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Ethics and Evidence: Is Evidence from Randomized Controlled Trials Necessary to Firmly Establish a New Therapy?

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Part of the Synthese Library book series (SYLI, volume 426)

Abstract

In this chapter, I explore ethical issues that may arise in conducting randomized controlled trials to test therapeutic hypotheses, and address the question of whether randomized controlled trials are always necessary to firmly establish a new therapy. I illustrate the ethical issues by discussing several studies of extracorporeal membrane oxygenation therapy in newborn infants, and subsequently describe two cases in which a new cancer therapy was firmly established without randomized trial data: combination chemotherapy and radiation therapy in cancer of the anal canal, and multi-drug chemotherapy for disseminated carcinoma of the testis. I conclude that considerable opinion exists that the primary duty of physicians (qua physicians) is to the patients under their care and that conducting research is secondary, notwithstanding the immense benefit of medical research to society. I also conclude that randomized controlled trial data are sometimes unnecessary when other convincing data are available.

References

  1. Bartelink, H., F. Roelofsen, F. Eschwege, P. Rougier, J.F. Bosset, D. Gonzalez Gonzalez, D. Peiffert, M. van Glabbeke, and M. Pierart. 1997. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. Journal of Clinical Oncology 15: 2040–2049.CrossRefGoogle Scholar
  2. Bartlett, Robert H. 1984, April. Extracorporeal oxygenation in neonates. Hospital Practice 19: 139–151.CrossRefGoogle Scholar
  3. Bartlett, Robert H., Alice F. Andrews, John M. Toomasian, Nick J. Haidue, and Alan B. Gazzaniga. 1982. Extracorporeal membrane oxygenation for newborn respiratory failure: Forty-five cases. Surgery 92: 425–433.Google Scholar
  4. Bartlett, Robert H., Dietrich W. Roloff, Richard G. Cornell, Alice French Andrews, Peter W. Dillon, and Joseph B. Zwischenberger. 1985. Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 76: 479–487.Google Scholar
  5. Beauchamp, Tom L., and James F. Childress. 1994. Principles of biomedical ethics. 4th ed. Oxford: Oxford University Press.Google Scholar
  6. Berry, Donald A. 1989. Comment: Ethics and ECMO. Statistical Science 4: 306–310.CrossRefGoogle Scholar
  7. Cowan, Dale H. 1981. The ethics of clinical trials of ineffective therapy. IRB: A Review of Human Subjects Research 3: 10–11.Google Scholar
  8. Cummings, B.J. 1993. Anal cancer − radiation alone or with cytotoxic drugs? International Journal of Radiation Oncology Biology Physics 27: 173–175.CrossRefGoogle Scholar
  9. Cummings, B.J., A.R. Harwood, T.J. Keane, G.M. Thomas, and W.D. Rider. 1980. Combined treatment of squamous cell carcinoma of the anal canal: Radical radiation therapy with 5-fluorouracil and mitomycin-C, a preliminary report. Diseases of the Colon and Rectum 23: 389–391.CrossRefGoogle Scholar
  10. Dworetz, April R., Fernando R. Moya, Barbara Sabo, Igor Gladstone, and Ian Gross. 1989. Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation. Pediatrics 84: 1–6.Google Scholar
  11. Einhorn, Lawrence H., and John Donohue. 1977. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Annals of Internal Medicine 87: 293–298.CrossRefGoogle Scholar
  12. Einhorn, Lawrence H., Stephen D. Williams, Michael Troner, Robert Birch, and Frank A. Greco. 1981. The role of maintenance therapy in disseminated testicular cancer. New England Journal of Medicine 305: 727–731.CrossRefGoogle Scholar
  13. Field, David. 1995. Ethics of consent for babies in randomised clinical trials. Lancet 345: 1370.CrossRefGoogle Scholar
  14. Flam, Marshall, Madhu John, Thomas F. Pajak, Nicholas Petrelli, Robert Myerson, Scotte Doggett, Jeanne Quivey, et al. 1996. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. Journal of Clinical Oncology 14: 2527–2539.CrossRefGoogle Scholar
