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 ?

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Presentation transcript:

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

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

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 Time for a Large Scale Clinical Trial ?

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

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

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

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

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

Stanley K, Circulation 2007;115: Characteristics of a High-Quality RCT

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

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

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

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

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