Biosimilars: Issues and Concerns for their Adoption in ... ... 9/30/15 5 Safety Concerns with Biologicals

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  • 9/30/15


    Biosimilars: Issues and Concerns for their Adoption in Health Care?

    Dennis  W.  Raisch,  PhD,  MS,  RPh   Professor    


    §  Maarten  J.  IJzerman,  PhD   §  University  of  Twente,  Health  Technology    and  Services   Research  

    §  Conceptual  framework,  analysis  plan,  interpretaEon  of  results   for  mulE-­‐criteria  decision  analysis  (MCDA)  

    §  Charles  L.  BenneL,  MD,  PhD   §  University  of  South  Carolina  College  of  Pharmacy   §  Post-­‐markeEng  safety  research  in  oncology  

    §  University  of  New  Mexico,  College  of  Pharmacy  

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    Conflict  of  Interests  

    •  Funding  sources  for  studies:   – NaEonal  InsEtutes  of  Health  grants  

    •  NaEonal  Cancer  InsEtute:  R01  CA102713-­‐03A2   •  NaEonal  Cancer  InsEtute:  R01  CA165609-­‐01A1  

    – PaEent-­‐Centered  Outcomes  Research  InsEtute   (PCORI):  CER  1310-­‐08323  

    – Paclitaxel/Docetaxel  Research  funded  by  Abraxis,   Inc.  Funding  ended  in  2010  

    •  No  other  conflicts  to  report  

    Learning  ObjecEves   •  Pharmacists  

    –  Describe  basic  principles  regarding  the  approval  of  biosimilars   –  Contrast  the  key  concerns  regarding  effecEveness,  safety,  and  

    immunogenicity  of  biosimilars   –  Explain  how  biosimilars  may  lower  costs  of  treatments   –  Describe  the  relaEve  importance  of  post-­‐markeEng  studies  of  efficacy,  

    safety  and  immunogenicity  of  biosimilars   •  Technicians

    –  Explain  what  biosimilars  and  reference  biologicals  are   –  Describe  differences  in  biosimilars  compared  to  reference  biological   –  Contrast  how  costs  differ  between  biosimilars  and  reference  biological   –  Describe  safety  concerns  with  biosimilars

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    Outline of Presentation

    •  Definitions •  Expanding role of biologicals in medicine,

    especially cancer treatments •  Safety and immunogenic concerns with

    biologicals •  The case for biosimilars •  Uptake of biosimilars

    DefiniEons  for  this  PresentaEon   •  Biological  medicinal  product  (AKA  biopharmaceu=cal)  -­‐  A  macromolecule  

    medicinal  (proteins)  or  nucleic  acid-­‐based  drug       –  Engineered  from  biological  Essue  (human,  animal  or  micro-­‐organism)   –  May  be  gene-­‐based  or  cellular-­‐derived  

    •  FDA  definiEon  -­‐  virus,  therapeuEc  serum,  toxin,  anEtoxin,  vaccine,   blood,  blood  derivaEve,  allergenic  product,  protein    

    •  Reference  biological  (AKA  the  Originator)  –  the  original  patented  product   receiving  FDA  approval  as  a  new  drug  under  a  BLA  

    •  Biosimilar  -­‐    “Highly  similar”  to  the  reference  product,  approved  by  the   FDA  ager  patent  expiraEon  of  the  reference  biological   –  Studies  demonstrate  no  clinical  differences  in  effecEveness  or  safety   –  Minor  differences  in  inacEve  components   –  FDA  developed  specific  regulaEons  for  biosimilars  subsequent  to  

    passage  of  the  Affordable  Care  Act  

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    Expanding Role of Biologicals in Medicine

    •  Fastest growing portion of pharmaceutical market •  Marked advances in therapeutics and

    personalized medicine –  Growth factors (epoetin, filgrastim, human growth

    hormone, etc) –  Monoclonal antibiodies for cancer and other chronic

    conditions (ritiuximab, adalimumab, brentuximab, trastuzumab etc)

    –  Tyrosine kinase inhibitors for cancer (imatinib, gefitinib, erlotinib. etc)