  15. Freedman, Benjamin. 1987. Equipoise and the ethics of clinical research. New England Journal of Medicine 317: 141–145.CrossRefGoogle Scholar
  16. Fried, Charles. 1974. Medical experimentation: Personal integrity and social policy. Amsterdam: North-Holland.Google Scholar
  17. Glasziou, Paul, Iain Chalmers, Michael Rawlins, and Peter McCulloch. 2007. When are randomised trials unnecessary? Picking signal from noise. British Medical Journal 334: 349–351.CrossRefGoogle Scholar
  18. Golden, Gerald T., and J. Shelton Horsley III. 1976. Surgical management of epidermoid carcinoma of the anus. American Journal of Surgery 131: 275–280.CrossRefGoogle Scholar
  19. Goodman, Kenneth W. 2003. Ethics and evidence-based medicine. Fallibility and responsibility in clinical science. Cambridge: Cambridge University Press.Google Scholar
  20. Green, Jerold P., Willis C. Schaupp, Simeon T. Cantril, and Gerald Schall. 1980. Anal carcinoma: Current therapeutic concepts. American Journal of Surgery 140: 151–155.CrossRefGoogle Scholar
  21. Greenhalgh, Trisha. 2010. How to read a paper: The basics of evidence-based medicine. 4th ed. Chichester: Wiley.Google Scholar
  22. Gunderson, Leonard L., Kathryn A. Winter, Jaffer A. Ajani, John E. Pedersen, Jennifer Moughan, Al B. Benson III, Charles R. Thomas Jr., et al. 2012. Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. Journal of Clinical Oncology 30: 4344–4351.CrossRefGoogle Scholar
  23. Hill, Austin Bradford. 1963. Medical ethics and controlled trials. British Medical Journal 1: 1043–1049.CrossRefGoogle Scholar
  24. Lantos, John D. 1997. Was the UK Collaborative ECMO trial ethical? Paediatric and Perinatal Epidemiology 11: 264–268.CrossRefGoogle Scholar
  25. Marwick, Charles. 1990. NIH ‘Research Risks Office’ reprimands hospital institutional review board. Journal of the American Medical Association 263: 2420.CrossRefGoogle Scholar
  26. McGlynn, Elizabeth A., Steven M. Asch, John Adams, Joan Keesey, Jennifer Hicks, Alison DeCristofaro, and Eve A. Kerr. 2003. The quality of health care delivered to adults in the United States. New England Journal of Medicine 348: 2635–2645.CrossRefGoogle Scholar
  27. Miller, Franklin G., and Steven Joffe. 2011. Equipoise and the dilemma of randomized clinical trials. New England Journal of Medicine 364: 476–480.CrossRefGoogle Scholar
  28. Newman, Howard K., and Stuart H.Q. Quan. 1976. Multi-modality therapy for epidermoid carcinoma of the anus. Cancer 37: 12–19.CrossRefGoogle Scholar
  29. Nigro, Norman D., V.K. Vaitkevicius, and Basil Considine Jr. 1974. Combined therapy for cancer of the anal canal: A preliminary report. Diseases of the Colon and Rectum 17: 354–356.CrossRefGoogle Scholar
  30. O’Rourke, P. Pearl, Robert K. Crone, Joseph P. Vacanti, James H. Ware, Craig W. Lillehei, Richard B. Parad, and Michael F. Epstein. 1989. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: A prospective randomized study. Pediatrics 84: 957–963.Google Scholar
  31. Pelligrino, Edmund D. 1979. Humanism and the physician. Knoxville: University of Tennessee Press.Google Scholar
  32. Pocock, Stuart J. 1993. Statistical and ethical issues in monitoring clinical trials. Statistics in Medicine 12: 1459–1469.CrossRefGoogle Scholar
  33. Richie, Jerome P. 1998. Neoplasms of the testis. In Campbell’s urology, ed. Patrick C. Walsh, Alan B. Retig, E. Darracott Vaughan Jr., and Alan J. Wein, 7th ed., 2411–2452. Philadelphia: W. B. Saunders.Google Scholar
  34. Royall, Richard M. 1991. Ethics and statistics in randomized clinical trials. Statistical Science 6: 52–62.CrossRefGoogle Scholar
  35. Sackett, David L., William M.C. Rosenberg, J.A. Muir Gray, R. Brian Haynes, and W. Scott Richardson. 1996. Evidence based medicine: What it is and what it isn’t. British Medical Journal 312: 71–72.CrossRefGoogle Scholar
