Main Paper
Ethical considerations in industry-sponsored Multiregional clinical trials†‡
Ekopimo Ibia,
Bruce Binkowitz, Jean-Louis Saillot,
Steven Talerico, Chin Koerner, Irene Ferreira, Anupam Agarwal, Craig Metz, Marianne Maman,
Corresponding Author
Ekopimo Ibia
Merck & Co., Inc., Whitehouse Station, NJ, USA
601 Pennsylvania Avenue, NW, Suite 1200 North Building, Washington, DC 20004, USA Search for more papers by this authorJean-Louis Saillot
Merck & Co., Inc., Whitehouse Station, NJ, USA
Search for more papers by this authorMarianne Maman
Novartis Pharmaceutical Corp, Rockville, MD, USA
Search for more papers by this authorEkopimo Ibia,
Bruce Binkowitz, Jean-Louis Saillot,
Steven Talerico, Chin Koerner, Irene Ferreira, Anupam Agarwal, Craig Metz, Marianne Maman,
Corresponding Author
Ekopimo Ibia
Merck & Co., Inc., Whitehouse Station, NJ, USA
601 Pennsylvania Avenue, NW, Suite 1200 North Building, Washington, DC 20004, USA Search for more papers by this authorJean-Louis Saillot
Merck & Co., Inc., Whitehouse Station, NJ, USA
Search for more papers by this authorMarianne Maman
Novartis Pharmaceutical Corp, Rockville, MD, USA
Search for more papers by this author†
This article represents the views of the authors, and not necessarily the positions of their respective companies or affiliations.
‡
This article is published in Pharmaceutical Statistics as a special issue on Multi-regional Clinical Trials–What are the challenges?, edited by Sue Jane Wang, Office of Biostatistics, Office of Translational Sciences, CDER, U.S. Food and Drug Administration, MD, USA
Abstract
During the last several decades, the scientific and ethics communities have addressed important ethical issues in medical research, resulting in the elaboration and adoption of concepts, guidelines, and codes.
Ethical issues in the conduct of Multiregional Clinical Trials have attracted significant attention mainly in the last two decades. With the globalization of clinical research and the rapid expansion to countries with a limited tradition of biomedical research, sponsors must proactively address local ethical issues, the adequacy of oversight as well as the applicability and validity of data, and scientific conclusions drawn from diverse patient populations.
This paper highlights some core ethical principles and milestones in medical research, and, from an industry perspective, it discusses ethical issues that the clinical trial team may face when conducting Multiregional Clinical Trials (MRCT, clinical trials conducted at sites located across multiple geographic regions of the world). This paper further highlights the areas of consensus and controversies and proposes points to consider. Copyright © 2010 John Wiley & Sons, Ltd.
REFERENCES
- 1Thiers FA, Sinskey AJ, Berndt ER. Trends in the globalization of clinical trials. Nature Reviews Drug Discovery 2008; 7: 13–14.
- 2Glickman SW, McHutchison JG, Peterson ED et al. Ethical and scientific implications of the globalization of clinical research. New England Journal of Medicine 2009; 360: 816–823.
- 3The European Group on Ethics in Science and New Technologies Website. Ethical aspects of clinical research in developing countries. Opinion of the European Group on ethics in science and new technologies to the European Commission, 4 February 2003. Available at: www.ec.europa.eu/european_group_ethics/docs/avis17_en.pdf (accessed 20 December 2009).
- 4 Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Fair benefits for research in developing countries. Science 2002; 298: 2133–2134.
- 5Saillot J, Paxton M. Industry efforts at simultaneous global development. Drug Information Journal 2009; 43: 339–347.
- 6European Medicines Agency (EMEA) Website. Reflection paper on the extrapolation of results from clinical studies conducted outside Europe to the EU-population (Draft) 2009. EMEA/CHMP/EWP/692702/2008. Available at: http://www.emea.europa.eu/pdfs/human/ewp/69270208en.pdf (accessed 26 September 2009).
- 7Brody BA, McCullough LB, Sharp RR. Consensus and controversy in clinical research ethics. Journal of the American Medical Association 2005; 294: 1411–1414.
