Embed Size (px)
Citation preview
Introduction to Biosimilars
Biologicals Marketing Authorization DirectorateCentral Administration for Pharmaceutical Affairs
Presented by:Dr/Kholoud Mamdouh
Biosimilar concept (Q,S and E pov)
2
Pharmaceutical product
Innovator Generic
Biological product
Innovator Biosimilar
Biosimilars are not generics
WHY
EMA concept
3
EMA concept
Generic• The applicant is not required to provide the results of pre-clinical 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 pre-clinical 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.
4
Similar Versions
5
Generic Vs
Biosimilar
Generic Vs Biosimilar
6
Innovator Generic Biosimilar
sameness profile
A generic drug is identical to a brand name drug in dosage form, safety, strength,
route of administration,
quality, performance characteristics and
intended use
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
Quality Complete and independant product
information
Complete and independant product
information meet the same
specifications as brand
Complete and independant product information with
comprehensive comparability with reference
Preclinical
Complete preclinical studies
Reduced preclinical comparability-In vitro PD
- In vivo repeat dose toxicity
Clinical Complete clinical studies
Bioequivalence study
Reduced clinical comparability-Phase 1 PK/PD
Phase III- Immunogenicity
Chemical Vs Biological
• Aspirin Vs Monoclonal antibody
Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011
Chemical Vs Biological
Chemical BiologicalProduct
characteristicSmall, simple
moleculeLarge complex
molecules, Higher order structures, post
translational modifications
Production Produced by chemical synthesis
Produced from biological origin
Analytical testing
Well defined chemical structure
Heterogenous, difficult to characterize
Process dependence
Not sensitive to manufacturing
process changes
Sensitive to minor changes in
manufacturing process
Identity and purity
Often meeting pharmacopeia or
other standards of identity
Most have no pharmacopeia monographs
8
Product is the process
9
The Rule in Biologicals
The product is the process
Guidelines for changing the process
10
Guidelines addressing the changes in the manufacturing process for biological
product
FDA (April 1996)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
Comparability of biotechnological/biological products subject to changes in their manufacturing process
11
Comparability of biotechnological/biological products subject to changes in their manufacturing process
12
Guidance for Industry Comparability Protocols Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information
13
Problems issued from changing process of Epotin alfa
14
Eprex formulationsWith 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
Change in formulation
15Immune-response and adverse reactions: PRCA case example Nicole Casadevall - EMA
Change in formulation continue
16
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.
Biosimilars guidance world wide
17
Biosimilars guidance world wide
18
Health Authority Date of guidance releaseEMA 2005
WHO 2009
MHLW(Japan) 2009
HC 2010
KFDA 2010
FDA Draft 2012
SFDA 2012
CDSCO (India) 2012
EMA (Biosimilars)
19
• 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
Approved EMA Biosimilar Products
20
Product Name Active Substance
Authorisation Date
Manufacturer/Company Name
Abseamed epoetin alfa 28 Aug 2007 Medice Arzneimittel Pütter GmbH & Co KG
Binocrit epoetin alfa 28 Aug 2007 Sandoz GmbHBiograstim Filgrastim 15 Sep 2008 CT Arzneimittel GmbHEpoetin alfa Hexal
epoetin alfa 28 Aug 2007 Hexal AG
Filgrastim Hexal
Filgrastim 6 Feb 2009 Hexal AG
Filgrastim ratiopharm
Filgrastim 15 Sep 2008Withdrawn on 20 Apr 2011
Ratiopharm GmbH
Nivestim Filgrastim 8 Jun 2010 Hospira UK LtdOmnitrope Somatropin 12 Apr 2006 Sandoz GmbHRatiograstim Filgrastim 15 Sep 2008 Ratiopharm GmbHRetacrit epoetin zeta 18 Dec 2007 Hospira UK LtdSilapo epoetin zeta 18 Dec 2007 Stada R & D AGTevagrastim Filgrastim 15 Sep 2008 Teva Generics GmbHValtropin Somatropin 24 Apr 2006 BioPartners GmbHZarzio filgrastim 6 Feb 2009 Sandoz GmbH
FDA (Biosimilars/Follow-on protein)
21
(ANDA) process in section
505(j)
pathway described in
section 505(b)(2)
ABBREVIATED APPROVAL PATHWAYS
PHS ActFDC Act
section 505 Section 351
Generic drugs
Follow on
proteins
Ammendment BPCI Act
Biosimilars
Follow-On Protein Products: Regulatory and Scientific Issues Related to Developing
22
FDA (Follow on proteins)
23
Sept 2004Feb 2005Dec 2005
FDA (Follow on proteins)
24
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)
Approved follow-on proteins in FDA
25
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])
Case Study: Omnitrope
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.
26
Omnitrope is the first recombinant human growth hormone product approved through the abbreviated pathway, Specifically, the approval was based on the following:
FDA (Biosimilars)
27
Scope:The guidance focuses on therapeutic protein productsProtein 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
WHO (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:
28
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
29
Korean FDA (Biosimilars)• Scope:
Similar to EMA Concept• Reference:
should be a biological product authorized in Korea.
• Preclinical and Clinical aspectsSimilar to WHO
30
• Scope:• , well characterized
proteins derived through modern biotechnological methods such as use of recombinant DNA technology
• Rerefence: • Registrered in
CDSCO (Indian) (Similar Biologic)
Thank You
