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Strategic  Clinical  Innova1on  

April  15,  2012  

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Candida  Fratazzi  MD  President  

BBCR,  LLC  www.bostonclinicalresearch.com  

Rising  interest  in  the  Rare  Disease  model  could  have    a  cri1cal  role  into  Biomarker’s  implementa1on    

for  Stra1fied  Medicine  

S023  room  350  D-­‐F      10:30-­‐  11:30AM    

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•  Understand  drug  development  challenges  

•  Biomarkers  per  pa1ents  selec1on  and  efficacy  evalua1on:  an  orphan  disease  case  study    

•  Discuss  strategic  clinical  innova1on  and  stra1fied  medicine  

Learning  Objec1ves  

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Innova1ve  Strategies  are  overdue  

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•  Gaps,  that  cost  1me  and  money,  appear  in  the  clinical  research  process    

•  Protocols  wriVen  for  top  line  visualiza1on  that  may  be  lacking  scien1fic  rigor  

•  Clinical  strategies  and  plans  may  be  myopic  and  miss  greater  op1ons  

•  Increasing  regulatory  demand  for  transparent  study  results  and  cross  AEs  

Which  are  the  causes  

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S t r a t e g y   a n d   I n n o v a1on  

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Focus  on  clinical  strategy,  early  plan  and  study  design  

Bridging  research  and  clinical  trials  

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•  Links  preclinical  data  with  unmeet  medical  needs  

•  Matches  study  endpoints  with  study  objec1ves  •  Connects  product  poten1al  to  treatment  benefits  

•  Creates  cohesive  phase  I/II  studies  to  support  first  in  man/POC  objec1ves  

Strategic  Clinical  Innova1on  is  a  bridge  

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 Bridging  the  Chasm    

Pre-­‐clinical  research  meets  FPI    

Discovery  /  Pre-­‐Clinical  

Protocol  Im

plem

enta:o

n/CR

O  

Strategy  

Safety  /  Tox  Data  

Discovery  Data  

Biomarkers  Trial  Design  

Objec1ves/  Endpoints  

Pa1ents  Selec1on  

Pa1ents  Safety  

Regula1on  Disease  Staging/  KOL  

Protocol  Synopsis  

Pa1ents’  Needs  

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S t r a 1fi ed  Med i c i n e   i s   t h e   g o a l  

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Choose  the  RIGHT  DRUG  at  the  RIGHT  DOSE  for  the  RIGHT  GROUP  OF  PEOPLE  

Non-Responders

Responders

Adverse Drug Events

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 Beneficial  to  some  

 

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Harmful  to  others  

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•  Avoid  adverse  events  Ø  2.2  million  people  are  hospitalized  and  100,000  

deaths  occur  each  year  due  to  adverse  effects  of  prescrip1on  drugs  

•  BeFer  treat  disease  Ø  Development  of  predic1ve  markers  would  allow  for  

earlier  treatment  •  Iden:fy  novel  drug  targets  

Ø   Current  drugs  are  based  on  less  than  500  targets    

Advantages  of  Stra1fied  Medicine  

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B i oma r k e r s   a r e   t h e   t o o l s  

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Why  Biomarkers  are  important  

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A  molecule  that  indicates    an  altera1on  of  the  physiological  state  of  an  individual  in    rela1onship  to  health  or  disease  state,    

drug  treatment,  toxins  etc.      

       Biomarkers  are,  by  virtue  of  their  short  term  availability,  predictors  of  long  term  events  

Biomarker  defini1on  

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Biomarkers  connect  

Qualified  biomarkers  

Biology   Clinical    endpoints    

A qualified biomarker must link biology and clinical end-points

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•  Screening  markers:  markers  discrimina1ng  the  healthy  state  from  beginning  of  disease  state  preferen1ally  in  an  asymptoma1c  phase  (  cancer  makers  for  early  diagnos1c)  

•  Prognos:c  markers:  once  the  disease  state  is  established  predict  the  likely  course  of  the  disease    

 

Different  types  of  biomarkers  

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•  Stra:fica:on  markers:  predict  the  likelihood  of  a  response    to  a  drug  before  star1ng  treatment  classifying  pa1ents  in  “responders”  and  “non-­‐responders”  

•  Efficacy  markers:  monitor  the  efficacy  of  a  drug  treatment  

 

Different  types  of  biomarkers  

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Biomarkers  in  clinical  innova1on  

•  Biomarkers  that  validate  the  importance  of  the  target  in  human  disease  

