Biosimilars in Europe

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					Biosimilars in Europe
From Approval to Clinical Practice
Biosimilars 2008, G. Washington University, WDC

                                         22 September 2008

Thomas Bols,
Director Government Affairs, Europe
     Biologics differ from chemical drugs
     In molecular properties and complexity of manufacturing

                                                           Biotech drugs                                        Chemical drugs

                   Size                      Large                              Interferon-α2b                                    Small

                   Structure                 Complex                                                                             Simple

                   Stability                 Unstable                                                                            Stable

                   Modification              Many options                                                                  Well-defined

                                             Unique line of living cells
                                                                                                         Predictable chemical process
         Manufacturing                       Impossible to make identical
                                                                                                         Identical copy can be made

                                             Impossible to characterize
         Characterization                    fully due to a mixture of                                   Easy to characterize fully
                                             related molecules

Source: Graphic taken from 2000 Schering-Plough Research Institute/ EuropaBio
     Biosimilars are similar…
     …not identical to original biotech products

               Biosimilars are similar...                                        ....not identical

             Due to the complexity & variability of a biological, the quality profile (and hence the
              clinical profile) is determined by the manufacturing process
             Differences in process are inevitable between different manufacturers
                    Minor differences in process can lead to marked differences in clinical profile

             Biosimilars are not generics
                    Generics are structurally identical to their reference products
                    Biosimilars are not identical to their reference products
             Long terms safety profile has not yet been established (as with all new products)
             Prescribers and patients should be aware of this to ensure appropriate introduction into
              clinical practice
Source: Pictures taken from
Biosimilars are a reality in Europe
But there are still issues to be resolved

              2004     2005     2006    2007     2008     2009

Approval          pathway
standards            EMEA regulatory


Discussion                                       Labelling
on clinical
 practice                                          Naming


Europe recognized uniqueness of biosimilars
Established science-based framework for approval

              Determined new legal pathway to bring
               biosimilars to market
 European          i.e. not the generic pathway

              Finalized guidelines on quality, non-clinical, and
               clinical requirements for biosimilars
                   ie. full quality dossier and appropriate clinical &
                    non-clinical data

   EU law and practice clearly differentiates between biosimilars and
       chemically-derived generics, both legally and scientifically

   EU law stipulates 8+2+1 data protection period for all medicines
      Interchangeability/substitutability is left to Member States
    Overview of EMEA guidelines
    Recognition of difference to generics via scientific & clinical class guidelines

 Application        Topic                         Guideline title

                                Guideline on similar biological medicinal products     Generic standards do not apply

General:                         Guideline on similar biological medicinal products    Similar, but not identical
Applies to all                  containing biotechnology-derived proteins as active    Must justify any differences
biosimilars      Quality
                                             substance: quality issues                 Greater differences require more
                                                                                        clinical data

                                                                                       Efficacy may not be greater or
                                 Guideline on similar biological medicinal products     less
                 Non-clinical   containing biotechnology-derived proteins as active
                 & clinical                                                            Similar safety (not worse)
                                      substance: non-clinical & clinical issues
                                                                                       Similar immunogenic potential

 Specific:       Annexes         EPO          G-CSF          Insulin        HGH        Actual non-clinical and clinical
 Product data                                                                           requirements
 requirements                                                                          Study designs, post-marketing
                 and clinical          More to come: Heparin, Interferon, etc           commitments etc.

In Europe, we have already arrived at the
following situation
Biosimilars approved/positive opinion                                   ...with distinct names
                   Omnitrope (Sandoz)                     •   Some brand names
Two somatropins
                   Valtropin (BioPartners)                •   Some INN + Name manufacturer
                                                          •   Some identical INN (Epo alfa)
                   Abseamed/ Binacrit/ Hexal (Medice/
                   Sandoz/ Hexal)                         •   Some different INN (Epo Zeta, possibly Epo
Two epoetins
                                                              Theta) but reference product is EPO alfa
                   Silapo/ Retacrit (Stada/ Hospira)

                   Ratiograstim/ Filgrastim ratiopharm/
One filgrastim                                                      ...with distinct characteristics
                   Biograstim/ Tevagrastim (ratiopharm
                   x2/ Arzneimittel/ Teva)                • Some with all, others with some indications
                                                          • Some with the same others with different route
Biosimilars rejected/ withdrawn to date                     of administration
                                                          • Some with own data for indication, others
One interferon     Alpheon (BioPartners)                    indications received via extrapolation
                                                          • Differences in dosing
One insulin        Marvel LifeSciences

               Perhaps less relevant for approval as a biosimilar..
          But very important for clinical practice and value discussions

Four open issues in Europe
Clarification needed to ensure patient safety in clinical practice

                                                                                          4) Pharma-
    1) Substitution                  2) Label                     3) Name

 • Automatic/ generic         The label should be        • Naming convention         • Pharmacovigilance
   substitution should not     transparent and              should ensure clear         systems should
   apply to biologics          provide clear                identification              differentiate between
                                                                                        the different product
                               guidance for
 • Inappropriate                                          • Recommend                   to accommodate
   substitution* should                                     approach with               traceability (e.g. to
   be prevented by law         professionals and            common stem and             ensure appropriate AE
   or through appropriate      patients regarding           unique qualifier for        attribution)
   prescription rules          Interchangeability/          each biotech product
                               substitution and
                               biosimilar status