  36. Samuels, Melvin L., Douglas E. Johnson, and Paul Y. Holoye. 1975. Continuous intravenous bleomycin (NSC-125066) therapy with vinblastine (NSC-49842) in stage III testicular neoplasia. Cancer Chemotherapy Reports 59: 563–570.Google Scholar
  37. Schafer, Arthur. 1982. The ethics of the randomized clinical trial. New England Journal of Medicine 307: 719–724.CrossRefGoogle Scholar
  38. Schapira, David, and Alfonso Solimano. 1988. Is extra corporeal membrane oxygenation (ECMO) necessary to reduce mortality and morbidity in patients with meconium aspiration syndrome (MAS)? Abstract. Pediatric Research 23: 424A.Google Scholar
  39. Sischy, Benjamin, John H. Remington, Sidney H. Sobel, and Edwin D. Savlov. 1980. Treatment of carcinoma of the rectum and squamous carcinoma of the anus by combination chemotherapy, radiotherapy and operation. Surgery, Gynecology & Obstetrics 151: 369–371.Google Scholar
  40. Toomasian, John M., Sandy M. Snedecor, Richard G. Cornell, Robert E. Cilley, and Robert H. Bartlett. 1988. National experience with extracorporeal membrane oxygenation for newborn respiratory failure. Data from 715 cases. ASAIO Transactions 34: 140–147.CrossRefGoogle Scholar
  41. Truog, Robert D. 1993. Randomized controlled trials: Lessons from ECMO. Clinical Research 40: 519–527.Google Scholar
  42. Tsimberidou, Apostolia-Maria, Fadi Braiteh, David J. Stewart, and Razelle Kurzrock. 2009. Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. Journal of Clinical Oncology 27: 6243–6250.CrossRefGoogle Scholar
  43. Tukey, John W. 1977. Some thoughts on clinical trials, especially problems of multiplicity. Science 198: 679–684.CrossRefGoogle Scholar
  44. UK Collaborative ECMO Trial Group. 1996. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 348: 75–82.CrossRefGoogle Scholar
  45. Ware, James H., and Michael F. Epstein. 1985. Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 76: 849–851.Google Scholar
  46. Wei, L.J., and S. Durham. 1978. The randomized play-the-winner rule in medical trials. Journal of the American Statistical Association 73: 840–843.CrossRefGoogle Scholar
  47. Welton, Mark Lane, and Nalini Raju. 2011. Anal cancer. In The ASCRS textbook of colon and rectal surgery, ed. David E. Beck, Patricia L. Roberts, Theodore J. Saclarides, Anthony J. Senagore, Michael J. Stamos, and Steven D. Wexner, 2nd ed., 337–357. New York: Springer.CrossRefGoogle Scholar
  48. Williams, Stephen D., Robert Birch, Lawrence H. Einhorn, Linda Irwin, F. Anthony Greco, and Patrick J. Loehrer. 1987. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. New England Journal of Medicine 316: 1435–1440.CrossRefGoogle Scholar
  49. Wilson, Stephen M., Oliver H. Beahrs, and Roberto Manson. 1976. Squamous cell carcinoma of the anus. Surgery Annual 8: 297–303.Google Scholar
  50. Worrall, John. 2007. Evidence in medicine and evidence-based medicine. Philosophy Compass 2 (6): 981–1022.CrossRefGoogle Scholar
  51. ———. 2008. Evidence and ethics in medicine. Perspectives in Biology and Medicine 51: 418–431.CrossRefGoogle Scholar
  52. Wung, Jen-Tien, L. Stanley James, Eitan Kilchevsky, and Edward James. 1985. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 76: 488–494.Google Scholar
  53. Wyatt, John K., and Lloyd N. McAninch. 1967. A chemotherapeutic approach to advanced testicular carcinoma. The Canadian Journal of Surgery 10: 421–426.Google Scholar
  54. Zelen, M. 1969. Play the winner rule and the controlled clinical trial. American Statistical Association Journal 64: 131–146.CrossRefGoogle Scholar
  55. Zelen, Marvin. 1979. A new design for randomized clinical trials. New England Journal of Medicine 300: 1242–1245.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Birmingham Radiological GroupBirminghamUSA

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