     

•  Biomarkers  that  define  the  direct  interac1on  of  the  compound  with  its  discrete  target  

   

•  Biomarkers  that  define  consequences  of  compound  interac1on  with  the  target  rela1ve  to  PK  

     

•   Biomarkers  that  correlate  with  disease        •   Biomarkers  that  define  likelihood  of  pa1ents  to  respond  

(or  not)  to  the  compound  

Target/Compound  Interac1on     Pharmacodynamic  Ac1vity  (PK/PD)  

Target  Valida1on    

Disease  Biomarker  &  Disease  Modifica1on      Pa1ent  selec1on  and  Stra1fica1on  

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O r p h an   D i s e a s e   i s   t h e  mode l :  C a s e   S t u d y  

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Challenge  Develop  the  new  ERT  in  an  orphan  popula1on  when  a  very  similar  product  had  the  market  monopoly  for  about  15  years  

•  Very  limited  number  of  naïve  pa1ents  

•  Newly  diagnosed  pa1ents  presented  with  early  symptoms  

•  Treated  pa1ents  had  improvement  on  many  of  the  clinical  features  

Gaucher  disease  Type  1    

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Strategy    Create  a  clinical  innova1ve  strategy  and  trial  designs,  which  would  require  a  feasible  number  of  pa1ents,  and  1ght  pa1ents’  selec1on  with  study  endpoints.  Select  validated  biomarkers’  assay  with  known  intra-­‐assay  and  intra-­‐personal  variability.  Work  with  the  Regulatory  agency  upfront  to  validate  approach.  Understand  physicians  and  pa1ents  expecta1ons  versus  current  standards  of  care.  

Gaucher  disease  Type  1    

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•  Rare  disease  with  a    prevalence  1:50,000-­‐  100,000;  Type  1  is  the  most  common  Gaucher  variant  

•  Disease  expression  varies  from  asymptoma1c  to  significant  morbidity  

•  Disease  progression  in  Type  1  Gaucher  disease  occurs  over  decades,  possibly  shortens  life  expectancy  

 

Gaucher  Disease  

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•  Inherited  deficiency  of  lysosomal  enzyme  glucocerebrosidase  (GCD)  

•  Accumula1on  of  glucocerebroside  in  macrophage  lysosomes  (liver,  spleen,  bone  marrow,  brain)  

•  3  variants:  type  1,  2,  and  3  

Gaucher  Disease  

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•  Hepatosplenomegaly  

•  Hypersplenism  

•  Hematological  abnormali1es  (anemia,  thrombocytopenia)  

•  Lung  disease  •  Bone  disease  (pain  crises,  fractures,  osteonecrosis)    •  Non-­‐neuronopathic  (Types  2  &  3  are  neuronopathic)    

Gaucher  Disease  type  1  -­‐  Clinical  Features  

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•  Change  from  baseline    

– Hemoglobin  

– Platelet  count  – Spleen  volume  

– Liver  volume  

Study  Endpoints  

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The  proposed  clinical  strategy  was  successful,    and  the  product  was  approved    

Summary  

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•  Overall  clinical  development  program  well  planned  

•  Clinically  meaningful  endpoints  

– Natural  history  well  understood    •  Each  trial  had  a  dis1nct  purpose  – studies  supported  an1cipated  use  in  both  treatment  naïve  and  switching  pa1ents  

 Clinical  Strategy  Success  

 

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C o n c l u s i o n  

Sample  pre-­‐1tle  

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Safer  and  more  Effec1ve  drugs  

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•  Develop  Early  Roadmap    

•  Create  Strategic  Clinical  Plan  •  Customize  trial  design  

•  Op1mize  pa1ent  selec1on  

•  Visualize  goals,  ac1on  plan  and  op1ons  •  Maximize  early  stage  product-­‐value  

 

Strategic  Clinical  Innova1on  approach    

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•  Accelerate  enrolment  

•  Increase  inves1gators’    interest  •  Facilitate  IRB  approval  •  Reduce  pa1ents  withdrawn  from  the  study  

•  Reduce  blames  for  bad  trial  execu1on  

•  Increase  study  success  rate  

 

Strategic  Clinical  Innova1on  advantages  

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Que s t i o n s    ?  ? !

Sample  pre-­‐1tle  

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Disclosure  

 

 

I  have  no  relevant  financial  rela1onship    

in  rela1on  to  this  educa1onal  ac1vity