         Issues apply not only to biosimilars, but to all biotech medicines

*Inappropriate substitution = physician not involved in the decision-making process                        -8-
Avoid automatic/ generic substitution & ensure traceability

              Biosimilars are similar but not identical to original product

        Patients may respond differently to a similar but not identical product
                           (e.g. immunogenic response)

   Substitution may have clinical             Repeated switching will confound
    consequences (See factor VIII)              accurate pharmacovigilance

   Automatic or generic substitution          Accurate pharmacovigilance and
    should not apply to biotech                 correct attribution of adverse events
    medicines                                   is vital to trace source of adverse

     Prescription/dispensing policies are a national
     competency, but guidance from EMEA is authoritative
          National authorities regulate drug

                            Law on non-substitutability of
                             biotech medicines
                               French Parliament legislation
                               bans automatic substitution
                               based on precautionary

                            Non-substitutable lists
                               In Spain, biotech drugs
                               maybe included in non-
                               substitutable list

         Many countries have followed
                                                                Attached to individual biosimilar medicine’s European Public
                                                                 Assessment Reports (EPARs)
                                                                Sent to all Regulatory Agencies
                                                                On EMEA website

Source: (c) 2007. The Associated Press
                                                                                                                                - 10 -
Biosimilar products should have transparent and clear labels

Physicians, pharmacists and patients should be aware of the data available
                         to support a medicine

SmPC should be transparent and include the following:
    1. Identify the product as a biosimilar
    2. Identify the reference product
    3. Identify how each indication was approved
    4. Identify the safety and efficacy data generated with the reference
       product (rather than with the biosimilar)
    5. Include safety and efficacy data generated with the biosimilar itself

   “Label” should contain summary of differences to reference product

                                                                               - 11 -
Naming convention
Should consider existing guidance from WHO on clear identification

 WHO’s guidelines on INNs
 1. Aim of the INN is to identify each pharmaceutical substance
 2. INNs are important for clear identification, safe prescription and dispensing of
    medicines to patients
 3. INNs are important for communications and exchange of information
                                                             Safe prescription and           Communication and
        Clear identification
                                                                  dispensing               exchange of information

 • Designed for chemically                              • Prescribing by INN strongly     • INN is crucial in adverse
   derived medicines                                      encouraged in many countries      event reporting

 • No two biotech products are                          • INN often used as signal for    • “ support
   identical                                              substitution                      pharmacovigilance
                                                                                            monitoring, the specific
 • Minor differences can have                           • Similar biotech medicines are
                                                                                            medicinal product given to the
   clinical consequences                                  not interchangeable
                                                                                            patient should be clearly

                    Additionally, brand name not mandatory in EU law for any type of medicine
(1) WHO Publication WHO/PHARM S/NOM 1570, 1997
                                                                                            INN: International Non-proprietary Names
(2) Guideline on Similar Biological Medicinal Products, 30 Oct 2005
                                                                                                                                   - 12 -
Biotech Medicines Should Have a Distinct Name

               Approach                                            Application

   New products = new names                         New chemical or biological drugs
   Identical products = identical names             Small molecule generics
   Similar products = similar, but distinct names   Biosimilars

                 Each biologics produced by a different manufacturer
                           should be given a unique name

                                                                                        - 13 -
Key takeaways

   1.   Biosimilars are not identical to originators
           Poses some unique challenges
           Generic framework and thinking does not apply

   2.   There are still open issues to resolve in Europe
           Substitution
           Labeling
           Naming
           Pharmacovigilance

   3.   US needs to pursue a prudent approach that protects patient safety
        and incentives for innovation
           Robust and science based framework
           Amgen stands ready to participate and offer our expertise in any
            discussions you may have on these complex topics

                                                                               - 14 -
    Seven Biosimilar Approvals In Europe to
            Trade Name                        Common Name                         Biosimilar               Reference               Decision                  Date
                                                 (International                    Sponsor                  Product                                       Biosimilar
                                              Nonproprietary Name)
   Omnitrope                                somatropin                          Sandoz                   Genotropin                Approve             April 12, 2006

   Valtropin                                somatropin                          BioPartners              Humatrope                 Approve             April 24, 2006

   Alpheon                                  Interferon alfa-2a                  BioPartners              Roferon-A                 Reject              June 28, 2006
   Abseamed1                                epoetin alfa                        Medice                   Eprex                     Approve             Aug. 28, 2007

   Binocrit1                                epoetin alfa                        Sandoz                   Eprex                     Approve             Aug. 28, 2007

   epoetin alfa Hexal1                      epoetin alfa                        Hexal                    Eprex                     Approve             Aug. 28, 2007

   Retacrit2                                epoetin zeta                        Hospira                  Eprex                     Approve             Dec. 18, 2007

   Silapo2                                  epoetin zeta                        STADA                    Eprex                     Approve             Dec. 18, 2007

   Insulin Rapid Marvel                     Insulin                             Marvel                   Humulin                   Withdraw            Jan. 16, 2008

   Insulin Long Marvel                      Insulin                             Marvel                   Humulin                   Withdraw            Jan. 16, 2008

   Insulin 30/70 Mix                        Insulin                             Marvel                   Humulin                   Withdraw            Jan. 16, 2008

     1The   EMEA approved three licenses for the same EPO made by Sandoz, with two additional licenses being granted to marketing partners Hexal and Medice Arzneimittel.
     2The   EMEA approved two licenses for the same EPO made by Hospira/STADA
                                                                                                                                                                            - 16 -
Rev. Mar. 4, 2008