How do researchers decide early clinical trials?
- 292 Downloads
Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research.
KeywordsDecision-making Research ethics Risk/benefit Phase 1 trials Policy Translational research
This work was funded by Forte and the EU Commission under a COFAS Marie Curie Fellowship.
Compliance with ethical standards
Conflict of interest
JK is a member of ISSCR and is co-chairing the effort to revise its clinical translation guidelines—guidelines that are mentioned in this paper. HG has no relevant competing interests to declare.
- ASCO (American Society of Clinical Oncology). 1997. Critical role of phase I clinical trials in cancer treatment. Journal of Clinical Oncology 15(2): 853–859.Google Scholar
- Casper, M.J. 1998. The making of the unborn patient: A social anatomy of fetal surgery. New Brunswick, NJ: Rutgers University Press.Google Scholar
- CIOMS (Council for International Organizations of Medical Sciences). 2002. International ethical guidelines for biomedical research involving human subjects. Geneva.Google Scholar
- EMA (European Medicines Agency). 2007. Guidelines on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf. Accessed 10 Oct 2014.
- FDA (Food and Drug Administration). 2013. In Guidance for industry: Preclinical assessment of investigational cellular and gene therapy products, ed. Services USDoHH.Google Scholar
- FDA (Food and Drug Administration). 1995. In Guidance for industry: Content and format of investigational new drug applications (INDs) for phase I studies of drugs, including well-characterized, therapeutic, biotechnology-derived products, ed. Services USDoHH.Google Scholar
- Fox, R.C., and J.P. Swazey. 1992. Spare parts: Organ replacement in American society. New York, NY: Oxford University Press.Google Scholar
- Geison, G.L. 1995. The private science of Louis Pasteur. Princeton, Chichester, West Sussex, NJ: Princeton University Press.Google Scholar
- Grady, D., and G. Kolata. 2003. Gene therapy used to treat patients with Parkinson’s. New York Times 19 August.Google Scholar
- Grankvist, H. 2011. Making doable problems within controversial science: US and Swedish Scientists’ experience of gene transfer research. Linköping: Linköping Studies in Arts and Science, LiU-tryck.Google Scholar
- ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). 2009. ICH harmonised tripartite guideline: NonClinical evaluation for anticancer pharmaceuticals—S9. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S9/Step4/S9_Step4_Guideline.pdf. Accessed 10 Oct 2014.
- ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). 2000. ICH harmonised tripartite guideline: Safety pharmacological studies for human pharmaceuticals—S7A. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf. Accessed 10 Oct 2014.
- ISSCR (International Society for Stem Cell Research). 2008. Guidelines for the clinical translation of stem cells. http://www.isscr.org/docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf. Accessed 10 Oct 2014.
- Kimmelman, J., and V. Henderson. 2015. Assessing risk/benefit for trials using preclinical evidence: A proposal. Journal of Medical Ethics. doi: 10.1136/medethics-2015-102882.
- Lowy, I. 1996. Between bench and bedside: Science, healing and interleukin-2 in a cancer ward. Cambridge, MA: Harvard University Press.Google Scholar
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1978. The Belmont report: Ethical principles and guidelines for the protection of human subjects of research. Washington, DC: US Government Printing Office. (DHEW Publication # (OS) 78-0012).Google Scholar
- Nuremberg Military Tribunals. 1949. Trials of war criminals before the Nuremberg military tribunals under control council law, 181–182. Washington, DC: US Government Printing Office.Google Scholar
- RIGOR. 2012. Improving the quality of NINDS-supported research through rigorous study design and transparent reporting. http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf. Accessed 14 Oct 2014.
- Wechsler, L.R., D. Steindler, C. Borlongan, M. Chopp, S. Savitz, R. Deans, L. Caplan, D. Hess, R.W. Mays, and The STEPS Participants. 2009. Stem cell therapy as an emerging paradigm for stroke (STEPS): Bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 40(2): 510–515.CrossRefGoogle Scholar
- WMA (World Medical Association). 2013. Declaration of Helsinki: Ethical principles for medical research involving human subjects. Journal of the American Medical Association 301: 2191–2194.Google Scholar
- 21 CFR 314. 2015. Food and drugs—Applications for FDA approval to market a new drug. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:22.214.171.124.4.9. Accessed 3 Sept 2015.
- 21 CFR 601. 2015. Food and drugs—Licensing. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=601&showFR=1&subpartNode=21:126.96.36.199.2.8. Accessed 3 Sept 2015.