Cell-based therapies for cardiac repair NON-CLINICAL ASPECTS - - PowerPoint PPT Presentation

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cell based therapies for cardiac repair
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Cell-based therapies for cardiac repair NON-CLINICAL ASPECTS - - PowerPoint PPT Presentation

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Cell-based therapies for cardiac repair NON-CLINICAL ASPECTS Presented by: Beuneu Claire CAT-DGTI-GSCN Workshop, 11 September 2014, Dresden An agency of the European Union Drug development Pre-marketing development Post-marketing Basic

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An agency of the European Union

Cell-based therapies for cardiac repair

NON-CLINICAL ASPECTS

Presented by: Beuneu Claire CAT-DGTI-GSCN Workshop, 11 September 2014, Dresden

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 1

Drug development

Post-marketing Basic research Non-clinical studies Clinical trials Pre-marketing development Clinical trial applications Marketing Autorisation Application

  • proof of concept
  • safety
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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 2

EMA guidance – cell based products

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 3

Cell based products: main risks

 infections  loss of function  immunogenicity  tumourigenicity  ectopic engraftment

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 4

Non-clinical questions

1- Proof of concept and dose-finding studies 2- Biodistribution/migration and persistence of the cells in the body 3- Safety studies: general organ toxicity, tumourigenicity…

Appropriate model

small versus large species

Duration of the studies Appropriate level of testing

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 5

Non-clinical issues

?

Proof of concept Dose Biodistribution/Persistence Safety Route of administration Product Intended mode

  • f action

3R

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 6

Non-clinical questions

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 7

Large animal models : pros and cons

Pro

  • Proof of concept
  • Safety, feasibility
  • Training

Con

  • Healthy young animals
  • Laborious and expensive

Route of administration Allogeneic versus autologous Use of specific medical devices …

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 8

Method of cell delivery

van der Spoel, et al, JCMM 2012; 91(4): 649-658. Porcine model of ischaemic cardiomyopathy

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 9

Non-clinical models: meta-analysis

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Non-clinical models: meta-analysis

304 publications (pig,dog,sheep)

Review process:small species, reviews, comments, functionnal endpoints, quality of reporting, etc

52 studies included 34 RCT 18 cohorts

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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 11

Results

  • Results RCT = comparable to clinical

meta-analysis

  • No increased mortality
  • Effect fading away after 8 weeks
  • Type of cell
  • Timing of treatment
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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 12

Cell type

Circ Res. 2014 Sep 3. [Epub ahead of print] Similar Effect of Autologous and Allogeneic Cell Therapy for Ischemic Heart Disease: Systematic Review and Meta-Analysis of Large Animal Studies. Jansen Of Lorkeers SJ1, Eding JE1, Vesterinen HM2, van der Spoel TI1, Sena ES2, Duckers HJ1, Doevendans PA1, Macleod MR2, Chamuleau SA3.

  • 82 controlled preclinical trials (1415 animals)
  • unmanipulated stem cells
  • large animal models
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CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014 13

Conclusions

  • Large species are relevant for translational research
  • Interests and limitations of metanalysis:
  • Publication bias
  • Incomplete data set
  • Variety of protocols

 CAMARADES www.camarades.info  www.preclinicaltrials.eu 3R