Scope:
In principle , the concept of similar biological medicinal product is applicable to any biological product.
However , in practice , the success of such a development approach will depend on the ability to
characterise the product and therefore to demonstrate the similar nature of the concerned product
• Reference
• Should be licensed in EMA
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Product Name Active
Substance
Abseamed epoetin alfa
Binocrit
Biograstim
Epoetin alfa
Hexal epoetin alfa
Filgrastim epoetin alfa
Filgrastim Hexal Filgrastim
Filgrastim ratiopharm
Filgrastim
Nivestim
Omnitrope
Ratiograstim
Retacrit
Silapo
Tevagrastim
Valtropin
Zarzio
Filgrastim
Somatropin
Filgrastim epoetin zeta epoetin zeta
Filgrastim
Somatropin filgrastim
Authorisation
Date
28 Aug 2007
28 Aug 2007
15 Sep 2008
28 Aug 2007
Manufacturer/Company Name
Medice Arzneimittel Pütter GmbH
& Co KG
Sandoz GmbH
CT Arzneimittel GmbH
Hexal AG
6 Feb 2009
15 Sep 2008
Withdrawn on
20 Apr 2011
8 Jun 2010
12 Apr 2006
15 Sep 2008
18 Dec 2007
18 Dec 2007
15 Sep 2008
24 Apr 2006
6 Feb 2009
Hexal AG
Ratiopharm GmbH
Hospira UK Ltd
Sandoz GmbH
Ratiopharm GmbH
Hospira UK Ltd
Stada R & D AG
Teva Generics GmbH
BioPartners GmbH
Sandoz GmbH
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FDC Act PHS Act section 505 Section 351
(ANDA) process in section
505(j)
Generic drugs pathway described in section
505(b)(2)
Follow on proteins
Ammendment
BPCI Act
Biosimilars
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FDA (Follow on proteins)
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The Agency indicated its intention to issue guidance documents to specifically address human growth hormone and insulin. But, as our knowledge of this issue expanded, we reconsidered our focus and determined it would be more appropriate to initially promulgate guidance that is more broadly applicable to follow-on protein products in general. We are in the process of developing such guidance with respect to products approved under the FDC Act
(updated 7/2009)
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FDA (Follow on protein)
• Hylenex (hyaluronidase recombinant human)
• Hydase (hyaluronidase)
• Fortical (calcitonin salmon recombinant) Nasal Spray
• Amphadase
(hyaluronidase)
• GlucaGen (glucagon recombinant for injection)
• Omnitrope (somatropin
[rDNA origin])
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Omnitrope is the first recombinant human growth hormone product approved through the abbreviated pathway, Specifically, the approval was based on the following:
Physicochemical testing that established, among other things, that the structure of the active ingredient in Omnitrope is highly similar to the structure of the active ingredient in Genotropin;
New non-clinical pharmacology and toxicology data specific to Omnitrope;
Vast clinical experience and a wealth of published literature concerning the clinical effects
(safety and effectiveness) of human growth hormone;
Pharmacokinetic, pharmacodynamic, and comparative bioavailability data that established, among other things, that Omnitrope and Genotropin are highly similar based on pharmacokinetic parameters and pharmacodynamic responses;
Clinical efficacy and safety data from controlled trials comparing Omnitrope to Genotropin and from long-term trials with Omnitrope in pediatric patients; and
FDA's conclusions that Genotropin is safe and effective for the indications for which approval was sought in the Omnitrope application and that Omnitrope is highly similar to Genotropin.
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Scope:
The guidance focuses on therapeutic protein products
Protein means any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.
Reference:
Should be licensed in
US
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(Similar Biotherapeutic Products SBPs)
• Scope:
• Applies to well-established and well-characterized biotherapeutic products such as recombinant
DNA-derived therapeutic proteins.
• Vaccines, plasma derived
products, and their recombinant analogues are excluded from the scope
• Reference:
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Health Canada (Subsequent Entry Biologic SEBs)
• Scope :
• The guidance applies to biologic drugs that contain, as their active substances, well characterized proteins derived through modern biotechnological methods such as use of recombinant
DNA and/or cell culture
• Canadian Guidelines shares the similar concept of the WHO
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• Scope:
Similar to EMA Concept
• Reference: should be a biological product authorized in Korea.
• Preclinical and Clinical aspects
Similar to WHO
• Scope:
• , well characterized proteins derived through modern biotechnological
methods such as use of recombinant DNA technology
• Rerefence:
• Registrered in
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