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Table of Contents
Vol. 110, No. 2, 2008
Issue release date: April 2008
Cardiology 2008;110:73–80
(DOI:10.1159/000110483)

Similarities and Differences in Design Considerations for Cell Therapy and Pharmacologic Cardiovascular Clinical Trials

Lewis R.M. · Gordon D.J. · Poole-Wilson P.A. · Borer J.S. · Zannad F.
aAccess BIO, Boyce, Va., bNational Heart, Lung, and Blood Institute, Washington, D.C., cWeill Medical College of Cornell University, New York, N.Y., USA; dImperial College London, London, UK; eHypertension and Preventive Cardiology Division, Department of Cardiovascular Disease, Centre d’Investigations Cliniques INSERM-CHU, Nancy, France

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Abstract

Cell therapies hold the potential for suppression, modification, or cure of disease. Several unique challenges have been recognized as this field has developed. Many of these involve considerations of trial design. This paper summarizes the discussion and suggestions constructed during the 8th Cardiovascular Clinical Trialists Workshop, a meeting involving cardiovascular clinical trialists, biostatisticians, National Institutes of Health scientists, European and United States regulators, and pharmaceutical industry scientists. Investigators must adapt research methods to accommodate the scientific advances associated with cell therapy. Safety and efficacy of cell therapy for cardiovascular indications should be evaluated with the same degree of scientific rigor required of pharmacologic agents, and the same fundamental regulatory requirements and scientific processes apply to both. Clinical trials for these indications should also meet standards similar to those set for drug therapies. Safety should be determined throughout development, dose responsiveness should be established and, while surrogate endpoints are important development tools, the ultimate demonstration of efficacy must rely on clinical benefit. The establishment of a global safety database for cell therapy would significantly advance the field. Efforts to discover innovative therapies must be balanced by a commitment to comprehensively evaluate the safety and efficacy of the new treatments.



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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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References

  1. Srivastava D, Ivey KN: Potential of stem-cell-based therapies for heart disease. Nature 2006;441:1097–1099.
  2. Al-Radi OO, Rao V, Li RK, Yau T, Weisel RD: Cardiac cell transplantation: closer to bedside. Ann Thorac Surg 2003;75:S674–S677.
  3. Tang GH, Fedak PW, Yau TM, Weisel RD, Kulik A, Mickle DA, Li RK: Cell transplantation to improve ventricular function in the failing heart. Eur J Cardiothorac Surg 2003;23:907–916.
  4. Jain M, DerSimonian H, Brenner DA, Ngoy S, Teller P, Edge AS, Zawadzka A, Wetzel K, Sawyer DB, Colucci WS, Apstein CS, Liao R: Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 2001;103:1920–1927.
  5. Li RK, Jia ZQ, Weisel RD, Mickle DA, Zhang J, Mohabeer MK, Rao V, Ivanov J: Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 1996;62:654–660.
  6. Li RK, Jia ZQ, Weisel RD, Merante F, Mickle DA: Smooth muscle cell transplantation into myocardial scar tissue improves heart function. J Mol Cell Cardiol 1999;31:513–522.
  7. Sakai T, Li RK, Weisel RD, Mickle DA, Jia ZQ, Tomita S, Kim EJ, Yau TM: Fetal cell transplantation: a comparison of three cell types. J Thorac Cardiovasc Surg 1999;118:715–724.
  8. Sakai T, Li RK, Weisel RD, Mickle DA, Kim EJ, Tomita S, Jia ZQ, Yau TM: Autologous heart cell transplantation improves cardiac function after myocardial injury. Ann Thorac Surg 1999;68:2074–2080.
  9. Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, Jia ZQ: Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100:II247–II256.