- 8O'Reilly KB. Outsourcing clinical trials: is it ethical to take drug studies abroad? AMedNews.com. Available at: http://www.ama-assn.org/amednews/2009/09/07/prsa0907.htm (accessed 25 September 2009).
- 9Beauchamp TL, Childress JF. Principles of Biomedical Ethics ( 5th edn). Oxford University Press: New York, 2001.
- 10Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? Journal of the American Medical Association 2000; 283: 2701–2711.
- 11World Medical Association Website. Declaration of Geneva. Available at: http://www.wma.net/en/30publications/10policies/c8/index.html (accessed 20 October 2009).
- 12Office of Human Research Protections Website. OHRP 45 CFR part 46 frequently asked questions (FAQs). Available at: http://www.hhs.gov/ohrp/45CFRpt46faq.html (accessed 10 October 2009).
- 13Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987; 317: 141–145.
- 14National Institutes of Health, Office of Human Subjects Research Website. Regulations and ethical guidelines. Available at: http://ohsr.od.nih.gov/guidelines/index.html (accessed 10 October 2009).
- 15United Nations Website. Universal declaration of human rights. Available at: http://www.un.org/en/documents/udhr/ (accessed 10 October 2009).
- 16World Medical Association Website. Declaration of Helsinki – ethical principles for medical research involving human subjects. Available at: http://www.wma.net/en/30publications/10policies/b3/index.html (accessed 25 September 2009).
- 17 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH E6(R1): Good Clinical Practice, vol. 62, Federal Register 1997; pp. 25691–25709.
- 18World Health Organization Website. Research ethics. Available at: http://www.who.int/rpc/research_ethics/en/ (accessed 20 October 2009).
- 19Hollister LE, Page IH, Pfeiffer CC, Visscher MB. The Kefauver-Harris amendments of 1962: a critical appraisal of the first five years. Journal of Clinical Pharmacolology Journal of New Drugs 1968; 8: 69–73.
- 20Abraham J. Partial progress: governing the pharmaceutical industry and the NHS, 1948–2008. Journal of Health Politics Policy and Law 2009; 34: 931–977.
- 21Mann H. Controversial choice of a control intervention in a trial of ventilator therapy in ARDS: standard of care arguments in a randomised controlled trial. Journal of Medical Ethics 2005; 31: 548–553.
- 22Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting, part I. Adverse Drug Reactions and Acute Poisoning Reviews 1985; 4: 213–230.
- 23Griffin JP, Weber JCP. Voluntary systems of adverse reaction reporting, part II. Adverse Drug Reactions and Acute Poisoning Reviews 1986; 1: 23–55.
- 24Griffin JP. Survey of the spontaneous ADR reporting schemes in 15 countries. British Journal of Clinical Pharmacology 1986; 22: 83S–100S.
- 25Edwards IR, Lindquist M. The WHO database DII. Drug Information Journal 1992; 26: 481–486.
10.1177/009286159202600404 Google Scholar
- 26Papaluca M. Ethnic differences in response to pharmaceuticals across Europe. In The Relevance of Ethnic Factors in the Clinical Evaluation of Medicines. S Walker (ed.). Kluwer Academic Publishers: Dordrecht; 1994.
10.1007/978-94-011-1420-2_6 Google Scholar
- 27Joelson S, Joelson I, Wallander M. Geographical variation in adverse event reporting rates in clinical trials. Pharmacoepidemiology and Drug Safety 1997; 3: S31–S35.
- 28McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. British Medical Journal 2006; 332: 1177–1181.
- 29Hayashi K, Walker AM. Japanese and American reports of randomized trials: differences in the reporting of adverse effects. Controlled Clinical Trials 1996; 17: 99–110.
- 30 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH E10: Choice of Control Group and Related Issues in Clinical Trials, vol. 66, Federal Register, 2001; pp. 24390–24391.
- 31Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebo-controlled trials and the Declaration of Helsinki. Lancet 2002; 359: 1337–1340.
