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4th International Symposium on Stem Cell Therapy Madrid, April 26-27, 2007

Stem Cell Thertapy for STEMI. Is is Time for a Large Scale Clinical Trial ? Contra. 4th International Symposium on Stem Cell Therapy Madrid, April 26-27, 2007. Cardiac Cell Therapy. Lessons Fom Early Trials - Heterogeneity of patient populations and outcome measurements

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4th International Symposium on Stem Cell Therapy Madrid, April 26-27, 2007

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  1. Stem Cell Thertapy for STEMI. Is is Time for a Large Scale Clinical Trial ? Contra 4th International Symposium on Stem Cell Therapy Madrid, April 26-27, 2007

  2. Cardiac Cell Therapy Lessons Fom Early Trials - Heterogeneity of patient populations and outcome measurements - Usual lack of full characterization of the final cell therapy product - Diversity of dosing protocols, application schedules and routes of cell delivery

  3. Time for a Large Scale Clinical Trial ? • Issues • Cell-specific • Skeletal myoblasts • Bone marrow-derived cells • - General • Origin • Delivery, engraftment and survival • Non invasive imaging

  4. Time for a Large Scale Clinical Trial ? Skeletal Myoblasts - Isolation of precursors of cardiomyocytes - Prevention of arrhythmias by connexin-43 engineering - Identification of an immature subpopulation featuring a low antigenicity

  5. Time for a Large Scale Clinical Trial ? Bone Marrow-Derived Cells - Cell type (MNC, CD34+/CD133+ progenitors, MSC) - Dose ranging - Enhancement of myocardial homing

  6. Time for a Large Scale Clinical Trial ? • Issues • - Cell-specific • Skeletal myoblasts • Bone marrow-derived cells • General • Origin • Delivery, engraftment & survival • Non invasive imaging

  7. Autologous Allo/Xenogeneic Availability +++ +++ Reproductibility - +++ Immunogenicity - ++/+++ Cost +++ + Autologous vs. Allo/Xenogeneic Cell Therapy Products : A Difficult Trade-Off

  8. Cell Therapy : EMEA Guidelines • Objectives of Preclinical Development • To demonstrate proof-of-principle • To provide information allowing : • to select safe doses for clinical trials • to support the route of administration, duration of exposure and application schedule • to indicate the duration of follow-up time for detecting adverse reactions • To identify target organs for toxicity and parameters to monitor in patients

  9. Cell Therapy : EMEA Guidelines • Quality & Manufacturing Aspects • Traceability of starting and raw materials • Manufacturing process ensuring product consistency • Characterization of the final product in terms of identity (phenotypic and genotypic profiles), purity, potency, viability & tumourigenicity • Quality controls (release criteria, stability testing) • - Validation of the manufacturing process

  10. The MAGIC Trial : Preliminary Lessons Difficulties of Surgical Trials - Declining referrals for CABG - Restricted space for additional improvements - Background noise due to heterogeneity in practice patterns

  11. Characteristics of a High-Quality RCT Stanley K, Circulation 2007;115:1819-22.

  12. J Thorac Cardiovasc Surg 2006;132:243-4 Begg et al. JAMA 1996;276:637-9.

  13. Importance of Placebo Groups Adapted from the Coronary Drug Project Research Group, New Engl J Med 1980;303:1038-41

  14. Importance of Placebo Groups Adapted from the Coronary Drug Project Research Group, New Engl J Med 1980;303:1038-41

  15. Awareness of the CONSORT Statement and Views of Authors Reporting RCTs in Major Cardiothoracic Journals Tiruvoipati et al. J Thorac Cardiovasc Surg 2006;132:233-40.

  16. Randomized Multicentre Trials • Errors in Trial Design & Assessment • - Inappropriate control groups • Inadequate sizing of study groups • Lack of blinding during outcome assessment • - Uncautious use of composite end points • Failure to correct for repeated data analysis during the trial • Excessive reliance on  = 0.05 and lack of correction for multiple comparisons

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