    External Resources

  10. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP: Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004;94:92–95.
  11. Fazel S, Tang GH, Angoulvant D, Cimini M, Weisel RD, Li RK, Yau TM: Current status of cellular therapy for ischemic heart disease. Ann Thorac Surg 2005;79:S2238–S2247.
  12. Fuchs S, Satler LF, Kornowski R, Okubagzi P, Weisz G, Baffour R, Waksman R, Weissman NJ, Cerqueira M, Leon MB, Epstein SE: Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol 2003;41:1721–1724.
  13. Galinanes M, Loubani M, Davies J, Chin D, Pasi J, Bell PR: Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans. Cell Transplant 2004;13:7–13.
  14. Herreros J, Prosper F, Perez A, Gavira JJ, Garcia-Velloso MJ, Barba J, Sanchez PL, Canizo C, Rabago G, Marti-Climent JM, Hernandez M, Lopez-Holgado N, Gonzalez-Santos JM, Martin-Luengo C, Alegria E: Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003;24:2012–2020.
  15. Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo LD, Sohn DW, Han KS, Oh BH, Lee MM, Park YB: Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004;363:751–756.
  16. Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D: Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078–1083.
  17. Pagani FD, DerSimonian H, Zawadzka A, Wetzel K, Edge AS, Jacoby DB, Dinsmore JH, Wright S, Aretz TH, Eisen HJ, Aaronson KD: Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003;41:879–888.
  18. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT: Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107:2294–2302.
  19. Schachinger V, Assmus B, Britten MB, Ho-nold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimme-ler S, Zeiher AM: Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004;44:1690–1699.
  20. Smits PC, van Geuns RJ, Poldermans D, Bountioukos M, Onderwater EE, Lee CH, Maat AP, Serruys PW: Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003;42:2063–2069.
  21. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G: Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361:45–46.
  22. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P: Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–1918.
  23. Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP: Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003;361:47–49.
  24. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H: Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141–148.
  25. Zohlnhofer D, Ott I, Mehilli J, Schomig K, Michalk F, Ibrahim T, Meisetschlager G, von Wedel J, Bollwein H, Seyfarth M, Dirschinger J, Schmitt C, Schwaiger M, Kastrati A, Schomig A: Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006;295:1003–1010.
  26. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F: Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006;367:113–121.
  27. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM: Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006;355:1222–1232.
  28. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K: Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006;355:1199–1209.
  29. Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H: Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006;113:1287–1294.
  30. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210–1221.
  31. Ge J, Li Y, Qian J, Shi J, Wang Q, Niu Y, Fan B, Liu X, Zhang S, Sun A, Zou Y: Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI). Heart 2006;92:1764–1767.
  32. Bartunek J, Dimmeler S, Drexler H, Fernandez-Aviles F, Galinanes M, Janssens S, Martin J, Mathur A, Menasche P, Priori S, Strauer B, Tendera M, Wijns W, Zeiher A: The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for repair of the heart. Eur Heart J 2006;27:1338–1340.
  33. Brass EP, Lewis RJ, Lipicky R, Murphy J, Hiatt WR: Risk assessment in drug development for symptomatic indications: a framework for the prospective exclusion of unacceptable cardiovascular risk. Clin Pharmacol Ther 2006;79:165–172.
  34. Shih WJ: Group sequential, sample size re-estimation and two-stage adaptive designs in clinical trials: a comparison. Stat Med 2006;25:933–941.
  35. Minami E, Reinecke H, Murry CE: Skeletal muscle meets cardiac muscle. Friends or foes? J Am Coll Cardiol 2003;41:1084–1086.
  36. Penn MS: Stem-cell therapy after acute myocardial infarction: the focus should be on those at risk. Lancet 2006;367:87–88.
  37. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM: Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002;106:3009–3017.
  38. Kang WJ, Kang HJ, Kim HS, Chung JK, Lee MC, Lee DS: Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med 2006;47:1295–1301.
  39. Rosenzweig A: Cardiac cell therapy – mixed results from mixed cells. N Engl J Med 2006;355:1274–1277.
  40. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H: Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 2005;111:2198–2202.
  41. Food and Drug Administration: A proposed approach to regulation of cellular and tissue-based products. www.fda.gov/cber/gdlns/celltissue pdf 1997; Accessed November 2, 2006.


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