- 32European Medicines Agency (EMEA) Website. Position statement on the use of placebo in clinical trials with regard to the revised Declaration of Helsinki. Available at: http://www.ema.europa.eu/pdfs/human/press/pos/1742401en.pdf (accessed 19 December 2009).
- 33 Office of the Federal Register, National Archives and Records Administration. Title 21 Code of Federal Regulation Part 314.126, 2009; pp. 148–150.
- 34European Commission Website. Annex 1 to Directive 2001/83/EC, as amended by Directive 2003/63/EC. Available at: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2003_63/dir_2003_63_en.pdf (accessed 9 November 2009).
- 35Lurie P, Wolfe SM. The developing world as the ‘answer’ to the dreams of pharmaceutical companies: the Surfaxin story. In Ethical issues in international biomedical research, JV Lavery, C Grady, ER Wahl, EJ Emanuel (eds). Oxford University Press: Oxford, 2007; pp. 159–170.
- 36Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 1997; 337: 853–855.
- 37Angell M. The Ethics of clinical research in the third world. New England Journal of Medicine 1997; 337: 840–847.
- 38Emanuel E, Miller F. The ethics of placebo-controlled trials—a middle ground. New England Journal of Medicine 2001; 345: 915–919.
- 39Emanuel E, Currie X, Herman A. Undue inducement in clinical research in developing countries: is it a worry? The Lancet 2005; 366: 336–340.
- 40EFPIA/IFPMA/JPMA/PhRMA. Available at: http://clinicaltrials.ifpma.org/fileadmin/files/pdfs/EN/November_10_2009_Updated_Joint_Position_on_the_Disclosure_of_Clinical_Trial_Information_via_Clinical_Trial_Registries_and_Databases.pdf (accessed 14 May 2010).
- 41Greenland P, Sridharan L. Editorial policies and publication bias: the importance of negative studies. Archives of Internal Medicine 2009; 169: 1022–1023.
- 42International Committee of Medical Journal Editors (ICMJE) Website. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. Available at: http://www.icmje.org/ (accessed 7 November 2009).
- 43PhRMA Website. Principles on conduct of clinical trials and communication of clinical trial results. Available at: http://www.phrma.org/files/attachments/042009_Clinical%20Trial%20Principles_FINAL.pdf (accessed 24 December 2009).
- 44Matcham J, Julious S, Pyke S, O'Kelly M, Todd S, Seldrup J, Day S. Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry-sponsored clinical trials. Pharmaceutical Statistics 2010; DOI: 10.1002/pst.417.
- 45 DAMOCLES Study Group. A proposed charter for clinical trial Data Monitoring Committees: helping them do their job well. Lancet 2005; 365: 711–722.
- 46 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH E5(R1): Ethnic factors in the acceptability of foreign clinical trials, vol. 63, Federal Register, 1998; pp. 31790–31796.
- 47United States Food and Drug Administration Website. Guidance for clinical trial sponsors on the establishment and operation of clinical trial data monitoring committees. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf (accessed 15 October 2009).
- 48Marscher, IC. Regional differences in multinational trials. Clinical Trials 2010; 7: 147–156.
- 49Chen J, Quan H, Binkowitz B et al. Assessing consistent treatment effect in a multi-regional clinical trial: a systematic review. Pharmaceutical Statistics, published online (www.interscience.wiley.com). DOI: 10.1002/pst.438.
- 50European Medicines Agency (EMEA) Website. Committee for Medicinal Products for Human Use (CHMP). Guideline on data monitoring committees. Available at: http://www.emea.europa.eu/pdfs/human/ewp/587203en.pdf (accessed 25 October 2009).
- 51Doumbo OK. It takes a village: medical research and ethics in Mali. Science 2005; 307: 679–681.
- 52Slack C, Stobie M, Milford C et al. Provision of HIV treatment in HIV preventive vaccine trials: a developing country perspective. Social Science and Medicine 2005; 60: 1197–1208.
Citing Literature
Special Issue: Multi‐Regional Clinical Trials – What Are The Challenges?
July/September 2010
Pages 230-241