    Expanding Role of Biologicals in Medicine

    •  Achieve  efficacy  not  possible  from  nonbiological   small  molecules  

    •  Therapy  for  complex,  life-­‐threatening  condiEons   –  Complexity  in  structure  and  manufacturing  process  

    •  $170  Billion  in  2012  in  EU  and  USA  1   – Monoclonal  anEbodies    account  for  greatest   spending  

    •  Predicted:  By  2016,  5  of  the  top  10  drug   expenditures  

    •  Market  exclusivity  extends  beyond  patent   expiraEon  

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    Safety Concerns with Biologicals

    •  Expanding use = potential for overuse and increased risk –  Epoetin - increased risk of mortality and thrombosis in patients

    with higher hemoglobin levels2

    •  Side effects among high risk patients –  Hepatitis C reactivation with rituximab3 –  Progressive multifocal leukoencephalopathy (PML) with

    rituximab4, brentuximab5 –  Pancreatitis with brentuximab6

    Immunogenic Reactions from Biologicals

    •  Pure red cell aplasia from epoetin –  Cause = a manufacturing change causing an interaction

    between the excipients and the syringe stopper7

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    Post-marketing Surveillance– Peganesitide8

    •  An erythropoieEn, less expensive than other marketed epoetins

    •  Approval required a REMS post-marketing study for cardiotoxicity

    •  Active surveillance study performed at adoption by a large dialysis organization (LDO) – 25,000 treatments –  Ten sites out of 2100 in US used peginesatide

    conducted a 7 month trial, beginning July 2012 –  Then, expanded to 348 sites for 2 weeks

    Post-marketing Surveillance– Peganesitide8  

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    Post-marketing Surveillance– Peganesitide8

    •  In 2 months •  8 cases of anaphylaxis •  2 deaths, 3 grade IV events

    •  By February 12, 2013 •  28 anaphylaxis events by active surveillance versus •  10 events in FDA MedWatch •  Incidence = 1.4/1,000

    •  Withdrawn from market on 2/23/2013 •  Active surveillance resulted in more rapid identification and

    more complete reporting

    Post-marketing Surveillance– Peganesitide8  

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    The Case for Biosimilars9,10 •  Regulations intended to establish

    interchangeability (without prescriber contact) –  European Medicines Agency (EMA)

    •  As early as 10 years after approval of reference biological (RB)

    –  FDA Biologics  Price  CompeEEon  and  InnovaEon  Act •  As early as 12 years after approval of RB

    •  Development and production costs for biosimilars - much higher than small molecules

    •  Cost savings – Likely to be 25% or more •  Expanding markets make biosimilars lucrative

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    Naming  of  Biosimilars  

    •  FDA  guidance  seeking  comment  (August  2015)   hLp:// Guidances/UCM459987.pdf  

    •  The  reference  product’s  “original  proper  name,  plus  the   designated  suffix  a5ached  with  a  hyphen”  

    –  4  lowercase  (unique  and  meaningless)  leLers   –  Example:  FilgrasEm-­‐abcd  

    Patent Expirations of Some Biologicals1  

    Biological   EU     US   Adalimumab  (Humira)   2018   2018   Etanercept  (Enbrel)   2015   2015   Infliximab  (Remicade)   Expired   2015   Insulin  Glargine  (Lantus)   2014   2014   Rituximab  (Mabthera)   2013   2013   Bevacizumab  (AvasEn)   2019   2019   Insulin  Aspart  (Novomix,  Novorapid)   2015   2015  

    Interferon  Beta-­‐1A  (Avonex,  Rebif)   Expired   Expired  

    Trastuzumab  (HercepEn)   2014   2014   GlaEramer  Acetate  (Copaxone)   2016   2016   Adalimumab  (Humira)   2018   2018   Etanercept  (Enbrel)   2015   2015  

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    Biosimilar Approval Requirements9,10

    •  One  (or  more)  equivalence  (or  non-­‐inferiority)   study  compared  to  the  originator  biological,  with   or  without  a  placebo  arm  

    •  Demonstrated  equivalence  (no  clinic